The Nuts and Bolts of Psychedelic Research

In the guidance, FDA focuses on the “unusual characteristics” of psychedelic drugs – including the hypotheses that psychedelic drugs have “both rapid-onset and long-term benefits after only one or a few doses,” as well as the recognition that the development of psychedelic drugs in this manner is new and developing. The guidance addresses chemistry, manufacturing, and controls; nonclinical research; clinical pharmacology; and abuse potential.    

• Chemistry, Manufacturing, and Controls: FDA makes clear that sponsors must provide sufficient chemistry, manufacturing, and controls information to ensure proper identification, quality, purity, and strength of the investigational drug substance and drug product. If plant material, algae, macroscopic fungi, or some combination is used, FDA refers readers to its Botanical Drug Development guidance.
• Nonclinical: While FDA recommends that nonclinical programs for psychedelic drugs should follow recommendations outlined in the guidance Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals, FDA also recognizes that there are unique considerations for psychedelics.
  • Recognizing that prior clinical studies may provide sufficient information about the lack of safety concerns with human exposure, it may be reasonable for clinical studies with certain psychedelics to be initiated under an IND. FDA clarifies, however, that psychedelics without an adequate history of clinical exposure should not be tested in humans until the safety has been established in nonclinical studies, which should be used to support further development of the use of psychedelic drugs.  If the treatment effect is not durable and repeat dosing is expected, nonclinical studies should be provided to support chronic or chronic-intermittent dosing.  The particular treatment paradigm will dictate the number and types of nonclinical studies needed to support approval.
• Clinical Pharmacology: FDA also addresses clinical programs, highlighting the importance of considering the unique properties of psychedelics and their clinical aspects. These aspects include, for instance, the effect of a high-fat meal on the pharmacokinetics of an oral psychedelic drug, drug-drug and drug-disease interactions, long-term exposure to 5-HT2B agonists, and known pharmacodynamic interactions. Additionally, FDA suggests that sponsors take appropriate steps to characterize the dose-response relationship.
• Clinical: FDA suggests that just like other drugs, the substantial evidence standard applies to psychedelics. But it does highlight the following unique considerations that it recognizes may present challenges and offers some suggestions:
  • The use of a traditional placebo may be difficult for assessing adequacy for psychedelics. Functional unblinding may be inevitable given the “intense perceptual disturbances that can develop.”
  • Blinded researchers and questionnaires should be considered.
  • Complementary trial designs should be considered – including for example “a trial using a low, middle, and high dose without a placebo” with a “placebo-controlled trial.”
  • Particularly unique in this arena is the fact that “[m]any of the psychedelic drug development programs involve administering the investigational drug and then engaging in a psychological support or psychotherapy.”  This additional variable complicates the assessment of effectiveness and presents a challenge for future labeling.
  • Subjects receiving active treatment with psychedelics may remain in a vulnerable state for as long as 12 hours; accordingly, safety-monitoring should be implemented and FDA endeavors to provide additional guidance on this subject.
  • Clear, informed consent should be utilized.
  • Sponsors should address mitigation of adverse events or serious risks during the clinical studies.
• Abuse Potential Assessment: According to FDA, because psychedelics act on the central nervous system and produce psychoactive effects, abuse potential should be evaluated during drug development. FDA also highlights that activities associated with investigations under an ID for Schedule I controlled substances must comply with applicable DEA regulations.

The Implications of the Draft Guidance on the Cannabis Industry

We previously asked whether the advancement of the psychedelic industry was a zero-sum proposition vis-à-vis the cannabis industry or whether we would see a rising tide phenomenon for both of the new therapies. FDA’s draft guidance on psychedelic research raises that question anew.

In January of this year, FDA issued final guidance for clinical research for the development of human drugs containing cannabis or cannabis-derived compounds. When we compare the two, the draft psychedelic guidance seems to further the perception – right or wrong – that the research on the medical benefits of psychedelics has been more clinical in nature. While the psychedelic guidance focuses largely on parameters for clinical studies, the cannabis guidance focuses much more extensively on sourcing the cannabis. Some sources have attributed the difference in perception to the fact that psychedelics have been shown in some initial studies to have clinical benefits, while cannabis became mainstream largely through legislation as opposed to clinical studies. 

There are certainly positive takeaways for the cannabis industry though. A review of the psychedelics guidelines highlights a concern with respect to psychedelics that we have not seen as much with cannabis – the purported “high potential” for abuse with psychedelics. Additionally, we think much of this guidance could help sponsors and researchers looking for new ways to use cannabis medically (see Medical Marijuana Research Act; Medical Marijuana and Cannabidiol Research Expansion Act; VA Medicinal Cannabis Research Act of 2023). 

We’re bobbing on the surface, and time will tell whether the federal government advances psychedelics or cannabis more quickly as a therapeutic. We continue to think the psychedelic industry has the momentum, but it also faces new challenges that are all too familiar to the cannabis industry. We could have come so very far, but we suspect little will be accomplished in an election year. But stay tuned as we follow the progress of these novel therapies and the government’s acceptance of them, which we believe is a matter of when, not if.