Revolutionizing PTSD Treatment: The Promise Of MDMA-Assisted Therapy

A recent study published in the journal Nature explores the results of a Phase III clinical trial evaluating whether MDMA-assisted therapy (MDMA-AT) is more effective versus placebo plus therapy for treating moderate to severe post-traumatic stress disorder (PTSD).

Whew, that’s a mouthful. But as always, we’re going to take it step-by-step and get through it together. Group hug at the end!

Study Background

About PTSD

First, some quick hitters on PTSD:

• PTSD is a mental health condition resulting from exposure to real or threatened injury, sexual assault, or death. PTSD causes both cognitive and functional disability and impairment.

• About 61% to 80% of individuals experience a traumatic event at some point in life. It’s estimated that about 5% to 10% of individuals develop PTSD after the trauma. Rates vary depending on the specific population analyzed.

• Current treatments for PTSD involve both talk therapy (such as cognitive behavior therapy, or CBT) and medications. There is significant room for improvement. For example, CBT has been shown to improve daytime PTSD symptoms after a single session, but has also demonstrated a smaller impact on long-term outcomes in some studies and typically has a high patient dropout rate.

Why MDMA?

• It’s thought that MDMA helps promote openness and prosocial behavior. This can help patients open up about their feelings, emotions, and thinking during therapy – particularly with respect to traumatic events.

• For people with PTSD, the reminder of the traumatic event brings about an aversive response. MDMA also helps reconsolidate “fear memory”. Essentially, our memories are subject to modification – such as integration of new information. With a “fear memory” – the memory of a traumatic event, for example – we may be able to lessen the trauma-related aversive response to the memory by integrating “new” information during a therapy session. For example – talking through the emotions and feelings related to the event may help a patient open up about feeling guilt over what happened, and help the patient stop blaming themselves for their trauma.

• MDMA also enhances “fear extinction”, which is a “decline in conditioned fear responses (CRs) following nonreinforced exposure to a feared conditioned stimulus (CS).” Put simply: unlearning the conditioned fear response when experiencing a trigger that reminds the patient of the traumatic event.

More About the Study

Finally, here’s some quick info on the study and its participants:

• This trial was a multisite, double-blind, randomized controlled trial (RCT).

• Participants were randomly divided into one of two treatment groups: MDMA w/therapy vs. placebo w/therapy.

• Treatment consisted of three 8-hour dosing sessions in conjunction with therapy, spaced about 1 month apart. Patients were given either a split dose of 120 – 180 mg of MDMA or placebo. In the first experimental session, researchers used an initial dose of 80 mg, followed by a supplemental half-dose of 40 mg. For experimental sessions #2 and #3, the 120-mg initial dose was followed by a supplemental half-dose of 60 mg.

• 6.9% (28/104) of participants had moderate PTSD, and 73.1% (76/104) of participants had severe PTSD

• Participants were ethnoracially diverse: 28 of 104 (26.9%) identified as Hispanic/Latino, and 35 of 104 (33.7%) identified as other than White

Alright – let’s look at the study results.

Study Results

When discussing a clinical study, one of the most important aspects is looking at the outcomes measured by researchers. Outcomes explain the events the researchers were measuring and analyzing.

The “primary endpoint” (main study objective) for this study looked at changes in the CAPS-5 total severity score. Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) is a tool used to diagnose PTSD, as well as assess the severity of a patient’s PTSD symptoms over the past week or month. Scoring is a bit complicated – for our sake, just know that a greater decline in CAPS-5 score means a better improvement in symptom severity.

People who received MDMA plus therapy had a least squares (LS) average CAPS-5 score change of -23.7. In comparison, this score was -14.8 in people who received placebo plus therapy.

A secondary endpoint for this study looked at changes to the Sheehan Disability Scale (SDS), which measures impairment in day-to-day functioning due to symptoms of a mental health condition (such as PTSD). People who received MDMA plus therapy had a least squares (LS) average SDS score change of -3.3. In comparison, this score was -2.1 in people who received placebo plus therapy.

What About Side Effects?

No deaths were reported in any group. 53 out of 53 (100%) of participants who received MDMA reported at least one side effect, and 49 out of 51 (96.1%) of people who received placebo reported at least one side effect. Muscle tightness, nausea, decreased appetite, sweating, and feeling hot or cold were reported by both groups, but were much more common in the MDMA group. (These are just a few examples – check out the study to see the full list of side effects.)

Cardiac-related side effects occurred in both groups. Examples include heart palpitations, and short-term increases to heart rate and/or blood pressure.

Severe side effects were rare in either group. Of note, suicidal ideation occurred in two participants in the MDMA group and two participants in the placebo group This is complicated by the fact that over 80% of study participants had a lifetime history of suicidal ideation.

Implications and Looking Ahead

This study shows MDMA plus therapy to be effective for treating moderate to severe PTSD in a diverse patient population. Currently, psychotherapy for PTSD has struggled to offer long-term beneficial outcomes and has a high dropout rate, indicating patients are still looking for more out of treatment. MDMA-assisted therapy had a low dropout rate in this study.

Important to note – certain people were excluded from participating in the study. This includes people with a high suicidality risk, anyone with a co-occurring personality disorder (such as narcissistic personality disorder), and persons with cardiovascular disease.

An ideal next study would compare MDMA-assisted therapy against SSRIs for treating PTSD. It’s one thing to show superiority to placebo. Proving MDMA plus therapy to be non-inferior, or even superior, to current pharmacologic agents would turn up the heat further on regulators and legislators to reclassify MDMA out of Schedule I and to a more appropriate classification based on actual science and evidence, rather than fear-mongering.