Federal Scientists Outline the Challenges Facing Clinical Cannabis Research in New Paper
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Significant changes in United States’ drug policies over the past few years have accelerated cannabis-related research and led to the approval of new cannabis-based medicines by the US Food and Drug Administration. However, on the grander scale, there are still significant barriers to the advancement of cannabis research.
In a new paper published in JNCI Monographs, experts from the National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH), US Food and Drug Administration (FDA), and two clinical researchers at the University of California have outlined the major challenges to conducting cannabis research studies according to each of their unique perspectives.
The challenges named by the group include the complex regulatory status of cannabis, sourcing high-quality cannabis products for study, and issues surrounding funding and support for newer researchers.
The regulatory status of cannabis leads to confusion
While the 2018 Farm Bill effectively removed hemp-derived CBD from the US’s Controlled Substances Act (CSA), it did not remove synthetically-derived CBD, the expert authors explain. Although the molecule in question is exactly the same, the origins of the compound define its regulatory standing, and so synthetic CBD is still considered a schedule I controlled substance.
This means that, despite CBD products being legally marketed and sold at gas stations across the US, most researchers wishing to study the action of CBD will have to apply for a schedule 1 license from the Drug Enforcement Administration (DEA) and deal with the additional hurdles that this brings with it. For example, prior to receiving a license, research protocols will need to be approved by an institutional review board (IRB) and the FDA and storage facilities that meet the DEA requirements for schedule 1 drugs will need to be obtained.
The regulatory situation is even more confusing for delta-9-THC, which can be classified as a schedule I, schedule II, or schedule III substance depending on the exact formulation used. Oral capsules of the synthetic THC drug dronabinol are classified as a schedule III substance, while the liquid formulation of dronabinol (sold as Syndros) is considered to be schedule II. All other forms of dronabinol are still considered to be schedule I substances, despite the drugs being the same molecule. This can make it difficult for researchers to know whether they require a schedule I license or not, especially if they are new to the field and do not have the benefit of proper guidance and support from experienced colleagues.
“Right now, we are really quite stuck by the lack of regulation surrounding cannabis,” Joshua Levy, an assistant professor of otolaryngology and director of resident research at Emory University’s Department of Otolaryngology, told Analytical Cannabis last year.
At the time, Levy and his colleagues had recently published a paper in the New England Journal of Medicine outlining the state of cannabis research-related legislation in 2020 and recommending future advancements to improve research capabilities.
“It is differentially regulated on both state, local, and federal levels,” Levy continued. “Because of that, physicians and other researchers who seek to appropriately study this potential medicine are really hamstrung.”
Sourcing cannabis and cannabinoids for studies remains challenging
An often-overlooked obstacle for researchers is the difficulty in sourcing adequate cannabis material for study. For more than fifty years, the sole, federally-approved source for research-grade cannabis has been a grow facility based at the University of Mississippi contracted to the NIDA.
This federal cannabis source has been criticized in the past for producing cannabis that is “ junk, ill-suited for clinical trials, and genetically closer to hemp than the marijuana available from dispensaries and used by Americans nationwide,” according to one lawsuit that has been filed against the facility. The DEA itself also recognizes that this cannabis source needs to begin to provide a wider variety of product and formulation types, in a range of potencies, and with variable terpene content.
“Even if we do follow the rules that are prescribed by the government and we use the only federally-regulated source for the plant, we’re actually still not studying the exact material that is being sold by state dispensaries and that is being attributed to reported health benefits,” Levy previously commented to Analytical Cannabis.
An additional aspect of this is the sourcing of placebo drugs for placebo-controlled clinical trials. These require the use of a matched placebo drug, which the JNCI Monographs authors say should ideally be manufactured by the same producer as the study drug. To this end, a federally-approved cannabis source should also be looking to provide effectively matched placebos for the drugs it provides.
In a positive step forward for the research sector, the DEA announced earlier this year that it would be moving forward with a number of applications from other cultivation facilities looking to produce federally-approved cannabis for research. If these applications are successful, this will greatly widen the supply and diversity of supply available to scientific researchers. However, the DEA has previously been slow to take action on these applications, so it remains to be seen when these extra sources of research cannabis might come into play.
Lack of funding and support for clinical studies
The monograph authors identified funding as being the “ultimate limitation to research in this field”. Despite some positive developments – NIH cannabis research support increased from $111.3 million in 2015 to $189 million in 2019 – overall, it still remains incredibly challenging to obtain adequate funding in nearly all areas of cannabis and cannabinoid research.
“With limited funding opportunities and the highly competitive nature of those that exist, a proposal’s impact and novelty are weighed alongside the study’s feasibility and potential for success in trial initiation and completion,” the authors wrote.
“A key component of study feasibility for cannabis and cannabinoid studies is the existing infrastructure needed for this type of research, including institutional support for this research, investigator expertise, and a schedule I license, if required for the study medication proposed in the grant application.”
As a result, researchers are more likely to receive funding if they can demonstrate extensive experience in the field and have the institutional support necessary to apply for a schedule I license. Scientists new to the field, therefore, are effectively shut out from conducting cannabis research, as it would be too difficult to navigate all of these regulatory requirements and obtain funding for their projects.
Without adequate funding, it is impossible to run satisfactory trials. The monograph highlights one case of a study into cannabis and sickle cell disease, which was only given enough funding to support two treatment arms – and one of these had to be a placebo. With so many potential THC:CBD ratios and delivery methods to consider, the authors question how an investigator is expected to decide what to use in such a tightly limited trial?
The future of cannabis research
In addition to exploring these three primary barriers, the monograph authors also highlight some recent changes in policy that represent positive steps forward – for example, the removal of CBD from the CSA and the recent growth in federal funding for cannabis research. The promised action on expanding the number of federally-approved sources of research cannabis would also be a welcome development for the field if these currently pending applications are accepted.
To navigate the barriers that continue to exist, the authors believe that future collaborations between experienced researchers and institutions with those who are new to the field could help to address some of the barriers to entry for cannabis research. International partnerships may also offer new opportunities by potentially avoiding some of the more difficult-to-meet regulations that exist in the United States, they say.