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(R)-MDMA

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(R)-MDMA
Clinical data
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; MM-402; MM402
Routes of
administration		Oral[1][2]
Drug classSerotonin–norepinephrine releasing agent; Serotonin 5-HT2A receptor agonist; Entactogen; Empathogen[3][4]
Pharmacokinetic data
MetabolismCYP2D6[2]
Elimination half-life11–14 hours[1][2]
Identifiers
  • (2R)-1-(1,3-benzodioxol-5-yl)-N-methylpropan-2-amine
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC11H15NO2
Molar mass193.246 g·mol−1
3D model (JSmol)
  • C[C@H](CC1=CC2=C(C=C1)OCO2)NC
  • InChI=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
  • Key: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.[3][2] Like MDMA, (R)-MDMA is an entactogen or empathogen.[3][2] It is taken by mouth.[3][2]

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 and MM-402, it is under development for the treatment of post-traumatic stress disorder (PTSD), social phobia, and pervasive development disorders (PDDs) such as autism.[7][8][9] It is thought that (R)-MDMA might have a better safety profile than MDMA itself whilst retaining its therapeutic benefits.[3]

Pharmacology

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Pharmacodynamics

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Preclinical studies

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Activities of MDMA, its enantiomers, and related compounds
Compound Monoamine release (EC50Tooltip half-maximal effective concentration, nM)
Serotonin Norepinephrine Dopamine
Amphetamine ND ND ND
  (S)-Amphetamine (d) 698–1765 6.6–7.2 5.8–24.8
  (R)-Amphetamine (l) ND ND ND
Methamphetamine ND ND ND
  (S)-Methamphetamine (d) 736–1291.7 12.3–13.8 8.5–24.5
  (R)-Methamphetamine (l) 4640 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 3700
MDEA 47 2608 622
  (S)-MDEA (d) 465 RI RI
  (R)-MDEA (l) 52 651 507
MBDB 540 3300 >100000
MDAI 114 117 1334
Notes: The smaller the value, the more strongly the compound produces the effect. Refs: [4][10][11][12][13][14][15]

MDMA is a well-balanced serotonin–norepinephrine–dopamine releasing agent (SNDRA).[16][4][10] (R)-MDMA and (S)-MDMA are both SNDRAs similarly.[16][4][10] 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][10][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][10][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][17] 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] Based on these findings, (R)-MDMA may be more psychedelic-like than (S)-MDMA.[2]

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]

Clinical studies

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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]

Pharmacokinetics

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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

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(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]

Clinical development

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(R)-MDMA is under development separately by Empath Biosciences (EmpathBio) and MindMed.[7][9][8][18] It is being developed by Empath Biosciences for the treatment of PTSD and social phobia[7][9] and it is being developed by MindMed for the treatment of PDDs or autism.[8][18] As of 2024, the drug is in phase 1 clinical trials for both PTSD, social phobia, and PDDs/autism.[7][8]

References

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  1. ^ a b c d e f g h i j k l Bedi G (October 2024). "Is the stereoisomer R-MDMA a safer version of MDMA?". Neuropsychopharmacology. doi:10.1038/s41386-024-02009-8. PMID 39448866.
  2. ^ a b c d e f g h i j k l m n o p q r s t u v w x Straumann I, Avedisian I, Klaiber A, Varghese N, Eckert A, Rudin D, et al. (August 2024). "Acute effects of R-MDMA, S-MDMA, and racemic MDMA in a randomized double-blind cross-over trial in healthy participants". Neuropsychopharmacology. doi:10.1038/s41386-024-01972-6. PMID 39179638.{{cite journal}}: CS1 maint: overridden setting (link)
  3. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad Pitts EG, Curry DW, Hampshire KN, Young MB, Howell LL (February 2018). "(±)-MDMA and its enantiomers: potential therapeutic advantages of R(-)-MDMA". Psychopharmacology. 235 (2): 377–392. doi:10.1007/s00213-017-4812-5. PMID 29248945.
  4. ^ a b c d e f g h Rothman RB, Baumann MH (2006). "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry. 6 (17): 1845–1859. doi:10.2174/156802606778249766. PMID 17017961.
  5. ^ a b c d e f g Curry DW, Young MB, Tran AN, Daoud GE, Howell LL (January 2018). "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. doi:10.1016/j.neuropharm.2017.10.003. PMC 5714650. PMID 28993129.
  6. ^ a b c Anderson GM, Braun G, Braun U, Nichols DE, Shulgin AT (1978). "Absolute configuration and psychotomimetic activity". NIDA Research Monograph (22): 8–15. PMID 101890.
  7. ^ a b c d "EMP 01 (R-MDMA)". AdisInsight. 20 August 2024. Retrieved 28 October 2024.
  8. ^ a b c d "R(-)-Methylenedioxymetamfetamine (MM-402; R(-)-MDMA)". AdisInsight. 30 January 2024. Retrieved 28 October 2024.
  9. ^ a b c "Delving into the Latest Updates on EMP-01 with Synapse". Synapse. 1 November 2024. Retrieved 2 November 2024.
  10. ^ a b c d e Setola V, Hufeisen SJ, Grande-Allen KJ, Vesely I, Glennon RA, Blough B, et al. (June 2003). "3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro". Molecular Pharmacology. 63 (6): 1223–1229. doi:10.1124/mol.63.6.1223. PMID 12761331. S2CID 839426.{{cite journal}}: CS1 maint: overridden setting (link)
  11. ^ Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, et al. (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse. 39 (1): 32–41. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID 11071707. S2CID 15573624.
  12. ^ Rothman RB, Partilla JS, Baumann MH, Lightfoot-Siordia C, Blough BE (April 2012). "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. doi:10.1124/jpet.111.188946. PMC 3364510. PMID 22271821.
  13. ^ Marusich JA, Antonazzo KR, Blough BE, Brandt SD, Kavanagh PV, Partilla JS, et al. (February 2016). "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. doi:10.1016/j.neuropharm.2015.09.004. PMC 4681602. PMID 26362361.
  14. ^ 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. PMID 17223101.
  15. ^ Halberstadt AL, Brandt SD, Walther D, Baumann MH (March 2019). "2-Aminoindan and its ring-substituted derivatives interact with plasma membrane monoamine transporters and α2-adrenergic receptors". Psychopharmacology (Berl). 236 (3): 989–999. doi:10.1007/s00213-019-05207-1. PMC 6848746. PMID 30904940.
  16. ^ a b Rothman 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. PMID 14612135.
  17. ^ 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. PMID 17564678.
  18. ^ a b "Delving into the Latest Updates on MM-402 with Synapse". Synapse. 1 November 2024. Retrieved 2 November 2024.
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