The US Food and Drug Administration (FDA) denied approval for 3,4- methylenedioxymethamphetamine (MDMA) assisted therapy, and the academic and medical journal Psychopharmacology retracted three papers related to the trial. The FDA denial and Psychopharmacology’s response to ethical concerns cited drug trial participant selection, study design, and data manipulation. For future consideration, the FDA required an additional Phase III trial by Lykos Therapeutics.

Background

Post Traumatic Stress Disorder (PTSD) affects approximately six to nine percent of the North American population during their lifetimes. The average diagnosed individual experiences symptoms for at least six years. Half of all impacted individuals remain untreated. Current first-line treatment involves individual trauma-focused psychotherapy. However, many patients discontinue therapy due to highly variable, sometimes negative, results. Forty to sixty percent of patients do not experience symptom resolution post-treatment.

In recent years, MDMA-assisted psychotherapy (MAP) interest gained traction and support from members of Congress, veterans, and the medical community at large. Lykos Therapeutics began Phase I trials in 2001 and Phase III in 2017.

Ethical Concerns in Study Design

One concern cited by the FDA and the journal Psychopharmacology related to the participant selection. In the Phase III trial, seventy-seven percent of the participants used MDMA recreationally. Further investigation into volunteer selection found recruiting methods targeted communities who consumed MDMA outside therapeutic settings. This tactic violates fair subject selection as dictated by the National Institute of Health (NIH) guidelines for ethical clinical research, raising questions about the scientific validity of the data collected.

Additional Concerns

Psychopharmacology’s decision to retract the three related papers stemmed from participant selection, study design protocol violations, and data manipulation relating to undeclared bias, mimicking the reasoning for the FDA denial. When the authors submitted the papers for review by third-party experts and publication, they failed to report their involvement in organizations invested in reporting positive efficacy. The journal requires all authors to disclose any potential competing interests, such as those that would cause the aforementioned bias, up to three years before the start of the studies relating to proffered articles. This oversight violated the submission guidelines of Psychopharmacology as detailed on their website. When questioned, the lead author of the retracted papers argued the journal should have allowed the papers to be corrected to include the authors’ competing interests instead of issuing full retractions.

The journal’s additional concerns related to the researcher’s use of a participant pool familiar with the effects of the test drug. When properly conducted, participant selection focuses on recruitment from diverse populations, all of whom would be unfamiliar with the study drug and its effects. In this case, the recipients knew they were administered the placebo or MDMA due to its unique euphoria cited by the US Drug Enforcement Agency (DEA) as being one of the reasons for its abuse potential. By participants knowing their study group, the overall statistical significance of the findings cannot be discerned because of a lessened placebo effect. An additional inquiry found that volunteers and administering therapists held strong prior beliefs in the treatment’s effectiveness, leading to skewed reporting in trial outcomes.

Future Outlook

Off-label treatment of PTSD with FDA-approved Ketamine Assisted Psychotherapy (KAP), used in major depression without psychosis, offers one potential treatment option. Ketamine therapy without psychotherapy, also FDA-approved, is covered by most insurance companies in all fifty states. As of 2024, insurance companies in New York and California cover KAP.

Regarding MDMA-assisted psychotherapy, future attempts at FDA approval require a significant revision of the researchers’ methods to remove bias and familiarity with recreational MDMA in data collection from both researchers and volunteers. The FDA requires Lykos Therapeutics to mitigate the potential for substance abuse and negative health impacts, such as those related to cardiac health, in a future Phase III trial attempt.

MDMA is listed by the DEA as a Schedule I drug, meaning it has a high potential for abuse and no known medical use. FDA approval of MDMA requires a revision of its DEA scheduling, adding to the burden of proof necessary. The June 4, 2024 Phase III trial results document submitted to the FDA by Lykos Therapeutics may be found here for further reading.

 Editor: Lucy Cafiero