The ‘Breakthrough Therapy’ for PTSD

Research suggest MDMA could cure PTSD: Here’s the neuroscientific evidence behind this therapy

Alongside other psychedelics like LSD, psilocybin, ayahuasca, and ketamine, MDMA is the next mind-altering drug that shows enormous potential for treating mental health issues. MDMA has proven popular with recreational users over the past several decades as street drug ecstasy. However, in the last decade researchers have been looking into the other aspects of life MDMA could help in, with a particular interest in treating post-traumatic stress disorder (PTSD).

With the rise in awareness towards psychedelic-assisted therapy recently, MDMA-assisted therapy could be the new, innovative tool in psychiatry for treating PTSD.

PTSD

PTSD is a psychiatric disorder triggered by exposure to a psychologically traumatic event and is characterized by anxiety, hypervigilance, avoidance behavior, sleep disturbance, and intrusive thoughts and memories about the trauma. To satisfy diagnostic criteria, symptoms must continue at least 1-month after exposure and cause significant distress and social, occupational, or other dysfunction, as well as, changes in cognition and mood.

The current standards of care for PTSD in the United States consist of two trauma-focused therapies and antidepressants. However, one-quarter of patients drop out of trauma-focused therapy while one-half is left with significant residual symptoms, and the antidepressants are effective in less than 60% of patients.

MDMA

3,4-methylenedioxymethamphetamine (MDMA), better known as ecstasy or molly, is a small molecule that has played a prominent role in the culture of today’s teenagers and young adults, much like LSD did in the 1960s.

First synthesized in 1912 by the German pharmaceutical company Merck, MDMA was only used by several psychotherapists in the 1980s as an adjunct to psychotherapy. Current research readopted this approach a few years ago and has continued on the use of MDMA in the therapy of PTSD.

MDMA has demonstrated efficacy for the treatment of PTSD in military veterans and it has therefore been designated by the U.S Food and Drug Administration (FDA) as a “breakthrough therapy”.

The benefits from MDMA-assisted therapy were believed to arise from a decrease in fear response upon accessing painful memories, increased self-examination, and the advancement of trust between patients and their therapists.

Phase 3 Trials of MDMA-Assisted Therapy for PTSD

On the 10th of May 2021, Nature Medicine published a peer-reviewed paper detailing the results of the first Phase 3 trial of any psychedelic-assisted therapy. A total of 90 participants with severe, chronic PTSD from any cause with an average duration of 14 years were accepted for this randomized blinded study. Forty-six participants received MDMA therapy and forty-four participants received therapy with placebo.

At the two-month follow-up, among the participants in the MDMA-assisted therapy group, 88% experienced a clinically significant reduction in symptoms, while a staggering 67% of the participants no longer qualified for PTSD diagnosis after 3 MDMA-assisted therapy sessions. In the placebo group, 32% no longer qualified for PTSD diagnosis and 60% experienced a significant reduction in symptoms.

Jennifer Mitchel, Ph.D., and lead author of this paper stated:

“MDMA is an experiential therapeutic and therefore necessitates the appropriate set and setting to truly guide change and recovery. While many forms of PTSD therapy involve recalling previous trauma, the unique ability of MDMA to raise compassion and understanding while tamping down fear is likely what enables it to be so effective.”

So, what happens in the brain after MDMA administration?

Neurobiological Mechanisms

Scientists are getting closer to understanding the complex working mechanism of the therapeutic effects of MDMA.

Reversal of transport mechanism

MDMA has the ability to bind and inhibit the transport mechanisms of various neuromodulators, i.e., serotonin, norepinephrine, and dopamine, leading to increased extracellular levels of these chemicals. Antidepressants like Prozac bind to the same proteins blocking the reabsorption of the same neurochemicals.

But, MDMA takes it a step further in this process. It has the ability to strengthen the chemical signal by pumping serotonin into the synapses via the same proteins. MDMA also has the capability to inhibit the protein monoamine-oxidase to protect the neuromodulators from degrading.

Hormones

Therapeutic benefits are thought to arise from increased extracellular levels of neuromodulators and by the subsequent release of various hormones. This synergistic activity may act through several receptors within brain networks to reduce fear and defense mechanisms surrounding trauma memories, enhance therapeutic alliance, and allow for an alternative, present-moment perspective of the trauma memory.

One study revealed that post-MDMA increased levels of dehydroepiandrosterone (DHEA) were found and significantly correlated with feelings of euphoria while another study revealed that increases in blood oxytocin levels were correlated with subjective prosocial feelings.

The neuropeptide oxytocin regulates the autonomic nervous system’s fear response and mediates complex social behaviors concerning pair-bonding, affiliative behavior, and prosocial feelings.

Amygdala & prefrontal cortex

Oxytocin modulates key brain areas, particularly the amygdala and prefrontal cortex, which show increased and decreased activity, respectively, in patients with PTSD.

The amygdala is responsible for initiating a fast, automatic response a.k.a the fight-and-flight response. It acts as an alarm system that sounds when danger is coming. It prepares your body to respond, either by getting away from the threat or dealing with it.

The prefrontal cortex on the other hand helps return the body to a normal state, acting as a braking system, when you realize that the threat has passed or doesn’t pose a danger.

In patients with PTSD the part of the brain that triggers the fight-and-flight response responds too strongly, while at the same time, the part of the brain that is responsible for calming this reaction doesn’t work well enough.

Neuroimaging Research

One of the first functional magnetic resonance imaging or functional MRI (fMRI) studies showed that MDMA induced decreased activity in the amygdala in response to angry faces but not fearful faces, and enhanced ventral striatum activity in response to happy faces. The findings of reduced response to threat and enhanced responses to reward are in line with a later study.

Robin Carhart-Harris and his team investigated the effect of MDMA on the recollection of favorite and worst autobiographical memories (AMs) using fMRI. Favorite memories were experienced with more intents positive affect and greater vividness after MDMA than placebo.

Earlier research has found a relationship between increased activation from the hippocampal during recollection of AMs and the strength of the emotion upon recollection, however, only increased activation in the bilateral fusiform gyri was found under influence of MDMA, which is known to be involved in the processing of high-level visual stimuli such as faces.

The researchers reported: “Thus, increased fusiform gyri activations under MDMA may relate to the reports of increased recollection vividness under the drug — particularly since many of the favorite memories contained references to people.”

Moreover, perhaps the more relevant finding for the application of MDMA-assisted psychotherapy, participants revealed that worst memories were rated as less negative, without changing the strength of the emotion. Significantly lower activity of the left anterior temporal lobe and greater activation of the dorsal medial prefrontal cortex (mPFC)/superior frontal gyrus was measured.

One participant reported: “When I reached back for the bad memories [under MDMA] they did not seem as bad; In fact, I saw them as fatalistic necessities for the occurrence of later good events.”

With the caveat that this study involved healthy participants and not patients, it is suggested that, during MDMA-assisted psychotherapy, weakened activity in the temporal lobe may neutralize perception of traumatic memories while still allowing painful emotions to be treated through enhanced mPFC activation.

Subjective effects

Additionally, research suggests that MDMA enhances various subjective effects reported by healthy volunteers or patients.

First of all, there is evidence that MDMA increases empathy for positive emotional situations and enhances interpersonal empathy in social interactions, it improves the self-reported perception of and responses to emotional stimuli with social content, and it influences how people talk about significant others. Research showed significant changes in enhanced accuracy in decoding positive stimuli but a decreased ability to decode negative stimuli.

Wardle and de Wit suggested that the ‘socially selective’ effects influence prosocial behavior through an increased ability to compare and judge closeness with social contact and others. Another study reported significant correlations between MDMA and improvement of users’ perception of trustworthiness and cooperative behaviors.

Conclusion

In short, MDMA is primarily a serotonin releasing agent and fMRI studies revealed that it represses activity in the amygdala and increases activity in the mPFC.

MDMA diminishes the emotional memory circuit while still allowing patients with PTSD to relive their traumatic memories without the associated painful emotions during psychotherapy sessions. This, in combination with the increased prosocial feelings and behaviors induced which strengthen the therapeutic alliance, can result in overcoming and eventually extinguishing the intense emotions that go with the traumatic memories of these patients.

Further research is needed to fully understand the neurobiological working mechanism and the therapeutic benefits of MDMA in treating PTSD. The positive results of the Phase 3 trials of MDMA-assisted therapy are an important step to the medical approval of MDMA.

However, the FDA needs a second positive Phase 3 trial, which is currently underway with 100 participants, before MDMA-assisted therapy can be approved for therapeutic use.

If those results are getting close to the positive results of the last Phase 3 trials MDMA will be the first-ever approved psychedelic-assisted therapy for therapeutic use.

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