Medication-Assisted Psychotherapy: Moving Forward

FROM THE EDITOR

The US Food and Drug Administration (FDA) did not vote to deny approval of midomafetamine (MDMA)-assisted psychotherapy on June 4, 2024, contrary to all the buzz in the media saying they did. However, the full FDA committee may very well deny approval when they vote on this decision on August 11, 2024.

The June 4 vote was by an outside expert advisory board comprising 11 individuals with various expertise who reviewed the data presented to them by the FDA, listened to public comment and discussion about the pros and cons of FDA approval, and then voted on the 2 following questions:

In the Lykos Therapeutics application for FDA approval, do the data demonstrate that MDMA-assisted psychotherapy is effective for treating posttraumatic stress disorder (PTSD)? They voted 9 to 2 that it is not effective.

Do the data demonstrate that the benefits of MDMA-assisted psychotherapy for PTSD outweigh its risks? They voted 10 to 1 that the benefits do not outweigh the risks.^1,2

During my own research for this editorial, I visited the FDA’s website and found a briefing document created by the FDA specifically for the advisory committee panel members that contains a comprehensive trove of background information for the panel to review in preparation for the meeting.³ Among this information is an excellent 92-slide PowerPoint overview created by Tiffany R. Farchione, MD, director of the Division of Psychiatry at the FDA; I strongly recommend that interested readers view this document.⁴

According to the presentation, the original investigational new drug application (NDA) for MDMA for the treatment of PTSD was filed back in 2001, incorporating a summary of the time line of the ongoing correspondence with the FDA. In July 2017, a special protocol assessment request was submitted to the FDA, which issued a special protocol agreement letter stating that “design and planned analysis of studies adequately address objectives necessary to support a regulatory submission.” In August 2017, MDMA for PTSD received breakthrough therapy designation based on the results of phase 1 and phase 2 studies. A cogent bullet point in this presentation states that “acute effects of MDMA make it nearly impossible to blind studies.”⁴

My Assessment

Correspondence and clinical trial design discussions with the FDA for a future NDA using MDMA to assist psychotherapy began 24 years ago, and fast track status was approved 7 years ago. Many of the issues raised by the advisory board had already been well established and discussed at length with the FDA over this time frame. The FDA’s acknowledgment that it is “nearly impossible to blind studies” with MDMA suggests that a modification to the historical ideal clinical design of a blinded study may be necessary when studying current and future medications that have notable consciousness-altering effects. The same holds true for psilocybin and lysergic acid diethylamide, and it has likely been the case in the past with clinical trials of anesthetics and psychostimulants.

The Risk/Benefit Equation

In my view, the advisory board’s 10-to-1 vote declaring that the benefits do not outweigh the risks requires viewing through a different lens—let’s call it a “real-world” lens. A significant subset of individuals with severe PTSD are veterans who suffer on a daily basis with a paucity of effective medical treatments available to help them manage their symptoms and possibly recover. Only 2 medications are FDA approved to treat PTSD—the selective serotonin reuptake inhibitors sertraline (Zoloft) and paroxetine (Paxil)—and both of those have only modest benefits.

The risk and harm to these individuals due to a lack of novel effective treatments should be part of the risk/benefit equation. The psychiatric literature is replete with publications documenting the significant increase in suicidality, homelessness, completed suicides, estrangement, family discord, and severe psychological distress that is common in veterans.^5-11

The Pipeline

The current FDA review of MDMA-assisted psychotherapy for PTSD affords a timely opportunity for the FDA to update its approval process not only for MDMA but also for a large number of candidate drugs currently being studied for use in a similar fashion as MDMA. Psilocybin is the most well-known example of a drug that will be used in a similar manner if it is approved by the FDA. What these drugs have in common is that a very small number of doses are used in their treatment protocols, and the primary treatment is the psychotherapy.

Without FDA-approved options for drugs that have proven efficacy and adequate safety, with the implementation of a risk evaluation and mitigation strategy (REMS), if necessary, this void will be filled by the reckless use of psychoactive drugs that are not approved for medication-assisted psychotherapy and/or are not controlled in their manufacturing, dispensing, and patient administration. We already see this occurring throughout the United States with ketamine- and psilocybin-assisted psychotherapy, which are being administered outside of FDA-registered treatment trials.

My commonly used analogy is that of ketamine, which was FDA approved as an anesthetic in 1970. Over the ensuing decades, it became a diverted, misused, and abused recreational drug, with the familiar name of “special K.” Use in unregulated environments, especially in high doses, can cause serious long-term harm, including tolerance/dependance/withdrawal, cognitive dysfunction, depression, psychosis, abdominal pain, and urinary system disease. When its isomer esketamine (Spravato) was developed and showed efficacy in treatment-resistant depression, it was approved by the FDA in 2019 with a REMS protocol that has proven very effective in creating safe and appropriate use.

Concluding Thoughts

As medicine evolves, there needs to be plasticity in how our regulatory agencies assess novel treatment paradigms. I would argue that such is the case with medication-assisted psychotherapy. Because the FDA does not regulate psychotherapy, there may need to be a collaborative review with experts who have the knowledge and expertise to assess the combined treatment protocol. The conclusions, findings, and recommendations of the FDA’s advisory board should be carefully evaluated, and if any of the concerns and critical public comments turn out to be accurate, further data mining, trial participant interviews, and possible additional clinical trials may be necessary.

We are in uncharted territory, and we at Psychiatric Times will continue to keep you informed at each step of the process. Please email us any feedback or clinical examples related to this important topic.

Dr Miller is Medical Director, Brain Health, Exeter, New Hampshire; Editor in Chief, Psychiatric Times; Staff Psychiatrist, Seacoast Mental Health Center, Exeter; Consulting Psychiatrist, Insight Meditation Society, Barre, Massachusetts.

References

1. Reardon S. MDMA therapy for PTSD rejected by FDA panel. Nature. June 5, 2024. Accessed June 14, 2024. https://www.nature.com/articles/d41586-024-01622-3

2. Stone W. FDA advisors reject MDMA therapy for PTSD, amid concerns over research. NPR. Updated June 4, 2024. Accessed June 16, 2024. https://www.npr.org/sections/shots-health-news/2024/06/04/nx-s1-4991112/mdma-therapy-ptsd-fda-advisors

3. Updated meeting time and public participation information: June 4, 2024: meeting of the Psychopharmacologic Drugs Advisory Committee meeting announcement. Updated June 13, 2024. Accessed June 16, 2024. https://www.fda.gov/advisory-committees/advisory-committee-calendar/updated-meeting-time-and-public-participation-information-june-4-2024-meeting-psychopharmacologic#:~:text=UPDATED%20INFORMATION%20(as%20of%20May,5%3A30%20p.m.%20Eastern%20Time

4. Farchione TR. Midomafetamine capsules (NDA 215455). FDA. June 4, 2024. Accessed June 14, 2024. https://www.fda.gov/media/179061/download

5. Holliday R, Borges LM, Stearns-Yoder KA, et al. Posttraumatic stress disorder, suicidal ideation, and suicidal self-directed violence among U.S. military personnel and veterans: a systematic review of the literature from 2010 to 2018. Front Psychol. 2020;11:1998.

6. PTSD: National Center for PTSD. US Department of Veterans Affairs. Accessed June 14, 2024. https://www.ptsd.va.gov/understand/common/common_veterans.asp

7. Holliday R, Forster JE, Desai A, et al. Association of lifetime homelessness and justice involvement with psychiatric symptoms, suicidal ideation, and suicide attempt among post-9/11 veterans. J Psychiatr Res. 2021;144:455-461.

8. Koven SG. PTSD and suicides among veterans—recent findings. Public Integrity. 2016;19(5):1-13.

9. Tsai J, Trevisan L, Huang M, Pietrzak RH. Addressing veteran homelessness to prevent veteran suicides. Psychiatr Serv. 2018;69(8):935-937.

10. Tsai J, Cao X. Association between suicide attempts and homelessness in a population-based sample of US veterans and non-veterans. J Epidemiol Community Health. 2019;73(4):346-352.

11. Cooper SA, Szymanski BR, Bohnert KM, et al. Association between positive results on the primary care-posttraumatic stress disorder screen and suicide mortality among US veterans. JAMA Netw Open. 2020;3(9):e2015707.