PTSD: Current Treatments & Future Research

The collective sentiment following the now infamous FDA ADCOM meeting about Lykos Therapeutic’s Midomafetamine Assisted-Therapy (AKA MDMA Assisted-Therapy) might be described as ‘on the knife’s edge’ or ‘hanging in the balance’ as we await the final verdict from the FDA on August 11th.

The final product of the all-day meeting was the committee’s vote on two questions:

1. Do the available data show that the drug is effective in patients with post-traumatic stress disorder?

2. Do the benefits of midomafetamine with FDA’s proposed risk evaluation and mitigation strategy (REMS) outweigh its risks for the treatment of patients with PTSD?

As I’m sure you recall, the committee voted 9-2 and 10-1 AGAINST each question, respectively.

If you asked people two months ago if MDMA Assisted-Therapy would get approval, it was a foregone conclusion.

Now? Not so much.

Much has been deliberated in the fortnight since the meeting, and the message I come away from these discussions is reminiscent of the great scene from the legendary 1994 comedy Dumb and Dumber: So you’re telling me there’s a chance.

The most impressive sense-making effort in the aftermath of the committee’s decision came from Tactogen CEO Matthew Baggot in an hour-long presentation and Q & A session a week after (the slides of which are graciously available here) whose verdict (as I recall) was that he wouldn’t be surprised by approval or if it took another cycle.

A second data point worth mentioning is a 2023 study in JAMA Health Forum—aptly titled The Real Question the FDA Is Asking Its Advisory Committees—found that when advisory committees recommended approval of a drug application, the FDA agreed 97% of the time.

However, when advisory committees did not recommend approval, the FDA only agreed 67% of the time.

So you’re telling me there’s a chance.

Current Treatments

But I wanted to understand a perspective shared by several members of the advisory committee about the currently available treatment options for PTSD.

I am talking about a comment made by psychologist Melissa Barone from the Department of Veterans Affairs in Maryland:

“The other thing I think about is that we already have evidence-based treatments for PTSD. And yes, you know, they do have dropout rates, but they do have really strong outcomes and those treatments usually take around 12 hours of therapy. They're, you know, covered by insurance. So lots of people have access to them, and they do have strong outcomes. And so, when you think about that, compared to a treatment that's, you know, 42 hours of treatment, I mean, how do you even compare them…”

In reflecting on this meeting, I wanted to get a sense of what MDMA Assisted Therapy is being compared to in the minds of the committee members—what are these evidence-based treatments Dr. Barone was referring to?

To get an answer, I consulted the Departments of Veterans Affairs and Defense (VA/DoD) Clinical Practice Guidelines (CPG).

Current CPGs recommend three PTSD-specific psychotherapies:

Prolonged Exposure (PE)—a specific type of cognitive-behavioral therapy (CBT) where the patient revisits and recounts the traumatic memory in a controlled, therapeutic setting, and in vivo exposure, where the patient confronts real-life situations that are safe but have been avoided due to trauma-related fear.

Cognitive Processing Therapy (CPT)—involves identifying and challenging unhelpful thoughts and beliefs related to the trauma, known as "stuck points," which may be causing emotional distress and maladaptive behaviors. Through structured sessions, patients learn to reframe and modify these thoughts to reduce their impact and improve emotional well-being.

Eye Movement Desensitization and Reprocessing (EMDR)—a modality in which the therapist guides the patient to recall distressing memories while simultaneously engaging in bilateral stimulation, typically through side-to-side eye movements.

According to one study, PE therapy is estimated to be 65%-80% effective. That is pretty impressive, however the dropout rate was 55%.

A study that compared PE to CPT found CPT to be slightly more effective and with a lower dropout rate (46%).

Evidence for EMDR also looks pretty good at face value, with one particularly impressive study finding that 84-90% of single-trauma victims no longer had PTSD after only three 90-minute EMDR sessions.

The obvious caveat here is that the type of research that supports a form of psychotherapy and the type of research used to support a New Drug Application are radically different, so I don’t think they can be compared directly with MDMA Assisted Therapies.

But, if you’ll allow me to play Monday Morning Quarterback for a moment:

MAPS should have used one of these psychotherapy formats in the MDMA trials.

Hindsight is always 20/20, but given how big of a hurdle the advisory committee’s befuddlement with “non-directive” therapy and “Inner Healing Intelligence” as laid out in MAPS’/Lykos’ Therapy Manual was the FDA’s decision may hinge upon this single choice in particular.

Future Research

There will be much consternation over the next month and a half about the decision coming from the FDA, but regardless of the decision, one area that research needs to go is in answering the question: “What is the effect of adding psychedelic experiences to established evidence-based psychotherapies?”

If therapists at the VA and elsewhere already employ certain psychotherapy techniques, then we should be asking: does MDMA (or psilocybin, etc.) make them more effective?

The dominant theory is that these compounds are “non-specific amplifiers”— that is, they magnify the effect of the set, setting, and intention. 

As far as the therapeutic use of psychedelics goes, the biggest factor in set and setting is the therapeutic relationship and the particular framework.

For example, in an early trial of psilocybin-assisted therapy for smoking cessation, the researchers added psilocybin dosing sessions to an established 15-week program designed to help people quit smoking.

The 15-week smoking cessation program itself was a course in Cognitive Behavioral Therapy (CBT)—an established evidence-based therapy—with modifications specific to quitting smoking.

This open-label trial achieved an 80% success rate compared to 35% for the 15-week program alone.

This is where the research needs to go.