(R)-MDMA

(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
IUPAC name
  • (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)
SMILES
  • C[C@H](CC1=CC2=C(C=C1)OCO2)NC
InChI
  • 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, developed by atai Life Sciences,[7] and MM-402, developed by 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]

Pharmacology

Pharmacodynamics

Preclinical studies

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) 698–1,765 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 (EC50Tooltip half-maximal effective concentration = 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]

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 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]

Clinical studies

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

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]

Clinical development

(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 in phase 1 clinical trials for both PTSD, social phobia, and PDDs/autism.[9][10]

See also

References

  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. 50 (2): 360–361. doi:10.1038/s41386-024-02009-8. PMC 11631934. 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. 50 (2): 362–371. doi:10.1038/s41386-024-01972-6. PMC 11631982. 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. ^ "atai Life Sciences Announces Positive Topline Results from Single Ascending Dose Phase 1 Study with EMP-01 (R-MDMA)".
  8. ^ "MM-402 by Mind Medicine MindMed for Autism Spectrum Disorder (ASD): Likelihood of Approval".
  9. ^ a b c d "EMP 01 (R-MDMA)". AdisInsight. 20 August 2024. Retrieved 28 October 2024.
  10. ^ a b c d "R(-)-Methylenedioxymetamfetamine (MM-402; R(-)-MDMA)". AdisInsight. 30 January 2024. Retrieved 28 October 2024.
  11. ^ a b c "Delving into the Latest Updates on EMP-01 with Synapse". Synapse. 1 November 2024. Retrieved 2 November 2024.
  12. ^ a b c d e f 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)
  13. ^ 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.
  14. ^ 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.
  15. ^ 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.
  16. ^ 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.
  17. ^ 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.
  18. ^ Blough B (July 2008). "Dopamine-releasing agents" (PDF). In Trudell ML, Izenwasser S (eds.). Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. pp. 305–320. ISBN 978-0-470-11790-3. OCLC 181862653. OL 18589888W.
  19. ^ 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.
  20. ^ 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.
  21. ^ Kaur H, Karabulut S, Gauld JW, Fagot SA, Holloway KN, Shaw HE, et al. (2023). "Balancing Therapeutic Efficacy and Safety of MDMA and Novel MDXX Analogues as Novel Treatments for Autism Spectrum Disorder". Psychedelic Medicine. 1 (3): 166–185. doi:10.1089/psymed.2023.0023. PMC 11661495.
  22. ^ Dunlap LE (2022). Development of Non-Hallucinogenic Psychoplastogens (Thesis). University of California, Davis. Retrieved 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.
  23. ^ 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. ISBN 978-3-662-55878-2. PMC 5787039. PMID 28224459. [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).
  24. ^ Lewin AH, Miller GM, Gilmour B (December 2011). "Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class". Bioorg Med Chem. 19 (23): 7044–7048. doi:10.1016/j.bmc.2011.10.007. PMC 3236098. PMID 22037049.
  25. ^ 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. PMID 7824160.
  26. ^ Kolaczynska KE, Ducret P, Trachsel D, Hoener MC, Liechti ME, Luethi D (June 2022). "Pharmacological characterization of 3,4-methylenedioxyamphetamine (MDA) analogs and two amphetamine-based compounds: N,α-DEPEA and DPIA" (PDF). Eur Neuropsychopharmacol. 59: 9–22. doi:10.1016/j.euroneuro.2022.03.006. PMID 35378384.
  27. ^ a b "Delving into the Latest Updates on MM-402 with Synapse". Synapse. 1 November 2024. Retrieved 2 November 2024.
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