Is MDMA a Safe and Effective Therapy for PTSD?

Post-traumatic stress disorder (PTSD) is a common disorder in the general population. Risk factors for developing PTSD include being female, having a history of personal or family psychiatric disorder, a history of child maltreatment or childhood traumas, and a lack of social support.

Treatment options are limited and for many, not adequate. The Food and Drug Administration granted “breakthrough therapy” status in 2017 to 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy due to preliminary evidence supporting its efficacy for PTSD. Here's what we know about it so far.

The Evidence on MDMA and PTSD

MDMA was invented in 1912 by Merck. By the 1980s, psychotherapists introduced MDMA into their practice due to its potential ability to accelerate the therapeutic process. It reliably enhances mood, increases empathy, and promotes euphoria by abruptly enhancing the release of serotonin (in humans) from neuronal axon terminals.

Is MDMA an effective therapy for PTSD? Overall, yes. Six phase-II clinical trials using MDMA for treatment-resistant PTSD demonstrated it is relatively effective and well tolerated. A single, phase III trial has reported similar results.

The therapies typically consisted of three oral doses of 75 mg to 125 mg MDMA, often with supplemental doses from 50 to 100 mg. During the MDMA experience, participants acquire heightened clarity about the traumatic event and can view it as something of the past. The participants report that they could process painful emotions and were able to change their relationship with their emotions and trauma narrative. The changes in brain function induced by MDMA appear to be long-lasting; symptom improvement continued for at least twelve months post-treatment.

How Does MDMA Work for PTSD?

The drug may produce benefits by dampening that patient’s conditioned fear responses. Neuroimaging studies on individuals with PTSD prior to treatment show an enhanced and uncontrolled response from the amygdala in response to trauma-specific cues. Treatment with MDMA decreased the response of the amygdala (a structure that generates strong emotional responses, especially fear) in response to seeing angry faces. MDMA also reduced activation within the left anterior temporal lobe.

This action is thought to explain why the patients’ worst autobiographical memories were experienced less negatively. After MDMA, the patients are able to handle their traumatic memories better.

Is MDMA Safe?

The answer depends on your definition of safety. Acutely, MDMA is very toxic; at high doses, it can be lethal. Studies in humans and animals have clearly shown that it acts on the mitochondria to destroy the liver, muscles, kidneys, and brain.

MDMA’s therapeutic benefits and toxicity are directly related to its ability to abruptly increase the release of serotonin from neuronal terminals. Experimental studies on rodents and primates (including my own) have shown that MDMA produces a dose-dependent loss of serotonin, the destruction of serotonin nerve terminals, and the degeneration of serotonin neurons.

However, caution must be applied when translating these results to humans. The doses of MDMA given to experimental animals are often five times higher than those given under therapeutic conditions.

It is important to understand how the human body responds to MDMA. MDMA is always toxic; exactly how toxic depends on how much is consumed and how fast the body can metabolize it.

This is where things get complicated. Unlike most other drugs, MDMA exhibits “non‐linear pharmacokinetics.” That means that very small increases in the dose of MDMA lead to highly disproportionate rises in MDMA brain levels.

Why? MDMA appears to slow its own metabolism and this effect is highly variable between different users. The user’s age, sex, health status, inherited vulnerability, and past exposure to similar-acting drugs all influence the potentially toxic effects of MDMA. Obviously, these factors make it very hard to predict who will be negatively affected by a therapeutic dose of MDMA.

Taken together, our current understanding of the actions of MDMA is consistent with the hypothesis that pathological changes are present in the absence of observable negative behavioral changes. For example, several studies have found no detrimental effects of MDMA on cognitive performance, such as working memory or attentional abilities.

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However, cognitive deficits are unmasked when the brain is challenged. For example, during sleep deprivation, MDMA users, but not controls, became increasingly impulsive, performing more rapidly at the expense of accuracy on tasks of working and short-term memory.

Overall, the beneficial and toxic effects of MDMA vary according to the dose, frequency, and duration of the use. Low doses induce acute positive effects. MDMA consistently induces toxic effects whose degree of manifestation and severity are influenced by physiological, environmental, and pharmacokinetic factors.

In conclusion, MDMA may offer immediate benefits to patients with PTSD, however, this benefit is not without the risk of long-term consequences due to the subtle pathological changes that accumulate with repeated treatments.