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α-Ethyltryptamine:A Ratiocinatory Reviewof a Forgotten Antidepressant

RichardA Glennon1,Mal̵gorzata Dukat1,*
1Department of Medicinal Chemistry,School of Pharmacy, Virginia CommonwealthUniversity, Richmond, Virginia 23298, United States
*

Email:mdukat@vcu.edu.

Received 2023 Jul 5; Accepted 2023 Oct 19; Revised 2023 Oct 17; Collection date 2023 Dec 8.

© 2023 American Chemical Society
PMCID: PMC10714429  PMID:38093842

Abstract

graphic file with name pt3c00139_0005.jpg

α-Ethyltryptamine (AET) is quite an interesting,but perhapslong-forgotten, centrally acting agent. Known for more than 75 years,AET was once clinically available as an antidepressant but was withdrawnshortly after its introduction. AET was subsequently controlled asa U.S. Schedule I substance due to its perceived abuse liability and/ortoxicity but remains an agent of interest. Hallucinogenic tryptamines(that is, serotonergic psychedelic agents) are now in vogue as noveland exciting chemotherapeutics for the treatment of various neuropsychiatricdisorders, including treatment-resistant depression and anxiety. DoesAET represent a serotonergic psychedelic agent? Does AET (or its analogs)deserve further investigation? Here, the history of AET is criticallyreviewed in detail, and an argument is made that AET might have beenan agent well ahead of its time. It possesses many of the hallmarksof an antidepressant, suggesting that AET derivatives and particularlytheir optical isomers are deserving of further investigation.

Keywords: serotonergic psychedelics, serotonin receptors, hallucinogens, monoamine transporters, MDMA, optical isomers

Key Concepts

  • Various psychedelic or hallucinogenic tryptamines arecurrently in clinical trials for use in treatment-resistant depressionand certain other neuropsychiatric disorders.

  • α-Ethyltryptamine (AET) was used in the 1960sas an antidepressant but later withdrawn due to undesirable side effects;its mechanism of action had not been clearly established.

  • Pertinent preclinical and clinical datafor AET publishedover the past 60 years are reviewed here with a focus on possibleactions and mechanisms of action.

  • Preclinicalstudies with AET continue; there is currentlyincreased interest in its individual optical isomers that seem toproduce nonidentical effects.

1

α-Ethyltryptamine (;Figure1), a structural cousin of two well-recognized,documented, and controlled (U.S. Schedule I) tryptaminergic hallucinogenicagents, α-methyltryptamine (α-MeT;2) andN,N-dimethyltryptamine (DMT;3), is an intriguing centrally acting agent that has been intermittentlyinvestigated since its discovery 75 years ago. This is the first comprehensivereview of α-ethyltryptamine that is also known as U17312E (asits racemate), α-ET, etryptamine, and AET (an acronym that willbe used herein and typically to its acetate salt unless otherwisementioned). At one time, AET was clinically available as an antidepressant(under the clinically approved name of Monase) but was withdrawn shortlyafter its introduction, and subsequently controlled as a U.S. ScheduleI substance due to its perceived abuse liability and/or potentialtoxicity. There is currently a resurgence of interest in the use ofso-called psychedelic indolealkylamine or tryptamine hallucinogensfor the treatment of neuropsychiatric disorders.1−3 For example,DMT (3) is currently in clinical trials for the potentialtreatment of depression and anxiety.4,5 Tryptaminergic(and other) classical hallucinogens such as DMT seem to produce theircommon behavioral effects primarily, although perhaps not exclusively,via the activation of brain 5-HT2A serotonin receptors(reviewed in ref (6)). Although still somewhat controversial,7 it has been argued that activation of brain 5-HT2A serotoninreceptors is essential for tryptamine-based psychedelics to produceantidepressant-like effects in rodents, and that their hallucinogenicand therapeutic effects are mediated through activation of the samecommon receptor.8 This might be a consequenceof differences in subsequent downstream trafficking.1,9 Hence, the subjective effects induced by hallucinogens or serotonergicpsychedelics might,10 or might not,11,12 be necessary to produce long-lasting changes in mood and behavior,and their therapeutic utility seems to involve their ability to promoteneuroplasticity (reviewed in refs (1) and (13)). Given the structural similarity between the tryptamineDMT (3), its derivatives such as psilocybin (i.e., 4-phosphoryloxyDMT), and AET (1), and with the awareness that AET wasonce clinically available as an antidepressant, there might be valuein re-examining what is currently known about AET.

Figure 1.

Figure 1

Chemical structures ofracemic α-ethyltryptamine (α-ETor AET;1), α-methyltryptamine (α-MeT;2), andN,N-dimethyltryptamine(DMT;3). The asterisk (*) indicates the chiral centerof AET (1) that results in two optical isomers:(S)1 and(R)1; the actionsof the racemate and optical isomers of AET are considered here.

The first mention of AET (free base) as a chemicalentity was bySnyder and Katz14 in 1947 as a syntheticintermediate in the preparation of certain β-carbolines. Govieret al.15 prepared AET hydrochloride, andlater, Upjohn employees Heinzelman et al.16 prepared several different salts of AET (including its hydrochlorideand acetate salts, the latter being termed Monase) and provided additionalsynthetic detail. The synthesis of AET was also described in a patentby Upjohn (initially in 1959, later revised and subsequently abandoned,and eventually refiled in 1970).17 Monasewas clinically available as an antidepressant and/or a “psychicenergizer” for about a year (circa 1961). Although it was administeredto >5,000 individuals/patients,18 itwassubsequently withdrawn from the market because of an incidence ofagranulocytosis in several patients.19 Antidepressantscan produce a variety of undesirable side effects, with agranulocytosisbeing among one of the more serious; several (currently and previously)clinically employed antidepressants have exhibited such actions.20

Human Doses

To serve as a guide to the relative humandoses used for Monase,in one clinical study in 1961 this agent produced “notableeffects” in 18 out-patients with symptoms of depression whenorally administered for 3–7 days at an average effective doseof 30–40 mg/day.21 In the same study,doses of 60 to (and in most cases) 300 mg administered to hospitalizedschizophrenic patients were without effect, except for noticeablepsychomotor activation. Another clinical study examined a varietyof dose ranges in depressed patients.22 A dose range of 30–40 mg/day was quite typical of early studiesfor the treatment of “depressed” patients, althoughdoses sometimes increased to about 75 mg/day. It might be noted thatnearly an entire supplement of theJournal of Psychiatry was devoted to preclinical and clinical studies with AET in 1961,and the effect and effectiveness of different oral human doses ofAET were described.220 Only some selectedpapers will be cited here, but the supplement provides a wealth ofadditional preclinical and clinical information. In 1967, Hoffer andOsmond23 very briefly reviewed some ofthe early studies.

Toxicity

For the purpose of comparison, regarding thetoxicity of AET, apublished MSDS sheet (dated July 3, 2019) for AET as its acetate salt(although it is clearly indicated that the toxicological effects ofthe product have not been thoroughly studied) provides the followinginformation: LD50 = rat (p.o.) 5,600 mg/kg, rat (i.p.)400 mg/kg, rabbit (p.o.) 14,200 mg/kg; a human oral LDLO (lowest dosecausing death) of 143 mg/kg is also reported.24 An earlier Chemical Toxicity Database (dated March 1995) that citesmany older studies offers somewhat different information: LD50 = rat (p.o.) 49 mg/kg, mouse (p.o.) 105 mg/kg, mouse (i.p.) 72 mg/kg,mouse (i.v.) 45 mg/kg.25 Given the disparityin available information, new studies on the toxicity of AET are probablywarranted.

Subsequently, probably beginning in the early tomid-1980s afteryears of relative obscurity, AET made an appearance on the illicitdrug market. The U.S. DEA first encountered illicit AET in a clandestinelaboratory in 1986 where it was being sold as Trip or ET and thenin Europe as Love Pearls or Love Pills.26 Several fatalities were reported as of 1986. One fatality reportindicated that an approximate (but unconfirmed) quantity of 700 mgin a single subject might have been consumed.27 Morano and co-workers28 later reportedanother fatality. Shortly thereafter, AET became a permanently controlled(U.S. Schedule I) substance.26 Some toxicologicaldata for 40 tryptamine analogs, including AET, have been reviewed;29 although little is discussed about AET beyondthe two studies mentioned above, the review is a good source of informationwhen comparing the toxicity of various tryptamines.

AET as a Possible Hallucinogenic Agent

Is AET a hallucinogenicagent? Because of its inclusion in reviewarticles and books about hallucinogenic agents (e.g., Hoffer and Osmond;23 Brimblecombe and Pinder),30 AET is often considered by inference to be an hallucinogenicagent. At nearly the same time that Monase was in the clinic, Murphreeet al.31 compared the effects of AET (1) (30 to 150 mg, p.o.) and α-methyltryptamine (α-MeT;2) (10 and 20 mg, p.o.) with those of LSD. Administrationof 150 mg of AET resulted in 8 of 11 human volunteers reporting “a feeling of being elated or intoxicated”, with twosubjects equating AET as being “something like” LSD. In the same study, by contrast, the most common effectsreported by those receiving 20 mg (p.o.) of α-MeT were nervoustension and restlessness, and the subjects “likenedthe effects to a long-lasting lysergic acid-like compound”.31 Years later, it was reported,following total oral AET doses of 50–160 mg, that 50 mg produced“no effect of any kind”, 105 mg producedan effect “like speed without the cardiovascular orlike a psychedelic without the visuals”, and thata dose of 120 mg produced “pure euphoria”;32 the number of human subjects involvedwas not mentioned.

Corne and Pickering33 identified a relativelysimple, yet quantitative, correlation between human hallucinogenicactivity and a behavioral response in mice: the mouse head-twitchresponse. Following s.c. administration, both α-MeT (2) and DMT (3) produced this effect with ED50 doses of 11.0 and 2.8 mg/kg, respectively; AET (1)was without effect.33

In drug discriminationstudies using rats trained to discriminatethe hallucinogenic agent 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane(DOM;4,Figure2) from vehicle, a statistically significant correlation (r > 0.9) was found between the stimulus generalization(i.e.,substitution) potency in these studies, 5-HT2A serotoninreceptor affinity, and the human hallucinogenic potency of an extendedseries of hallucinogenic agents when any two of these three measureswere compared (reviewed6). This, in part,led to the concept of “classical hallucinogens”. The structurally related DOB (5) and DOI (6), two of the more potent DOM-like agents, have also beenused as training drugs in rats.6

Figure 2.

Figure 2

Structuresof selected phenylisopropylamines discussed inthe text.

Administration (i.p.) of AET (1) toDOM-trained ratsresulted in substitution (i.e., stimulus generalization) (ED50 = 6.62 mg/kg) as did α-MeT (2) (ED50 = 3.13 mg/kg) and DMT (3) (ED50 = 5.80 mg/kg).34 Although this finding indicated that AET canproduce DOM-like stimulus effects in rats, the results might havebeen anomalous. That is, DOM-stimulus generalization also occurredto the nonhallucinogen 5-HT releasing agent fenfluramine (7,Figure2).35 Interestingly, fenfluramine did not substitutefor DOM in DOM-trained Rhesus monkeys.36 DOI (6;Figure2), an agent that substitutes for DOM regardless of which ofthe two agents is used as training drug in drug discrimination studies,35 only partially substituted in rats trained todiscriminate fenfluramine from vehicle.37 Nevertheless, fenfluramine substituted for the training drug inLSD-trained rats.38 More recently, Halberstadtet al.39 demonstrated a robust correlationbetween the head-twitch response in mice, previously published drugdiscrimination data (using LSD- and DOM-trained rats), and human hallucinogenicpotency. Fenfluramine produced the head-twitch response in mice followingi.p. administration of 5, 10, and 15 mg/kg.40 Hence, in both the mouse head-twitch assay and drug discriminationstudies using DOM- and LSD-trained rats, fenfluramine produced aneffect consistent with those of a classical hallucinogen; nevertheless,fenfluramine might be producing a “false positive”.The results are, in any event, difficult to reconcile. However, asan aside, it might be noted that norfenfluramine, the major metaboliteof fenfluramine, is a 5-HT2A (as well as a 5-HT2B and 5-HT2C) receptor partial agonist.41

Overall, there is fairly little support (other thanthat from drugdiscrimination studies with rats where AET might be a “falsepositive”, and the 1961 Murphree et al.31 study, with only few human subjects reporting an LSD-likeeffect) for the concept that AET is an hallucinogenic agent. Thisis particularly telling when so little (actually, nothing) is mentionedabout this (i.e., hallucinogenic) effect, considering that AET hasbeen administered to a large number of subjects/patients at oral dosesof up to 300 mg. It should also be noted that we have stated on multipleoccasions that drug discrimination studies with DOM as training drugarenot a model of hallucinogenic action;42 such studies merely provide working hypothesesthat can be further evaluated.

Stimulant and Amphetamine-like Actions of AET

Almostsince its inception, AET has been reported to produce acentral stimulant effect in animals (or a “psychic energizer”effect in humans suffering with depression). Paradoxically, some patientstreated with Monase felt sedated.220

AET significantly increased mouse locomotor activity 1 h post administrationand was at least as effective as (+)amphetamine as a psychomotor stimulant;but, unlike with amphetamine (8), the hyperlocomotoreffects of AET were still evident 3 h following administration.43 Hence, AET seems to be a long-acting agent inthis regard. In the same study, it was shown that, following serotonindepletion by pretreatment of the animals with reserpine, AET was stillactive, whereas (+)amphetamine was not. It was suggested that AETproduces its hyperlocomotor actions via a mechanism that differs fromthat produced by (+)amphetamine.43 Thismechanistic argument has been noted for other structurally relatedagents, as well. For example, PMA orpara-methoxyamphetamine(9) and amphetamine (8) produced hyperlocomotoreffects in rats, but PMA seems to act as a serotonin releasing agentwhereas the effects of amphetamine might be related more to dopaminerelease.44,45

Doses of AET (5, 10, and 20 mg/kg)significantly increased mousehorizontal locomotor activity and global motor activity over a 2-htest session, and significantly decreased investigatory behavior.46 Because the serotonin reuptake inhibitor fluoxetineattenuated the locomotor hyperactivity produced by AET, the authorssuggested that AET acts via serotonin (i.e., the serotonin transporteror SERT) release.46

In the early1990s we submitted a sample of racemic AET to theCPDD (College on Problems of Drug Dependence) who, at the time, hadas a service the evaluation of potential central stimulant or depressantcompounds. Evaluated blind (as CPDD-0041),47 mouse locomotor activity was examined at doses of 2–30 mg/kgat different time intervals (5–15, 35–50, 65–95,and 125–185 min). The effect of AET was slow in onset and prolongedin duration with the higher doses (10–30 mg/kg) being mosteffective, and the last time interval providing the peak effect.47 Thus, AET was assessed to be a psychomotor stimulant.

In drug discrimination studies with rats trained to discriminate(+)amphetamine from vehicle, AET failed to substitute (i.e., AET producedonly ca. 41% drug-appropriate responding,48 but see further discussion below on the action of AET optical isomers).In three Rhesus monkeys, AET engendered 63.5% (+)amphetamine-appropriateresponding in one monkey following intragastric administration of17 mg/kg, and little to no drug-lever responding by the other twomonkeys at 10 mg/kg.47 Evidence suggestedthat AET is, to some extent, a psychomotor stimulant, although itsmechanism of action was undefined and additional drug doses were notexamined.

MDMA-like Actions of AET

Following an early reporton the human effect of the empathogenMDMA (12),49 an agent currentlyundergoing clinical trials,50 Nichols showedthat the α-methyl group of MDMA could be homologated or extendedto an α-ethyl substituent without much change in action.51 These and related findings are, perhaps, whatled some to examine the α-ethyl homologue of α-MeT (i.e.,AET) for possible MDMA-like effects. Using rats trained to discriminateMDMA from vehicle, AET (ED50 = 3.5 mg/kg) substituted forMDMA but was about 4-fold less potent than the training drug (MDMA,ED50 = ca. 0.8 mg/kg).48 Ina related study, using serotonergic dysfunctional Fawn-hooded rats,AET substituted (ED50 = 1.822 mg/kg) for MDMA (ED50 = 0.136 mg/kg) as the training drug but was about 13-fold less potentthan MDMA.52 More will be said about theoptical isomers of AET in the AET isomers section below. Geyer andcolleagues examined a number of behavioral properties of AET (e.g.,rat locomotor activity and multiple components of the startle reflex)and concluded that AET produces an MDMA-like profile of behavioralchanges.46,53,54 Yet, it wasshown that habituation to the apparatus employed (i.e., a BehavioralPattern Monitor) and light-cycle interact to influence MDMA- and AET-inducedhyperactivity somewhat differently.55

According to the DEA, AET was being clandestinely marketed as anMDMA-like substance,26 and it has beenreported that oral doses of AET (100 and 160 mg) produced MDMA-likeeffects in (an unspecified number of) human subjects.32 Taken together, this evidence suggests that AET can produceat least some behavioral effects reminiscent of MDMA.

AET as an Inhibitor of Monoamine Oxidase

AET was initiallydescribed as an in vitro and in vivo inhibitorof MAO (i.e., as a MAOI) by Greig et al.56 and Heinzelman et al.;16 this was followedby a more detailed report shortly thereafter.57 AET produced 50% MAO inhibition at 2.6 × 10–4 M; however, the main focus of the investigation was on the opticalisomers of the 7-methyl analog of AET which were nearly equipotent(50% inhibition at 2.1 × 10–5 and 2.6 ×10–5 M for the (−)- and (+)-isomers, respectively).Other compounds examined included, for example, the 5-methoxy, 6-methoxy,6-fluoro, and 6-amino analogs of AET, as well as the inactive majormetabolite of AET (i.e., 6-hydroxy AET; 0% inhibition at 10–3 M). The 6-hydroxy metabolite of AET was investigated and characterizedas its creatinine sulfate salt.57 AET appearsto be a reversible MAOI inhibitor (see Greig et al.43,58 and references therein).

Robie compared the effect of AET(25–75 mg/day p.o.) in70 patients relative to other MAOIs available at the time, and theoverall results were favorable.59 Thismight be due, in part, because unlike the other MAOIs used for comparison,AET is not an irreversible inhibitor of MAO.60 Nevertheless, in its effect on 5-hydroxytryptamine brain metabolismin vivo, AET was somewhat more active than (+)amphetamine, but lesspotent than harmaline; it was concluded that it seems doubtful whetherthe relatively weak action of AET on monoamine brain content is amajor contributing factor to its stimulant effect on the central nervoussystem.61 Also, as cited by Renyi,62 AET produced 80% inhibition of MAO-A. Perhapsdue to its reversible nature, AET continues to be employed, on occasion,as a MAOI in preclinical scientific studies.63 As a curious aside, a patent for AET mentioned that “MAO inhibition is not the mechanism by which the remarkable antidepressantaction [of AET]is achieved in humans...”,17 although no other information was provided.

AET and Neurotransmission

Early studies suggested thatthe actions of AET, in addition toMAO inhibition, likely involve the neurotransmitter serotonin. A comparisonof AET (1), α-MeT (2), and DMT (3) using an isolated rat fundus preparation (now known topossess 5-HT2-like, specifically 5-HT2B, serotoninreceptors) showed that the affinity of AET was 10-fold lower thanthat of α-MeT and 5-fold lower than that of DMT; for comparison,the (−)-isomer of α-MeT displayed nearly 10-fold higheraffinity than its (+)-isomer.64,65 AET (IC50 = 9,500 nM displayed lower affinity for rat brain 5-HT1 receptors labeled with [3H]5-HT than either α-MeT(IC50 = 5,700 nM) or DMT (IC50 = 137 nM);64 however, it is now realized that multiple populationsof 5-HT receptors were being labeled. For example, both isomers ofAET have more recently been shown to bind at human 5-HT1E and 5-HT1F receptors, but with only modest affinity (Ki = 1,580 and 4,849 nM forS(+)AET, and 2,265 and 8,376 nM forR(−)AETat 5-HT1E and 5-HT1F receptors, respectively)and little to no selectivity or stereoselectivity.66

Ross and Ask67 found thatnonhydroxylatedtryptamines, including AET, can act at the serotonin transporter.The release of tritium from rat occipital cortex slices previouslyloaded with [3H]5-HT demonstrated the action of AET asa serotonin releasing agent.60,67,68 Also, AET had no significant effect on dopamine or norepinephrinelevels in rat cortex or hippocampus, but increased serotonergic markersand the number of serotonin uptake sites.69 More recently, Blough et al.70 examinedAET at the serotonin (SERT, EC50 = 23.2 nM), dopamine (DAT,EC50 = 232 nM), and norepinephrine (NET, EC50 = 640 nM) transporters and found it to be at least 10-fold selectivefor SERT as a releasing agent and somewhat more selective than α-MeT(EC50 = 21.7, 78.6, and 112 nM for SERT, DAT, and NET,respectively). They also found that AET lacked agonist action at aconcentration of 10,000 nM in a 5-HT2A-mediated calciummobilization assay.70 More will be saidbelow about the action of the AET optical isomers.

AET Optical Isomers

The two optical isomers of AETwere first described in a patentby Anthony in 1970;17 seeFigure1 to identify the α chiral(*) center of AET (1). It might be consideredthat this was an effort by Upjohn and co-workers to overcome theirwithdrawal of racemic AET from the clinic. That is, the undesiredagranulocytosis evident with racemic AET that led to its withdrawalmight have been associated with one or the other of the isomers; however,clinical investigation of the isomers apparently was never completed(or at least never published), and an individual isomer was nevermarketed. It has yet to be determined which of the AET optical isomers(if not both) is responsible for this adverse effect.

Inhibition of MAO and Locomotor Activity

Relativelyfew studies have since focused on the individual optical isomers ofAET. Both isomers [(−)-isomer: 50% inhibition at 1.5 ×10–4 M; (+)isomer: 79% inhibition at 10–3 M)] acted as MAOIs.71 (−)AET at20 μmol/kg (rats, i.p.) significantly increased locomotor activityas measured for 30 min when administered 30 min presession.72

Drug Discrimination Studies

Having found that the opticalisomers of the recognized hallucinogen MDA (11), theN-desmethyl analog of MDMA (12), produce distinct discriminative stimulus effects in rats73 and that the behavioral effects ofR(−)MDA in mice but not those ofS(+)MDA,R(−)MDMA, orS(+)MDMA could be attenuatedby pretreatment of the animals with the 5-HT2 receptorantagonist pirenperone (implicating 5-HT2 receptor involvementin the action of the former),74 we initiatedan investigation of AET optical isomers. Some years ago we proposeda Venn relationship (Figure3) to explain the discriminative stimulus properties of certainphenylalkylamines.75,76 Using groups of rats trainedto discriminate the classical phenylalkylamine hallucinogen DOM (4), the central stimulant phenylalkylamine (+)amphetamine[(+)8], and the abused (but of unknown mechanism) phenylalkylaminePMMA (10) (i.e., the 4-methoxy analogue of methamphetamine)from vehicle, animals trained to one of these three agents did notrecognize (i.e., generalize or substitute for) either of the othertwo. Given its structural similarity to amphetamine, it might havebeen expected that PMMA would be a locomotor stimulant; however, PMMAfailed to produce hyperlocomotor effects in mice at doses of up to30 mg/kg.77 Interestingly, more recentlocomotor studies in rats have produced mixed results showing thatPMMA somewhat increased,78 or decreased,79 locomotor effects. It should be noted, though,that there were early warnings about the potential toxicity of PMMA,77 and PMMA has since been shown to be a very dangeroussubstance resulting in a substantial number of human fatalities andhas also been found as an adulterant in MDMA samples.80 On the illicit market, PMMA has been termed “Death”or “Dr. Death” (for example, see Nicol et al.).81

Figure 3.

Figure 3

Venn relationship (left) between the unique stimulus characterof DOM (4), (+)amphetamine (theS(+)isomer of8), and PMMA (10). Certain agents(see the text) produced more than one effect. AET optical isomers(top right) produced different effects.

Certain phenylalkylamines produced more than oneeffect. For example,R(−)MDA produced DOM-and PMMA-like, but not amphetamine-like,effects (which would situate it in the D/P intersect ofFigure3), whereasS(+)MDA produced amphetamine-like and PMMA-like, but not DOM-like,effects (which would place it in the P/A intersect). Racemic MDAproduced all three effects (which would place it in the common intersect).Substitution occurred upon administration of theN-monomethyl analog of MDA (i.e., MDMA;12) to amphetamine-and PMMA-trained animals suggesting MDMA might be classified as aP/A-type agent. Furthermore, PMMA was several-fold more potent thanMDMA in rats trained to discriminate either PMMA or MDMA from vehicle.82 However, there were also some indications thatthe two agents produced somewhat different discriminative stimuluseffects. For example, using rats trained to discriminate either PMMAor MDMA from vehicle, tests of stimulus generalization with variousagents argued that the stimulus effects produced by MDMA and PMMAare similar, but nonidentical, and that PMMA is the less “stimulant-like”of the two.83 Furthermore,S(+)PMMA (ED50 = 0.32 mg/kg) was found to be at least aspotent as PMMA (ED50 = 0.41 mg/kg) in PMMA-trained animals,whereasR(−)PMMA failed to result in completestimulus generalization.84 Some of theabove-mentioned drug discrimination data, emphasizing the importanceof the evaluation of individual optical isomers, are summarized inTable1. Notably, MDMA fullysubstituted in rats trained to discriminateR(−)DOMfrom vehicle, but generalization was asymmetric in thatR(−)DOM elicited only 51% drug-appropriate responding in MDMA-trainedanimals. Even though DOM and LSD substitute for one another, MDMAproduced only 56% LSD-appropriate responding.85

Table 1. Drug Discrimination Resultsa.

trainingdrug
agentDOMAETMDMAPMMA(+)Amph
AET6.61.33.5n.d.(41%)
(+)AET2.71.32.01.4(53%)
(−)AETNG1.61.31.67.8
DOM0.40.4NGNGNG
(+)AmphNG(40%)(49%)NG0.42
(±)PMMANGn.d.0.20.44NG
(+)PMMANGn.d.n.d.0.32n.d.
(−)PMMANGn.d.n.d.NGn.d.
(+)MDMANGn.d.0.761.42.6
(−)MDMANGn.d.(65%)1.6NG
a

Effect of AET and its optical isomers,and several other selected agents, in rats trained to discriminatevarious agents from vehicle; where substitution (i.e., stimulus generalization)occurred, an ED50 dose in mg/kg is provided. All data shownhere are from the authors’ laboratories. Investigations wereconducted using the same operant equipment and similar techniques,and results have been extracted from our previously published literature.35,48,75,82−84,86−88 Where stimulus generalization (i.e., ≥80% drug-appropriateresponding) occurred, an ED50 dose is shown in mg/kg. Here,NG indicates no stimulus generalization (i.e., < 20% drug-appropriateresponding). Figures in parentheses indicate maximal percent drug-appropriateresponding followed by disruption of the animals’ behaviorwhen the agent was evaluated at a slightly higher dose(s), and “n.d.”signifies that the data are unavailable.

AET (1) behaved much in the same manneras MDA (11). That is, racemic AET substituted in DOM-and PMMA-trainedrats and partially substituted in (+)amphetamine-trained animals (vide supra; seeTable1). However, although (+)AET substituted in DOM- andPMMA-trained animals, it did not substitute in (+)amphetamine-trainedrats; conversely, (−)AET substituted in (+)amphetamine- andPMMA-trained animals, but not in animals trained to discriminate DOM.Hence, (+)AET seems to be a D/P-type agent, whereas (−)AETwould be better classified as a P/A-type agent89 (seeFigure3). Moreover, both AET optical isomers substituted in MDMA-trainedanimals with (−)AET being just under twice as potent as (+)AET(ED50 = 1.3 and 2.0 mg/kg, respectively, using rats trainedto discriminate 1.5 mg/kg of MDMA).89

α-Ethyltryptamine has also been used as a training drug inrats.90 Once established, the AET stimulusgeneralized to (−)AET, (+)AET, DOM, and PMMA (Table1), but only partially generalized(ca. 40% maximal drug-appropriate responding) to (+)amphetamine.The results suggested that racemic α-ET produces a complex stimulus.

Possible Mechanisms of Action

Upon examination of AETisomers on neurotransmitter release, (+)AET was found to be a potentreleasing agent at SERT and DAT, with lower potency at the NET, whereas(−)AET seemed more selective for SERT (Table2). Interestingly, (+)PMMA displayed someselectivity as a SERT versus DAT releasing agent, with <4-foldselectivity versus NET (Table2). The (−)PMMA isomer was nearly inactive at DAT.

Table 2. Monoamine Releasing Potency (EC50 Values) for AET (1) and Its Optical Isomersand the Isomers of PMMA (13)a.

 SERT(nM)
DAT(nM)
NET(nM)
agentref 76ref 70ref 76ref 70ref 76ref 70
(±)AETn.d.23n.d.232n.d.>10,000
(+)AET20356458>10,000592
(−)AET6855900654>10,0003,670
(+)PMMA41n.d.1,000n.d.147n.d.
(−)PMMA134n.d.>14,000n.d.1,600n.d.
a

Values have been rounded offto the nearest whole number. “n.d.” indicates that datawere not reported.

Drug discrimination data from rats trained to discriminateeitherDOM or LSD as a training drug suggested that AET, or at least (+)AET,might be considered an hallucinogenic agent. Actually, apart fromthe human study with racemic AET by Murphree et al.,31 these are the only data suggesting that AET might be consideredas being potentially hallucinogenic. For example, racemic AET didnot produce the head-twitch response in rodents (now considered ahallmark or surrogate measure of hallucinogenic action, although withsome caveats), and administration of Monase to many clinically depressedpatients, even at doses of up to 300 mg, failed to evince such actionas an undesirable side effect. So, is AET a certifiable hallucinogenicagent? The nonhallucinogenic SERT releasing agent fenfluramine (7), as discussed above, unexpectedly substituted for DOM insome (rat but not primate) drug discrimination studies using DOM astraining drug. Is it possible that DOM trained rats recognize AETbecause it is a relatively SERT-selective releasing agent, as is fenfluramine?Yet, substitution occurred with the isomers of AET in PMMA-trainedanimals. Then again, PMMA and DOM produce different stimulus effectsregardless of which is used as training drug (Table1). For comparison, MDMA is also a SERT releasingagent (EC50 = 61 nM), but it did not substitute for DOM;however, it is nonselective and nearly comparable as a releasing agentat DAT and NET (EC50 = 75 and 72 nM, respectively) andproduced >95% of the maximal effect at all three transporters.91

Clearly indicated are additional studieson AET, particularlyon its individual optical isomers. Racemic AET lacks 5-HT2A receptor agonist action–in contrast to many classical hallucinogens(e.g., Glennon et al., 2000).92 Althoughracemic AET and (−)AET are functionally inactive as agonistsat 5-HT2A receptors, (+)AET is a partial (61% maximal effect)5-HT2A receptor agonist (EC50 = 1,250 nM) ina calcium mobilization assay.70 Hence,it is possible that (+)AET results in stimulus generalization in DOM-trainedrats due to its action as a SERT releasing agent, a partial agonistat 5-HT2 receptors, or a combination of both.

Arylalkylamine Homologation and the Venn Relationship

Agents shown inFigure1 are indolealkylamines (or tryptamines), and those inFigure2 are phenylalkylamines(or phenylisopropylamines); collectively, they are considered arylalkylamines.Homologation or extension of the α-methyl group (when present)of arylalkylamines to an α-ethyl group results in some interestingeffects. For example, homologation of the α-methyl group of(+)amphetamine [(+)8] to an ethyl group resulted in anagent that failed to substitute for (+)amphetamine in rat drug discriminationstudies.93 This does not necessarily implythat it is devoid of all amphetamine-like action. For example, thiscompound produced, although minimal, hyperlocomotor action in rats,and, although active, was substantially less potent than (+)amphetamineas a DAT (by ca. 55-fold) or NET (by 10-fold) releasing agent in ratbrain synaptosomes;94 nevertheless, althoughless potent than (+)amphetamine, the α-ethyl homologue of amphetaminewas self-administered by rats.95

The findings presented above are in contrast to the effect onstimulus generalization studies upon homologation of the α-methylsubstituent of MDMA (12) to MBDB (13;Figure4). Although neitherMBDB nor either of its optical isomers substituted in rats trainedto discriminate LSD from vehicle, MBDB and both of its optical isomers,as well as both optical isomers of MDMA, (+)amphetamine, but neitherLSD nor DOM, substituted in MDMA-trained rats.96,97 A (+)amphetamine stimulus failed to generalize to racemic MDMA,racemic MBDB, or either of their optical isomers.97 In rats trained to discriminate (+)MBDB from vehicle, stimulusgeneralization occurred with MDMA but not with DOM, LSD, nor (+)amphetamine,leading to the conclusion that “the primary behavioralactivity of MDMA-like compounds is unlike that of hallucinogens andstimulants”.98

Figure 4.

Figure 4

Chemical stucturesof some α-homologated phenyalkylamines:MBDB, α-EH PMMA, and BL-3812 or α-EH DOM.

With respect toFigure3, the question arose regarding the effectof α-methylhomologation of PMMA to its α-ethyl homologue α-EH PMMA(14). α-EH PMMA substituted in MDMA-trained ratswas slightly less potent than MDMA (ED50 = 1.29 and 0.76mg/kg, respectively). Furthermore, both optical isomers of α-EHPMMA substituted for training drug in PMMA-trained animals (ED50 = 0.8, 2.0, and 0.4 mg/kg for the (+) and (−) isomersof α-EH PMMA, and racemic PMMA, respectively).99 These findings suggested relatively similar effects uponhomologation in the MDMA and PMMA series.

What remains, withconsideration ofFigure3, is an examination of the effect of homologationon the DOM series. Bristol-Myers examined a series of α-ethylhomologues of phenylalkylamines in the late 1970s as agents for thepotential treatment of neuropsychiatric disorders; among these wasBL-3912 (15).100,101 Evidence suggestedthat BL-3912 (which might be viewed as α-EH DOM;15) lacked hallucinogenic-like action, including in human clinicaltrials. It has been reported that α-EH DOM is “not really a stimulant of any kind, certainly it was not a psychedelic”, and that theR-isomer was more effectivethan its opposite enantiomer.102

α-EH DOM (15) substituted in LSD-trained rats37 as well as in DOM-trained animals (Table3) as did its morepotentR(−)-isomer (ED50 = 4.59mg/kg); theS(+)-isomer resulted in partial generalization(a maximum of 59% DOM-appropriate responding).34 α-EH DOM failed to substitute in (+)amphetamine-trained,but substituted in MDMA-trained, animals (Table3).47

Table 3. Comparison of Stimulus GeneralizationStudies with DOM, α-MeT, and Their α-Ethyl Homologuesα-EH DOM and AET (or the α-EH of α-MeT), Respectively,in Rats Trained to Discriminate either DOM, (+)Amphetamine, or MDMAfrom Vehiclea.

 trainingdrug
agentDOM(+)AmphMDMA
DOM0.4(32%)NG
α-EH DOM6.44(52%)1.3
α-MeT3.13(57%)(35%)
AET6.62(41%)3.5
a

ED50 (mg/kg) values areprovided where stimulus generalization occurred. See text for references.NG indicates no substitution whereas numbers in parentheses representmaximal percent drug-appropriate responding.

Based on the results described above, homologationof the α-methylgroup of amphetamine to an ethyl group is not tolerated in stimulusgeneralization studies, whereas it is tolerated by MDMA and PMMA.Of particular interest is that the corresponding homologation of DOMresulted in decreased DOM-like potency but in the emergence of MDMA-likestimulus action. Interestingly, similar results were obtained withα-MeT; that is, α-MeT is a DOM-like agent that failedto substitute in (+)amphetamine- or MDMA-trained animals; however,α-homologation to an ethyl group (i.e., AET, which might beviewed as α-EH of α-MeT) resulted in MDMA stimulus generalization(Table3). So, here,as with DOM, homologation of α-MeT to AET resulted in decreasedDOM-like potency but in the emergence of MDMA-like action.

Recently,Cunningham et al.103 reinvestigatedBL-3912 (15). BL-3912 displayed affinity for h5-HT2A receptors (Ki = 120, 53, and220 nM for the racemate,R(−), andS(+) isomer, respectively), the racemate andR(−) isomer demonstrated partial 5-HT2A agonistaction, and the racemate showed a “markedly attenuated” head-twitch response in mice relative to control. The authorsargued that on the basis of their studies (not all of which are discussedhere), and the lack of hallucinogenic action in humans, that this“provides the strongest support for the therapeuticpotential of non-hallucinogenic 5-HT2Areceptor agonists”.103 They also suggested thatweak 5-HT2A signaling efficacy might account for the lackof hallucinogenic action.

Conclusions

On the available preclinical and clinicalliterature, there islittle doubt that AET is a psychoactive substance, but evidence thatit is a hallucinogenic agent is rather tenuous. Interestingly, AETseems to produce a mild but long-lasting stimulant effect that mightbe related more to one of its optical isomers than the other and empathogeniceffects (as suggested by preclinical and clinical data implying possibleMDMA-like action). In addition to its actions as a reversible MAOI,AET (or at least one of its optical isomers) seems to influence monoaminetransporters and displays partial agonist action at 5-HT2A receptors, actions that have been previously associated with otherpsychotherapeutic agents. It would seem that continued studies withthis agent, in particular, with analogs of AET and, more specifically,with optical isomers thereof, might prove fruitful for the developmentof novel psychotherapeutic agents. AET is an agent with demonstratedantidepressant action in humans that might have been years ahead ofits time had it not been for its undesirable side effect of agranulocytosis.With the advances in our understanding of neurotransmission mechanismsand scientific technology made since the 1960s to better investigatesuch agents (e.g., in radioligand binding assays, electrophysiology,second-messenger systems and trafficking, toxicology), and findingsthat the optical isomers of AET produce nonidentical effects, thereis adequate rationale for the further study of AET-related agents.

Glossary

Abbreviations

AET

α-ethyltryptamine

DAT

dopamine transporter

DMT

N,N-dimethyltryptamine

DOM

1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane

LSD

lysergic acid diethylamide

MAO

monoamine oxidase

MDA

3,4-methylenedioxyamphetamine

MDMA

3,4-methylenedioxymethamphetamine

NET

norepinephrinetransporter

PMA

para-methoxyamphetamine

PMMA

para-methoxymethamphetamine

SERT

serotonin transporter

5-HT

5-hydroxytrptamine; serotonin

Data Availability Statement

All data providedin this review have been previously published and appropriately cited.

Although some dataprovidedherein from the authors’ laboratories were previously supportedby NIH grants from NIDA and the NIMH (as described in their citedliterature), no funds were available for the preparation of this reviewarticle.

The authorsdeclare no competing financial interest.

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