The Efficacy of MDMA (3,4- Methylenedioxymethamphetamine) for Post- traumatic Stress Disorder in Humans : A Systematic Review and Meta-Analysis, Sarah Tedesco et al., 2021

The Efficacy of MDMA (3,4- Methylenedioxymethamphetamine) for Post- traumatic Stress Disorder in Humans : A Systematic Review and Meta-Analysis

Sarah Tedesco , Ganeya Gajaram , Shahzad Chida , Arham Ahmad , Meghan Pentak , Marina Kelada , Layth Lewis , Deepa Krishnan , Carolyn Tran , Oladipo T. Soetan , Lawrance T. Mukona , Ayodeji Jolayemi

Cureus, 13, (5), e15070.

Doi : 10.7759/cureus.15070



Background : 3,4-methylenedioxymethamphetamine (MDMA), known recreationally as “Molly” or “Ecstasy”, is a triple monoamine reuptake inhibitor. MDMA specifically acts as a weak 5-HT1 and 5-HT2 receptor agonist, targeting 5-HT2A, 5-HT2B, and 5-HT2C receptors. Its potential use for therapeutic purposes with these pharmacological profiles remains a controversial subject. Studies have shown the potential benefits in clinical trials for post-traumatic stress disorder (PTSD). A larger amount of data has been provided for the push in support of MDMA-assisted psychotherapy in these patients.

Objective : The aim of this article is to compute a meta-analysis and conduct a systematic review of the effects of MDMA on PTSD, discussing the potential benefits and adverse events relative to dosing and stability of treatment.

Methods: Articles were collected and analyzed for systematic review: 16 articles were included in the systematic review that met the criteria for the use of MDMA in the treatment of PTSD as well as assessing the safety and efficacy of the drug in human participants. Ten studies were used for the meta-analysis, with a cumulative sample size of 168 patients. The significance of the findings on dosing and efficacy of MDMA in healthy human participants was quantified based on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) and PTSD symptom scores.

Results : The disorders for which MDMA demonstrated a net positive or net negative effect on symptoms are presented separately. Adverse events in patients across all disease classes are presented. The therapeutic index for patients who demonstrated a benefit is also presented. An odds ratio for beneficial and adverse events is used to determine treatment-resistant patients who may benefit from clinical trials of MDMA.

Discussion : Findings show promising evidence for the potential therapeutic use of MDMA alongside psychotherapy in the treatment of PTSD. The pharmacological profile of MDMA may provide direction for future drug developments to treat patients with treatment-resistant psychiatric disorders.

Categories : Neurology, Psychiatry, Psychology

Keywords : posttraumatic stress, ptsd diagnosis and treatment, ptsd, mdma-assisted psychotherapy, mdma


Introduction And Background

3,4-methylenedioxymethamphetamine (MDMA), known recreationally as “Molly” or “Ecstasy”, is a triple monoamine reuptake inhibitor that acts as a stimulant and hallucinogen [1]. It is a recreational drug that produces an energizing effect, distortions in time and perception, and enhanced enjoyment from sensory experiences [1]. Years of reported experiences by recreational users combined with research data collected over the last 50 years have allowed the once “dangerous and messy drug” to be approved by the United States Food and Drug Administration (FDA) for its use in psychiatric treatment [2]. Studies on psychiatric treatments for mental illness have shown that there is a general dose-dependent benefit of MDMA in assisted psychotherapy, where the Clinician-Administered PTSD Scale (CAPS) total scores at the primary endpoint showed changes proportional to the dosage amount [3]. There are, however, adverse health effects with recreational use due to overdosing, such as hypertension, faintness, panic attacks, and, in severe cases, loss of consciousness and seizures [4]. There is still much to be learned about MDMA’s therapeutic dosing effect and its support with psychotherapy treatment of PTSD.

Post-traumatic Stress Disorder (PTSD) is a complex mental illness affecting 7.7 million adults in the United States every year, with 1 in 11 people diagnosed with PTSD in their lifetime [2]. PTSD affects more than twice as many women (10%) as men (4%) with sexual assault being the leading traumatic event [5]. As per the diagnostic criteria in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), PTSD is included as a new category in DSM-5, Trauma and Stressor-Related Disorders [5]. All the conditions included in this classification require exposure to a traumatic or stressful event as a diagnostic criterion. At least one criterion in each of the following categories must be met in order to validate a PTSD diagnosis: exposure to death, threatened death, serious injury or actual/threatened sexual violence; persistent re- experience of the traumatic event; avoidance behaviors; negative alterations in cognitions and mood; vivid trauma-related arousal and reactivity that began or worsened after the trauma, and functional significance with symptoms lasting for more than 1 month [5].

The mainstay treatment for PTSD has traditionally consisted of exposure-based therapies directed at the revisualization of the patient’s initial traumatic experiences [6]. When patients are exposed to occurrences that trigger traumatic events while under the therapeutic treatment, this enables them to reactivate their fear response and work on separating these traumatic triggers from the conditioned response [4]. MDMA- assisted psychotherapy theoretically targets both the memory reconsolidation and fear extinction processes [4]. The term “memory reconsolidation” describes a type of neuroplasticity that involves the process of an established memory being reactivated, destabilized, and then modified or updated with additional information [4]. 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 [4]. This mismatch of experiences, such as recall of memory with strong fear/anxiety versus recall with emotions such as love or empathy, would allow for an update of the information through molecular mechanisms [4]. MDMA increases the release of dopamine (DA) in the striatum and midbrain. Dopamine positively correlates with prediction error, and therefore, MDMA-stimulated DA efflux may amplify and drive a prediction error related to the traumatic memory [4].

Clinicians have found that MDMA can be purified and used to facilitate the above-mentioned therapeutic effects [6]. MDMA promotes the release of dopamine, serotonin, and norepinephrine in the mesolimbocortical circuitry of the brain, as well as the neurohormonal signaling of oxytocin, cortisol, prolactin, and vasopressin [7]. The comprehensive effect of these neurochemicals has been shown to enhance therapeutic success as well as decrease nonresponse and dropout rates [7]. Long-lasting PTSD remission and a reduction in symptoms have been reported after only two to three MDMA-assisted therapy sessions [7]. MDMA specifically acts as a weak 5-HT1 and 5-HT2 receptor agonist, targeting 5-HT2A, 5-HT2B, and 5-HT2C receptors. 5-HT2A affects neural activity, perception, cognition, and mood, playing a role in the regulation of behavior, including responses to anxiogenic situations and psychoactive substances. Studies have shown that MDMA-induced emotional excitability and positive mood are linked to the actions of 5- HT2A receptors [8]. 5-HT2B may play a role in the perception of pain and in the regulation of behavior, including impulsive behavior. 5-HT2C regulates neuronal activity via the activation of short transient receptor potential calcium channels in the brain, and thereby modulates the activation of proopiomelanocortin neurons and the release of cortisol releasing hormone, which then regulates the release of corticosterone. 5-HT2C has also demonstrated playing a role in responses to anxiogenic stimuli or stress, and in the regulation of appetite and eating behavior. This can be understood by the appetite- suppressing effects of MDMA use [8]. The pharmacokinetics of MDMA in humans has been characterized using oral doses of up to 150 mg [9]. MDMA disposition in the body demonstrates nonlinear pharmacokinetics. Metabolism of the drug has shown to result in N-demethylation to 3,4- methylenedioxyamphetamine (MDA). The MDMA metabolite MDA is a potent 5-HT2B agonist which could contribute to a change in the perception of pain and in the regulation of behavior, including impulsive behavior [10]. It also undergoes further demethylation and its metabolites are known to be excreted in the urine as conjugated glucuronide or sulfate metabolites [9].

A commonly observed neurological feature of PTSD is the reduction of hippocampal volume [3]. The hippocampus is involved in the control of stress responses, declarative memory, and contextual aspects of fear conditioning [3]. Magnetic resonance imaging (MRI) studies demonstrated smaller hippocampal volumes in patients with PTSD compared with healthy controls [3]. MDMA has been shown to acutely decrease activity in the left amygdala and increase blood flow to the prefrontal cortex in the brain [11-13].

Diving deeper into the neurochemical features of PTSD, there is an array of abnormal chemical regulations to be found. These tend to include serotonin, dopamine, (nor)epinephrine, acetylcholine, glutamate brain- derived neurotrophic factor (BDNF), oxytocin, and cortisol, all of which are found in brain circuits that regulate and collaboratively integrate stress and fear responses [3]. While MDMA releases serotonin, norepinephrine, and dopamine in the brain, it also indirectly increases levels of the neurohormones oxytocin, arginine vasopressin, and cortisol in humans. The combined neurobiological effects of MDMA increase compassion and reduces defenses and fear of emotional injury while enhancing communication and introspection. MDMA also releases other downstream signaling molecules (BDNF) to dynamically modulate emotion memory circuits [4]. By reducing activation in brain regions implicated in the expression