Cannabis has been used for thousands of years as a therapeutic substance and the discovery of the different cannabinoids contained in the plant has helped scientists better understand its medicinal value.1 But to date, only four cannabinoid medicines have been approved by the FDA and moved out of the Drug Enforcement Administration’s (DEA) Schedule I classification.2,3,4,5
To understand the DEA scheduling of cannabis, it helps to review the history of the Federal Comprehensive Drug Abuse Prevention and Control Act, also known as the Controlled Substances Act or CSA, which was signed into law nearly 50 years ago. The Act sought to control the manufacturing, importation/exportation, distribution, and dispensing of controlled substances considered to be easily abused. The CSA was established to keep track of manufacturers, distributors, researchers, importers/exporters, and dispensers of controlled substances, requiring registration with the DEA of individuals and businesses engaged in these activities. This registration allows for a ‘‘closed system’’ of controlled substance distribution, tracing products from initial manufacturer to final dispensing to a patient.6
Part of the CSA also categorizes substances according to the potential for abuse and value as a medical treatment. There are currently five classifications or schedules (see Table 1) ranging from Schedule I, which are considered to have a high abuse potential with no accepted medical use and cannot be prescribed or administered outside of a federally-approved research program to Schedule V, which are considered low abuse risk. Currently marijuana containing more than 0.3% THC remains a Schedule I substance despite known medicinal benefits of certain FDA-approved cannabinoid products.
According to federal law, all parts of the Cannabis Sativa L. plant, and every compound, manufacture, salt, derivative, mixture, or preparation of such plant are considered a Schedule I substance, excluding hemp and FDA-approved cannabinoid therapy, Epidiolex, which was de-scheduled in April 2020.7,8 Hemp was de-scheduled in 2018 with the passage of the Farm Bill and defined as the Cannabis Sativa L. plant, and any part of that plant with a delta-9 tetrahydrocannabinol (THC) concentration of no more than 0.3 percent by dry weight.9 The nuances of the level of THC concentration, as well as the known safety and efficacy of FDA-approved formulations of specific cannabinoid-based therapies, like Epidiolex, is what causes many to question its current scheduling.
Table 1: DEA Scheduling1
|Schedule I||Medications with a very high misuse potential and considered to have no FDA-approved medical use. These medications are prohibited from being prescribed or distributed.||Heroin, ecstasy, lysergic acid diethylamide (LSD), marijuana, and gamma-hydroxybutyric acid|
|Schedule II||Medications with a high misuse potential with or without known probability of developing dependence, yet accepted clinician use.||Cocaine, morphine, codeine, hydromorphone, methadone, fentanyl, synthetic THC, nabilone and dronabinol (oral solution)|
|Schedule III||Medications that have an intermediate level of misuse potential.||Anabolic steroids, ketamine, synthetic THC, dronabinol (capsules)|
|Schedule IV||Medications considered to have some misuse potential but less risk than schedule III.||Clonazepam, diazepam, midazolam, phenobarbital, and tramadol|
|Schedule V||Medications with the lowest potential for misuse.||Pregabalin, diphenoxylate/atropine, and promethazine|
In determining which schedule a drug should be placed, or whether a substance should be de-scheduled or rescheduled, certain factors are considered. These factors include, but are not limited to actual or relative potential for abuse, scientific evidence of pharmacological effect, as well as what, if any, risk there is to public health.7
Ultimately more placebo-controlled, randomized clinical trials are essential to demonstrate a fuller picture of cannabis-based products as medicine, while revealing the capacity for safe use in specific patient populations. The four FDA-approved cannabinoid medicines prove that it is possible to successfully navigate the existing regulatory hurdles required to conduct research on Schedule I substances, yet the CSA continues to act as a hurdle. The FDA recently announced draft guidance outlining its current thinking on several topics relevant to such research.10 Rescheduling or de-scheduling cannabis and cannabis extracts when manufactured, distributed, or possessed for FDA-authorized medical research would significantly aid in both basic research and the clinical development of FDA-approved cannabis-based products as medicine.
Investigating promising therapeutic agents and bringing them to market through the FDA review and approval process is resource intensive, as it should be. However, the CSA does provide a mechanism for substances to be added to or transferred between schedules or de-scheduled, which has been proposed for marijuana. These proceedings can be initiated by the DEA, the Department of Health and Human Services (HHS), or by petition from any interested party, including: the manufacturer of a drug, a medical society or association, a pharmacy association, a public interest group, a state or local government agency or an individual citizen.11
For decades, medical professionals, patient advocates, and legislators have called for federal rescheduling of cannabis. The reason most often cited is that it would facilitate research into cannabis’ medical benefits.12 Others advocate for de-scheduling completely to eliminate penalties for growing, cultivating, distributing, and possessing marijuana given the diversity and disparity between state and federal laws. Regardless of the path taken, federal action is needed to facilitate robust medical research that is aligned with the FDA drug development pathway that will ensure patient safety and product efficacy. The FDA’s draft guidance surrounding clinical research of cannabis and cannabis-derived compounds, with interest in comments and insights from industry, is a start; placement of cannabis into a less restrictive schedule could also help in incentivizing further research.
1Pertwee RG. Cannabinoid pharmacology: the first 66 years. Brit J Pharmacol. 2006;147(Suppl 1):S163-S171.
2Marinol [package insert]. North Chicago, IL: AbbVie Inc; 2017.
3Syndros [package insert]. Chandler, AZ: Insys Therapeutics, Inc; 2018.
4EPIDIOLEX [package insert]. Carlsbad, CA: Greenwich Biosciences, Inc.; 2020.
5Cesamet [package insert]. Somerset, NJ: Meda Pharmaceuticals Inc; 2015.
6Gabay, Michael, PharmD, JD, BCPS. “The Federal Controlled Substances Act: Schedules and Pharmacy Registration.” Hosp Pharm 2013;48(6):473–474. Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3839489/pdf/hpj4806-473.pdf. Accessed June 16, 2020.
7U.S. Department of Justice, Drug Enforcement Administration, Diversion Control Division, SUBCHAPTER I — CONTROL AND ENFORCEMENT, Definitions. Available at https://www.deadiversion.usdoj.gov/21cfr/21usc/802.htm. Accessed August 17, 2020.
8 GW Pharmaceuticals, “GW Pharmaceuticals plc and Its U.S. Subsidiary Greenwich Biosciences, Inc. Announce That EPIDIOLEX® (cannabidiol) Oral Solution Has Been Descheduled And Is No Longer A Controlled Substance.” April 6, 2020. Available at https://www.globenewswire.com/news-release/2020/04/06/2012160/0/en/GW-Pharmaceuticals-plc-and-Its-U-S-Subsidiary-Greenwich-Biosciences-Inc-Announce-That-EPIDIOLEX-cannabidiol-Oral-Solution-Has-Been-Descheduled-And-Is-No-Longer-A-Controlled-Substan.html
9Agriculture Improvement Act of 2018. https://www.agriculture.senate.gov/imo/media/doc/Agriculture%20Improvement%20Act%20of%202018.pdf, accessed 11/8/19
10United States Food & Drug Administration. Cannabis and Cannabis-Derived Compounds: Quality Considerations for Clinical Research Guidance for Industry. July 2020. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cannabis-and-cannabis-derived-compounds-quality-considerations-clinical-research-guidance-industry. Accessed July 23, 2020.
11United States Drug Enforcement Administration. The Controlled Substance Act. “CONTROLLING DRUGS OR OTHER SUBSTANCES THROUGH FORMAL SCHEDULING.” https://www.dea.gov/controlled-substances-act. Accessed July 13, 2020.
12Drug Policy Alliance, “Removing Marijuana from the Schedule of Controlled Substances.” January 2019. https://www.drugpolicy.org/sites/default/files/marijuana-scheduling_january_2019_0.pdf. Accessed July 14, 2020.