APSY19 • Addiction Psychology Special

Table of Contents

APSY19 • Addiction Psychology Special

How to Receive Credit

NetCE 5 Hour Course #66912 • Novel Psychoactive Substances: Trends in Drug Abuse

66912 • Novel Psychoactive Substances: Trends in Drug Abuse

1. INTRODUCTION

2. BACKGROUND OF NOVEL PSYCHOACTIVE SUBSTANCES

3. NPS EMERGENCE AND EXPANSION

4. EPIDEMIOLOGY

5. PHENETHYLAMINE DERIVATIVES

6. SYNTHETIC CATHINONES AND AMPHETAMINE/MDMA DERIVATIVES

7. CANNABIMIMETICS

8. TRYPTAMINES

9. ARYLCYCLOHEXYLAMINE DISSOCIATIVE ANESTHETICS

10. OPIOIDS

11. BOTANICAL PRODUCTS

12. ASSESSMENT, DIAGNOSIS, AND TREATMENT OF NPS TOXICITY

13. NPS USE DISORDERS

14. HARM REDUCTION

15. PREVENTION

16. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

17. CONCLUSION

Works Cited

NetCE 5 Hour Course #66944 • Cocaine Use Disorder

66944 • Cocaine Use Disorder

1. DEFINITION OF COCAINE ABUSE AND DEPENDENCE

2. HISTORY AND BACKGROUND OF COCAINE USE

3. EPIDEMIOLOGY AND DEMOGRAPHICS OF COCAINE ABUSE AND DEPENDENCE

4. COCAINE USE

5. EFFECTS OF COCAINE USE

6. TREATMENT OF COCAINE USE DISORDER

7. WITHDRAWAL FROM COCAINE

8. TREATMENT OF CONDITIONS ASSOCIATED WITH COCAINE USE

9. ALTERNATIVE/COMPLEMENTARY TREATMENT OF COCAINE USE DISORDER

10. PROGNOSIS

11. CONCLUSION

12. RESOURCES

Works Cited

NetCE 10 Hour Course #66564 • Alcohol and Alcohol Use Disorder

66564 • Alcohol and Alcohol Use Disorder

1. INTRODUCTION

2. HISTORY

3. CURRENT ESTIMATES OF ALCOHOL USE

4. BENEFITS

5. RISK AND PROTECTIVE FACTORS

6. ALCOHOL USE DISORDER

7. COMPLICATIONS

8. OTHER PSYCHIATRIC DISORDERS ASSOCIATED WITH ALCOHOL USE DISORDERS

9. DETECTING ALCOHOL USE DISORDERS

10. BRIEF INTERVENTION

11. TREATMENT

12. CONCLUSION

13. RESOURCES

Works Cited

Evidence-Based Practice Recommendations Citations

APSY19 • Addiction Psychology Special

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2025 NetCE, All rights reserved.

APSY19 • Addiction Psychology Special

Expiration Date: 11/30/2024

How to Receive Credit

To complete this Special Offer for continuing education credit please go to http://www.netce.com/specials in your browser.

For assistance with receiving continuing education credit, please contact us at help@netce.com.

66912 • Novel Psychoactive Substances: Trends in Drug Abuse

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2021 NetCE, All rights reserved.

The term "novel psychoactive substance" (or synthetic drug) refers to a new category of drugs on the market that have been created to circumvent existing laws on illicit drugs. This course will provide the most up-to-date information available on novel psychoactive substances, including the evolution of synthetic drug use; demographic characteristics of novel psychoactive substance users; the pharmacology, mechanism of action, and acute effects of novel psychoactive substances; approaches to reverse or manage acute toxicity; possible long-term effects; and prevention or treatment of novel psychoactive substance abuse.

Table of Contents

66912 • Novel Psychoactive Substances: Trends in Drug Abuse

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planner

Division Planner Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. BACKGROUND OF NOVEL PSYCHOACTIVE SUBSTANCES

3. NPS EMERGENCE AND EXPANSION

THE NPS PHENOMENON

NPS EXPANSION AND PROLIFERATION

PROLIFERATION AND TURNOVER IN NPS MARKETS

NPS USE TODAY

4. EPIDEMIOLOGY

PREVALENCE OF NPS USE

HIGH-USE SUBGROUPS

5. PHENETHYLAMINE DERIVATIVES

STRUCTURE-FUNCTION RELATIONSHIPS

MECHANISM OF ACTION

NEUROTOXICITY

RING-SUBSTITUTED PHENETHYLAMINES

6. SYNTHETIC CATHINONES AND AMPHETAMINE/MDMA DERIVATIVES

HISTORY

PHARMACOLOGY

CATHINONES AND AMPHETAMINE DERIVATIVES GROUPED BY PHARMACOLOGIC ACTIVITY

CHARACTERISTICS OF SPECIFIC CATHINONES

ROUTES OF ADMINISTRATION

SIDE EFFECT PROFILE

7. CANNABIMIMETICS

DEVELOPMENT AND INTRODUCTION AS NPS

PHARMACOLOGY

ACUTE EFFECTS

8. TRYPTAMINES

INDOLE RING-UNSUBSTITUTED TRYPTAMINES

5-POSITION RING-SUBSTITUTED TRYPTAMINES

9. ARYLCYCLOHEXYLAMINE DISSOCIATIVE ANESTHETICS

10. OPIOIDS

11. BOTANICAL PRODUCTS

KHAT

SALVIA DIVINORUM

KRATOM

12. ASSESSMENT, DIAGNOSIS, AND TREATMENT OF NPS TOXICITY

GENERAL ASSESSMENT

NPS TOXICITY SYNDROMES

DIFFERENTIAL DIAGNOSIS

MANAGEMENT OF ISOLATED ADVERSE EFFECTS

MANAGEMENT OF NPS TOXICITY SYNDROMES

13. NPS USE DISORDERS

NPS ABUSE POTENTIAL

ASSESSMENT AND TREATMENT OF NPS USE DISORDERS

14. HARM REDUCTION

15. PREVENTION

16. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

17. CONCLUSION

Works Cited

66912 • Novel Psychoactive Substances: Trends in Drug Abuse

Education Category. Psychiatric / Mental Health

Release Date. 12/01/2021

Expiration Date. 11/30/2024

Course Overview

The term "novel psychoactive substance" (or synthetic drug) refers to a new category of drugs on the market that have been created to circumvent existing laws on illicit drugs. This course will provide the most up-to-date information available on novel psychoactive substances, including the evolution of synthetic drug use; demographic characteristics of novel psychoactive substance users; the pharmacology, mechanism of action, and acute effects of novel psychoactive substances; approaches to reverse or manage acute toxicity; possible long-term effects; and prevention or treatment of novel psychoactive substance abuse.

Audience

This introductory course is designed for psychologists who are involved in the evaluation or treatment of persons who use novel psychoactive substances or whose past use has resulted in untoward effects.

Course Objective

The purpose of this course is to allow psychologists to effectively identify, diagnose, treat, and provide appropriate referrals for patients who use novel psychoactive substances.

Learning Objectives

Upon completion of this course, you should be able to:

1. Recall the history and epidemiology of the use of novel drugs of abuse.

2. Analyze the effects and management of synthetic cathinones and other amphetamine analogs.

3. Outline the pharmacology and effects of synthetic cannabinoids.

4. Identify other synthetic drugs of abuse and emerging botanical products.

5. Discuss strategies for the prevention and treatment of novel drug abuse and/or dependence.

Faculty

Mark Rose, BS, MA, LP, is a licensed psychologist in the State of Minnesota with a private consulting practice and a medical research analyst with a biomedical communications firm. Earlier healthcare technology assessment work led to medical device and pharmaceutical sector experience in new product development involving cancer ablative devices and pain therapeutics. Along with substantial experience in addiction research, Mr. Rose has contributed to the authorship of numerous papers on CNS, oncology, and other medical disorders. He is the lead author of papers published in peer-reviewed addiction, psychiatry, and pain medicine journals and has written books on prescription opioids and alcoholism published by the Hazelden Foundation. He also serves as an Expert Advisor and Expert Witness to law firms that represent disability claimants or criminal defendants on cases related to chronic pain, psychiatric/substance use disorders, and acute pharmacologic/toxicologic effects. Mr. Rose is on the Board of Directors of the Minneapolis-based International Institute of Anti-Aging Medicine and is a member of several professional organizations.

Faculty Disclosure

Contributing faculty, Mark Rose, BS, MA, LP, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planner

James Trent, PhD

Division Planner Disclosure

The division planner has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

A unique trend in recreational and problematic drug use began to emerge in the United States around 2008, with the introduction and proliferation of previously unknown psychoactive substances. By 2015, this trend became an established element of domestic and global recreational drug cultures. Novel psychoactive substances (NPS) describe a diverse range of emerging recreational drugs with molecular structures intended to circumvent existing drug laws. Unique to this group of NPS is their Internet and retail promotion, sales, and use as "legal high" substitutes for the standard illicit drugs cannabis, cocaine, amphetamines, 3,4-methylenedioxy-methamphetamine (MDMA), and lysergic acid diethylamide (LSD). This marketing approach has had some factual basis, as many NPS molecules have been derivatives, or have been designed to mimic the effects, of banned drugs [1]. Although the rates of NPS use peaked in 2011–2012 and have been steadily declining, education regarding NPS for healthcare professionals is necessary due to the substantially greater risks of adverse effects and toxicity syndromes than the illegal drugs whose prohibition spurred their introduction.

Users of NPS are attracted by the low cost, easy Internet and retail access, and the lack of legal risk (until banned) [2,29]. People on probation/parole or in certain vocations may gravitate to NPS to evade urine drug testing. The NPS phenomenon is characterized by an evolutionary arms race. Novel drugs are introduced, become banned, and are rapidly replaced by unregulated substances that become banned and rapidly replaced. Earlier NPS (2008–2012) were originally synthesized in academic or pharmaceutical laboratories for research or clinical use, and some briefly entered clinical practice. Post-2012, NPS generations are more likely to be unknown molecular entities that may be more toxic than previous NPS. Potential substances are introduced if the drug shows interesting market potential, has not been banned under a controlled substance act, and/or there is increasing scarcity of an established drug [3].

Synthetic cathinones and cannabimimetics remain the most widely used NPS classes and are sold under numerous product and brand names. NPS market turnover is high, but many NPS resemble their banned parent compound molecularly and pharmacologically [29].

Understanding the molecular structures and pharmacology of NPS classes can help clinicians predict their clinical effects and toxicity. NPS are undetected by drug toxicology screening, but NPS toxicity/overdose is readily managed by identifying the characteristic toxicity syndrome. This helps link substance to clinical effect, and understanding the pharmacologic profiles of the underlying molecular group can facilitate effective patient care [4,30]. Following emergency department care for NPS toxicity/overdose, many patients experience persistent neuropsychiatric symptoms. These can be effectively managed in the primary care setting but require clinician knowledge and education.

The American Academy of Family Physicians (AAFP) identified substantial knowledge gaps between published research evidence and clinical care of patients using NPS [5]. The AAFP also states these knowledge deficits can be remedied by continuing education that provides primary care providers with the information necessary to understand the clinical effects of NPS and the assessment, differential diagnosis, and management of medical and neuropsychiatric problems from NPS use [5].

This course will provide the most up-to-date information available on NPS while avoiding the more time-sensitive aspects of this "moving target." Discussion will include the evolution of their use; demographic characteristics of users; the pharmacology, mechanism of action, and acute effects of NPS; signs and symptoms of NPS intoxication; differential diagnosis and clinical management of severe adverse effects and toxicity from NPS use; possible long-term adverse effects; and prevention and treatment of NPS abuse and addiction. The bulk of this course addresses synthetic cathinones and cannabimimetics. These broad substance categories have been the most widely used NPS. As synthetic cathinones carry the potential for severe and fatal toxicity, assessment, diagnosis, and management of toxicity syndromes following their use is detailed.

2. BACKGROUND OF NOVEL PSYCHOACTIVE SUBSTANCES

NPS represents a broadly diverse category of novel substances, primarily those synthesized from phenethylamines, amphetamines, cathinones, aminoindanes, benzofurans, tryptamines, opioids, and arylcyclohexylamines; however, cannabimimetics and natural botanical products are also included. The molecular structure of common drugs is altered to produce a novel drug agent with shared pharmacologic and clinical properties of the parent drug that, owing to the novel molecular structure, falls outside of legal and regulatory control. This allows for their distribution and sales as "legal" alternatives to the established but banned drugs [6,7,8].

NPS are marketed as purportedly non-ingestible consumer products, most commonly legal highs, herbal incense (cannabimimetics), bath salts (synthetic cathinones), and also as potpourri, plant food, room deodorizer, and electronic-device cleaner [9,10]. All NPS are labeled by distributors "not for human consumption" in order to evade controlled substance analogue statutes for which prosecution requires the intent for human consumption. NPS purchased on the Internet are often labeled "research chemicals" (or RC), "intended for scientific research only," and "not for human consumption" [8,10]. Cannabimimetics now appear in liquid form for use in electronic cigarettes and vaporizer devices [12].

The brand names given to these products become associated with the drug effect; for example, Spice and K2 are popular brand names of cannabimimetic products packaged and sold as herbal incense and are purchased with the expectation of attaining a cannabis-like drug effect. Despite numerous product and brand names, "bath salts" and "Spice" have stuck and are generic terms for synthetic cathinones and cannabimimetics, respectively [9,10]. The popularity of NPS as "legal highs" has been propagated by online marketing, media coverage, and availability (without age restriction) in gas stations, convenience stores, "head shops," and on the Internet [9].

3. NPS EMERGENCE AND EXPANSION

THE NPS PHENOMENON

Since early humans first experienced euphoria with psychotropic plants more than 6,000 years ago, creative individuals have explored new ways of achieving drug-induced euphoria without getting in trouble with the law or dying [13]. These same human tendencies—the quest for novel yet legal psychoactive experiences—are driving the NPS phenomenon.

Although NPS emerged domestically in 2008, use has been widespread in Europe for years, prompted by recreational drug scarcity. Banned in 1985, MDMA (also referred to as Ecstasy) has remained very popular for its mild stimulant, euphoric, and entactogenic/empathogenic effects. The standard MDMA chemical precursor, safrole, is extracted from camphor trees (Cinnamomum camphora) in Southeast Asia. During the 1990s and 2000s, interdiction of safrole shipments into Europe and safrole oil at extraction sites limited precursor supplies for MDMA production, decreasing MDMA purity and availability in Europe. Another precursor, piperonyl methyl ketone (PMK), is banned, but in 2012, Chinese chemists introduced PMK-glycidate, a precursor easily converted to PMK. This reversed long-term scarcity, and from 2013 to 2015, Europe was flooded with high-potency MDMA pills produced by labs in the Netherlands and Belgium, with reports in 2016 indicating that seizures and stopped shipments were being seen in France, Bulgaria, and Spain, suggesting diversifying trafficking routes [14,15]. The MDMA resurgence continues, with the 2018 European Drug Report indicating 1 kg of piperonal, 1,077 liters of PMK, 63 liters of safrole, 5,905 kg PMK-glycidate, and 123 kg of N-tert-butoxycarbonyl-MDMA (Nt-BOC-MDMA) seized in 2016. Additionally, stopped shipment of 7,700 kg of piperonal and 1,000 kg of PMK-glycidate occurred in Europe in 2016 [14]. The European Drug Report indicates increased rates of seizure for both PMK and non-scheduled chemicals (PMK-glycidate and Nt-BOC-MDMA) for MDMA production [14].

Concurrently, the interception of cocaine shipments into Europe from South America made cocaine scarce and poor in quality. The European emergence of cathinones in the early to mid-2000s filled the void of MDMA and cocaine by promising users a legal-high substitute. Cathinones began replacing MDMA in Ecstasy and were introduced as over-the-counter "bath salt" products. The decreasing MDMA content in Ecstasy coincided with the 2009 emergence of cathinones in the United States, which were promoted as less expensive "legal high" Ecstasy and cocaine alternatives [3].

The 2021 European Drug Report indicates that the drug with the most increase of quantity being seized was methamphetamine (0.6 tons in 2018 versus 2.9 tons in 2019), when comparing a two-year period. This has also been proven to be the case when using a 10-year comparison (2009–2019). Increases in the quantity of drug seized within the decade are as follows [11]:

- Methamphetamine (+931%)

- MDMA (+456 %)

- Cocaine (+279 %).

- Herbal Cannabis (+226%)

- Amphetamine (+180%)

- Heroin (+17 %)

- Cannabis resin (-19%)

NPS EXPANSION AND PROLIFERATION

The Internet has emerged as the new marketplace for NPS and plays an essential role in the NPS phenomenon through a variety of mechanisms. Most users and manufacturers obtain information from the Internet for acquisition, synthesis, extraction, identification, and use of NPS and other substances. The Internet also serves as the marketplace that connects manufacturers, suppliers, retailers, and end users. It is increasingly common that manufacturers, suppliers, retailers, web-hosting, and payment processing services are based in different countries, and this decentralization of the online drug markets adds to the difficulty for law enforcement control [14,15,16].

Information and transactions occur on the surface web as well as the "deep web." The "deep web" is a part of the Internet not accessible to traditional search engines, and the "dark web" is a small portion of the deep web intentionally hidden and inaccessible through standard web browsers, typically to evade detection of illicit activities. The dark web hosts drug cryptomarkets, which are only accessible through encryption software that provides a high level of anonymity. Cryptomarkets resemble online marketplaces such as eBay and provide sellers and buyers with an infrastructure to conduct transactions and services, including seller and buyer ratings and discussion forums. Cryptocurrencies like Bitcoin are used as the medium of exchange to facilitate anonymous transactions, and stealth packaging is used to facilitate transportation of small quantities of drugs through established commercial channels. Evidence suggests that many illicit drug purchases made on the deep web are intended for resale [14,15].

Internet facilitation of NPS began in the 2000s. 4-Methylmethcathinone (mephedrone) was "rediscovered" in the early 2000s and marketed as a "legal cocaine" and MDMA substitute and became the most widely used NPS in the European Union by 2009. Internet centrality in seller and user information exchange led to mephedrone being dubbed "the first Internet drug" [17]. Today, NPS Internet information-sharing and transactions are usually referred to as the "research chemical market."

The profit potential is also fueling the pace of NPS expansion. In 2010, a store in Missouri was selling the cannabimimetic product K2 for $20 per 3-gram packet. The owner stated he was making $7,000 per day in K2 sales [18].

A more recent example of the fast pace of NPS expansion and change is the potent synthetic cathinone alpha-pyrrolidinovalerophenone (alpha-PVP) or "flakka." Emerging in Florida and other U.S. regions in 2014 and 2015, "flakka" was sold to users in quantities as small as 100 mg for as little as $5. Bulk alpha-PVP was being purchased from China (via the Internet) for around $1,500/kg and shipped by worldwide express to local mid-level dealers. One kilogram provides 10,000 doses, which can yield $50,000 in sales—$48,500 in profit. This profit margin required a high sales volume. However, the $5 retail price means it is affordable for most users, and the high abuse/addiction potential of alpha-PVP assures repeat business. Younger and poorer populations are increasingly targeted as customers, and alpha-PVP is actively sold to, and by, homeless people [19]. However, since 2015, alpha-PVP was given attention through many law enforcement agencies and legislation, and other similar NPS that can circumvent legal action have become developed, illustrating the rapid growth and decline of many synthesized drugs [160,161]. In 2016, China banned 116 NPS, including "flakka," resulting in a dramatic reduction in the drug in the United States, especially Florida [21].

Non-chemists can synthesize NPS compounds with readily available raw materials or directly obtain the synthetic compounds. Most NPS chemicals are produced in China, in suburban laboratories near Chinese port cities for easy and rapid shipment to North America and Europe using ordinary commercial delivery services. Bulk quantities are also available and may be shipped to wholesalers in the United States and packaged for retail distribution [20].

PROLIFERATION AND TURNOVER IN NPS MARKETS

The number of recently emergent NPS is unprecedented. In the United States between 2009 and 2014, 233 new synthetic compounds were identified, including 95 cannabimimetics, 51 synthetic cathinones, and 87 other NPS compounds [12]. The United Nations reported that 803 NPS were identified by member nations between 2009 and 2017, including cannabimimetics (31%), synthetic cathinones (18%), and phenethylamines (17%) [47]. As of late 2020, the European Union was tracking approximately 830 psychoactive substances, 46 of which were first reported in 2020, and almost all of which are NPS [11,14]. These figures are constantly becoming outdated and staying abreast of rapid changes in the NPS market is difficult [11,13].

The term "generation" is used to demarcate the time points before and after successive legislation actions and resultant bans of NPS, as reflected by specific NPS prevalence [23]. This generational turnover in market presence was more evident between 2009 and 2012. After 2012, some NPS have begun to maintain market presence or vanish and later reappear with widespread regional use after their ban.

Cathinone and Amphetamine Derivative Generations

Record of chemical name by year was once an effective way to track changes in cathinone and amphetamine derivative generations [23]. However, the quick pace at which chemicals structures are altered to create newer versions of drugs in order to circumvent drug laws eventually made it reasonable to change the system of classification of these derivatives.

Because of the rapid changes to this class of synthetic drug and because several drugs are no longer prevalent, today many researchers and law enforcement personnel refer to the chemical makeup rather than year to track changes in NSP. Although there is no standard international nomenclature among different agencies, cathinone derivatives have been categorized into four groups by chemical structure, with novel drugs being created by slightly altering each structure [163]:

- Group 1: N-alkyl compounds or those with an alkyl or halogen substituent at any possible position of the aromatic ring. First synthetic cathinones, including ethcathinone, ephedrone, mephedrone, flephedrone, buphedrone, and pentedrone, are part of group 1.

- Group 2: Methylenedioxy-substituted compounds with substituents at any given position of aromatic ring, such as methylone, pentylone, and butylone. In terms of their structure and pharmacologic effect, these compounds are quite similar to MDMA.

- Group 3: Analogs of natural cathinone with an N-pyrrolidinyl substituent. Most frequently encountered in the designer drug market.

- Group 4: Compounds with both methylenedioxyl and N-pyrrolidinyl substituents.

Cannabimimetic Generations

- Through mid-2011: JWH-018, JWH-073, JWH-200, CP47,497

- July 2011 to July 2012: AM-2201, JWH-019, JWH-081, JWH-122, JWH-203, JWH-210, JWH-250, RCS-8

- August 2012 to early 2013: UR-144, XLR-11, AKB-48, STS-135, MAM-2201

- 2013: PB-22, 5-fluoro AKB-48, 5-fluoro-PB-22, BB-22

- 2013 to 2014: AB-PINACA, AB-FUBINACA, ADB-PINACA

- 2014 to early 2015: THJ-018, FUB-PB-22

- 2015: MAB-CHMINACA, ADB-CHMINACA

- 2016: 5F-ADB, 5FMDMB-PINACA, 5F-AMB, 5F-APINACA, 5F-AKB48, ADB-FUBINACA, MDMB-CHMICA, MMB-CHMINACA, MDMB-FUBINACA

- 2018 to 2019: 5FEDMB-PINACA, 5F-MDMB-PICA, FUB-AKB48, FUB-APINACA, AKB48, 5F-CUMYLPINACA, SGT-25), FUB-144

- 2020 to July 2021: NM2201 or CBL2201, 5F-ABPINACA, 4-CN-CUMYL-BUTINACA, 4-cyano-CUMYL-BUTINACA; 4-CN-CUMYL BINACA, CUMYL-4CN-BINACA, SGT-78, MMB-CHMICA, AMB-CHMICA, 5F-CUMYL-P7AICA

As noted, the NPS arena is characterized by an evolutionary "arms race" between manufacturers and regulators. The U.S. Drug Enforcement Administration (DEA) broadens prohibition of NPS agents and structures, with manufacturers introducing NPS that circumvent these legislative actions. The hazard from this process is that manufacturer efforts to circumvent new drug laws will lead to NPS entry with greater toxicity and morbidity risk, as already observed with fluorinated cannabimimetics and likely with synthetic cathinones and other NPS [25,28].

NPS Epidemic Cycles

A predictable pattern, termed a drug epidemic cycle, has long been observed with some recreational drugs. The cycle begins when the drug first becomes used by a narrow population segment, followed by dramatic increases in its use, possibly fueled by accounts of highly desired effect, perceived safety, or legality. With widespread use come initial reports of addiction or adverse effects from its use, followed by medical and public health alarm, extensive and sometimes sensationalized media reporting, rushed legislation criminalizing its use or possession, and then declining prevalence of its use [17]. This pattern unfolded in the United Kingdom (UK) during the 2000s with the NPS mephedrone and MDPV, and in 2012 the United States followed trend with the enactment of the Synthetic Drug Abuse Prevention Act and subsequent decline in use [17,24].

NPS Regulation

Schedule I is the most restrictive category under the Controlled Substances Act (CSA) and is reserved for drugs with no recognized medical use and a high abuse liability (e.g., heroin, LSD). The DEA has placed numerous NPS into Schedule I [26]. This is an ongoing process, and the most recent list of temporary and permanent NPS placed in Schedule I is found on the DEA website at https://www.deadiversion.usdoj.gov/schedules.

Other attempts at regulating NPS are still being developed. The UK responded to emerging NPS by enacting the European Psychoactive Substances Act of 2016, making it illegal to produce or supply many drugs including NPS. Though more research is needed, one survey showed a modest put positive reduction in the online availability of MDMB-CHMICA (from 47 to 38 websites offering the substance) one month after implementation of the Act. Some websites removed information indicating they were based in the UK, three stated that they could no longer supply customers in the UK, and two websites specifically referred to the Act [162]. In the United States, House Bill 1732: Synthetic Drug Control Act of 2017 was introduced to amend the Controlled Substances Act to include several NPS as Schedule I drugs; the HB was not passed. In 2019, the Stop Importation and Manufacturing of Synthetic Analogues (SIMSA) Act was introduced, but no action was taken. As noted, in July 2021, HB 4459: SIMSA Act of 2021 was reintroduced as a result of increased drug overdoses in 2019 and 2020 [33,89]. In addition, many individual states have enacted legislation to regulate the distribution and use of NPS [54].

NPS USE TODAY

Although patterns of use are rapidly changing, the information in this section helps show the direction of movement in NPS use, distribution, and associated public health concerns. It is believed that the NPS climate in Europe reliably forecasts emerging domestic trends by roughly two years, as illustrated by 2014–2015 European Union data suggesting use patterns in the following few years in the United States [27]. It should be noted that 2014–2015 was the year that NPS began receiving more attention and drugs were rapidly produced; therefore, much information and studies regarding NPS occurred during these years. More current information is provided when available.

The DEA produces an annual Emerging Threat Report that compiles seizure and drug analysis information to provide a snapshot of new psychoactive substances in the United States [38]. Results from the Emerging Threat Report analyzed in 2020 produced roughly 5,550 records (Table 1) [38].

Table 1: MOST COMMON NPS TESTED IN THE UNITED STATES, 2020

Chemical Class

Psychoactive Substances

Substituted amphetamines

2F-deschloroketamine, 2-methoxymethamphetamine and mitragynine

Cathinones

Eutylone,α-Pi HP

Benzodiazepines

Flualprazolam, etizolam

Tryptamines

5-MeO-DBT, AcO-DMT

Fentanyl analogs

Fentanyl, 4-ANPP, Acetylfentanyl

Synthetic cannabanoids

5F-MDMB-PICA, MDMB-4en-PINACA, 4F-MDMB-BUTINACA

Source: [38]

These results suggest a fair number of non-cannabimimetic/cathinone NPS in use, with the DEA's Emerging Trends Program reporting nearly 88% of NPS tested being comprised of opioids, most commonly fentanyl (90% of all opioids) compared with 5.3% of benzodiazepines, 3.6% of cathinones, and 2.4% cannabimimetics identified [38]. According to data from these sources, a high proportion (53%) of samples purchased as fentanyl contained only fentanyl and no other substance and 31% of fentanyl identifications contained fentanyl and heroin [38].

In 2020, the United States indicated a 30% increase in overall drug overdoses (including non-synthetic drugs), the largest increase in nearly three decades. The National Center for Health Statistics notes that the increase is likely higher; however; concrete data are not yet available. The catalyst behind the sharp increase is likely due to the coronavirus pandemic (COVID-19), with reasons of poor mental health due to stress and isolation, in combination with more lethal variations of synthetic drugs, such as fentanyl [34].

There is a rapidly changing landscape of synthetic drug us that is occurring with the ongoing COVID-19 pandemic. While there is lack of statistics thus far, it is postulated that there has been a lower rate of "social drugs" such as MDMA, and a higher rate of cannabinoid and dissociative drugs as individuals adjust to socially distanced environments and greater time in the home. The highest rate is consistent with the opioid epidemic that has become prevalent in the past several years. Early data from the 2021 European Drug Report indicate that individuals are consuming alcohol more regularly as a "socially acceptable" alternative to drugs. In addition, it was noted that there is likely a decline or cease of drug use in individuals that only occasionally used, while there is likely an increase in those that used them regularly prior to COVID-19 [11].

NPS Outbreaks

Rapidly spreading local/regional outbreaks of NPS use, toxicity/overdose requiring emergency medical services (EMS), and fatalities all increased through 2014 and 2015 (Table 2). Especially hard-hit were Broward County, Florida, with county hospitals averaging 20 emergency department admits per day for alpha-PVP overdose or excited delirium, and Washington, DC, where cannabimimetic toxicity led to 439 emergency department admits in one month. Many DC toxicities were excited delirium; two homicides were committed during cannabimimetic-induced excited delirium, with one victim stabbed 40 times on a subway [19,31].

Table 2: OUTBREAKS OF NPS USE, MORBIDITY, AND MORTALITY

Timeframe

Locality

Patient Admits

Deaths

Confirmed NPS

Cathinones

March to June 2015

Broward County, Florida

20 ED admits per day average

—

Alpha-PVP

Late 2014 to May 2015

Unknown

30

Alpha-PVP, ethylone

Cannabimimetics

February to April 2018

Chicago and surrounding area, Illinois, extending to eight other states

>150 ED admits in Chicago area; 38 in other states

4

Unknown, but cannabinoid users all tested positive for brodifacoum, a long-acting vitamin K antagonist used in rodenticides, suggesting contamination

October 2017 to January 2018

Utah

52 admits

—

4-cyano CUMYL-BUTINACA (4-CCB)

March to May 2015

Mississippi

>1,200 ED admits

17

MAB-CHMINACA

Alabama

>1,000 ED admits

5

Unknown

May to September 2015

Austin, Texas

873 ED admits

—

Unknown

May to June 2015

Washington, DC

439 ED admits

—

Unknown

2 weeks in April 2015

New York City

>160 hospital admits

—

Unknown

October 2014

Baton Rouge and Lafayette, Louisiana

>150 hospital admits

—

MAB-CHMINACA, ADB-CHMINACAa

Late 2013 (one month)

Colorado

221 ED admits

—

ADB-PINACA

ED = emergency department

aSold as Spice, K2, and other brand names

Source: [19,31,32,39]

4. EPIDEMIOLOGY

PREVALENCE OF NPS USE

The brief lifecycle of many NPS, under-detection and under-reporting of NPS morbidity and mortality, and polysubstance presence in many suspected cases makes accurate epidemiologic capture of current NPS use difficult. Time delays in data reporting often render epidemiologic sources and peer-reviewed publications outdated at their publication. However, NPS use has appeared to decline since the 2011–2012 peak, with the only exception being a notable increase and subsequent decrease in cannabimimetics reported in 2015. Data collected since 2014 have illustrated growing frequency and size of local/regional outbreaks of severe toxicity and death from specific NPS, although it is unclear how recent events (e.g., ongoing opioid epidemic, COVID-19 pandemic) [11].

Data from Poison Control Centers

Reports to the network of 55 poison control centers in the United States provide valuable information on population-level trends in the abuse of specific and class-wide substances. According to the American Association of Poison Control Centers, use of synthetic cathinones resulting in toxic effects peaked in 2012 and cannabimimetics reached highest rates in 2015, although 2011 shows the highest rates combined for the two categories (Table 3) [36].

Table 3: TOXIC EXPOSURES TO SYNTHETIC CATHINONES AND CANNABIMIMETICS REPORTED TO THE AMERICAN ASSOCIATION OF POISON CONTROL CENTERS

Year

Exposure

Synthetic Cathinones

Cannabimimetics

Total

2010

—

—

—

2011

6,137

6,968

13,105

2012

2,691

5,230

7,921

2013

995

2,668

3,663

2014

582

3,682

4,264

2015

522

7,797

8,319

2016

107

2,706

2,813

2017

7

1,959

1,966

2018

290

1,993

2,283

2019

268

1,163

1,431

Source: [36]

It should be noted, beginning in 2013, poison control call counts are lower than actual NPS toxicities, as emergency department staff has become increasingly adept in identifying and managing NPS toxicity [19].

Current NPS exposure report data are available at https://www.poison.org/poison-statistics-national.

Past-Year Use Among Adolescents and Young Adults

From the peak of past-year use in 2011–2012, cannabimimetic use has declined among adolescents and young adults (Table 4). For example, among 12th graders, 11.3% used synthetic marijuana, decreasing to 3.3% in 2020 [36]. The same trends have followed among 10th and 8th grade students [39]. This decline likely reflects the greater numbers of identified and banned NPS and/or an increase in the perception of harm [39,47]. High school and college students and adults 19 to 30 years of age have indicated an increased perception of risk of trying synthetic marijuana once or twice, with an average of 29.5% in 2012 to 43.9% in 2020. In both years, the perceived risk was higher if using synthetic marijuana occasionally (versus once or twice), with 37.4% in 2012 and 52.4% in 2020 [39].

Table 4: PAST-YEAR CANNABIMIMETIC USE: ADOLESCENTS AND YOUNG ADULTS

Grade Level/Age

2011

2012

2013

2014

2015

2016

2017

2018

2019

2020

8th grade

—

4.4%

4.0%

3.3%

3.1%

2.7%

2.0%

1.6%

2.7%

2.7%

10th grade

—

8.8%

7.4%

5.4%

4.3%

3.3%

2.7%

2.9%

2.6%

2.6%

12th grade

11.4%

11.3%

7.9%

5.8%

5.2%

3.5%

3.7%

3.5%

3.3%

3.3%

College

7.4%

5.3%

2.3%

0.9%

1.5%

1.3%

0.5%

1.6%

1.8%

0.5%

19 to 30 years

7.4%

5.3%

2.3%

1.3%

1.5%

1.0%

0.9%

1.3%

1.1%

1.2%

Source: [39]

Cathinone use has also declined since 2012, although not as dramatically as users of cannabimimetics, given the overall lower usage rate (>1% annually). Very high rates of perceived danger from even single-use synthetic cathinones may explain the lower rates, with rates of perceived risk of 45% to 49% in 2012, compared with 68% to 72% in 2017 [39]. As of 2019, questions regarding cathinones has been removed from the annual National Survey Results on Drug Use study to study other emerging drugs [36].

HIGH-USE SUBGROUPS

NPS users are defined as those who research, discuss, and share NPS information in Internet forums and websites and who purchase NPS online or offline. Those who discuss and obtain the substances online appear to be distinct from NPS users making retail or street purchases.

Persons Subjected to Urine Drug Screening

A study of cannabimimetic users found the majority used these substances to avoid drug-testing detection due to probation/parole, seeking employment, residing in a sober facility, or joining the military. Most report using cannabimimetics as a cannabis substitute during drug-testing periods and resuming cannabis when drug testing has ended. In one study, nearly all learned of cannabimimetics from someone using the substances to avoid drug-testing detection [40].

Military Personnel

The difficulty in detecting cannabimimetics and cathinones by urine drug screens has made their use attractive to active U.S. Armed Forces members. Beginning in early 2011, the extent these drugs were used became evident, with reports of numerous incidents involving the detection and subsequent discharge of large numbers of service members from individual military bases or deployments. Among these reports was an event in 2011 in which an Army combat medic with two deployments to Iraq asphyxiated his young son and then shot and killed his wife and himself during synthetic cathinone intoxication [1]. Increasingly, soldiers have begun requiring emergency department admission or police intervention for medical and behavioral toxicity from these agents. These cases raised sufficient alarm for the military to enact regulations banning the use, possession, or sales of cannabimimetics and cathinones in 2011 [41].

Persons on Probation/Parole

Hard data are difficult to find, but persons on parole and/or probation have been mentioned as among the most likely groups to use NPS for escaping detection by urine drug testing. Considering the number on probation/parole with untreated addiction and limited resources and the availability of a low-cost street purchase sufficient for intoxication, this may represent a sizeable number of NPS users [19,31].

Music and Nightlife Subcultures

Music and club subcultures and recreational drug preferences have evolved in tandem. Cocaine was favored in the 1970s and 1980s disco scene. Underground raves started appearing in the late 1980s and early 1990s, and MDMA (sold and referred to as Ecstasy) was the favored psychoactive at these events. MDMA remained favored by participants in the domestic rave, club, and warehouse party scenes during the 1990s to early 2000s, along with gamma-hydroxybutyrate (GHB) and ketamine. Other growing scenes were gay nightclubs and circuit parties, with methamphetamine the preferred circuit party drug [25]. Efforts to improve safety through harm-reduction approaches (e.g., testing pills, information dissemination) developed during this period.

In the 2000s, electronic dance music grew out of rave culture, with indoor club or warehouse productions and outdoor festivals. Outdoor electronic dance music events are often large, with tens of thousands of participants and corporate sponsorships. These events have been plagued by NPS-related emergency department admissions and fatalities among participants. Independent harm-reduction groups began offering free drug sample testing to inform participants about the true contents of what was sold to them as MDMA or LSD. However, event promoters and venue owners have banned drug testing groups from admission, concerned that allowing their entrance would appear to condone drug use. This stance is a consequence of the 2003 Reducing Americans' Vulnerability to Ecstasy (RAVE) Act, which holds promoters legally responsible for drug dealing at their events. Some law enforcement members began misinterpreting the harm-reduction services and conflating them with drug promotion [42]. Drug testing groups have begun to sneak equipment past security to provide services, but violent retaliation by drug dealers is an ongoing concern [25].

Polysubstance Ingestion

Polysubstance ingestion before, during, and after NPS use is common and can occur without intent by the frequent addition of multiple NPS and other psychoactives to NPS products. NPS users often co-ingest cocaine, amphetamines, MDMA, caffeine, hallucinogens, Mitragyna speciosa (kratom), and/or cathinones to enhance stimulant and entactogen effects; alcohol and beta-blockers to suppress tachycardia; zopiclone to produce visual hallucinations; pregabalin, omeprazole, and domperidone to counteract stomach pain; and cannabis and benzodiazepines to counteract anxiety [43]. Self-administration of the second-generation antipsychotic drug olanzapine has become widely endorsed on Internet forums as the "ideal" molecule to terminate NPS-related psychotic crises/"bad trips," typically at a dosage range of 5–50 mg/day [44].

A 2010 survey of mephedrone users in London found that use of this drug was intended to augment, but not replace, pre-established use patterns of cocaine, Ecstasy, and MDMA. This pattern increases the risks of drug interaction toxicities in users [45].

Importantly, data suggest polysubstance use may be more or less prevalent in users of specific NPS, rather than endemic. Several studies found significantly higher rates of mono-substance use in cannabimimetic-related emergency department admissions than in patients with synthetic cathinone-related admissions. This may importantly influence management of patients with acute NPS toxicity [40].

5. PHENETHYLAMINE DERIVATIVES

An astonishing diversity of structural families and subgroups of NPS and psychoactive drugs have been synthesized from the single parent molecule phenethylamine [46]. Phenethylamines are a broad molecular class that includes amphetamine, methamphetamine, MDMA, and their beta-keto analogs; mescaline; ring-substituted phenethylamines, such as the 2C series and their NBOMe analogs; benzodifurans; aminoindanes; and others (e.g., p-methoxymethamphetamine [PMMA]) [47]. For the purposes of this course, phenethylamines (plural) refers to phenethylamine derivatives as a class.

Phenethylamine, or phenylethylamine, is the parent molecule of many psychoactive substances, including synthetic cathinones, benzofurans and benzodifurans, the 2C and NBOMe series, aminoindanes, mescaline, and the classic recreational drugs amphetamine, methamphetamine, and MDMA (Figure 1). The structural similarity of phenethylamine to the neurotransmitter dopamine is readily apparent.

Figure 1: PSYCHOACTIVE DRUGS SYNTHESIZED FROM PHENTHYLAMINE

Source: [12]

Phenethylamine contains a phenyl ring joined to an amino group via an ethyl sidechain. In substituted phenethylamines, the phenyl ring, sidechain, and/or amino group is modified by substituting another group for one of the hydrogen atoms [8,48]. Manipulation of the phenethylamine structure forms new compounds with stimulant, empathogenic, or hallucinogenic effects or their combination, influenced by the location and molecular make-up of the substitution.

STRUCTURE-FUNCTION RELATIONSHIPS

Amphetamine is a substituted phenethylamine, formed by adding an alpha-methyl group to yield alpha-methyl-phenylethylamine. Amphetamine is modified to produce substituted amphetamines. Methylation of the terminal amine forms methamphetamine. A methylenedioxy substitution on the phenyl ring forms MDMA. Adding a ketone oxygen group at the beta position of the side-chain forms cathinone, termed beta-keto-amphetamine. Amphetamine, cathinone, and MDMA are likewise parent structures of numerous stimulant and empathogenic (MDMA-like) NPS; cathinone is the parent of most "bath salts" NPS [49].

MECHANISM OF ACTION

All phenethylamines produce their stimulant, entactogenic, and/or hallucinogenic effects by increasing synaptic monoamine levels. Dopamine, serotonin (5-hydroxytryptamine or 5-HT), and norepinephrine are the monoamine neurotransmitters. Normally, dopamine, serotonin, or norepinephrine is released into the synaptic cleft, and then cleared from the synapse through uptake by their respective transporter. The last step involves vesicular monoamine transporter-2 (VMAT-2) located on the vesicular membrane. VMAT-2 uptakes the monoamines retrieved from the synapse and packages and stores them in synaptic vesicles for later release [48,71].

Phenethylamines increase synaptic monoamine levels by acting as inhibitors (blockers) or substrate releasers. Blockers inhibit monoamine transporter (re)uptake by competing with monoamine for binding sites on reuptake transporters to reduce synaptic clearance [72]. Releasers induce the release of newly synthesized monoamine pools and release monoamines from pre-synaptic vesicle stores. The drug molecule permeates the intracellular space to inhibit vesicular reuptake of monoamines within the cell, induce transporter-mediated sodium currents (i.e., depolarization), and initiate transporter-mediated monoamine efflux (i.e., reverse transport or release). Outflow of cytoplasmic monoamines into the synaptic cleft is increased [48,71,73].

The net result of increased synaptic monoamine concentration is greater activation of post-synaptic dopamine, norepinephrine, or serotonin receptors, which transmit the amplified electrochemical signaling downstream for relay through various pathways to produce clinical effects of the phenethylamine derivative. Phenethylamines differ by monoamines targeted, relative monoamine activating potencies, and mechanism of monoamine increase (i.e., blockers, releasers, or both). Differences in potency, duration of effect, desired and adverse effects, abuse potential, acute toxicity syndromes, and neurotoxicity potential result from these varied interactions with monoamine systems and from interaction with non-monoamine transmitter systems [71].

NEUROTOXICITY

Substrate releaser-induced depolarization puts neurons at risk, as seen with methamphetamine-associated dopamine neuron dysfunction and serotonin neuronal depletion from the use of fenfluramines [71]. Releasers also disrupt vesicular storage to induce monoamine release, potentially contributing to persistent functional deficit in monoamine neurons through neurotransmitter depletion and loss of functional transporters. These potential neurotoxic mechanisms are not found in inhibitors [74,75].

RING-SUBSTITUTED PHENETHYLAMINES

Ring-substituted phenethylamines comprise many NPS groups with hallucinogenic properties. For example, addition of methoxy-groups at the 2 and 5 positions of phenethylamine, with any hydrophobic substitution at the 4 position, confers hallucinogenic activity and produces the 2C series. Adding a 2-methoxybenzyl (MeOB) unit onto the nitrogen molecule of 2C drugs confers substantially greater potency and forms the NBOMe series. The primarily stimulant-substituted phenethylamines—MDMA, mephedrone, and methcathinone—also co-activate psychedelic pathways through serotonin receptor activation [8,48].

Ring-substituted, or hallucinogenic, phenethylamines include the 2C series and their NBOMe analogs; the 2D series; benzofurans and benzodifurans; aminoindanes; and the para-(4)-phenyl-substituted amphetamines paramethoxyamphetamine (PMA) and PMMA [8,47]. The phenethylamines are distinct from the indoleamines and piperazines [23,50].

The hallucinogenic properties of 2C drugs are further enhanced by a methyl-group at the alpha-carbon, forming the D-Series or ring-substituted (hallucinogenic) amphetamines produced decades ago such as 2,5-dimethoxy-4-methylamphetamine (DOM). All ring-substituted phenethylamines are potent serotonin (5-HT2A) receptor agonists, and many have strong activity in other receptor complexes [8].

The 2C Phenethylamines

There are 27 known 2C compounds, all originally produced by Alexander Shulgin. The powerful hallucinogen 2C-B was the first 2C synthesized, in 1974, by simple alterations to the natural phenylethylamine molecule mescaline [47]. The more commonly encountered 2Cs in the United States are 2C-B, 2C-I, and 2C-T-7, known by the street names Nexus, Bromo, Blue Mystic, and T7.

The effect following oral use in the lower dose range (<8 mg for 2C-B, 3–25 mg for 2C-I, and 10–50 mg for 2C-T-7) lasts six to eight hours and is often described as relaxation, awareness of integration between sensory perception and emotional state, and euphoria with increased body awareness and enhanced receptiveness of visual, auditory, olfactory, and tactile sensation. Dosing in the upper limits results in greater stimulant effects and a state of substantially greater intoxication. Even higher dosing produces LSD-like visual and auditory effects and potentially extremely fearful hallucinations and morbid delusions. User reports of 2C drug effects describe a blend of MDMA-like empathy and entactogenic effects with LSD-like psychedelic effects. 2C-B is used primarily as a club drug in the rave culture and circuit party scene, where some users ingest 2C-B in combination with LSD (a "banana split") or MDMA (a "party pack"). Several fatalities have been reported from co-ingestion of 2C-T-7 and MDMA [51,52,53].

Possible adverse effects include nausea, vomiting, agitation, tachycardia, hypertension, respiratory depression, seizures, psychosis, and suicidal thoughts. Excited delirium with agitation and violent behavior, hyperactivity, hyperthermia, and cardiopulmonary arrest have been documented following 2C use [23]. Several fatalities have resulted from co-ingesting 2C-T-7 and MDMA. Treatment of 2C toxicity is supportive, but immediate action is required with excited delirium, hyperthermia, and seizure activity, because presence of vomiting, agitated behavior, and seizures are risk factors for fatal 2C toxicity [18,55].

The NBOMe Compounds

The NBOMe series was first developed in the early to mid-2000s for the purpose of researching mammalian serotonin receptor distribution. Initial Internet discussion and law enforcement attention both occurred in 2010 [56]. They are commonly known by the street names N-Bomb, Smiles, 25I, 25C, and 25B.

As noted, the NBOMes are synthesized from 2C phenethylamines by the addition of a 2-methoxybenzyl (MeOB) unit onto the nitrogen molecule. This molecular appendage confers greater potency than its 2C counterpart; for example, the dose of 2C-I is roughly 20 mg versus 50–100 mcg with 25I-NBOMe. The hallucinogenic effects are mediated by highly potent and selective agonist activity at 5-HT2A receptors [56].

The NBOMe series is sold as powder, liquid solution, or soaked into blotter paper. NBOMe appears in products sold as LSD, a widespread counterfeiting practice that is encouraged by the cheaper cost of NBOMe [57,58]. This poses a potentially serious health risk to the user, who instead of ingesting the physiologically benign LSD, unsuspectingly ingests NBOMe and risks potentially severe and fatal adverse effects [59].

The effects of NBOMe last 6 to 10 hours with sublingual ingestion. Users report desired effects of euphoria, mental/physical stimulation, feelings of love/empathy, altered consciousness, and unusual body sensations. Negative effects include confusion, shaking, nausea, insomnia, paranoia, and intense negative emotions. Users with severe NBOMe toxicity show violent, severely agitated, and hallucinating presentations and require hospitalization, as hyperthermia, tachycardia, hypertension, seizures, metabolic acidosis, elevated creatine kinase, and acute renal injury are usually present [56]. Even small amounts can cause seizures, cardiac and respiratory arrest, and death [57]. Many fatalities have occurred following NBOMe use, typically preceded by excited delirium [60,61].

Benzofurans and Benzodifurans

Benzofurans include 1-(benzofuran-5-yl)-propan-2-amine (5-APB), 6-APB, and their dihydro-derivatives 5-APDB and 6-APDB. Benzofurans are analogs of MDMA and MDA, first synthesized in the 1990s at Purdue University for researching structure-activity relationships of MDMA-like molecules. In 2010, 5/6-APB entered the UK market as an MDMA replacement "legal high" under the brand name Benzofury (derived from benzofuran) and became very popular. Other benzofurans include IAP and 5-APDI, which replace both oxygen atoms of MDA with methylene groups; 5- and 6-API, which replace the oxygen atom in the heterocyclic rings of 5/6-APB with a nitrogen atom; and 5-MAPB, an N-methyl analogue of 5-APB [62].

Benzofurans are dopamine, norepinephrine, and serotonin inhibitors, with greatest potency at dopamine and norepinephrine receptors. As full 5-HT2B agonists, 5/6-APB may be cardiotoxic with long-term use. User reports describe an empathogenic and stimulant effect, with 5-APB more potent than 6-APB. Several fatalities have been attributed to benzofurans, with hyperpyrexia noted in several cases. Emergency department admissions for benzofuran toxicity have noted tachycardia, elevated blood pressure, and fever [62].

Benzodifurans are termed the "fly" drugs in reference to their insect-resembling molecular structure. They include tetrahydrobenzodifuranyl (Fly), 2C-B-Fly, 3C-B-Fly, and the most potent and widely used drug of this category, benzodifuranyl aminoalkane (Bromo-Dragonfly or B-Fly). The phenyl ring bound between two dihydrofuran rings in B-Fly produces much greater potency and duration of action than most phenethylamine derivatives. B-Fly mechanism of action is mediated primarily by agonist activity at 5-HT2A receptors and, to some degree, 5-HT1 and 5-HT2C receptors [63].

Recreational use of B-Fly was first noted in 2001 and became widespread in 2008, primarily through Internet mediation [63]. B-Fly is sold for oral use in blotter paper or liquid. Following a typical 200–800 mcg dose, the onset of effects can take six hours. Many users assume the initial dose ineffective and ingest another dose or other substances. The drug effect commonly lasts two to three days and is described as profound hallucinations (mainly visual, with geometric patterns and lights), sound alterations, a sense of connection/belonging with other realities, a sense of peace and well-being, emotional stimulation, and meeting with metaphysical entities. Commonly reported adverse effects include nausea and vomiting, headache, tachycardia, elevated blood pressure, lung collapse, gastrointestinal disturbances, muscle tension, tremor, anxiety, panic attacks, arrhythmias, heart murmurs, convulsions, flashbacks, memory disturbances, confusion, and paranoid ideation. Several fatalities have been reported in Europe, but attribution is unclear, as polysubstance use (particularly with ketamine) is common with B-Fly [63].

Aminoindanes

Aminoindanes were first synthesized in the 1970s and investigated for their significant bronchodilating and analgesic properties, though they were later found to produce psychoactive effects. Aminoindanes are amphetamine analogs, with their molecule characterized by a closed five-membered ring system next to the parent six-membered system. This configuration bestows minimal to no neurotoxicity (in preclinical studies) and higher serotonin than dopamine activation (which dampens drug craving). Together with Internet availability as "research chemicals," these actions form the basis of predictions that aminoindanes will become the next wave of NPS [64,65].

2-Aminoindane (2-AI) produces a stimulant effect similar to amphetamine but at one-sixth the potency. It also induces an analgesic effect that, in contrast to morphine, does not depress the brain respiratory center and is not counteracted by nalorphine. In contrast to amphetamines, 2-AI does not increase motor activity but does decrease food consumption. 5-Methoxy-6-methyl-2-aminoindane (MMAI) is a potent serotonin releaser but minimally inhibits dopamine uptake. By stimulating serotonergic neurotransmission, it can increase secretion of hormones such as adrenocorticotropic hormone. Compared with MDMA, 5-IAI is a greater serotonin and dopamine releaser and minimally inhibits their reuptake. Both are non-neurotoxic [66,67]. Some 1-AIs are promising candidates for psychosis treatment, and the substituted derivative rasagiline is used in the treatment for Parkinson disease [64,68]. The finding of potent 5-HT2B receptor full agonist activity with 5-IAI suggests cardiotoxic potential with long-term use, as this mechanism is shared by all drugs that induce heart valvular disease in humans, including fenfluramine, MDMA, and various ergolines [69].

Following oral ingestion of powder or crystals, aminoindanes produce empathogenic and entactogenic effects similar to other serotonin-releasing drugs (such as MDMA) and a mild stimulant effect similar to amphetamine [70].

Pipradrol Derivatives

The pipradrol derivatives diphenylprolinol (D2PM) and desoxypipradrol (2-DPMP) are selective and very potent monoamine transporter inhibitors without substrate-releasing properties. This pharmacologic profile closely resembles MDPV and alpha-PVP and predicts high risk of abuse potential and psychiatric morbidity. First appearing in 2010 as "Ivory Wave," clinical toxicity from 2-DPMP/D2PM is long-lasting (24 to 72 hours), with sympathomimetic symptoms of hypertension, agitation, and hallucinations [8].

6. SYNTHETIC CATHINONES AND AMPHETAMINE/MDMA DERIVATIVES

In plural, cathinones and amphetamines refer to all synthetics/derivatives of the respective parent. Most stimulant NPS are cathinones, but NPS amphetamines have also begun to emerge as significant drugs of abuse.

HISTORY

More than 120 years ago, cathinone, the parent compound of this drug class, was isolated from Catha edulis (khat), a plant cultivated and chewed as a recreational and stimulant drug in Africa and the Arabian Peninsula for centuries [1]. Beginning with the synthesis of methcathinone in 1928 and mephedrone in 1929, many cathinone derivatives and analogs were synthesized and investigated or introduced into clinical use as anorectics, CNS stimulants, or antidepressants. Overall, problems with abuse and dependence have limited their clinical utility. Methcathinone was used in the former Soviet Union as an antidepressant in the 1930s and 1940s but was removed from clinical use due to problems with its abuse. It has been most widely used as a drug of abuse in countries formerly part of the Soviet Union [73]. Another derivative, pyrovalerone, is a stimulant first synthesized in 1964. It was investigated for use in treating chronic fatigue, lethargy, and obesity but was withdrawn due to abuse and dependency in users [73,77]. Methylone was created and patented by Jacob Peyton and Alexander Shulgin in 1996 as an antidepressant but never entered clinical use [78]. MDPV was developed by Boehringer Ingelheim in 1969 and subsequently prescribed for chronic fatigue and lethargy before its abuse liability became apparent [79].

As of 2021, only two cathinones are in clinical use in the United States. Diethylpropion is used as an anorectic but is infrequently prescribed due to abuse and dependence liability. It has also shown neurotoxicity in preclinical studies. The most successful cathinone derivative is bupropion, a ring-substituted cathinone widely used in the United States and Europe as an antidepressant and smoking-cessation aid under the brand names Wellbutrin and Zyban. This drug has no abuse liability [80].

The first documented large-scale abuse of synthetic cathinones occurred with methcathinone in the former Soviet Union in the 1970s and 1980s. Clandestine methcathinone manufacture first appeared in the United States in Michigan in 1991, followed by significant problems with abuse in the early 1990s [80]. In Europe, novel cathinone compounds emerged later in the 1990s, immediately followed by the rising prominence of "bath salts," which began appearing in the United States in 2009 [1].

PHARMACOLOGY

Molecular Structures

Cathinone and its derivatives are closely related to phenethylamine, MDMA, and the classic stimulants amphetamine and methamphetamine in use in various settings since the 1930s. Cathinone, amphetamine, and MDMA are parent molecules of all known synthetic cathinones on the NPS market sold through the Internet, retailers, or street dealers [8].

As discussed, adding an alpha-methyl group to phenethylamine forms amphetamine. Methylation of the terminal amine then forms methamphetamine and greater CNS potency. Some cathinones are beta-ketone analogs of amphetamines. The parent cathinone is formed by adding a ketone oxygen group at the beta-carbon position on the amino side-chain of amphetamine, making cathinone its beta-keto analog (or bk-amphetamine). A ketone group added to methamphetamine forms methcathinone and the N-methyl derivative of cathinone [8].

MDMA is formed by a methylenedioxy substitution on the phenyl ring of amphetamine. Other cathinones are formed from MDMA and derivatives by adding a ketone group; thus, MDMA forms methylone or bk-MDMA; methylenedioxyethylamphetamine (MDEA or "Eve") forms ethylone or bk-MDEA; and N-methyl-1,3-benzodioxolylbutanamine (MBDB) forms butylone or bk-MBDB [46,81].

The molecular structure of cathinone is modified to form new cathinones through N-alkylation, which is achieved by substitutions in the phenyl (aromatic) ring or at the alpha-carbon position [17,82]. Cathinones without ring substitution produce mainly stimulant effects. Ring substitution with a secondary or cyclic amino group (usually alkyl, alkoxy, or methylenedioxy) confers varying degrees of entactogenic and other effects similar to MDMA. All cathinones, whether or not ring substituted, possess primary stimulant properties [8,82].

Mechanism of Action

As with amphetamines and MDMA, the subjective and physiologic effects of cathinones result from increased synaptic concentrations of the monoamines dopamine, norepinephrine, and serotonin. In addition to those discussed for phenethylamines, cathinones inhibit monoamine oxidase (MAO), especially MAO-B, reducing the breakdown of dopamine and phenethylamine [48].

CATHINONES AND AMPHETAMINE DERIVATIVES GROUPED BY PHARMACOLOGIC ACTIVITY

Several cathinones and amphetamine derivatives are now pharmacologically characterized in humans, allowing their grouping by mechanisms of action resembling classic stimulants, which can help in the understanding of their clinical effects [46,83].

Cocaine-MDMA-Mixed Cathinones

Similar to cocaine, cocaine-MDMA-mixed cathinones show a ratio of dopamine versus serotonin inhibition ranging from 1 to 5 (dopamine>serotonin). With methylone, ethylone, and butylone, their corresponding non-beta-keto analog entactogens MDMA, MDEA ("Eve"), and MBDB are 10-fold more selective for serotonin compared with dopamine. These cathinones are more dopaminergic in monoamine transporter inhibition activity than their serotonergic entactogen analogs. Overall, the cocaine-MDMA-mixed cathinones are comparable to MDMA in monoamine-releasing activity, although the overall pharmacologic effects of mephedrone and methylone share the dopamine system-stimulating properties of amphetamine and methamphetamine [46,83].

Mephedrone is equally potent at dopamine and serotonin inhibition. It is a more potent releaser of dopamine than MDMA and produces a rapid and pronounced increase in nucleus accumbens dopamine levels, similar to amphetamine and unlike MDMA. However, mephedrone produces strong increases in extracellular serotonin similar to MDMA and unlike amphetamine.

Methylone is a slightly more potent dopamine inhibitor than a serotonin inhibitor. It has been found to elevate extracellular monoamine levels in the nucleus accumbens, similar to MDMA. Ethylone is an equipotent dopamine, serotonin, and norepinephrine inhibitor and releases serotonin. Butylone also releases serotonin, but it is a slightly more potent dopamine than serotonin inhibitor.

Naphyrone shows a monoamine uptake transporter inhibition profile similar to cocaine, with equal potency at all three transporters and no monoamine releaser activity. Naphyrone is structurally related to pyrovalerone and its derivative MDPV, but it is functionally distinct due to its greater absolute and relative serotonin-inhibiting potency [84].

MDMA-Like Para-(4)-Substituted Methcathinones and Amphetamines

This group of NPS includes mephedrone, 4-ethylmethcathinone (4-EMC), 4-FMC, 4-bromomethcathinone (4-BMC or brephedrone), 4-FA, and 4-fluoromethamphetamine (4-FMA). Substances in this group are more serotonergic (i.e., have a lower dopamine/serotonin ratio) than their amphetamine, methamphetamine, and methcathinone analogs [85].

The 4-methyl, 4-ethyl, and 4-bromo groups show enhanced serotonergic properties versus the 4-fluoro group. The para-substituted amphetamines release norepinephrine and dopamine; 4-FA, 4-FMA, 4-MEC, and 4-EMC also release serotonin (similar to MDMA). Most para-substituted amphetamines show 5-HT2A receptor affinity, without relevant 5-HT2B receptor activation. The enhanced direct and indirect serotonergic agonist properties of para-substituted amphetamines/cathinones are associated with greater MDMA-like effects [85].

Methamphetamine-Like Cathinones

Cathinone and methcathinone show pharmacologic profiles highly similar to their non-beta-keto analogs amphetamine and methamphetamine, including their relative monoamine transporter inhibition profiles with high inhibitory potencies at dopamine and low potencies at serotonin. They are potent releasers of dopamine but not of serotonin [46,83].

Flephedrone inhibits dopamine but not serotonin, similar to its analog 4-FA. It has a dopamine/serotonin selectivity profile equal to the methamphetamine-like cathinones, but with higher 5-HT2A receptor binding and agonism, similar to mephedrone and MDMA [46,83].

Pyrovalerone Cathinones

Pyrovalerone and its derivative MDPV are very potent dopamine inhibitors—at least 10-fold more potent than cocaine and methamphetamine. They are weak serotonin inhibitors and thus show dopamine/serotonin inhibition ratios greater than 100. MDPV and pyrovalerone are also highly potent norepinephrine inhibitors. Pyrovalerone and MDPV do not produce dopamine efflux, and the activity of pyrovalerone-derivative cathinones is purely transporter uptake inhibition [46,83,85].

Para-(4)-Phenyl-Substituted Amphetamines

PMA and PMMA are potent norepinephrine and serotonin transporter inhibitors and releasers and have been sold as MDMA. However, they are substantially more toxic. In 2014, PMA/PMMA sold as MDMA led to 29 deaths in the UK [8,14].

4-MTA, the methyl-thio analog of PMA, has dominant serotonergic action and a high risk of serotonin toxicity. Methedrone is the beta-keto analog of PMMA, and whether this cathinone carries the toxicity of its parent compound is not known [8].

CHARACTERISTICS OF SPECIFIC CATHINONES

Mephedrone

Mephedrone can produce the sought-after entactogenic effects of MDMA, particularly the feeling of enhanced emotional and physical connection to others. Other desired effects include intense stimulation, alertness, euphoria, sociability and talkativeness, moderate sexual arousal, perceptual distortions, and intensification of sensory experiences. The numerous unwanted effects are common to all cathinones and result from hyper-dopaminergic, hyper-adrenergic, and hyper-serotonergic output [1]. The effects are often followed by intense compulsion to re-dose. Tolerance develops quickly, and brief drug effect and urge to re-dose can lead users to ingest successive doses, often in excess of 1 g [86,87,88].

Following single-dose mephedrone, brain dopamine peaks in 20 minutes and returns to baseline within two hours, 10 times faster than MDMA and two times faster than amphetamine [73]. Dopamine levels increase 496% following a single dose of mephedrone, compared with 412% with amphetamine and 235% with MDMA. Serotonin levels increase by 941% with mephedrone, 165% with amphetamine, and 911% with MDMA [1]. An intranasal dose of 25–75 mg or an oral dose of 150–250 mg can induce intense craving and compulsion to re-dose—stronger than that experienced with MDMA. Intranasal users rate mephedrone as more addictive than cocaine. Mephedrone alone is not neurotoxic to dopamine neuron terminals, but its co-administration with MDMA, amphetamine, and methamphetamine enhances neurotoxicity [88].

Methylone

Relative to MDMA, 100–200 mg oral methylone produces calm euphoria, alertness, restlessness, a strong feeling of empathy, and milder stimulation. Unlike methamphetamine, methylone is a weak motor stimulant, and unlike MDMA, methylone induces minimal hyperthermia and little long-term cortical or striatal amines alteration. It has shown antidepressant effects and demonstrates little long-term cortical or striatal amine alteration. The side effect profile primarily reflects sympathomimetic activity. Fatalities attributed to methylone often involve polysubstance use [9,16,73].

MDPV

Entering the domestic NPS market in late 2010, MDPV quickly rose in prominence and notoriety [77]. Its pharmacologic actions closely resemble pyrovalerone and alpha-PVP. Rapid blood-brain barrier penetration confers high potency. Full effects peak at 90 minutes and last three hours. Relative to cocaine, MDPV shows 50-fold greater dopamine potency and 10-fold greater norepinephrine potency, predictive of pronounced sympathomimetic stimulation and euphoria [48,74].

MDPV imposes risks from the slim dose-response margin between desired (2–10 mg oral) and adverse (>10 mg oral) effects. Effects include physical and mental stimulation, increased sociability, euphoria, and potentially severe prolonged panic attacks, agitation, anhedonia, confusion, intense paranoia, and depression. An unpleasant comedown, significant craving, compulsion to re-dose, and rapid tolerance are often reported [90]. Users have repeatedly re-dosed from intense craving and to counteract unpleasant comedown symptoms, increasing the risks of overdose and toxicity. More than other cathinones, MDPV is linked to excited delirium syndrome [16,91].

4-MEC

4-MEC is a methcathinone derivative that produces stimulant, euphoric, and empathogenic effects. 4-MEC users frequently report multiple re-dosing and difficulty refraining from re-dosing if more 4-MEC is available. Tolerance quickly develops [16].

ROUTES OF ADMINISTRATION

As noted, mephedrone can be nasally ingested (snorted), but most cathinones are orally ingested. They cannot be smoked because their free bases are highly labile. Mephedrone, MDPV, 4-MEC, and pentedrone are water soluble, allowing injection. Mephedrone has been injected with heroin to simulate IV heroin/cocaine effects ("speedball") [48,80]. Other ingestion approaches are "bombing," with mephedrone powder wrapped in cigarette paper and swallowed, and "keying," an approach to get a crude dose estimate by dipping a car or house key into powder and then ingesting nasally. It is thought the powder from five to eight "keys" amounts to 1 gram [73].

SIDE EFFECT PROFILE

The side effect profile of cathinones reflects relative contribution from dopamine, serotonin, and/or norepinephrine activation. Sympathomimetic effects common to all cathinones include tachycardia, tremor, sweating, hypertension, mydriasis, or hyperthermia. Excessive dopamine release can induce psychosis and confusion, while excessive serotonin release can induce myoclonus, nausea and vomiting, and agitation [6,80,92]. Additional possible side effects include seizures, bruxism, prolonged panic attacks, insomnia, headache, tinnitus, vertigo, muscle twitching, dizziness, altered vision, short-term memory problems, anhedonia, depression, and suicidal thoughts [42]. Cathinones closely resemble amphetamines in molecular structure, but differ by greater potential for severe and protracted adverse effects, potentially even from a single dose [92].

Severe Adverse Effects and Excited Delirium Syndrome

Excited delirium syndrome is a life-threatening and potentially fatal state of agitated delirium and autonomic dysregulation. It is the most severe manifestation of toxicity/overdose with cathinones use. Cannabimimetics and other NPS can also induce excited delirium, but cathinones-induced excited delirium is the most documented in the scientific literature and the lay media.

Cathinones-induced agitated delirium or psychosis may persist for weeks, even from a single dose. Close to 80% of patients presenting for emergency medical care following cathinone use exhibit agitation ranging from mild to severe psychosis requiring chemical and physical restraint [50,73]. With severe agitation, the patient may require restraint and transport to a medical setting by law enforcement personnel. Agitation can be exacerbated by concurrent use of alcohol or other drugs, such as cocaine. Dramatic cases of disorganized and agitated behavior manifesting in severe aggression, violence, homicidal combative behavior, self-mutilation, or suicide have received media coverage due to injury and loss of life. Delusions of persecution and auditory hallucinations during binge use have been described in users with a negative history of psychosis [93,94,95,96].

The bizarre, aberrant behavior during cathinone-induced psychosis encountered by poison control and emergency medical experts led to their description as embodying the combined worst attributes of methamphetamine, cocaine, phencyclidine, LSD, and MDMA [97]. In a case series, poison control experts in Kentucky and Louisiana described their encounters with individuals displaying "aggressive violent behavior, hallucinations, and paranoia in higher percentages than previously reported" following synthetic cathinone use [98]. Behavioral descriptions included those who were found "jumping out of a window to flee from non-existent pursuers; requiring electrical shock (Taser) and eight responders to initially subdue the patient; repeatedly firing guns out of the house windows at 'strangers' who were not there; walking into a river in January to look for a friend who was not there; leaving a 2-year-old daughter in the middle of a highway because she had demons; climbing into the attic of the home with a gun to kill demons that were hiding there; and breaking all the windows in a house and wandering barefoot through the broken glass" [98]. Also described was a patient fatality from a self-inflicted gunshot wound while delusional. Investigation into possible causality in each of these cases found that MDPV was present in every case and that MDPV was the sole cause of the behavioral toxicity [98].

MDPV has been the primary cathinone detected in patients hospitalized for synthetic cathinone toxicity and overdose in the United States and has become the cathinone most responsible for excited delirium [74,98]. MDPV cross-reacts with the phencyclidine (PCP) immunoassay used in hospitals, suggesting some cases of severe neuropsychiatric toxicity following MDPV use may have been falsely attributed to PCP [74]. In addition to paranoia, psychosis, and agitation associated with all cathinones, high-dose MDPV use can induce extreme anxiety and intense prolonged panic attacks, aggressive behavior, "superhuman" strength, combativeness, and potentially terrifying hallucinations [94].

The first case report of fatality following acute MDPV toxicity described a sequence beginning with arrival to the emergency department, where the patient went into cardiac arrest with pulseless electrical activity. Despite rapid aggressive intervention that restored spontaneous circulation, the patient subsequently developed coagulopathy, rhabdomyolysis, renal failure, hepatic failure, and anoxic brain injury and ultimately died [77].

Numerous cases of organ damage and other life-threatening sequelae have been documented following cathinone use, including acute tubular necrosis and renal failure resulting from severe renal tubular vasospasm and elevated creatine kinase [99]. Seizure activity or anion gap metabolic acidosis has resulted from excessive anaerobic metabolism induced by excessive systemic monoamine elevation. Several fatalities following mephedrone use were linked to severe hyponatremia and cerebral edema [73]. MDPV exposure in one patient led to fulminant hepatic failure and disseminated intravascular coagulation. Most fatalities following cathinone use have resulted from aggression/self-harm in the context of severe agitation and psychosis [77,100].

7. CANNABIMIMETICS

Cannabis refers to the natural cannabis plant, primarily Cannabis sativa or C. indica. Cannabinoids are any natural or synthetic compounds with pharmacologic activity resembling the primary psychoactive effects of cannabis plants (via delta-9-tetrahydrocannabinol or THC) through cannabinoid receptor (CB)-1 or CB2 activity. Cannabimimetics have been called "synthetic marijuana," which can be misleading because while these substances functionally resemble THC, they also produce a range of pharmacologic and clinical effects uncharacteristic of cannabis [7,18,48].

The psychoactive components of cannabimimetics are primarily manufactured in China. These bulk chemicals are shipped as powder or dissolved in acetone or other solvents to U.S. distributors, who spray or coat the compound onto dried herbs and package the product for retail sales as herbal incense or potpourri. Of the numerous brands cannabimimetics have sold under, "Spice" has the highest name recognition and has become synonymous with cannabimimetic products. Herbal products saturated with cannabimimetics were introduced in Europe in 2004 and the United States in 2008, marketed as legal-high alternatives to cannabis [6,7,101]. Spice products were smoked until the entrance of oral/e-liquid/injectable cannabimimetic formulations for use in e-cigarettes or "vaping." Identically labeled products vary by cannabimimetic dosage, composition, and concentration. Some contain multiple cannabimimetic agents and other substances identified in samples as psychoactive herbs and plants, benzodiazepines, tryptamines, phenethylamines, NBOMe compounds, cathinones, and opioids [26,102].

The actual herbal plant materials in cannabimimetic products are listed on the packaging, typically a combination of purportedly psychoactive plants such as Indian warrior (Pedicularis densiflora) and Lion's tail (Leonotis leonurus). Some of the plants may have been chosen because of their actual historical use as cannabis substitutes, but little is known of their pharmacology and toxicology and concern has been raised over potential heavy-metal residue content. When these products first appeared in Europe, it was thought the mixture of legal herbs produced the "high." However, laboratory analysis revealed cannabimimetics as the psychoactive constituent [41,86]. Identification of the true psychoactive drug was delayed by several plausible factors, including psychoactivity from the labeled botanical products, the complex evaluation methods necessary, the addition of large amounts of masking agents such as vitamin E (tocopherol) to conceal the active substance, and distribution through legal Internet or retail establishments instead of clandestine production and illegal distribution that would have led to law enforcement interception and analysis [86]. Consumer perception in the United States that herbal smoking blends were safe, legal cannabis alternatives with the "high" produced by the proprietary herbal combinations persisted as their use became widespread [6].

DEVELOPMENT AND INTRODUCTION AS NPS

Cannabimimetics entering domestic NPS markets between 2009 and 2012 were "rediscovered" molecules originally developed for research or clinical use. Following the discovery of THC in the 1960s, researchers synthesized numerous cannabimimetics during concerted efforts to isolate the psychoactive effects from desired therapeutic properties by modifying the THC structure. Their synthesis was described in scientific publications and later replicated for NPS market entry. Earlier cannabimimetic molecules bear a prefix denoting their origin. The first THC analogs were synthesized at Hebrew University, and these molecules are designated HU- (e.g., HU-210). The best known, nabilone and dronabinol, received U.S. Food and Drug Administration (FDA) approval in 1985 for the treatment of chemotherapy-induced nausea and vomiting. In the 1970s, Pfizer developed the cyclohexylphenols (CP) series and their N-alkyl homologues [1,103]. John W. Huffman and his team at Clemson University synthesized more than 450 cannabinoids during the 1990s to study interactions between molecular structure, receptor activity, and physiologic response. Their structural groups are indoles, pyrroles, and indenes [104,105]. These substances bear the prefix JWH- (e.g., JWH-018).

Newer cannabimimetics fluorinate the aliphatic side chain of older indole-based substances to strongly increase potency; this may also enhance blood-brain barrier penetration [7,23]. For example, fluorinated JWH-018 forms AM-2201, and fluorinated UR-144 forms XLR-11. AB-FUBINACA, AB-CHMINACA, and similar substituted indazole compounds have been introduced using this method. Many indazole compounds are fluorinated, and all are very potent, with high CB1 binding affinity. Receptor binding affinity is one potency test, with a lower affinity constant value indicating increased potency (Table 5) [18,48].

Table 5: COMPARISON OF THC AND CANNABIMIMETICS CB1 BINDING POTENCY

Origin

Examples

Structure

Potency and Selectivity

CB1 Binding Affinity

Delta-9-THC

Cannabis

Dibenzopyran

CB1 partial agonist

35–80 nM

Hebrew University

HU-210

Dibenzopyran ring, THC analog

Full CB1/CB2 agonist

0.06 nM

Pfizer

CP47,497

Cyclohexylphenol

Potent selective CB1 agonist

9.54 nM

John W. Huffman, Clemson University

JWH-018

Naphthoylindole

Potent CB1 agonist

9 nM

JWH-122

Naphthoylindole

Potent CB1 agonist

0.69 nM

NPS

AM-2201

Fluorinated JWH-018 analog

CB1 agonist

1 nM

Source: [18,48]

PHARMACOLOGY

THC and cannabimimetics bind and activate CB1 receptors to produce their euphoric effects. Compared to the partial CB1 agonist THC, full agonist cannabimimetics have greater potency, with toxicity and overdose potential uncharacteristic of cannabis [106]. As a partial agonist, THC is limited in the extent it activates CB1 and shows a direct dose-response effect until a plateau is reached, with further dose escalation failing to increase drug effect. This partial agonist property contributes to the infrequent toxicity from cannabis use and the perception of cannabis as a "safe" drug. In contrast, the full CB1 agonist cannabimimetics do not possess a dose-response plateau and further use increases overdose and toxicity risk [103].

Cannabimimetics produce a substantially greater drug effect than THC, with CB1 receptor binding affinities 5 to 10,000 times greater and significantly higher dose-response efficacy. CB1 agonists inhibit GABAergic neurons that project to the nucleus accumbens, which disinhibits nucleus accumbens dopaminergic neurons that activate the mesolimbic dopaminergic pathways and contribute to the rewarding properties and abuse potential of cannabinoids. Because cannabimimetics more powerfully activate CB1, they produce more intense euphoria and reward. This greater inhibition of GABA-mediated neurotransmission also disrupts the balance of GABA/glutamate release in neuronal projections from the prefrontal cortex, which over-activates dopaminergic systems in the prefrontal cortex and striatum, inducing paranoia, agitation, anxiety, psychoses, and convulsions [18,102].

Importantly, evidence and growing consensus indicates that absence of cannabidiol (CBD) in the presence of THC strongly contributes to more frequent, severe toxicity. Cannabidiol is a cannabinoid and natural constituent of cannabis with demonstrated anxiolytic, antipsychotic, and anticraving effects. The presence of cannabidiol in cannabis is thought to counter the psychotomimetic and anxiogenic properties of THC in a concentration-dependent manner. Cannabidiol is absent in cannabimimetics, which may increase the risks of acute psychosis [7,8,18,47,48,102].

Many cannabimimetics possess indole-derived structures similar to serotonin, which may facilitate 5-HT2A receptor dysfunction associated with hallucinations, psychosis, and serotonin syndrome [7,107]. Some cannabimimetics show additional activity as N-methyl-D-aspartate (NMDA) receptor antagonists and/or MAO inhibitors. This may increase the risk of serious drug interaction toxicity [102]. Cannabimimetic products are often contaminated with clenbuterol, a beta2-adrenergic receptor agonist that potentiates sympathomimetic effects and may result in hypertension, tachycardia, nausea/vomiting, chest pain, and myocardial infarction [106].

ACUTE EFFECTS

Natural cannabis and cannabimimetics overlap mechanistically through CB1 receptor binding and activation to produce the shared subjective effects of relaxation, euphoria, perceptual changes (e.g., altered sense of time, intensified sensory experiences), cognitive impairment (e.g., amnestic symptoms, slowed reaction time), and the physiologic effects of xerostomia, conjunctival injection, and tachycardia [50]. Acute changes in mood, anxiety, perception, thinking, memory, and attention are common to both. Agitation, aggression, paranoia, anxiety, and psychoses are common with cannabimimetic use and less common or rare with cannabis use. As discussed, the more frequent and severe psychosis, agitation, and sympathomimetic effects with cannabimimetic use reflect greater potency, full CB1 agonist action, and absence of CBD [102,108].

The quality and intensity of adverse effects also differ. Unlike cannabis, cannabimimetics can induce severe agitation, psychosis, and paranoid delusions; command hallucinations are more likely with prolonged, heavy use. The greatest safety concern is psychosis, which can occur in persons without previous history and persist five months or longer [109]. Young and first-time users may be particularly vulnerable to cannabimimetic-induced psychoses [110]. The severity of distress during panic attacks and other psychologic effects has driven some cannabimimetic users to suicide [50].

Cannabimimetic use has repeatedly led to excited delirium, and some users die before reaching an emergency department [32]. Others may seek emergent care for paranoia, hallucinations, or physical violence emergencies. Increased activity from severe agitation and struggle can lead to rhabdomyolysis and the risk of renal failure. Seizures can induce anoxia, hyperthermia, acidosis, and long-term end-organ damage; these are fatal in 2% of cases [32,106].

8. TRYPTAMINES

Tryptamines are monoamine alkaloids synthesized by decarboxylation of tryptophan and are quite varied. They include natural neurotransmitters (e.g., serotonin, melatonin); hallucinogens found in plants, fungi, and animals (dimethyltryptamine [DMT], 5-MeO-DMT, bufotenin); synthetic pharmaceutical products (e.g., sumatriptan and zolmitriptan to treat migraine); and various synthetic hallucinogenic compounds, such as alpha-methyltryptamine (AMT), diisopropyltryptamine (DiPT), 5-MeO-DiPT, 5-MeO-AMT, diethyltryptamine (DET), and 5-MeO-DET [47]. Use of tryptamines for psychoactive effect began in the late 1950s with psilocybin, the natural ingredient in certain mushroom species. Synthetic tryptamines appeared on the illicit drug market in the United States during the 1990s [8; 111]. The use of tryptamines as an NPS has declined in recent years, as indicated by the DEA's 2018 Emerging Threat Report and 2020 National Drug Threat Assessment, which classifies tryptamines under the category of "other" [38]. However, due to the rise-and-fall nature of NPS drugs over short periods of time, there is a potential for tryptamines to make a comeback.

Tryptamines have an indole ring structure (a fused pyrrole and benzene double-ring) joined to an amino group by a 2-carbon side chain. Psychoactive effects are closely related to their structural influence on receptor affinity. Tryptamines produce dominant hallucinogenic/psychedelic effects as 5-HT2A/1A/2C receptor agonists. Alpha methylation leads to stimulant activity, as with AMT and 5-MeO-AMT. Many synthetic tryptamines are monoamine releasers, increasing the risks of serotonin syndrome and sympathomimetic toxicity. With primarily serotonergic action, tryptamines lack reinforcement and abuse liability [8,112]. Tryptamines are grouped by structure as indole ring-unsubstituted tryptamines, 4-position ring-substituted tryptamines (e.g., psilocybin), 5-position ring-substituted tryptamines, and ergolines (or complex tryptamines) (e.g., LSD, lysergic acid amide). Of these groups, the indole ring-unsubstituted and the 5-position ring-substituted tryptamines are considered NPS.

INDOLE RING-UNSUBSTITUTED TRYPTAMINES

Indole ring-unsubstituted tryptamines include AMT (banned in 2004), alpha-ethyltryptamine (AET), DMT, DET, dipropyltryptamine (DPT), and DiPT. AMT and AET were developed as antidepressants in the 1960s by Upjohn but were withdrawn from brief clinical use due to the risk for psychoses and other adverse effects. With a 15–40 mg oral dose of AMT, effects have onset in three to four hours. Visual hallucinations, altered sensory perception, and euphoria persist for 12 to 24 hours. Frequently reported adverse effects include anxiety, nausea, moderately severe dysphoria, and next-day depression. AET produces psychedelic, stimulant, and entactogenic effects but may induce serotonin neurotoxicity [112].

DPT was synthesized in the 1950s and was first used in 1973 as an adjunct to psychotherapy in the treatment of alcoholism. An oral dose of 100–250 mg induces psychedelic effects, with increased music and color intensity, flashes of light and sparkles, ego loss, and seeing apparitions of faces. These effects last two to four hours [112].

5-POSITION RING-SUBSTITUTED TRYPTAMINES

All 5-position ring-substituted tryptamines inhibit monoamine reuptake but have few monoamine releasing effects. 5-MeO-AMT is a psychedelic tryptamine with structural similarity to amphetamines. Oral use of 2.5–4.5 mg produces effects lasting 12 to 18 hours. Excessive dosing can induce sympathomimetic effects and has led to several hospitalizations and fatalities.

5-MeO-DiPT, termed Foxy or Foxy Methoxy, was first synthesized by Andrew Shulgin and emerged as a drug of abuse in 1999. The effects resemble 2C-B, with a psychoactive threshold of 4 mg. Doses of 6–20 mg produce full-blown effects that peak at 60 to 90 minutes and last three to six hours. The initial nausea and muscular hyper-reflexia are followed by euphoria, relaxation with emotional enhancement, talkativeness, and behavioral disinhibition. Higher doses can produce abstract closed-eye imagery [113]. Adverse effects include restlessness, agitation, gastrointestinal distress, muscle tension, and rhabdomyolysis. Fatalities have been associated with 5-MeO-DiPT [47].

5-MeO-MiPT or "Moxy" is an analog of 5-MeO-DiPT. Following an oral dose of 4–6 mg, this drug produces euphoria, increased tactile sensations, relaxation, and visual distortions that dissipate by 10 hours, followed by difficulty sleeping.

9. ARYLCYCLOHEXYLAMINE DISSOCIATIVE ANESTHETICS

Phencyclidine or PCP was discovered in 1956 by Parke-Davis. Initially showing great promise as a potent anesthetic, evidence of the alarming adverse effects delirium, hallucinations, and violent behavior led to PCP being declared "clinically unacceptable," halting clinical trials in 1965. However, recreational use of PCP was widespread in the late 1970s. Efforts to isolate useful from undesirable properties produced more than 300 PCP analogs, including ketamine. Aside from PCP and ketamine, PCP-like pharmacology was found in 22 phenylcyclohexylamine (PCA) and PCP analogs, with eight later appearing as abused drugs [114].

PCP and ketamine are arylcyclohexylamines with an aryl group attached to a cyclohexane ring and a basic amine function. The first arylcyclohexylamine NPS sold online was the low-potency PCP analogue methoxydine (4-MeO-PCP) in 2008 [48]. The ketamine analog methoxetamine (MXE) or 2-(3-methoxyphenyl)-2-(ethylamino)-cyclohexanone was developed as an alternative free of urinary tract morbidity. After its 2010 Internet entrance, it became the most popular dissociative NPS. Compared with ketamine, the 3-methox substituent provides higher serotonin transporter affinity and euphoria and greater duration/potency from the N-ethyl group [48].

MXE and ketamine both produce dissociative anesthetic effects and act as NMDA receptor antagonists and dopamine reuptake inhibitors. MXE is also an agonist at dopamine D2, 5-HT2, muscarinic cholinergic, sigma-1, and opioid mu and kappa receptors. Ketamine has shown efficacy in alleviating severe, treatment-resistant depression, and the mechanistic profile of MXE suggests comparable clinical use [115,116]. MXE is ingested through numerous routes, and a 15–40 mg oral dose can produce euphoria, a sense of calm and serenity, and distortion or loss of sensory perception. Adverse effects include severe dissociation, depersonalization, anxiety, paranoia, loss of consciousness, and nausea and vomiting [117]. MXE users report compulsive re-dosing and ingesting more than intended [18].

2-Methoxyphenidine (2-MXP or MXP) is an NPS dissociative and structural analog of diphenidine, introduced to meet growing demand for alternatives to the arylcyclohexylamines and to replace banned MXE. Aside from anecdotal reports suggesting greater potency than MXE, with dissociation, visual effects, and seizures at higher doses, little is known of this drug. Use of 2-MXP has led to three confirmed fatalities [118].

10. OPIOIDS

Analogs of fentanyl and meperidine, members of the piperidine class of opioids, comprise most opioid NPS. Fentanyl analogs first appeared in California in the late 1970s and early 1980s and were dubbed "designer drugs," the origin of this term. MPPP, a reverse ester of meperidine, emerged during this period but contained MPTP, an impurity converted in the body to the neurotoxin MPP+. Most who used the distributed MPPP developed an irreversible parkinsonian-like syndrome [114].

Fentanyl is used in surgical anesthesia and chronic pain analgesia. With potency roughly 100 times greater than morphine and 30 to 50 times greater than heroin, as little as 0.25 mg can be fatal. Fentanyl and its analogs are often laced in heroin, making their resurgence deadly; fentanyl distribution in Detroit and Cleveland between 2005 and 2007 contributed to more than 1,000 deaths [119]. Acetyl fentanyl, with one-third the potency of fentanyl, has appeared sporadically in the United States during 2014 and 2015 and resulted in at least 60 fatalities, a probable underestimate, suggesting, and correctly predicting, a fentanyl analog resurgence that began during the opioid crisis [38,119]. The DEA identified 15 novel fentanyl analogs during 2013–2014; in 2017, they identified 2,825 new fentanyl analogs [12]. A rapid rise in fentanyl use occurred between 2015 to 2017, and fentanyl and fentanyl analogs now account for the majority of tested and seized NPS, with the 2017 Emerging Threat Report showing a 116% increase in identification from 2016 alone [35,38]. Of the almost 3,000 identified substances, fentanyl accounted for 66% of identifications, followed by furanylfentanyl (10%) and U-47700 (7%) [38]. As of the 2020 report, fentanyl accounted for 89% of the identifications, followed by 4-ANPP at 5% [38].

AH-7921 is an atypical opioid synthesized in the 1970s to structurally and pharmacologically resemble fentanyl and phencyclidine. Its addiction potential and online availability have generated concern [48]. Shortly after initial detection in Europe, AH-7921 and MT-45, another novel opioid, contributed to more than 40 deaths [22].

11. BOTANICAL PRODUCTS

KHAT

Catha edulis is a flowering shrub native to East Africa and the Arabian Peninsula. Its leaves are chewed for psychoactive effect and are referred to as khat (or alternatively, qat, kat, Chat, Miraa, or Quaadka). Khat has been widely used since the thirteenth century as a recreational drug in Africa and the Middle East [120]. The acute effects of khat include euphoria, increased alertness and energy, hyperactivity, anorexia, and decreased fatigue; many users report feeling relaxed and talkative. The sympathomimetic effects mimic those of amphetamines. Following the 90- to 180-minute effect, users report diminished concentration, numbness, and insomnia [120]. Widespread khat use in the United States is unlikely [43].

SALVIA DIVINORUM

Salvia divinorum is a member of the mint family native to Oaxaca, Mexico, and has been used by Mazatec shamans for divination and spiritual healing for more than 500 years [121]. It is used in the United States for its intense hallucinogenic effects, sometimes under the street names Sally-D, Diviner's Sage, Magic Mint, and Mystic Sage [122]. Salvinorin A, the primary psychoactive constituent, is a potent and selective kappa opioid receptor agonist that, unlike LSD, psilocybin, and DMT, lacks serotonin receptor activity [122]. Salvinorin A is the most highly potent known hallucinogen found in nature.

Salvia is usually taken by smoking the dried leaves, which produces a rapid onset with peak effect within two minutes and dissipation by 20 to 30 minutes. User reports describe intense, highly unusual experiences of changes in spatial orientation, sensations of energy or pressure on different areas of the body, revisiting childhood memories, cartoon-like imagery, and contact with entities. Other descriptions include dysphoria, uncontrolled laughter, a sense of bodily loss, overlapping realities, hallucinations, bright lights, vivid colors and shapes, and body or object distortions [121,122]. Adverse effects can include incoordination, dizziness, and slurred speech. No clinically meaningful changes occur in cardiovascular parameters [50,121,123]. Salvia divinorum and salvinorin A are not currently DEA scheduled, but several states have enacted regulatory controls for either or both agents [122].

KRATOM

Kratom (Mitragyna speciosa korth) is a tree indigenous to Southeast Asia, used by natives for its therapeutic and recreational effects (as an opium substitute) and to manage opioid withdrawal symptoms. In the United States, kratom has been promoted as a legal psychoactive product [124]. However, in 2016, the DEA announced it would be placing the active compounds in kratom into Schedule I [159].

Mitragynine is the primary active alkaloid of kratom. Kratom leaves are ingested by chewing or boiling into tea. The effects last two to five hours. Low doses produce increased alertness, physical energy, talkativeness, and sociable behavior. High doses produce an opioid-like effect with sedation and euphoria. Undesired effects include nausea, itching, sweating, dry mouth, constipation, increased urination, and loss of appetite [124].

Addiction to kratom has been documented and is associated with anorexia, weight loss, insomnia, skin darkening, dry mouth, frequent urination, and constipation. Isolated cases of psychosis have occurred from chronic use. A withdrawal syndrome is also characterized, with hostility, aggression, emotional lability, muscle and bone ache, and jerky movement of the limbs.

12. ASSESSMENT, DIAGNOSIS, AND TREATMENT OF NPS TOXICITY

Patients presenting for medical attention following NPS use may exhibit intact or altered mental status. Mentally lucid patients may be intensely distressed with anxiety or panic, highly concerned with physical symptoms, or both. Symptoms are typically isolated and not systemic. If possible, information from patient history-taking and interview, together with patient signs and symptoms, directs management. However, patient presentations with altered mental status are not amenable to history-taking or interview, in which case management is directed by identifying the specific toxicity syndrome. Most toxicity/overdose symptoms are expressed through common pathways that allow markedly similar interventions despite pharmacologic diversity of causal NPS agent(s). This is fortunate, as toxicology confirmation of ingested NPS is rarely possible [7].

GENERAL ASSESSMENT

An attempt should be made to obtain information from all patients, with added information from lucid, coherent patients. The initial approach to assessing NPS intoxication and toxicity is evaluation of presenting signs and symptoms [61]. With cathinone use, this may include mydriasis, excited delirium syndrome, and sympathomimetic toxidromes. Cannabimimetic intoxication may present with conjunctival injection, signs/symptoms of cannabis intoxication with THC-negative urine drug screen, and sudden-onset psychosis not otherwise explained. Being subject to urine drug testing (e.g., active military duty, probation/parole) should be considered a risk factor for cannabimimetic use. A standard toxicology screening of illicit drugs should be obtained to anticipate drug interaction toxicities or the need for closer/prolonged monitoring.

Clinicians should have a working knowledge of NPS and other substances common to their region to facilitate recognition of toxicities. Knowledge of NPS street names can improve patient communication/rapport. Patients should be directly asked about recent NPS use, especially younger patients with signs/symptoms of possible substance-related toxicity. Inconsistencies between observed and expected presentations from self-reported or screen-detected drug class may indicate NPS use. If the patient and/or friend or family member has additional unused NPS and/or the package, the brand and possible NPS should be identified. Any unused NPS may be sent for laboratory analysis.

If severe muscle spasms, swelling and pain in the extremities, or seizures are present, a laboratory workup should be obtained, including complete blood count, metabolic panel, cardiac enzymes, and creatine kinase for suspected rhabdomyolysis. Very high lactic acid concentration, very low pH, and high creatinine/creatine kinase suggests rhabdomyolysis, metabolic acidosis, and potential renal failure.

NPS TOXICITY SYNDROMES

The constellation of signs and symptoms in severe NPS toxicities reflects dysregulation of autonomic, sympathetic, dopaminergic, and/or serotonergic systems. These are termed syndromes or toxidromes.

Excited Delirium Syndrome

As discussed, excited delirium syndrome, the most serious NPS-induced toxicity, is a severe, life-threatening state of agitated delirium and autonomic dysregulation. This syndrome is characterized by sympathetic hyperarousal (e.g., hyperthermia, vital sign abnormalities, metabolic acidosis), delirium (altered consciousness with diminished awareness of one's environment), rhabdomyolysis, and agitated or violent behavior. Patients with excited delirium are incoherent and combative; emergency department arrival is often by EMS transport or police escort in physical restraints. Many sustain traumatic injuries before first responder contact and intensely struggle even when struggle is futile, resulting in self-harm. Some patients may strip naked, reflecting the combined hyperthermia and altered mental status [125,126].

Stimulant toxicity resulting in excited delirium syndrome has been described with MDMA, cocaine, amphetamine, and more recently, NPS such as cathinones and cannabimimetics. The hyper-dopaminergic state associated with intoxication with these drugs overloads dopamine circuitry with electrochemical signaling, triggering a surge in extreme motor hyperactivity, delirium, agitation, and violent behavior. Action pathways lead to peripheral sympathomimetic stimulation that predisposes to cardiac arrhythmia and cardiomyopathy, and with sufficient activation of the neurocardiac axis, sudden death [127,128]. Autopsy results have shown a diminished concentration of D3 dopamine receptors relative to controls, suggesting a deficit in normal compensatory measures in response to rapid changes in dopamine levels [129,130].

Hyperthermia contributes to excited delirium-associated morbidity and mortality and primarily results from agitation that drives muscular hyperactivity, rhabdomyolysis, and renal failure. Even with patient survival of an initial cardiac arrest, persistent hyperthermia contributes to the developing coagulopathy, rhabdomyolysis, and multisystem organ failure [77,131].

Effective Calming of Patients with Excited Delirium Syndrome

The ability of EMS or emergency department staff to safely subdue patients with excited delirium has been elusive. Delays in medical treatment and the use of conventional restraints can be fatal. The behavioral symptoms of excited delirium impose a serious safety hazard to EMS, emergency department staff, and the patient [19]. TASER and physical restraints are standard control measures but produce further destruction of muscle tissue, exacerbating the risks of subsequent renal failure and cardiopulmonary collapse [127]. Benzodiazepines and haloperidol are used by some EMS to calm patients with excited delirium before attempting emergency transport. In this setting, IV administration is usually impossible, intramuscular administration delays the onset, and the dose required to sedate violent patients risks adverse hemodynamic and respiratory complications. Antipsychotic drugs interfere with already-compromised dopamine function [132].

Intramuscular ketamine has rapid onset and efficacy, a wide therapeutic window, and favorable side effect profile. It is becoming favored by EMS for calming patients with excited delirium before emergency transport with support from several studies [132,133]. However, some patients develop laryngospasm and hypoxia, resolved by endotracheal intubation. In one study of 52 patients receiving ketamine 4 mg/kg IM, effective sedation and medical control was achieved within 150 seconds in 96% of cases; all remained sedated following emergency department arrival (mean: 19 minutes) [132]. In another study of 35 agitated, combative patients with possible excited delirium, 91% were successfully sedated by ketamine IM (mean dose: 324 mg), 17% required additional post-ketamine sedation by EMS or emergency department staff, and 23% required post-ketamine intubation [133]. Emergence reactions, well described with ketamine, also developed but were resolved with benzodiazepines [134,135]. Rapid calming from ketamine reduces extreme physiologic stress from extended struggles with police and continued agitation with physical restraints. Excited delirium syndrome requires IV initiation to begin end-organ, life-preserving treatment, which is nearly impossible until severely agitated, combative patients are sedated [132,133,134].

Sympathomimetic Toxidrome

Sympathomimetic toxidrome resembles excited delirium, differing by dominant hyperadrenergic symptoms of tachycardia, hypertension, nausea/vomiting, and diaphoresis and a lack of violent agitation. Excited delirium syndrome and sympathomimetic toxidrome can co-occur. The presumed underlying hyperdopaminergic and hyperadrenergic states of excited delirium and sympathomimetic toxidrome, respectively, are intertwined. As such, co-occurrence in NPS toxicity is probably frequent, and management is highly similar [18].

Serotonin Syndrome

Serotonin syndrome is a state of excess serotonin activity from serotonergic agent overdose or synergistic toxicity. Serotonin syndrome shares some features with excited delirium and sympathomimetic toxidrome, but patients are rarely aggressive and violent. Patients typically present with psychomotor agitation, and cognitive (e.g., confusion, delirium), neuromuscular (e.g., akathisia, ataxia, myoclonus, hyper-reflexia), and autonomic (e.g., dizziness, nausea/vomiting, tachycardia, sweating) symptoms. It can be differentiated from sympathomimetic toxidrome by the presence of shivering, rigidity, myoclonus, and hyper-reflexia. Serotonin syndrome is characterized by a rapid onset of neuromuscular symptoms with markedly increased muscle tone, along with shivering, tremors, hyper-reflexia, akathisia, ataxia, and myoclonus. Sweating may decrease and contraction of opposing muscle groups generates heat more rapidly than vasodilatation, leading to hyperpyrexia and cardiovascular instability. The mortality rate is 10% to 15% [48,136].

Acute Hyponatremia

Acute hyponatremia has led to numerous MDMA fatalities. These deaths usually result from prolonged (8 to 12 hours) dancing to electronic dance music (e.g., techno, house). Indoor settings with poor ventilation and high ambient temperature contribute further. Hyperthermic complications from MDMA stem from exertional hyperpyrexia, hyponatremia, and serotonin syndrome [136].

DIFFERENTIAL DIAGNOSIS

Rapid identification of NPS-induced toxicity is essential in patients who present with agitation, altered mental status, hyperthermia, and autonomic dysregulation. Conditions that resemble NPS toxicity should be ruled out first (Table 6) [93]. This narrows the field to identify the NPS toxicity syndrome or toxidrome.

Table 6: POSSIBLE CONDITIONS ACCOUNTING FOR AGITATION, FEVER, ALTERED MENTAL STATUS, AND HYPERDYNAMIC VITAL SIGNS

Medical

Substance-Induced

Toxidromes

GABA-agonist substance withdrawal

Malignant catatonia

Systemic inflammatory response syndrome

Encephalitis

Post-head injury with autonomic dysfunction syndrome

Cocaine

Methamphetamine

Ketamine

Phencyclidine

MDMA

Tryptamines

Cathinones

Serotonin syndrome

Malignant hyperthermia

Anticholinergic toxicity

Neuroleptic malignant syndrome

GABA = gamma-aminobutyric acid.

Source: [93]

Medical Conditions

A GABA agonist withdrawal syndrome from substances such as alcohol or benzodiazepines is a common medical condition that shares autonomic hyperarousal, agitation, and altered mental status with NPS toxicity [93,137,138]. Neurologic trauma or disease, including traumatic brain injury, hydrocephalus, brain tumor, and subarachnoid or intracerebral hemorrhage, can produce an intense autonomic dysregulation syndrome similar to that seen with NPS use. These patients may also display hypertension, fever, tachycardia, tachypnea, and pupillary dilation [139,140,141].

Some psychiatric disorders may have similar presentations to acute NPS toxicity, including bipolar disorder and paranoid schizophrenia. Patients may display an emotional rage reaction in response to acute psychologic stressors. In addition, psychotropic drug withdrawal and emergent symptoms from medication noncompliance may precipitate symptoms similar to an excited delirium or serotonin syndrome.

Systemic inflammatory response syndrome (SIRS) is related to systemic inflammation, organ dysfunction, or organ failure and is broadly classified as infectious or noninfectious. With infection, the condition is termed sepsis. Noninfectious SIRS origins include trauma, burns, pancreatitis, ischemia, and hemorrhage, and dysregulated and uninhibited pro-inflammatory pathways result in altered mental status, fever, or hyperdynamic vital signs [93,142].

Encephalitis of viral, bacterial, fungal, or autoimmune origin can manifest in neuropsychiatric disturbances and altered mental status with severe headache, fever, confusion, agitation, personality changes, seizures, hallucinations, or impairment in speech or hearing. Limbic encephalitis of paraneoplastic origin can produce severe neuropsychiatric symptoms, marked agitation, and autonomic dysfunction [93,143].

Malignant catatonia is a neuropsychiatric syndrome seldom seen clinically, is highly lethal, and initially presents as nonspecific insomnia and mood changes, progressing to severe anxiety, delusions, hallucinations, and agitation. Other symptoms can include severe, nonpurposeful hyperkinetic movements, high fever, tachycardia, and labile blood pressure [93,144].

Endocrine system disorders can appear as agitation, autonomic instability, and fever. In thyrotoxic crisis, cardiac failure, arrhythmia, or hyperthermia can result from a massive surge in thyroid hormone. Tumors of the sympathetic ganglia can produce hypertension, tachycardia, sweating, and panic attacks from increased sympathetic tone. Less commonly, fever and delirious agitation may be noted [93]. In patients with diabetes, hypoglycemia may precipitate violent outbursts and an appearance of intoxication. Hypoglycemia may be diagnosed rapidly and conclusively via blood glucose testing and glucose response.

Anticholinergic Toxidromes

Anticholinergic toxidromes can resemble NPS toxicity, with altered consciousness, agitation, confusion, disorientation, delirium, hallucinations, tachycardia, tachypnea, and hyperthermia [145]. Sympathomimetic toxidrome may be differentiated from anticholinergic toxidromes by presence of marked diaphoresis (instead of dry skin) and lack of bowel sounds [145]. The presence of neuromuscular abnormalities is specific to serotonin syndrome and is not seen in patients with anticholinergic toxidromes.

MANAGEMENT OF ISOLATED ADVERSE EFFECTS

Most nonpsychiatric symptoms of NPS toxicity appear self-limited and resolve within one to several days with supportive treatment. Panic attacks, intense anxiety, agitation, or paranoia can be treated with benzodiazepines. Antipsychotics are second-line agents for more severe agitation or paranoia because they increase the risk of seizure if cathinones or phenethylamines were taken [61].

MANAGEMENT OF NPS TOXICITY SYNDROMES

The similar core features of NPS toxicities allow symptom-directed management independent of (presumed) causal substance. Management of common core features and those specific to excited delirium, sympathomimetic toxidrome, and serotonin syndrome is discussed in this section.

Immediate Interventions

If treatment of excited delirium or sympathomimetic toxidrome is neglected, delayed, or inadequate, the outcome is often multiple end-organ damage or death [94]. The most essential aspect of the management of cathinone toxicity is rapid, aggressive sedation with benzodiazepines. Benzodiazepines are the agents of choice because they decrease excessive heart rate, blood pressure, neural stimulation, and muscular activity; prevent seizures; protect against physical violence; and reduce muscular hyperactivity that drives fever, rhabdomyolysis, and renal failure. Benzodiazepines have a wide safety margin and, contrary to common belief, do not dangerously decrease cardiovascular or respiratory parameters unless used with potent sedatives. Immediate calming may require IM lorazepam, midazolam, or ketamine to allow for safe placement of IV access. With access in place, IV diazepam may be initiated, the preferred agent for effective rapid titration because full onset of each dose occurs within five minutes, allowing repeat dosing without the "overshooting" risk with slower-onset lorazepam. Patients may require very high doses for effective sedation. Propofol or barbiturates in those appearing refractory to high-dose benzodiazepine [18,93,94,146,147,148]. Antipsychotic drugs interfere with already-compromised systemic dopaminergic function and should be avoided in patients with suspected excited delirium [127].

Management of serotonin syndrome targets agitation, hyperthermia, and autonomic dysfunction. Benzodiazepines are preferred to induce sedation and reduce muscle rigidity. With causal substance(s) typically unidentified and benzodiazepine efficacy across NPS toxicity syndromes, benzodiazepines should be used instead of serotonin antagonists [149].

All toxicities with hyperpyrexia require aggressive cooling through high-rate IV fluids and external cooling measures. The combination of sedation, fluids, and cooling reverses hyperthermia and metabolic acidosis and prevents further muscular and hepatorenal injury. Enteral or parenteral vasodilators should be used for persistent hypertension, while beta-blockers should be avoided because unopposed alpha-receptor stimulation can induce systemic vasoconstriction. Sodium bicarbonate may be considered for rhabdomyolysis and acidosis [106]. Antipyretics are ineffective for hyperthermia because the origin is increased muscular activity, not hypothalamic temperature dysregulation [149].

Postdischarge Care

Following resolution of the autonomic storm and return to normal reflexes and muscle tone, clinicians should be aware that psychosis, dysphoria, and irritable unrest can persist in patients hospitalized for NPS toxicity after medical stability is achieved. These lingering psychiatric symptoms best respond to dopamine blockade with neuroleptics. This aspect of persistent cathinone toxicity makes post-hospital care challenging and heightens the importance of care providers in multiple specialties to understand this toxidrome and the associated phases of illness [93]. Fatalities following cannabimimetic use have occurred in patients discharged home with lingering paranoia and depression [50].

13. NPS USE DISORDERS

NPS ABUSE POTENTIAL

Multiple lines of evidence have captured the abuse and addiction potential of cathinones. These data have primarily involved mephedrone, but it is reasonable to extrapolate the findings to other cathinones with similar pharmacologic, clinical, and behavioral properties [93].

Synthetic Cathinones

The abuse potential of synthetic cathinones can be predicted by pharmacologic activity. The ratio of dopamine to serotonin increase influences episodic (i.e., recreational) versus compulsive (i.e., addictive) use patterns [9]. Cathinones release more dopamine than serotonin (similar to methamphetamine and cocaine), which predicts drug craving, urge to re-dose, and addiction liability [76]. Drugs that release higher serotonin than dopamine levels (e.g., MDMA) tend to have a dampening effect on craving and urge to re-dose and a lower abuse potential [74,75].

A survey of 1,500 mephedrone users found more than 50% considered it addictive [150]. Of 1,006 students older than 21 years of age in Scotland, 4.4% were daily mephedrone users and 17.5% of users reported addiction/dependence symptoms [151]. In a study of 100 British mephedrone users, 47% had binged on mephedrone, 30% met Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV) criteria for mephedrone dependence, and 44% described mephedrone as at least as addictive as cocaine [92]. More than 50% developed tolerance after continued use and described withdrawal symptoms of tiredness, difficulty concentrating, depression/anxiety, irritability, and ongoing cravings for mephedrone [92]. Another study found that 22.4% of mephedrone users experienced intense cravings when they stopped [152].

Frequent high-dose methcathinone, mephedrone, and MDPV use induces tolerance, dependence, craving, and a withdrawal syndrome with cessation characterized by depression, anxiety, sleep disorders, and fatigue, with craving, anhedonia, and anergia that can last several weeks [153]. Class-wide, cathinone withdrawal symptoms include depression, impulsivity, anhedonia, and cognitive complaints of poor concentration and attention [18].

Cannabimimetics

A survey found that 36% of cannabimimetic users experienced tolerance and 12% developed dependence [102]. Long-term cannabimimetic use has been associated with a severe withdrawal syndrome with drug craving, tachycardia, tremor, profuse sweating, nightmares/insomnia, headache, anxiety, irritability, feelings of emptiness, depressive symptoms, and somatic complaints [102]. However, little has been published on the prevalence or natural history of cannabimimetic use disorder [154].

Other NPS

The abuse liability of many other NPS is anecdotal, and while pharmacologic profiles can help predict risks of craving and compulsive use (as discussed), little is known of the prevalence, natural history, or withdrawal syndromes in patients with heavy/prolonged use [3].

ASSESSMENT AND TREATMENT OF NPS USE DISORDERS

Engagement

Helping motivate and empower patients with NPS use disorder to seek help is a challenge. Research suggests many patients with NPS use disorder do not identify as needing conventional drug treatment, with many stating they will not enroll in such services [25]. However, specialized NPS treatment programs in the UK report high demand and offer specialist assessments, detoxification, psychologic and psychosocial treatment, and support/referral for drug-related health problems [25,155].

Hospitalization for NPS overdose/toxicity presents an excellent window of opportunity (the "teachable moment") for advising patients to decrease their substance use or to engage them in treatment. Provider awareness and patient education are cornerstones of public health initiatives to confront the new challenges from NPS. Simple admonitions are insufficient, and adolescents/younger adults are wary of any communication with a judgmental, heavy-handed abstinence tone [25,61]. Patients identified with NPS use disorder in the emergency department or inpatient setting should be linked to information on local addiction treatment resources (Table 7) [61].

Table 7: RESOURCES FOR PATIENTS WITH NPS USE DISORDER

American Society of Addiction Medicine

https://www.asam.org

American Academy of Addiction Psychiatry

https://www.aaap.org

National Association for Alcohol and Drug Abuse Counselors

https://www.naadac.org

Substance Abuse and Mental Health Services Administration Behavioral Health Services Treatment Locator

https://findtreatment.samhsa.gov

Source: [61]

Patient Motivation/Empowerment to Change

Because patients with problematic NPS use may be ambivalent about changing behavior, clinicians should demonstrate respect for patient autonomy by expressing empathy without confrontation. Providing appropriate, accurate information on the relative risks and unknown harms of NPS empowers patients in making informed decisions to continue NPS use, attempt to quit, or seek treatment [61].

In the primary care setting, patients with NPS-related problems may present with concerns over their NPS use or with problems they suspect are NPS-related. Alternatively, patients may describe an NPS-related problem without linking it to NPS use. Motivational interviewing is suggested because this technique is proven useful in resolving patient ambivalence over change with numerous clinical conditions. This approach involves first appreciating and addressing patient concerns and withholding advice until greater clarity emerges. This empowers active patient participation and facilitates positive behavioral change. To begin this process, gain patient permission before questioning about substance use [156]. If granted, mention confidentiality. If concern is from a family member, explore further, ask about their coping, and provide info on relevant support if needed. With assessment of patients acknowledging drug use-related problems, invite active patient contribution by asking open-ended questions, such as:

- "Tell me about your drug use."

- "What is your drug use during an average week?"

- "What concerns do you have?"

- "You mentioned discomfort when urinating—how might that be related to your drug use?" (e.g., ketamine abuse associated with urinary complications)

To help build rapport, ask about drug jargon and drug effects. Giving feedback with specific reference to patient concerns can help patients re-frame their drug use and consequences.

After the basic situation and clinical picture has been established, the next steps should be determined. Further questions may include:

- "Where would you like to go with this next?"

- "Is there anything I can specifically help with?"

This can involve further information about the presenting problem or drug use, harm-reduction advice, guidance on managing physical or psychiatric problems, exploration of abstinence, or specialist referral.

Patients who clearly link drug use with a problem are likely to ask questions and be receptive to expert input. Apply a circular process to engage patient interest:

- "Would you like to know some more about how MDPV can affect your mood?"

- "When people use stimulants over a weekend and don't get any sleep, it can reduce chemicals in the brain that help keep our mood stable and feeling happy."

- "How does that fit with your experience?"

Avoid assuming the patient wants to change or needs expert help to change. Instead, introduce the concept of change by asking:

- "We've discussed some concerns you have, and how they might be related to your drug use. Where do we go from here?"

- "Would you like to do something about your drug use?"

If a patient expresses the wish to change, ask how he or she might do this and whether professional support is needed. In patients unsure about what they should do, consider harm-reduction advice. As little is known about NPS, give general harm reduction advice such as limiting use, a period of cessation to observe improvement in health concerns, and total avoidance in high-risk patients (e.g., those with a history of psychiatric illness, addiction). The appointment should end with permission to revisit the subject in the future [156].

Treatment of NPS Use Disorders

Patients in treatment for NPS use disorder may need to address premorbid or NPS-induced psychiatric or medical conditions or symptoms. As with other patients, those recovering from NPS use disorder probably require long-term support, professional contact, and possibly multiple short-term acute treatment episodes. Treatment typically involves components similar to those in general use, including individual and group counseling, cognitive-behavioral therapy, motivational enhancement therapy, and 12-step facilitation. Family members should be considered for involvement in the treatment program, especially with adolescent or young adult patients. Little data are available to guide pharmacologic management of acute and post-acute NPS withdrawal symptoms and ongoing NPS craving. Treatment is more complex for patients with backgrounds of polysubstance abuse, young age at initiation of regular drug use, lingering neuropsychologic impairment, or psychiatric disorders. Patients with intermittent NPS use in social settings may perceive they have less of a problem [61]. Encouragement of 12-step program involvement, such as Narcotics Anonymous, can provide patients the means for support, a non-substance-using social network, and other benefits conducive to recovery.

Bupropion

Bupropion is a ring-substituted cathinone and a dopamine and norepinephrine reuptake inhibitor. Its close structural and functional similarity with psychoactive cathinones suggests it may be beneficial in the treatment of cathinone addiction and craving. There is some evidence of benefit in treating selected methamphetamine-dependent patients with bupropion, although effectiveness has not been consistently shown [157,158].

14. HARM REDUCTION

Harm reduction neither condones nor condemns drug use, but recognizes that some risks from recreational NPS use can be mitigated. DanceSafe is the largest harm-reduction organization for North American nightlife/electronic dance music communities. Efforts by DanceSafe are directed at non-addicted recreational users, who comprise the largest number of drug users but are underserved by conventional harm reduction that targets addicted users. DanceSafe objectives include reducing drug misuse and empowering users to make informed decisions about their health and safety by providing unbiased educational literature on the effects/risks of specific drugs; remote and, when possible, on-site adulterant screening (drug testing); on-site free water and electrolytes to help prevent hyperthermia; free ear plugs; free safe sex tools to avoid pregnancy and sexually transmitted infections; and first point of contact for adverse drug effects [91]. Many other American and European harm-reduction groups use common objectives and methods.

15. PREVENTION

The most effective measure against problems from NPS use is preventive, especially in educating and informing adolescents, young adults, and the general public. Helpful educational materials are available that target specific age groups, educators, parents, healthcare workers, and the public and that address health and medical consequences and the legal status of NPS [17].

16. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

As a result of the evolving racial and immigration demographics in the United States, interaction with patients for whom English is not a native language is inevitable. Because specific details about the patient's history are crucial to diagnosing NPS toxicity, effective communication is required. Communicating effectively is more challenging when the patient's primary language differs from that of the practitioner. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required.

17. CONCLUSION

NPS are broadly diverse in molecular structure and pharmacology. Many carry potential risks of serious adverse psychiatric effects or life-threatening toxicity. Frequent inclusion of multiple psychoactive substances in NPS products increases the risk of toxic drug interaction. Although past-year NPS use appears to have been declining since 2013–2014, intermittent regional resurgences in synthetic cathinone and cannabimimetic use, and a rapid increase in opioid and fentanyl analog use and spikes in hospital admissions and overdose/toxicity fatalities have been noted through 2021. Intrinsic NPS properties, their frequent adulteration with other substances, and highly prevalent polysubstance ingestion heighten risks of overdose and toxicity reactions urgently requiring medical care. NPS market growth is likely to continue in the near future, making it essential for primary care providers to understand the spectrum of emerging drugs in order to identify and manage potential acute and persistent effects.

Works Cited

1. Loeffler G, Hurst D, Penn A, Yung K. Spice, bath salts, and the U.S. military: the emergence of synthetic cannabinoid receptor agonists and cathinones in the U.S. armed forces. Mil Med. 2012;177(9):1041-1048.

2. Cottencin O, Rolland B, Karila L. New designer drugs (synthetic cannabinoids and synthetic cathinones): review of literature.Curr Pharm Des. 2014;20(25):4106-4111.

3. Brunt TM, Poortman A, Niesink RJM, van den Brink W. Instability of the ecstasy market and a new kid on the block: mephedrone. J Psychopharmacol. 2011;25(11):1543-1547.

4. Nelson ME, Bryant SM, Aks SE. Emerging drugs of abuse. Emerg Med Clin N Am. 2014;32(1):1-28.

5. American Academy of Family Physicians. 2019 Scientific Assembly Needs Assessment: Substance Use and Misuse. Available at https://www.aafp.org/dam/AAFP/documents/events/fmx/needs/fmx19-na-psy-substance-use-and-misuse.pdf. Last accessed October 26, 2021.

6. Jerry J, Collins G, Streem D. Synthetic legal intoxicating drugs: the emerging "incense" and "bath salt" phenomenon.Cleve Clin J Med. 2012;79(4):258-264.

7. Schifano F, Orsolini L, Papanti GD, Corkery JM. Novel psychoactive substances of interest for psychiatry. World Psychiatry. 2015;14(1):15-26.

8. Liechti ME. Novel psychoactive substances (designer drugs): overview and pharmacology of modulators of monoamine signaling. Swiss Med Wkly. 2015;145:w14043.

9. Watterson LR, Hood L, Sewalia K, et al. The reinforcing and rewarding effects of methylone, a synthetic cathinone commonly found in "bath salts." J Addict Res Ther. 2012;Suppl 9.

10. United Nations Office on Drugs and Crime. UNODC Early Warning Advisory on New Psychoactive Substances. Available at https://www.unodc.org/LSS/Page/NPS. Last accessed October 26, 2021.

11. European Monitoring Centre for Drugs and Drug Addiction. European Drug Report 2021: Trends and Development. Available at https://www.emcdda.europa.eu/system/files/publications/13838/TDAT21001ENN.pdf. accessed November 8, 2021.

12. Guzman AR. United States Encounters and Efforts against Synthetic Designer Drugs. Presentation at the 22nd National Conference on Pharmaceutical and Chemical Diversion. Available at https://www.deadiversion.usdoj.gov/mtgs/drug_chemical/2014/guzman.pdf. Last accessed November 8, 2021.

13. Mycyk MB. Emerging drugs of abuse: what was new yesterday is new today. J Med Toxicol. 2012;8(1):1-2.

14. European Monitoring Centre for Drugs and Drug Addiction. European Drug Report 2018: Trends and Development. Available at https://www.emcdda.europa.eu/system/files/publications/8585/20181816_TDAT18001ENN_PDF.pdf. accessed October 26, 2021.

15. European Monitoring Centre for Drugs and Drug Addiction. European Drug Report 2015. Available at https://www.emcdda.europa.eu/system/files/publications/974/TDAT15001ENN.pdf. Last accessed November 8, 2021.

16. Karila L, Megarbane B, Cottencin O, Lejoyeux M. Synthetic cathinones: a new public health problem. Curr Neuropharmacol. 2015;13(1):12-20.

17. Biliński P, Holownia P, Kapka-Skrzypczak L, Wojtyla A. Designer drug (DD) abuse in Poland: a review of the psychoactive and toxic properties of substances found during seizures of illegal drug products and resulting legal consequences thereof. Part I: cannabinoids and cathinones. Ann Agric Environ Med. 2012;19(4):857-870.

18. Scalzo AJ. Synthetic Drugs: Cannabinoids and Cathinones, Amphetamines, 2C Drugs
Toxicology and Case Studies. Presented at: 2015 Midwest Pediatric Trauma Conference; May 15, 2015; St. Charles, MO.

19. United Way of Broward County Commission on Substance Abuse. Drug Abuse Trends
in Broward County, Florida Annual Report: June 2015. Available at http://cdn.trustedpartner.com/docs/library/UWBCCommissionSubstanceAbuse2011/Content/Documents/Data%20Central/June%202015%20Broward%20Annual%20Trends%20Report.pdf. Last accessed November 8, 2021.

20. Carpenter TG, Cato Institute. Designer Drugs. A New, Futile Front in the War on Illegal Drugs. Policy Analysis Number 774. Available at https://www.cato.org/sites/cato.org/files/pubs/pdf/pa774_1.pdf. Last accessed November 8, 2021.

21. United Way of Broward County Commission on Substance Abuse. Drug Abuse Trends
in Broward County, Florida Annual Report: June 2017. Available at https://www.unitedwaybroward.org/sites/default/files/images/Commission%20on%20Behavioral%20Health%20%26%20Drug%20Prevention/Prevention%20Resource%20Center/June-2017-Broward-Substance-Abuse-Trends-Report.pdf. Last accessed November 8, 2021.

22. European Monitoring Centre for Drugs and Drug Addiction. New Psychoactive Substances in Europe: An Update from the EU Early Warning System. Available at https://www.emcdda.europa.eu/publications/rapid-communications/2015/new-psychoactive-substances_en. Last November 18, 2021.

23. National Institute of Standards and Technology, U.S. Drug Enforcement Administration. Emerging Trends in Synthetic Drugs Workshop. Available at https://www.nist.gov/news-events/events/2013/04/emerging-trends-synthetic-drugs-workshop. Last accessed November 8, 2021.

24. Weinstein AM, Rosca P, Fattore L, London ED. Synthetic cathinone and cannabinoid designer drugs pose a major risk for public health. Front Psychiatry. 2017;8:156.

25. Boyce N. Novel Psychoactive Substances. Presented at: Third Annual Addictions and Mental Health Conference; May 25, 2015; Ontario. Available at https://www.slideshare.net/OHSUTP/novel-psychoactive-substances-an-analyis-of-the-2015-psa-cookin-with-molly. Last accessed November 8, 2021.

26. Federal Register. Health and Public Welfare. Available at https://www.federalregister.gov. Last accessed November 8, 2021.

27. Engebretsen KM. Clinical Professor, University of Minnesota, and President-elect, American Board of Applied Toxicology. Personal communication with the author, September 14, 2015.

28. Howlett AC, Thomas BF, Huffman JW. The spicy story of cannabimimetic indoles. Molecules. 2021;26(6190):1-30.

29. Weinstein AM, Rosca P, Fattore L, London ED. Synthetic cathinone and cannabinoid designer drugs pose a major risk for public health. Front Psychiatry. 2017;8:156.

30. Liu L, Wheeler SE, Venkataramanan, et al. Newly emerging drugs of abuse and their detection methods: an ACLPS critical review. Am J Clin Pathol. 2018;149(2):105-116.

31. NDEWS. National Drug Early Warning System. Available at https://ndews.org. Last accessed November 15, 2021.

32. Trecki J, Gerona RR, Schwartz MD. Synthetic cannabinoid-related illnesses and deaths. N Engl J Med. 2015;373(2):103-107.

33. U.S. Congress. HR.4459: Stop the Importation and Manufacturing of Synthetic Analogues Act of 2021 Available at https://www.congress.gov/bill/117th-congress/house-bill/4459. Last accessed November 14, 2021.

34. Centers for Disease Control and Prevention. Vital Statistics Rapid Release: Provisional Drug Overdose Death Counts. Available at https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm. Last accessed November 13, 2021.

35. Zawilska JB. An expanding world of novel psychoactive substances: opioids. Front Psychiatry. 2017;8:110.

36. American Association of Poison Control Centers. National Poison Data System. Available at https://aapcc.org/national-poison-data-system. Last accessed November 15, 2021.

37. Sacco LN, Finklea K, Congressional Research Service. Synthetic Drugs: Overview and Issues for Congress. Available at https://sgp.fas.org/crs/misc/R42066.pdf. Last accessed November 15, 2021.

38. U.S. Drug Enforcement Administration. National Drug Threat Assessment, 2020. Available at https://cesar.umd.edu/sites/cesar.umd.edu/files/pubs/DEA-Emerging-Threat-Report-2020-Annual.pdf. Last accessed November 14, 2021.

39. Schulenberg JE, Patrick ME, Johnston LD, et al. Monitoring the Future National Survey Results on Drug Use, 1975–2020: Volume II, College Students and Adults Ages 19–60. Available at http://www.monitoringthefuture.org/pubs/monographs/mtf-vol2_2020.pdf. Last accessed November 15, 2021.

40. University of Maryland Center for Substance Abuse Research. CESAR FAX Synthetic Cannabinoid Series May 9, 2011 to October 12, 2015 (updated October 13, 2015). Available at http://www.cesar.umd.edu/cesar/pubs/SyntheticCannabinoidCESARFAX.pdf. Last accessed November 15, 2021.

41. Berry-Cabán CS, Kleinschmidt PE, Rao DS, Jenkins J. Synthetic cannabinoid and cathinone use among U.S. soldiers. US Army Med Dep J. 2012;Oct-Dec:19-24.

42. Gardiner R. Banning Raves in California Won't Save Lives. Available at https://mixmag.net/feature/banning-raves-in-california-wont-save-lives. Last accessed November 16, 2021.

43. Coppola M, Mondola R. Synthetic cathinones: chemistry, pharmacology and toxicology of a new class of designer drugs of abuse marketed as "bath salts" or "plant food." Toxicol Lett. 2012;211(2):144-149.

44. Valeriani G, Corazza O, Bersani FS, et al. Olanzapine as the ideal "trip terminator"? Analysis of online reports relating to antipsychotics' use and misuse following occurrence of novel psychoactive substance-related psychotic symptoms. Hum Psychopharmacol. 2015;30(4):249-254.

45. Moore K, Dargan PI, Wood DM, Measham F. Do novel psychoactive substances displace established club drugs, supplement them or act as drugs of initiation? The relationship between mephedrone, ecstasy and cocaine. Eur Addict Res. 2013;19(5): 276-282.

46. Hohmann N, Mikus G, Czock D. Effects and risks associated with novel psychoactive substances: mislabeling and sale as bath salts, spice, and research chemicals. Dtsch Arztebl Int. 2014;111(9):139-147.

47. United Nations Office on Drugs and Crime. World Drug Report 2021. Available at https://www.unodc.org/unodc/en/data-and-analysis/wdr2021.html. Last accessed November 16, 2021.

48. Baumeister D, Tojo LM, Tracy DK. Legal highs: staying on top of the flood of novel psychoactive substances. Ther Adv Psychopharmacol. 2015;5(2):97-132.

49. United Nations Office on Drugs and Crime. Recommended Methods for the Identification and Analysis of Amphetamine, Methamphetamine and Their Ring-Substituted Analogues
in Seized Materials. Available at https://www.unodc.org/pdf/scientific/stnar34.pdf. Last accessed November 16, 2021.

50. Wilson B, Tavakoli H, DeCecchis D, Mahadev V. Synthetic cannabinoids, synthetic cathinones, and other emerging drugs of abuse. Psychiatr Ann. 2013;43(12):558-564.

51. U.S. Drug Enforcement Administration. 4-Bromo-2,5-dimethoxyphenethylamine. Available at https://www.deadiversion.usdoj.gov/drug_chem_info/bromo_dmp.pdf. Last accessed November 17, 2021.

52. U.S. Drug Enforcement Administration. 2C-I, 4-Iodo-2,5-dimethoxyphenethylamine. Available at https://www.deadiversion.usdoj.gov/drug_chem_info/2c_i.pdf. Last accessed November 17, 2021.

53. U.S. Drug Enforcement Administration. 2,5-Dimethoxy-4-(n)-propylthiophenethylamine. Available at https://www.deadiversion.usdoj.gov/drug_chem_info/2ct7.pdf. Last accessed November 17, 2021.

54. National Alliance for Model State Drug Laws. Novel Psychoactive Substances and Analogues: Summary of State Laws. Available at https://namsdl.org/wp-content/uploads/Novel-Psychoactive-Substances-and-Analogues-Summary-of-State-Laws.pdf. Last accessed November 21, 2021.

55. Dean BV, Stellpflug SJ, Burnett AM, Engebretsen KM. 2C or not 2C: phenethylamine designer drug review. J Med Toxicol. 2013;9(2):172-178.

56. Advisory Council on the Misuse of Drugs. NBOMe Compounds: A Review of the Evidence of Use and Harm. Available at https://www.gov.uk/government/publications/nbome-compounds-a-review-of-the-evidence-of-use-and-harm. Last accessed November 15, 2021.

57. U.S. Drug Enforcement Administration. 25-NBOMe. 25I-NBOMe, 25C-NBOMe, and 25B-NBOMe. Available at http://www.deadiversion.usdoj.gov/drug_chem_info/nbome.pdf. Last accessed November 15, 2021.

58. Erowid E, Erowid F. LSD Field Tests Differentiate LSD from 25I-NBOMe. Available at https://www.erowid.org/chemicals/lsd/lsd_testing3.shtml. Last accessed November 17, 2021.

59. Ninnemann A, Stuart GL. The NBOMe series: a novel, dangerous group of hallucinogenic drugs. J Stud Alcohol Drugs. 2013;74(6):977-978.

60. Hill SL, Doris T, Gurung S, et al. Severe clinical toxicity associated with analytically confirmed recreational use of 25I-NBOMe: case series. Clin Toxicol. 2013;51(6)487-492.

61. Weaver MF, Hopper JA, Gunderson EW. Designer drugs 2015: assessment and management. Addict Sci Clin Pract. 2015;10:8.

62. Advisory Council on the Misuse of Drugs. Benzofurans: A Review of the Evidence of Use and Harm. Available at https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/261783/Benzofuran_compounds_report.pdf. Last accessed November 17, 2018.

63. Corazza O, Schifano F, Farre M, et al. Designer drugs on the Internet: a phenomenon out-of-control? Analysis of anecdotal online reports relating to the hallucinogenic drug Bromo-Dragonfly. Curr Clin Pharmacol. 2011;6(2):125-129.

64. Biliński P, Holownia P, Kapka-Skrzypczak L, Wojtyla A. Designer drug (DD) abuse in Poland: a review of the psychoactive and toxic properties of substances found during seizures of illegal drug products and resulting legal consequences thereof. Part II: piperazines/piperidines, phenylethylamines, tryptamines and miscellaneous "others." Ann Agric Environ Med. 2012;19(4): 871-882.

65. Sainsbury PD, Kicman AT, Archer RP, King LA, Braithwaite RA. Aminoindanes: the next wave of "legal highs?" Drug Test Anal. 2011;3(7-8):479-482.

66. Nichols DE, Johnson MP, Oberlender R. 5-Iodo-2-aminoindan, a nonneurotoxic analogue of p-iodoamphetamine. Pharmacol Biochem Behav. 1991;38(1):135-139.

67. Rudnick G, Wall SC. Non-neurotoxic amphetamine derivatives release serotonin through serotonin transporters. Mol Pharmacol. 1993;43(2):271-276.

68. Graham JM, Coughenour LL, Barr BM, Rock DL, Nikam SS. 1-Aminoindanes as novel motif with potential atypical antipsychotic properties. Bioorg Med Chem Lett. 2008;18(2):489-493.

69. Iversen L, Gibbons S, Treble R, Setola V, Huang XP, Roth BL. Neurochemical profiles of some novel psychoactive substances. Eur J Pharmacol. 2013;700(1-3):147-151.

70. United Nations Office on Drugs and Crime. Details for Aminoindanes. Available at https://www.unodc.org/LSS/SubstanceGroup/Details/8fd64573-c567-4734-a258-76d1d95dca25. Last accessed November 15, 2021.

71. Sitte HH, Freissmuth M. Amphetamines, new psychoactive drugs and the monoamine transporter cycle. Trends Pharmacol Sci. 2015;36(1):41-51.

72. Cozzi NV, Sievert MK, Shulgin AT, Jacob P 3rd, Ruoho AE. Inhibition of plasma membrane monoamine transporters by beta-ketoamphetamines. Eur J Pharmacol. 1999;381(1):63-69.

73. Prosser JM, Nelson LS. The toxicology of bath salts: a review of synthetic cathinones. J Med Toxicol. 2012;8(1):33-42.

74. Baumann MH, Partilla JS, Lehner KR. Psychoactive "bath salts:" not so soothing. Eur J Pharmacol. 2013;698(1-3):1-5.

75. Baumann MH, Ayestas MA Jr, Partilla JS, et al. The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue. Neuropsychopharmacology. 2012;(5)37:1192-1203.

76. Rothman RB, Baumann MH. Monoamine transporters and psychostimulant drugs. Eur J Pharmacol. 2003;479(1-3):23-40.

77. Murray BL, Murphy CM, Beuhler MC. Death following recreational use of designer drug "bath salts" containing 3,4-methylenedioxypyrovalerone (MDPV). J Med Toxicol. 2012;8(1):69-75.

78. National Alliance for Model State Drug Laws. An Introduction to Synthetic Drugs. Available at https://namsdl.org/wp-content/uploads/An-Introduction-to-Synthetic-Drugs.pdf. Last accessed November 18, 2021.

79. Watterson LR, Kufahl PR, Nemirovsky NE, et al. Potent rewarding and reinforcing effects of the synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV). Addict Biol. 2014;19(2):165-174.

80. Capriola M. Synthetic cathinone abuse. Clin Pharmacol. 2013;5:109-115.

81. Paillet-Loilier M, Cesbron A, Le Boisselier R, Bourgine J, Debruyne D. Emerging drugs of abuse: current perspectives on substituted cathinones. Subst Abuse Rehabil. 2014;5:37-52.

82. Advisory Council on the Misuse of Drugs. ACMD Report on the Consideration of the Cathinones. Available at https://www.gov.uk/government/publications/acmd-report-on-the-consideration-of-the-cathinones. Last accessed November 18, 2021.

83. Simmler LD, Buser TA, Donzelli M, et al. Pharmacological characterization of designer cathinones in vitro. Br J Pharmacol. 2013;168(2):458-470.

84. Saha K, Partilla JS, Lehner KR, et al. Second-generation mephedrone analogs, 4-MEC and 4-MePPP, differentially affect monoamine transporter function. Neuropsychopharmacology. 2015;40(6):1321-1331.

85. Rickli A, Hoener MC, Liechti ME. Monoamine transporter and receptor interaction profiles of novel psychoactive substances: para-halogenated amphetamines and pyrovalerone cathinones. Eur Neuropsychopharmacol. 2015;25(3):365-376.

86. European Monitoring Centre for Drugs and Drug Addiction. Synthetic Cathinones Drug Profile. Available at http://www.emcdda.europa.eu/publications/drug-profiles/synthetic-cathinones. Last accessed November 18, 2021.

87. U.S. Drug Enforcement Administration. 4-Methylmethcathinone (Mephedrone). Available at http://www.deadiversion.usdoj.gov/drug_chem_info/mephedrone.pdf. Last accessed November 17, 2021.

88. Angoa-Pérez M, Kane MJ, Briggs DI, et al. Mephedrone does not damage dopamine nerve endings of the striatum but enhances the neurotoxicity of methamphetamine, amphetamine and MDMA. J Neurochem. 2013;125(1):102-110.

89. National Alliance for Model State Drug Laws. Novel Psychoactive Substances and Analogues: 2017 Legislative Session Bill Status Update. Available at http://namsdl.dynamicwebware.com/News%20Tab/Highlighted%20Issues/NPS%20and%20Analogues%202017%20Bill%20Status%20Update.pdf. Last accessed November 14, 2021.

90. U.S. Drug Enforcement Administration. 3,4-Methylenedioxypyrovalerone (MDPV). Available at https://www.deadiversion.usdoj.gov/drug_chem_info/mdpv.pdf. Last accessed November 21, 2021.

91. DanceSafe. Available at https://dancesafe.org. Last accessed November 20, 2021.

92. Winstock AR, Mitcheson LR, Deluca P, et al. Mephedrone, new kid for the chop? Addiction. 2011;106(1):154-161.

93. Keary CJ, Nejad SH, Rasimas JJ, Stern TA. Intoxications associated with agitation, tachycardia, hypertension, and fever: differential diagnosis, evaluation, and management. Prim Care Companion CNS Disord. 2013;15(3).

94. Ross EA, Reisfield GM, Watson MC, Chronister CW, Goldberger BA. Psychoactive "bath salts" intoxication with methylenedioxypyrovalerone. Am J Med. 2012;125(9):854-858.

95. Penders TM, Gestring RE, Vilensky DA. Intoxication delirium following use of synthetic cathinone derivatives. Am J Drug Alcohol Abuse. 2012;38(6):616-617.

96. Goshgarian AM, Benford DM, Caplan JP. Bath salt abuse: neuropsychiatric effects of cathinone derivatives. Psychosomatics. 2011;52(6):593-594.

97. Goodnough A, Zezima K. An Alarming New Stimulant, Legal in Many States. Available at https://www.nytimes.com/2011/07/17/us/17salts.html?_r=0. Last accessed November 17, 2021.

98. Spiller HA, Ryan ML, Weston RG, Jansen J. Clinical experience with and analytical confirmation of "bath salts" and "legal highs" (synthetic cathinones) in the United States. Clin Toxicol (Phila). 2011;49(6):499-505.

99. Adebamiro A, Perazella MA. Recurrent acute kidney injury following bath salts intoxication. Am J Kidney Dis. 2012;59(2):273-275.

100. Borek HA, Holstege CP. Hyperthermia and multiorgan failure after abuse of "bath salts" containing 3,4-methylenedioxypyrovalerone. Ann Emerg Med. 2012;60(1):103-105.

101. National Institute on Drug Abuse. Synthetic Cathinones ("Bath Salts") DrugFacts. Available at https://www.drugabuse.gov/publications/drugfacts/synthetic-cathinones-bath-salts. Last accessed November 17, 2021.

102. Papanti D, Orsolini L, Francesconi G, Schifano F. "Noids" in a nutshell: everything you (don't) want to know about synthetic cannabimimetics. Adv Dual Diagn. 2014;7(3):137-148.

103. European Monitoring Centre for Drugs and Drug Addiction. Understanding the "Spice" Phenomenon. Available at https://www.emcdda.europa.eu/publications/thematic-papers/understanding-spice-phenomenon_en. Last accessed November 18, 2021.

104. European Monitoring Centre for Drugs and Drug Addiction. Synthetic Cannabinoids and "Spice" Drug Profile. Available athttps://www.emcdda.europa.eu/publications/drug-profiles/synthetic-cannabinoids. Last accessed November 18, 2021.

105. Huffman JW. CB2 receptor ligands. Mini Rev Med Chem. 2005;5(7):641-649.

106. Goss C. Treatment considerations for patients using so-called legal recreational drugs. JEMS. 2015;40(7):1-12.

107. Sullivan JW. New Drugs of Abuse. Available at http://www.upstate.edu/poison/pdf/community/synthetic_drugs_sullivan.pdf. Last accessed November 18, 2021.

108. Spaderna M, Addy PH, D'Souza DC. Spicing things up: synthetic cannabinoids. Psychopharmacology (Berl). 2013;228(4):525-540.

109. Hurst D, Loeffler G, McLay R. Psychosis associated with synthetic cannabinoid agonists: a case series. Am J Psychiatry. 2011;168(10):1119.

110. van Amsterdam J, Brunt T, van den Brink W. The adverse health effects of synthetic cannabinoids with emphasis on psychosis-like effects. J Psychopharmacol. 2015;29(3):254-263.

111. Gatch MB, Forster MJ, Janowsky A, Eshleman AJ. Abuse liability profile of three substituted tryptamines. J Pharmacol Exp Ther. 2011;338(1):280-289.

112. Tittarelli R, Mannocchi G, Pantano F, Romolo FS. Recreational use, analysis and toxicity of tryptamines. Curr Neuropharmacol. 2015;13(1):26-46.

113. U.S. Drug Enforcement Administration. 5-Methoxy-N,N-diisopropyltryptamine. Available at https://www.deadiversion.usdoj.gov/drug_chem_info/5meodipt.pdf. Last accessed November 18, 2021.

114. Carroll FI, Lewin AH, Mascarella SW, Seltzman HH, Reddy PA. Designer drugs: a medicinal chemistry perspective. Ann N Y Acad Sci. 2012;1248:18-38.

115. European Monitoring Centre for Drugs and Drug Addiction. Europol Joint Report on a New Psychoactive Substance: Methoxetamine (2-(3-methoxyphenyl)-2-(ethylamino)cyclohexanone). Available at https://www.emcdda.europa.eu/publications/joint-report/methoxetamine. Last accessed November 18, 2021.

116. Coppola M, Mondola R. Methoxetamine: from drug of abuse to rapid-acting antidepressant. Med Hypotheses. 2012;79(4):504-507.

117. Kjellgren A, Jonsson K. Methoxetamine (MXE): a phenomenological study of experiences induced by a "legal high" from the Internet. J Psychoactive Drugs. 2013;45(3):276-286.

118. Elliott SP, Brandt SD, Wallach J, Morris H, Kavanagh PV. First reported fatalities associated with the "research chemical" 2-methoxydiphenidine. J Anal Toxicol. 2015;39(4):287-293.

119. Lynch K, American Association for Clinical Chemistry. Drug Testing: the Moving Target. Available at https://www.aacc.org/~/media/files/meetings-and-events/resources-from-past-events/conferences/2015/profprac/slides-and-handouts/designerdrugs_handouts_lynch.pdf?la=en. Last accessed November 18, 2021.

120. U.S. Drug Enforcement Administration. Khat. Available at https://www.dea.gov/factsheets/khat. Last accessed November 18, 2021.

121. Johnson MW, MacLean KA, Reissig CJ, Prisinzano TE, Griffiths RR. Human psychopharmacology and dose-effects of salvinorin A, a kappa-opioid agonist hallucinogen present in the plant Salvia divinorum. Drug Alcohol Depend. 2011;115(1-2):150-155.

122. U.S. Drug Enforcement Administration. Salvia divinorum and Salvinorin A. Available at https://www.deadiversion.usdoj.gov/drug_chem_info/salvia_d.pdf. Last accessed November 18, 2021.

123. Addy PH, Garcia-Romeu A, Metzger M, Wade J. The subjective experience of acute, experimentally-induced Salvia divinorum inebration. J Psychopharmacol. 2015;29(4):426-435.

124. U.S. Drug Enforcement Administration. Kratom (Mitragyna speciosa korth). Available at https://www.deadiversion.usdoj.gov/drug_chem_info/kratom.pdf. Last accessed November 18, 2021.

125. Vilke GM, Bozeman WP, Dawes DM, Demers G, Wilson MP. Excited delirium syndrome (ExDS): treatment options and considerations. J Forensic Leg Med. 2012;19(3):117-121.

126. American College of Emergency Physicians, ACEP Excited Delirium Task Force. White Paper Report on Excited Delirium Syndrome. Available at https://www.prisonlegalnews.org/media/publications/acep_report_on_excited_delirium_syndrome_sept_2009.pdf. Last accessed November 18, 2021.

127. Penders TM, Gestring RE, Vilensky DA. Excited delirium following use of synthetic cathinones (bath salts). Gen Hosp Psychiatry. 2012;34(6):647-650.

128. Karch SB. Cathinone neurotoxicity ("the "3Ms"). Curr Neuropharmacol. 2015;13(1):21-25.

129. Takeuchi AT, Ahern TL, Henderson SO. Excited delirium. West J Emerg Med. 2011;12(1):77-83.

130. Mash D, Duque L, Pablo J, et al. Brain biomarkers for identifying excited delirium as a cause of sudden death. Forensic Sci Int. 2009;190(1-3):e13-e19.

131. Lusthof KJ, Oosting R, Maes A, Verschraagen M, Dijkhuizen A, Sprong AG. A case of extreme agitation and death after the use of mephedrone in the Netherlands. Forensic Sci Int. 2011;206(1-3):e93-e95.

132. Scheppke KA, Braghiroli J, Shalaby M, Chait R. Prehospital use of IM ketamine for sedation of violent and agitated patients.West J Emerg Med. 2014;15(7):736-741.

133. Keseg D, Cortez E, Rund D, Caterino J. The use of prehospital ketamine for control of agitation in a metropolitan firefighter-based EMS system. Prehosp Emerg Care. 2015;19(1):110-115.

134. Burnett AM, Peterson BK, Stellpflug SJ, et al. The association between ketamine given for prehospital chemical restraint with intubation and hospital admission. Am J Emerg Med. 2015;33(1):76-79.

135. Burnett AM, Salzman JG, Griffith KR, Kroeger B, Frascone RJ. The emergency department experience with prehospital ketamine: a case series of 13 patients. Prehosp Emerg Care. 2012;16(4):553-559.

136. van Loggerenberg CJ. Emergency management of drug abuse in South Africa. S Afr Med J. 2012;30(11):409-412.

137. Addolorato G, Leggio L, Abenavoli L, Gasbarrini G, Alcoholism Treatment Study Group. Neurobiochemical and clinical aspects of craving in alcohol addiction: a review. Addict Behav. 2005;30(6):1209-1224.

138. Clapp P, Bhave SV, Hoffman PL. How adaptation of the brain to alcohol leads to dependence: a pharmacological perspective. Alcohol Res Health. 2008;31(4):310-339.

139. Baguley IJ, Heriseanu RE, Cameron ID, Nott MT, Slewa-Younan S. A critical review of the pathophysiology of dysautonomia following traumatic brain injury. Neurocrit Care. 2008;8(2):293-300.

140. Baguley IJ, Heriseanu RE, Nott MT, Chapman J, Sandanam J. Dysautonomia after severe traumatic brain injury: evidence of persisting overresponsiveness to afferent stimuli. Am J Phys Med Rehabil. 2009;88(8):615-622.

141. Srinivasan S, Tchoyoson Lim CC, Thirugnanam U. Paroxysmal autonomic instability with dystonia. Clin Auton Res. 2007;17(6):378-381.

142. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest. 2009;136(5 Suppl):e28.

143. Dalmau J, Tüzün E, Wu HY, et al. Paraneoplastic anti-N-methyl-d-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol. 2007;61(1):25-36.

144. Fink M, Taylor MA. The many varieties of catatonia. Eur Arch Psychiatry Clin Neurosci. 2001;251(Suppl 1):I8-I13.

145. Iqbal MM, Basil MJ, Kaplan J, Iqbal T. Overview of serotonin syndrome. Ann Clin Psychiatry. 2012;24(4):310-318.

146. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352:1112-1120.

147. Gold JA, Rimal B, Nolan A, Nelson LS. A strategy of escalating doses of benzodiazepines and phenobarbital administration reduces the need for mechanical ventilation in delirium tremens. Crit Care Med. 2007;35(3):724-730.

148. Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM. 2003;96(9):635-642.

149. Prator BC. Serotonin syndrome. J Neurosci Nurs. 2006;38(2):102-105.

150. Carhart-Harris RL, King LA, Nutt DJ. A web-based survey on mephedrone. Drug Alcohol Depend. 2011;118(1):19-22.

151. Dargan PI, Albert S, Wood DM. Mephedrone use and associated adverse effects in school and college/university students before the UK legislation change. QJM. 2010;103(11):875-879.

152. Winstock A, Mitcheson L, Ramsey J, Davies S, Puchnarewicz M, Marsden J. Mephedrone: use, subjective effects and health risks. Addiction. 2011;106(11):1991-1996.

153. Coppola M, Mondola R. 3,4-methylenedioxypyrovalerone (MDPV): chemistry, pharmacology and toxicology of a new designer drug of abuse marketed online. Toxicol Lett. 2012;208(1):12-15.

154. Zimmermann US, Winkelmann PR, Pilhatsch M, et al. Withdrawal phenomena and dependence syndrome after the consumption of "spice gold." Dtsch Arztebl Int. 2009;106(27):464-467.

155. Advisory Council on the Misuse of Drugs. Consideration of the Novel Psychoactive Substances ("Legal Highs"). Available at https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/119139/acmdnps2011.pdf. Last accessed November 21, 2021.

156. Winstock AR, Mitcheson L. New recreational drugs and the primary care approach to patients who use them. BMJ. 2012;344:e288.

157. Karila L, Weinstein A, Aubin HJ, Benyamina A, Reynaud M, Batki SL. Pharmacological approaches to methamphetamine dependence: a focused review. Br J Clin Pharmacol. 2010;69(6):578-592.

158. Rose ME, Grant JE. Pharmacotherapy for methamphetamine dependence: a review of the pathophysiology of methamphetamine addiction and the theoretical basis and efficacy of pharmacotherapeutic interventions. Ann Clin Psychiatry. 2008;20(3):145-155.

159. U.S. Drug Enforcement Administration. DEA Announces Intent to Schedule Kratom. Available at https://www.dea.gov/press-releases/2016/08/30/dea-announces-intent-schedule-kratom. Last accessed November 18, 2021.

160. Wright TH, Harris C. Twenty-One Cases Involving Alpha-Pyrrolidinoyalerophenone (α-PVP). J Anal Toxicol. 2016;40(5):396-402.

161. U.S. Drug Enforcement Administration. About Synthetic Drugs. Available at https://www.deadiversion.usdoj.gov/synthetic_drugs/about_sd.html. Last accessed November 8, 2021.

162. M Haden, D M Wood, P I Dargan. The impact of the Psychoactive Substances Act 2016 on the online availability of MDMB-CHMICA. QJM. 2017;110(10):619-622.

163. Majchrzak M, Celiński R, Kuś P, et al. The newest cathinone derivatives as designer drugs: an analytical and toxicological review. Forensic Toxicol. 2018;36(1):33-50.

66944 • Cocaine Use Disorder

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2023 NetCE, All rights reserved.

Although cocaine has been a drug of abuse for decades, research on the treatment of cocaine use disorder was delayed until the later part of the 20th century. The introduction and widespread use of crack cocaine in the 1980s, the severity of the addiction, and comorbid problems prompted the scientific community to investigate treatment options. Topics covered in this review include the history and demographics of the current cocaine epidemic; risk factors, background characteristics and comorbid conditions of persons who abuse cocaine; the biologic and behavioral characteristics of cocaine addiction; structural and functional changes to the brain caused by chronic stimulant abuse; and treatment options and their effectiveness. Also covered are the highly-relevant subjects of protracted withdrawal, psychoses, craving, and aggressive and violent behavior and their management.

Table of Contents

66944 • Cocaine Use Disorder

Course Overview

Audience

Accreditations & Approvals

Designations of Credit

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planner

Division Planner Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. DEFINITION OF COCAINE ABUSE AND DEPENDENCE

2. HISTORY AND BACKGROUND OF COCAINE USE

FIRST WAVE

SECOND WAVE

3. EPIDEMIOLOGY AND DEMOGRAPHICS OF COCAINE ABUSE AND DEPENDENCE

4. COCAINE USE

PHARMACODYNAMICS

PHARMACOKINETICS

USE CHARACTERISTICS OF COCAINE ABUSE

5. EFFECTS OF COCAINE USE

ACUTE EFFECTS

CHRONIC EFFECTS

NEONATAL EFFECTS

DIFFERENTIAL DIAGNOSIS

COMORBID ALCOHOL USE DISORDER

6. TREATMENT OF COCAINE USE DISORDER

PSYCHOSOCIAL THERAPY

PHARMACOTHERAPY

IMMUNIZATION AND VACCINE THERAPY

7. WITHDRAWAL FROM COCAINE

8. TREATMENT OF CONDITIONS ASSOCIATED WITH COCAINE USE

POLYSUBSTANCE DEPENDENCE

ADHD

MAJOR DEPRESSION

9. ALTERNATIVE/COMPLEMENTARY TREATMENT OF COCAINE USE DISORDER

ACUPUNCTURE

SELF-HELP AND 12-STEP THERAPY

INTERVENTIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

10. PROGNOSIS

11. CONCLUSION

12. RESOURCES

Works Cited

66944 • Cocaine Use Disorder

Education Category. Psychiatric / Mental Health

Release Date. 04/01/2023

Expiration Date. 03/31/2026

Course Overview

Although cocaine has been a drug of abuse for decades, research on the treatment of cocaine use disorder was delayed until the later part of the 20th century. The introduction and widespread use of crack cocaine in the 1980s, the severity of the addiction, and comorbid problems prompted the scientific community to investigate treatment options. Topics covered in this review include the history and demographics of the current cocaine epidemic; risk factors, background characteristics and comorbid conditions of persons who abuse cocaine; the biologic and behavioral characteristics of cocaine addiction; structural and functional changes to the brain caused by chronic stimulant abuse; and treatment options and their effectiveness. Also covered are the highly-relevant subjects of protracted withdrawal, psychoses, craving, and aggressive and violent behavior and their management.

Audience

This intermediate course is designed for psychologists who are involved in the evaluation or treatment of persons who use cocaine.

Accreditations & Approvals

Continuing Education (CE) credits for psychologists are provided through the co-sponsorship of the American Psychological Association (APA) Office of Continuing Education in Psychology (CEP). The APA CEP Office maintains responsibility for the content of the programs. NetCE is recognized by the New York State Education Department's State Board for Psychology as an approved provider of continuing education for licensed psychologists #PSY-0240. This course is considered self-study by the New York State Board for Psychology.

Designations of Credit

NetCE designates this continuing education activity for 5 credit(s).

Course Objective

The purpose of this course is to provide a current, evidence-based overview of cocaine use disorder and its treatment, in order to allow healthcare professionals to more effectively identify, treat, or refer patients who abuse cocaine.

Learning Objectives

Upon completion of this course, you should be able to:

1. Describe the history and background of cocaine use, including the development of different forms of the drug.

2. Discuss the epidemiology of cocaine use.

3. Describe the pharmacodynamics and pharmacokinetics of cocaine.

4. Review the acute and chronic effects of cocaine use, including effects on fetal development.

5. Select possible treatment modalities for cocaine use disorder, including psychosocial therapy, pharmacotherapy, immunotherapy options, alternative/complementary approaches, and interventions for non-English-proficient patients.

6. Recognize the withdrawal syndrome associated with cessation of cocaine use.

Faculty

Mark Rose, BS, MA, LP, is a licensed psychologist in the State of Minnesota with a private consulting practice and a medical research analyst with a biomedical communications firm. Earlier healthcare technology assessment work led to medical device and pharmaceutical sector experience in new product development involving cancer ablative devices and pain therapeutics. Along with substantial experience in addiction research, Mr. Rose has contributed to the authorship of numerous papers on CNS, oncology, and other medical disorders. He is the lead author of papers published in peer-reviewed addiction, psychiatry, and pain medicine journals and has written books on prescription opioids and alcoholism published by the Hazelden Foundation. He also serves as an Expert Advisor and Expert Witness to law firms that represent disability claimants or criminal defendants on cases related to chronic pain, psychiatric/substance use disorders, and acute pharmacologic/toxicologic effects. Mr. Rose is on the Board of Directors of the Minneapolis-based International Institute of Anti-Aging Medicine and is a member of several professional organizations.

Faculty Disclosure

Contributing faculty, Mark Rose, BS, MA, LP, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planner

Margaret Donohue, PhD

Division Planner Disclosure

The division planner has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. DEFINITION OF COCAINE ABUSE AND DEPENDENCE

Stimulant drugs are substances that activate the central nervous system (CNS) and peripheral nervous system. There are two main categories of commonly used illicit stimulants: cocaine and amphetamine and its derivatives and analogs, such as methamphetamine. Prescription stimulants (e.g., methylphenidate [Ritalin], mixed salts of amphetamine [Adderall]) used to treat attention deficit hyperactivity disorder (ADHD), narcolepsy, and other disorders, may also be used illicitly. Cocaine and nonprescription amphetamines have the highest potential for abuse and dependence and constitute a serious public health, medical, and criminal justice concern due to the number of individuals addicted to these agents. Repeated use in escalating doses over time can lead to the development of addiction [1,2].

The syndrome of substance abuse and dependence is highly similar regardless of the particular substance and is best conceptualized as a brain disorder, with a chronically waxing and waning course of relapse and remission. It is associated with neurobiologic changes that result in craving for the substance[3,4,5,6]. The etiology of dependence in any one person is multifactorial, representing the convergence of a multitude of biologic, psychologic, social, and interpersonal factors[1,5].

Cocaine addiction is best described as a chronic relapsing disease. It is characterized by the compulsive seeking and use of cocaine accompanied by functional and molecular changes to the brain[4,5]. The single most defining aspect of cocaine use disorder is the salience of the relationship with the drug. The stronger the relationship, the more likely the patient is to continue problematic use despite internal and external consequences. Psychologic dependence, whereby the patient believes the drug is necessary to complete daily activities, alleviate stress, and cope with problems, is a symptom of stimulant dependence. Physiologic adaptation, evidenced by tolerance and withdrawal, is often present but is not sufficient for a diagnosis of cocaine use disorder. Cocaine use disorder is diagnosed behaviorally and is evidenced by at least two of the following within a 12-month period [7,8]:

- Persistent desire or unsuccessful attempts to cut down or control use

- Great deal of time spent in activities necessary to obtain the drug

- Craving

- Failure to fulfill obligations at work, home, or school as a result of cocaine use

- Continued use despite persistent or recurrent social or interpersonal problems caused by cocaine use

- Important activities abandoned or reduced

- Recurrent cocaine use in physically hazardous situations

- Continued use despite knowledge of a problem likely to have been caused by or exacerbated by cocaine use

- Tolerance

- Withdrawal

Cocaine abuse is a condition of frequent, binge-type use and continued use despite negative consequences, but with less severity and fewer behavioral symptoms than a use disorder [7,8,9]. In this course, the term cocaine use disorder will be used interchangeably with cocaine addiction.

2. HISTORY AND BACKGROUND OF COCAINE USE

FIRST WAVE

Cocaine, a tropane alkaloid, is extracted from the leaves of the Erythroxylumcoca bush, which contain 0.6% to 1.8% of the alkaloid [3,5,10]. Archeologic evidence indicates that use of these leaves for their stimulant and anesthetic properties by South American natives dates back to 2000 B.C.E.[11]. Although Spanish explorers discovered the mild stimulant effects of the leaves and returned to Europe with them in the 16th century, their use did not become widespread for more than 300 years, partially because the leaves lost much of their potency on the journey back to Europe[12].

Cocaine was first isolated and synthesized in 1859 in Germany, and its medicinal effects were first documented in the 1880s[13,14]. Among the proponents of cocaine during this period was Sigmund Freud, who initially lauded the use of cocaine to treat a variety of conditions (most of which he retracted in 1887), including depression, alcoholism, and morphine addiction, in an 1884 paper titled On Cocaine. The surgeon William Halstead also utilized the drug for its local anesthetic effects [13,14]. Both men developed documented cocaine addictions. In 1886, the soft drink Coca-Cola, which contained cocaine and caffeine, was introduced. The ability of cocaine to reduce hunger, fatigue, and the need for sleep was highly valued during the industrial revolution in the late 19th century, and its use was encouraged to promote worker productivity[13,15]. The demand for cocaine skyrocketed during this period; the pharmaceutical company Merck produced 0.75 pounds of cocaine in 1883 and 158,352 pounds in 1884[9,12]. Cocaine was widely available during this period in cigarettes, inhalers, candy, elixirs, solutions, and over-the-counter products, as well as in wine and soft drinks[13,15]. Use of cocaine eventually reached epidemic proportions. In 1910, President Taft declared cocaine to be a public enemy, and strict controls were enacted at the state level[9,15]. Cocaine was removed from the Coca-Cola formulation in 1903, and the passage of the Harrison Narcotic Act in 1914 severely restricted the manufacture, distribution, and sale of cocaine in the United States. Cocaine use plummeted and remained very low for the next six decades[9,15].

SECOND WAVE

Cocaine use did not experience a resurgence until the late 1960s, coinciding with the tighter regulatory control and decreased use of amphetamines [12,16]. The seriousness of cocaine abuse and dependence was discounted in the 1960s and 1970s, and little effort was made to understand the mechanism of cocaine addiction and its treatment, partially because heroin addiction was seen as the most significant drug-related public health concern[17]. The introduction, widespread use, and substantial morbidity and mortality of freebase and crack cocaine in the early 1980s alerted scientists and clinicians of the urgency in understanding the nature of cocaine addiction and in developing effective treatments.

The increase in cocaine use in the 1980s correlated with the introduction of new forms of the drug. When cocaine is treated with hydrochloric acid (HCl), it becomes cocaine HCl, which is highly soluble in water and highly lipophilic. Until the late 1970s, this was the predominant illicit form[9]. Cocaine HCl may be administered intranasally, mixed with water and used intravenously, or combined with heroin and injected, which is referred to as a "speedball"[5,9]. Freebase cocaine is a highly pure form created by removing the hydrochloride base and is not water soluble. Unlike cocaine in the powdered hydrochloride form, which is destroyed by heat, freebase is smokable. Crack cocaine is made by dissolving cocaine HCl in water, mixing in baking soda, and heating the mixture to create a hard substance that is cut into "rocks"[12]. In the early 1980s, cheap and readily available crack cocaine was introduced, resulting in a rapidly escalating number of regular users and addicts[9].

3. EPIDEMIOLOGY AND DEMOGRAPHICS OF COCAINE ABUSE AND DEPENDENCE

In 2021, 4.8 million Americans (1.7%) had used cocaine within the past year, with 1.4 million individuals 12 years of age or older classified as dependent on or abusing cocaine [18]. Every day, 1,310 people use a cocaine product for the first time, with 60% of initiates 18 to 25 years of age and 39% of initiates 26 years of age or older[18]. Between 2002 and 2021, the number of annual initiates of cocaine declined from 1,032,000 to 478,000[18]. Older estimates in the United States have shown that cocaine is used primarily by young men, who outnumber female users by approximately 2 to 1[19]. Past-year cocaine use rates do not differ significantly by race/ethnicity, except among multiracial (defined as more than one race, but not Hispanic or Latino) individuals, of whom 3.2% reportedly used cocaine in the past year [18]. Overall, environmental and social factors (e.g., approached by someone selling cocaine, parental involvement, religious beliefs, scholastic environment) account for risk of cocaine use considerably more than race or ethnicity[19].

Based on the Substance Abuse and Mental Health Services Administration (SAMHSA) Treatment Episode Data Set (TEDS), primary cocaine treatment admissions decreased from 60 per 100,000 in 2010 to 26 per 100,000 in 2020, with the highest rates of admissions in the Middle Atlantic and New England regions[20]. The primary reported substances used at admission in 2020 were: alcohol (31.2%), opioids (26.9%), stimulants (12.7%), marijuana/hashish (9.8%), and cocaine (5.1%)[20]. In 2010, cocaine treatment admissions for persons 12 years of age or older represented 8.3% of all treatment admissions, compared with 5.1% in 2020[20]. Data in the 2020 SAMHSA publication represented 49 states, Puerto Rico, and the District of Columbia, and of the 1,416,357 reported treatment admissions for all substances, approximately 71,725 were for primary cocaine use[20]. Approximately 60% of these admissions were for smoked (crack) cocaine.

Cocaine, in general, was the fifth most common illicit drug among treatment admissions in 2020, accounting for 5.1% of TEDS admissions, with smoked cocaine accounting for 3% of total admissions. Cocaine users who ingest cocaine by routes other than smoking were more likely to be White and male than those who smoke cocaine[20]. Of those admitted for smoked cocaine, approximately 51% were Black and 40% were White[20]. Women comprised 36.8% of cocaine treatment admissions in 2020, with 63.8% of women being treated for smoked cocaine and 3.2% of women being pregnant. Hispanic/Latino individuals accounted for 13.3% of treatment admissions in 2020 [20].

Certain populations are more vulnerable to cocaine-induced toxicity, primarily due to their inefficient capacity for metabolism and clearance of the drug and its breakdown products. These include the elderly, infants, fetuses, pregnant women, and patients with liver disease[13]. Other factors that influence individual variation in susceptibility to cocaine-induced toxicity include age, sex, body mass, hepatic and renal function, drug-drug interactions, and genetic variability[21]. Black American users are more likely than non-black users to experience rhabdomyolysis, excited delirium, and changes in cardiac rhythm[13].

Gender differences in the effects of cocaine have also been observed. Men who use cocaine experience higher blood concentration levels and greater drug effect than women, and women are more sensitive to the cardiovascular effects than men[12,22]. Women presenting for treatment of cocaine dependence are more likely than males to be severely dependent, to abuse other drugs, to have a briefer period of abstinence, and to have childhood histories of physical or sexual abuse[17]. Gender differences in comorbidity have also been found, with female cocaine abusers more likely to have major depression and male cocaine abusers more likely to have antisocial personality disorder[17].

4. COCAINE USE

PHARMACODYNAMICS

Cocaine's specific mechanism of action involves increasing the synaptic transmission of dopamine, serotonin, and norepinephrine by interaction with plasma membrane transporters to block presynaptic reuptake. Action involving the dopamine transporter is the most important in producing the reinforcing effects, which lead to dependence [23]. The increased postsynaptic dopamine activity following its blocked presynaptic reuptake forms the basis of cocaine action[17].

Dopamine receptors are grouped into two families: dopamine D1-like (D1 and D5) and dopamine D2-like (D2, D3, and D4). Both D1-like and D2-like receptors are believed to mediate the acute and chronic effects of cocaine[24,25]. A study employing multiple regression analysis to identify the biochemical receptor mechanism most associated with the reinforcing properties of cocaine examined dopamine, serotonin, choline, and norepinephrine receptors and their transporters[26]. Researchers found that cocaine binding to the dopamine transporter or cocaine inhibition of dopamine uptake accounted for most of the variability[27].

The basal ganglia, the brain region with the highest density of dopamine receptors, is the site with the highest concentration of cocaine binding[28]. In addition to affinity for mesocorticolimbic dopamine receptors, cocaine also inhibits activity in the locus coeruleus and the pons, providing an anxiolytic effect[12].

PHARMACOKINETICS

Cocaine can be absorbed through any mucous membrane. Different routes of cocaine delivery into the body produce different patterns and levels of blood cocaine concentration. Intranasally administered cocaine is absorbed and distributed into the body gradually, while the onset of effect is rapid when smoked or injected. The effect of cocaine is experienced most rapidly and intensely when smoked, with an onset of effects typically occurring within 8 to 10 seconds; thus, cocaine is most addictive when smoked [23]. Injected cocaine takes twice as long to enter the brain (i.e., 16 to 20 seconds), and snorted cocaine begins to act in three to five minutes[12]. The lungs are the most rapid and efficient cocaine delivery modality because of the large surface area of absorption and rapidity of arterial circulation to the brain[9,29].

Peak plasma levels of cocaine occur 20 to 40 minutes following intranasal ingestion, with a typical concentration of 100–500 mcg/L. Toxicity is rarely seen at this dose level. Plasma half-life ranges from 31 to 82 minutes, with a mean of 38 minutes[13].

Cocaine has long been used medicinally as a local anesthetic agent and is believed to be the only naturally occurring agent with this specific property[30]. Cocaine interferes with sodium channel activity, leading to diminished or blocked nerve conductivity. By entering the sodium channel and binding to the membrane interior, the drug further inhibits membrane sodium activity in electrically active cells, such as myocardium and nerve cells[29,30].

The majority of cocaine (i.e., 75% to 90%) is hydrolyzed by plasma and hepatic esterases to ecgonine methyl ester and benzoylecgonine, while a smaller proportion undergoes hepatic demethylation to produce the CNS-active norcocaine[29,30,31]. Hepatic metabolism occurs with cytochrome P450-2C9, 2C19, 3A4, and 2D6[21]. Decreased hepatic perfusion results in prolonged elevation of cocaine levels[29]. Concurrent alcohol use produces the metabolite cocaethylene, which has a longer plasma half-life than cocaine[21,29]. The rapid metabolism of cocaine in the liver accounts for its short half-life, which also influences the duration of the subjective "high" from a single dose. It is believed that both the intensity of the high and its brief duration contribute to the addictive properties of the drug[23,29].

USE CHARACTERISTICS OF COCAINE ABUSE

Cocaine users often begin in the evening and use the drug continuously over several hours [32]. Over a longer period of time, cocaine use appears to follow what has been described as an "up-top-down" trajectory[33,34]. This means that use generally increases to a peak, then decreases. However, this may be more true of certain delivery routes than of others.

5. EFFECTS OF COCAINE USE

ACUTE EFFECTS

The intensity and quality of CNS effects of cocaine are influenced by the quantity and route of ingestion, as well as past drug use. One hundred milligrams is considered a fairly modest dose, with a high dose being several hundred milligrams [12]. Tolerance to the desired effects of cocaine can result from as little as one week of regular use, although the rapidity of the onset of tolerance varies by the route of administration, dose, and frequency of ingestion[12]. Subjective and behavioral effects from single- and multiple-dose acute ingestion of cocaine include euphoria, increased heart rate, restlessness, anxiety and panic, delusions, heightened alertness, and insomnia (Table 1).

Table 1: EFFECTS OF COCAINE USE

Type of Use

Psychologic Symptoms

Physiologic Signs

Acute ingestion

Euphoria

Heightened self-confidence, well-being, energy, and alertness

Restlessness

Reduced need for food

Insomnia

Elevated arterial pressure

Increased heart rate and respiration

Coronary vasoconstriction

Increased myocardial oxygen demand

Hyperthermia secondary to cutaneous vasoconstriction

Increased locomotor activity

Chronic ingestion

Dysphoria

Agitation

Anxiety and panic

Loss of concentration

Diminished libido

Paranoia

Visual or auditory hallucinations

Delusions

Pacing

Restlessness

Hyperactivity

Grinding of teeth

Mood lability

Insomnia

Source: [2,9,17]

CHRONIC EFFECTS

The effects of chronic cocaine use on brain neuronal pathways are influenced by the duration and intensity of cocaine use, length of abstinence, and vulnerability to the effects of cocaine [35]. Long-term use of the drug induces a partial depletion of presynaptic dopamine reserves in the targeted brain regions, which is compensated by an increase in the number of dopamine receptors in the striatal region of the brain[12]. This results in the symptoms of dysphoria, anxiety, restlessness, and paranoia.

Cocaine obtained illicitly is always adulterated, or "cut," resulting in wide variations in concentration and purity. Consequently, users may underestimate the purity of the drug and overdose, which can result in toxicity or even death. Certain adulterants can produce harmful effects, as evidenced by the exaggerated sympathetic stimulation caused by ephedrine, Parkinson-type symptoms caused by manganese salts, and the increased likelihood of seizures with the addition of lidocaine[13]. Cocaine use is responsible for more hospital admissions than any other recreational or illicit drug, and the actual incidence of cocaine-induced toxicity is likely to be under-reported[29,30].

CNS Effects

The sympathomimetic and vasoconstrictive effects of cocaine can induce migraine-like headaches. Cocaine use is also associated with the development of cerebrovascular pathology, including [29]:

- Ischemic strokes

- Hemorrhagic strokes

- Thromboembolic strokes

- Primary and secondary seizures

- Cocaine-induced excited delirium

- Hyperthermia

Cocaine-induced dopamine accumulation in the basal ganglia may result in movement disorders that can present as Tourette syndrome, dystonic reactions, tardive dyskinesia, and akathisia [12,30].

Neurocognitive Effects

Chronic and heavy cocaine use can lead to the development of diverse neuropsychologic sequelae [36]. Many studies have been performed utilizing a variety of brain imaging techniques, including brain blood flow studies employing transcranial Doppler; single photon emission computed tomography (SPECT); magnetic resonance angiography (MRA); computed tomography (CT); magnetic resonance imaging (MRI); diffusion tensor imaging (DTI); and positron emission tomography (PET)[36]. Evidence obtained from these brain-imaging studies of patients with cocaine use disorder indicates that cocaine use leads to functional, structural, and molecular changes, including dysfunction in the prefrontal cortex, anterior cingulated gyrus, and basal ganglia. This corresponds with functional impairment in abilities related to executive functioning; error detection and performance monitoring and adjustment; and cognition and movement[36]. However, studies attempting to elucidate the durable structural and functional changes to the brain from cocaine use are not longitudinal, and thus cannot rule out the possibility that structural and functional deficits predispose or contribute to cocaine-induced pathology[35,37,38].

Cardiovascular Effects

Drugs that increase brain monoamine concentration also have the potential to elevate peripheral monoamine activity [28]. Cocaine stimulates dopamine and alpha- and beta-adrenergic receptors in the CNS and in the peripheral nervous system, which is the underlying basis of the adverse systemic effects of this drug[12,29]. The cerebrovascular complications caused by cocaine are the result of its effect on noradrenergic neurotransmission and include vasoconstriction and resultant decrease in blood flow, inflammation of blood vessel walls, and hyperpyrexia[23,29].

Cocaine produces cardiovascular pathology in susceptible users by altering the myocardium and vasculature in a manner that may eventually manifest as cardiac disease, hypertension, or atherosclerosis[30]. The cocaine molecule has a high affinity for cardiac tissue, and both acute and chronic cocaine use can induce a variety of cardiac complications in persons with a negative history of such conditions, primarily from the powerful sympathomimetic properties of the drug[28,39]. Specific cocaine-induced cardiac conditions include myocardial infarction, ischemia, arterial thrombosis, ventricular tachycardia, ventricular fibrillation, and sudden death. Other cardiac conditions attributable to cocaine use include dilated cardiomyopathy, hypertension, myocarditis, and coronary artery occlusion[12,29].

Cigarette smoking acts synergistically with the adrenergic effects of cocaine to further increase vasoconstriction[29,31]. Other risk factors predisposing users to cocaine-induced cardiovascular disease or events include[29,30]:

- Myocarditis

- Hypercoagulability

- Early-onset atherosclerosis

- Heavy or chronic alcohol use

- Hyperadrenergic syndrome

- Previous history of excited delirium

- Aneurysm or stroke

- High-risk behaviors for sepsis, such as injecting drug use or unsafe sex practices

Pulmonary Effects

Most of the pulmonary complications from cocaine use involve smoked cocaine in the form of crack or freebase. These effects usually develop shortly after inhalation. The more common symptoms include productive cough, chest pain, shortness of breath, and worsening of pre-existing asthma. Other pulmonary conditions include thermal injury to the airway, asthma severe enough to necessitate mechanical ventilation, interstitial pneumonitis, pneumothorax, pulmonary edema, pulmonary hemorrhage, and degraded pulmonary function [12,29].

Gastrointestinal Effects

Malnutrition is the most common gastrointestinal (GI) complication from cocaine use. This is influenced by the adverse effect of cocaine on food and beverage consumption, taste, and nutrient absorption. Other GI complications from cocaine use are less common and include gastroduodenal ulceration, acute bowel perforation, liver toxicity, and pancreatic and endocrine disease [12].

Sexually Transmitted Infections

Cocaine abuse is associated with increased transmission of sexually transmitted infections (STIs), primarily as the result of unsafe and/or high-risk sexual practices. The transmission of human immunodeficiency virus (HIV) has been a particular concern and may stem from exchanging sex for money or cocaine and high numbers of homosexual unprotected sexual encounters, particularly anal receptive sex [9,40,41].

NEONATAL EFFECTS

Because a number of people in the United States are believed to use cocaine during pregnancy (estimated at up to 10,000 each year), serious concern has been raised regarding the effects of cocaine on fetal development [19]. There were approximately 800 admissions with positive pregnancy status to treatment centers for primary cocaine use in 2020, compared with 1,300 in 2013[20,42].

The adverse effects of cocaine on fetal development stem from its diffusion across the placental barrier, where its vasoconstrictive effect diminishes the flow of blood and oxygen. The resultant hypoxia can retard fetal somatic and CNS development. Damage to the developing fetus can occur in both early and later pregnancy. Although ascertaining the impact of prenatal cocaine exposure is complicated by the influence of other factors (e.g., maternal nutrition, exposure to STIs/STI treatments, amount and route of ingestion of cocaine, use of alcohol, use of tobacco/nicotine, other illicit drug use, the postnatal environment), it is believed that the cocaine-induced effects originate in systems mediated by dopamine function, encompassing the cognitive, motor, emotional, and reward development of the infant[2,12,43,44]. However, some of these effects may be minor in severity and transient in nature, and there is no specific syndrome or condition associated with prenatal cocaine exposure[44,45]. Other adverse effects from maternal cocaine ingestion include spontaneous abortion, stillbirth, prematurity, and low birth weight[2,12,46].

A 2013 systematic review found that the effects of prenatal cocaine exposure may not be as clearly clinically significant as once thought[44]. Although there are obvious early effects (e.g., prematurity, low birth weight) and possible effects on childhood development (e.g., reduced cognition/school performance), test scores and developmental measures were within normal limits in nearly all studies. It is difficult to accurately assess the role of prenatal cocaine exposure on adolescent outcomes due to a host of environmental factors in the prenatal period and during childhood (e.g., violence exposure, second-hand smoke, malnutrition, toxic exposures). One study demonstrated that prenatal cocaine exposure had direct effects on young adult emotion regulation problems, arrest history, and conduct disorder not explained by earlier adolescent behavior[47]. It is safe to say that cocaine exposure can cause premature birth or low birth weight, which are known risk factors for hyperactivity disorders[48].

DIFFERENTIAL DIAGNOSIS

Repeated heavy cocaine use can lead to the development of symptoms that resemble distinct psychiatric and neurologic conditions; therefore, a thorough differential diagnosis is vital. Careful history, observation, and monitoring are useful in performing an accurate differential diagnosis [48]. Some conditions to consider in the differential diagnosis process include mood and psychotic disorders.

The affect and behavior of patients intoxicated with cocaine can mimic a broad spectrum of mood disorders, including the elevated and expansive mood, hypertalkativeness, euphoria, irritability, and sleep and appetite reduction of mania; the volatile cycling of euphoria and dysphoria of bipolar disorder; and the dysphoria, anergia, anhedonia, and suicidal ideation that characterizes acute withdrawal resembling major depression[48]. Cocaine use can also induce the paranoia and delusional thinking that resemble a psychotic disorder[49]. The most frequent delusion types observed in cocaine abusers are the persecutory, jealous, and somatic types[48].

COMORBID ALCOHOL USE DISORDER

Cocaine has a profound liability of abuse and dependency associated with its use [50]. Perhaps the most serious condition associated with repeated use of cocaine is the development of addiction, which may extend to other substances.

Alcohol is a frequently abused substance among patients who use stimulants. Many patients are dependent on both cocaine and alcohol, presenting a challenge for researchers and clinicians in optimizing treatment outcomes[28,29,42].

Cocaine abusers consume alcohol for several reasons, including the enhancement and prolongation of euphoria and minimization of the undesired effects. The rewarding effects of both substances are mediated through the mesocorticolimbic dopamine pathway. As noted, the combined effects of cocaine and alcohol can also be explained by the formation of cocaethylene, a metabolic byproduct of ingestion of both substances. Cocaethylene is speculated to be less anxiogenic than cocaine and thus may counteract or mask the dysphoria that can accompany cocaine use. Cocaethylene shares many neurochemical and pharmacologic properties with cocaine and is also an indirect dopamine agonist. Alcohol enhancement of cocaine toxicity is partially explained by the presence of cocaethylene, which increases heart rate and systolic blood pressure. As the result of the substance's cardiotoxic effects, it contributes to the increase in ischemia, infarction, and arrhythmia seen in patients abusing both cocaine and alcohol. Additionally, cocaethylene may elevate the potential of violent ideation, threatening behavior, and violent behavior[51,52].

Differences in the patterns of combined cocaine and alcohol use have been observed between persons who smoke cocaine compared with those who use intranasally. Users of intranasally administered cocaine typically use alcohol both concurrently and in alternating doses. They also tend to use alcohol excessively. These users usually increase the quantity of both substances when using them together. Crack cocaine users, however, are more likely to ingest alcohol at the end of an episode of use and to drink less alcohol when using cocaine[52]. Co-abusers are also more likely to use alcohol to alleviate the unpleasant after-effects of cocaine use.

6. TREATMENT OF COCAINE USE DISORDER

Cocaine use disorder shares many characteristics with general substance dependence. However, it also includes specific identifying symptoms. According to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5-TR), an early sign of cocaine use disorder is difficulty resisting using cocaine whenever it is available [7]. Physiologic dependence is associated with a higher risk for cocaine-related problems. Because frequent dosing is necessary to maintain the desired effects, patients with cocaine use disorder must often deal with the effects of spending large amounts of money on the drug.

Although cocaine has been a drug of abuse for decades, research on the treatment of cocaine use disorder was delayed until the later part of the 20th century. The introduction and widespread use of crack cocaine in the 1980s, severity of the addiction, and comorbid problems finally prompted the scientific community to investigate treatment options[17].

Regardless of therapeutic modality, the goals of treatment for cocaine abuse or dependence are to retain the patient in treatment, disrupt the binge cycle, and prevent relapse[17,53,54,55]. Inpatient treatment is perhaps the most desirable option. It allows the patient to be shielded from the environmental cues that are associated with cocaine use and the resultant euphoria and craving that are triggered by these cues[17].

After the patient has detoxified and acute withdrawal is over, rehabilitation is implemented, typically in three stages. The initial emphasis is on motivating the patient to remain abstinent. This is accomplished by educational lectures, family outreach, and group therapy. Treatment personnel who are themselves recovering can serve as positive role models, and self-disclosure in this context is appropriate and even therapeutic. During this phase, the patient is also introduced to self-help groups such as Alcoholics Anonymous (AA), Cocaine Anonymous (CA), and Narcotics Anonymous (NA) [1,56].

The second stage of rehabilitation focuses on helping patients rebuild their lives without substances. Patients are given the strategies and tools needed to acquire a sober social network, appropriately cope with stress, and use free time constructively without using cocaine. The third stage of rehabilitation focuses on relapse prevention, which can be addressed in group therapy or individual counseling. Orientation and encouragement of 12-step program involvement occurs during all three stages of treatment. The three-stage treatment modality for stimulant abuse incorporates behavioral, cognitive, and psychologic elements and provides the basis of psychosocial treatment[1]. The use of pharmacotherapy may also be necessary in each stage.

PSYCHOSOCIAL THERAPY

Treatment of substance use and dependence with psychosocial or behavioral therapy is based on the assumption that addictive behavior is developed and maintained by specific mechanisms [55]:

- Expectancies and modeling

- Reinforcing properties of the drug

- Secondary social reinforcement

The goal of these types of treatments is to modify drug-seeking and other behavioral aspects of drug dependency [53]. Psychosocial therapy and pharmacotherapy are not mutually exclusive; in fact, some drug therapies for substance abuse are considered useless without a psychosocial/behavioral component[53,55].

Psychosocial therapies for stimulant abuse disorders can be divided into two broad categories. The first category consists of therapies that were originally developed for patients with anxiety and depression and modified for use with patients with addictive disorders. This group of therapeutic approaches includes cognitive-behavioral therapy (CBT), the behavioral therapies, and interpersonal therapy. The second group of psychosocial therapies was developed explicitly for substance-abusing patients and includes motivational interviewing and motivation enhancement therapy[53,57]. All psychotherapies are intended to be delivered in a supportive, empathic manner that minimizes confrontation.

Drug counseling is a widely used therapy approach with cocaine and other substance abusers. It consists of a focus on abstinence, problem solving, and 12-step orientation and involvement. Drug counseling is usually provided by counselors who have a certificate in addiction counseling. A fair number of addiction counselors are themselves recovering from alcohol and/or substance abuse disorders[57].

Contingency Management

There is considerable evidence that cocaine use is sensitive to the application of contingencies. Contingencies occur on a spectrum from contrived to naturalistic. Contingency management (CM) and vouchers are examples of contrived interventions, while 12-step programs are examples of naturalistic interventions [56]. Contrived contingencies may be effective in initially engaging patients in abstinence, but relapse to drug use may occur following removal of the reinforcer. In contrast, naturalistic contingencies are more likely to maintain the initial gains made by the patient and to facilitate the sustained change of behavior over time[58].

The goal of CM interventions is to increase the opportunity cost of stimulant use by arranging an environment where drug use results in the forfeiture of a predetermined item or privilege, referred to as an alternate reinforcer[59]. Treatment with a CM component was first used with cocaine-abusing methadone patients, a highly suitable population for two reasons: cocaine abuse is prevalent among patients with opioid use disorder receiving methadone maintenance, and methadone patients are required to report to the clinic daily to receive their medication under staff supervision. Daily clinic appointments are often considered a significant constraint on employment, travel, and other activities. Patients who are able to abstain from drugs of abuse, as measured by a urine drug screen, may be allowed several days of take-home methadone doses, which can act as a behavioral contingent[60]. Several studies have shown that this contingent condition has led to greater treatment retention and reductions in cocaine use than those found in comparison treatment conditions, although this effect dissipates with longer-term follow-up[58,61,62,63].

Community Reinforcement

Community reinforcement approaches (CRAs) are biopsychosocial interventions designed to engage and change the lifestyle of the drug abuser by addressing the role of environmental cues and alternative reinforcers in influencing behavior. The theoretical basis of the CRA is that substance abuse is maintained by substance-related reinforcers as well as by the absence of competing alternative reinforcers. The primary goal of the CRA is to build and strengthen relationships, recognize appropriate leisure activities, and identify vocational interests of the patient to provide competing reinforcement with cocaine use and the drug-using lifestyle [64]. CRA aims to increase abstinence by increasing or highlighting the opportunity cost of relationships and social support the patient stands to lose through drug use[58]. In addition to integrating cognitive-behavioral and, in some cases, pharmacologic approaches, CRA may also include the use of vouchers, whereby tokens are given to the patient for producing substance-free urine samples, which are then used to purchase goods and services desired by the patient.

A review of four studies utilizing CRA with patients with cocaine use disorder found evidence that CRA employing abstinence-contingent incentives in the form of vouchers was more effective in promoting abstinence than CRA using noncontingent incentives and usual care. Patients assigned to CRA incorporating abstinence-contingent incentives experienced a greater reduction in disease severity as measured by the Addiction Severity Index than comparison groups[64]. Despite early, promising reports of CRA with patients with alcohol use disorder and evidence that patients receiving CRA have demonstrated more favorable drug use outcomes than patients receiving standard outpatient counseling, CRA is seldom used because of the relatively high cost and labor intensity[53,65].

Motivational Interventions

Motivational interventions for substance abuse stem from the theory that targeting and enhancing motivation to quit drugs will increase positive outcome; positive outcome is increased when motivation comes internally rather than when it is externally imposed. Specifically, motivational-enhancement therapies (MET) are based on the Transtheoretical Stages of Change Theory, which postulates that patients pass through a series of stages of thought, planning, and action in the process of behavior change [66]. MET is intended to enhance motivation and commitment to change, activate patient resources, and facilitate movement along the readiness-to-change spectrum[67]. MET helps patients build internal motivation through the resolution of issues related to ambivalence. The therapeutic approach is characterized by nonconfrontive, nonjudgmental interviewing that helps the patient consider the pros and cons of change. MET also strives to enhance patient self-efficacy[66]. MET seems to be more effective in patients with low initial levels of motivation when used for patients with cocaine use disorder. It tends to result in less relapse to cocaine use and fewer total days of cocaine use[68].

Coping and Social Skill Training

Coping and social skill training (CSST) evolved from social learning theory and is used to improve the inadequate coping skills found in many addicted persons, including deficits in regulation of emotion and in effectively coping with social situations. CSST addresses four primary areas [69]:

- Interpersonal skills

- Cognitive and affective regulation

- Coping skills to manage stressful life events

- Coping skills when substances or substance-related cues are encountered

An added emphasis on drug-related cues is used when CSST is employed with patients with cocaine use disorder [69].

An inventory of high-risk situations for recovering cocaine abusers was developed and validated with a sample of 179 cocaine abusers. The Cocaine High-Risk Situations Questionnaire identified the following situations as the most evocative of urges to use cocaine[70]:

- Negative emotional states, such as depression, fear, or anger

- Peer or other external pressure to use

- Spontaneous urges to use

- Desire to augment positive or elevated mood

- Direct using cues, such as receiving a paycheck or cash

CSST has incorporated these findings into the treatment approach used with cocaine users. Preliminary results indicate some benefit of cocaine-specific CSST in reducing frequency of cocaine use and increasing duration of abstinence from cocaine, although these results have not been replicated in subsequent research [68,69].

Drug Counseling

A large treatment study performed by the National Institute on Drug Abuse randomized 487 cocaine-dependent outpatients to four treatment conditions [71]. All patients received group drug counseling once a week for six months. In addition, the four groups received individual drug counseling, CBT, supportive-expressive therapy twice a week for three months, or no additional therapy. All drug counseling was 12-step oriented. At six-month follow-up, the entire sample exhibited an overall decline in cocaine use, from an average of 10 times per month at baseline to once per month, with corresponding reductions in psychiatric symptoms. Reductions in cocaine use and in the Addiction Severity Index-Drug Use Composite scores were significantly greater in the group that received individual plus group drug counseling than in either of the psychotherapy groups[57,71]. Further analysis found that patients assigned to individual drug counseling who were regular participants in 12-step programs achieved the best outcomes of any treatment subgroup[72].

PHARMACOTHERAPY

Because dropout and relapse rates are high among patients in treatment for stimulant abuse, pharmacologic therapy has been used to augment standard psychosocial therapy, with the goal of increasing retention in treatment, reducing relapse rate, and treating coexisting psychiatric disorders that may contribute to poorer prognoses. Pharmacotherapy is based on the classic medical model that addresses any given disorder as the manifestation of neurochemical or biologic imbalance and dysregulation. This imbalance is viewed either as a precursor for addictive behavior or the consequence of repeated exposure to alcohol or drugs [53].

Pharmacotherapy for cocaine use disorder follows the model used in the treatment of alcoholism and heroin addiction, which targets the neurobiologic and behavioral components of addiction[23]. Agonist therapy is a component of several different pharmacotherapy strategies for stimulant abuse and dependence; it partially replaces the effects of the abused drug to stabilize the patient. Antagonist therapy, which blocks the abused drug effect, may be utilized to preclude use, alleviate symptoms of use or withdrawal, or treat comorbid conditions. A combination of these approaches may also be utilized[73].

Although a large number of medications have been used in patients with cocaine use disorder, all are either U.S. Food and Drug Administration (FDA)-approved drugs used off label or investigational drugs[2,5]. The following overview is comprised mainly of review papers that summarize the efficacy in individual therapeutic classes of drugs.

Antidepressants

The theoretical basis for antidepressant treatment of cocaine addiction is to enhance synaptic monoamine transmission by blocking the presynaptic reuptake of brain catecholamines. The goal of this therapy is the alleviation of cravings for cocaine and reduction of withdrawal symptoms, including dysphoria, depressed mood, and cognitive dysfunction [23,74]. Three types of antidepressants have been studied: tricyclics, such as desipramine and imipramine; selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine and sertraline; and atypical antidepressants, such as bupropion.

A Cochrane review of 31 randomized, double-blind, placebo-controlled studies found only five trials that reported significant differences between the study drug and placebo[74]. Among the reviewed studies, desipramine showed a trend in reducing the frequency of cocaine-positive urine samples; however, the effect was not statistically significant. There were no significant differences between antidepressants and placebo on measures of percentage of abstinent days or total abstinence. There was some evidence that fluoxetine reduced the intensity of craving for cocaine and increased treatment retention, although these findings were inconsistent. Overall, the reviewers' findings did not support the clinical use of antidepressants in the treatment of cocaine use disorder[74].

Psychostimulants

Selegiline is a monoamine oxidase-B (MAO-B) inhibitor used in the treatment of Parkinson disease. However, it has been found to reduce the subjective sensation of "high" and to alter the cerebral metabolism of cocaine. Though promising, more research is needed to confirm the possible efficacy of selegiline and other psychostimulant agents (e.g., bupropion, dexamphetamine, lisdexamfetamine, methylphenidate, modafinil, mazindol, methamphetamine, mixed amphetamine salts) in the treatment of cocaine use disorder [24,75]. A Cochrane review noted that sustained abstinence was most pronounced with bupropion and dexamphetamine; however, there was high attrition in all included studies, which complicated interpretation of the results[75].

Modafinil is a novel stimulant used to treat narcolepsy and excessive daytime sleepiness, with a pharmacologic mechanism opposite the effects of cocaine-induced neuroadaptation on brain reward systems. This action serves as the basis for its use in cocaine use disorder[76,77,78]. Preliminary evidence has suggested that this agent may play an important role in blocking cocaine-induced euphoria, enhancing periods of cocaine abstinence, and reducing total cocaine use, although replication is needed in larger trials for greater study periods[63,75,79,80,81,82,83,84].

Dopamine Agonists

The difficulties many cocaine addicts encounter in early abstinence, with intense drug craving, fatigue, dysphoria, depression, and difficulties with concentration, are believed to originate from dopamine depletion in key brain systems following chronic enhancement of dopamine transmission. This is the theoretical basis for dopamine agonist treatment [85]. The three most studied dopamine agonists in the treatment of cocaine addiction are amantadine, bromocriptine, and pergolide. A Cochrane review of 24 randomized controlled trials and controlled clinical trials concluded that there were significant forms of bias, including selection bias, performance bias, and detection bias, in all of the studies. The findings did not support the clinical use of dopamine agonists in the treatment of cocaine use disorder[85]. Also, the side effects common with this class of drugs further limit their therapeutic appeal[23]. There is evidence that amantadine may be effective in more severe cases of cocaine withdrawal, but confirmation is needed from additional research[24].

Methylphenidate, a drug used to treat ADHD, shares many of the pharmacologic properties of cocaine, including the inhibition of dopamine, serotonin, and norepinephrine reuptake. On this basis, it has been proposed as an agonist therapy strategy for cocaine use disorder. Evaluation of controlled trials employing methylphenidate have suggested better treatment retention, but no differences have been observed between active drug and placebo groups, indicating a lack of efficacy in the treatment of cocaine use disorder[24,75]. Methylphenidate has been found to induce craving for cocaine only when administered concomitantly with cocaine cues (e.g., video scenes of subjects self-administering cocaine)[86].

Overall, results from dopamine agonist trials have been disappointing, with neither direct agents, such as bromocriptine and pergolide, or indirect dopaminergic agonists, such as methylphenidate or amantadine, demonstrating consistent efficacy in reduction of withdrawal symptoms[39,87,88].

Dopamine Antagonists

Dopamine antagonists, typically D2 antagonists, have been used primarily to block the euphoric or reinforcing drug effect of cocaine. Antipsychotic drugs, such as risperidone, ecopipam, and olanzapine, are usually employed for this use. Studies of these drugs have been typified by high subject attrition, frequent side effects, and poor compliance, resulting in this class being largely discounted as having therapeutic potential [63,73,88]. An unfortunate side effect observed during trials of the D1 antagonist ecopipam was that cocaine self-administration increased[89].

Disulfiram

Disulfiram is an oral medication used for decades as aversive therapy for alcohol dependence. It acts by inhibiting aldehyde dehydrogenase, thereby increasing the amount of the toxic alcohol metabolite acetaldehyde. Disulfiram also inhibits the enzyme that converts dopamine to norepinephrine. This increase in dopamine has been hypothesized to make disulfiram a helpful drug for cocaine use disorder. Several studies have been performed with patients with cocaine use disorder, and researchers have found that, relative to placebo, use of disulfiram results in decreased craving for cocaine, increased dysphoria in patients who have ingested cocaine concurrently, decreased quantity and frequency of cocaine use, and reduced number of cocaine-positive urine samples. These results are encouraging. However, additional trials are needed to determine the optimal dose and duration of treatment [24,80,90]. A small 2016 trial sought to determine if supplementing CBT with disulfiram would enhance abstinence outcomes but found no benefit with addition of the drug[91].

Gamma-Amino Butyric Acid Agents

Gamma-amino butyric acid (GABA) is the primary inhibitory neurotransmitter in the brain, and evidence suggests that GABA modulates both dopamine brain pathways and the subjective effects of cocaine. There are two primary subtypes of GABA receptors: GABAa and GABAb. GABAa is involved in mediating the effects of antiepileptics, benzodiazepines, barbiturates, and neurosteroids such as progesterone. GABAb is distinct from GABAa in that it mediates the slow inhibitory response to GABA; the antispasm drug baclofen is a GABAb receptor agonist [24].

A rationale for treating cocaine addiction with antiepileptic drugs is the observation of the "kindling" effect of cocaine, whereby repeated administration of subthreshold electrical impulses to specific brain structures increases seizure activity[9]. Randomized, placebo-controlled trials of several GABAergic antiepileptic drugs have produced encouraging results. The antiepileptic and mood stabilizer valproic acid has led to reductions in the frequency and severity of cocaine cravings, self-reported cocaine use, and total number of days of cocaine use in a dose-dependent manner[92]. Topiramate, also an antiepileptic, was found to decrease the total number of cocaine-positive urine screens, although these results require replication[79,83,93].

Tiagabine is another antiepileptic drug that increases synaptic GABA levels. Studies with cocaine abusers on methadone maintenance found that patients randomized to tiagabine exhibited less cocaine use than subjects receiving gabapentin or placebo. Baclofen also demonstrated superior ability to reduce cocaine use than placebo, with some evidence of greater efficacy among more severe cocaine addicts[92]. Its use in the treatment of alcohol/cocaine codependence has also been supported[94].

Gabapentin is a GABA analog used as an antiseizure drug and mood stabilizer. Gabapentin has been found to block some of the reinforcing effects of smoked cocaine, although other trials have found no differences between gabapentin and placebo in reducing cocaine use among cocaine-abusing methadone patients[95].

One systematic review of 20 studies and 2,068 patients compared the anticonvulsants carbamazepine, gabapentin, lamotrigine, phenytoin, tiagabine, topiramate, and vigabatrin with placebo. The authors found no evidence supporting the use of anticonvulsants in the treatment of cocaine dependence[96].

Progesterone possesses GABA agonist, glutamate antagonist, and alpha-adrenergic antagonist properties. Laboratory studies have found that progesterone attenuates some of the reinforcing effects of smoked cocaine among women in the early follicular stage of the menstrual cycle and attenuates some of the subjective and physiologic effects of cocaine. However, it did not alter cocaine self-administration in a mixed-gender sample[24,92].

Alpha-Adrenergic Antagonists

Cocaine is a powerful stimulator of central and peripheral adrenergic activity. Adrenergic systems mediate several of cocaine's effects, such as increased heart rate, heightened blood pressure, and increased arousal. Adrenergic blockers have been utilized in clinical trials with patients with cocaine use disorder. Labetalol, an alpha- and beta-adrenergic blocker, attenuates some of the physiologic effects of cocaine but has not been shown to alter the subjective drug effect [97]. On the other hand, carvedilol, which has similar pharmacology as labetalol but greater CNS potency, blocked not only some of the cardiovascular effects of acute cocaine ingestion but also some of the subjective effects when given in a lower dose. Use of the beta1- and beta2-adrenergic antagonist propranolol results in greater treatment retention and more frequent drug-free urine samples than placebo among patients with more severe withdrawal symptoms, an effect not observed among subjects with milder withdrawal symptoms[24,79]. Propranolol administered at a dose of 100 mg/day has been found to be effective in reducing withdrawal symptoms and improving treatment retention among patients with greater cocaine addiction severity[98,99]. In a separate randomized, placebo-controlled study, a 40-mg dose of propranolol was found to reduce subjective cocaine craving and objective cue reactivity (e.g., heart rate, blood pressure) in response to a video of people using cocaine and in vivo cues (e.g., forms of preferred simulated cocaine/drug paraphernalia)[100]. Overall, adrenergic receptor antagonists seem to be effective in reducing or blocking the physiologic effects of acute cocaine ingestion and may be helpful in symptom reduction in a subset of patients with greater withdrawal severity. However, the American Heart Association has recommended that these agents be avoided for the treatment of cocaine toxicity in the acute setting[101].

IMMUNIZATION AND VACCINE THERAPY

Pharmacotherapy for cocaine use disorder targets brain neuronal pathways, whereas immunotherapy for cocaine use disorder acts peripherally to inhibit the effects of cocaine by blocking or delaying entry of the cocaine molecule into the brain [24]. The impetus for the development and evaluation of biologic therapies for cocaine use disorder stems, in part, from the potential side effects and disappointing results of pharmacotherapy trials targeting reward pathways that mediate the addictive effects of cocaine[23].

The two biologic-based therapies for cocaine use disorder that have been subjected to empirical evaluation are immunization and vaccination. Both are variants of the concept of antagonist therapy to block drug effect[73]. In passive immunization, the catalytic antibodies that bind with and convert circulating cocaine molecules to an inactive molecule through hydrolysis are injected into the patient. The action of the antibody breaks down cocaine into ecgonine methyl ester and benzoic acid, resulting in a lack of desired effects. Active immunization employs vaccination, which triggers the production of antibodies against cocaine through the administration of a cocaine-protein conjugate. Both inactive and active immunization prevent induction of the positive effects of cocaine ingestion. Several drawbacks to vaccine therapy for cocaine use disorder have been identified. These include the lack of protection against drugs that are structurally distinct from cocaine, but that produce the same effect; lack of effect on craving; wide variation in antibody formation across individuals; and patient motivational factors[102,103].

7. WITHDRAWAL FROM COCAINE

Physiologic adaptation and psychologic dependence may result from regular, long-term use of cocaine. Withdrawal symptoms are a result of the increased receptor density and receptor supersensitivity to neurotransmitters that characterize the adaptation to chronic cocaine use. Craving may occur either spontaneously or in response to environmental cues. Craving diminishes gradually in most users, but in severe users, it may never become fully extinguished [13,104].

A triphasic abstinence syndrome from heavy cocaine use has been identified[17]. Phase one is acute withdrawal, or the "crash." Immediately upon cessation of use, a withdrawal syndrome can manifest, consisting initially of a rapidly declining mood and energy level, agitation, and retarded major depression. Depression and dysphoria are observed and reported, as well as agitation, sweating, tachycardia, and unstable blood pressure. Symptoms of paranoia peak and then decline during this period. Patients experience overwhelming cravings to use cocaine at this point, partially to terminate the extreme discomfort of the withdrawal symptoms. However, many patients will attempt to use sedatives, opioids, alcohol, or cannabis to terminate anxiety and agitation and to induce sleep. Phase one can last up to four days[12,17].

Phase two can last one to ten weeks, during which time patients are likely to experience prolonged anhedonia, impaired motivation, dysphoria, and craving. It is during this period that patients are at highest risk of relapse. Outpatients are especially vulnerable to environmental cue-induced triggers for cocaine use. Persons, places, and things associated with cocaine use stimulate vivid recollection and cocaine-induced euphoria that, when contrasted with the ongoing dysphoria, can make resumption of use irresistible. If relapse occurs during this phase, it can activate the vicious cycle of heavy use, attempts to quit, and relapse[17].

Phase three consists of episodic craving that is gradually diminished if the cocaine user is able to remain abstinent[17]. The severity and duration of the symptoms of cocaine abstinence syndrome may be considerably less in the inpatient setting, where the patient is removed from the ubiquity of triggers encountered in the using environment[17,104,105].

8. TREATMENT OF CONDITIONS ASSOCIATED WITH COCAINE USE

POLYSUBSTANCE DEPENDENCE

As noted, patients with cocaine use disorder are often found to be addicted to or abuse other substances, such as alcohol, opioids, and benzodiazepines. These patients should be treated with therapies with established efficacy to manage the coexisting substance dependence, such as methadone or buprenorphine for patients with opioid use disorder, or naltrexone, acamprosate, or disulfiram for alcohol dependence [39].

Treatment Issues for Patients with Opioid Use Disorder Who Use Cocaine

Stimulant abuse and dependence is a significant problem among heroin addicts being treated with methadone maintenance therapy and one of the most treatment-resistant behaviors among this population. Numerous studies have evaluated the efficacy of pharmacotherapeutic agents in reducing cocaine use in this patient population [60]. A review of several randomized, double-blind, placebo-controlled studies failed to find superior efficacy on measures of cocaine use and dropout rate among patients receiving any antidepressant for cocaine use disorder[74]. A review of 17 studies involving amantadine, bromocriptine, and pergolide failed to show significant differences in rates of cocaine-positive urine samples[85]. Pergolide has since been withdrawn for human use[106].

The efficacy of voucher-based incentive programs for reducing cocaine use among patients with cocaine use disorder on methadone maintenance is well established and has been extended to the treatment of alcohol, cannabis, nicotine, and opioid dependence[107]. One study demonstrated a 50% abstinence rate at 12 weeks for patients receiving vouchers contingent on abstinence, compared with only 15% abstinence among patients receiving vouchers with no contingency[108]. Another multisite study included patients receiving methadone maintenance for opioid use disorder who exhibited intractable stimulant abuse. These patients were randomized to either usual care or usual care plus voucher-contingent incentive delivered on an intermittent-reinforcement schedule[60]. Results showed that intermittently providing incentives essentially doubled the likelihood of stimulant- and alcohol-free urine samples on any given clinic visit. Patients in the incentive groups were 11 times more likely to achieve 12 or more weeks of continuous abstinence than patients receiving usual care only.

ADHD

As discussed, methylphenidate has not been shown to be effective in reducing cocaine use in patients with cocaine use disorder and comorbid ADHD. However, it does substantially reduce ADHD symptoms [109]. The FDA warns that priapism may occur in men taking methylphenidate products, particularly after a dosage increase or following drug abstinence or an unusually long length of time between doses[110].

MAJOR DEPRESSION

Mood disorders are associated with substance abuse in general, and cocaine abuse and dependence are specifically associated with depression. Lifetime rates of major depression range from 25% to 61% among cocaine-dependent inpatients [111]. Managing both disorders is essential because the presence of one of these disorders decreases the likelihood of remission from the other[111]. With many depressive symptoms resolving in early abstinence, the traditional approach has been to monitor depressive symptoms during the first four weeks of treatment and withhold antidepressant treatment until the end of the four weeks. However, this approach often is not practical, as many cocaine-addicted patients cannot abstain during the initial four weeks. This problem is compounded by the increasing scarceness of resources for inpatient treatment, which underscores the importance of treating both conditions simultaneously[112].

Results from numerous clinical trials support the use of antidepressants in patients with comorbid depression and cocaine abuse. Research has suggested that the more activating antidepressants, such as bupropion and the tricyclics, are more effective than SSRIs, supporting the observation that substance-abusing patients respond preferentially to medications whose direct or side effect profiles resemble the effects of their drug of choice[111]. Unfortunately, tricyclics have worse side effects, tolerability, and safety profiles than SSRIs and should be used with extreme caution in depressed patients[112]. As previously noted, there is no empirical support for antidepressant treatment to reduce cocaine usage in these patients. Although limited, research on behavioral therapy treatment of comorbid depression and cocaine abuse suggests that CBT can promote greater treatment retention and longer periods of abstinence, and patients receiving motivational interviewing remain engaged in aftercare longer and have fewer depression-related hospitalizations following treatment[63,111].

9. ALTERNATIVE/COMPLEMENTARY TREATMENT OF COCAINE USE DISORDER

ACUPUNCTURE

Auricular (ear) acupuncture has become a widely used treatment for cocaine use disorder and is employed by hundreds of treatment centers and clinics in the United States. The procedure, which was developed at Lincoln Hospital in New York City in the 1970s, entails the placement of needles in five ear locations that represent the lung, kidney, liver, sympathetic, and shen men (a universal enhancer) points. This specific methodology has become a standardized treatment for substance abuse and is not specific to cocaine use disorder or abuse [113].

Gates et al. performed a review of seven randomized, controlled trials enrolling 1,433 subjects of auricular acupuncture with cocaine use disorder[113]. Overall, there was little evidence of significant improvement among acupuncture recipients compared to groups receiving either nonaccupoint acupuncture or no acupuncture on measures of severity of dependence, cocaine use self-report, cocaine use assessed by urine toxicology screen, and cocaine craving. As is the case with many studies of addiction, high rates of subject attrition limited the quality of evidence. With any alternative therapy, it is difficult to separate the therapeutic effect of the intervention from the nonspecific effects of interaction with the practitioner and the heightened expectancy of therapeutic benefit. These limitations result in unreliable evidence.

SELF-HELP AND 12-STEP THERAPY

Twelve-step programs for stimulant and other drug abuse and dependence, such as NA and CA, are modeled after AA, an abstinence-based support and self-improvement program that is based on the 12-step model of recovery [114,115]. AA is widely considered the most successful treatment program for alcoholism and has helped hundreds of thousands of alcoholics achieve sobriety. The 12-step model emphasizes acceptance of addiction as a chronic progressive disease that can be arrested through abstinence but not cured. Additional elements of the AA model include spiritual growth, personal responsibility, and helping other addicted individuals. By inducing a shift in the consciousness of the addict, 12-step programs offer a holistic solution and a resource for emotional support[116,117].

The understanding of drug addiction as a chronic and relapsing disorder has helped professionals gain a better understanding of the vital role played by 12-step programs. All patients attempting to recover from a substance use disorder will encounter a time when they face urges to use without having access to the resources or assistance of addiction professionals. Twelve-step programs are not considered substitutes for treatment. Instead, they provide ongoing and indefinite support in the achievement and maintenance of abstinence and in personal growth and character development[117,118].

Part of the effectiveness of AA, NA, and CA is rooted in their ability to provide a competing and alternative reinforcer to drug use. Involvement in a 12-step program can enhance the quality of social support and the social network of the member, which is a potentially highly reinforcing aspect that would be forfeited if drug use was resumed[72]. Other reinforcing elements of 12-step involvement include recognition for increasingly durable periods of abstinence and frequent awareness of the consequences of drug and alcohol use through attendance at meetings[58]. Research has shown that establishing a pattern of 12-step program attendance early in treatment predicts the level of ongoing involvement. Thus, healthcare providers should emphasize and facilitate early engagement in a 12-step program[119].

Although research on efficacy and patient outcome in NA and CA is limited, many prominent addiction researchers have emphasized the important role that ongoing involvement in a 12-step program plays in recovery from substance abuse[118]. An important finding related to 12-step program efficacy was observed by Weiss et al., who found that 12-step attendance was not associated with decreased drug use, but that 12-step involvement (i.e., speaking or performing service work at a meeting, working with a sponsor outside of the meeting, reading 12-step literature, or working on a step) was[72,119]. In particular, active involvement in a given month predicted a significant reduction in cocaine use the following month. An interesting finding was that patients who involved themselves in 12-step program activities but whose attendance at meetings was inconsistent achieved rates of drug use reduction that were comparable to those who regularly attended and were involved in the 12-step meetings and program.

One study found that the majority of cocaine-dependent outpatients who attended 12-step programs actually attended AA more often than CA. The authors speculated that in addition to AA being more established and available than CA, some patients might have urges for cocaine triggered by the explicit cocaine-related discussion content found in CA[72].

Narcotics Anonymous (NA)

NA was founded in California in 1952 and has grown to include 67,000 weekly meetings in 139 countries. The following demographic information was obtained in a survey returned by almost half of the 22,803 attendees at the 2015 NA World Convention held in Rio de Janeiro, Brazil [115]:

- Gender: 59% male, 41% female

- Ethnicity: 74% white, 11% African American, 6% Hispanic, 4% multiracial, 3% Asian, and 1% Native American/Alaska Native

- Average abstinence/recovery period: 8.3 years

- Substance(s) used by members:

- Alcohol: 79%

- Cannabis: 68%

- Cocaine: 55%

The NA website provides additional information regarding sponsors and meetings.

INTERVENTIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

For patients who are not proficient in English, it is important that information regarding the risks associated with the use of cocaine and available resources be provided in their native language, if possible. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required. Interpreters can be a valuable resource to help bridge the communication and cultural gap between patients and practitioners. Interpreters are more than passive agents who translate and transmit information back and forth from party to party. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers who ultimately enhance the clinical encounter. In any case in which information regarding treatment options and medication/treatment measures are being provided, the use of an interpreter should be considered. Print materials are also available in many languages, and these should be offered whenever necessary.

10. PROGNOSIS

Despite numerous interventions that have demonstrated a degree of efficacy in clinical trials, patients in outpatient treatment for cocaine use disorder exhibit very high rates of dropout and relapse, with an average of approximately 50% of patients enrolled in 90-day outpatient programs terminating prematurely [120]. Among outpatients, abstinence upon treatment entry and in the initial weeks of treatment has been associated with abstinence during post-treatment follow-up, with severity of cocaine abstinence symptoms negatively correlated with outcome[61,120]. Environmental factors that increase the risk of resumption of cocaine use include contact with drug users or a drinking environment[17]. Craving often precedes relapse to cocaine use. One study that measured the effect of extinguishing the reinstating or priming effect of cocaine found it to be an unreliable approach to relapse prevention[121]. Patients addicted to crack cocaine are believed to have a higher relapse rate because of the greater intensity of drug craving, which can be triggered by aspects of the using environment[17,122].

Factors associated with poor prognosis include a dual diagnosis of psychiatric illness, including comorbid major depression[123]. Antidepressants seem to be less effective in managing the depression in these patients and are not generally effective in reducing cocaine use. Such patients have a poorer prognosis than nondepressed cocaine abusers, possibly due to a unique feature that lowers the response rate to antidepressants. The higher rates of character pathology, higher psychiatric distress, and lower psychosocial functioning found in these patients also are believed to affect outcomes[112].

Patients who abuse both cocaine and alcohol constitute a large proportion of those seeking treatment for cocaine abuse and dependence. Addressing dependence to both substances is important, as polysubstance abusers are more likely than monosubstance cocaine abusers to relapse back to cocaine abuse as the result of alcohol consumption[51]. The severity of cocaine use disorder, initial urine drug screen results, and frequency of recent cocaine use also have been shown to significantly impact treatment outcomes in patients with comorbid alcoholism[124].

A study of situational, interpersonal, and intrapersonal factors associated with cocaine relapse was performed in a sample of 132 cocaine-dependent outpatients[125]. At two years following treatment, single variable analysis found that abstinence commitment, self-efficacy, positive mood, family support, employment, attendance at aftercare, and participation in a 12-step program predicted less cocaine use. However, multivariate analysis found that the degree of participation in a 12-step program was the single most robust predictor of reduced cocaine use. The authors of the study concluded that these results further validated the important role that 12-step program involvement plays in abstinence; increasing the emphasis to patients on the importance of 12-step program participation could increase positive outcomes[125].

Another study sought to identify the ways in which different social networks foster substance use change in individuals with cocaine dependence[126]. The authors used data from two studies of 489 adults with cocaine use disorder enrolled in intensive outpatient programs between 2004 and 2009. A greater degree of perceived social support from friends was associated with a greater readiness to change, whereas a greater degree of perceived social support from family was associated with a change in substance use goal. A greater degree of social support from both friends and family were associated with less substance use[126].

Short-term outpatient treatment of stimulant abuse and dependence seldom results in abstinence for any sustained period. The traditional view that program failure is a patient problem is being replaced by the view that program failure is reflective of program shortcoming[120,127].

11. CONCLUSION

Until the 1980s, cocaine was considered a relatively innocuous recreational drug, and research on the pathophysiology and treatment of cocaine addiction was limited. The introduction and widespread use of crack cocaine, with the associated serious morbidity and profound addiction liability associated with its use, introduced a new emphasis on stemming and treating cocaine use and dependency. The development of pharmacologic interventions and psychosocial therapies for cocaine use disorder has been the focus of much research. It is the goal of this course to provide the knowledge necessary to identify, treat, and provide an appropriate referral to patients with cocaine use or dependence disorders.

12. RESOURCES

Cocaine Anonymous World Services

https://www.ca.org

Narcotics Anonymous World Services

https://www.na.org

National Institute on Drug Abuse

https://www.drugabuse.gov

Substance Abuse and Mental Health Services Administration

https://www.samhsa.gov

Works Cited

1. Schuckit MA. The treament of stimulant dependence.Addiction. 1994;89(11):1559-1563.

2. National Institute on Drug Abuse. Cocaine: DrugFacts. Available at https://nida.nih.gov/publications/drugfacts/cocaine. Last accessed March 30, 2023.

3. Orson FM, Kinsey BM, Singh RA, Wu Y, Kosten TR. Vaccines for cocaine abuse. Hum Vaccin. 2009;5(4):194-199.

4. National Institute on Drug Abuse. Methamphetamine: DrugFacts. Available at https://nida.nih.gov/publications/drugfacts/methamphetamine. Last accessed March 30, 2023.

5. National Institute on Drug Abuse. Cocaine Research Report: What is Cocaine? Available at https://nida.nih.gov/publications/research-reports/cocaine/what-cocaine. Last accessed March 30, 2023.

6. Kreek MJ, Levran O, Reed B, Schlussman SD, Zhou Y, Butelman ER. Opiate addiction and cocaine addiction: underlying molecular neurobiology and genetics. J Clin Invest. 2012;122(10):3387-3393.

7. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Text Revision. Arlington, VA: American Psychiatric Publishing; 2022.

8. Gold MS, Paczynski RP. Cocaine and crack: clinical aspects. In: Lowinson JH, Ruiz P, Strain EC (eds). Substance Abuse: A Comprehensive Textbook. 5th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2011: 191-213.

9. Cornish JW, O'Brien CP. Crack cocaine abuse: an epidemic with many public health consequences. Annu Rev Public Health. 1996;17:259-273.

10. Ries RK, Fiellin DA, Miller SC, Saitz R. Principles of Addiction Medicine. 5th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2014.

11. Negrete JC. Cocaine problems in the coca-growing countries of South America. Ciba Found Symp. 1992;166:40-50.

12. Brownlow HA, Pappachan J. Pathophysiology of cocaine abuse. Eur J Anaesthesiol. 2002;19(6):395-414.

13. Prakash A, Das G. Cocaine and the nervous system. Int J Clin Pharmacol Ther Toxicol. 1993;31(12):575-581.

14. Gootenberg P (ed). Cocaine: Global Histories. New York, NY: Routledge; 1999.

15. Das G. Cocaine abuse in North America: a milestone in history. J Clin Pharmacol. 1993;33(4):296-310.

16. Musto DF. Cocaine's history, especially the American experience. Ciba Found Symp. 1992;166:7-14.

17. Withers NW, Pulvirenti L, Koob GF, Gillin JC. Cocaine abuse and dependence. J Clin Psychopharmacol. 1995;15(1):63-78.

18. Center for Behavioral Health Statistics and Quality. Key Substance Use and Mental Health Indicators in the United States: Results from the 2021 National Survey on Drug Use and Health. Available at https://www.samhsa.gov/data/sites/default/files/reports/rpt39443/2021NSDUHFFRRev010323.pdf. Last accessed March 30, 2023.

19. Substance Abuse and Mental Health Services Administration. Results from the 2012 National Survey on Drug Use and Health: Summary of National Findings and Detailed Tables. Available at https://www.samhsa.gov/data/sites/default/files/NSDUH-FFR1-2015/NSDUH-FFR1-2015/NSDUH-FFR1-2015.htm. Last accessed March 30, 2023.

20. Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality. Treatment Episode Data Set (TEDS) 2020: Admissions to and Discharges from Publicly-Funded Substance Use Treatment. Available at https://www.samhsa.gov/data/sites/default/files/reports/rpt38665/2020_TEDS Annual Report-508 compliant_1182023_FINAL.pdf. Last accessed March 30, 2023.

21. Maurer HH, Sauer C, Theobald DS. Toxicokinetics of drugs of abuse: current knowledge of the isoenzymes involved in the human metabolism of tetrahydrocannabinol, cocaine, heroin, morphine, and codeine. Ther Drug Monit. 2006;28(3):447-453.

22. Zakharova E, Wade D, Izenwasser S. Sensitivity to cocaine conditioned reward depends on sex and age. Pharmacol Biochem Behav. 2009;92(1):131-134.

23. National Institute on Drug Abuse. How is Cocaine Abuse Treated. Available at https://nida.nih.gov/publications/research-reports/cocaine/what-treatments-are-effective-cocaine-abusers. Last accessed March 30, 2023.

24. Sofuoglu M, Kosten TR. Novel approaches to the treatment of cocaine addiction. CNS Drugs. 2005;19(1):13-25.

25. Farnsworth SJ, Volz TJ, Hanson GR, Fleckenstein AE. Cocaine alters vesicular dopamine sequestration and potassium-stimulated dopamine release: the role of D2 receptor activation. J Pharmacol Exp Ther. 2009;328(3):807-812.

26. Ritz MC, Lamb RJ, Goldberg SR, Kuhar MJ. Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science. 1987;237(4819):1219-1223.

27. Thomsen M, Hall FS, Uhl GR, Caine SB. Dramatically decreased cocaine self-administration in dopamine but not serotonin transporter knock-out mice. J Neuroscience. 2009;29(4):1087-1092.

28. Fowler JS, Volkow ND, Wang GJ, Gatley SJ, Logan J. Cocaine: PET studies of cocaine pharmacokinetics, dopamine transporter availability and dopamine transporter occupancy. Nucl Med Biol. 2001;28(5):561-572.

29. Burnett LB, Roldan CJ, Adler J. Cocaine Toxicity. Available at http://emedicine.medscape.com/article/813959-overview. Last accessed March 30, 2023.

30. Knuepfer MM. Cardiovascular disorders associated with cocaine use: myths and truths. Pharmacol Ther. 2003;97(3):181-222.

31. Schwartz BG, Rezkalla S, Kloner RA. Cardiovascular effects of cocaine. Circulation. 2010;122(24):2558-2569.

32. Zickler P. Methamphetamine, Cocaine Abusers Have Different Patterns of Drug Use, Suffer Different Cognitive Impairments. Available at https://www.ehd.org/health_meth_13.php. Last accessed March 30, 2023.

33. Zuffa G. Cocaine: Towards a Self-Regulation Model. Available at https://www.tni.org/en/briefing/cocaine-towards-self-regulation-model. Last accessed March 30, 2023.

34. National Institutes of Health. Tiny RNA Molecule in the Brain Curbs Cocaine Use. Available at https://www.nih.gov/news-events/nih-research-matters/tiny-rna-molecule-brain-curbs-cocaine-use. Last accessed March 30, 2023.

35. London ED, Bonson KR, Ernst M, Grant S. Brain imaging studies of cocaine abuse: implications for medication development.Crit Rev Neurobiol. 1999;13(3):227-242.

36. Nnadi CU, Mimiko OA, McCurtis HL, Cadet JL. Neuropsychiatric effects of cocaine use disorders. J Natl Med Assoc. 2005;97(11): 1504-1515.

37. Woicik PA, Moeller SJ, Alia-Klein N, et al. The neuropsychology of cocaine addiction: recent cocaine use masks impairment. Neuropsychopharmacology. 2009;34(5):1112-1122.

38. Orsini CA, Colon-Perez LM, Heshmati SC, Setlow B, Febo M. Functional connectivity of chronic cocaine use reveals progressive neuroadaptations in neocortical, striatal, and limbic networks. eNeuro. 2018;5(4):0081-0118.

39. van den Brink W, van Ree JM. Pharmacological treatments for heroin and cocaine addiction. Eur Neuropsychopharmacol. 2003;13(6):476-487.

40. Baum MK, Rafie C, Lai S, Sales S, Page B, Campa A. Crack-cocaine use accelerates HIV disease progression in a cohort of HIV-positive drug users. J Acquir Immune Defic Syndr. 2009;50(1):93-99.

41. Goldenberg SM, Gallardo Cruz M, Strathdee SA, Nguyen L, Semple SJ, Patterson TL. Correlates of unprotected sex with female sex workers among male clients in Tijuana, Mexico. Sex Transm Dis. 2010;37(5):319-324.

42. Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality. Treatment Episode Data Set (TEDS): 2003–2013 National Admissions to Substance Abuse Treatment Services. Available at https://www.samhsa.gov/data/sites/default/files/2013_Treatment_Episode_Data_Set_National/2003_2013_Treatment_Episode_Data_Set_National_Body.html. Last accessed March 30, 2023.

43. Science Daily. Cocaine Exposure During Pregnancy Leads To Impulsivity In Male, Not Female, Monkeys. Available at https://www.sciencedaily.com/releases/2009/10/091022114309.htm. Last accessed March 30, 2023.

44. Buckingham-Howes S, Berger SS, Scaletti LA, Black MM. Systematic review of prenatal cocaine exposure and adolescent development. Pediatrics. 2013;131(6):e1917-e1936.

45. Ganapathy V. Drugs of abuse and human placenta. Life Sci. 2011;88(21-22):926-930.

46. Richardson GA, De Genna NM, Goldschmidt L, Larkby C, Donovan JE. Prenatal cocaine exposure: direct and indirect associations with 21-year-old offspring substance use and behavior problems. Drug Alcohol Depend. 2019;195:121-131.

47. Richardson GA, Goldschmidt L, Larkby C, Day NL. Effects of prenatal cocaine exposure on adolescent development. Neurotoxicol Teratol. 2015;49:41-48.

48. Mendoza R, Miller BL. Neuropsychiatric disorders associated with cocaine use. Hosp Community Psychiatry. 1992;43(7):677-678, 680.

49. Pavarin R, Lugoboni F, Mathewson S, Ferrari AM, Guizzardi G, Quaglio G. Cocaine-related medical and trauma problems: a consecutive series of 743 patients from a multicentre study in Italy. Eur J Emerg Med. 2011;18(4):208-214.

50. Mathias R. [Archive]. Rate and Duration of Drug Activity Play Major Roles in Drug Abuse, Addiction, and Treatment. Available at https://archives.drugabuse.gov/news-events/nida-notes/1997/04/rate-duration-drug-activity-play-major-roles-in-drug-abuse-addiction-treatment. Last accessed March 30, 2023.

51. Ahmadi J, Kampman KM, Oslin DM, Pettinati HM, Dackis C, Sparkman T. Predictors of treatment outcome in outpatient cocaine and alcohol dependence treatment. Am J Addict. 2009;18(1):81-86.

52. Gossop M, Manning V, Ridge G. Concurrent use of alcohol and cocaine: differences in patterns of use and problems among users of crack cocaine and cocaine powder. Alcohol Alcohol. 2006;41(2):121-125.

53. Stitzer ML, Walsh SL. Psychostimulant abuse: the case for combined behavioral and pharmacological treatments. Pharmacol Biochem Behav. 1997;57(3):457-470.

54. National Institute on Drug Abuse. A "New Vista" for Treating Cocaine Addiction. Available at https://nida.nih.gov/news-events/science-highlight/new-vista-treating-cocaine-addiction. Last accessed March 30, 2023.

55. Penberthy JK, Ait-Daoud N, Vaughan M, Fanning T. Review of treatment for cocaine dependence. Curr Drug Abuse Rev. 2010;3(1):49-62.

56. National Institute for Health and Care Excellence. Drug Misuse in Over 16s: Psychosocial Interventions. Available at https://www.nice.org.uk/guidance/cg51. Last accessed March 30, 2023.

57. Woody GE. Research findings on psychotherapy of addictive disorders. Am J Addict. 2003;12(Suppl 2):S19-S26.

58. Stoops WW, Lile JA, Rush CR. Monetary alternative reinforcers more effectively decrease intranasal cocaine choice than food alternative reinforcers. Pharmacol Biochem Behav. 2010;95(2):187-191.

59. Barry D, Sullivan B, Petry NM. Comparable efficacy of contingency management for cocaine dependence among African American, Hispanic, and White methadone maintenance clients. Psychol Addict Behav. 2009;23(1):168-174.

60. Peirce JM, Petry NM, Stitzer ML, et al. Effects of lower-cost incentives on stimulant abstinence in methadone maintenance treatment: a National Drug Abuse Treatment Clinical Trials Network study. Arch Gen Psychiatry. 2006;63(2):201-208.

61. Higgins ST, Heil SH, Dantona R, Donham R, Matthews M, Badger GJ. Effects of varying the monetary value of voucher-based incentives on abstinence achieved during and following treatment among cocaine-dependent outpatients. Addiction. 2007;102(2):271-281.

62. Stitzer ML, Petry NM, Peirce J. Motivational incentives research in the National Drug Abuse Treatment Clinical Trials Network.J Subst Abuse Treat. 2010;38(Suppl 1):S61-S69.

63. Herin DV, Rush CR, Grabowski J. Agonist-like pharmacotherapy for stimulant dependence: preclinical, human laboratory, and clinical studies. Ann NY Acad Sci. 2010;1187:76-100.

64. García-Fernández G, Secades-Villa R, García-Rodríguez O, et al. Long-term benefits of adding incentives to the community reinforcement approach for cocaine dependence. Eur Addict Res. 2011;17(3):139-145.

65. Meyers RJ, Roozen HG, Smith JE. The community reinforcement approach: an update of the evidence. Alcohol Res Health. 2011;33(4):380-388.

66. Prochaska JO, DiClemente CC, Norcross JC. In search of how people change: applications to addictive behaviors. Am Psychol. 1992;47(9):1102-1114.

67. Crits-Christoph P, Gallop R, Temes CM, et al. The alliance in motivational enhancement therapy and counseling as usual for substance use problems. J Consult Clin Psychol. 2009;77(6):1125-1135.

68. Rohsenow DJ, Monti PM, Martin RA, et al. Motivational enhancement and coping skills training for cocaine abusers: effects on substance use outcomes. Addiction. 2004;99(7):862-874.

69. Monti PM, O'Leary TA. Coping and social skills training for alcohol and cocaine dependence. Psychiatr Clin North Am. 1999;22(2): 447-470.

70. Michalec E, Zwick WR, Monti PM, et al. A Cocaine High-Risk Situations Questionnaire: development and psychometric properties.J Subst Abuse. 1992;4(4):377-391.

71. Crits-Christoph P, Siqueland L, Blaine J, et al. Psychosocial treatments for cocaine dependence: National Institute on Drug Abuse Collaborative Cocaine Treatment Study. Arch Gen Psychiatry. 1999;56(6):493-502.

72. Weiss RD, Griffin ML, Gallop RJ, et al. The effect of 12-step self-help group attendance and participation on drug use outcomes among cocaine-dependent patients. Drug Alcohol Dependence. 2005;77(2):177-184.

73. Grabowski J, Shearer J, Merrill J, Negus SS. Agonist-like, replacement pharmacotherapy for stimulant abuse and dependence. Addict Behav. 2004;29(7):1439-1464.

74. Pani PP, Trogu E, Vecchi S, Amato L. Antidepressants for cocaine dependence and problematic cocaine use. Cochrane Database Syst Rev. 2011;(12):CD002950.

75. Castells X, Cunill R, Pérez-Mañá C, Vidal X, Capellà D. Psychostimulant drugs for cocaine dependence. Cochrane Database Syst Rev. 2016;9:CD007380.

76. Anderson AL, Reid MS, Li SH, et al. Modafinil for the treatment of cocaine dependence. Drug Alcohol Depend. 2009;104(1-2):133-139.

77. Schmitt KC, Reith ME. The atypical stimulant and nootropic modafinil interacts with the dopamine transporter in a different manner than classical cocaine-like inhibitors. PLoS One. 2011;6(10):e25790.

78. Morgan PT, Pace-Schott E, Pittman B, Stickgold R, Malison RT. Normalizing effects of modafinil on sleep in chronic cocaine users.Am J Psychiatry. 2010;167(3):331-340.

79. Sofuoglu M, Kosten TR. Emerging pharmacological strategies in the fight against cocaine addiction. Expert Opin Emerg Drugs. 2006;11(1):91-98.

80. Dackis CA, Kampman KM, Lynch KG, Pettinati HM, O'Brien CP. A double-blind, placebo-controlled trial of modafinil for cocaine dependence. Neuropsychopharmacology. 2005;30(1):205-211.

81. Morgan PT, Pace-Schott E, Pittman B, Stickgold R, Malison RT. Normalizing effects of modafinil on sleep in chronic cocaine users.Am J Psychiatry. 2010;167(3):331-340.

82. Martinez-Raga J, Knecht C, Cepeda S. Modafinil: a useful medication for cocaine addiction? Review of the evidence from neuropharmacological, experimental and clinical studies. Curr Drug Abuse Rev. 2008;1(2):213-221.

83. Quintero GC. Role of nucleus accumbens glutamatergic plasticity in drug addiction. Neuropsychiatr Dis Treat. 2013;9:1499-1512.

84. Sangroula D, Motiwala F, Wagle B, Shah VC, Hagi K, Lippmann S. Modafinil treatment of cocaine dependence: a systematic review and meta-analysis. Subst Use Misuse. 2017;52(10:1292-1306.

85. Minozzi S, Amato L, Pani PP, et al. Dopamine agonists for cocaine dependence. Cochrane Database Syst Rev. 2015;(5):CD003352.

86. Goldstein RZ, Woicik PA, Maloney T, et al. Oral methylphenidate normalizes cingulate activity in cocaine addiction during a salient cognitive task. Proc Natl Acad Sci U S A. 2010;107(38):16667-16672.

87. Minozzi S, Amato L, Pani PP, et al. Dopamine agonists for the treatment of cocaine dependence. Cochrane Database Syst Rev. 2015;(5):CD003352.

88. Indave BI, Minozzi S, Pani PP, Amato L. Antipsychotic medications for cocaine dependence. Cochrane Database Syst Rev. 2016;3:CD006306.

89. Pierce RC, O'Brien CP, Kenny PJ, Vanderschuren LJ. Rational development of addiction pharmacotherapies: successes, failures, and prospects. Cold Spring Harb Perspect Med. 2012;2(6):a012880.

90. Pani PP, Trogu E, Vacca R, Amato L, Vecchi S. Davoli M. Disulfiram for the treatment of cocaine dependence. Cochrane Database Syst Rev. 2010;1:CD007024.

91. Carroll KM, Nich C, Petry NM, Eagan DA, Shi JM, Ball SA. A randomized factorial trial of disulfiram and contingency management to enhance cognitive behavioral therapy for cocaine dependence. Drug Alcohol Depend. 2016;160:135-142.

92. Johnson BA. Recent advances in the development of treatments for alcohol and cocaine dependence: focus on topiramate and other modulators of GABA or glutamate function. CNS Drugs. 2005;19(10):873-896.

93. Prince B, Bowling KC. Topiramate in the treatment of cocaine use disorder. Am J Health Syst Pharm. 2018;75(1):e13-e22.

94. Shorter D, Kosten TR. Novel pharmacotherapeutic treatments for cocaine addiction. BMC Medicine. 2011;9:119.

95. Alvarez Y, Farré M, Fonseca F, Torrens M. Anticonvulsant drugs in cocaine dependence: a systematic review and meta-analysis.J Subst Abuse Treat. 2010;38(1):66-73.

96. Minozi S, Cinquini M, Amato L, et al. Anticonvulsants for cocaine dependence. Cochrane Database Syst Rev. 2015:4:CD006754.

97. Damodaran S. Cocaine and beta-blockers: the paradigm. Eur J Intern Med. 2010;21(2):84-86.

98. Young R, Glennon RA. S(-)Propranolol as a discriminative stimulus and its comparison to the stimulus effects of cocaine in rats. Psychopharmacology (Berl). 2009;203(2):369-382.

99. Kampman KM, Dackis C, Lynch KG, et al. A double-blind, placebo-controlled trial of amantadine, propranolol, and their combination for the treatment of cocaine dependence in patients with severe cocaine withdrawal symptoms. Drug Alcohol Depend. 2006;85(2):129-137.

100. Saladin ME, Gray KM, McRae-Clark AL, et al. A double blind, placebo-controlled study of the effects of post-retrieval propranolol on reconsolidation of memory for craving and cue reactivity in cocaine dependent humans. Psychopharmacology (Berl). 2013;226(4):721-737.

101. McCord J, Jneid H, Hollander JE, et al. Management of cocaine-associated chest pain and myocardial infarction: a scientific statement from the American Heart Association Acute Cardiac Care Committee of the Council on Clinical Cardiology. Circulation. 2008;117:1897-1907.

102. Kantak KM. Vaccines against drugs of abuse: a viable treatment option? Drugs. 2003;63(4):341-352.

103. Carfora A, Cassandro P, Feola A, La Sala F, Petrella R, Borriello R. Ethical implications in vaccine pharmacotherapy for treatment and prevention of drug of abuse dependence. J Bioeth Inq. 2018;15(1):45-55.

104. Weiss F, Martin-Fardon R, Ciccocioppo R, Kerr TM, Smith DL, Ben-Shahar O. Enduring resistance to extinction of cocaine-seeking behavior induced by drug-related cues. Neuropsychopharmacology. 2001;25(3):361-372.

105. Weiss F, Ciccocioppo R, Parsons LH, et al. Compulsive drug-seeking behavior and relapse: neuroadaptation, stress, and conditioning factors. Ann N Y Acad Sci. 2001;937:1-26.

106. U.S. Food and Drug Administration. Pergolide (Marketed as Permax) Information. Available at https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/pergolide-marketed-permax-information. Last accessed March 30, 2023.

107. Higgins ST, Alessi SM, Dantona RL. Voucher-based incentives: a substance abuse treatment innovation. Addict Behav. 2002;27(6):887-910.

108. Silverman K, Higgins ST, Brooner RK, et al. Sustained cocaine abstinence in methadone maintenance patients through voucher-based reinforcement therapy. Arch Gen Psychiatry. 1996;53(5):409-415.

109. Schubiner H, Saules KK, Arfken CL, et al. Double-blind placebo-controlled trial of methylphenidate in the treatment of adult ADHD patients with comorbid cocaine dependence. Exp Clin Psychopharmacol. 2002;10(3):286-294.

110. U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA Warns of Rare Risk of Long-Lasting Erections in Males Taking Methylphenidate ADHD Medications and Has Approved Label Changes. Available at https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-rare-risk-long-lasting-erections-males-taking. Last accessed March 30, 2023.

111. Rounsaville BJ. Treatment of cocaine dependence and depression. Biol Psychiatry. 2004;56(10):803-809.

112. Torrens M, Fonseca F, Mateu G, Farre M. Efficacy of antidepressants in substance use disorders with and without comorbid depression: a systematic review and meta-analysis. Drug Alcohol Dependence. 2005;78(1):1-22.

113. Gates S, Smith LA, Foxcroft DR. Auricular acupuncture for cocaine dependence. Cochrane Database Syst Rev. 2006;1:CD005192.

114. Cocaine Anonymous. About CA. Available at https://ca.org/about-ca/. Last accessed March 30, 2023.

115. Narcotics Anonymous. 2015 Membership Survey. Available at https://www.na.org/admin/include/spaw2/uploads/pdf/pr/MembershipSurvey_2016.pdf. Last accessed March 30, 2023.

116. Humphreys K, Wing S, McCarty D, et al. Self-help organizations for alcohol and drug problems: toward evidence-based practice and policy. J Subst Abuse Treat. 2004;26(3):151-158.

117. Kelly JF, Stout RL, Magill M, Tonigan JS, Pagano ME. Spirituality in recovery: a lagged meditational analysis of Alcoholics Anonymous' principal theoretical mechanism of behavior change. Alcohol Clin Exp Res. 2011;35(3):454-463.

118. Chappel JN, DuPont RL. Twelve-step and mutual-help programs for addictive disorders. Psychiatr Clin North Am. 1999;22(2):425-446.

119. Weiss RD, Griffin ML, Gallop R, et al. Self-help group attendance and participation among cocaine dependent patients. Drug Alcohol Dependence. 2000;60(2):169-177.

120. Ahmadi J, Kampman K, Dackis C. Outcome predictors in cocaine dependence treatment trials. Am J Addict. 2006;15(6):434-439.

121. Girardeau P, Navailles S, Durand A, Vouillac-Mendoza C, Guillem K, Ahmed SH. Relapse to cocaine use persists following extinction of drug-primed craving. Neuropharmacology. 2019;155:185-193.

122. Dackis CA, O'Brien CP. Cocaine dependence: a disease of the brain's reward centers. J Subst Abuse Treat. 2001;21(3):111-117.

123. Davis L, Uezato A, Newell JM, Frazier E. Major depression and comorbid substance use disorders. Curr Opin Psychiatry. 2008;21(1): 14-18.

124. Ahmadi J, Kampman KM, Oslin DM, Pettinati HM, Dackis C, Sparkman T. Predictors of treatment outcome in outpatient cocaine and alcohol dependence treatment. Am J Addict. 2009;18(1):81-86.

125. McKay JR, Lynch KG, Shepard DS, Pettinati HM. The effectiveness of telephone-based continuing care for alcohol and cocaine dependence: 24-month outcomes. Arch Gen Psychiatry. 2005;62(2):199-207.

126. Lookatch SJ, Wimberly AS, McKay JR. Effects of social support and 12-step involvement on recovery among people in continuing care for cocaine dependence. Subst Use Misuse. 2019;54(13):2144-2155.

127. Gossop M, Stewart D, Marsden J. Attendance at Narcotics Anonymous and Alcoholics Anonymous meetings, frequency of attendance and substance use outcomes after residential treatment for drug dependence: a 5-year follow-up study. Addiction. 2008;103(1):119-125.

66564 • Alcohol and Alcohol Use Disorder

Mark S. Gold, MD, DFASAM, DLFAPA

www.netce.com

Copyright © 2024 NetCE, All rights reserved.

No substance, legal or illegal, has a more paradoxical mythology than alcohol. It is undeniably one of the most widely and safely used intoxicants in the world; however, it is also potent and dangerous, both from a psychologic and physiologic viewpoint. Alcohol is currently responsible for more deaths and personal destruction than any other known substance of abuse, with the exception of tobacco. All of this is known with scientific certainty. Alcohol is legal, easily obtained, and supported by a multi-billion-dollar worldwide industry. Alcohol consumption reduces social inhibitions and produces pleasure and a sense of well-being. It also can have some rather impressive positive medical effects, such as a reduced risk of cardiovascular disease. This course will include core competencies related to alcohol use and abuse as well as knowledge, assessment, and treatment-based competencies.

Table of Contents

66564 • Alcohol and Alcohol Use Disorder

Course Overview

Audience

Accreditations & Approvals

Designations of Credit

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planner

Division Planner Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

SUBSTANCE ABUSE AND ADDICTION

2. HISTORY

3. CURRENT ESTIMATES OF ALCOHOL USE

COSTS OF ALCOHOL USE DISORDERS

DEFINITIONS

4. BENEFITS

WHAT TO ADVISE PATIENTS ABOUT DRINKING ALCOHOL

5. RISK AND PROTECTIVE FACTORS

ALCOHOL AND GENETICS

PSYCHOLOGICAL AND SOCIOENVIRONMENTAL RISK FACTORS MODELS

KNOWN RISK FACTORS FOR ALCOHOL USE DISORDER

ABUSE AND ADVERSE CONDITIONS IN THE HOME

PROTECTIVE FACTORS

6. ALCOHOL USE DISORDER

WITHDRAWAL

INCREASED TOLERANCE

IMPAIRED CONTROL OF DRINKING

PREOCCUPATION WITH ALCOHOL

USE OF ALCOHOL DESPITE ADVERSE CONSEQUENCES

DENIAL AS A DEFENSE MECHANISM

RELAPSE

PHYSICAL CLUES THAT MAY SUGGEST ALCOHOL USE DISORDER

7. COMPLICATIONS

LIVER DISEASE

ALCOHOL/ACETAMINOPHEN INTERACTION

CARDIOVASCULAR DISORDERS

CANCER

GASTROINTESTINAL DISORDERS

CHRONIC PANCREATITIS

BODY WEIGHT

MALNUTRITION

INFECTIOUS DISEASES

SLEEP DISORDERS

NERVOUS SYSTEM DYSFUNCTION

COMPLICATIONS SPECIFIC TO WOMEN

EFFECTS ON FAMILIES

VIOLENCE

TRAFFIC ACCIDENTS

8. OTHER PSYCHIATRIC DISORDERS ASSOCIATED WITH ALCOHOL USE DISORDERS

DEPRESSIVE DISORDERS

BIPOLAR DISORDER

ANXIETY

PAIN

ABUSE/DEPENDENCE ON OTHER DRUGS

EATING DISORDERS

PATHOLOGIC GAMBLING

SEXUAL DYSFUNCTION

9. DETECTING ALCOHOL USE DISORDERS

RECOMMENDED STANDARDIZED QUESTIONS OR TESTS

ADDITIONAL STANDARDIZED QUESTIONS OR TESTS

SCREENING FOR ALCOHOL ABUSE IN NON-ENGLISH-PROFICIENT PATIENTS

LABORATORY TESTS

10. BRIEF INTERVENTION

COMMON ELEMENTS OF BRIEF INTERVENTION

EFFECTIVENESS OF BRIEF INTERVENTION

READINESS TO CHANGE

11. TREATMENT

PHASES OF TREATMENT

ALCOHOLICS ANONYMOUS AND OTHER 12-STEP PROGRAMS

COUNSELING

MEDICATIONS USED TO TREAT ALCOHOL USE DISORDER

TREATMENT OF ALCOHOL WITHDRAWAL

MANDATORY TREATMENT

12. CONCLUSION

13. RESOURCES

Works Cited

Evidence-Based Practice Recommendations Citations

66564 • Alcohol and Alcohol Use Disorder

Education Category. Psychiatric / Mental Health

Release Date. 06/01/2024

Expiration Date. 05/31/2027

Course Overview

No substance, legal or illegal, has a more paradoxical mythology than alcohol. It is undeniably one of the most widely and safely used intoxicants in the world; however, it is also potent and dangerous, both from a psychologic and physiologic viewpoint. Alcohol is currently responsible for more deaths and personal destruction than any other known substance of abuse, with the exception of tobacco. All of this is known with scientific certainty. Alcohol is legal, easily obtained, and supported by a multi-billion-dollar worldwide industry. Alcohol consumption reduces social inhibitions and produces pleasure and a sense of well-being. It also can have some rather impressive positive medical effects, such as a reduced risk of cardiovascular disease. This course will include core competencies related to alcohol use and abuse as well as knowledge, assessment, and treatment-based competencies.

Audience

This intermediate course is designed for psychologists involved in the treatment or care of patients who consume alcohol.

Accreditations & Approvals

Continuing Education (CE) credits for psychologists are provided through the co-sponsorship of the American Psychological Association (APA) Office of Continuing Education in Psychology (CEP). The APA CEP Office maintains responsibility for the content of the programs. NetCE is recognized by the New York State Education Department's State Board for Psychology as an approved provider of continuing education for licensed psychologists #PSY-0240. This course is considered self-study by the New York State Board for Psychology.

Designations of Credit

NetCE designates this continuing education activity for 10 credit(s).

Course Objective

The purpose of this course is to address the ongoing alcohol competency educational needs of practicing psychologists. The material will include core competencies as well as knowledge, assessment, and treatment-based competencies.

Learning Objectives

Upon completion of this course, you should be able to:

1. Review facts about the history, costs, and prevalence of alcohol use and abuse.

2. Define moderate drinking and take a history of alcohol use as defined by the standard drink equivalency.

3. Identify benefits reported in the literature for moderate alcohol consumption.

4. Distinguish between genetic and environmental risk and protective factors for developing alcohol problems.

5. Describe clinical characteristics of alcohol use disorder, intoxication, and withdrawal.

6. List complications associated with alcohol use disorders.

7. Recognize mental health diagnoses associated with alcohol use disorders.

8. Discuss screening instruments for detecting alcohol use disorders, including considerations for non-English-proficient patients.

9. Explain brief intervention efficacy and techniques.

10. Describe and evaluate treatment modalities.

Faculty

Mark S. Gold, MD, DFASAM, DLFAPA, is a teacher of the year, translational researcher, author, mentor, and inventor best known for his work on the brain systems underlying the effects of opiate drugs, cocaine, and food. Dr. Gold was a Professor, Eminent Scholar, Distinguished Professor, Distinguished Alumni Professor, Chairman, and Emeritus Eminent Scholar during his 25 years at the University of Florida. He was a Founding Director of the McKnight Brain Institute and a pioneering neuroscience-addiction researcher funded by the NIH-NIDA-Pharma, whose work helped to de-stigmatize addictions and mainstream addiction education and treatment. He also developed and taught courses and training programs at the University of Florida for undergraduates and medical students.

He is an author and inventor who has published more than 1,000 peer-reviewed scientific articles, 20 text books, popular-general audience books, and physician practice guidelines. Dr. Gold was co-inventor of the use of clonidine in opioid withdrawal and the dopamine hypothesis for cocaine addiction and anhedonia. Both revolutionized how neuroscientists and physicians thought about drugs of abuse, addiction, and the brain. He pioneered the use of clonidine and lofexidine, which became the first non-opioid medication-assisted therapies. His first academic appointment was at Yale University School of Medicine in 1978. Working with Dr. Herb Kleber, he advanced his noradrenergic hyperactivity theory of opioid withdrawal and the use of clonidine and lofexidine to ameliorate these signs and symptoms. During this time, Dr. Gold and Dr. Kleber also worked on rapid detoxification with naloxone and induction on to naltrexone.

Dr. Gold has been awarded many state and national awards for research and service over his long career. He has been awarded major national awards for his neuroscience research including the annual Foundations Fund Prize for the most important research in Psychiatry, the DEA 30 Years of Service Pin (2014), the American Foundation for Addiction Research’s Lifetime Achievement Award (2014), the McGovern Award for Lifetime Achievement (2015) for the most important contributions to the understanding and treatment of addiction, the National Leadership Award (NAATP) from addiction treatment providers for helping understand that addiction is a disease of the brain, the DARE Lifetime Achievement Award for volunteer and prevention efforts, the Silver Anvil from the PR Society of America for anti-drug prevention ads, the PRIDE and DARE awards for his career in research and prevention (2015), and the PATH Foundation’s Lifetime Achievement Award (2016) as one of the “fathers” of addiction medicine and MAT presented to him by President Obama’s White House Drug Czar Michael Botticelli. He was awarded Distinguished Alumni Awards at Yale University, the University of Florida, and Washington University and the Wall of Fame at the University of Florida College of Medicine. Gold was appointed by the University President to two terms as the University’s overall Distinguished Professor, allowing him to mentor students and faculty from every college and institute. The University of Florida College of Medicine’s White Coat Ceremony for new medical students is named in his honor.

Since his retirement as a full-time academic in 2014, Dr. Gold has continued his teaching, mentoring, research, and writing as an Adjunct Professor in the Department of Psychiatry at Washington University and an active member of the Clinical Council at the Washington University School of Medicine’s Public Health Institute. He regularly lectures at medical schools and grand rounds around the country and at international and national scientific meetings on his career and on bench-to-bedside science in eating disorders, psychiatry, obesity, and addictions. He continues on the Faculty at the University of Florida College of Medicine, Department of Psychiatry as an Emeritus Distinguished Professor. He has traveled extensively to help many states develop prevention, education, and treatment approaches to the opioid crisis.

Faculty Disclosure

Contributing faculty, Mark S. Gold, MD, DFASAM, DLFAPA, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planner

Margaret Donohue, PhD

Division Planner Disclosure

The division planner has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

No substance, legal or illegal, has a more paradoxical mythology than alcohol. It is undeniably one of the most widely and safely used intoxicants in the world; however, it is also potent and dangerous, both from a psychological and a physiologic viewpoint. Alcohol is currently responsible for more deaths and personal destruction than any other known substance of abuse, with the exception of tobacco. All of this is known with scientific certainty. Alcohol is legal, easily obtained, and supported by a multi-billion-dollar worldwide industry. Alcohol consumption at reasonable doses reduces social inhibitions and produces pleasure and a sense of well-being. It also can have some rather impressive positive medical effects, such as a reduced risk of cardiovascular disease[1,2].

SUBSTANCE ABUSE AND ADDICTION

Alcohol is defined as a substance of abuse by self-administration in lab animals and man. All drugs of abuse affect the brain's reward pathways. The effects of alcohol appear to be related to complex multiple interactions with the dopamine, gamma-aminobutyric acid (GABA), serotonin, opioid, and N-methyl-D aspartate (NMDA) neurotransmitter systems [3,4]. Studies suggest that the reinforcing effect of alcohol is partially mediated through nicotinic receptors in the ventral tegmental area, which when combined with nicotine may be a factor in the high incidence of smoking among those with alcohol use disorder [5,6,7]. Alcohol, food, and other drugs of abuse have similar effects on dopamine receptors. The development of addiction, including to alcohol, is affected by genetic predisposition and influenced by alterations in the rewarding chemicals released per dose.

Substances of abuse are often put into categories based on their effects. Alcohol has effects similar to other depressants. Characteristics include:

- Decreased cognitive function while intoxicated

- Decreased inhibition and increased impulsivity

- Risk of overdose

- Development of depressive symptoms in heavy users

- Withdrawal symptoms similar to other depressants

- Symptoms of anxiety during withdrawal

- Substance-induced psychoses in some heavy users

The established criteria for the diagnosis of alcohol abuse and dependence will be discussed in detail later in this course.

2. HISTORY

From the earliest days of colonial settlement to the present, Americans have been drinking alcohol. The early American experience with alcohol provides a glimpse of patterns of use, as well as controversies involving alcohol. The argument could be made that alcohol, in one form or another, was used more in early revolutionary America than it is today. Drinking had almost religious support, with alcohol portrayed as a gift from God; a gift that could be abused by excessive drinking or drunkenness.

The story of alcohol in America begins with the Mayflower. The Mayflower dropped anchor in Plymouth, Massachusetts, in February 1621. The passengers were out of beer, and the crew was in no mood to share. Running out of beer or spirits was no laughing matter. So seriously did the crew take this lack of spirits that they quickly dropped the passengers off the Mayflower into very harsh conditions at Plymouth. This preference for beer was at least partly because it was a reliable source of nonpathogenic hydration, as bacteria and parasites are killed during the boiling stage of brewing.

In 1741, Benjamin Franklin, when listing the thirteen cardinal virtues, started with "Temperance: Drink not to elevation." Still, he noted that beer, applejack, and other alcohol-containing beverages of the day were safer to drink than the water in Boston or Philadelphia. Like Londoners, the colonists drank beer with breakfast after a sherry eye-opener, and drank beer at lunch and brandy if it was cold. They would have wine with dinner and punch or other liqueurs thereafter. Dr. Benjamin Rush, a signer of the Declaration of Independence who is also known as the father of American psychiatry, became alarmed by what he viewed as rampant health problems caused by alcohol and called for temperance. He described addiction and identified alcohol as an addictive substance. He argued that addiction was like a disease, and that the alcoholic victim was completely unable to control his consumption. Dr. Rush, a citizen of the Enlightenment Age, accurately described and anticipated the fifth revised edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5-TR) description of alcohol use disorder. However, he also suggested that alcoholism could be treated by whippings, bleeding, shame, emetics, oaths, and plunging the patient in cold water.

American attitudes about alcohol have flip-flopped from a free marketplace in the 18th and 19th centuries, to Prohibition in the 1920s, to the repeal of Prohibition in the 1930s, to lowering of the legal drinking age in most states during the late 1960s and early 1970s, and a return to the 21-years-of-age limit with the National Minimum Drinking Age Act of 1984. Alcohol consumption tends to be high during war years and was lowest during the Great Depression [8]. It was very high in the early 1980s, perhaps due to the lowered drinking age and poor economy. Like other consumer goods, alcohol consumption is generally inversely affected by changes in taxes and prices [9]. But interesting trends have been noted in the United States. While inflation-adjusted prices of alcohol declined between the late 1970s through the late 1990s, per capita alcohol consumption has also been declining since the mid-1980s [8,10]. One study revealed that changing demographics, such as a shift to an older population that consumes less alcohol, could have more of an impact on consumption levels than falling prices. Other sources cite increased health awareness, national drunk-driving campaigns, and a less tolerant public attitude toward heavy drinking and youth intoxication [8].

This roller coaster of historical attitudes toward alcohol use results from conflicting sociologic and psychological factors. For centuries, alcohol has been part of our social fabric and part of holidays and traditions. Simultaneously, our society has either shunned or punished those who succumbed to alcohol abuse, treating dependence as a legal issue or a moral failing rather than as a mental health problem. On one hand, alcohol is readily and cheaply accessible, safe for most people, moderately beneficial to health, and an important sector of our economy. However, we also understand that some individuals are at a high risk of losing control over alcohol.

3. CURRENT ESTIMATES OF ALCOHOL USE

As many as 90% of adults in the United States have had some experience with alcohol [11]. People drink alcohol for a variety of reasons:

- The pleasurable feeling that often accompanies drinking, including reduced tension and/or anxiety

- Enjoyment of the taste

- Social inclusion

- Self-medication

- Peer pressure

- Behavioral and physical addiction

Nearly one-half (47.4%) of all Americans older than 12 years of age reported being current consumers of alcohol in the 2022 National Survey on Drug Use and Health [12]. This translates to an estimated 137.5 million people, slightly less than the 2019 estimate of 139.7 million people [12]. An estimated 21.7% of Americans participated in binge drinking at least once in the 30 days prior to the survey. This represents approximately 61.1 million people. Heavy drinking was reported by 5.7% of the population 18 years of age and older (16.0 million people) [12]. The 2022 estimates for binge and heavy drinking are lower than the 2019 estimates [12].

There is some evidence that drinking and alcohol-related injuries increased during the COVID-19 pandemic [13]. National mortality data revealed a 25% increase in alcohol-related deaths from 2019 to 2020, outpacing the all-cause increase in mortality over the same period (16.6%).

Binge drinking among various races is 10.9% for Asian Americans, 21.3% for Black Americans, 26.5% for persons reporting two or more races, 22.2% for White Americans, and 23.1% for Hispanic Americans [12].

Use of alcohol is higher for college graduates compared to those with only a high school diploma (66.2% and 33.8%, respectively) [12]. However, binge and heavy use is slightly higher for young adults 18 years of age and older who have not completed college [12]. The pattern of higher rates of current alcohol use, binge alcohol use, and heavy alcohol use among full-time college students, compared with rates for others 18 to 22 years of age, has remained consistent since 2002 [14]. In a 2002 study of alcohol use on college campuses, researchers at Harvard University reported that of the more than 14,000 students surveyed, 31% met the criteria for alcohol abuse and an additional 6% met the criteria for diagnosis of alcohol dependence [15]. In the study, alcohol abuse was defined as a positive response to any one of the four abuse criteria and the absence of dependence. Alcohol dependence was defined as a positive response to any three or more of seven dependence criteria. Percentages of students meeting specific alcohol abuse and dependence criteria are presented in Figure 1[15]. Male students are at greater risk than female students. Almost 10% of male students and 5% of female college students younger than 24 years of age met the criteria for a 12-month diagnosis of alcohol dependence [15].

Figure 1: PERCENTAGE OF COLLEGE STUDENTS MEETING SPECIFIC ABUSE AND DEPENDENCE CRITERIA

Source: [15]

About 40% of people who drink have experienced an alcohol-related problem [11]. Between 3% and 8% of women and 10% to 15% of men will develop alcohol use disorder at some point in their lives. While alcohol use disorders can develop at any age, repeated intoxication at an early age increases the risk of developing an alcohol use disorder [11]. Usually, dependence develops in the mid-twenties through age forty.

COSTS OF ALCOHOL USE DISORDERS

The National Institute on Drug Abuse (NIDA) and the National Institute on Alcohol Abuse and Alcoholism (NIAAA) estimated that the annual economic cost of alcohol and drug abuse was $365.4 billion in 1998 [9]. This estimate represents roughly $1,350 each year for every man, woman, and child living in the United States. Alcohol use disorders generated about half of the estimated costs ($184.6 billion). This figure rose to $249 billion in 2010, representing approximately $807 for every man, woman, and child living in the United States [16].

Nearly three-fourths (72%) of the costs of alcohol abuse are related to lost workplace productivity ($179 billion); 11% are related to healthcare expenses for treating problems caused by excessive drinking ($28 billion); 10% are law enforcement and other criminal justice expenses ($25 billion); and 5% are losses from motor vehicle crashes related to excessive alcohol use ($13 billion) [16]. Binge drinking is responsible for the majority of the cost at $191 billion [16]. Alcohol use disorder generally reduces the lifespan by 15 years [11]. Approximately $99.6 billion of the total costs of alcohol abuse is paid by federal, state, and local governments [16]. When both direct and indirect costs are included, the estimated annual cost of alcohol-related problems alone may be much greater [16].

DEFINITIONS

Tolerance: Either (1) a need for markedly increased amounts of the substance to achieve intoxication or desired effect; or (2) a markedly diminished effect with continued use of the same amount of the substance [17].

A Standard Drink: 1.5 ounces of 80-proof distilled spirits, 5 ounces of table wine, or 12 ounces of standard beer [18,19].

Alcohol Intoxication: Clinically significant problematic behavioral or psychological changes (e.g., inappropriate sexual or aggressive behavior, mood lability, impaired judgment) that developed during, or shortly after, alcohol ingestion [17]. Changes include slurred speech, loss of coordination, unsteady walking or running, impairment of attention or memory, nystagmus, stupor, or coma.

Alcohol Withdrawal: The presence of certain symptoms after stopping or reducing heavy and prolonged alcohol use [17]. The symptoms of alcohol withdrawal may develop within a few hours to a few days after stopping or reducing use and symptoms cause significant physical and emotional distress in social, occupational, or other important areas of functioning. Symptoms include increased hand tremor, sweating, increased pulse rate, nausea, vomiting, insomnia, temporary hallucinations or illusions, anxiety, psychomotor agitation, and generalized tonic-clonic seizures. Fewer than 5% of persons who develop alcohol withdrawal experience severe symptoms such as seizures and death [20].

Blood Alcohol Concentration (BAC): The percentage of alcohol present in the bloodstream. The BAC is usually what is measured by police officers to determine legal intoxication. It can be measured directly from a blood sample or a breath sample collected by a "Breathalyzer." The national legal limit for intoxication is a BAC of 0.08.

Moderate Drinking: No more than one drink per day for women and no more than two drinks per day for men [19].

Current Use: At least one drink in the past 30 days [16].

Binge Drinking: Consuming five or more drinks on the same occasion in the past 30 days [16,19].

Heavy Drinking: Five or more drinks on the same occasion on each of 5 or more days in the past 30 days [16].

Fetal Alcohol Syndrome (FAS): A severe fetal alcohol spectrum disorder (FASD), FAS is a lifelong syndrome in children with confirmed prenatal exposure to alcohol. Signs include growth deficiencies, facial abnormalities, and neurocognitive deficits that may lead to problems with vision, hearing, attention, learning, memory, or any combination thereof [21]. There is no safe recommended level of alcohol use in pregnancy.

4. BENEFITS

Alcohol is consumed sensibly by the vast majority, but it can also be a cause of considerable damage and death when used excessively. Alcohol is part of many cultures, and most individuals learn from their bad experiences to moderate their drinking. Consequently, the majority of people do not have accidents or develop alcohol use disorder. Additionally, data suggests that moderate consumption of alcohol does have some health benefits.

The French consume large amounts of wine and high-cholesterol foods, yet they have a low incidence of heart disease. The Japanese drink large amounts of sake, but eat basically low-cholesterol foods and have a low incidence of heart disease. Other cultures traditionally drink whiskey and beer. Should we be drinking more, more regularly, or less on both counts?

Data for health benefits associated with low-to-moderate drinking appear to be common in many medical journals [22]. Light-to-moderate alcohol intake from beer, wine, or spirits is associated with a reduction in all-cause mortality, possibly due to its ability to decrease cardiovascular diseases, especially coronary heart disease (CHD). The relationship between alcohol intake and reduced risk of coronary disease is generally accepted as a U-shaped curve of low-dose protective effect and higher doses producing a loss of protective effects and increased all-cause deaths [23,24,25,26,27,28,29,30]. The World Health Organization (WHO) reported that there is convincing evidence that low-to-moderate alcohol intake decreases risk for heart disease [31].

Many researchers have replicated the finding that moderate alcohol consumption is associated with a reduced risk of coronary artery disease, peripheral artery disease, sudden death, and stroke and suggest that this effect is to a large extent mediated by increases in high-density lipoproteins (HDLs) [1]. A 2011 meta-analysis inclusive of 84 out of 4,235 studies on the benefits of alcohol concluded that the lowest risk of CHD mortality was conferred by one to two drinks per day and that the lowest stroke mortality risk was conferred by consuming one or fewer drinks per day [2]. Research suggests that the protective effect may be a result of an interaction between diet and genetics, specifically related to a genetic variation in alcohol dehydrogenase (ADH) [32]. Moderate drinkers who are homozygous for the slow-oxidizing ADH3 allele have higher HDL levels and a substantially decreased risk of myocardial infarction [32]. An acute protective effect of alcohol consumption was also found for regular drinkers who consumed one or two drinks in the 24 hours preceding the onset of cardiac symptoms. Risk of a major coronary event is lowest among men who report daily drinking and among women who report one or two drinks daily. Alcohol does have effects on several markers for coronary risk factors, such as blood pressure, HDL cholesterol, low-density-lipoprotein (LDL) cholesterol, fibrinogen, clotting factors, and insulin sensitivity.

Prescribing alcohol to patients is not recommended, but research should continue in an attempt to identify the beneficial effects of alcohol alone. The psychiatric and other medical costs associated with drinking should be considered. Epidemiologists and other researchers are weighing the benefits of moderate alcohol consumption against the risks of addiction and accidents.

Alcohol clearly causes detrimental effects on a number of critical organs and systems in the human body when taken in large doses over time. Excessive alcohol consumption increases cardiovascular risk factors and mortality. Alcohol abuse is often considered the second most common cause of preventable death in the United States [33]. However, light-to-moderate drinking may protect against ischemic stroke and abstaining from alcohol may increase the risk of stroke [2]. A prospective study of moderate alcohol consumption and risk of peripheral arterial disease in U.S. male physicians found that any alcohol consumption decreases the risk of peripheral artery disease [1]. No evidence exists for a reduction in cardiovascular mortality in anyone younger than 40 years of age. Because almost no one dies of coronary artery disease before age 40, the studies to see if drinking in individuals younger than 40 years of age is particularly protective in later life have yet to be done.

Cardiovascular protection occurs primarily through blood lipids such as HDL, especially HDL subfraction 2 [1]. Moderate alcohol consumption inhibits platelets, especially after a fatty meal, suggesting an aspirin-like effect for moderate alcohol consumption [34]. Alcohol's effects on clotting appear to be related to the findings that drinking reduces acute heart attack risk. Certain alcoholic beverages, namely red wine, may also have an additional positive antioxidant effect as it contains flavonoids, which possibly slow oxidation of unsaturated fatty acids [35]. Additionally, low amounts of drinking can also enhance insulin sensitivity, reduce fasting insulin, and may also reduce stress.

Risk-to-benefit analysis should take into account a person's age, sex, family history, likelihood of an adverse effect on blood pressure, cancer risk, medication interaction, accidents, and dependency. Light-to-moderate alcohol consumption reduces overall risk of ischemic stroke; however, greater alcohol consumption has no additional benefit and can be harmful [2].

It has been questioned whether the cardiac protective effects can be easily generalized to women, in whom the risk of breast cancer complicates alcohol risks. For example, the consumption of seven or more drinks per week is associated with a twofold increase in postmenopausal hormone-sensitive breast cancers; however, several studies have shown that moderate alcohol consumption reduces the mortality of breast cancer [36,37,38]. It should also not be forgotten that alcohol increases the risk of certain other cancers (e.g., liver, mouth, esophageal, laryngeal, pharyngeal) that affect both men and women. Multiple case-control studies and meta-analyses have reported on the relationship between alcohol and cardiovascular disease and mortality. Many of these studies reported that low-to-moderate alcohol consumption decreases the number of adverse cardiovascular events and deaths when compared with abstinence. Beginning in the early 2000s, the cardioprotective effects of low doses of alcohol were refuted by the results of large epidemiological studies. Since that time, alcohol use is consistently associated with cardiac arrhythmias, dilated cardiomyopathy, arterial hypertension, atherosclerotic vascular disease, and type 2 diabetes [39,40].

Moderate drinking is heart-healthy for diabetics in the same way it is for other people, easing concerns that alcohol may disrupt diabetics' blood-sugar balance. In a 12-year study, diabetics who had one or two drinks daily were up to 80% less likely to die of heart disease than diabetics who did not drink [41]. However, alcohol consumption is a marker for poorer adherence to diabetes self-care behaviors [42,43].

WHAT TO ADVISE PATIENTS ABOUT DRINKING ALCOHOL

Although alcohol appears to have some moderate health benefits, physicians need not alter the drinking habits of those who consume low-to-moderate amounts of alcohol. It is problematic to advise a patient who is abstinent or who drinks infrequently to begin or increase alcohol consumption. In addition, social and religious factors may already dictate the patient's drinking habits.

Vulnerability to alcohol use disorders, depression, and alcohol-related pathologies varies greatly among individuals and cannot always be predicted before a patient begins or escalates drinking. Some individuals may be genetically predisposed to acquiring problems with alcohol use disorder. Similarly, excessive consumption often escapes detection before the onset of related health consequences. The balance of risk to benefit appears to favor encouraging some patients in midlife who are very infrequent drinkers to increase slightly the frequency of drinking. Again, this is debatable and will vary with the individual patient. Consuming alcohol is not the only means to reduce the risk of cardiovascular disease. Exercising, not smoking, lowering fat intake and lipids, and other health-related lifestyle issues should also be addressed.

For those who already have heart disease, it is clear that heavy drinkers should reduce their consumption or abstain and that everyone should avoid heavy and binge drinking. Data does not support advising abstainers with a history of myocardial infarction or decreased left ventricular function to start drinking for their health [44]. In general, moderate drinkers with these conditions should be able to continue to drink alcohol in moderation [44].

Alcohol is not without risks. Alcohol abuse worsens the course of psychiatric disorders. In countries with high alcohol consumption, the suicide rate is also high. One should ask whether the promotion of moderate alcohol consumption, justified on the basis of a biomedical effect (e.g., a reduction in all-cause mortality), might change a patient's quality of life or cause them to take offense. However, existing public educational efforts that target reductions in hazardous and harmful drinking and at the same time encourage drinkers to consume alcohol at responsible levels are appropriate and ethical.

5. RISK AND PROTECTIVE FACTORS

ALCOHOL AND GENETICS

Research has shown that genetic factors play a strong role in whether a person develops alcohol use disorder, accounting for 40% to 60% of the risk [45,46]. In fact, family transmission of alcohol use disorder has been well established. Individuals who have relatives with alcohol use disorder are at three- to five-times greater risk of developing alcohol use disorder than the general population. The presence of alcohol use disorder in one or both biologic parents is more important than the presence of alcohol use disorder in one or both adoptive parents. The genetic risk of alcohol use disorder increases with the number of relatives with alcohol use disorder and the closeness of the genetic relationship [46]. However, most children of parents with alcohol use disorder do not become alcoholics themselves, and some children from families where alcohol is not a problem develop alcohol use disorders when they get older. Alcohol use disorder is seen in twins from alcoholic parents, even when they are raised in environments where there is little or no drinking. Identical twins adopted into households with an alcoholic stepfather do not show more alcohol use disorders than the general population. Children with close biologic relatives with alcohol use disorder, who are adopted into a never drinking, even religiously opposed family, can readily develop alcohol problems [47].

As mentioned previously, genetic factors are thought to account for 40% to 60% of the risk of developing alcohol use disorder [25,46]. Animal studies have shown that genetic factors may be responsible for enhanced brain reward produced by alcohol, decreased initial impairment, or even altered metabolism of alcohol [48,49,50,51,52,53,54].

Genetic factors appear to influence the level of response (LR) to alcohol, as measured by the intensity with which one reacts to a given quantity [55]. The level of response to alcohol varies from individual to individual depending on the tolerance. Low LR at an early age contributes to the risk of alcohol use disorder later in life [55,56].

Genetic differences in metabolic or other biologic processes may play a role in the development of alcohol use disorder in specific individuals. Studies using a self-rated scale have shown consistent results in sons of alcoholic fathers scoring themselves lower than sons of nonalcoholic fathers on feelings of drunkenness, dizziness, drug effect, and sleepiness following alcohol consumption [57]. This suggests that sons of alcoholic fathers have a less intense reaction to alcohol than sons of nonalcoholic fathers. Low reaction to alcohol suggests tolerance and impaired ability to recognize even modest levels of alcohol intoxication, indicators of tendency towards dependence [58,59]. High alcohol sensitivity in men is associated with substantially decreased risk of alcohol use disorder. Understanding reactions to alcohol could establish a better understanding of future risk of developing alcohol use disorder in these men.

Studies have found similar results of higher tolerance for alcohol among daughters of parents with alcohol use disorder. One study examined the drinking patterns of 38 daughters of alcoholics compared with 75 family-history-positive men from the same families and 68 men with no family history of alcohol use disorder [60]. Family-history-positive men and women both displayed low reaction to alcohol. This indicates that the degree of genetic influence on alcohol-related behavior is similar for both men and women with family history of alcohol use disorder. In a study of adolescent and young adult offspring from families where alcohol use disorders are prevalent, researchers found both neurophysiologic and neuroanatomical differences, such as reduced right amygdala volume, when comparing these offspring to controls [61]. Another study assessed the relationship between amygdala and orbitofrontal cortex volumes obtained in adolescence and substance use disorder outcomes in young adulthood among high-risk offspring and low-risk controls [62]. A total of 78 participants 8 to 19 years of age (40 high-risk, 38 low-risk) from a longitudinal family study underwent magnetic resonance imaging. Volumes were obtained with manual tracing. Outcomes were assessed at approximately one-year intervals. The ratio of orbitofrontal cortex volume to amygdala volume significantly predicted substance use disorder survival time across the sample. A reduction in survival time was seen in participants with smaller ratios; this was true for both high-risk and low-risk participants [62].

Native Americans and Alaskan Natives have a lower level of response and an increased risk of alcohol use disorder [46]. The alcohol metabolizing enzymes are another important genetic influence, especially for persons of Asian descent. About 50% of Japanese, Chinese, and Korean persons flush and have a more intense response to alcohol because they have a form of alcohol dehydrogenase (ADH) that causes high levels of acetaldehyde. Forms of ADH and aldehyde dehydrogenase (ALDH) (e.g., homozygous or heterozygous) contribute to a higher rate of alcohol metabolism, intensify the response to alcohol, and lower the risk of alcohol use disorder. High levels of impulsivity/sensations seeking/disinhibition are also genetically influenced and may impact alcohol use disorder risk [46].

An estimated 178,000 people (approximately 120,000 men and 59,000 women) die from alcohol-related causes annually. According to NIAAA, alcohol is a significant cause of death, disease, and disability, currently ranked as one of the leading preventable causes of death in the United States [63]. According to a 2022 SAMSHA survey reported by NSDUH, 29.5 million Americans 12 years of age and older (10.5% of this age group) have alcohol use disorder [63]. Almost 1 in 4 adults have had a heavy drinking event in the past year (defined as five or more drinks for men and four or more drinks for women). The NIH and the CDC report increasing alcohol problems, deaths, and alcohol use disorders. An analysis of death certificates from 2019 and 2020 showed that deaths involving alcohol rose from approximately 79,000 to more than 99,000, a 25.5% increase [64]. Increases in alcohol-related deaths are consistent with reports of increased alcohol sales, consumption, alcohol-involved emergency department visits, and hospitalizations. The most recent alcohol data provide more evidence of increasing heavy alcohol use and associated consequences during the COVID-19 pandemic [65]. A 2023 study demonstrated that only individuals with prepandemic history of alcohol use disorder reported greater increases in drunkenness frequency during the COVID-19 pandemic [66]. Increased alcohol use may also worsen medical and mental health problems. Among people who die by suicide, alcohol use disorder is the second most common mental disorder and involved in an estimated one in four deaths by suicide [64].

PSYCHOLOGICAL AND SOCIOENVIRONMENTAL RISK FACTORS MODELS

Researchers who study risk factors have developed models of how known risk factors may interact to create pathways in children that lead to alcohol use disorders.

Children with Conduct Problems

One model focuses on children who have temperaments that make it difficult for them to regulate their emotions and control their impulses. Clearly, these children are difficult to parent, and if one or both of their parents have alcohol use disorder, it is likely that they will be poorly socialized and have trouble getting along in school [67,68]. Poor academic performance and rejection by more mainstream peers at school may make it more likely for these children to join peer groups where drinking and other risky behaviors are encouraged. Parents with alcohol use disorders will likely not monitor their children closely and will lose control over them at an early age. These children will begin drinking early, often before 15 years of age [69]. If such a child is genetically predisposed to alcohol use disorders, these environmental factors may further increase the tendency [70].

Stress and Distress

Another model of risk factors leading to alcohol use disorder focuses on drinking to regulate inner distress [71]. Some children have temperaments that make them highly reactive to stress and disruption. This type of child may be born into a family with history of alcohol use disorder, where the stressors may be intense, or a nonalcoholic family, with everyday types of low-level stressors. Regardless of the child's family environment, he or she maintains higher levels of inner distress (anxious and depressed feelings) than other children. When they take their first drink, the inner distress dissipates for a while. This leads to more drinking and may lead to alcohol use disorder. However, for some individuals, at certain doses, alcohol may induce rather than reduce the stress response. Research demonstrates that alcohol actually induces the stress response by stimulating hormone release by the hypothalamus, pituitary, and adrenal glands [72]. Research also demonstrates a bidirectional relationship between alcohol and stress [73]. More research is required before the role of stress as a risk factor in alcohol use disorders is understood.

Sensitivity to Alcohol's Effects

A third risk factor model focuses on sensitivity to the effects of alcohol, both to its sedative properties and its stimulating qualities [74]. The stimulant-like (increased heart rate and blood pressure) and sedative properties (impaired vigilance and psychomotor performance) depend on the quantity of alcohol consumed, the time elapsed since consumption, and individual differences in response [75,76]. Researchers believe that this subjective response to alcohol may be an important endophenotype in understanding genetic influences on drinking behavior and alcohol use disorders. While subjective response predicts alcohol use and problems, the exact pattern of association remains unclear [77,78,79]. Two prominent models of subjective response have been discussed in the literature. The low level of response model suggests that high-risk individuals experience decreased sensitivity to the full range of the effects of alcohol. The differentiator model suggests that high risk for alcohol problems is associated with increased sensitivity to alcohol's positive effects but decreased sensitivity to its negative effects [77,78]. A literature review of studies that employed challenge paradigms to assess a range of the effects of alcohol (i.e., impairment, stimulation, sedation) found some support for both models [77]. Results of a quantitative review and meta-analysis suggest that the two models may describe two distinct sets of phenotypic risk with different etiologies and predictions for development of alcohol use disorder [78]. A total of 32 independent samples were combined to produce estimates of the effects of risk-group status (i.e., positive family history of alcohol use disorder or heavy alcohol consumption). Groups with positive family history for alcohol experienced reduced overall subjective response relative to groups with negative family history, as predicted by the low level of response model. In contrast, consistent with the differentiator model, heavy drinkers of both genders responded less on measures of sedation than did lighter drinkers, but more on measures of stimulation [78].

The effects of alcohol on the electroencephalogram (EEG) of subjects at risk for developing alcoholism are well known [80,81,82]. Researchers found that low EEG response to small amounts of alcohol may be associated with future development of alcohol use disorder. Additionally, differences in EEG response to alcohol may have ethnic variations [82]. Other studies have shown that heavy drinkers had less sedation and cortisol response after alcohol consumption than light drinkers. In addition, heavy drinkers were more sensitive to the positive stimulant-like properties as blood alcohol levels increased [74,83].

KNOWN RISK FACTORS FOR ALCOHOL USE DISORDER

With these three models in mind, a review of some of the research findings on genetic and psychosocial risk factors may provide a better understanding of the factors leading to alcohol use disorders [11,84]:

- Temperament: Moodiness, negativity, and provocative behavior may lead to a child being criticized by teachers and parents. These strained adult-child interactions may increase the chances that a child will drink.

- Hyperactivity: Hyperactivity in childhood is a risk factor for the development of adult alcohol use disorders. Children with attention deficit hyperactivity disorder (ADHD) and conduct disorders have increased risk of developing an alcohol use disorder. Childhood aggression also may predict adult alcohol abuse.

- Parents: The most compelling and largest body of research shows parents' use and attitudes toward use to be the most important factor in an adolescent's decision to drink.

- Gender: Among adults, heavy alcohol use is almost three times more common among men than women and also more common among boys in middle or high school than among girls. Men with ADHD and/or conduct disorders are more likely to use alcohol than men without these disorders, while women who experience more depression, anxiety, and social avoidance as children are more likely to begin using alcohol as teens than women who do not experience these negative states.

- Psychology: Bipolar disorder, schizophrenia, antisocial personality disorder, and panic disorder all also increase the risk of a future alcohol use disorder.

ABUSE AND ADVERSE CONDITIONS IN THE HOME

Childhood abuse is a significant risk factor for later alcohol and substance abuse [85]. Women who were physically abused are 1.5 to 2 times more likely to abuse alcohol than non-abused adults. Children from crowded, noisy, and disorderly homes without rules or religion are more likely to abuse alcohol as teens. Children who are quick to anger, who perceive themselves to be highly stressed, who are resentful of parents' absences, or who have repeated conflicts at home are more likely to abuse alcohol as teens.

PROTECTIVE FACTORS

An exciting area of research is focused on protective factors and poses the question, "What protects children from taking one of the risk pathways to alcohol use disorder?"

In 1997, some good news came from the National Longitudinal Study on Adolescent Health, a survey in which nearly 12,000 students in grades 7 through 12 were given lengthy interviews timed one year apart. The researchers were trying to determine what kept children, over the course of that year, from taking health risks in four areas: substance abuse (cigarettes, alcohol, and marijuana), sexuality, violence, and emotional health [86]. The researchers found two factors that protected these children in all four areas. They named the factors: parent-family connectedness and school connectedness.

Children identified as having parent-family connectedness said they felt close to their mother or father, felt that their mother or father cared about them, felt satisfied with their relationship with their mother or father, and felt loved by family members [86]. School connectedness was experienced as a feeling of being part of one's school and a belief that students were treated fairly by the teachers.

There is broad evidence of the protective role of parenting on adolescent health risks. Another well-established protective factor is adolescents' perceived disapproval of alcohol use by their parents [87,88,89,90,91]. In 2022, the National Survey on Drug Use and Health asked children 12 to 17 years of age about their perceptions of the level of parental disapproval of substance use initiation, including alcohol [12]. Most adolescents (88.9%) reported that their parents would strongly disapprove of them having one or two alcoholic drinks nearly every day. This percentage was similar to percentages in most years since 2002, with rates ranging from 88.5% to 91.2% [12]. The number of past-year initiates 12 years of age or older for alcohol also remained stable between 2002 and 2022 [12].

6. ALCOHOL USE DISORDER

Alcohol use disorder, also referred to as alcohol abuse and/or alcohol dependence, is defined in the DSM-5-TR as a problematic pattern of use with two or more of the following criteria over a one-year period [17]:

- Alcohol often taken in larger amounts or over a longer period than was intended

- A persistent desire or unsuccessful efforts to cut down or control alcohol use

- A great deal of time spent in activities necessary to obtain alcohol, use alcohol, or recover from its effects

- Craving, or a strong desire or urge to use alcohol

- Recurrent alcohol use resulting in a failure to fulfill major role obligations at work, school, or home

- Continued alcohol use despite having persistent or recurrent social or inter-personal problems caused or exacerbated by the effects of alcohol

- Important social, occupational, or recreational activities given up or reduced because of alcohol use

- Recurrent alcohol use in situations in which it is physically hazardous

- Alcohol use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by alcohol

- Tolerance

- Withdrawal

Alcohol use disorder is extremely amenable to brief intervention. Brief intervention usually includes giving patients information about problems associated with excessive drinking and advising them to cut down on their drinking or abstain. Without intervention, 10% will likely progress to dependence and 50% to 60% will continue to experience problems over the next five years [92,93].

Alcohol use disorder is a primary and chronic disease that is progressive and often fatal; it is not a symptom of another physical or mental condition. It is a disease in itself, like cancer or heart disease, with a very recognizable set of symptoms that are shared by others with the same disorder. About 29.5 million people in the United States met DSM-5-TR criteria for alcohol use disorder in 2022, with an additional 5.3 million abusing or dependent on both alcohol and illicit drugs [12,94].

Like cancer and many other chronic diseases, alcohol use disorder progresses over time. People with alcohol use disorder experience physical, emotional, and other changes in their lives and relationships. These changes may worsen if drinking continues and if treatment specifically targeted to alcohol use disorder is not initiated. Left untreated, alcohol use disorders may lead to premature death through overdose or through damage to the brain, liver, heart, and many other organs. Excessive alcohol consumption is highly associated with suicide, motor vehicle accidents, violence, and other traumatic events [94]. People with untreated alcohol use disorders often lose their jobs, their families, their relationships, and other freedoms that were once important to them.

Evidence Based Practice Recommendation

The U.S. Preventive Services Task Force (USPSTF) recommends screening for unhealthy alcohol use in primary care settings in adults 18 years of age or older, including pregnant women, and providing persons engaged in risky or hazardous drinking with brief behavioral counseling interventions to reduce unhealthy alcohol use.

https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/unhealthy-alcohol-use-in-adolescents-and-adults-screening-and-behavioral-counseling-interventions

Last Accessed: May 20, 2024

Strength of Recommendation/Level of Evidence: B (The USPSTF recommends that clinicians provide this service to eligible patients based on at least fair evidence that the service improves important health outcomes and concludes that benefits outweigh harms.)

As noted, alcohol problems can often be prevented by early identification and brief intervention. A weak link in the early identification of problems is the lack of skill and competencies necessary to perform such an assessment and the experience to confidently move to more specific questions and suggestions for change.

Alcohol dependence is included in the DSM-5-TR umbrella definition of alcohol use disorder [17]. The symptoms of withdrawal and tolerance have been the hallmarks of more severe disease, though alone they are neither necessary for nor sufficient to make the diagnosis.

Healthcare professionals should understand the criteria and warning signs of alcohol use disorder. This enables confrontation and intervention earlier in the course of the illness rather than relying on toxic liver markers. Verifying the facts that show a person is at risk for alcohol use disorder and confronting the impaired individual with those facts is the definition of an office or brief intervention. Brief intervention is most effective before dependence is reached. Once diagnosable, the patient needs more comprehensive intervention.

WITHDRAWAL

Individuals with alcohol use disorder often experience a severe, potentially fatal withdrawal syndrome when they either abruptly discontinue or sharply reduce their alcohol consumption. The symptoms may include sweating, rapid heartbeat, hypertension, tremors, anorexia, insomnia, agitation, anxiety, nausea, and vomiting. Tremors of the hands are usually the earliest symptom of alcohol withdrawal. Hallucinosis, seizures, and delirium tremens (DTs) are the most severe form of alcohol withdrawal. Hallucinosis, when it occurs, occurs one to two days after decreasing or abstaining from alcohol. While the effects of DTs can be life threatening, all other symptoms, with or without treatment, usually resolve several hours or days after appearance. Alcohol withdrawal in tolerant individuals can occur before the BAC has dropped below the established legal limit for intoxication. Some persons with alcohol use disorder have symptoms of irritability, emotional lability, insomnia, and anxiety that persist for weeks to months after alcohol withdrawal. The symptoms may be due to the residual effects of alcohol toxicity on the central nervous system and can be post-acute withdrawal symptoms; members of Alcoholics Anonymous (AA) refer to this as being a "dry drunk." AA considers alcoholics who are only abstaining from alcohol but who are not working a recovery program and remaining in essentially the same emotional state as they were when they were drinking to be "dry drunks."

INCREASED TOLERANCE

Long-term heavy drinking and genetic predisposition can result in the development of tolerance, which is the body's adaptation to the presence of alcohol. As tolerance develops, the drinker requires increasing amounts of alcohol to feel the same effect. For this reason, the usual reported effects for various BAC levels do not apply to individuals with tolerance. In our society, people are often admired for their ability to "hold their drinks." But the fact is, tolerance may be an early warning sign that a physical dependence on alcohol is developing. During the late stages of alcohol use disorder, reverse-tolerance occurs, meaning the individual becomes intoxicated more quickly and with less alcohol.

IMPAIRED CONTROL OF DRINKING

Impaired control over drinking means that a person is consistently unable to limit the number of occasions when alcohol is used or the amount of alcohol ingested on those occasions. Often, because of the damage alcohol causes in their lives, people with alcohol use disorder will express a strong and persistent desire to cut down or stop drinking. Often they may be able to do so, sometimes for a matter of weeks, a month, or even longer. One does not need to be a daily drinker to meet criteria for alcohol use disorder, as even those who go weeks or months without a drink may binge and meet diagnostic criteria. However, because alcohol use disorder is a chronic progressive disease, once patients with alcohol use disorder resume drinking, even after years of sobriety, they typically return to the previous quantities of consumption, with worsening adverse consequences.

PREOCCUPATION WITH ALCOHOL

Individuals with alcohol use disorder may have a preoccupation with alcohol, defined as a noticeable shift in priorities, with a focus on obtaining and consuming an adequate supply of alcohol. Drinking alcohol becomes a central focus in their lives. Over time, the energies of individuals with alcohol use disorder are diverted from people, places, and things that were once important to them.

Another highly noticeable feature of the preoccupation with alcohol may be the large amount of time that drinking consumes. Thinking about alcohol, obtaining alcohol, drinking alcohol, and recovering from the effects of alcohol take more and more of the individual's time. Hobbies and other activities once enjoyed are abandoned one by one, and the only pleasure seems to come from drinking.

USE OF ALCOHOL DESPITE ADVERSE CONSEQUENCES

Continued drinking despite adverse consequences is characterized by the inability of individuals with alcohol use disorder to stop drinking even when they recognize that their family, interpersonal, spiritual, occupational, legal, and financial problems are the result of their drinking. Furthermore, alcohol may be causing serious health and psychological problems (e.g., anemia, gastritis, liver disease, neurologic disorders, depression) and still the dependent individual cannot stop.

DENIAL AS A DEFENSE MECHANISM

Denial is a common characteristic distortion in thinking that becomes profound in people with alcohol use disorder. For decades, those who have treated individuals with alcohol use disorder, and recovering alcoholics themselves, have puzzled over why these persons continue to drink when the link between alcohol and the losses they suffer is so clear. Denial is an integral part of the disease of alcohol use disorder and a major obstacle to recovery. Although the term denial is not specifically used in the wording of the diagnostic criteria, it underlies the primary criteria described as, "drinking despite adverse consequences."

RELAPSE

Because alcohol use disorder is a chronic disease, another symptom that is increasingly being recognized and treated is relapse. Although alcohol use disorder is a treatable, chronic disease, as yet, no cure has been found. This means that even if individuals with alcohol use disorder have been sober for a long time and have regained their health and reclaimed other important aspects of their lives, they may experience a relapse that will require further treatment in order to return to remission.

PHYSICAL CLUES THAT MAY SUGGEST ALCOHOL USE DISORDER

While a strong attachment to alcohol is the hallmark of early dependency, if the patient refuses to acknowledge a problem and no one from home or work helps to confirm the diagnosis, healthcare professionals are often left with nothing more than clinical intuition, resulting in a missed diagnosis. However, late in the course of alcohol use disorder, physical clues typically become increasingly apparent and suggestive of alcohol abuse and/or dependence. Alcohol abuse and dependence are often referred to as the "Great Masquerader" because many of the signs and symptoms are also commonly found in other conditions [95].

Elevated Laboratory Findings

- Serum glutamic oxaloacetic transaminase (SGOT)

- Lactic acid dehydrogenase (LDH)

- Cholesterol

- Gamma-glutamyltransferase (GGT)

- Mean corpuscular volume (MCV)

- Alkaline phosphatase

- Triglycerides

- Blood alcohol concentration (BAC)

- Urinary ethyl glucuronide (EtG) and ethyl sulfate (EtS)

- Whole blood phosphatidylethanol (PEth)

- Serum transferrin

- Uric acid

Gastrointestinal Signs/Symptoms

- Nausea

- Vomiting

- Reflux

- Diarrhea

- Gastritis

- Ulcers

- Esophagitis

Cardiopulmonary Signs/Symptoms

- Hypertension

- Palpitations

- Arrhythmias

- Recurrent respiratory infections

Central Nervous System (CNS) Signs/Symptoms

- Anxiety

- Insomnia

- Memory impairment

- Depression

- Irritability

- Panic

- Suicide attempt(s)

- Suicidal thinking

Behavioral Clues

- Loss of interest in previously favorite activities and people

- Marital and financial problems

- Positive family history

- Cigarette smoking

- Problems at home and work

- Anger when someone asks about drinking

- Legal difficulties

- Higher than normal scores on screening questionnaires, such as the Michigan Alcohol Screening Test (MAST) and CAGE

Miscellaneous Signs/Symptoms

- Gout

- Impotence

- Bloated face

- Parotid swelling

- Trauma injuries

- Aches and pains

- Unusual accidents

- Broken bones

- Driving accidents, multiple citations, and other problems

7. COMPLICATIONS

Alcohol use disorders are often associated with physical disorders and related problems.

LIVER DISEASE

The liver is a particularly vulnerable organ to alcohol consumption, in large part because it is where alcohol is metabolized prior to elimination from the body. As few as six drinks a day for men have been found to be associated with liver damage. The most common manifestation among persons with alcohol use disorder is called "fatty liver." Among heavy drinkers, the incidence of fatty liver is almost universal. For some, a fatty liver may precede the onset of alcoholic cirrhosis. Fatty deposits have been associated with men who have six or more drinks a day and women who have only one or two drinks daily.

Alcoholic hepatitis is a condition that, when severe, is characterized by jaundice, fever, anorexia, and right upper-quadrant pain. Between 10% and 35% of heavy drinkers (those drinking five or six standard drinks a day or more) develop alcoholic hepatitis and 10% to 20% develop cirrhosis [96,97]. More than 60% of persons who develop both alcoholic hepatitis and cirrhosis will die within four years. Drinking 12 beers a day for 20 years has been associated with a 50% incidence of cirrhosis. It is not known which individuals will develop cirrhosis. Studies have shown that women develop liver disease faster and at lower levels of alcohol consumption than men [97,98]. Women also have a higher incidence of alcoholic hepatitis and higher mortality rate from cirrhosis [99].

Alcohol use disorder is also a strong predictive factor for the development of hepatocellular cancer [100]. The presence of other hepatic risk factors, including hepatitis C, fatty liver disease, smoking, and obesity, further increases this risk.

Liver Transplantation

The leading indication for liver transplantation in the United States is chronic hepatitis C [101]. Cirrhosis due to alcoholic liver disease is the second most common cause for a person to require a liver transplantation [101]. Candidates for liver transplantation should be adequately screened for alcohol use disorders and receive appropriate treatment both perioperatively and as part of long-term follow-up. Patient survival after transplantation for both of these conditions is surprisingly good, with 72% of patients surviving after five years [101]. Short-term survival is similar; however, long-term survival for patients with hepatitis C now appears to be compromised by universal recurrence. When patients have both alcohol use disorder and chronic hepatitis C, they do worse than when both diseases occur independently. One study demonstrated that patients' short-term survival is the same for those who have alcohol use disorder, hepatitis C, or both diseases [102].

ALCOHOL/ACETAMINOPHEN INTERACTION

Chronic heavy drinking appears to activate the enzyme CYP2E1, which may be responsible for transforming the over-the-counter pain reliever acetaminophen into toxic metabolites that can cause liver damage [103]. Even when acetaminophen is taken in standard therapeutic doses, liver damage has been reported in this population [104,105]. A review of studies of liver damage resulting from acetaminophen-alcohol interaction reported that, in individuals with alcohol use disorder, these effects may occur with as little as 2.6 grams of acetaminophen (four to five "extra-strength" pills) taken over the course of the day by persons consuming varying amounts of alcohol [106]. The damage caused by alcohol-acetaminophen interaction is more likely to occur when acetaminophen is taken after, rather than before, the alcohol has been metabolized [107]. Moderate drinkers should also be made aware of this potential for interaction. There is now a warning label on the bottle that states, "If you consume three or more alcoholic drinks every day, ask your doctor whether you should take acetaminophen or other pain relievers/fever reducers." Further, in 2014 the U.S. Food and Drug Administration (FDA) issued a statement that combination prescription pain relievers containing more than 325 mg acetaminophen per dosage unit should no longer be prescribed due to reported severe liver injury with acetaminophen in patients who took more than the prescribed dose in a 24-hour period; took more than one acetaminophen-containing product at the same time; or drank alcohol while taking acetaminophen products [108].

CARDIOVASCULAR DISORDERS

Alcohol can have a detrimental effect on the heart, including a decrease in myocardial contractility, hypertension, atrial and ventricular arrhythmias, and secondary nonischemic dilated cardiomyopathy [109]. A common complication in alcohol use disorder is elevated pulse and blood pressure, often in the hypertension range. Younger people with alcohol use disorder and those without existing hypertension are less likely to have an elevation than those who are older and predisposed to some hypertension. When drinking stops, the blood pressure often returns to normal over a period of a few days. One study found that people who had six or more drinks a day were twice as likely to suffer from hypertension than moderate drinkers (two or fewer drinks per day) or nondrinkers. Increased serum GGT levels may be an indicator of an individual's susceptibility to the hypertensive effect of alcohol [110].

Aside from hypertension, chronic heavy drinking can adversely affect the heart primarily through direct toxicity to striated muscle, leading to a form of cardiomyopathy [109,111]. Alcoholic cardiomyopathy is probably more common than is currently thought because of underdiagnosis of alcohol use disorder in general. The reported prevalence of alcoholic cardiomyopathy has varied widely from 4% to 40% or more, depending on the characteristics of the study population and the threshold of alcohol consumption used to identify the disorder [112].

The association between heavy alcohol consumption and rhythm disturbances, particularly supraventricular tachyarrhythmias in apparently healthy people, is called "holiday heart syndrome" [111,113]. The syndrome was first described in persons with heavy alcohol consumption, who typically presented on weekends or after holidays, but it may also occur in patients who usually drink little or no alcohol [111,114]. The most common rhythm disorder is atrial fibrillation, which usually converts to normal sinus rhythm within 24 hours. The incidence of holiday heart syndrome depends on the drinking habits of the studied population, but it continues to be a prevalent occurrence in emergency department settings, with alcohol serving as a precipitating factor for atrial fibrillation in 35% to 62% of cases, particularly 12 to 36 hours post-binge drinking [115]. Additionally, the observed trend for increased binge alcohol use in younger adults may be associated with an increased incidence of atrial fibrillation in this population [116]. Holiday heart syndrome should be considered as a diagnosis particularly in patients without overt heart disease presenting with new onset atrial fibrillation. Though recurrences occur, the clinical course is benign and specific antiarrhythmic therapy is usually not warranted [111,113,114].

Vitamin Deficiency, Alcohol, and Cardiovascular Disease

Abnormally high plasma levels of the amino acid homocysteine have been shown in studies to increase the risk for cardiac and other vascular diseases [117]. Even small increases in homocysteine appear to increase the risk of heart disease. Vitamins like folate, B12, and B6 are required for homocysteine disposal within cells. The lower the concentration of these and other vitamins, the greater the concentration of homocysteine. A number of nutritional problems have been reported in people with alcohol use disorder. Malnourished persons with alcohol use disorder and liver diseases have been found to have B6 and folate deficiencies. In addition, average homocysteine levels are twice as high in patients with chronic alcohol use disorder when compared to nondrinking controls. Thus, homocysteine may contribute to the cardiovascular complications experienced by many with chronic alcohol use disorder. Lowering homocysteine with B vitamin supplementation may reduce cardiovascular risk [118,119]. Further research is necessary to determine whether abstinence and recovery reverses the risk of cardiovascular disease, and whether folate and vitamins B12 and B6 should be considered as appropriate nutritional supplements for patients with alcohol use disorder [120].

CANCER

Heavy drinking increases the risk of cancer of the upper gastrointestinal and respiratory tracts [121]. Almost 50% of cancers of the mouth, pharynx, and larynx and approximately 75% of esophageal cancers in the United States are associated with chronic, excessive alcohol consumption [122,123,124]. When alcohol consumption is combined with tobacco use, the risk of esophageal cancer increases markedly, as much as 130-fold in one study [125,126]. Alcohol increases production of estradiol, and increased levels of estradiol have been linked to an increased risk of breast cancer in women who drink [127].

GASTROINTESTINAL DISORDERS

Alcohol produces irritation and inflammation of the mucosal lining of the gastrointestinal tract and influences the motility in the esophagus, stomach, and small bowel [128]. Frank ulceration may occur with chronic excessive alcohol use. This well-known alcohol related "heartburn" is due to esophageal reflux with esophagitis that commonly occurs with irritation and inflammation of the gastroesophageal junction. Severe vomiting from alcohol gastritis may result in mucosal tears at the gastroesophageal junction, resulting in frank, usually transient pain in the upper gastrointestinal tract.

Short-term and long-term alcohol ingestion are associated with gastritis, erosive gastritis, gastric ulceration, atrophic gastritis, and gastric hemorrhage. Furthermore, duodenitis and duodenal ulcerations are a direct result of chronic excessive alcohol irritation and inflammation.

Patients who have undergone gastric bypass surgery for obesity have higher breath-alcohol levels after drinking the same amount as other people. Many bypass surgeries attach the jejunum directly to the stomach, allowing delivery of alcohol more rapidly to the jejunal site of primary absorption as well minimizing the effect of the stomach's alcohol dehydrogenase. Findings from a small study suggest that it takes much longer for their levels to return to zero [129].

CHRONIC PANCREATITIS

Alcohol consumption is the leading cause of chronic pancreatitis, accounting for approximately 70% of cases in the United States; however, fewer than 10% of heavy alcohol drinkers develop the disease [130,131,132,133,134]. While there are many theories regarding the pathophysiology of chronic pancreatitis, the most prevalent for alcohol-induced chronic pancreatitis involves the effect of toxic metabolites on the pancreas. This theory suggests that inflammation and fibrotic changes in the pancreas are the direct result of premature activation of enzymes due to ethanol's effect on the Golgi complex [132,134,135]. Another theory suggests that pancreatic hypoxia results from decreased blood flow to the pancreas. Alcohol-induced acinar injury may reduce capillary flow and result in edema and capillary compression [132]. Individuals with alcohol use disorder may develop diabetes mellitus or hyperglycemia as a result of chronic pancreatitis, when the islet cells in the pancreas are eventually destroyed. Once alcohol-induced chronic pancreatitis has developed, ingestion of even small amounts can result in severe flare-up requiring hospitalization.

BODY WEIGHT

Although alcohol has a relatively high caloric value, 7.1 calories per gram (1 gram of fat contains 9 calories), alcohol consumption does not necessarily result in increased body weight. Moderate, regular doses of alcohol added to the diets of lean men and women do not seem to lead to weight gain. However, in some studies obese patients have gained weight when alcohol is added to their diets.

An analysis of data collected from the first National Health and Nutrition Examination Survey (NHANES I) found that although drinkers had significantly higher intakes of total calories than nondrinkers, drinkers were not more obese than nondrinkers. In fact, women drinkers had significantly lower body weight than nondrinkers. As alcohol intake among men increased, their body weight decreased. An analysis of data from the second National Health and Nutrition Examination Survey (NHANES II) and other large U.S. studies found similar results for women [136]. When chronic heavy drinkers substitute alcohol for food in their diets, they typically lose weight and weigh less than their nondrinking counterparts [137].

Many older studies, such as those discussed, have focused on total volume of alcohol based on intake over time (e.g., number of drinks per week), an average that reveals little about the actual drinking habits of individuals. This has led to a very inconsistent array of data on the relationship of drinking and body mass index (BMI). One study sought a better understanding of the relationship between BMI and regular/moderate versus infrequent binge drinking [138]. Researchers found that although individuals of similar height might consume the same weekly average of alcohol (e.g., 14 drinks per week), individuals who consume two drinks each day of the week typically have low BMIs and individuals who consume seven drinks on each of two days of the week typically have high BMIs. A 2018 study examined the associations of alcoholic beverage consumption with dietary intake, waist circumference, and BMI [139]. A total of 7,436 men and 6,939 women 20 to 79 years of age were included in the study. By average daily drinking volume, the differences in waist circumference and BMI between former and moderate drinkers were +1.78 cm and +0.65, respectively, in men and +4.67 cm and +2.49, respectively, in women. Compared with moderate drinking, heavier drinking volume (three drinks/day or more in men, two drinks/day or more in women) was not associated with higher waist circumference or BMI, whereas drinking five or more drinks/day was associated with higher waist circumference and BMI in men. There were no significant differences in women who consumed four or more drinks/day compared with women who consumed one drink/day [139].

It is also important to note those individuals who have undergone bariatric surgery. According to a research study conducted at a substance abuse treatment facility, bariatric surgery patients were more likely to be diagnosed with alcohol withdrawal than those who had not had the surgery [140]. In another study of patients in active weight management being considered for bariatric surgery, an inverse relationship was found between BMI and alcohol consumption—the more overweight the patient, the less alcohol was consumed [141]. Past-year alcohol consumption actually decreased as BMI increased. Surgeons felt it rare to have a patient excluded for bariatric surgery due to excessive alcohol consumption. The authors concluded that it is likely that food and alcohol compete at brain reward sites.

MALNUTRITION

Excessive drinking may interfere with the absorption, digestion, metabolism, and utilization of nutrients, particularly vitamins. Individuals with alcohol use disorder often use alcohol as a source of calories to the exclusion of other food sources, which may also lead to a nutrient deficiency and malnutrition. In the late stage of the disease, patients may develop anorexia or severe loss of appetite, and refuse to eat. Persons with alcohol use disorder account for a significant proportion of patients hospitalized for malnutrition [137].

Direct toxic effects of alcohol on the small bowel causes a decrease in the absorption of water-soluble vitamins (e.g., thiamine, folate, B6). Studies have suggested that alcoholism is the most common cause of vitamin and trace-element deficiency in adults in the United States. Alcohol's effects are dose dependent and the result of malnutrition, malabsorption, and ethanol toxicity [142]. Vitamins A, C, D, E, K, and the B vitamins are deficient in some individuals with alcohol use disorder. All of these vitamins are involved in wound healing and cell maintenance. Because vitamin K is necessary for blood clotting, deficiencies can cause delayed clotting and result in excess bleeding. Vitamin A deficiency can be associated with night blindness, and vitamin D deficiency is associated with softening of the bones. Deficiencies of other vitamins involved in brain function can cause severe neurologic damage (e.g., deficiencies of folic acid, pyridoxine, thiamine, iron, zinc).

Thiamine deficiency from chronic heavy alcohol consumption can lead to devastating neurologic complications, including Wernicke-Korsakoff syndrome, cerebellar degeneration, dementia, and peripheral neuropathy [143]. Thiamine deficiency in patients with alcohol use disorder who are suffering from Wernicke-Korsakoff syndrome leads to lesions and increased microhemorrhages in the mammillary bodies, thalamus, and brainstem. This syndrome can also be associated with diseases of the gastrointestinal tract when there is inadequate thiamine absorption. All patients with alcohol use disorders should receive supplemental thiamine whenever entered into hospitalization or treatment to reduce this possibility.

INFECTIOUS DISEASES

Alcohol abuse is a major risk factor for many infectious diseases, especially pulmonary infections [144]. Studies have shown that alcohol abuse increases the risk for acute respiratory distress syndrome and chronic obstructive pulmonary disease [145,146,147,148]. Pneumonia, tuberculosis, and other pulmonary infections are frequent causes of illness and death among patients with alcohol use disorder [149]. Other infectious diseases that are over-represented among individuals with alcohol use disorder are bacterial meningitis, peritonitis, and ascending cholangitis. Less serious infections are chronic sinusitis, pharyngitis, and other minor infections.

Acute and chronic alcohol abuse also increase the risk for aspiration pneumonia. Alcohol use disorders are associated with increased risk of aspiration of gastric acid and/or oropharyngeal flora, decreased mucus-facilitated clearance of bacterial pathogens from the upper airway, and impaired pulmonary host defenses [150]. In addition, pathogenic colonization of the oropharynx is more common in patients with alcohol use disorder.

The consumption of alcohol alters T-lymphocyte functions, immunoglobulin production by B cells, NK cell function, and neutrophil and macrophage activities making patients with alcohol use disorder more susceptible to septic infection [151,152,153]. Studies have shown that animals given ethanol are unable to suppress infections that can ultimately result in progressive organ damage and death [154,155,156].

SLEEP DISORDERS

Although some people believe that alcohol helps them sleep, chronic excessive drinking can induce sleep disorders by disrupting the sequence and duration of sleep states and by altering total sleep time, as well as the time required to fall asleep [157,158]. Specifically, drinking within an hour of bedtime appears to disrupt the second half of the sleep period [159]. The person may sleep poorly during the second half of sleep, awakening from dreams and returning to sleep with difficulty, resulting in daytime fatigue and sleepiness [157,160].

Individuals with alcohol use disorder may be at increased risk for sleep apnea, a disorder in which the upper air passage narrows or closes during sleep [161,162,163,164]. The combination of alcohol, obstructive sleep apnea, and snoring increases a person's risk for heart attack, arrhythmia, stroke, and sudden death [165]. Obstructive sleep apnea significantly increases the risk of stroke or death from any cause, independent of other risk factors, including hypertension [166,167].

NERVOUS SYSTEM DYSFUNCTION

The most common neurologic abnormality among patients with alcohol use disorder is dementia syndrome, which manifests primarily as impairment in recent memory, and more subtle fluctuations in abstractions, calculations, and other aspects of cognitive functions. As previously stated, one specific neurologic complication resulting from thiamine deficiency is Wernicke-Korsakoff syndrome, which involves delirium, clouded sensorium, confusion, ophthalmoplegia, nystagmus, and ataxia [168]. Immediate administration of thiamine is usually successful in treating the symptoms, but in some cases permanent memory loss occurs [168]. Once delirium and confusion resolve, there is sometimes a profound loss in recent memory (out of proportion to the other cognitive deficits) and alcoholic peripheral neuropathy, which results in diminished sensitivity to touch, pinprick, and vibration (objectively, and paraesthesias subjectively).

The acute effects of alcohol on the nervous system are signs people commonly think of when they envision an intoxicated person, such as slurred speech, loss of coordination, unsteady gait, impairment of attention or memory, nystagmus, stupor, or coma. The degree to which the central nervous system is impaired is directly proportional to the BAC and degree of tolerance.

Alcohol and the Brain

Alcohol affects most neurochemical systems including NMDA, GABA, serotonin, dopamine (DA), and opioid systems.

Alcohol inhibits NMDA systems, which may contribute to feeling intoxicated. NMDA receptors change as tolerance develops. These receptor systems are overactive during withdrawal. Alcohol also enhances the action of the GABA system, producing some of the symptoms of acute intoxication. GABA receptors are especially sensitive to alcohol. The GABA system is underactive during withdrawal, and the genes that control these receptors may have an impact on the risk of alcohol use disorder [169,170].

Alcohol causes the release of 5-HT, or serotonin. Lower 5-HT levels in the brain are associated with increased alcohol intake in animals and humans, while higher 5-HT levels are associated with slightly reduced alcohol intake. Several 5-HT genes may be related to the genetic risk of alcohol use disorder [11,46].

Alcohol activates DA in the reward system in the ventral tegmental area of the brain. Alcohol also causes the release of DA. Several DA receptors may be related to the genetic risk of alcohol use disorder [11,46].

Finally, alcohol causes the release of endogenous opioids. Opioid receptors change with tolerance and withdrawal. Some receptors may affect genetic predisposition for alcohol use disorder, and opioid antagonists can decrease voluntary alcohol consumption. Alcohol may also affect acetylcholine, norepinephrine, and steroids.

Most people who drink do not develop brain damage. However, studies do indicate that impaired cognition and motor abilities occur in some individuals who are heavy drinkers. Older persons with alcohol use disorder exhibit more brain tissue loss than both older and younger persons without alcohol use disorder. These results suggest that aging may render a person more susceptible to the effects of chronic excessive alcohol. Most studies suggest that, following long-term abstinence, most brain changes resolve.

Magnetic resonance imaging has been used to measure changes in the brain structure and volume in persons with alcohol use disorder at three weeks after abstinence from alcohol [171]. The results indicated that the brain volume in men and women with alcohol use disorder was significantly reduced as compared with healthy men and women. The differences, however, were much more significant in women than in men [172]. These results indicate that alcohol inflicts greater neurotoxic effects in women with alcohol use disorder than men, but again, these brain changes may resolve with long-term abstinence. Results from a 2021 study found significant impacts of age, but not sex, on white matter microstructure in individuals with alcohol use disorder [173].

COMPLICATIONS SPECIFIC TO WOMEN

Although the literature on gender differences in addiction can appear at times to be inconsistent, as a whole men are more substance dependent than women for all substances except benzodiazepines and analgesics, on which women are equally or more frequently dependent [174]. However, on average, women show the effects of alcohol more immediately, more intensely, and for longer periods of time than men. They achieve higher concentrations of alcohol in the blood after drinking the same amounts of alcohol [175]. Women also produce a lower level of the enzymes required to break down alcohol. In addition, female hormones make women's bodies more susceptible to alcohol at certain times of the menstrual cycle. Women also tend to be shorter and weigh less than men. Because women generally have a higher percentage of body fat, they reserve alcohol in the body for longer periods of time. This is important because when a person drinks a large amount of alcohol, it is deposited in fatty tissues. Neurophysiology is more compromised in women with alcohol use disorder than men [176].

It may be because of these factors that women develop alcohol problems more quickly than men, and their progression to severe complications, such as liver disease, is more rapid. The death rate among women with alcohol use disorder is 50% to 100% greater than that of men because of their increased risk for suicide, alcohol-related accidents, cirrhosis, and hepatitis [177]. It is important to note, however, that women are more likely than men to obtain help, participate in treatment, and have long-term involvement in AA, and therefore are more likely to have better life outcomes [178].

International studies of gender differences indicate that the greater the societal gender equality in a country, the smaller the gender differences in drinking behavior. The gender gap in alcohol drinking is one of the few universal gender differences in human social behavior [179].

Fetal Alcohol Spectrum Disorders

Evidence Based Practice Recommendation

The World Health Organization recommends that healthcare providers should offer a brief intervention to all pregnant women using alcohol.

https://www.who.int/publications/i/item/9789241548731

Last Accessed: May 20, 2024

Strength of Recommendation/Level of Evidence: Strong/Low

The dangers of drinking while pregnant are well-documented. Pregnant women who drink risk the chance of their child developing FASD. Prenatal alcohol exposure is known to be toxic to the developing fetus and is one of the leading known preventable causes of intellectual disability. Excess fetal mortality secondary to drinking is most prevalent during the first trimester of pregnancy. Even drinking as little as one beer a day has been associated with decreased birth weights and spontaneous abortions. Although FASD has received a great deal of publicity, the majority of people may not understand it correctly. For example, one large study of adults 18 to 44 years of age found that the majority of respondents incorrectly assumed that FAS referred to infants born with an addiction to alcohol.

FASDs refer to the whole range of conditions that can affect the offspring of mothers who drank alcohol during pregnancy. These conditions can affect each person in different ways and can range from mild to severe. A person with an FASD might have [180]:

- Abnormal facial features, such as a smooth ridge between the nose and upper lip (the philtrum)

- Small head size

- Shorter-than-average height

- Low body weight

- Poor coordination

- Hyperactive behavior

- Difficulty with attention

- Poor memory

- Difficulty in school (especially with math)

- Learning disabilities

- Speech and language delays

- Intellectual disability or low IQ

- Poor reasoning and judgment skills

- Sleep and sucking problems as an infant

- Vision or hearing problems

- Problems with the heart, kidneys, or bones

There are a variety of conditions that are considered FASDs. Alcohol-related neurodevelopmental disorder (ARND) is associated with intellectual difficulties and problems with behavior and learning. Patients with ARND may do poorly in school, with particular issues with math, memory, attention, judgment, and impulse control [180]. Offspring of mothers who consumed alcohol, during pregnancy may also develop alcohol-related birth defects, including congenital malformations of the heart, kidneys, and/or bones or hearing problems.

The most commonly studied FASD is FAS. FAS is defined by the existence of certain physical characteristics of children whose mothers drank during pregnancy. These characteristics include [180]:

- Intellectual disability

- Growth deficiencies

- Central nervous system dysfunction

- Decreased brain size

- Low birth weight

- Distorted facial features

- Behavioral maladjustments

- Abnormal joints and limbs

Other less visible symptoms of FAS include [181,182,183,184,185,186,187,188,189,190]:

- Verbal learning and memory problems

- Visual-spatial learning problems

- Attention deficits and hyperactivity

- Increased reaction time/slow information processing

- Executive function problems

- Structural and functional changes in the brain

Alcohol apoptotic neurodegeneration has been shown to appear in the forebrain when rats are injected with alcohol. Seven-day-old rats were divided into a group receiving saline solution and another group receiving alcohol solution. The brains were examined after 24 hours of ingesting alcohol or saline. The alcohol group showed a very dense, widely distributed area of deterioration (cell death). When alcohol is administered, various neurons in the forebrain show sensitivity. Also, the brain weight of the alcohol-treated rats was much lower than the saline group. Exposure of the developing rat brain to alcohol for a certain period of time during a specific developmental stage induces destruction of brain cells that deletes large numbers of neurons from several areas of the brain. This period of time in humans is the last three months of gestation [191].

Alcohol is especially neurotoxic to the developing fetus. Vulnerability is highest at six months' gestation to several years after birth. During this period, alcohol exposure can kill millions of neurons in the developing brain. This helps to explain reduced brain size and behavior disturbances associated with FAS. The most disabling effects are hyperactivity and learning disabilities, depression, and psychosis. Depending on the time of exposure to alcohol, different neurons are depleted, which shows evidence of alcohol being an agent that can contribute to many mental disabilities.

The Centers for Disease Control and Prevention (CDC) reported in 2022 that nearly 14% (or 1 in 7) pregnant women 18 to 44 years of age used alcohol and 5.0% (1 in 20) were binge drinkers [192]. According to the CDC, the cost to the United States for FAS alone is more than $4 billion annually [192]. Additionally, an estimated 6 to 9 out of 1,000 U.S. school children may have FASDs [180]. Binge drinking among pregnant women increased from 4.7% in 2021 to 5.3% in 2022[12]. FASD is 100% preventable when pregnant women abstain from drinking alcohol [180,193].

EFFECTS ON FAMILIES

Living with a non-recovering family member with alcohol use disorder can contribute to stress for all members of the family. Children raised in these families have different life experiences than children raised in nonalcoholic families. For example, children living with a non-recovering alcoholic score lower on measures of family cohesion, intellectual cultural orientation, active recreational orientation, and independence. They also experience higher levels of conflict within the family. Many children of alcoholics experience other family members as distant and noncommunicative and may be hampered by their inability to grow in developmentally healthy ways. The level of dysfunction or resiliency of the nonalcoholic spouse is a key factor in the effects of problems impacting the children. Support groups, such as Children of Alcoholics, are available to help people deal with these issues.

Alcohol use disorder usually has strong negative effects on marital relationships. Separated and divorced men and women were three times as likely as married men and women to say they had been married to a person with alcohol use disorder or problem drinker. Almost two-thirds of separated and divorced women and almost one-half of separated or divorced men younger than 45 years of age have been exposed to alcohol use disorder in the family at some time. As of 2022, approximately 29.7 million Americans met the diagnostic criteria for alcohol use disorder; this number represents an increase from 18.1 million Americans in 2002 [12].

Child Abuse

The majority of studies suggest an increased prevalence of alcohol use disorder among parents who abuse children. Existing research suggests that alcoholism is more strongly related to child abuse than are other disorders, such as parental depression, but the most important factor is whether the abusive parent was abused themselves or witnessed a parent or sibling being abused. Although several studies report very high rates of alcoholism among the parents of incest victims, much additional research in this area is needed [194,195].

VIOLENCE

Among some individuals and subgroups, excess alcohol consumption is associated with the risk of violent behavior. Alcohol may encourage aggression or violence by disrupting normal brain function, especially in levels of serotonin [196]. There is considerable overlap among nerve cell pathways in the brain that regulate aspects of aggression, sexual behavior, and alcohol consumption. Alcohol may weaken brain mechanisms that normally restrain impulsive behaviors, including inappropriate aggression.

Drinking and violence may occur together by chance. Also, violent criminals who drink heavily are more likely to be caught and consequently are over-represented in samples of people arrested for violent behavior. Antisocial personality disorder (ASPD) and early-onset alcoholism are common traits in many criminals. A person who intends to engage in a violent act may drink to bolster his or her courage or in hopes of evading punishment or censure. The motive of drinking to avoid censure is encouraged by the popular view of intoxication as a "time-out," during which a person is not subject to the same rules of conduct as when sober. Such alcohol-violence interactions are not readily treated. However, ongoing research has identified medications that have the potential to reduce violent behavior in both alcoholic and nonalcoholic subjects.

Young men who exhibit violent and antisocial behaviors often "burn out" with age [197]. By the time they reach 40 years of age, serotonin concentrations are increasing and testosterone concentrations are decreasing, both of which help to restrain violent behavior [198].

Research suggests that increasing the unit price of alcohol by raising alcohol taxes is an effective strategy for reducing excessive alcohol consumption and related harms, including violent behavior [199]. An examination of the impact of the price of alcoholic beverages on violence and other delinquent behavior among college students found that an increase in the price of beer could reduce the overall number of students involved in some sort of violent behavior by 4% [200]. In a study that used data from the National Household Survey on Drug Abuse, higher taxes on beer led to significant reductions in crime (e.g., property damage, use of force), with the largest impact among individuals younger than 21 years of age [201]. Another study that examined the impact of tax increases and advertising bans on reducing the prevalence of underage drinking and subsequent alcohol-related harms found both interventions to be effective [202]. A literature review of studies of underage populations found that increased taxes were significantly associated with reduced consumption and alcohol-related harms [203]. Public policies that affect the price of alcohol appear to have significant effects on alcohol-related disease and injury rates. The results of one systematic review suggest that doubling the tax on alcoholic beverages could reduce alcohol-related violence by 2% and crime by 1.4% [204].

According to the National Council on Alcoholism and Drug Dependence, on college campuses each year an estimated 696,000 students 18 to 24 years of age are assaulted by another student who has been drinking, and 97,000 students report experiencing alcohol-related sexual assault or date rape [205]. Four out of every five juvenile and teen arrestees are under the influence of alcohol or drugs while committing their crimes, test positive for drugs, are arrested for committing an alcohol- or drug-related offense, admit having substance abuse problems, or share some combination of these characteristics [206].

TRAFFIC ACCIDENTS

In 2022, 10,317 people died in alcohol-related traffic fatalities, accounting for 32% of all traffic-related deaths in the United States [207]. Of the 1,090 traffic-related fatalities in 2020 among children 0 to 14 years of age, 229 (21%) involved an alcohol-impaired driver [208]. Of the estimated 127 million episodes of alcohol-impaired driving among U.S. adults, 1 million drivers were arrested for driving under the influence [208]. The CDC estimates that 32 people in the United States die in alcohol-related crashes every day [208]. In a study of persons who have been convicted of driving while impaired, 85% of women and 91% of men reported a lifetime alcohol use disorder [209]. Psychiatric comorbidity may be a key element distinguishing driving under the influence (DUI) offenders from others and in distinguishing repeat offenders from first-time offenders [210].

A study found that although marijuana's effects on driving performance were small or moderate when taken alone, the effects were severe when combined with even a low dose of alcohol. These findings are very serious considering the frequency with which these two substances are combined, especially in young inexperienced drivers [211,212,213,214,215]. One study conducted at seven trauma centers involving 4,243 drivers who were seriously injured in crashes found that 54% of these drivers tested positive for alcohol and/or drugs from September 2019 to July 2021. Of these, 22% of the drivers tested positive for alcohol, 25% tested positive for cannabis, 9% tested positive for opioids, 10% tested positive for stimulants, and 8% tested positive for sedatives [216].

8. OTHER PSYCHIATRIC DISORDERS ASSOCIATED WITH ALCOHOL USE DISORDERS

Persons with alcohol use disorder, like other addicts, generally have comorbid disorders, meaning they have alcohol problems as well as other illnesses or conditions [217]. These problems may include personality disorders (formerly Axis II disorders), other drug use (especially tobacco use disorders), or a number of psychiatric disorders, from major depression and bipolar illness to eating disorders and anxiety disorders. One study reported that 50% of women and 33% of males with a history of alcohol use disorders have at least one other psychiatric disorder [209]. Treatment of the comorbid disorder is absolutely essential in preventing relapses to drinking and in preventing other adverse consequences, such as suicide among patients with depression and alcohol use disorder.

DEPRESSIVE DISORDERS

Alcohol is both a stimulant and a depressant, depending on the levels and time after drinking. Patients with alcohol use disorder are often misdiagnosed with depression because of the many symptoms that mimic depression. Insomnia, reduced appetite, and decreased energy are just a few of the symptoms that can occur in both diseases. Alcohol can cause temporary depressive symptoms, even in persons who have no history of depression. In fact, as many as 80% of men and women with alcohol use disorder complain of depressive symptoms, and at least one-third meet the criteria for a major depressive disorder (excluding, of course, criterion D) [218]. Depression is often a comorbid disorder but can also be solely or partially due to alcohol. This carries important implications in the way depressive symptoms are evaluated and treated in patients with alcohol use disorders. Alcohol intoxication, especially binge drinking, can also cause mood swings that mimic the "highs" of people with manic depression/bipolar disorder. Thirty to fifty percent of persons with alcohol use disorder suffer from major depression at the same time [218,219]. Studies have found that many cases initially diagnosed as substance-induced depression were later reclassified as independent depression (i.e., not substance-induced) because the condition persisted after a period of abstinence [220].

How alcohol use disorder is related to depression is not clear. Some studies have suggested that both conditions may share common risk factors. For example, both problems may run in families. Co-occurrence is very common, but likely has independent though inter-related etiology.

Treatment professionals have found that after two to three weeks of abstinence from alcohol and with good nutrition, the temporary depressive effects of alcohol dissipate. However, there are subgroups of individuals with alcohol use disorder who have a co-occurring depression or manic depression, and it is critically important to diagnose and treat these illnesses during alcohol treatment. If true co-occurring depression is left untreated, many patients will drop out of treatment and relapse to drinking. Alcohol use disorders and depression are important risk factors for suicidal thinking or actions. Because alcohol can increase impulsivity and make depression worse, even intolerable, alcohol is often a factor in suicides.

Suicide

Suicide is the 2nd leading cause of death among persons 25 to 34 years of age and the 3rd leading cause of death among persons 15 to 24 years of age [221]. Most people who attempt suicide and 90% of suicide victims have a diagnosable psychiatric disorder [222]. Alcohol is the number one drug of abuse associated with suicide. In 2021, 48,183 people in the United States died by suicide and an estimated 1.7 million attempted suicide [221]. Among people who attempt suicide, alcohol use disorder is a common diagnosis. Major depression and alcohol use disorder, respectively, are the most commonly diagnosed psychiatric disorders in patients who die by suicide. They also are more common among planned suicide attempts than among impulsive attempts [223]. Next to age, alcohol and drug addictions are the second most important risk factors in suicide. As many as 85% of individuals who die by suicide suffer from depression or alcohol use disorder, and 70% of patients with comorbid alcohol use disorder and depression report that they have made a suicide attempt at some point in their lives [224]. The reported likelihood of suicide in diagnosed alcoholism is between 60 and 120 times that of persons without mental illness [225]. Suicide attempts among women with alcohol use disorder are more mental health-related, whereas suicide attempts among men are more related to the severity of alcohol use disorder [226].

Alcohol intoxication can exaggerate depression and increase the likelihood of an impulsive act like suicide or other forms of violence. Alcohol use is frequently detected in suicide methods involving firearms, driving a vehicle, or overdosing. Alcohol impairs judgment and lowers the threshold to attempt suicide, explaining its association with suicide methods that involve a high level of pain [227]. In a case-control study, researchers examined the relationship between near fatal suicide attempts and aspects of alcohol consumption, such as amount and frequency of drinking, alcoholism, binge drinking, and drinking within three hours of a suicide attempt, and found a J-shaped relationship between alcohol exposure and near lethal attempts for all measures [228].

In a comprehensive review of the subject, it is estimated that the lifetime suicide risk among individuals with alcohol use disorder is 10% to 15%, a figure 5 to 10 times greater than seen in the general population [227,229]. Between 15% and 20% of persons with alcohol use disorder will attempt suicide, and of those who have attempted in the past, 15% to 20% will attempt suicide again in the next five years [229]. Approximately 40% of all patients seeking treatment for alcohol use disorder report at least one suicide attempt at some point in their lives [227].

One study conducted in Japan showed that, among drinkers, the risk of suicide increased with the amount of alcohol consumed. An unusual finding of this study was a U-shaped relationship between alcohol and suicide. Abstainers also have a significantly increased risk, similar to heavy drinkers. Among middle-aged males, moderate drinkers had the lowest risk for suicide [230].

In order to be most effective at the prevention of suicide, healthcare providers should be adept at eliciting both a substance use history and a psychiatric history. Risk factors associated with completed suicide with alcohol use disorder include comorbid major depression, active drinking, serious medical illness, living alone, and interpersonal loss and conflict.

Treatment of Patients with Comorbid Depression and Alcohol Use Disorder

Male, alcoholic, and depressed are the most common descriptors for suicide attempters. Always evaluate persons with alcohol use disorder for depression, suicide, and appropriate referral to a psychiatrist or psychologist. Depression and alcohol use disorder are common problems in the United States. Both are at the top of the list of problems that commonly require psychiatric treatment. Unfortunately, both problems are difficult to diagnose by physicians due to patient fears and stigma and the realities of a busy medical office. Treating one problem but not the other is also very common. In order to successfully treat alcohol use disorder and depression it is important that healthcare providers diagnose and treat both problems.

Treatment of alcohol use disorder begins with evaluation, stabilization, and detoxification and the appropriate level of treatment, which may include a 12-step program. Adding an antidepressant and treating the depression requires a number of subtle changes in thinking. First, the physician must be convinced that the depression is not transient and related to alcohol or detoxification or so severe that the patient is unable to do treatment work. Next, the patient must be willing to accept and adhere to simultaneous, coordinated treatment.

The next issue is determining which antidepressant to use. Lithium and tricyclics used to treat depression alone may not be effective or could have serious adverse effects when used in patients with comorbid depression and alcohol use disorder. Another class of antidepressants, selective serotonin reuptake inhibitors (SSRIs), has been studied to treat depression after failing to treat alcohol use disorder. SSRIs generally cause less serious adverse effects than tricyclics, but some, like fluoxetine, work slowly and cause sexual performance side effects. SSRIs, such as fluoxetine, sertraline, and paroxetine, and herbal remedies such as St. John's wort have been tried in a variety of studies and are generally able to help alleviate depression, but do not appear to help with drinking outcomes. Results of a systematic review found only low-quality evidence to support the use of antidepressants for the treatment of co-occurring depression and alcohol use disorder [231]. A Japanese study observed lower response to antidepressant treatment in patients with comorbid depression and alcohol use disorder [232]. Venlafaxine and bupropion appear to be especially effective in treating patients with depression and alcohol use disorder. Venlafaxine is well suited to treat alcohol use disorder with depression and even depression with anxiety [233]. Venlafaxine is effective in mild and severe depression with anhedonia. Bupropion is effective as well, but it has seizure risks in this population [234]. One study that evaluated treatment outcomes in patients with comorbid alcohol use disorder and depression found venlafaxine and bupropion to be less effective than antidepressants [235]. Men with depression who are using alcohol appear very sensitive to the sexual side effects of the SSRIs and may discontinue their use and drop out of treatment. Both pharmacologic and behavioral treatments have demonstrated efficacy for patients with comorbid depression and alcohol use disorder; however, treatment response is modest, particularly for drinking outcomes [236]. Transcranial magnetic stimulation is now available for refractory depression, and studies are in progress for its use in treating substance use disorder [237].

BIPOLAR DISORDER

A 2000 study analyzed the substance/alcohol abuse patterns of 89 patients with a confirmed diagnosis of bipolar disorder (71 with bipolar I and 18 with bipolar II) [238]. The diagnosis was confirmed by a structured clinical interview for DSM-IV Axis I, an attending psychiatrist, a medical records review, and family members. The age of the patients ranged from 18 to 65 years. Among those with bipolar disorder I, 41 patients (57.8%) abused or were dependent on one or more substances (including alcohol), 28.2% abused or were dependent on two substances, and 11.3% abused or were dependent on three or more substances. Among those with bipolar disorder II, 39% of patients abused or were dependent on one or more substances, 17% were dependent on two or more substances, and 11% were dependent on three or more substances. The risk for substance or alcohol abuse was higher among patients with bipolar I disorder than with bipolar disorder II. Patients with both bipolar disorders I and II abused alcohol more often than any other substances [238]. One study sought to identify the demographic and clinical differences between patients with bipolar disorder both with and without alcohol use disorder [239]. Data from 238 patients with bipolar disorder included alcohol use, social demographics, longitudinal course of bipolar disorder, clinical features of depressive episodes, comorbid physical diseases, anxiety disorder, and other substance use disorder. Of the 238 patients with bipolar disorder, 74 had alcohol use disorder, with the best predictors of alcohol use disorder being male sex, younger age, and comorbidity with other unclassified substance dependence [239].

ANXIETY

Alcohol withdrawal causes many of the signs and symptoms of anxiety and can even mimic panic attacks. Alcohol works much like a benzodiazepine; many people who abuse and are dependent on alcohol have learned to drink to temporarily relieve anxious feelings.

Special problems exist for people who drink to self-medicate the symptoms of a true generalized anxiety disorder, social phobia, or panic disorder. Alcohol may provide temporary relief, but it is not a good treatment for shyness or an anxiety disorder. The price a person may pay for self-medication are two diseases: anxiety and alcohol use disorder. Social anxiety can be a major impediment to active participation and even attendance to group therapy and 12-step meetings.

PAIN

Pain is a subjective experience, and the perception of being in pain is an important factor of the alcohol use disorder. It is hypothesized, as well as established in some research, that individuals in pain will drink as a means to decrease their perception of pain or as a reaction to painful stimuli [240]. According to the National Institute on Alcohol Abuse and Alcoholism, an estimated one in four adults in chronic pain reports self-medicating with alcohol and 43% to 73% of people with alcohol use disorder report experiencing chronic pain [241].

ABUSE/DEPENDENCE ON OTHER DRUGS

All drugs of abuse, including alcohol, cause dopamine release in the mesolimbic system in the brain. This dopamine system, sometimes referred to as the neuroanatomy of pleasure or reinforcement, starts in the ventral tegmental area and projects to the nucleus accumbens. Alcohol- or drug-taking results in a dopamine reward that stimulates its taking. Pavlovian conditioning to environmental cues (e.g., sights, smells, and sounds of a bar) that precede use become associated with use of the drug. Notably, this sense of "reward," which confers evolutionary fitness, is more likely to be perceived as crucial than even that produced by natural, survival-oriented stimuli (e.g., food, sex). This conditioning is reflective of synaptic strengthening mediated by the glutamatergic system, with neuroplasticity changes in brain areas thought to mediate drug-taking behavior, including the amygdala (stress and anxiety), hippocampus (memory), and dorsal striatum (routine motor movements). Natural stimuli (e.g., food, sex, other previously pleasurable activities) become less enjoyable, resulting in a profound state of anhedonia. With time, alcohol use disorders become ingrained. Ultimately, this preference for alcohol compared to natural rewards is mediated through a process of "bad learning," or neuroplasticity changes in the extended amygdala, also referred to as the antireward system. The anti-reward system involves stress-response hormones, including corticotrophin-releasing hormone and dynorphin. Long- or short-term abstinence activates the antireward system, and with more abstinence, it becomes even more difficult to ignore with the attendant anxiety, dysphoria, craving, and anhedonia. Over time, with repeated administration, nucleus accumbens dopamine receptors desensitize, leading to a functional decrease in available dopamine, anhedonia, and decreased sense of pleasure. Real-world examples include an individual with alcohol dependence developing a sudden craving for a drink when watching a beer commercial, walking by a bar, or seeing a place where s/he drinks. This stage reveals one of the remarkable properties of addiction; the act of drug-taking transitions from being impulsive (i.e., pleasure-seeking without afterthought) to compulsive (i.e., undertaken to relieve stress, tension, or physical signs such as pain).

Alcohol use disorders are often associated with dependence on or abuse of other substances, such as marijuana, cocaine, opioids, amphetamines, anxiolytics, designer or "club drugs," and tobacco. Alcohol may be used to alleviate the unwanted effects of these other substances or to augment their effects or substitute for them when they are not available.

Cocaine

According to the most recent National Survey on Drug Use and Health, about 5.2 million Americans 12 years of age and older were past year cocaine users in 2019 [12]. Many cocaine addicts also use alcohol to enhance euphoria, to reduce the mania associated with intoxication, or to calm or reduce the impact of dysphoria caused by cocaine withdrawal. Use of cocaine impairs both mental and physical functions, including learning and memory, hearing and seeing, motor coordination, speed of information processing, and problem-solving ability. Alcohol use has its own set of impairments, but many overlap with cocaine use. The negative impact exerted by alcohol and cocaine on either mental or physical activities has been found to be greater than when either is used alone. This is due to the production of a compound called cocaethylene. Cocaethylene is a novel compound that is produced in the bodies of individuals using cocaine and alcohol. Cocaethylene has been linked to cardiotoxicity, neurotoxicity, overdose deaths, and acute functional impairment [242,243]. The combination of cocaine and alcohol may be associated with other neurologic changes, including poor memory and poorer judgment. Alcohol use can also be a trigger for cocaine relapse.

Nicotine Addiction

As many as 50% of persons with alcohol use disorder smoke, compared with about 18% of the general population [12,244]. In a cohort study of 845 persons who had been treated for alcohol use disorder, more than 25% of the sample had died within 12 years [245]. Approximately one-half of the deaths were related to tobacco use and one-third were related to alcohol. Smoking and excessive alcohol use are risk factors for cardiovascular and lung diseases and some forms of cancer. Compared to nonsmoking nondrinkers, the risk for developing mouth and throat cancer is seven times greater for those who use tobacco, six times greater for those who use alcohol, and 300 times greater for those who use both tobacco and alcohol [246].

Both nicotine and alcohol consumption cause the release of dopamine in the nucleus accumbens. Neurobiology may make the combination of the two substances more rewarding than if either substance was taken alone. Certain enzymes in the liver (i.e., microsomal enzymes) convert some of the ingredients found in tar from cigarette smoke into chemicals that can cause cancer [247]. Long-term excessive alcohol consumption may activate these enzymes as well as decrease the body's ability to respond to infections or abnormal states. Smoking and excessive alcohol use are significant risk factors for cancer of the mouth, throat, and esophagus [246].

A 2000 study revealed that people who smoke, drink alcohol (one or more drinks per day) and develop non-small cell lung cancer had more mutations in the p53 gene when compared to those who smoked only or did not smoke or drink [248]. Mutations in the p53 gene have been seen in smoking-associated tumors and were present more often in alcohol drinkers who smoked cigarettes, than in nondrinkers who smoked cigarettes or in nondrinkers who did not smoke. Seventy-six percent of patients who consumed one or more alcoholic drinks per day and smoked were found to have mutations in the p53 gene. In contrast, 42% of smokers who did not drink (consuming less than one drink per day) had gene mutations [248].

A 2006 study sought to determine how nicotine delivered by tobacco smoke influences alcohol intake. Findings suggest that smoking increases alcohol consumption in at least a subset of smokers [249]. Animal studies have found that chronic nicotine use leads to escalation of alcohol self-administration through a dysregulation in opioid signaling [250,251].

One of the major barriers to treating tobacco dependence in patients with a co-occurring alcohol use disorder is the notion that it is too difficult to quit both alcohol and tobacco and that attempts to quit tobacco might adversely affect the patient's recovery from alcoholism [252,253]. Treatment facilities often concentrate on the "primary" addiction to alcohol and treat tobacco use as a more benign addiction. Fewer than 1 in 10 treatment facilities ban tobacco use on their grounds and many treatment facilities do not screen for or treat tobacco dependence [254]. Moreover, many treatment facilities enable patient smoking by adjourning meetings for "smoke breaks" and allowing staff to smoke openly with patients [255]. In fact, studies show that quitting smoking does not cause abstinent alcoholics to relapse and may actually decrease the likelihood of relapse [256]. Further, quitting smoking has been found to facilitate drinking cessation among tobacco and alcohol co-users [257].

EATING DISORDERS

Alcohol use disorder and eating disorders are commonly comorbid conditions, with patterns of comorbidity differing by eating disorder subtype [258]. A community-based sample of women found that those with lifetime alcohol use disorder or nicotine dependence were at higher risk for eating disorders [259]. The process of alcohol detoxification and treatment is often accompanied by overeating with weight gain, and in some cases food becomes a replacement for alcohol [141,260].

PATHOLOGIC GAMBLING

As lotteries proliferate and states legalize casino gambling, pathologic or compulsive gambling is being recognized as a major public health problem. Alcohol use disorder is often a comorbid condition among compulsive gamblers. As with depression, each disorder can make the other more serious. Individuals with alcohol use disorder may bet more money and may be reluctant to quit chasing their losses. In one study, subjects received either three alcoholic drinks or an equal volume of a nonalcoholic beverage (placebo) [261]. The alcohol group persisted for twice as many gaming trials as the placebo group. One-half of the alcohol group lost their entire cash stake, compared with 15% of the placebo group [261].

Another study examined how alcohol affects judgment and decision-making during gambling, with a focus on sequential decision-making, including the gambler's fallacy (i.e., thinking that a certain event is more or less likely, given a previous series of events) [262]. Thirty-eight male participants completed a roulette-based gambling task 20 minutes after receiving either an alcoholic or placebo beverage. The task measured color choice decisions (red/black) and bet size, in response to varying lengths of color runs and winning/losing streaks. Color choice affected run length in line with the gambler's fallacy, which further varied by previous wins or losses. Bet size increased particularly for losing streaks. The alcohol group placed higher bets following losses than did the placebo group [262].

SEXUAL DYSFUNCTION

Alcohol metabolism alters the balance of reproductive hormones in men and women. In men, alcohol can impair the synthesis of testosterone and reduce sperm production. In women, chronic excessive alcohol use may cause a decreased interest in sex.

9. DETECTING ALCOHOL USE DISORDERS

Problem drinking described as severe is given the medical diagnosis of alcohol use disorder. An estimated 28.8 million adults 18 years of age and older in the United States have an AUD, including 17.1 million men and 11.7 million women. In addition, an estimated 753,000 adolescents 12 to 17 years of age had an alcohol use disorder [63].

AUD is a chronic relapsing addiction previously called alcoholism and characterized by an impaired ability to stop or control alcohol use despite adverse social, occupational, or health consequences. To be diagnosed with alcohol use disorder, individuals must meet the specific DSM criteria. Using the DSM-5-TR, anyone meeting any 2 of the 11 criteria during the same 12-month period receives a diagnosis of alcohol use disorder. The severity of the disorder—mild, moderate, or severe—is assigned based on the number of criteria met.

RECOMMENDED STANDARDIZED QUESTIONS OR TESTS

A variety of screening instruments are available to detect unhealthy alcohol use in adults. After conducting a systematic evidence review of trials published between 1985 and 2011 on screening and behavioral counseling interventions for unhealthy alcohol use in adults, the U.S. Preventive Services Task Force (USPSTF) recommends that clinicians screen all patients 18 years of age or older for alcohol abuse using one of the following tools [263,264]:

- The abbreviated three-question AUDIT-Consumption (AUDIT-C)

- The NIAAA-recommended Single Alcohol Screening Question (SASQ)

Evidence Based Practice Recommendation

For patients in general medical and mental healthcare settings, Veterans Affairs recommends recommend screening for unhealthy alcohol use periodically using the three-item Alcohol Use Disorders Identification Test, Consumption (AUDIT-C) or Single Item Alcohol Screening Questionnaire (SASQ).

https://www.healthquality.va.gov/guidelines/mh/sud

Last Accessed: May 20, 2024

Strength of Recommendation: Strong for

The USPSTF concludes that there is insufficient evidence to determine the benefits and harms of screening for unhealthy alcohol use in adolescents 12 to 17 years of age [263].

The three questions on the Alcohol Use Disorders Identification Test-Concise (AUDIT-C) inquire about frequency of alcohol use, typical amount of alcohol use, and occasions of heavy use. The test takes one to two minutes to administer. Preliminary evidence suggests that the USAUDIT-C (based on U.S. standards) may be more valuable in identifying at-risk college drinkers [265]. In contrast, the SASQ inquires about past-year alcohol use and takes less than one minute to administer [263].

The CAGE questionnaire is the best known and most often studied screening tool used to detect alcohol problems. In an office setting, the four CAGE questions are often used to detect alcohol problems [266]. The first question, "Have you ever felt the need to cut down on your drinking?" is an easy question to ask. It is not threatening and at the same time suggests to the patient that you understand their pathologic attachment to alcohol [266]. A positive answer to the first and second questions strongly suggests further evaluation and brief intervention [263]. However, by itself, the CAGE questionnaire is not an adequate screening for alcohol use problems; it should trigger more intensive screening if positive [266,267].

CAGE Questionnaire

Ask current drinkers the CAGE questions:

1. Have you ever felt that you should cut down on your drinking?

2. Have people annoyed you by criticizing your drinking?

3. Have you ever felt bad or guilty about your drinking?

4. Have you ever had a drink first thing in the morning to steady your nerves or get rid of a hangover (eye opener)?

If there is a positive response to any of these questions:

- Ask if this occurred during the past year.

A patient may be at risk for alcohol-related problems if:

- Alcohol consumption is:
Men:

14 drinks per week or

4 drinks per occasion

Women:

7 drinks per week or

3 drinks per occasion

Or

- One or more positive responses to the CAGE that have occurred in the past year

When is screening for alcohol problems appropriate?

- As part of a routine health examination

- Before prescribing a medication that interacts with alcohol

- In response to presenting problems that may be alcohol related

One "yes" response to the CAGE questionnaire suggests an alcohol use problem. More than one "yes" is a strong indication that a problem exists [267,268].

AUDIT Questionnaire

If a patient is CAGE positive, or if clinical suspicion remains high, the AUDIT questionnaire may be administered and can be extremely useful in detecting alcohol problems [252]. The AUDIT was developed by the WHO to identify persons whose alcohol consumption has become problematic to their health [253]. Research has shown that the AUDIT may be especially useful when screening women and minorities and has shown promise when tested in adolescents and young adults [254]. The AUDIT consists of 10 screening questions with three questions about the frequency and amount of drinking, three about dependence, and four questions about problems caused by alcohol [246,249,255].

1. How often do you have a drink containing alcohol?
0 Never

1 Monthly or less

2 2 to 4 times a month

3 2 to 3 times a week

4 4 or more times a week

2. How many drinks containing alcohol do you have on a typical day when you are drinking?
0 1 or 2

1 3 or 4

2 5 or 6

3 7 or 8

4 10 or more

3. How often do you have 6 or more drinks on one occasion?
0 Never

1 Less than monthly

2 Monthly

3 Weekly

4 Daily or almost daily

4. How often during the past year have you found that you were not able to stop drinking once you had started?
0 Never

1 Less than monthly

2 Monthly

3 Weekly

4 Daily or almost daily

5. How often during the past year have you failed to do what was normally expected from you because of drinking?
0 Never

1 Less than monthly

2 Monthly

3 Weekly

4 Daily or almost daily

6. How often during the past year have you needed a first drink in the morning to get yourself going after a heavy drinking session?
0 Never

1 Less than monthly

2 Monthly

3 Weekly

4 Daily or almost daily

7. How often during the past year have you had a feeling of guilt or remorse after drinking?
0 Never

1 Less than monthly

2 Monthly

3 Weekly

4 Daily or almost daily

8. How often during the past year have you been unable to remember what happened the night before because you had been drinking?
0 Never

1 Less than monthly

2 Monthly

3 Weekly

4 Daily or almost daily

9. Have you or someone else been injured as a result of your drinking?
0 No

2 Yes, but not in the past year

4 Yes, during the past year

10. Has a relative or friend or a doctor or other health worker been concerned about your drinking or suggested you cut down?
0 No

2 Yes, but not in the past year

4 Yes, during the past year

The minimum score is 0 and the maximum possible score is 40. A score of 8 or more indicates a strong likelihood of hazardous or harmful alcohol consumption [203].

AUDIT-C Questionnaire

The AUDIT-C is a 3-question screening tool that can help identify persons who are at-risk drinkers (who may not be alcohol dependent) or who have active alcohol use disorders, including alcohol abuse or dependence [256].

1. How often do you have a drink containing alcohol?
0 Never

1 Monthly or less

2 2 to 4 times a month

3 2 to 3 times a week

4 4 or more times a week

2. How many standard drinks containing alcohol do you have on a typical day?
0 1 or 2

1 3 or 4

2 5 or 6

3 7 or 8

4 10 or more

3. How often do you have six or more drinks on one occasion?
0 Never

1 Less than monthly

2 Monthly

3 Weekly

A score of 4 or more in men and 3 or more in women (when not all points are from question 1) is considered positive for hazardous drinking or alcohol use disorder [273].

Single Alcohol Screening Question (SASQ)

The SASQ consists of one question: "How many times in the past year have you had X or more drinks in a day?" [263]. The question is individualized based on sex, with X being five for men and four for women. A response of more than one is considered positive and requires additional assessment.

ADDITIONAL STANDARDIZED QUESTIONS OR TESTS

Michigan Alcohol Screening Test (MAST)

The Michigan Alcohol Screening Test (MAST) continues to be a good screening test for alcohol abuse and dependence, but for optimal results it should be used with a questionnaire that asks about the amount and frequency of alcohol consumption. The following questions are from the 13-item Short MAST (SMAST) regarding the respondent's involvement with alcohol during the past 12 months [249]:

1. Do you think you are a normal drinker? (By normal we mean you drink less than or as much as most other people.)
No = 1 Yes = 0

2. Does your wife, husband, a parent, or other near relative ever worry or complain about your drinking?
No = 0 Yes = 1

3. Do you feel guilty about your drinking?
No = 0 Yes = 1

4. Do friends or relatives think you are a normal drinker?
No = 1 Yes = 0

5. Are you able to stop drinking when you want to?
No = 1 Yes = 0

6. Have you ever attended a meeting of Alcoholics Anonymous?
No = 0 Yes = 1

7. Has drinking ever created problems between you and your wife, husband, a parent, or other near relative?
No = 0 Yes = 1

8. Have you ever gotten into trouble at work because of your drinking?
No = 0 Yes = 1

9. Have you ever neglected your obligations, your family, or your work for two or more days in a row because you were drinking?
No = 0 Yes = 1

10. Have you ever gone to anyone for help about your drinking?
No = 0 Yes = 1

11. Have you ever been in a hospital because of drinking?
No = 0 Yes = 1

12. Have you ever been arrested for drunken driving, driving while intoxicated, or driving under the influence of alcoholic beverages?
No = 0 Yes = 1

13. Have you ever been arrested, even for a few hours, because of drunken behavior?
No = 0 Yes = 1

Key: There are two definitions for this test.

Seltzer Definition:

0-1 points = Nonalcoholic

2 points = Possibly alcoholic

3 or "yes" to 6, 10, or 11 = Alcoholic

Ross Definition:

5 points = Alcohol abuse

Comorbidity-Alcohol Risk Evaluation Tool (CARET)

There are certain risks and comorbidities (e.g., psychiatric and medical conditions requiring pharmacologic treatment) that may modify the criteria of at-risk drinking, especially within the geriatric population [275]. It is important for healthcare providers to assess each patient's threshold for alcohol use, taking into account their level of risk and comorbidities. The Comorbidity-Alcohol Risk Evaluation Tool (CARET) may be helpful in this task, with comorbidity-specific measures to place patients in "at-risk" or "not-at-risk" groups [276].

SCREENING FOR ALCOHOL ABUSE IN NON-ENGLISH-PROFICIENT PATIENTS

Communication with patients regarding history and current alcohol use patterns is a necessary step in determining if alcohol use has become a problem. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required. Frequently, this may be easier said than done, as there may be institutional and/or patient barriers.

If an interpreter is required, the practitioner should acknowledge that an interpreter is more than a body serving as a vehicle to transmit information verbatim from one party to another. Instead, the interpreter should be regarded as part of a collaborative team, bringing to the table a specific set of skills and expertise [277]. Several important guidelines should be adhered to in order to foster a beneficial working relationship and a positive atmosphere.

When interpreters are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers, who ultimately enhance the clinical encounter. When providing care for patients for whom English is a second language, the consideration of the use of an interpreter and/or patient education materials in their native language may improve patient understanding and outcomes.

In addition, several organizations provide information and toolkits in languages other than English. The National Hispanic Medical Association offers an alcohol screening kit in Spanish, including patient education sheets [278]. The National Institute on Alcohol Abuse and Alcoholism also provides patient education brochures and pamphlets in English and Spanish [279].

LABORATORY TESTS

The FDA has approved a test to detect alcohol use disorder and alcohol-related diseases. The test detects the level of carbohydrate-deficient transferrin (CDT) in the body, which is elevated in persons with alcohol use disorder and remains elevated even several weeks after drinking is stopped [280]. The advantages of the CDT test are reliability and the availability of automated test results within four hours [281,282]. The CDT is often used in combination with other screening tests, such as the gamma-glutamyl transferase (GGT) test. While both CDT and GGT are independently associated with alcohol abuse, combining tests may dramatically increase sensitivity [267,283]. CDT is less sensitive/specific in women than in men [267].

Tests for Recent Alcohol Use (Hours)

The relationship between alcohol and the liver serves as the basis for many of the tests that identify possible alcohol abusers. Alcohol markers for recent alcohol ingestion include urine/breath/blood, AlcoPatch, methanol, urinary ethyl glucuronide (EtG) and ethyl sulfate(ES), whole blood phosphatidylethanol, and the ratio of 5-hydroxytryptophol (5-HTOL) to 5-hydroxyindole-3-acetic acid (5-HIAA) [267,284].

Tests for Less Recent Alcohol Use (Weeks)

The CDT test is often used to assess prolonged ingestion of high amounts of alcohol (more than 50–80 g/day for two to three weeks) [267]. Another test examines hemoglobin or whole blood acetaldehyde adducts. In a study of almost 3,000 women and 4,000 men, the combination of CDT and GGT compared with either alone shows a higher diagnostic sensitivity and specificity and is correlated more strongly with alcohol consumption than either test alone (Table 1) [285,286,287].

Table 1: LABORATORY MARKERS FOR ALCOHOL USE

Markers

Sensitivity

Specificity

Men

CDT

73%

96%

GGT

65%

89%

CDT with GGT

90%

84%

Women

CDT

52%

94%

GGT

54%

97%

CDT with GGT

76%

91%

Source: [285]

Tests for Chronic Alcohol Use (Years)

Tests in this category look at the classic toxic markers that use of alcohol leaves on the body. They include [267]:

- Liver function tests

- GGT

- Aspartate aminotransferase (AST)

- Alanine aminotransferase (ALT)

- Red blood cell index

- Mean corpuscular volume (MCV)

10. BRIEF INTERVENTION

Despite the fact that alcohol abuse complications have caused grave illness and many deaths, physicians are not always good at detecting alcohol and other drug abuse in their patients. Even when physicians and other health professionals identify an individual with alcohol use disorder, they are sometimes unsure of how to proceed. At times, the physician will offer help but the patient refuses. Nevertheless, the addiction specialist or the primary care physician with a continuous, comprehensive, patient-centered approach to the medical, psychosocial, and family issues is the ideal person to offer intervention, treatment, and recovery support.

Evidence Based Practice Recommendation

For patients without documented alcohol use disorder who screen positive for unhealthy alcohol use, Veterans Affairs suggest providing a single initial brief intervention regarding alcohol-related risks and advising to abstain or drink within established limits for daily and weekly consumption.

https://www.healthquality.va.gov/guidelines/mh/sud

Last Accessed: May 20, 2024

Strength of Recommendation: Weak for

Almost 20% of patients treated in a primary care setting drink at levels that may place them at risk for developing alcohol-related problems [267,288]. Brief intervention, as part of primary healthcare, can help reduce this risk. Brief intervention is generally conducted over one to a few visits with each session lasting from just a few minutes up to one hour. The type of brief intervention varies depending on how severe the problem. Brief intervention is often used with patients who have not yet developed alcohol use disorder and the goal may be to reduce drinking rather than abstinence. For persons with alcohol use disorder, the goal of brief intervention is abstinence, and for these individuals, referral to a more comprehensive treatment may be necessary. The USPSTF recommends that clinicians provide patients who are engaged in risky or hazardous drinking with brief behavioral counseling interventions to reduce alcohol misuse [263].

COMMON ELEMENTS OF BRIEF INTERVENTION

Miller and Sanchez proposed six elements, summarized by the acronym FRAMES, to describe the key elements of brief intervention: feedback, responsibility, advice, menu of strategies, empathy, and self-efficacy [289]. How these elements enhance effectiveness has been supported in other reviews [290,291]. Goal setting, follow-up, and timing are also important in brief intervention [292,293].

- Feedback of Personal Risk: Health professionals use current drinking behaviors, lab test results, and actual or potential consequences of drinking to provide patients with feedback on the risk of developing a problem.

- Responsibility of the Patient: Brief intervention often includes encouraging the patient to recognize that it is his or her responsibility and choice to change the behavior. This gives patients a sense of personal control in the process of change.

- Advice to Change: Brief intervention may also include recommendations about moderate- or low-risk drinking and advice on cutting down or eliminating alcohol consumption.

- Menu of Ways to Reduce Drinking: Patients are advised about how to cut back or avoid alcohol consumption. Health professionals can help patients set limits, recognize reasons for drinking, and acquire skills to avoid high risk drinking. Often, self-help materials such as drinking diaries are given to patients to help monitor their progress.

- Empathetic Counseling Style: Confrontational methods of brief intervention are not as effective as when health professionals use a more empathetic counseling approach.

- Self-Efficacy or Optimism of the Patient: Patients should be encouraged during brief intervention to help themselves by creating a plan to change their behavior and to think positively about their ability to reduce or stop drinking. Health professionals often use motivation-enhancing techniques.

In addition to FRAMES, the following items are important:

- Establishing a drinking goal: Patients should be encouraged to set a drinking goal with help from their physician. In some cases it is helpful to put the goal in writing. The drinking goal may be abstinence.

- Follow-up: It is important that the healthcare provider follows the patient's progress by telephone calls, or repeat tests or visits.

Patients are more likely to change their behavior when they recognize they have a problem and when they are optimistic about prospects for change; therefore, evaluating readiness to change is an important part of brief intervention. Some patients are not ready to change at the start of brief intervention, but may be ready when they experience adverse consequences of alcohol use. One study found that 77% of patients who were very confident and motivated were able to reduce their alcohol consumption by using self-help instructions and drinking diaries [291]. Motivation techniques are more useful to the resistant patient than self-help instructions.

Motivational interviewing is a method of brief intervention that is used to help move individuals from the precontemplation, contemplation, or determination/preparation stage into the action stage of change related to their drinking. In addition to focusing on the patient's view of the problem and consequences of the behavior, the interview often includes a comprehensive assessment of drinking behaviors with personalized feedback. Motivational interviewing therapists emphasize personal responsibility and support their patients' feelings of self-efficacy for making a change in their drinking. This method has demonstrated empirical efficacy with problem drinkers [294].

EFFECTIVENESS OF BRIEF INTERVENTION

Many studies have documented that brief intervention can assist patients without clinical alcohol use disorder to reduce alcohol consumption [295,296,297,298,299]. Brief intervention can also help motivate the patient with alcohol use disorder to enter treatment. One study in an emergency care setting found that 65% of individuals with alcohol use disorder who received brief counseling kept a follow-up appointment for treatment, compared with only 5% percent of those who did not have counseling [295]. Some studies have found that brief intervention may be as effective as more specialized treatment for some patients with alcohol use disorder [296,300].

Researchers conducted a comprehensive meta-analysis of controlled studies of brief intervention in treatment and nontreatment settings [301]. In this meta-analysis, effect sizes were calculated for several outcome variables, including amount and timing of alcohol consumed, abstinence rates and duration, proportion and duration of non-problem drinking, frequency of intoxication, laboratory markers, ratings of drinking severity, ratings of improvements, dependence symptoms, and problems resulting from drinking [301]. Two types of investigations were examined. The first group of studies (N=34) compared brief intervention to control conditions in non-treatment-seeking patients and generally did not include persons with severe alcohol problems. The second group of investigations (N=20) included persons who had more severe alcohol problems in a treatment setting. The effect size for brief intervention on alcohol consumption was noted at between three to six months in studies that excluded more severe alcohol problems [301]. This meta-analysis provides further documentation of the effectiveness of brief intervention provided by healthcare professionals to patients with alcohol problems, especially during the first three to six months after intervention. Effectiveness may decrease over time, so progress should be monitored and referrals made if necessary. For those with more severe alcohol problems in a treatment setting, brief intervention may be appropriate as an initial treatment with nonresponders receiving more extensive/intensive treatment [301].

In summary, brief intervention can help patients without disordered alcohol consumption reduce or stop drinking, can help motivate patients with alcohol use disorder to enter treatment, and can be used to treat some patients with alcohol use disorder. One study reported that brief intervention is associated with decreased alcohol consumption and decreased healthcare utilization, motor vehicle events, and other related costs [302]. The study also reported that the cost-benefit analysis suggests that for every $10,000 invested in early intervention, there will be a $43,000 decrease in future healthcare costs [302]. A meta-analysis of brief alcohol interventions for adolescents and young adults found that the interventions yielded modest, but clinically significant positive effects on problematic alcohol use trajectories among youth [303].

READINESS TO CHANGE

Readiness to Change was Dimension 4 of the third edition of the American Society of Addiction Medicine's (ASAM's) Six Dimensions of Multidimensional Assessment (also known as the ASAM Criteria) that is the standard for placement, continued stay, transfer, or discharge of patients with substance use disorder and co-occurring conditions [304]. Readiness to Change is now considered within each of the six dimensions in the fourth edition of the ASAM Criteria. The six dimensions of the fourth edition include: intoxication, withdrawal, and addiction medications; biomedical conditions; psychiatric and cognitive conditions; substance use-related risks; recovery environment interactions; and person-centered considerations (new). This new sixth dimension considers barriers to care, patient preferences, and need for motivational enhancement [304]. Several factors influence a person's readiness and ability to change behaviors. It is useful to help patients to weigh the risks of continued alcohol consumption and benefits of decreasing or eliminating alcohol consumption. Physicians can help motivate the patient to become ready for treatment if the patient appears ready to change.

Is the patient ready to change? The role of motivation is an important part of changing behavior. Table 2 summarizes the "pros" and "cons" of changing [305].

Table 2: MOTIVATIONS FOR CHANGE

Patients are more likely to seek treatment if:

- There are few actual or perceived barriers to treatment.

- The expectation is that treatment will work and that it is a positive change.

- They think they need help

- They "hit bottom."

- They no longer feel in control.

- They cannot change on their own.

- They want to change their behavior.

- They perceive that treatment will suit their needs

- There is social pressure to stop drinking or get treatment.

- They experience notable or multiple problems (e.g., black-outs, DUI arrest, etc.).

Patients are less likely to seek treatment if:

- There are numerous real or perceived barriers to treatment.

- They fear being unable to cope without alcohol.

- There are negative perceptions of treatment or changing behavior.

- They think that treatment will not work.

- There is fear of withdrawal.

- They think they will be stigmatized.

- They believe that they will be unable to stop.

- They fear failure.

- They perceive continued use as positive.

Source: [305]

The Stages of Change Model is also useful in determining where a patient is in the process of change [306]. The stages of change include:

- Precontemplation

- Contemplation

- Preparation

- Action

- Maintenance

- Relapse

11. TREATMENT

Treatment works. People who make the decision to stop drinking will be able to find the treatment and support they need to quit, remain sober, and regain their lives. However, as with treatment for any other disease, it is important to have a good idea of the options available in order to make informed choices.

PHASES OF TREATMENT

To understand treatment and make the right treatment choices, it helps to have an overview. Treatment should be seen as having three phases.

- Phase 1: Assessment and evaluation of disease symptoms and accompanying life problems including co-occurring medical and psychiatric conditions utilizing ASAM Criteria, detoxification (withdrawal management), acute stabilization of comorbid conditions, making treatment choices, and developing a plan

- Phase 2: Residential treatment or therapeutic communities, intensive and regular outpatient treatment, medications to help with alcohol craving and to discourage alcohol use, medications to treat concurrent psychiatric illnesses, treatment of concurrent medical conditions, trauma and family therapy, 12-step programs, other self-help and mutual-help groups

- Phase 3: Maintaining sobriety and relapse prevention with ongoing outpatient treatment as needed, facilitated group meetings, contingency management, 12-step programs, other self-help and mutual-help groups

Drug testing frequently, randomly, and for-cause should be a mandatory component of all phases. Transition from one phase to the next should not be based on time but on individual symptoms and progress.

Getting Started

First, the individual with alcohol use disorder must overcome denial and distorted thinking and develop the willingness to begin treatment—what AA calls the desire to stop drinking. At this stage, it is important to obtain the help of someone knowledgeable about treatment and the options available.

When getting started, some people have lost control over alcohol to such an extent that they will only be able to make immediate decisions and set the most basic goal of quitting drinking. Development of a detailed treatment plan with goals and choices may have to wait until after detoxification. On the other hand, getting started is exactly the place where some people with alcohol problems get stuck. In being stuck, denial is always a problem, but complete denial is not universal: people have various levels of awareness of their alcohol use problems, which means they are in different stages of readiness to change their drinking behavior. Professionals have taken advantage of this insight about alcohol use disorder to develop treatment approaches that are matched to a person's readiness to change. Addiction specialists can best decide which treatment is best and which is the less restrictive at specific times during recovery.

Detoxification

Individuals with alcohol use disorder must stop using in order to be able to progress in treatment, which can be done on either an inpatient or outpatient basis. Medical evaluation and treatment are particularly important at this stage. A large proportion of persons with alcohol use disorder develop dangerous withdrawal symptoms that must be medically managed either in a hospital or on an outpatient basis.

Although detoxification is a critical step for many with alcohol use disorder, most treatment professionals are reluctant to call it treatment, and for good reason. Treatment is what helps a person develop a commitment to change, keep the motivation to change, create a realistic plan to change, and put the plan in action. Successful treatment means a person begins to experience the rewards of seeing the plan work. Just taking away the alcohol does not automatically produce any of these outcomes.

Withdrawal Symptoms and Medical Management

Abrupt discontinuation or even cutting down on the amount of drinking by persons who are physiologically dependent on alcohol produces a characteristic withdrawal syndrome with sweating, rapid heartbeat, hypertension, tremors, anorexia, insomnia, agitation, anxiety, nausea, and vomiting [307]. In some ways, alcohol withdrawal resembles withdrawal from opioids, but unlike opioid withdrawal, which is rarely life-threatening in and of itself, alcohol withdrawal can be fatal. As many as 15% of persons with alcoholism progress from the autonomic hyperactivity and agitation common to withdrawal from other drugs to seizures and, for some, even death. In some cases, DT may occur within the first 48 to 72 hours and can include disorientation, confusion, auditory or visual hallucinations, and psychomotor hyperactivity [307].

The Revised Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-Ar) is a symptom-triggered, 10-item scale that quantifies the risk and severity of alcohol withdrawal [307]. However, in order to be most useful, it requires patient input, which may not be feasible in patients undergoing severe DTs. If the patient is able, the assessment takes only minutes and aids in identification of patients who may need immediate pharmacologic treatment to prevent further complications. Very mild withdrawal usually corresponds with a score of 9 or less, mild withdrawal with a score between 10 and 15, modest withdrawal with a score between 16 and 20, and scores greater than 20 indicate severe withdrawal [308]. Patients scoring less than 9 may not require pharmacologic intervention. However, reassessment of symptoms should be performed every one to two hours until withdrawal is resolved.

Pharmacologic management of acute alcohol withdrawal generally involves the use of benzodiazepines, which reduce related anxiety, restlessness, insomnia, tremors, DT, and withdrawal seizures [307]. While benzodiazepines may have abuse liability in some patients, they have been safely used for years [309,310,311]. These medications may be administered either on a fixed interval or symptom-triggered schedule. However, both short-acting and long-acting benzodiazepines have their problems. The long-acting benzodiazepines can decrease rebound symptoms and work for long periods of time, but intramuscular absorption can be very erratic. Short-acting benzodiazepines have less risk of oversedation, no active metabolites, and considerable utility in patients with liver problems or disease. Yet, breakthrough symptoms can and do occur, and risk of seizure is imminent.

Patients with withdrawal symptoms are generally treated with diazepam or chlordiazepoxide until withdrawal subsides [307,309,310]. These medications are preferred due to their long action, which decreases the risk of rebound symptoms. If intramuscular administration is necessary, lorazepam is the drug of choice. More severe withdrawal is generally treated in a hospital setting. In patients with severe hepatic dysfunction, benzodiazepines that are metabolized outside the liver (lorazepam and oxazepam) are preferred. Treatment-resistant withdrawal warrants the use of phenobarbital or propofol, both with demonstrated efficacy in management [311].

Other medications may be used in conjunction with benzodiazepines for the treatment of withdrawal. Anticonvulsants, especially carbamazepine, are used safely to treat withdrawal [309]. They do not have abuse liability and have anticonvulsant and antikindling effects. Nevertheless, they also have problems. They do not reduce delirium and can have liver toxicity. The anticonvulsant gabapentin has demonstrated efficacy for mild alcohol withdrawal and early abstinence, but there is concern about its potential for abuse [312]. Alpha-adrenergic agonists like clonidine can reverse many of the behavioral symptoms of withdrawal but do not prevent seizure and can cause hypotension. However, for those patients with coronary artery disease, use of an alpha-adrenergic agonist or beta blocker may be indicated. It is important to note that these agents do not prevent seizures and can mask some signs of worsening withdrawal. They should be used only in conjunction with benzodiazepines [313]. More research is necessary regarding the efficacy of calcium channel antagonists in the treatment of alcohol withdrawal [314]. Studies have shown that those who have withdrawal seizures may have a worse prognosis than those who do not [92,93].

In the earliest views of alcohol use disorder, relapse to alcohol use was primarily seen as the patient's failure to respond to withdrawal treatment. After all, if the addicted person's primary problem was the trap of withdrawal, it would be reasonable to expect that the newly freed prisoner would gratefully and persistently grasp onto alcohol-free status, never to return voluntarily to the prison of addiction. But many people returned repeatedly for detoxification.

The medical profession was remarkably slow to recognize the ineffectiveness of repeated detoxification. Rather than question the underlying assumption that medical diagnosis and treatment of withdrawal was the solution to the problem of dependence, physicians seemed content to recycle people through one emergency room or detoxification experience after another for what often proved to be an addiction-shortened lifetime. Detoxification is only the first step in the treatment process, and the beginning of a lifelong process.

As the detoxification process occurs, careful evaluation should be done to identify co-occurring medical and psychiatric conditions that require acute stabilization. This should be done before facilitating a smooth transition to phase 2.

It is crucial to decide if the patient requires acute hospitalization or inpatient detoxification. It has been established that hospitalization can be cost-effective, but this is not always a possibility. However, if a patient appears to have acute intoxication, exhibits or will exhibit withdrawal symptoms that will require medical management, has failed outpatient detoxification, appears to be depressed or suicidal, relapses shortly after previous detoxification, has an extremely unstable home situation, or has the possibility of family disruption or job loss, then inpatient hospitalization is likely indicated. If you are in doubt, call a physician who is a member of the ASAM or the American Academy of Addiction Psychiatry who specializes in these problems.

Active Treatment

The next step is what has been commonly known as "active treatment." Relapse to alcohol use disorder is most likely to occur in the first three to six months after a person stops drinking; a period characterized by physiologic abnormalities, mood changes, and complaints of anxiety, depression, insomnia, and hormone and sleep problems. Getting active help and support during the early months of sobriety is critical for treatment to succeed.

This is the stage in which a person gains the motivation necessary to maintain a commitment to sobriety, the knowledge and skills necessary to stay sober, and the support systems necessary to cope with all the problems of daily life (the problems that everyone has to face) without resorting to the old "solution" of drinking. This is when the assistance of a treatment professional is important. A professional can help patients better understand how alcohol has affected their lives, so they can set goals and develop a plan to stay sober. In addition, the treatment professional can assist the patient in choosing the treatment options that are right for them.

Some proven medications are available to help with alcohol craving and to discourage alcohol use and will be discussed in detail later in this course. The treatment professional will also need to choose medications and treatments for concurrent psychiatric illnesses, like depression or anxiety, if appropriate, or for a variety of health problems that often accompany alcohol use disorder.

Research has shown that the longer people stay in treatment, remain sober, and are actively committed to sobriety, the more likely it is that they will maintain sobriety. Some treatment professionals think of the phase of active treatment as lasting from 6 to 12 months. During the first critical months of treatment, people often need a variety of supports, especially drug testing and AA or other self-help groups, to achieve and maintain lasting sobriety.

Maintaining Sobriety and Relapse Prevention

It is often difficult to pinpoint when the active treatment phase ends and a person enters the maintenance phase of recovery. In phase 2, people learn what they need to do to stay sober and they develop the many skills they will use to avoid relapse. A person could be said to enter this maintenance and growth stage when he or she is comfortable with these skills and has had a chance to rely on them to stay sober when life throws them the inevitable curveballs, either as a crisis or an everyday problem. Many people in recovery attribute their ongoing sobriety to participation in a support group such as AA or Women for Sobriety.

A promising approach to maintain gains made in active treatment is a low-intensity, telephone-based approach. In a 2005 study, this program of follow-up care was compared with two more intensive face-to-face continuing care interventions. Patients with alcohol use disorder who had completed 4-week intensive outpatient programs were provided three 12-week continuing care treatments. Telephone-based continuing care was found to be an effective form of step-down treatment for most patients with alcohol use disorder who complete an initial stabilization treatment, compared with more intensive face-to-face interventions [315].

ALCOHOLICS ANONYMOUS AND OTHER 12-STEP PROGRAMS

The grandfather of successful alcohol treatment is Alcoholics Anonymous, a self-help organization founded in 1935 that changed the way professionals thought about alcohol use disorder and treatment. AA developed a very successful 12-step program that combines self-help with a spiritual foundation and is based on the fellowship of recovering alcoholics. Although there is a spiritual foundation in AA, one is not required to be religious. The organization is run entirely by recovering alcoholics and reaches into virtually every community with a specific program as well as around-the-clock assistance. Membership is available to anyone wishing to join, and there are no financial dues. AA has probably done more to promote the self-help concept than any other organization.

For many people with alcohol use disorder, attending an AA meeting is like brushing their teeth. Prevention of relapse is an active daily process. AA provides fellowship that can be exceptionally positive and counterbalance the feelings of loss, grief, and shame often associated with alcohol use disorder.

AA and other 12-step programs are effective treatment programs that facilitate long-term abstinence after treatment, especially for patients with low psychiatric severity [316]. AA provides important peer-led support for individuals with alcohol use disorder. AA also helps individuals with relapse and relapse prevention by prescribing that people keep it simple, take it one day at a time, and avoid the people, places, and things associated with their use. They also help recovering alcoholics to develop positive lifestyles and find new ways to solve old problems. The feeling of fellowship, the support, and guidance to sobriety makes recovery more likely. Reduction of shame and guilt and acceptance of powerlessness over drinking may be reported by individuals with alcohol use disorder after attending meetings every day. An AA meeting may take one of several forms, but at any meeting you will find alcoholics talking about what drinking did to their lives and personalities, what actions they took to help themselves, and how they are living their lives today.

Patients can find the listing for a nearby AA group in the telephone book or online. Typically, a person in recovery will answer the telephone. Websites provide printable lists of all local meetings with time, location, types of meeting, and often directions. One of AA's principles is the value of performing services that will help other alcoholics. Answering the telephone at the local AA office is one of these services, reserved for those who have been in recovery long enough to answer questions in a knowledgeable manner and provide a nonjudgmental ear.

A Cochrane review found that AA, the premier mutual aid peer-recovery program definitely helps people get sober [317]. In addition, AA has significantly higher rates of continuous sobriety compared with evidence-based professional mental health therapy, such as cognitive-behavioral therapy, alone. AA was often was found to be markedly better than other interventions or quitting cold turkey. One study found the program 60% more effective than alternatives [317].

The study by Harvard and Stanford addiction researchers of 10,565 subjects determined that AA was nearly always found to be more effective than psychotherapy in achieving abstinence [317].This review concluded that AA participation improved the duration of abstinence and the amount they reduced their drinking (if they continued drinking). AA had harm reduction features as well, reducing the medical consequences of drinking and related healthcare costs. While not a random assignment treatment comparison study, in this analysis, AA was never found less effective than other treatments. As such, AA could be a helpful addition to any treatment for alcohol use disorder. For example, adding AA to naltrexone would be expected to be better than pharmacotherapy alone. Recent studies and the preponderance of evidence supports the effectiveness of 12-step program involvement in sustaining abstinence [10]. Stable and long-term abstinence was associated with living longer, better mental health, better marriages, being more responsible parents, and being successful employees.

A brain imaging study by Yale researchers showed that those diagnosed with alcohol use disorder showed disruptions of activity between the ventromedial prefrontal cortex and striatum, a brain network linked to decision making [318]. Time is necessary for re-learning how to be sober but also for brain recovery. The more recent the last drink, the more severe the disruption, and the more likely the individual will relapse to drinking. The Yale researchers also found that the severity of disruption between these brain regions recovers very slowly, day after day, gradually over time. They conclude the longer subjects with alcohol use disorder abstain from alcohol, the better. The number of days of alcohol abstinence at treatment initiation significantly affected functional disruption of the prefrontal-striatal responses to alcohol cues in patients with alcohol use disorder and brain imaging abnormalities [318].

COUNSELING

Cognitive-behavioral therapies (CBTs) are among the most frequently evaluated approaches used to treat substance use disorders [319,320]. CBTs have been shown to be effective in several clinical trials of substance users [321]. Characteristics of CBTs include:

- Social learning and behavioral theories of drug abuse

- An approach summarized as "recognize, avoid, and cope"

- Organization built around a functional analysis of substance use (i.e., understanding substance use with respect to its antecedents and consequences)

- Skill training focused on strategies for coping with craving, fostering motivation to change, managing thoughts about drugs, developing problem-solving skills, planning for and managing high-risk situations, and cultivating drug refusal skills

Basic principles of CBTs are that [322,323]:

- Basic skills should be mastered before more complex ones are given.

- Material presented by the therapist should be matched to patient needs.

- Repetition fosters the development of skills.

- Practice is needed for mastery of skills.

- The patient is an active participant in treatment.

- Skills taught are general enough to be applied to a variety of problem areas.

Structured behavior therapy techniques can be effective components of alcohol use disorder treatment. Contingent incentive procedures are designed to enhance a patient's motivation to meet treatment goals by offering concrete rewards for specific performance outcomes.

Behavioral therapy techniques are often part of CBT. In this approach, substance use is believed to develop from changes in behavior and a reduction in opportunities for reinforcement of positive experience. The goal is to increase the person's engagement in positive or socially reinforcing activities. Techniques such as having patients complete a schedule of weekly activities, engaging in homework to learn new skills, role-playing, and behavior modification are used. Activity, exercise, and scheduling are major components of this approach based on the following:

- Drug abuse patients need motivation and skills to succeed in stopping drug use.

- Research has shown that drug abuse behavior can be reduced by offering contingent incentives for abstinence.

- The most striking successes have come from positive reinforcement programs that provide contingent incentives for abstinence using money-based vouchers as rewards.

- Research provides examples, but treatment providers may need to be creative in discovering reinforcers that can be used for contingency management in their own clinical settings.

Family therapy is a highly effective treatment for alcohol use disorder, especially in adolescents. While most treatments emphasize the individual as the target of intervention, the defining characteristic of family therapy is the transformation of family interactions. Repetitive patterns of family interactions are the focus of treatment. Changing these patterns results in diminished antisocial behavior including alcohol abuse. Family therapy can work with a broad range of family and social network populations. Family therapy approaches have developed specific interventions for engaging and keeping reluctant, unmotivated adolescents and family members in treatment.

MEDICATIONS USED TO TREAT ALCOHOL USE DISORDER

Alcohol drinking is an immensely complex human behavior, but it has been modeled in laboratory animals. Two similar strains of alcoholic rats, the alcohol-preferring (P) rats and the high-alcohol-drinking (HAD) rats, have been successfully used to study alcohol use disorders. Like patients with DSM-5-TR qualifying alcohol use disorders, these rats self-administer alcohol, show tolerance, lose control over alcohol, and spend a lot of time. They also have cravings and physical stigmata of withdrawal, providing psychopharmacologic researchers with excellent face validity with animal models. Models have helped us develop anti-withdrawal, anti-craving, and harm-reducing treatments.

Several medications are available to help treat alcohol use disorder [324,325]. Some are used for detoxification and others are used to prevent relapse. Research has shown that medications are most effective when used in conjunction with other therapies.

Disulfiram

Disulfiram, commonly known as Antabuse, was the first drug to be made available for the treatment of alcohol use disorder. It was approved for treatment of alcohol use disorder by the FDA in 1951 and has been used safely and effectively for more than half a century. It works by blocking an enzyme, aldehyde dehydrogenase, that helps metabolize alcohol. Taking even one drink while on disulfiram causes the alcohol at the acetaldehyde stage to accumulate in the blood. This produces nausea, vomiting, sweating, and even difficulty breathing. More alcohol in the patient's system produces more severe reactions (e.g., respiratory depression, cardiovascular collapse, unconsciousness, convulsions, death) [325,326]. Patients must also be mindful of consuming even minute amounts of alcohol in foods, over-the-counter medications, mouthwash, and even topical lotions. Disulfiram can be effective for people who have completed alcohol withdrawal, are committed to staying sober, and are willing to take the medication under the supervision of a family member or treatment program [325]. Due to more modern and improved medication modalities, many clinicians prescribe disulfiram as a last resort intervention. Although widely used, it is less clearly supported by clinical trial evidence [327,328,329].

The recommended dose for disulfiram is 250 mg/day, which can be increased to 500 mg based upon whether a patient experiences the disulfiram-ethanol reaction [330]. Doses may need to be reduced in patients older than 60 years of age [325]. Labeling for disulfiram includes several precautions regarding drug-drug interactions; therefore, caution should be used when prescribing it to older adults at risk for polypharmacy [325]. Due to the physiologic changes that occur with use, use of disulfiram is not recommended in patients with diabetes, cardiovascular or cerebrovascular disease, or kidney or liver failure. It also is contraindicated in the presence of psychoses and pregnancy and in those with high levels of impulsivity and suicidality [325].

Naltrexone

Naltrexone (ReVia) is an opioid antagonist that interferes with the rewarding or pleasurable effects of alcohol and reduces alcohol craving [331,332,333]. The exact mechanisms by which naltrexone induces the reduction in alcohol consumption observed in patients with alcohol use disorder is not entirely understood, but preclinical data suggest involvement of the endogenous opioid system [325]. Naltrexone has been shown to reduce alcohol relapses, decrease the likelihood that a slip becomes a relapse, and decrease the total amount of drinking [325]. The FDA approved the use of oral naltrexone in alcohol use disorder in December 1994 [325,333]. In 2006, the FDA approved an extended-release injectable formulation, which is indicated for use only in patients who can refrain from drinking for several days prior to beginning treatment [325]. In 2010, the FDA approved the injectable naltrexone for the prevention of relapse to opioid dependence following opioid detoxification [325]. Naltrexone, which has long been used to treat heroin addicts, was not known as a treatment that could reduce alcohol relapse until the 1980s. In 1980, researchers reported reductions in monkey ethanol self-administration when they were pretreated with naltrexone [334].

By 1992, researchers reported a six-week, double-blind placebo-controlled outpatient naltrexone trial with 70 individuals with alcohol use disorder. They found that the naltrexone-treated patients had a lower relapse rate, fewer drinking episodes, longer time to relapse, and reduced tendency for a slip to become a relapse [335]. These and other data suggested that endogenous opioids were important in alcohol reinforcement.

Also in 1992, researchers compared naltrexone with placebo and found that naltrexone-treated patients had lower rates of relapse to heavy drinking, consumed fewer drinks per drinking-day, and had lower dropout rates than placebo-treated patients with alcohol use disorder [336]. These results have since been supported by other studies [337]. Research suggests that naltrexone may be most effective for individuals with alcohol use disorder and a family history of alcohol use disorder [338]. However, one study found no significant effects for naltrexone in individuals with a family history of alcoholism on percentage of days abstinent, drinks per drinking day, and percentage of heavy drinking days [339].

Another study investigated pretreatment social network variables as potential moderators of naltrexone's treatment effects [340]. The study sample included 1,197 participants from the COMBINE study, the largest pharmacotherapy trial conducted for alcoholism in the United States. In treatment conditions involving combined CBT and medical management, the effects of naltrexone on heavy drinking were significantly greater for individuals with frequent drinkers in their social network and greater frequency of contact with those drinkers, indicating patterns of environmental exposure to alcohol [40,341]. In an attempt to replicate and extend the findings of the COMBINE study, researchers conducted a secondary analysis of a 12-week randomized clinical trial of daily or targeted naltrexone among problem drinkers, with a focus on those who received a daily dose of either naltrexone or placebo [342]. Four reward/relief phenotypes were identified: low reward/low relief; low reward/high relief; high reward/low relief; and high reward/high relief. When compared with the placebo group, individuals in the high reward/low relief phenotype who received daily naltrexone had significantly fewer drinks per drinking day and a lower proportion of heavy drinking days [342].

After a complete history, physical exam, and laboratory testing, most patients are started on 50 mg orally per day [234]. For most patients, this is the safe and effective dose of naltrexone. However, in a four-month study period, the COMBINE study demonstrated efficacy of naltrexone at a dose of 100 mg daily [343]. Some treatment providers give patients a naltrexone identification card or ask them to order a MedicAlert bracelet that clearly indicates that they are maintained on an opioid antagonist, so if they need an opiate drug or medication for pain relief, the dose of the pain medication can be adjusted higher. Meta-analyses have revealed that approximately 70% of previous clinical trials that measured reductions in "heavy or excessive drinking" demonstrated an advantage for prescribing naltrexone over placebo [344]. In another trial, naltrexone was determined to have the greatest impact on reducing daily drinking when craving for alcohol was highest [345]. The approved dose of the extended-release formulation is 380 mg IM once per month. Pretreatment with oral naltrexone is not required before induction onto extended-release injectable naltrexone [325].

The most common side effects of naltrexone are light-headedness, diarrhea, dizziness, and nausea. Pain or tenderness at the injection site is a side effect unique to the extended-release injectable formulation [325]. Most side effects tend to disappear quickly in most patients. Naltrexone is not recommended for patients with acute hepatitis or liver failure, for adolescents, or for pregnant or breastfeeding women [325,343]. Weight loss and increased interest in sex have been reported by some patients. In general, patients maintained on opioid antagonists should be treated with nonopioid cough, antidiarrheal, headache, and pain medications. The patient's family or physician should call the treating physician if questions arise about opioid blockade or analgesia. It is important to realize that naltrexone is not disulfiram; drinking while maintained on naltrexone does not produce side effects or symptoms.

Naltrexone works best when it is used in the context of a full spectrum of treatment services, possibly including traditional 12-step fellowship-based treatments. Studies show also that naltrexone is effective when coupled with CBT. Patients receiving medical management with naltrexone, CBT, or both fared better on drinking outcomes [343].

Acamprosate

Acamprosate (Campral) is a synthetic compound that has a chemical structure similar to that of the naturally occurring amino acid neurotransmitters taurine and GABA [234]. Because chronic alcohol use is associated with decreased GABA and glutamate activity, a hyperexcitable glutamate system is one possible alcohol withdrawal mechanism. Glutamate systems may become unstable for 12 months after a person stops drinking. In a review of published, double-blind, placebo-controlled clinical trials evaluating the safety and efficacy of acamprosate in the treatment of alcohol use disorder, Mason reported that acamprosate appeared to improve treatment completion rate, abstinence rate and/or cumulative abstinence during treatment, and time to first drink, than placebo [346]. The effect on abstinence, combined with an excellent safety profile, lend support to the use of acamprosate across a broad range of patients with alcohol use disorder. A dose of 2,000 mg/day is associated with the greatest efficacy regardless of body weight [347]. It is important to note that medication in combination with therapies can improve outcomes.

In July 2004, after many years of safe use in Europe and around the world, the FDA approved the use of acamprosate for the maintenance of alcohol abstinence [333]. As in the case of naltrexone, acamprosate reduces the reinforcing (pleasurable) effects of alcohol to reduce craving. Oral dosing is two 333-mg delayed-release tablets three times daily [234,325]. Common side effects include diarrhea, anxiety, insomnia, nausea, dizziness, and weakness. Some research indicates that acamprosate may worsen depression and/or suicidal ideation; so, patients with a history of major depression should be monitored closely or prescribed a different medication [234]. Acamprosate is contraindicated in patients with severe renal impairment [234,325]. Due to risk of diminished renal function in patients 65 years of age and older, baseline and frequent renal function tests should be performed in this population. Dose reductions also may be necessary [325].

The effectiveness of acamprosate in promoting abstinence has not been demonstrated in individuals who have not completed detoxification or who have not achieved alcohol abstinence before beginning treatment [325]. An analysis of many studies of acamprosate showed a benefit in maintaining abstinence when coupled with CBT [343]. A systematic review found similar benefit [348]. Results of other research into the effectiveness of acamprosate have been mixed. One study showed no improvement in measures of psychological well-being or health status when compared to treatment with placebo. Another study demonstrated both safety and effectiveness of acamprosate for treating alcohol use disorder [349].

Baclofen

Baclofen is a GABA agonist that may prove to be a unique therapeutic alternative to reduce alcohol craving and consumption. In a small, 12-week trial, patients with alcohol use disorder were given 10 mg of baclofen three times daily paired with motivational enhancement therapy. Patients experienced a reduction in number of drinks, drinking days, anxiety, and craving [350]. In a study of patients with alcohol use disorder and liver cirrhosis, baclofen was also found to work favorably in maintenance of alcohol abstinence. Seventy-one percent of baclofen-treated patients maintained abstinence as compared with 29% of the placebo group [351]. A 2018 meta-analysis of 12 randomized controlled trials that compared the efficacy of baclofen to placebo found that baclofen was associated with higher rates of abstinence than placebo but that its effects were not superior to placebo in increasing the number of abstinent days or in decreasing heavy drinking, craving, depression, or anxiety [352]. A 2023 systematic review of 17 randomized controlled trials involving 1,818 participants found that baclofen reduces the risk of relapse to any drinking and increases the percentage of abstinent days, mainly among detoxified participants. The agent was not found to reduce the number of heavy drinking days or the number of drinks per drinking days [353].

Anticonvulsants

Research has demonstrated that topiramate is efficacious in decreasing heavy drinking among individuals with alcohol use disorder [354]. In a controlled study, topiramate produced significant and meaningful improvement in a wide variety of drinking outcomes [355]. Topiramate may suppress the craving and rewarding effects of alcohol [356]. In a double-blind, controlled trial, 150 patients with alcohol use disorder were randomized to escalating doses of topiramate (25–300 mg/day) or placebo. Those on topiramate had a reduction in self-reported drinking (number of drinks and drinking days), alcohol craving, and plasma y-glutamyl transferase (an indicator of alcohol consumption) [357]. Side effects of topiramate include numbness in the extremities, fatigue, confusion, paresthesia, depression, change in taste, and weight loss. Use of topiramate for alcohol use disorder is off-label [234].

Carbamazepine has proven effective for treating acute alcohol withdrawal [358]. Its side effects include nausea, vomiting, drowsiness, dizziness, chest pain, headache, trouble urinating, numbness in extremities, liver damage, and allergic reaction [234]. In a 12-month, double-blind, placebo-controlled trial, 29 patients were assigned to carbamazepine three times daily (to reach an average blood level of 6 mg/liter) or placebo. Those treated with carbamazepine showed a delay in time to first drink and a decrease in number of drinks and drinking days [359].

Oxcarbazepine is a carbamazepine derivative, with fewer side effects and contraindications, used to prevent relapse in patients with alcohol use disorder by blocking alcohol withdrawal [358]. A group of 84 patients with alcohol use disorder following detoxification were randomized to 50 mg naltrexone, 1,500–1,800 mg oxcarbazepine, or 600–900 mg oxcarbazepine for 90 days. Approximately 58.6% of the high-dose oxcarbazepine patients remained alcohol-free, a significantly larger number as compared to the low-dose (42.8%) and naltrexone groups (40.7%) [360].

Treatment in Special Populations

Ondansetron is a serotonin antagonist and antiemetic that may block the rewarding effects of alcohol, specifically in the early-onset alcoholic subgroup. Early-onset alcoholism differs from late-onset in its association with abnormal serotonin and antisocial behavior. In a double-blind, controlled trial of ondansetron as an adjunct to cognitive-behavioral therapy, ondansetron was shown to reduce self-reported drinking and increase abstinence as compared to placebo. These results were confirmed by measure of plasma carbohydrate deficient transferring, a biomarker of alcohol consumption [361]. One hypothesis suggests that ondansetron may reduce drinking in individuals with alcohol use disorder with the LL genotype [362].

Buspirone hydrochloride is a dopamine antagonist and partial agonist for serotonin, exhibiting anxiolytic properties. In a 12-week randomized, placebo-controlled trial among 61 patients with alcohol use disorder and anxiety, buspirone was associated with slower return to heavy alcohol consumption and fewer drinking days [363]. One study found buspirone to be effective in treatment of comorbid anxiety disorder and alcohol use disorder [364].

Clozapine is an atypical antipsychotic approved to treat schizophrenia and its resultant symptoms (e.g., hallucinations, suicidal behavior). In case studies, it has shown promise in the treatment of comorbid substance use. In a study of 151 individuals with schizophrenia with comorbid substance use, 36 were given clozapine [365]. Those who abused alcohol experienced a reduction in drinks and drinking days.

Other drugs under trial for use in the treatment of alcohol use disorder include varenicline and lithium. Varenicline does appear to help reduce drinking in some individuals with alcohol use disorder; however, concerns exist regarding reports of an association between the drug and an increased risk for suicidal thoughts and cardiovascular events [366]. Studies have demonstrated that varenicline helps reduce alcohol craving and consumption in patients with alcohol use disorder and in individuals with alcohol use disorder who also smoke [367,368,369]. None of the medications mentioned for alcohol use disorder are recommended for women who are pregnant or breastfeeding.

TREATMENT OF ALCOHOL WITHDRAWAL

Benzodiazepines have been used for 30 years in the United States as the primary medical treatment for alcohol withdrawal syndrome. All benzodiazepines appear similarly effective in the treatment of alcohol withdrawal syndrome [370]. Although benzodiazepines are the drugs of choice, there are concerns about the side effects and, as stated, problems of abuse, especially for outpatient detoxification. Benzodiazepines are sedatives and cause deficiencies in psychomotor abilities that, when combined with alcohol, can cause accidents and affect the ability to think clearly. However, benzodiazepines are, and have been, effective in treating alcohol withdrawal symptoms and preventing most seizures. Other regimens for alcohol withdrawal syndrome include barbiturates, propofol, and ethanol [371,372,373].

A desirable alternative to benzodiazepines would be a nonsedative anticonvulsant that has less potential for abuse and dependence. Valproic acid has been used in Europe safely and successfully for many years for alcohol withdrawal syndrome, but is only approved by the FDA for the treatment of mania, seizures, and migraines. Valproic acid should be used as an adjunctive therapy, not as monotherapy [370]. According to clinical reports, valproic acid is an anticonvulsant with no potential for abuse and is better tolerated by patients. Valproic acid also has less cognitive impairment and causes fewer deficiencies of psychomotor abilities than benzodiazepines; however, benzodiazepines have allowed for safe detoxification for patients with alcohol use disorder since they were approved. While detoxification is not treatment, and detoxification problems have not been the most important problem area in successful treatment of the patient with alcohol use disorder, these are important findings.

Recognizing that relapse prevention and harm-reducing medications are safe and effective in alcohol use disorders, fewer than 10% of these patients are given medication-assisted treatment. In a 2018 meeting of the American Psychiatric Association, experts suggested [374]:

- Naltrexone or acamprosate should be offered to those patients with moderate- to-severe alcohol use disorder that have a goal of reducing consumption or achieving abstinence, prefer pharmacotherapy, or have not responded to nonpharmacologic therapies, and have no contraindications.

- Disulfiram should be offered to patients with severe alcohol use disorder that seek to achieve abstinence, prefer the therapy, or have not responded (or are intolerant) to naltrexone or acamprosate, and have no contraindications. Additionally, patients must understand the risks associated with consuming alcohol while on disulfiram.

- Topiramate or gabapentin should be offered to patients with moderate-to-severe alcohol use disorder when they aim to reduce or achieve abstinence, prefer them to other medications, or have not responded to naltrexone or acamprosate and have no contraindications.

- Benzodiazepine use is discouraged except in patients with alcohol use disorder who require treatment for acute alcohol withdrawal.

MANDATORY TREATMENT

Even coerced or court-mandated treatment for alcohol use disorder can work. In a follow-up study (six months to one year) of Florida physicians with alcohol use disorder, 84% had positive outcomes, defined as positive counselor and physician assessment, negative alcohol testing, group attendance, and full return to work [375].

12. CONCLUSION

In a society where alcohol use is ubiquitous, it is important for healthcare professionals to recognize the signs and symptoms of alcohol abuse and intervene before a state of dependence is reached. It is critical to stress upon patients the negative health effects of excessive alcohol consumption, especially the synergistic effects of alcohol and tobacco use, beginning at an early age. Owing to the several benefits provided by low to moderate drinking as discussed in this course, certain patients can be advised to drink more regularly, provided alcohol use is not contraindicated due to drug or herb interactions.

13. RESOURCES

Al-Anon Family Groups

The mission of Al-Anon is to provide support for friends and families of problem drinkers.

https://al-anon.org

Alcoholics Anonymous

https://www.aa.org

American Society of Addiction Medicine (ASAM)

The nation's medical specialty society dedicated to educating physicians and improving the treatment of individuals suffering from alcoholism and other addictions. The mission of the ASAM is to:

- Increase access to and improve the quality of addiction treatment

- Educate physicians, medical and osteopathic students, other healthcare providers, and the public

- Promote research and prevention

- Promote the appropriate role of the physician in the care of patients with addiction

- Establish addiction medicine as a specialty recognized by the American Board of Medical Specialties

https://www.asam.org

301-656-3920

MedicAlert Foundation

https://www.medicalert.org

Works Cited

1. Camargo CA Jr, Stampfer MJ, Glynn RJ, et al. Prospective study of moderate alcohol consumption and risk of peripheral arterial disease in US male physicians. Circulation. 1997;95(3):577-580.

2. Ronksley PE, Brien SE, Turner BJ, Mukamal KJ, Ghali WA. Association of alcohol consumption with selected cardiovascular disease outcomes: a systematic review and meta-analysis. BMJ. 2011;342:d671.

3. Grant KA. Emerging neurochemical concepts in the actions of ethanol at ligand-gated ion channels. Behav Pharmacol. 1994;5(4, 5):383-404.

4. Koob GF,Rassnick S, Heinrichs S, Weiss F. Alcohol, the reward system and dependence. In: Jansson B, Jörnvall H, Rydberg U, Terenius L, Vallee BL (eds). Toward a Molecular Basis of Alcohol Use and Abuse. Basel: Birkauser; 1994:103-114.

5. Tizabi Y, Copeland RL Jr, Louis VA, Taylor RE. Effects of combined systemic alcohol and central nicotine administration into ventral tegmental area on dopamine release in the nucleus accumbens. Alcohol Clin Exp Res. 2002;26(3):394-399.

6. Tizabi Y, Bai L, Copeland RL Jr, Taylor RE. Combined effects of systemic alcohol and nicotine on dopamine release in the nucleusaccumbens shell. Alcohol Alcohol. 2007;42(5):413-416.

7. Tolu S, Marti F, Morel C, et al. Nicotine enhances alcohol intake and dopaminergic responses throughβ2* andβ4* nicotinic acetylcholine receptors. Sci Rep. 2017;7:45116.

8. Nies MA, McEwen M. Community/Public Health Nursing: Promoting the Health of Populations. 5th ed. St. Louis, MO: Elsevier Saunders; 2010.

9. U.S. Department of Health and Human Services. 10th Special Report to the U.S. Congress on Alcohol and Health. Available at https://webarchive.library.unt.edu/eot2008/20090113011041/http://pubs.niaaa.nih.gov/publications/10report/intro.pdf. Last accessed April24, 2024.

10. Nelson JP. Economic and demographic factors in U.S. alcohol demand: a growth-accounting analysis. Empirical Econ. 1997;22(1):83-102.

11. Schuckit MA. Drug and Alcohol Abuse: A Clinical Guide to Diagnosis and Treatment. 6th ed. New York, NY: Springer; 2010.

12. Substance Abuse and Mental Health Services Administration. 2022 National Survey on Drug Use and Health Releases: Detailed Tables. Available at https://www.samhsa.gov/data/release/2022-national-survey-drug-use-and-health-nsduh-releases#detailed-tables. Last accessed April 24, 2024.

13. White AM, Castle JP, Powell PA, et al. Alcohol-related deaths during the COVID-19 pandemic. JAMA. 2022;327(17):1704-1706.

14. Substance Abuse and Mental Health Services Administration. Results from the 2013 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-48, HHS Publication No. (SMA) 14-4863. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2014.

15. Knight JR, Wechsler H, Kuo M, Seibring M, Weitzman ER, Schuckit MA. Alcohol abuse and dependence among U.S. college students. J Stud Alcohol. 2002;63(3):263-270.

16. Centers for Disease Control and Prevention. Excessive Drinking is Draining the U.S. Economy. Available at https://www.cdc.gov/alcohol/features/excessive-drinking.html. Last accessed April 24, 2024.

17. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Association; 2013.

18. Dufour MC. What is moderate drinking? Defining "drinks" and drinking levels. Alcohol Res Health. 1999;23(1):5-14.

19. U.S. Department of Health and Human Services. 2020-2025 Dietary Guidelines for Americans and Online Materials. Available at https://www.dietaryguidelines.gov/resources/2020-2025-dietary-guidelines-online-materials. Last accessed April 24, 2024.

20. Trevisan LA, Boutros N, Petrakis IL, Krystal JH. Compilations of alcohol withdrawal: pathophysiological insights. Alcohol Health Res World. 1998;22(1):61-66.

21. Bertrand J, Floyd RL, Weber MK, et al. Fetal Alcohol Syndrome: Guidelines for Referral and Diagnosis. Atlanta, GA: Centers for Disease Control and Prevention; 2004.

22. MukamalKJ, Rimm EB. Alcohol's effects on the risk for coronary heart disease. Alcohol Res Health. 2001;25(4):255-261.

23. Beulens JWJ, Rimm EB, Ascherio A, Spiegelman D, Hendriks HFJ, Mukamal KJ. Alcohol consumption and risk of coronary heart disease among men with hypertension. Ann Intern Med. 2007;146(1):10-19.

24. Rimm EB. Alcohol consumption and good health. In: Gold MS (ed). Addiction and Psychiatry. Gainesville, FL: University of Florida College of Medicine; 2007.

25. Kitamura A, Iso H, Sankai T, et al. Alcohol intake and premature coronary heart disease in urban Japanese men. Am J Epidemiol. 1998;147(1):59-65.

26. Klatsky AL, Armstrong MA, Friedman GD. Red wine, white wine, liquor, beer, and risk for coronary artery disease hospitalization. Am J Cardiol. 1997;80(4):416-420.

27. Rehm JT, Bondy SJ, Sempos CT, Vuong CV. Alcohol consumption and coronary heart disease morbidity and mortality. Am J Epidemiol. 1997;146(6):495-501.

28. Renaud SC, Guéguen R, Siest G, Salamon R. Wine, beer, and mortality in middle-aged men from eastern France. Arch Intern Med. 1999;159(16):1865-1870.

29. MukamalKA, Conigrave KM, Mittleman MA, et al. Roles of drinking pattern and type of alcohol consumed in coronary heart disease in men. N Engl J Med. 2003;348(2):109-118.

30. Hvidtfeldt UA, Tolstrup JS, Jakobsen MU, et al. Alcohol intake and risk of coronary heart disease in younger, middle-aged, and older adults. Circulation. 2010;121(14):1589-1597.

31. World Health Organization. Diet, Nutrition and the Prevention of Chronic Diseases: Report of the Joint WHO/FAO Expert Consultation. WHO Technical Report Series, No. 916. Available at https://www.who.int/publications/i/item/924120916X. Last accessed April 24, 2024.

32. Hines LM, Stampfer MJ, Ma J, et al. Genetic variation in alcohol dehydrogenase and the beneficial effect of moderate alcohol consumption on myocardial infarction. N Engl J Med. 2001;344(8):549-555.

33. Zahler R, Piselli C. Smoking, alcohol and drugs. In: Zaret BL, Moser M, Cohen LS (eds). Yale University School of Medicine Heart Book. New York, NY: Hearst Books; 1992.

34. Renaud SC, Beswick AD, Fehily AM, Sharp DS, Elwood PC. Alcohol and platelet aggregation: the Caerphilly Prospective Heart Disease Study. Am J Clin Nutr. 1992;55(5):1012-1017.

35. Lippi G, Franchini M, Favaloro EJ, Targher G. Moderate red wine consumption and cardiovascular disease risk: beyond the "French paradox." Semin Thromb Hemost. 2010;36(1):59-70.

36. Reding KW, Daling JR, Doody DR, O'Brien CA, Porter PL, Malone KE. Effect of prediagnostic alcohol consumption on survival after breast cancer in young women. Cancer Epidemiol Biomarkers Prev. 2008;17(8):1988-1996.

37. Franceschi S, Dal Maso L, Zucchetto A, et al. Prospective analysis of case-control studies on environmental factors and health (PACE) study group: alcohol consumption and survival after breast cancer. Cancer Epidemiol Biomarkers Prev. 2009;18(3):1011-1012.

38. Li CI, Chlebowski RT, Freiberg M, et al. Alcohol consumption and risk of postmenopausal breast cancer by subtype: the women's health initiative observational study. J Natl Cancer Inst. 2010;102(18):1422-1431.

39. Stătescu C, Clement A, Serban IL, Sascau R. Consensus and controvery in the debate over the biphasic impact of alcohol consumption on the cardiovascular system. Nutrients. 2021;13(4):1076.

40. Puddey IB, Mori TA, Barden AE, Beilin LJ. Alcohol and hypertension – new insights and lingering controversies. Curr Hypertens Rep. 2019;21(10):79.

41. Tanasescu M, Hu FB, Willett WC, Stampfer MJ, Rimm EB. Alcohol consumption and risk of coronary heart disease among men with type 2 diabetes mellitus. J Am Coll Cardiol. 2001;38(7):1836-1842.

42. Ahmed AT, Karter AJ, Liu J. Alcohol consumption is inversely associated with adherence to diabetes self-care behaviours. Diabet Med. 2006;23(7):795-802.

43. Ahmed AT, Karter AJ, Warton EM, Doan JU, Weisner CM. The relationship between alcohol consumption and glycemic control among patients with diabetes: the Kaiser Permanente Northern California Diabetes Registry. J Gen Intern Med. 2008;23(3):275-282.

44. Klatsky AL. Should patients with heart disease drink alcohol? JAMA. 2001;285(15):2004-2006.

45. Kendler KS, Prescott CA, Neale MC, Pedersen NL. Temperance board registration for alcohol abuse in a national sample of Swedish male twins, born 1902 to 1949. Arch Gen Psychiatry. 1997;54(2):178-184.

46. Schuckit MA. Vulnerability factors for alcoholism. In: Davis KL, Charney D, Coyle JT, Nemeroff C (eds). Neuropsychopharmacology: The Fifth Generation of Progress. An Unofficial Publication of the College of Neuropharmacology. Philadelphia, PA: Lippincott Williams & Wilkins; 2002.

47. Prescott CA. Sex differences in the genetic risk for alcoholism. Alcohol Res Health. 2002;26(4):264-273.

48. Bowers BJ, Owen EH, Collins AC, Abeliovich A, Tonegawa S, Wehner JM. Decreased ethanol sensitivity and tolerance development in gamma-protein kinase C null mutant mice is dependent on genetic background. Alcohol Clin Exp Res. 1999;23(3):387-397.

49. Engel SR, Allan AM. 5-HT3 receptor over-expression enhances ethanol sensitivity in mice. Psychopharm. 1999;144(4):411-415.

50. Hwang BH, Suzuki R, Lumeng L, Li TK, McBride WJ. Innate differences of neuropeptide Y (NPY) in hypothalamic nuclei and central nucleus of the amygdala between selectively bred rats with high and low alcohol preference. Alcohol Clin Exp Res. 1999;23(6):1023-1030.

51. Risinger FO, Doan AM, Vickrey AC. Oral operant ethanol self-administration in 5-HT1b knockout mice. Behav Brain Res. 1999;102(1-2):211-215.

52. Roberts AJ, McDonald JS, Heyser CJ, et al. mu-Opioid receptor knockout mice do not self-administer alcohol. J Pharm Exp Ther. 2000;293(3):1002-1008.

53. Thiele TE, Marsh DJ, Ste. Marie L, Bernstein IL, Palmiter RD. Ethanol consumption and resistance are inversely related to neuropeptide Y levels. Nature. 1998;396(6709):366-369.

54. Yagi T, Yasuda M, Niki H. Ethanol sensitivity and molecular function of Fyn tyrosine kinase. In: Hoek JB, Gordon AS, Mochly-Rosen D, Zakhari S (eds). Ethanol and Intracellular Signaling: From Molecules to Behavior. Bethesda, MD: NIAAA; 2000: 195-202.

55. Schuckit MA. Biological, psychological and environmental predictors of the alcoholism risk: a longitudinal study. J Stud Alcohol. 1998;59(5):485-494.

56. Krystal JH, Tabakoff B. Ethanol abuse, dependence, and withdrawal: neurobiology and clinical implications. In: Davis KL, Charney D, Coyle JT, Nemeroff C (eds). Neuropsychopharmacology: The Fifth Generation of Progress. An Unofficial Publication of the College of Neuropharmacology. New York, NY: Lippincott Williams & Wilkins; 2002.

57. Schuckit MA, Smith TL. The relationships of a family history of alcohol dependence, a low level of response to alcohol and six domains of life functioning to the development of alcohol use disorders. J Stud Alcohol. 2000;61(6):827-835.

58. Paulus MP, Schuckit MA, Tapert SF, et al. High versus low level of response to alcohol: evidence of differential reactivity to emotional stimuli. Biol Psychiatry. 2012;72(10):848-855.

59. Bates ME, Mun EY, Buckman JF, et al. Getting to the heart of low sensitivity to alcohol: context moderates low cardiovascular response to alcohol in persons with a family history of alcohol use disorder. Alcohol Clin Exp Res. 2020;44(3):589-599.

60. Schuckit MA, Smith TL, Kalmijn J, Tsuang J, Hesselbrock V, Bucholz K. Response to alcohol in daughters of alcoholics: a pilot study and a comparison with sons of alcoholics. Alcohol Alcohol. 2000;35(3):242-248.

61. Hill SY, DeBellis MD, Keshavan MS, et al. Right amygdala volume in adolescent and young adult offspring from families at high risk for developing alcoholism. Biol Psychiatry. 2001;49(11):894-905.

62. O'Brien JW, Hill SY. Neural predictors of substance use disorders in young adulthood. Psychiatry Res. 2017;268:22-26.

63. National Institute on Alcohol Abuse and Alcoholism. Alcohol Facts and Statistics. Available at https://www.niaaa.nih.gov/publications/brochures-and-fact-sheets/alcohol-facts-and-statistics. Last accessed April 24, 2024.

64. National Institute on Alcohol Abuse and Alcoholism. Alcohol-Related Deaths Increasing in the United States. Available at https://www.niaaa.nih.gov/news-events/news-releases/alcohol-related-deaths-increasing-united-states. Last accessed April 24, 2024.

65. Grossman ER, Benjamin-Neelon SE, Sonnenschein S. Alcohol consumption during the COVID-19 pandemic: a cross-sectional survey of US adults. Int J Environ Res Public Health. 2020;17(24):9189.

66. Meyers JL, McCutcheon VV, Horne-Osipenko KA, et al. COVID-19 pendemic stressors are associated with reported increases in frequency of drunkenness among individuals with a history of alcohol use disorder. Transl Psychiatry. 2023;13(1):311.

67. Cadoret RJ, Yates WR, Troughton E, Woodworth G, Stewart MA. Adoption study demonstrating two genetic pathways to drug abuse. Arch Gen Psychiatry. 1995;52(1):42-52.

68. Kendler KS, Ohlsson H, Sundquist K, Sundquist J. The rearing environment and risk for drug abuse: a Swedish national high-risk adopted and not-adopted co-sibling control study. Psychol Med. 2016;46(7):1359-1366.

69. Grant BF, Stinson FS, Harford TC. Age at onset of alcohol use and DSM-IV alcohol abuse and dependence: a 12-year follow-up. J Subst Abuse. 2001;13(4):493-504.

70. Goodwin DW,Schulsinger F, Moller N, Hermansen L, Winokur G, Guze SB. Drinking problems in adopted and nonadopted sons of alcoholics. Arch Gen Psychiatry. 1974;31(2):164-169.

71. Conrod PJ, Pihl RO, Ditto B. Autonomic reactivity and alcohol-induced dampening in men at risk for alcoholism and men at risk for hypertension. Alcohol Clin Exp Res. 1995;19(2):482-489.

72. Söderpalm AH, de Wit H. Effects of stress and alcohol on subjective state in humans. Alcohol Clin Exp Res. 2002;26(6):818-826.

73. Childs E, O'Connor S, de Wit H. Bidirectional interactions between acute psychosocial stress and acute intravenous alcohol in healthy men. Alcohol Clin Exp Res. 2011;35(10):1794-1803.

74. 74. Volavka J, Czobor P, Goodwin DW, et al. The electroencephalogram after alcohol administration in high-risk men and the development of alcohol use disorders 10 years later. Arch Gen Psychiatry. 1996;53(3):258-263.

75. Holdstock L, de Wit H. Individual differences in the biphasic effects of ethanol. Alcohol Clin Exp Res. 1998;22(9):1903-1911.

76. Holdstock L, de Wit H. Individual differences in responses to ethanol and d-amphetamine: a within-subject study. Alcohol Clin Exp Res. 2001;25(4):540-548.

77. Morean ME, Corbin WR. Subjective response to alcohol: a critical review of the literature. Alcohol Clin Exp Res. 2010;34(3):385-395.

78. Quinn PD, Fromme K. Subjective response to alcohol challenge: a quantitative review. Alcohol Clin Exp Res. 2011;35(10):1759-1770.

79. Ray LA, Bujarski S, Roche DJ. Subjective response to alcohol as a research domain criterion. Alcohol Clin Exp Res. 2016;40(1):6-17.

80. Rangaswamy M, Porjesz B. Understanding alcohol use disorders with neuroelectrophysiology. Handb Clin Neurol. 2014;125:383-414.

81. Stenberg G, Sano M, Rosen I, et al. EEG topography of acute ethanol effects in resting and activated normals. J Stud Alcohol. 1994;55:645-656.

82. 82. Ehlers CL, Phillips E, Wall TL, et al. EEG alpha and level of response to alcohol in Hispanic- and non-Hispanic-American young adults with a family history of alcoholism. J Stud Alcohol. 2004;65:301-308.

83. Kahkonen S, Kesaniemi M, Nikouline VV, et al. Ethanol modulates cortical activity: direct evidence with combined TMS and EEG. Neuroimage. 2001;14:322-332.

84. Sullivan MA, Rudnik-Levin F. Attention deficit/hyperactivity disorder and substance abuse: diagnostic and therapeutic considerations. Ann NY Acad Sci. 2001;931:251-270.

85. Schuck AM, Widom CS. Childhood victimization and alcohol symptoms in females: causal inferences and hypothesized mediators. Child Abuse Negl. 2001;25(8):1069-1092.

86. Resnick MD, Bearman PS, Blum RW, et al. Protecting adolescents from harm: findings from the National Longitudinal Study on Adolescent Health. JAMA. 1997;278(10):823-832.

87. Donovan JE. Adolescent alcohol initiation: a review of psychosocial risk factors. J Adolesc Health. 2004;35(6):e7-e18.

88. Nash SG, McQueen A, Bray JH. Pathways to adolescent alcohol use: Family environment, peer influence, and parental expectations. J Adolesc Health. 2005;37(1):19-28.

89. Galambos NL, Barker ET, Almeida DM. Parents do matter: Trajectories of change in externalizing and internalizing problems in early adolescence. Child Dev. 2003;74(2):578-594.

90. Lansford JE, Criss MM, Pettit GS, Dodge KA, Bates JE. Friendship quality, peer group affiliation, and peer antisocial behavior as moderators of the link between negative parenting and adolescent externalizing behavior. J Res Adolesc. 2003;13(2):161-184.

91. Mrug S, Windle M. Moderators of negative peer influence on early adolescent externalizing behaviors: The roles of individual behavior, parenting, and school connectedness. J Early Adolesc. 2009;29:518-540.

92. Schuckit MA, Smith TL, Landi NA. The 5-year clinical course of high-functioning men with DSM-IV alcohol abuse or dependence. Am J Psychiatry. 2000;157(12):2028-2035.

93. Schuckit MA, Smith TL, Danko GP, et al. Five-year clinical course associated with DSM-IV alcohol abuse or dependence in a large group of men and women. Am J Psychiatry. 2001;158(7):1084-1090.

94. National Institute on Alcohol Abuse and Alcoholism. Alcohol Facts and Statistics. Available at https://www.niaaa.nih.gov/alcohols-effects-health/alcohol-topics/alcohol-facts-and-statistics. Last accessed April 24, 2024.

95. Thompson W, Lande RG, Kalapatapu RJ. Alcoholism. Available at https://emedicine.medscape.com/article/285913-overview. Last accessed April 24, 2024.

96. National Institute on Alcohol Abuse and Alcoholism. Alcohol's Effects on the Body. Available at https://www.niaaa.nih.gov/alcohols-effects-health/alcohols-effects-body. Last accessed April 24, 2024.

97. Heuman DM, Mihas AA, Hung PD. Alcoholic Hepatitis. Available at https://emedicine.medscape.com/article/170539-overview. Last accessed April 24, 2024.

98. Gavaler JS, Arria AM. Increased susceptibility of women to alcoholic liver disease: artifactual or real? In: Hall P (ed). Alcoholic Liver Disease: Pathology and Pathogenesis. 2nd ed. London: Edward Arnold; 1995:123-133.

99. Hall P. Factors influencing individual susceptibility to alcoholic liver disease. In: Hall P (ed). Alcoholic Liver Disease: Pathology and Pathogenesis. 2nd ed. London: Edward Arnold; 1995: 299-316.

100. Grewal P, Viswanathen VA. Liver cancer and alcohol. Clin Liver Dis. 2012;16(4):839-850.

101. Luu L. Liver Transplants. Available at https://emedicine.medscape.com/article/776313-overview. Last accessed April 24, 2024.

102. Dhar S, Omran L, Bacon BR, Solomon H, Di Bisceglie AM. Liver transplantation in patients with chronic hepatitis C and alcoholism. Dig Dis Sci. 1999;44(10):2003-2007.

103. Gómez-Moreno G, Guardia J, Cutando A. Interaction of paracetamol in chronic alcoholic patients: importance for odontologists. Med Oral Patol Oral Cir Bucal. 2008;13(4):E235-E238.

104. Girre C, Hispard E, Palombo S, N'Guyen C, Dally S. Increased metabolism of acetaminophen in chronically alcoholic patients. Alcohol Clin Exp Res. 1993;17(1):170-173.

105. Seeff LB, Cuccherini BA, Zimmerman HJ, Adler E, Benjamin SB. Acetaminophen hepatotoxicity in alcoholics: a therapeutic misadventure. Ann Intern Med. 1986;104(3):399-404.

106. Black M. Acetaminophen hepatotoxicity. Ann Rev Med. 1984;35:577-593.

107. 107. Kuffner EK, Green JL, Bogdan GM, et al. The effect of acetaminophen (four grams a day for three consecutive days) on hepatic tests in alcoholic patients: a multicenter randomized study. BMC Med. 2007;30:13.

108. U.S. Food and Drug Administration. Acetaminophen Prescription Combination Drug Products with More than 325 mg: FDA Statement: Recommendation to Discontinue Prescribing and Dispensing. Available at https://wayback.archive-it.org/7993/20170406123735/https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm381650.htm. Last accessed April 24, 2024.

109. Schoppet M, Maisch B. Alcohol and the heart. Herz. 2001;26(5):345-352.

110. Lee DH, Ha MH, Kim JR, Gross M, Jacobs DR. Gamma-glutamyltransferase, alcohol, and blood pressure: a four year follow-up study. Ann Epidemiol. 2002;12(2):90-96.

111. Rosenthal L. Holiday Heart Syndrome. Available at https://emedicine.medscape.com/article/155050-overview. Last accessed April 24, 2024.

112. Rafie IM, Colucci WS. Alcohol-Induced Cardiomyopathy. Available at https://www.uptodate.com/contents/alcohol-induced-cardiomyopathy. Last accessed April 24, 2024.

113. Menz V, Grimm W, Hoffmann J, Maisch B. Alcohol and rhythm disturbance: the holiday heart syndrome. Herz. 1996;21(4):227-231.

114. Ettinger PO, Wu CF, De La Cruz C, et al. Arrhythmias and the "holiday heart:" alcohol-associated cardiac rhythm disorders. Am Heart J. 1978;95(5):555-562.

115. 115. Hansson A, Madsen-Härdig B, Olsson SB. Arrhythmia-provoking factors and symptoms at the onset of paroxysmal atrial fibrillation: a study based on interviews with 100 patients seeking hospital assistance. BMC Cardiovasc Disord. 2004;3:4-13.

116. Noessler N, Schweintzger S, Kurath-Koller S. Holiday heart syndrome: an upcoming tachyarrhythmia in today's youth? Cardiol Young. 2021;31(6):1054-1056.

117. Mangoni AA, Jackson SH. Homocysteine and cardiovascular disease: current evidence and future prospects. Am J Med. 2002;112(7):556-565.

118. 118. Chambers JC, Ueland PM, Obeid OA. Improved vascular endothelial function after oral B vitamins: an effect mediated through reduced concentrations of free plasma homocysteine. Circulation. 2000;102(20):2479-2483.

119. Debreceni B, Debreceni L. The role of homocysteine-lowering B-vitamins in the primary prevention of cardiovascular disease. Cardiovasc Ther. 2014;32(3):130-138.

120. Martí-Carvajal AJ, Solà I, Lathyris D, Dayer M. Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev. 2017;(8):CD006612.

121. Weber A, Tannapfel A, Wittekind C, Bootz F. Carcinogen-induced site-specific mutagenesis and genetic susceptibility in squamous cell carcinoma of the head and neck. Onkologie. 2002;25(1):8-13.

122. Stinson FS, DeBakey SF. Alcohol-related mortality in the United States, 1979–1988. Br J Addict. 1992;87(5):777-783.

123. Peng Q, Chen H, Huo JR. Alcohol consumption and corresponding factors: a novel perspective on the risk factors of esophageal cancer. Oncol Lett. 2016;11(5):3231-3239.

124. International Agency for Research on Cancer. Alcohol consumption and ethyl carbamate In: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Lyon: IARC Press, International Agency for Research on Cancer; 2010.

125. Castellsagué X, Muñoz N, De Stefani E, et al. Independent and joint effects of tobacco smoking and alcohol drinking on the risk of esophageal cancer in men and women. Int J Cancer. 1999;82(5):654-657.

126. Zambon P, Talamini R, La Vecchia C, et al. Smoking, type of alcoholic beverage and squamous-cell oesophageal cancer in northern Italy. Int J Cancer. 2000;86(1):144-149.

127. Drummond J. Alcohol and Hormones. Available at https://integrativewomenshealthinstitute.com/alcohol-and-hormones/. Last accessed April 24, 2024.

128. Stermer E. Alcohol consumption and the gastrointestinal tract. Isr Med Assoc. 2002;4(3):200-202.

129. Hagedorn JC, Encarnacion B, Brat GA, Morton JM. Does gastric bypass alter alcohol metabolism? Surg Obes Relat Dis. 2007;3(5):543-548.

130. Bisceglie AM, Segal I. Cirrhosis and chronic pancreatitis in alcoholics. J Clin Gastroenterol. 1984;6(3):199-200.

131. Etemad B, Whitcomb DC. Chronic pancreatitis: diagnosis, classification, and new genetic developments. Gastroenterology. 2001;120(3):682-707.

132. Ferrone C, Rattner DW. Chronic pancreatitis. In: Rakel RE, Bope ET (eds). Conn's Current Therapy, 2014. Philadelphia, PA: W.B. Saunders; 2002: 515-516.

133. Gumaste VV. Alcoholic pancreatitis: unraveling the mystery. Gastroenterology. 1995;108(1):297-299.

134. Witt H, Apte MV, Keim V, Wilson JS. Chronic pancreatitis: challenges and advances in pathogenesis, genetics, diagnosis, and therapy. Gastroenterology. 2007;132:1557-1573.

135. Apte MV, Wilson JS. Mechanisms of pancreatic fibrosis. Dig Dis. 2004;22:273-279.

136. National Institute on Alcohol Abuse and Alcoholism. Alcohol Metabolism. Available at https://www.niaaa.nih.gov/publications/alcohol-metabolism. Last accessed April 24, 2024.

137. Moses S. Lab Markers of Malnutrition. Available at https://fpnotebook.com/Pharm/Lab/LbMrkrsOfMlntrtn.htm. Last accessed April 24, 2024.

138. Breslow RA, Smothers BA. Drinking patterns and body mass index in never smokers: National Health Interview Survey, 1997–2001. Am J Epidemiol. 2005;161(4):368-376.

139. Butler L, Popkin BM, Poti JM. Associations of alcoholic beverage consumption with dietary intake, waist circumference, and body mass index in U.S. adults: National Health and Nutrition Examination Survey 2003–2012. J Acad Nutr Diet. 2018;118(3):409-420.

140. Saules KK, Wiedemann A, Ivezaj V, Hopper JA, Foster-Hartsfield J, Schwarz D. Bariatric surgery history among substance abuse treatment patients: prevalence and associated features. Surg Obes Relat Dis. 2010;6(6):615-621.

141. Kleiner KD, Gold MS, Frost-Pineda K, Lenz-Brunsman B, Perri MG, Jacobs WS. Body mass index and alcohol use. J Addict Dis. 2004;23(3):105-118.

142. Van den Berg H, van der Gaag M, Hendriks H. Influence of lifestyle on vitamin bioavailability. Int J Vitam Nutr Res. 2002;72(1):53-59.

143. Thomson AD. Mechanisms of vitamin deficiency in chronic alcohol misusers and the development of the Wernicke-Korsakoff syndrome. Alcohol Alcohol. 2000;35(1):2-7.

144. Zhang P, Bagby GJ, Happel KI, Summer WR, Nelson S. Pulmonary host defenses and alcohol. Front Biosci. 2002;7:d1314-d1330.

145. Kaphalia L, Calhoun WJ. Alcoholic lung injury: metabolic, biochemical and immunological aspects. Toxicol Lett. 2013;222(2):171-179.

146. Sarmiento X, Guardiola JJ, Soler M. Alcohol and acute respiratory distress syndrome: casuality or causality? Med Clin (Barc). 2013;140(12):546-553.

147. Joshi PC, Guidot DM. The alcoholic lung: epidemiology, pathophysiology, and potential therapies. Am J Physiol Lung Cell Mol Physiol. 2007;292(4):L813-L823.

148. Liang Y, Yeligar SM, Brown LA. Chronic-alcohol-abuse-induced oxidative stress in the development of acute respiratory distress syndrome. Scientific World J. 2012;740308.

149. Liang Y, Harris FL, Brown LA. Alcohol induced mitochondrial oxidative stress and alveolar macrophage dysfunction. Biomed Res Int. 2014;371593.

150. Kershaw CD, Guidot DM. Alcoholic lung disease. Alcohol Res Health. 2008;31(1):66-75.

151. MacGregor RR. Alcohol and immune defense. JAMA. 1986;256(11):1474-1479.

152. National Institutes for Health. Alcohol Abuse, HIV, and Infectious Disease. Available at https://grants.nih.gov/grants/guide/pa-files/PA-95-067.html. Last accessed April 24, 2024.

153. Shi X, DeLucia AL, Bao J, Zhang P. Alcohol abuse and disorder of granulopoiesis. Pharmacol Ther. 2019;198:206-219.

154. Astry CL, Warr GA, Jakab GJ. Impairment of poly-morphonuclear leukocyte immigration as a mechanism of alcohol-induced suppression of pulmonary antibacterial defenses. Am Rev Respir Dis. 1983;128(1):113-117.

155. 155. Davis CC, Mellencamp MA, Preheim LC. A model of pneumococcal pneumonia in chronically intoxicated rats. J Infect Dis. 1991;163(4):799-805.

156. Melvan JN, Siggins RW, Stanford WL, et al. Alcohol impairs the myeloid proliferative response to bacteremia in mice by inhibiting the stem cell antigen-1/ERK pathway. J Immunol. 2012;188(4):1961-1969.

157. Vitiello MV. Sleep, alcohol and alcohol abuse. Addict Biol. 1997;2(2):151-158.

158. Roehrs T, Roth T. Sleep, sleepiness, sleep disorders and alcohol use and abuse. Sleep Med Rev. 2001;5(4):287-297.

159. Thakkar MM, Sharma R, Sahota P. Alcohol disrupt sleep homeostasis. Alcohol. 2015;49(4):299-310.

160. 160. Landolt HP, Roth C, Dijk D, Borbely A. Late-afternoon ethanol intake affects nocturnal sleep and the sleep EEG in middle-aged men. J Clin Psychopharmacol. 1996;16(6):428-436.

161. Yang S, Guo X, Liu W, Li Y, Liu Y. Alcohol as an independent risk factor for obstructive sleep apnea. Ir J Med Sci. 2022;191(3):1325-1330.

162. Simou E, Britton J, Leonardi-Bee J. Alcohol and the risk of sleep apnoea: a systematic review and meta-analysis. Sleep Med. 2018;42:38-46.

163. Kolla BP, Foroughi M, Saeidifard F, Chakravorty S, Wang Z, Mansukhani MP. The impact of alcohol on breathing parameters during sleep: a systematic review and meta-analysis. Sleep Med Rev. 2018;42:59-67.

164. Taveira KVM, Kuntze MM, Berretta F, et al. Association between obstructive sleep apnea and alcohol, caffeine and tobacco: a meta-analysis. J Oral Rehabil. 2018;45(11):890-902.

165. Bassetti C, Aldrich MS. Alcohol consumption and sleep apnea in patients with TIA and ischemic stroke. Sleep Res. 1996;25:400.

166. Yaggi HK, Concato J, Kernan WN, Lichtman JH, Brass LM, Mohsenin V. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med. 2005;353(19):2034-2041.

167. Rich J, Raviv A, Raviv N, Brietzke SE. All-cause mortality and obstructive sleep apnea severity revisited. Otolaryngol Head Neck Surg. 2012;147(3):583-587.

168. Xiong GL. Wernicke-Korsakoff Syndrome. Available at https://emedicine.medscape.com/article/288379-overview. Last accessed April 24, 2024.

169. Schuckit MA, Mazzanti C, Smith TL, et al. Selective genotyping for the role of 5-HT2A, 5-HT2C, and GABA alpha 6 receptors and the serotonin transporter in the level of response to alcohol: a pilot study. Biol Psychiatry. 1999;45(5):647-651.

170. Cope LM, Munier EC, Trucco EM, et al. Effects of the serotonin transporter gene, sensitivity of response to alcohol, and parental monitoring on risk for problem alcohol use. Alcohol. 2017;59:7-16.

171. Hommer D,Momenan R, Rawlings R, et al. Decreased corpus callosum size among alcoholic women. Arch Neurol. 1996;53(4):359-363.

172. Ruiz SM, Oscar-Berman M, Sawyer KS, Valmas MM, Urban T, Harris GJ. Drinking history associations with regional white matter volumes in alcoholic men and women. Alcohol Clin Exp Res. 2013;37(1):110-122.

173. Kisner MA, Sussman L, Manuweera T, et al. Evaluating effects of sex and age on white matter microstructural alterations in alcohol use disorder: a diffusion tensor imagins study. Alcohol Clin Exp Res. 2021;45(9):1790-1803.

174. Albayrak O, Krug S,Scherbaum N. Sex-specific aspects of addiction. MMW Fortschr Med. 2007;149(24):29-32.

175. Frezza M, di Padova C, Pozzato G, Terpin M, Baraona E, Lieber CS. High blood alcohol levels in women: the role of decreased gastric alcohol dehydrogenase activity and first-pass metabolism. N Engl J Med. 1990;322(2):95-99.

176. Glazkov VA, Sviderskaia NE. Gender differences in chronic alcoholism: EEG analysis. Zh Vyssh Nerv Deiat Im I P Pavlova. 2006;56(5):597-602.

177. Walter H, Dvorak A, Gutierrez K, Zitterl W, Lesch OM. Gender differences: does alcohol affect females more than males? Neuropsychopharmacology Hung. 2005;7(2):78-82.

178. Moos RH, Moos BS, Timko C. Gender, treatment and self-help in remission from alcohol use disorders. Clin Med Res. 2006;4(3):163-174.

179. Bloomfield K, Gmel G, Wilsnack S. Introduction to special issue: gender, culture and alcohol problems: a multi-national study. Alcohol Alcohol Suppl. 2006;41(1):i3-i7.

180. Centers for Disease Control and Prevention. Fetal Alcohol Spectrum Disorders. Available at https://www.cdc.gov/ncbddd/fasd/facts.html. Last accessed April 24, 2024.

181. Coles CD, Platzman KA, Raskind-Hood CL, et al. A comparison of children affected by prenatal alcohol exposure and attention deficit, hyperactivity disorder. Alcohol Clin Exp Res. 1997;21(1):150-161.

182. Jacobson SW, Jacobson JL, Sokol RJ. Effects of fetal alcohol exposure on infant reaction time. Alcohol Clin Exp Res. 1994;18(5):1125-1132.

183. Kodituwakku PW,Handmaker NS, Cutler SK, Weathersby EK, Handmaker SD. Specific impairments in self-regulation in children exposed to alcohol prenatally. Alcohol Clin Exp Res. 1995;19(6):1558-1564.

184. Mattson SN, Riley EP. A review of the neurobehavioral deficits in children with fetal alcohol syndrome or prenatal exposure to alcohol. Alcohol Clin Exp Res. 1998;22(2):279-294.

185. Mattson SN, Riley EP, Delis DC, Stern C, Jones KL. Verbal learning and memory in children with fetal alcohol syndrome. Alcohol Clin Exp Res. 1996;20(5):810-816.

186. Roebuck TM, Mattson SN, Riley EP. Behavioral and psychosocial profiles of alcohol-exposed children. Alcohol Clin Exp Res. 1999;23(6):1070-1076.

187. Roebuck TM, Mattson SN, Riley EP. A review of the neuro-anatomical findings in children with fetal alcohol syndrome or prenatal exposure to alcohol. Alcohol Clin Exp Res. 1998;22(2):339-344.

188. Institute of Medicine, Stratton K, Howe C (eds). Fetal Alcohol Syndrome: Diagnosis, Epidemiology, Prevention, and Treatment. Washington, DC: National Academy Press; 1996.

189. Streissguth AP, Barr HM, Sampson PD, Parrish-Johnson JC, Kirchner GL, Martin DC. Attention, distraction, and reaction time at age 7 years and prenatal alcohol exposure. Neurobehav Toxicol Teratology. 1986;8(6):717-725.

190. Uecker A, Nadel L. Spatial locations gone awry: object and spatial memory deficits in children with fetal alcohol syndrome. Neuropsychologia. 1996;34(3):209-223.

191. IkonomidouC, Bittigau P, Ishimaru MJ, et al. Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science. 2000;287(5455):1056-1060.

192. Centers for Disease Control and Prevention. Fetal Alcohol Spectrum Disorders: Data and Statistics on FASDs. Available at https://www.cdc.gov/ncbddd/fasd/data.html. Last accessed April 24, 2024.

193. Quick S. Fetal alcohol syndrome: the nurse practitioner perspective. J Am Acad Nurse Pract. 1996;8(7):343-349.

194. Carson DK, Council JR, Volk MA. Temperament, adjustment, and alcoholism in adult female incest victims. Violence Vict. 1988;3(3):205-216.

195. Rose SM, Peabody CG, Stratigeas B. Undetected abuse among intensive case management clients. Hosp Community Psychiatry. 1991;42(5):499-503.

196. Higley JD, Suomi SJ, Linnoila M. A nonhuman primate model of type II excessive alcohol consumption? Part 1. Low cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations and diminished social competence correlate with excessive alcohol consumption. Alcohol Clin Exp Res. 1996;20(4):629-642.

197. Robins LN. Deviant children grown up. Eur Child Adolesc Psychiatry. 1996;5(1 Suppl):44-46.

198. Brown GL, Linnoila MI. CSF serotonin metabolite (5-HIAA) studies in depression, impulsivity, and violence. J Clin Psychiatry. 1990;51(Suppl):31-43.

199. Centers for Disease Control and Prevention. Pricing Strategies for Alcohol Products. Available at https://www.cdc.gov/policy/hi5/alcoholpricing/. Last accessed April 24, 2024.

200. Grossman M, Markowitz S. Alcohol regulation and violence on college campuses. In: Grossman M, Hsieh CR, eds. Economic Analysis of Substance Use and Abuse: The Experience of Developed Countries and Lessons for Developing Countries. Cheltenham, UK: Edward Elgar; 2001.

201. Saffer H. Substance abuse control and crime: evidence from the National Survey of Drug Abuse. In: Grossman M, Hsieh CR, eds. Economic Analysis of Substance Use and Abuse: The Experience of Developed Countries and Lessons for Developing Countries. Cheltenham, UK: Edward Elgar; 2001.

202. Hollingworth W, Ebel BE, McCarty CA, Garrison MM, Christakis DA, Rivara FP. Prevention of deaths from harmful drinking in the United States: the potential effects of tax increases and advertising bans on young drinkers. J Stud Alcohol. 2006;67(2):300-308.

203. Elder RW, Lawrence B, Ferguson A, et al. The effectiveness of tax policy interventions for reducing excessive alcohol consumption and related harms. Am J Prevent Med. 2010;38(2):217-229.

204. Wagenaar AC, Tobler AL, Kornro KA. Effects of alcohol tax and price policies on morbidity and mortality: a systematic review. Am J Public Health. 2010;100(11):2270-2278.

205. National Council on Alcoholism and Drug Dependence. Alcohol, Drugs and Crime. Available at https://ncadd.us/about-addiction/addiction-update/alcohol-drugs-and-crime. Last accessed April24, 2024.

206. American Addiction Centers. How Drugs and Alcohol Can Fuel Violent Behaviors. Available at https://americanaddictioncenters.org/rehab-guide/addiction-and-violence. Last accessed April 24, 2024.

207. U.S. Department of Transportation. National Highway Traffic Safety Administration. Traffic Safety Facts. Overview of Motor Vehicle Traffic Crashes in 2022. Available at https://crashstats.nhtsa.dot.gov/Api/Public/ViewPublication/813560. Last accessed April 24, 2024.

208. Centers for Disease Control and Prevention. Transportation Safety: Impaired Driving: Get the Facts. Available at https://www.cdc.gov/transportationsafety/impaired_driving/impaired-drv_factsheet.html. Last accessed April 24, 2024.

209. 209. Lapham SC, Smith E, C'de Baca J, et al. Prevalence of psychiatric disorders among persons convicted of driving while impaired. Arch Gen Psychiatry. 2001;58(10):943-949.

210. Nelson SE, Belkin K, LaPlante DA, Bosworth L, Shaffer HJ. A prospective study of psychiatric comorbidity and recidivism among repeat DUI offenders. Arch Sci Psychol. 2015;3(1):8-17.

211. Robbe H. Marijuana's impairing effects on driving are moderate when taken alone but severe when combined with alcohol. Hum Psychopharmacol Clin Exp. 1998;13(S2):S70-S78.

212. Lacey JH, Kelley-Baker T, Furr-Holden D, et al. National Roadside Survey of Alcohol and Drug Use By Drivers: Drug Results. Washington, DC: National Highway Traffic Safety Administration; 2007.

213. 213. Biecheler MB, Peytavin JF, Facy F, Martineau H. SAM survey on "drugs and fatal accidents:" search of substances consumed and comparison between drivers involved under the influence of alcohol or cannabis. Traffic Inj Prev. 2008;9:11-21.

214. Walsh JM, Flegel R, Atkins R, Cangianelli LA, Cooper C, Welsh C, Kerns TJ. Drug and alcohol use among drivers admitted to a level-1 trauma center. Accid Anal Prev. 2005;37:894-901.

215. Berning A, Compton R, WochingerK. Results of the 2013–2014 National Roadside Survey of Alcohol and Drug Use by Drivers. Available at https://www.nhtsa.gov/sites/nhtsa.dot.gov/files/812118-roadside_survey_2014.pdf. Last accessed April 24, 2024.

216. Thomas FD, Darrah J, Graham L, et al. Alcohol and Drug Prevalence Among Seriously or Fatally Injured Road Users (Report No. DOT HS 813 399). Washington, DC: U.S. Department of Transportation, National Highway Traffic Safety Administration; 2022.

217. Stephen RJ, Martin PR. Co-occurring psychiatric disorders and alcoholism. Handb Clin Neurol. 2014;125:573-588.

218. Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse. JAMA. 1990;264(19):2511-2518.

219. Davis L,Uezato A, Newell JM, Frazier E. Major depression and comorbid substance use disorders. Curr Opin Psychiatry. 2008;21(1):14-18.

220. Nunes EV, Liu X, Samet S, et al. Independent versus substance-induced major depressive disorder in substance-dependent patients: observational study of course during follow-up. J Clin Psychiatry. 2006;67(10):1561-1567.

221. Centers for Disease Control and Prevention. WISQARS Leading Causes of Death Visualization Tool. Available at https://wisqars.cdc.gov/lcd/?. Last accessed April 24, 2024.

222. Mann JJ. A current perspective of suicide and attempted suicide. Ann Intern Med. 2002;136(4):302-311.

223. Kim J, Lee KS, Kim DJ, et al. Characteristic risk factors associated with planned versus impulsive suicide attempters. Clin Psychopharmacol Neurosci. 2015;13(3):308-315.

224. Cornelius JR, Salloum IM, Day NL, Thase ME, Mann JJ. Patterns of suicidality and alcohol use in alcoholics with major depression. Alcohol Clin Exp Res. 1996;20(8):1451-1455.

225. Murphy GE, Wetzel RD. The lifetime risk of suicide in alcoholism. Arch Gen Psychiatry. 1990;47(4):383-392.

226. 226. Pandey S, Bolstad I, Lien L, Walby FA, Myhre MO, Bramness JG. Sex-specific factors associated with lifetime suicide attempt among patients with alcohol use disorders. BJPsych Open. 2022;8(4):e135.

227. Pompili M, Serafini G, Innamorati M, et al. Suicidal behavior and alcohol abuse. Int J Environ Res Public Health. 2010;7(4):1392-1431.

228. Powell KE, Kresnow MJ, Mercy JA, et al. Alcohol consumption and nearly lethal suicide attempts. Suicide Life Threat Behav. 2001;32(1 Suppl):30-41.

229. 229. Preuss UW, Schuckit MA, Smith TL, et al. Comparison of 3190 alcohol-dependent individuals with and without suicide attempts. Alcohol Clin Exp Res. 2002;26(4):471-477.

230. Akechi T, Iwasaki M, Uchitomi Y, Tsugane S. Alcohol consumption and suicide among middle-aged men in Japan. Bri J Psychiatry. 2006;18(8):231-236.

231. Agabio R, Trogu E, Pani PP. Antidepressants for the treatment of people with co-occurring depression and alcohol dependence. Cochrane Database Syst Rev. 2018;(4):CD008581.

232. Hashimoto E, Tayama M, Ishikawa H, Yamamoto M, Saito T. Influence of comorbid alcohol use disorder on treatment response of depressive patients. J Neural Transm (Vienna). 2015;122(2):301-306.

233. Garcia-Portilla MP, Bascarán MT, Saiz PA, et al. Effectiveness of venlafaxine in the treatment of alcohol dependence with comorbid depression. Actas Esp Psiquiatr. 2005;33(1):41-45.

234. LexiComp Online. Available at https://online.lexi.com. Last accessed April 24, 2024.

235. Tang VM, Yu D, Weissman CR, et al. Treatment outcomes in major depressive disorder in patients with comorbid alcohol use disorder: a STAR*D analysis. J Affect Disord. 2023;339:691-697.

236. McHugh RK, Weiss RD. Alcohol use disorder and depressive disorders. Alcohol Res. 2019;40(1):arcr.v40.1.01.

237. Addolorato G, Leggio L, Hopf FW, Diana M, Bonci A. Novel therapeutic strategies for alcohol and drug addiction: focus on GABA, ion channels and transcranial magnetic stimulation. Neuropsychopharmacology. 2012;37(1):163-177.

238. Chengappa KN, Levine J, Gershon S, Kupfer DJ. Lifetime prevalence of substance or alcohol abuse and dependence among subjects with bipolar I and II disorders in a voluntary registry. Bipolar Disord. 2000;2(3 Pt 1):191-195.

239. Xia Y, Ma D, Perich T, Hu J, Mitchell PB. Demographic and clinical differences between bipolar disorder patients with and without alcohol use disorders. Front Psychiatry. 2020;11:570574.

240. Brennan PL, Schutte KK, Moos RH. Pain and use of alcohol to manage pain: prevalence and 3-year outcomes among older problem and non-problem drinkers. Addiction. 2005;100(6):777-786.

241. National Institute on Alcohol Abuse and Alcoholism. The Complex Relationship Between Alcohol and Pain. Available at https://niaaa.scienceblog.com/231/the-complex-relationship-between-alcohol-and-pain/. Last accessed April 24, 2024.

242. Pennings EJ, Leccese AP, Wolff FA. Effects of concurrent use of alcohol and cocaine. Addiction. 2002;97(7):773-83.

243. Fettiplace MR, Pichurko A, Ripper R, et al. Cardiac depression induced by cocaine or cocaethylene is alleviated by lipid emulsion more effectively than by sulfobutylether-β-cyclodextrin. Acad Emerg Med. 2015;22(5):508-517.

244. Patten CA, Martin JE, Owen N. Can psychiatric and chemical dependency treatment units be smoke free? J Subst Abuse Treat. 1996;13(2):107-118.

245. Hurt RD, Offord KP, Croghan IT, et al. Mortality following inpatient addictions treatment: role of tobacco use in a community-based cohort. JAMA. 1996;275(14):1097-1103.

246. Pelucchi C, Gallus S, Garavello W, Bosetti C, La Vecchia C. Cancer risk associated with alcohol and tobacco use: focus on upper aero-digestive tract and liver. Alcohol Res Health. 2006;29(3):193-198.

247. Centers for Disease Control and Prevention. 2014 Surgeon General's Report: The Health Consequences of Smoking – 50 Years of Progress. Available at https://archive.cdc.gov/#/details?url=https://www.cdc.gov/tobacco/sgr/50th-anniversary/index.htm. Last accessed April 24, 2024.

248. Ahrendt SA, Chow JT, Yang SC, et al. Alcohol consumption and cigarette smoking increase the frequency of p53 mutations in non-small cell lung cancer. Cancer Res. 2000;60(12):3155-3159.

249. Barrett SP, Tichauer M, Leyton M, Pihl RO. Nicotine increases alcohol self-administration in non-dependent male smokers. Drug Alcohol Depend. 2006;81(2):197-204.

250. Montanari C, Secci ME, Driskell A, McDonald KO, Schratz CL, Gilpin NW. Chronic nicotine increases alcohol self-administration in adult male Wistar rats. Psychopharmacology (Berl). 2021;238(1):201-213.

251. Domi E, Xu L, Pätz M, et al. Nicotine increases alcohol self-administration in male rats via a μ-opioid mechanisms within the mesolimbic pathway. Br J Pharmacol. 2020;177(19):4516-4531.

252. Walsh RA, Bowman JA, Tzelepis F, et al. Smoking cessation interventions in Australian drug treatment agencies: a national survey of attitudes and practices. Drug Alcohol Rev. 2005;24:235-244.

253. Zullino DF, Besson J, Favrat B, et al. Acceptance of an intended smoking ban on an alcohol dependence clinic. Eur Psychiatry. 2003;18:255-257.

254. Richter KP, Choi AS, Alford DP. Smoking policies in U.S. outpatient drug treatment facilities. Nicotine Tob Res. 2005;7(3):475-480.

255. 255. Ziedonis DM, Guydish JW, Steinberg M, Foulds J. Barriers and solutions to addressing tobacco dependence in addiction treatment programs. Alcohol Res Health. 2007;9(3):228-235.

256. Hughes JR, Callas PW. Past alcohol problems do not predict worse smoking cessation outcomes. Drug Alcohol Depend. 2003;71:269-273.

257. Wang R, Li B, Jiang Y, Guan Y, Wang G, Zhao G. Smoking cessation mutually facilitates alcohol drinking cessation among tobacco and alcohol co-users: a cross-sectional study in a rural area of Shanghai, China. Tob Induc Dis. 2019;17:85.

258. Bulik CM, Klump KL, Thornton L, et al. Alcohol use disorder comorbidity in eating disorders: a multicenter study. J Clin Psychiatry. 2004;65(7):1000-1006.

259. Munn-Chernoff MA, Few LR, Matherne CE, et al. Eating disorders in a community-based sample of women with alcohol use disorder and nicotine dependence. Drug Alcohol Depend. 2020;212:107981.

260. Hodgkins CC, Jacobs WS, Gold MS. Weight gain after adolescent drug addiction treatment and supervised abstinence. Psychiatric Annals. 2003;33(2):112-116.

261. Kyngdon A, Dickerson M. An experimental study of the effect of prior alcohol consumption on a simulated gambling activity. Addiction. 1999;94(5):697-707.

262. Tobias-Webb J, Limbrick-Oldfield EH, Verancombe S, Duka T, Clark L. The effects of alcohol on sequential decision-making biases during gambling. Psychopharmacology (Berl). 2020;237(2):395-407.

263. Moyer VA. Screening and behavioral counseling interventions to reduce unhealthy alcohol use in adolescents and adults: U.S. Preventive Services Task Force Recommendation Statement. JAMA. 2018;320(18):1899-1909.

264. O'Connor EA, Perdue LA, Senger CA, et al. Screening and Behavioral Counseling Interventions in Primary Care to Reduce Unhealthy Alcohol Use in Adolescents and Adults: Updated Systematic Review for the US Preventive Services Task Force: Evidence Synthesis No. 171. Rockville, MD: Agency for Healthcare Research and Quality; 2018. AHRQ publication 18-05242-EF-1.

265. Madson MB, Schutts JW, Jordan HR, Villarosa-Hurlocker MC, Whitley RB, Mohn RS. Identifying at-risk college student drinkers with the AUDIT-US: a receiver operating characteristic curve analysis. Assessment. 2020;27(6):1089-1099.

266. National Institute on Alcohol Abuse and Alcoholism. Core Resource on Alcohol. Available at https://www.niaaa.nih.gov/health-professionals-communities/core-resource-on-alcohol/screen-and-assess-use-quick-effective-methods. Last accessed April 24, 2024.

267. Thompson W, Lande RG, Kalapatapu RK. Alcoholism. Available at https://emedicine.medscape.com/article/285913-overview. Last accessed April 24, 2024.

268. U.S. Department of Health and Human Services, National Institute on Alcohol Abuse and Alcoholism. The Physicians' Guide to Helping Patients with Alcohol Problems. Rockville, MD: National Institute on Alcohol Abuse and Alcoholism; 1995.

269. Saunders JB, Aasland OG, Babor TF, de la Fuente JR, Grant M. Development of the alcohol use disorder identification test (AUDIT): WHO collaborative project on early detection of persons with harmful alcohol consumption-II. Addiction. 1993;88(6):791-804.

270. Babor TF, Biddle-Higgins JC, Saunders JB, Monteiro MG. AUDIT: The Alcohol Use Disorders Identification Test. Guidelines for Use in Primary Health Care. 2nd ed. Geneva, Switzerland: World Health Organization; 1992.

271. Reinert DF, Allen JP. The Alcohol Use Disorders Identification Test (AUDIT): a review of recent research. Alcohol Clin Exp Res. 2002;26(2):272-279.

272. 272. AUDIT. Available at https://auditscreen.org/. Last accessed April 24, 2024.

273. AUDIT-C for Alcohol Use. Available at https://www.mdcalc.com/calc/2021/audit-c-alcohol-use. Last accessed April 24, 2024.

274. Substance Abuse and Mental Health Services Administration. Treatment Improvement Protocol (TIP) Series, No. 24. Rockville (MD): Centers for Substance Abuse Treatment; 1997.

275. Barnes AJ, Moore AA, Xu H, et al. Prevalence and correlates of at-risk drinking among older adults: the Project SHARE Study. J Gen Intern Med. 2010;25(8):840-846.

276. Moore AA,Giulu L, Gould R, et al. Alcohol use, comorbidity, and mortality. J Am Geriatr Soc. 2006;54(5):757-762.

277. Lee E. Cross-cultural communication: therapeutic use of interpreters. In: Lee E (ed). Working with Asian Americans: A Guide for Clinicians. New York, NY: The Guilford Press; 1997: 477-489.

278. National Hispanic Medical Association (NHMA). NHMA Screening and Brief Intervention Toolkit for the Hispanic Patient. National Hispanic Medical Association. Washington, DC; 2008.

279. National Institute on Alcohol Abuse and Alcoholism. Treatment for Alcohol Problems: Finding and Getting Help. Available at https://www.niaaa.nih.gov/publications/brochures-and-fact-sheets/treatment-alcohol-problems-finding-and-getting-help. Last accessed April 24, 2024.

280. 280. Bell H, Tallaksen CME, Try K, Haug E. Carbohydrate deficient transferrin and other markers of high alcohol consumption: a study of 502 patients admitted consecutively to a medical department. Alcohol Clin Exp Res. 1994;18(5):1103-1108.

281. Sorvajärvi K, Blake JE, Israel Y, Niemelä O. Sensitivity and specificity of carbohydrate-deficient transferrin as a marker of alcohol abuse are significantly influenced by alterations in serum transferrin. Alcohol Clin Exp Res. 1996;20(3):449-454.

282. Cylwik B, Chrostek L, Szmitkowski M. New methods for the determination of transferrin isoforms in the diagnostics of alcohol abuse. Postepy Hig Med Dosw. 2006;60:101-112.

283. Mayo Clinic. Test ID: CDTA. Available at https://www.mayocliniclabs.com/test-catalog/Specimen/82425. Last accessed April 24, 2024.

284. Arndt T, Gilg T, Soyka M. Diagnosis of alcoholism: CDT test does help. MMW Fortschr Med. 2000;146(26-27):10-11.

285. Sillanaukee P, Massot N, Jousilahti P, et al. Dose response of laboratory markers to alcohol consumption in a general population. Am J Epidemiol. 2000;152(8):747-751.

286. Hannuksela ML, Liisanantti MK, Nissinen AE, Savolainen MJ. Biochemical markers of alcoholism. Clin Chem Lab Med. 2007;45(8):953-61.

287. Niemelä O. Biomarkers in alcoholism. Clin Chim Acta. 2007;377(1-2):39-49.

288. Anderson G. Management of alcohol problems: the role of the general practitioner. Alcohol Alcohol. 1993;28(3):263-272.

289. Miller WR, Sanchez VC. Motivating young adults for treatment and lifestyle change. In: Howard G, Nathan P (eds). Alcohol Use and Misuse by Young Adults. Notre Dame, IN: University of Notre Dame Press; 1994.

290. Bien TH, Miller WR, Tonigan JS. Brief interventions for alcohol problems: a review. Addiction. 1993;88(3):315-335.

291. Mattoo SK, Prasad S, Ghosh A. Brief intervention in substance use disorders. Indian J Psychiatry. 2018;60(Suppl 4):S466-S472.

292. Graham AW, Fleming MS. Brief interventions. In: Graham AW, Schultz TK, Wilford BB (eds). Principles of Addiction Medicine. 3rd ed. Chevy Chase, MD: American Society of Addiction Medicine, Inc.; 2003: 361-372.

293. Henry-Edwards S, Humeniuk R, Ali R, Monteiro M, Poznyak V. Brief Intervention for Substance Use: A Manual for Use in Primary Care. Geneva: World Health Organization; 2003.

294. Carroll KM, Ball SA,Nich C, et al. Motivational interviewing to improve treatment engagement and outcome in individuals seeking treatment for substance abuse: a multisite effectiveness study. Drug Alcohol Depend. 2006;81(3):301-312.

295. Chafetz ME, Blane HT, Abram HS, et al. Establishing treatment relations with alcoholics. J Nerv Ment Dis. 1962;134(5):395-409.

296. National Institute on Alcohol Abuse and Alcoholism. Matching alcoholism treatments to client heterogeneity: Project MATCH posttreatment drinking outcomes. J Stud Alcohol. 1997;58(1):7-29.

297. Whitlock EP, Green CA, Polen MR, et al. Behavioral Counseling Interventions in Primary Care to Reduce Risky/Harmful Alcohol Use. Systematic Evidence Reviews, No. 30. Rockville, MD: Agency for Healthcare Research and Quality; 2004,

298. McCambridge J, Rollnick S. Should brief interventions in primary care address alcohol problems more strongly? Addiction. 2014;109(7):1054-1058.

299. Hyman Z. Brief interventions for high-risk drinkers. J Clin Nurs. 2006;15(11):1383-1396.

300. National Institute on Alcohol Abuse and Alcoholism. Matching alcoholism treatments to client heterogeneity: Project MATCH three-year drinking outcomes. Alcohol Clin Exp Res. 1998;22(6):1300-1311.

301. Moyer A, Finney JW, Swearingen CE, Vergun P. Brief interventions for alcohol problems: a meta-analytic review of controlled investigations in treatment-seeking and non-treatment-seeking populations. Addiction. 2002;97(3):279-292.

302. Fleming MF, Mundt MP, French MT, et al. Brief physician advice for problem drinkers: long-term efficacy and benefit-cost analysis. Alcohol Clin Exp Res. 2002;26(1):36-43.

303. Tanner-Smith EE, Risser MD. A meta-analysis of brief alcohol interventions for adolescents and young adults: variability in effects across alcohol measures. Am J Drug Alcohol Abuse. 2016;42(2):140-151.

304. American Society of Addiction Medicine. About the ASAM Criteria. Available at https://www.asam.org/asam-criteria/about-the-asam-criteria. Last accessed April 24, 2024.

305. Donovan DM, Rosengren DB. Motivation for behavior change and treatment among substance abusers. In: Tucker JA, Donovan DM, Marlatt GA (eds). Changing Addictive Behavior: Bridging Clinical and Public Health Strategies. New York, NY: The Guilford Press; 1999: 127-159.

306. Prochaska JO, Norcross JC, DiClemente CC. Changing for Good: The Revolutionary New Program that Explains the Six Stages of Change and Teaches You How to Free Yourself from Bad Habits. New York, NY: William Morrow; 1994.

307. Bayard M, McIntyre J, Hill KR, Woodside J Jr. Alcohol withdrawal syndrome. Am Fam Physician. 2004;69(6):1443-1450.

308. Merck Manual. CIWA-Ar Clinical Institute Withdrawal Assessment for Alcohol Scale. Available at https://www.merckmanuals.com/professional/multimedia/clinical-calculator/ciwa-ar-clinical-institute-withdrawal-assessment-for-alcohol-scale. Last accessed April 24, 2024.

309. Kattimani S, Bharadwaj B. Clinical management of alcohol withdrawal: a systematic review. Ind Psychiatry J. 2013;22(2):100-108.

310. Sachdeva A, Choudhary M, Chandra M. Alcohol withdrawal syndrome: benzodiazepines and beyond. J Clin Diagn Res. 2015;9(9):VE01-VE07.

311. 311. Long D, Long B, Koyfman A. The emergency medicine management of severe alcohol withdrawal. Am J Emerg Med. 2017;35(7):1005-1011.

312. Modesto-Lowe V, Barron GC, Aronow B, Chaplin M. Gabapentin for alcohol use disorder: a good option, or cause for concern? Clev Clin J Med. 2019;86(12):815-823.

313. Toohey S. Delirium Tremens (DTs) Medication. Available at https://emedicine.medscape.com/article/166032-medication#. Last accessed April 24, 2024.

314. Addolorato G, Leggio L, Hopf FW, Diana M, Bonci A. Novel therapeutic strategies for alcohol and drug addiction: focus on GABA, ion channels, and transcranial magnetic stimulation. Neuropsychopharmacology. 2012;37:163-177.

315. McKay JR, Lynch KG, Shepard DS, Pettinati HM. The effectiveness of telephone-based continuing care for alcohol and cocaine dependence 24-month outcomes. Arch Gen Psychiatry. 2005;62(2):199-207.

316. National Institute on Alcohol Abuse and Alcoholism. NIAAA Reports Project MATCH Main Findings. Available at https://www.niaaa.nih.gov/news-events/news-releases/niaaa-reports-project-match-main-findings. Last accessed April 24, 2024.

317. Kelly JF, Abry A, Ferri M, Humphreys K. Alcoholics Anonymous and 12-step facilitation treatments for alcohol use disorder: a distillation of a 2020 Cochrane Review for clinicians and policy makers. Alcohol Alcohol. 2020;55(6):641-651.

318. Hathaway B. Why "One Day at a Time" Works for Recovering Alcoholics. Available at https://news.yale.edu/2020/08/27/why-one-day-time-works-recovering-alcoholics. Last accessed April 24, 2024.

319. Dutra L, Stathopoulou G, Basden SL,Leyro TM, Powers MB, Otto MW. A meta-analytic review of psychosocial interventions for substance use disorders. Am J Psychiatry. 2008;165:179-187.

320. Magill M, Ray LA. Cognitive-behavioral treatment with adult alcohol and illicit drug users: A meta-analysis of randomized controlled trials. J Stud Alcohol Drugs. 2009;70:516-527.

321. Liese BS, Beck AT. Beyond the therapeutic alliance: keeping the drug-dependent individual in treatment. In: Simon Onken L, Blaine JD, Boren JJ (eds). Back to Basics: Fundamental Cognitive Therapy Skills for Keeping Drug-Dependent Individuals in Treatment: NIDA Research Monograph 165. Rockville, MD: National Institute on Drug Abuse; 1997: 207-232.

322. Shawe-Taylor M, Rigby J. Cognitive behaviour therapy: its evolution and basic principles. J R Soc Promot Health. 1999;119(4):244-246.

323. Wright JH, Thase ME, Beck AT. Cognitive therapy. In: Hale RE, Yudofsky SC, Talbott JA (eds). The American Psychiatric Press Textbook of Psychiatry. 4th ed. Arlington, VA: American Psychiatric Publishing; 2008.

324. Kranzler HR. Pharmacotherapy of alcoholism: gaps in knowledge and opportunities for research. Alcohol Alcohol. 2000;35(6):537-547.

325. Substance Abuse and Mental Health Services Administration and National Institute on Alcohol Abuse and Alcoholism. Medication for the Treatment of Alcohol Use Disorder: A Brief Guide. HHS Publication No. (SMA) 15-4907. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2015.

326. Miller NS, Gold MS. Alcohol. In: Gold MS (ed). Drugs of Abuse: A Comprehensive Series. New York, NY: Plenum Medical Book Co.; 1991.

327. 327. Garbutt JC, West SL, Carey TS, Lohr KN, Crews FT. Pharmacological treatment of alcohol dependence: a review of the evidence. JAMA. 1999;281(14):1318-1325.

328. Yoshimura A, Kimura M, Nakayama H, et al. Efficacy of disulfiram for the treatment of alcohol dependence assessed with a multicenter randomized controlled trial. Alcohol Clin Exp Res. 2014;38(2):572-578.

329. Skinner MD, Lahmek P, Pham H, Aubin HJ. Disulfiram efficacy in the treatment of alcohol dependence: a meta-analysis. PLoS One. 2014;9(2):e87366.

330. Fuller RK, Gordis E. Does disulfiram have a role in alcoholism treatment today? Addiction. 2004;99(1):21-24.

331. Agency for Healthcare Quality and Research. Pharmacotherapy for Alcohol Dependence: Evidence Report/Technology Assessment No. 3. Available athttps://archive.ahrq.gov/clinic/epcsums/alcosumm.htm. Last accessed April 24, 2024.

332. Volpicelli JR, Volpicelli LA, O'Brien CP. Medical management of alcohol dependence: clinical use and limitations of naltrexone treatment. Alcohol Alcohol. 1995;30(6):789-798.

333. Clapp P. Current progress in pharmacologic treatment strategies for alcohol dependence. Expert Rev Coin Pharmacol. 2012;5(4):427-435.

334. Altshuler HL, Phillips PE, Feinhandler DA. Alteration of ethanol self-administration by naltrexone. Life Sci. 1980;26(9):679-688.

335. Volpicelli JR, Alterman AI, Hayashida M, O'Brien CP. Naltrexone in the treatment of alcohol dependence. Arch Gen Psychiatry. 1992;49(11):876-880.

336. O'Malley SS, Jaffe AJ, Chang G, Schottenfeld RS, Meyer RE, Rounsaville B. Naltrexone and coping skills therapy for alcohol dependence: a controlled study. Arch Gen Psychiatry. 1992;49(11):881-887.

337. O'Malley SS, Jaffe AJ, Chang G, et al. Six-month follow-up of naltrexone and psychotherapy for alcohol dependence. Arch Gen Psychiatry. 1996;53(3):217-224.

338. Monterosso JR, Flannery BA, Pettinati HM, et al. Predicting treatment response to naltrexone: the influence of craving and family history. Am J Addict. 2001;10(3):258-268.

339. Capone C, Kahler CW, Swift RM, O'Malley SS. Does family history of alcoholism moderate naltrexone's effects on alcohol use? J Stud Alcohol Drugs. 2011;72(1):135-140.

340. Worley MJ, Witkiewitz K, Brown SA, Kivlahan DR, Longabaugh R. Social network moderators of naltrexone and behavioral treatment effects on heavy drinking in the COMBINE study. Alcohol Clin Exp Res. 2015;39(1):93-100.

341. National Institute on Alcohol Abuse and Alcoholism. A Multisite Trial of Combined Pharmacotherapies and Behavioral Interventions (COMBINE) for Alcohol Dependence. Available at https://www.niaaa.nih.gov/multisite-trial-combined-pharmacotherapies-and-behavioral-interventions-combine-alcohol-dependence. Last accessed April 24, 2024.

342. Witkiewitz K, Roos CR, Mann K, Kranzler HR. Advancing precision medicine for alcohol use disorder: replication and extension of reward drinking as a predictor of naltrexone response. Alcohol Clin Exp Res. 2019;43(11):2395-2405.

343. Anton RF, O'Malley SS, Ciraulo DA, et al. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA. 2006;295(17):2003-2017.

344. Pettinati HM, O'Brien CP, Rabinowitz AR, et al. The status of naltrexone in the treatment of alcohol dependence: specific effects on heavy drinking. J Clin Psychopharmacol. 2006;26(6):610-625.

345. Richardson K, Baillie A, Reid S, et al. Do acamprosate or naltrexone have an effect on daily drinking by reducing craving for alcohol? Addiction. 2008;103(6):953-959.

346. Mason BJ. Treatment of alcohol-dependent outpatients with acamprosate: a clinical review. J Clin Psychiatry. 2001;62(Suppl 20):42-48.

347. Tempesta E, JaniriL, Bignamini A, Chabac S, Potgieter A. Acamprosate and relapse prevention in the treatment of alcohol dependence: a placebo-controlled study. Alcohol Alcohol. 2000;35(2):202-209.

348. Rösner S, Hackl-Herrwerth A, Leucht S, Lehert P, Becchi S, Soyka M. Acamprosate for alcohol dependence. Cochrane Database Syst Rev. 2010;(9):CD004332.

349. Mason BJ. Acamprosate for alcohol dependence: an update of the clinician. Focus. 2006;4:505-511.

350. Flannery BA, Garbutt JC, Cody MW, et al. Baclofen for alcohol dependence: a preliminary open-label study. Alcohol Clin Exp Res. 2004;28(10):1517-1523.

351. Addolorato G, Leggio L, Ferrulli A, et al. Effectiveness and safety of baclofen for maintenance of alcohol abstinence on alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study. Lancet. 2007;370(9603):1915-1922.

352. Rose AK, Jones A. Baclofen: its effectiveness in reducing harmful drinking, craving, and negative mood: a meta-analysis. Addiction. 2018;113(8):1396-1406.

353. Agabio R, Saulle R, Rosner S, Minozzi S. Baclofen for alcohol use disorder. Cochrane Database Syst Rev. 2023;1:CD012557.

354. Guglielmo R, Martinotti G, Quatrale M, et al. Topiramate in alcohol use disorders: review and update. CNS Drugs. 2015;29(5):383-395.

355. Johnson BA, Rosenthal N, Capece JA, et al., for the Topiramate for Alcoholism Advisory Board and the Topiramate for Alcoholism Study Group. Topiramate for treating alcohol dependence: a randomized controlled trial. JAMA. 2007;298(14):1641-1651.

356. Williams SH. Medications for treating alcohol dependence. Am Fam Physician. 2005;72(9):1775-1780.

357. Johnson BA, Ait-Daoud N, Bowden CL, et al. Oral topiramate for treatment of alcohol dependence: a randomised controlled trial. Lancet. 2003;361(9370):1677-1685.

358. Barrons R, Roberts N. The role of carbamazepine and oxcarbazepine in alcohol withdrawal syndrome. J Clin Pharm Ther. 2010;35(2):153-167.

359. Mueller TI, Stout RL, Rudden S, et al. A double-blind, placebo-controlled pilot study of carbamazepine for the treatment of alcohol dependence. Alcohol Clin Exp Res. 1997;21(1):86-92.

360. Martinotti G, Di Nicola M, Romanelli R, et al. High and low dosage oxcarbazepine versus naltrexone for the prevention of relapse in alcohol-dependent patients. Hum Psychopharmacol Clin Exp. 2007;22(3):149-156.

361. 361. Johnson BA, Roache JD, Javors MA, et al. Ondansetron for reduction of drinking among biologically predisposed alcoholic patients: a randomized controlled trial. JAMA. 2000;284(8):963-971.

362. Kenna GA, Zywiak WH, Swift RM, et al. Ondansetron reduces naturalistic drinking in nontreatment-seeking alcohol-dependent individuals with the LL 5'-HTTLPR genotype: a laboratory study. Alcohol Clin Exp Res. 2014;38(6):1567-1574.

363. Kranzler HR, Burleson JA, Del Boca FK, et al. Buspirone treatment of anxious alcoholics: a placebo-controlled trial. Arch Gen Psychiatry. 1994;51(9):720-731.

364. Gimeno C, Dorado ML, Roncero C, et al. Treatment of comorbid alcohol dependence and anxiety disorder: review of the scientific evidence and recommendations for treatment. Front Psychiatry. 2017;8:173.

365. 365. Drake RE, Xie H, McHugo GJ, Green AI. The effects of clozapine on alcohol and drug use disorders among patients with schizophrenia. Schizophr Bull. 2000;26(2):441-449.

366. Lowry F. Drug May Aid in Alcohol Dependence, but Safety Concerns Linger. Available at https://www.medscape.com/viewarticle/805427. Last accessed April 24, 2024.

367. Schacht JP, Anton RF, Randall PK, Li X, Henderson S, Myrick H. Varenicline effects on drinking, craving and neural reward processing among non-treatment-seeking alcohol-dependent individuals. Psychopharmacology (Berl). 2014;231(18):3799-3807.

368. Erwin BL, Slaton RM. Varenicline in the treatment of alcohol use disorders. Ann Pharmacother. 2014;48(11):1445-1455.

369. 369. Mitchell JM, Teague CH, Kayser AS, Bartlett SE, Fields HL. Varenicline decreases alcohol consumption in heavy-drinking smokers. Psychopharmacology (Berl). 2012;223(3):299-306.

370. McKeown NJ, West PL. Withdrawal Syndromes. Available at https://emedicine.medscape.com/article/819502-overview. Last accessed April 24, 2024.

371. Fisher CM. Prompt responses to the administration of ethanol in the treatment of the alcohol withdrawal syndrome (AWS). Neurologist. 2009;15(5):24í2-244.

372. Hayner CE, Wuestefeld NL, Bolton PJ. Phenobarbital treatment in a patient with resistant alcohol withdrawal syndrome. Pharmacotherapy. 2009;29(7):875-878.

373. Weinberg JA, Magnotti LJ, Fischer PE, et al. Comparison of intravenous ethanol versus diazepam for alcohol withdrawal prophylaxis in the trauma ICU: results of a randomized trial. J Trauma. 2008;64(1):99-104.

374. American Psychiatric Association. The American Psychiatric Association Practice Guideline for the Pharmacological Treatment of Patients with Alcohol Use Disorder. Available at https://psychiatryonline.org/doi/book/10.1176/appi.books.9781615371969. Last accessed April 24, 2024.

375. Hall J, Pomm R, Frost-Pineda K, Gold MS. Treatment of alcohol dependent physicians: impact of alcohol use during medical school. Biol Psychiatry. 2002;51(8S):573.

Evidence-Based Practice Recommendations Citations

1. U.S. Preventive Services Task Force. Unhealthy Alcohol Use in Adolescents and Adults: Screening and Behavioral Counseling Interventions. Available at https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/unhealthy-alcohol-use-in-adolescents-and-adults-screening-and-behavioral-counseling-interventions. Last accessed May 20, 2024.

2. World Health Organization. Guidelines for the Identification and Management of Substance Use and Substance Use Disorders in Pregnancy. Geneva: World Health Organization; 2014. Available at https://www.who.int/publications/i/item/9789241548731. Last accessed May 20, 2024.

3. Management of Substance Use Disorders Work Group. VA/DoD Clinical Practice Guideline for the Management of Substance Use Disorders. Washington, DC: Department of Veterans Affairs, Department of Defense; 2021. Available at https://www.healthquality.va.gov/guidelines/mh/sud. Last accessed May 20, 2024.