Among the most difficult to overcome: Subjects in the placebo arm of the trials — who got dummy MDMA — knew they didn’t get the real drug because they didn’t experience distortions in consciousness, according to the draft report by the nonprofit Institute for Clinical and Economic Review. In other words, the trial was not “blinded” for purposes of comparing the drug’s effect, which undermines the results.
ICER researchers also said trials may have been skewed by therapist participants who are boosters of MDMA as a mental health treatment, as well as large numbers of subjects who had previous experience taking MDMA. The report cited concerns that some participants that received MDMA felt “pressured to report good outcomes and suppress bad outcomes,” and flagged a documented case of therapist misconduct that raised safety risks.
Meanwhile, a separate group of researchers is petitioning the FDA, which put MDMA–assisted therapy on a fast track for approval, to slow down and convene an extended public hearing to consider the many unique issues at play.
The potential of psychedelics has bloomed in recent years as a treatment for mental health disorders and addiction, with technology luminaries and investors betting hundreds of millions of dollars on companies developing a range of treatments, from psilocybin to ibogaine. MDMA is the first of these to reach the doorstep of FDA approval, and leaders in the psychedelic medicine field say the agency’s decision could lay the groundwork for how the federal government regulates drugs that do not fit the mold of traditional pharmaceuticals.
“It is a huge decision with pretty sweeping consequences,” said Shane Pennington, a Washington D.C. attorney who specializes in FDA regulations involving controlled substances. “It’s going to be the first shot fired. It’s going to be precedential.”
ICER’s report highlights the complexity of the FDA’s decision as well as considerations for insurers, who use ICER’s assessments to inform decisions about coverage. While ICER staff acknowledged that some PTSD patients experienced “substantial benefit,” they found that the evidence in two positive, late-stage trials of therapy with MDMA was too murky to determine a net benefit or a fair price, according to the draft report last month.
“This is pretty unusual all the way through,” said David Rind, ICER’s chief medical officer. “If this is the best trial that can be done, it’s not that good.”
Lykos Therapeutics, the company seeking the drug approval, has said the FDA is expected to make a decision by August and said it supports the agency scheduling an open public hearing.
“We stand behind the design and results of our clinical trials and are grateful to the patients and investigators who participated in them,” a spokesperson for the company said in response to questions from The Washington Post. In a bid to preserve neutrality, the company said, patients’ PTSD symptoms were evaluated by staff who didn’t know whether participants received the drug or placebo.
Brett Waters, executive director of psychedelic advocacy group Reason for Hope, said the ICER report gives too much weight to concerns from a small number of people, and that the benefits of MDMA therapy greatly outweigh the risks. “If we overregulate, people won’t be able to afford it and it will be driven to the underground,” he said, adding that MDMA research has already proved its bona fides.
Until recently, Lykos was a wholly owned subsidiary of a nonprofit, the Multidisciplinary Association for Psychedelic Studies. MAPS, as it is known, was founded by Rick Doblin, who in the 1980s unsuccessfully tried to block the federal government from criminalizing MDMA. “I knew that the only way to bring it back was through the FDA,” he said at a 2022 event.
So MAPS embarked on a decades-long effort to prove that the drug had merit as a medicine, raising $140 million from donors to pay for clinical trials. The organization formed what is now Lykos a decade ago as a public-benefit corporation, in anticipation that MDMA-assisted therapy would win FDA approval and start to reap taxable revenue that it couldn’t manage as a nonprofit. In January, Lykos announced it had raised more than $100 million from investors, and MAPS is now a minority shareholder.
The FDA said it couldn’t comment on pending applications. The agency last summer published guidance for companies developing psychedelic medications, acknowledging “unique challenges” of taking them through clinical trials.
Zoloft and Paxil are approved by the agency to treat PTSD — a condition that affects about 5 percent of U.S. adults — but the drugs don’t always deliver relief. MDMA releases chemicals in the body that affect mood and behavior, and subdues brain activity associated with fear while promoting trust, according to MAPS researchers, enabling patients to openly discuss traumas and unlocking their “inner healer.”
The application to the FDA pairs the drug with various types of therapy, some of which critics say fall outside the mainstream of accepted science. That includes “nurturing touch” and “holotropic breathwork,” according to a MAPS manual for treating PTSD.
“It’s very kind of new age with spiritual components,” said Bruce E. Wampold, a counseling psychology professor emeritus at the University of Wisconsin at Madison who has studied the effectiveness of psychotherapy in clinical trials. “It’s on the periphery of what I would say evidence-based treatments would be.”
The Drug Enforcement Administration lists MDMA in its most restrictive category of drugs that have a high potential for abuse and no accepted medical purpose.
In late-stage clinical trials that generated buzz about what could be a fundamentally new treatment, participants who received the drug reported significantly reduced symptoms of PTSD relative to the placebo group.
Patients in the MDMA and placebo groups reported a variety of undesirable side effects, including suicidal thoughts and self-harm. Such adverse events weren’t significantly more common in the treatment group, and no participants reported an outcome that was disabling, life-threatening or required hospitalization, according to published studies.
Some researchers doubt those safety results.
Nese Devenot, a psychedelics ethics researcher who co-authored the petition, cited published accounts of MDMA trial participants describing how their symptoms worsened afterward. “I just don’t think you can make a case that the data that they’ve provided to FDA is an accurate representation of what’s actually going on in the
trials,” Devenot, who has been critical of MAPS, said in an interview.
ICER staffers — who spoke to a handful of former patients and people associated with MAPS trials — noted the some of the adverse effects they learned about were not reflected in data they had seen. The report said pressure to gloss over negative impacts of MDMA may be skewed by the zeal of the psychedelic enthusiasts involved as both patients and researchers, though ICER staff couldn’t determine this extent of this dynamic.
“It would have been preferable to have maybe a little more space between the organization that was promoting MDMA assisted therapy and the organization researching it,” ICER’s Rind said.
ICER staff also spoke with people involved in a podcast by New York Magazine, which probed the ethics of the MAPS clinical trials and interviewed some patients who said they were victimized by their therapists or pressured to report positive outcomes. In one account, a woman who participated in one of MAPS’s smaller trials described being abused by her therapists.
“MAPS views these violations as a breach of trust between patient and clinician and a violation” of its ethics code, the nonprofit said previously.
“Boundaries, including sexual boundaries, were severely crossed with at least one patient,” ICER wrote in its draft report.
Compounding ICER’s concerns, the report said, was that in the second late-stage trial published last year, 94 percent of participants who received MDMA, and 75 percent of those who got the placebo, correctly guessed their group.
Patients who know they got the treatment might — consciously or subconsciously — report better outcomes to please researchers, even if those effects are not completely accurate, said Asbjorn Hrobjartsson, a professor of clinical research methodology at the University of Southern Denmark.
“Patients, like most people, are polite individuals and they react on the social atmosphere of being in a trial,” Hrobjartsson said.
To counteract this risk of biasing the results, the FDA suggests that a company could run two clinical trials: one comparing the drug against a placebo to better gauge its safety, and another with a control group that receives a “subperceptual dose” of the psychedelic drug or other drugs that “mimic some aspects of the psychedelic experience.”
MAPS and Lykos, however, had already completed their trials when the FDA published its guidance.