American Journal of Therapeutics 31(2):p e141-e154, March/April 2024.
Shinozuka, Kenneth BA1,2,*; Tabaac, Burton J. MD, FAHA3,4; Arenas, Alejandro MD5; Beutler, Bryce D. MD6; Cherian, Kirsten PhD7; Evans, Viviana D. BA8; Fasano, Chelsey BA9; Muir, Owen S. MD, DFAACAP10,11
Background:
After becoming notorious for its use as a party drug in the 1980s, 3,4-methylenedioxy-methampetamine (MDMA), also known by its street names “molly” and “ecstasy,” has emerged as a powerful treatment for post-traumatic stress disorder (PTSD).
Areas of Uncertainty:
There are extensive data about the risk profile of MDMA. However, the literature is significantly biased. Animal models demonstrating neurotoxic or adverse effects used doses well beyond the range that would be expected in humans (up to 40 mg/kg in rats compared with roughly 1–2 mg/kg in humans). Furthermore, human samples often comprise recreational users who took other substances in addition to MDMA, in uncontrolled settings.
Therapeutic Advances:
Phase III clinical trials led by the Multidisciplinary Association for Psychedelic Studies (MAPS) have shown that MDMA-assisted psychotherapy has an effect size of d = 0.7–0.91, up to 2–3 times higher than the effect sizes of existing antidepressant treatments. 67%–71% of patients who undergo MDMA-assisted psychotherapy no longer meet the diagnostic criteria for PTSD within 18 weeks. We also describe other promising applications of MDMA-assisted psychotherapy for treating alcohol use disorder, social anxiety, and other psychiatric conditions.
Limitations:
Thus far, almost all clinical trials on MDMA have been sponsored by a single organization, MAPS. More work is needed to determine whether MDMA-assisted therapy is more effective than existing nonpharmacological treatments such as cognitive behavioral therapy.
Conclusions:
Phase III trials suggest that MDMA is superior to antidepressant medications for treating PTSD. Now that MAPS has officially requested the Food and Drug Administration to approve MDMA as a treatment for PTSD, legal MDMA-assisted therapy may become available as soon as 2024.
CLINICAL CASE
A 32-year-old man with a history of treatment-resistant post-traumatic stress disorder (PTSD) presents for evaluation at a specialized clinic for service-connected disabled veterans. He had been an Air Force combat reconnaissance photographer in his military service, under the Joint Special Operations Command, and although he declines to provide a detailed description on initial evaluation of his myriad deployments, he identifies a number of Category A trauma events over his 15 years of military service. Prior treatments include prolonged exposure psychotherapy, venlafaxine (up to 225 mg), prazosin (up to 25 mg), and quetiapine (up to 600 mg QHS), which is the only medication he is continuing to take at this time. He presents to this specialized setting in the context of insufficient relief from his disabling nightmares, flashbacks, and irritable outbursts which have led to filing for divorce from his spouse of 12 years. On physical examination, he is 280 pounds. He is notably hypervigilant on mental status evaluation, but he evidences no other problems from his neurological or physical examination, although he reports that his urination has become more frequent on his current regimen, compared with when he was on prazosin. His hemoglobin A1C is 7.3 on pre-evaluation bloodwork, and his total cholesterol is 214, with a low-density lipoprotein cholesterol of 143. Absent successful treatment with prior attempts, he was willing to present for MDMA treatment evaluation in this specialized setting, noting “some of my buddies were in the trial for this, and they told me it was worth checking out.”
BACKGROUND
History
MDMA, also known by the street names ecstasy, E, molly, mandy, pills, and pinger, was created and patented by Merck, a German pharmaceutical company, in 1912, out of a desire to develop a novel precursor for the synthesis of a chemical that prevents blood clotting.1 However, MDMA did not gain widespread recognition until famed chemist Alexander Shulgin synthesized it himself and introduced it to psychotherapists in America,2 who took interest in the drug because it seemed to be less toxic than chemically similar yet therapeutically promising substances.3 While therapists were using MDMA for couples therapy and as a tool for treating psychosis, PTSD, cancer, and other illnesses in the 1970s and 80s,3 MDMA started to become widely available as a club drug. Its popularity grew in tandem with rave culture; MDMA fueled the rise of house and techno music. These genres of music, in clubs and similar settings, were experienced as synergistic with the subjective experience of the drug. However, MDMA’s use as a “party drug” led the Drug Enforcement Administration (DEA) to classify it as a Schedule I substance in 1985.
Before the federal ban on MDMA, American activist Rick Doblin petitioned the DEA to maintain the legality of MDMA-assisted therapy. When his efforts proved unsuccessful, Doblin founded the nonprofit Multidisciplinary Association for Psychedelic Studies (MAPS) in 1986 to fund research on MDMA (see 4 for a review on the history of MAPS). After funding some initial studies on the safety of MDMA use in dogs and rats,5 MAPS applied for the Food and Drug Administration (FDA) to grant Investigational New Drug (IND) status to MDMA for the treatment of pain, anxiety, and depression in patients with cancer. In 1994, the FDA conducted a phase I study on MDMA to establish the dose–response safety of MDMA, which established that changes in body temperature and heart rate on MDMA were transient and that MDMA use was well-tolerated in healthy participants.6
Chemistry and mechanism of action
Unlike LSD, N,N-dimethyltryptamine (DMT), and psilocybin, MDMA is not a classic psychedelic; it is an amphetamine derivative. However, because MDMA, unlike amphetamines, has a functional group (methylenedioxy) attached to its aromatic ring, its chemical structure resembles that of mescaline.7 Thus, MDMA is often grouped together with psychedelic drugs. Another characteristic that distinguishes MDMA from amphetamines is the profound feeling of euphoria, compassion, and trust that MDMA elicits. It has historically been referred to as the “love drug.” MDMA promotes empathy, and in therapeutic contexts, it enables users to access and heal from traumatic memories.8
Because MDMA is not a classic psychedelic, its psychoactive effects are not primarily mediated by the serotonin-2A (5-HT2A) receptor. (That being said, its interaction with 5-HT2A does have a secondary effect on its hallucinogenic9,10 and therapeutic properties, as discussed below.) Instead, MDMA acts on the serotonin transport systems, of which there are 2 types in the brain.11,12 In the first, the serotonin transporter (SERT or 5-HTT) brings serotonin across the plasma membrane of a neuron, mediating the reuptake of serotonin from the synaptic cleft.13 The other transporter, the vesicular monoamine transporter 2 (VMAT2), takes intracellular serotonin from the cytosol and stores it into vesicles, such that they will later be released into the synaptic cleft.14 Early research demonstrated that, by binding to SERT, MDMA not only prevents serotonin from entering the plasma membrane but also reverses the normal direction of serotonin flow, causing serotonin to leave the membrane and flood the synapse.15 Furthermore, by inhibiting VMAT2, MDMA also blocks serotonin from getting stored into vesicles, massively increasing the concentration of serotonin inside the neuron. This further facilitates the outflow of serotonin into the synapse.16
MDMA’s mechanism of action is not entirely different from that of SSRIs, which similarly prevent the reuptake of serotonin by binding to SERT.17 However, unlike SSRIs, MDMA additionally releases large amounts of serotonin into the synapse.18 The subsequent increase in the concentration of extracellular serotonin is potentially much more substantial and rapid on MDMA than on SSRIs.19 However, owing to the shared mechanism of action at the SERT transporter, taking SSRIs together with MDMA mitigates the subjective intensity and physiological effects, such as increased blood pressure and heart rate, of MDMA.20
In addition to inhibiting SERT, MDMA also binds directly to serotonin receptors, such as 5-HT1B, 5-HT2A, and 5-HT2C.9 5-HT1B and 5-HT2A fully and dose-dependently mediate the heightened motor behavior that occurs on MDMA, respectively,21–24 whereas 5-HT2C inhibits this hyperactivity.25,26 In addition to regulating motor behavior on MDMA, 5-HT2A also moderates the emotional response to MDMA. Blocking 5-HT2A with the antagonist ketanserin diminishes the emotional excitation caused by MDMA, as well as some hallucinogenic effects.27 Ketanserin also diminishes the elevated mood induced by MDMA.28
MDMA’s interaction with both SERT and 5-HT2A may mediate its therapeutic effects by promoting “fear extinction,” or the loss of a fearful response to an adverse stimulus29 conditioned mice to fear-inducing stimuli by pairing a neutral stimulus (i.e. an auditory tone) with an aversive stimulus (i.e. a footshock). To investigate the hypothesis that MDMA’s action at SERT is necessary for fear extinction, the authors then treated mice with a SERT inhibitor, a 5-HT2A antagonist, or placebo. Then, they administered MDMA and exposed the mice to extinction training, in which the neutral stimulus was played without the aversive stimulus. MDMA enhanced fear extinction, and this effect was blocked by both SERT and the 5-HT2A antagonist. (However, a subsequent study found that administering MDMA before fear extinction training actually augmented subsequent fear responses, but MDMA treatment during the reconsolidation phase, i.e., immediately after reactivation of the fear-inducing memory, successfully reduced the fear response.30)
An earlier study by the authors of31 with a similar protocol, albeit without the 5-HT2A antagonist, demonstrated that MDMA enhanced the expression of brain-derived neurotrophic factor (BDNF),31 which is known to play a key role in neuroplasticity; dysregulation of BDNF is associated with maladaptive neuroplasticity in depression.32,33 The study only observed increases in BDNF within the amygdala, a region in the brain that is involved in regulating fear.34 Meanwhile, neuroimaging studies on humans have discovered that MDMA decreases cerebral blood flow, a measure of brain activity, in the amygdala.35 In addition, MDMA elevates functional connectivity between the amygdala and hippocampus35,36 (note that the second study only found a trend-level effect), a region that supports the encoding and retrieval of memories.37 Taken together, these findings from both humans and rodents seem to be consistent with the clinical observation that MDMA-assisted therapy facilitates access to traumatic memories that were previously repressed. By upregulating BDNF, MDMA may stimulate neuroplasticity and restore impaired synaptic connections within the amygdala, and enhanced connectivity with the hippocampus may then “unlock” the memory of the trauma.38 Furthermore, reduced blood flow in the amygdala may correspond to a decrease in anxiety,35,39 enabling recipients of MDMA-assisted therapy to face the traumatic memory with less fear.
Aside from serotonin, MDMA releases 2 other neurotransmitters: norepinephrine and, to a lesser extent, dopamine. While antagonizing dopamine receptors or deleting dopamine receptor genes has little effect on the behavioral response to MDMA,40,41 MDMA actually binds with higher affinity to the norepinephrine transporter (NET) than to the serotonin and dopamine transporters.42,43 Furthermore, blocking NET reduces the intensity of the MDMA high, as well as physiological effects of MDMA like elevations in blood pressure and heart rate.44 NET inhibition lowered subjective ratings of stimulation in response to MDMA, whereas SERT inhibition more strongly suppressed positive mood ratings,20 suggesting that norepinephrine mediates the stimulant-like effects of MDMA.
In addition, MDMA stimulates the hormone oxytocin, which plays a vital role in parent–infant bonding45 and social affinity.46 Thus, MDMA’s interaction with oxytocin underlies not only the general empathogenic qualities of MDMA47 but also the strong sense of trust that MDMA promotes between the therapist and the patient, which is believed to contribute to its uniquely powerful therapeutic effects.48 Furthermore, oxytocin receptors in the nucleus accumbens may mediate the “critical period” of synaptic plasticity that MDMA reopens, thereby facilitating social reward learning.49
AREAS OF UNCERTAINTY
Ever since the seminal study of Schmidt and colleagues in 1986,50 the first to report the persistent depletion of serotonin and its metabolite, 5-hydroxyindoleactic acid (5-HIAA), in rat brains for up to a week after a high-dose injection of MDMA, numerous studies have provided apparent evidence that MDMA has neurotoxic effects (see ref. 51 for a comprehensive review). Much of the early research on rats focused on long-term reductions in the concentration of serotonin, 5-HIAA, and tryptophan hydroxylase, an enzyme that facilitates the synthesis of serotonin; damage to axon terminals that take up serotonin; and loss of 5-HTT binding sites.52–60 MDMA dose-dependently depleted serotonin by anywhere between 16% and 75% in the rat cortex.61,62 Serotonin concentration declines in the first 3 hours after dosing, recovers between 6 and 24 hours later, and gradually decreases again between 1 and 7 days later.63 However, many of these studies administered very high, “binge-like” doses of MDMA to rats; for example, the study that reported a 75% reduction in serotonin gave four 10 mg/kg doses to rats, whereas a therapeutic dose of MDMA in humans is considered to be no higher than <2 mg/kg followed by one <1 mg/kg supplemental dose, assuming an average human weight of >60 kg64 (note: In this study, the administered dose of MDMA did not depend on weight). Other studies on neurotoxicity administered MDMA doses that were nearly 100 times the standard recreational or therapeutic dose of MDMA.65
Furthermore, measured declines in serotonin levels do not reliably correlate with damage to brain tissue. MDMA-induced serotonin depletion does not always lead to loss of serotonin axon terminals.66 These data suggest that reductions in serotonin constitute an adaptive, counteractive response to the effects of MDMA, rather than leading to damage of serotonin terminals.67 In addition, serotonin concentrations recover between 6 months and 1 year after MDMA exposure, though not always in all brain regions.62,68 While initial histological research directly revealed degenerating axon terminals, dendrites, and cell bodies in striatal slices of rats that were administered extremely high doses of MDMA (up to 40 mg/kg),56,57,65,69 a reappraisal of the early research found no evidence for cell death.67 In particular, several of the studies that used histological stains found evidence of neurodegeneration in nonserotonergic neurons.65,69,70 Thus, it seems unlikely that serotonin-specific pathways were related to the neurotoxicity observed in those studies. Moreover, because of the very high doses of MDMA that were administered, adverse effects like hyperthermia—excessive heating of the body, which is known to scale with the dose of MDMA71—may have been the primary causes of neurotoxicity. Indeed, in one of these histological studies,70 MDMA-induced neurodegeneration only occurred in rats that experienced hyperthermia of >41°C.
MDMA also does not seem to elicit the so-called “universal reaction to brain injury,” reactive gliosis, in which the cell bodies of astrocytes grow excessively.72 A tell-tale sign of reactive gliosis is the increased synthesis of glial fibrillary acidic protein (GFAP).73 While an old study found that GFAP was significantly elevated in rats that received extremely high doses of MDMA (75–150 mg/kg), changes in GFAP were not related to levels of serotonin depletion.74 Two more recent studies demonstrated that MDMA did not affect GFAP expression.75,76
However, one mechanism that does seem to contribute to MDMA-induced neurotoxicity is oxidative stress.77,78 Oxidative stress occurs when mitochondria produce too many reactive oxygen species (ROS), such as hydroxyl “free radicals” (-OH), which are metabolic byproducts of biological processes like protein phosphorylation.79 If their concentrations are not kept in check, free radicals will excessively oxidize lipids, proteins, and other macromolecules, leading to cancer and cardiovascular disease.80 MDMA is metabolized into organic compounds known as quinones, which lead to the formation of free radicals81,82 that in turn may impair the healthy functioning of mitochondria.83,84 Multiple studies have claimed that the quinone metabolites of MDMA, rather than the MDMA itself, are the source of the drug’s neurotoxicity,85–87 especially since direct injection of the MDMA into local brain regions (without metabolization in the liver) does not cause much neurotoxicity.88 However, several MDMA metabolites that get oxidized into quinones are not neurotoxic,89,90, p. 199 and some have claimed that the deamination (breakdown of amino acids) and oxidation of dopamine released by MDMA may play a more pivotal role in MDMA-induced neurotoxicity than the metabolites themselves.91 One metabolite in particular facilitates the uptake of dopamine into serotonergic neurons; the subsequent oxidation of dopamine, not MDMA, produces reactive and toxic quinones.92
Thankfully, there is an abundance of evidence that the oxidative stress induced by MDMA can be prevented by antioxidant supplements, which inactivate free radicals. When administered before MDMA, the antioxidant alpha-lipoic acid was found to block serotonin depletion and changes in GFAP expression,93 and the antioxidant ascorbate, more commonly known as vitamin C, achieves similar effects.94,95 Nutrients like acetyl-l-carnitine are not directly antioxidative, but they seem to strengthen the cell membranes of mitochondria, thus preserving the expression of mitochondrial complexes that are otherwise impaired by MDMA.83 Based on the scientific evidence, recreational users of MDMA have compiled “supplement packs” (e.g. rollsafe.org), consisting of nutrients and antioxidants to take alongside MDMA to avert the neurotoxic effects. That being said, none of these supplement packs, as far as we are aware, have been examined in peer-reviewed research.
So far, this section has covered research on cell and mouse models of MDMA. Next, we evaluate direct evidence for the neurotoxic effects of MDMA on humans. A multitude of PET and SPECT studies have demonstrated reduced SERT density in human users of MDMA.96–105 Furthermore, MDMA use has been associated with cognitive impairment, in particular deficiencies in sustained or complex attention; short-term and working verbal, spatial, and visual memory; semantic recognition; and verbal reasoning, as well as exacerbation of unfavorable personality traits like hostility and impulsivity.98,100,105–113 However, 12 of the 18 studies mentioned above do not control for polydrug use. As revealed by the studies themselves, many MDMA users also consume other illicit substances, such as amphetamines and cocaine, which are known to cause long-term cognitive impairments (for comprehensive reviews, see refs. 114, 115). Therefore, in studies that do not control for polydrug use, it is unclear whether it is the MDMA or the other substances that are contributing to the neurotoxic or adverse cognitive effects. (It is also worth noting that in 2 of these studies, significant differences were only found for heavy MDMA users and not for ‘normal’ MDMA users.103,108) The remaining 6 studies putatively controlled for polydrug use by including a group of control participants who were taking illicit substances but had never consumed MDMA. However, in four of these studies, MDMA users consumed much higher quantities of amphetamines and/or cocaine than the non-MDMA, polydrug users.105,107,110,113 Finally, a fifth study measured drug-induced neurotoxicity with SERT density, but it found that non-MDMA, polydrug users exhibited higher binding of SERT than drug-naive participants.96 This study calls into question the notion that SERT density is a valid metric of neurotoxicity. Only a single study to date has measured cognitive ability in MDMA users who have minimal exposure to other illicit substances, likely because such users are rather uncommon.116, p. 201 Based on a battery of 15 cognitive tests, there was little evidence for cognitive impairment. The only significant difference was that MDMA users exhibited increased impulsivity; this could be a common, baseline trait of drug users, who are likely to be more risk-taking than the general population.117
Finally, studies of MDMA-induced neurotoxicity in humans are confounded by uncertainty about the authenticity or purity of the MDMA ingested. In all these studies, participants used MDMA that they had purchased illegally, rather than receiving MDMA from a licensed laboratory. MDMA can often be adulterated with other substances, such as synthetic cathinones and fentanyl,118 which are both harmful.119–121 Therefore, in uncontrolled recreational use, it is unclear whether the neurotoxic effects of MDMA can be reliably attributed to the compound itself.
Anecdotal reports commonly describe a steep emotional “comedown” as one of the major adverse effects of MDMA. This comedown is often referred to as “Blue Monday” or the “Tuesday Blues” because the comedown sometimes does not occur until 2 days after the MDMA experience.122 Intriguingly, in a recent study in which MDMA was administered for alcohol use disorder, participants did not report negative changes in mood in the 7 days after the MDMA session.123 In fact, participants reported an emotional “afterglow,” or a consistently elevated mood, after receiving the MDMA treatment. The authors attribute anecdotal accounts of comedowns to the harmful conditions in which MDMA is often taken when consumed recreationally; people who use MDMA at raves tend to exhaust themselves by dancing all night, get poor sleep, and take other drugs simultaneously. However, a critique of this study pointed out that it apparently did not take baseline measurements of mood.124 Another study that administered MDMA to 166 healthy participants did find significant adverse effects 24 hours after the session, including headache, lack of appetite, lack of energy, and difficulty concentrating, especially in participants who were given a high (125 mg) rather than a medium (75 mg) dose; that being said, there were no differences in depressed mood between the MDMA and placebo groups nor did any “serious” adverse effects occur.125
Methodological issues notwithstanding, Sessa’s findings are consistent with observations in clinical studies in which MDMA was administered in a controlled, therapeutic setting, unlike recreational contexts. In a recent phase III trial of MDMA for treating PTSD, only one of 46 participants in the MDMA group experienced an adverse event of depressed mood; otherwise, there were no incidences of lowered mood.64 In the other phase III trial, there do not seem to be any significant differences in incidences of suicidal ideation between the MDMA and placebo groups.126
THERAPEUTIC ADVANCES
Early anecdotal reports of MDMA-assisted psychotherapy suggested that MDMA was potentially useful for treating PTSD because it enabled people to access repressed emotions or memories, such as traumas, while also feeling greater self-compassion.127 MAPS pivoted toward pursuing MDMA as a treatment for PTSD and released their first protocol for MDMA-assisted psychotherapy for chronic, treatment-resistant PTSD in 2001. Phase II trials commenced in 2004, administering 125 mg of MDMA to 12 participants with PTSD (and placebo to 8 other participants) over 2 sessions. Participants also went through 8 integration sessions with therapists to discuss and process the MDMA session. To assess symptoms of PTSD, clinicians measured scores on the Clinician-Administered PTSD Scale (CAPS) at baseline, 4 days after each session, and 2 months after the second session. Remarkably, 83% of participants exhibited clinical response, defined as a greater than 30% reduction in CAPS scores, whereas the clinical response rate in the control group (placebo with therapy) was only 25% (Table 1).128 Participants in the placebo group were given the opportunity to receive MDMA therapy at the 2-month follow-up. Among the 7 control participants who crossed over into the MDMA group after failing to respond to the placebo therapy or relapsing into PTSD symptoms, 100% exhibited a clinical response. A long-term follow-up that took place 17–74 months after the second session reported that almost all the participants who received MDMA maintained low CAPS scores.129 Five subsequent MAPS-sponsored phase II trials, 3 of which were published,130–132 reported similarly promising results, although one of them found that reductions in CAPS scores from MDMA-assisted therapy did not meet the threshold for statistical significance.131 Two of these studies also demonstrated that the therapeutic effects of MDMA were dose-dependent; the effect sizes of medium (75–100 mg) and high (125 mg) doses were much greater than that of low (30–40 mg) doses, and participants who crossed over from the low-dose group to the medium-dose or high-dose group exhibited significant improvements in PTSD symptomatology.130,132 A review of all 6 phase II trials concluded that 54% of participants across all the MDMA groups no longer met the diagnostic criteria for PTSD, compared with only 23% of placebo participants.133
The large effect sizes from the phase II trials led MDMA to receive Breakthrough Therapy Designation from the FDA in 2017, and they paved the way for 2 phase III studies. In the first, 46 participants were assigned to receive 3 sessions, spaced 4 weeks apart, of MDMA-assisted therapy across multiple sites in the United States, Canada, and Israel.64 (Another 44 were randomized to the control group.) The first session consisted of an initial dose of 80 mg and a supplemental half-dose of 40 mg, which was taken 1.5–2.5 hours later. In the second and third sessions, participants were administered 120 mg and a supplemental half-dose of 60 mg. After each session, participants underwent 3 integration sessions, which took place a week apart from one another. Eighteen weeks after baseline, MDMA significantly reduced CAPS scores relative to placebo (d = 0.91, P < 0.0001); the mean change in CAPS scores was nearly 1.76x higher in the MDMA group (−24.4) than in the placebo group (−13.9), and 67% of the participants in the MDMA group no longer met the diagnostic criteria for PTSD, compared with just 32% of the placebo group. The second confirmatory phase III trial, which enrolled 104 participants and followed the same experimental procedure, produced similarly positive results.126 Mean change in CAPS scores was 1.6x higher in the MDMA group (−23.7) than in the placebo group (−14.8), and 72% of participants in the MDMA group no longer met the diagnostic criteria for PTSD by the end of the study, compared with just 48% in the placebo group. In December 2023, MAPS officially requested the FDA to approve MDMA-assisted therapy as a treatment for PTSD.134 Approval is anticipated as early as 2024.
How does MDMA compare with existing treatments for PTSD? At the moment, sertraline and paroxetine, which are both antidepressants of the SSRI (selective serotonin reuptake inhibitor) class, are the only FDA-approved pharmacological treatments. Across all 6 phase II trials, the effect size of MDMA-assisted psychotherapy was nearly 2 times higher than that of paroxetine and 3 times higher than that of sertraline.135 There are several other advantages that MDMA-assisted therapy has over sertraline or paroxetine. First, sertraline and paroxetine must be taken on a daily basis for anywhere between 2 and 12 weeks to observe any changes in PTSD symptoms, whereas just a single MDMA dose is sufficient to significantly reduce CAPS scores only 3–5 days later.135 Second, dropout rates are 1.7 times lower for MDMA therapy than for paroxetine and 4.1 times lower than for sertraline, perhaps because of the swift and powerful therapeutic effects of MDMA.135 However, regarding effect size, MDMA is nearly as effective as or perhaps less effective than trauma-focused psychotherapies, such as eye-movement desensitization reprocessing (EMDR), exposure therapy, cognitive behavioral therapy (CBT), art therapy, and more.135–138
MDMA shows promise for treating other conditions, such as anxiety disorders, alcohol use disorder (AUD), substance use disorders, eating disorders (EDs), and more. Just as psilocybin has reduced end-of-life anxiety in terminally ill populations,139 a MAPS-sponsored phase II trial found that MDMA-assisted therapy significantly reduced State-Trait Anxiety Inventory scores, although the difference between the MDMA and placebo groups was just under the threshold for statistical significance.140 Another MAPS-sponsored phase II trial explored the efficacy of MDMA for treating social anxiety in adults with autism, who are at a much greater risk for social anxiety disorder than the general population.141 MDMA significantly reduced scores on the Leibowitz Social Anxiety Scale for autistic adults who previously had very severe social anxiety.142
With regard to addiction, a recent study found that MDMA caused a staggering drop in alcohol consumption, from 130.6 units per week to 18.7 units per week, in a group of 14 participants with AUD.143 During one phase III trial on MDMA for PTSD, researchers also measured changes in measures of hazardous alcohol and substance use over the course of treatment, and they reported that MDMA-assisted therapy for PTSD led to a concomitant, significant reduction in these measures.144 A subset of participants (32%) in the phase III trial were also at high risk for EDs, according to baseline measurements of Eating Attitudes Test 26 (EAT-26) scores. MDMA therapy for PTSD significantly reduced EAT-26 scores.145 These results are expected given that AUD and EDs are comorbidities with PTSD.146,147 MAPS is now planning a phase II trial on MDMA for anorexia nervosa and binge-eating disorder in a group of 18 participants.148
Table 1. – Contemporary (21st-century) clinical trials on MDMA.
| Study | Type | Dosing | Sample | Findings |
| 128,129 | Double-blind, inactive placebo-controlled RCT (phase II) | Stage 1: 2 blinded sessions, each with one dose of 125 mg + optional supplemental dose of 62.5 mg 2–2.5 hours later. Stage 2: Placebo group allowed to cross over into the MDMA group (2 sessions), and the MDMA group were allocated an additional open-label session. |
20 patients with PTSD | Stage 1, at 2 months: significant decrease in CAPS scores (MD: −33.6; P = 0.013); 83% clinical response rate in MDMA group, compared with 25% in placebo group. Stage 2, at 4–6 weeks: significant decrease in mean CAPS scores for crossover participants (MD: −31.7; P < 0.05). At long-term follow-up (mean: 45.4 mo), all participants: decreases in CAPS scores were sustained, except for 2 relapses. |
| 131 | Double-blind, active placebo-controlled RCT (phase II) | Stage 1: 3 blinded sessions, each with one of 2 doses: 25 mg (active control) or 125 mg. Optional supplemental dose at half the initial dose. Stage 2: 25 mg group allowed to cross over into 125 mg group (3 sessions). Stage 3: Nonresponders in 125 mg group in Stage 1 were allocated 2 additional open-label sessions. |
12 patients with PTSD | Stage 1, at 3 weeks: insignificant decrease in CAPS scores (MD: −15.7, P = 0.066), Stage 1, at 2 months: 50% clinical response rate. Stage 2: 100% clinical response rate. Stage 3: no further improvements in CAPS scores. At long-term follow-up (12 mo), all participants: 24-point decrease in CAPS scores relative to baseline for the full-dose group in Stage 1, 35-point decrease for crossover group; 42% of all participants no longer met diagnostic criteria for PTSD. |
| 130 | Double-blind, dose-response RCT (phase II) | Stage 1: 2 blinded sessions, each with one of 3 doses: 30 mg (active control), 75 mg, or 125 mg. Optional supplemental dose at half the initial dose. Stage 2: 30 and 75 mg groups allowed to cross over into high-dose group (3 sessions), and 125 mg group were allocated an additional open-label session. |
26 veterans and first responders with PTSD | Stage 1, at 1 mo: significant decrease in CAPS-IV scores (MD between 75 mg and 30 mg groups: −46.9, d = 2.8, P = 0.001; MD between 125 mg and 30 mg groups: −32.9, d = 1.1, P = 0.001); 58% in 125 mg group, 86% in 75 mg group, and 29% in 30 mg group no longer met PTSD diagnostic criteria. Stage 2, at 1 mo: significant decrease in CAPS-IV scores (MD relative to end of Stage 1: −27.0) for crossover participants; 33% no longer met PTSD diagnostic criteria. At long-term follow-up (12 mo), all participants: significant decrease in CAPS-IV scores relative to baseline (MD: −48.3, P < 0.0001); 67% no longer met PTSD diagnostic criteria. |
| 132 | Double-blind, dose-response RCT (phase II) | Stage 1: 2 blinded sessions, each with one of 3 doses: 40 mg (active control), 100 mg, or 125 mg. Optional supplemental dose at half the initial dose. Stage 2: 40 mg group allowed to cross over into 100–125 mg groups (3 sessions). 100 and 125 mg groups allocated an additional open-label session. |
28 patients with PTSD | Stage 1, at 1 mo: significant decrease in CAPS-IV scores for 125 mg group, per protocol subset (MD relative to 40 mg group: −33.0, d = 1.12, P = 0.01); insignificant decrease in CAPS-IV scores for 100 mg group, per protocol subset (MD: −20.4, d = 0.73, P = 0.10); 42% in 125 mg group, 44% in 100 mg group, and 33% in 40 mg group no longer met PTSD diagnostic criteria, intent-to-treat subset. Stage 2, at 2 months: significant decrease in CAPS-IV scores (MD relative to end of Stage 1): −34.7, P = 0.01 and 80% no longer met PTSD diagnostic criteria, intent-to-treat subset. At long-term follow-up (12 mo), all participants: significant decrease in CAPS-IV scores relative to baseline (MD: −61, P < 0.0001) and 76% no longer met PTSD diagnostic criteria, intent-to-treat subset. |
| 64,144,145 | Double-blind, inactive placebo-controlled RCT (phase III) | 3 blinded sessions: first with 80 mg + supplemental 40 mg half-dose, second and third with 120 mg + supplemental 60 mg half-dose. No crossover. | 90 patients with PTSD, 28 of whom met clinical criteria or had high risk for an ED. | At 18 weeks: significant decrease in CAPS-5 scores relative to placebo (MD: −11.9, d = 0.91, P < 0.0001); 67% in MDMA group no longer met PTSD diagnostic criteria, compared with 32% in placebo group; significant decrease in AUDIT scores for all participants relative to placebo (MD: −1.42, g = 0.45, P = 0.0436); significant decrease in EAT-26 scores for all participants relative to placebo (MD: −2.36, g = 0.33, P = 0.0335), although RCI values indicated that change from baseline was not reliable. |
| 126 | Double-blind, inactive placebo-controlled RCT (phase III) | 3 blinded sessions: first with 80 mg + supplemental 40 mg half-dose, second and third with 120 mg + supplemental 60 mg half-dose. No crossover. | 104 PTSD patients | At 18 weeks: significant decrease in CAPS-5 scores relative to placebo (MD: −8.9, d = 0.7, P < 0.001); 71% in MDMA no longer met PTSD diagnostic criteria, compared with 48% in placebo group. |
| 142 | Double-blind, inactive placebo-controlled RCT (pilot) | Stage 1: 2 blinded sessions: first with 75–100 mg and second with 100–125 mg. Stage 2: Placebo group allowed to cross over to MDMA group (2 sessions; data not presented.) |
12 people with SAD and autism | Stage 1, at 1 mo: significant decreases in LSAS scores relative to placebo (MD: −24.8, d = 1.4, P = 0.037); clinical response rate of 86% in MDMA group, compared with 50% in placebo group Stage 1, at 6 mo: significant decrease in LSAS scores relative to placebo (MD: −24.4, d = 1.1, P = 0.036); clinical response rate of 75% in MDMA group, compared with 50% in placebo group |
| 140 | Double-blind, inactive placebo-controlled RCT (pilot) | Stage 1: 2 blinded sessions, each with 125 mg + optional supplemental dose of 62.5 mg Stage 2: Placebo group allowed to cross over to MDMA group (3 sessions). MDMA group allocated an additional open-label session. |
18 patients with anxiety from an LTI | Stage 1, at 1 mo: insignificant decreases in STAI-Trait scores relative to placebo (MD: −14.7, g = 1.03, P = 0.0558). Stage 2, at 1 mo after second session: decrease in STAI-Trait scores relative to 1 mo after stage 1 (MD: −4.2). At long-term follow-up (12 mo), all participants: significant decrease in STAI-Trait scores relative to baseline (MD: −26.9, P < 0.0001). |
| 143 | Open-label | 2 sessions, each with 125 mg + supplemental dose of 62.5 mg. MDMA therapy began after completion of detox program. | 14 patients with AUD | At 9 months after detox: large decrease in alcohol consumption relative to predetox (MD: −111.9 units/week); abstinence in 64% of participants. |
CONCLUSIONS
Preliminary evidence suggests that MDMA in conjunction with psychotherapy may be a highly effective treatment for PTSD, as well as other conditions such as AUD, ED, anxiety, and more. By inhibiting the serotonin transporter, stimulating plasticity in the amygdala, and enhancing connectivity between the amygdala and hippocampus, MDMA enables users to process repressed memories of traumatic events without experiencing the fear that typically arises with them. While MDMA abuse in recreational contexts can lead to cognitive impairments, clinical research has shown that MDMA does not induce any psychological or neurological deficits when it is administered in a controlled, therapeutic context. More trials are needed to confirm the promising effect sizes of MDMA-assisted psychotherapy.
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