How ecstacy (a serotonergic agonist) could help alleviate PTSD

Colin McElvennyAbnormal Psychology, Biological Psychology

Could the active ingredient in ecstacy have a positive effect in psychotherapy? By Colin McElvenny

Ecstasy has been a popular party drug since the 1980s. The active ingredient,  MDMA (3,4-methylenedioxy-N-methylamphetamine), can cause feelings of euphoria, increased empathy, enhanced sensations (e.g.; touch, sight, and auditory) and a positive mindset. Due to being categorized by the US’ Drug Enforcement Agency as Schedule 1 which is described as,  “…substances, or chemicals…with no currently accepted medical use and a high potential for abuse”, there has been little research done on its beneficial impact in treating mental illness. However, recent clinical trials using MDMA to treat PTSD have resulted in the FDA labelling MDMA as a Breakthrough Therapy which should lead to more research on its benefits.

Agonists and MDMA

Previous research has shown that SSRIs can have a positive effect in reducing the symptoms of PTSD. As shown in studies like Marshall (2001), Isper (2006), and MacNamara (2016).  SSRIs block the presynaptic neuron from the reuptake of serotonin, thus increasing the level of serotonin absorption in the postsynaptic neuron. Agonists, on the other hand, can increase the effect of a neurotransmitter by binding to a receptor and triggering a biological reaction. MDMA is a serotonin agonist that causes serotonin stored in the vesicles of the neuron to release, thus increasing the amount available for absorption in the synapse (Rothman & Baumann, .2002). It can also bind directly to the receptor sites of serotonin and send signals this way. MDMA has a complex impact on other neurotransmitters (dopamine, noradrenaline) and hormones (oxytocin, prolactin), but for now we’ll focus only on serotonin to keep it simple.

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Once neurotransmitters bind to receptors and send their signal, they are either broken down in the synapse by enzymes or reabsorbed by the pre-synaptic neuron to be released again (a process called “reuptake”). SSRIs block this process, thus increasing the signal of serotonin in the synapse. MDMA might have a similar effect, although it’s through increasing the amount released from the vesicles in the first place.


The link between MDMA and PTSD is nebulous since the empirical evidence is still somewhat in the nascent stages. However, there has been some intriguing research that has examined the activity of the brain while under the influence of MDMA. Carhart-Harris et al. (2015) used a repeated measures design which was counterbalanced, placebo-controlled and double-blind. The 25 healthy participants had their brain activity measured with an fMRI after taking MDMA and then after taking the placebo. There were a few interesting results that help explain how it might influence patterns of brain activity linked with PTSD.

  1. There was a decrease in limbic activity. The amygdala is an integral component of this region of the brain. A hyper-responsive amygdala can result in an anxious, heightened state of threat that many PTSD patients experience. 
  2. Another common neurological factor related to PTSD is a decreased connection between the amygdala and hippocampus which likely is the reason for their inability to accurately contextualize emotional stimuli. The results showed that taking  MDMA increases the coupling between the amygdala and hippocampus.
  3. Other studies have shown that the prefrontal cortex (PFC) had increased activity and the hippocampus reduced activity after taking MDMA (e.g., Gamma, 2000). This is beneficial to those with PTSD as the PFC is responsible for down regulating negative affect generated by the amygdala

This helps us understand why MDMA may have an influence on PTSD, but we need to confirm if it is actually effective in reducing symptoms.

Key study: MDMA as a Treatment of PTSD (Mithoefer et al, 2019)

Aim: To test the effectiveness of MDMA in reducing symptoms of PTSD

Methods: Mithoefer et al (2019) analyzed 6 clinical trials which were randomized and double-blind. 3 trials occurred in the USA while the other 3 occurred in Canada, Israel, and Switzerland. Participants included men and women of varying backgrounds (civilians, first responders, and veterans) who had PTSD and did not adequately respond to psychotherapy or pharmacotherapy previously. Those taking any psychiatric medications gradually stopped their usage before participation. Participants received either an active dose of MDMA or a placebo during 2 psychotherapy sessions which were a month apart. They were assessed using the Clinician Administered PTSD Scale (CAPS-IV) after each session. 

Results: the MDMA group has significant reductions in their CAPS-IV scores compared to the control group. 54.2% of the treatment group did not meet PTSD criteria any longer. 

Psychotherapy and  PTSD 

MDMA is effective in reducing symptoms of PTSD because of the previously discussed neurological effects which make patients more receptive to psychotherapeutic approaches. Psychotherapy often involves revisiting past memories that are traumatic in nature which can be quite a painful process that likely reduces its efficacy. MDMA helps patients recall their past experiences without being overcome by negative affect. This is because over the lowered activity of the limbic system. When a patient recalls a traumatic memory, this would typically activate the amygdala and likely the stress response. However, MDMA prevents this from happening. Here we see that combining treatments might be more effective in treating mental illness than a single treatment alone.


Test Yourself

  • What is an agonist ?
  • How does MDMA affect the transmission of serotonin?
  • Why might MDMA be effective in treating PTSD?
  • Why might MDMA combined with psychotherapy be effective in treating PTSD?
  • What were the results of Mithoefer et al.’s  (2019) study?


Teacher Tips:

Students can use this to answer questions regarding agonists, neurotransmission, biological treatments, and effectiveness of treatments. It also links well with the concepts discussed in the Themantic Approach on etiologies of PTSD. I highly recommend the video below as it includes the experiences of a veteran’s use of MDMA and the research shown seems to be from the key study above.




Carhart-Harris, R. L., Murphy, K., Leech, R., Erritzoe, D., Wall, M. B., Ferguson, B., … Nutt, D. J. (2015). The Effects of Acutely Administered 3,4-Methylenedioxymethamphetamine on Spontaneous Brain Function in Healthy Volunteers Measured with Arterial Spin Labeling and Blood Oxygen Level–Dependent Resting State Functional Connectivity. Biological Psychiatry, 78(8), 554–562. doi:10.1016/j.biopsych.2013.12.015 

Gamma, A. (2000). 3,4-Methylenedioxymethamphetamine (MDMA) Modulates Cortical and Limbic Brain Activity as Measured by [H215O]-PET in Healthy Humans. Neuropsychopharmacology, 23(4), 388–395. doi:10.1016/s0893-133x(00)00130-5 

Mithoefer, M. C., Feduccia, A. A., Jerome, L., Mithoefer, A., Wagner, M., Walsh, Z., … Doblin, R. (2019). MDMA-assisted psychotherapy for treatment of PTSD: study design and rationale for phase 3 trials based on pooled analysis of six phase 2 randomized controlled trials. Psychopharmacology. doi:10.1007/s00213-019-05249-5 

Rothman, R. B., & Baumann, M. H. (2002). Therapeutic and adverse actions of serotonin transporter substrates. Pharmacology & Therapeutics, 95(1), 73–88. doi:10.1016/s0163-7258(02)00234-6