D2-MDMA

D2-MDMA

d2-MDMA
Clinical data
Other namesDeuterated-MDMA; D-MDMA; d2-3,4-Methylenedioxymethamphetamine; Deumidomafetamine; d2-Midomafetamine
Drug classEntactogen; Stimulant
ATC code
  • None
Identifiers
  • 1-(2,2-dideuterio-1,3-benzodioxol-5-yl)-N-methylpropan-2-amine
PubChem CID
Chemical and physical data
FormulaC11H15NO2
Molar mass193.246 g·mol−1
3D model (JSmol)
  • [2H]C1(OC2=C(O1)C=C(C=C2)CC(C)NC)[2H]
  • 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/i7D2
  • Key:SHXWCVYOXRDMCX-RJSZUWSASA-N

d2-MDMA, also known as d2-3,4-methylenedioxymethamphetamine or as deuterated-MDMA (D-MDMA), is an entactogen and stimulant of the phenethylamine, amphetamine, and MDxx families related to MDMA ("ecstasy").[1][2][3][4][5][6] It is the deuterated isotopologue of MDMA in which the hydrogen atoms on the carbon atom of the 3,4-methylenedioxy ring have been replaced with the deuterium isotopes.[1][2][6]

MDMA is known to produce serotonergic neurotoxicity and associated cognitive deficits and emotional and behavioral changes.[1][2] The neurotoxicity of MDMA may be due in part to metabolism of MDMA via opening of the 3,4-methylenedioxy ring or O-demethylation to form catechol metabolites like 3,4-dihydroxyamphetamine (HHA; α-methyldopamine) and 3,4-dihydroxymethamphetamine (HHMA; α,N-dimethyldopamine).[1][2] These metabolites may subsequently undergo further metabolism into reactive oxygen species (ROS) that damage serotonergic neurons.[1][2] In relation to this, d2-MDMA is thought to be more resistant to metabolism in this location due to the kinetic isotope effect, metabolically requiring a greater duration for relevant cytochrome P450 enzymes to break deuterium–carbon bonds compared to hydrogen–carbon bonds.[1][2] As a result, d2-MDMA may have less neurotoxic potential than MDMA.[1][2] On the other hand, whereas the pharmacokinetics and neurotoxicity of d2-MDMA may be altered compared to MDMA, it is thought that the drug will have similar or near-identical pharmacodynamics as MDMA, for instance interactions with monoamine transporters and serotonin receptors, aside from differing metabolites.[1][2]

d2-MDMA produces hyperlocomotion, stereotypy, and sensitization in rodents similarly to MDMA and with comparable potency.[1] However, there were some slight differences between d2-MDMA and MDMA in terms of these effects at certain doses.[1] In addition, d2-MDMA at high doses might be less lethal via serotonin syndrome in rodents than MDMA based on preliminary findings.[1] d2-MDMA fully substitutes for MDMA in rodent drug discrimination tests and with equal potency and efficacy.[2] The drug produced hyperthermia in rodents similarly to d2-MDMA, but this effect was shorter-lasting and of lower magnitude in comparison.[2] However, this might have simply been related to potency differences in terms of this effect.[2] The in-vitro pharmacodynamics and other effects of d2-MDMA have not yet been studied or reported.[2]

d2-MDMA was studied by William E. Fantegrossi and colleagues and described by these researchers in 2017,[3] 2018,[4] and 2020.[1][2] It is of potential interest for use in medicine as a better-tolerated and safer alternative to MDMA in the treatment of conditions like post-traumatic stress disorder (PTSD) and social anxiety disorder.[1][2] On the other hand, d2-MDMA also has potential to emerge as a novel designer recreational drug.[6] Deuterated analogues of MDMA have been patented by Nicholas Cozzi and Paul Daley of the Alexander Shulgin Research Institute (ASRI).[7][8]

Other deuterated and related analogues of MDMA, such as MDMA-d3, have also been described.[9]

See also

References

  1. ^ a b c d e f g h i j k l m Berquist MD, Leth-Petersen S, Kristensen JL, Fantegrossi WE (February 2020). "Locomotor effects of 3,4-methylenedioxymethamphetamine (MDMA) and its deuterated form in mice: psychostimulant effects, stereotypy, and sensitization". Psychopharmacology. 237 (2): 431–442. doi:10.1007/s00213-019-05380-3. PMC 7388080. PMID 31729537.
  2. ^ a b c d e f g h i j k l m n Berquist MD, Leth-Petersen S, Kristensen JL, Fantegrossi WE (March 2020). "In vivo effects of 3,4-methylenedioxymethamphetamine (MDMA) and its deuterated form in rodents: Drug discrimination and thermoregulation". Drug and Alcohol Dependence. 208 107850. doi:10.1016/j.drugalcdep.2020.107850. PMID 31954950.
  3. ^ a b Berquest MD, Leth-Petersen S, Fantegrossi WE (2017). Poster 2-29 Locomotor stimulant effects of MDMA and its putatively less toxic deuterated form in mice (PDF). 2017 Behavior, Biology, and Chemistry: Translational Research in Addiction. p. 33.
  4. ^ a b Berquest MD, Leth-Petersen S, Fantegrossi WE (2018). Poster 2-17 Thermoregulatory and discriminative stimulus effects of MDMA and its putatively less toxic deuterated form in rodents (PDF). 2018 Behavior, Biology, and Chemistry: Translational Research in Addiction. p. 31.
  5. ^ Chandra Mouli HM, Vinod A, Kumari S, Tiwari AK, Kathiravan MK, Ravichandiran V, et al. (June 2023). "Deuterated driven new chemical entities: An optimistic way to improve therapeutic efficacy". Bioorganic Chemistry. 135 106490. doi:10.1016/j.bioorg.2023.106490. PMID 37001472. MDMA (3,4-Methylenedioxymethamphetamine) has resurfaced as an adjunct pharmacotherapy in the treatment of posttraumatic stress disorder (PTSD). Deuterium substitution at the methylenedioxy (-OCH2-O-) ring of MDMA slows down the metabolism, thereby reduces the adverse effects. Nevertheless, the d2-MDMA 9 has no differences in ED50 value as compared to its parent drug. Overall, the d2-MDMA retained the desirable subjective effects required to treat PTSD. In animal models, both MDMA and d2-MDMA affected the body temperature and locomotor activity [58].
  6. ^ a b c Stemmerich K, Sewell AC, Arndt T (2022). "Deuterated Drugs: Weighty Times Ahead for the Lab?" (PDF). TIAFT Bulletin. 52 (4). 3.3. 'Heavy' drugs as drugs of abuse In experiments with mice, d2-MDMA (d2-3,4- methylenedioxymethamphetamine) showed properties comparable to the stimulatory effects of MDMA [43]. Consequently, d2-MDMA could show potential as a substance of abuse. Berquist et al. [43] suggested that a different deuteration could maximise the therapeutic effect in the treatment of patients with post-traumatic stress disorder (PTSD) while minimising the adverse effects of MDMA. This may be equally true in reverse for the abusive properties, which could also be altered by appropriate deuteration of the molecule.
  7. ^ US 12221428, Cozzi NV, Daley PF, "Use of deuterated empathogens as therapeutic agents", published 2025-02-11, issued 11 February 2025, assigned to Alexander Shulgin Research Institute Inc 
  8. ^ US 12043605, Cozzi NV, Daley PF, "Deuterated empathogens", published 2024-07-23, issued 23 July 2024, assigned to Alexander Shulgin Research Institute Inc 
  9. ^ Baumann MR, Walther D, Daley P, Cozzi N (2026). "Effects of Deuteration or Fluorination of MDMA-Like Empathogen Compounds on Monoamine Transporter Activities (Abstract ID: 228967)". The Journal of Pharmacology and Experimental Therapeutics. 393 (5) 104084. doi:10.1016/j.jpet.2026.104084.

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