Trimethoxyamphetamines

Trimethoxyamphetamines (TMAs) are a family of positionally isomeric psychedelic hallucinogenic drugs.^[1][2] There exist six different TMAs that differ only in the positions of the three methoxy groups: TMA (TMA-1), TMA-2, TMA-3, TMA-4, TMA-5, and TMA-6.^[1][2] The TMAs are substituted amphetamines and are analogues of the phenethylamine cactus alkaloid mescaline and the DOx drugs.^[1][2]

The mechanism of action of the TMAs is different from that of the unsubstituted compound amphetamine, probably involving agonist activity on serotonin receptors such as the 5-HT_2A receptors instead of the monoamine releasing agent actions typical of most amphetamines. This action on serotonergic receptors likely underlies the psychedelic effects of these compounds.

TMA was first synthesized by Hey, in 1947.^[3] Synthesis data as well as human activity data has been published by Alexander Shulgin in his book PiHKAL.^[1][2]

The most important TMA compound from a pharmacological standpoint is TMA-2, as this isomer has been much more widely used as a recreational drug and sold on the grey market as a so-called research chemical; TMA (sometimes referred to as "mescalamphetamine" or TMA-1) and TMA-6 have also been used in this way to a lesser extent. These three isomers are significantly more active as hallucinogenic drugs, and have consequently been placed onto the illegal drug schedules in some countries such as the Netherlands and Japan. The other three isomers TMA-3, TMA-4, and TMA-5 are not known to have been used as recreational drugs to any great extent. According to Shulgin, at the doses tested, TMA-3 was completely inactive, whereas TMA-4 and TMA-5 were said to produce effects comparable to lysergic acid diethylamide (LSD).^[1]

2,4,6-TMA (TMA-6) is a potent monoamine oxidase A (MAO-A) inhibitor, with an IC₅₀Tooltip half-maximal inhibitory concentration of 400 nM.^[4] Conversely, 2,4,5-TMA (TMA-2) and 3,4,5-TMA (TMA-1) are inactive as MAO-A inhibitors (IC₅₀ = >100,000 nM).^[4] Other 6-substituted amphetamines also tend to be potent MAO-A inhibitors.^[4]

TMA Chemical name 1-(3,4,5-Trimethoxyphenyl)propan-2-amine, 3,4,5-trimethoxyamphetamine, α-methylmescaline Melting point 220 - 221 °C (hydrochloride) SMILES NC(C)CC1=CC(OC)=C(OC)C(OC)=C1 CAS number 1082-88-8 UNII_Ref =  Y UNII = P2K02L3YON

TMA-2 Chemical name 1-(2,4,5-Trimethoxyphenyl)propan-2-amine, 2,4,5-trimethoxyamphetamine Melting point 188.5 - 189.5 °C (hydrochloride) SMILES NC(C)CC1=C(OC)C=C(OC)C(OC)=C1 CAS number 1083-09-6 UNII_Ref =  Y UNII = 713Z3SL0TJ

TMA-3 Chemical name 1-(2,3,4-Trimethoxyphenyl)propan-2-amine, 2,3,4-trimethoxyamphetamine Melting point 148 - 149 °C (hydrochloride) SMILES NC(C)CC1=CC=C(OC)C(OC)=C1OC CAS number 1082-23-1 UNII_Ref =  Y UNII = 9T3SO4A6HM

TMA-4 Chemical name 1-(2,3,5-Trimethoxyphenyl)propan-2-amine, 2,3,5-trimethoxyamphetamine Melting point 118 - 119 °C (hydrochloride) SMILES NC(C)CC1=CC(OC)=CC(OC)=C1OC CAS number 23693-14-3 UNII_Ref =  Y UNII = LEL94CV318

TMA-5 Chemical name 1-(2,3,6-Trimethoxyphenyl)propan-2-amine, 2,3,6-trimethoxyamphetamine Melting point 124 - 125 °C (hydrochloride) SMILES NC(C)CC1=C(OC)C=CC(OC)=C1OC CAS number 20513-16-0 UNII_Ref =  Y UNII = E0NJ557A3E

TMA-6 Chemical name 1-(2,4,6-Trimethoxyphenyl)propan-2-amine, 2,4,6-trimethoxyamphetamine Melting point 207 - 208 °C (hydrochloride) SMILES NC(C)CC1=C(OC)C=C(OC)C=C1OC CAS number 15402-79-6 UNII_Ref =  Y UNII = 2X84DCO6GA

Note: Because they are isomers, the TMAs have the same chemical formula, C₁₂H₁₉NO₃, and the same molecular mass, 225.28 g/mol.

It is scheduled in the F2 class (prohibited psychotropics) of the Brazilian Controlled Drugs and Substances Act.^[5]

Sveriges riksdag added TMA-2 to schedule I ("substances, plant materials and fungi which normally do not have medical use") as narcotics in Sweden as of Dec 30, 1999, published by Medical Products Agency in their regulation LVFS 2004:3 listed as 2,4,5-trimetoxiamfetamin (TMA-2).^[6]

Illegal under the Psychoactive Substances Act 2016.

3,4,5-Trimethoxyamphetamine is listed as a Schedule 1 controlled substance, along with positional isomers 2,4,5-Trimethoxyamphetamine (TMA-2), 2,4,6-Trimethoxyamphetamine (TMA-6) and escaline. ^[7]

• Dimethoxyamphetamine
• Trimethoxyphenethylamine
• Methoxyamphetamine
• Dimethoxyphenethylamine
• α-Ethylmescaline

• PiHKAL entries:
  • TMA
  • TMA in PiHKAL • info
  • TMA-2
  • TMA-2 in PiHKAL • info
  • TMA-3
  • TMA-3 in PiHKAL • info
  • TMA-4
  • TMA-4 in PiHKAL • info
  • TMA-5
  • TMA-5 in PiHKAL • info
  • TMA-6
  • TMA-6 in PiHKAL • info
• Erowid TMA vault
• EMCDDA Report on the risk assessment of TMA-2 in the framework of the joint action on new synthetic drugs