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MDMA

A comparison page: a synthetic compound studied alongside the natural psychedelics, what the research shows, where it is thin, and what Metanoia asks

Research page · fullLast reviewed 5 October 2026

Read this first. This page is education, not instructions to use. Metanoia does not supply any substance. In the United States, most of the substances discussed here are Schedule I under federal law (21 CFR 1308.11), their legal status differs between countries and between US states, and none of this is legal advice. Nothing here is medical advice, and nothing here describes or recommends a dose. "Healthy adults" means people with no diagnosed psychiatric or major medical condition, the population Metanoia studies. Most of the controlled MDMA research was done in small groups of screened volunteers or in people with post-traumatic stress disorder (PTSD), so the text names the group each study used, because that changes what the result can mean for everyone else.

What it is

MDMA, short for 3,4-methylenedioxymethamphetamine, is a synthetic compound that is sold illegally as "ecstasy" or "Molly". Researchers call it an entactogen or empathogen, words that point to the closeness and emotional openness people report with it [1]. Classic psychedelics such as psilocybin and LSD are typically understood to act by switching on the serotonin 2A receptor, a docking site on brain cells [31]. MDMA acts mainly on the transporters that clear serotonin, norepinephrine and dopamine from the gaps between neurons, releasing large amounts of those chemicals, serotonin above all [14].

Why a synthetic compound has a page on this site

Metanoia is a California 501(c)(3) public charity advancing the science of natural psychedelics for personal growth and human flourishing in healthy adults. Not treating illness. Expanding potential.

MDMA is synthetic, and its main mechanism differs from that of the classic psychedelics. It is on this site only as a comparison, outside the natural psychedelics that are Metanoia's focus, because its pharmacology shows another route into the same human capacities. Empathy and social connection are two of the twelve dimensions Metanoia asks about, and MDMA has a small controlled literature on both. Metanoia does not provide, sell or direct anyone toward MDMA.

A short history

The molecule was first made at Merck in 1912, psychotherapists began using it in the 1970s after Alexander Shulgin described its emotional effects, and it spread into recreational use by the early 1980s. In 1985 the U.S. Drug Enforcement Administration placed it in Schedule I on a temporary basis, in a notice published on 31 May 1985 that took effect on 1 July 1985 [32]. This is a secondhand account from a peer-reviewed narrative review (Grade 1) [14]. Apart from the 1985 scheduling, checked against the Federal Register notice, the dates were not checked against primary sources, and the later steps that kept MDMA in Schedule I were not read.

What is known

How it works

MDMA blocks the serotonin, norepinephrine and dopamine transporters, in that order of strength, and also enters the neurons and makes the transporters run in reverse, flooding the space between cells with serotonin. MDMA also binds to several receptors with modest strength, including the serotonin 2A receptor, so the contrast with the classic psychedelics is one of emphasis and does not mean this receptor plays no part. These mechanisms follow a 2026 review [14].

The body clears MDMA mainly through the liver enzyme CYP2D6, and in a pooled analysis of 194 healthy participants people whose version was more active had lower MDMA blood levels [2].

The acute effects repeat from laboratory to laboratory

A cross-laboratory comparison gives the most solid base. Research groups in Basel, San Francisco and Chicago had given MDMA to a combined 220 healthy volunteers (44 percent women) under double-blind conditions. Despite different countries, settings and drug histories, the heart rate and blood pressure rises and the main subjective ratings were very similar at all three sites [3]. Volunteers tested alone in Chicago rated themselves more anxious than those tested with researchers in the room, which the authors suggest may reflect the social setting. The Basel volunteers were mostly MDMA-naive, the others not [2][3]. People with more past MDMA use reported a weaker overall drug effect, clearly so in Chicago and only as a trend in San Francisco, but the authors point out that this appeared on a single rating and may not reflect true pharmacological tolerance. They contrast MDMA's stability across settings with the context dependence they attribute to hallucinogenic drugs [3]. In the pooled Basel analysis, blood concentration was the strongest single predictor for a large share of the responses (16 of 24 measures, and 8 after correction for multiple comparisons) [2].

Empathy, closeness and social behavior

This is where MDMA touches Metanoia's own dimensions, and the evidence is mixed.

The most cited healthy-volunteer study is a placebo-controlled, double-blind crossover trial in 32 volunteers at the University of Basel (16 women, average age 25, most MDMA-naive) [1]. MDMA raised ratings on a test of emotional empathy but did not change cognitive empathy, and in a task where people split real money with an unseen other person it increased the share given away. In post hoc tests both effects were significant in men and not in women. The statistical interaction with sex, however, was significant for a second, implicit measure of emotional empathy and for the money task, and only a trend for the explicit empathy rating (p = 0.092), so the sex pattern is weaker than the split by sex suggests. MDMA also made people worse at recognising emotions in faces, mainly fearful, angry, disgusted and surprised ones, and sad faces as well in women. The authors point out that most volunteers worked out their treatment, that only one amount was tested, and that the study ran many statistical comparisons [1].

Other work agrees. In the Chicago trial, the higher amount reduced recognition of angry and fearful faces and raised the wish to be with others [4]. In 36 healthy young adults who had each used MDMA 4 to 40 times before, MDMA but not methamphetamine raised the rated pleasantness of slow touch, and at the higher amount it increased visual attention to happy faces, while neither drug changed the pleasantness of watching others being touched [5]. A non-systematic review finds both shared and distinctive effects against other stimulants [7]. A second review, which its authors call a systematic overview of 49 articles with searches to June 2015, finds consistent increases in social approach and social feeling and calls the evidence for enhanced empathy mixed [8].

A null result belongs here. A London trial in 25 healthy poly-drug users (average age 34), each with at least one past MDMA experience, gave MDMA and placebo in a double-blind crossover. MDMA raised self-rated closeness and euphoria, yet it did not significantly change empathy, trust or cooperative behavior on the behavioral tasks. Bayesian analysis favored no difference for empathy, for the rating of how trustworthy faces looked and for every cooperation game, but favored neither direction in the investment task that measures trust. The authors say that pronounced drug effects probably unblinded participants and that the laboratory may be a poor stand-in for real social settings [6].

Do men and women respond differently?

In the Basel trial the sex-specific effects held up only in part as an interaction, and its women received roughly a quarter more per kilogram and reached higher blood concentrations [1]. In the pooled analysis of 194 volunteers sex stopped predicting the response once the amount per kilogram of body weight was taken into account, which its authors link to women's lower body weight [2]. The cross-laboratory study of 220 volunteers saw no sex differences in cardiovascular or subjective effects [3], so a sex difference in social effects was seen in one trial and not confirmed elsewhere. For physical effects the picture is mixed. In the pooled safety analysis of 166 volunteers, women reported more complaints and "adverse effect" ratings, the latter persisting after correction for body weight and blood concentration, while men showed the larger rise in blood pressure [9]. The pooled sodium trials found no sex difference [10], and higher rates in women come from observational reports [11]. A 2026 Basel trial of a supplemental second administration (the supplemental-administration trial below) found higher complaint scores in women and in people under 65 kilograms, an exploratory finding in which sex and body weight could not be separated [30].

Personality and mood before the session

In the pooled Basel analysis, openness to experience went with more closeness, and neuroticism or trait anxiety with more dread of losing the sense of self. Feeling anxious, depressed or withdrawn right before the drug predicted more anxiety in the session. The sample was young, mostly drug-naive and healthy, so the results may not carry over to people with psychiatric conditions [2].

In people with PTSD: a clinical population

The large trials of MDMA were done in people with PTSD, a diagnosed condition, with MDMA given together with psychotherapy. None of these results describes healthy adults. They appear here because they shape the regulatory record.

The second confirmatory Phase 3 trial, known as MAPP2, randomized 104 adults with moderate or severe PTSD to MDMA-assisted therapy (53 people) or placebo with the same therapy (51 people). The effect size on the clinician-rated PTSD scale was d = 0.7, and smaller (d = 0.4) for functional impairment. Nearly every participant had at least one adverse event. Five in the MDMA arm (9.4 percent) and two in the placebo arm (3.9 percent) had a severe one, and none had a serious one [17]. At the end, 94.2 percent of the MDMA arm (49 of 52) and 75 percent of the placebo arm (33 of 44) correctly guessed their treatment, so blinding largely failed. People with high suicide risk, certain personality disorders and cardiovascular disease were excluded, and treatment expectancy was not measured. The arms were unbalanced by sex (60 and 82 percent women). Several authors worked for the sponsor, and a 2024 correction only added names of collaborators to the author list and changed no data or results [17][18]. The effect size is larger than in antidepressant trials, but the authors say superiority over those drugs cannot be assumed without a direct comparison [17].

The FDA decision of August 2024

On 4 June 2024 the FDA's advisory committee voted 9 to 2 against the statement that the available data show MDMA to be effective for PTSD, and 10 to 1 against the statement that its benefits outweigh its risks under the proposed safety program. The first question concerned MDMA together with the accompanying psychological intervention [20]. The FDA then issued a complete response letter, a formal refusal to approve the application in its current form, signed 8 August 2024 in the agency's public database [19]. It names three problems. The trials had not collected information on events that participants or therapists saw as positive, and FDA inspections found unreported adverse events at two sites. The benefit had not been shown to last beyond 18 weeks, and long-term follow-up was a single visit, between 6 months and 2 years later, by only some participants. About 40 percent of participants had used MDMA before, far more than expected among people with PTSD, which raises the chance of selection bias and of participants recognising their treatment. The letter asked for a new randomized trial and an independent audit of the existing records. Separately, it asked sponsors to work out how much the psychotherapy contributes and to complete cardiac and laboratory safety data [19].

A trade-press report from August 2026 says that the company it calls Resilient Pharmaceuticals, the successor to the original sponsor, resubmitted the application without a new Phase 3 trial. This is not verified in any official source. The report rests on anonymous sources, and the original research nonprofit issued a statement that repeats the claim and says it has no active role in the program. Both are Grade 3 sources, trade press and an interested organization, so neither confirms the claim [21][22]. No notice from the FDA and no statement from the company was found. A search of the Federal Register from 1 June 2025 to 4 October 2026 turned up no FDA approval notice and no DEA rescheduling notice for MDMA, and the agency's database still lists the application as unapproved [19][36]. A Phase 1 study in 32 healthy adults sponsored by Resilient Pharmaceuticals is open-label and, according to the registry, not designed to evaluate efficacy [23].

The FDA's final guidance of July 2026 on clinical investigations of psychedelic drugs uses "psychedelic drug" to cover both the classic psychedelics and entactogens such as MDMA. That is a grouping for trial design in medical conditions and does not make MDMA a classic psychedelic. The guidance says the contribution of psychotherapy has not been characterized, and asks trials to assess expectancy before assignment and again at the end, with a blinding questionnaire. It approves no use and is not a sign that MDMA will be approved [31].

Safety in healthy adults

This section covers what was found, in which people and under what conditions. It is not guidance for anyone. Controlled findings come from supervised settings with screened volunteers and say less about unsupervised use, mixed substances, crowded hot rooms or people with health conditions.

Heart rate, blood pressure and temperature

In a safety analysis of nine placebo-controlled studies with 166 healthy volunteers, MDMA raised systolic blood pressure above 160 mmHg in 33 percent of participants (and above 180 mmHg in 4 percent), heart rate above 100 beats per minute in 29 percent and body temperature above 38 degrees Celsius in 19 percent. All three were more common at the higher of the two amounts tested. No body temperature above 40 degrees was recorded, no serious adverse events occurred in this pooled set, and liver and kidney function were unchanged about a month later. Brief flashback-like experiences within 8 to 50 hours were reported by 9 percent. The authors warn that risks are probably higher in people with cardiovascular disease, are untested in people with psychiatric disorders, and that rare events cannot be ruled out [9]. The figures come from the authors' accepted manuscript and need checking against the published paper before exact quotation, and the absence of serious events applies to that pooled set only. The supplemental-administration trial, a double-blind crossover in healthy participants with 23 completers, reported one serious adverse event, an acute angle-closure glaucoma attack in a participant during a single-administration session. It needed an overnight hospital stay, resolved fully, and narrow eye angles were found afterward [30]. MAPP2 recorded mild, transient rises in blood pressure and pulse [17], and the FDA's letter called the cardiac safety assessment incomplete [19].

Low blood sodium

Hyponatremia is a drop in blood sodium that can cause confusion, seizures and brain swelling. A pooled analysis of four crossover trials in 96 healthy participants found it in 31 percent after a single administration of MDMA, with an average sodium of 133 mEq/L. In one trial of 15 participants, fluid restriction was recommended if sodium fell and was not set in advance for everyone, and that group also received a lower amount of MDMA and was older on average (about 36 years against 28). None of the 15 developed low sodium, against 30 of the 81 others (37 percent). The analysis had no placebo group and the groups came from different trials with different sex mixes, so this is a descriptive observation only and does not test whether a fluid limit prevents the condition. It found no difference by sex in the rate of low sodium and no link between sodium and copeptin, a vasopressin marker [10].

Outside the laboratory, a peer-reviewed narrative review (Grade 1) reporting other researchers' data summarizes a festival survey in which 14.3 percent of 63 MDMA users had low sodium (26.7 percent of the women, 3 percent of the men) and an Amsterdam intensive care series in which about 23 percent of MDMA intoxications involved hyponatremia, with one death. It notes that toxicity correlates poorly with the amount taken [11].

Mood in the days afterward

Reports of lowered mood in the days after use are common [16], but the controlled evidence is thin and does not agree. In the London crossover trial of 25 healthy poly-drug users, mood three days after MDMA did not differ from mood after placebo [6]. A 2026 review notes that mild, temporary fatigue and loss of pleasure may follow single administrations in healthy volunteers [14]. Two observational studies in regular recreational users, which cannot isolate the drug, differ. One found modest worsening of negative mood that was marginal once sleep and alcohol were considered [15]. The other followed 35 users who planned to take ecstasy that week and 21 regular users who abstained and found no link between ecstasy use and later depressive, anxious or aggressive symptoms. Slightly lower first-day mood in both groups disappeared once hours of sleep were taken into account. The groups differed in age, sex mix and other substance use, and the authors ask for replication [16]. In the 2026 supplemental-administration trial, well-being questionnaires showed no change over seven days [30]. No study read for this page followed healthy, drug-naive adults closely and for long enough to settle the question.

Difficult psychological reactions

How often difficult reactions occur in healthy adults is not settled by the studies read here, and none compared MDMA directly with classic psychedelics. In the pooled Basel safety analysis, nine participants (about 6 to 7 percent, depending on whether the results or the discussion section is read) reported anxiety as an acute adverse effect at the higher of the two amounts, and none did at the lower [9]. In the 2026 supplemental-administration trial, two women left after their first session, both in the condition that included a second administration and both on their first-ever MDMA experience. After headache and nausea, each had an unsettled mental state that lasted weeks. In one, anxiety, confusion and reduced ability to work improved over months. In the other, anxiety, restlessness and fear of being alone lasted about a week, with a return to normal almost two months after the session [30]. These are individual cases in a small sample beside reassuring group-level figures. MAPP2, in a clinical population, recorded suicidal ideation, insomnia and anxiety most often, in both arms [17].

The neurotoxicity question

For decades the main worry was lasting damage to serotonin neurons. The human evidence comes mostly from people who used illegal ecstasy repeatedly, and it is hard to read. A 2016 meta-analysis of seven imaging studies, with 157 ecstasy users and 148 controls who had partial or full use of other drugs, found lower serotonin transporter binding in 10 of 14 brain regions, with an overall effect size of 0.52 and large variation between studies. An eleventh region, the insula, just missed significance (p = 0.06), although the abstract counts it, which is why it reports 11 of 14. There was no difference in the caudate, putamen or midbrain. The comparison was cross-sectional. The authors note low statistical power (about 46 percent), possible publication bias (p = 0.08) and that data from six further eligible studies were not obtained [13].

A US study took more care over confounders, comparing 52 ecstasy users with 59 non-users from the same dance subculture and excluding people with heavy other drug use. On 15 cognitive tests the users differed on only a few measures, mainly poorer strategic self-regulation, which might have been present before they took the drug. Verbal and visual memory did not differ. The median time since last use was 121 days, and only six users had taken ecstasy 150 times or more, so effects of very heavy use could have been missed. The authors call the question unresolved [12]. The 2026 review calls the evidence for harm in heavy users inconclusive and reports temporary memory impairment after single controlled administrations in healthy volunteers, back to baseline by the next day [14]. None of this speaks to repeated use over years.

Abuse potential

The FDA's letter treats the abuse potential of MDMA as something the trials did not adequately characterize [19]. In MAPP2, run in people with PTSD, no abuse, dependence or diversion events were reported [17]. None of the sources read for this page gives a reliable rate of dependence in healthy adults after controlled use.

Legal status

Each entry names the jurisdiction and its official source and was checked on 4 October 2026 unless it says not verified. This describes the law for readers of research and grants no permission.

United States, federal. MDMA is listed as item (11) of the hallucinogenic substances in Schedule I at 21 CFR 1308.11(d), with DEA controlled substances code 7405. The electronic Code of Federal Regulations text was up to date as of 1 October 2026 (accessed 4 October 2026), and the latest amendment note on that section, dated 21 September 2026, concerns a different substance [25]. A search of the Federal Register from 1 June 2025 to 4 October 2026 found no DEA notice rescheduling MDMA and no FDA notice approving it [36]. State law is not covered here and is not verified. The FDA's public database of complete response letters (updated 13 August 2026) holds the Lykos letter and lists the application as unapproved, without saying whether a resubmission is pending [19].

Australia. Since 1 July 2023, MDMA for PTSD has been in Schedule 8 of the national Poisons Standard. Outside clinical trials it can be prescribed only by specialist psychiatrists with human research ethics committee approval and specific authorisation from the Therapeutic Goods Administration (TGA) under its Authorised Prescriber scheme. For every other purpose MDMA remains a prohibited substance in Schedule 9, limited to research, and possession without authority or a valid prescription is illegal [26][27]. The TGA guidance page was last updated on 22 June 2026. The Schedule 9 statement rests on the two TGA pages, and the Poisons Standard itself was not read. States and territories do not have to adopt the national amendment in full, and possession or supply may remain an offence under state law even where the national schedule allows prescribing [27].

Canada, federal. MDMA is a restricted drug. Since January 2022, health care practitioners can ask Health Canada's Special Access Program for it for one named patient at a time when conventional treatments have failed, are unsuitable or are unavailable. The notice, dated 27 February 2023, says an authorization is not a statement that the drug is safe or effective, and that the program is not meant to bypass clinical trials or drug review [28]. The notice was still on the official page on 4 October 2026, and later changes were not checked.

Other countries and the international treaty schedules were not verified for this page.

What is not known

No randomized trial of MDMA in healthy adults with growth outcomes as the main endpoint turned up in the searches for this page. The closest is a registered Zurich trial of 122 healthy volunteers that compared MDMA, psilocybin and methylphenidate and measured empathy and prosocial behavior four weeks later. The registry marks it completed on 22 September 2025 with no results posted [24]. A 2026 paper on blinding in a randomized trial of the same three compounds in 120 healthy volunteers probably reports from this trial, though that link was not confirmed. It was read from its abstract only, which says blinding was inadequate, with psilocybin showing the highest functional unblinding, MDMA a moderate level and methylphenidate the lowest [35]. The empathy and prosocial results were not found.

Two registrations by Resilient Pharmaceuticals come nearer to Metanoia's question than most. NCT01404754 (MT-1) is a placebo-controlled crossover study in 107 healthy volunteers undergoing training as therapists, with mood on the session day as the measure and interpersonal closeness among secondary outcomes. It was completed on 5 August 2022 with no results shown [33]. Its planned successor, NCT04073433 (MT-2), was meant to test self-compassion scores nine weeks after a session and was withdrawn before anyone was enrolled [34]. A basic search found no published MT-1 results, which does not show that none exist. These are registry entries and not evidence.

The controlled social studies read here are small (25 to 65 people each), mostly acute, and mostly unblinded in practice, because the drug's effects are obvious to the person taking it. The sex differences in social effects rest on one trial and conflict with others. Whether any social or emotional change outlasts the session in healthy people is the central open question. Context is a further gap, because effects shift with the setting [3] and the PTSD trials never separated the drug from the psychotherapy [19].

What Metanoia asks

Metanoia's work centers on natural psychedelics, so the questions MDMA raises are mostly about comparison and method. This section lists questions and does not describe a study.

  • Does a compound that releases serotonin change the same twelve dimensions as compounds that act at the 2A receptor, and does it need different outcome measures or a different design? Empathy and social connection are the obvious places to compare.
  • Do the acute social changes seen in the laboratory persist in healthy people, and are the sex differences real once body weight is accounted for?
  • How much of any change belongs to the substance, and how much to the room, the people and the person's expectations? The FDA's questions about psychotherapy contribution, prior use and unblinding are problems that any record of exposure and outcome in healthy adults will meet.
  • Which of the safety signals above (heart rate and blood pressure, body temperature, blood sodium, mood afterward) would matter for any future protocol in healthy adults, and what screening questions would they imply?
  • Does genetic variation in drug metabolism, such as the CYP2D6 effect seen in the pooled Basel data, explain part of the variation in response?

Metanoia's own record-keeping standards cover what the material was, what exposure occurred, the surrounding context and the outcome, with an outcome measure under development for the twelve dimensions. None of that infrastructure has yet been applied to MDMA.

Sources

Grade key: 1 = primary source or any peer-reviewed publication (including narrative and systematic reviews and meta-analyses), and official primary records such as law, registries and agency documents. 2 = reliable secondary source that is not peer reviewed. 3 = grey or community source, including trade press and statements by companies or organizations. 4 = traditional or ethnographic source. Grades 3 and 4 are source types, not lower quality. Grade describes the type of source, not the strength of the design, which is given in the text and in each entry. "Read in full" and "abstract only" describe what the page author read. Where an entry says author manuscript, the figures were read from the authors' own version and should be checked against the published version before they are quoted exactly.

  1. Hysek CM, Schmid Y, Simmler LD, et al. Soc Cogn Affect Neurosci 2014, 9(11):1645-1652. DOI 10.1093/scan/nst161 PMID 24097374. Grade 1. Randomized, double-blind, placebo-controlled, random-order crossover, 32 healthy volunteers (16 women). Read in full (main text, supplement not read). Detail moved from the text: explicit emotional empathy rating F(1,31) = 6.05, p = 0.019, and money task F(1,31) = 4.42, p = 0.044. MDMA also raised blood levels of oxytocin, cortisol and prolactin, and these hormone changes did not track the empathy and prosocial changes from person to person.
  2. Studerus E, Vizeli P, Harder S, Ley L, Liechti ME. J Psychopharmacol 2021, 35(5):556-565. DOI 10.1177/0269881121998322 PMID 33781103. Grade 1. Pooled analysis of 10 placebo-controlled crossover studies, 194 healthy participants. Read in full. Detail moved from the text: the CYP2D6 finding comes from 10 placebo-controlled crossover studies with 194 healthy participants. In the pooled Basel data 79 percent were MDMA-naive. People higher in neuroticism or trait anxiety also reported a feeling of impaired control, and the sample's average openness to experience was above the population norm.
  3. Kirkpatrick MG, Baggott MJ, Mendelson JE, et al. Psychopharmacology 2014, 231(19):3899-3905. DOI 10.1007/s00213-014-3528-z PMID 24633447. Grade 1. Comparison of placebo-controlled studies at three sites, 220 healthy volunteers. Read in full (author manuscript). Detail moved from the text: the San Francisco volunteers reported more closeness than the Basel volunteers, which the authors suggest may reflect the social setting.
  4. Kirkpatrick MG, Lee R, Wardle MC, Jacob S, de Wit H. Neuropsychopharmacology 2014, 39:1654. DOI 10.1038/npp.2014.12 PMID 24448644. Grade 1. Double-blind within-between-subjects trial, 65 young adults with prior MDMA use. Read in full (main text, supplement not read). Detail moved from the text: 65 young adults with light to moderate past MDMA use. Oxytocin given by nasal spray produced only small effects on sociability, and the authors concluded that oxytocin is unlikely to be the sole route by which MDMA works.
  5. Bershad AK, et al. Neuropsychopharmacology 2019, 44:1698-1705. DOI 10.1038/s41386-019-0402-z PMID 31042696. Grade 1. Double-blind crossover, 36 healthy young adults with prior MDMA use. Read in full (main text, supplement not read).
  6. Borissova A, Ferguson B, Wall MB, et al. J Psychopharmacol 2021, 35(5):547-555. DOI 10.1177/0269881120926673 PMID 32538252. Grade 1. Double-blind placebo-controlled crossover, 25 healthy poly-drug users (7 women), null result. Read in full (main text, supplement not read). Detail moved from the text: 7 of the 25 participants were women.
  7. Bershad AK, Miller MA, Baggott MJ, de Wit H. J Psychopharmacol 2016, 30(12):1248-1258. DOI 10.1177/0269881116663120 PMID 27562198. Grade 1. Peer-reviewed narrative review, not systematic. Read in full (author manuscript). Detail moved from the text: the review concludes that few studies compare MDMA directly with other stimulants.
  8. Kamilar-Britt P, Bedi G. Neurosci Biobehav Rev 2015, 57:433-446. DOI 10.1016/j.neubiorev.2015.08.016 PMID 26408071. Grade 1. Peer-reviewed systematic overview of controlled studies in humans and laboratory animals (49 articles, searches to June 2015). Read in full (author manuscript).
  9. Vizeli P, Liechti ME. J Psychopharmacol 2017, 31(5):576-588. DOI 10.1177/0269881117691569 PMID 28443695. Grade 1. Pooled safety analysis of nine placebo-controlled studies, 166 healthy volunteers. Read in full, from the authors' accepted manuscript and not the published version. Detail moved from the text: subjective effects lasted about four hours on average, with a range from about 1.4 to 8.2 hours.
  10. Atila C, et al. JAMA Netw Open 2024, 7(11):e2445278. DOI 10.1001/jamanetworkopen.2024.45278 PMID 39546312. Grade 1. Ad hoc secondary analysis of four randomized crossover trials, 96 healthy participants, MDMA sessions only and no placebo group in the analysis. Read in full (main text, supplement and protocols not read). Detail moved from the text: oxytocin rose by an average of 433 percent, and larger rises went with larger drops in blood sodium.
  11. Garcia MR, Gomes NGM, Dias-da-Silva D. Addiction 2026, 121(3):713-718. DOI 10.1111/add.70255 PMID 41360080. Grade 1. Peer-reviewed narrative review of MDMA and hyponatremia, without a methods section. Read in full. Detail moved from the text: the review points to heat, prolonged dancing, water intake and individual variation as contributing factors to toxicity.
  12. Halpern JH, Sherwood AR, Hudson JI, Gruber S, Kozin D, Pope HG. Addiction 2011, 106(4):777-786. DOI 10.1111/j.1360-0443.2010.03252.x PMID 21205042. Grade 1. Case-control field study, 52 ecstasy users and 59 non-users. Read in full (author manuscript). Detail moved from the text: recent use was checked with hair, urine and breath tests. Small differences in vocabulary, a coding test and fine hand control appeared without correction for multiple comparisons. The authors note that their result contradicts their own earlier pilot.
  13. Roberts CA, Jones A, Montgomery C. Neurosci Biobehav Rev 2016, 63:158-167. DOI 10.1016/j.neubiorev.2016.02.003 PMID 26855234. Grade 1. Meta-analysis of seven imaging studies, 157 ecstasy users and 148 controls with partial or full use of other drugs. Read in full, from an open-access copy of the paper. Detail moved from the text: I-squared 89 percent. The summary was read in full from an open-access copy of the paper.
  14. Ramaekers JG, Kuypers KPC, Vollenweider FX. Mol Psychiatry 2026, 31:4799-4810. DOI 10.1038/s41380-026-03602-7 PMID 41951837. Grade 1. Peer-reviewed narrative review of placebo-controlled single-administration studies in healthy volunteers. Read in full. Detail moved from the text: pretreatment with drugs that block the serotonin and norepinephrine transporters markedly reduces the subjective effects, which is why those two systems are seen as the main drivers. Raised blood pressure, heart rate and body temperature are put down mainly to the dopamine and adrenaline-type systems. The mild fatigue and loss of pleasure afterward are tied to a short-lived depletion of the chemicals MDMA releases.
  15. Huxster JK, Pirona A, Morgan MJ. J Psychopharmacol 2006, 20(2):281-290. DOI 10.1177/0269881106060513 PMID 16510486. Grade 1. Observational study, 38 regular ecstasy users. Abstract only. The full text was not accessible on 4 October 2026.
  16. Scott RM, Hides L, Allen JS, Lubman DI. J Psychopharmacol 2013, 27(1):53-61. DOI 10.1177/0269881112463467 PMID 23095244. Grade 1. Observational study, 35 users and 21 abstainers. Read in full (author manuscript). Detail moved from the text: fewer hours and poorer sleep went with more distress on day 3.
  17. Mitchell JM, Ot'alora G M, van der Kolk B, et al. Nat Med 2023, 29(10):2473-2480. DOI 10.1038/s41591-023-02565-4 PMID 37709999. Grade 1. Randomized, double-blind Phase 3 trial in a clinical population (PTSD), n = 104, with sponsor-affiliated authors. Read in full (main text, supplement not read). Detail moved from the text: 26.9 percent of participants had moderate and 73.1 percent severe PTSD. The average change on the clinician-rated scale was 23.7 points with MDMA and 14.8 with placebo (p < 0.001), and the functional impairment difference had p = 0.03. One person in the MDMA arm and eight in the placebo arm dropped out.
  18. Mitchell JM, et al. Author Correction. Nat Med 2024, 30(11):3382. DOI 10.1038/s41591-024-03331-w PMID 39375459. Grade 1. Published author correction. Read in full. It added names of study collaborators to the author list and changed no data or results.
  19. U.S. Food and Drug Administration, Center for Drug Evaluation and Research. Complete response letter, NDA 215455, midomafetamine capsules, Lykos Therapeutics, signed 8 August 2024. Source: openFDA CRL database, https://api.fda.gov/transparency/crl.json?search=company_name:Lykos (database updated 13 August 2026), file CRL_NDA215455_20240808.pdf. Grade 1. Regulatory document. Read in full 4 October 2026. Detail moved from the text: the letter also asked sponsors to study interactions with antidepressants, and described its separate comments as not grounds for the refusal.
  20. U.S. Food and Drug Administration. Psychopharmacologic Drugs Advisory Committee meeting transcript, 4 June 2024, https://www.fda.gov/media/180703/download. Grade 1. Official transcript of 425 pages. Pages 412 to 420 (both votes, at pages 414 and 419, and the members' reasons) and the FDA draft questions (https://www.fda.gov/media/178981/download) read in full. The remainder of the transcript was not read.
  21. Psychedelic Alpha. "Two years after rejection, Resilient quietly refiles MDMA for PTSD application", August 2026, https://psychedelicalpha.com/news/two-years-after-rejection-resilient-quietly-refiles-mdma-for-ptsd-application/. Grade 3. Trade press citing anonymous sources, treated as a grey source for that reason. Read in full 4 October 2026. The company has not commented publicly, and no official confirmation was found.
  22. MAPS. Statement responding to the report of an FDA resubmission, 10 August 2026, https://maps.org/2026/08/10/maps-responds-to-report-of-progress-for-mdma-assisted-therapy-for-ptsd-with-fda/. Grade 3. Statement by an interested organization, not a confirmation from the FDA or the company. Read in full 4 October 2026.
  23. ClinicalTrials.gov NCT07584720. Phase 1 open-label study of midomafetamine in healthy adults, Resilient Pharmaceuticals, 32 participants, single site, https://clinicaltrials.gov/study/NCT07584720. Grade 1. Registry record, no results. Read in full 4 October 2026. Detail moved from the text: the study began on 23 April 2026, was listed as active and not recruiting on 4 October 2026, and measures heart rhythm among its secondary outcomes.
  24. ClinicalTrials.gov NCT06081179. University of Zurich, MDMA, psilocybin and methylphenidate on prosocial behavior in 122 healthy volunteers, https://clinicaltrials.gov/study/NCT06081179. Grade 1. Registry record, no results. Read in full 4 October 2026.
  25. Code of Federal Regulations, Title 21, section 1308.11 (Schedule I). Electronic CFR, https://www.ecfr.gov/current/title-21/chapter-II/part-1308/subpart-B/section-1308.11 (eCFR up to date as of 1 October 2026, accessed 4 October 2026, last issue 30 September 2026). Grade 1. The section structure, the heading of paragraph (d) and entry (11) were read on 4 October 2026, and the other entries were not.
  26. Therapeutic Goods Administration (Australia). "Accessing MDMA (3,4-methylenedioxy-methamphetamine) and psilocybine as a psychiatrist", https://www.tga.gov.au/resources/guidance/accessing-mdma-34-methylenedioxy-methamphetamine-and-psilocybine-psychiatrist, published 13 February 2023, last updated 22 June 2026. Grade 1. Official guidance. Read in full on 4 October 2026. Detail moved from the text: the TGA does not accept protocols that let patients take the medicine home. Psilocybin for treatment-resistant depression moved to Schedule 8 on the same date.
  27. Therapeutic Goods Administration (Australia). "Re-scheduling of psilocybin and MDMA in the Poisons Standard: questions and answers", https://www.tga.gov.au/resources/publication/scheduling-decisions-final/notice-final-decision-amend-or-not-amend-current-poisons-standard-june-2022-acms-38-psilocybine-and-mdma/re-scheduling-psilocybin-and-mdma-poisons-standard-questions-and-answers, last updated 10 February 2023. Grade 1. Official page. Read in full on 4 October 2026.
  28. Health Canada. "Notice to stakeholders: Requests to the Special Access Program (SAP) involving psychedelic-assisted psychotherapy", 27 February 2023, https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/announcements/requests-special-access-program-psychedelic-assisted-psychotherapy.html. Grade 1. Official notice. Read in full on 4 October 2026.
  29. Kock P, et al. J Subst Abuse Treat 2022, 138:108717. DOI 10.1016/j.jsat.2021.108717 PMID 35012793. Grade 1. Systematic review of ibogaine. Abstract only. The full text was blocked on 4 October 2026. Cited in the notes below, not in the text.
  30. Humbert-Droz M, Becker AM, Valenta J, Rudin D, Luethi D, Vukalovic I, Eckert A, Liechti ME, Mueller L. Transl Psychiatry 2026, 16:402. DOI 10.1038/s41398-026-04148-6 PMID 42243076. Grade 1. Double-blind, placebo-controlled crossover study in Basel of a supplemental second administration of MDMA, 25 healthy participants enrolled and 23 completed. Partly funded by Lykos Therapeutics, and the senior author has consulted for Lykos and Definium Therapeutics (formerly Mind Medicine Inc.). Read in full (supplement not read).
  31. U.S. Food and Drug Administration, Center for Drug Evaluation and Research. Psychedelic Drugs: Considerations for Clinical Investigations. Guidance for industry, July 2026, https://www.fda.gov/media/169694/download. Notice of availability: Federal Register 2026-14158, 14 July 2026, docket FDA-2023-D-1987. Grade 1. Official guidance. The guidance was read in full on 4 October 2026, and the Federal Register notice only at summary level.
  32. Drug Enforcement Administration. Schedules of Controlled Substances: Temporary Placement of 3,4-Methylenedioxymethamphetamine (MDMA) Into Schedule I. Federal Register 50(105), 31 May 1985, p. 23118 (50 FR 23118). Grade 1. Official notice. Read in full on 4 October 2026, from a copy of the page and not from the govinfo file.
  33. ClinicalTrials.gov NCT01404754 (MT-1). A Phase 1 placebo-controlled, double-blind crossover study to assess psychological effects of MDMA when administered to healthy volunteers. Sponsor: Resilient Pharmaceuticals. 107 participants, started 9 April 2011, completed 5 August 2022, https://clinicaltrials.gov/study/NCT01404754. Grade 1. Registry record, no results. Read in full 4 October 2026. Detail moved from the text: the planned follow-up was two months.
  34. ClinicalTrials.gov NCT04073433 (MT-2). A Phase 1 open-label, multi-site study to assess psychological effects of MDMA-assisted psychotherapy when administered to healthy volunteers. Sponsor: Resilient Pharmaceuticals. Status withdrawn, 0 participants, https://clinicaltrials.gov/study/NCT04073433. Grade 1. Registry record, no results. Read in full 4 October 2026.
  35. Belinger L, et al. Blinding integrity in psychedelic research: evidence from a comparative randomized controlled trial of psilocybin, MDMA, and methylphenidate in healthy volunteers. Eur Neuropsychopharmacol 2026, 111:112879. DOI 10.1016/j.euroneuro.2026.112879 PMID 42208423. Grade 1. 120 healthy volunteers. Abstract only. The full text was blocked on 4 October 2026.
  36. Federal Register, search of the public API (api.federalregister.gov) for the terms MDMA and midomafetamine, 1 June 2025 to 4 October 2026, run 4 October 2026. Grade 1. A search result from the official register. It shows that no matching notice was indexed under those terms, and it is not a reading of the register as a whole.

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