by Lisa Jarvis
What could have been a huge moment in psychedelics’ quest for medical legitimacy was instead a major misstep for the field. Last week, the Food and Drug Administration’s expert advisers sent a strong message that Lykos Therapeutics Inc.’s MDMA-assisted therapy for post-traumatic stress disorder was not ready for prime time. The FDA doesn’t have to take its advisers’ advice, though in this case it should. Lykos simply made too many mistakes to ignore.
MDMA, which most people know as the street drug ecstasy, is the first psychedelic to make it this far in the regulatory review process, setting the stage for all the other street drugs-turned-mental health treatments to come. Whatever the FDA decides in this case will be seen as setting a precedent for how others are evaluated.
Getting to this point has taken decades. The nonprofit Multidisciplinary Association for Psychedelic Studies, which later spun out the public benefit corporation Lykos, first asked the FDA for permission to begin human tests of MDMA in 2001. In the intervening years, a growing number of biotech companies have gambled on finding benefits to the therapeutic use of LSD, psilocybin, DMT and other hallucinogens. Recreational psychedelics have become brain candy for Silicon Valley titans and coping tools for stressed-out moms.
That momentum put a spotlight on the regulatory review for Lykos’s drug, which would become the first new drug for PTSD in roughly 25 years. Approval wouldn’t only help the 13 million Americans who suffer from PTSD each year. It would reveal a regulatory path for other companies to follow and lend medical credibility to psychedelics.
Unfortunately, Lykos blew it. Yes, the company’s data were promising. Most of the people who received the drug alongside therapy in two Phase 3 trials saw their symptoms improve and many saw their condition go into remission. But the process had flaws too deep and too numerous for the agency’s advisors to ignore. Ultimately, only 2 of the 11 committee members felt the efficacy data was compelling, while just one believed its benefits outweighed its risks.
Some of those flaws were expected. As I’ve written before, psychedelics present fundamental challenges to running placebo-controlled trials. The most basic is that their mind-altering qualities mean people know when they’re getting them. That sets up a so-called expectation bias, a phenomenon wherein people believe they are improving because they know they are receiving the drug.
Another issue complicating matters is that MDMA on its own doesn’t resolve PTSD, but allows people to confront and process difficult and intrusive memories in the context of a licensed therapist. But there are also some fundamental unknowns about what that therapy looked like in the trial — and should look like in the real world. Are certain types of talk therapy more effective than others? How much does the trust built between a therapist and patient matter to MDMA’s benefits?
Moreover, therapy does not fall under the FDA’s purview. That means the agency has little control over the quality of that essential component of MDMA-assisted care.
All companies pushing for approval of hallucinogens will face such challenges. And Lykos made an already-tough case that much harder with several egregious missteps.
Among the company’s head-scratching errors: The company failed to collect lab samples from patients, a standard component of clinical drug development that allows regulators to ascertain, for example, that a treatment doesn’t cause liver damage.
And then there were hints of all-out misconduct. Some patients reportedly had been dissuaded from participating in a long-term follow-up study, data that was critical for showing not only that MDMA’s effects were lasting and safe, but also that patients did not later seek out illicit MDMA. And during the public commentary portion of the meeting, some patients suggested Lykos had ignored worrisome side effects.
Last, but certainly not least, a horrifying report of sexual misconduct by therapists during an early clinical study — caught on video — hung over the daylong meeting. MDMA puts people in an extremely vulnerable position. That’s its point: to crack open and process deep-seated memories. But in the hands of a bad actor, that quality is also its biggest liability.
As Melissa Decker Barone, a psychologist with the VA Maryland Health Care System, pointed out during the discussion, any one of these problems might have been something the panel could overlook. But taken together, they leave open too many questions about the efficacy and durability of the treatment.
Some of the FDA’s advisors noted that it was especially hard to ignore these flaws when evidence-backed options for treating PTSD already exist. That’s true, but there’s no doubt that better treatments are needed.
Many PTSD-sufferers aren’t helped by the existing approaches. The two available medicines leave a lot of room for improvement: Less than 20–30% of people who use them permanently recover. Psychotherapy on its own can feel long and slow. Many give up.
People with PTSD, many of whom are veterans or survivors of sexual trauma, need and deserve relief. There’s good reason to believe that the next wave of investor-backed biotech companies developing psychedelics are doing a better job of following the rules of engagement for clinical trials — and many of the agency’s advisors noted that MDMA shows great promise. But Lykos’s performance at this week’s hearing sent stocks down across the field, and it’s not hard to see why.
Last year, for the first time, the FDA provided draft guidance on what it needs to see out of clinical trials for psychedelics. The next wave of companies doesn’t seem likely to repeat all of Lykos’s mistakes, but if they truly intend to bring this field into conventional medical practice, they might want to re-read it.
