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MDAI

Clinical data
Other names	5,6-Methylenedioxy-2-aminoindane; 5,6-Methylenedioxy-2-aminoindan; Methylenedioxyaminoindane; Methylenedioxyaminoindan
Routes of administration	Oral
Drug class	Serotonin–norepinephrine releasing agent; Entactogen
ATC code	None
Legal status
Legal status	BR: Class F2 (Prohibited psychotropics) DE: NpSG (Industrial and scientific use only) UK: Under Psychoactive Substances Act Illegal in China
Pharmacokinetic data
Duration of action	2–6 hours
Identifiers
IUPAC name 6,7-Dihydro-5H-cyclopenta benzodioxol-6-amine
CAS Number	132741-81-2
PubChem CID	125558
ChemSpider	111694
UNII	0DMJ6G3XBF
ChEBI	CHEBI:189818
ChEMBL	ChEMBL162375
CompTox Dashboard (EPA)	DTXSID60157741
Chemical and physical data
Formula	C10H11NO2
Molar mass	177.203 g·mol
3D model (JSmol)	Interactive image
SMILES C1C(CC2=CC3=C(C=C21)OCO3)N
InChI 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 Key:FQDRMHHCWZAXJM-UHFFFAOYSA-N

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.

It acts as a selective serotonin and norepinephrine releasing agent (SNRA). 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.

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

Uses

Scientific 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.

Recreational drug

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. MDAI is only non-neurotoxic in isolation but may become neurotoxic when mixed with other drugs. 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.

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. In addition to inducing the release of the monoamine neurotransmitters, MDAI also inhibits their reuptake. For comparison to MDAI, MDA and MDMA are well-balanced releasing agents of serotonin, norepinephrine, and dopamine (SNDRAs). 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.

In contrast to MDMA, MDAI shows no affinity for any of the serotonin receptors (K_i = all >10 μM). This notably includes the serotonin 5-HT_2A receptor, which is implicated in producing psychedelic effects, and the serotonin 5-HT_2B receptor, which is implicated in causing cardiac valvulopathy. However, MDAI shows significant affinity for all three of the α₂-adrenergic receptors (K_i = 322 to 1121 nM).

Effects

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.

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

Neurotoxicity

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

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.

Pharmacokinetics

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

Chemistry

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

• 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 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, using a Pd/C catalyst in glacial acetic acid with catalytic H₂SO₄.

Society and culture

Legal Status

China

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

Denmark

MDAI is illegal in Denmark as of September 2015.

Finland

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

Switzerland

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

References

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• Drugs not assigned an ATC code
• Benzodioxoles
• Designer drugs
• Entactogens and empathogens
• Euphoriants
• Monoaminergic neurotoxins
• Serotonin-norepinephrine releasing agents