Updated June 04, 2024 at 20:10 PM ET
A panel of experts advising the Food and Drug Administration on the use of the psychedelic MDMA for post-traumatic stress disorder found on Tuesday that the available evidence fails to show that the drug is effective or that its benefits outweigh its risks.
It represents a major setback for proponents of the drug and its sponsor Lykos Therapeutics, potentially jeopardizing FDA approval of the treatment.
Following public comment and discussion, the panel voted 9-2 that MDMA 鈥� in combination with talk therapy 鈥� is not effective for treating PTSD. And they voted 10-1 that the benefits of MDMA treatment don鈥檛 outweigh its risks.
While the FDA puts stock in the panel鈥檚 advice, it does not have to follow their recommendation.
However, that would be surprising given the host of concerns raised during the all-day meeting.
Remarks during the meeting from FDA staff and members of the advisory panel highlighted some major shortcomings in the clinical research. These include uncertainties and gaps in the data, unanswered questions about its potential for abuse and a lack of evidence supporting the psychological approach used in the therapy sessions.
鈥泪t seems like there are so many problems with the data,鈥� said Melissa Barone, one of the panelists and a psychologist with the VA Maryland Health Care System. 鈥淓ach one alone might be okay, but when you pile them up on top of each other...鈥�
Many members of the panel brought up allegations that have surfaced about possible misconduct and bias in the trials that could have skewed the results.
鈥泪 have real concerns with the validity of the data and the allegations of misconduct,鈥� said Elizabeth Joniak-Grant, a sociologist and a member of the panel. 鈥泪 can't in good conscience support something where these many harms are being reported.鈥�
Scientists with the FDA didn鈥檛 share details, but acknowledged the agency was investigating some of the claims, which have surfaced in a petition to the agency and outside reports on the trials.
Dr. Walter Dunn, a psychiatrist at UCLA, was one of the few who voted in favor of the treatment's efficacy. He acknowledged the misconduct allegations, but said ultimately the effect sizes of the treatment were large enough to indicate it can be effective for PTSD.
A big moment for psychedelics
The significance of the moment was not lost on those in attendance though.
There are only two FDA-approved treatments for PTSD and MDMA would be the first to come on the market in decades. It would also be a milestone for the broader effort to expand access to psychedelics.
鈥淲e are charting new territory,鈥� said Kim Witczak, a consumer representative on the FDA鈥檚 advisory committee. 鈥淲e want to set it up right.鈥�
Representatives of Lykos emphasized the positive findings in clinical data collected during two nearly identical randomized controlled trials.
For example, one of those studies showed 67% of participants in the MDMA treatment arm no longer met the diagnostic criteria for PTSD following three dosing sessions with MDMA, compared to about 32% in the placebo group who underwent the therapy sessions but did not receive an active drug.
鈥泪n totality, these results support [that] MDMA in combination with psychological intervention provides significant and meaningful reductions in PTSD symptoms and functional impairment in patients with PTSD,鈥� said Berra Yazar-Klosinski, chief scientific officer for Lykos.
FDA staff and the advisers did not dwell on those rosy results, though.
While the study took steps to 鈥渂lind鈥� study participants, there was considerable discussion around the fact many of those in the study could tell they had received the experimental drug, leading to what鈥檚 known as 鈥渇unctional unblinding,鈥� which can ultimately affect the results.
鈥淎lthough we do have two positive studies, the results are in the context of dramatic functional unblinding,鈥� says Dr. David Millis, clinical reviewer for the FDA.
Another potential sticking point was the lack of data about how patients experienced the acute effects of the drug, including feelings like 鈥渆uphoria鈥� or 鈥渆levated mood.鈥� That data helps inform the FDA鈥檚 assessments of the drug鈥檚 abuse potential.
鈥淲e noticed a striking lack of abuse-related adverse events,鈥� said Millis, noting that the FDA had advised the study sponsors to collect this type of data.
While MDMA is currently listed as a Schedule I drug, the agency鈥檚 review found it has the same abuse potential as a , a category that includes cocaine.
鈥淲e're actually managing more and more severe cases of MDMA overdose, and so I'm less concerned about the safety in the acute setting, but more chronically if they go on to abuse MDMA,鈥� said Maryann Amirshahi, a professor of emergency medicine at Georgetown University and a member of the committee.
About 40% of those enrolled in the MDMA study had a history of using it prior to the study.
Alongside its positive findings on the short-term effects of MDMA, Lykos presented data from a follow-up observational study intended to suss out the staying power of the treatment.
While not yet published in a peer-reviewed journal, that data 鈥渟uggest evidence of MDMA鈥檚 durability to at least six months,鈥� said Yazar-Klosinski with Lykos.
However, the FDA staff highlighted various issues with that long-term data, including a dropout rate of 25% and the fact that some participants sought therapy and, in some cases, used illicit drugs, including MDMA.
The form of talk therapy used in the MDMA sessions also troubled some on the panel who noted there wasn鈥檛 strong data to support its use outside of the trial. 鈥淭he psychological intervention is still for me a bit of a black box,鈥� said Dr. Paul Holtzheimer with the National Center for PTSD. 鈥淲hat was described is really a relatively vague, ill-defined treatment.鈥�
Hearing from patients
Some of the strongest arguments for approval came from patients who spoke during the public comment period about the urgent need for an effective treatment. Some had taken part in the MDMA trials and said they found the medication to be transformative.
鈥泪 was fortunate enough to enroll and get accepted, ultimately changing my life forever,鈥� said Nick Brown, a military veteran from Colorado, who described how the treatment gave him self-compassion and allowed him to 鈥済et better sleep, have better relationships, and live what feels like a completely new life.鈥�
Other groups representing veterans echoed these sentiments.
鈥泪 fear what will happen to them if this therapy is not approved,鈥� said Jonathan Lubecky, a veteran who underwent MDMA-assisted therapy ten years ago, 鈥泪magine how many lives your vote could save. Imagine how many will be lost if you did vote against this vital therapy.鈥�
But for all the promising anecdotes of recovery, there were also many involved in psychedelic research who raised concerns about how the trials were run and the persistent problems in the data.
Harsh critics speak out
Some of the harshest criticism came from several researchers who had initially to hold the public hearing, including Ne艧e Devenot, a researcher at Johns Hopkins University, who said the model of therapy 鈥渋ncentivized boundary violations.鈥�
Data shared from Lykos showed a range of adverse events.
The majority of those in the study had a history of suicidal ideation in their lifetime, but during the study period 鈥渢he frequency of these symptoms was comparable between the two groups, said Dr. Alia Lilienstein, senior medical director for Lykos Therapeutics.
鈥淥f note there were no suicidal behaviors or attempts reported in the MDMA group,鈥� she said.
That point is particularly contentious because of recent allegations that certain adverse events were not reported. The petition calling for the advisory meeting outlined these concerns and others, citing an unnamed former employee of the drug company.
There is already a well-documented case of two therapists in the Phase 2 trials with a participant who said they engaged in inappropriate contact with her while she was under the influence of MDMA. The videos of the two therapists in bed with the participant were eventually
鈥淟et's try to not gloss over this misconduct. It was sexual misconduct. That's particularly important,鈥� said Joniak-Grant, a sociologist and a member of the panel.
Several other panelists asked questions about the potential that MDMA, once available widely in therapeutic settings, could lead to other instances of unethical behavior.
Last month, a report from the Institute for Clinical and Economic Review, a group that evaluates clinical data and drug prices, concluded there was insufficient evidence to assess the overall net benefit of MDMA-assisted therapy, after a lengthy investigation into the trial data.
That report stated that it鈥檚 possible those involved in the trials including therapists and investigators encouraged the reporting of positive events and downplayed adverse events.
The drug company has pushed back on the allegations and said it stands behind the data.
A one trial participant said her therapist encouraged her to view 鈥渨orsening symptoms as evidence of healing and 鈥榮piritual awakening鈥欌�� and that she and other participants later struggled with suicidality following the trial.
When asked if some participants may have been discouraged from participating in the long term durability study, Lillenstein said those claims had been investigated.
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