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Was the FDA Panel Right to Recommend Against MDMA Approval?

— Psychedelic treatments have potential, and taking an evidence-based approach is what's needed

Ƶ MedicalToday
 A photo of signage outside of FDA headquarters in Silver Spring, Maryland.
Das is an addiction psychiatrist.

Untreated mental health concerns remain devastating for our nation, and there is an ongoing need for expanded options and access. In the past few years, there has been a resurgence in interest in psychedelic treatments -- for example, various states have passed or introduced legislation to "medicalize" psilocybin, and most recently, midomafetamine (MDMA) has been under FDA review.

Last week, the FDA's scientific advisory committee voted 9-2 against recommending an MDMA pharmaceutical, in combination with talk therapy, as a safe and effective treatment for post-traumatic stress disorder (PTSD). Patients with PTSD should be given the same promise of scientific rigor as those with any other health condition. For this reason, I agree with the committee's decision to recommend that FDA not approve MDMA for these patients, given the current state of evidence.

Examining the Evidence: Efficacy

The flaws with current research on the efficacy of MDMA for PTSD make the evidence less sound than what we expect for approval.

The FDA advisory committee was presented clinical data from two randomized, double-blind, placebo-controlled phase III trials of MDMA in PTSD, MAPP1 and MAPP2. In these trials, participants received three dosing sessions of MDMA in addition to psychological support sessions before and after dosing.

My first concern is that because some participants knew what to expect from past MDMA use, the results are not generalizable. In fact, FDA reviewers emphasized that participants could tell whether or not they had taken MDMA. This is known as functional unblinding: many participants were likely unblinded by the effects of the medication. I'm also concerned that, among psychedelic-enthused researchers, therapists, and participants, there may have been a natural affinity to this research and perhaps a bias toward wanting it to be effective.

The results showed that both the placebo and active drug groups had their PTSD scores decrease, but the MDMA users had a more significant improvement in symptoms. Participants who were interested in enrolling in the study and randomized to placebo may have been let down by lack of psychoactive effect and perhaps even further distressed. Finally, some of the participants used other treatments or substances between assessment points, therefore making it unclear whether the intervention was the most influential factor.

Another important point is that the committee was asked to assess MDMA to be used in conjunction with psychotherapy. The research involved approximately 84 hours of psychotherapist time, which is more than what many people with PTSD or any psychiatric disorder receive. If I had even a handful of patients with PTSD who received just half that amount of psychotherapy, I suspect their mental health would improve too.

Furthermore, the psychotherapy provided drew on existing therapies, but has not been studied in isolation. So, we have no benchmark of evidence to draw from with respect to the therapy. Also of note, the FDA does not regulate psychotherapy.

Examining the Evidence: Safety

Outside of concerns with efficacy, the FDA reviewers raised safety concerns. The treatment group in the trials experienced a greater number of adverse events. For example, minor issues like muscle tightness and nausea occurred in twice the proportion of MDMA participants as placebo, while other symptoms like blurry vision and tremors occurred in an even greater proportion of participants taking the drug compared to placebo. Other side effects of MDMA can include increased blood pressure, faster pulse, and risk of arrhythmia. Liver injury has not been ruled out due to the small sample size and time course of the study.

I also worry about the potential of MDMA. Acute use of MDMA has been associated with insomnia, restlessness, nervousness, and panic attacks. Users may be impaired and vulnerable for hours. This means that any safe use would require experienced clinical supervision. Second, the effects reported as pleasurable, such as euphoria, can be reinforcing and could lead people to use the drug more out of the context of pharmaceutical treatment. Finally, MDMA can carry a heightened risk when the drug is combined with alcohol or other drugs, including prescription drugs like antidepressants as well as illicit drugs.

As an addiction psychiatrist, I would love to know about longer-term outcomes around misuse. This goes beyond those who would be treated if the drug were approved (which seems unlikely given the committee's recommendation) and extends to those who might see headlines touting MDMA and go use the drug on their own as a quick mental health fix.

Looking Ahead

While this review is unlikely to move MDMA toward FDA approval (a decision is expected by August 11), there will be more instances of psychedelics presented to FDA. As noted previously, we already have medicalization of psychedelics through legislation in many states. As we review novel treatments, FDA approval should be accompanied by rigorous regulations, strict prescribing and dispensing controls, comprehensive patient education, and ongoing monitoring systems -- just as with any other drug or treatment. The point about monitoring is especially important for examining the long-term effects of MDMA, from cardiac toxicity to liver consequences to the potential for abuse. Strict standards for patient protection are also essential, requiring clear inclusion/exclusion criteria.

As legislation, headlines, and industry players tout psychedelics, the general consumer may see this as appealing, offering a fast solution. But I worry about vulnerable patients investing time, money, and hope into something that is not yet well-proven and may carry risks. They could miss out on the opportunity for an evidence-based option (certain therapy, medications, and combinations of the two), which should be considered before psychedelics.

I am hopeful about the potential for new psychedelic treatments, but we must be wary of entities that place premature access before safety and efficacy.

is a member of the psychedelic working group at the American Psychiatric Association (APA) and immediate past chair of the APA Council on Addictions. She is also a clinical associate professor of psychiatry and behavioral sciences at the Stanford University School of Medicine in California.