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| Other names | 2,4,6-TMA; TMA-6; ψ-TMA-2; NSC-367445 |
| Routes of administration | Oral[1] |
| Drug class | Serotonin receptor modulator;Serotonergic psychedelic;Hallucinogen |
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| Chemical and physical data | |
| Formula | C12H19NO3 |
| Molar mass | 225.288 g·mol−1 |
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2,4,6-Trimethoxyamphetamine (2,4,6-TMA), also known asTMA-6 orψ-TMA-2, is apsychedelic drug of thephenethylamine,amphetamine, andΨ-PEA families.[1][2][3] It is one of thepositional isomers oftrimethoxyamphetamine (TMA).[1][2][3]
In his 1991 bookPiHKAL (Phenethylamines I Have Known and Loved),Alexander Shulgin gave a dose range for TMA-6 of 25 to 50 mg and aduration of 12 to 16 hours.[1] Threshold effects occur at 20 mg, a fullhallucinogenic state occurs at 30 to 40 mg, and erratic results have been reported for 40 to 80 mg.[3] The drug is said to have about 8 to 10 times thepotency ofmescaline.[4][5][6]
Its effects at 25 to 50 mg included ease with concepts and writing,body tingling,walking unsteadiness, thinking difficulty orintoxication, difficulty with tasks, funniness, hilarity, and laughter,difficulty sleeping, inner chill, visual sparkle,stomach queasiness,diarrhea,reduced appetite, fluctuating emotions, personal insights,visuals, colors, and feelings of "energy flow".[1] Additional reported effects include enjoyablelightheadedness,euphoria,perceptual distortion,synesthesia, andnausea.[4][7]
TMA-6 showsaffinity forserotonin receptors in rat stomach fundus strips (A2 = 525 nM) as well as in rat brain membranes (IC50Tooltip half-maximal inhibitory concentration = 25,000 nM).[2][8][9] In a later study, it showed no affinity for theserotonin5-HT1A ordopamineD2 receptors (Ki = >10,000 nM).[10] It was inactive as amonoamine reuptake inhibitor andreleasing agent in rat brainsynaptosomes (IC50Tooltip half-maximal inhibitory concentration andEC50Tooltip half-maximal effective concentration = >100,000 nM, respectively).[11][12][13] The drug is apotentmonoamine oxidase A (MAO-A)inhibitor, with anIC50Tooltip half-maximal inhibitory concentration of 400 nM.[14] This is in contrast toTMA (3,4,5-TMA) andTMA-2 (2,4,5-TMA), which are inactive in this regard.[14]
TMA-6 fully substitutes for thepsychedelic drugsDOM and5-MeO-DMT in rodentdrug discrimination tests.[2][15][16] It also partially substitutes fordextroamphetamine in rodent drug discrimination tests.[2][17]
A number ofanalogues of TMA-6 with a 2,4,6- substitution pattern have been described, such asΨ-DOM andψ-2C-T-4, among others.[1][18][19][20][21]Alexander Shulgin only limitedly explored the 2,4,6- substitution pattern.[22][20]
TMA-6 was first described in thescientific literature by 1954.[2][3][23]Alexander Shulgin discovered its psychedelic effects in 1964[3] and first described its hallucinogenic effects in the literature in 1969, where he stated its potency relative to mescaline and noted that these findings were previously unpublished.[24][5][25][26] Shulgin subsequently gave the drug the nameTMA-6 in 1970.[25] He more thoroughly described TMA-6 inPiHKAL in 1991.[1] The drug was encountered as a noveldesigner drug inEurope in 2009.[27]
As apositional isomer of TMA, TMA-6 is said to be aSchedule Icontrolled substance in theUnited States.[2]
3.1.10. 2,4,6-Trimethoxyphenylisopropylamine: The symmetrical, sixth isomer of trimethoxyphenylisopropylamine is TMA-6 (43, 2,4,6-trimethoxyphenylisopropylamine, 2,4,6-trimethoxyamphetamine). This base was first synthesized over 20 years ago (Benington et al., 1954) and its psychotomimetic properties were discovered 10 years later (Shulgin, 1964, unpublished data). A threshold of central activity is apparent at an oral dose of 20 mg, and the dosage range for a fully developed psychotomimetic intoxication state is 30-40 mg. There is a visually entertaining aspect to the experience, although its extended action (maximum effects can persist into the sixth hour) can be both tiring and anxiety-provoking. Naranjo (1967, personal communication) has investigated TMA-6 with 13 subjects in the 40-80 mg range and has found that these higher doses lead to erratic results. With several patients there was neither a prolongation nor an intensification of effects; and with at least one, there was the generation of a convincing psychotic episode. The recorded potency of TMA-6 (ten times that of mescaline; effective dose about 30 mg) can be used in quantitative comparisons with confidence (Shulgin et at., 1969).
The symmetrical isomer (2,4,6-trimethoxyphenylisopropylamine, TMA-6, 17) is without known analogy in the essential oils, but this ring substitution pattern is extremely common throughout the many plant products related to the chromones and the flavonoids. The styles of central activity of 15 and 17 are similar to one another in that at threshhold [sic?] levels there is noted only an enjoyable light-headedness coupled with distinct euphoria and a minimum of perceptive distortion. At effective dosages there again is the nausea reminiscent of that seen with mescaline, and the visual distortions can become quite extensive. The sensory disturbances and syntheses so often found to be entertaining or instructive in the case of mescaline intoxication, are found to be disturbing with these latter drugs. TMA-6, 17, is about half as potent as 15, thus having some ten times the effectiveness of mescaline.
The symmetrical isomer [2,4,6-trimethoxyphenylisopropylamine, TMA-6 (LXVII)] has a substitution pattern common throughout the many plant products related to the chromones and the flavanoids. The central activity of (LXIII) and (LXVII) are similar to one another in that at threshold levels there is noted only an enjoyable light-headedness coupled with distinct euphoria and a minimum of perceptive distortion. At effective dosages there again is the nausea reminiscent of that seen with mescaline, and the visual distortions can become quite extensive; (LXVII) is about half as potent as (LXIII).
The 2,4,6 trisubstitution pattern has received very little attention, but appears quite interesting. The 2,4,6-trimethoxyamphetamine 38 appears to be active in humans in the 30-40 mg range, not too far removed from the potency of 2,4,5-trimethoxyamphetamine (Shulgin and Shulgin, 1991). Further, 2,6-dimethoxy-4-methylamphetamine (39), a positional isomer of DOM, has been reported to be active in humans in the 15-25 mg range (Shulgin and Shulgin, 1991). Based on the known structure-activity relationships in the 2,4,5-substituted series, one might anticipate that more hydrophobic 4 substituents in this series would lead to quite active compounds. However, no additional members of the series have been reported, nor have any animal or biochemical pharmacological studies been carried out to indicate whether the mechanism of action of the 2,4,6-substituted series is similar to that of compounds with the other substituent orientations.
The second group has a 2,4,6-substitution pattern. The majority of the compounds listed in the last few tables has carried the 3,4,5- or the 2,4,5-substitution pattern. The similarity of potency between TMA-2 and TMA-6 (the latter with the 2,4,6 substitution pattern, see table 5) has opened up a new family of hallucinogenic amphetamines, one of the authors' current areas of research. With this group also, the 4-position appears to dictate the potency and nature of response. It seems that each of the 2,4,5-substituted materials may have an active 2,4,6-counterpart. The isomer that corresponds to DOM (2,6-dimethoxy-4-methylamphetamine [pseudo-DOM]) is active at 15 to 25 mg orally. Synthetic procedures are now in hand to prepare the pseudo analogs of the 2C-T family with various alkylthio groups at the 4-position.
This review to date has considered the relatives of the 3,4,5-trisubstitution ring pattern (modest activity) and the considerably more potent 2,4,5-trisubstitution pattern. As was noted in the comments comparing TMA-2 with TMA-6, the 2,4,6-orientation bids fair to be every bit as important as the 2,4,5-system, although it has as yet been almost unexplored, either chemically or pharmacologically. A nomenclature that has been used to refer to this branch which is parallel to the 2,4,5-group, is to use the code name of the drug and precede it with the Greek letter psi. This was introduced above with the compound Ψ-2C-T-4. Thus, the lead drug of this section (DOM or 2,5-dimethoxy-4-methylamphetamine) becomes Ψ-DOM (2,6-dimethoxy-4-methylamphetamine). Clinical studies have shown it to be active as a hallucinogen in the 15—25mg range, with a mescaline equivalency of 15. There is too little data at the present time to determine any quantitative relationship between the 2,4,5-normal series and the but it appears quite possible that the two parallel families are, at least as to their quantitative properties, quite similar.
