Substituted methoxyphenethylamine

MMDA, an example of a methylenedioxyphenethylamine.

Methoxyphenethylamines (MPEAs), as well as methoxyamphetamines (MAs) in the case of the amphetamine (α-methylphenethylamine) homologues, are substituted phenethylamines with one or more methoxy groups.^[1]^[2]^[3] In some cases, one or more of the methoxy groups may also be extended to form other alkoxy and related groups such as ethoxy or propoxy.^[1]^[2] Methoxyphenethylamines may have additional substitutions as well.^[1]^[2]^[3]

Many methoxyphenethylamines that have multiple methoxy groups in the 2- through 5-positions of the phenyl ring, for instance mescaline, 2C-B, TMA, DOM, and 25I-NBOMe, are serotonin 5-HT_2A receptor agonists and serotonergic psychedelics.^[1]^[2]^[3] Other methoxyphenethylamines, particularly monomethoxyamphetamines like para-methoxyamphetamine (PMA), are monoamine releasing agents of serotonin, norepinephrine, and/or dopamine, with stimulant and/or entactogen-related effects.^[1]^[2]

Compounds closely related to methoxyphenethylamines include methylenedioxyphenethylamines (MDxx) like MDA, MDMA, and MMDA, in which two adjacent methoxy groups are bridged, and FLY compounds like 2C-B-FLY, in which methoxy groups are cyclized into furan rings to create benzofuran ring systems.^[1]^[2]^[3]

Almost all known psychedelic phenethylamines are either methoxyphenethylamines or closely related compounds like MDxx or benzofurans.^[1]^[2] There are only a few known exceptions, such as fenfluramine^[4] and lorcaserin, which can both produce psychedelic effects at high and supratherapeutic doses.^[1]^[2]^[5] This is in notable contrast to substituted tryptamines such as DET, which require no specific ring substitutions to be psychedelic.^[6]^[7]

List of methoxyphenethylamines

Phenethylamines

Monomethoxyphenethylamines (MPEAs) (e.g., 2-MPEA, 3-MPEA, 4-MPEA)
Dimethoxyphenethylamines (DMPEAs) (e.g., 2,5-DMPEA (2C-H), 3,4-DMPEA, 3,5-DMPEA (DMPEA-6), MEPEA, macromerine)
- 2Cs (4-substituted 2,5-DMPEAs) (e.g., 2C-B, 2C-C, 2C-D, 2C-E, 2C-I, 2C-T-2)
  - TWEETIOs (e.g., 2CD-2-ETO, 2CD-5-ETO, 2CE-5-ETO, 2CT2-5-ETO, ASR-2001 (2CB-5PrO))
- Scalines (4-substituted 3,5-DMPEAs) (e.g., 4-desoxymescaline (DESOXY; 4-Me-3,5-DMPEA))
- Ψ-PEAs (4-substituted 2,6-DMPEAs) (e.g., Ψ-2C-T-4)
Trimethoxyphenethylamines (TMPEAs) (e.g., 2,4,5-TMPEA (TMPEA-2; 2C-O), mescaline (3,4,5-TMPEA), isomescaline (2,3,4-TMPEA))
- 2Cs (4-substituted 2,5-DMPEAs) (e.g., 2C-O, 2C-O-2, 2C-O-4, 2C-O-22)
- Scalines (4-substituted 3,5-DMPEAs) (e.g., mescaline, escaline, proscaline, allylescaline, methallylescaline)
- Ψ-PEAs (4-substituted 2,6-DMPEAs) (e.g., Ψ-2C-O (TMPEA-6), Ψ-2C-DFMO (ψ-2C-O-35))
- Other substitution patterns (e.g., isomescaline, CT-5172)
Tetramethoxyphenethylamines (TeMPEAs) (e.g., TeMPEA (2,3,4,5-TeMPEA), TeMPEA-2 (2,3,4,6-TeMPEA), TeMPEA-3 (2,3,5,6-TeMPEA))
Pentamethoxyphenethylamine (PeMPEA or 2,3,4,5,6-PeMPEA)
25-NB or NBOMes (N-benzyl-MPEAs) (e.g., 25I-NBOMe, NBOMe-mescaline)
PEA-NDEPAs (e.g., 3,4-DMPEA-NDEPA, 25D-NM-NDEAOP (25D-NM-NDEPA), M-NDEPA)

Amphetamines

Monomethoxyamphetamines (MAs) (e.g., OMA (2-MA), MMA (3-MA), PMA (4-MA), 3-methoxy-4-methylamphetamine (MMA), 4-ETA, 2-TOM, 5-TOM, 2-TOET, 5-TOET, TOMSO)
- N-Alkyl MAs (e.g., methoxyphenamine (OMMA), MMMA, PMMA, PMEA)
Dimethoxyamphetamines (DMAs) (e.g., 2,4-DMA (DMA-3), 2,5-DMA (DMA-4; DOH), 3,4-DMA, 3,5-DMA (DMA-6), 3,4-DMMA, methoxamine (β-OH-2,6-DMA))
- DOx (4-substituted 2,5-DMAs) (e.g., DOB, DOC, DOET, DOI, DOM, Aleph (DOT))
  - N-Alkyl DOx (e.g., Beatrice (methyl-DOM; MDOM), N-methyl-DOET, methyl-DOB (MDOB), N-methyl-DOI, IDNNA (N,N-dimethyl-DOI))
- 3Cs (4-substituted 3,5-DMAs) (e.g., 4-Br-3,5-DMA, 4-PhPr-3,5-DMA)
- Ψ-PEAs (4-substituted 2,6-DMAs) (e.g., Ψ-DOM)
Trimethoxyamphetamines (TMAs) (e.g., TMA (3,4,5-TMA), TMA-2 (2,4,5-TMA), TMA-3 (2,3,4-TMA), TMA-4 (2,3,5-TMA), TMA-5 (2,3,6-TMA), TMA-6 (2,4,6-TMA))
- DOx (4-substituted 2,5-DMAs) (e.g., TMA-2, MEM, MPM, MALM, MMALM, MTFEM)
- 3Cs (4-substituted 3,5-DMAs) (e.g., TMA, 3C-E, 3C-P, 3C-IP, 3C-AL, 3C-MAL, 3C-FE)
- Ψ-PEAs (4-substituted 2,6-DMAs) (e.g., TMA-6 (Ψ-TMA-2), Ψ-DODFMO)
Tetramethoxyamphetamines (TeMAs) (e.g., TeMA (2,3,4,5-TeMA), TeMA-2 (2,3,4,6-TeMA), TeMA-3 (2,3,5,6-TeMA))
Pentamethoxyamphetamine (PeMPA or 2,3,4,5,6-PeMPA)
25-NB or NBOMes (N-benzyl-MAs) (e.g., DOM-NBOMe, DOB-NBOMe, DOI-NBOMe)
AMPH-NDEPAs (e.g., DOB-NDEPA, DOI-NDEPA, DOM-NDEPA, DOTFM-NDEPA, TMA-2-NDEPA)

Phenylisobutylamines

4Cs (4-substituted 2,5-dimethoxyphenylisobutylamines) (e.g., Ariadne (4C-D), 4C-B, 4C-C, 4C-E, 4C-I, 4C-T-2)
Others (e.g., α-ethylmescaline)

α-Propylphenethylamines

5Cs (4-substituted 2,5-dimethoxy-α-propylphenethylamines) (e.g., 5C-D)
Others (e.g., α-propylmescaline)

Others and related compounds

Ring-extended phenethylamines

Methylenedioxyphenethylamines (MDxx) (e.g., MDPEA, MDMPEA, MDA, MDMA, MDEA, BDB (J), MBDB (methyl-J), BDP (K), MPAP (propyl-K), methylone (MDMC))
- Monomethoxymethylenedioxyphenethylamines (MMPEAs) (e.g., lophophine (MMDPEA; 2C-MMDA-1), 2C-MMDA-2 (MMDPEA-2), 2C-MMDA-3a, 2C-MMDA-4, MMDA, MMDA-2, MMDA-3a, MMDA-3b, MMDA-4, MMDA-5, EMDA-2)
- Dimethoxymethylenedioxyphenethylamines (DMMPEAs) (e.g., 2C-DMMDA, 2C-DMMDA-2, DMMDA, DMMDA-2, DMMDA-3, DMMDA-4, DMMDA-5, DMMDA-6)
Ethylenedioxyphenethylamines (EDxx) (e.g., EDA, EDMA, EDMC)
Benzofurans and FLY compounds (e.g., 5-APB, 6-APB, 5-APDB, 6-APDB, 2C-B-FLY, DOB-FLY, Bromo-DragonFLY, TFMFly, F, F-2, F-22)

Rigid/constrained phenethylamines

Tetrahydroisoquinolines (e.g., anhalinine, pellotine, lophophorine, DOM-CR, DOB-CR)
Phenylcyclopropylamines (e.g., DMCPA, TMT)
1-Aminomethylindanes (1-AMIs) (e.g., 2CB-Ind, AMMI, jimscaline)
2-Aminoindanes (2-AIs) (e.g., DOM-AI, MDAI, MDMAI, MEAI, MMAI)
2-Aminotetralins (2-ATs) (e.g., DOM-AT, MDAT, MDMAT)
Benzocyclobutenes (e.g., 2CBCB-NBOMe, TCB-2, tomscaline)
3-Phenylpiperidines (e.g., LPH-5, LPH-48, DEMPDHPCA-2C-D)
Others (e.g., 2C-B-aminorex, 2C-B-morpholine, 2C-B-PYR, 2C-B-5-hemiFLY-α6, 2CBecca, 2CJP, 2CLisaB, 2CLisaH, CT-5126, DMBMPP (juncosamine), TFMBOX, ZC-B)

Other psychedelic phenethylamines

There are few known psychedelic phenethylamines that are not methoxyphenethylamines or related compounds like methylenedioxyphenethylamines or benzofurans.^[1]^[2] Those that are known include the 3-trifluoromethyl phenethylamine fenfluramine,^[4]^[8]^[9] the rigid 4-chloro phenethylamine lorcaserin,^[5] and the benzothiophenes 5-APBT and 6-APBT.^[1]^[2]^[10] Certain other phenethylamines, like naphthylaminopropane (NAP; PAL-287), are also known to act as serotonin 5-HT_2A receptor agonists, but have not been assessed in terms of psychedelic-type effects in animals or humans.^[11]^[12] 4-Fluoroamphetamine (4-FA) has been described as producing a very mild "psychedelic" state, intermediate between that of amphetamine and MDMA, although it is unclear whether this is related to induction of monoamine release or serotonin 5-HT_2A receptor agonism.^[13]

Compounds by substituents and substitution patterns

v
t
e
Substituted methoxyphenethylamine extended at the 4 position
Substituent	No ether (4-)				4-Ether (4-O-)				4-Thioether (4-S-)
Substituent	2C	DOx	Scaline	3C	2C-O-x	DOO-x	Scaline-O-x	3C-O-x	2C-T-x	DOT-x	Scaline-T-x	3C-T-x
H	2C-H	2,5-DMA	3,5-DMPEA	3,5-DMA	–	DOOH	DESMETHYL	α-Me-DES…	2C-T-0	–	–	–
Methyl	2C-D	DOM	DESOXY	4-Me-3,5-DOM	2C-O	TMA-2	Mescaline	TMA	2C-T	Aleph	4-Thiomescaline	α-Me-4-TM
Ethyl	2C-E	DOET	DE	4,3,5-DOET	2C-O-2	MEM	Escaline	3C-E	2C-T-2	Aleph-2	4-Thioescaline	–
Methallyl	2C-1MV	–	–	–	2C-O-3	MMALM	Methallylescaline	3C-MAL	2C-T-3	Aleph-3	–	–
Isopropyl	2C-IP	DOiP	DIP	–	2C-O-4	MIPM	Isoproscaline	3C-IP	2C-T-4	Aleph-4	–	–
Cyclohexyl	–	–	–	–	–	–	–	–	2C-T-5	Aleph-5	–	–
Phenyl	2C-Ph	–	Biscaline	–	–	–	Phescaline	–	2C-T-6	Aleph-6	–	–
Propyl	2C-P	DOPR	DPR	4,3,5-DOPR	2C-O-7	MPM	Proscaline	3C-P	2C-T-7	Aleph-7	4-Thioproscaline	–
Cyclopropylmethyl	–	DOCPM	–	–	–	–	Cyclopropylmescaline	3C-CPM	2C-T-8	Aleph-8	–	–
tert-Butyl	2C-tBu	DOTB	–	–	–	–	–	–	2C-T-9	–	–	–
Pyridin-2-yl	–	–	–	–	–	–	–	–	2C-T-10	–	–	–
4-Bromophenyl	–	–	–	–	–	–	–	–	2C-T-11	–	–	–
Morpholin-4-yl	2C-MOR	–	–	–	–	–	–	–	2C-T-12	–	–	–
2-Methoxyethyl	–	DOMeOEt	–	–	–	–	4-Methoxyescaline	–	2C-T-13	–	–	–
2-Methylthioethyl	–	DOMeSEt	–	–	–	–	4-Methylthioescaline	–	2C-T-14	–	–	–
Cyclopropyl	2C-CP	–	–	–	–	–	Cycloproscaline	–	2C-T-15	–	–	–
Allyl	2C-AL	–	DAL	–	2C-O-16	MALM	Allylescaline	3C-AL	2C-T-16	Aleph-16	–	–
sec-Butyl	2C-sBu	DOSB	–	–	–	–	sec-Buscaline	–	2C-T-17	–	–	–
Cyclobutyl	2C-CB	–	–	–	–	–	–	–	2C-T-18	–	–	–
Butyl	2C-Bu	DOBU	–	–	2C-O-19	MBM	Buscaline	3C-B	2C-T-19	Aleph-19	4-Thiobuscaline	α-Me-4-TB
2-Fluoroethyl	2C-EF	DOEF	–	–	2C-O-21	MFEM	2-Fluoroescaline	3C-FE	2C-T-21	Aleph-21	–	–
2,2-Difluoroethyl	2C-DFE	–	–	–	2C-O-21.5	MDFEM	2,2-Difluoroescaline	3C-DFE	2C-T-21.5	–	–	–
2,2,2-Trifluoroethyl	2C-TFE	DOTFE	DTFE	–	2C-O-22	MTFEM	3,3,3-Trifluoroescaline	3C-TFE	2C-T-22	–	–	–
Cyclopentyl	2C-CPe	–	–	–	–	–	Cyclopentscaline	–	2C-T-23	–	–	–
Diethylamino	–	–	–	–	–	–	–	–	2C-T-24	–	–	–
Isobutyl	2C-iBu	DOIB	–	–	–	–	Isobuscaline	3C-IB	2C-T-25	–	–	–
1,3-Difluoroisopropyl	–	–	–	–	–	–	1,3-Difluoroisoprosc…	–	2C-T-26	–	–	–
Benzyl	2C-BN	DOBz	–	–	2C-O-27	MBZM	Benzscaline	3C-BZ	2C-T-27	–	–	–
3-Fluoropropyl	2C-FP	DOPF	–	–	2C-O-FP	–	3-Fluoroproscaline	3C-FP	2C-T-28	–	–	–
Propargyl	2C-YNP	–	–	–	–	–	PROPYNYL	–	2C-T-29	–	–	–
4-Fluorobutyl	–	–	–	–	–	–	–	–	2C-T-30	–	4F-TB	–
4-Trifluoromethylbenzyl	–	–	–	–	–	–	–	–	2C-T-31	–	–	–
Pentafluorobenzyl	–	–	–	–	–	–	–	–	2C-T-32	–	–	–
3-Methoxybenzyl	2C-MBM	DO3MeOBZ	–	–	–	–	–	–	2C-T-33	–	–	–
Fluoromethyl	2C-FM	DOFM	–	–	–	DOFMO	Fluoromescaline	–	2C-T-34	–	–	–
Difluoromethyl	2C-DFM	DODFM	–	–	–	DODFMO	Difluoromescaline	3C-DFM	2C-T-35	–	–	–
Trifluoromethyl	2C-TFM	DOTFM	DTFM	–	2C-O-TFM	DOTFMO	Trifluoromescaline	–	2C-T-36	Aleph-TFM	4-TM-TFM	–
Amyl	2C-AM	DOAM	±	±	–	MAM	Amylescaline	3C-A	±	Aleph-S-amyl	TA	–
Hexyl	2C-Hx	DOHx	–	–	–	–	Hexylescaline	3C-H	–	–	–	–
Ethenyl	2C-V	DOV	DV	–	–	–	Viscaline	–	–	–	–	–
Ethynyl	2C-YN	DOYN	DYN	–	–	–	–	–	–	–	–	–
Methoxymethyl	2C-MOM	DOMOM	4-MeOMe…	–	–	–	4-Methoxymescaline	–	–	–	–	–
Ethoxymethyl	2C-EOM	DOMOE	–	–	–	–	–	–	–	–	–	–
4-Methoxyphenyl	2C-BI-8	–	–	–	–	–	–	–	–	–	–	–
Phenylethyl	2C-PhEt	DOPhEt	–	–	–	–	Phenescaline	–	–	Aleph-S-PhEt	–	–
3-Phenylpropyl	2C-PhPr	DOPP	–	4-PhPr-3,5-DMA	–	–	–	–	–	–	–	–
Notes: (1) The "2C-X-20" row is absent because "2C-X-3" and "2C-X-20" are synonyms/the same compounds. (2) Missing compounds can be found at Isomer Design.

References

^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j 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.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j Alexander T. Shulgin; Ann Shulgin (1991). PiHKAL: A Chemical Love Story (1st ed.). Berkeley, CA: Transform Press. ISBN 978-0-9630096-0-9. OCLC 25627628.
^ ^a ^b ^c ^d Nichols DE (2018). Chemistry and Structure-Activity Relationships of Psychedelics. Current Topics in Behavioral Neurosciences. Vol. 36. pp. 1–43. doi:10.1007/7854_2017_475. ISBN 978-3-662-55878-2. PMID 28401524.
^ ^a ^b Connell, P. H. (1979). "Drug dependence liability of anorectic drugs: a clinical viewpoint, with particular reference to fenfluramine". Current Medical Research and Opinion. 6 (sup1): 153–159. doi:10.1185/03007997909117502. ISSN 0300-7995. Griffith et al.6 compared fenfluramine with d-amphetamine and noted that fenfluramine was usually identified as LSD by subjects, and LSD scale scores after fenfluramine were significantly elevated. Three subjects receiving 240 mg fenfluramine experienced a psychedelic state characterized by visual and olfactory hallucination, cyclic alterations of mood, distorted time sense, fleeting paranoia, and sexual ideation. They noted that fenfluramine was a weak hallucinogen and, although sharing some features in common with amphetamine, "its overall profile of effects is quite different".
^ ^a ^b Collins GT, Gerak LR, France CP (November 2018). "The behavioral pharmacology and therapeutic potential of lorcaserin for substance use disorders". Neuropharmacology. 142: 63–71. doi:10.1016/j.neuropharm.2017.12.023. PMC 5997497. PMID 29246856.
^ Shulgin, A. (1997). Tihkal: The Continuation. Transform Press. #53. T. ISBN 978-0-9630096-9-2. Retrieved 17 August 2024. (with 250 mg, intravenously) "Tryptamine was infused intravenously over a period of up to 7.5 minutes. Physical changes included an increases in blood pressure, in the amplitude of the patellar reflex, and in pupillary diameter. The subjective changes are not unlike those seen with small doses of LSD. A point-by-point comparison between the tryptamine and LSD syndromes reveals a close similarity which is consistent with the hypothesis that tryptamine and LSD have a common mode of action."
^ Martin, W. R.; Sloan, J. W. (1977). "Pharmacology and Classification of LSD-like Hallucinogens". Drug Addiction II. Berlin, Heidelberg: Springer Berlin Heidelberg. pp. 305–368. doi:10.1007/978-3-642-66709-1_3. ISBN 978-3-642-66711-4. MARTIN and SLOAN (1970) found that intravenously infused tryptamine increased blood pressure, dilated pupils, enhanced the patellar reflex, and produced perceptual distortions.
^ Griffith, John D. (1977). "Structure-Activity Relationships of Several Amphetamine Drugs in Man". Cocaine and Other Stimulants. Advances in Behavioral Biology. Vol. 21. Boston, MA: Springer US. pp. 705–715. doi:10.1007/978-1-4684-3087-5_36. ISBN 978-1-4684-3089-9. Fenfluramine (60, 120, 240 mg orally) [...] caused a marked dilation of pupils and elevation of the LSD Scale. [...] Fenfluramine was more often identified as an "LSD" or "barbiturate-like" substance. An unexpected response [...] was observed among 3 subjects who manifested hallucinatory states characterized by visual and olfactory hallucinations, rapid and polar changes of mood, distorted time sense, fleeting paranoia, and sexual hallucinations. [...] The remaining five subjects receiving the largest dose of fenfluramine experienced a chlorpromazine-like sedation without hallucinations or other psychedelic effects (Griffith, Nutt, and Jasinski, 1975). Chlorphentermine (50, 100, 200 mg) was similarly assessed. In certain respects, chlorphentermine resembles fenfluramine (Fig. 4), especially in terms of its mydriatic and sedative effects [...] On the other hand, chlorphentermine [...] is not hallucinogenic. [...] the utility of [amphetamine aromatic ring substitution] may be limited by the emergence of certain side-effects [...] e.g., dysphoria, sedation, and/or psychedelic properties.
^ Griffith JD, Nutt JG, Jasinski DR (November 1975). "A comparison of fenfluramine and amphetamine in man". Clin Pharmacol Ther. 18 (5 Pt 1): 563–570. doi:10.1002/cpt1975185part1563. PMID 1102234. dl-Fenfluramine hydrochloride (60, 120, 240 mg), d-amphetamine sulfate (20, 40 mg), and placebo were compared in 8 postaddict volunteers, each dose given orally [...] Fenfluramine [...] caused a marked dilation of pupils [...] While fenfluramine produced euphoria in some subjects, its overall effects were unpleasant, sedative, and qualitatively different from amphetamine. Three subjects given 240 mg of fenfluramine experienced brief but vivid hallucinogenic episodes characterized by olfactory, visual, and somatic hallucinations, abrupt polar changes in mood, time distortion, fleeting paranoia, and sexual ideation. These observations indicate that fenfluramine is a hallucinogenic agent with a pharmacologic profile in man that is not amphetamine-like.
^ Rudin D, McCorvy JD, Glatfelter GC, Luethi D, Szöllősi D, Ljubišić T, Kavanagh PV, Dowling G, Holy M, Jaentsch K, Walther D, Brandt SD, Stockner T, Baumann MH, Halberstadt AL, Sitte HH (March 2022). "(2-Aminopropyl)benzo[β]thiophenes (APBTs) are novel monoamine transporter ligands that lack stimulant effects but display psychedelic-like activity in mice". Neuropsychopharmacology. 47 (4): 914–923. doi:10.1038/s41386-021-01221-0. PMC 8882185. PMID 34750565.
^ Rothman RB, Blough BE, Baumann MH (December 2006). "Dual dopamine-5-HT releasers: potential treatment agents for cocaine addiction". Trends Pharmacol Sci. 27 (12): 612–618. doi:10.1016/j.tips.2006.10.006. PMID 17056126.
^ Rothman RB, Blough BE, Baumann MH (January 2007). "Dual dopamine/serotonin releasers as potential medications for stimulant and alcohol addictions". The AAPS Journal. 9 (1): E1-10. doi:10.1208/aapsj0901001. PMC 2751297. PMID 17408232.
^ Kuypers KP, De Sousa Fernandes Perna EB, Theunissen EL, Toennes SW, Mason NL, Hutten NR, Ramaekers JG (2019). "A First-in-Man Study with 4-Fluoroamphetamine Demonstrates it Produces a Mild Psychedelic State". J Psychoactive Drugs. 51 (3): 225–235. doi:10.1080/02791072.2019.1569286. PMID 30676284.