Ψ-PEA (psychedelics)

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TMA-6 (Ψ-TMA-2) is an example of a Ψ-PEA psychedelic.[1][2][3]

Ψ-Phenethylamines (Ψ-PEA), or psi-phenethylamines (psi-PEA), also known as 4-substituted 2,6-dimethoxyphenethylamines, are a family of psychedelic and related compounds of the phenethylamine family.[1][2][3] They are positional isomers of the 4-substituted 2,5-dimethoxyphenethylamines (e.g., 2Cs and DOx) and 4-substituted 3,5-dimethoxyphenethylamines (e.g., scalines and 3Cs).[1][2][3]

Like the preceding groups or substitution patterns of phenethylamine psychedelics, many Ψ-PEA derivatives are likewise potent serotonergic psychedelics and are known to act as serotonin 5-HT2A receptor agonists.[4][1][2][3] Examples of known psychedelic Ψ-PEAs include TMA-6 (Ψ-TMA-2) and Ψ-DOM, Ψ-2C-T-4, Ψ-2C-DFMO, and Ψ-DODFMO.[4][1][2][3] Conversely, Ψ-2C-O (TMPEA-6) was inactive.[1][4] Unlike many other psychedelic phenethylamines, Ψ-PEAs such as TMA-6, Ψ-Aleph, and Ψ-Aleph-2 are known to act as potent monoamine oxidase inhibitors (MAOIs).[1][5]

The Ψ-PEAs are relatively unexplored compared to the other major psychedelic phenethylamine groups.[1][2][3][6][7][8][9] Many Ψ-PEAs have been synthesized or described, but few are known to have been tested in humans.[1]

List and properties of Ψ-PEAs

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Doses and durations of Ψ-PEAs
Compound Chemical name Dose Duration
TMPEA-6 (Ψ-2C-O) 2,4,6-Trimethoxyphenethylamine >300 mg Unknown
TMA-6 (Ψ-TMA-2) 2,4,6-Trimethoxyamphetamine 25–50 mg 12–16 hours
Ψ-DOM 4-Methyl-2,6-dimethoxyamphetamine 15–25 mg 6–8 hours
Ψ-2C-T-4 4-Isopropylthio-2,6-dimethoxyphenethylamine ≥12 mg Unknown
Ψ-2C-DFMO (Ψ-2C-O-35) 4-Difluoromethoxy-2,6-dimethoxyphenethylamine ~17 mg ~18 hours
Ψ-DODFMO 4-Difluoromethoxy-2,6-dimethoxyamphetamine ~10 mg ~20 hours
Refs: [1][4][2][3]

See also

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References

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  1. ^ a b c d e f g h i j Trachsel, D.; Lehmann, D.; Enzensperger, C. (2013). Phenethylamine: von der Struktur zur Funktion [Phenethylamines: From Structure to Function]. Nachtschatten-Science (in German) (1 ed.). Solothurn: Nachtschatten-Verlag. pp. 881–892. ISBN 978-3-03788-700-4. OCLC 858805226. 8.6. 2,4,6-Trisubstituierte Phenylalkylamine: [...]
  2. ^ a b c d e f g Shulgin, Alexander; Shulgin, Ann (September 1991). PiHKAL: A Chemical Love Story. Berkeley, California: Transform Press. ISBN 0-9630096-0-5. OCLC 25627628.
  3. ^ a b c d e f g Shulgin, A.; Manning, T.; Daley, P.F. (2011). The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds. Vol. 1. Berkeley: Transform Press. ISBN 978-0-9630096-3-0.
  4. ^ a b c d Trachsel D (2012). "Fluorine in psychedelic phenethylamines". Drug Testing and Analysis. 4 (7–8): 577–590. doi:10.1002/dta.413. PMID 22374819.
  5. ^ Reyes-Parada M, Iturriaga-Vasquez P, Cassels BK (2019). "Amphetamine Derivatives as Monoamine Oxidase Inhibitors". Front Pharmacol. 10: 1590. doi:10.3389/fphar.2019.01590. PMC 6989591. PMID 32038257.
  6. ^ "Ask Dr. Shulgin Online". keeping freedom in mind -. 14 March 2002. Retrieved 4 July 2025.
  7. ^ Nichols DE, Glennon RA (1984). "Medicinal Chemistry and Structure-Activity Relationships of Hallucinogens". In Jacobs BL (ed.). Hallucinogens: Neurochemical, Behavioral, and Clinical Perspectives. New York: Raven Press. pp. 95–142. ISBN 978-0-89004-990-7. OCLC 10324237. 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.
  8. ^ Jacob P, Shulgin AT (1994). "Structure-activity relationships of the classic hallucinogens and their analogs" (PDF). NIDA Research Monograph. 146: 74–91. PMID 8742795. 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.
  9. ^ Shulgin AT (2003). "Basic Pharmacology and Effects". In Laing RR (ed.). Hallucinogens: A Forensic Drug Handbook. Forensic Drug Handbook Series. Elsevier Science. pp. 67–137. ISBN 978-0-12-433951-4. 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.