Because of recent legal changes at both the federal and state levels related to medical and/or recreational use, access to and interest in cannabinoids has been increasing. Patients may be asking about various cannabinoids, including safety and potential uses. Healthcare professionals should be well informed about these substances so that they can provide evidence-based recommendations and appropriate safety warnings.
This course is designed for healthcare professionals whose patients are taking or are interested in taking cannabinoid products.
The purpose of this course is to provide healthcare professionals in all practice settings the knowledge necessary to increase their understanding of the various cannabinoids.
Upon completion of this course, you should be able to:
- Explain the legal and chemical differences between hemp and cannabis.
- Summarize the evidence for the use of cannabidiol (CBD) for various conditions.
- Explain how various cannabinoids interact with the endocannabinoid system.
- Describe adverse effects and safety considerations for various cannabinoids.
- Identify potential drug interactions associated with cannabinoid use.
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.
#98011: Cannabinoid Overview
Cannabis refers to Cannabis sativa, Cannabis indica, and hybrids of these two plant species. Cannabis is a flowering annual plant that is grown worldwide and is commonly referred to as either cannabis or hemp. Concentrated in the flowers and leaves of Cannabis sativa are more than 100 cannabinoids which are known to exert a range of psychological and physiological effects on the human body [1].
Marijuana, the colloquial term for cannabis, generally refers to cannabis containing higher quantities of the main psychoactive cannabinoid, delta-9-tetrahydrocannabinol (THC). Hemp, on the other hand, has historically referred to cannabis harvested for its fibrous stalks for use in industrial applications, which include fiber, cosmetics, and clothing [2]. Hemp is also harvested for its seeds, which are used to make hemp seed oil. Hemp seed oil contains minimal amounts of cannabinoids, including THC and cannabidiol (CBD) [3]. In contrast, hemp oil is obtained from the flower and/or leaves of the cannabis plant and contains THC and higher amounts of CBD [4].
In 2018, the Agriculture Improvement Act, also known as the Farm Bill, completely changed the landscape for the sale of cannabinoid products in the United States.
This bill defines hemp as Cannabis sativa and any part of that plant, including the seeds thereof and all derivatives, extracts, cannabinoids, isomers, acids, salts, and salts of isomers, whether growing or not, with a THC concentration of not more than 0.3% on a dry weight basis. According to the Farm Bill, cannabis (or what we commonly refer to as marijuana) is considered Cannabis sativa containing more than 0.3% THC.
Prior to the passage of the 2018 Farm Bill, the Controlled Substances Act did not distinguish between cannabis, marijuana, and hemp products, treating them all as Schedule I substances under Drug Enforcement Agency (DEA) control. The Farm Bill removed hemp and its constituents, including CBD, from the definition of marijuana in the Controlled Substances Act, allowing them to be sold under FDA regulation [5]. The regulatory status of CBD has been evolving rapidly. Despite the approval of a prescription formulation of CBD (Epidiolex) in 2018, the FDA continues to maintain that CBD cannot be legally included in foods or dietary supplements. However, enforcement has been inconsistent, and products containing CBD are widely available for purchase [5].
The Farm Bill paved the way for the legal sale of various cannabinoids and hemp-based products without DEA oversight, which led to a surge in consumer interest and product availability that has only continued to increase.
The primary active constituents in cannabis are cannabinoids. While delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most well-known cannabinoids, the cannabis plant actually contains more than 100 different cannabinoids [6]. Cannabinoids in cannabis interact with the body's endocannabinoid system and bind to specific receptors distributed throughout the brain and body.
Humans also produce endogenous cannabinoids, called endocannabinoids [7]. Endocannabinoids, phytocannabinoids and synthetic cannabinoids bind to cannabinoid receptors to exert a range of psychological and physiological effects. The effects of cannabinoids are mainly mediated by cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2). CB1 are most abundant in the central and peripheral nervous systems and influence appetite, metabolism, motor control, and pain perception. CB2 are located primarily in immune cells, where they mediate immune function, inflammation, and pain responses [7].
Cannabinoids can be classified based on their psychoactive properties. For example, THC is the primary psychoactive cannabinoid and its use can lead to the characteristic "high" associated with cannabis. In contrast, many other cannabinoids are not psychoactive, but have garnered the interest of researchers and the general public for their potential therapeutic effects.
The following cannabinoids are the most studied and will be discussed in more detail throughout this course:
Tetrahydrocannabinol (THC)
Cannabidiol (CBD)
Cannabidivarin (CBDV)
Tetrahydrocannabidivarin (THCV)
Cannabinol (CBN)
Cannabigerol (CBG)
Cannabichromene (CBC)
While this course will focus on plant-derived cannabinoids, it is important to note that synthetic cannabinoids are also available. FDA-approved synthetic forms of THC, such as dronabinol and nabilone, are chemically identical and structurally very similar, respectively, to naturally occurring forms of THC and are regulated as prescription medications by the FDA [6]. Other unregulated synthetic cannabinoids such as K2/Spice, will not be extensively covered in this course.
THC is the most abundant and well-known psychoactive cannabinoid found in cannabis [8]. Recreational use of cannabis can be attributed to THC and its psychoactive effects. THC is classified as a schedule I controlled substance by the U.S. Drug Enforcement Agency (DEA), indicating that it is considered to have high potential for abuse and no accepted medical use at the federal level. This classification means it cannot legally be included in dietary supplements or foods [9]. However, the FDA has suggested that cannabis be reclassified from Schedule I to Schedule III to reflect its currently accepted medical uses, as well as the lower potential for abuse and dependence [10]. As a result, the DEA is considering reclassifying marijuana under federal drug laws, but the decision has been delayed repeatedly.
Over the years, selective breeding and genetic modification have altered the cannabis plant, leading to dramatically increased concentrations of THC. For example, analyses of the THC concentration in samples increased from 4% in 1995 to 12% in 2014 and from 9% in 2008 to 17% in 2017 [11,12]. This increase in potency can lead to ingestion of higher amounts of THC, resulting in more substantial impairment and a greater likelihood of adverse effects.
THC exerts its pharmacologic activity by binding to CB1 and CB2, the primary relevant receptors in the endocannabinoid system [7]. THC is a partial agonist of CB1, leading to psychoactive, analgesic, and antispastic effects [13].
Cannabis is often used recreationally, and it is theorized to help with conditions such as amyotrophic lateral sclerosis, dementia, HIV/AIDS-related wasting, Crohn disease, epilepsy, glaucoma, chronic pain, and chemotherapy-induced nausea and vomiting. However, good evidence supporting its efficacy for these conditions is often lacking. For example, there are some studies investigating the use of THC-containing products in patients with multiple sclerosis (MS) and in those with chronic pain, which will be discussed below, but overall, the current evidence is insufficient to recommend to patients and further research is needed.
Multiple Sclerosis (MS)
The American Academy of Neurology asserts that clinicians might offer oral cannabis extract to patients with multiple sclerosis to reduce patient-reported symptoms of spasticity and pain (excluding central neuropathic pain).
(https://www.aan.com/Guidelines/home/GuidelineDetail/641 Last Accessed: October 27, 2025)Level of Evidence: A (Established as effective for the given condition in the specified population.)
While it is unclear if smoking cannabis improves MS-related symptoms, certain oral products combining THC and CBD, such as nabiximols, seem to reduce spasticity in patients with MS. Nabiximols, a prescription oromucosal spray containing cannabis extract (Sativex) is available in most of Europe and Canada but is not yet approved in the United States. Each actuation is standardized to deliver THC 2.7 mg and CBD 2.5 mg. Meta-analyses show that nabiximols modestly reduces subjective spasticity but not bladder dysfunction or neuropathic pain [14,15]. Effects endure over 11 months, but discontinuation of use may cause rebound symptoms [16,17]. Another meta-analysis shows that taking oral cannabis extracts with THC 25–30 mg and CBD 8-18 mg daily for up to 15 weeks modestly reduces subjective spasticity, neuropathic pain, and bladder dysfunction, but not objective spasticity measures [14].
Based on low or moderate quality evidence, clinical practice guidelines for managing chronic pain in MS patients unresponsive to other pain management modalities recommend cannabinoid-based medicines as adjunct treatment for pain, muscle spasm, and sleep. Oils and capsules show the strongest evidence of benefit, and a daily dose of THC 10–15 mg [18]. In contrast, based on a mix of high, moderate, and low-quality evidence, the American Academy of Neurology states that prescription cannabis extracts may benefit spasticity symptoms, non-neuropathic pain, and urinary frequency but do not improve objective measures of spasticity, reduce the number of urinary incontinence episodes, or reduce MS-related tremors [19]. In 2020, this guidance was reaffirmed, indicating that its core recommendations regarding oral cannabis remain valid [20].
Pain (Chronic)
The National Institute for Health and Care Excellence recommends against starting Cannabis sativa extract to treat neuropathic pain in non-specialist settings, unless advised by a specialist to do so.
(https://www.nice.org.uk/guidance/cg173 Last Accessed: October 27, 2025)Level of Evidence: Expert Opinion/Consensus Statement
Non-inhaled THC alone or as an adjunct treatment might reduce chronic pain from various causes when standard treatments are insufficient. The British Medical Journal's 2021 guidelines weakly recommend using cannabinoids alongside standard pain management modalities for moderate to severe chronic pain since it may modestly improve pain, physical function, and sleep [21]. Based on low- and moderate-quality evidence, clinical practice guidelines for cannabis and cannabinoid-based medicines in the management of chronic pain and co-occurring conditions recommend cannabinoid-based medicines, especially THC-predominant formulations, as adjunct treatments for anxiety, pain, and sleep in chronic pain patients unresponsive or intolerant to non-pharmacologic treatments. Additionally, the guidelines weakly recommend the adjunct use of cannabinoid-based medicine for depression, mobility, nausea, and post-traumatic stress disorder (PTSD) in patients with chronic pain based on low-quality evidence [18].
Cannabis use is associated with a range of adverse effects, many of which are thought to be related to THC. These effects can vary depending on the dose, route of administration, and individual factors.
When consumed by any route, cannabis use is associated with dizziness, dry mouth, fatigue, headache, increased appetite, nausea, paranoid and dissociative thinking, and sedation. Intoxicating doses can impair memory, motor coordination, reaction time, and visual perception for up to eight hours [22]. When inhaled, cannabis use has been associated with upper respiratory tract symptoms, such as coughing and wheezing [22]
High doses of cannabis containing THC have been linked to acute coronary syndrome, arrhythmias, blood pressure changes, cannabinoid hyperemesis syndrome (CHS), hallucinations, pancreatitis, panic, psychosis, and seizures. It is unclear if these effects are due to THC, other constituents, or the combination [22].
Cannabis can be habit-forming. Meta-analyses suggest that about 47% of regular cannabis users develop dependence, and up to 9% of all users develop cannabis use disorder [23]. Withdrawal symptoms may include irritability, nervousness, difficulty sleeping, decreased appetite, depressed mood, stomach pain, tremors, sweating, fever, or headache. Symptoms typically last 7-14 days and may be more severe in individuals with pre-existing depression or anxiety [23,24].
Intoxicating doses of THC can impair driving for up to 8 hours. A study found that inhaling vaporized cannabis with 14 mg THC increased lane weaving for 100 minutes, similar to a 0.05% blood alcohol level. Acute cannabis use raises motor collision risk, especially when combined with alcohol or other drugs [25,26].
It's critical to consider the potential THC-drug interactions, especially in patients taking medications with a narrow therapeutic index (e.g., warfarin), or those who are regular cannabis users. Always gather information about cannabis use and include it in the patient's medical history. Evaluate the impact of cannabis use when patients start or stop a medication or report new side effects.
Antithrombotics
In vitro research and case reports suggest that cannabis use can increase the risk of bleeding when combined with drugs, herbs, and supplements that also increase the risk of bleeding [27,28]. Patients receiving warfarin, anticoagulants, or antiplatelets should be monitored closely for bleeding.
Cytochrome P450 (CYP450) Enzymes
Cannabis may affect certain CYP450 enzymes. In vitro research suggests that cannabis might inhibit or induce CYP450 enzymes, including CYP2C9, 2E1, and 3A4. Theoretically, this could increase or decrease the levels and corresponding effects of substrates of these enzymes [22].
Sedatives
Theoretically, using cannabis with drugs, herbs, and supplements with sedative properties may cause additive effects, including psychomotor impairment, sedation, and changes in mood and behavior [22]. Use caution with alcohol, barbiturates, and CNS depressants.
Pregnancy and Lactation
Cannabis crosses the placenta, and its use during pregnancy has been associated with numerous negative maternal and fetal outcomes in observational studies [22]. THC is excreted into the breast milk for at least six weeks after cessation and can cause delayed motor development in infants [29]. Patients should be informed of these risks and discouraged from using cannabis while pregnant or breastfeeding.
THC is the main psychoactive cannabinoid in cannabis, known for its recreational use. While THC shows potential for conditions like chronic pain and multiple sclerosis, evidence for its efficacy is insufficient to recommend to patients. Cannabis use can lead to adverse effects such as impaired driving and respiratory issues. THC may interact with medications, such as antithrombotics, sedatives, and CYP450 substrates.
CBD is a nonpsychoactive cannabinoid in cannabis, making up about 40% of cannabis extracts [8]. Because hemp is not subject to DEA regulation, hemp is the main source of most available CBD products.
The regulatory landscape of CBD is evolving. In May 2019, the FDA approved a specific, oil-based prescription formulation of CBD (Epidiolex) for treating seizures associated with Lennox-Gastaut and Dravet syndromes and tuberous sclerosis complex [30]. The 2018 Farm Bill legalized hemp and its constituents, including CBD, by removing them from the Controlled Substances Act. However, the FDA's approval of a prescription CBD product has added complexity to its legal status [5].
The FDA excludes ingredients approved as new drugs from being dietary supplements, so CBD, as an active ingredient in a prescription product, is technically not allowed in foods and supplements, yet inconsistent enforcement has left CBD products in a legal gray area [31].
Unlike THC, CBD does not act on cannabinoid receptors and therefore does not produce a "high." Instead, CBD interacts with endocannabinoid and non-endocannabinoid signaling systems. For instance, CBD inhibits cellular uptake and degradation of anandamide, a highly potent, endogenous agonist of CB1 and CB2. By altering its function, CBD can indirectly impact the endocannabinoid system.
CBD also acts on other receptors, including transient receptor vanilloid type 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1), which are ion channels expressed by sensory neurons that play an important role in various sensations, including pain, cold, itch, and other protective responses. CBD can also enhance the activity of 5-HT1A (serotonin) receptors and other receptors throughout the body, such as peroxisome proliferator-activated receptors (PPAR) [35].
CBD is frequently touted for mental health, pain management, sleep, substance use disorders, and gastrointestinal conditions. However, most of the evidence for CBD use is for treatment-resistant epilepsy. Research for other purported indications is inconclusive.
Treatment-Resistant Epilepsy
Research into the use of CBD for epilepsy has primarily been conducted with a specific prescription CBD product (Epidiolex). Prescription CBD is an oil-based oral solution standardized to contain CBD extract 100 mg/mL. The extract is highly purified from a plant source. Originally classified by the DEA as a Schedule V controlled substance, it was descheduled in April 2020.
A meta-analysis shows that CBD must be used by 4 patients taking antiepileptic treatment regimens with clobazam, and 8 patients without clobazam, to achieve one additional patient with a 50% greater reduction in seizures [32]. Research suggests that a specific prescription CBD product (Epidiolex) maintains efficacy long term [33]. A prospective open-label study indicates sustained seizure reduction over two years [34].
For Dravet syndrome, reduced seizure frequency tends to occur within two to four weeks of starting a specific prescription CBD product [35]. Clinical research shows that taking a specific prescription CBD product (Epidiolex) 20 mg/kg daily for 14 weeks reduces total convulsive seizure frequency by 39%, compared to 13% with placebo [36]. Up to 50% of patients experience at least a 50% reduction in convulsive seizures after 12 to 14 weeks [33]. An open-label extension study shows similar reductions sustained through 156 weeks [37].
For Lennox-Gastaut syndrome, taking a specific prescription CBD product (Epidiolex) for 14 weeks reduces drop seizures by up to 43% compared to a 22% reduction in the placebo group [36,38]. An open-label extension study shows similar reductions sustained through 156 weeks [37].
While this prescription formulation has also been evaluated for use in other forms of epilepsy, the available research is limited, and it is not approved for these uses. It is unclear if other CBD products are beneficial for use in seizure disorders.
Mental Health
Research on the use of CBD for mental health benefits is inconclusive. For example, research in patients with treatment-resistant anxiety shows that taking CBD up to 800 mg daily for 12 weeks reduces anxiety severity by 43% and modestly improves depression symptoms from baseline. However, benefits were not maintained at a six-month follow-up [39]. Current evidence is insufficient to recommend CBD for management of mental health conditions.
Pain
Although CBD products, both oral and topical, are frequently touted for pain relief, they do not seem to reduce acute pain, and the effects on chronic pain are unclear. Despite the popularity of CBD salves and balms for muscle and joint pain relief, there is little evidence supporting the topical absorption of CBD.
For example, in healthy volunteers with experimentally induced pain, several small clinical studies show that single oral doses of CBD 200–800 mg do not seem to reduce acute pain when compared with placebo [35]. In another study, patients with acute low back pain presenting to the emergency department, oral CBD 400 mg taken in combination with acetaminophen 1,000 mg and ibuprofen 400 mg does not reduce pain or the need for rescue analgesia with oxycodone over two hours when compared with placebo [40].
Although a recent clinical practice guideline recommends cannabinoid-based medicines for chronic pain management, suggesting that CBD-dominant products can be used with THC to reduce adverse events, the strongest evidence of benefit comes from THC-rich formulations, not CBD. The evidence for CBD-predominant formulations is unclear [18].
Sleep
Although CBD has demonstrated sedative effects in animal research, studies in humans are insufficient and conflicting on whether CBD improves sleep. Oral CBD has been evaluated as monotherapy or in combination with other ingredients, but the studies are low-quality, of short duration, and with unclear clinical significance.
For example, a large clinical trial in adults with poor sleep shows that taking gummies containing CBD (10 mg, 20 mg, or 100 mg) combined with 20 mg of another cannabinoid, cannabinol (CBN), daily for seven days does not improve sleep quality, sleep onset, unintended waking, or daytime fatigue compared to placebo [41]. However, another large clinical trial in adults with sleep disturbance found that taking CBD (15 mg) alone or in combination with other cannabinoids or melatonin daily for four weeks improves sleep quality compared to baseline. However, measures of sleep quality were not improved when CBD alone was compared with combination therapy or melatonin alone [42].
Substance Use Disorders
In patients with substance use disorders, CBD may help reduce cravings and substance use, but it is unclear if these benefits translate into relapse prevention. Unfortunately, most studies in this area are small and of low quality and do not provide enough information to recommend to patients.
In patients with cannabis use disorder, a small clinical study shows that taking synthetic CBD oil 400 mg or 800 mg daily for four weeks seems to reduce overall cannabis consumption based on urine metabolite levels when compared with placebo [43]. A small study in adults with heroin use disorder shows that taking CBD 400 or 800 mg daily for three days reduces cue-induced cravings and anxiety acutely and for seven days after the last dose compared to placebo [44]. CBD may also help with nicotine dependence. A small study in cigarette smokers suggests that inhaling one spray of CBD 400 mcg when craving a cigarette reduces the number of cigarettes smoked by 40% over one week compared to baseline [45].
Adults
CBD is possibly safe when used orally and appropriately in adults. Doses up to 200 mg daily have been used safely for up to 13 weeks, while higher doses of 700 mg daily for up to 6 weeks and 1,200 mg daily for up to 4 weeks have also been used safely. Prescription CBD oil (Epidiolex) has been used in doses of 5–20 mg/kg daily for up to 20 months [35].
Children
Prescription CBD oil (Epidiolex) is possibly safe for children 1 year and older at doses of 2–50 mg/kg daily, with a maximum recommended dose of 25 mg/kg/day [35]. The safety of other forms of CBD has not been evaluated in children.
Pregnancy
CBD is unsafe when used orally during pregnancy. The FDA strongly advises against the use of CBD during pregnancy [46]. CBD products might contain THC or other contaminants such as pesticides, heavy metals, bacteria, and fungus, which can be dangerous to the fetus [46,47].
CBD seems to be well tolerated when taken by mouth. The most commonly reported adverse effects include decreased appetite, drowsiness, dry mouth, fatigue, pyrexia, vomiting, and weight loss [55].
Prescription CBD is reported to cause somnolence in up to 30% of patients and diarrhea in up to 24% of patients. Note that high doses required for treatment-resistant epilepsy exceeding 15–20 mg/kg daily and/or taken in combination with other anticonvulsants (e.g., clobazam, valproic acid) are more likely to cause certain adverse effects like somnolence, decreased appetite, diarrhea, elevation of liver transaminases, and weight loss/gain [55].
There is some concern that CBD can be abused, but overall, these concerns are unfounded. Single 750-mg doses of CBD were rated no differently than placebo for "drug-liking," likelihood of repeat use, or occurrence of positive effects (e.g., feeling "high" or "stoned") among healthy recreational polydrug abusers in a clinical study [48]. Higher single doses of 1,500 mg or 4,500 mg were rated with a higher likelihood for repeat use and the presence of "positive effects," but these ratings were still lower than those for dronabinol, a synthetic version of THC, and alprazolam [48]. Abrupt discontinuation following short-term CBD use does not seem to be associated with withdrawal symptoms in healthy volunteers.
Clinical, animal, in vitro, and pharmacokinetic research show that CBD acts as a substrate, inducer, and inhibitor of multiple cytochrome P450 enzymes. This can alter drug plasma concentrations, impacting efficacy and safety (Table 1). The effects vary based on the drug, CBD dosage, treatment duration, and individual genetics. Healthcare providers should be cautious when CBD is used with medications that have a narrow therapeutic index or significant side effects [55].
KEY CBD-DRUG INTERACTIONS
| Drug Class | Evidence Type | Mechanism | Effect |
|---|---|---|---|
| CYP2C19 Substrates (Clobazam, Omeprazole) | Clinical | CYP2C19 inhibition | 60% to 280% increase in substrate levels |
| CYP3A4 Substrates (Tacrolimus, Midazolam) | Clinical | CYP3A4 inhibition | 56% to 300% increase in levels |
| CYP2C9 Substrates (Topiramate, Losartan) | Clinical | CYP2C9 inhibition | Increased plasma levels |
| CYP1A2 Substrates (Caffeine) | Clinical | CYP1A2 inhibition | 15% increase in peak, 95% increase in exposure |
| CNS Depressants | Clinical | Additive effects | Enhanced sedation and hypnotic effects |
| Valproate | Clinical | Unknown | Hepatotoxicity risk |
| SSRIs (Fluoxetine, Citalopram) | Clinical | CYP inhibition | Increased SSRI levels |
CBD inhibits multiple CYP enzymes (1A2, 2C9, 2C19, 3A4), potentially increasing levels of many medications. CBD may also interact with other specific agents, such as citalopram, omeprazole, and warfarin. Monitor closely when using CBD with narrow therapeutic index medications, such as tacrolimus, valproate, or warfarin.
CBDV is a nonpsychoactive cannabinoid that is structurally similar to CBD, and therefore acts through many of the same receptor pathways, exhibiting activity at CB2 but minimally at CB1 [49,68].
While there is interest in CBDV for conditions including autism, Crohn disease, Duchenne muscular dystrophy, Fragile X syndrome, multiple sclerosis, nausea, neuropathic pain, and ulcerative colitis, the current evidence is insufficient. Additionally, CBDV is being investigated for use in Rett syndrome, which is a rare, genetic neurodevelopmental disorder. CBDV has received orphan designation from the European Medicines Agency and the FDA [50,51]. Overall, CBDV does not currently have sufficient evidence to support its use for any conditions and additional research is needed to determine its efficacy, proper dosing, and safety.
Epilepsy
While there is interest in CBDV for epilepsy, it appears to be ineffective. A large, high-quality clinical study in patients with inadequately controlled focal seizures failed to show that adjunctive therapy with CBDV reduces seizure frequency when compared with placebo, prompting the industry sponsor to abandon research for this indication [52].
CBDV seems to be safe for short-term use in adults; oral doses of up to 800 mg twice daily for up to eight weeks have been evaluated in clinical research [52]. But there is no data for use of higher doses or for longer durations. Avoid CBDV during pregnancy or lactation, due to insufficient safety information in these cases. The most commonly reported adverse effects include abdominal pain, diarrhea, dizziness, headache, nausea, rash, and somnolence [53].
THCV is a nonpsychoactive analogue of THC found naturally in Cannabis sativa and may also be derived from cannabidivarin (CBDV) [49]. THCV acts on the endocannabinoid system, with a higher affinity for CB2 [68]. Laboratory and animal research suggests that it exhibits anti-inflammatory, antiemetic, and antitumor effects via CB1 and CB2 agonism. Additionally, research in healthy adults indicates that THCV might affect food intake through CB1 agonism in the brain [54].
This cannabinoid has not been extensively studied in humans, but there is growing interest in its potential as an anti-inflammatory, anticonvulsant, analgesic, antipsychotic, and appetite suppressant. Available research for these conditions is limited to in vitro and animal studies.
CBN, a mildly psychoactive cannabinoid and metabolite of THC, is present in cannabis in trace amounts [55]. CBN can also be derived from CBD when exposed to high temperatures, such as in e-cigarettes [56]. CBN binds to CB2 and demonstrates weak affinity for CB1, potentially affecting sleep, pain, and immune responses [55,57,58].
Although there is interest in using CBN for its analgesic, anti-inflammatory, and immunologic effects, it has not been evaluated in clinical studies. Due to its mild psychoactive effects, CBN has been studied for its potential benefits in treating insomnia, but the evidence available is inconclusive. For example, a clinical trial involving adults with self-reported poor sleep quality found that taking 20 mg of CBN 90 minutes before bed for a week did not improve sleep quality compared to a placebo [41]. More research is needed to determine the efficacy of CBN for insomnia.
CBN is possibly safe for short-term use in adults; oral doses of up to 20 mg daily for up to seven days have been evaluated in clinical research without serious adverse effects [68]. Avoid CBN in children and during pregnancy and lactation, due to insufficient safety information in these cases.
In vitro studies suggest that CBN is a substrate of certain CYP450 enzymes and also an inhibitor of certain CYP450 enzymes (e.g., CYP2B6, 2C9, and 3A4). These interactions haven't been substantiated in humans [59,60,61].
High doses of CBN might cause false positive results in certain THC urine tests [62].
CBG is a nonpsychoactive cannabinoid found naturally in Cannabis sativa and is abundant in industrial hemp [63]. It shares some of the same receptor pathways as CBD.
Although there is interest in using CBG for conditions such as cachexia, dyslipidemia, Huntington disease, and inflammatory bowel disease, available research is limited to in vitro and animal studies. Some research shows that the anti-inflammatory effects of CBG might be greater when used in combination with CBD. However, CBG also seems to reverse the antiemetic effects of CBD when used concomitantly.
CBC is a nonpsychoactive cannabinoid found abundantly in the cannabis plant [66]. It does not strongly affect CB1 but exerts activity at CB2 [67,68].
Although there is interest in using CBC for its anti-inflammatory, analgesic, antidepressant, and anticonvulsant effects, available research is limited to in vitro and animal studies [67,69,70,71,72]. Some research shows that the analgesic effects of CBC may be greater when used in combination with other cannabinoids (e.g., cannabinol) [71].
Animal research suggests that CBC might have sedative effects; however, this interaction has not been shown in humans [73]. Be aware that using CBC with drugs, herbs, or supplements with sedative properties may cause additive therapeutic and adverse effects.
Delta-8 THC, an isomer of THC, is another psychoactive cannabinoid found in cannabis. It is estimated to be 50% to 75% as psychoactive as delta-9 THC. The concentration of naturally occurring delta-8 THC in cannabis and hemp is low, and therefore most delta-8 THC is synthetically manufactured from CBD. Neither the safety nor efficacy of delta-8 THC has been evaluated in clinical studies or by the FDA, but significant safety concerns have emerged.
Delta-8 THC exists in a legal gray area because it is not specifically addressed in the 2018 Farm Bill and has not been evaluated for efficacy or safety by the FDA. It is banned or restricted in some states, while remaining legal in others [74]. The combination of its unclear regulatory status and its psychoactive effects have led to rapid increases delta-8 THC availability and interest.
Delta-8 THC lacks thorough evaluation of safety outcomes, although significant safety concerns have emerged. In the first seven months of 2021, hospitalization occurred in 18% of 661 reported exposures to delta-8 THC. Additionally, CDC's National Syndromic Surveillance Program has documented increased emergency department visits related to delta-8 THC [75].
According to data compiled from sources including the FDA, CDC, and the American Association of Poison Control Centers, common adverse effects include difficulty thinking and speaking, dreamlike state, euphoria, feeling "high," and vision and time distortion. More serious symptoms include vomiting, lethargy, hallucinations, lack of muscle coordination, altered heart rate, low blood pressure, difficulty breathing, and coma. Concerning safety signals include Brugada EKG pattern and CHS, frequently necessitating emergency care [76].
Children represent a vulnerable population, accounting for 39% of reported exposures in early 2021, with some requiring intensive care. Case reports document deep sedation with cardiovascular depression in children after accidental ingestion of delta-8 THC gummies, including a 2-year-old who developed acute encephalopathy following ingestion of an estimated 15 mg/kg dose [77].
Excessive and prolonged cannabis use (e.g., two to three times daily over two years) can trigger a condition called cannabinoid hyperemesis syndrome (CHS). This condition is characterized by cyclic episodes of severe nausea and vomiting resistant to conventional antiemetics. Patients commonly report temporary symptom relief with bathing in extremely hot water, and this is often a clue that points providers to a possible diagnosis. CHS has been documented with both inhaled and oral use and has been linked to severe complications, including several fatalities. The cornerstone of long-term treatment for CHS is complete discontinuation of cannabis use, but benzodiazepines and capsaicin also may play a role in short-term symptom management.
E-cigarette, or vaping, product-use associated lung injury (EVALI) has occurred among adults and children using e-cigarette, or vaping, products. Most patients with EVALI reported using THC-containing products within three months before symptom onset. The exact cause of EVALI is unclear, but most research indicates that it is due to additives in the vaping products. Due to this serious risk, the FDA has issued warnings against using all THC-containing vaping products [79].
Accidental ingestion of cannabis-containing edibles among children 12 years and younger has increased significantly. This trend correlates with recreational cannabis legalization and the proliferation of appealing food formulations like gummies. The effects of such accidental ingestion can include ataxia, coma, hypotonia, hypothermia, lethargy, nystagmus, respiratory depression, seizures, and tremors [80].
Cannabis products face significant concerns about contamination, increasing the risk of serious adverse effects with their use. Cannabis sativa is a phytoremediator, a plant that readily absorbs contaminants from soil. For this reason, cannabis products are vulnerable to contamination with pesticides, heavy metals, bacteria, and fungus [81].
Product quality is lacking and cross-contamination of cannabis products with other cannabinoids is abundant. Commercially available CBD products, especially those intended for vaping, have been frequently shown to be contaminated with THC or synthetic cannabinoids. An analysis of seven commercially available CBD e-liquid formulations found that two products were contaminated with an undeclared synthetic cannabimimetic (5F-ADB) and another two contained undeclared THC.
Off-the-shelf evaluations of commercially available oral CBD products have consistently demonstrated issues with product standardization and labeling. In an analysis of 84 commercially available CBD products in the United States, only 31% of products were accurately labeled and 21% of products contained unlabeled THC. Other assessments of 14 products commercially available in Europe and 25 products available in the United States found that up to 90% of the products were inaccurately labeled and that up to 86% of products contained detectable quantities of THC.
Commercially available CBD, especially products intended for vaping, may be contaminated with synthetic cannabinoids such as delta-8 THC, increasing the risk of serious associated adverse effects. Interestingly, when CBD is exposed to temperatures typically occurring in e-cigarettes, it can be converted to delta-8 THC, CBN, CBC, and other cannabinoids. One analysis found that products labeled as hemp-derived CBD contains undeclared delta-8 THC that are formed as a byproduct of the manufacturing process [82].
In general, THC can be detected in blood tests for up to three days, saliva tests for up to four days, urine tests for anywhere from three to 21 days, and hair tests for up to 90 days after cannabis use. Contamination in products can lead to false positive drug test results. Patients using CBD may test positive because these products can contain trace amounts of THC. Furthermore, using other cannabinoids might also cause false positives in certain urine tests for THC. Clinical research shows that high-dose CBD use resulting in cannabinol urine concentrations about five times greater than the minimum THC concentration can produce a positive THC signal on specific immunoassays [83]. Make sure patients are adequately informed of the risks and unknowns related to drug testing with cannabinoids and cannabinoid-containing products.
Cannabis and cannabinoid-containing products are becoming increasingly available as regulations evolve to allow increased access. While these products are often promoted for their therapeutic benefits, currently available evidence for their use is generally limited, particularly for non-prescription and unregulated formulations. Important safety considerations include the risk of adverse effects, drug interactions, and product contamination and quality concerns. When patients ask about using these products, healthcare providers should be prepared to discuss appropriate safety considerations, help patients understand the potential benefits and risks of cannabinoids, and provide evidence-based recommendations. It is essential to strike a delicate balance between acknowledging interest in these products while ensuring that they understand the current limitations in evidence and safety concerns with various cannabinoids.
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