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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.

Pharmacist’s Guide to CBD Oil

ABSTRACT: Cannabidiol (CBD) is becoming more prevalent, and pharmacists must be knowledgeable about these products in order to counsel patients effectively. CBD laws and regulations are determined at the state level in the United States. Non–FDA-approved CBD products are not regulated and may contain harmful chemicals. Pharmacists must counsel patients on where and how to obtain products and to check the amount of CBD and delta-9-tetrahydrocannabinol in the product. CBD has numerous drug interactions that should be evaluated by a pharmacist. CBD is most promising for treatment-resistant seizures, and more research is necessary to evaluate its use for other indications. Sativex is currently being investigated in the U.S. for treatment of spasticity associated with multiple sclerosis and schizophrenia. In general, more studies of CBD are needed.

Cannabidiol (CBD) is gaining popularity across the United States. Pharmacists must be able to answer patients’ questions about CBD and make recommendations. This article will provide specific information about CBD, including laws, how to select a non–FDA-approved CBD product, indications for use, side effects and warnings, drug interactions, dosing and directions, pharmacokinetics, and the future of CBD oil. After reading this article, pharmacists should feel confident about counseling patients about CBD and recommending CBD products.

Laws Concerning CBD

CBD was first isolated from the Cannabis sativa plant in the 1930s. CBD is a nonpsychoactive part of the plant, whereas delta-9-tetrahydrocannabinol (THC) is the major psychoactive part of the plant. In the 1970s, researchers evaluated CBD as a pharmacologic agent. 1 Epidiolex, a 100 mg/mL oral solution with less than 0.01% THC, became the first FDA-approved CBD-containing drug in June 2018. 2 The drug is Schedule V and indicated only as an anticonvulsant for Lennox-Gastaut syndrome or Dravet syndrome in patients aged 2 years and older. 3

In December 2018, the Agriculture Improvement Act, which removed hemp from Drug Enforcement Administration (DEA) regulation as a controlled substance, was passed and signed into U.S. law. Hemp is defined as a cannabis plant that contains no more than 0.3% THC. (In contrast, marijuana has a higher THC.) Hemp is now regulated by the U.S. Department of Agriculture and is legal in all 50 states. Laws and restrictions regarding the selling of hemp products vary by state, making it questionable to travel with CBD products. 2

U.S. laws and regulations concerning CBD are determined at the state level. Currently, 33 states have legalized CBD use for medical purposes, and 10 states (Alaska, California, Colorado, Maine, Massachusetts, Michigan, Nevada, Oregon, Vermont, and Washington) and the District of Columbia have legalized marijuana for recreational use. In states such as New York, Minnesota, and Connecticut, pharmacists are required to dispense the products in authorized dispensaries. Marijuana-derived CBD oil is still considered illegal under the Controlled Substances Act in accordance with the DEA’s classification of marijuana as a Schedule I substance. 2

Selecting a Non–FDA-Approved CBD Product

Pharmacists must educate patients about how to select an appropriate non–FDA-approved CBD product. These products are not tested for safety, efficacy, or quality. 4 The main concerns in picking a non–FDA-approved CBD product are that it may contain harmful chemicals and may not accurately list the correct amounts of CBD and THC it contains. These products could contain harmful contaminants (e.g., pesticides, heavy metals) or have high levels of THC, which would result in a positive urine drug test. 5 The patient should be advised to obtain CBD products from a medical dispensary because these products are regulated. The patient should also consider ordering products from states where CBD is legal because more testing is done in those states. When selecting a product, the patient should check the label to see if it lists the amount of CBD in each dose. 5,6 The manufacturer should provide a Certificate of Analysis, which shows an independent laboratory’s assessment of the product’s potency and the presence of contaminants. 5 When assessing quality, the patient should look for the Hemp Authority seal, which means that the product is legal and the manufacturer is adhering to quality standards. 7

Indications for CBD

As consumer demand in the U.S. has risen, along with the number of dispensaries, the number of studies addressing the therapeutic effects of CBD has increased. The studies performed, however, are insufficient; large randomized, placebo-controlled trials need to be conducted. CBD seems most promising for treatment-resistant seizures. There is limited evidence concerning the use of CBD for psychotic symptoms in Parkinson’s disease and for anxiety related to public speaking. CBD has not been proven effective for pain, nausea, or depression. 4 THC, conversely, is thought to be effective for these conditions because it has a different mechanism of action. THC activates the CB1 and CB2 receptors in the brain, and CBD does not. As mentioned previously, CBD does not have psychotropic effects and THC does. These differences are believed to account for the different uses of CBD and THC. 7,8

Patients with early-onset epilepsy who are resistant to conventional therapy may benefit from CBD oil. A trial that investigated the effect of CBD on drop seizures of Lennox-Gastaut syndrome found that CBD 10 mg/kg/day or 20 mg/kg/day, when added to conventional therapy, led to a greater reduction of drop seizures compared with placebo. 9 The most common adverse reactions were somnolence, decreased appetite, and diarrhea. Specific adverse events from CBD included elevated liver aminotransferase concentrations. 9

Clinical findings on the use of CBD oil in Parkinson’s disease (PD) remain unclear. Past studies have evaluated CBD’s efficacy in minimizing nonmotor symptoms of PD, such as cognitive deficits, sleep disturbances, psychosis, depression, and anxiety. 10 The neuroprotective properties of CBD have been studied in animals with PD, with results indicating that CBD appears to reduce psychotic symptoms. 11 Although patients with PD have reported fewer sleep disturbances as well as improvements in quality of life, treatment in humans requires further investigation on a larger scale, with longer durations and more standardized dosing. 12 Most studies have used combinations of CBD and THC extracts, including nabilone, a synthetic CB1 receptor agonist. CBD dosages of 150 mg/day for 4 weeks and titrated by 140 mg/week were found to be safe and well tolerated and did not worsen motor function. 10

More evidence is needed to support the use of CBD for anxiety. Studies have found that CBD 300 mg may be effective for anxiety related to public speaking, and doses of 400 mg to 600 mg may help patients with social anxiety disorder and public speaking–related anxiety. Studies are inconclusive concerning the utility of CBD for anxiety. 13

Side Effects and Warnings

Studies have reported various properties and potential benefits of CBD. Some undesired side effects of CBD use are decreased appetite, dry mouth, diarrhea, dizziness, drowsiness, fatigue, lightheadedness, orthostatic hypotension, psychomotor slowing, sedation, somnolence, weight loss, and increased risk of liver injury with dosages of 20 mg/kg/day or the use of clobazam or valproate. Monitoring of liver enzymes, weight, and cognitive function may be warranted. CBD can pass through the placenta, so it is recommended that CBD be avoided during pregnancy and while breastfeeding. Because CBD oils may contain trace amounts of THC, operating heavy machinery and driving should be avoided when treatment is initiated. 1

Drug Interactions

CBD is metabolized in the liver, mainly by CYP2C19, CYP3A4, and UGT. This can lead to interactions with prescription drugs, OTC medications, and herbal supplements. 1,14

The inhibition of CYP2C19 by CBD can increase levels of carisoprodol, citalopram, clopidogrel, diazepam, phenytoin, proton pump inhibitors (PPIs), valproic acid, and warfarin. As a strong CYP3A4 inducer, CBD may lessen the efficacy of amlodipine, atorvastatin, buprenorphine, bupropion, diltiazem, eplerenone, fentanyl, loperamide, midazolam, paclitaxel, pioglitazone, sildenafil, solifenacin, tamsulosin, testosterone, topiramate, zolpidem, and other 3A4 substrates. 7

More serious effects may occur with concomitant use of central nervous system depressants, such as barbiturates, benzodiazepines, fentanyl, morphine, and propofol. These effects are the result of the synergistic effects of sedation and hypnotic effects at high doses. Increased sedative effects may also be seen with herbal supplements, including kava, melatonin, S-adenosylmethionine, and St. John’s wort. 13,14

Other interactions to be aware of are presented in TABLE 1.

Dosing and Directions

In unregulated dispensaries, CBD oil sold comes in a sublingual formulation known as CBD tincture and is generally available in 30-mL bottles with dropper caps. 15 A bottle costs approximately $20. The concentration of the tincture ranges from about 1,500 mg to 3,000 mg per bottle. If a drop equals 0.05 mL, one bottle contains approximately 600 drops of CBD oil. Drops are usually placed under the tongue, and the patient should let the oil absorb into the lining of the mouth, without swallowing, for 30 seconds to 1 minute. Capsules and gummies are also available. 15

Epidiolex Dosing

As noted earlier, Epidiolex (CBD) is an FDA-approved oral solution for treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome. The cost of Epidiolex is approximately $2,708 per month. It is supplied as 100 mL of solution containing CBD 100 mg/mL. For both indications, the initial starting dosage is 2.5 mg/kg orally twice daily for 1 week. The dosage may be titrated weekly in increments of 2.5 mg/kg twice daily to a maintenance dosage of 5 mg/kg twice daily. The maximum dosage is 10 mg/kg twice daily or 20 mg/kg/day. Gradual tapering is recommended when Epidiolex is discontinued. 3

Starting at a low dosage is recommended for elderly patients and patients with moderate or severe hepatic impairment. The dosage should be 1.25 mg/kg to 5 mg/kg twice daily or 0.5 mg/kg to 2 mg/kg twice daily, respectively. 3

Pharmacokinetics

CBD reaches its maximum concentration in 2.5 to 5 hours. High-calorie and high-fat meals can increase the maximum concentration of drug fivefold and the AUC fourfold. 14 Owing to the first-pass effect, CBD is poorly absorbed, with a bioavailability of 13% to 19%. Better bioavailability has been reported with inhaled CBD (11% to 45%). CBD is 94% protein bound; therefore, interactions may occur with other highly protein bound drugs or in patients who have abnormal albumin levels. The volume of distribution is 20,963 L to 42,849 L, meaning that the drug is largely distributed into the tissues. CBD is metabolized by the gut and primarily by the liver. Epidiolex has an active metabolite, 7-OH-CBD, and is a 2C19 and 3A4 substrate and inhibitor of 2C19, 1A2, UGT1A9, and UGT2B7. Its elimination half-life is 56 to 61 hours. CBD is excreted primarily in the feces and urine. 3

The Future of CBD

Sativex (nabiximols) is an oromucosal spray that contains CBD and THC in a 1:1 ratio. The active ingredients are absorbed sublingually or buccally. Sativex is currently under investigation in the U.S.; however, more than 25 countries worldwide have approved Sativex for the treatment of spasticity associated with multiple sclerosis. Sativex is also being researched for potential treatment of schizophrenia and other conditions. 16

The Pharmacist’s Role

Some pharmacists are hesitant to get involved with CBD. Prosecution by federal law could lead to severe consequences, including fines, imprisonment, or loss of DEA registration for pharmacies, ultimately stripping them of their ability to dispense controlled substances. If U.S. laws and regulations were more uniform across states, many of the concerns surrounding CBD would be eliminated. Until then, patients must use caution when selecting a product from an unregulated source because of the possibility of contamination and product misbranding. 17 Although more testing is needed, it is imperative for pharmacists to understand what to recommend to patients. Pharmacists should counsel patients on the risks and benefits of treatment. Patients who are are using CBD should be reminded to obtain the product from a reputable manufacturer. 17

Conclusion

Pharmacists need to keep abreast of current information on CBD in order to assist patients who are interested in using it. While most studies are inconclusive, there currently is enough information to effectively guide patients in choosing a treatment. CBD has the most evidence for treatment-resistant seizures; other indications need further study. Patients must be counseled to choose an appropriate product from a reputable source. CBD may be misbranded or contaminated with harmful chemicals. Pharmacists are uniquely positioned to assess the numerous potential drug interactions with CBD. New prescription CBD products are currently being investigated in the U.S.