(R)-MDMA

Psychoactive drug taken by mouth vanc 6 (R)-MDMA (R)-MDMA structure.svg skin-invert-image 235px R-MDMA-3D-balls.png bg-transparent 250px Oral Serotonin–norepinephrine releasing agent; Serotonin 5-HT2A receptor agonist; Entactogen; Empathogen CYP2D6 11–14hours 3.5–5.2 hours 81262-70-6 667458 580842 3947754WXW 382757 (R)-Methylenedioxy-methamphetamine; (R)-MDMA; (R)-(−)-MDMA; R(−)-MDMA; (−)-MDMA; (R)-Midomafetamine; (R)-(−)-Midomafetamine; (−)-Midomafetamine; Armidomafetamine; levo-MDMA; l-MDMA; EMP-01; EMP01; DT-402; DT402; MM-402; MM402 (2R)-1-(1,3-benzodioxol-5-yl)-N-methylpropan-2-amine 11 15 1 2 C[C@H](CC1=CC2=C(C=C1)OCO2)NC 1S/C11H15NO2/c1-8(12-2)5-9-3-4-10-11(6-9)14-7-13-10/h3-4,6,8,12H,5,7H2,1-2H3/t8-/m1/s1 SHXWCVYOXRDMCX-MRVPVSSYSA-N (R)-3,4-Methylenedioxy-N-methylamphetamine ([R]-MDMA), also known as (R)-midomafetamine or as levo-MDMA, is the (R)- or levorotatory (l-) enantiomer of 3,4-methylenedioxy-N-methylamphetamine (MDMA; midomafetamine; "ecstasy"), a racemic mixture of (R)-MDMA and (S)-MDMA. Pitts EG, Curry DW, Hampshire KN, Young MB, Howell LL (±)-MDMA and its enantiomers: potential therapeutic advantages of R(−)-MDMA Psychopharmacology 235 2 377–392 February 2018 29248945 10.1007/s00213-017-4812-5 Like MDMA, (R)-MDMA is an entactogen or empathogen. It is taken by mouth. The drug is a serotonin–norepinephrine releasing agent (SNRA) and weak serotonin 5-HT2A receptor agonist. It has substantially less or no significant dopamine-releasing activity compared to MDMA and (S)-MDMA. In preclinial studies, (R)-MDMA shows equivalent therapeutic-like effects to MDMA, such as increased prosocial behavior, but shows reduced psychostimulant-like effects, addictive potential, and serotonergic neurotoxicity. In clinical studies, (R)-MDMA produces similar effects to MDMA and (S)-MDMA, but is less potent and has a longer duration. (R)-MDMA was first described in enantiopure form by 1978. Under the developmental code names EMP-01, developed by AtaiBeckley,atai Life Sciences Announces Positive Topline Results from Single Ascending Dose Phase 1 Study with EMP-01 (R-MDMA) https://atai.gcs-web.com/news-releases/news-release-details/atai-life-sciences-announces-positive-topline-results-single and DT402 (formerly MM402), developed by Definium Therapeutics (formerly MindMed),MM-402 by Mind Medicine MindMed for Autism Spectrum Disorder (ASD): Likelihood of Approval 9 February 2024 https://www.pharmaceutical-technology.com/data-insights/mm-402-mind-medicine-mindmed-autism-spectrum-disorder-asd-likelihood-of-approval/ it is under development for the treatment of post-traumatic stress disorder (PTSD), social phobia, and pervasive development disorders (PDDs) such as autism.EMP 01 (R-MDMA) AdisInsight 20 August 2024 https://adisinsight.springer.com/drugs/800062506 28 October 2024R(−)-Methylenedioxymetamfetamine (MM-402; R(−)-MDMA) AdisInsight 30 January 2024 https://adisinsight.springer.com/drugs/800066028 28 October 2024Delving into the Latest Updates on EMP-01 with Synapse Synapse 1 November 2024 https://synapse.patsnap.com/drug/90a996ec5ed140e18563b30133bd26c6 2 November 2024 It is thought that (R)-MDMA might have a better safety profile than MDMA itself whilst retaining its therapeutic benefits. Use and effects (R)-MDMA has a dose of 125 to 300mg orally and a duration of 3.5 to 5.2hours. It has been estimated that doses of 125mg MDMA, 100mg (S)-MDMA, and 300mg (R)-MDMA are equivalent. The first modern clinical study of the comparative effects of MDMA, (R)-MDMA, and (S)-MDMA was published in August 2024. Bedi G Is the stereoisomer R-MDMA a safer version of MDMA? Neuropsychopharmacology 50 2 October 2024 360–361 39448866 10.1038/s41386-024-02009-8 free 11631934 Straumann I, Avedisian I, Klaiber A, Varghese N, Eckert A, Rudin D, Luethi D, Liechti ME 6 Acute effects of R-MDMA, S-MDMA, and racemic MDMA in a randomized double-blind cross-over trial in healthy participants Neuropsychopharmacology 50 2 August 2024 362–371 39179638 10.1038/s41386-024-01972-6 free 11631982 It compared 125mg MDMA, 125mg (S)-MDMA, 125 and 250mg (R)-MDMA, and placebo. (R)-MDMA increased any drug effect, good drug effect, drug liking, stimulation, drug high, alteration of vision, and alteration of sense of time ratings similarly to MDMA and (S)-MDMA. However, (S)-MDMA 125mg was more potent in increasing subjective effects, including stimulation, drug high, happy, and open, among others, than (R)-MDMA 125 or 250mg or MDMA 125mg. Ratings of bad drug effect and fear were minimal with MDMA, (R)-MDMA, and (S)-MDMA. In contrast to expectations, (R)-MDMA did not produce more psychedelic-like effects than (S)-MDMA. Besides subjective effects, (R)-MDMA increased heart rate, blood pressure, and body temperature similarly to MDMA and (S)-MDMA, though it was less potent in producing these effects. Body temperature was notably increased to the same extent with (R)-MDMA 250mg as with MDMA 125mg and (S)-MDMA 125mg. The differences in effects between (R)-MDMA and (S)-MDMA may reflect the higher potency of (S)-MDMA rather than actual qualitative differences between the effects of (S)-MDMA and (R)-MDMA. It was estimated that equivalent effects would be expected with (S)-MDMA 100mg, MDMA 125mg, and (R)-MDMA 300mg. The findings of the study were overall regarded as not supporting the hypothesis that (R)-MDMA would produce equivalent therapeutic effects as (S)-MDMA or MDMA whilst reducing safety concerns. However, more clinical studies were called for to assess the revised estimated equivalent doses of MDMA, (R)-MDMA, and (S)-MDMA. Interactions MDMA#Interactions Trip killer#Antidotes of other hallucinogens MDMA/citalopram Pharmacology Pharmacodynamics + Activities of MDMA, its enantiomers, and related compounds Compound Monoamine release (EC50 half-maximal effective concentration, nM) Serotonin Norepinephrine Dopamine Amphetamine ND No data ND No data ND No data (S)-Amphetamine (d) 698–1,765 6.6–7.2 5.8–24.8 (R)-Amphetamine (l) ND No data 9.5 27.7 Methamphetamine ND No data ND No data ND No data (S)-Methamphetamine (d) 736–1,292 12.3–13.8 8.5–24.5 (R)-Methamphetamine (l) 4,640 28.5 416 MDA 160 108 190 (S)-MDA (d) 100 50 98 (R)-MDA (l) 310 290 900 MDMA 49.6–72 54.1–110 51.2–278 (S)-MDMA (d) 74 136 142 (R)-MDMA (l) 340 560 3,700 MDEA 47 2,608 622 (S)-MDEA (d) 465 RI Reuptake inhibitor RI Reuptake inhibitor (R)-MDEA (l) 52 651 507 MBDB 540 3,300 >100,000 MDAI 114 117 1,334 Notes: The smaller the value, the more strongly the compound produces the effect. Refs: Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin Synapse 39 1 32–41 January 2001 11071707 10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3 15573624 Rothman RB, Partilla JS, Baumann MH, Lightfoot-Siordia C, Blough BE Studies of the biogenic amine transporters. 14. Identification of low-efficacy "partial" substrates for the biogenic amine transporters The Journal of Pharmacology and Experimental Therapeutics 341 1 251–262 April 2012 22271821 3364510 10.1124/jpet.111.188946 Marusich JA, Antonazzo KR, Blough BE, Brandt SD, Kavanagh PV, Partilla JS, Baumann MH The new psychoactive substances 5-(2-aminopropyl)indole (5-IT) and 6-(2-aminopropyl)indole (6-IT) interact with monoamine transporters in brain tissue Neuropharmacology 101 68–75 February 2016 26362361 4681602 10.1016/j.neuropharm.2015.09.004 Nagai F, Nonaka R, Satoh Hisashi Kamimura K The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain European Journal of Pharmacology 559 2–3 132–137 March 2007 17223101 10.1016/j.ejphar.2006.11.075 Halberstadt AL, Brandt SD, Walther D, Baumann MH 2-Aminoindan and its ring-substituted derivatives interact with plasma membrane monoamine transporters and α2-adrenergic receptors Psychopharmacology (Berl) 236 3 989–999 March 2019 30904940 6848746 10.1007/s00213-019-05207-1 Blough B Dopamine-releasing agents Trudell ML, Izenwasser S Dopamine Transporters: Chemistry, Biology and Pharmacology 305–320 July 2008 978-0-470-11790-3 181862653 OL18589888W Wiley Hoboken [NJ] https://books.google.com/books?id=QCagLAAACAAJ https://bitnest.netfirms.com/external/Books/Dopamine-releasing-agents_c11.pdf MDMA is a well-balanced serotonin–norepinephrine–dopamine releasing agent (SNDRA). Rothman RB, Baumann MH Monoamine transporters and psychostimulant drugs European Journal of Pharmacology 479 1–3 23–40 October 2003 14612135 10.1016/j.ejphar.2003.08.054 Rothman RB, Baumann MH Therapeutic potential of monoamine transporter substrates Current Topics in Medicinal Chemistry 6 17 1845–1859 2006 17017961 10.2174/156802606778249766 Setola V, Hufeisen SJ, Grande-Allen KJ, Vesely I, Glennon RA, Blough B, Rothman RB, Roth BL 6 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro Molecular Pharmacology 63 6 1223–1229 June 2003 12761331 10.1124/mol.63.6.1223 839426 (R)-MDMA and (S)-MDMA are both SNDRAs similarly. However, (R)-MDMA is several-fold less potent than (S)-MDMA in vitro and is also less potent than (S)-MDMA in vivo in non-human primates. In addition, whereas MDMA and (S)-MDMA are well-balanced SNDRAs, (R)-MDMA is comparatively much less potent as a dopamine releasing agent (~11-fold less potent in releasing dopamine than serotonin), and could be thought of instead more as a serotonin–norepinephrine releasing agent (SNRA) than as an SNDRA. In non-human primates, (S)-MDMA demonstrated significant dopamine transporter (DAT) occupancy, whereas DAT occupancy with (R)-MDMA was undetectable. Similarly, MDMA and (S)-MDMA were found to increase dopamine levels in the striatum in rodents and non-human primates, whereas (R)-MDMA did not increase striatal dopamine levels. Acquas E, Pisanu A, Spiga S, Plumitallo A, Zernig G, Di Chiara G Differential effects of intravenous R,S-(+/-)-3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) and its S(+)- and R(−)-enantiomers on dopamine transmission and extracellular signal regulated kinase phosphorylation (pERK) in the rat nucleus accumbens shell and core Journal of Neurochemistry 102 1 121–132 July 2007 17564678 10.1111/j.1471-4159.2007.04451.x As such, (R)-MDMA may be less psychostimulant-like than MDMA or (S)-MDMA. In addition to its actions as an SNDRA, MDMA has weak affinity for the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors, where it acts as an agonist. (R)-MDMA shows higher affinity for the serotonin 5-HT2A receptor than (S)-MDMA or MDMA. In addition, (R)-MDMA is more potent as an agonist of the serotonin 5-HT2A receptor, acting as a weak partial agonist of this receptor, whereas (S)-MDMA shows very little effect. Conversely however, (S)-MDMA is more potent as an agonist of the serotonin 5-HT2C receptor. Kaur H, Karabulut S, Gauld JW, Fagot SA, Holloway KN, Shaw HE, Fantegrossi WE Balancing Therapeutic Efficacy and Safety of MDMA and Novel MDXX Analogues as Novel Treatments for Autism Spectrum Disorder 2023 Psychedelic Medicine 1 3 166–185 10.1089/psymed.2023.0023 40046567 11661495 Based on these findings, it has been hypothesized that (R)-MDMA may be more psychedelic-like than (S)-MDMA. However, although (R)-MDMA partially substitutes for lysergic acid diethylamide (LSD) in animal drug discrimination tests, it did not produce the head-twitch response, a behavioral proxy of psychedelic effects, at any tested dose.Dunlap Lee E. Development of Non-Hallucinogenic Psychoplastogens University of California, Davis 2022 https://escholarship.org/uc/item/5qr3w0gm 18 November 2024 Finally, since R-MDMA is known to partially substitute for LSD in animal models we decided to test both compounds in the head twitch response assay (HTR) (FIG 3.3C).3 The HTR is a well-validated mouse model for predicting the hallucinogenic potential of test drugs. Serotonergic psychedelics will cause a rapid back and forth head movement in mice. The potency measured in the HTR assay has been shown to correlate very well with the human potencies of psychedelics.18 Neither R-MDMA or LED produced any head twitches at all doses tested, suggesting that neither has high hallucinogenic potential. In any case, findings in this area are conflicting. Halberstadt AL, Geyer MA Behavioral Neurobiology of Psychedelic Drugs Effect of Hallucinogens on Unconditioned Behavior Current Topics in Behavioral Neurosciences 36 159–199 2018 28224459 5787039 10.1007/7854_2016_466 978-3-662-55878-2 [MDxx] have been assessed in head twitch studies. Racemic [MDA] and S-(+)-MDA reportedly induce WDS in monkeys and rats, respectively (Schlemmer and Davis 1986; Hiramatsu et al. 1989). Although [MDMA] does not induce the HTR in mice, both of the stereoisomers of MDMA have been shown to elicit the response (Fantegrossi et al. 2004, 2005b). 5-HT depletion inhibits the response to S-(+)-MDMA but does not alter the response to R-(−)-MDMA, suggesting the isomers act through different mechanisms (Fantegrossi et al. 2005b). This suggestion is consistent with the fact that S-(+)- and R-(−)-MDMA exhibit qualitatively distinct pharmacological profiles, with the S-(+)isomer working primarily as a monoamine releaser (Johnson et al. 1986; Baumann et al. 2008; Murnane et al. 2010) and the R-(−)-enantiomer acting directly through 5-HT2A receptors (Lyon et al. 1986; Nash et al. 1994). In contrast to their effects in mice, Hiramatsu reported that S-(+)- and R-(−)-MDMA fail to produce WDS in rats (Hiramatsu et al. 1989). The discrepant findings with MDMA in mice and rats may reflect species differences in sensitivity to the HTR (see below for further discussion). (R)-MDMA is inactive as an agonist of the human TAAR1, whereas (S)-MDMA shows very weak potency as an agonist of the receptor (EC50 half-maximal effective concentration = 74,000nM). Lewin AH, Miller GM, Gilmour B Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class Bioorg Med Chem 19 23 7044–7048 December 2011 22037049 3236098 10.1016/j.bmc.2011.10.007 MDMA is a well-known serotonergic neurotoxin and this has been demonstrated both in animals and in humans. There is evidence that the serotonergic neurotoxicity of MDMA may be driven primarily by (S)-MDMA rather than (R)-MDMA. (R)-MDMA shows substantially lower or potentially no neurotoxicity compared to (S)-MDMA in animal studies. This has been the case even when doses of (R)-MDMA were increased to account for its lower potency than (S)-MDMA. However, more research is needed to confirm this in other species, such as non-human primates. In contrast to (S)-MDMA, (R)-MDMA does not produce hyperthermia in rodents, and this may be involved in its reduced risk of neurotoxicity, as hyperthermia augments and is essential for the serotonergic neurotoxicity of MDMA. The reduced potency of (R)-MDMA as a dopamine releasing agent may also be involved in its reduced neurotoxic potential, as dopamine release is likewise essential for the neurotoxicity of MDMA. The hyperthermia of MDMA may in fact be mediated by dopamine release. As (R)-MDMA is less neurotoxic than (S)-MDMA and MDMA or even non-neurotoxic, it may allow for greater clinical viability and prolonged regimens of drug-assisted psychotherapy. (R)-MDMA and (S)-MDMA have shown equivalent effects in terms of inducing prosocial behavior in monkeys. However, (S)-MDMA shows higher potency, whereas (R)-MDMA shows greater maximal effects. Conversely, (S)-MDMA does not increase prosocial behavior in mice, whereas both MDMA and (R)-MDMA do so. MDMA and (S)-MDMA increase locomotor activity, a measure of psychostimulant-like effect, in rodents, whereas (R)-MDMA does not do so. Curry DW, Young MB, Tran AN, Daoud GE, Howell LL Separating the agony from ecstasy: R(−)-3,4-methylenedioxymethamphetamine has prosocial and therapeutic-like effects without signs of neurotoxicity in mice Neuropharmacology 128 196–206 January 2018 28993129 5714650 10.1016/j.neuropharm.2017.10.003 (R)-MDMA likewise showed fewer reinforcing effects than (S)-MDMA in non-human primates. These findings further add to (R)-MDMA showing reduced psychostimulant-like and addictive effects compared to MDMA and (S)-MDMA. + MDMA, MDA, and enantiomers at serotonin 5-HT2 receptors Compound 5-HT2A 5-HT2B 5-HT2C EC50 (nM) Emax EC50 (nM) Emax EC50 (nM) Emax Serotonin 53 92% 1.0 100% 22 91% MDA 1,700 57% 190 80% ND No data ND No data (S)-MDA 18,200 89% 100 81% 7,400 73% (R)-MDA 5,600 95% 150 76% 7,400 76% MDMA 6,100 55% 2,000–>20,000 32% ND No data ND No data (S)-MDMA 10,300 9% 6,000 38% 2,600 53% (R)-MDMA 3,100 21% 900 27% 5,400 27% Notes: The smaller the Kact or EC50 value, the more strongly the compound produces the effect. Refs: Nash JF, Roth BL, Brodkin JD, Nichols DE, Gudelsky GA Effect of the R(−) and S(+) isomers of MDA and MDMA on phosphatidyl inositol turnover in cultured cells expressing 5-HT2A or 5-HT2C receptors Neurosci Lett 177 1–2 111–115 August 1994 7824160 10.1016/0304-3940(94)90057-4 Kolaczynska KE, Ducret P, Trachsel D, Hoener MC, Liechti ME, Luethi D Pharmacological characterization of 3,4-methylenedioxyamphetamine (MDA) analogs and two amphetamine-based compounds: N,α-DEPEA and DPIA Eur Neuropsychopharmacol 59 9–22 June 2022 35378384 10.1016/j.euroneuro.2022.03.006 https://www.researchgate.net/publication/359686098 free Pharmacokinetics The elimination half-life of (S)-MDMA is 4.1hours, whereas the half-life of (R)-MDMA is 12 to 14hours. In the case of racemic MDMA administration, the half-life of (S)-MDMA is 5.1hours and the half-life of (R)-MDMA is 11hours. (R)-MDMA shows cytochrome P450 CYP2D6 inhibition and lower levels of the metabolite 4-hydroxy-3-methoxymethamphetamine (HMMA) than (S)-MDMA. History (R)-MDMA was first described in the scientific literature in enantiopure form by 1978. Anderson GM, Braun G, Braun U, Nichols DE, Shulgin AT Absolute configuration and psychotomimetic activity NIDA Research Monograph 22 8–15 1978 101890 https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=2ab674b010611df18c029a78f6d17e52dba5f82f It was described in a paper authored by Alexander Shulgin, David E. Nichols, and other colleagues. Society and culture Legal status Canada As an enantiomer of MDMA, (R)-MDMA is a Schedule I controlled substance in Canada.Controlled Drugs and Substances Act Department of Justice Canada 5 December 2025 https://laws-lois.justice.gc.ca/eng/acts/c-38.8/FullText.html 20 January 2026 United States As an enantiomer of MDMA, (R)-MDMA is a Schedule I controlled substance in the United States.Controlled Drugs and Substances Act Department of Justice Canada 5 December 2025 https://laws-lois.justice.gc.ca/eng/acts/c-38.8/FullText.html 20 January 2026 Research (R)-MDMA is under development separately by AtaiBeckley,Maddox Will Analysts see potential in MDMA drug after AtaiBeckley reports improvements in anxiety trial Fierce Biotech 26 February 2026 https://www.fiercebiotech.com/biotech/analysts-high-future-mdma-after-ataibeckleys-positive-top-line-data 1 March 2026 Empath Biosciences (EmpathBio) and Definium Therapeutics (formerly MindMed).Delving into the Latest Updates on MM-402 with Synapse Synapse 1 November 2024 https://synapse.patsnap.com/drug/0403fc76b1024469a8f89255b358a6d0 2 November 2024 It is being developed by AtaiBeckley for social anxiety disorder, by Empath Biosciences for the treatment of PTSD and social phobia and it is being developed by Definium Therapeutics for the treatment of PDDs or autism. As of February 2026, the drug is in phase 2 clinical trials for social phobia and autistic spectrum disorders, whereas no recent development has been reported for PTSD. The results of AtaiBeckley's phase 2a trial for treatment of social phobia have been released, with the drug showing moderate effectiveness and a generally favorable safety profile for this indication. See also Substituted methylenedioxyphenethylamine List of investigational hallucinogens and entactogens List of investigational autism and pervasive developmental disorder drugs List of investigational social anxiety disorder drugs References External links R-MDMA - Isomer Design R-MDMA in the spotlight - Matthew Baggott, PhD - LinkedIn Category:5-HT2A agonists Category:Alexander Shulgin Category:David E. Nichols Category:Enantiopure drugs Category:Entactogens Category:Entheogens Category:Experimental entactogens Category:Experimental hallucinogens Category:Experimental psychiatric drugs Category:MDMA Category:Methamphetamines Category:Methylenedioxyamphetamines Category:PiHKAL Category:Psychedelic phenethylamines Category:Serotonin-norepinephrine releasing agents Category:Serotonin receptor agonists Category:VMAT inhibitors