MAPS Bulletin Summer 2017: Vol. 27, No. 2
It’s my pleasure to share with you now the most important research update that has ever taken place in the Multidisciplinary Association for Psychedelic Studies (MAPS)’ entire 31-year history. On Friday, July 28, 2017, FDA sent MAPS an Agreement Letter for our Phase 3 clinical trial protocol of MDMA-assisted psychotherapy for people suffering from chronic, severe to extreme posttraumatic stress disorder (PTSD). This Agreement Letter marks the successful conclusion of a six-month protocol review under the FDA’s Special Protocol Assessment (SPA) process, during which FDA scrutinized our protocol in detail, impressing our staff with the rigorous nature of their evaluation.
Now that MAPS has obtained an Agreement Letter, we can proceed with Phase 3 research knowing that the FDA agrees with our protocol design, research methodology, the number of subjects, our primary outcome measure (the Clinician Administered PTSD Scale, or CAPS-5), and our Statistical Analysis Plan. Receiving an Agreement Letter after a successful SPA review process means that if our protocol does generate statistically significant evidence of safety and efficacy, that “as set forth in the SPA provisions in the FD&C Act, FDA will not change its position regarding the critical design elements agreed to as part of an SPA agreement unless a substantial scientific issue essential to determining the safety or effectiveness of the product has been identified after the trial begins.”
We can now start our Phase 3 studies in confidence, knowing that the protocol design itself is acceptable to the FDA. This is especially important since we have not been able to come up with a protocol design that fully solves the double-blind problem since psychedelics are drugs with powerful and recognizable effects on consciousness, or at least some noticeable side effect.
I thought I had solved the now-classic problem of the placebo in psychedelic research in my dissertation, by proposing to use low doses of the drug being tested and compare them to full doses. The low doses, I reasoned, could cause sufficient blinding by generating some confusion among subjects and therapists about whether a low dose or a full dose had been administered, while not providing a full therapeutic effect which would make it difficult to compare outcomes and show a difference between the two groups.
MAPS’ series of Phase 2 studies demonstrated that the lower doses did indeed result in a substantial increase in the percentage of incorrect guesses by subjects, therapists and CAPS raters, so the blinding was sufficient. However, to our surprise, we also found that low doses—while they were sufficient to produce a more effective blind—tended to make subjects anxious and uncomfortable, feeling emotionally activated but still not quite able to suppress their fear responses to their trauma. Lower doses of MDMA actually had the effect of reducing the benefits of therapy compared to an inactive placebo, thereby making it easier to show a statistically significant difference between our full dose and the control condition. Therefore, we proposed to the FDA that our Phase 3 design involve administering the same psychotherapy to both groups while administering full doses of MDMA to one group and inactive placebos to the control group. Now that FDA has provided MAPS with an Agreement Letter, we know that our final results will not be challenged on the basis of an unsuccessful double-blind.
As of this writing, we are waiting for the FDA’s response to our application for Breakthrough Therapy Designation for MDMA-assisted psychotherapy for PTSD. While it’s not as crucial as obtaining the Agreement Letter regarding our Phase 3 protocol design, obtaining Breakthrough Therapy Designation would be terrific, potentially speeding up the review process for our Phase 3 data.
Now that we’ve passed this crucial turning point, the path to Phase 3 lies open before us like never before. FDA approval for the prescription use of MDMA-assisted psychotherapy for PTSD now depends on fundraising commitments from our supporters, with $25 million needed and $12.5 million already raised or pledged. It also relies on the compassion and therapeutic skill of the 80 co-therapists, most of whom we have newly trained, who will work on our over one dozen Phase 3 sites in the US, Canada, and Israel. With the continued financial support of MAPS members, MDMA-assisted psychotherapy is on track for FDA approval by 2021!
Rick Doblin, Ph.D.
MAPS Founder and Executive Director