Dietary supplement use is increasingly common. In addition to their use for the management of medical conditions, dietary supplements are often misused or abused for recreation, body image concerns, athletic performance, and mood enhancement. Healthcare professionals should be well informed about these commonly abused supplements so that they can understand what they are and how they work and provide adequate safety warnings.
This course is designed for healthcare professionals whose patients are taking or are interested in taking dietary supplements.
The purpose of this course is to provide healthcare professionals in all practice settings the knowledge necessary to increase their understanding of the commonly abused supplements and their adverse effects.
Upon completion of this course, you should be able to:
- Describe motivations for the abuse of supplements such as caffeine, ephedra, kratom, phenibut, and tianeptine.
- Explain the mechanism of action of commonly abused supplements.
- List serious adverse effects related to commonly abused supplements.
- Identify notable drug interactions with commonly abused supplements.
- Discuss regulatory and quality concerns associated with commonly abused supplements.
Chelsey McIntyre, PharmD, is a clinical pharmacist who specializes in drug information, literature analysis, and medical writing. She earned her Bachelor of Science degree in Genetics from the University of California, Davis. She then went on to complete her PharmD at Creighton University, followed by a clinical residency at the Children’s Hospital of Philadelphia (CHOP). Dr. McIntyre held the position of Drug Information and Policy Development Pharmacist at CHOP until her move to Washington state in 2017, after which she spent the next six years as a clinical editor for Natural Medicines, a clinical reference database focused on natural products and alternative therapies. She continues to create rigorous professional analysis and patient education materials for various publications while also practicing as a hospital pharmacist. Her professional interests include provider and patient education, as well as the application of evidence-based research to patient care.
Contributing faculty, Chelsey McIntyre, PharmD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.
John M. Leonard, MD
Mary Franks, MSN, APRN, FNP-C
Alice Yick Flanagan, PhD, MSW
Margaret Donohue, PhD
The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.
Sarah Campbell
The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.
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.
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.
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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.
#98021: Commonly Abused Supplements
Use of dietary supplements continues to increase. In addition to their use for the management of medical conditions, dietary supplements are often misused or abused for recreation, body image concerns, athletic performance, and mood enhancement [1].
Poison control center data indicate that abuse and misuse of dietary supplements occurs across the life span, with reports ranging from adolescents to those over 60 years old [2]. Abuse refers to the use of a substance to gain a psychotropic effect, while misuse refers to the use of a substance for reasons other than a psychotropic effect [3]. Although, abuse and misuse of dietary supplements share similarities to other forms of substance abuse (e.g., prescription medications, alcohol, tobacco), they are distinct in several ways.
Many consumers perceive products that are natural to be synonymous with safe, which is certainly not the case. Additionally, availability of supplements reduces barriers to their access and may contribute to their inappropriate use [4]. While many other supplements may be abused, the focus of this course will be on the following commonly abused supplements, how they work, and their associated safety concerns, including:
Supplements potentially abused for weight loss and/or athletic performance
Stimulants (1,3-dimethylamylamine [1,3-DMAA], bitter orange, caffeine, ephedra, octopamine)
Laxatives (castor oil, senna)
Supplements potentially abused for recreational use
Gamma hydroxybutyrate (GHB)
Phenibut
Tianeptine
Supplements potentially abused for opioid-like effects
Kratom
Note that these select supplements are commonly abused in North America. Supplements commonly abused in other parts of the world are beyond the scope of this course.
Stimulants are a class of substances that speed up the body's systems and for this reason, they are commonly referred to as "uppers." There are numerous U.S. Food and Drug Administration (FDA)-approved stimulants that are safely used under medical supervision for accepted medical uses (e.g., nasal congestion, attention deficit hyperactivity disorder [ADHD]). Stimulant supplements are commonly touted for their energy-boosting beneficial effects on athletic performance and for promoting weight loss [5].
1,3-DMAA, also called methylhexaneamine, is a synthetic stimulant, meaning that it is prepared in a lab [6,7]. It was originally developed as an ingredient for relieving nasal congestion because of its vasoconstrictive activity [8,9]. It has more recently been marketed in dietary supplements for athletic performance and weight loss [10].
Quality Concerns
Formulations of 1,3-DMAA often list rose geranium oil, geranium oil, or geranium stems as an ingredient on the label. While some manufacturers claim that 1,3-DMAA is a natural compound found in geranium oil, this claim hasn't been confirmed by laboratory analysis [10]. In 2011, Health Canada determined that there's no credible evidence that 1,3-DMAA is derived from the geranium plant. As a result, there's concern that formulations purportedly containing "rose geranium oil," "geranium oil," and "geranium stems" may actually be adding the synthetic drug to their supplements [11].
Regulatory Concerns
In 2011, Health Canada determined that 1,3-DMAA should be considered a drug and should not allowed to be included in dietary supplements [11]. In 2013, the FDA declared products containing 1,3-DMAA to be illegal and to have potential health risks [12]. 1,3-DMAA has been included on the prohibited lists of the World Anti-Doping Agency (WADA) and the U.S. Department of Defense (DoD) for over 10 years now [13].
Safety
Although 1,3-DMAA has been associated with cardiovascular adverse effects, these concerns have rarely been reported in patients taking 1,3-DMAA alone. Most of the severe adverse effects related to 1,3-DMAA are associated with its use in combination products [10].
Palpitations and tachycardia are the most common adverse effects reported with 1,3-DMAA-containing products. Angina, atrial fibrillation, chest pressure, hypertension, hypotension, and myocardial infarction have also occurred [10]. In case reports of healthy young adults taking 1,3-DMAA-containing combination products prior to exercise, cardiac arrest causing death has occurred [6,14].
Bitter orange is a small, flowering, fruit-bearing tree whose flowers, leaves, and fruits (including peel) have stimulant effects. Bitter orange has numerous active constituents and pharmacologic effects which vary by plant part and preparation method [15,16].
The fruit and the peel of bitter orange contain the adrenergic agonists synephrine and octopamine, which are frequently cited on labels as active ingredients. Synephrine and octopamine are chemically similar and occur naturally in the body in small amounts. Structurally, synephrine is similar to epinephrine and octopamine is similar to norepinephrine [18].
Quality Concerns
Many marketed bitter orange products contain greater amounts of synephrine and other natural and synthetic amines than is stated on the label, increasing the risk for serious stimulant-related adverse effects [15]. In a laboratory analysis of marketed bitter orange products, only 22% of the products tested had synephrine content within 20% of the amount stated on labels. The analysis also confirmed the presence of the synthetic amines methylsynephrine and isopropyloctopamine, neither of which are permitted in dietary supplements [15].
Similarly, the amount of octopamine found in products marketed for athletic performance is much greater than the quantity found naturally occurring in some plants (e.g., bitter orange). Natural levels of octopamine in bitter orange are less than 0.03%. A review of 32 products showed that octopamine was present in two products at levels as high as 11% and 12.9%, suggesting that manufacturers are adding synthetic octopamine to supplement products [17]. In one analysis of bitter orange extract, octopamine was identified in all three products tested, although it only appeared on the label of two products [18].
Regulatory Concerns
Since the FDA banned ephedra in 2004 (which will be discussed later in the course), bitter orange has been frequently used in products labeled as "ephedra-free." Synephrine, a constituent of bitter orange, is considered a banned substance by the National Collegiate Athletic Association (NCAA). Similarly, octopamine has been included on the WADA prohibited list [13].
Safety
Most of the severe adverse effects related to bitter orange are associated with its use in combination products. Hypertension and tachycardia are the most common adverse effects reported with bitter orange-containing products, particularly in combination with caffeine and/or other stimulant ingredients. Other adverse effects reported with the use of bitter orange or synephrine-containing multi-ingredient products, with or without other stimulants, include blackout, cardiac arrest, collapse, ischemic stroke, myocardial infarction, QT prolongation, tachyarrhythmia, tachycardia, variant angina, ventricular fibrillation, and death [20].
Caffeine might be one of the best-known stimulants. It is a naturally occurring, bitter-tasting methylxanthine compound found in the leaves, seeds, or fruits of more than 60 plants, including coffee (Coffea arabica) beans, cacao (Theobroma cacao) beans, kola (Cola acuminata) nuts, guarana (Paullinia cupana) berries, and tea (Camellia sinensis) leaves [21]. It is structurally related to theophylline, theobromine, and uric acid and is a nonselective adenosine antagonist [22].
Caffeine is present in a wide variety of beverages [23,24]:
One cup of brewed coffee provides 95–200 mg of caffeine.
An 8-ounce serving of black tea provides 25–110 mg of caffeine.
An 8-ounce serving of green tea provides 30–50 mg of caffeine.
A 12-ounce soft drink (e.g., cola) provides 20–80 mg of caffeine.
A serving of sports or energy drinks typically provide 48–300 mg of caffeine.
Caffeine is also available alone or in combination with other ingredients in some prescription and OTC products that are approved for specific medical uses (e.g., to help restore mental alertness and wakefulness when experiencing fatigue or drowsiness). Caffeine tablets contain up to 200 mg of caffeine [25].
Keep in mind that only the amount of added caffeine must be stated on product labels, and the amount of caffeine from caffeine-containing natural ingredients (e.g., coffee, green tea) isn't required to be provided, making it difficult to determine the total amount of caffeine in a given product [21].
Regulatory Concerns
Caffeine has been demonstrated to improve athletic performance. It decreases perceived levels of exertion, enabling athletes to feel less tired and increase their performance. It can also improve anaerobic exercise performance [21]. National Collegiate Athletic Association (NCAA) lists caffeine as a banned substance, prohibiting urine concentrations above 15 mcg/mL during competition [26,27]., Reaching this threshold typically requires ingesting approximately 500 mg of caffeine, roughly six to eight cups of coffee, two to three hours before an event [26,28]. While the International Olympic Committee and the World Doping Agency (WADA) removed caffeine from their list of banned substances in 2004, WADA continues to monitor its use [29].
Despite its regulatory status, caffeine can pose significant health risks, particularly in highly concentrated or pure supplement forms. In 2018, the FDA declared bulk sales of such products directly to consumers as unlawful [30].
Safety
A review by Health Canada and a subsequent large meta-analysis conducted in the United States show that caffeine doses up to 400 mg daily are not associated with significant adverse cardiovascular, bone, behavioral, or reproductive effects in healthy adults [21,31]. Similarly, the U.S. Dietary Guidelines Advisory Committee states that there is strong and consistent evidence that consumption of caffeine 400 mg daily isn't associated with increased risk of major chronic diseases, such as cardiovascular disease or cancer, in healthy adults [31].
Caffeine is generally well tolerated, with regular use and in moderate doses. Common side effects include anxiety, diarrhea, diuresis, headache, insomnia, muscular tremors, nausea, and restlessness. However, caffeine can become unsafe when used long-term and/or in high doses [21].
Acute use of high doses, typically those exceeding 400 mg daily, have been associated with significant adverse effects, such as tachyarrhythmia and sleep disturbances [32]. Some people may experience serious toxicity even at lower doses, partly because caffeine effects may be being impacted by smoking status, age, and prior caffeine use [21].
Some caffeine products for supplement use are highly concentrated or pure formulations. These are most concerning because they have a high risk of being mistakenly used in excessive and potentially dangerous doses [30]. Powdered pure caffeine can contain as much as 3.2 grams of caffeine in a single teaspoon and concentrated liquid caffeine can contain about 2 grams of caffeine in as little as a half cup [28].
With large amounts of caffeine (more than 10 mg per kg daily), there have been reports of aortic dissection, atrial fibrillation, cardiac arrest, celiac artery trunk dissection, chest pain, coronary artery vasospasm, extrasystoles, hemorrhagic stroke, ischemic stroke, tachycardia, transient ischemic attack (TIA), and ventricular tachycardia [21].
The acute oral dose of caffeine resulting in death in adults is estimated to be 10–14 grams (150–200 mg per kg), although fatality has occurred at lower doses. Deaths typically have been attributed to ventricular fibrillation [21]. At least two deaths have been linked to the use of highly concentrated and pure formulations. In 2018, the FDA announced that highly concentrated and pure formulations of caffeine are unlawful when sold directly to consumers in bulk quantities [28].
There have been numerous case reports of seizures with excessive caffeine intake and when combining caffeine with other stimulants [21]. Life-threatening events are also more common after taking caffeine-containing energy or weight loss products when compared with non-caffeine containing products [34]. Deaths have occurred following consumption of caffeine alone or in combination with other stimulants or alcohol [21,35,36].
Ephedra, sometimes called ma huang, is a stimulant herb usually taken from the stem and branches of Ephedra sinica. It contains the principal alkaloid constituent's ephedrine, pseudoephedrine, and sometimes small amounts of phenylpropanolamine. It has a long history of use in traditional Chinese medicine [37,38]. It has traditionally been used for allergy symptoms, arthritis, asthma, bone pain, bronchitis, edema, headache, nephritis, and symptoms of the common cold and influenza [39]. It has also been marketed as "herbal ecstasy," for use as a recreational drug [40].
While most Ephedra species contain ephedrine alkaloids, Mormon tea (Ephedra nevadensis or Ephedra viridis) is a plant in the Ephedra genus that is devoid of ephedrine and other alkaloids [41]. Some other plants also contain ephedrine alkaloids, including Sida cordifolia and Pinellia ternate [42,43].
Regulatory Concerns
Because of the potential for serious safety concerns associated with its use, ephedra, Sida cordifolia, Pinellia ternata, or other ephedrine-containing herbs have been banned in the United States since 2004 [41]. Despite this ban, ephedra products can still be obtained on the internet, often in combination products containing caffeine and/or other stimulants (e.g., synephrine, phenylethylamine [PEA], and yohimbine) [38].
Like other stimulants, ephedra is sometimes touted for its performance enhancing effects, but these effects have not been substantiated in clinical studies [37]. Ephedra appears on the prohibited list of many large sports and other organizations, including the NCAA [41,44].
Quality Concerns
There is considerable inter- and intra-product variability in labeled ephedra content. This increases concerns about ephedra toxicity [45,46]. There is also significant variability in the amounts of constituents found in ephedra supplements [47]. In one study, ephedra supplements were found to contain 1.08–13.54 mg of ephedrine and 0.52–9.46 mg of pseudoephedrine per recommended dose [48]. In other studies, 1 gram of a dry extract of ephedra was found to contain 58.9 mg of total ephedrine alkaloids, comprised of 0.44 mg of norephedrine, 1.09 mg of methylephedrine, 1.01 mg of norpseudoephedrine, 11.21 mg of pseduoephdrine, and 45.15 mg of ephedrine [49,50]. Norpseudoephedrine is a Schedule IV controlled substance that has been found to be a contaminant in many ephedra products [51].
Safety
Prior to its removal from the U.S. market, ephedra accounted for less than 1% of herbal product sales but was responsible for 64% of herbal adverse reaction reports to poison control centers [38]. In a review of 926 cases of potential ephedra-related adverse effects reported to the FDA, 37 patients had serious or fatal adverse reactions [52,53].
Ephedra can cause severe life-threatening or disabling adverse effects in some people. It's been linked to significant cardiovascular effects, including cardiac arrhythmias, cardiac arrest, cardiomyopathy, heart failure, and myocardial infarction, as well as seizure, stroke, psychosis, and sudden death [39]. There is some evidence that taking more than 32 mg daily might increase the risk of hemorrhagic stroke, including subarachnoid hemorrhage and intracerebral hemorrhage, by more than threefold [52].
While prolonged use and high doses might increase the risk of serious adverse effects, serious adverse effects have also been reported at low doses (e.g., 20–60 mg of ephedra alkaloids) in the short-term [54,55]. It is impossible to determine who might be at the greatest risk from ephedra's adverse effects, but people with existing cardiovascular disease and those using combinations of stimulants might be at increased risk [39].
In addition to serious cardiovascular effects, cases of hepatotoxicity (e.g., acute hepatitis, liver failure) from ephedra-containing supplements have been reported after an average of three months of ephedra ingestion. Some cases of hepatotoxicity have resolved with discontinuation of ephedra, but others have required liver transplantation. Immune reactions and contamination have been proposed as potential causes of hepatotoxicity, but most evidence suggests that ephedra-related hepatotoxicity is idiosyncratic in nature [39].
Interactions with Lab Tests
Some stimulants might cause false-positive test results on urine amphetamine and/or methamphetamine drug screens. This should be considered when interpreting urine drug screen results in patients who deny amphetamine and/or methamphetamine use [56,57].
Interactions with Drugs and Supplements
Stimulants can have a fair amount of drug interactions. The most notable drug interaction concern is for the combination of a stimulant with other drugs or supplements that are stimulants or have stimulant properties. This combination can increase the risk of adverse effects, particularly cardiovascular adverse effects [39].
While laxatives themselves are not addictive, they are commonly misused for weight-loss effects. This course will review key considerations related to senna and castor oil. While other over-the-counter (OTC) laxatives also carry the potential for misuse, they will not be addressed in this course.
Senna is the fruit (pod) or leaf of the plant Senna alexandrina. Senna contains sennosides, which are high molecular weight dianthrone glycosides [58]. Because sennosides are prodrugs, they are not absorbed in the gastrointestinal (GI) tract and are instead activated by enzymes in the colon. The cathartic properties of the senna leaf are greater than the fruit. Effects usually occur within 6 to 10 hours after oral administration, primarily by increasing colon motility. This occurs through selective action on the nerve plexus of the intestinal smooth muscle, stimulating contractions and promoting bowel movements [58].
Senna is an FDA-approved, nonprescription stimulant laxative found in many commercially available products that are approved for the short-term treatment of constipation in adults and children 2 years of age or older [58,59]. These products contain the active ingredient, sennosides.
Senna is also available in dietary supplements containing variable amounts of the leaf. Senna leaf is sometimes added to weight loss products or "cleansing" teas, but these uses are unproven and may be unsafe [58].
Castor oil is the oil that comes from castor beans (seeds). Unlike the beans, castor oil does not contain the deadly poison, ricin [60]. It has been used as a stimulant laxative for centuries across various traditional medical systems, with its earliest known reference appearing more than 3,000 years ago in ancient Egypt [61].
Castor oil is hydrolyzed in the duodenum by pancreatic lipase to release ricinoleic acid, and while the exact mechanism of ricinoleic acid is unknown, laxative effects appear to result from a combination of fluid secretion and increased peristalsis [60]. The onset of action is usually within two, but sometimes up to six, hours [4]. Castor oil is sometimes flavored (e.g., with cinnamon, peppermint, or other flavorings) to mask its slightly bitter and nauseating taste overall [4].
Safety
Stimulant laxatives can cause abdominal pain and discomfort, bloating, cramping, diarrhea, faintness, flatulence, fecal urgency, and nausea. Use of laxatives at high doses and for long periods might be unsafe. Abuse of laxatives can cause fluid and electrolyte, particularly potassium, losses. Theoretically, this can increase the risk for arrhythmias. There is also a risk of malabsorption as a result of intestinal hypermotility [58,60].
Cases of "cathartic colon" have been described in the literature following chronic use of both senna and castor oil. Cathartic colon refers to radiographically diagnosed anatomic changes to the colon, such as benign narrowing, colonic dilation, and loss of colonic folds [63]. The clinical relevance of such changes is unclear.
Chronic use of senna can also cause pseudo melanosis coli (pigmented spots along the intestinal mucosa), but this condition is harmless, reverses with cessation, and has not been shown to be associated with an increased risk of developing colorectal adenoma or carcinoma [64].
Long-term use of laxatives is thought to result in habituation and/or tolerance. Habituation refers to a reduced or even absent laxative response, and tolerance refers to the need for increased doses in order to maintain the desired laxative response. Both habituation and tolerance could theoretically be induced by damage to the colon or by an adaptive mechanism counteracting the laxative's effect on motility and/or secretion [65].
Uncontrolled observational studies in humans and conflicting data from prospective animal studies have raised concerns that chronic stimulant laxative use can actually cause nerve or muscle damage to the colon, but these concerns have been largely disproved by higher quality studies [66]. While tolerance may occur in patients with severely slow colonic transit in whom other types of laxatives are ineffective, development of tolerance seems to be uncommon in the majority of users [67].
Interactions with Drugs
While not an exhaustive list, notable drug interactions of concern for stimulant laxatives are their combination with diuretics or other stimulant laxatives. This combination can increase the risk of adverse effects including increased risk for fluid and electrolyte loss [58,60].
Interactions with Conditions
Due to the risk of gastrointestinal irritant effects, senna should be avoided in patients with idiopathic abdominal pain, intestinal obstruction, diarrhea, or acute intestinal inflammation due to the risk of exacerbation [58]. Castor oil should be avoided in patients with intestinal obstruction abdominal pain of unknown origin, biliary tract obstruction, and other biliary disorders [60]. Be sure to ask patients about dietary supplement usage while obtaining their medication history. And be on the lookout for purchasing practices that might suggest inappropriate use.
Like prescription drugs, many supplements are abused on the party scene and for varying other recreational reasons. Among these is gamma-hydroxybutyrate (GHB) for its euphoric, amnestic, and calming effects [68].
GHB is a short-chain fatty acid made from gamma-amino-butyric acid (GABA). GHB is naturally occurring in the brains of mammals in very small amounts [69]. The highest concentrations in the brain are found in the basal ganglia. GHB is also found in other tissues, including the kidneys, liver, heart, skeletal muscle, and brown fat [70,71].
GHB abuse became popular among teens and young adults at dance clubs and raves in the 1990s, but use persists today. GHB is used as a party drug, for its euphoric and calming effects and for sexual arousal, and in cases of drug-facilitated sexual assault [72]. It is usually sold as a clear, colorless liquid or as a white powder that can be dissolved in liquid.
In the United States, GHB is federally classified as a Schedule I controlled substance, making production, sale, and possession outside of medical use illegal [69]. The major source of GHB is through clandestine synthesis by local operators [73].
There are FDA-approved prescription forms of the sodium salt of GHB, known as sodium oxybate (Lumryz, Xyrem), labeled for the treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age or older with narcolepsy. Sodium oxybate is a Schedule III controlled substance and seems to be safe when used appropriately under medical supervision [74,75].
Several chemically related analogs of GHB, including gamma butyrolactone (GBL) and 1,4-butanediol (BD), are rapidly converted to GHB in the body and have similar effects to the parent compound [69]. Popularity of these analogs increased with the regulatory restriction of GHB as a Schedule I controlled substance. These analogs are legally available as industrial solvents, but are also sold illicitly as supplements for bodybuilding, weight loss, reversal of baldness, drug addiction, and other uses. GBL and BD are abused for the same reasons as GHB. Routine toxicologic screens do not detect the presence of these analogs, so abuse can be difficult to identify [76].
When used orally without medical supervision (i.e., not as a prescription medicine), GHB is not safe for any use. Serious side effects include ataxia, cardiac arrest, coma, respiratory depression, tonic-clonic seizure, variable heart rate, and death. The analogs GBL and BD have also been associated with many reports of such serious adverse reactions [69].
The UK Department of Health asserts that persons providing services to patients who use GHB should advise these individuals to be aware of the added risks of mixing GHB with other sedative drugs.
(https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/673978/clinical_guidelines_2017.pdf Last Accessed: October 27, 2025)Level of Evidence: Consensus Statement/Expert Opinion
Concomitant use of GHB and its analogs with alcohol and some other co-ingestants can increase the risk of CNS and respiratory depression, as well as other severe adverse effects. Alcohol may also inhibit the clearance of GHB [69].
GHB is commonly used in cases of drug-facilitated sexual assault. Patients can help avoid becoming a victim by never taking a drink from a stranger and never leaving a drink unattended. If poisoning is suspected, call poison control at 1-800-222-1222. There is no antidote for GHB toxicity, and treatment is limited to supportive care. In patients with severe GHB intoxication, maintaining airway patency with intubation, if necessary, is the most important intervention. Because GHB can cause a rapid loss of consciousness, gastric lavage and induction of emesis are contraindicated.
Regular GHB use can also cause dependence requiring inpatient detoxification [77,78]. Withdrawal from GHB can cause agitation, anxiety, diaphoresis, delirium with auditory and visual hallucinations, hypertension, insomnia, panic, psychoses, rhabdomyolysis, tachycardia, terror, and tremor [69].
Notable drug interactions of concern for GHB include the combination with alcohol, CNS depressants, and other drugs or supplements with sedative properties. These combinations should be avoided due to the increased risk of adverse effects including CNS and respiratory depression, gastrointestinal disturbances, hypotension, and decreased oxygen saturation [69].
In patients with existing bradycardia, GHB can increase the risk of bradycardia [69]. In patients with epilepsy, GHB can potentially induce seizures [69]. Additionally, because GHB has CNS depressant effects, use within 2 weeks prior to surgery might cause additive CNS depression when combined with anesthesia or other medications during surgical procedures [69].
Phenibut (beta-phenyl-gamma-aminobutyric acid) is a chemical substance structurally similar to gamma-aminobutyric acid (GABA) and prescription medications including baclofen, pregabalin, and gabapentin. Phenibut is a central nervous system drug, initially discovered in the 1960s in Russia, and is used for alcohol withdrawal, anxiety, insomnia, and as a nootropic [79,80].
Phenibut is commonly used for a variety of reasons, most notably for self-medication to manage medical concerns such as insomnia and anxiety. Recreational use (as a substitute for other medications, including benzodiazepines), management of withdrawal from substances, and for performance enhancement have also been reported [81].
While phenibut is an approved product in Russia and some Eastern European countries, phenibut is not approved as a drug by the FDA and does not meet the definition of a dietary ingredient under the Federal Food, Drug, and Cosmetic Act (FDCA) in the United States [79,82,83]. Despite the lack of FDA approval for medical use, phenibut remains available through "head shops" or online vendors, often labeled as a dietary supplement [82]. The FDA has issued warnings to companies illegally marketing phenibut as a dietary supplement [81]. In 2018, phenibut was banned in Australia when the Therapeutic Goods Administration officially classified it as a Schedule 9 substance, prohibiting the sale, manufacture, possession, or use of phenibut [79,84].
Phenibut products sold online often show inconsistencies in quality and labeling due to a lack of regulatory oversight. These products, typically available in powder or capsule form through unregulated suppliers, may contain phenibut in amounts different than the product label, unlisted contaminants, or adulterants. Reported purity levels range from 10% to 98% [79].
Discrepancies between labeled and actual phenibut content have been confirmed in a single study. Among the six products analyzed, four were found to have lower amounts of phenibut than indicated, while two contained more, including one product that had approximately 160 mg more than stated. Additionally, all samples contained undeclared ingredients, notably, the nootropic aniracetam was detected in two products [85].
Phenibut is associated with a number of serious safety concerns and is likely unsafe when used orally. Phenibut is associated with delirium, decreased consciousness, respiratory depression, sedation, and in some cases death, even with short-term use. Common adverse effects include balance impairment, dizziness, drowsiness, lethargy, and nausea [79].
Phenibut is addictive, and there are concerns about dependence, withdrawal, and overdose. Prolonged use can cause tolerance and physical dependence. Withdrawal symptoms, which can appear after just a few days of use, include agitation, anxiety, confusion, depression, decreased appetite, hallucinations, hypertension, impulsivity, muscle aches, nausea, paranoid delusions, seizures, and tachycardia [79].
Overdose symptoms may initially include balance impairment, dizziness, drowsiness, lethargy, and nausea. At higher doses, phenibut can lead to agitated delirium, decreased consciousness, reduced respirations, sedation, and tachycardia [79]. There have also been reports of fatalities [86,87].
Although drug interactions with phenibut have not been rigorously assessed, there is theoretical concern that combining it with other substances with sedative or depressant properties could increase the risk of adverse effects, particularly excessive sedation and respiratory depression [79].
Tianeptine is an atypical antidepressant that was originally discovered and developed in France in the 1960s. Although structurally similar to tricyclic antidepressants, its exact mechanism is unknown. Tianeptine has shown beneficial effects in models related to depression, anxiety, and other stress-related disorders [88,89,90].
Tianeptine is increasingly misused due to its unique pharmacological profile, including its ability to produce euphoria, reduce anxiety, and its perceived effectiveness in managing opioid withdrawal symptoms, along with a reputation for enhancing cognitive function. To experience opioid-like effects, individuals often consume doses well beyond the typical therapeutic range of 25–37.5 mg used for treating depression [89,90].
Tianeptine is available as a prescription medication in some European, Asian, and Latin American countries, but is not approved by the FDA for uses in the United States [90]. Despite multiple FDA warnings, some companies continue to illegally market and sell tianeptine-containing products marketed under names like Tianna Red, Tianna Green, and Zaza [91].
Tianeptine is not currently under the federal Controlled Substances Act; however, a bill was introduced in 2024 in the United States House of Representatives to classify it as a Schedule III substance. Despite this, several states have passed legislation to regulate tianeptine due to reports of abuse and serious adverse effects. For example, Tennessee classified tianeptine as a Schedule II substance in 2022 [92].
Tianeptine is available as a prescription drug in some countries, typically as a 12.5-mg tablet. However, tianeptine has been sold improperly as a research chemical or as a dietary supplement, sometimes being injected. This misuse raises significant concerns about safety and quality control [90].
Because tianeptine is not regulated in the United States, there is considerable variability in the content and purity of products containing tianeptine. In a report from the New Jersey Poison Information and Education System on tianeptine-associated toxicity cases, an analysis of the involved products revealed contamination with various substances, including natural and synthetic cannabinoids [93].
Tianeptine is associated with a growing number of adverse events and is possibly unsafe when used orally. Prescription doses of tianeptine (25–37.5 mg) are generally well tolerated, but have the potential for serious adverse effects, as well as abuse and misuse. Chronic use can lead to tolerance and symptoms of withdrawal [90].
Common side effects include constipation, diarrhea, dizziness, drowsiness, headache, insomnia, nausea, and vomiting. Serious adverse events reported with tianeptine include agitation, asthenia, confusion, coma, hypertension, liver damage, myalgias, tachycardia, and tremors [90].
High doses of tianeptine can cause severe symptoms similar to opioid toxicity such as altered mental status, gastrointestinal distress, lethargy, loss of consciousness, respiratory depression, tachycardia, coma, or death. At therapeutic doses, withdrawal symptoms may resemble those of opioid withdrawal, including anxiety, agitation, chills, diarrhea, increased heart rate, muscle aches, nausea, and vomiting. However, these symptoms are more common with chronic use, especially at daily doses of 250 mg or higher [90].
The most notable drug interaction of concern is the combination of tianeptine with monoamine oxidase inhibitors. This combination can increase the risk of cardiovascular collapse, convulsions, fever, hypertension, and death [94].
Another concern includes the combination with CNS depressants, or other drugs or supplements that have sedative effects. These combinations can increase the risk for additive effects [95,96,97].
In patients with a history of substance use disorder, long-term use of tianeptine may lead to abuse, dependence, and withdrawal [90]. Additionally, because tianeptine has opioid-like sedative effects at higher doses, use within 2 weeks prior to surgery might cause additive CNS depression when combined with anesthesia or other medications during surgical procedures [90].
Similar to an opioid, kratom is mainly used for its opioid-like effects [98]. Kratom, Mitragyna speciosa, is a tropical tree that is native to Southeast Asia. The leaves are the part of the plant that's garnered interest, either when chewed as whole leaves, consumed as beverages prepared from the leaves (e.g., tea, juice), powdered and packaged into gel caps, or as an extract [99]. The leaves have also been crushed and then smoked, but kratom is mostly abused through oral ingestion [100].
Kratom contains a long list of constituents, including corynantheidine, isopaynantheine, mitraciliatine, paynantheine, speciociliatine, speciogynine, and 9-hydroxycorynantheidine, but the alkaloids mitragynine and 7-hydroxymitraginine are thought to be its main active constituents. Twenty kratom leaves are estimated to contain about 18 mg of mitragynine [99].
Kratom contains the mu-opioid receptor agonist, 7-hydroxymitragynine. 7-Hydroxymitragynine is estimated to be approximately 10 times as potent as morphine [99,101].
Kratom also contains a number of mu-opioid receptor partial agonists, including mitragynine. Mitragynine is estimated to be about 25% as potent as morphine, but it is present in much larger quantities than 7-hydroxymitragynine [99]. Mitragynine makes up about 60% of kratom's alkaloid content and 7-hydroxymytragynine makes up 2% [102].
Kratom has both stimulant- and opioid-like properties, and its effects when taken by mouth are dose-dependent. Higher doses of kratom (e.g., 5–15 grams) are said to produce analgesic opioid-like effects, while lower doses (e.g., 1–5 grams) have stimulating effects [99].
Kratom has been used for its psychoactive properties and opium-like effects [99]. It has been used for centuries in Thailand and Malaysia in socioreligious ceremonies, as an aid to combat fatigue in laborers, as an opioid substitute, and for other medical purposes [103]. Several recent surveys have identified self-treatment of acute or chronic pain as the primary use for kratom. But there's not enough information to support the use of kratom for any condition, and the risks certainly don't outweigh any potential benefits given its safety profile [104].
In the past, kratom use has not been widespread in the United States, but poison control center data show that interest seems to be growing. Between 2014 and 2019, U.S. poison control centers saw a rapid increase in kratom exposures [105].
In 2016, the Drug Enforcement Administration (DEA) attempted to ban kratom by making its mitragynine and 7-hydroxymitragynine constituents Schedule I substances in the United States under the Controlled Substances Act (CSA). This attempt to schedule these constituents was met with intense backlash from the public, industry, and some members of Congress [106]. While the DEA cited concerns of increases in the incidence of kratom-related seizures and calls to poison control centers related to kratom, the DEA ultimately withdrew its intent to schedule based on this strong opposition [99].
While the kratom tree and its leaves are illegal or restricted in some countries and states, it is not illegal in the United States. It is readily available for in-person purchase in many states, in addition to internet sales. The manufacturing, sale, or possession of kratom products are not currently regulated by the FDA or DEA, but the DEA has listed kratom as a drug and chemical of concern [99,107].
Kratom has been reported to be contaminated with various substances, including heavy metals and phenethylamine (PEA), an amphetamine-like substance [99]. In 2018, the Centers for Disease Control and Prevention (CDC) reported a salmonella outbreak sickening at least 134 people in more than 35 states that was found to be linked to kratom products [108,109].
Some kratom products have been suspected to be adulterated with respect to the active constituents. In a laboratory analysis, samples of some commercially available kratom products were found to contain 4.5-fold higher concentrations of 7-hydroxymitragynine than are usually present in kratom leaves [102].
The FDA has warned consumers on multiple occasions that kratom is unsafe. Kratom has been linked to serious adverse effects, including respiratory depression, aggression, hallucinations, delusions, vomiting, seizures, liver damage, severe withdrawal, and death. Short-term use, especially in combination with other substances, has been associated with cases of intrahepatic cholestasis, rhabdomyolysis, seizure, encephalopathy syndrome, and death. Long-term use has been associated with tolerance and withdrawal symptoms, including aggression, anxiety, muscle aches and spasms, nausea and vomiting, shakiness and tremors, and QT interval prolongation [99].
Kratom seems to inhibit many enzymes commonly involved in the metabolism of drugs, potentially increasing their levels and effects. It also might have overlapping effects with drugs that have similar mechanisms. For example, a drug interaction of concern is the combination with other CNS depressants due to the increased risk of adverse effects including drowsiness, coma, and severe or fatal respiratory depression [99].
In patients with alcohol use disorder or other psychiatric disorders, epidemiologic research suggests an increased risk of suicide with kratom use [111]. In patients with existing cardiac conditions, kratom use can increase the risk of tachycardia [99]. In animal studies, kratom seems to cross the placenta [112]. In humans, there have been multiple reports of neonatal abstinence syndrome (NAS) in infants born to patients using kratom during pregnancy [62,113].
Do not assume that potentially harmful use of supplements only occurs in young people. With kratom use on the rise among all demographics, increased use of kratom among older adults is particularly concerning as data have shown severe effects in this population [33].
Dietary supplement use continues to increase. As of 2025, the United States dietary supplement market is projected to exceed $40 billion, with expectations to continue to grow due to the increase focus on maintaining health and well-being [110]. Unfortunately, with increased use also comes increased abuse and misuse. Recreation, body image concerns, athletic performance, and mood enhancement continue to drive inappropriate use. Knowing the common culprits, how they work, and their potential adverse effects can enhance patient education and the detection of potential supplement abuse.
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