Chemistry:MDAI

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MDAI, also known as 5,6-methylenedioxy-2-aminoindane, is an entactogen drug of the 2-aminoindane group which is related to MDMA and produces similar subjective effects.[1][2][3][4]

It acts as a selective serotonin and norepinephrine releasing agent (SNRA).[5] The drug shows greatly reduced serotonergic neurotoxicity in comparison to MDMA in animals, although it still shows weak capacity for neurotoxicity with chronic use or in combination with amphetamine.[6][7][8]

MDAI was developed in the 1990s by a team led by David E. Nichols at Purdue University.[9] It has been encountered as a designer drug and has been used recreationally with reported street names such as "sparkle" and "mindy".[2][10][6][3] In addition to its recreational use, there has been interest in MDAI for potential use in medicine, for instance in drug-assisted psychotherapy.[1]

Use and effects

A 2024 study compared the effects of MDAI and MDMA in humans.[4] It found that MDAI produced comparable and very similar subjective effects to those of MDMA.[4] This included pleasurable drug effects, drug liking, stimulation, happiness, openness, trust, and closeness.[4] In addition, it included sense of well-being, emotional excitation, and extroversion, but not general activity or concentration, a profile of effects described as similar to that of MDMA.[4] Other effects included a blissful state, experience of unity, and changed meaning of percepts, also described as comparable to MDMA.[4] The effects of MDAI were slightly greater than those of 75 mg MDMA and slightly lower than those of 125 mg MDMA.[4] At the employed dose of 3.0 mg/kg, with 125 mg MDMA corresponding to 1.9 mg/kg, it was estimated that MDAI had about 60% of MDMA's potency in producing comparable psychoactive effects (hence, roughly 200 mg MDAI would be similar to 125 mg MDMA).[4] Aside from subjective effects, MDAI also increased blood pressure, cortisol levels, and prolactin levels similarly to MDMA.[4] Conversely, it did not increase heart rate or body temperature.[4]

Toxicity

Very high doses can be fatal in rats with a 50% fatality rate for those subcutaneously injected with 28 mg/kg of MDAI. This is a result of the way serotonin release interferes with thermoregulation.[11]

MDAI is only non-neurotoxic in isolation but may become neurotoxic when mixed with other drugs.[12] Three deaths were linked to MDAI use in the United Kingdom during 2011 and 2012, all involving symptoms consistent with serotonin syndrome. Two of these also involved other drugs while one death appeared to be from MDAI alone.[6]

Interactions

Pharmacology

Pharmacodynamics

MDAI acts as a selective and well-balanced serotonin and norepinephrine releasing agent (SNRA) with much less (~10-fold lower) effect on dopamine release.[5] In addition to inducing the release of the monoamine neurotransmitters, MDAI also inhibits their reuptake.[9] For comparison to MDAI, MDA and MDMA are well-balanced releasing agents of serotonin, norepinephrine, and dopamine (SNDRAs).[5] Conversely, the profile of monoamine release with MDAI is very similar to that of (R)-MDMA (levo-MDMA), which like MDAI is also a well-balanced SNRA with about 10-fold reduced impact on dopamine release, though MDAI is several-fold more potent than (R)-MDMA in vitro.[13][5]

In contrast to MDMA, MDAI shows no affinity for any of the serotonin receptors (Ki = all >10 μM).[5] This notably includes the serotonin 5-HT2A receptor, which is implicated in producing psychedelic effects, and the serotonin 5-HT2B receptor, which is implicated in causing cardiac valvulopathy.[5][14] However, MDAI shows significant affinity for all three of the α2-adrenergic receptors (Ki = 322 to 1121 nM).[5]

Activities of MDAI and related drugs
Compound Monoamine release (EC50, nM)
Serotonin Norepinephrine Dopamine
2-AI >10,000 86 439
MDAI 114 117 1,334
MMAI 31 3,101 >10,000
MEAI 134 861 2,646
d-Amphetamine 698–1,765 6.6–7.2 5.8–24.8
d-Methamphetamine 736–1,292 12.3–13.8 8.5–24.5
MDA 160 108 190
MDMA 49.6–72 54.1–110 51.2–278
  (R)-MDMA (l-MDMA) 340 560 3,700
MDEA 47 2,608 622
MBDB 540 3,300 >100,000
Notes: The smaller the value, the more strongly the compound produces the effect. See also Monoamine releasing agent § Activity profiles for a larger table with more compounds. Refs: [5][15][16][17][18][19][20]

The family of drugs typified by MDMA produce their effects through multiple mechanisms of action in the body, and consequently produce three distinct cues which animals can be trained to respond to: a stimulant cue typified by drugs such as methamphetamine, a psychedelic cue typified by drugs such as LSD and DOM, and an "entactogen-like" cue which is produced by drugs such as MDAI and MBDB. These drugs cause drug-appropriate responses in animals trained to recognize the effects of MDMA, but do not produce responses in animals trained selectively to respond to stimulants or hallucinogens. Because these compounds selectively release serotonin in the brain but have little effect on dopamine or noradrenaline levels, they can produce empathogenic effects but without any stimulant action, instead being somewhat sedating.[21][22][23][24][25][26][27]

MDAI shows substantially lower serotonergic neurotoxicity than MDMA in animals and has been described as a "non-neurotoxic" analogue of MDMA.[6][7][8] However, MDAI still shows weak serotonergic neurotoxicity both alone and particularly in combination with amphetamine in animals.[6][7][8] As such, MDAI does not appear to be a fully non-neurotoxic alternative to MDMA.[6][7][8]

Pharmacokinetics

The duration of MDAI in humans appears to be similar to that of MDMA at 2 to 5 hours[1] or up to around 6 hours.[4]

Chemistry

MDAI in powder form.

The chemical structure of MDAI is indirectly derived from that of the illicit drug MDA, but the α-methyl group of the alkyl amino amphetamine side chain has been bound back to the benzene nucleus to form an indane ring system, which changes its pharmacological properties substantially.

Society and culture

Recreational use

MDAI has been advertised as a designer drug. It started to be sold online from around 2007, but reached peak popularity between about 2010 to 2012, after bans on mephedrone came into effect in various countries. Many internet-sourced products claimed to be MDAI have been shown to contain mephedrone or other cathinones, while generally containing no MDAI. The number of internet searches for MDAI has been considerably higher in the United Kingdom compared to Germany and the United States.[10]

Analogues

  • 5,6-methylenedioxy-N-methyl-2-aminoindane
  • 5-methoxy-2-aminoindane
  • 5-methoxy-6-methyl-2-aminoindane
  • 5-iodo-2-aminoindane
  • 2-aminoindane
  • N-methyl-2-aminoindane

Synthesis

MDAI can be produced from 3-(3,4-methylenedioxyphenyl)propionic acid[28] which is converted to the acid chloride and then heated to produce 5,6-methylenedioxy-1-indanone. Treatment of the indanone with amyl nitrite in methanol with HCl afforded the hydroxyimino ketone. This is reduced to the 2-aminoindan following a modification of Nichols' earlier method from a paper discussing DOM analogues,[29] using a Pd/C catalyst in glacial acetic acid with catalytic H2SO4.

Society and culture

China

As of October 2015 MDAI is a controlled substance in China.[30]

Denmark

MDAI is illegal in Denmark as of September 2015.[31]

Finland

Scheduled in the "government decree on psychoactive substances banned from the consumer market".[32]

Switzerland

As of December 2011 MDAI is a controlled substance in Switzerland.[33]

Research

MDAI and other similar drugs have been widely used in scientific research, as they are able to replicate many of the effects of MDMA, but without causing the serotonergic neurotoxicity associated with MDMA and certain related drugs. No tests have been performed on cardiovascular toxicity.[28][34][35][36][37][38][39]

See also

  • Substituted 2-aminoindane
  • Cyclized phenethylamine

References

  1. ↑ 1.0 1.1 1.2 "Beyond ecstasy: Alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy". Journal of Psychopharmacology (SAGE Publications) 35 (5): 512–536. May 2021. doi:10.1177/0269881120920420. PMID 32909493. 
  2. ↑ 2.0 2.1 "Synthetic Aminoindanes: A Summary of Existing Knowledge". Frontiers in Psychiatry (Frontiers Media SA) 8. 17 November 2017. doi:10.3389/fpsyt.2017.00236. PMID 29204127. 
  3. ↑ 3.0 3.1 "Aminoindanes--the next wave of 'legal highs'?". Drug Testing and Analysis (Wiley) 3 (7–8): 479–482. 2011. doi:10.1002/dta.318. PMID 21748859. 
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 "Acute psychotropic, autonomic, and endocrine effects of 5,6-methylenedioxy-2-aminoindane (MDAI) compared with 3,4-methylenedioxymethamphetamine (MDMA) in human volunteers: A self-administration study". Drug Test Anal 16 (9): 1002–1011. September 2024. doi:10.1002/dta.3622. PMID 38056906. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 "2-Aminoindan and its ring-substituted derivatives interact with plasma membrane monoamine transporters and α2-adrenergic receptors". Psychopharmacology (Berl) 236 (3): 989–999. March 2019. doi:10.1007/s00213-019-05207-1. PMID 30904940. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 "MDAI (5,6-methylenedioxy-2-aminoindane; 6,7-dihydro-5H-cyclopenta[f][1,3]benzodioxol-6-amine; 'sparkle'; 'mindy') toxicity: a brief overview and update". Human Psychopharmacology 28 (4): 345–355. July 2013. doi:10.1002/hup.2298. PMID 23881883. 
  7. ↑ 7.0 7.1 7.2 7.3 "Novel serotonergic agents". Drug des Discov 9 (3–4): 299–312. 1993. PMID 8400010. https://chemistry.mdma.ch/hiveboard/rhodium/pdf/nichols/nichols-novel.serotonergic.agents.pdf. 
  8. ↑ 8.0 8.1 8.2 8.3 "Serotonin neurotoxicity in rats after combined treatment with a dopaminergic agent followed by a nonneurotoxic 3,4-methylenedioxymethamphetamine (MDMA) analogue". Pharmacol Biochem Behav 40 (4): 915–922. December 1991. doi:10.1016/0091-3057(91)90106-c. PMID 1726189. 
  9. ↑ 9.0 9.1 "[3H]monoamine releasing and uptake inhibition properties of 3,4-methylenedioxymethamphetamine and p-chloroamphetamine analogues". European Journal of Pharmacology 200 (1): 9–16. July 1991. doi:10.1016/0014-2999(91)90659-e. PMID 1685125. 
  10. ↑ 10.0 10.1 "5,6-Methylenedioxy-2-aminoindane: from laboratory curiosity to 'legal high'". Human Psychopharmacology 27 (2): 106–112. March 2012. doi:10.1002/hup.1255. PMID 22389075. 
  11. ↑ "Emerging toxicity of 5,6-methylenedioxy-2-aminoindane (MDAI): Pharmacokinetics, behaviour, thermoregulation and LD50 in rats". Progress in Neuro-Psychopharmacology & Biological Psychiatry 69: 49–59. August 2016. doi:10.1016/j.pnpbp.2016.04.004. PMID 27083855. 
  12. ↑ "Second generation mephedrone. The confusing case of NRG-1". BMJ 341. July 2010. doi:10.1136/bmj.c3564. PMID 20605894. 
  13. ↑ "(±)-MDMA and its enantiomers: potential therapeutic advantages of R(-)-MDMA". Psychopharmacology 235 (2): 377–392. February 2018. doi:10.1007/s00213-017-4812-5. PMID 29248945. 
  14. ↑ "Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine". ACS Chem Neurosci 9 (10): 2408–2427. October 2018. doi:10.1021/acschemneuro.8b00155. PMID 30001118. 
  15. ↑ "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry 6 (17): 1845–1859. 2006. doi:10.2174/156802606778249766. PMID 17017961. 
  16. ↑ "3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro". Molecular Pharmacology 63 (6): 1223–1229. June 2003. doi:10.1124/mol.63.6.1223. PMID 12761331. 
  17. ↑ "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse 39 (1): 32–41. January 2001. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID 11071707. 
  18. ↑ "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. April 2012. doi:10.1124/jpet.111.188946. PMID 22271821. 
  19. ↑ "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. February 2016. doi:10.1016/j.neuropharm.2015.09.004. PMID 26362361. 
  20. ↑ "The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain". European Journal of Pharmacology 559 (2–3): 132–137. March 2007. doi:10.1016/j.ejphar.2006.11.075. PMID 17223101. 
  21. ↑ "Stereochemical effects of 3,4-methylenedioxymethamphetamine (MDMA) and related amphetamine derivatives on inhibition of uptake of [3H]monoamines into synaptosomes from different regions of rat brain". Biochemical Pharmacology 36 (14): 2297–303. July 1987. doi:10.1016/0006-2952(87)90594-6. PMID 2886126. 
  22. ↑ "Drug discrimination studies with MDMA and amphetamine". Psychopharmacology 95 (1): 71–6. 1988. doi:10.1007/bf00212770. PMID 2898791. 
  23. ↑ "Differences between the mechanism of action of MDMA, MBDB, and the classic hallucinogens. Identification of a new therapeutic class: entactogens". Journal of Psychoactive Drugs 18 (4): 305–13. 1986. doi:10.1080/02791072.1986.10472362. PMID 2880944. 
  24. ↑ "(+)-N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine as a discriminative stimulus in studies of 3,4-methylenedioxy-methamphetamine-like behavioral activity". The Journal of Pharmacology and Experimental Therapeutics 255 (3): 1098–106. December 1990. doi:10.1016/S0022-3565(25)22947-0. PMID 1979813. 
  25. ↑ "Structural variation and (+)-amphetamine-like discriminative stimulus properties". Pharmacology, Biochemistry, and Behavior 38 (3): 581–6. March 1991. doi:10.1016/0091-3057(91)90017-V. PMID 2068194.  PMID
  26. ↑ "Behavioral effects of the highly selective serotonin releasing agent 5-methoxy-6-methyl-2-aminoindan". European Journal of Pharmacology 258 (1–2): 1–13. June 1994. doi:10.1016/0014-2999(94)90051-5. PMID 7925587. 
  27. ↑ "Chemistry and pharmacology of hallucinogens, entactogens and stimulants". Pharmacopsychiatry 31 (Suppl 2): 69–72. July 1998. doi:10.1055/s-2007-979349. PMID 9754836. 
  28. ↑ 28.0 28.1 "Nonneurotoxic tetralin and indan analogues of 3,4-(methylenedioxy)amphetamine (MDA)". Journal of Medicinal Chemistry 33 (2): 703–10. February 1990. doi:10.1021/jm00164a037. PMID 1967651. 
  29. ↑ "Potential psychotomimetics. 2. Rigid analogs of 2,5-dimethoxy-4-methylphenylisopropylamine (DOM, STP)". Journal of Medicinal Chemistry 17 (2): 161–6. February 1974. doi:10.1021/jm00248a004. PMID 4809251. 
  30. ↑ "关于印发《非药用类麻醉药品和精神药品列管办法》的通知" (in zh). China Food and Drug Administration. 27 September 2015. http://www.sfda.gov.cn/WS01/CL0056/130753.html. 
  31. ↑ "Lists of euphoriant substances subject to control in Denmark". The Danish Medicines Agency. September 2015. http://laegemiddelstyrelsen.dk/en/licensing/company-authorisations-and-registrations/euphoriant-substances/lists. 
  32. ↑ finlex.fi
  33. ↑ "812.121.11" (in de). Verordnung des EDI über die Verzeichnisse der Betäubungsmittel, psychotropen Stoffe, Vorläuferstoffe und Hilfschemikalien (Regulation of the EDI about the directories of drugs, psychotropic substances, precursors and auxiliary chemicals). Das Eidgenössische Departement des Innern (EDI). December 2011. https://www.admin.ch/opc/de/classified-compilation/20101220/201112010000/812.121.11.pdf. 
  34. ↑ "5-Iodo-2-aminoindan, a nonneurotoxic analogue of p-iodoamphetamine". Pharmacology, Biochemistry, and Behavior 38 (1): 135–9. January 1991. doi:10.1016/0091-3057(91)90601-w. PMID 1826785. 
  35. ↑ "Synthesis and pharmacological examination of 1-(3-methoxy-4-methylphenyl)-2-aminopropane and 5-methoxy-6-methyl-2-aminoindan: similarities to 3,4-(methylenedioxy)methamphetamine (MDMA)". Journal of Medicinal Chemistry 34 (5): 1662–8. May 1991. doi:10.1021/jm00109a020. PMID 1674539. 
  36. ↑ "Serotonin neurotoxicity in rats after combined treatment with a dopaminergic agent followed by a nonneurotoxic 3,4-methylenedioxymethamphetamine (MDMA) analogue". Pharmacology, Biochemistry, and Behavior 40 (4): 915–22. December 1991. doi:10.1016/0091-3057(91)90106-c. PMID 1726189. 
  37. ↑ "Novel serotonergic agents". Drug Design and Discovery 9 (3–4): 299–312. 1993. PMID 8400010. https://bitnest.netfirms.com/external/DrugDes.Disc/9.299. 
  38. ↑ "Studies on the mechanism of p-chloroamphetamine neurotoxicity". Biochemical Pharmacology 52 (8): 1271–7. October 1996. doi:10.1016/0006-2952(96)00482-0. PMID 8937435. 
  39. ↑ "Indan analogs of fenfluramine and norfenfluramine have reduced neurotoxic potential". Pharmacology, Biochemistry, and Behavior 59 (3): 709–15. March 1998. doi:10.1016/s0091-3057(97)00557-1. PMID 9512076. 



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