Psychedelics’ Use as Medicine Hits Significant Roadblock

Back to table of contents Previous article Next article Clinical both are in phase 3 trials.While the committee's vote is not binding, the agency often follows its recommendations. The FDA is expecting to render a final decision on the application by Lykos Therapeutics for its MDMA-assisted psychotherapy (MDMA-AP) by August 11. Lykos remains "committed to working with the FDA to address outstanding questions so that we may find a path forward," said Amy Emerson, Lykos Therapeutics' Chief Executive Officer, in a media release following the decision.Experts Weigh In"On paper, MDMA-AP is an extraordinarily effective treatment for PTSD. The numbers look quite good," said Sandeep Nayak, M.D., medical director for the Center for Psychedelic and Counsciousness Research at Johns Hopkins Medicine.MDMA, also known as ecstasy, is a psychedelic that elicits feelings of empathy or social connectedness. It may enhance the benefit users obtain from psychotherapy by reducing sensations of fear or threat."The concern is that this outcome data is not real, that these effects are driven by biased reporting, misrepresentation, overly enthusiastic therapists, or even wild placebo effects."Nayak told Psychiatric News that it's now hard to imagine the agency approving the medication in August. "It's not just relevant for MDMA, but the vote could have repercussions for all psychedelics being investigated as mental health treatments moving forward."One major issue raised by the committee – one that applies to all placebo-controlled research of psychedelics– is that their unmistakable effects result in "functional unblinding." In other words, nearly all participants who received MDMA easily guessed their treatment assignment, as did those who received the placebo. Research staff could likely tell as well. This could lead to biases, including expectations of improvement among those receiving the highly anticipated drug or disappointment among placebo users, which could significantly impact the outcome."The advisory committee gave no help and no advice and didn't seem to know what to do about the issue of functional unblinding," Jerrold F. Rosenbaum, M.D., psychiatrist-in-chief emeritus and director of the Center for the Neuroscience of Psychedelics at Massachusetts General Hospital, an affiliate of Harvard Medical School, told Psychiatric News."What if there were a treatment that worked for everyone who took it for a certain condition, whether arthritis, insomnia, or depression, but there was no mistaking who was on it? Would that mean the FDA would never approve it?" Rosenbaum said. "We must come up with a way to deal with this. One of the advisory committee members said, 'I've never seen an effect size this large.' Yet people couldn't figure out how to get past the issue of functional unblinding."States Consider Expanded Psychedelic AccessThere is concern that regulatory consideration of psychedelic treatments will only add fuel to the burgeoning nonmedical use of these substances across the country.Altogether, various psychedelic initiatives — from decriminalization and state research to pilot programs and supervised use — are ongoing in some 20 states and a handful of cities. Oregon Health Authority launched its program regulating the administration of psilocybin last year and has now issued permits to 30 "service centers" across the state, where clients consume psilocybin supervised by approved facilitators.Colorado legislation also created a regulatory structure designating "healing centers" where people may begin using psilocybin mushrooms under supervision in 2025, with mescaline becoming available in 2026."The last thing we want is for promising new treatments for serious mental health conditions to go off the rails with a conflation between rigorous, medically supervised use, evaluation, and follow-up, and recreational use outside of a clinical framework," said Jonathan E. Alpert, M.D., Ph.D., Chairperson of APA's Council on Research. "The conditions we're talking about, posttraumatic stress disorder or major depressive disorder, for example, are far too serious and impactful to allow their treatment to be pursued in this way." The Institute for Clinical and Economic Review (ICER) issued a research report in May rating the overall evidence presented by Lykos as "insufficient" and expressed substantial concerns about the clinical trial results' validity. Like the committee, ICER also took issue with the functional unblinding: "…These concerns are particularly heightened as we heard from multiple experts about the very strong prior beliefs of those involved in the trials (as investigators, therapists, and patients) about the benefits of MDMA-AP."The ICER report also noted allegations that some therapists involved in the trial encouraged participants to give the drug favorable reviews and discouraged participants from reporting substantial harms."Those allegations are extremely serious and should be independently investigated," Nayak said. "We should not simply assume there was undue influence and that it affected the outcome."Safety Concerns, Role of TherapyA few days prior to the advisory committee meeting, FDA staff raised other concerns around MDMA's safety, including significant increases in participants' blood pressure and pulse that could trigger cardiac problems, limited collection of clinical laboratory data, and incomplete QT-interval assessments. The committee also raised concerns about sexual abuse of participants that occurred during MDMA trials. Another concern was lack of data about the durability of the treatment's effect, particularly because 25% of participants dropped out of the long-term trial.Another big challenge is that MDMA is used to facilitate psychotherapy, a treatment modality that the agency is not authorized to regulate, Rosenbaum pointed out. "That meant that everyone was in a new place, which was going to require some thought."Jonathan E. Alpert, M.D., Ph.D., chairperson of APA's Council on Research, told Psychiatric News that all participants received an intensive novel therapy developed expressly for the MDMA clinical trial. It involved a male and female therapist simultaneously delivering three 8-hour treatment sessions, plus six additional 90-minute sessions over a four-month period. "Its influence was not controlled for, so we're left not knowing to what extent this particular form of therapy was essential to the results," said Alpert, who also serves as Silverman University Chair in the Department of Psychiatry and Behavioral Sciences and psychiatrist-in-chief at the Montefiore Medical Center and the Albert Einstein College of Medicine.Nayak said that because psychotherapy has become a major sticking point for Lykos' MDMA application, other psychedelics investigators will likely reduce or recharacterize psychotherapy in future trials. Patient safety could suffer as a result, he added. "The provision of therapy in these trials is protective of patients and administering psychedelics as pure drug treatments is riskier."APA submitted comments to the FDA advisory committee ahead of the meeting expressing support for research into the use of psychedelic agents in general, but stressed such endeavors must be conducted with the same scientific integrity and regulatory standards afforded to other emerging therapies. APA also urged a cautious approach: "Any FDA approval of MDMA must be accompanied by rigorous regulations, strict prescribing and dispensing controls, comprehensive patient education, and ongoing monitoring and surveillance systems," according to the letter.Alpert said the advisory committee meeting doesn't spell the end of psychedelics or novel treatment research, but rather points to an encouraging emphasis on safety and proven efficacy. "This is a promising area of science for the field of psychiatry, whether it leads to an approved psychedelic medication in the near future or to further research on new mechanisms of treatment for PTSD. This is an exciting and positive time." ■ResourcesAPA's "Position Statement on the Use of Psychedelic and Empathogenic Agents for Mental Health Conditions"FDA's MDMA briefing documentThe Institute for Clinical and Economic Review's "Midomafetamine-Assisted Psychotherapy for Post-Traumatic Stress Disorder" ISSUES NewArchived