Introduction

According to the U.S. Department of Veterans Affairs, post-traumatic stress disorder

(PTSD) is estimated to affect 6 out of every 100 individuals at some point in their lives.¹ The Clinical Practice Guideline for Management of PTSD defines the disorder as a mental health condition identified by “intrusive thoughts, avoidant behaviors, persistent negative mood, and/or alteration in arousal and reactivity through experience or witness.”² These symptoms persist beyond the initial month following a patient's diagnosis as outlined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). The DSM-5 outlines the diagnostic criteria for PTSD, which are linked to various environmental and biological risk factors that play a role in the onset and management of PTSD. The poor maintenance and treatment of PTSD are associated with “comorbid conditions that include childhood trauma, alcohol and substance use disorders, depression, suicidal ideation, and dissociation.”³

While trauma-focused psychotherapy remains the gold standard for PTSD treatment, the above-mentioned factors are associated with increased frequency of symptom exacerbation, persistent symptomatology, and dropping out of therapy.^4-7 Alternatively, selective serotonin reuptake inhibitors (SSRIs) such as sertraline and paroxetine form the current FDA-approved pharmacological basis of PTSD therapy. However, an estimated 35-47% of individuals are treatment-resistant with no response to therapy within 12 weeks.⁸

Therefore, there is a clear need for novel therapeutics. The answer may lie in MDMA, a synthetic stimulant that induces serotonin release by binding to presynaptic serotonin-transporters.⁹ Mice models have shown that MDMA, via an oxytocin-dependent mechanism, can modulate fear-memory reconsolidation and fear-memory extinction within a critical period of drug activity. This can, in turn, bolster social activity in mice.^10,11 These results have been seen in human studies as well, in randomized Phase III trials by Mitchell et al. MDMA-assisted therapy for moderate to severe PTSD has shown significant benefits in reducing the PTSD severity based on Clinician-Administered PTSD Scale (CAPS-V) scales and Sheehan-Disability Scores (SDS) over 18 weeks compared to placebo.¹² These findings are especially promising, as a meta-analysis of six Phase II trials of MDMA-assisted therapy for PTSD has shown that MDMA is well-tolerated at all therapeutic doses with good safety and efficacy profiles.¹³

This paper provides an in-depth analysis of MDMA from its early history and prevalence as a street drug to the current research on its clinical applications. First, the origins of MDMA are traced from its initial patent by Merck in 1912 through its growing popularity among psychotherapists in the 1970s. Next, we explain the pharmacological mechanisms of action underlying MDMA's psychoactive and potentially therapeutic effects. We review key studies demonstrating the efficacy of MDMA-assisted psychotherapy for PTSD treatment in Phase II and Phase III trials that have demonstrated improvements in CAPS scores. Finally, we draw parallels between cannabis and psychedelic drug policy reform to predict the likely trajectory for legal access to MDMA therapy. By reviewing the background of MDMA across chemical, clinical, and legal domains, this paper aims to assess the current state and future directions of MDMA-assisted psychotherapy. The promising clinical trial results warrant further investigation into the regulated medical use of MDMA for PTSD treatment, following models paved by marijuana legalization.

History of MDMA

MDMA: A Merck Patent

MDMA (3,4-methylenedioxymethamphetamine) is a psychedelic that flooded the streets of the United States in the early 1980s.¹⁴ In 1912, the German Pharmaceutical company, Merck, was the first to synthesize and patent the drug. For over 90 years, rumors held that MDMA was first developed as an appetite suppressant; yet recent evidence has proven otherwise. Dr. Anton Köllisch, a chemist at Merck, was the first to synthesize MDMA, designated as “Methylsafrylamin” in the company’s 1912 annual report.¹⁵ Archival evidence also implied that MDMA was patented because of Merck’s interest in developing synthetic hemostatic substances (agents that slow blood flow), not appetite suppressants.

After 1912, MDMA received little interest, with only a few mentions/records of testing and studying the drug across the span of the next 58 years. The first recorded pharmacological test of MDMA on animals dates back to 1927 when a Merck study showcased that MDMA displayed similar effects as adrenaline on vasoconstriction and muscle contraction. Subsequently, interest in stimulants and the effects of MDMA rose rapidly starting in the 1950s, with the first official MDMA chemical synthesis article being published in 1960.¹⁵

MDMA Circulating the Streets

It wasn’t until 1975 that MDMA began to gain a reputation as a potential assistant in psychotherapy. Intrigued by a student's description of MDMA's psychological effects, Dr. Alexander Shulgin, a chemist who first synthesized MDMA in 1965, resynthesized and personally tested it, leading him to advocate its use for self-reflection and mental clarity among his psychotherapist peers.¹⁶ In 1976, the “Boston Group,” composed of chemists interested in the religious issues of psychotherapy patients, began distributing MDMA pills to psychotherapists in the Boston region. The year 1977 marked a rise in MDMA-promotional activity among psychotherapists.¹⁷ Meanwhile, evidence for the recreational use of MDMA had also begun to appear in the early 1970s.¹⁶ At the time, MDMA could have been lawfully incorporated into psychotherapy if its use met the Food and Drug Administration’s safety standards. However, despite the growing popularity of MDMA among psychiatrists in the 1970s and ‘80s, the drug did not gain media coverage, largely owing to its secret manufacture, its use in clinical psychotherapy, and the reluctance of physicians to impart any clinical findings to the media. Psychiatrists feared that the public’s knowledge may bring forth scrutiny and the DEA’s intervention. Soon, however, MDMA caught the attention of the DEA anyway when MDMA advocacy groups such as the “Texas Group” multiplied their activity to produce and distribute thousands of MDMA pills weekly.¹⁷

The Scheduling of MDMA

Following the surge in reported MDMA overdoses and trafficking, the DEA initiated the scheduling process in 1984 with the intent of a Schedule 1 placement. The DEA based its decision on four key factors: the chemical and pharmacological resemblance between MDMA and MDA (a Schedule 1 psychedelic banned for its neurotoxicity), the absence of any apparent medical benefits, reports of MDMA being trafficked, and the reported medical dangers associated with its high abuse potential. However, a group of 16 therapists and physicians protested the hastened scheduling and asked the DEA for a hearing based on the reported efficacy of MDMA-assisted treatments of psychological disorders. The psychiatrists presented Judge Francis Young with the case for MDMA’s potential breakthroughs in the field of psychiatry as they shared their powerful experiences of their use of MDMA in treating patients suffering from PTSD, depression, anxiety, and phobias. The therapists attempted to refute the DEA’s stance that MDMA, like MDA, posed a hazard to human life and made their case, not for the prevention of the scheduling, but for safeguarding the right to research the drug’s effects in humans. Despite Judge Young’s subsequent recommendation that MDMA be classified as Schedule 3, the DEA feared uncontrolled recreational use and resorted to an emergency classification of MDMA as Schedule 1, overruling the Judge’s recommendation in 1986.¹⁷ In response to the “illegal emergency scheduling,” Dr. Lester Grinspoon objected and sued the DEA, which led to the temporary removal of MDMA from Schedule 1 designation for 2 months and forced a 6-month hold on its next scheduling. This appeal proved ultimately unsuccessful, though, with the court ultimately ruling in favor of the DEA. In March 1988, MDMA was reclassified as Schedule 1. The DEA’s initiative soon influenced the World Health Organization (WHO), forcing 180 countries to impose the strictest scheduling on the drug.^18,19

Pharmacological Analysis

MDMA is a synthetic drug that belongs to the amphetamine class of agents structurally similar to methamphetamine and phentermine. These compounds, recognized as entactogens or empathogens, induce a profound 'touching within' feel.²⁰ MDMA, renowned for its capacity to elevate serotonin, dopamine, and norepinephrine neurotransmitter levels in the brain, exemplifies this unique effect. The methamphetamine component of the drug is responsible for the dopaminergic effects of reward, pleasure, mood regulation, cognition, and attention. Unlike methamphetamine or other amphetamines that are responsible for only blocking the reuptake of dopamine, MDMA takes it a step further by blocking the reuptake of dopamine and serotonin through the methylene component of the compound. The increase in levels of serotonin that MDMA creates is at least 3-8x greater than the amount of dopamine released.²¹ This combination of both serotonin and dopamine increase is what results in highly unusual but potential clinical benefits for PTSD, giving one mood elevation and stimulation.

When evaluating the potential therapeutic benefits of MDMA-assisted therapy in PTSD, it is essential to understand the mechanism of action of the drug. Though MDMA has a distinct mechanism that pertains to all amphetamine drugs, MDMA is unique, offering a therapeutic impact that sets it apart from the rest:

1. Reuptake inhibition - MDMA inhibits the function of transport proteins located in the presynaptic cell that is responsible for the reuptake of neurotransmitters back into the postsynaptic cell. This leads to an increased level of neurotransmitters in the synaptic cleft, resulting in an enhanced binding to neurotransmitter receptors.
2. Potent release - MDMA takes an extra step and inhibits transporter proteins by entering neurons and disrupting the storage of neurotransmitters in synaptic vesicles. As a result, serotonin, dopamine, and norepinephrine build up inside the neurons. The buildup of neurotransmitters causes them to be released into the synaptic cleft, increasing neurotransmitter receptor activity.

Digging Deeper

During the normal reuptake of serotonin back into the presynaptic neuron, the protein VMAT (vesicular monoamine transporter) facilitates the movement of serotonin from the cytoplasm back into the designated vesicles. These vesicles are storage sites for these neurotransmitters, primarily serotonergic vesicles that collect any wandering serotonin molecules inside the neuron with the help of VMAT.

When an action potential (electrical signal) travels through the neuron and reaches the nerve terminal, these vesicles release serotonin into the synapse via exocytosis, allowing proper serotonin receptor binding to occur. The principle of homeostasis finely tunes this intricate regulatory process within the brain by managing the amount of serotonin released, the time it stays in the synapse, and the subsequent reuptake of presynaptic neurotransmitters.²² However, MDMA inhibits the function of VMAT which disrupts the storage and the overall neurological homeostasis. As a result, there is an accumulation of serotonin within the presynaptic neuron causing MDMA to reverse the function of the serotonin reuptake receptors by spewing out the neurotransmitter into the synaptic cleft. Typically, the accumulation of serotonin is managed through exocytosis and the serotonin reuptake transporter; however, MDMA disrupts this process causing excess serotonin within the synaptic cleft.

MDMA & Talk Therapy

This distinctive mechanism of action of MDMA has called for its use to treat PTSD. Crucially, MDMA is not employed as a standalone therapy for the treatment of PTSD, but rather as an adjunct to talk therapy. Though there are large increases in both dopamine and serotonin, serotonin and the serotonin transporter are particularly important in the generation, consolidation, retrieval, and reconsolidation of fear memories.³ Heig et al. examined the neurotransmitters responsible for the prosocial effects of MDMA in mice. Their findings suggested that the release of dopamine is responsible for the rewarding effects of MDMA, leading participants to associate an experience with a sense of reward. This rewarding effect is directly associated with the release of serotonin and activation of serotonin 1b receptors within the nucleus accumbens, reinforcing the rewarding aspect of social interaction.²³ The social connection is strongly reinforced by this increase in serotonin, making it more likely that individuals will experience enhanced social connectivity once the effects of the drug are worn off^.23 Patients described often feeling more empathy and compassion for themselves during the sessions but also after long periods when the drug had worn off.³

Extensive research has shown that depletion in serotonin transporter levels increases the chances of developing PTSD and inducing fear and anxiety-related behaviors. As seen in mice, MDMA inhibits the fear memory in the amygdala by primarily affecting the serotonin 1b receptors.²⁴ Activation of this receptor plays a pivotal role in fostering trust and social engagement. It allows one to go beyond mere willingness, encompassing an intense desire for connection with others or the therapist. The intense desire to partake in connection correlates directly to the dopamine system in the brain. In combination with the serotonin system, participants feel the desire to bond and create trust while discussing positive but difficult topics.²⁵ MDMA-assisted therapy uniquely presents a ‘window of tolerance,’ enabling participants to revisit and process traumatic content without becoming overwhelmed.³ MDMA’s effects on prosocial interaction are defined by Bedi et al. who examined MDMA’s impact on the perception of socially threatening (angry and fearful

faces) and socially rewarding (happy faces) stimuli. The study found that MDMA attenuated amygdala activation when viewing angry faces while also enhancing the central reward processing system (the ventral striatum) when seeing happy faces.²⁶ MDMA has a reciprocal effect on the perception of others’ emotions: participants will rate a happy event as more positive if initially described as positive and are less likely to rate a threatening face more threatening.

Toxicology

While the therapeutic usage of MDMA is being evaluated, it is necessary to first recognize its toxicology. Structurally, MDMA is a class of phenethylamine similar to amphetamine and other psychoactive drugs. With a 1:1 racemate of R and S-enantiomers, and with the S-enantiomer being metabolized faster than the R-enantiomer, it is thought that the S-enantiomer is more potent in producing the psychoactive effects that MDMA is known for.²⁷ As an amine that can exist as free bases or as salts of different acids, it can theoretically be inhaled. However, it is most often taken orally as single-dose tablets. Other forms of administration can include snorting the powder and intravenous injection, but this is not commonly seen. MDMA is absorbed through the intestinal tract and reaches peak plasma concentrations around 2.5 hours after oral administration.²⁸ There are two major metabolic pathways: 1) MDMA is N-demethylated in the liver by the cytochrome P450 enzymes CYP2D6 and CYP1A2 producing metabolite 3,4-Methylenedioxyamphetamine (MDA) which is further metabolized into 3,4-dihydroxyamphetamine (HHA) by CYP2D6 through O-demethylation,²⁹ or 2) MDMA undergoes O-demethylation by CYP2D6 into metabolite 3,4-dihydroxymethamphetamine (HHMA). HHA and HHMA can be further metabolized, but it is suggested that MDMA and MDA are more important determinants of neurotoxicity. It is still unclear whether MDMA itself or its metabolites are responsible for neurotoxicity.³⁰

It is clear, however, that taking MDMA can cause neurotoxicity in humans, particularly in serotonergic neurons. A degeneration of the axons on these neurons is observed in both humans and animals upon MDMA usage, and serotonergic neurons are critical in controlling mood, sleep, and appetite.³¹ Therefore, frequent MDMA users experience depression, insomnia, and weight loss, even long after it has been eliminated from the system. Interestingly, these effects are suggested to be reversible. Studies have shown a significant recovery of serotonin axons upon MDMA deprivation for several months to a year.

Conversely, the acute toxic effects of MDMA are better understood. As mentioned, MDMA inhibits the reuptake of serotonin and other neurotransmitters while enhancing its release. This causes an accumulation of serotonin inside of the neuron, and an increase in its concentration in the synaptic cleft. High levels of serotonin inside the synaptic cleft can lead to the neurotransmitter reaching extrasynaptic receptors which may result in serotonin syndrome.³² Serotonin syndrome has a wide spectrum of symptoms, notably hyperthermia, hypertension, hyponatremia, confusion, and nausea. Although not directly associated with death, these symptoms may lead to behaviors that are lethal in some cases. Hyperthermia can lead to the person overhydrating. In return, this causes a decrease in sodium levels in the blood, causing hyponatremia. Is it important, therefore, to regulate hydration when taking MDMA. Although regulation of hydration is critical in preventing hyponatremia, the major elimination pathway of MDMA and its metabolites is through the urine. With a half-life of 8 hours in the blood plasma, elimination of this drug is moderately slow.³³ As it takes around 5 half-lives to have the majority of MDMA cleared from the body, symptoms of toxicity may persist for up to a few days.

Evidence of MDMA-assisted Therapy

Currently, there are only two FDA-approved treatment options for PTSD: sertraline and paroxetine, which are both SSRIs. Unfortunately, an estimated 35–60% of individuals do not respond to treatment to these SSRIs.^6,8 Meta-analyses have found paroxetine, but not sertraline, performed better than placebo, and that SSRIs had a small to modest effect size with respect to PTSD symptom reduction.³⁵

Phase I Trials

Mithoefer et al. completed the first Phase I clinical trial for MDMA-assisted therapy to evaluate the safety and viability of MDMA use in psychotherapy of patients with moderate to severe PTSD. Overall, 10 out of 12 (83%) participants responded to the MDMA-assisted therapy while only 2 out of 8 (25%) participants responded to the placebo-coupled therapy. Given the potential side effects of MDMA consumption, several safety measures were implemented, notably no-drug psychotherapy sessions. A team of male and female co-therapists, a psychiatrist, and a psychiatric nurse were present at all therapy sessions. The patients were maintained in a comfortable resting position after receiving the 125 mg first MDMA dose while therapists attempted to offer the patients equal time for verbal expression and then self-examination. Furthermore, a supplemental but optional dose of 62.5 mg was administered according to the investigator’s discretion, and the therapists remained with the patients until all apparent symptoms of MDMA use faded away and the subjects were declared mentally stable. As a stipulation, participants were required to stay overnight at the outpatient office after the 8-10-hour MDMA-assisted therapy, and the clinicians were supplied with medical equipment and drugs to respond to any of the participants’ medical emergencies. Lastly, an assigned investigator maintained daily telephone contact with the test subjects throughout the week following each MDMA-assisted therapy session.³⁶

Phase II and III Trials

Since the FDA granted breakthrough therapy designation to MDMA-assisted psychotherapy for PTSD in 2017, there has been an upsurge in the number of studies assessing the efficacy of MDMA, including six Phase II clinical trials and two Phase III clinical trials to date.^3,12,37 The aggregate findings are overwhelmingly positive in that MDMA-assisted psychotherapy significantly improved the attainment of clinically relevant reductions in PTSD symptoms, leading to a decrease in scores substantial enough to no longer classify individuals as having PTSD, without observed statistical heterogeneity. The therapy was generally deemed safe, and common reported side effects included bruxism, anxiety, jitteriness, headache, and nausea.

The primary outcome scale used for PTSD is the Clinician-Administered PTSD Scale

(CAPS-IV), a measure outlined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). A total CAPS-IV score ≥ 50 units constitutes a severe case of PTSD. The DSM-IV recommended using a 10-point difference in CAPS-IV units as a minimum threshold for determining whether the improvement is clinically meaningful.³⁸ Although different studies may have decided to use different significance thresholds, many past studies have supported this 10-15 point threshold.^{39,40,41,42,43}

Between 2004 and 2016, the six Phase II clinical trials adopted a similar experimental protocol: three preparatory psychotherapy sessions, followed by two to three blinded, 8-hour experimental psychotherapy sessions with MDMA (75–125 mg) or placebo (0–40 mg MDMA). The experimental sessions, which were scheduled approximately a month apart, were followed by three 90-minute non-drug integrative psychotherapy visits.

A cohort of 107 participants with moderate to severe PTSD were enrolled across the six Phase II studies. Eight participants did not finish treatment, and among them, six underwent at least one experimental session before discontinuing their involvement.³⁷ The last of the Phase II trials delved into MDMA’s potential to expedite psychotherapy of participants diagnosed with PTSD for more than 6 months prior. The study extended across about 4 years and involved participants over the age of 18 who identified as unresponsive to other PTSD treatments.⁴⁴

Among those who did complete treatment, a notable decrease in CAPS-IV total severity score was observed from the initial assessment to treatment exit (1-2 months after the last active MDMA session). The findings indicate a statistically significant difference in the CAPS-IV total scores between the active dose group and the control group. On average, there was a larger decrease in CAPS-IV total scores for the active group (−44.8 units; standard error = 2.8; p < .0001) compared to the control group at treatment exit. CAPS-IV total severity scores decreased further from treatment exit to long-term follow up (LTFU), 12 months post final MDMA session (−5.2 units; standard error = 2.3; p < .05), demonstrating the efficacy and stability of treatment outcomes of MDMA-assisted psychotherapy. Of these, 56% of participants no longer met PTSD criteria according to the CAPS-IV at treatment exit. This number increased to 67% at the LTFU.⁴⁵ 82% of participants achieved a clinically significant drop of 15 points or greater in CAPS-IV total scores at treatment exit, and 26.4% had a 15-point or greater decrease from treatment exit to LTFU. 12.1% of the participants experienced a relapse, a 15-point or greater drop in CAPS-IV scores at treatment exit followed by a 15-point or greater increase in scores from treatment exit to LTFU.³⁷ Some side effects such as anxiety, jaw clenching, reduced appetite, dizziness, and nausea were observed, yet no life-threatening adverse effects were recorded. Lastly, none of the participants new to MDMA before the Phase II study reported consuming ecstasy outside of the trial's setting.⁴⁵

Mitchell et al. conducted the first FDA-regulated Phase III study, evaluating the effectiveness of MDMA-assisted therapy in contrast with placebo plus therapy. The Phase III clinical trials opted for a very similar protocol to that of the Phase II trials, the only difference being dosage. The 2021 trial included a selection of 91 screened individuals, fitting a randomized experimental setup.³ The experiment followed a repeating treatment cycle with multiple steps: 1) a 90-minute preparatory therapy session without MDMA, 2) an 8-hour session with either MDMA-assisted therapy or a placebo plus therapy, and 3) three 90-minute integrative therapy sessions, with the first on the same day as Step 2, and the others spread out over the next 35 days after the participant received MDMA (or placebo). The administered MDMA dose was set to 80 mg for the first experimental session and then to be either kept constant or increased to 120 mg for the second and third therapy sessions. Out of the 91 participants, 46 were assigned to the MDMA-assisted psychotherapy group and 44 to the placebo and psychotherapy group, while one individual withdrew before dosing began. Four participants in the MDMA-assisted psychotherapy withdrew, with only 1 of the 4 leaving because of his inability to cope with the testing and therapy requirements.

Notably, 6 out of MDMA-AT’s 46 participants and 13 out of 44 placebo group participants had dissociative subtype PTSD, 3 suggesting severe and long-term struggle with PTSD that had led to a derealization of their perspectives.⁴⁶ After the first Phase III clinical trial, Mitchell et al. pursued a second one. Similar to the first, the second Phase III trial addressed the effectiveness of MDMA-assisted therapy in treating moderate to severe PTSD cases. In addition, the study was randomized, double-blind, and was carried out at different clinics across the United States. The CAPS-V test and SDS (Sheehan-disability score), a scale designed to assess functional impairment and disability in individuals with psychiatric disorders, were used to assess treatment progress.¹² Of the 324 screened candidates, 104 individuals from diverse ethnic backgrounds were selected, with the average participant having PTSD for about 16.2 ± 13.3 years. 53 participants were allotted to the

MDMA-assisted therapy group, from which one participant discontinued treatment before the final therapy session. 51 participants were assigned to the placebo and therapy group, from which 8 participants opted out for personal reasons and 4 experienced adverse events that led them to miss one of the CAPS-V tests.¹²

In terms of efficacy, both studies found milder but still statistically significant reductions in CAPS-V scores compared to the placebo group. In the 2021 trial, the mean change in CAPS-V scores after 18 weeks was −24.4 (s.d. 11.6) in the MDMA-assisted therapy group compared with −13.9 (s.d. 11.5) in the placebo group. Consequently, 67% of the MDMA-assisted therapy group no longer qualified as PTSD patients. In fact, 14 out of the 42 participants in the MDMA-assisted treatment group were classified “in remission” after only three treatment sessions, compared with just two of the 37 patients in the placebo group.³

Moreover, the Cohen’s d-effect size between the MDMA-assisted therapy group and placebo plus therapy group was d=0.91, the biggest recorded effect between a placebo plus therapy group and a pharmaceutical-assisted PTSD therapy, emphasizing the effectiveness of MDMA in facilitating psychotherapy.³

Similarly, the 2023 study found the mean change in CAPS-V to be −23.7 units (s.d.3.24) for MDMA versus −14.8 (s.d. 3.48) for placebo after 18 weeks. This study found that 86.5% of the participants treated with MDMA achieved a clinically significant benefit, and 71.2% of participants no longer met criteria for PTSD by the end of the study. The Cohen’s d-effect size between the MDMA-assisted therapy group and the placebo-coupled therapy group was d= 0.7.12 The studies also showed MDMA significantly mitigated depressive symptoms and did not increase the occurrence of suicidality among patients.

Legal Analysis

The recent wave of marijuana legalization has marked a significant shift in societal attitudes toward drug policy. This change has sparked discussions about the potential benefits of reassessing the legal status of other substances, such as MDMA. This argument advocates for the future legalization of MDMA for therapeutic use, leaning on parallels with the evolving approach to marijuana legalization.

Similar to marijuana, MDMA is a Schedule 1 drug under the Controlled Substances Act, meaning it has a “high potential for abuse, no currently accepted medical use in treatment in the United States, and a lack of accepted safety for use under medical supervision.”⁴⁷ This designation made it very difficult to study MDMA-assisted psychotherapy for many years. As already outlined, however, MDMA has recently demonstrated great promise in clinical settings, with research indicating that MDMA-assisted psychotherapy can be effective in treating PTSD. These therapeutic benefits warrant the development of evidence-based regulations for MDMA that prioritize public health and safety. Recognizing impeding factors such as public stigma behind the drug and a divided political landscape, though, we recommend following in the footsteps of marijuana reform.

In 2013, the Department of Justice released “the Cole memo,” declaring that state-legalized marijuana was still considered illegal under federal law, but that it would not be a priority for the federal government to block state legalization efforts as long as certain regulations were followed.⁴⁸ Five years later, this memo was rescinded, leaving federal policy regarding the drug in somewhat of an awkward legal limbo. Because the federal government neither supports nor opposes cannabis regulations, current policies appear to mirror those articulated in the Cole memo.⁴⁹ A similar arrangement could be established for those engaging in state-legal psychedelic markets.⁵⁰

An analytic model based on marijuana legalization using data from psychedelic reform bills across the country projects that most states will legalize psychedelics by 2033–2037. Since 2019, 25 states have collectively considered 74 bills, 10 of which have been signed into law, and all of which either contradict or circumvent the Controlled Substances Act. In fact, psychedelic reform may progress faster than cannabis reform due to the higher likelihood of FDA approval, early bipartisan legislative support, and early interest in reform at the federal level. This likely stems from the precedent marijuana reform has set in increasing access to Schedule 1 drugs. However, potential roadblocks include FDA disapprovals, adverse public perceptions of psychedelic risks compared to cannabis, and the impact of lobbying on legislative reform.⁵⁴ The fate of MDMA in the

United States depends on the results of ongoing clinical trials, verdicts by the FDA and/or DEA to alter the classification of psychedelics and state-level legislative changes. Much like cannabis legalization, which largely resulted from state-level reforms despite remaining a Schedule 1 drug and lacking FDA approval, similar legislative changes at the state level are shaping the future landscape for MDMA therapy and drug enforcement.

Conclusion/Recommendations

The accumulating evidence for MDMA-assisted psychotherapy makes a compelling case for its therapeutic potential in treating PTSD. MDMA has a unique mechanism of action that enhances the therapeutic process by increasing feelings of trust, compassion, and ability to revisit traumatic memories without feeling overwhelmed. Multiple double-blind, placebo-controlled Phase II and Phase III clinical trials have demonstrated MDMA's outstanding safety and efficacy in augmenting psychotherapy outcomes for PTSD patients previously unresponsive to medications or therapy alone. In fact, results showed up to 71% of PTSD patients no longer met diagnostic criteria for PTSD after MDMA-assisted psychotherapy. These results are extremely promising for this notoriously difficult-to-treat illness.

However, MDMA remains classified by the DEA as a Schedule 1 substance denoting high abuse potential, no accepted medical use, and lack of safety. This presents regulatory hurdles for MDMA’s therapeutic access. Following the model of marijuana legalization at the state level despite federal prohibition, legislation is starting to be introduced in many states to legalize clinical use of MDMA and other psychedelics. One analysis projects most states will legalize psychedelic-assisted therapy within the next 10-15 years.

Given the apparent clinical benefits and precedent set by marijuana legalization, MDMA warrants rescheduling and regulation rather than a blanket prohibition. Therefore, we recommend state-by-state efforts to legalize medical use of MDMA continue regardless of its Schedule 1 status. If federal descheduling does not occur, psychedelic reform should take a similar path as cannabis by establishing state programs that follow responsible health-focused regulations. Following public health models rather than criminal justice approaches has the highest chance of providing access for this innovative PTSD treatment while preventing recreational abuse. This approach will not only increase access to MDMA therapy but also generate more evidence to eventually justify reconsidering its restrictive federal classification. With growing calls for reform, MDMA-assisted psychotherapy brings hope that innovative treatments can overcome outdated policies to provide a lifeline for PTSD patients in need.