The Many Controversies of Cannabidiol
January 1, 2024 34 minutes read
EXECUTIVE SUMMARY
Cannabidiol (CBD) is the second most common component of marijuana, after delta-9-tetrahydrocannabinol (THC). The potency of marijuana is determined by the THC content. THC is responsible for the euphoric effects or mind-altering “highs” seen with marijuana. CBD in its purified form has not been associated with those effects.
- In January 2023, the U.S. Food and Drug Administration (FDA) released a position statement outlining its concerns about the ineffectiveness of current regulatory paths for CBD. To provide the public with accurate information about CBD while protecting them from harm, the FDA stated it will work with Congress to find solutions for clarity on this topic, keeping the safety of consumers at the forefront.
- The effects and properties of CBD have been the subject of much research over the past 60 years. To date, randomized clinical trials do not support the claims of efficacy of CBD for Parkinson’s disease, schizophrenia, cancer palliation and treatment, chronic pain and spasticity, depression, anxiety disorder, insomnia, and inflammation.
- There is not yet enough evidence to support claims of benefit in bipolar disease, Crohn’s disease, diabetes, dystonia, Huntington’s disease, multiple sclerosis, and numerous other conditions for which non-purified pharmaceutical-grade CBD products are marketed.
- CBD most often is taken sublingually, by inhalation or vaporization, by ingestion, or applied locally in its topical form. Oral administration delays the onset of action because of first-pass liver effects. The bioavailability of CBD is low when ingested.
- Without standardized dosing, CBD-containing products are unpredictable. Topical products need to be absorbed sufficiently and predictably. Numerous CBD formulations have shown adverse effects without clinical benefit. CBD is quite lipophilic, affected by fatty meals when ingested. Gastrointestinal effects, such as reduced appetite and diarrhea, may be seen, along with an elevation of liver transaminase concentrations in approximately 10% of patients.
- CBD may interact with many different drug classes, with CBD strongly inhibiting cytochrome P450 enzymes CYP3A4, CYP2C19, CYP2C9, and CYP2D6 because of competitive inhibition. If a patient is taking concomitant medications that can be affected, CBD can block these enzymes, enabling more of the other medication to stay in the body at a higher level for a longer period than expected.
- The only FDA-approved prescription CBD (purified CBD) is in the form of an oral solution. Epidiolex, the brand name, is a single entity agent containing 0.1% or less of delta-9 THC. Epidiolex holds FDA approval for three childhood-onset epileptic syndromes.
- On Feb. 23, 2023, the Substance Abuse and Mental Health Services Administration issued its latest advisory on CBD. It describes the increasing popularity of CBD, its unapproved use for health conditions, and concerns for especially vulnerable populations, such as children and those with comorbid health conditions for whom products are being promoted. While one out of three Americans used a product labeled as CBD in 2020, studies have shown that the labeling often is inaccurate, with adulterated CBD very often being reported.
Current trends in cannabinoid research, federal and state cannabis legislation, multi-sourced information, as well as misinformation, all drive consumer interest in cannabidiol (CBD).
The August 2020 issue of Primary Care Reports covered the “ABCs of CBD,” explaining the various sources of CBD.
CBD and marijuana are not to be equated. Cannabinol is the second most common component of marijuana, after delta-9-tetrahydrocannabinol (THC). The potency of marijuana is determined by the THC content. THC is responsible for the euphoric effects or mind-altering “highs” seen with marijuana. CBD in its purified form has not been associated with those effects.1 Marijuana is a plant containing about 400-plus components; 113 have been identified as cannabinoids.2 Marijuana (also called cannabis) varies in its content from strain to strain, based on a variety of factors, including climate, growing environment, and genetics. Because of the dramatic variations found in marijuana samples, the value of repeatability to predict effects can be a challenge. In other words, one person’s exposure may be quite different from another’s.3 The THC:CBD ratio is an important predictor of the effects of a particular sample, with THC content increasing when CBD content lowers. To be called marijuana, the cannabis plant sample must contain greater than 0.3% THC by dry weight. If the sample contains 0.3% or less of THC, then it is called hemp. CBD can be derived from hemp or from non-hemp marijuana plant varieties, but it also must contain 0.3% or less THC.4
With no clear consensus on terminology, broad use of the term “CBD” is confusing at best. The term “CBD products” may be used to refer to varied combinations of THC and CBD, as might be sourced from marijuana, whereas the term also may denote products having only trace amounts of THC (perhaps from hemp). More broadly, “cannabis products” or “cannabis-derived products” often refers to “THC-containing” products or products with a mix of THC with other cannabinoids.5 This has led to inaccurate assumptions about products claiming to contain CBD. The idea that these products are all of the exact same content, characterized by a single compound identified as CBD, has been shown to be false.6 This has led to inaccurate generalizations. This review refers to CBD or CBD products generally, whether labeled accurately or mislabeled; in other words, possibly containing CBD, with or without other substances.
Regulatory Oversight
In January 2023, the U.S. Food and Drug Administration (FDA) released a position statement outlining its concerns about the ineffectiveness of current regulatory paths for CBD.7 To provide the public with accurate information about CBD while protecting them from harm, the FDA stated it will work with Congress to find solutions for clarity on this topic, keeping the safety of consumers at the forefront.
With the increased use of CBD products, increased incidents of poisonings are being reported, including those involving children and pets. With confusion on policy, on potential benefits and harms, and on long-term chronic effects often seen with excessive use, determining the facts is increasingly problematic for healthcare practitioners and consumers. These issues prioritize the need for clinicians, especially in primary care, to stay current on developments related to CBD and other cannabinoids. Highlights of the FDA’s timeline of evidentiary responses and actions can be found in Table 1.8
The effects and properties of CBD have been the subject of much research over the past 60 years. To date, randomized clinical trials (RCTs) do not support the claims of efficacy of CBD for Parkinson’s disease, schizophrenia, cancer palliation and treatment, chronic pain and spasticity, depression, anxiety disorder, insomnia, and inflammation.9 There is not yet enough evidence to support claims of benefit in bipolar disease, Crohn’s disease, diabetes, dystonia, Huntington’s disease, multiple sclerosis, and numerous other conditions for which non-purified pharmaceutical-grade CBD products are marketed.9 Several research-focused corporations have begun heeding FDA recommendations to follow the FDA drug approval process via investigational new drug (IND) applications to make therapeutic claims for potential CBD drug candidates, using unique drug delivery formulations to develop purified CBD candidates for study. This area of research should be watched closely as these candidates go into their Phase I, II, and III drug trials.
CBD rarely is found in its pure form, defined as a “pharmaceutical grade” concentration containing 0.1% or less THC.9 CBD typically is derived from hemp because of the low THC concentration in hemp, while THC typically is derived from marijuana plants, which contain higher amounts of THC. CBD products often contain substances other than CBD itself and often are purposefully adulterated by manufacturers and growers. If mixed with other substances, CBD products might not contain even small amounts of CBD, while being promoted as “CBD.”
These products can vary dramatically, with different potencies of CBD, THC, other cannabinoids, heavy metals (especially lead and cadmium), pesticides, illicit and prescription drugs, flavorings, and numerous other potentially harmful chemicals.9-11 Medical fraud, mislabeling, and contamination commonly have been associated with CBD products, leading to a long history of legal challenges and fraud.9,12
Although touted as a “wonder drug,” CBD product advertisements often claim it to be safe, legal, and generally useful for all that ails. But reports of adverse effects abound, with adverse events and poisonings increasingly common, including interference with other medications.9 Researchers from Johns Hopkins reported in 2022 that only 24% of 105 CBD labeled products, sampled in retail establishments or from those chosen online for the study, contained accurately labeled amounts of CBD.13 Many cannabis and hemp products, sold online or in retail stores today, may not be legal, often have minimal if any quality assurance, may mislead with false medical claims, and may contribute to harmful health effects, lacking safety and effectiveness data.
The Farm Bill, termed the Agriculture Improvement Act of 2018, removed hemp from the definition of marijuana under the Controlled Substances Act (CSA).14,15 Hemp previously was defined as cannabis (Cannabis sativa L). With the Farm Bill revisions, hemp cannot contain more than 0.3% THC by dry weight concentration, per section 10113 of the Farm Bill, effectively removing it from the definition of marijuana under the CSA.14,15 The Farm Bill preserves the FDA’s authority, including under the Federal Food, Drug, and Cosmetic Act (FD&C Act) and Public Service Health Act, such that hemp products, while not controlled under the CSA, still are subject to the requirements of FDA-regulated products containing any other substance. This allows the FDA to continue enforcing the law to protect patients and the public while also providing potential regulatory pathways, to the extent permitted by law, for products containing cannabis and cannabis-derived compounds, including CBD.6,9,16 Regarding sources of origin, any C. sativa plant with more than 0.3% THC still is considered marijuana.17 CBD can be derived from hemp or non-hemp (marijuana) plants, creating opportunities for CBD to be found in high-potency THC mixtures, which defines the sample as marijuana and not as CBD.
The Effects of CBD and its Therapeutic Uses
Routes of Administration
CBD most often is taken sublingually, by inhalation or vaporization, by ingestion, or applied locally in its topical form. Oral administration delays the onset of action because of first-pass liver effects. The bioavailability of CBD is low when ingested. Very few studies have been done to evaluate the effectiveness of various routes of CBD administration, although numerous corporations now are exploring new drug delivery methods as FDA IND applications are beginning to be filed for purified forms of CBD and research continues.
Without standardized dosing, CBD-containing products are unpredictable. Topical products need to be absorbed sufficiently and predictably. Numerous CBD formulations have shown adverse effects without clinical benefit. CBD is quite lipophilic, affected by fatty meals when ingested.18 Gastrointestinal effects, such as reduced appetite and diarrhea, may be seen, along with an elevation of liver transaminase concentrations in approximately 10% of patients.
Although there is little evidence to support clinical utility for topical applications to date, one research firm has formulated a synthetic transdermal CBD gel showing more sustained predictable dosing.19
Mechanism of Action
The various mechanisms of action of CBD have not been fully understood and are quite complex. (See Table 2.) Cannabinoid receptors (CBs) are highly prevalent in the human nervous system (CB1) and in immune cells (CB2).20 Unlike THC, CBD has a small affinity to bind CB1 and CB2 receptors, even inhibiting THC binding at CB1 receptors.21 At low concentrations, CBD has weak CB1 and CB2 antagonistic effects.20
Table 2. Possible Mechanisms of CBD |
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Receptor |
Effect |
Potential Pharmacologic Outcome |
CB1 |
Direct antagonism and negative allosteric antagonism |
Attenuation of impaired learning, memory, hypothermic, and psychosis effects induced by delta-9-THC |
CB2 |
Antagonist + inverse agonist |
Anti-inflammatory effects |
GPR55 |
Antagonist |
Anticancer effects |
5HT1-alpha |
Agonist |
Pain relieving (allosterically regulated mu and sigma opioid receptors) and anti-anxiety effects |
TRPV-1 |
Agonist |
Anti-inflammatory, pain relieving, and sebum-producing effects |
Adenosine A2A |
Enhanced adenosine concentrations |
Anti-inflammatory effects |
CBD: cannabidiol; THC: tetrahydrocannabinol Source: U.S. Food and Drug Administration. Safety of CBD in humans – a literature review (as of December 12, 2019). https://www.fda.gov/media/152317/download |
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In the nervous system, CBD may behave as a negative allosteric modulator of CB1, meaning that CBD does not activate the receptor directly, but it changes the efficacy and potency of THC and 2-arachidonoylglycerol at the CB1 receptor.20 Other potential actions of CBD include inhibition of gamma aminobutyric acid (GABA), modulation of intracellular calcium by various transient receptor potential (TRP) channels, and modulation of tumor necrosis factor-alpha release or inhibition of adenosine reuptake.21 CBD also has activity at the serotonin 5HT1A receptor.20,22
In the immune system, CBD has been shown to inhibit neutrophil chemotaxis and proliferation. It may reduce stimulation of arachidonic acid release, reducing prostaglandin E2 and nitric oxide production. CBD changes the expression of interleukins (ILs) by macrophages, reducing IL-12 while increasing IL-11.23 It is a direct agonist at the adenosine A2A receptor and the peroxisome proliferator-activated gamma (PPARgamma) receptor.24
CBD Metabolism and Pharmacokinetics
CBD may interact with many different drug classes, with CBD strongly inhibiting cytochrome P450 enzymes CYP3A4, CYP2C19, CYP2C9, and CYP2D6 due to competitive inhibition.25,26 If a patient is taking concomitant medications that can be affected, CBD can block these enzymes, enabling more of the other medication to stay in the body at a higher level for a longer period of time than expected.
Both CBD and THC potently inhibit cytochrome enzymes. Warfarin, antivirals, benzodiazepines, antidepressants, and cardiac and hypertensive medications may be included. Omeprazole, a modest inhibitor of CYP2C19, did not alter the plasma concentration of CBD in one study. 25-27 As identified previously, CBD is associated with liver transaminase abnormalities. The FDA has warned that CBD can cause liver damage.
Like THC, CBD is subjected to a significant first-pass effect; however, unlike THC, a large proportion of the dose is excreted unchanged in the feces.27 Edible CBD products, such as gummies, may not show signs of onset of action until several hours after ingestion, often creating a false sense of safety. Then, the duration of activity may be prolonged. Overdoses may occur when consumers continue to consume more until they feel the onset of action.
Therapeutic Uses
Despite the promotion of CBD via testimonials and other less legitimate commercial advertisements, few clinical studies reveal the therapeutic value of using CBD in its purified forms. Other CBD-containing products sold online or in retail stores are sold without having done clinically relevant safety or efficacy studies. One cannot compare one product to the next. Extensive literature reviews, meta-analyses, and systematic reviews provide strong support for only one therapeutic use for CBD at this time. This use is specific to one proprietary purified CBD oil, in oral solution, which is a prescription formulation of CBD used as add-on therapy for three rare epilepsy syndromes in children.
There is recent news of investigations into IND candidates in anxiety, psychosis, and arthritis or neuropathy in early phase trials through the FDA.28 These potential pathways to FDA drug approval through IND trials of purified forms of CBD could change the CBD horizon at any time, if well-done RCTs of a particular purified CBD formulation can be shown to have a significant effect on any disorder. Until such time, the fraudulent marketers and false claims will continue to catch media attention, motivating consumers to try various products, often promoted as “risk-free.”
Epilepsy. The only FDA-approved prescription CBD (purified CBD) is in the form of an oral solution. Epidiolex, the brand name, is a single entity agent containing 0.1% or less of delta-9-THC. Nearly all the THC from the Cannabis sativa plant has been extracted from the product to create Epidiolex.28-30
Epidiolex holds FDA approval for three childhood-onset epileptic syndromes: Dravet syndrome, Lennox-Gastaut syndrome, and seizures associated with tuberous sclerosis complex. Initially indicated for Lennox-Gastaut syndrome and Dravet syndrome for those age 2 years and older, Epidiolex now has approval for the third disease in those 1 year of age and older. Dravet’s and Lennox-Gastaut patients 1 year of age and older now may receive Epidiolex.8,28,30
The FDA, through ongoing evaluation, has made adjustments to scheduling the drug and dosing as experience with the product has been gained.
Epidiolex rarely is prescribed as a first-line drug, but instead is used in conjunction with numerous other anti-epileptics, such as clobazam. Devinsky reported on a double-blind, placebo-controlled trial that compared the CBD proprietary oil (now known as Epidiolex) at a dose of 20 mg/kg/day with placebo as add-on therapy in 120 children and adults with Dravet syndrome. The study showed a statistically significant reduction in seizure frequency in the CBD group.31
It is notable that two-thirds of patients in the CBD group were taking clobazam concurrently. CBD can increase the plasma concentration of clobazam and its active metabolite, N-desmethylclobazam, three-fold to five-fold, requiring a dosage adjustment for clobazam.31,32 It is uncertain if the observed improvement in seizure frequency is the result of CBD directly or caused by an increase in the plasma level of N-desmethylclobazam.21 In clinical trials, common adverse effects of CBD at the dose of 20 mg/kg/day included somnolence in 25% of patients, decreased appetite in 22% of patients, diarrhea in 20% of patients, and serum transaminase elevations in 16% of patients. Side effects were dose-related, with CBD seemingly not causing intoxication or euphoria.31,32
With the potential for liver enzyme elevations, drug interactions with concomitantly administered medications, and liver toxicity, concurrent use of drugs that induce (vs. inhibit) CYP3A4 or CYP2C19 can decrease serum CBD concentrations, reducing its efficacy. For epilepsy patients for whom Epidiolex is prescribed as an add-on to valproate, liver function tests often have been reported as abnormal.30,32,33 While Epidiolex has been a helpful entity for some, it comes with concern for prescribers, caregivers, and patients, especially with dosing readjustment of concomitantly prescribed medications. A careful balance is required for overall benefit.30
Psychiatric Disorders. Black performed a systematic review and meta-analysis of cannabinoids in patients with mental disorders in 2019. No RCTs of CBD for depression were found. Two studies examined the effect of CBD in patients with social anxiety disorder with no significant improvement in anxiety symptoms compared with placebo.34 In a 2022 open-label study by Dahlgren et al, 14 patients with anxiety were treated for four weeks with a cannabis-derived product with a high CBD content, administered under the tongue three times per day. All patients knew they were being given CBD. At the end of the four-week treatment period, patients reported reduced anxiety, with improvements in mood, sleep, quality of life, and measures reflecting self-control and flexible thinking. Patients did not report any serious negative effects during this study.35
O’Sullivan et al reviewed the medical literature on the therapeutic uses of purified CBD in 2023. The authors concluded that the areas in which there is the most clinical evidence supporting the use of CBD are in the treatment of anxiety (positive data in seven uncontrolled studies and 17 RCTs), psychosis and schizophrenia (positive data in one uncontrolled study and eight RCTs), post-traumatic stress disorder (PTSD) (positive data in two uncontrolled studies and four RCTs), and substance abuse (positive data in two uncontrolled studies and three RCTs). They noted that the evidence base is limited by the small number of patients in small numbers of trials, along with investigating only acute effects of CBD or testing CBD in healthy volunteers.28
An IND application was filed in 2021 by a research corporation for the use of a purified CBD formulation to be tested for PTSD symptoms and neurocognitive impairment in patients with PTSD and with PTSD co-morbid with traumatic brain injury. The drug delivery formulation appears to enhance the effectiveness and stability of CBD.36 Little is known publicly to comment on the status of this and other formulations in the midst of investigation.
No studies examined the efficacy of CBD in attention-deficit hyperactivity disorder or Tourette syndrome.34 In RCTs of CBD in psychosis, CBD did not improve total symptoms, positive symptoms, or negative symptoms compared with placebo or active comparators. CBD did not significantly improve cognitive or emotional functioning but did lead to improvement in global functioning compared with placebo.34
Opioid Use Disorder. The FDA has approved the IND for evaluating a purified CBD formulation for adjunctive treatment in patients with opioid use disorder (OUD).37 It is important to recognize this would be a drug candidate of a purified formulation and not a product available in national retail stores or online from manufacturers touting various medical claims in a fraudulent manner. Years may go by before conclusions can be made on various purified CBD formulations currently under investigation as IND candidates.
Arthritis. CBD is thought to have potential for arthritis treatment because, theoretically, it has analgesic, anti-inflammatory, and antioxidant effects. There are no controlled clinical studies in people with arthritis to support any claims of efficacy.38 A single, placebo-controlled, randomized trial of synthetic transdermal CBD gel in 320 patients with knee osteoarthritis did not show a statistically significant reduction in pain scores, although secondary outcomes favored CBD.39 Two of three RCTs support the analgesic effects of topical CBD treatment to affected areas in neuropathy and arthritis.28
Pain. The available clinical evidence does not support the acute analgesic effects of purified CBD. There is no evidence to date that oral CBD is an effective analgesic.28
Cancer. Although preclinical and animal models show promise for CBD in cancer treatment, this has not translated into evidence of benefit in humans. In preclinical models, CBD inhibited the survival of both estrogen-receptor-positive and estrogen-receptor-negative breast cancer cell lines.40 CBD also has been demonstrated to exert a chemo-preventive effect in a mouse model of colon cancer.38
According to the National Cancer Institute, no ongoing clinical trials of cannabis as a treatment for cancer in humans were identified in a PubMed search.41 CBD oil extracts have been illegally promoted as potential cancer cures.42 These particular oil formulations have not been evaluated in any clinical trials for anti-cancer activity or safety. Because CBD is a potential inhibitor of certain cytochrome P450 enzymes, CBD used concurrently with conventional therapies that are metabolized by these enzymes potentially could increase the toxicity or decrease the effectiveness of these therapies.43-45
Other Uses and Current Research
Although anecdotal and observational studies suggest CBD improves sleep (usually comorbid to another condition), there is little RCT evidence to support this. Seven uncontrolled studies support the use of CBD to improve sleep quality, but this has only been verified in one small RCT.28
Although inconclusive, Parkinson’s disease patients may experience improvements in anxiety-related symptoms and overall quality of life.46 There is no evidence to support the use of CBD in Huntington’s disease.28 Clinical data currently are lacking to support the use of purified CBD in gastrointestinal disorders.28
As of September 2023, there were more than 900 clinical trials of CBD registered on the ClinicalTrials.gov website.47 Of these, 61 were Phase IV trials and 166 were Phase III trials. The Phase IV trials include studying Epidiolex (CBD oil) to treat seizure disorders or Rett syndrome. Many of the Phase III trials also were for seizure disorders or other painful conditions, such as arthritis, neuropathic pain, post-operative pain, or cancer-related pain. Several trials were focused on Parkinson’s disease, PTSD, and OUD.47,48
New formulations with creative drug delivery systems are under investigation generally.49 Extended-release forms with intestinal drug delivery are being evaluated for Crohn’s disease. An inhaled dry powder CBD formulation is being designed for pulmonary administration. Topical gels and creams are under development, as are ophthalmic hydrogels.49 Time will tell if efficacy and safety will be at a level to approve these products.
Recent work evaluated whether CBD might be used to counter the intoxicating effects of THC. At four different THC:CBD ratios commonly found in medicinal and recreational cannabis products, researchers found no evidence supporting CBD being protective against the acute adverse effects of cannabis, specifically the psychoactive component of THC. Continued diligence at assessing this and other similar issues, often touted as beneficial characteristics of CBD, needs to have priority status in drug development strategies for CBD.50
CBD as an Ingredient in Cosmetics (Including Use for Skin Ailments). CBD has garnered significant attention in recent years for its anecdotal therapeutic potential for skin and cosmetic disorders. Although pre-clinical evidence suggests topical applications may be beneficial for conditions such as eczema and psoriasis, supporting data of value have not been achieved at this time to condone the use of any purified CBD product.51
The cosmetic industry has a multimillion to multibillion dollar interest in this topic. As part of the ongoing pressure to evaluate the regulatory framework surrounding CBD, the Cosmetic Ingredient Review Panel plans to prioritize a CBD review in 2024 at the request of the FDA. The FDA maintains that CBD-containing cosmetics cannot be misbranded, adulterated, or marketed in such a way to promote affecting the body structure/function or to treat or prevent disease, including any reference to treating skin ailments.52
CBD-infused beauty products are bound by the same rules that apply to other cosmetics. The FDA has issued warning letters to cosmetic companies for ignoring guidance regarding the regulation of CBD.53
SAMHSA Speaks Out on CBD
On Feb. 23, 2023, the Substance Abuse and Mental Health Services Administration (SAMHSA) issued its latest advisory on CBD. Titled “Potential Harms, Side Effects, and Unknowns,” it describes the increasing popularity of CBD, its unapproved use for health conditions, and concerns for especially vulnerable populations, such as children and those with comorbid health conditions for whom products are being promoted.5
While one out of three Americans used a product labeled as CBD in 2020, studies have shown that the labeling often is inaccurate, with adulterated CBD very often being reported.5,8,54 With other unlabeled substances mixed into the concoction, including delta-9 THC, delta-8 THC, or numerous other non-cannabis-related compounds, these readily available products are not “CBD” but instead cannabis-derived products (also referred to as CBD products). Delta-8 THC is of particular concern since it typically is manufactured from CBD and has significant psychoactive effects. It is a major metabolite of delta-9 THC.5
Marketing CBD Products in General
Under the FD&C Act, any product intended to have a therapeutic or medical use, and any product (other than a food) that is intended to affect the structure or function of the body of humans or animals, is a drug, subject to the IND application process using clinical human trials. This is the only path for FDA drug approval. Other than Epidiolex, no FDA-approved drug products containing purified CBD are available. All other CBD-containing products intended as drugs are considered unapproved and are illegal to sell.
The FDA has concluded that it is prohibited to introduce or deliver into commerce any food (including animal feed or animal food) to which CBD (or THC) is added.42 Since dietary supplements are considered food additives, CBD and THC are prohibited as such. Despite prohibitive regulations, companies still market “CBD products” to treat diseases using false claims or to recommend their products for other therapeutic purposes, which is illegal under federal law.5,8
There is a lack of evidence to support most claims associated with CBD.1,42 Many manufacturers of CBD-containing products do little to protect consumers or to assure the quality and potency of their products. The U.S. Drug Enforcement Agency classifies all products containing CBD and not FDA-approved as Schedule 1, an illegal drug, as stipulated in the Controlled Substances Act.8,51 Some research corporations have moved to file for IND applications to do research with specific purified drug formulations of CBD.
With the advancement in late 2022 of a law signed by President Biden, the Medical Marijuana and Cannabidiol Research Expansion Act allows for investigation of purified cannabis products to become more mainstream following the FDA drug approval process. Several companies now have trials underway to evaluate measurable, comparable endpoints with purified, reproducible drug products. This is very different than what often takes place with counterfeit or adulterated CBD-containing products found on the internet or purchased at gas stations or head shops. As of Sept. 30, 2023, poison centers across the country have managed 1,734 cases related to cannabidiol in 2023.55 The FDA has issued numerous warning letters, with concurrent alerts to consumers.4,8 Significant problems often occur with use of CBD during pregnancy or while breastfeeding (see Table 3), and the FDA strongly advises against the use of CBD by pregnant people.5,8
Reproductive disorders, including those related to the male reproductive system, have been demonstrated in animal studies. While this is confusing to consumer users, healthcare clinicians need to share this information with patients for both cannabis-containing products and “CBD-containing” products, while keeping patient safety intact.5,8
It is notable that the use of cannabis or CBD for morning sickness is on the increase, with easy access in states where medicinal marijuana or recreational marijuana is legal. Fetal cannabinoid syndrome can be devastating to the fetus and newborn, with no available beneficial treatment for this attention-deficit hyperactivity disorder-mimicking condition.1,5,8
Selling unapproved products with unsubstantiated therapeutic claims not only is a violation of the law, but it can put patients at risk without proof of safety or effectiveness. The deceptive marketing of unproven treatments also raises significant public health concerns because patients and other consumers may be influenced not to use FDA-approved therapies of value to treat serious, potentially fatal diseases.8
CBD May Have a Role in Cannabinoid Hyperemesis Syndrome
The use of marijuana- and cannabinoid-derived products containing THC, including CBD products, can cause acute psychiatric symptoms such as acute anxiety or psychosis or worsening of chronic psychiatric conditions. Cardiovascular events, including myocardial infarction and ventricular dysrhythmia, also can occur. These often present after the use of edible cannabis or CBD products.56
Cannabinoid hyperemesis syndrome (CHS) is a paradoxical condition of episodic intractable vomiting usually arising after long-term daily cannabis use, with complete abatement in a matter of hours or days, only with cannabinoid abstinence.54,57,58 Vomiting usually is intense and overwhelming. Conventional antiemetic therapy, such as ondansetron, promethazine, or metoclopramide, is not effective treatment, but relief from nausea can be achieved intermittently by bathing in hot water.59 Patients may be unable to eat because of slowed gastric emptying and will require intravenous fluid replacement along with proton pump inhibitors, pain medications, and, perhaps, medications such as haloperidol or topical capsaicin applied to the arm or abdomen. Patients often undergo unnecessary diagnostic tests, scans, and other procedures when clinicians and patients are unaware of the linkage of CHS to chronic marijuana (THC) use. Clinicians should be careful when treating these patients with multiple medications, since there is significant opportunity for drug interactions, particularly with opioids and benzodiazepines, requiring tapering before adding additional drugs.
Although CBD appears to have both antiemetic and pro-emetic dose-related effects, CHS patients will specifically have a history of chronic THC (marijuana) use.59 Both cannabidiol and cannabigerol have been implicated, along with THC, in the pathogenesis of CHS. The role of cytochrome P450 metabolism and genetic polymorphisms might increase susceptibilities of patients to CHS. It appears that chronic THC exposure is required for episodic hyperemesis.59
Consumers’ Perceptions of CBD and CBD Products
A recent study, characterizing both the use of and patient perceptions for CBD, found that approximately 60% of CBD users in the United States, and more than half of Canadian users, believe CBD oil is good for their health. Despite using CBD for health conditions for which there is little or no efficacy, consumers may need enhanced, accurate public health information regarding the risks vs. benefits of these products.1,5 Because of the 2018 U.S. Farm Bill, the legal status of CBD varies from state to state, with few restrictions blocking hemp-derived CBD products under state laws despite CBD being illegal under federal statute.5,59 CBD as dietary supplements (considered food additives) are illegal, creating confusion because of illicit CBD sales (from beverages to dietary supplements to foods and cosmetics to over-the-counter-type products).5,8,50 Federal prohibitions kick in when interstate transport of CBD products occurs.
One study identifies the three most common mental health conditions for which consumers use CBD products: anxiety (49.7%), depression (33.2%), and PTSD/traumatic events (14.6%). In treating physical health, study participants used it most commonly for pain (50.8%), headaches/migraines (32.6%), and problems sleeping (27.2%). Previous data in this report showcase the lack of substantiation to date of these claims in humans.
There are little or no data to justify efficacious use of CBD or CBD products purchased over the counter in any form. Almost 60% of users in the study believed that CBD oil is good or very good for health — with users more likely than nonusers to perceive CBD oil as good or very good.60,61
Consumer perceptions of the therapeutic benefits of CBD exceed clinical results for most conditions for which it is promoted.5,60 Previous research shows most consumers find their CBD-related information on the internet or from other informal sources, with fewer than one out of 10 receiving CBD-related information from a physician.5,8,60 Asking patients (in a nonjudgmental manner) seen in the clinic if they use other products intermittently or regularly for their health or to treat any medical symptoms may extract vital information about CBD and other products that may not fit into specific categories.
Studies Evaluating CBD Products
A 2020 study looked at whether CBD products contained specific quantities of CBD, as labeled. Results showed that, of the 102 products indicating a specific amount of CBD, 18 products (18%) contained less than 80% of the amount of CBD indicated, 46 products (45%) contained CBD within 20% of the amount indicated, and 38 products contained more than 120% of the amount specified. Of particular interest and concern is that nearly half (49%) of the products tested positive for THC, meaning the CBD may have come from marijuana and not hemp.9,62
Another recent study published in JAMA showed that, out of 84 CBD product samples purchased in various retail establishments, THC was detected in 18 (21%), with only 30.95% of the samples labeled accurately.63
Another study from Johns Hopkins found that 59% of the CBD products reviewed had detectible levels of CBD, but the average ratio of THC to CBD content was 36 to 1.64
Warnings for Clinicians to Share with Consumers Using CBD Products
Adverse reactions to CBD products abound, as reported by America’s Poison Centers and emergency departments across the United States.55 Consumers should be aware and watchful of possible negative effects of these potentially adulterated products, such as impaired judgment, impaired thinking, impaired motor skills, problems operating hazardous machinery or vehicles, suicidality, or hypersensitivity.
With CBD product exposure in children, risks in infants and children younger than 2 years of age have been widely reported. Pets are vulnerable to unintentional poisoning and may be poisoned by well-intentioned administration of products marketed for calming, anxiety-reducing effects. Edible products with erratic pharmacokinetics and low oral bioavailability need tighter scrutiny for regulatory and quality assurance.12
A challenge for clinicians is to identify ways to raise patient awareness to the facts surrounding CBD and CBD-containing products (see Table 4). The FDA is clearly elucidating their concerns through their commitment to reevaluate the topic regularly while attempting to protect vulnerable consumers, including children and pets.
Table 4. Potential Warnings, Harms, and Side Effects of CBD1,4,5 |
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CBD: cannabidiol; THC: tetrahydrocannabinol |
America’s Poison Centers maintain the National Poison Data System, the national database of information logged by the country’s regional poison control centers. The American Poison Centers safety tips regarding CBD are available in Table 5.55
Table 5. Safety Tips for Consumers Using CBD Products55,65 |
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CBD: cannabidiol; THC: tetrahydrocannabinol; FDA: Food and Drug Administration |
For further information on adverse health effects associated with marijuana and medical marijuana use, see “Deciphering Medical Marijuana,” Primary Care Reports, May 2019.
References
- Centers for Disease Control and Prevention. CBD: What you need to know. Last reviewed Aug. 8, 2022. https://www.cdc.gov/marijuana/featured-topics/cbd.html
- Mehmedic Z, Chandra S, Slade D, et al. Potency trends of delta-9 THC and other cannabinoids in confiscated cannabis preparations from 1993 to 2008. J Forensic Sci 2010;55:1209-1217.
- National Institute on Drug Abuse. Cannabis (Marijuana) DrugFacts. December 2019. https://nida.nih.gov/publications/drugfacts/cannabis-marijuana
- U.S. Food and Drug Administration. FDA regulation and quality considerations for cannabis and cannabis-derived compounds. Content current as of Feb. 7, 2023. https://www.fda.gov/drugs/cder-small-business-industry-assistance-sbia/fda-regulation-and-quality-considerations-cannabis-and-cannabis-derived-compounds
- Substance Abuse and Mental Health Services Administration. Cannabidiol (CBD) – Potential harms, side effects, and unknowns. SAMHSA Advisory. Published February 2023. https://store.samhsa.gov/sites/default/files/pep22-06-04-003.pdf
- U.S. Food and Drug Administration. Safety of CBD in humans – a literature review (as of December 12, 2019). https://www.fda.gov/media/152317/download
- U.S. Food and Drug Administration. FDA concludes that existing regulatory frameworks for foods and supplements are not appropriate for cannabidiol, will work with Congress on new way forward. Published Jan. 26, 2023. https://www.fda.gov/news-events/press-announcements/fda-concludes-existing-regulatory-frameworks-foods-and-supplements-are-not-appropriate-cannabidiol
- U.S. Food and Drug Administration. FDA regulation of cannabis and cannabis-derived products, including cannabidiol (CBD). Current as of Sept. 28, 2023. https://www.fda.gov/news-events/public-health-focus/fda-regulation-cannabis-and-cannabis-derived-products-including-cannabidiol-cbd
- Evans DG. Medical fraud, mislabeling, contamination: All common in CBD products. Mo Med 2020;117:394-399.
- Hande K. Cannabidiol: The need for more information about its potential benefits and side effects. Clin J Oncol Nurs 2019;23:131-134.
- ClassAction.org. Davis v. CBD American Shaman, LLC. Case no. 0.20-cv-60897. https://www.classaction.org/media/davis-v-cbd-american-shaman-llc.pdf
- Sabaghi D. Nearly 60% of CBD products are mislabeled, a new study finds, with some containing heavy metals. Forbes. Published Aug. 29, 2022. https://www.forbes.com/sites/dariosabaghi/2022/08/29/nearly-60-of-cbd-products-are-mislabeled-and-containing-heavy-metals-study-finds/amp/
- Spindle TR, Sholler DJ, Cone EJ, et al. Cannabinoid content and label accuracy of hemp-derived topical products available online and at national retail stores. JAMA Netw Open 2022;5:e2223019.
- National Institute of Standards and Technology. NIST to help labs achieve accurate THC, CBD measurements. Published July 21, 2020. https://www.nist.gov/news-events/news/2020/07/nist-help-Labs-achieve-accurate-thc-cbd-measurements
- U.S. Department of Agriculture. Agriculture Improvement Act of 2018: Highlights and implications. Economic Research Service. Last updated July 12, 2022. https://www.ers.usda.gov/agriculture-improvement-act-of-2018-highlights-and-implications/
- U.S. Food and Drug Administration. Statement from FDA Commissioner Scott Gottlieb, M.D., on signing of the Agriculture Improvement Act and the agency’s regulation of products containing cannabis and cannabis-derived compounds. Published Dec. 20, 2018. https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-signing-agriculture-improvement-act-and-agencys
- Wilson WB, Urbas AA, Scott F. Study reveals inaccurate labeling of marijuana as hemp. National Institute of Justice. Published Oct. 17, 2022. https://nij.ojp.gov/topics/articles/study-reveals-inaccurate-labeling-marijuana-hemp
- Kramer JL. Medical marijuana for cancer. CA Cancer J Clin 2015;65:109-122.
- O’Brien TJ, Berkovic SF, French JA, et al.; STAR 1/STAR 2 Study Group. Adjunctive transdermal cannabidiol for adults with focal epilepsy: A randomized clinical trial. JAMA Netw Open 2022;5:e2220189.
- Larsen C, Shahinas J. Dosage, efficacy and safety of cannabidiol administration in adults: A systemic review of human trials. J Clin Med Red 2020;12:129-141.
- Samanta D. Cannabidiol: A review of clinical efficacy and safety in epilepsy. Pediatr Neurol 2019;96:24-29.
- VanDolah HJ, Bauer BA, Mauck KF. Clinicians’ guide to cannabidiol and hemp oils. Mayo Clin Proc 2019;94:1840-1851.
- Sermet S, Li J, Bach A, et al. Cannabidiol selectively modulates interleukin (IL)-1β and IL-6 production in toll-like receptor activated human peripheral blood monocytes. Toxicology 2021;464:153016.
- Urits I, Borchart M, Hasegawa M, et al. An update of current cannabis-based pharmaceuticals in pain medicine. Pain Ther 2019;8:41-51.
- Horn JR, Hansten PD. Drug interactions with marijuana. Pharmacy Times. Published Dec. 9, 2014. https://www.pharmacytimes.com/view/drug-interactions-with-marijuana#
- Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: A systematic review. Drug Metab Rev 2014;46:86-95.
- Chayasirisobhon S. Mechanisms of action and pharmacokinetics of cannabis. Perm J 2020;25:1-3.
- O’Sullivan SE, Jensen SS, Nikolajsen GN, et al. The therapeutic potential of purified cannabidiol. J Cannabis Res 2023;5:21.
- Abu-Sawwa R, Stehling C. Epidiolex (cannabidiol) primer: Frequently asked questions for patients and caregivers. J Pediatr Pharmacol Ther 2020;25:75-77.
- U.S. Food and Drug Administration. Epidiolex prescribing information. Revised March 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/210365Orig1s011lbl.pdf
- Devinsky O, Cross JH, Laux L, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med 2017;376:2011-2020.
- [No authors listed]. Cannabidiol (Epidiolex) for epilepsy. Med Lett Drugs Ther 2018;60:182-184.
- Huestis MA, Solimoni R, Pichini S, et al. Cannabidiol adverse effects and toxicity. Curr Neuropharmacol 2019;17:974-989.
- Black N, Stockings E, Campbell G, et al. Cannabinoids for the treatment of mental disorders and symptoms of mental disorders: A systematic review and meta-analysis. Lancet Psychiatry 2019;6:995-1010.
- Dahlgren MK, Lambros AM, Smith RT, et al. Clinical and cognitive improvement following full-spectrum, high-cannabidiol, high-cannabidiol treatment for anxiety: Open-label data from a two-stage, phase 2 clinical trial. Commun Med (Lond) 2022;2:139.
- BioSpace. ANANDA Scientific and NYU Grossman School of Medicine announce clinical trial utilizing Liquid Structure cannabidiol (CBD) for treatment of post-traumatic stress disorder (PTSD). Published Jan. 21, 2021. https://www.biospace.com/article/releases/ananda-scientific-and-nyu-grossman-school-of-medicine-announce-clinical-trial-utilizing-liquid-structure-cannabidiol-cbd-for-treatment-of-post-traumatic-stress-disorder-ptsd-/
- Langendorf J. Nantheia ATL5: A new hope for beating opioid addiction. Treatment Magazine. Published Jan. 26, 2022. https://treatmentmagazine.com/nantheia-atl5-a-new-hope-for-beating-opioid-addiction/
- Fitzcharles MA, Niaki OZ, Hauser W, et al. Position statement: A pragmatic approach for medical cannabis and patients with rheumatic diseases. J Rheumatol 2019;46:532-538.
- Hunter D, Oldfield G, Tich N, et al. Synthetic transdermal cannabidiol for the treatment of knee pain due to osteoarthritis. Osteoarthritis Cartilage 2018;26:S26. doi: https://doi.org/10.1016/j.joca.2018.02.067
- Shrivastava A, Kuzontkoski PM, Groopman JE, Prasad A. Cannabidiol induces programmed cell death in breast cancer cells by coordinating the cross-talk between apoptosis and autophagy. Mol Cancer Ther 2011;10:1161-1172.
- National Academy of Sciences, Engineering, and Medicine. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. The National Academies Press; 2017.
- U.S. Food and Drug Administration. FDA warns companies marketing unproven products, derived from marijuana, that claim to treat or cure cancer. Published Nov. 1, 2017. https://www.fda.gov/news-events/press-announcements/fda-warns-companies-marketing-unproven-products-derived-marijuana-claim-treat-or-cure-cancer#
- Yamaori S, Okamoto Y, Yamamoto I, Watanabe K. Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for CYP2D6. Drug Metab Dispos 2011;39:2049-2056.
- Jiang R, Yamaori S, Okamoto Y, et al. Cannabidiol in a potent inhibitor of the catalytic activity of cytochrome P450 2C19. Drug Metab Pharmacokinet 2013;28:332-338.
- Iffland K, Grotenhermen F. An update on safety and side effects of cannabidiol: A review of clinical data and relevant animal studies. Cannabis Cannabinoid Res 2017;2:139-154.
- Chagas MHN, Zuardi AW, Tumas V, et al. Effects of cannabidiol in the treatment of patients with Parkinson’s disease: An exploratory double-blind trial. J Psychopharmacol 2014;28:1088-1098.
- ClinicalTrials.gov. CBD clinical trials search. https://clinicaltrials.gov/search?term=CBD
- National Institutes of Health. Can CBD treat opioid use disorder? Updated Oct. 12, 2023. https://heal.nih.gov/news/stories/can-cbd-treat-opioid-use-disorder
- Stella B, Baratta F, Della Pepa C, et al. Cannabinoid formulations and delivery systems: Current and future options to treat pain. Drugs 2021;81:1513-1557.
- Englund A, Oliver D, Chesney E, et al. Does cannabidiol make cannabis safer? A randomized, double-blind, cross-over trial of cannabis with four different CBD:THC ratios. Neuropsychopharmacology 2023;48:869-876.
- Baswan SM, Klosner AE, Glynn K, et al. Therapeutic potential of cannabidiol (CBD) for skin health and disorders. Clin Cosmet Investig Dermatol 2020;13:927-942.
- Nelson R. US FDA’s stance on CBD in cosmetics hasn’t changed, and neither have marketing challenges. HBW Insight. Published Oct. 5, 2020. https://hbw.citeline.com/RS150536/US-FDAs-Stance-On-CBD-In-Cosmetics-Hasnt-Changed-And-Neither-Have-Marketing-Challenges
- Spicer M. VMS industry wants into CBD market, plus enforcement on firms already there. HBW Insight. Published June 4, 2019. https://hbw.citeline.com/RS148877/VMS-Industry-Wants-Into_CBD-Market-Plus-Enforcement-On-Firms-Already-There
- Simonetto DA, Oxentenko AS, Herman ML, Szostek JH. Cannabinoid hyperemesis: A case series of 98 patients. Mayo Clin Proc 2012;87:114-119.
- America’s Poison Centers. Cannabidiol (CBD). https://www.aapcc.org/CBD-Alert
- Monte AA, Shelton SK, Mills E, et al. Acute illness associated with cannabis use, by route of exposure: An observational study. Ann Intern Med 2019;170:531-537.
- Lapoint J, Meyer S, Yu CK, et al. Cannabinoid hyperemesis syndrome: Public health implications and a novel model treatment guideline. West J Emerg Med 2018;19:380-386.
- Pergolizzi JV Jr, LeQuang JA, Bisney JF. Cannabinoid hyperemesis. Med Cannabis Cannabinoids 2018;1:73-95.
- Kellogg A, Anderson C, Michiels M. A cannabis conflict of law: Federal vs. state law. American Bar Association. Published March 21, 2022. https://www.americanbar.org/groups/business_law/resources/business-law-today/2022-april/a-cannabis-conflict-of-law-federal-vs-state-law
- Brenan M. 14% of Americans say they use CBD products. Gallup. Published Aug. 7, 2019. https://news.gallup.com/poll/263147/americans-say-cbd-products.aspx
- Goodman S, Wadsworth E, Schauer G, Hammond D. Use and perceptions of cannabidiol products in Canada and the United States. Cannabis Cannabinoid Red 2022;7:355-364.
- HempIndustryDaily. Report to the U.S. House Committee on Appropriation and the U.S. Senate Committee on Appropriations: Sampling Study of the Current Cannabidiol Marketplace to Determine the Extent That Products Are Mislabeled or Adulterated. https://hempindustrydaily.com/wp-content/uploads/2020/07/CBD-Marketplace-Sampling_RTC_FY20_Final.pdf
- Bonn-Miller MO, Loflin MJE, Thomas BF, et al. Labeling accuracy of cannabidiol extracts sold online. JAMA 2017;318:1708-1709.
- Johns Hopkins Medicine. Medical marijuana edibles mostly mislabeled, study shows. Published June 23, 2015. https://www.hopkinsmedicine.org/news/media/releases/medical_marijuana_edibles_mostly_mislabeled_study_shows#
- U.S. Food and Drug Administration. Medwatch: The FDA safety information and adverse event reporting program. Current as of Dec. 11, 2023. https://www.fda.gov/safety/medwatch-fda-safety-information-and-adverse-event-reporting-program
Current trends in cannabinoid research, federal and state cannabis legislation, multi-sourced information, as well as misinformation, all drive consumer interest in cannabidiol (CBD). With the increased use of CBD products, increased incidents of poisonings are being reported. With confusion on policy, on potential benefits and harms, and on long-term chronic effects often seen with excessive use, determining the facts is increasingly problematic for healthcare practitioners and consumers. These issues prioritize the need for clinicians, especially in primary care, to stay current on developments related to CBD and other cannabinoids.
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