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Just as we did, the Food and Drug Administration has recognized the growing enthusiasm for exploring opportunities to use psychedelic medications to treat mental health disorders. In June, FDA issued for the first time draft guidance providing considerations for those developing psychedelic drugs for the treatment of medical conditions. The guidance explicitly focuses on “classic psychedelics,” which are “typically understood” as “5-HT2 agonists” like psilocybin and LSD, as well as entactogens or empathogens like MDMA. Has this put a wedge between psychedelics and cannabis?
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.