Hey readers,
It's Oshan Jarow here. For 38 years, the Multidisciplinary Association for Psychedelic Studies, or MAPS, has been working toward undoing the prohibition of psychedelic drugs. Their strategy: gain FDA approval for MDMA, the club drug turned novel PTSD treatment. But a few weeks ago, the FDA rejected the MDMA therapy proposed by Lykos Therapeutics, the for-profit outgrowth of MAPS.
I've previously reported how choosing the drug, MDMA, and the condition, PTSD, were political choices. In 2022, a letter from the US Health and Human Services Department's assistant secretary for mental health and substance use signaled that even the Biden administration expected MDMA therapy to pass.
But echoing concerns around how well the Lykos data actually demonstrated safety and efficacy prior to the August vote, the FDA asked the company for another Phase 3 clinical trial, which would take millions of dollars more and several years, at least. Shortly after, Lykos cut 75 percent of its staff; the founder of MAPS, Rick Doblin, resigned from the Lykos board; and the journal Psychopharmacology retracted three papers that had been part of the evidence base for MDMA therapy.
The hope for Lykos's treatment was to launch a new era of medicine for the mind and body. (Maybe even one that assumes less of a distinction between the two). Instead, proponents for the mainstreaming of psychedelics are now wondering whether the path forward includes therapy at all.
Will the psychedelic therapy bundle unravel?
It's worth acknowledging the simplest answer as to why things went sideways. The most obvious explanation is still probably one of the most relevant: The data just wasn't compelling enough to satisfy the FDA.
The safety database assembled by Lykos included data from 476 participants, which the FDA said was too small to make confident assessments on some of the potential risks, like heart complications from elevated blood pressure and heart rate. Other data was left uncollected, like positive reactions to MDMA that help regulators gauge abuse potential.
And there was the specter of functional unblinding: when participants can pretty accurately guess whether or not they've been given a psychedelic, placebo controls are less effective in reducing biased results. That cast doubt on how much of the improvements — roughly 70 percent of participants with PTSD across the two Phase 3 clinical trials showed enough healing to no longer meet the criteria for having the condition — were actually attributable to the drug versus people's expectations of healing, or disappointment at receiving a placebo.
But the drug is only half of the equation. The other component is psychotherapy, which received surprisingly little attention, let alone clinical trials to determine the safety and efficacy of the actual therapy protocol.
That's especially strange since the therapy protocol MAPS used across all of its clinical trials is unusual, particularly from a regulatory perspective. One of its core ideas, the mechanism of healing, is encouraging "the participant to trust their inner healing intelligence," or a person's "innate capacity to heal the wounds of trauma." It also mentions that "the participant may have transpersonal experiences that might transcend conventional Western concepts of consciousness." This is all language I would absolutely love to be a fly on the wall as the FDA discusses.
Some critics worried that the unusual protocol, with its allowance of certain forms of physical contact between therapist and patient (like holding a participant's hand, or "focused body work" where therapists give patients resistance to push against), can actually incentivize boundary violations.
But in all likelihood, the FDA probably didn't discuss inner healing or the Western concepts of consciousness, because it doesn't regulate therapy. That left the agency in a difficult spot, having to consider approving a treatment where a very consequential half — in terms of both safety and efficacy — was beyond its control.
Given the decades of preparation, certainty of intense scrutiny, and intention to break away from the psychedelic stereotype of hippies and love-is-all-you-need, it's interesting that MAPS still built its therapy protocol around something as far-out, at least relative to mainstream psychology, as an inner-healing intelligence.
I asked MAPS about this. Director of communications Betty Aldworth responded that "the only thing about the MDMA-assisted therapy protocol that is alien to mainstream psychiatry is the eight-hour session." She pointed to the rise of integrative therapy techniques — a category defined by flexibility and tuning techniques to meet a patient's particular needs in which they see their own treatment protocol — which has been gaining wider acceptance since the 1990s.
Still, I find it hard to imagine that if MAPS had chosen to integrate MDMA with a mode of therapy grounded in more evidence and mainstream familiarity, like cognitive behavioral therapy (CBT), it would have faced less turbulence.
That being said, I'm not sure that MDMA plus CBT would make for better patient outcomes than a protocol more specifically tuned to the nuances of working with a substance like MDMA. CBT was not designed for psychedelic drugs. It wields the powers of rational reflection to try and reprogram unhelpful or harmful patterns of thought. Given the strange power of psychedelics, designing a therapy protocol that works with that power, rather than ignores it, does make sense.
But doing so might have also harmed their chances at FDA approval.
Does evangelism undermine scientific integrity?
Questions around therapy aside, both MAPS and Lykos faced another issue: the ethics of having passionate advocates leading psychedelic research.
In a letter submitted to the FDA shortly before the June 6 advisory committee meeting, a participant from MAPS's first Phase 3 trial recalls her therapist telling her she was "helping make history," that she was "part of a movement," and reminding her that her actions during and after the trial "could jeopardize legalization."
This kind of pressure should never be placed on patients, much less when suggestibility-enhancing drugs are involved, and even less when you're trying to convince the world that psychedelic science is legitimate and trustworthy.
Through the past year, allegations that a culture of "psychedelic evangelism" is undermining the integrity of psychedelic science have been mounting.
Aldworth, the MAPS director of communications, couldn't speak to the specific incident, but said that such external pressure to "perform well" can interfere with a person's treatment and cause intense suffering. She added that the trial therapists were explicitly trained not to "bring the psychedelic hype into the sessions," and noted that Lykos used independent adherence raters to observe recordings of randomly selected sessions to ensure therapists were following protocol.
The incident wasn't exactly isolated. Former MAPS staffers have spoken out about "a culture that brushed ethical issues under the rug," as Anna Silman of Business Insider recently reported.
I don't think it's necessarily a problem to be funding science, even managing clinical trials, about something you believe in. But it does raise the risk of bias, and demands an even higher commitment to strategies for mitigating those risks.
Rather than zooming in on what MAPS or Lykos can do differently to guard against bias, the best thing that can happen for the quality of psychedelic science is to expand and diversify the field. The more points of view, types of organizations, research questions, and sources of funding, the more psychedelic science can insulate itself from the blind spots or biases of any one in particular.
What's next for psychedelic therapy?
So should emerging psychedelic companies bend their treatment protocols toward what has the best chance of passing the system as it is? Or, should they commit to optimizing for patient outcomes, which even former director of the National Institute of Mental Health Thomas Insel writes means emphasizing therapy, while making the overall treatment "ill-suited for FDA review"?
Some psychedelic therapies, like the biotech company Compass Pathways's psilocybin treatment for depression, already use a scaled-back form of therapy, which they call "psychological support."
That's at least in part due to the differences between MDMA and psilocybin. On the former, you generally still have your wits about you — so a talk therapy session is a perfectly viable thing to do. Your usual sense of self is largely still there, just with an infusion of more neurotransmitters like serotonin and oxytocin. Or, from the first-person perspective: love. On psilocybin, carrying on a conversation with a therapist could be a bit more of a challenge, and even undermine the potency of the experience.
But, crucially, the FDA's decision doesn't change much for the other, ongoing realms of the psychedelic revival. State legalizations, religious exemptions, and academic research can all carry on largely unaffected. There already exists an immense base of historical and anthropological evidence for their efficacy in other domains, like spiritual and religious practices. (FDA approval of Lykos's treatment wouldn't have automatically guaranteed rescheduling or legalization of all MDMA, anyway.)
Whatever happens with questions around the unbundling of psychedelics and therapy, reporting on this saga over the past few months has left me with a sense that there's a larger unbundling in order: that of psychedelic medicine from the psychedelic revival at large. The two are, frankly, different ball games. The quicker we can untangle them, and avoid conflating one with the other, the better for both.
—Oshan Jarow, staff writer
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