# (R)-MDMA

(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. 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-HT$_{2A}$ 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 atai Life Sciences, and MM-402, developed by MindMed, it is under development for the treatment of post-traumatic stress disorder (PTSD), social phobia, and pervasive development disorders (PDDs) such as autism. It is thought that (R)-MDMA might have a better safety profile than MDMA itself whilst retaining its therapeutic benefits.

## Pharmacology
### Pharmacodynamics
#### Preclinical studies

Activities of MDMA, its enantiomers, and related compounds :
| Compound | Monoamine release (EC$_{50}$Tooltip half-maximal effective concentration, nM) | Monoamine release (EC$_{50}$Tooltip half-maximal effective concentration, nM) | Monoamine release (EC$_{50}$Tooltip half-maximal effective concentration, nM) |
| Compound | 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: ||||
MDMA is a well-balanced serotonin–norepinephrine–dopamine releasing agent (SNDRA). (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. 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-HT$_{2A}$, 5-HT$_{2B}$, and 5-HT$_{2C}$ receptors, where it acts as an agonist. (R)-MDMA shows higher affinity for the serotonin 5-HT$_{2A}$ receptor than (S)-MDMA or MDMA. In addition, (R)-MDMA is more potent as an agonist of the serotonin 5-HT$_{2A}$ 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-HT$_{2C}$ receptor. 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. In any case, findings in this area are conflicting. (R)-MDMA is inactive as an agonist of the human TAAR1, whereas (S)-MDMA shows very weak potency as an agonist of the receptor (EC$_{50}$Tooltip half-maximal effective concentration = 74,000 nM).
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. (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-HT$_2$ receptors :
| Compound | 5-HT$_{2A}$ | 5-HT$_{2A}$ | 5-HT$_{2B}$ | 5-HT$_{2B}$ | 5-HT$_{2C}$ | 5-HT$_{2C}$ |
| Compound | EC$_{50}$ (nM) | V$_{max}$ | EC$_{50}$ (nM) | E$_{max}$ | EC$_{50}$ (nM) | V$_{max}$ |
| Serotonin | 53 | 92% | 1.0 | 100% | 22 | 91% |
| MDA | ND | ND | 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 | ND | ND | 2,000 | 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 K$_{act}$ or EC$_{50}$ value, the more strongly the compound produces the effect. Refs: |||||||

#### Clinical studies

The first modern clinical study of the comparative effects of MDMA, (R)-MDMA, and (S)-MDMA was published in August 2024. It compared 125 mg MDMA, 125 mg (S)-MDMA, 125 and 250 mg (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 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. 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 250 mg as with MDMA 125 mg and (S)-MDMA 125 mg.
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 100 mg, MDMA 125 mg, and (R)-MDMA 300 mg. 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.

### Pharmacokinetics

The elimination half-life of (S)-MDMA is 4.1 hours, whereas the half-life of (R)-MDMA is 12 to 14 hours. 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. (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. It was described in a paper authored by Alexander Shulgin, David E. Nichols, and other colleagues.

## Clinical development

(R)-MDMA is under development separately by Empath Biosciences (EmpathBio) and MindMed. It is being developed by Empath Biosciences for the treatment of PTSD and social phobia and it is being developed by MindMed for the treatment of PDDs or autism. As of 2024, the drug is in phase 1 clinical trials for both PTSD, social phobia, and PDDs/autism.