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INTRODUCTION

Marijuana has been used medically for more than 5000 years, has been listed in the United States Pharmacopeia (USP) for almost 100 years, has been illegal in the U.S. for the past 80 years, and has been approved for medical use in 33 states and recreational use in 11 states for the past 2 decades. The changeable attitudes towards marijuana continue today as public sentiment for legalization grows.¹

The psychoactive properties of marijuana’s most widely known active component, Δ-9-tetrahydrocanninol (THC), is believed by many to contribute to marijuana’s numerous highly promising, but largely unproven, therapeutic actions,² but the drug’s abuse potential has been a source of reluctance on the part of regulators, politicians, and some health professionals to support its wider acceptance as a medicine. As a result, THC and marijuana remain classified as Schedule I drugs under the federal Controlled Substances Act (CSA; see below). ³ But what if a marijuana-derived product could retain the therapeutic potential of THC without the mind-altering properties and abuse potential? Among the many chemicals that could exert therapeutic activity in marijuana, growing evidence suggests cannabidiol (CBD) may fit this description.

CBD is reported to possess many potentially desirable pharmacologic characteristics, especially anti-seizure activity, and has been approved for medical use in some manner in all but 2 states, but not at the federal level. In October 2018, FDA approved the use of a specific formulation of CBD (Epidiolex) for treating rare but serious seizure disorders in children. As a consequence of the approval process, the Drug Enforcement Administration (U) has down-scheduled this individual product. Another event in 2018, passage of the Farm Bill, removed hemp from the list of controlled substances. Do these actions signal a reconsideration of marijuana-based substances as a medicine and a softening in their tight control?

This continuing education activity will briefly review CBD’s pharmacologic and clinical effects and discuss the fluid regulatory status of marijuana with an emphasis on CBD. Pharmacists and technicians should be prepared to expect more questions and issues as CBD becomes more readily available accompanied by a turbulent period of regulatory oversight.

CANNABIS

Cannabis is 1 of the oldest known cultivated plants.^4,5 It is believed that Cannabis sativa has been grown for at least 12,000 years, initially as a source of textile fiber and food.^4,5 The earliest use of cannabis as a medicine is believed to date to around 2700 BC. That use is attributed to the Chinese Emperor Shen Nung, considered by many as a father of Chinese Medicine. Cannabis appears in Chinese pharmacopeias believed to be written in the second century.^4,5 Ancient Egyptian papyri dating back to approximately 1800 BC also describe the use of cannabis for many indications including infections, pain, and vaginal contractions, and ancient Sumerian tablets from the same time period reference the use of a cannabis-like plant for convulsive disorders.^4,5

In Western Europe, hemp (low THC Cannabis) was used more commonly than the high THC products used in Asia.^6,7 English colonists brought hemp to the U.S. when they settled in Jamestown, Virginia in 1607 and it became an important commercial crop in the southern U.S.,^2,7 and recent Congressional efforts (see below) are designed to rekindle this phenomenon.

In the 19^th century, medical use of marijuana in Europe and the U.S. grew. The Irish physician William O′Shaughnessy returned from Asia and described reports about using hemp tincture as a remedy for rheumatism, cholera, tetanus, and, especially, infantile convulsions.⁷ Other Western physicians extolled the use of cannabis extracts and tinctures for migraine, tremors of Parkinson’s disease, and convulsive disorders,⁷ uses which researchers are reassessing in the 21^st century.⁸

Many cannabis-containing products were marketed in the U.S. in the 1900s, and manufacturers included well-known pharmaceutical companies including Parke-Davis, Eli Lilly, and Squibb. From 1850 to 1941, cannabis was listed in the U.S. Pharmacopeia (USP) and National Formulary (NF) and in European formularies.^7,9 Popular medical uses included treatment of inflammation, cough, cramps, insomnia, arthritis, gout, epilepsy, and even venereal disease.⁹ 

In the early 20^th century, medical use of cannabis products began to decline as western medicine turned to the use of isolated plant compounds and synthetic drugs instead of plant-derived extracts and tinctures.⁹ In the 1930’s, the regulation of marijuana increased culminating in passage of the Marijuana Tax Act in 1937 which ended the approved medical use of marijuana.¹⁰

Cannabis Chemicals

The Cannabis sativa plant contains numerous phytochemicals of commercial and medical interest; more than 540 phytochemicals have been described in hemp, representing 23 different chemical classes.^8,11 The most widely known are the cannabinoids, a group of 21- or 22- carbon (some being carboxylated) terpenophenolic compounds that are predominantly found in cannabis.¹² The phytochemicals are primarily found in the flowers and leaves of the plant with very low concentrations in the seeds, stems, and stalk.¹² More than 100 cannabinoids have been identified.^11,13 The most abundant phytocannabinoids are THC and CBD along with cannabinolic acid.¹² THC and CBD have attracted the greatest interest for their potential therapeutic activity and markedly differ in their effects on the central nervous system (CNS). THC produces strong intoxicating effects on the CNS. CBD is commonly referred to as “non-psychoactive” in the lay literature but at least 1 prominent researcher has recommended that it should be preferably labeled as “non-intoxicating”, since non-psychoactive would be inconsistent with its purported benefit in anxiety, schizophrenia, opiate dependence, and depression.¹⁴ Non-intoxicating would instead indicate a low risk of abuse liability.

In addition to cannabinoids, marijuana contains many other potentially noteworthy compounds that may contribute to its pharmacologic and clinical properties. The largest group of compounds are terpenes, with more than 100 molecules identified in cannabis.^11,12 Terpenes are responsible for the distinctive odor and flavor of different cannabis strains.¹² Phenolic compounds are also found In cannabis, including nearly 20 identified flavonoids.¹²

The cannabinoids are believed to be the primary source of marijuana’s medicinal effects. However, researchers have proposed complex, unique, and synergistic interactions among the different constituents—termed the entourage effect—although the exact nature of these interactions are unknown.^11,12 Some possible mechanisms include¹²

• modifications in bioavailability and binding to target proteins
• metabolic activation and deactivation, and
• synergistic effects at different points of the same signaling cascade.

Pharmacists should be aware that these interactions raise the potential that different clinical responses may result when comparing whole plant extracts and powders with individual components.

CBD THERAPEUTICS AND PHARMACOKINETICS

Pharmacists and technicians will increasingly face questions about CBD’s uses as its presence continues to grow. CBD has been touted for a very wide range of therapeutic indications, largely with little reliable evidence. A full description of CBD’s uses is beyond the scope of this manuscript; the interested reader may consult some recent reviews for more information. ^2,13,15-17 Included among CBD’s possible indications are seizure disorders, pain, anxiety, neurodegenerative diseases, inflammatory disorders, autoimmune disorders, schizophrenia, opiate abuse and dependence, and cancer.^2,13 Particular attention has been given to the treatment of seizure disorders with the approval of a form of CBD by FDA (see below). Marijuana’s efficacy as a treatment for seizures has been recognized in Western medicine since at least the 19^th century.¹⁸

Generally, cannabinoids are most efficiently absorbed when smoked.^19,20 Sublingual absorption is modest and oral dosing results in relatively low tissue levels and a longer onset of action. THC and other cannabinoids are metabolized by the cytochrome P450 isozymes primarily in the liver and to a lesser extent in the small intestine and brain.^19,20,21 CBD is metabolized primarily by isozymes CYP3A4, CYP2C19 and to a lesser extent by CYP1A1, CYP1A2, CYP2C9, and CYP2D6.^19,20 Pharmacists should be on the lookout for potential pharmacodynamic and pharmacokinetic drug interactions.^19,20,21 A general rule of thumb for pharmacists would be to monitor for common CYP2C9, CYP2C19, and CYP3A4 inhibitors and substrates since cannabinoids could affect clinical activity.

Pharmacology

Cannabinoids act on receptors termed cannabinoid (CB) receptors, members of the large G-protein coupled receptor family, in the brain and other organs. At least 2 cannabinoid receptors have been identified, CB1 which is found predominately in the nervous system and CB2 which is located mostly in cells and organs mediating immune functions and other peripheral responses.^2,22

Phyto-cannabinoids as well as newer synthetic drugs bind to the cannabinoid receptors with varying affinity and efficacy.² Endogenous substances (termed endocannabinoids) such as anandamide and 2-arachidonylglycerol exist and are the natural ligands for these receptors.² The endocannabinoids are released from cells in a stimulus-dependent manner by cleavage of membrane lipid precursors and likely function as neurotransmitters or neuromodulators.²³ After release, they are rapidly inactivated by cellular uptake by a carrier-mediated mechanism and enzymatic hydrolysis by fatty acid amide hydrolase (FAAH).^2,23,24 Some cannabis phytochemicals and newer synthetic drugs may also target the uptake and breakdown of endocannabinoids, rather than acting directly on the receptor.²

The endocannabinoid system regulates a large number of bodily functions including emotional behavior, anxiety and depression, neurologic activity, nociception, the immune system, cardiovascular function, reproductive organ function, gastrointestinal (GI) motility, metabolism, and it may be involved in neuroprotection.²⁴ This widespread array of potential therapeutic targets has stimulated great interest in cannabinoid drugs for treating neurological, neurodegenerative and psychological disorders, pain, immune and inflammatory diseases, GI and metabolic disorders, and even drug addiction and cancer.

CBD has a very low affinity for CB1 and CB2 receptors, estimated in the low micromolar range.^2,25 Unlike the partial agonist THC, CBD may act as a negative allosteric modulator of the CB receptors at low concentrations and antagonize THC’s effects,^2,15 accounting for its lack of euphoric properties. It may also positively modulate endocannabinoid function.²

Like all cannabinoids, CBD has both cannabinoid and non-cannabinoid activity which contribute to its unique effects. CBD affects a variety of different neuron systems (see Table 1). It is likely that the non-cannabinoid mechanisms are responsible for the anti-seizure and other therapeutic effects of CBD.²⁷

LEGAL STATUS OF MARIJUANA

The Marijuana Tax Act passed in 1937 restricted the sale and possession of marijuana. The Act was modeled after the earlier Harrison Act (enacted in 1914) which taxed and regulated opioids. At the time the Marijuana Tax Act was passed, all the states had already legislated regulations against trafficking in marijuana.¹⁰ The Act required persons producing, importing, selling, or otherwise dealing with the drug to pay an occupational tax and to register with the Internal Revenue Service. Transfer of marijuana required a written order form and payment of a transfer tax.^10,28 Possession without a written order was considered presumptive evidence of noncompliance and subjected the violator to a fine of up to $2000 and/or imprisonment for up to 5 years.²⁹ The high taxes also made marijuana very expensive to buy legally.

Congress approved the Act with little debate (although the American Medical Association objected to it).^10,28 Passage has been attributed to many factors including hysteria about the drug’s alleged contribution to moral decay, anti-immigrant and racial bias, and pressure from the Federal Bureau of Narcotics.^28,29

The Controlled Substances Act (CSA) was enacted in 1970 and combined all previous controlled substances laws into a single statute¹⁰ and remains the law regulating abused substances today. The Drug Enforcement Agency was formed in 1973 to enforce the CSA. With the passage of the CSA in 1970, marijuana was temporarily placed in Schedule I where it continues to reside more than 4 decades later.^28,29 A drug is classified as C-I if the DEA concludes that it does not have a recognized medical use and cannot be safely “prescribed” by a health care practitioner, nor possessed in any amount.³⁰

A report by the National Commission on Marijuana and Drug Abuse in 1972 (known as the Shafer Commission) was intended to provide Congress and then-President Richard Nixon with an “independent, nonpartisan appraisal of the nature of marihuana and the consequences of its use” and concluded that “(t)he existing social and legal policy is out of proportion to the individual and social harm engendered by the use of the drug”³¹ and essentially recommended decriminalization. The recommendations were ignored by the President and Congress and the drug remains a C-I drug today.²⁹ Numerous unsuccessful attempts have been undertaken over the past 4 decades to change its scheduling.

LEGAL STATUS OF CBD

Undoubtedly, all pharmacists and technicians have received emails or seen web sites promoting CBD’s alleged healing powers and offering products for sale and wondered are sales of CBD legal? Judging from its ubiquitous presence on the Internet and the prolific displays in convenience stores across the U.S., one could easily conclude that it is a fully legal OTC product. However, this is a misconception, at least at present. The appropriate answer is “complex,” “confusing,” and “evolving.”

Until recently, the answer to this question was a simple “no.” DEA has classified CBD as a Schedule I drug, despite its low abuse potential. Marijuana and THC are specifically listed in Schedule 1. CBD and other cannabinoids are incorporated by reference as a “derivative,” component, or resin preparation.³²

DEA’s full definition of marijuana is: “The term ’marihuana’ means all parts of the plant Cannabis sativa L., whether growing or not; the seeds thereof; the resin extracted from any part of such plant; and every compound, manufacture, salt, derivative, mixture, or preparation of such plant, its seeds or resin. Such term does not include the mature stalks of such plant, fiber produced from such stalks, oil or cake made from the seeds of such plant, any other compound, manufacture, salt, derivative, mixture, or preparation of such mature stalks (except the resin extracted therefrom), fiber, oil, or cake, or the sterilized seed of such plant which is incapable of germination.”³³ These designations reflect the relative abundance of cannabinoids in different plant parts.

The CSA does not define nor exclude “hemp” from the definition of marijuana,³² (but see below for recent changes). The CSA however does exempt certain parts of the Cannabis plant which produce very low concentrations of cannabinoids (stalk, fiber and sterilized seeds).³²

While the DEA continues to view CBD as a Schedule I drug, 3 events have clouded this interpretation and will be discussed further. These are: (1) state medical marijuana laws; (2) FDA approval of a single prescription CBD product; and (3) the 2014 and 2018 Farm Bills.

State Laws

Thirty-three states had approved use of marijuana for medical purposes as of December 2018.³⁴ In all of these states, marijuana and cannabinoid products may be purchased, and in some cases grown, for medical use under state law. These laws differ from state-to-state and are still in conflict with Federal law (i.e., the CSA). In addition, 17 states specifically recognize the use of CBD, most commonly for seizure disorders in children.³⁴ Note that some states have separate marijuana and a CBD programs; currently there are only 2 outliers (Idaho, Nebraska) that have not approved CBD for medical use.³⁴ [In addition, (as of August 2019) 11 states have approved the non-medical (or recreational ) use of marijuana by adults.]

Ordinarily, these state laws regulating CBD place limits on the cannabinoid content, typically a limit on the minimum CBD content (commonly 10% or more) and a limit on the maximum THC content (commonly 0.3% although it is higher in some states). Some states (e.g., Kentucky) do not explicitly authorize CBD use, but instead remove CBD from the definition of “marijuana.”³⁴

The characteristics of these laws vary among the states and may have more specific requirements.³⁴ For example, Texas allows the use of cannabis oil that is no more than 0.5% THC and at least 10% CBD for intractable epilepsy if approved by 2 certified specialists. South Dakota removed CBD from the definition of marijuana and placed it in Schedule IV but specified that the CBD must be a product approved by FDA. Kansas permits the use of CBD products containing up to 5% THC to treat debilitating medical conditions if the patient is being treated by a licensed physician. Texas permits physicians to “prescribe” CBD which is against Federal law. Usually, states permit physicians to “recommend” marijuana products, and the Texas law defines “prescribe” as entry into a compassionate use registry³⁴ rather than prescribing as it is typically understood.

Cannabidiol (CBD) (Epidiolex): One form of CBD is unquestionably legal. In October of 2018, FDA approved an oral cannabidiol solution (Epidiolex) for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (Severe Myoclonic Epilepsy of Infancy) in patients 2 years of age and older.³⁵ LGS and Dravet are rare and severe pediatric seizure disorders characterized by frequent and prolonged seizures, developmental delays, and possible increased mortality risk. There are few if any alternatives approved for their treatment.^36,37 Epidiolex is a purified extract of CBD from plants and is available as a liquid formulation of known purity with only trace THC amounts.

The most common adverse events reported from clinical trials are sleepiness, sedation, and lethargy; fatigue, malaise and weakness; insomnia and poor-quality sleep; infections; elevated liver enzymes; decreased appetite; diarrhea; and rash.³⁸ The most serious risks include suicidal ideation and attempts to commit suicide, which are not uncommon with anti-seizure drugs; agitation; new or worsening depression; aggression and panic attacks; and liver injury. Available from specialty pharmacies, Epidiolex must be dispensed with a patient Medication Guide describing the drug’s uses and risks . ³⁸

As with most anti-seizure medications, the exact mechanism by which CBD produces its anticonvulsant effect is complex and not completely understood.²⁷ The activity is likely not mediated through the cannabinoid receptors nor voltage-gated sodium channels. CBD modulates a number of systems which may contribute to its anti-convulsant effect, including GABA, intracellular calcium modulation via TRPV, VDA and GPR55, adenosine, glycine, and serotonin.

Significantly, FDA granted a “Fast Track” designation (“Providing for more frequent meetings and communications with FDA to discuss the drug’s development plan and ensure collection of appropriate data needed to support drug approval, including such things as the design of the proposed clinical trials and use of biomarkers.”) to Epidiolex in 2016 as well as other marijuana derived products, indicating a willingness to “aid the development of drugs derived from marijuana.”³⁵ For an interesting description of the path that led to the approval of Epidiolex see reference 18.

FDA’s approval of Epidiolex necessitated a revision in CBD’s regulatory classification. The CSA defines a Schedule I drug as one with no currently accepted medical use and a high potential for abuse.³⁰ Clearly, FDA approval of Epidolex for treating pediatric seizure disorders conflicts with this definition.

Since the U.S. is a signatory to the “Single Convention,” a 1961 international treaty designed to control trafficking in controlled substances, U.S. Department of Justice was required to place appropriate controls on CBD as a substance listed in the treaty.³³ Previously, all forms of cannabidiol were C-I under the CSA. DEA acknowledged that “Epidiolex no longer meets the criteria for placement in schedule I of the CSA” since it received FDA approval and can no longer be considered to be without medical use.³³ DEA could have placed the drug in Schedule II, but elected, with advice from FDA(the DEA is required by statute to seek advice from FDA when scheduling), to designate it as a Schedule V drug instead.³³ While DEA placed Epidiolex in Schedule V, pharmacists need to be aware of possible different classifications at the state level.

However, the DEA added a very important detail: “In taking this action, DEA decided to limit the rescheduling of CBD to a specific formulation of an FDA-approved drug product and re-emphasized that except for this specific formulation, CBD remains a Schedule I substance.”³³

OTHER MARIJUANA-RELATED PRODUCTS

Although Epidiolex is the first plant-based marijuana extract to be approved by FDA, it is not the first marijuana-related product to receive approval.³⁹

FDA approved dronabinol (Marinol), a synthetic form of delta-9-THC, in 1985 and it is available as an oral dosage form.³⁹ It is approved for the relief of nausea and vomiting associated with cancer chemotherapy and to assist with the loss of appetite in patients infected with human immunodefiency virus (HIV). The active ingredient is dissolved in sesame oil to discourage potential abusers from smoking it. It is currently classified as a Schedule III drug. DEA claims that dronabinol is superior to smoked marijuana since it is a pure drug and does not deliver the variety of chemicals that would be found in marijuana smoke, including potential carcinogens.³⁹ Syndros (C-II), approved in 2016, is a liquified form of dronabinol approved for reducing the nausea associated with cancer chemotherapy and the loss of weight associated with AIDS-related anorexia.³⁹

Nabilone (Cesamet) is a synthetic, substituted cannabinoid originally developed by Eli Lilly and approved by FDA (C-II) in 2006.³⁹ Nabilone is used to treat nausea and vomiting from cancer chemotherapy.

Sativex (ingredients to be known as nabiximols) was approved in Canada in 2005 for treatment of neuropathic pain in patients with MS and as an adjunct for pain in cancer patients.⁴⁰ Sativex is derived from an extract of specifically bred cannabis varieties and is a 1:1 standardized mixture of delta-9-THC and cannabidiol, plus other plant-derived substances. It differs from other products in that it is an oral/mucosal spray that allows more flexible dosing. The drug has been approved in 25 countries but has not received approval yet in the U.S., although it has completed Phase III clinical trials in the U.S.⁴⁰

FARM ACTS

The largest impacts on CBD regulation have come from the 2014 and especially 2018 Farm bills. The 2014 bill³² authorized State Agricultural Departments and institutions of higher education to grow industrial hemp for research purposes and agricultural pilot programs. Some interpreted the bill as providing authority to license independent, private hemp cultivators who would be permitted to grow hemp, extract the CBD, and sell the resulting products on the retail market, but this interpretation was contradicted by several federal agencies.³²

The 2018 bill is much more far reaching. The goal of the Farm Bill (Agricultural Improvement Act of 2018⁴¹) is to encourage the agriculturally-produced hemp to be used in commercial products. Effective January 1, 2019, the Farm Bill removes “hemp” as defined in the bill from the CSA definition of “marijuana,” and expressly excludes THC from “hemp” from scheduling and control under the CSA (i.e., any THC extracted from the legally defined hemp, but not THC from legally defined marijuana).^41,42 The 2018 bill conforms to the definition of “industrial hemp” under the Agricultural Act of 2014. It defines “hemp” as “the plant Cannabis sativa L. and any part of that plant, including the seeds thereof and all derivatives, extracts, cannabinoids, isomers, acids, salts, and salts of isomers, whether growing or not, with a delta-9 tetrahydrocannabinol [“THC”] concentration of not more than 0.3% on a dry weight basis.”⁴¹

Consequently, any cannabis plant or plant part with a THC concentration of 0.3% or less is no longer a controlled substance, and any product derived from that plant or parts of that plant is also not controlled.⁴² However, a cannabis plant or any part of the plant containing a THC concentration above 0.3% on a dry weight basis is not “hemp” as legally defined and remains a schedule I controlled substance unless otherwise excluded from the CSA definition of marijuana.⁴²

This general framework carries over to CBD and other cannabinoids as well. Cannabinoids derived from plants or parts that fall under the definition of “hemp” (less than 0.3% THC) are no longer controlled while those derived from plants not defined as “hemp” (i.e., where the THC content exceeds 0.3%) are still Schedule I substances.^32,42 To put it simply, if CBD is derived from a plant producing less than 0.3% THC, it is not an illegal substance.

It is important for pharmacists and technicians to appreciate that even if hemp-derived CBD is no longer classified as a controlled substance, there are still many regulatory hurdles to overcome before CBD can unequivocally be considered legal.. CBD promoted as a medicine is under the jurisdiction of FDA. FDA has been consistently unfavorable towards CBD products that may be advertised as having health benefits. It has also been concerned with their quality control.

FDA has noted that the Farm Bill “explicitly preserved FDA’s authority to regulate products containing cannabis or cannabis-derived compounds under the FD&C Act” (Food Drug and Cosmetic Act). FDA’s position is that “even if a CBD product meets the definition of "hemp" under the 2018 Farm Bill … it still must comply with all other applicable laws, including the FD&C Act.”⁴³

Furthermore, FDA stated that this “allows FDA to continue enforcing the law to protect patients and the public while also providing potential regulatory pathways for products containing cannabis and cannabis-derived compounds”⁴³ FDA will treat any cannabis-derived substance as they do any other FDA-regulated products, meaning that they will be subject to the same authority and requirements as any other FDA-regulated product. This includes the requirement that if a cannabis product is marketed with a claim for a therapeutic benefit (intended for use in the diagnosis, cure, mitigation, treatment, or prevention of diseases; the statutory definition of a drug) it must be approved by FDA for its intended use before it may be introduced into interstate commerce.⁴⁴ In other words, a CBD preparation may not be C-I, but if it is promoted with a therapeutic claim, it is considered a drug and cannot be sold without FDA approval. FDA has approved Epidiolex, after it navigated the normal FDA drug approval process.

FDA’s position is that “unapproved products with unsubstantiated therapeutic claims” raise significant public health concerns and place patients at risk. The “deceptive marketing of unproven treatments” may expose patients to drugs that are not safe or effective and preclude patients from accessing more appropriate therapies to treat serious or life-threatening diseases.^43.44 FDA has also cited the risk of liver injury and other adverse effects which were revealed during the clinical trial with Epidiolex.⁴⁵

FDA has also taken the position that CBD (or THC) products may not be sold as dietary supplements, even if derived from hemp.^43,46 CBD and THC are active ingredients in drugs which have already been the subject of a previously approved IND and more recently an FDA-approved drug (i.e., Epidiolex). The Federal Food, Drug, and Cosmetic Act prohibits the introduction of previously approved drug ingredients into the food supply or marketing as a dietary supplement. FDA has indicated that this prohibition applies across the board to food products (including animal food) that contain an active drug ingredient.^43.46

FDA also restated that hulled hemp seeds, hemp seed protein, and hemp seed oil may be marketed in human food having completed a review of their safety and determining that they comply with the requirements to be designated as “Generally Recognized as Safe,” so long as they do not make therapeutic claims.⁴³

FDA has noted that they “remain concerned about the proliferation and illegal marketing of unapproved CBD- containing products with unproven medical claims.”³³ FDA has taken action against several companies which claimed that CBD products could be used to treat or cure serious diseases.

FDA warned companies for illegal marketing of CBD products as drugs and has threatened violators with seizures of products and injunctions for failure to comply. For example, FDA criticized 1 large manufacturer⁴⁷ for statements found on its website and social media accounts promoting, in FDA’s view, unapproved drugs in violation of the FDCA. Some statements which caught FDA’s attention include the use of CBD “for chronic pain” or “arthritic pain,” “CBD is known for its anti-anxiety properties that can promote relaxation and stress relief,” “effective in treating Parkinson’s Disease and Alzheimer’s Disease,” “CBD has been demonstrated to have properties that counteract the growth or spread of cancer,” and claims for therapeutic benefits in dogs.

Recently, the Federal Trade Commission (FTC)⁴⁸ also sent letters to 3 CBD manufacturers that market various formulations of CBD, warning them that it is “illegal to advertise that a product can prevent, treat, or cure human disease without competent and reliable scientific evidence to support such claims.” The products claimed to treat degenerative diseases, cancer, autism, diabetes, and asthma among others. The FTC letter urged the companies to review their claims to ensure they are supported by competent, reliable scientific evidence or face legal action.

Another problem that has occurred with the selling of unregulated CBD products has been quality control and mislabeling of products.⁴⁶ One study examining the CBD content of products purchased from Internet sources found that only 30% were accurately labeled (90%-110% of labeled value); 27% were below the concentration on the label and 43% contained higher concentrations than the labeled amount.⁴⁹ Oil-based products tended to be the most accurate. THC was detected in 21% of the analyzed products. A Florida study found similar instances of under- and over-labeling and inconsistent results in batches from the same manufacturer.⁵⁰ FDA has also found products with less than 1% of the labeled amounts of CBD and some contained THC that was not reported on the label; FDA has sent warnings to some companies.^18,46,49 Where possible, patients should be directed to preparations with a certified analysis and evidence of good manufacturing and quality control. Patients may have difficulty obtaining a certificate of analysis (CoA). Many states already require a CoA for products produced for medical use, and in those states, the medical marijuana program will have the CoAs. Hopefully the FDA will issue some guidelines on quality control. Not all manufacturers are scrupulous and pharmacists may be able to act as gatekeepers and direct patients to products from reputable manufacturers. 

Further complicating the legal status of CBD is the patchwork of non-uniform state laws. Some states (e.g., Colorado) have a very permissive attitude on CBD sales and use.⁵¹ Missouri even permits CBD to be served with alcoholic products.⁵¹ (It should be noted that the Treasury Department’s Alcohol and Tobacco Tax and Trade Bureau does not currently approve the use of CBD in alcoholic beverages.⁵²) Many other governmental bodies are restricting the use of CBD in food products.

In 2019, New York became the first city to enforce a ban on CBD products sold in restaurants, stating that CBD has not shown to be safe as a food additive. Effective July 1, violators of the ban are subject to a $650 fine, and authorities are confiscating CBD-infused cookies.⁵³ Maine, where recreational marijuana is legal, has also ordered businesses to remove CBD-infused edible products from stores, and in Los Angeles use of CBD in prepared food and drink can lead to loss of points in Health Department inspections.⁵³ Part of the problem worrying local officials is that there are no labeling standards of dosing guidelines. Consumers can’t know how much CBD they are eating and in some cases if their snack contains CBD or not.⁵³ (This is different from CBD containing “edibles” sold in registered medical marijuana dispensaries.)

In Ohio, CBD oil is only available through state-licensed dispensaries.⁵³ In parts of Texas, Ohio and Nebraska, people are being arrested for selling CBD-containing products, regardless of the THC content. In some states, truck drivers transporting CBD products from other states are being charged with drug trafficking.⁵¹

SUMMARY AND CONCLUDING COMMENTS

Is CBD a miracle drug, a fad, or the latest overhyped health craze? The answer is elusive but the effect on pharmacy practice will be significant.

CBD can seemingly be purchased anywhere: dispensaries, grocery and convenience stores, smoke shops, sex shops, massage parlors, restaurants, natural food outlets, and the Internet among others. Several large drug chains have also announced that they will begin selling CBD as well. Reportedly, manufacturers such as Ben and Jerry’s, Oreo, Coca-Cola, Coors, and tobacco and water companies are also preparing to enter the marketplace.^50,54

This expanded availability and acceptance has implications for pharmacists and technicians. While standing in line waiting to pick up a prescription at my local chain pharmacy, an elderly gentleman in front of me was asking the clerk where he could find CBD (which he called CDB) for his wife who was bedridden with arthritis. This is a situation ripe with obvious opportunities for a discussion. Pharmacists should expect to have experiences similar to mine, if they haven’t already.

For pharmacists and patients, many issues arise.⁵⁵ All the factors normally considered when taking a supplement should be addressed. Patients taking CBD may view it as a natural product sold without restrictions and conclude that it is completely risk-free. They need to be reminded that CBD, while relatively safe, is a drug and, as such, has adverse effects, including potential liver damage. Dosing issues and modes of delivery also need to be considered. Patients taking CBD need to be made aware of potential pharmacokinetic and pharmacodynamic interactions with other medications. They may not voluntarily include it in medication lists or discussions with health care providers and may even substitute CBD for more traditional medications they have been prescribed.

Patients also need to be alerted to the potential for issues of quality control. CBD preparations are available from many manufacturers. They are not subject to the same quality standards and factory inspections as FDA-regulated prescription and OTC products.³⁷ As noted above, the purity and potency of CBD preparations may vary among producers and even among batches from the same producer. CBD may be contaminated with variable concentrations of THC or with pesticides, heavy metals, toxins, and even drugs (e.g., sildenafil and related products).⁵⁰

It should be quite apparent that pharmacists need to stay abreast of changes in CBD’s regulatory status at both the federal and state level. It is a paradox that the approved form of CBD is tightly regulated, while the unapproved forms are more loosely controlled. One physician/researcher has commented that “some of these companies have zero science behind what they’re doing” and added that “the quality control and regulatory oversight for CBD is not much beyond what it is for Snickers bars.”⁵⁴

Many questions remain unanswered including the safety and efficacy of cannabis products, whether single ingredient or mixtures are superior, standards for quality and purity, and whether there will be an economic incentive for companies to submit to FDA approval process.¹¹

FDA is considering potential regulatory pathways that would facilitate the legal marketing of CBD products while protecting the public health.⁵⁶ To this end, FDA conducted public hearings commencing on May 31, 2019 and accepted comments until July 2. FDA has indicated that some significant unanswered questions include⁵⁶:

• How much CBD is safe to consume in a day? How does it vary depending on what form it’s taken?
• Are there drug interactions that need to be monitored?
• What are the impacts to special populations, like children, the elderly, and pregnant or lactating women?
• What are the risks of long-term exposure?

Certainly, these are questions of special interest to pharmacists.

These deliberations may offer some clarity on CBD’s legal status, but FDA has indicated that it may take some time for any proposals to be announced. In the meantime, pharmacists and technicians will have to cope with the uncertainty and need to stay abreast of the latest developments.

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