Methoxyphenethylamines (MPEAs), as well asmethoxyamphetamines (MAs) in the case of theamphetamine (α-methylphenethylamine)homologues, aresubstituted phenethylamines with one or moremethoxy groups.[1][2][3] In some cases, one or more of the methoxy groups may also be extended to form otheralkoxy and relatedgroups such asethoxy orpropoxy.[1][2] Methoxyphenethylamines may have additionalsubstitutions as well.[1][2][3]
Many methoxyphenethylamines that have multiple methoxy groups in the 2- through 5-positions of thephenyl ring, for instancemescaline,2C-B,TMA,DOM, and25I-NBOMe, areserotonin5-HT2A receptoragonists andserotonergic psychedelics.[1][2][3] Other methoxyphenethylamines, particularlymonomethoxyamphetamines likepara-methoxyamphetamine (PMA), aremonoamine releasing agents ofserotonin,norepinephrine, and/ordopamine, withstimulant and/orentactogen-related effects.[1][2]
Compounds closely related to methoxyphenethylamines includemethylenedioxyphenethylamines (MDxx) likeMDA,MDMA, andMMDA, in which two adjacent methoxy groups arebridged, andFLY compounds like2C-B-FLY, in which methoxy groups arecyclized intofuranrings to createbenzofuranring systems.[1][2][3]
Almost all known psychedelic phenethylamines are either methoxyphenethylamines or closely related compounds like MDxx orbenzofurans.[1][2] There are only a few known exceptions, such asfenfluramine[4] andlorcaserin, which can both produce psychedelic effects at high and supratherapeutic doses.[1][2][5] This is in notable contrast totryptamines such asdimethyltryptamine (DMT), which require no specific ring substitutions to be psychedelic.[6][7]
There are few knownpsychedelicphenethylamines that are not methoxyphenethylamines or related compounds likemethylenedioxyphenethylamines orbenzofurans.[1][2] Those that are known include the 3-trifluoromethyl phenethylaminefenfluramine,[4][8][9] thecyclized phenethylaminelorcaserin,[5] and thebenzothiophenes5-APBT and6-APBT.[1][2][10] Certain other phenethylamines, likenaphthylaminopropane (NAP; PAL-287), are also known to act asserotonin5-HT2A receptoragonists, 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 ofamphetamine andMDMA, although it is unclear whether this is related toinduction of monoamine release or serotonin 5-HT2A receptor agonism.[13]
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".
(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 and SLOAN (1970) found that intravenously infused tryptamine increased blood pressure, dilated pupils, enhanced the patellar reflex, and produced perceptual distortions.
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.
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.