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The cannabis compound known as CBD is being touted as a treatment for a variety of conditions. But the substance’s uncertain legal status is stalling serious investigation. The FDA is working to answer questions about the science, safety, and quality of products containing cannabis and cannabis-derived compounds, particularly CBD. Cannabidiol in Anxiety and Sleep: A Large Case Series Cannabidiol (CBD) is one of many cannabinoid compounds found in cannabis. It does not appear to alter consciousness or trigger a “high.” A

The reality behind cannabidiol’s medical hype

The cannabis compound known as CBD is being touted as a treatment for a variety of conditions. But the substance’s uncertain legal status is stalling serious investigation.

    Michael Eisenstein

    Michael Eisenstein is a freelance writer in Philadelphia, Pennsylvania.

    You can also search for this author in PubMed Google Scholar

    Cannabidiol oil has purported health benefits, including helping to relieve chronic pain. Credit: Don Bartletti/Los Angeles Times/Getty

    Cannabidiol (CBD) is an illegal drug with no redeeming value. It is also a useful prescription medicine for epilepsy, with considerable potential for treating numerous other conditions. And it is a natural dietary supplement or ‘nutraceutical’ with countless evangelists in the health and wellness community. Although contradictory, all three statements are true from different perspectives, and clinical researchers are frustrated.

    “In New York City, you can go to a latte shop and get a CBD product, but if I want to do a clinical trial, I’ve got to get a 2,000-pound safe and go through six months of paperwork and licensing,” says Orrin Devinsky, director of the NYU Langone Comprehensive Epilepsy Center in New York City. Like the cannabis plant from which it is derived, CBD, a type of cannabinoid, is classified by the US Drug Enforcement Administration in the same way as are heroin and lysergic acid diethylamide (LSD) — schedule 1 substances with “high potential for abuse” and “no currently accepted medical use”.

    Part of Nature Outlook: Cannabis

    This flies in the face of current evidence. Numerous studies have shown that CBD is a safe and non-habit-forming substance that does not produce the ‘high’ associated with tetrahydrocannabinol (THC), the main psychoactive component of cannabis 1 . In 2018, the US Food and Drug Administration (FDA) determined that Epidiolex — a purified CBD product developed by GW Pharmaceuticals in Histon, UK — effectively reduces the frequency of seizures in certain rare forms of paediatric epilepsy. This approval has heartened the cannabinoid research community, which has long recognized the medicinal potential of CBD but come up against scepticism and regulatory constraints on the road to the clinic.

    But at the same time, the many manufacturers that promote CBD-laden oils, lotions and foods as a panacea for various health issues, often with minimal regard for local laws or medical evidence, are putting CBD’s medical advocates in an uncomfortable position. “I get calls and e-mails all the time — not just from families, but from physicians who have no clue how to address the requests they get from patients,” says Yasmin Hurd, director of the Addiction Institute of Mount Sinai in New York City. “It’s a real problem.”

    Stuck in the weeds

    The breakthrough approval of Epidiolex was driven by strong investment from GW Pharmaceuticals, as well as vigorous advocacy from families of children with epilepsy who had heard tantalizing anecdotes about CBD’s effects from jurisdictions in which medical cannabis is legal. “About eight years ago, a patient’s father said he was hearing stories about families in Colorado and California who use high-CBD strains for their kids’ epilepsy,” says Devinsky. “He asked me to do a trial.” As a medical student, he had been taught the history of medicinal cannabis, including well-documented uses of the plant by nineteenth-century physicians to treat seizures. Indeed, cannabis has been part of the clinical armamentarium for epilepsy for more than 4,000 years.

    Research on CBD in the 1970s and 1980s focused on its interplay with other cannabinoids, and particularly THC. “Whereas THC can induce psychotic symptoms, impair cognition and make people anxious, CBD appears to do the opposite,” says Philip McGuire, a psychiatrist at King’s College London.

    The first clues that CBD might suppress epileptic episodes came from a small clinical trial 2 in 1980. It was led by Raphael Mechoulam, a chemist at the Hebrew University of Jerusalem, whose work on the synthesis and biochemical characterization of cannabinoids in the 1970s had led researchers to begin to explore the medicinal properties of CBD. A number of other trials that explored the compound’s pharmaceutical properties followed, although scientists conducting early forays into CBD clinical research faced an uphill battle. F. Markus Leweke, a psychiatrist who specializes in mental illness at Sydney Medical School, Australia, recalls struggling for seven years to publish findings from a randomized controlled trial that demonstrated that CBD might offer an effective treatment for psychotic symptoms in schizophrenia 3 . “We got about 15 rejection letters,” says Leweke. “And this is a paper that has since been cited almost 500 times.”

    Claims about the health benefits of cannabis are often overstated and lack supporting evidence. Credit: Rodger Bosch/AFP/Getty

    Forty years on from Mechoulam’s initial work, extensive randomized controlled trials have decisively shown that this purified cannabinoid can profoundly benefit children with certain epileptic disorders. “Over those trials, we saw about a 26–28% reduction in frequency over placebo in all convulsive seizures for Dravet syndrome and drop seizures for Lennox–Gastaut syndrome,” says Devinsky, who has led several such studies 4 , 5 . “Some of the patients became, and remain, seizure-free.”

    Preclinical data from rodent and cell-culture studies have hinted at the possible benefits of using CBD to help treat disorders that range from Parkinson’s disease to chronic pain. The range of conditions in which CBD is being tested might seem diverse, but it is a compound with far-reaching, if poorly understood, physiological effects. Antonio Zuardi, a psychiatrist at the University of São Paulo in Brazil, notes that something on the order of 20 possible mechanisms of action have been described to date for CBD. “These multiple pharmacological effects may justify the wide range of possible therapeutic activities.”

    The mechanism of CBD’s action on cannabinoid receptors, at least, is well understood. CBD can bind to the cannabinoid receptor CB1, which is the same receptor that THC seeks out in the brain. Unlike THC, however, CBD restrains rather than activates CB1 signalling, and therefore doesn’t induce the psychoactive effects of its cannabinoid cousin.

    But CBD wears many hats. It seems to mediate its antiepileptic effects by binding to a protein called GPR55, which can otherwise trigger the onset of seizures by promoting the hyperactivation of neurons 6 . In addition, CBD acts on receptors that mediate pain signalling and inflammation, as well as at least one receptor for the neurotransmitter serotonin, 5-HT1A 7 . Gabriella Gobbi, a psychiatrist and neuroscientist at McGill University in Montreal, Canada, has found that CBD’s physiological effect on the brain resembles that of selective serotonin reuptake inhibitor (SSRI) drugs 8 , which are used to treat clinical depression. “After a few days, you get this desensitization of 5-HT1A, like you would with an SSRI, and increased serotonin signalling,” she says. Further experiments in rats failed to capture an antidepressant effect, but her team found that CBD-mediated modulation of 5-HT1A could relieve neuropathic pain in the animals.

    Multitasking molecule

    Beyond epilepsy, clinical data to support the medicinal benefits of CBD are more limited, mainly due to the small scale and inconsistent design of trials. “We have very few double-blind, randomized placebo-controlled trials,” says Gobbi. But exciting progress is being made towards treating several conditions.

    Psychosis — particularly in the context of schizophrenia — is one such area of promise. In 1995, Zuardi and Mechoulam reported the case of a person with schizophrenia who experienced meaningful relief from their symptoms when treated with high doses of CBD 9 . Several subsequent small-scale clinical studies detected similar hints of efficacy. In their groundbreaking trial 3 , Leweke and his colleagues put the compound through a particularly rigorous test by comparing its effects with those of amisulpride, a potent medication for schizophrenia. “We saw a significant decrease in symptoms over time for both compounds, and CBD beat amisulpride in terms of side effects, by far,” Leweke says. The team also found a clue to the mechanism by which CBD might exert its antipsychotic effects: treatment with CBD was associated with elevated levels of anandamide, a cannabinoid produced by the body that seems to offer protection from psychosis.

    McGuire and his colleagues conducted a randomized controlled trial that showed that CBD can have an additive effect when used with conventional antipsychotic drugs 10 . Together, they were better able to control symptoms such as hallucinations and delusions than could conventional medication alone. His team has received funding for a large, international trial to test whether CBD can be developed as a licensed medicine for treating psychosis.

    Anxiety disorders are another mental-health condition that CBD has been shown to help alleviate. Zuardi and his colleagues used a test that simulates speaking in public to show that pretreatment with a single dose of CBD can reduce the associated discomfort in people with social anxiety disorder 11 . A similar effect has been observed in healthy people in anxiety-inducing situations 12 , and several researchers are exploring CBD as a means of soothing social stress in people with autism spectrum disorder. Devinsky notes that many of his patients with epilepsy have also been diagnosed with autism spectrum disorder, and he is involved in two clinical trials that aim to test whether CBD can meaningfully reduce the irritability and anxiety of those with autism. “Many parents wanted to keep their children on it even if the seizures didn’t improve, because they’re calmer and sleeping better,” he says.

    And although cannabis been demonized as a gateway to more dangerous substances, Hurd has found that it might actually contain an effective antidote for potentially deadly addictions. After observing that rats with a heroin addiction were less likely to seek out the opioid when treated with CBD, she began to investigate whether CBD might have the same effect on people with an opioid dependency. On the basis of an encouraging pilot study, Hurd and her team conducted a randomized controlled trial in 42 abstinent heroin users, who had avoided taking the drug for up to three months after years of routine or heavy use 13 . The researchers then exposed the participants to drug paraphernalia and videos that showed heroin use — cues that normally provoke strong cravings in people with a dependency — and then measured participant-reported responses and physiological indicators of stress and anxiety. “Cue-induced craving is associated with increased cortisol levels and increased heart-rate, and CBD reduced those,” she says. Participants receiving CBD also reported lower levels of drug craving and anxiety relative to placebo group, and Hurd notes that the beneficial effects persisted for a week after the final administration of CBD.

    A difficult delivery

    Despite its promise, CBD’s impact as a drug has been mixed. Importantly, it is relatively safe. The side effects most commonly associated with a high dose of Epidiolex include digestive problems, rash and drowsiness, as well as the potential for liver damage in patients taking certain other medications. For example, Devinsky notes that patients who are receiving valproic acid to treat seizures or migraines might be at an elevated risk. But in many of the CBD trials conducted so far — particularly in the realm of antipsychotic drugs, which are known for their strong side effects — CBD has proved more tolerable than existing alternatives. “The side effects weren’t significantly worse than with placebo,” says McGuire of his 2018 study of CBD in people with schizophrenia 10 .

    This is important because people typically require large doses of the drug to experience a clinical benefit — in many studies, the doses used are as high as 1 gram or more. This is because CBD is poorly absorbed by the body, with most of every dose being excreted before it can take effect. “If you take it orally, the bioavailability is in the range of 4–6%, which is terrible,” says Devinsky. “If you take it after a fatty meal, you can get that up to 16–20%.” Zuardi notes that his group routinely observes a bell-shaped dose–response curve for CBD. For example, whereas 300 milligrams of CBD might reduce a person’s anxiety, the same person might not get any relief from a dose of either 100 milligrams or 900 milligrams. To complicate matters further, this sweet spot for CBD dosing can differ not only between symptoms, but also between patients.

    Campaigners show support for legalizing cannabis for medical use in Atlanta, Georgia. Credit: Erik S. Lesser/EPA/Shutterstock

    This is one of several reasons why researchers caution against self-medication with CBD products targeted at consumers. CBD is available in shops worldwide, but the legality of such sales varies widely. In Canada, selling cannabis and its derivatives is legal, whereas the European Union authorizes the sale of CBD derived from hemp (low-THC varieties of cannabis) but not from marijuana (high-THC cannabis). In the United States, the latest Farm Bill, which was enacted in 2018, potentially legalizes the production of CBD from hemp under certain conditions — although the sale of CBD products generally remains ostensibly illegal. Regardless of the legal situation at the federal level, CBD commercialization remains something of a free-for-all in the United States — individual states are making their own laws, and the FDA has taken only limited action to enforce federal laws on CBD. “They’ve sent some notices to companies that have made medical claims, but that’s about it,” says Marcel Bonn-Miller, a psychologist at the University of Pennsylvania, Philadelphia, and global scientific director at Canopy Growth Corporation, a cannabis company in Smiths Falls, Canada. (An FDA spokesperson responded that the agency “is working quickly to continue to clarify our regulatory authority over products containing cannabis and cannabis-derived compounds like CBD”.)

    More from Nature Outlooks

    Many such claims lie beyond the bounds of medical evidence — including that regarding CBD preparations that purport to prevent cancer or to treat Alzheimer’s disease. However, even products that make more modest claims could be problematic. In 2017, Bonn-Miller and his colleagues performed chemical analyses on 84 products purchased online from 31 companies, and found that only 31% were accurately labelled with regard to CBD content 14 . What’s more, many commercially available preparations have been found to be contaminated with intoxicating doses of THC, heavy metals and pesticides, as well as toxic solvents from the CBD extraction process. In a case reported by the US Centers for Disease Control and Prevention, up to 52 people in Utah became seriously ill or were hospitalized after using a CBD oil that contained an intoxicating synthetic cannabinoid drug. The possibility of such contamination is concerning to all potential users, and especially to people who are seeking relief from the effects of a health condition. “It’s one thing if you’ve got too much THC in gummy bears you’re using with friends, but something entirely different if it’s a kid you’re giving CBD for medical reasons,” says Bonn-Miller. “I don’t trust any CBD product until I’ve done the tests.”

    Between two worlds

    The regulatory disconnect that surrounds CBD creates an odd situation in which the public can self-medicate using a potentially questionable product, while scientists face a struggle to perform high-quality clinical trials. “The fact that CBD remains schedule 1 in the United States is unconscionable,” says Devinsky. That restrictive classification, he says, “is impairing research”.

    Obtaining sufficient quantities of pharmaceutical-grade CBD to conduct a well-powered clinical trial is already difficult. “It’s extremely expensive,” says Leweke. “You need about one gram a day, and the list price is about 60 euros [US$67] per gram.” This is because the process of extracting CBD from the cannabis plant is complex and arduous — and when the goal is to obtain CBD for use in people, the substance must meet the high bar set for clinical-grade preparations, under which only minimal quantities of THC or other contaminants are permissible. Several companies have developed strategies for manufacturing fully synthetic CBD, an approach that essentially eliminates concerns about purity. But synthetic CBD still falls under the schedule 1 classification in the United States, which creates extra economic and bureaucratic hurdles for clinical trials. Even in Canada, where recreational cannabis has been legalized, Gobbi describes a complex application process and a more than six-month wait to obtain government authorization to conduct a CBD study in people or animals.

    Unfortunately, if studies such as these are not done — or not done properly — then consumers will be left to fend for themselves in a poorly monitored marketplace. In that scenario, the signal of true clinical benefit would almost certainly be drowned out by the noise from personal anecdotes and the placebo effect, which could jeopardize the future of a potentially valuable medicine. “Humans are notoriously bad when they think they see patterns,” says Devinsky. “When everyone is convinced that they’re right with no data, I call that religion — and CBD is currently religion for the average person.”

    Nature 572, S2-S4 (2019)

    This article is part of Nature Outlook: Cannabis, an editorially independent supplement produced with the financial support of third parties. About this content.

    Updates & Corrections

    Correction 23 July 2020: An earlier version of this Outlook article misquoted Gabriella Gobbi. She said that 5-HT1A is desensitized in response to cannabidiol, not sensitized.

    References

    World Health Organization. Cannabidiol (CBD): Critical Review Report (World Health Organization, 2018).

    Cunha, J. M. et al. Pharmacology 21, 175–185 (1980).

    Leweke, F. M. et al. Transl. Psychiatry 2, e94 (2012).

    Devinsky, O. et al. N. Engl. J. Med. 376, 2011–2020 (2017).

    Devinsky, O. et al. N. Engl. J. Med. 378, 1888–1897 (2018).

    Kaplan, J. S., Stella, N., Catterall, W. A. & Westenbroek, R. E. Proc. Natl Acad. Sci. USA 114, 11229–11234 (2017).

    White, C. M. J. Clin. Pharmacol. 59, 923–934 (2019).

    De Gregorio, D. et al. Pain 160, 136–150 (2019).

    Zuardi, A. W., Morais, S. L., Guimarães, F. S. & Mechoulam, R. J. Clin. Psychiatry 56, 485–486 (1995).

    McGuire, P. et al. Am. J. Psychiatry. 175, 225–231 (2018).

    Bergamaschi, M. M. et al. Neuropsychopharmacology 36, 1219–1226 (2011).

    Linares, I. M. et al. Braz. J. Psychiatry 41, 9–14 (2019).

    Hurd, Y. L. et al. Am. J. Psychiatry https://doi.org/10.1176/appi.ajp.2019.18101191 (2019).

    Bonn-Miller, M. O. et al. J. Am. Med. Assoc. 318, 1708–1709 (2017).

    What You Need to Know (And What We’re Working to Find Out) About Products Containing Cannabis or Cannabis-derived Compounds, Including CBD

    The FDA is working to answer questions about the science, safety, and quality of products containing cannabis and cannabis-derived compounds, particularly CBD.

    • Cannabis is a plant of the Cannabaceae family and contains more than eighty biologically active chemical compounds. The most commonly known compounds are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is the component that produces the “high” associated with marijuana use. Much interest has been seen around CBD and its potential related to health benefits.
    • Marijuana is different from CBD. CBD is a single compound in the cannabis plant, and marijuana is a type of cannabis plant or plant material that contains many naturally occurring compounds, including CBD and THC.
    • The FDA has approved only one CBD product, a prescription drug product to treat seizures associated with Lennox Gastaut syndrome (LGS), Dravet syndrome (DS), or tuberous sclerosis complex (TSC) in people one year of age and older.
    • It is currently illegal to market CBD by adding it to a food or labeling it as a dietary supplement.
    • The FDA has seen only limited data about CBD safety and these data point to real risks that need to be considered before taking CBD for any reason.
    • Some CBD products are being marketed with unproven medical claims and are of unknown quality.
    • The FDA will continue to update the public as it learns more about CBD.

    Potential harm, side effects and unknowns

    1. CBD has the potential to harm you, and harm can happen even before you become aware of it.
      • CBD can cause liver injury.
      • CBD can affect how other drugs you are taking work, potentially causing serious side effects.
      • Use of CBD with alcohol or other drugs that slow brain activity, such as those used to treat anxiety, panic, stress, or sleep disorders, increases the risk of sedation and drowsiness, which can lead to injuries.
      • Male reproductive toxicity, or damage to fertility in males or male offspring of women who have been exposed, has been reported in studies of animals exposed to CBD.
    2. CBD can cause side effects that you might notice. These side effects should improve when CBD is stopped or when the amount used is reduced.
      • Changes in alertness, most commonly experienced as somnolence (drowsiness or sleepiness).
      • Gastrointestinal distress, most commonly experienced as diarrhea and/or decreased appetite.
      • Changes in mood, most commonly experienced as irritability and agitation.
    3. There are many important aspects about CBD that we just don’t know, such as:
      • What happens if you take CBD daily for sustained periods of time?
      • What level of intake triggers the known risks associated with CBD?
      • How do different methods of consumption affect intake (e.g., oral consumption, topical , smoking or vaping)?
      • What is the effect of CBD on the developing brain (such as on children who take CBD)?
      • What are the effects of CBD on the developing fetus or breastfed newborn?
      • How does CBD interact with herbs and other plant materials?
      • Does CBD cause male reproductive toxicity in humans, as has been reported in studies of animals?

    Unanswered questions about the science, safety, and quality

    You may have noticed that cannabidiol (CBD) seems to be available almost everywhere, and marketed as a variety of products including drugs, food, dietary supplements, cosmetics, and animal health products. Other than one prescription drug product to treat seizures associated with Lennox Gastaut syndrome (LGS), Dravet syndrome (DS), or tuberous sclerosis complex (TSC) in people one year of age and older, the U.S. Food and Drug Administration (FDA) has not approved any other CBD products, and there is very limited available information about CBD, including about its effects on the body.

    The FDA recognizes the significant public interest in cannabis and cannabis-derived compounds, particularly CBD. However, there are many unanswered questions about the science, safety, and quality of products containing CBD. The agency is working on answering these questions through ongoing efforts including feedback from a recent FDA hearing and information and data gathering through a public docket.

    Despite the 2018 Farm Bill removing hemp — defined as cannabis and cannabis derivatives with very low concentrations (no more than 0.3% on a dry weight basis) of THC — from the definition of marijuana in the Controlled Substances Act, CBD products are still subject to the same laws and requirements as FDA-regulated products that contain any other substance.

    The FDA is concerned that people may mistakenly believe that using CBD “can’t hurt.” The agency wants to be clear that we have seen only limited data about CBD’s safety and these data point to real risks that need to be considered. As part of the drug review and approval process for the prescription drug containing CBD, it was determined that the risks are outweighed by the benefits of the approved drug for the particular population for which it was intended. Consumer use of any CBD products should always be discussed with a healthcare provider. Consumers should be aware of the potential risks associated with using CBD products. Some of these can occur without your awareness, such as:

    • Liver Injury: During its review of the marketing application for Epidiolex — a purified form of CBD that the FDA approved in 2018 for use in the treatment of two rare and severe seizure disorders — the FDA identified certain safety risks, including the potential for liver injury. This serious risk can be managed when an FDA-approved CBD drug product is taken under medical supervision, but it is less clear how it might be managed when CBD is used far more widely, without medical supervision, and not in accordance with FDA-approved labeling. Although this risk was increased when taken with other drugs that impact the liver, signs of liver injury were seen also in patients not on those drugs. The occurrence of this liver injury was identified through blood tests, as is often the case with early problems with the liver. Liver injury was also seen in other studies of CBD in published literature. We are concerned about potential liver injury associated with CBD use that could go undetected if not monitored by a healthcare provider.
    • Drug Interactions: Information from studies of the FDA-approved CBD drug Epidiolex show that there is a risk of CBD impacting other medicines you take – or that other medicines you take could impact the dose of CBD that can safely be used. Taking CBD with other medications may increase or decrease the effects of the other medications. This may lead to an increased chance of adverse effects from, or decreased effectiveness of, the other medications. Drug interactions were also seen in other studies of CBD in published literature. We are concerned about the potential safety of taking other medicines with CBD when not being monitored by a healthcare provider. In addition, there is limited research on the interactions between CBD products and herbs or other plant-based products in dietary supplements. Consumers should use caution when combining CBD products with herbs or dietary supplements.
    • Male Reproductive Toxicity: Studies in laboratory animals showed male reproductive toxicity, including in the male offspring of CBD-treated pregnant females. The changes seen include decrease in testicular size, inhibition of sperm growth and development, and decreased circulating testosterone, among others. Because these findings were only seen in animals, it is not yet clear what these findings mean for human patients and the impact it could have on men (or the male children of pregnant women) who take CBD. For instance, these findings raise the concern that CBD could negatively affect a man’s fertility. Further testing and evaluation are needed to better understand this potential risk.

    In addition, CBD can be the cause of side effects that you might notice. These side effects should improve when CBD is stopped or when the amount used is reduced. This could include changes in alertness, most commonly experienced as somnolence (sleepiness), but this could also include insomnia; gastrointestinal distress, most commonly experienced as diarrhea and/or decreased appetite but could also include abdominal pain or upset stomach; and changes in mood, most commonly experienced as irritability and agitation.

    The FDA is actively working to learn more about the safety of CBD and CBD products, including the risks identified above and other topics, such as:

    • Cumulative Exposure: The cumulative exposure to CBD if people access it across a broad range of consumer products. For example, what happens if you eat food with CBD in it, use CBD-infused skin cream and take other CBD-based products on the same day? How much CBD is absorbed from your skin cream? What if you use these products daily for a week or a month?
    • Special Populations: The effects of CBD on other special populations (e.g., the elderly, children, adolescents, pregnant and lactating women).
    • CBD and Animals: The safety of CBD use in pets and other animals, including considerations of species, breed, or class and the safety of the resulting human food products (e.g., meat milk, or eggs) from food-producing species.

    Unproven medical claims, unsafe manufacturing practices

    Some CBD Products are Being Marketed with Unproven Medical Claims and Could be Produced with Unsafe Manufacturing Practices

    Unlike the FDA-approved CBD drug product, unapproved CBD products, which could include cosmetics, foods, products marketed as dietary supplements, and any other product (other than Epidiolex) making therapeutic claims, have not been subject to FDA evaluation regarding whether they are effective to treat a particular disease or have other effects that may be claimed. In addition, they have not been evaluated by the FDA to determine what the proper dosage is, how they could interact with other drugs or foods, or whether they have dangerous side effects or other safety concerns.

    Misleading, unproven, or false claims associated with CBD products may lead consumers to put off getting important medical care, such as proper diagnosis, treatment, and supportive care. For that reason, it’s important to talk to your doctor about the best way to treat diseases or conditions with available FDA-approved treatment options.

    In addition to safety risks and unproven claims, the quality of many CBD products may also be in question. The FDA is also concerned that a lack of appropriate processing controls and practices can put consumers at additional risks. For example, the agency has tested the chemical content of cannabinoid compounds in some of the products, and many were found to not contain the levels of CBD they claimed. We are also investigating reports of CBD potentially containing unsafe levels of contaminants (e.g., pesticides, heavy metals, THC).

    CBD products are also being marketed for pets and other animals. The FDA has not approved CBD for any use in animals and the concerns regarding CBD products with unproven medical claims and of unknown quality equally apply to CBD products marketed for animals. The FDA recommends pet owners talk with their veterinarians about appropriate treatment options for their pets.

    The FDA’s top priority is to protect the public health. This priority includes making sure consumers know about products that put their health and safety at greatest risk, such as those claiming to prevent, diagnose, treat, mitigate, or cure serious diseases. For example, the agency has warned companies to stop selling CBD products they claim are intended to prevent, diagnose, treat, mitigate, or cure serious diseases such as cancer, Alzheimer’s disease, psychiatric disorders and diabetes. While we have focused on these types of products, we will continue to monitor the marketplace for any product that poses a risk to public health, including those with dangerous contaminants, those marketed to vulnerable populations, and products that otherwise put the public health at risk.

    Evaluation of the regulatory frameworks

    The FDA is Continuing to Evaluate the Regulatory Frameworks for Products Containing Cannabis and Cannabis-Derived Compounds

    The FDA continues to believe the drug approval process represents the best way to ensure that safe and effective new medicines, including any drugs derived from cannabis, are available to patients in need of appropriate medical therapy. The agency is committed to supporting the development of new drugs, including cannabis and cannabis-derived drugs, through the investigational new drug and drug approval process.

    We are aware that there may be some products on the market that add CBD to a food or label CBD as a dietary supplement. Under federal law, it is illegal to market CBD this way.

    The FDA is evaluating the regulatory frameworks that apply to certain cannabis-derived products that are intended for non-drug uses, including whether and/or how the FDA might consider updating its regulations, as well as whether potential legislation might be appropriate. The information we have underscores the need for further study and high quality, scientific information about the safety and potential uses of CBD.

    The FDA is committed to setting sound, science-based policy. The FDA is raising these safety, marketing, and labeling concerns because we want you to know what we know. We encourage consumers to think carefully before exposing themselves, their family, or their pets, to any product, especially products like CBD, which may have potential risks, be of unknown quality, and have unproven benefits.

    Our Consumer Update includes a practical summary of what we know to date. As we learn more, our goal is to update you with the information you need to make informed choices about CBD products. Also, as the regulatory pathways are clarified we will take care to inform all stakeholders as quickly as possible.

    Cannabidiol in Anxiety and Sleep: A Large Case Series

    Cannabidiol (CBD) is one of many cannabinoid compounds found in cannabis. It does not appear to alter consciousness or trigger a “high.” A recent surge in scientific publications has found preclinical and clinical evidence documenting value for CBD in some neuropsychiatric disorders, including epilepsy, anxiety, and schizophrenia. Evidence points toward a calming effect for CBD in the central nervous system. Interest in CBD as a treatment of a wide range of disorders has exploded, yet few clinical studies of CBD exist in the psychiatric literature.

    Objective

    To determine whether CBD helps improve sleep and/or anxiety in a clinical population.

    Design

    A large retrospective case series at a psychiatric clinic involving clinical application of CBD for anxiety and sleep complaints as an adjunct to usual treatment. The retrospective chart review included monthly documentation of anxiety and sleep quality in 103 adult patients.

    Main Outcome Measures

    Sleep and anxiety scores, using validated instruments, at baseline and after CBD treatment.

    Results

    The final sample consisted of 72 adults presenting with primary concerns of anxiety (n = 47) or poor sleep (n = 25). Anxiety scores decreased within the first month in 57 patients (79.2%) and remained decreased during the study duration. Sleep scores improved within the first month in 48 patients (66.7%) but fluctuated over time. In this chart review, CBD was well tolerated in all but 3 patients.

    Conclusion

    Cannabidiol may hold benefit for anxiety-related disorders. Controlled clinical studies are needed.

    INTRODUCTION

    The Cannabis plant has been cultivated and used for its medicinal and industrial benefits dating back to ancient times. Cannabis sativa and Cannabis indica are the 2 main species.1 The Cannabis plant contains more than 80 different chemicals known as cannabinoids. The most abundant cannabinoid, tetrahydrocannabinol (THC), is well known for its psychoactive properties, whereas cannabidiol (CBD) is the second-most abundant and is nonpsychoactive. Different strains of the plant are grown containing varying amounts of THC and CBD. Hemp plants are grown for their fibers and high levels of CBD that can be extracted to make oil, but marijuana plants grown for recreational use have higher concentrations of THC compared with CBD.2 Industrial hemp must contain less than 0.3% THC to be considered legal, and it is from this plant that CBD oil is extracted.3

    Many different cultures have used the Cannabis plant to treat a plethora of ailments. Practitioners in ancient China targeted malaria, menstrual symptoms, gout, and constipation. During medieval times, cannabis was used for pain, epilepsy, nausea, and vomiting, and in Western medicine it was commonly used as an analgesic.4,5 In the US, physicians prescribed Cannabis sativa for a multitude of illnesses until restrictions were put in place in the 1930s and then finally stopped using it in 1970 when the federal government listed marijuana as a Schedule I substance, claiming it an illegal substance with no medical value. California was the first state to go against the federal ban and legalize medical marijuana in 1996.6 As of June 2018, 9 states and Washington, DC, have legalized recreational marijuana, and 30 states and Washington, DC, allow for use of medical marijuana.7 The purpose of the present study is to describe the effects of CBD on anxiety and sleep among patients in a clinic presenting with anxiety or sleep as a primary concern.

    CBD has demonstrated preliminary efficacy for a range of physical and mental health care problems. In the decade before 2012, there were only 9 published studies on the use of cannabinoids for medicinal treatment of pain; since then, 30 articles have been published on this topic, according to a PubMed search conducted in December 2017. Most notable was a study conducted at the University of California, San Diego’s Center for Medicinal Cannabis Research that showed cannabis cigarettes reduced pain by 34% to 40% compared with placebo (17% to 20% decrease in pain).8 In particular, CBD appears to hold benefits for a wide range of neurologic disorders, including decreasing major seizures. A recent large, well-controlled study of pediatric epilepsy documented a beneficial effect of CBD in reducing seizure frequency by more than 50%.9 In addition to endorphin release, the “runner’s high” experience after exercise has been shown to be induced in part by anandamide acting on CB1 receptors, eliciting anxiolytic effects on the body.10 The activity of CBD at 5-HT1A receptors may drive its neuroprotective, antidepressive, and anxiolytic benefits, although the mechanism of action by which CBD decreases anxiety is still unclear.11 CBD was shown to be helpful for decreasing anxiety through a simulated public speaking test at doses of 300 mg to 600 mg in single-dose studies.12–14 Other studies suggest lower doses of 10 mg/kg having a more anxiolytic effect than higher doses of 100 mg/kg in rats.15 A crossover study comparing CBD with nitrazepam found that high-dose CBD at 160 mg increased the duration of sleep.16 Another crossover study showed that plasma cortisol levels decreased more significantly when given oral CBD, 300 to 600 mg, but these patients experienced a sedative effect.17 The higher doses of CBD that studies suggest are therapeutic for anxiety, insomnia, and epilepsy may also increase mental sedation.16 Administration of CBD via different routes and long-term use of 10 mg/d to 400 mg/d did not create a toxic effect on patients. Doses up to 1500 mg/d have been well tolerated in the literature.18 Most of the research done has been in animal models and has shown potential benefit, but clinical data from randomized controlled experiments remain limited.

    Finally, the most notable benefit of cannabis as a form of treatment is safety. There have been no reports of lethal overdose with either of the cannabinoids and, outside of concerns over abuse, major complications are very limited.19 Current research indicates that cannabis has a low overall risk with short-term use, but more research is needed to clarify possible long-term risks and harms.

    Given the promising biochemical, physiologic, and preclinical data on CBD, a remarkable lack of randomized clinical trials and other formal clinical studies exist in the psychiatric arena. The present study describes a series of patients using CBD for treatment of anxiety or sleep disturbances in a clinical practice setting. Given the paucity of data in this area, clinical observations can be quite useful to advance the knowledge base and to offer questions for further investigation. This study aimed to determine whether CBD is helpful for improving sleep and/or anxiety in a clinical population. Given the novel nature of this treatment, our study also focused on tolerability and safety concerns. As a part of the evolving legal status of cannabis, our investigation also looked at patient acceptance.

    METHODS

    Design and Procedures

    A retrospective chart review was conducted of adult psychiatric patients treated with CBD for anxiety or sleep as an adjunct to treatment as usual at a large psychiatric outpatient clinic. Any current psychiatric patient with a diagnosis by a mental health professional (psychiatrist, psychiatric nurse practitioner, or physician assistant) of a sleep or anxiety disorder was considered. Diagnosis was made by clinical evaluation followed by baseline psychologic measures. These measures were repeated monthly. Comorbid psychiatric illnesses were not a basis for exclusion. Accordingly, other psychiatric medications were administered as per routine patient care. Selection for the case series was contingent on informed consent to be treated with CBD for 1 of these 2 disorders and at least 1 month of active treatment with CBD. Patients treated with CBD were provided with psychiatric care and medications as usual. Most patients continued to receive their psychiatric medications. The patient population mirrored the clinic population at large with the exception that it was younger.

    Nearly all patients were given CBD 25 mg/d in capsule form. If anxiety complaints predominated, the dosing was every morning, after breakfast. If sleep complaints predominated, the dosing was every evening, after dinner. A handful of patients were given CBD 50 mg/d or 75 mg/d. One patient with a trauma history and schizoaffective disorder received a CBD dosage that was gradually increased to 175 mg/d.

    Often CBD was employed as a method to avoid or to reduce psychiatric medications. The CBD selection and dosing reflected the individual practitioner’s clinical preference. Informed consent was obtained for each patient who was treated and considered for this study. Monthly visits included clinical evaluation and documentation of patients’ anxiety and sleep status using validated measures. CBD was added to care, dropped from care, or refused as per individual patient and practitioner preference. The Western Institutional Review Board, Puyallup, WA, approved this retrospective chart review.

    Setting and Sample

    Wholeness Center is a large mental health clinic in Fort Collins, CO, that focuses on integrative medicine and psychiatry. Practitioners from a range of disciplines (psychiatry, naturopathy, acupuncture, neurofeedback, yoga, etc) work together in a collaborative and cross-disciplinary environment. CBD had been widely incorporated into clinical care at Wholeness Center a few years before this study, on the basis of existing research and patient experience.

    The sampling frame consisted of 103 adult patients who were consecutively treated with CBD at our psychiatric outpatient clinic. Eighty-two (79.6%) of the 103 adult patients had a documented anxiety or sleep disorder diagnosis. Patients with sole or primary diagnoses of schizophrenia, posttraumatic stress disorder, and agitated depression were excluded. Ten patients were further excluded because they had only 1 documented visit, with no follow-up assessment. The final sample consisted of 72 adult patients presenting with primary concerns of anxiety (65.3%; n = 47) or poor sleep (34.7%; n = 25) and who had at least 1 follow-up visit after CBD was prescribed.

    Main Outcome Measures

    Sleep and anxiety were the targets of this descriptive report. Sleep concerns were tracked at monthly visits using the Pittsburg Sleep Quality Index. Anxiety levels were monitored at monthly visits using the Hamilton Anxiety Rating Scale. Both scales are nonproprietary. The Hamilton Anxiety Rating Scale is a widely used and validated anxiety measure with 14 individual questions. It was first used in 1959 and covers a wide range of anxiety-related concerns. The score ranges from 0 to 56. A score under 17 indicates mild anxiety, and a score above 25 indicates severe anxiety. The Pittsburg Sleep Quality Index is a self-report measure that assesses the quality of sleep during a 1-month period. It consists of 19 items that have been found to be reliable and valid in the assessment of a range of sleep-related problems. Each item is rated 0 to 3 and yields a total score from 0 to 21. A higher number indicates more sleep-related concerns. A score of 5 or greater indicates a “poor sleeper.”

    Side effects and tolerability of CBD treatment were assessed through spontaneous patient self-reports and were documented in case records. Any other spontaneous comments or complaints of patients were also documented in case records and included in this analysis.

    Data Analysis

    Deidentified patient data were evaluated using descriptive statistics and plotted graphically for visual analysis and interpretation of trends.

    RESULTS

    The average age for patients with anxiety was 34 years (range = 18–70 years) and age 36.5 years for patients with sleep disorders (range = 18–72 years). Most patients with an anxiety diagnosis were men (59.6%, 28/47), whereas more sleep-disordered patients were women (64.0%, 16/25). All 72 patients completed sleep and anxiety assessments at the onset of CBD treatment and at the first monthly follow-up. By the second monthly follow-up, 41 patients (56.9%) remained on CBD treatment and completed assessments; 27 patients (37.5%) remained on CBD treatment at the third monthly assessment.

    Table 1 provides means and standard deviations for sleep and anxiety scores at baseline and during the follow-up period for adults taking CBD. Figure 1 graphically displays the trend in anxiety and sleep scores over the study period. On average, anxiety and sleep improved for most patients, and these improvements were sustained over time. At the first monthly assessment after the start of CBD treatment, 79.2% (57/72) and 66.7% (48/72) of all patients experienced an improvement in anxiety and sleep, respectively; 15.3% (11/72) and 25.0% (18/72) experienced worsening symptoms in anxiety and sleep, respectively. Two months after the start of CBD treatment, 78.1% (32/41) and 56.1% (23/41) of patients reported improvement in anxiety and sleep, respectively, compared with the prior monthly visit; again, 19.5% (8/41) and 26.8% (11/41), respectively, reported worsening problems as compared with the prior month.

    These results demonstrated a more sustained response to anxiety than for sleep over time. Patient records displayed a larger decrease in anxiety scores than in sleep scores. The sleep scores demonstrated mild improvement. The anxiety scores decreased within the first month and then remained decreased during the study duration.

    CBD was well tolerated, with few patients reporting side effects. Two patients discontinued treatment within the first week because of fatigue. Three patients noted mild sedation initially that appeared to abate in the first few weeks. One patient with a developmental disorder (aged 21 years) had to be taken off the CBD regimen because of increased sexually inappropriate behavior. The CBD was held, and the behavior disappeared. The behavior reappeared on redosing 2 weeks later, and the CBD regimen was formally discontinued. The treating psychiatrist thought this was related to disinhibition because the patient’s anxiety responded dramatically. One patient noted dry eyes. Reasons for patients not following-up at later assessment points are largely unknown but are probably because of standard attrition experienced in usual clinical practice. There was no evidence to suggest patients discontinued care because of tolerability concerns. The attrition rates were similar in nature and size to those found in routinely scheduled visits in this clinic.

    The treatment with CBD was in general well accepted, as judged by the clinicians’ and patients’ responses. Four patients declined CBD treatment because of religious or ethical concerns about the relation to cannabis. Nearly all patients easily provided informed consent once the nature of the treatment was explained. Most patients appreciated the opportunity to try something natural and avoid further or initial psychiatric medication use.

    DISCUSSION

    In an outpatient psychiatric population, sleep scores displayed no sustained improvements during the 3-month study. Anxiety scores decreased fairly rapidly, and this decrease was sustained during the study period. These results are consistent with the existing preclinical and clinical data on CBD. CBD was well accepted and well tolerated in our patients. Side effects were minimal (mainly fatigue) and may be related to dosing.

    The doses used in this study (25 mg/d to 175 mg/d) were much lower than those reported in some of the clinical literature (300 mg/d to 600 mg/d)12–14,17 for 2 reasons. The first is that in our experience lower doses appear to elicit an adequate clinical response. Second, the current retail cost of CBD would make the use of 600 mg/d cost prohibitive.

    Study Limitations

    These results must be interpreted cautiously because this was a naturalistic study, all patients were receiving open-label treatment, and there was no comparison group. Concurrent psychiatric medications were employed as in routine clinical care. This is both a limitation and strength, as very few publications exist in this population. Other researchers have noted that the large societal notoriety about cannabis and medical marijuana probably contributes to a larger-than-normal placebo effect.20 Any study that explores efficacy in this therapy probably will struggle with a potentially inflated placebo effect that will make these determinations more difficult. Likewise, the clinical population in this case series is skewed younger than typical for our clinic, and future studies could explore the possible selection bias inherent in this treatment option. Most patients were also taking psychiatric medications and receiving other mental health services, such as counseling, which limits the ability to make any causal links to CBD treatment. Clinical attrition is evident in the dataset. The reason for this might be related to CBD ingestion or not, so the overall component remains unclear. Furthermore, patients at our clinic often express a desire to reduce or to avoid use of psychiatric medications, which may contribute to an enhanced placebo effect or additional bias. The length of clinical monitoring may help to decrease this concern. However, the clinical data in this analysis show a trend toward clinically significant relief of anxiety upon the start of CBD treatment.

    Legality of Cannabidiol

    The legality of CBD is not clear. Like the issues surrounding the legality of cannabis in general, CBD presents the clinician with a confusing state vs federal legal quandary, and this keeps the issue in question. CBD is legal in the 33 states that have legalized medical or recreational use of marijuana and in 17 other states that have legalized some form of CBD, according to the National Organization for the Reform of Marijuana Laws (NORML).21 But like marijuana, it is still not legal at the federal level. The federal government has announced that it is not focused on this compound in terms of enforcement or interdiction.22 However, CBD is interpreted by the Drug Enforcement Administration, Food and Drug Administration, and Congress to be a Schedule I substance, and therefore it is illegal in all 50 states.23 Pragmatically, CBD is widely available on the Internet, with sales expected to reach $1 billion by 2020. Pending federal legislation to redefine the legal status of cannabis would clarify this complex issue. Canada’s move to legalize cannabis in October 2018 further highlights the need for a speedy resolution to this question.24

    CONCLUSION

    Formal studies on efficacy and dose finding are much needed. Some urgency exists, given the explosion of lay interest in this topic and the rush to market these compounds. Current understanding of the physiology and neurologic pathways points to a benefit with anxiety-related issues. The results of our clinical report support the existing scientific evidence. In our study, we saw no evidence of a safety issue that would limit future studies. In this evaluation, CBD appears to be better tolerated than routine psychiatric medications. Furthermore, CBD displays promise as a tool for reducing anxiety in clinical populations, but given the open-label and nonrandomized nature of this large case series, all results must be interpreted very cautiously. Randomized and controlled trials are needed to provide definitive clinical guidance.

    Acknowledgments

    CV Sciences Inc, Las Vegas, NV, provided cannabidiol products for the study. CV Sciences was not involved in the data collection, data interpretation, preparation of the report, or decision to submit the report for publication. No other financial support was provided. The authors would like to express their deep appreciation to the staff and clinicians at Wholeness Center for their professionalism.

    Kathleen Louden, ELS, of Louden Health Communications provided editorial assistance.

    Footnotes

    Disclosure Statement

    Dr Shannon has published several professional books on integrative mental health. Dr Shannon is a Principal Investigator for a Phase 3 study of 3,4-methylenedioxy-methamphetamine (MDMA)-assisted psychotherapy for severe posttraumatic stress disorder and receives compensation for his clinical work from the Multidisciplinary Association for Psychedelic Studies, Santa Cruz, CA. The other authors have no conflicts of interests to disclose.

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