FDA advisors expressed concerns about the clinical data, selection bias, and expectation bias, as well as the safety risks associated with MDMA. Functional unblinding occurred when participants or study staff were able to infer the participant’s treatment based on behavior during sessions. This could lead to expectation bias, where participants who believed they received active treatment anticipated benefits, while those receiving a placebo may have felt worse due to disappointment from not experiencing expected effects.
Dr. Holtzheimer raised concerns about the impact of functional unblinding on the outcomes of the MDMA clinical trials. He noted that expectation bias could exaggerate the effect of the active treatment or diminish the effect of the placebo. This could potentially explain the differences in outcomes between the true treatment groups, leaving him skeptical of the treatment’s efficacy.
In addition, the lack of diversity in the study population, safety concerns, and undisclosed reasons for participant dropouts were raised by Ms. Elizabeth Joniak-Grant. She also expressed worries about potential cardiovascular adverse events associated with the drug.
Furthermore, concerns were raised about the addictive qualities of MDMA, with data suggesting regular use could lead to adaptations in neurotransmitter systems associated with substance use disorders. Questions were posed about the increase in illicit MDMA use post-study and the potential for chronic abuse.
Overall, issues surrounding the blinding process, treatment efficacy, safety profile, and potential for substance abuse were highlighted during the meeting, raising doubts about the validity and impact of the MDMA clinical trials. Moreover, it frequently prompts individuals to engage in conversations about emotionally-charged memories.
As MDMA triggers an excessive release of serotonin, which is responsible for its mood-enhancing properties, it also results in a significant depletion of serotonin in the brain. This depletion contributes to the negative psychological effects experienced for days following MDMA use, including potential instances of “serotonin syndrome.”
Low serotonin levels can lead to issues such as poor memory and depression, which may explain why regular MDMA users often experience confusion, depression, paranoia, anxiety, and impaired memory.
Potential long-term health consequences include arrhythmia, high blood pressure, heart damage, heart disease, decreased cognitive function, difficulty concentrating, aggression, impulsivity, sleep disturbances, and difficulty concentrating.
Public Comments
During the public comment section of the meeting, various individuals and organizations shared their concerns and support for Lykos Therapeutic’s MDMA drug application. Some suggested that the manufacturer had spiritual motives, while others expressed hope for a new PTSD treatment.
Brian Dempsey, the director of government affairs at the Wounded Warrior Project, spoke positively about the adoption of MDMA-assisted psychotherapy for treating veterans with PTSD. He mentioned that the organization is dedicated to finding new care options for deserving veterans.
Michael Abrams, a senior health researcher from the Public Citizen’s Health Research Group, highlighted the potential bias in the manufacturer’s clinical trials due to their “functionally unblinded” nature.
“The two pivotal randomized clinical trials were functionally unblinded, likely biased towards favorable drug effects. Patients and therapists probably knew who received the drug, and there are anecdotes suggesting that some therapists manipulated patient beliefs using this knowledge,” said Mr. Abrams.
Dr. Jonathan Alpert, the chair of the American Psychiatric Association’s research council and the Department of Psychiatry and Behavioral Sciences at the Albert Einstein College of Medicine, emphasized the unmet therapeutic needs of approximately 13 million U.S. adults struggling with PTSD. However, he expressed reservations about using MDMA for treatment, in line with a written statement submitted by the APA to the FDA before the meeting.
Dr. Alpert raised concerns about the functional unblinding of the clinical trial data, the high rate of MDMA use among participants, the intensive nature of eight-hour psychotherapy sessions, practical implementation challenges, and the lack of long-term safety and relapse data post-treatment.
“The APA advocates for research and therapeutic exploration of psychedelic agents conducted with the same scientific rigor and regulatory standards applied to other promising medical therapies,” he added.
