As seen in Psychology Today.

Recent media reports have described that medical professionals are using MDMA (3,4-methylenedioxymethamphetamine) to treat post-traumatic stress disorder (PTSD). This may seem like an unorthodox approach or the musings of a few fringe figures. While unorthodox, neither is the case. The treatment has been rigorously tested, and the United State Food and Drug Administration (FDA) has allowed the treatment to progress to Phase 3 clinical trials. It has also received Breakthrough Therapy status.

While the potential dangers of MDMA are very real and the recreational use of the drug remains illegal and not recommended, medical professionals who have made limited use of the drug in conjunction with psychotherapy while treating PTSD have reported significant results. One of the most notable studies, which involved 26 veterans and first responders who were diagnosed with chronic PTSD, found that 52.7 percent of participants who were given active doses of MDMA (75-125 mg), and then participated in therapy sessions involving two therapists, one male and one female, no longer met the criteria for PTSD at the primary endpoint of the study. This was more than double the rate when compared with participants in the control group (22.6 percent). Symptom reduction was reported as long as 3.5 years following the trial.

What is MDMA?

MDMA is a psychoactive substance that promotes the release of neurotransmitters like dopamine, serotonin, and norepinephrine, as well as neurohormones, most notably oxytocin. As MDMA is an amphetamine derivative, it produces effects similar to other stimulants, such as cocaine. However, its more salient effects involve a heightened sense of empathy or connectivity to others, euphoria, and reduced fear responses.

MDMA is commonly referred to as ecstasy, molly, or E. It was criminalized in 1985, and then designated as a Schedule I drug by the Drug Enforcement Agency in 1986. According to the DEA, such a designation means that the drug has “no currently accepted medicinal use and a high potential for abuse.” Other Schedule I drugs include heroin, LSD, and peyote.

The fact that MDMA is considered to be a potentially dangerous drug is beyond repute. Individuals who are experiencing the acute effects of the drug may engage in reckless behavior that is potentially life-threatening. Additionally, MDMA modestly increases blood pressure and body temperature (hyperthermia). While not particularly life-threatening in isolation, this phenomenon can lead to heat stroke if an individual is rigorously dancing at a party or nightclub. As illicit MDMA continues to have a strong presence at dance clubs, this is not an uncommon occurrence.

Frequent use can produce more pernicious effects, interfering with concentration, sleep, and appetite. Heavy use can lead to depression, heart disease, and decreased cognitive function. However, addiction is uncommon. The Diagnostic and Statistical Manual of Mental Disorders (DSM-V) claims that it is one of the rarest substance use disorders.

What Is Post-Traumatic Stress Disorder?

Post-traumatic stress disorder (PTSD) is a biopsychosocial condition affecting as many as 8 million adults in the United States. It is characterized by a state of anxiety following a traumatic event. It is not the case that all individuals who live through traumatic events develop PTSD. However, all patients with PTSD have endured at least one traumatic event. In some cases, the event is a protracted experience, such as being kidnapped, being tortured, or fighting in or living through a war. In other cases, it may be associated with a single episode, as is the case with victims of assault (whether sexual in nature or not), witnesses of gruesome acts of violence, or survivors of catastrophic events ranging from severe car accidents to natural or man-made disasters.

The symptoms of PTSD are not uniform. In some cases, the most salient feature of PTSD is a patient’s avoidant behavior. They may avoid memories of the traumatic event(s) or external reminders of the event(s), such as people, places, activities, situations, or objects. In other cases, the patient may not remember the traumatic event(s) due to dissociative amnesia. In still other cases, the patient may develop persistent and reoccurring dissociative symptoms. Dissociative symptoms may manifest in either depersonalization, wherein the patient feels as if they are detached from their own body, or derealization, wherein patients feel as though the surrounding world is distant or dreamlike.

Additionally, patients may project exaggerated negative feelings onto themselves or others; blame themselves for the traumatic event(s); endure persistent trepidation, despondence, or indifference to pleasurable experiences anhedonia; find themselves incapable of feeling positive emotions; or suffer from feelings of estrangement or detachment. Additional symptoms may include angry outbursts, self-destructive behavior, paranoia, hypervigilance, the inability to concentrate, and difficulty sleeping.

Due to the large range of symptoms, not all patients with PTSD behave in the same manner. Some patients may be able to function well in regular settings, but may experience extreme psychological distress when in the presence of stimuli associated with the event(s). Others may feel as though they are reliving the traumatic event(s) due to frequent intrusive and involuntary recollections or nightmares of the event(s) even without the presence of negatively associated stimuli. In other cases, the patient may ruminate upon the traumatic event and become increasingly withdrawn, anxious, or depressed.

Yet another common feature of PTSD is its high rates of comorbidity with major depressive disorder, anxiety disorders, and substance abuse disorders. Those who suffer from PTSD are also at an increased risk of ailments associated with substance abuse disorders (heart disease, liver disease, memory loss), and may experience impaired social functioning resulting in unemployment, homelessness, and marital instability.

How MDMA May Help Individuals With PTSD

There have been numerous approaches to treating PTSD. Unfortunately, few have been truly effective. Of those who receive traditional treatments, less than half retain remission of symptoms after 40 months. Among veterans, the data is even more discouraging: Upwards of 72 percent of veterans who received treatments involving either cognitive processing therapy or prolonged exposure therapies (two of the most common non-pharmacological treatments for PTSD) still met the criteria for PTSD following treatment. Given this context, it is no surprise why there is so much excitement following the successful phase 2 trials for treatments involving MDMA.

However, the question remains: Why does it seem to work so well?

This requires an understanding of how the brain stores episodic memories in clusters of neurons known as engrams (for additional information on engrams and negative memory bias, see my previous post here). Individual engrams are not merely stored as objective pieces of information. Memory is tied to emotion via the brain’s limbic system, which includes the thalamus, hippocampus, and amygdala—the latter being responsible for responding to potentially dangerous stimuli and triggering fight or flight responses. In other words, one not only remembers the details of the event, but the emotional state they were in at the time the engram was created. When a memory is reactivated, the emotional state may be reactivated, too. If the memory is traumatic enough, the corresponding psychological distress may push the amygdala into overdrive.

Researchers believe that engrams are not impervious to change. They can be influenced by a patient’s emotional state upon recollection, meaning that it is theoretically possible to uncouple the non-emotional components of the traumatic engram from the emotional components. In many ways, this kind of fear extinction learning and retention is the same theoretical approach behind one of the most conventional treatment modalities for PTSD, prolonged exposure. Both therapies that involve MDMA and prolonged exposure rely on memory reconsolidation, a term that “…describes a type of neuroplasticity that involves the process of an established memory being reactivated, destabilized, and then modified or updated with additional information,” according to a recent review on the trials involving MDMA.

“A prediction error or mismatch of the memory trace to present moment happenings may be a particularly strong signal to induce a malleable state of the engram,” they continued. “Hypothetically, when trauma memories are retrieved while under the influence of MDMA during therapy, a strong prediction error is generated by the unique internal state of MDMA-stimulated elevation of neurochemicals/hormones and the supportive therapeutic setting.”

MDMA is an unconventional treatment for PTSD. However, the underlying theory behind why it is effective at treating the non-dissociative subtype of PTSD appears to be sound. Additionally, the mechanisms that it seeks to employ are not that different from traditional exposure therapies that have been in use since at least the 1950s. The euphoric effects of the drug merely accelerate the decoupling of fear-inducing stimuli from psychological trauma, and this decoupling continues after the effects of the drug have worn off.

While it is certain that more studies are needed to confirm the results of phase 2 trials, and that more tests need to focus on how this approach affects the subset of PTSD patients with dissociative symptoms, this appears to be a promising avenue of research for a condition that is very often resilient to treatment.

Dr. Ahmad reports no conflict of interest. He is not a speaker, advisor, or consultant and has no financial or commercial relationship with any biopharmaceutical entity whose product/device may have been mentioned in this article.