3,4,5-Trimethoxyamphetamine

3,4,5-Trimethoxyamphetamine (TMA, TMA-1, or 3,4,5-TMA), also known as α-methylmescaline or mescalamphetamine, is a psychedelic drug of the phenethylamine and amphetamine families.^[1][2] It is one of the trimethoxyamphetamine (TMA) series of positional isomers.^[1][2] The drug is notable in being the amphetamine (i.e., α-methylated) analogue of mescaline (3,4,5-trimethoxyphenethylamine).^[1][2]

3,4,5-Trimethoxyamphetamine

Clinical data
Other names	Trimethoxyamphetamine; TMA; TMA-1; 3,4,5-TMA; α-Methylmescaline; alpha-Methylmescaline; AMM; Mescalamphetamine; 3,4,5-Trimethoxy-α-methylphenethylamine; EA‐1319; EA1319
Routes of administration	Oral[1][2]
Drug class	Serotonergic psychedelic; Hallucinogen; Serotonin 5-HT2A receptor agonist
Legal status
Legal status	US: Schedule I[2][3]
Pharmacokinetic data
Duration of action	6–8 hours[1][2]
Identifiers
IUPAC name 1-(3,4,5-trimethoxyphenyl)propan-2-amine
CAS Number	1082-88-8
PubChem CID	31016
DrugBank	DB01516
ChemSpider	28775
UNII	P2K02L3YON
KEGG	C22747
ChEMBL	ChEMBL30336
CompTox Dashboard (EPA)	DTXSID00862529
Chemical and physical data
Formula	C12H19NO3
Molar mass	225.288 g·mol−1
3D model (JSmol)	Interactive image
SMILES CC(CC1=CC(=C(C(=C1)OC)OC)OC)N
InChI InChI=1S/C12H19NO3/c1-8(13)5-9-6-10(14-2)12(16-4)11(7-9)15-3/h6-8H,5,13H2,1-4H3 Key:WGTASENVNYJZBK-UHFFFAOYSA-N

Use and effects

TMA is a serotonergic psychedelic and produces hallucinogenic effects.^[1][2] It is said to be active at doses of 100 to 250 mg and to have a duration of 6 to 8 hours.^[1][4][5] 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.^[6] 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.^[7]

Interactions

See also: Psychedelic drug § Interactions, and Trip killer § Serotonergic psychedelic antidotes

Pharmacology

TMA activities

Target	Affinity (Ki, nM)
5-HT1A	1,678–>5,600
5-HT1B	2,855
5-HT1D	3,035
5-HT1E	3,369
5-HT1F	ND
5-HT2A	>10,000 (Ki) 41.3–1,700 (EC50Tooltip half-maximal effective concentration) 40–96% (EmaxTooltip maximal efficacy)
5-HT2B	477 (Ki) >10,000 (EC50)
5-HT2C	4,600–>10,000 (Ki) 47.4 (EC50) 92% (Emax)
5-HT3	>10,000
5-HT4	ND
5-HT5A	>10,000
5-HT6	>10,000
5-HT7	749
α1A, α1B	>10,000
α1D	ND
α2A	2,071–4,030
α2B	>10,000
α2C	5,014
β1, β2	>10,000
D1–D5	>10,000
H1–H4	>10,000
M1, M3, M4	ND
M2, M5	>10,000
nACh	260–>10,000
TAAR1	1,800 (Ki) (mouse) 3,200 (Ki) (rat) >10,000 (EC50) (human)
I1	>10,000
σ1	537
σ2	537
SERTTooltip Serotonin transporter	>10,000 (Ki) >100,000 (IC50Tooltip half-maximal inhibitory concentration) 16,000 (EC50) (rat)
NETTooltip Norepinephrine transporter	>10,000 (Ki) >100,000 (IC50) >100,000 (EC50) (rat)
DATTooltip Dopamine transporter	>10,000 (Ki) >100,000 (IC50) >100,000 (EC50) (rat)
MAO-ATooltip Monoamine oxidase A	>200,000 (IC50)
MAO-BTooltip Monoamine oxidase B	>200,000 (IC50)
Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. Refs: [8][9][10][11][12][13][14][15]

TMA is a low-potency serotonin 5-HT_2A receptor partial agonist, with an affinity (K_i) of >12,000 nM, an EC₅₀Tooltip half-maximal effective concentration of 1,700 nM, and an E_maxTooltip maximal efficacy of 40%.^[11] 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).^[11] 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 (EC₅₀ > 10,000 nM).^[11]

TMA is also a very low-potency serotonin releasing agent (SRA), with an EC₅₀ value of 16,000 nM.^[12] In contrast, it is inactive as a releasing agent and reuptake inhibitor of dopamine and norepinephrine (EC₅₀ > 100,000 nM).^[12] Despite its apparent SRA activity in vitro, TMA did not increase brain serotonin or dopamine levels in rodents in vivo.^[15] TMA is similarly inactive as a monoamine oxidase inhibitor (MAOI), including of both monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) (IC₅₀Tooltip half-maximal inhibitory concentration > 200,000 nM).^[14][15]

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 EC₅₀ of 10,000 nM, and an E_max of 56% in the same study.^[11] For comparison, DOM has shown an affinity (K_i) of 88 nM and an EC₅₀ of 4 to 24 nM.^[16]

History

TMA was first synthesized by Gordon Alles around 1937.^[17][18] He assessed it in both animal studies and self-experiments and documented its effects, but these were not reported until 1959.^[17][18] The drug was first described in the scientific literature in 1947 and its psychedelic effects were first described in 1955.^{[19][20][21][22]} TMA was studied at Edgewood Arsenal under the code name EA‐1319 in 1953 and 1954.^[17] The drug was further characterized by Alexander Shulgin and described in his book PiHKAL.^[1][2]

Society and culture

Legal status

TMA is a Schedule I controlled substance in the United States.^[2][3]

See also

• Substituted methoxyphenethylamine
• 3C (psychedelics) (4-substituted 3,5-dimethoxyamphetamines)
• α-Ethylmescaline (3,4,5-trimethoxy-α-ethylphenethylamine)
• 3,4-Dimethoxyamphetamine (3,4-DMA)
• 4-PhPr-3,5-DMA