Trimethoxyamphetamines

{{Short description|Chemical compound}}

Trimethoxyamphetamines (TMAs) are a family of positionally isomeric psychedelic hallucinogenic drugs.{{Cite book | vauthors = Shulgin AT, Shulgin A | title = PiHKAL: A Chemical Love Story | date = 1991 | publisher = Transform Press | isbn = 9780963009609 | edition = 1st | location = Berkeley, CA | oclc = 25627628 }}{{cite book | vauthors = Shulgin A, Manning T, Daley PF | title=The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds | publisher=Transform Press | location=Berkeley | volume=1 | year=2011 | isbn=978-0-9630096-3-0 }} 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. The TMAs are substituted amphetamines and are analogues of the phenethylamine cactus alkaloid mescaline and the DOx drugs.

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.{{cite journal |last1=Hey |first1=P |title=The synthesis of a new homologue of mescaline |journal=Quart. J. Pharm. Pharmacol. |date=1947 |volume=20 |issue=2 |pages=129–134 |pmid=20260568 }} Synthesis data as well as human activity data has been published by Alexander Shulgin in his book PiHKAL.

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).

2,4,6-TMA (TMA-6) is a potent monoamine oxidase A (MAO-A) inhibitor, with an {{Abbrlink|IC₅₀|half-maximal inhibitory concentration}} of 400{{nbsp}}nM.{{cite journal | vauthors = Reyes-Parada M, Iturriaga-Vasquez P, Cassels BK | title = Amphetamine Derivatives as Monoamine Oxidase Inhibitors | journal = Front Pharmacol | volume = 10 | issue = | pages = 1590 | date = 2019 | pmid = 32038257 | pmc = 6989591 | doi = 10.3389/fphar.2019.01590 | doi-access = free | url = }} Conversely, 2,4,5-TMA (TMA-2) and 3,4,5-TMA (TMA-1) are inactive as MAO-A inhibitors ({{Abbr|IC₅₀|half-maximal inhibitory concentration}} = >100,000{{nbsp}}nM). Other 6-substituted amphetamines also tend to be potent MAO-A inhibitors.

List of TMAs

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class="wikitable" style="margin: 0 0 1em 1em; float: right;"

! colspan="2" | TMA

| 1-(3,4,5-Trimethoxyphenyl)propan-2-amine,
3,4,5-trimethoxyamphetamine,
α-methylmescaline

| 220 - 221 °C (hydrochloride)

| {{small|1=NC(C)CC1=CC(OC)=C(OC)C(OC)=C1}}

CAS number
1082-88-8

File:Trimethoxyamphetamine.svg

UNII_Ref = {{fdacite|correct|FDA}}

| UNII = P2K02L3YON

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class="wikitable" style="margin: 0 0 1em 1em; float: right;"

! colspan="2" | TMA-2

| 1-(2,4,5-Trimethoxyphenyl)propan-2-amine,
2,4,5-trimethoxyamphetamine

| 188.5 - 189.5 °C (hydrochloride)

| {{small|1=NC(C)CC1=C(OC)C=C(OC)C(OC)=C1}}

CAS number
1083-09-6

File:Trimethoxyamphetamine-2.svg

UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 713Z3SL0TJ

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class="wikitable" style="margin: 0 0 1em 1em; float: right;"

! colspan="2" | TMA-3

| 1-(2,3,4-Trimethoxyphenyl)propan-2-amine,
2,3,4-trimethoxyamphetamine

| 148 - 149 °C (hydrochloride)

| {{small|1=NC(C)CC1=CC=C(OC)C(OC)=C1OC}}

CAS number
1082-23-1

File:Trimethoxyamphetamine-3.svg

UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 9T3SO4A6HM

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class="wikitable" style="margin: 0 0 1em 1em; float: right;"

! colspan="2" | TMA-4

| 1-(2,3,5-Trimethoxyphenyl)propan-2-amine,
2,3,5-trimethoxyamphetamine

| 118 - 119 °C (hydrochloride)

| {{small|1=NC(C)CC1=CC(OC)=CC(OC)=C1OC}}

CAS number
23693-14-3

File:Trimethoxyamphetamine-4.svg

UNII_Ref = {{fdacite|correct|FDA}}

| UNII = LEL94CV318

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class="wikitable" style="margin: 0 0 1em 1em; float: right;"

! colspan="2" | TMA-5

| 1-(2,3,6-Trimethoxyphenyl)propan-2-amine,
2,3,6-trimethoxyamphetamine

| 124 - 125 °C (hydrochloride)

| {{small|1=NC(C)CC1=C(OC)C=CC(OC)=C1OC}}

CAS number
20513-16-0

File:Trimethoxyamphetamine-5.svg

UNII_Ref = {{fdacite|correct|FDA}}

| UNII = E0NJ557A3E

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! colspan="2" | TMA-6

| 1-(2,4,6-Trimethoxyphenyl)propan-2-amine,
2,4,6-trimethoxyamphetamine

| 207 - 208 °C (hydrochloride)

| {{small|1=NC(C)CC1=C(OC)C=C(OC)C=C1OC}}

CAS number
15402-79-6

File:Trimethoxyamphetamine-6.svg

UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 2X84DCO6GA

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

Properties<ref name="PiHKAL" />

Compound \|\| Pattern \|\| Dose \|\| Duration \|\| Effects
class="wikitable"
align="center" \| bgcolor="#eeeeee" \| TMA	3,4,5	100 – 250 mg	6 - 8 h	Psychedelic
align="center" \| bgcolor="#eeeeee" \| TMA-2	2,4,5	20 – 40 mg	8 - 12 h	Psychedelic
align="center" \| bgcolor="#eeeeee" \| TMA-3	2,3,4	> 100 mg	unknown	None
align="center" \| bgcolor="#eeeeee" \| TMA-4	2,3,5	≥ 80 mg	~ 6 h	Psychedelic
align="center" \| bgcolor="#eeeeee" \| TMA-5	2,3,6	≥ 30 mg	8 - 10 h	Stimulant, psychedelic
align="center" \| bgcolor="#eeeeee" \| TMA-6	2,4,6	25 – 50 mg	12 - 16 h	Psychedelic

Legality

=Brazil=

It is scheduled in the F2 class (prohibited psychotropics) of the Brazilian Controlled Drugs and Substances Act.{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-07-24 |title=RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 804 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-804-de-24-de-julho-de-2023-498447451 |url-status=live |archive-url=https://web.archive.org/web/20230827163149/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-804-de-24-de-julho-de-2023-498447451 |archive-date=2023-08-27 |access-date=2023-08-27 |publisher=Diário Oficial da União |language=pt-BR |publication-date=2023-07-25}}

=Sweden=

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).{{Cite web | url=http://www.lakemedelsverket.se/upload/lvfs/LVFS_2004-3.pdf | title=Läkemedelsverkets föreskrifter - LVFS och HSLF-FS | language=sv | trans-title=The Swedish Medicines Agency's regulations - LVFS and HSLF-FS}}

=United Kingdom=

Illegal under the Psychoactive Substances Act 2016.

=United States of America=

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. {{Cite web | url=https://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf | title=Lists of: Scheduling Actions Controlled Substances Regulated Chemicals | access-date=2024-07-17 | date=April 2024}}

See also

References

{{Reflist}}

External links

PiHKAL entries:
[http://www.erowid.org/library/books_online/pihkal/pihkal157.shtml TMA]
[http://pihkal.info/read.php?domain=pk&id=157 TMA in PiHKAL • info]
[http://www.erowid.org/library/books_online/pihkal/pihkal158.shtml TMA-2]
[http://pihkal.info/read.php?domain=pk&id=158 TMA-2 in PiHKAL • info]
[http://www.erowid.org/library/books_online/pihkal/pihkal159.shtml TMA-3]
[http://pihkal.info/read.php?domain=pk&id=159 TMA-3 in PiHKAL • info]
[http://www.erowid.org/library/books_online/pihkal/pihkal160.shtml TMA-4]
[http://pihkal.info/read.php?domain=pk&id=160 TMA-4 in PiHKAL • info]
[http://www.erowid.org/library/books_online/pihkal/pihkal161.shtml TMA-5]
[http://pihkal.info/read.php?domain=pk&id=161 TMA-5 in PiHKAL • info]
[http://www.erowid.org/library/books_online/pihkal/pihkal162.shtml TMA-6]
[http://pihkal.info/read.php?domain=pk&id=162 TMA-6 in PiHKAL • info]
[http://www.erowid.org/chemicals/tma2/tma2.shtml Erowid TMA vault]
[http://www.emcdda.europa.eu/index.cfm?fuseaction=public.Content&nNodeID=431 EMCDDA Report on the risk assessment of TMA-2 in the framework of the joint action on new synthetic drugs]

{{Psychedelics}}

{{Serotonin receptor modulators}}

{{Sigma receptor modulators}}

{{Phenethylamines}}

{{Chemical classes of psychoactive drugs}}

Category:Designer drugs

Category:Methoxyphenethylamines

Category:Phenol ethers

Category:Psychedelic phenethylamines

Category:Substituted amphetamines