The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research.
15 Challenges and Barriers in Conducting Cannabis Research
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REGULATORY AND SUPPLY BARRIERS
Regulatory Barriers
Investigators seeking to conduct research on cannabis or cannabinoids must navigate a series of review processes that may involve the National Institute on Drug Abuse (NIDA), the U.S. Food and Drug Administration (FDA), the U.S. Drug Enforcement Administration (DEA), institutional review boards, offices or departments in state government, state boards of medical examiners, the researcher's home institution, and potential funders. A brief overview of some of these review processes is discussed.
Researchers conducting clinical research on biological products such as cannabis must submit an investigational new drug (IND) application to the FDA. As a next step, the investigator may contact NIDA, an important source of research-grade cannabis, to obtain an administrative letter of authorization (LOA). An LOA describes the manufacturer's facilities, as well as the availability and pertinent characteristics of the desired cannabis product (e.g., strains, quality, strength, pharmacology, toxicology). To safeguard against the acquisition of cannabis or cannabinoids for non-research purposes, investigators must also apply for a DEA registration and site licensure before conducting studies involving cannabis or any of its cannabinoid constituents, irrespective of their pharmacologic activity.5 The investigator must submit the IND and LOA to the FDA and the DEA for review (FDA, 2015).
After submitting an IND application, researchers must wait at least 30 days before initiating research, during which period the FDA reviews the application to ensure that research participants will not be exposed to unreasonable risk (FDA, 2016a). If the FDA determines that the proposed research would expose study participants to unreasonable risk or that the IND application is in some other way deficient, a clinical hold postponing the research may be imposed. This hold is not lifted until and unless the sponsoring researchers have resolved the deficiencies (FDA, 2016b).
It is important to note that the Controlled Substances Act of 1970 classified cannabis as a Schedule I substance, the highest level of drug restriction.6 As defined by the Act, Schedule I substances are those that (1) have a high potential for abuse; (2) have no currently accepted medical use in treatment in the United States; and (3) have a lack of accepted safety for their use under medical supervision.7 Other substances classified in Schedule I include heroin, LSD, mescaline, hallucinogenic amphetamine derivatives, fentanyl derivatives (synthetic opioid analgesics), and gammahydroxybutyrate (GHB).8 By contrast, Schedule II substances—though they also have a high potential for abuse and may lead to severe psychological or physical dependence—are defined as having a currently accepted medical use and can be prescribed with a controlled substance prescription (DEA, 2006).9
In some states, researchers conducting clinical research on cannabis or cannabinoid products must also apply for and receive a controlled substance certificate from a state board of medical examiners or a controlled substance registration from a department of the state government in order to conduct clinical trials or any other activity involving Schedule I substances (Alabama Board of Medical Examiners, 2013; MDHSS, n.d.). Some state governments require additional approvals. For example, California requires that all trials involving Schedule I or II controlled substances be registered with and approved by the Research Advisory Panel of California (CADOJ/OAG, 2016). When the necessary approvals are secured, only then can the investigator apply for a DEA registration and site licensure to conduct research on a Schedule I controlled substance (see Box 15-1 for examples of research barriers).
Researchers conducting trials of Schedule I substances must additionally submit a research protocol to the DEA that includes details regarding the security provisions for storing and dispensing the substance.10 Previously, nonfederally funded studies on cannabis were also required to undergo an additional review process conducted by the Public Health Service. This review process was determined to unnecessarily duplicate the FDA's IND application process in several ways and, as of June 2015, is no longer required.11
To ensure that controlled substances obtained for research purposes will be stored and accessed in accordance with DEA security requirements, local DEA officials may perform a preregistration inspection of the facility where the proposed research will take place (University of Colorado, 2016). DEA security requirements include storing cannabis in a safe, a steel cabinet, or a vault, and limiting access to the storage facility to “an absolute minimum number of specifically authorized employees.12 The extent of the security measures required by DEA varies with the amount of cannabis being stored,13 and among local DEA jurisdictions (Woodworth, 2011). Funders must bear the costs of meeting the necessary security requirements.
Additionally, as with any human clinical trial, approval from an institutional review board must be sought.14 Obtaining this approval confirms that an appropriate plan to protect the rights and welfare of human research subjects has been outlined in the proposed research efforts. If a study is being conducted in a clinical research center, a separate review may be required by this entity's medical or research advisory committee.
In summary, basic and clinical researchers seeking to obtain cannabis or cannabinoids from NIDA for research purposes—including efforts to determine the value of cannabis or cannabinoids for treating a medical condition or achieving a therapeutic end need—must obtain a number of approvals from a range of federal, state, or local agencies, institutions, or organizations. This process can be a daunting experience for researchers. The substantial layers of bureaucracy that emerge from cannabis's Schedule I categorization is reported to have discouraged a number of cannabis researchers from applying for grant funding or pursuing additional research efforts (Nutt et al., 2013). Given the many gaps in the research of the health effects of cannabis and cannabinoids, there is a need to address these regulatory barriers so that researchers will be better able to address key public health questions about the therapeutic and adverse effects of cannabis and cannabinoid use.
CONCLUSION 15-1 There are specific regulatory barriers, including the classification of cannabis as a Schedule I substance, that impede the advancement of cannabis and cannabinoid research.15
Barriers to Cannabis Supply
In the United States, cannabis for research purposes is available only through the NIDA Drug Supply Program (NIDA, 2016a). The mission of NIDA is to “advance science on the causes and consequences of drug use and addiction and to apply that knowledge to improve individual and public health,” rather than to pursue or support research into the potential therapeutic uses of cannabis or any other drugs (NIDA, 2016b). As a result of this emphasis, less than one-fifth of cannabinoid research funded by NIDA in fiscal year 2015 concerns the therapeutic properties of cannabinoids (NIDA, 2016c).16 Because NIDA funded the majority of all the National Institutes of Health (NIH)-sponsored cannabinoid research in fiscal year 2015 (NIDA, 2016c),17 its focus on the consequences of drug use and addiction constitutes an impediment to research on the potential beneficial health effects of cannabis and cannabinoids.
All of the cannabis that NIDA provides to investigators is sourced from the University of Mississippi, which is currently the sole cultivator of the plant material and has been since 1968 (NIDA, 1998, 2016a).18 In the past, the varieties of cannabis that were available to investigators through NIDA were limited in scope and were not of comparable potency to what patients could obtain at their dispensaries (Stith and Vigil, 2016). Because of restrictions on production and vicissitudes in supply and demand, federally produced cannabis may have been harvested years earlier, is stored in a freezer (a process that may affect the quality of the product) (Taschwer and Schmid, 2015; Thomas and Pollard, 2016), and often has a lower potency than cannabis sold in state-regulated markets (Reardon, 2015; Stith and Vigil, 2016). In addition, many products available in state-regulated markets (e.g., edibles, concentrates, oils, wax, topicals) are not commonly available through federal sources (NIDA, 2016d). Since the products available through the federal system do not sufficiently reflect the variety of products used by consumers, research conducted using cannabis provided by NIDA may lack external validity. In July 2016, NIDA posted a formal request for information on the varieties of cannabis and cannabis products of interest to researchers (NIDA, 2016e). Reflecting the perceived shortcomings of cannabis and cannabis products currently provided by NIDA, a summary of the comments received in response to this request states that “the most consistent recommendation was to provide marijuana strains and products that reflect the diversity of products available in state dispensaries” (NIDA, 2016e).
Naturally, it is difficult for a single facility at the University of Mississippi to replicate the array and potency of products available in dispensaries across the country. It is worth noting, however, that NIDA has been increasingly responsive to the needs of clinical investigators. For example, NIDA has contracted with the University of Mississippi to produce cannabis strains with varying concentrations of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) (NIDA, 2016d), and NIDA has previously authorized development of cannabis extracts, tinctures, and other dosage formulations for research purposes (Thomas and Pollard, 2016). As mentioned above, NIDA has sought public comment on the needs of cannabis researchers in order to inform efforts to “expand access to diverse marijuana strains and products for research purposes” (NIDA, 2016e). In addition, cannabis is made available to research investigators funded by NIH at no cost.19 Finally, the DEA has adopted a new policy that increases the number of entities that may be registered under the Controlled Substances Act (CSA) to grow (manufacture) marijuana to supply legitimate researchers in the United States.20 Under this new policy, the DEA will facilitate cannabis research by increasing the number of private entities allowed to cultivate and distribute research-grade cannabis. As of December 2016, the University of Mississippi remains the sole cultivator of cannabis provided to researchers by NIDA (NIDA, 2016a).
Although new plans are being made to provide a wider array of more clinically relevant cannabis products for research, at present this issue is still a significant barrier for conducting comprehensive research on the health effects of cannabis use. How the proposed changes will affect cannabis research in the future remains to be seen.
CONCLUSION 15-2 It is often difficult for researchers to gain access to the quantity, quality, and type of cannabis product necessary to address specific research questions on the health effects of cannabis use.
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Originally Posted by Swordsmyth
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