On Friday, the fledgling field of psychedelic medicine suffered a major setback. The FDA declined to approve MDMA-assisted therapy for PTSD, instead asking the drugmaker Lykos Therapeutics to conduct another clinical trial to better show that the treatment is safe and effective. The agency’s full reasoning was shared only in a private letter to the company, but an advisory committee previously raised concerns about missing data on adverse events, accusations of misconduct that endangered patients, and concern that participants knew whether they received the drug or the placebo.
The FDA’s decision, its first on a psychedelic drug, will likely only delay psychedelic medicine’s official debut in mainstream medicine. Lykos plans to ask the agency to reconsider. But even this initial rejection could prompt major shifts in how researchers, drug companies, and regulators deal with a poorly understood and hotly contested part of psychedelic therapy—the therapy itself. To many proponents of psychedelics, the combination of therapy and drugs has the greatest potential to change how the U.S. deals with mental health. Friday’s rejection highlights the difficulty in pushing this combo through the drug-focused FDA. Now some experts worry that approval might hinge on dropping the therapy component, turning psychedelics into just more pills to pop.
Although many drugs work best when taken in a therapeutic context—think antidepressants and psychotherapy—psychedelic therapy traditionally requires it. Intentionally combining mind-bending substances with talk therapy is thought to be safer, and to catalyze changes that neither a drug nor therapy could spark alone. Yet the majority of research has focused on the effects of MDMA, psilocybin, and other psychedelics because the future of these substances depends on the FDA approving the drugs. That focus has left many questions about the therapy itself unanswered, which ultimately complicated regulatory approval for Lykos.
Taking time to more carefully research the role that therapy plays in treating patients with psychedelic drugs could force the field to actually suss out what’s working, and why. But Lykos’s initial failure could push the field away from therapy-heavy approaches altogether. “If I were running a drug company that’s not interested in revolutionizing mental-health care, I’d be stripping out the therapeutic components,” Boris Heifets, a neuroscientist at Stanford University, told me. “I think that’s unfortunate, but it’s the least risky path to approval.”
Lykos’s version of MDMA-assisted therapy traces its origin to the early days of psychedelic research, when mystical ideas about the nature of the self intermixed with science. A key tenet of the therapy, designed to treat PTSD, is that people possess an inner wisdom or intuition that “might have a sense for how to move forward,” says Ingmar Gorman, a psychologist and the CEO of Fluence, a psychedelic-therapy-training organization. MDMA helps unlock this inner wisdom, the thinking goes, by bringing up difficult experiences. The therapist tries to let these experiences guide the session but uses their own intuition to help the patient through. Afterward, integration sessions help the patient process the experience. This general approach, in which therapists help people make sense of often profound and difficult psychedelic journeys, underlies the bulk of promising psychedelic studies to date.
But across nearly all of these studies, the role of talk therapy isn’t rigorously examined. It’s held more or less constant for treatment and placebo groups, to isolate the effects of the drugs. That’s important, of course, but leaves a key part of the psychedelic equation largely unexamined. Such studies can’t say what elements of this elaborate and extended therapy are actually helping patients. “It’s a problem,” Amy McGuire, a bioethicist at Baylor College of Medicine, told me. “As a field, we don’t really understand how much the therapy contributes to the efficacy of the drug.” Lykos’s data couldn’t clarify this question, and although the FDA doesn’t regulate therapy, per se, “they’re concerned about it and want to understand what role it’s playing,” McGuire said.
That’s doubly important given that patients can sometimes get worse because of the intense and distressing experiences they can have on psychedelics. In Lykos’s trials, three people who got MDMA told The Wall Street Journal that their suicidal ideation worsened during or after the therapy, and some patients reported misconduct from therapists, including unwanted touching and restraint, that caused lasting psychological harm. Lykos says it investigates all allegations of misconduct, and has taken action against two therapists in one instance. Neşe Devenot, a psychedelics researcher at Johns Hopkins University who studies bioethics, argues that Lykos’s intuition-guided model puts patients at risk of harm and abuse. “They have this assumption that, under MDMA, you can get people to have a greater tolerance to enduring the stress that they would ordinarily recoil from,” she told me. That can help some overcome their illness, but “I’ve talked to people who just got a lot worse from that,” she said. “The therapy component matters, and we need to pause and assess these models.”
Lykos’s approach to therapy isn’t the only option in psychedelic medicine. Some researchers are studying how more traditional psychotherapies—including cognitive behavioral therapy, and acceptance and commitment therapy—could be blended with psychedelics to make treatment breakthroughs. But here, too, little rigorous research has evaluated what parts of these therapies are most useful.
A good relationship with a therapist might be all that matters for good outcomes, instead of the precise form of therapy. Or certain psychotherapeutic concepts, such as questioning unhelpful core beliefs, might prove especially important in certain groups. Understanding which parts of psychotherapy are necessary and which could be dangerous for different mental illnesses would be crucial in making sure approved therapies will work well in the real world, experts told me.
Some researchers hope Lykos’s rejection signals other companies to do more rigorous research. “It’s an opportunity to better understand what’s necessary, from a psychotherapeutic perspective, to maximize efficacy,” McGuire told me. To start, that could involve trials that compare a treatment regime like Lykos’s nondirective approach to patients that receive a drug with minimal therapeutic intervention. Researchers could also compare different psychotherapeutic approaches, pitting CBT against exposure therapy but keeping the drug constant, for instance.
But psychotherapy trials can be hard to do. “Because there’s so many common factors among different psychotherapies, you need a large sample to really unearth that unique ingredient in each psychotherapy,” Jacob Aday, an experimental psychologist at the University of Michigan, told me. Such trials require significant time and money, considering that each participant receives hours and hours of care. As valuable as they might be, companies have little financial incentive to invest that time and money, Suresh Muthukumaraswamy, a neuropharmacologist at the University of Auckland, says. “You can’t patent the delivery of a pattern of words and actions.”
Many companies with psychedelic drugs in the regulatory pipeline are trying to minimize therapy as much as possible. Compass Pathways, a London-based psychedelic start-up, is pushing a model of psilocybin therapy that tones down the role of psychotherapy, calling it “psychological support.” MindMed, a U.S.-based biotech company, earned an FDA breakthrough-therapy designation for an LSD-based treatment for anxiety that the company says involves no psychotherapy whatsoever. “I think biotechs are going to adapt what they offer to fit through the specific regulating requirements of the FDA,” Jules Evans, who directs the Challenging Psychedelic Experiences Project, told me “But that doesn’t necessarily translate to the optimum treatment for patients.”
Such stripped-down approaches are still controversial in a field where many hold strong convictions that robust therapy, in some form, really matters for lasting benefits. But if therapy-lite approaches start showing some benefit without all the baggage, they could come to dominate the market. Although that would undoubtedly help meet the tremendous need for new mental-health treatments, it could deflate attempts to fully understand whether therapy matters, and what forms are most transformative.