The Food and Drug Administration (FDA) has issued a draft guidance that provides general factors that should be taken into consideration by the sponsors and researchers developing therapeutic psychedelic drugs. The 14-page document was released just two days after bipartisan congressional lawmakers introduced the bill. This draft document has the promising potential to contribute to the development of psychedelic medicines.
In recent years, there has been a growing interest in psychedelic medicines, with many states across America legalizing some of these substances for medical use or considering decriminalization. Scientific research has demonstrated the potential of these medicines for mental health conditions like treatment-resistant depression, eating disorders, addiction, and post-traumatic stress disorder (PTSD). The FDA has granted breakthrough therapy designation to MDMA and psilocybin-assisted therapies, putting them on a regulatory fastrack for approval. Clinical trials have shown these medicines to be more effective than traditional medications and therapies, with limited side effects and long-lasting results (1), (2). Though these medicines show great promise in treating certain disorders, there is still much research to be done on their long-term safety and efficacy. The creation of this draft guidance will help researchers consider any challenges to psychedelic drug development programs, allowing them to design solid studies that can be used to support future drug applications.
In the guidance, the term “psychedelics” refers to classic 5-HT2 agonists like psilocybin, lysergic acid diethylamide (LSD), methylenedioxymethamphetamine (MDMA), and other substances that interact with the brain’s serotonin system. The FDA outlines several considerations for psychedelic drug development programs, noting that they are “open to discussing various approaches to address these considerations,” however, they suggest that “sponsors should engage divisions early in the drug development process.”
The FDA advises that sponsors should provide information about the drug’s chemistry, manufacturing, and quality. This requirement should apply throughout the different phases of clinical trials, and sponsors can either submit their own data or use previously submitted data. This section of the guidance also distinguishes the difference between drug products derived from plants and fungi and those genetically modified or highly purified. The drugs that are manufactured must follow specific regulations to ensure safety and quality, and different requirements would apply to drugs used in phase 1 and phase 2 studies. Each phase of the drug investigation should have enough information to prove that the substance is safe and effective.
Nonclinical studies for psychedelic medicines should follow the recommended ICH safety guidelines. In some cases, clinical studies can be initiated without animal testing if there is extensive human exposure data from previous clinical studies and no major safety concerns. There must be adequate information on the pharmacological and toxicological research included in the Investigational New Drug (IND) application. The nonclinical studies should support intermittent dosing if the drug’s treatment effect is not long-lasting. Researchers should evaluate how the drug binds to serotonin receptors, specifically 5-HT2B, due to potential heart valve issues, and there must be a thorough evaluation of the patient’s heart in every repeat-dose toxicity study for any 5-HT2B agonist psychedelic drugs.
The way that psychedelic drugs are processed in the body, and their effects should be studied in both laboratory settings and living beings. Researchers should also examine the impact of how the body processes oral psychedelic drugs after eating a high-fat meal and look into any potential interactions with other medications or health conditions. By doing so, they can create a criterion on prohibited practices, medications, and more for labeling purposes and studies. The long-term use of 5-HT2B agonists in psychedelic drugs can lead to the stiffening of cardiac valves, so any subjects with preexisting heart valve problems or pulmonary hypertension should be excluded from multiple dose studies until scientists better understand the risks. Furthermore, since the dosage and response for most psychedelic drugs are not yet well studied, sponsors should attempt to characterize this relationship for more effective treatments and patient safety.
The FDA highlights the importance of assessing the abuse potential of a drug to evaluate its safety. These drugs should be evaluated during their development, and the data from the abuse potential assessment and drug scheduling proposal should be added to an IND application. Previously published investigations can be used to support the drug’s abuse potential assessment. Since many psychedelic drugs are considered Schedule I substances due to their high abuse potential, sponsors must comply with DEA regulations for Schedule I psychedelic drugs. Abuse-related adverse events during clinical studies must be monitored and reported, and abuse potential studies should be conducted only after determining the therapeutic dose range. The proposed protocols for abuse-related studies must be submitted to the FDA for review and comment. Researchers are encouraged to communicate with the FDA and Controlled Substance Staff during the drug development process to discuss plans and obtain guidance.
Psychedelic drugs must undergo the same standards as other drugs, undergoing well-controlled clinical studies to establish their effectiveness. Designing effective psychedelic studies can be challenging due to issues with placebo controls and biases; however, alternative controls may be considered instead of inert placebos. This section recognizes that the combination of psychotherapy and psychedelic medicine makes it harder to measure the effectiveness of a drug, and the impact of psychotherapy on treatment outcomes is not yet fully understood. As a result, efforts should be made to minimize any biases resulting from the subject’s expectations of the drug. For chronic conditions, the effects of the treatment should be evaluated for a minimum of 12 weeks past the study, with an extended follow-up. In the case that a drug shows an unreasonable and significant risk to human subjects, the FDA may place a study on clinical hold. Treatment sessions should involve two observers for safety monitoring, including a healthcare professional. Additionally, measures should be taken to mitigate adverse events, and risks should be addressed during the studies and following the drug’s approval.
The FDA’s release of this draft coincides with the increasing interest of lawmakers and health officials in expanding the research of psychedelic medicine and therapy. Just a few days prior to the release of the draft guidance, Reps. Dan Crenshaw (R-TX), Mariannette Miller-Meeks (R-IA), and Ro Khanna (D-CA) filed a legislation urging the FDA commissioner to issue for public comment draft guidance on considerations for conducting clinical trials for psychedelic-assisted therapy, including how those seeking an investigational use exemption for such clinical trials should request interactive support by the Food and Drug Administration.” If passed, this legislation would have given the FDA 180 days to release the draft guidance, but the agency released it significantly sooner. Though guidance is still in its draft stages, the bill will require the FDA to finalize this guidance within the time period.
Although the guidance has not yet been finalized, it’s a significant move in assisting researchers with the creation of future studies to further the scientifically backed knowledge behind psychedelic medicines and therapies. “Right now, it’s difficult for researchers to pursue these trials without any direction at all from FDA,” says Rep. Crenshaw. “We need the FDA to issue clinical trial guidance for psychedelic-assisted therapy so that the industry can actually invest in this.”
Upon publication and finalization of the guidance, the FDA’s current position on the advancement of psychedelic therapy studies will be revealed. With additional FDA approval, the federal restrictions on these substances may be reduced, allowing for increased prioritization of psychedelic research. As a result, these medicines would be one step closer to becoming a viable and accessible treatment option for individuals who could potentially benefit from them.
The FDA will provide a public register for people to provide comments on the draft guidance. The Federal Register will publish a notification about the document, allowing a 60-day period for interested parties to give feedback on shaping the final guidance.