(R)-MDMA has a dose of 125 to 300mgorally and aduration of 3.5 to 5.2hours.[2] It has been estimated that doses of 125mg MDMA, 100mg (S)-MDMA, and 300mg (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 125mg MDMA, 125mg (S)-MDMA, 125 and 250mg (R)-MDMA, andplacebo.[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 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.[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 increasedheart rate,blood pressure, andbody 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 250mg as with MDMA 125mg and (S)-MDMA 125mg.[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 100mg, MDMA 125mg, and (R)-MDMA 300mg.[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]
MDMA is a well-balancedserotonin–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 lesspotent than (S)-MDMAin vitro and is also less potent than (S)-MDMAin 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 adopamine releasing agent (~11-fold less potent in releasing dopamine than serotonin), and could be thought of instead more as aserotonin–norepinephrine releasing agent (SNRA) than as an SNDRA.[4][12][3][5] In non-human primates, (S)-MDMA demonstrated significantdopamine transporter (DAT) occupancy, whereas DAT occupancy with (R)-MDMA was undetectable.[3] Similarly, MDMA and (S)-MDMA were found to increasedopamine levels in thestriatum in rodents and non-human primates, whereas (R)-MDMA did not increase striatal dopamine levels.[3][20] As such, (R)-MDMA may be lesspsychostimulant-like than MDMA or (S)-MDMA.[2][5]
In addition to its actions as an SNDRA, MDMA has weakaffinity for theserotonin5-HT2A,5-HT2B, and5-HT2C receptors, where it acts as anagonist.[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 anagonist of the serotonin 5-HT2A receptor, acting as a weakpartial 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 morepsychedelic-like than (S)-MDMA.[2] However, although (R)-MDMA partially substitutes forlysergic acid diethylamide (LSD) in animaldrug discrimination tests, it did not produce thehead-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 humanTAAR1, whereas (S)-MDMA shows very weak potency as an agonist of the receptor (EC50Tooltip half-maximal effective concentration = 74,000nM).[24]
MDMA is a well-knownserotonergic 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 inanimal 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 producehyperthermia 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 ofdrug-assisted psychotherapy.[3]
(R)-MDMA and (S)-MDMA have shown equivalent effects in terms of inducingprosocial 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)-MDMAincrease locomotor activity, a measure of psychostimulant-like effect, in rodents, whereas (R)-MDMA does not do so.[5] (R)-MDMA likewise showed fewerreinforcing 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]
MDMA, MDA, and enantiomers at serotonin 5-HT2 receptors
(R)-MDMA is under development separately by Empath Biosciences (EmpathBio) and MindMed.[9][11][10][27] 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][27] As of 2024, the drug is inphase 1clinical trials for both PTSD, social phobia, and PDDs/autism.[9][10]
^Nagai F, Nonaka R, Satoh Hisashi Kamimura K (March 2007). "The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain".European Journal of Pharmacology.559 (2–3):132–137.doi:10.1016/j.ejphar.2006.11.075.PMID17223101.
^abRothman RB, Baumann MH (October 2003). "Monoamine transporters and psychostimulant drugs".European Journal of Pharmacology.479 (1–3):23–40.doi:10.1016/j.ejphar.2003.08.054.PMID14612135.
^Acquas E, Pisanu A, Spiga S, Plumitallo A, Zernig G, Di Chiara G (July 2007). "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.doi:10.1111/j.1471-4159.2007.04451.x.PMID17564678.
^Dunlap LE (2022).Development of Non-Hallucinogenic Psychoplastogens (Thesis). University of California, Davis. Retrieved18 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.
^Halberstadt AL, Geyer MA (2018). "Effect of Hallucinogens on Unconditioned Behavior".Behavioral Neurobiology of Psychedelic Drugs. Current Topics in Behavioral Neurosciences. Vol. 36. pp. 159–199.doi:10.1007/7854_2016_466.ISBN978-3-662-55878-2.PMC5787039.PMID28224459.[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).
^Nash JF, Roth BL, Brodkin JD, Nichols DE, Gudelsky GA (August 1994). "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.doi:10.1016/0304-3940(94)90057-4.PMID7824160.
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