MDMA Comes of Age

An effective treatment for PTSD moves closer to reality

Earlier this month, results of a Phase 3 Clinical trial to treat PTSD using MDMA were published in Nature Medicine, “MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study.1

The results of the study were overwhelmingly positive: 18 weeks after the study began, 67 percent of the participants who received the active drug no longer met the diagnostic criteria for PTSD. Thirty-two percent of those in the placebo group no longer met the diagnostic criteria. While the active drug group fared better than the control, it’s important to note that one-third of those in the control group also saw a positive change. This improvement was most likely due to the ongoing in-person psychotherapy sessions both groups received throughout the duration of the trial.

The chemical compound, 3,4 methylenedioxymethamphetamine—MDMA—was originally developed as an intermediate chemical involved in the production of a styptic (a compound that stops bleeding), hydrastinine. It is a phenylisopopylamine derived from safrole, an aromatic oil found in sassafras, nutmeg, and other plants. The drug manufacturer Merck patented MDMA in 1912. Human investigations did not begin until the 1950s, when the US Army began animal experiments, possibly to explore developing the compound for use as drug for enhanced interrogation.

The chemist Alexander Shulgin, who for many years ran a psychopharmacology experimentation lab in his Lafayette, California garden shed, gave MDMA he formulated to a psychotherapist friend, Leo Zeff, in Oakland, California. Zeff was the first therapist to use it as a psychotherapeutic adjunct in the 1970s.

In 1978, Dr Shulgin and chemist and pharmacologist David E. Nichols published a report on the drug’s psychoactive effect in humans. They described MDMA as inducing “an easily controlled altered state of consciousness with emotional and sensual overtones. It can be compared in its effects to marijuana, to psilocybin devoid of the hallucinatory component.2

MDMA causes decreased activity in the amygdala—the brain structure associated with memory formation and emotional response—and an increase in activity in the prefrontal cortex—the brain region where cognitive functions are processed, including ethical judgments. It also produces a marked increase in levels of the neurohormone oxytocin, the so-called “love hormone” which plays a role in social bonding.

MDMA is an “entactogen,” or a drug that touches from within. MDMA unsticks PTSD sufferers from rigid patterns of emotional reaction brought about by fear. Drugs like MDMA are a catalyst, allowing patients to process changes in their own feelings. Under the influence of MDMA, the interior space wherein a person experience feelings broadens and widens. Subjects can revisit shocking events and past experiences without extreme reactions, allowing them to stay emotionally engaged while revisiting traumas. They are able to stay in the moment without becoming emotionally overwhelmed, or flooded by feelings of terror or panic. This feature alone is invaluable for PTSD sufferers. Training oneself to stay in the present with traumatic memories is one of the key skills in overcoming complex PTSD – that is, PTSD related to childhood abuse.

The studies investigators did find one result surprising: MDMA was as effective with the most severe type of PTSD, the so-called dissociative subtype. According to a paper published by the National Center for PTSD, a research branch of the Veterans administration, the dissociative subtype: “captures people who additionally respond to trauma-related stimuli with dissociative symptoms (depersonalization or derealization) and associated emotional detachment.” This state, when it occurs, creates its own kind of danger. Those with dissociative PTSD are likely to have serious accidents, such as traffic accidents, or falls, when they’re in this state. By itself, this disturbing reaction to trauma can be life threatening.

“People with the most difficult-to-treat diagnoses, often considered intractable, respond just as well to this novel treatment as other study participants,” said Jennifer Mitchell, PhD, lead author of the Nature Medicine paper, in a press release. “In fact, participants diagnosed with the dissociative subtype of PTSD experienced a greater reduction in symptoms than those without the dissociative subtype.”

This study is one of two Phase 3 clinical trials required by the FDA for MDMA assisted therapy to be approved as a legal treatment for PTSD. The most important thing to note about MDMA therapy for PTSD: MDMA is not a standalone pill. One of the absolute requirements of MDMA therapy is that it is used in conjunction with preparatory and integrative therapeutic sessions. In other words: going to a rave isn’t going to be a shortcut to treating PTSD.

PTSD is a serious and growing health problem in the US as well as worldwide.

The Bureau of Labor Statistics reports as of 2020, approximately 4.7 million US veterans report a service-related disability, costing the US government approximately $73 billion per year.

Among non-veterans, that is in the general adult population in the US, who have not experienced active combat, 7.8 percent will develop PTSD during their lifetimes, caused by childhood abuse, sexual abuse, domestic violence and a number of other factors. That is: approximately 24,874,200 people. The fallout from the Covid-19 pandemic will produce a huge new wave of trauma survivors who require immediate treatment: those first-line health care workers who triaged and treated affected patients. Among the general population, very high rates of psychological and mental health impairment could be with us for years to come and are likely to impart a considerable emotional and economic burden. The need for broadly available effective treatment for PTSD is already upon us.


Mitchell, J.M., Bogenschutz, M., Lilienstein, A. et al. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nat Med (2021).


Shulgin, Alexander T & Richards, David (1978). Characterization of Three New Psychomimetics. In RC Stillman & RE Willette (Eds), The Psychopharmacology of Hallucinogens (pp 74-83). Pergamon.