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MDAI

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MDAI
Clinical data
Other names5,6-Methylenedioxy-2-aminoindane; 5,6-Methylenedioxy-2-aminoindan; Methylenedioxyaminoindane; Methylenedioxyaminoindan
Routes of
administration		Oral[1]
Drug classSerotonin–norepinephrine releasing agent;[2] Entactogen[1]
ATC code
  • None
Legal status
Legal status
Pharmacokinetic data
Duration of action2–6 hours[4][1]
Identifiers
  • 6,7-Dihydro-5H-cyclopenta[f] [1,3]benzodioxol-6-amine
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC10H11NO2
Molar mass177.203 g·mol−1
3D model (JSmol)
  • C1C(CC2=CC3=C(C=C21)OCO3)N
  • InChI=1S/C10H11NO2/c11-8-1-6-3-9-10(13-5-12-9)4-7(6)2-8/h3-4,8H,1-2,5,11H2 checkY
  • Key:FQDRMHHCWZAXJM-UHFFFAOYSA-N checkY

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.[4][5][6][1]

It acts as a selective serotonin and norepinephrine releasing agent (SNRA).[2] 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.[7][8][9]

MDAI was developed in the 1990s by a team led by David E. Nichols at Purdue University.[10] It has been encountered as a designer drug and has been used recreationally with reported street names such as "sparkle" and "mindy".[5][11][7][6] In addition to its recreational use, there has been interest in MDAI for potential use in medicine, for instance in drug-assisted psychotherapy.[4]

Uses

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Scientific research

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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.[12][13][14][15][16][17][18]

Recreational drug

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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. Internet-sourced products claimed to be MDAI have been shown variously to contain mephedrone or other substituted cathinone derivatives, and mixed compositions of inorganic substances, 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.[11] MDAI is only non-neurotoxic in isolation but may become neurotoxic when mixed with other drugs.[19] Three deaths were linked to MDAI use in the UK during 2011–2012, all involving symptoms consistent with serotonin syndrome. Two of these also involved other drugs while one death appeared to be from MDAI alone.[7]

Pharmacology

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Pharmacodynamics

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MDAI acts as a selective and well-balanced serotonin and norepinephrine releasing agent (SNRA) with much less (~10-fold lower) effect on dopamine release.[2] In addition to inducing the release of the monoamine neurotransmitters, MDAI also inhibits their reuptake.[10] For comparison to MDAI, MDA and MDMA are well-balanced releasing agents of serotonin, norepinephrine, and dopamine (SNDRAs).[2] 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.[20][2]

In contrast to MDMA, MDAI shows no affinity for any of the serotonin receptors (Ki = all >10 μM).[2] 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.[2][21] However, MDAI shows significant affinity for all three of the α2-adrenergic receptors (Ki = 322 to 1121 nM).[2]

Activities of MDAI and related drugs
Compound Monoamine release (EC50Tooltip half-maximal effective concentration, nM)
Serotonin Norepinephrine Dopamine
2-AI >10000 86 439
MDAI 114 117 1334
MMAI 31 3101 >10000
MEAI 134 861 2646
Dextroamphetamine 698–1765 6.6–7.2 5.8–24.8
Dextromethamphetamine 736–1291.7 12.3–13.8 8.5–24.5
MDA 160 108 190
MDMA 49.6–72 54.1–110 51.2–278
  (R)-MDMA (levo-MDMA) 340 560 3700
MDEA 47 2608 622
MBDB 540 3300 >100000
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: [2][22][23][24][25][26][27]

Effects

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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.[28][29][30][31][32][33][34]

A 2024 study compared the effects of MDAI and MDMA in humans.[1] It found that MDAI produced comparable and very similar subjective effects to those of MDMA.[1] This included pleasurable drug effects, drug liking, stimulation, happiness, openness, trust, and closeness.[1] 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.[1] Other effects included a blissful state, experience of unity, and changed meaning of percepts, also described as comparable to MDMA.[1] The effects of MDAI were slightly greater than those of 75 mg MDMA and slightly lower than those of 125 mg MDMA.[1] 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).[1] Aside from subject effects, MDAI also increased blood pressure, cortisol levels, and prolactin levels similarly to MDMA.[1] Conversely, it did not increase heart rate or body temperature.[1]

Neurotoxicity

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MDAI shows substantially lower serotonergic neurotoxicity than MDMA in animals and has been described as a "non-neurotoxic" analogue of MDMA.[7][8][9] However, MDAI still shows weak serotonergic neurotoxicity both alone and particularly in combination with amphetamine in animals.[7][8][9] As such, MDAI does not appear to be a fully non-neurotoxic alternative to MDMA.[7][8][9]

Toxicity

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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.[35]

Pharmacokinetics

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

Chemistry

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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.

Analogues

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Synthesis

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MDAI can be produced from 3-(3,4-methylenedioxyphenyl)propionic acid[12] 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,[36] using a Pd/C catalyst in glacial acetic acid with catalytic H2SO4.

Society and culture

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China

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As of October 2015 MDAI is a controlled substance in China.[37]

Denmark

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MDAI is illegal in Denmark as of September 2015.[38]

Finland

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Scheduled in the "government decree on psychoactive substances banned from the consumer market".[39]

Switzerland

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As of December 2011 MDAI is a controlled substance in Switzerland.[40]

References

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  1. ^ a b c d e f g h i j k l m n Angerer V, Schmid Y, Franz F, Gnann H, Speer JM, Gnann A, et al. (September 2024). "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. doi:10.1002/dta.3622. PMID 38056906.
  2. ^ a b c d e f g h i 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.
  3. ^ Anvisa (2023-07-24). "RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 804 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-07-25). Archived from the original on 2023-08-27. Retrieved 2023-08-27.
  4. ^ a b c d Oeri HE (May 2021). "Beyond ecstasy: Alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy". Journal of Psychopharmacology. 35 (5). SAGE Publications: 512–536. doi:10.1177/0269881120920420. PMC 8155739. PMID 32909493.
  5. ^ a b Pinterova N, Horsley RR, Palenicek T (17 November 2017). "Synthetic Aminoindanes: A Summary of Existing Knowledge". Frontiers in Psychiatry. 8. Frontiers Media SA: 236. doi:10.3389/fpsyt.2017.00236. PMC 5698283. PMID 29204127.
  6. ^ a b Sainsbury PD, Kicman AT, Archer RP, King LA, Braithwaite RA (2011). "Aminoindanes--the next wave of 'legal highs'?". Drug Testing and Analysis. 3 (7–8). Wiley: 479–482. doi:10.1002/dta.318. PMID 21748859.
  7. ^ a b c d e f Corkery JM, Elliott S, Schifano F, Corazza O, Ghodse AH (July 2013). "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. doi:10.1002/hup.2298. PMID 23881883. S2CID 12322724.
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  9. ^ a b c d Johnson MP, Huang XM, Nichols DE (December 1991). "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. doi:10.1016/0091-3057(91)90106-c. PMID 1726189.
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  12. ^ a b Nichols DE, Brewster WK, Johnson MP, Oberlender R, Riggs RM (February 1990). "Nonneurotoxic tetralin and indan analogues of 3,4-(methylenedioxy)amphetamine (MDA)". Journal of Medicinal Chemistry. 33 (2): 703–10. doi:10.1021/jm00164a037. PMID 1967651.
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  16. ^ Nichols DE, Marona-Lewicka D, Huang X, Johnson MP (1993). "Novel serotonergic agents". Drug Design and Discovery. 9 (3–4): 299–312. PMID 8400010.
  17. ^ Sprague JE, Johnson MP, Schmidt CJ, Nichols DE (October 1996). "Studies on the mechanism of p-chloroamphetamine neurotoxicity". Biochemical Pharmacology. 52 (8): 1271–7. doi:10.1016/0006-2952(96)00482-0. PMID 8937435.
  18. ^ Cozzi NV, Frescas S, Marona-Lewicka D, Huang X, Nichols DE (March 1998). "Indan analogs of fenfluramine and norfenfluramine have reduced neurotoxic potential". Pharmacology, Biochemistry, and Behavior. 59 (3): 709–15. doi:10.1016/s0091-3057(97)00557-1. PMID 9512076. S2CID 41048219.
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  22. ^ 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.
  23. ^ 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.
  24. ^ 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.
  25. ^ 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.
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  28. ^ Steele TD, Nichols DE, Yim GK (July 1987). "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. doi:10.1016/0006-2952(87)90594-6. PMID 2886126.
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  31. ^ Oberlender R, Nichols DE (December 1990). "(+)-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. PMID 1979813.
  32. ^ Oberlender R, Nichols DE (March 1991). "Structural variation and (+)-amphetamine-like discriminative stimulus properties". Pharmacology, Biochemistry, and Behavior. 38 (3): 581–6. doi:10.1016/0091-3057(91)90017-V. PMID 2068194. S2CID 19069907. PMID
  33. ^ Marona-Lewicka D, Nichols DE (June 1994). "Behavioral effects of the highly selective serotonin releasing agent 5-methoxy-6-methyl-2-aminoindan". European Journal of Pharmacology. 258 (1–2): 1–13. CiteSeerX 10.1.1.688.1895. doi:10.1016/0014-2999(94)90051-5. PMID 7925587.
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  35. ^ Páleníček T, Lhotková E, Žídková M, Balíková M, Kuchař M, Himl M, et al. (August 2016). "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. doi:10.1016/j.pnpbp.2016.04.004. PMID 27083855. S2CID 33032545.
  36. ^ Nichols DE, Barfknecht CF, Long JP, Standridge RT, Howell HG, Partyka RA, et al. (February 1974). "Potential psychotomimetics. 2. Rigid analogs of 2,5-dimethoxy-4-methylphenylisopropylamine (DOM, STP)". Journal of Medicinal Chemistry. 17 (2): 161–6. doi:10.1021/jm00248a004. PMID 4809251.
  37. ^ "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 Chinese). China Food and Drug Administration. 27 September 2015. Retrieved 1 October 2015.
  38. ^ "Lists of euphoriant substances subject to control in Denmark". The Danish Medicines Agency. September 2015.
  39. ^ https://finlex.fi/fi/laki/ajantasa/2014/20141130
  40. ^ "812.121.11" (PDF). 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) (in German). Das Eidgenössische Departement des Innern (EDI). December 2011.
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