Given the diverse nature of cannabis and cannabinoid research, differences in state laws, and varied institutional regulations, every scientist will likely have a unique experience when initiating cannabis and cannabinoid work. In fact, with rapid changes in oversight and regulations, one cannot necessarily predict how to navigate regulatory hurdles for future studies based on one’s own previous experiences. The following account is from personal experience working with cannabis and cannabinoids in 2 states and 2 institutions. This account highlights the arduous path of starting a research program focusing on controlled administration of cannabis and cannabinoids in humans and demonstrates that the pathway to embarking on this research is demanding both of the researcher’s time and resources. This experience is important to stress as more researchers become interested in delving into this field but are required to start from scratch to get projects off the ground. Because of the time, expenses, and regulatory knowledge required to get a single study started in this field, researchers will frequently opt not to pursue work in this area. Consequently, although more issues need to be addressed by diverse experts, pipp drying racks the field will likely continue to be limited to those institutions and researchers who have historically pursued this work. Below is a description of the 3 primary hurdles to conducting cannabis and cannabinoid research in the United States.
Although the US regulatory status of cannabis and cannabinoids is a US-specific barrier, the other barriers—the paucity of funding available for investigations and the availability of test medications that can be studied—are global and limit the expansion of work in the field. Similarly, although some barriers are unique to this field, it should be noted that clinical research in general is difficult and burdensome, regardless of the study medication under investigation. However, many hurdles detailed below are unique to studying cannabis and cannabinoids in the United States. These challenges are intertwined with one another, creating a situation where overcoming one obstacle requires success in surmounting the others, as depicted in Figure 1.As mentioned earlier, the most obvious regulatory hurdle in conducting cannabis and cannabinoid research is the schedule I status of cannabis and specific cannabinoids. Although there has been movement in the field to relax regulations, including the landmark change decontrolling CBD derived from hemp, many changes have, in fact, made the regulatory landscape more confusing and difficult to navigate for the researcher. For example, in the case of CBD, according to the DEA interim final rule that outlines DEA’s amendments to the CSA made by the Agriculture Improvement Act of 2018 , products with CBD specifically derived from the plant that contain less than 0.3% delta-9-THC are now decontrolled, yet synthetic CBD remains on schedule I according to the CSA.
Despite the fact that the molecule is the same, its origins define its regulatory standing. Another example of these confusing laws relates to the classification of delta-9-THC, which has 3 distinct schedules based on the source of production and the formulation. For example, dronabinol, synthetic delta-9-THC, is categorized on 3 different schedules: oral capsules of the synthetic delta-9-THC dronabinol is classified as schedule III, yet the FDA-approved liquid dronabinol is schedule II, and dronabinol not packaged according to FDA formulations is schedule I . Currently, all forms of delta-9-THC derived from the cannabis plant are schedule I. These are a few examples of the confusing nature of cannabinoid scheduling that require near mastery to successfully identify whether a proposed trial with a potential study medication requires a schedule I DEA license. Without proper guidance and support from people in the field, a researcher is likely to get lost in the regulatory quagmire that is rapidly evolving. Once it has been determined that the test material is indeed schedule I, the investigator is required to apply and be approved for schedule I registration. Prior to applying for this license, 2 significant milestones must be met: approval of a research protocol that employs the schedule I substance for which the license is being sought and identification of a storage facility that will meet DEA requirements . Regulatory Approvals. A study assessing the effects of cannabis and/or cannabinoid administration is required to be submitted to and approved by the IRB and the FDA. Protocols submitted to the IRB must be justified scientifically, meet the ethical principles of the Belmont Report , and include steps to minimize risk. This protocol is also submitted to the FDA as an Investigational New Drug application alongside detailed information regarding the chemistry, manufacturing, and control data of the agent to be studied as described in Section titled Role of the FDA in the Regulation of Cannabis Products.
Finally, state regulatory approvals must also be obtained. Some states have separate controlled substance licensing requirements. For example, in New York State, the investigator must apply for and receive a license from the Bureau of Narcotic Enforcement. Other states may require that protocols be approved by the state board of medical examiners. For example, in the state of California, the Research Advisory Panel of California, under the state attorney general’s office, reviews and authorizes studies involving schedules I and II substances to ensure the safety and protection of participating human research subjects, in addition to the security provisions in place for the controlled substances used in the study. This panel also evaluates the scientific validity of the studies. Therefore, studies can be rejected if deemed to “produce conclusions of little scientific value, or would not justify the exposure of California subjects to the risk of research” . If any of these bodies request modifications to the protocol, amendments must be submitted to and reviewed by the other agencies. This approval process can take several months even if no modifications are required. Application to the DEA for a schedule I license includes the above-mentioned approved regulatory documents; the investigator’s qualifications, including a curriculum vitae; a description of the research project, including its statement of purpose; the name and amount of substances to be used; a description of and the number of research subjects; drug doses to be administered; mode of administration; and the duration of the study. Details regarding where the study will be conducted and security provisions for storing the drug must also be included. Finally, an institutional letter of support must be provided, as well as an indication of approved funding provided, if applicable . Once the application is received, pipp horticulture the DEA communicates with the FDA to determine the merits of the study and the qualifications and competency of the submitting investigator, which is a process that takes at least 30 days. The local DEA inspector will then make an appointment to inspect the facility. Security issues noted during the inspection need to be resolved before the license is granted. Security Requirements for Schedule I Material. Requirements for schedule I drug storage are complicated, and the specifics outlined in Title 21 of the Code of Federal Regulations may not realistically correspond to an investigator’s study needs. For example, drugs may be required to be frozen to maintain stability . As such, researchers develop ways to maintain the integrity of their drug product while still adhering to the DEA code.
In general, small amounts of the drug must be stored in a safe or steel cabinet that weighs at least 750 pounds and complies with the following specifications: protected for “30 man-minutes against surreptitious entry, 10 man-minutes against forced entry, 20 man hours against lock manipulation, and 20 man-hours against radiological techniques.” If the safe or cabinet is not 750 pounds, it needs to be bolted or cemented to the floor or wall. The safe or steel cabinet should be equipped with an alarm that signals acentral protection agency, a police agency, or a 24-hour control station operated by the registrant in the event of an unauthorized entry. Guidance for practitioners is modified to state that “Controlled substances listed in Schedule I shall be stored in a securely locked, substantially constructed cabinet” , however, there is not a detailed account of what type of safe meets this definition and may be left up to the local DEA jurisdiction and agent. The storage facility is required to be in a space that is only accessible to a minimum number of specifically authorized employees. This stipulation requires that the institution secure space for the researcher that cannot be accessible to anyone other than the investigator and employees authorized to have access to the drug. These requirements place a significant burden on the investigator embarking on a path to researching cannabis and cannabinoids. The security provisions can only be met with institutional support and commitment and with sufficient funding to establish a secure drug storage area that adheres to the DEA’s standards.Whereas the schedule I status of cannabis and many cannabinoids is a significant barrier to research, identifying a drug for clinical studies continues to be a principal obstacle, regardless of the drug’s scheduling status. The challenges related to the single source of cannabis are outlined earlier in this paper . Although the limitations related to a single source of cannabis is clearly related to its schedule I status, a challenge that is frequently overlooked is identifying sources of any cannabinoid study drug independent of the drug’s scheduling. These challenges lie in the issues raised in Section 4.0, addressing the need for a study drug to meet the FDA’s standards for human study. Therefore, even if cannabis and schedule I cannabinoids shed their classification and are removed from the CSA, researchers would still bear the burden of identifying a product that adheres to the FDA’s Good Manufacturing Practice requirements. For example, hemp-derived CBD was recently removed from the CSA. This evolution should have improved research in this area substantially, yet there are few manufacturers that make plant-derived CBD according to the FDA’s standards. When a manufacturer of clinical-grade, hemp-derived CBD is identified, the product can only be considered for use if the manufacturer agrees to provide the materials needed for the researcher’s FDA Investigational New Drug submission and provides enough study drug to cover the needs of the investigation at a cost that is not prohibitively expensive for a typical research budget. In addition, for a placebo-controlled study, a matched placebo is also required, ideally manufactured by the company providing the study drug. As such, providing a study drug for clinical trials is time intensive and resource heavy for the manufacturer, and few manufacturers are creating these materials for direct sale to customers and researchers. This presents a conundrum where the types of cannabis products available to the public continue to increase, yet research is limited to only a handful of cannabinoids, modes of delivery, and doses. Another issue with respect to feasibility of clinical trials with schedule I material is the lack of clear federal guidance on the limitations or restrictions for taking such study medication across state lines. Researchers would be advised to check with individual state governments if such scenarios are planned. Because of the various scheduling and availability issues of cannabis and cannabinoids, identifying the source of a drug for a particular study is absolutely integral when developing the protocol and applying for funding . In fact, given the limitations of study drug availability, a study’s premise, objective, and design are usually crafted based on what is available.The ultimate limitation to research in this field is the availability of funding. As noted before, funding is difficult to obtain for nearly all areas of research, but this is especially true for cannabis and cannabinoid research. Until recently, there were very few opportunities to fund research dedicated to the therapeutic effects of cannabis and cannabinoids. The NIH Research, Condition, and Disease Categorization system tracks expenditures by the NIH institutes. In 2019, the NIH budget for research projects was approximately $9.6 billion, with an overall funding rate of 19% . Despite laws restricting research, the NIH cannabis and cannabinoid research portfolio is significant and growing and includes the provision of cannabis materials for research. The cannabinoid research category includes the endocannabinoid system, CBD, and therapeutic cannabinoids.