First published by Mad in America on August 14th 2024
Concerns, from functional unblinding to sexual assault in the clinical trials, led this week to a full repudiation of Lykos’ MDMA-assisted therapy.
Lykos Therapeutics experienced a double blow this week, with the FDA’s rejection of their proprietary MDMA-assisted therapy for PTSD and the retraction of three articles on MDMA’s supposed efficacy.
In a way, neither of these events is surprising—the research has been marred by controversy for years and the FDA advisory committee in June voted against approval. But in another sense, these are surprising wins for science in a world that is dominated by industry marketing.
Still, we are just beginning to consider the down-the-road implications of this decision.
MDMA, the club drug known as ecstasy or molly, has long been the poster child for the possible approval of illegal psychedelics as medical interventions for psychiatric conditions. The trials of this drug, beginning in the early 2000s, seemed to bring a sense of “real” medical research to a field plagued with small sample sizes, lack of control groups, unblinding, and other major methodological limitations. By late 2023, the general public perception was of two strong phase 3 trials that demonstrated the treatment’s efficacy in healing those with PTSD.
But when subjected to the FDA advisory committee’s scrutiny, the supposed strengths of these trials fell apart. That appearance of methodological rigor was revealed to be an illusion. And the ethical concerns that dogged the trials finally blew up for the journal Psychopharmacology, which realized—perhaps thanks to the advocacy of a few whistleblowers—that the researchers conducting these studies had hidden unethical conduct and protocol violations, and failed to fully disclose all their financial relationships.
According to a Medpage Today article about the FDA’s decision: “In a 9-2 vote, the Psychopharmacologic Drugs Advisory Committee said available data failed to show that MDMA was effective in treating patients with PTSD. The committee also voted 10-1 that the risks outweigh the benefits, even with a proposed risk evaluation and mitigation strategy (REMS).”
Some of the concerns were medical, involving the harmful cardiac effects of the drug. Some concerns were methodological: concerns about efficacy largely rest on the small sample size and the fact that almost all patients could tell whether they received the placebo or the drug. (An Institute for Clinical and Economic Review (ICER) report calls the studies “functionally unblinded,” meaning that the supposed methodological rigor of these trials just isn’t there.)
But other concerns raised by the advisory committee involved the allegations of unethical conduct—including sexual assault—that occurred in the MDMA trials. For one, the safety data was reported by the psychedelic guides, rather than by unblinded reviewers, and concerns were raised about sexual assault and suicidality going unreported. (Lykos’ MDMA protocol explicitly encourages the “guide” to engage in physical touch with the participant, which is particularly concerning when the participant is in an altered state from a drug known to break down boundaries.)
As the ICER report notes, “Even in carefully controlled clinical trials with two therapists of different sexes, therapist misbehavior occurred. We heard concerns about much greater risks if MDMA-AP is administered outside of such controlled settings.”
These are the concerns that led to Psychopharmacology’s retractions. The retraction notice takes strong language:
“The Editors have retracted this article after they were informed of protocol violations amounting to unethical conduct at the MP4 study site by researchers associated with this project. The authors have subsequently confirmed that they were aware of these violations at the time of submission of this article, but did not disclose this information to the journal or remove data generated by this site from their analysis. Additionally, the authors also did not fully declare a potential competing interest. Several of the authors are affiliated with either the Multidisciplinary Association for Psychedelic Studies (MAPS) or MAPS Public Benefit Corporation (MAPS PBC), a subsidiary that is wholly owned by MAPS. As is stated in the Funding declaration, MAPS fully funded and provided the MDMA that was used in this trial, and MAPS PBC organised the trial.”
Still, the pressure on the FDA to approve Lykos’ application was strong. A bipartisan group of over 60 politicians signed on to a letter urging the approval of MDMA-assisted therapy. Moreover, the evidence—two phase 3 trials that both found a positive effect of the drug treatment group compared to the placebo group—seemed more powerful than that in other recent FDA approvals, such as those for esketamine and aducanumab.
And the FDA is not required to follow the advice of its advisory committees.
Aducanumab and Esketamine
The case of Alzheimer’s drug aducanumab provides an example. By 2019, two Phase 3 trials of aducanumab were terminated early because the drug wasn’t improving outcomes and was clearly causing harm (a large percentage of the participants were experiencing brain bleeding known as ARIA). Yet the FDA worked secretly with drugmaker Biogen for two years to find new ways to analyze the data. Eventually, they managed to massage the data into showing a statistically significant effect in a subgroup of patients in one of the trials.
The FDA’s advisory board rejected this evidence, voting 10-0 (with 1 “uncertain”) against approving the drug. But the FDA approved the drug anyway based on a surrogate outcome that researchers have criticized for lack of clinical significance.
The case of esketamine, too, showcased an approval despite evidence of harms and lack of efficacy. Though there were six four-week efficacy trials of the drug for treatment-resistant depression, it failed to beat placebo in five. The drug eked out statistical—though not clinical—significance in one of the six trials, and the FDA considered that evidence strong enough to approve the drug.
Yet both of those decisions led to an outcry in the research world. Erick Turner, who was on the FDA’s advisory committee that approved esketamine, said that “Accepting just one short-term trial as being enough is a historic break from precedent.” In the same publication, antidepressant researcher Glen Spielmans added, “Based on the evidence provided in Janssen’s application, the FDA should not have approved the drug.”
After aducanumab’s approval, three advisory board members resigned in protest, and one of them called it “the worst drug approval decision in recent U.S. history.” A congressional inquiry into the approval “raise[d] serious concerns about FDA’s lapses in protocol,” and concluded that Biogen was planning to offset the negative press about the drug’s harms and ineffectiveness with billions of dollars in marketing.
The ultimate conclusion of the aducanumab scandal was that “The FDA is failing the American people.”
Perhaps it was to avoid a similar blowback and congressional investigation that the FDA was more cautious with Lykos’ application. Or perhaps the rejection of Lykos’ drug reveals something else: the powerful influence of the traditional pharmaceutical lobby at the cost of the upstart psychedelic industry.
The FDA usually bends over backwards to approve new drugs, particularly psychiatric drugs. Yet, in this instance, the advisory board complained about a lack of blinding and possible underreporting of harms. That is surely a problem, but it’s also a documented problem for other drugs. Why isn’t this concern raised about, say, antidepressants? After all, the FDA also just approved an expansion of escitalopram for seven-year-olds with anxiety, despite lack of benefit and clear evidence of increased suicidality in youth.
Perhaps because MDMA-assisted therapy isn’t a simple drug to be prescribed by psychiatrists. Moreover, Lykos is a small company bringing it to market, one that emerged out of a psychedelic research nonprofit (MAPS). And since SSRIs are prescribed for PTSD, this would be a treatment competing with pharmaceutical giants. Could their pressure—pharma giants’ influence on the FDA—have led to this decision? We may never know.
Where Might This All Lead?
Still, in this case the FDA followed the evidence, in a startling break from two recent decisions, and rejected Lykos’ treatment. Certainly, psychedelic promoters and the psychedelic industry will consider this a problem. And there are those who believe that the FDA should have no role in safeguarding the consumer from expensive and potentially harmful treatments that can’t clearly show benefit. But there’s another problem, too, and that’s how the industry is going to interpret this decision.
Already, writers are arguing that the next FDA submissions for psychedelic treatment are going to involve the drug alone, thereby omitting the troubling ethical concerns about providing therapy.
If the industry takeaway from the FDA’s rejection of MDMA-assisted therapy is to focus on the drugs and drop the therapeutic component, that would be a shame. Lykos didn’t fail because it included therapy, it failed because individual psychotherapy is a poor substitute for the psychedelic ritual. The focus on including therapy ironically revealed the emptiness of the current cultural understanding of psychedelics in Western medicine.
Maybe the real takeaway from this decision should be that the techno-utopianism of psychedelics as medicine—ushered through the bureaucratic regulatory system as part of a for-profit industry—is at odds with the life-changing profundity that many people report experiencing from these drugs. The rituals that bind indigenous communities together are diametric opposites of the psychiatric use of drugs as individual medical treatments for “mental illness.” Those ancient rituals make space for, even deliberately create, extreme states—of revelation, of intense connection with others, and of connection to the secret power of the universe—that are more akin to the very experiences psychiatry considers pathological.
Indeed, psychiatry’s goal with esketamine and other drugs is to tap into a supposed chemical healing power these drugs have without engendering an extreme experience. Esketamine nasal spray is meant to be a treatment you can do in complete isolation, without ever leaving your home, and supposedly without causing the dissociative state that has led to ketamine’s popularity as a recreational drug.
In a way, then, Lykos’ MDMA treatment is a bridge between these two worlds, the world of individual drug treatment sans experience, and the world of a ritual connecting you to others. But it’s a false bridge because the core belief is firmly rooted on the side of Western medicine—seeking FDA approval as a medical treatment will do that. Lykos’ words about “integrating the experience” and “intuition” are merely colonized language: co-opting the language of a true psychedelic ritual without bothering to include the ritual itself. Mixing psychotherapy with a drug ends up still being a dismissal of the importance of the ancient psychedelic ritual. It’s a hubristic notion, that individual psychotherapy can easily substitute for a community-binding extreme experience.
And in a culture of hype for the “next big thing,” where psychedelics are taken behind closed doors, in sessions led by odd “scientists” who think themselves gurus and act without accountability, in a culture of for-profit industry and publish-or-perish academia, the incentives for unethical behavior pile up.
Ultimately, Lykos’ failures—of ethics and of science—reveal that co-opting the powerful ritual experience that has been part of humanity for millennia and marketing it as medicine is a more difficult task than the techno-futurists hoped.