View source for Trimethoxyamphetamines

{{Short description|Chemical compound}}

'''Trimethoxyamphetamines''' ('''TMAs''') are a family of [[positional isomer|positionally isomer]]ic [[psychedelic drug|psychedelic]] [[hallucinogenic drug|hallucinogenic]] [[psychoactive drug|drugs]].<ref name="PiHKAL">{{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 }}</ref><ref name="ShulginManningDaley2011">{{cite book | vauthors = Shulgin A, Manning T, Daley PF | title=[[The Shulgin Index|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 }}</ref> There exist six different TMAs that differ only in the positions of the three [[methoxy]] [[Functional group|groups]]: [[3,4,5-trimethoxyamphetamine|TMA]] (TMA-1), [[2,4,5-trimethoxyamphetamine|TMA-2]], TMA-3, TMA-4, TMA-5, and TMA-6.<ref name="PiHKAL" /><ref name="ShulginManningDaley2011" /> The TMAs are [[substituted amphetamine]]s and are [[structural analog|analogue]]s of the [[phenethylamine]] [[cactus]] [[alkaloid]] [[mescaline]] and the [[DOx]] drugs.<ref name="PiHKAL" /><ref name="ShulginManningDaley2011" />

The [[mechanism of action]] of the TMAs is different from that of the unsubstituted compound [[amphetamine]], probably involving [[agonist]] activity on [[serotonin receptor]]s such as the [[5-HT2A receptor|5-HT<sub>2A</sub> receptor]]s 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 [[chemical synthesis|synthesized]] by Hey, in 1947.<ref>{{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 }}</ref> Synthesis data as well as [[human]] activity data has been published by [[Alexander Shulgin]] in his book ''[[PiHKAL]]''.<ref name="PiHKAL" /><ref name="ShulginManningDaley2011" />

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).<ref name="PiHKAL" />

2,4,6-TMA (TMA-6) is a [[potency (pharmacology)|potent]] [[monoamine oxidase A]] (MAO-A) [[monoamine oxidase inhibitor|inhibitor]], with an {{Abbrlink|IC<sub>50</sub>|half-maximal inhibitory concentration}} of 400{{nbsp}}nM.<ref name="Reyes-ParadaIturriaga-VasquezCassels2019">{{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 = }}</ref> Conversely, 2,4,5-TMA (TMA-2) and 3,4,5-TMA (TMA-1) are inactive as MAO-A inhibitors ({{Abbr|IC<sub>50</sub>|half-maximal inhibitory concentration}} = >100,000{{nbsp}}nM).<ref name="Reyes-ParadaIturriaga-VasquezCassels2019" /> Other 6-substituted amphetamines also tend to be potent MAO-A inhibitors.<ref name="Reyes-ParadaIturriaga-VasquezCassels2019" />

== List of TMAs ==
{{col-begin|width=auto}}
{{col-break}}
{| class="wikitable" style="margin: 0 0 1em 1em; float: right;"
! colspan="2" | [[3,4,5-Trimethoxyamphetamine|TMA]]
|-
| [[IUPAC nomenclature|Chemical name]]
| 1-(3,4,5-Trimethoxyphenyl)propan-2-amine,<br />3,4,5-trimethoxyamphetamine,<br />α-methylmescaline
|-
| [[Melting point]]
| 220 - 221&nbsp;°C (hydrochloride)
|-
| [[Simplified molecular input line entry specification|SMILES]]
| {{small|1=NC(C)CC1=CC(OC)=C(OC)C(OC)=C1}}
|-
| [[CAS registry number|CAS number]]<br />1082-88-8 || [[File:Trimethoxyamphetamine.svg|152px|center|Chemical structure of TMA]]
|-
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = P2K02L3YON
|}
{{col-break}}
{| class="wikitable" style="margin: 0 0 1em 1em; float: right;"
! colspan="2" | [[2,4,5-Trimethoxyamphetamine|TMA-2]]
|-
| [[IUPAC nomenclature|Chemical name]]
| 1-(2,4,5-Trimethoxyphenyl)propan-2-amine,<br />2,4,5-trimethoxyamphetamine
|-
| [[Melting point]]
| 188.5 - 189.5&nbsp;°C (hydrochloride)
|-
| [[Simplified molecular input line entry specification|SMILES]]
| {{small|1=NC(C)CC1=C(OC)C=C(OC)C(OC)=C1}}
|-
| [[CAS registry number|CAS number]]<br />1083-09-6 || [[File:Trimethoxyamphetamine-2.svg|152px|center|Chemical structure of TMA-2]]
|-
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 713Z3SL0TJ
|}
{{col-break}}
{| class="wikitable" style="margin: 0 0 1em 1em; float: right;"
! colspan="2" | TMA-3
|-
| [[IUPAC nomenclature|Chemical name]]
| 1-(2,3,4-Trimethoxyphenyl)propan-2-amine,<br />2,3,4-trimethoxyamphetamine
|-
| [[Melting point]]
| 148 - 149&nbsp;°C (hydrochloride)
|-
| [[Simplified molecular input line entry specification|SMILES]]
| {{small|1=NC(C)CC1=CC=C(OC)C(OC)=C1OC}}
|-
| [[CAS registry number|CAS number]]<br />1082-23-1 || [[File:Trimethoxyamphetamine-3.svg|154px|center|Chemical structure of TMA-3]]
|-
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 9T3SO4A6HM
|}
{{col-end}}
{{col-begin|width=auto}}
{{col-break}}
{| class="wikitable" style="margin: 0 0 1em 1em; float: right;"
! colspan="2" | TMA-4
|-
| [[IUPAC nomenclature|Chemical name]]
| 1-(2,3,5-Trimethoxyphenyl)propan-2-amine,<br />2,3,5-trimethoxyamphetamine
|-
| [[Melting point]]
| 118 - 119&nbsp;°C (hydrochloride)
|-
| [[Simplified molecular input line entry specification|SMILES]]
| {{small|1=NC(C)CC1=CC(OC)=CC(OC)=C1OC}}
|-
| [[CAS registry number|CAS number]]<br />23693-14-3 || [[File:Trimethoxyamphetamine-4.svg|153px|center|Chemical structure of TMA-4]]
|-
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = LEL94CV318
|}
{{col-break}}
{| class="wikitable" style="margin: 0 0 1em 1em; float: right;"
! colspan="2" | TMA-5
|-
| [[IUPAC nomenclature|Chemical name]]
| 1-(2,3,6-Trimethoxyphenyl)propan-2-amine,<br />2,3,6-trimethoxyamphetamine
|-
| [[Melting point]]
| 124 - 125&nbsp;°C (hydrochloride)
|-
| [[Simplified molecular input line entry specification|SMILES]]
| {{small|1=NC(C)CC1=C(OC)C=CC(OC)=C1OC}}
|-
| [[CAS registry number|CAS number]]<br />20513-16-0 || [[File:Trimethoxyamphetamine-5.svg|118px|center|Chemical structure of TMA-5]]
|-
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = E0NJ557A3E
|}
{{col-break}}
{| class="wikitable" style="margin: 0 0 1em 1em; float: right;"
! colspan="2" | TMA-6
|-
| [[IUPAC nomenclature|Chemical name]]
| 1-(2,4,6-Trimethoxyphenyl)propan-2-amine,<br />2,4,6-trimethoxyamphetamine
|-
| [[Melting point]]
| 207 - 208&nbsp;°C (hydrochloride)
|-
| [[Simplified molecular input line entry specification|SMILES]]
| {{small|1=NC(C)CC1=C(OC)C=C(OC)C=C1OC}}
|-
| [[CAS registry number|CAS number]]<br />15402-79-6 || [[File:Trimethoxyamphetamine-6.svg|152px|center|Chemical structure of TMA-6]]
|-
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 2X84DCO6GA
|}
{{col-end}}

Note: Because they are isomers, the TMAs have the same [[chemical formula]], C<sub>12</sub>H<sub>19</sub>NO<sub>3</sub>, and the same [[molecular mass]], 225.28 g/mol.

== Properties<ref name="PiHKAL" /> ==
{| class="wikitable"
|- 
! Compound || Pattern || Dose || Duration || Effects
|- align="center"
| bgcolor="#eeeeee" | '''[[3,4,5-Trimethoxyamphetamine|TMA]]''' || 3,4,5 || 100 – 250&nbsp;mg || 6 - 8 h || Psychedelic
|- align="center"
| bgcolor="#eeeeee" | '''[[2,4,5-Trimethoxyamphetamine|TMA-2]]''' || 2,4,5 || 20 – 40&nbsp;mg || 8 - 12 h || Psychedelic
|- align="center"
| bgcolor="#eeeeee" | '''TMA-3''' || 2,3,4 || > 100&nbsp;mg || ''unknown'' || None
|- align="center"
| bgcolor="#eeeeee" | '''TMA-4''' || 2,3,5 || ≥ 80&nbsp;mg || ~ 6 h || Psychedelic
|- align="center"
| bgcolor="#eeeeee" | '''TMA-5''' || 2,3,6 || ≥ 30&nbsp;mg || 8 - 10 h || Stimulant, psychedelic
|- align="center"
| bgcolor="#eeeeee" | '''TMA-6''' || 2,4,6 || 25 – 50&nbsp;mg || 12 - 16 h || Psychedelic
|-
|}

==Legality==

===Brazil===
It is scheduled in the [[Brazilian Controlled Drugs and Substances Act#Class F2|F2 class]] (prohibited psychotropics) of the [[Brazilian Controlled Drugs and Substances Act]].<ref>{{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}}</ref>

===Sweden===
[[Riksdag|''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 (Sweden)|''Medical Products Agency'']] in their regulation LVFS 2004:3 listed as 2,4,5-trimetoxiamfetamin (TMA-2).<ref>{{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}}</ref>

===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]]. <ref>{{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}}</ref>

== See also ==
* [[Substituted methoxyphenethylamine]]
* [[Dimethoxyamphetamine]]
* [[Trimethoxyphenethylamine]]
* [[Methoxyamphetamine]]
* [[Methoxyphenethylamine]]
* [[Dimethoxyphenethylamine]]
* [[α-Ethylmescaline]]
* [[Substituted mescaline analogue]]

==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]]