Leading Experts Discuss FDA's Pending Decision on MDMA-Assisted Therapy for PTSD

In less than a week on August 11, 2024, the US Food and Drug Administration (FDA) will deliver a decision that could transform PTSD treatment: the approval of MDMA-assisted therapy.¹ This highly anticipated ruling holds significant promise for veterans and others struggling with this debilitating condition, potentially ushering in a new era of hope and healing.

However, the FDA expressed concerns about MDMA-assisted therapy regarding safety, cardiovascular risks, and issues related to functional unblinding in trial settings.² On June 4, 2024, the FDA's Psychopharmacologic Drugs Advisory Committee (PDAC) voted 2-9 against MDMA-assisted therapy for PTSD. Despite this, many individuals with PTSD and clinicians remain hopeful about the potential of this new treatment.

Currently, the FDA has only approved 2 pharmacotherapies for PTSD: sertraline (Zoloft) and paroxetine (Paxil). Notably, these medications were not even specifically developed for PTSD—they were designed to treat depression.

The push for MDMA-assisted therapy has even reached the White House.³ On August 5, 2024, 61 members of the House, 19 Senators, and > 700 veterans and first responders sent letters of support to President Joe Biden and FDA Commissioner Robert Califf.

Clinical trials have shown 68% of participants in MDMA-assisted therapy no longer met PTSD criteria.¹ MAPS PBC, now Lykos Therapeutics, has studied this therapy for > 30 years. The FDA submission package included 2 randomized, double-blind, placebo-controlled phase 3 trials (MAPP1 and MAPP2), which assessed the efficacy and safety of MDMA-assisted therapy versus placebo in participants with moderate and severe PTSD.

Both trials achieved significant improvements in PTSD symptoms compared to traditional psychotherapy, as measured by the Clinician-Administered PTSD Scale for DSM-5. They also met the secondary endpoint, showing improvements in functional impairment associated with PTSD, measured by changes from baseline on the Sheehan Disability Scale.

For more perspective on this historic decision and the prospect of psychedelic therapies in PTSD, HCPLive psychiatry reached out to a trio of leading subject matter experts for their opinions. Below, we highlight responses from these experts to a series of questions on the topic.

Subject Matter Experts:

• Casey A. Paleos, MD, psychiatrist and principal investigator for the MAPS-sponsored MDMA-Assisted Therapy for PTSD Phase 3 Clinical Trials (2018-2023), co-founder of Nautilus Sanctuary, and founding board member of the International Alliance of MDMA Practitioners. He is also the Chief Medical Officer of InnerMost PBC.
• Angela Moreland, PhD, associate professor at the National Crime Victims Research and Treatment Center (NCVC) at the Medical University of South Carolina (MUSC).
• Gus Alva, MD, a psychiatrist and medical director of ATP Clinical Research.

Editor’s note: These responses have been edited for grammar and clarity with the assistance of artificial intelligence tools.

HCPLive: Can you give a brief overview of current options and unmet need in PTSD?

Paleos: There is a significant unmet need in PTSD treatment, particularly from a psychopharmacologic perspective. Currently, there are only two FDA-approved medications, Paxil and Zoloft, both of which are SSRIs. These medications are ineffective for up to 60% of people with PTSD. While there are psychotherapies that are combined with SSRIs, these are often not sufficient to meet the needs of all patients. Conventional treatments, such as prolonged exposure therapy and cognitive restructuring, have high failure rates, around 50 to 60%.

Prolonged exposure therapy, for instance, has strong evidence supporting its effectiveness, but it also has very high dropout rates. This is because the therapy is distressing, as it involves re-experiencing traumatic memories, which can be re-traumatizing for many individuals. The concept of the "window of tolerance" is important here. It refers to the emotional bandwidth within which a person can engage with traumatic memories without becoming overwhelmed or numb. For those with PTSD, this window is often very narrow, making it difficult to engage in traditional treatments.

MDMA-assisted therapy is showing promise because it can widen this window of tolerance, allowing patients to engage with their traumatic memories in a therapeutic setting without becoming overwhelmed. This can make strategies similar to prolonged exposure more effective, as patients can work through their trauma within this expanded window, leading to a different, more positive resolution to the re-experiencing of traumatic memories. This allows the nervous system to reconfigure itself, making the memory less triggering over time.

Moreland: Within PTSD, we do have various evidence-based treatments, so the unmet need isn't necessarily because there are no available treatments. PTSD is an area with a lot of research and gold-standard methods for addressing it. The unmet need is more about access to treatment and the stigma around seeking it. Often, people's symptoms of PTSD, like avoidance, can prevent them from going into treatment. If someone has PTSD and avoidance is one of the key symptoms, that symptom can get in the way of them seeking help. Additionally, in many areas, there just isn't access to trauma-focused therapists who are specifically trained to work with PTSD. This is where the real unmet need lies—ensuring that people have access to the treatments and specialized care they need.

Alva: Yes, there is definitely an unmet need. Traditionally, treatments like sertraline (Zoloft) and paroxetine (Paxil), which are serotonin-specific reuptake inhibitors, are used for PTSD. There are six drugs in this category, and while they might help with serotonin reuptake, they don’t always provide the full benefit needed. Additionally, there are four different agents in the class of serotonin-norepinephrine reuptake inhibitors that have been considered. However, many people still don’t get the full benefit from these treatments.

Nightmare content and sleep disturbances are often managed with various agents, but the results can be hit or miss. Trials conducted by the VA have shown that dosing can vary widely, from low to very high doses, and benefits are not always consistent.

So, yes, there is an unmet need. Current treatments have limited success. Even new approaches, such as combining sertraline with an atypical antipsychotic like brexpiprazole, are being explored for FDA approval. This combination approach reflects ongoing efforts to address the gaps in current PTSD treatments.

HCPLive: What is your outlook on the potential of psychedelic therapies in PTSD looking forward?

Paleos: If the FDA were to delay its approval or even decide to reject it, it would be a setback for the field. However, the data on its efficacy are too strong and convincing for that to be likely. I believe it's now a question of when, not if, and under what circumstances. Psychedelic-assisted therapy, particularly MDMA-assisted therapy, is providing powerful tools for a condition that is not being adequately addressed by existing treatments. There are no other treatments with similar efficacy in the pipeline, and the inadequacy of current options will persist until we have better ones. This sets the stage for the inevitability of these treatments being approved for PTSD. The key questions are when and under what conditions, including what risk evaluation and mitigation strategies will be required. These details remain to be seen, but I believe we will see these modalities approved for PTSD in the foreseeable future.

Moreland: I think it really depends on the research. Not knowing the research very well, I think it is a prolific and growing area. So the outlook is good—not necessarily in terms of whether it will be approved, but in determining whether it’s an evidence-based treatment. The research needs to continue, building that base and ensuring it is evidence-based and the correct treatment for certain people who meet the criteria.

Alva: We can't just dive in without sufficient information. That's why, as I mentioned, we're actively participating in the study. For example, we're doing all this additional work. In my clinic, we use ketamine, which doesn't have FDA approval, but we inform patients about it. Take esketamine, for example—not only is it indicated for treatment-resistant depression, but also for individuals with suicidal ideation alongside their depression. A patient I saw today had a vagal nerve stimulator but still wasn't improving. After two treatments with esketamine, she's doing better. So is it important to keep an open mind? Absolutely. We can't just give up and say we've exhausted all options. Instead, we need to explore and understand how these treatments work.

With ketamine and esketamine, we're tapping into the glutamatergic pathway, which is phenomenal. With MDMA, we're affecting the monoamines and also looking at hormones like oxytocin, prolactin, cortisol, and vasopressin. We then figure out what this means for the patient—potentially a solution to a long-standing problem. So, while I'm open to new treatments, I'm also cautious and focused on reviewing the data carefully. As you've pointed out, there's been a lot of discussion about the design of studies rather than the overall effect, and it's important to consider that.

HCPLive: What do you consider to be the most pertinent unanswered questions surrounding MDMA-assisted therapy for PTSD?

Paleos: One question is, obviously, when will there be approval for it? That’s a big question. Another question is, what will the REMS look like? What are the circumstances or conditions that the FDA will stipulate need to be in place for MDMA to be prescribed and delivered? That’s a big unanswered question at this point. Also, how will we ensure that psychotherapists receive proper training for this work? How do we ensure they get good clinical oversight after being trained? What systems will we have in place to regulate the quality of psychotherapy? This is a more complex question than just what the REMS will be because REMS are limited to prescribing and not designed to regulate psychotherapy.

I think the REMS will likely require that a licensed and trained psychotherapist is involved in the delivery of the drug, but they won’t get into the specifics of what type of psychotherapy is happening. Regulation of the psychotherapy component will be important, and it’s not entirely clear how this will be managed yet. I am a founding member of the International Alliance of MDMA Practitioners, a new organization consisting of trainers and supervisors from the phase three trials. We hope to serve as a repository for knowledge and wisdom around this technique and provide expert information to both the public and professionals interested in this work. Although we are still establishing ourselves, we aim to address some of these currently unmet needs.

Moreland: I think it’s important to know not only whether the research shows effectiveness, but also for whom it is effective. We need to look at the differences among various types of presentations. Just because someone is diagnosed with PTSD or has certain symptoms doesn't mean that any particular treatment is the best fit for them. It’s about choosing an evidence-based treatment that works broadly but then individualizing that decision for each specific person.

Alva: The longer-term effects are very important. If you take into consideration what MDMA might do, it becomes an interesting story. You could potentially evoke a deleterious issue over the long haul, and that's something we really need to study more, but I think we've gotten some good information here.

It's not just PTSD—there are a lot of additional problems that MDMA might address, such as alcohol dependence. That’s something that pops out right away where it could potentially help individuals even further. The other important thing is that we have psychotherapeutic modalities with guidelines laid out for doing this appropriately. So, for me, the focus would be on obtaining longer-term data and fulfilling post-marketing commitments.

References

1. ^{Derman, C. MDMA-Assisted Therapy for PTSD Is Backed by Positive Data. HCPLive. April 4, 2024. https://www.hcplive.com/view/mdma-assisted-therapy-for-ptsd-is-backed-by-positive-data. Accessed August 6, 2024.}
2. ^{Kunzmann, K. FDA Psychopharmacologic Advisory Committee Votes Against Supporting Effectiveness of MDMA for PTSD. HCPLive. June 4, 2024. https://www.hcplive.com/view/live-updates-fda-psychopharmacologic-advisory-committee-meeting-mdma-ptsd. Accessed August 5, 2024}
3. ^{Letter to President Biden from VSOs and Veterans. https://drive.google.com/file/d/1AEAsV4RZ0PiWBnZVv42Y6-nNZeHHBRwY/view.}