Addiction Doctor Endorses MDMA-AT for Treatment of PTSD 

Below is a letter I sent to Robert M. Califf, MD, Commissioner of Food and Drugs at the FDA, concerning the administration’s imminent decision on August 11 whether to approve MDMA-assisted therapy for PTSD. Because of the heartfelt interest these matters have generated in multiple stakeholder groups, I am also publishing this correspondence here as an open letter.

Dear Dr. Califf,

I am writing to endorse midomafetamine-assisted therapy for PTSD because I believe that the benefits outweigh the risks.

I am aware that the FDA received advice from the Psychopharmacology Drugs Advisory Committee on June 4, 2024. The following is intended to supplement that advice from the perspective of a clinician, with specialties distinct from those represented on the committee.

Please be aware that I am writing to you with a great deal of respect for the challenges facing the FDA in this decision. I also write to you in the public spiritedness that prescribers can demonstrate in assisting the FDA in gathering both pre-marketing and post-marketing data and perspectives.

I understand that one of the concerns raised by the advisory committee was around potential for abuse of MDMA. And particularly in the context of the opiate crisis, the FDA needs to comprehensively assess the abuse liability of any approved medication. I am qualified by my experience as an addiction and pain medicine specialist (board certified) for over 30 years to speak particularly to whether or not MDMA presents a serious abuse liability risk. In my experience with actual patients, the real world evidence of such risk is quite low.

In addition to the experience cited above, I was also board certified in emergency medicine over a forty year period (https://recoverywithoutwalls.com/our-team/). I have not been involved in the MPBC/Lykos phase III trials, though I have watched the field carefully. My involvement in an earlier MDMA trial was limited to a 2002 advisory letter to clarify treatment recommendations for the unlikely but theoretical development of a hypertensive emergency during a session.

In addition to private practice, I have taught in the pain and addiction fellowship programs at UCSF for over twenty five years and was an early adopter and published author on the role of buprenorphine in both pain as well as addiction (see recent article from the Journal of the San Francisco Marin Medical Society “Treating Chronic Pain in 2024 — Let’s Refocus on Buprenorphine”). I have, however, no role or financial interest in any pharmaceutical company. Nor am I involved in any of the litigation regarding these medications. My long familiarity with the opiate crisis and with the life saving potential of buprenorphine, which was invented in the late 1960’s but which did not achieve FDA approval for the treatment of opiate use disorder until 2002, can help frame the upcoming FDA decision. A favorable decision on buprenorphine was made despite known risks, including instances internationally of buprenorphine abuse. The FDA also approved buprenorphine despite both the stigmatization of the medication strategy itself and the population with opioid use disorder it would serve. The development of buprenorphine, as hopefully will happen with MDMA, progressed successfully: a shining example of private/public/regulatory partnerships which elevated the public health of the American people.

In my decades of practice, I have treated many hundreds of patients with histories of misuse issues with a myriad of drugs. Although many, if not most, patients in certain demographics report having used MDMA, I saw very infrequent instances where the past use was noted as problematic, and in no case was any medical intervention required for recovery.

I am aware that in recreational, unsupervised settings, MDMA ingestion can be associated with life threatening hyperthermia, water intoxication, co-ingestion with alcohol or other drugs, excessive dosing, and unpredictable behavior, but these problems will not be occurring with therapeutic use.

I have neither seen MDMA as a gateway drug to a more dangerous addiction nor heard of instances of continuously sustained overuse of the drug, though I am aware of reports in the literature, which can be limited by uncertainty of the purity of the drug ingested. Epidemiological trends document continued recreational and episodic overuse but it has been difficult to identify a dependency pattern, long-term sequelae, or a distinct withdrawal syndrome.

Unlike other drugs with higher abuse liability, such as opiates, cocaine, amphetamine derivatives, or benzodiazepines, continued use of MDMA is rarely experienced as rewarding. The experience of pleasure or euphoria that can be seen as a risk factor for misuse with MDMA has been noted in my patient’s histories as reliably dissipating with frequent use.

A euphoric phase, which under psychotherapeutic guidance can blend into fear extinction and insight generation, is an integral and often necessary part of the therapeutic experience of MDMA for PTSD. In this regard, the noted absence of data tracking by the sponsor of this pleasurable phase as an adverse event, data that can be challenging to interpret as it is part of the therapeutic effect, should not be overprioritized in the FDA’s decision.

Compared to the abuse liability of schedule II opiates and amphetamine derivatives and schedule IV benzodiazepine and related sedatives, which are dosed either daily or frequently, the addiction issues with three sessions of MDMA-assisted psychotherapy appear to be comparatively small. As additional precaution, the REMS can formally limit the dosing to the three sessions studied, to the mandatory use of an adequately robust clinical environment, and to other measures to be developed in pre- and post-marketing study.

Another concern raised by the advisory committee was around functional unblinding. As a frequent reader of The Medical Letter, I review FDA trials for newly approved drugs on a regular basis for my continuing medical education. I know that there is a wide variety of studies that the FDA deems adequate for approval, particularly when there is a significant unmet need.

I do not believe that the functional unblinding or expectation bias in the two phase three trials, challenges that are common in FDA-approved psychopharmacology studies, should invalidate the large effect size demonstrated. The use of independent raters blind to the participant’s treatment would have served to significantly mitigate these concerns.

With respect to the risks of inappropriate boundary crossings in the psychotherapy component, which can arise in any clinical or research encounter, I believe that these can be effectively prevented by a combination of a REMS framework, the use of at least two therapists, and educational campaigns at the professional society and licensing board levels.

The flaws mentioned above can be guides to better future studies and a stronger REMS and post-marketing framework. These deficiencies, however, do not invalidate the strong efficacy and safety data that emerge from these trials.

Over the years, I have frequently treated disabling PTSD in the context of patients with co-morbid addiction and/or chronic pain. The need for new tools for PTSD in our practice has never been greater.

It is also worth noting that in 2023, Australia approved the use of MDMA-assisted therapy for designated psychiatrists, and in June of 2024, a government-appointed panel of experts in the Netherlands found that there was sufficient evidence for the effectiveness and safety of MDMA-assisted therapy. Regarding the Dutch panel’s decision, the recommendation stressed the urgency of implementing this treatment protocol, stating, “The government must act expeditiously to enable the therapeutic use of MDMA.”

Because of the extremely tight deadline of August 11 that the FDA has approaching and the heartfelt and legitimate interest these matters have generated in multiple stakeholder groups, I will be also posting this correspondence online as an open letter. However, regardless of how the FDA decides to proceed, I look forward to supporting the FDA staff and leadership in the difficult decisions on emerging medications for the intractable mental health and recovery issues that afflict our nation.

It is a privilege to practice medicine in an era in which these conversations are possible. Thank you again for the opportunity to strongly recommend approval of midomafetamine for the treatment of PTSD.

Sincerely,

Howard Kornfeld, MD
Distinguished Fellow, American Society of Addiction Medicine (ASAM)

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