Legal and Regulatory Issues Governing Cannabis and Cannabis-Derived Products in the United States
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This chapter provides an in-depth discussion of the legal and regulatory frameworks surrounding cannabis in the United States, including federal law—as dictated by the Controlled Substances Act (CSA) and governed by various federal agencies like the FDA and DEA—as well as state law—as regulated by each state’s laws and regulations authorizing medical and/or adult use cannabis. First, the chapter discusses the definition and classification of cannabis under the CSA, including scheduling under the CSA as well as the process for and potentiality of removing cannabis from Schedule I. Then, it describes the activities relating to industrial hemp that are permitted under the 2014 and 2018 Farm Bill. Next, the chapter addresses state-level cannabis laws. The chapter also analyzes the question of whether state cannabis laws are invalidated and superseded by federal law. Moreover, this section examines the factors underlying the extent of the Department of Justice’s enforcement actions relating to state-authorized cannabis activities. The chapter then turns to CBD (cannabidiol) in particular, discussing CBD’s legal status under the CSA; the FDA’s role in regulating and approving CBD products for medical purposes; and the steps required to take an investigational CBD product through that approval process. The chapter concludes by contending that, while cannabis has had a long and twisting history, and although cannabis-derived products face daunting obstacles to achieving FDA approval as well as rescheduling under both federal and state law, the recent success of one product (Epidiolex ® ) should inspire other manufacturers to develop additional cannabis-derived products through the FDA process.
Keywords: cannabidiol, cannabis, schedule I, rescheduling, controlled substances, PREEMPT, farm bill, HEMP
A Brief History
Over the centuries, cannabis has been used for religious, industrial, therapeutic, and other purposes (Crowther et al., 2010; Potter, 2014). However, in the past 150 years, prominent social and political controversies involving cannabis have emerged around the world. Cannabis extracts and tinctures were widely prescribed in Europe and North America by physicians for a variety of medical conditions from the mid-1800s through the first few decades of the 20th century (Russo, 2004). However, in the United States in the early 1900s, smoked cannabis (then known by the slang term marijuana or marihuana) became associated with certain maligned ethnic and racial minorities, and many states prohibited its use (Bonnie and Whitebread, 1999; Schlosser, 1994). This ultimately resulted in the enactment of the federal Marihuana Tax Act of 1937 (Musto, 1972), which imposed taxes and other administrative burdens on both the medical and non-medical uses of cannabis.
In the United States in the years following the Act, and as the physician’s armamentarium expanded with new medication options, interest in the therapeutic effects of cannabis and cannabinoids waned until cannabis use increased in the 1960s, coincident, and indeed entwined, with antiwar and other social protest movements (Crowther et al., 2010). Young people around the United States experimented with cannabis and other drugs, and a number of them discovered that cannabis was helpful for certain medical conditions (Joy et al., 1999). In addition, research in Israel by Dr. Raphael Mechoulam demonstrated that tetrahydrocannabinol (THC) was the primary psychoactive component of the cannabis plant (Mechoulam et al., 1970).
These developments had several consequences. On the one hand, societal alarm over this increased use of cannabis reignited concerns about its deleterious effects and prompted research into its psychoactive and potentially addictive properties (The Medicalization of Cannabis, 2009). On the other, the concept of “medical marijuana” was born, and renewed interest in the medical properties of cannabis began slowly to emerge (Randall and O’Leary, 1998).
However, persistent negative attitudes about cannabis in certain countries, including the United States, culminated in the promulgation of the Single Convention on Narcotic Drugs (1961) (Mead, 2014). Under the Single Convention, cannabis and cannabis resin were placed in the most restrictive category 1 , and signatory parties were effectively required (subject to some flexibility for a party’s “good faith” determinations) to prohibit their manufacture, distribution, sale, etc. The United States was a party to the Single Convention, and, after the Marihuana Tax Act was struck down by the United States Supreme court in Leary v. United States [395 U.S. 6 (1969)], Congress enacted the Controlled Substances Act of 1970 (CSA), which consolidated all previous federal laws governing the handling of narcotics, stimulants, depressants, hallucinogens, etc. Title II of the Comprehensive Drug Abuse Prevention and Control Act of 1970, Pub. L. 91–513, 84 Stat. 1236.
The Classification of Marijuana Under the Controlled Substances Act
The CSA was enacted in part to implement the United State’s obligations under the Single Convention. 21 USC 801(7). Its purposes were twofold: (1) it recognized that many controlled substances have a useful and legitimate medical purpose and are necessary to maintain the health and welfare of the public and (2) illegal importation, manufacture, distribution, and possession and improper use of such substances have a “substantial and detrimental effect” on public health and welfare. 21 USC 801 (1), (2). Under the CSA, substances are categorized into five schedules, depending on their therapeutic benefit and their potential to result in abuse, diversion, dependency, and addiction (Yeh, 2012). Schedule I is the most restrictive. Marijuana and tetrahydrocannabinols (THCs) are classified as hallucinogens in Schedule I, along with mescaline, peyote, psilocybin, MDMA, and LSD. 21 CFR 1308.11(d). Opium and virtually all opioids, coca leaves and cocaine, amphetamines, and a number of other substances are in Schedule II. 21 CFR 1308.12.
As a general rule, all substances, and the products containing or derived from such substances, are classified in the same schedule. However, there is a limited precedent for differential scheduling. For example, THC and its isomers are in Schedule I, but FDA-approved formulations of a THC isomer (delta-9) are in lower schedules. Compare 21 CFR section 1308.11(27) with 21 CFR section 1308.13(g)(1).
Under the CSA, marijuana is defined as:
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 there from), fiber, oil, or cake, or the sterilized seed of such plant which is incapable of germination. 21 USC 802(16) (emphasis added).
As the definition indicates, marijuana includes its compounds and derivatives, as well as synthetic versions thereof. Therefore, the more than 100 (Brenneisen, 2007) cannabinoids found in the cannabis plant are also classified in Schedule I by operation of definition, and not as a result of a scientific analysis of their abuse potential. Only THC is separately and specifically listed in the CSA as a Schedule I substance.
Substances in Schedule I have no currently accepted medical use in the United States and a high potential for abuse. Schedule II substances similarly have a high potential for abuse, but they do have a currently accepted medical use. Schedules III–V substances have an accepted medical use and less (relative to each preceding schedule) abuse potential. 21 USC 812(b). Neither the CSA nor the Code of Federal Regulations (its implementing regulations) defines the concept of accepted medical use, but the United States Drug Enforcement Administration (DEA) has developed criteria that must be met in order to establish accepted medical use:
The federal courts have thus far upheld DEA’s use of these criteria (Alliance for Cannabis Therapeutics vs. DEA, 1994). The existence of anecdotal reports of medical use (no matter how many) and the existence of state “medical marijuana” laws (no matter how many) are not sufficient to meet these criteria. However, FDA approval of a product as a prescription medication is sufficient (albeit not necessary) to demonstrate its accepted medical use. Grinspoon v. DEA, 828 F.2d 881(1st Cir. 1987).
Schedule I substances can be dispensed only in federally authorized research programs [Investigational New Drug (IND) authorized by FDA and DEA Schedule I research registration]. Schedule I status entails restrictive requirements for security, recordkeeping, storage, transport, and other activities. Schedule I substances cannot be imported into, or exported from, the United States, even for personal medical use, and even if the patient is enrolled in a clinical trial.
Escaping From Schedule I
Rescheduling under federal law is generally conducted through an administrative process (Drug Enforcement Administration [DEA], 2010, 2016; Hoffman et al., 2018). Under this process, the FDA initially conducts a full assessment of the substance’s abuse potential, called an “eight-factor analysis” (8FA), because there are eight statutory factors that bear on abuse potential. 21 USC §811(c). DEA is bound by FDA’s medical and scientific determinations, but may consider additional data, such as the extent of abuse and diversion. DEA publishes a proposed rule in the Federal Register, which gives the public notice, and an opportunity to comment, object, or request an administrative law judge hearing. The DEA responds to the public’s comments and objections and then, if no persuasive request for a hearing has been made, publishes a Final Rule rescheduling the product or substance. If a hearing request is made and granted, this can delay the final rescheduling action for 2 years or more. 21 USC §811(j).
This rescheduling process can be initiated by DEA, by the Department of Health and Human Services/FDA as part of the new drug approval process, or by an interested person. 21 CFR 1308.44. Of course, Congress has the power to enact a law to schedule, reschedule, or entirely deschedule a substance. In doing so, Congress need not examine abuse of potential data or the results of an 8FA.
The Status of Hemp Under Federal Law
Cannabis is an umbrella term, and numerous varieties—with different cannabinoid ratios or other content, such as terpene profiles—exist in nature or as a result of breeding. Informally, it could be said that cannabis varieties may be classified as either “drug-type” or as hemp. In Europe, there is a robust and well-established hemp industry (Vantreese, 2002; Commission of the European Communities, 2004). However, “hemp” is not actually defined under European law. Rather, certain pedigreed seed varieties may be cultivated, which have been bred historically for their fiber or seed, and which have a very low percentage of THC (not more than 0.2% by dry wieght) (Commission of the European Communities, 1989).
In the United States, the CSA does not define hemp. As indicated above, it defines marijuana, but certain parts of the marijuana/cannabis plant—stalk/fiber, sterilized seeds, and preparations thereof—are exempted from that definition. In other words, sterilized seeds and cannabis fiber (separated from the plant) are not marijuana and may be imported or otherwise used in commerce. However, there is an exception to the exemption: if “resin” is extracted from any part of the plant (including the excepted parts), that resin is still marijuana. Since all cannabinoids are located in resinous trichomes 2 located on the inflorescences and upper leaves of the plant, in theory all extracts 3 of cannabinoids from cannabis are defined as marijuana (Potter, 2014).
However, in December 2018, the 2018 “Farm Bill” [The Agriculture Improvement Act of 2018, Pub. L. 115-334 amending 21 USC §§802(16), 812(c)] was signed into law 4 . The 2018 Farm Bill defines hemp as the cannabis plant, or any part thereof, including its extracts and cannabinoids, having a THC concentration of not more than 0.3% on a dry weight basis. “Hemp,” as so defined, is removed from the definition of marijuana under the CSA and is no longer a controlled substance under federal law. The bill does not authorize interference with interstate commerce (although it does not affirmatively authorize such commerce); presumably, such commerce is lawful, at least between states that allow such commerce.
The 2018 Farm Bill requires hemp cultivation to be licensed and regulated pursuant to “state plans” promulgated by a state, which must contain, among other things, provisions for THC testing. If a state does not wish to issue a plan, the United States Department of Agriculture is authorized to do so. The USDA has authority to issue regulations and guidances, but the law explicitly preserves the existing jurisdiction of the FDA.
The Development of State Cannabis Laws
In 1996, during the AIDS crisis in California, the voters approved an initiative to decriminalize certain cannabis-related activities by specific categories of persons. Proposition 215, the Compassionate Use Act of 1996, allowed a qualifying patient and his/her caregiver to cultivate and possess cannabis for medical purposes. CA Health and Safety Code, Article 2 (Cannabis), §11362.5. Oregon and Washington followed shortly thereafter. Medical use was limited in the years that immediately followed, since many patients and caregivers were not able to cultivate their own cannabis, and many physicians were unwilling to provide the “recommendations” necessary to qualify the patient for legal protection. However, beginning in about 2004, retail dispensaries began to appear, as well as larger numbers of physicians who were willing to provide recommendations. In 2012, Colorado became the first state to approve, by initiative, the recreational or “adult use” of cannabis. Amendment 64 (Use and Regulation of Marijuana); Article 18, §16 of the Colorado Constitution.
Fast forward to today. Thirty-three states and the District of Columbia have enacted laws allowing the use of cannabis for therapeutic purposes (NCSL). Eleven states and the District of Columbia permit recreational or “adult use” of cannabis (ProCon, 2018b). Seventeen additional states only permit products that are high in cannabidiol (CBD) and low in THC 5 .
The provisions of medical cannabis laws vary significantly by states (ProCon, 2018a). In most states with medical use laws, physicians, and sometimes other types of health care providers, must recommend that the patient use cannabis or advise that the patient might benefit from such use (because cannabis is a Schedule I substance, physicians cannot prescribe it). Physicians are often exempt from professional and other liability that is premised solely on the fact that they issued such a recommendation or advice. However, physicians can still be liable for issuing recommendations in a manner that falls outside the standard of care (Medical Board of California, 2018) or that aids and abets a violation of federal law (Conant v. Walters, 2002). The medical use laws generally include a list of “qualifying” medical conditions, with which a patient must be diagnosed. These lists may be derived from published scientific studies or case reports, from testimony of individuals or advocacy groups, or other sources. While they vary, these lists often contain conditions like epilepsy and cancer.
Similar to the medical laws, adult use laws vary by state as well (ProCon, 2018a,b). Apart from Vermont and D.C., which do not allow commercial sales—the other ten states allowing commercial activity established regulatory systems that allow for possession and personal cultivation as well as commercial cultivation and sales. All recreational states require individuals possessing or cultivating cannabis to be 21 or over. The quantities of cannabis an individual can possess range by state (generally around an ounce or two), and so do the number of plants one can have (generally up to six). Across the recreational states, medical marijuana laws are, overall, more permissive regarding individual possession and cultivation, as they often permit patients to purchase and cultivate larger quantities as well as access more potent products and enjoy a lower tax rate.
In terms of commercial systems, the 10 states that permit it feature differing regulatory systems, but generally allow for state-licensed businesses to engage in commercial production, distribution, and sales of cannabis and cannabis products. Additionally, different states have different methods of regulating their medical and recreational systems. California, for instance, features a singular, harmonized regulatory framework—the Medicinal and Adult-Use Cannabis Regulation and Safety Act (SB 94) (CA Business and Professions Code [BPC], 2016) [need the full statutory citation in the code]—but divides medical and recreational into separate market streams. Somewhat differently, Colorado has separate constitutional amendments for each system, while also dividing medical and adult use into separate market streams.
Last, the quality control (including testing) and label requirements for both medical and recreational are quite uneven and may be non-existent in some states (Klieger et al., 2017). Some states—like California (recreational and medical)—require laboratory testing of cannabis and cannabis products to make sure that they meet quality and safety standards, while other states—such as Arizona (just medical)—do not have state-mandated testing (Milley, 2018). Since, for prescription medications, these requirements are generally determined by FDA, it may be challenging for states to develop such requirements and to find adequate resources to enforce them. However, a number of international standard-setting organizations, such as ASTM and AOAC, are engaged in developing standards for the testing, quality control, etc., of cannabis and cannabis products. Several cannabis quality control guidance documents are available from the American Herbal Products Association and from American for Safe Access, and these are being employed by a number of states to establish quality standards.
State and Federal Law Conflict?
Under the Supremacy Clause of the United States Constitution, federal law preempts or supersedes state laws that are inconsistent, or in conflict, with federal law in certain ways (Todd, 2012; Mead, 2014). However, there is a specific provision in the federal CSA that states that state drug laws are only preempted if there is an “affirmative conflict” with the CSA. Indeed, state law is the primary enforcement authority for drug-related offenses.
The state cannabis laws described above—particularly the early laws—can be said merely to decriminalize certain cannabis-related activities under state criminal laws. They do not require private individuals or businesses to conduct cannabis-related activities. If an individual/business wishes to avoid a violation of the federal CSA, that person or entity can simply avoid cannabis-related activities altogether. As a result, most state and federal courts that have considered this issue have found that these state laws are not invalidated by the CSA (Brilmayer, 2017; Guenthner, 2017).
Individuals and entities who choose to engage in cannabis-related activities would violate the federal CSA. However, the federal government generally does not prosecute individuals who possess (or share) small amounts of cannabis, instead focusing their enforcement priorities on larger cannabis commercial entities or drug trafficking organizations, particularly those involved in interstate transport or foreign importation (see section “Reasons for Limited Federal Enforcement of the Controlled Substances Act”).
Reasons for Limited Federal Enforcement of the Controlled Substances Act
Under the Obama administration, the Department of Justice (DOJ) took a less aggressive stance toward cannabis-related activities than it had under previous administrations. In 2013, DOJ issued a memorandum intended to guide United States attorneys in the exercise of enforcement discretion (Cole, 2013). The memo essentially stated that it was not a DOJ priority to take enforcement action against persons or entities involved in cannabis activities if those activities were lawful under state cannabis laws (whether medical or recreational). However, DOJ would consider enforcement action if those activities negatively impacted eight specific federal interests 6 . This memo also applied to the cultivation and manufacture of hemp outside of the authority of the Farm Bill (US Attorney Marshall Letter to Rep. Blumenauer, 2018).
Former Attorney General Jeff Sessions rescinded this memo (Sessions, 2018). However, no notable enforcement action has been taken. This may be a result of other factors. An amendment to the Consolidated Appropriations Act of 2018 prohibits the DOJ from using any funds to prevent states from implementing their medical (not adult use) marijuana laws and prevents DOJ/DEA and other federal agencies from using funds to prevent hemp-related activities that are lawful under the Farm Bill. 115th Congress, Pub. L. No. 115-141. This Appropriations Act is valid through September 2018 but is likely to be extended by one or more Continuing Resolutions. In addition, there are Members of Congress who, for various reasons, would likely oppose significant DOJ/DEA enforcement against state-authorized cannabis activities. Finally, the country is facing a prescription drug abuse crisis—largely involving opioids—and DOJ/DEA have other enforcement priorities. These factors may explain the lack of aggressive enforcement of the CSA against cannabis-related activities. The current Attorney General William Barr has indicated that he will follow the spirit of the Cole memo (Angell, 2019).
The Emergence of Cannabidiol
Public interest in cannabidiol (CBD) has exploded in the past few years. CBD can be purchased online, in cannabis dispensaries, and, increasingly, in grocery and natural foods stores, and other retail outlets. How did CBD emerge into the public eye?
Unlike THC, CBD does not have euphoriant properties (Pertwee, 2004). Although the identity and structure of CBD have been known for decades, limited research had been conducted to explore its therapeutic potential. Preclinical studies suggested a wide range of potential applications (Pertwee, 2004), but clinical studies in several indications, including epilepsy, had produced uneven and unconvincing results. In 2003, researchers at the National Institutes of Health (NIH) secured a patent claiming a method of treating diseases caused by oxidative stress, such as neurodegenerative or ischemic disease, by the administration of non-psychoactive cannabinoids (Hampson et al., 2003).
In 2007, the laboratory of Professor Ben Whalley conducted a series of preclinical studies that robustly demonstrated that CBD had anti-seizure properties (Jones et al., 2010, 2012). Once disseminated at scientific conferences and published, these studies caused a great deal of interest in the United States. A small non-profit, Project CBD, was formed, which publicized the results (Project CBD, 2018). Cannabis growers, who had inadvertently discarded CBD-rich varieties in the effort to breed varieties rich in THC, took note. A newly established analytical testing laboratory examined plant samples and determined that some CBD-rich varieties still remained, and a few extracts were made. The Discovery Channel in 2011 filmed one parent administering a CBD extract to his son who had a catastrophic form of epilepsy (Discovery Channel, “Weed war chronicles”), and word traveled in the community of parents with children with similarly intractable epilepsies.
A California family, learning about CBD from their nurse, tried several types or products with their son who had an intractable epilepsy. Unfortunately, he had had a very uneven response to those products. Upon reading the recent preclinical research, they realized that GW Pharmaceuticals, the sponsor of the research, had a standardized form of CBD, and they undertook to contact the company to request access to the product (Vogelstein, 2015).
A Colorado family, who had seen the Discovery Channel segment on YouTube, also searched for CBD for their daughter who also had a devastating type of epilepsy. They located a local source of CBD, which significantly reduced their daughter’s seizures (Maa and Figi, 2014). Her dramatic response was captured in August 2013 in a documentary entitled “Weed,” produced by Dr. Sanjay Gupta of CNN. The program unleashed a tidal wave of interest among families with similarly afflicted children. Families moved to Colorado in search of access to the product that came to be known as “Charlotte’s Web”; states passed laws permitting possession and sometimes manufacture of high-CBD, low-THC products, and within a few years, a wide variety of CBD products were available, purporting to treat a multitude of medical conditions.
Sources of Cannabidiol
As indicated above, over 100 cannabinoids are found in the plant. The cannabis plant (including hemp varieties) produces cannabinoids in glandular trichomes, which resemble little golf balls, often on a small stalk. These trichomes are concentrated in the inflorescences and, to a more limited extent, in the upper leaves (Potter, 2013, 2014). The stalk and seeds have essentially no cannabinoids (Wassem et al., 2018) 7 . Hence, although hemp seed oil offers a good source of Omega 3 and 6 fatty acids, it contains effectively no cannabinoids.
THC and CBD are the most prevalent cannabinoids. Beginning in the 1970s, cannabis growers began to breed cannabis varieties that expressed ever-increasing concentrations of THC, since most people believed that all of the effects of cannabis—both psychoactive and therapeutic—lay in the THC. When CBD was “rediscovered” in the United States, as described above, the “CBD-rich” varieties that were available to be extracted were “drug-type” varieties, rather than classic hemp varieties. Subsequently, in the wake of the 2014 Farm Bill, hemp varieties became the primary source of CBD.
Classic hemp varieties, i.e., those originating in Europe, are not efficient sources of CBD. The original varieties contained 0.5–4.0% CBD by dry weight (European Hemp Industries Association, 2018), although, as a result of breeding, newer varieties may contain as much as 7–8% CBD (Lee, 2016). Even at that higher level, a large quantity of hemp must be cultivated in order to extract a meaningful amount of CBD. Since hemp is a “phytoremediator,” i.e., it absorbs heavy metals from the soil (Cascardi, 2018), it is essential that the conditions of cultivation be carefully controlled.
Cannabidiol may still be derived from drug-type varieties of cannabis and then purified to remove some or all of the THC. Alternatively, CBD may be manufactured via a synthetic process. However, in that case, it is important that the manufacturer select an appropriate synthetic process that produces the same CBD isomer as that produced by the plant. A different isomer could have a very different therapeutic and/or toxicological profile (Hanus et al., 2005).
Legal Status of Cannabidiol Under the Controlled Substances Act
As indicated above, CBD is classified in Schedule I of the CSA because it is considered a compound or derivative of cannabis/marijuana. 21 USC 802. However, as indicated above, the 2018 Farm Bill has descheduled hemp as it is defined under that law. Therefore, commercial activity with hemp (including its extracts and cannabinoids) is now lawful. A DEA registration is no longer required to cultivate hemp or to conduct research with hemp. However, if clinical research, i.e., involving human subjects, is involved, an investigational new drug exemption (IND) must still be opened with FDA, and the investigational product must be manufactured in a facility that complies with good manufacturing practice (GMP) requirements.
Cannabidiol and the FDA
The Food, Drug and Cosmetic Act (FDCA) prohibits any product from being sold in interstate commerce if it is intended to be used in the treatment, mitigation, diagnosis, or cure of a disease or a disorder—unless that product has been approved by FDA as a prescription medication. 21 USC section 321(g)(1). In determining “intended use,” FDA will examine a wide variety of sources—labels, advertisements, websites, social media—to ascertain a product’s intended use (FDA, 2018b). In 2015–2018, FDA has sent warning letters to manufacturers of CBD products (sold online and in other retail outlets), informing them that their products were misbranded and hence illegal as a result of medical claims (FDA, Warning Letters and Test Results for Cannabidiol-Related Products; FDA, 2018b).
In addition, in 2015 and 2016, FDA tested many of the CBD products and determined that more than 90% of them contained much less CBD than the labeled amount, some had no CBD at all, and some had greater amounts of THC (US FDA, Warning Letters and Test Results for Cannabidiol-Related Products). This quality-control concern has been affirmed by a study of CBD products sold in dispensaries (Bonn-Miller et al., 2017).
In 2018, FDA issued the first CBD Warning Letter that relied in part on deficiencies in Good Manufacturing Practices (for pharmaceutical products, not for dietary supplements) (FDA, 2018b). FDA also targeted, for the first time, topical products for which medical claims were being made.
Furthermore, beginning in 2016, FDA stated in its Warning Letters that CBD cannot be sold as an ingredient in a food or dietary supplement. FDA relied on sections 21 USC 201(ff)(3)(B)(ii) and 21 USC 321(ff)(3)(B)(ii) of the FDCA, which provide that, if a substance is being studied in substantial clinical trials [i.e., as part of a new drug application (NDA) process], a different manufacturer cannot attempt to do a “shortcut” around the lengthy and expensive NDA process by incorporating the substance into a food or dietary supplement. The only exception to this prohibition is for a substance that was already being marketed as a food or dietary supplement before the clinical trials began. The substance must have been overtly marketed, that is, not merely present as an unlabeled impurity. An argument can also be made that the marketing must not have been violative of a federal law like the CSA.
FDA considered the evidence and determined that CBD had been studied initially under an investigational new drug exemption (IND) in 2006 and again in 2014, and that CBD had not been marketed as a food or dietary supplement before that time (FDA, 2018a). Immediately after the 2018 Farm Bill was signed into law, Then-FDA Commissioner Gottlieb issued a statement emphasizing that, while hemp and cannabinoids derived from it are no longer scheduled substances, CBD and THC cannot lawfully be sold in food or in dietary supplements. The Commissioner did note that, under the above provisions, FDA has authority to issue a regulation allowing a substance to be marketed in food or dietary supplements and that the agency would hold a public meeting to take input from stakeholders on whether it should pursue such a process (Gottlieb, 2018, That meeting took place on May 31, 2019).
A number of manufacturers are apparently attempting to avoid FDA’s statement concerning section 321(ff)(3)(B)(ii) by marketing their products as “hemp extracts” (Mister, 2019). However, many of these products still provide the CBD content on the label, website, or certificate of analysis (COA). It remains to be seen whether FDA will determine that these products are violative of the FDCA.
How Can a Cannabis-Derived Product Go Through the FDA Approval Process?
Media reports on cannabis often include the contention that, since it is a Schedule I substance, cannabis (and its derivatives) cannot be researched in the United States, much less move successfully through the rigors of the FDA approval process. This statement is, for the most part, false.
Schedule I status certainly increases the level of complexity for any research study. For example, all researchers—whether preclinical or clinical—must obtain Schedule I research registrations. 21 CFR section 1301.18. By contrast, researchers who have DEA Practitioner registrations in Schedules II–V (which most physicians would have) may conduct research in Schedules II–V as a “coincident activity” to their Practitioner registrations and do not need to secure any additional registrations or licenses. 21 CFR section 1301.13. Since cannabis is a controlled substance, a researcher cannot obtain cannabis from dispensaries or from patients in order to test the therapeutic effects of varieties that patients may be using. The cannabis must come from a cultivator who is registered with DEA as a Schedule I manufacturer. In other words, a researcher with a Schedule I research registration must obtain cannabis from another DEA registrant.
In addition to the DEA Schedule I registration, researchers must generally also obtain Schedule I research licenses from the state-controlled drugs authority. The application process for these Schedule I registrations/licenses, including research site inspections, generally do not take place concurrently, but rather are sequential, with the state usually going first.
Furthermore, the University of Mississippi is currently the only federally lawful United States source of research-grade cannabis. The United States “single source” position has historically been based on its perceived obligations under the Single Convention on Narcotic Drugs, 1961. Under the Single Convention, if a signatory country affirmatively authorizes the domestic cultivation of cannabis, the cannabis stocks must be exclusively owned and controlled by a national agency. The United States national agency is the National Institute on Drug Abuse (NIDA) part of NIH. NIDA contracts with the University of Mississippi to produce research-grade cannabis. Even academic researchers who are conducting investigator-initiated trials (IITs) must secure research cannabis through NIDA.
This single-source requirement is a particular problem for manufacturers since those who wish to conduct United States research on a cannabis-derived product that will lead to an NDA (including Phase 1–3 research and the necessary body of preclinical safety and toxicology studies) must be able to cultivate a large quantity of a specific variety of cannabis under the same consistently controlled conditions. The investigational material used in the Phase 3 studies must be the same as that used in the toxicology studies, or bridging studies must be conducted. The Phase 3 material must be the same as that used in the commercialized product (FDA, 2016). The typical annual outdoor yield from the University of Mississippi 12 acre “farm” is 500 kg of plant material (University of Mississippi, 2018. Marijuana Research). By way of comparison, in order to produce enough material for Phase 3 clinical trials and commercialization of its CBD product Epidiolex ® , GW Pharmaceuticals cultivates a high-CBD expressing chemovar in a 45-acre glasshouse.
Drug enforcement administration announced in 2016 that it would register additional cultivators to produce research-grade cannabis, as well as cannabis to be used in the manufacture of FDA-approved, cannabis-derived products, but thus far, no registrations have been issued (Drug Enforcement Administration [DEA], 2016).
However, this national agency requirement applies only to cannabis that is cultivated within that country’s border. Investigational cannabis products may be manufactured outside the country and, in the United States, imported under an IND for purposes of research. Two cannabis-derived products (Sativex ® and Epidiolex ® ) 8 were researched in the United States in this manner, and United States researchers have recently been permitted by DEA to import cannabis capsules from Canada for purposes of research (Johnston).
Of course, any cannabis-derived investigational product must demonstrate quality, safety, and efficacy in order to achieve FDA approval. Putting aside the hurdles described above, a complex cannabis product, i.e., comprised of major and minor cannabinoids, as well as terpenes and flavonoids, faces significant standardization and quality control issues. It is important to build quality into the botanical starting materials. Outdoor cultivation can introduce the risk of contamination from adjacent pesticide and synthetic fertilizer use, bird droppings, etc. In order to ensure consistency in cannabis content, plants should be propagated by clones or some similar process, rather than seeds. The growth medium should be devoid of heavy metals. Ideally, no pesticides or fungicides would be used. Specifications for the botanical raw material (BRM), botanical drug substance (BDS) (the processed or extracted material), and the finished botanical drug product (BDP) must be set and agreed upon by the FDA. Since cannabinoids are present almost exclusively in the acid form (THCA and CBDA) in the plant, the material must undergo decarboxylation to remove a carboxyl group, if the neutral form (THC and CBD) is desired. This decarboxylation step can be challenging to conduct properly—without leaving incompletely decarboxylated material or degrading the cannabinoids—particularly on a large commercial scale (Wang et al., 2016). If the dosage form requires extraction of the cannabinoids, it is important that the extraction process does not result in a BDS with residual dangerous solvents. If the finished product will be composed of a single cannabinoid, a complex crystallization process is required (Wang et al., 2016). Stability studies on both the BDS and BDP must support the expiration date, usually 2–3 years (Ng, 2015).
FDA has issued a guidance to assist sponsors in developing botanically complex prescription medications (US Dep’t of Health and Human Services and US FDA, 2016). While this guidance allows some flexibility in the early stages of research, by the time the product reaches Phase 3, the requirements are essentially the same as for any product composed of a single synthetic molecule. If the product is composed solely of a purified cannabinoid, it is subject to all such requirements.
As with any investigational product, the FDA will inspect all manufacturing sites and processes to ensure that a Quality Management System is in place and that all current good manufacturing practices (cGMP) for pharmaceutical products are being followed (Ng, 2015). This inspection is very extensive and can take 5–7 business days.
Both a BDP and a purified cannabinoid product must undergo a full range of preclinical and clinical safety and efficacy testing, including drug/drug and food/drug interaction studies. In addition, because a cannabinoid product is derived from the cannabis plant and is therefore generally considered to be active in the central nervous system, the product must go through a battery of tests to determine the extent (or not) of its abuse potential: receptor binding and preclinical studies, as well as a special human abuse liability study.
As part of the NDA, the manufacturer/sponsor will analyze these studies and make a rescheduling proposal to FDA. FDA will assess these data and, shortly before or after the product is approved, FDA will make a rescheduling recommendation to DEA. Under the recent Improving Regulatory Transparency in New Medical Therapies Act, 21 USC section 811(j), DEA has 90 days within which to evaluate all data and make a rescheduling decision, which is published in the Federal Register in the form of an interim final rule (IFR). Under the IFR, the product may be sold.
Drug enforcement administration will subsequently conduct the full administrative rescheduling process described earlier, with public notice and opportunity to comment, object, or request an administrative law judge hearing. It is unlikely (but possible), at the completion of this process, that DEA would modify the schedule, since all material scientific evidence would presumably already have been considered by the agencies in the initial rescheduling action. However, if an international treaty requires a specific scheduling placement, DEA will issue a Final Rule (not an IFR or a Proposed Rule) rescheduling the product 9 .
If this were any other NCE product (usually comprised of a single synthetic molecule), the IFR would effectively mark the end of the process, and the product would be available to be marketed in all the states. Having been scheduled for the first time by the DEA during the NDA process, the NCE product is not yet scheduled under state law. Since it is unscheduled, it may be prescribed by physicians and dispensed by pharmacies.
However, this is not true for cannabis-derived products. Virtually all of the states have adopted their own version of the federal CSA (Uniform Controlled Substances Act, 1994), and marijuana and its derivatives are in Schedule I under most of those state laws (even in states with adult use and/or medical access laws). Few states automatically change the schedule of a product or substance merely because the DEA has done so. The rest either require that rescheduling be conducted by a state agency through a sometimes-prolonged administrative process or by legislation enacted by the state legislature, and many legislative sessions occur only during the first 4 months of the year or every other year (National Council of State Legislatures [NCSL], 2018). This can delay patient access to a new cannabis-derived product by as much as 2 years in many states (American Medical Association, 2018).
Cannabis has traveled a long and twisting road across the centuries. Its social acceptability is gradually increasing around the world. In the United States, significant legal changes have occurred; at the state level, cannabis is legal for some medical purposes in 47 states and legal for adult use in 11 of those. However, cannabis and its cannabinoids are classified in Schedule I of the federal CSA, which imposes strict controls on possession, manufacturing, distribution, and dispensing. Schedule I substances may be dispensed only in a federally authorized research program, and cannabis used for research must be obtained only from the University of Mississippi. The 2018 Farm Bill has removed hemp and its extracts (as defined) from the schedules of the CSA, thereby facilitating research and commercial activity with hemp. Nevertheless, the FDA has indicated that CBD and THC cannot be lawfully sold as an ingredient in foods or dietary supplements under the FDCA, although the FDA is currently considering the possibility of creating a lawful regulatory pathway for such products. Developing cannabis-derived products into prescription medications faces some unique research challenges. However, on June 25, 2018, FDA approved Epidiolex ® , a highly purified, plant-derived CBD product, for the treatment of seizures associated with two types of devastating childhood-onset epilepsies, Dravet syndrome and Lennox–Gastaut syndrome, in patients 2 years and older. Hopefully, the success of Epidiolex ® will encourage other manufacturers to bring additional cannabis-derived products through the FDA process, thereby increasing treatment options for patients.
The author confirms being the sole contributor of this work and has approved it for publication.
Conflict of Interest Statement
AM is an employee of Greenwich Biosciences, which manufactures Epidiolex, an FDA approved prescription cannabidiol (CBD) medication.
1 The Expert Committee on Drug Dependence of the World Health Organization has recently recommended, among other things, that cannabis and cannabis resin be removed from the most restrictive schedule of the Single Convention (Schedule IV) and be retained in Schedule I, a less restrictive schedule, suggesting that WHO/ECDD has concluded that these materials have medical potential as well as abuse potential. These recommendations may be considered by the Commission on Narcotic Drugs at its March 2019 meeting. WHO, 41st Report of the Expert Committee on Drug Dependence Annex 1n (2018). https://mjbizdaily.com/wp-content/uploads/2019/01/Annex-1-41-ECDD-recommendations-cannabis-22Jan19.pdf.
2 A trichome is the small epidermal appendage that exists on the plant vegetation where cannabinoids, terpenes, and flavonoids are produced.
3 The DEA has created a separate Schedule I category for “marihuana extracts.” All synthetic copies of botanical cannabinoids, and cannabis itself, remain in the category “marihuana.”
4 Under the previous 2014 Farm Bill [section 7606 of the Agriculture Act of 2014, (Public Law 113–79), 7 U.S. C. 5940 (2014)], state departments of agriculture and institutions of higher learning were authorized to conduct research with industrial hemp.
6 According to the Cole memo, these eight enforcement priorities include preventing the distribution of marijuana to minors; preventing revenue from the sale of marijuana from going to criminal enterprises, gangs, and cartels; preventing the diversion of marijuana from states where it is legal under state law in some form to other states; preventing state-authorized marijuana activity from being used as a cover or protect for the trafficking of other illegal drugs or other illegal activity; preventing violence and the use of firearms in the cultivation and distribution of marijuana; preventing drugged driving and the exacerbation of other adverse public health consequences associated with marijuana use; preventing the growing of marijuana on public lands and the attendant public safety and environmental dangers posed by marijuana production on public lands; and preventing marijuana possession on or use on federal property.
7 Cannabinoids were recently detected in the root.
8 Sativex ® is approved in over 25 countries outside the United States, and Epidiolex ® was approved by the FDA in June 2018 for the treatment of seizures associated with two types of rare, serious, childhood-onset epilepsies.
9 This is what occurred with Epidiolex ® , a pharmaceutical formulation of plant-derived, highly purified cannabidiol (CBD). The DEA issued a Final Rule placing botanically derived CBD, when containing not more than 0.1% THC, and when incorporated into an FDA-approved product, into Schedule V. 83 Fed. Reg. 48950 (September 28, 2018).
FDA Regulation of Cannabis and Cannabis-Derived Products, Including Cannabidiol (CBD)
There is a significant interest in the development of therapies and other consumer products derived from cannabis and its components, including cannabidiol (CBD). FDA recognizes the potential opportunities that cannabis or cannabis-derived compounds may offer and acknowledges the significant interest in these possibilities. However, FDA is aware that some companies are marketing products containing cannabis and cannabis-derived compounds in ways that violate the Federal Food, Drug and Cosmetic Act (FD&C Act) and that may put the health and safety of consumers at risk. The agency is committed to protecting the public health while also taking steps to improve the efficiency of regulatory pathways for the lawful marketing of appropriate cannabis and cannabis-derived products. FDA has a number of resources available that address cannabis and cannabis-derived products, such as CBD, and the agency wants to ensure that consumers and other stakeholders have access to these resources in a centralized location.
Questions and Answers
Below are a number of frequently asked questions and answers on this topic.
1. What are cannabis and marijuana?
A. 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). Parts of the Cannabis sativa plant have been controlled under the Controlled Substances Act (CSA) since 1970 under the drug class “Marihuana” (commonly referred to as “marijuana”) [21 U.S.C. 802(16)]. “Marihuana” is listed in Schedule I of the CSA due to its high potential for abuse, which is attributable in large part to the psychoactive effects of THC, and the absence of a currently accepted medical use of the plant in the United States.
2. How does the 2018 Farm Bill define hemp? What does it mean for FDA-regulated products?
A. At the federal level, the Agriculture Improvement Act of 2018, Pub. L. 115-334, (the 2018 Farm Bill) was signed into law on Dec. 20, 2018. Among other things, this new law changes certain federal authorities relating to the production and marketing of hemp, defined 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 concentration of not more than 0.3 percent on a dry weight basis.” These changes include removing hemp from the CSA, which means that cannabis plants and derivatives that contain no more than 0.3 percent THC on a dry weight basis are no longer controlled substances under federal law.
The 2018 Farm Bill, however, explicitly preserved FDA’s authority to regulate products containing cannabis or cannabis-derived compounds under the FD&C Act and section 351 of the Public Health Service Act (PHS Act). FDA treats products containing cannabis or cannabis-derived compounds as it does any other FDA-regulated products — meaning they’re subject to the same authorities and requirements as FDA-regulated products containing any other substance. This is true regardless of whether the cannabis or cannabis-derived compounds are classified as hemp under the 2018 Farm Bill.
3. Has FDA approved any medical products containing cannabis or cannabis-derived compounds such as CBD?
A. To date, the agency has not approved a marketing application for cannabis for the treatment of any disease or condition. FDA has, however, approved one cannabis-derived and three cannabis-related drug products. These approved products are only available with a prescription from a licensed healthcare provider.
FDA has approved Epidiolex, which contains a purified form of the drug substance CBD for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients 1 years of age and older. It has also approved Epidiolex for the treatment of seizures associated with tuberous sclerosis complex in patients 1 year of age or older. That means FDA has concluded that this particular drug product is safe and effective for its intended use.
The agency also has approved Marinol and Syndros for therapeutic uses in the United States, including for the treatment of anorexia associated with weight loss in AIDS patients. Marinol and Syndros include the active ingredient dronabinol, a synthetic delta-9- tetrahydrocannabinol (THC) which is considered the psychoactive component of cannabis. Another FDA-approved drug, Cesamet, contains the active ingredient nabilone, which has a chemical structure similar to THC and is synthetically derived.
4. Aside from Epidiolex, are there other CBD drug products that are FDA-approved? What about the products I’ve seen in stores or online?
A. No. There are no other FDA-approved drug products that contain CBD. We are aware that some firms are marketing CBD products to treat diseases or for other therapeutic uses , and we have issued several warning letters to such firms. Under the FD&C Act, any product intended to have a therapeutic or medical use, and any product (other than a food) that is intended to affect the structure or function of the body of humans or animals, is a drug. Drugs must generally either receive premarket approval by FDA through the New Drug Application (NDA) process or conform to a “monograph” for a particular drug category, as established by FDA’s Over-the-Counter (OTC) Drug Review. CBD was not an ingredient considered under the OTC drug review. An unapproved new drug cannot be distributed or sold in interstate commerce.
FDA continues to be concerned at the proliferation of products asserting to contain CBD that are marketed for therapeutic or medical uses although they have not been approved by FDA. Often such products are sold online and are therefore available throughout the country. Selling unapproved products with unsubstantiated therapeutic claims is not only a violation of the law, but also can put patients at risk, as these products have not been proven to be safe or effective. This deceptive marketing of unproven treatments also raises significant public health concerns, because patients and other consumers may be influenced not to use approved therapies to treat serious and even fatal diseases.
Unlike drugs approved by FDA, products that have not been subject to FDA review as part of the drug approval process have not been evaluated as to whether they work, what the proper dosage may be if they do work, how they could interact with other drugs, or whether they have dangerous side effects or other safety concerns.
The agency has and will continue to monitor the marketplace and take action as needed to protect the public health against companies illegally selling cannabis and cannabis-derived products that can put consumers at risk and that are being marketed for therapeutic uses for which they are not approved. At the same time, FDA recognizes the potential therapeutic opportunities that cannabis or cannabis-derived compounds could offer and acknowledges the significant interest in these possibilities. FDA continues to believe that the drug approval process represents the best way to help ensure that safe and effective new medicines, including any drugs derived from cannabis, are available to patients in need of appropriate medical therapy. The Center for Drug Evaluation and Research (CDER) is committed to supporting the development of new drugs, including cannabis and cannabis-derived drugs, through the investigational new drug (IND) and drug approval process (see Question #16).
5. Why hasn’t FDA approved more products containing cannabis or cannabis-derived compounds for medical uses?
A. FDA is aware that unapproved cannabis or cannabis-derived products are being used for the treatment of a number of medical conditions including, for example, AIDS wasting, epilepsy, neuropathic pain, spasticity associated with multiple sclerosis, and cancer and chemotherapy-induced nausea.
To date, FDA has not approved a marketing application for cannabis for the treatment of any disease or condition and thus has not determined that cannabis is safe and effective for any particular disease or condition. The agency has, however, approved one cannabis-derived and three cannabis-related drug products (see Question #2).
FDA relies on applicants and scientific investigators to conduct research. The agency’s role, as laid out in the FD&C Act, is to review data submitted to the FDA in an application for approval to ensure that the drug product meets the statutory standards for approval.
The study of cannabis and cannabis-derived compounds in clinical trial settings is needed to assess the safety and effectiveness of these substances for the treatment of any disease or condition. FDA’s December 2016 Guidance for Industry: Botanical Drug Development provides specific recommendations on submitting INDs for botanical drug products, such as those derived from cannabis, in support of future marketing applications for these products. The agency’s July 2020 draft guidance, Cannabis and Cannabis-Derived Compounds: Quality Considerations for Clinical Research Guidance for Industry, highlights quality considerations for anyone wishing to conduct clinical research in this area, particularly those who are less familiar with the FDA.
The FDA will continue to facilitate the work of companies interested in appropriately bringing safe, effective, and quality products to market, including scientifically-based research concerning the medicinal uses of cannabis. Additional information concerning research on the medical use of cannabis is available from the National Institutes of Health, particularly the National Cancer Institute (NCI) and National Institute on Drug Abuse (NIDA).
6. What is FDA’s reaction to states that are allowing cannabis to be sold for medical uses without the FDA’s approval?
A. The FDA is aware that several states have either passed laws that remove state restrictions on the medical use of cannabis and its derivatives or are considering doing so. It is important to conduct medical research into the safety and effectiveness of cannabis products through adequate and well-controlled clinical trials. We welcome the opportunity to talk with states who are considering support for medical research of cannabis and its derivatives, so that we can provide information on Federal and scientific standards.
7. Has the agency received any adverse event reports associated with cannabis use for medical conditions?
A. The agency has received reports of adverse events in patients using cannabis or cannabis-derived products to treat medical conditions. The FDA reviews such reports and will continue to monitor adverse event reports for any safety signals, with a focus on serious adverse effects. Consumers and healthcare providers can report adverse events associated with cannabis or cannabis-derived products via the FDA’s MedWatch reporting system, either online or by phone at 1-800-FDA-1088. For more information, please see the FDA’s webpage on MedWatch.
Information from adverse event reports regarding cannabis use is extremely limited; the FDA primarily receives adverse event reports for approved products. General information on the potential adverse effects of using cannabis and its constituents can come from clinical trials that have been published, as well as from spontaneously reported adverse events sent to the FDA. Additional information about the safety and effectiveness of cannabis and its constituents is needed. Clinical trials of cannabis conducted under an IND application could collect this important information as a part of the drug development process.
8. Is it legal for me to sell CBD products?
A. It depends, among other things, on the intended use of the product and how it is labeled and marketed. Even if a CBD product meets the definition of “hemp” under the 2018 Farm Bill (see Question #2), it still must comply with all other applicable laws, including the FD&C Act. The below questions and answers explain some of the ways that specific parts of the FD&C Act can affect the legality of CBD products.
We are aware that state and local authorities are fielding numerous questions about the legality of CBD. There is ongoing communication with state and local officials to answer questions about requirements under the FD&C Act, to better understand the landscape at the state level, and to otherwise engage with state/local regulatory partners.
9. Can THC or CBD products be sold as dietary supplements?
A. No. Based on available evidence, FDA has concluded that THC and CBD products are excluded from the dietary supplement definition under section 201(ff)(3)(B) of the FD&C Act [21 U.S.C. § 321(ff)(3)(B)]. Under that provision, if a substance (such as THC or CBD) is an active ingredient in a drug product that has been approved under section 505 of the FD&C Act [21 U.S.C. § 355], or has been authorized for investigation as a new drug for which substantial clinical investigations have been instituted and for which the existence of such investigations has been made public, then products containing that substance are excluded from the definition of a dietary supplement. FDA considers a substance to be “authorized for investigation as a new drug” if it is the subject of an Investigational New Drug application (IND) that has gone into effect. Under FDA’s regulations (21 CFR 312.2), unless a clinical investigation meets the limited criteria in that regulation, an IND is required for all clinical investigations of products that are subject to section 505 of the FD&C Act.
There is an exception to section 201(ff)(3)(B) if the substance was “marketed as” a dietary supplement or as a conventional food before the drug was approved or before the new drug investigations were authorized, as applicable. However, based on available evidence, FDA has concluded that this is not the case for THC or CBD.
FDA is not aware of any evidence that would call into question its current conclusions that THC and CBD products are excluded from the dietary supplement definition under section 201(ff)(3)(B) of the FD&C Act. Interested parties may present the agency with any evidence that they think has bearing on this issue. Our continuing review of information that has been submitted thus far has not caused us to change our conclusions.
When a substance is excluded from the dietary supplement definition under section 201(ff)(3)(B) of the FD&C Act, the exclusion applies unless FDA, in the agency’s discretion, has issued a regulation, after notice and comment, finding that the article would be lawful under the FD&C Act. To date, no such regulation has been issued for any substance.
Ingredients that are derived from parts of the cannabis plant that do not contain THC or CBD might fall outside the scope of this exclusion, and therefore might be able to be marketed as dietary supplements. However, all products marketed as dietary supplements must comply with all applicable laws and regulations governing dietary supplement products. For example, manufacturers and distributors who wish to market dietary supplements that contain “new dietary ingredients” (i.e., dietary ingredients that were not marketed in the United States in a dietary supplement before October 15, 1994) generally must notify FDA about these ingredients (see section 413(d) of the FD&C Act [21 U.S.C. § 350b(d)]). Generally, the notification must include information demonstrating that a dietary supplement containing the new dietary ingredient will reasonably be expected to be safe under the conditions of use recommended or suggested in the labeling. A dietary supplement is adulterated if it contains a new dietary ingredient for which there is inadequate information to provide reasonable assurance that the ingredient does not present a significant or unreasonable risk of illness or injury (see section 402(f)(1)(B) of the FD&C Act [21 U.S.C. 342(f)(1)(B)]).
Numerous other legal requirements apply to dietary supplement products, including requirements relating to Current Good Manufacturing Practices (CGMPs) and labeling. Information about these requirements, and about FDA requirements across all product areas, can be found on FDA’s website.
10. Is it legal, in interstate commerce, to sell a food (including any animal food or feed) to which THC or CBD has been added?
A. No. Under section 301(ll) of the FD&C Act [21 U.S.C. § 331(ll)], it is prohibited to introduce or deliver for introduction into interstate commerce any food (including any animal food or feed) to which has been added a substance which is an active ingredient in a drug product that has been approved under section 505 of the FD&C Act [21 U.S.C. § 355], or a drug for which substantial clinical investigations have been instituted and for which the existence of such investigations has been made public. There are exceptions, including when the drug was marketed in food before the drug was approved or before the substantial clinical investigations involving the drug had been instituted or, in the case of animal feed, that the drug is a new animal drug approved for use in feed and used according to the approved labeling. However, based on available evidence, FDA has concluded that none of these is the case for THC or CBD. FDA has therefore concluded that it is a prohibited act to introduce or deliver for introduction into interstate commerce any food (including any animal food or feed) to which THC or CBD has been added. FDA is not aware of any evidence that would call into question these conclusions. Interested parties may present the agency with any evidence that they think has bearing on this issue. Our continuing review of information that has been submitted thus far has not caused us to change our conclusions.
When this statutory prohibition applies to a substance, it prohibits the introduction into interstate commerce of any food to which the substance has been added unless FDA, in the agency’s discretion, has issued a regulation approving the use of the substance in the food (section 301(ll)(2) of the FD&C Act [21 U.S.C. § 331(ll)(2)]). To date, no such regulation has been issued for any substance.
Ingredients that are derived from parts of the cannabis plant that do not contain THC or CBD might fall outside the scope of 301(ll), and therefore might be able to be added to food. For example, as discussed in Question #12, certain hemp seed ingredients can be legally marketed in human food. However, all food ingredients must comply with all applicable laws and regulations. For example, by statute, any substance intentionally added to food is a food additive, and therefore subject to premarket review and approval by FDA, unless the substance is generally recognized as safe (GRAS) by qualified experts under the conditions of its intended use, or the use of the substance is otherwise excepted from the definition of a food additive (sections 201(s) and 409 of the FD&C Act [21 U.S.C. §§ 321(s) and 348]). Aside from the three hemp seed ingredients mentioned in Question #12, no other cannabis or cannabis-derived ingredients have been the subject of a food additive petition, an evaluated GRAS notification, or have otherwise been approved for use in food by FDA. Food companies that wish to use cannabis or cannabis-derived ingredients in their foods are subject to the relevant laws and regulations that govern all food products, including those that relate to the food additive and GRAS processes.
11. In making the two previous determinations about THC, why did FDA conclude that THC is an active ingredient in a drug product that has been approved under section 505 of the FD&C Act? In making the two previous determinations about CBD, why did FDA determine that substantial clinical investigations have been authorized for and/or instituted, and that the existence of such investigations has been made public?
A. THC (dronabinol) is the active ingredient in the approved drug products, Marinol capsules (and generics) and Syndros oral solution. CBD is the active ingredient in the approved drug product, Epidiolex.
The existence of substantial clinical investigations regarding THC and CBD have been made public. For example, two such substantial clinical investigations include GW Pharmaceuticals’ investigations regarding Sativex. (See Sativex Commences US Phase II/III Clinical Trial in Cancer Pain )
12. Can hulled hemp seed, hemp seed protein powder, and hemp seed oil be used in human food?
A. In December 2018, FDA completed its evaluation of three generally recognized as safe (GRAS) notices for the following hemp seed-derived food ingredients: hulled hemp seed, hemp seed protein powder, and hemp seed oil. FDA had no questions regarding the company’s conclusion that the use of such products as described in the notices is safe. Therefore, these products can be legally marketed in human foods for the uses described in the notices, provided they comply with all other requirements. These GRAS notices related only to the use of these ingredients in human food. To date, FDA has not received any GRAS notices for the use of hemp-derived ingredients in animal food (see Question #25).
Hemp seeds are the seeds of the Cannabis sativa plant. The seeds of the plant do not naturally contain THC or CBD. The hemp seed-derived ingredients that are the subject of these GRAS notices contain only trace amounts of THC and CBD, which the seeds may pick up during harvesting and processing when they are in contact with other parts of the plant. Consumption of these hemp seed-derived ingredients is not capable of making consumers “high.”
The GRAS conclusions can apply to ingredients for human food marketed by other companies, if they are manufactured in a way that is consistent with the notices and they meet the listed specifications. Some of the intended uses for these ingredients include adding them as source of protein, carbohydrates, oil, and other nutrients to beverages (juices, smoothies, protein drinks, plant-based alternatives to dairy products), soups, dips, spreads, sauces, dressings, plant-based alternatives to meat products, desserts, baked goods, cereals, snacks and nutrition bars. Products that contain any of these hemp seed-derived ingredients must declare them by name on the ingredient list.
These GRAS conclusions do not affect the FDA’s position on the addition of CBD and THC to food.
13. What is FDA’s position on cannabis and cannabis-derived ingredients in cosmetics?
A. A cosmetic is defined in 201(i) as “(1) articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body or any part thereof for cleansing, beautifying, promoting attractiveness, or altering the appearance, and (2) articles intended for use as a component of any such articles; except that such term shall not include soap.”
Under the FD&C Act, cosmetic products and ingredients are not subject to premarket approval by FDA, except for most color additives. Certain cosmetic ingredients are prohibited or restricted by regulation, but currently that is not the case for any cannabis or cannabis-derived ingredients. Ingredients not specifically addressed by regulation must nonetheless comply with all applicable requirements, and no ingredient – including a cannabis or cannabis-derived ingredient – can be used in a cosmetic if it causes the product to be adulterated or misbranded in any way. A cosmetic generally is adulterated if it bears or contains any poisonous or deleterious substance which may render it injurious to users under the conditions of use prescribed in the labeling, or under such conditions of use as are customary or usual (section 601(a) of the FD&C Act [21 U.S.C. § 361(a)]).
If a product is intended to affect the structure or function of the body, or to diagnose, cure, mitigate, treat or prevent disease, it is a drug, or possibly both a cosmetic and a drug, even if it affects the appearance. (See Question #3 for more information about drugs.)
FDA can take action if it has information that an ingredient or cosmetic product is unsafe to consumers. Consumers can report adverse events associated with cosmetic products via the FDA’s MedWatch reporting system, either online or by phone at 1-800-FDA-1088, or by contacting your nearest FDA district office consumer complaint coordinator. For more information, please see the FDA’s webpage on how to report a cosmetic-related complaint.
14. Will FDA take action against cannabis or cannabis-related products that are in violation of the FD&C Act?
A. The FDA has sent warning letters in the past to companies illegally selling CBD products that claimed to prevent, diagnose, treat, or cure serious diseases, such as cancer. Some of these products were in further violation of the FD&C Act because they were marketed as dietary supplements or because they involved the addition of CBD to food.
When a product is in violation of the FD&C Act, FDA considers many factors in deciding whether or not to initiate an enforcement action. Those factors include, among other things, agency resources and the threat to the public health. FDA also may consult with its federal and state partners in making decisions about whether to initiate a federal enforcement action.
15. Can I import or export cannabis-containing or cannabis-derived products?
A. General information about the import/export of drug products regulated by FDA can be found online here. The Drug Enforcement Administration (DEA) is the federal agency responsible for enforcing the controlled substance laws and regulations in the U.S. and, as such, should be consulted with respect to any regulations/requirements they may have regarding the import or export of products containing cannabis. Please see here for information about importing or exporting food ingredients.
Regarding imports, if it appears that an article is adulterated, misbranded, in violation of section 505 of the FD&C Act, or prohibited from introduction or delivery for introduction into interstate commerce under section 301(ll) of the FD&C Act, such article will be refused admission (see section 801(a)(3) of the FD&C Act [21 U.S.C. § 381(a)(3)]).
Research and Expanded Access
16. What is FDA’s role when it comes to the investigation of cannabis and cannabis-derived products for medical use?
A. To conduct clinical research that can lead to an approved new drug, including research using materials from plants such as cannabis, researchers need to work with the FDA and submit an IND application to the Center for Drug Evaluation and Research (CDER). The IND application process gives researchers a path to follow that includes regular interactions with the FDA to support efficient drug development while protecting the patients who are enrolled in the trials. For research for use as an animal drug product, researchers would establish an investigational new animal drug (INAD) file with the Center for Veterinary Medicine to conduct their research, rather than an IND with CDER.
As discussed above (see Question #2), the 2018 Farm Bill removed hemp from the CSA. This change may streamline the process for researchers to study cannabis and its derivatives, including CBD, that fall under the definition of hemp, which could speed the development of new drugs.
As also discussed above (see Question #5) the agency also issued a draft guidance in July 2020, Cannabis and Cannabis-Derived Compounds: Quality Considerations for Clinical Research Guidance for Industry, for individuals considering clinical research in this area.
Conducting clinical research using cannabis-related substances that are scheduled by the DEA often involves interactions with several federal agencies. This includes: a registration administered by the DEA; obtaining the cannabis for research from NIDA, within the National Institutes of Health, or another DEA-registered source; and review by the FDA of the IND or INAD application and research protocol. Additionally:
- For a Schedule I controlled substance under the CSA, DEA provides researchers with investigator and protocol registrations and has Schedule I-level security requirements at the site cannabis will be studied.
- NIDA provides research-grade cannabis for scientific study. The agency is responsible for overseeing the cultivation of cannabis for medical research and has contracted with the University of Mississippi to grow cannabis for research at a secure facility. Cannabis of varying potencies and compositions is available. DEA also may allow additional growers to register with the DEA to produce and distribute cannabis for research purposes.
- Researchers work with the FDA and submit an IND application to the appropriate division in the Office of New Drugs in CDER depending on the therapeutic indication. Based on the results obtained in studies conducted at the IND stage, sponsors may submit a marketing application for formal approval of the drug.
17. Does the FDA object to the clinical investigation of cannabis for medical use?
A. No. The FDA believes that scientifically valid research conducted under an IND application is the best way to determine what patients could benefit from the use of drugs derived from cannabis. The FDA supports the conduct of that research by:
- Providing information on the process needed to conduct clinical research using cannabis.
- Providing information on the specific requirements needed to develop a drug that is derived from a plant such as cannabis. In December 2016, the FDA updated its Guidance for Industry: Botanical Drug Development, which provides sponsors with guidance on submitting IND applications for botanical drug products.
- Providing specific support for investigators interested in conducting clinical research using cannabis and its constituents as a part of the IND process through meetings and regular interactions throughout the drug development process.
- Providing general support to investigators to help them understand and follow the procedures to conduct clinical research through the FDA Center for Drug Evaluation and Research’s Small Business and Industry Assistance group.
18. How can patients gain access to cannabis or cannabis-derived products for medical use through expanded access?
A. Expanded access is a potential pathway for a patient with a serious or life-threatening disease or condition to try an investigational medical product (drug, biologic, or medical device) for treatment outside of clinical trials when there are no comparable or satisfactory therapies available. Manufacturers may be able to make investigational drugs available to individual patients in certain circumstances through expanded access, as described in the FD&C Act and implementing regulations.
19. Can patients gain access to cannabis or cannabis-derived products for medical use through Right to Try?
A. Information for patients on Right to Try (RTT) is available on our website. RTT is designed to facilitate access to certain investigational drugs through direct interactions between patients, their physicians and drug sponsors – FDA is not involved in these decisions. Sponsors developing drugs for life-threatening conditions are responsible for determining whether to make their products available to patients who qualify for access under RTT. If you are interested in RTT, you should discuss this pathway with your licensed physician. Companies who develop drugs and biologics, also known as sponsors, can provide information about whether their drug/biologic is considered an eligible investigational drug under RTT and if they are able to provide the drug/biologic under the RTT Act.
Children and Pregnant/Lactating Women
20. Does the FDA have concerns about administering a cannabis product to children?
A. We understand that parents are trying to find treatments for their children’s medical conditions. However, the use of untested drugs can have unpredictable and unintended consequences. Caregivers and patients can be confident that FDA-approved drugs have been carefully evaluated for safety, efficacy, and quality, and are monitored by the FDA once they are on the market. The FDA continues to support sound, scientifically-based research into the medicinal uses of drug products containing cannabis or cannabis-derived compounds, and will continue to work with companies interested in bringing safe, effective, and quality products to market. With the exception of Epidiolex, Marinol, and Syndros, no product containing cannabis or cannabis-derived compounds (either plant-based or synthetic) has been approved as safe and effective for use in any patient population, whether pediatric or adult.
21. Does the FDA have concerns about administering a cannabis product to pregnant and lactating women?
A. The FDA is aware that there are potential adverse health effects with use of cannabis products containing THC in pregnant or lactating women. Published scientific literature reports potential adverse effects of cannabis use in pregnant women, including fetal growth restriction, low birth weight, preterm birth, small-for-gestational age, neonatal intensive care unit (NICU) admission, and stillbirth. [1, 2, 3] Based on published animal research, there are also concerns that use of cannabis during pregnancy may negatively impact fetal brain development. [4, 5, 6 ] The American College of Obstetricians and Gynecologists (ACOG) recommends that women who are pregnant or contemplating pregnancy should be encouraged to discontinue cannabis use. In addition, ACOG notes that there are insufficient data to evaluate the effects of cannabis use on breastfed infants; therefore, cannabis use is discouraged when breastfeeding.  Pregnant and lactating women should talk with a health care provider about the potential adverse health effects of cannabis use.
22. What does the FDA think about making CBD available to children with epilepsy?
A. The FDA has approved Epidiolex, which contains a purified form of the drug substance CBD, for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients 1 years of age and older. It has also approved Epidiolex for the treatment of seizures associated with tuberous sclerosis complex in patients 1 year of age or older. That means the FDA has concluded that this particular drug product is safe and effective for its intended use. Controlled clinical trials testing the safety and efficacy of a drug, along with careful review through the FDA’s drug approval process, is the most appropriate way to bring cannabis-derived treatments to patients. Because of the adequate and well-controlled clinical studies that supported this approval, and the assurance of manufacturing quality standards, prescribers can have confidence in the drug’s uniform strength and consistent delivery that support appropriate dosing needed for treating patients with these complex and serious epilepsy syndromes.
23. What should I do if my child eats something containing cannabis?
A. With the exception of products such as the hemp seed ingredients discussed in Question #12, which have been evaluated for safety, it is important to protect children from accidental ingestion of cannabis and cannabis-containing products. FDA recommends that these products are kept out of reach of children to reduce the risk of accidental ingestion. If the parent or caregiver has a reasonable suspicion that the child accidentally ingested products containing cannabis, the child should be taken to a physician or emergency department, especially if the child acts in an unusual way or is/feels sick.
Pets and other Animals
24. I’ve seen cannabis products being marketed for pets. Are they safe?
A. FDA is aware of some cannabis products being marketed as animal health products. We want to stress that FDA has not approved cannabis for any use in animals, and the agency cannot ensure the safety or effectiveness of these products. For these reasons, FDA cautions pet-owners against the use of such products and recommends that you talk with your veterinarian about appropriate treatment options for your pet.
Signs that your pet may be suffering adverse effects from ingesting cannabis may include lethargy, depression, heavy drooling, vomiting, agitation, tremors, and convulsions.
If you have concerns that your pet is suffering adverse effects from ingesting cannabis or any substance containing cannabis, consult your veterinarian, local animal emergency hospital or an animal poison control center immediately.
While the agency is aware of reports of pets consuming various forms of cannabis, to date, FDA has not directly received any reports of adverse events associated with animals given cannabis products. However, adverse events from accidental ingestion are well-documented in scientific literature. If you feel your animal has suffered from ingesting cannabis, we encourage you to report the adverse event to the FDA. Please visit Reporting Information about Animal Drugs and Devices to learn more about how to report an adverse event related to an animal drug or for how to report an adverse event or problem with a pet food.
25. Can hemp be added to animal food?
A. All ingredients in animal food must be the subject of an approved food additive petition or generally recognized as safe (GRAS) for their intended use in the intended species. If an animal food contains an ingredient that is not the subject of an approved food additive petition or GRAS for its intended use in the intended species, that animal food would be adulterated under section 402(a)(2)(C)(i) of the FD&C Act [21 U.S.C. § 342(a)(2)(C)(i)]. In coordination with state feed control officials, CVM also recognizes ingredients listed in the Official Publication (OP) of the Association of American Feed Control Officials (AAFCO) as being acceptable for use in animal food. At this time, there are no approved food additive petitions or ingredient definitions listed in the AAFCO OP for any substances derived from hemp, and we are unaware of any GRAS conclusions regarding the use of any substances derived from hemp in animal food. Learn more about animal food ingredient submissions here.
With respect to products labeled to contain “hemp” that may also contain THC or CBD, as mentioned above it is a prohibited act under section 301(ll) of the FD&C Act to introduce or deliver for introduction into interstate commerce any animal food to which THC or CBD has been added.
26. Can approved human drugs containing CBD or synthetic THC be used extralabel in animals?
A. The Animal Medicinal Drug Use Clarification Act of 1994 (AMDUCA), permits veterinarians to prescribe extralabel uses of approved human and animal drugs for animals under certain conditions. Extralabel use must comply with all the provisions of AMDUCA and its implementing regulation at 21 CFR § 530. Among other limitations, these provisions allow extralabel use of a drug only on the lawful order of a licensed veterinarian in the context of a valid veterinarian-client-patient relationship and only in circumstances when the health of an animal is threatened or suffering, or death may result from failure to treat.
In addition, under 21 CFR 530.20, extralabel use of an approved human drug in a food-producing animal is not permitted if an animal drug approved for use in food-producing animals can be used in an extralabel manner for the use. In addition, under 21 CFR 530.20(b)(2), if scientific information on the human food safety aspect of the use of the approved human drug in food-producing animals is not available, the veterinarian must take appropriate measures to ensure that the animal and its food products will not enter the human food supply.
For more information on extralabel use of FDA approved drugs in animals, see Extralabel Use of FDA Approved Drugs In Animals.
 Gray, et al. Identifying Prenatal Cannabis Exposure and Effects of Concurrent Tobacco Exposure on Neonatal Growth. Clinical Chemistry. 2010; 56(9): 1442-1450.
 Gunn, et al. Prenatal Exposure to cannabis and maternal and child health outcomes: a systematic review and meta-analysis. BMJ Open. 2016; 6:e009986.
 Hayatbakhsh, et al. Birth Outcomes associated with cannabis use before and during pregnancy. Pediatric Research. 2012; 71 (2): 215-219.
 Silva, et al. Prenatal tetrahydrocannabinol (THC) alters cognitive function and amphetamine response from weaning to adulthood in the rat. Neurotoxicol and Teratol 2012; 34(1): 63-71.
 Trezza, et al. Effects of perinatal exposure to delta-9-tetrahydrocannabinol on the emotional reactivity of the offspring: a longitudinal behavioral study in Wistar rats. Psychopharmacology (Berl) 2008; 198(4): 529-537.
 Campolongo, et al. Perinatal exposure to delta-9-tetrahydrocannabinol causes enduring cognitive deficits associated with alteration of cortical gene expression and neurotransmission in rats. Addict Biol 2007; 12(3-4): 485–495.
Leagl regulations for cannabis seeds and documentation
Microsoft® Word for Microsoft 365
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