Authors
David J Nutt, Tadeusz Hawrot, Peter Hunt and Anne Katrin Schlag
Published
October 10, 2024
Introduction
MDMA (now called midomafetamine by the FDA) is a substituted amphetamine first synthesised in 1912 by Merck that has been developed over the past 30 years by the Multidisciplinary Association for Psychedelic Studies (MAPS) as a novel treatment for post-traumatic stress disorder (PTSD). It is administered in three doses at least a week apart, during a 14-week course of psychotherapy. Six phase 2 trials (Mithoefer et al., 2019) as well as two large phase 3 trials (Mitchell et al. 2021, 2023) have demonstrated clear clinical efficacy, even in patients who have not responded adequately to other treatments (Mitchell et al. 2021). These findings led the FDA to grant breakthrough therapy status for MDMA as a treatment for PTSD. Based on these positive findings, the company Lykos was established to introduce MDMA into medical use. The first stage in this process is the submission of a clinical efficacy and safety dossier to the US FDA which will be adjudicated in August 2024.
As a prelude to this, the FDA held a public advisory committee (AdCom) hearing in early June 2024. This committee almost unanimously rejected both the evidence of efficacy and the benefit–risk profile for MDMA-assisted therapy (MDMA-AT) submitted by Lykos. This decision surprised many in the field given that the clinical efficacy data had been available in peer-reviewed and often high-impact journals (e.g. Mitchell et al. 2021, 2023) and appeared to meet the FDA requirements of two placebo-controlled randomised controlled trials (RCTs) for proof of efficacy. Moreover, there has been an urgent need for innovation in the treatment of PTSD for decades: it has been nearly 30 years since two SSRIs were licensed, and these rarely produce full remission.
An added clinical benefit of MDMA-assisted therapy is that the drug is administered just three times in total unlike other psychiatric medicines such as SSRIs, which are generally given chronically, hence can carry an ongoing side-effect burden. This is often seen as a significant advancement in terms of massively reducing the total exposure of the person to the pharmacological ingredient. This lowers the risk of drug interactions, allergic effects and tolerance development with the risk of withdrawal in addition to a reduced side-effect burden. Additionally, this limited dosing schedule could lead to significant long-term cost savings for healthcare systems by minimising ongoing treatment expenses.
These data at face value fulfil the FDA rule that requires two placebo-controlled trials demonstrating efficacy and a positive benefit–risk ratio to permit marketing authorisation. The Lykos data showed that this requirement was met with a between-subjects effect size of approximately 1 (a large effect size). This is about three times greater than that of the only class of licensed medicine used for PTSD, the SSRIs (fluoxetine sertraline venlafaxine and paroxetine) (Hoskins et al. 2015). (Note the between-subjects effect size subtracts the effect of the therapy from the effect of the therapy plus MDMA, leaving the effect only of the MDMA. A more clinically relevant effect size is the within-subjects effect size, 2.1 in MAPP1 and 1.95 in MAPP2.) The MDMA effect size is even more remarkable given that many of the patients in the MAPS trials were treatment-resistant, that is, those who had failed to adequately respond to both SSRIs and psychotherapy, a situation common for a substantial group of PTSD sufferers.
The high statistical significance of the clinical results indicates that some assessors voted against the therapy due to doubts about aspects other than the statistics. Perhaps it was the very uniqueness of this treatment that concerned the AdCom panel. The AdCom's consumer representative Kim Witczak said in an email: ‘This is a new territory and it must be treaded carefully, the time to be cautious is now, not afterwards’. Yet the flipside of being overly cautious means that suffering patients may be denied the opportunity of experiencing a medical therapy that could make a positive difference to their lives.
To access the full publication from the Drug Science Policy and Law journal, please see below: