(R)-MDMA
Psychoactive drug taken by mouth
From Wikipedia, the free encyclopedia
(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.[3][2] Like MDMA, (R)-MDMA is an entactogen or empathogen.[3][2] It is taken by mouth.[3][2]
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| Other names | (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 |
| Routes of administration | Oral[1][2] |
| Drug class | Serotonin–norepinephrine releasing agent; Serotonin 5-HT2A receptor agonist; Entactogen; Empathogen[3][4] |
| Pharmacokinetic data | |
| Metabolism | CYP2D6[2] |
| Elimination half-life | 11–14 hours[1][2] |
| Duration of action | 3.5–5.2 hours[2] |
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| Chemical and physical data | |
| Formula | C11H15NO2 |
| Molar mass | 193.246 g·mol−1 |
| 3D model (JSmol) | |
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The drug is a serotonin–norepinephrine releasing agent (SNRA) and weak serotonin 5-HT2A receptor agonist.[3][4] It has substantially less or no significant dopamine-releasing activity compared to MDMA and (S)-MDMA.[3][4] 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.[3][5] In clinical studies, (R)-MDMA produces similar effects to MDMA and (S)-MDMA, but is less potent and has a longer duration.[1][2]
(R)-MDMA was first described in enantiopure form by 1978.[6] Under the developmental code names EMP-01, developed by atai Life Sciences,[7] and DT402 (formerly MM402), developed by Definium Therapeutics (formerly MindMed),[8] it is under development for the treatment of post-traumatic stress disorder (PTSD), social phobia, and pervasive development disorders (PDDs) such as autism.[9][10][11] It is thought that (R)-MDMA might have a better safety profile than MDMA itself whilst retaining its therapeutic benefits.[3]
Use and effects
(R)-MDMA has a dose of 125 to 300 mg orally and a duration of 3.5 to 5.2 hours.[2] It has been estimated that doses of 125 mg MDMA, 100 mg (S)-MDMA, and 300 mg (R)-MDMA are equivalent.[2]
The first modern clinical study of the comparative effects of MDMA, (R)-MDMA, and (S)-MDMA was published in August 2024.[1][2] It compared 125 mg MDMA, 125 mg (S)-MDMA, 125 and 250 mg (R)-MDMA, and placebo.[1][2] (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.[2] However, (S)-MDMA 125 mg was more potent in increasing subjective effects, including stimulation, drug high, happy, and open, among others, than (R)-MDMA 125 or 250 mg or MDMA 125 mg.[1][2] Ratings of bad drug effect and fear were minimal with MDMA, (R)-MDMA, and (S)-MDMA.[2] In contrast to expectations, (R)-MDMA did not produce more psychedelic-like effects than (S)-MDMA.[1][2] 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.[2] Body temperature was notably increased to the same extent with (R)-MDMA 250 mg as with MDMA 125 mg and (S)-MDMA 125 mg.[2]
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.[1][2] It was estimated that equivalent effects would be expected with (S)-MDMA 100 mg, MDMA 125 mg, and (R)-MDMA 300 mg.[1][2] 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.[1][2] However, more clinical studies were called for to assess the revised estimated equivalent doses of MDMA, (R)-MDMA, and (S)-MDMA.[1][2]
Interactions
Pharmacology
Pharmacodynamics
| Compound | Monoamine release (EC50, nM) | ||
|---|---|---|---|
| Serotonin | Norepinephrine | Dopamine | |
| Amphetamine | ND | ND | ND |
| (S)-Amphetamine (d) | 698–1,765 | 6.6–7.2 | 5.8–24.8 |
| (R)-Amphetamine (l) | ND | 9.5 | 27.7 |
| Methamphetamine | ND | ND | ND |
| (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 | RI |
| (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: [4][12][13][14][15][16][17][18] | |||
MDMA is a well-balanced serotonin–norepinephrine–dopamine releasing agent (SNDRA).[19][4][12] (R)-MDMA and (S)-MDMA are both SNDRAs similarly.[19][4][12] 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.[4][12][3] 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.[4][12][3][5] In non-human primates, (S)-MDMA demonstrated significant dopamine transporter (DAT) occupancy, whereas DAT occupancy with (R)-MDMA was undetectable.[3] 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.[3][20] As such, (R)-MDMA may be less psychostimulant-like than MDMA or (S)-MDMA.[2][5]
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.[3] (R)-MDMA shows higher affinity for the serotonin 5-HT2A receptor than (S)-MDMA or MDMA.[3] 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.[3] Conversely however, (S)-MDMA is more potent as an agonist of the serotonin 5-HT2C receptor.[3][21] Based on these findings, it has been hypothesized that (R)-MDMA may be more psychedelic-like than (S)-MDMA.[2] 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.[22] In any case, findings in this area are conflicting.[23] (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 = 74,000 nM).[24]
MDMA is a well-known serotonergic neurotoxin and this has been demonstrated both in animals and in humans.[3] There is evidence that the serotonergic neurotoxicity of MDMA may be driven primarily by (S)-MDMA rather than (R)-MDMA.[3] (R)-MDMA shows substantially lower or potentially no neurotoxicity compared to (S)-MDMA in animal studies.[3] This has been the case even when doses of (R)-MDMA were increased to account for its lower potency than (S)-MDMA.[3] However, more research is needed to confirm this in other species, such as non-human primates.[3] 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.[3][5] 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.[3] The hyperthermia of MDMA may in fact be mediated by dopamine release.[3][5] 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.[3]
(R)-MDMA and (S)-MDMA have shown equivalent effects in terms of inducing prosocial behavior in monkeys.[3] However, (S)-MDMA shows higher potency, whereas (R)-MDMA shows greater maximal effects.[3] Conversely, (S)-MDMA does not increase prosocial behavior in mice, whereas both MDMA and (R)-MDMA do so.[3][5] MDMA and (S)-MDMA increase locomotor activity, a measure of psychostimulant-like effect, in rodents, whereas (R)-MDMA does not do so.[5] (R)-MDMA likewise showed fewer reinforcing effects than (S)-MDMA in non-human primates.[3] These findings further add to (R)-MDMA showing reduced psychostimulant-like and addictive effects compared to MDMA and (S)-MDMA.[3]
| 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 | ND |
| (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 | ND |
| (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: [25][12][26] | ||||||
Pharmacokinetics
The elimination half-life of (S)-MDMA is 4.1 hours, whereas the half-life of (R)-MDMA is 12 to 14 hours.[1][2] In the case of racemic MDMA administration, the half-life of (S)-MDMA is 5.1 hours and the half-life of (R)-MDMA is 11 hours.[2] (R)-MDMA shows cytochrome P450 CYP2D6 inhibition and lower levels of the metabolite 4-hydroxy-3-methoxymethamphetamine (HMMA) than (S)-MDMA.[2]
History
(R)-MDMA was first described in the scientific literature in enantiopure form by 1978.[6] It was described in a paper authored by Alexander Shulgin, David E. Nichols, and other colleagues.[6]
Society and culture
Legal status
Canada
As an enantiomer of MDMA, (R)-MDMA is a Schedule I controlled substance in Canada.[27]
United States
As an enantiomer of MDMA, (R)-MDMA is a Schedule I controlled substance in the United States.[27]
Research
(R)-MDMA is under development separately by Empath Biosciences (EmpathBio) and MindMed.[9][11][10][28] It is being developed by Empath Biosciences for the treatment of PTSD and social phobia[9][11] and it is being developed by MindMed for the treatment of PDDs or autism.[10][28] 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.[9][10] The results of a 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.[29]