# 3,4,5-Trimethoxyamphetamine

Trimethoxyamphetamine (TMA or TMA-1), also known as 3,4,5-trimethoxyamphetamine (3,4,5-TMA), α-methylmescaline, or mescalamphetamine, is a psychedelic drug of the phenethylamine and amphetamine families. It is one of the trimethoxyamphetamine (TMA) series of positional isomers. The drug is notable in being the amphetamine (i.e., α-methylated) analogue of mescaline (3,4,5-trimethoxyphenethylamine).

## Use and effects

TMA is a serotonergic psychedelic and produces hallucinogenic effects. It is said to be active at doses of 100 to 250 mg and to have a duration of 6 to 8 hours. For comparison, mescaline is typically used at doses of 200 to 500 mg and is said to have a duration of 10 to 12 hours or longer. TMA's positional isomer 2,4,5-trimethoxyamphetamine (2,4,5-TMA or TMA-2) is much more potent than TMA, with a dosage of 20 to 40 mg and a duration of 8 to 12 hours.

## Pharmacology

TMA activities :
| Target | Affinity (K$_i$, nM) |
| 5-HT$_{1A}$ | 1,678–>5,600 |
| 5-HT$_{1B}$ | 2,855 |
| 5-HT$_{1D}$ | 3,035 |
| 5-HT$_{1E}$ | 3,369 |
| 5-HT$_{1F}$ | ND |
| 5-HT$_{2A}$ | >10,000 (K$_i$) 41.3–1,700 (EC$_{50}$Tooltip half-maximal effective concentration) 40–96% (E$_{max}$Tooltip maximal efficacy) |
| 5-HT$_{2B}$ | 477 (K$_i$) >10,000 (EC$_{50}$) |
| 5-HT$_{2C}$ | 4,600–>10,000 (K$_i$) 47.4 (EC$_{50}$) 92% (E$_{max}$) |
| 5-HT$_3$ | >10,000 |
| 5-HT$_4$ | ND |
| 5-HT$_{5A}$ | >10,000 |
| 5-HT$_6$ | >10,000 |
| 5-HT$_7$ | 749 |
| α$_{1A}$, α$_{1B}$ | >10,000 |
| α$_{1D}$ | ND |
| α$_{2A}$ | 2,071–4,030 |
| α$_{2B}$ | >10,000 |
| α$_{2C}$ | 5,014 |
| β$_1$, β$_2$ | >10,000 |
| D$_1$–D$_5$ | >10,000 |
| H$_1$–H$_4$ | >10,000 |
| M$_1$, M$_3$, M$_4$ | ND |
| M$_2$, M$_5$ | >10,000 |
| nACh | 260–>10,000 |
| TAAR$_1$ | 1,800 (K$_i$) (mouse) 3,200 (K$_i$) (rat) >10,000 (EC$_{50}$) (human) |
| I$_1$ | >10,000 |
| σ$_1$ | 537 |
| σ$_2$ | 537 |
| SERTTooltip Serotonin transporter | >10,000 (K$_i$) >100,000 (IC$_{50}$Tooltip half-maximal inhibitory concentration) 16,000 (EC$_{50}$) (rat) |
| NETTooltip Norepinephrine transporter | >10,000 (K$_i$) >100,000 (IC$_{50}$) >100,000 (EC$_{50}$) (rat) |
| DATTooltip Dopamine transporter | >10,000 (K$_i$) >100,000 (IC$_{50}$) >100,000 (EC$_{50}$) (rat) |
| MAO-ATooltip Monoamine oxidase A | >200,000 (IC$_{50}$) |
| MAO-BTooltip Monoamine oxidase B | >200,000 (IC$_{50}$) |
| Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. Refs: ||
TMA is a low-potency serotonin 5-HT$_{2A}$ receptor partial agonist, with an affinity (K$_i$) of >12,000 nM, an EC$_{50}$Tooltip half-maximal effective concentration of 1,700 nM, and an E$_{max}$Tooltip maximal efficacy of 40%. Conversely, it was inactive at the serotonin 5-HT$_{1A}$, 5-HT$_{2B}$ and 5-HT$_{2C}$ receptors and at several other receptors, at least at the assessed concentrations (up to 10,000 nM). It showed affinity for the mouse and rat trace amine-associated receptor 1 (TAAR1) (K$_i$ = 1,800 nM and 3,200 nM, respectively), whereas it was inactive at the human TAAR1 (EC$_{50}$ > 10,000 nM).
TMA is also a very low-potency serotonin releasing agent (SRA), with an EC$_{50}$ value of 16,000 nM. In contrast, it is inactive as a releasing agent and reuptake inhibitor of dopamine and norepinephrine (EC$_{50}$ > 100,000 nM). Despite its apparent SRA activity in vitro, TMA did not increase brain serotonin or dopamine levels in rodents in vivo. TMA is similarly inactive as a monoamine oxidase inhibitor (MAOI), including of both monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) (IC$_{50}$Tooltip half-maximal inhibitory concentration > 200,000 nM).
The low potency of TMA as a serotonin 5-HT$_{2A}$ receptor agonist is analogous to the case of mescaline, which is a well-known and widely used psychedelic but is likewise a very low-potency agonist of this receptor, showing an affinity (K$_i$) of 9,400 nM, an EC$_{50}$ of 10,000 nM, and an E$_{max}$ of 56% in the same study. For comparison, DOM has shown an affinity (K$_i$) of 88 nM and an EC$_{50}$ of 4 to 24 nM.

## Legal status

TMA is a Schedule I controlled substance in the United States.