Mescaline: The Chemistry and Pharmacology of its Analogs

Alexander T. Shulgin
1183 Shulgin Road, Lafayette, California

This was presented April 24, 1972 at the Symposium on Peyote, Houstan Texas

Abstract. - Although mescaline (3.4.5-trimethoxyphenethylamine the principal

alkaloid of the Peyote plant Lophophora williamsii) has been extensively explored

in man as a hallucinogenic intoxicant. only a few of the natural alkaloids that accom-

pany it in nature have been evaluated as chemical individuals. It appears that these

congeners do not contribute to the reported action of the intact plant. Synthetic

modifications of the structure of mescaline have been more rewarding in the search

for relationships between the details of chemical structure and of biological activity.

The most thoroughly investigated analogs are the substituted phenylisopro-

pylamines. These carry the carbon skeleton of amphetamine, as is found in natural

bases such at ephedrine. Ring substitution arrangements that imitate the peyote

alkaloids and the phenylpropenes from the essential oils, have led to a number of hal-

lucinogens generally more potent than mescaline. These all reflect some botanical

precedent.

Other analogs are based largely on changes in the length of the carbon chain. or in

the nature of the substituent in the 4-position (para to the aliphatic chain). The

shortening of the chain always decreases the observed potency, but any lengthening

invariably changes the pharmacological action from hallucinogenesis to relaxants or

to psychic energizers. The para-substitution changes involving alkyl groups, halides,

or cyclic ethers have led to a retention of mescaline-like activity, but with a consistent

increase in potency.

The preceding three papers of this symposium have reviewed much of our

current knowledge concerning Peyote. Dr. McLaughlin has introduced the

plant with a geographic and botanical definition, and with some mention of its

native usage. Dr. Kapadia has presented an up-to-date picture of the dozens of.

organic compounds isolated from, or identified in it. Dr. Paul has discussed the

possible pathways employed in their biosynthesis. I should like to round out

this picture with a brief review of the pharmacological effects of the plant, its

components, and a number of closely allied analogs, as have been reported in

clinical studies in humans.

From the botanical point of view, I shall restrict this review to the single

plant Lophophara williamsii (Lemaire) Coulter although note must be taken

of a small residual justification for keeping the name Anhalonium lewinii

alive. Although the alkaloid, mescaline, has been observed in a number of

unrelated cacti, to pursue these and consequently other congeners, would lead

too far away from the symposium topic, peyote.

From the chemical point of view, I intend to center this entire discussion on

the parent structure of mescaline (1). Although it is of comparatively low

potency, it is nonetheless one of the most dramatic drugs known from the stand

point of sensory synthesis. Mescaline is probably the principle active component

of the plant peyote and is certainly the best studied. This component is an

easily defined and easily reproduced tool in both sociological and clinical studies.

Chemically it displays a deceptively simple structure against which the structures of

the more recently studied analogs can be easily compared.

From the pharmacological side, I shall limit this review to those compounds

that are of known activity in man. In the large area of substituted phene-

thylamines related to mescaline there are literally hundreds of thousands of

compounds which have been isolated from nature, or synthesized in the lab-

oratory and described in the chemical literature. Many thousands of these

have been put into one animal or another, therefore providing the raw data that

have contributed to countless technical papers in the pharmaceutical and

pharmacological literature. However, less than a hundred of these compounds

are of known activity in man, and I shall restrict my discussion to these alone.

Clinical studies in this area can be best divided into three epochs of research,

Frier to the turn of the century, reports stemmed from the initial observations

of Lewin both in plant description and in anthropological detail. This period

also produced the earliest chemical descriptions of Heffter, and the first writings

of human activity. A second period of interest flourished in the 1920's with the

reports of Rouhier and Beringer describing the action of the entire plant and its

principle components in man. The work of Gordon Alles, that of Hoffer and

Smythies, and much of my own work has appeared over the last decade, and has

concentrated to a large measure on homologs and analogs of the parent mescaline

structure.

This body of pharmacological detail can be organized into three divisions:

the first deals with the natural material itself and the components isolated from

it which might contribute to the total effect of the intact plant; the second is a

discussion of chemicals which are biosynthetically reasonable although of syn-

thetic origin; and the third is an extension of this group to include compounds

without natural precedent, but which seem to duplicate much of the physical

and psychological action of mescaline.

PANPEYOTE

The first group defined above includes those materials actually found in the

peyote plant. One must not only consider the entire plant, but also the ex-

tracts of the plant and the pharmacological properties which have been ascribed

to the "active" components of the plant. The term panpeyote has frequently

been employed for preparations in which there have been no attempts to frac-

tionate the components of the cactus. Most of the early studies of either the

peyote buttons themselves, or of the panpeyote isolates, have been reported by

sociologists, anthropologists, and chemists. The medical literature is sparse

and, by modern standards, unsophisticated.

The first medical report of the effects, in human subjects, of the intact peyote

buttons appear to be that of Ptentiss and Morgan (1). This study employed

dosages of several buttons (from three to seven per experiment) but variability

of button size and potency, and of individual sensitivity to the plant, make com-

parisons difficult. Lewin describes the normal Indian usage of twice this num-

ber, yet recounts a thorough intoxication produced by a fraction of a single

button (2). Both infusions (3) and extractions (4) of the whole plant have

been evaluated. The Tincture of Peyote is an extraction of the pulverized

dry plant with 70% ethanol and appears to contain all active components.

This style of preparation has been employed in a number of studies (5, 6). In

fact, a tincture was the form employed in the first recorded non-Indian report

of medical utility (1886) (7).

Another form that has been evaluated in man is called Basic Panpeyote.

This is the residue that is obtained by the evaporation of a chloroform extract

of the pulverized plant. This residue contains over 30% alkaloidal material

(6) and satisfactorily duplicates the human pharmacology of the intact plant (5).

From such studies it was apparent that biological activity was associated with .

the plant's alkaloid components, and a study of this fraction would circumvent

many of the problems arising from variability of plant material. The term Soluble

Peyote is a reference to an aqueous solution that results from the hack-extraction

into dilute hydrochloric acid of a chloroform solution of the residue of an am-

moniacal alcohol extract of the plant. This solution is also referred to as In-

jectable Peyote.

By the turn of the century a number of reports had appeared using one or

another of these preparations, and there was a generally expressed satisfaction

that both the nature and the chronology of the induced intoxication seemed to

parallel that seen with the use of the plant itself. Unfortunately, most of these

were concerned more with the details of the intoxication than with the composi-

tion of the intoxicant. In those reports that do concern themselves with the

quantitative aspects of clinical study, it seems that when the tincture of peyote

is employed, about 800 mg of alkaloidal material is required to produce full

effects. With basic panpeyote, about 600 mg of alkaloids are required. All

early work with both intact peyote and the various panpeyote preparations has

been reviewed by Rouhier (6).

MESCALINE

With the isolation of mescaline (1) as the alkaloid principally responsible

for the intoxicative action of the cactus (8) and its correct structural assignment

and successful synthesis by Spath in 1919 19), the emphasis of pharmacological

study shifted from the inconsistent plant to the readily synthesized compound.

The pure chemical appears to duplicate most of the reported effects of the total

plant in dosages compatible with its weight contribution either in the plant or

in panpeyote.

At a nominally active dosage level of 350 mg, there is a generally predictable

chronology of events. The first signs of change are largely physical. At about

a half hour following ingestion there is an onset of nausea, often accompanied

with active vomiting. There is occasionally the development of diarrhea. A mild

tachycardia and slight rise in blood pressure is often seen during this initial

phase, but this may be associated with anxiety and apprehension. The initial

indication of sensory change is noted in about one hour. The development of

central effects ends the "physical distress" phase of the intoxication, and this

"sensory" phase continues to develop to a plateau of intensity during the next.

two to three hours The physical changes noted during this period are minor.

There is a cardiovascular quieting with the pulse rate and blood pressure drop-

ping below their initial base levels, and a constant, extensive, but reactive,

mydriasis. A gradual diminution of the central intoxication over the following

few hours leads to a complete recovery generally within twelve hours. There

is consistently an excellent recall of the impressions and events that occurred

during the experiment.

Whereas this time pattern and sequence of events is quite predictable from

one person to another and from one occasion to another, the content and direc-

tion taken by the subject's imagination as directed by his interpretive capacities

are completely unpredictable and are unique to each experience.

Some sensory changes are regularly noted and can be expected to contribute

to the overall impact of the drug's effects. There is a shimmering and intensi-

fication of the visual field, far more intense than one might expect from the

mydriasis-induced photophobia. There is an intensification of color perception,

an extreme amplification of minor differences in both color and texture. Fre-

quently observed is the generation of patterned imagery, sometimes in a grid

structure, sometimes with undulating shapes, but usually with some color

contribution There is a benign empathy shown to both inanimate and living

things, especially to small things.

Many reviews, theses, and books have been based on the content of individual

mescaline responses, and such unique anecdotal material lies outside the scope

of this symposium. Reference to Beringer's studies (10) will show the

range of observed responses, and Huxley (1l) has explored in depth a single

experiment. This review will be restricted to general pharmacological pro-

perties, principally quantitative in nature, of the several compounds structurally

related to mescaline.

An important question has as yet no satisfactory answer: To what extent does

mescaline account for all of the alleged activity of peyote itself? I know of no

experiment in which the two substances, the pure chemical and the total plant,

have been directly compared. The pure chemical is usually assayed with a

single administered dose. The plant is generally consumed over an extended

period of time. The chemical is almost always investigated in a single, often

isolated, subject. On the other hand the sacramental use of peyote is a group

experience invoking the added variable of social interaction. The setting of a

mescaline experiment is often clinical and frequently tainted with some moral

reservations, whereas the peyote ceremony is an accepted ritual. Some of these

factors may contribute to differences in the detail of the intoxicated state.

MESCALINE CONGENERS

Some of the suspected pharmacological differences between the pure corn-

pound mescaline and the total plant substance, may be due to any of several

congeners known to be present in quantities potentially adequate to modify the

intoxication syndrome. Four of the tetrahydroisoquinoline alkaloids known

to be present have been evaluated in human subjects. Two of these are phenols

and two are methylenedioxy ethers.

Peyotline a phenolic tetrahydroisoquinoline methylated at both the

1- and 2-positions. This compound has played an interesting role in the early

research history of peyote. Heffter originally made reference to two species of

peyote (13). One he called Anhalonium lewinii and although he reported

the presence of mescaline and other alkaloids in it, he was unable to detect the

presence of any peyotline. This variant he called "mescalinica" A second

species called Anhalonium williamsii in his writing, appeared to contain

only peyotline. This he referred to as "peyotlinica". The generic name of

the latter variant has been modified and it has subsequently been referred to as

Lophophora williamsii. This has led understandably to some confusion. It

is now proper to use a single binomial for peyote (see p. 4, this issue) yet these

two mutually exclusive analyses must be rationalized. A disturbing note is

that while these two "variants" were morphologically indistinguishable, still

they were separated into their definitional classes.

The pharmacological action of peyotline in human subjects is one of calming

or sedation. rather than that of a hallucinogen. Jolly 14) has reported the

production of an uneventful sleep in patients with a dosage of 50 mg. At levels

of as much as 2~0 mg (total dosage) there are no indications of sensory distor-

dons (5). There is a dizziness and a generalized tiredness that undergoes a

gentle transition into sleep. This latter quantity of drug is greater than that

which would be encountered in a single dosage unit of peyote. It is certainly

possible that peyotline could contribute to the pharmacological picture asso-

ciated with peyote as this sedative action is noted at levels that might well be

encountered in the total cactus. At low levels in man i15-30 mg) there has

been described a calming effect, without overt hypnosis (14).

Anhalonidine (3) is the homologue of peyotline in which the N-methyl group

is absent. In man it appears to act in a manner parallel to peyotline (leading

to a heavy-headedness and sedation) but with only about one-fourth the potency.

At oral levels of between 100 and 250 mg there was a marked sedation, but no

sensory changes whatsoever (5). It is unlikely that this compound contributes

to the reported action of panpevote.

The two remaining tetrahydroisoquinoline principles of peyote are methvl-

enedioxy ethers rather than phenols. The first of these is lophophorine

the methylenedioxy analog of peyotline. This alkaloid has been considered the

most toxic of the natural components of peyote, but this claim is based solely

on animal studies. In man (5) oral dosages of 20 mg led to a distinct vasodiIa-

tion accompanied by an immediate headache and a warm flushed feeling. These

responses are lost within the hour. The level of lophophorine found in peyote

varies over a wide range and no estimate can be made concerning its contribu-

tion to the action of the entire plant,

Anhalonine (5) is the rnethylenedioxy ether analog of anhalonidine and the

N-demethyl homolog of lophophorine. This alkaloid appears to show pharma-

cological properties similar both quantitatively and qualitatively to its phenolic

counterpart anhalonidine. A single reported experiment with 100 mg orally

(5) led to an uneventful tiredness without any noticed central effects of a sen-

sory nature.

The term "amorphous anhalonine" is occasionally encountered in the early

literature on peyote. This has been shown not to be a single substance but a

mixture of peyotline and lophophorine.

Five additional compounds warrant mention here, for although they are all

either tract components in peyote or arguable as being possibly present on bio-

synthetic grounds, they have been explored in man pharmacologically.

N-acetylmescaline (6) has been isolated as a trace component in the peyote

plant (15) and has been identified as a metabolite of mescaline in man (16). It

has been explored in acute trials in human subjects at levels between 300 and

750 mg total dosage. Only at the highest levels were any effects noticed, and

they were summed up as being merely a mild degree of drowsiness (16).

N-methylmescaline (7) similarly is a trace component of peyote (17). Hu-

man studies have shown no effects either peripheral or central at levels of 25

mg (18) but even this level represents many times that which would be en-

countered in a nominal dose of peyote.

The homologous N,-Ndimethylmescaline (trichocerine, 8) has never been

observed in peyote, although it has been observed in a number of closely related

cacti. It has been included in this report because of its close relationship to the

well-documented presence of the mono-methyl homolog, and the known presence

of methylating enzymes in the peyote plant. The compound has been found

devoid of any central activity in humans even following parentetaly admin-

istered dosages of more than 500 mg (19).

A fourth compound is homomyristicylamine (lophophine, 9) which also has

never been observed in the peyote plant, but which presents an obvious theoretical

potential as a biosynthetic precursor of the tetrahydroisoquinoline alkaloids

such as lophophorine and anhalonine. This compound is active in man at dosage

levels of 150 to 200 mg, about twice the potency of mescaline (18). The quali-

tative description of its action is quite similar to that of mescaline, in that there

is a peaceful elevation of mood, the generation of an euphoric state, and the

enhancement of visual perception especially in the color sense. There are dis-

similarities, particularly in that there is little if any nausea and there is no

visual distortion. These latter differences disappear at dosages of 300 mg and

there is the generation of eyes-closed imagery similar to that observed with

mescaline.

Some comment is in order concerning these responses to mescaline, to

homomyristicylamine, and to a number of materials to be described below.

This response has been given many names. It has been called hallucinogenesis,

a concept that insists that there is the generation of hallucinations. The defini-

tion of a hallucination is certainly controversial, and there are very few drugs

that are generally accepted as being able to produce them. 'It has been called

psychotomimesis and the drugs producing it, psychotomimetics. This term

suggests that the response resembles the psychotic state, and there is scant

medical support for such a stand. The term psychedelic has come to imply

social virtue and sanction in the use of these drugs. Each of these terms, as

with others such as psychodysleptic, is clearly biased and incomplete.

A compound, 3,4-dimethoxyphenethyiamine (DMPEA. 10), has received

wide attention due to its association with urine analysis of patients diagnosed

as schizophrenic (20). This compound has recently been reported as a trace

component of peyote (21) although it is a well established component in a

number of closely related cactus species. Investigation of this chemical in

humans, at levels of a full gram, failed to produce any observable disturbances

(22, 23).

It thus appeals that there is a structural requirement necessary for the

production in human subjects of the pharmacological properties characteristic of

mescaline. This is the 3,4,5- trisubstituted phenethylanine system, as illus-

trated by mescaline (of natural sources) and by lophophine (unnatural, but bio-

synthetically logical), both active at about 5 mg, kg in man. There are many

chemicals however, compounds with structures related to mescaline through

botanical analogy, that show this same psychopharmacological response but with

greatly increased potency. Three classifications of these "quasi-natural" com-

pounds may be made, based simply upon the nature of the chemical structural

variation. Included are those homologs that result from an extension of the

aliphatic chain, the isomers that can result from the variation of the position

and the number of the methoxyl groups present. and finally those analogs that

result from the substitution of a methylenedioxyheterocyclic ring for two ad-

jacent methoxyl groups.

MESCALINE: HOMOLOGS

The aliphatic chain that lies between the aromatic ring system, and the

basic nitrogen, for almost all alkaloids in the plant kingdom, is two carbons long.

The phenethylamine or indolethylamine (Tryptamine) system is a foundation of

nearly all known pharmaceutical agents that are based upon alkaloids. The

monomethylene or trimethylene homologs that have been prepared have to a

large measure proved to be uninteresting pharmacologically. The most re-

warding studies have come from chain lengthenings that have involved homol-

ogous families in which the basic nitrogen atom (the amine group) has been

maintained in the beta-position (two carbon atoms removed from the aromatic

ring). These are the so-called alpha-alkyl homologs such as the phenyliso-

ptopylamines and the phenylsec-butylamines.

The simplest of these homologs, the alphamethylphenethylamines, are

stimulants of both natural and man-made origins. The compound ephedrine

(11) is a component of the plant material that, and is a principle alkaloid in

several of the species of Ephedra. Further, this simple molecular configuration

has led to the study of the completely unsubstituted analog, phenylisopropyl-

amine (amphetamine, 12). This latter compound appears to produce a simple

sympathomimetic stimulation at least at low dosages, and if there ate any

"psychotomimetic" developments they are to be found only at high usage

levels which can be achieved only through the development of a tolerance to

the normally expected debilitating effects.

The actions of a compound that results from the combination of the fea-

tures of mescaline and of amphetamine have been described (24). This com-

pound is 3,4,5-trimethoxyamphetamine (3,4,5-trimethoxyphenylisopropylamine,

TMA, 13) and it has been established as being an effective sensory distorting

agent at levels of about 175 mg (25). It is thus about twice as potent as mes-

caline.3 An extension of this chain to the 4-carbon homolog (alpha-ethyl-

mescaline, 14) produces a compound that lacks all central and peripheral activity

in human subjects at acute levels as high as 220 mg (27).

These several chemicals have laid the groundwork for all of the substances

to be discussed below, namely that the three carbon chain, the phenyiisopropyl-

amine or amphetamine structure, has proved to be optimum for the generation ·

of these sensory distortion effects. A decrease of the chain length to two car-

[ The carbon skeleton end positional location of the ether oxygen atom in 13 (end in

MMDA. 25. below) are identical to that found in elemicin end myristicin. components

of the spice nutmeg. These Latter nitrogen-free essential cils have recently been

shown capable of being converted into the above mentioned amphetamine

analogs under biological conditions (26).]

-bons (the loss of the alpha-methyl group) usually retains the nature of activity

but with some decrease in potency. A lengthening of the chain to four carbons

(the substitution of an alpha-ethyl group) changes the qualitative nature of the

pharmacological response.

MESCALINE ANALOGS

Variations of the substitution pattern of the methoxyl groups within this

generalization of a three-carbon chain optimum, have led to extensive changes

in potency. Using 13 as a parent structure, there are five possible positional

isomers. These have been synthesized (28) and clinically evaluated in man (29).

The first of these positional isomers (2,4,5-trimethoxyphenylisopropylamine,

TMA-2, 15) is also related to a series of essential oils, the unconjugated 2,4,5-

trimethoxy- l-allylbenzene found in Caesulia axillaries (30) and the conjugated

counterpart in a number of species of Asarum and Acorus (31). The isomer

has proven to be the most potent of all six, with an effective dosage level of 20

mg, about a twentieth that required for effective mescaline intoxication. The

vicinal analog (2,3,4-tiimethoxyphenylisopropylamine, TMA-3, 16) has neither

natural counterparts nor central activity.

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 If

ate similar to one another in that at threshold levels there is noted only an en-

joyable 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, If, is about half as potent as 15, thus having some

ten times the effectiveness of mescaline.

The two remaining possible isomers are known, have been titrated clinically

to determine their relative potencies, but have not been explored to an extent

adequate for generalizations concerning the qualitative nature of their actions.

2,3,5-Trimethoxyphenyiisopropylamine (TMA-4, 18) is an effective central

intoxicant at a 90 mg dosage, and 2,3,6 -trimethoxyphenyli sopropylamine

(TMA-5, 19) has similar activity at 30 mg. Both ate thus clearly more potent

than mescaline,

A number of isomers of 13 have been studied wherein the variation is with the

number of methoxy groups rather than with their position. A single tetra-

methoxy analog is known, 2,3,4,5- tetramethoxyphenylisopropylamine (20). As

with others of the active phenylisopropylamines, there is a corresponding es-

sential oil in nature. This exact carbon skeleton is found in 2,3,4,5-tetra-

methoxy-l-allyl benzene, one of the major constituents of the seed oil of Apium

spp. (32). Compound 20 is effective in man at a dosage of 60 mg, i.e., six times

as potent as mescaline (29).

Three of the six possible dimethoxyphenylisopropylamines have been ex-

plored pharmacologically. The compound most closely allied with both botan-

ical and mammalian biochemistry is 3,4-dimethoxyphenylisopropylamine (DMA,

21). The plant correlation is to methyleugenol and methylisoeugenol, common

essential oils found in a host of plants. In animal chemistry, 3,4-dihydroxy-

phenethylamine (dopamine) is an intermediate in the synthesis of the trans-

mitter norepinephrine, and- 21 is its trimethyl homolog. The role and action of

the two-carbon analog 10 have been discussed above. Compound 21 is slightly

less potent than mescaline (33) in that levels of about 700 mg were required

parenterally to produce the color syntheses and other sensory distortions ascribed

to mescaline. The other two dimethoxy isomers that have been studied, 2,4-

dimethoxyphenylisopropylamine (22) and 2,5-dimethoxyphenylisopropylamine

(23), are considerably more potent, being active at 70 mg and 45 mg orally, resp.

(29).

Only one monomethoxy analog has been explored clinically. In animal

studies, this compound (4-methoxyphenylisopropylamine, PMA, 24) is reported

to have an hallucinogenic potential parallel to LSD (34).. In man, however,

some 75 mg is required (orally) for effective central activity, thus being closer

to mescaline than LSD in potency. Arguments that this compound might be

an active metabolite of amphetamine in cases of amphetamine-induced psychoses,

have been answered by the reported failure to observe this compound in human

urine samples following heavy amphetamine administration. It could only be

found as an excretory product following its own administration to human

subjects (35).

Bases that contain a methylenedioxy ring in place of two adjacent methoxyl

groups constitute a large family of compounds that parallel most of the above-

mentioned polymethoxylated phenylisopropylamines . In nature, this form of

biosynthetic relationship is frequently seen. It occurs within the tetrahydroiso-

quinoiine alkaloids of peyote itself. A generalized qualitative comment can be

made concerning the methylenedioxyphenylisoptopylamines itemized here. In

almost every case in which a specific comparison is available between a methyl

enedioxy compound and its dimethoxy counterpart, the methylenedioxy com

pound shows less potential for visual distortion, it is generally more controllable

in its extremes of central activity and, as a rule, it is more potent. Of this

family only two compounds, 25 and 33, have been sufficiently studied to warrant

extended discussion of qualitative subtleties.

Just as there are six possible trimethoxy-substitution isomers of amphetamine,

so there are six possible methoxymethylenedioxy isomers. Five of these six

have been described chemically and pharmacologically. Their trivial names

relate the position of the oxygen substituents directly to the trimethoxy counter

part; i.e., MMDA-5 and TMA-5 are both 2,3,6-substitution products.

The isomer that is the direct relative of mescaline (1) and the theoretical

lophophine (9) is 3-methoxy-4,5-methyienedioxyphenyiisopro (MMDAI

25). The carbon skeleton in this instance is that of myristicin and isomyristicin,

essential oils found throughout the plant kingdom. This compound was syn-

thesized and evaluated independently in two separate laboratories (36, 37).

The compound is active in man at 130 mg, and so has nearly three times the

potency of mescaline. Unlike mescaline, however, its actions are largely free of

perceptual distortions, and seem not to inflexibly command the complete atten-

tion of the subject. There is an element of choice in the degree of compliance

to the intoxication, and there seems to be some valid access to memory material.

These properties have been discussed in a recent monograph (38). The com-

pound analogous to TMA-2 (15) is 2-methoxy-4,5-methylenedioxyphenyliso-

propylamine (MMDA-2, 26). An essential oil (carpacin) with this substitu-

tion pattern has been isolated from Cinnamomumspp. (39). The base 26

is only slightly less active in human triais (30 mg) than the trimethoxy counter-

part. Two possible 2,3,4- trisubstituted compounds can exist that correspond

to 16. These are 2-methoxy-3,4-methylenedioxyphenylisopro (MMDA-

39, 21) and 4-methoxy-2,3 -methylenedioxyphenyiisopropylamine (MMDA-3b,

28). The first of these has a natural counterpart in the ether croweacin iso-

lated from Eriostemon crowei (40); the second has no known analogy in

nature. Although the trimethoxy compound with this vicinal substitution

pattern was not active, both of these compounds have been shown to be effective

intoxicants, the first at a 35 mg dose (41) and the second at 120 mg (29). The

fifth of these methoxy methylenedioxy isomers is 6-mtthoxy-2,3-methylent-

dioxyphenylisopropylamine (MMDA-5, 30) which corresponds exactly to

TMA-5 (19) both in substitution pattern and in potency (42). No successful

synthesis yet exists for 5-methoxy-2.3-methylenedioxvphenylisopro

(MMDA-4, 29). The analog to TMA-6 (lit) cannot of course exist.

Only three methylenedioxy compounds that are not trisubstituted have beer

studied in man. Two of these are the tetrasubstituted analogs of apiole and

dill-apiole, both well explored essential oils from a number of spices. These

are 2,5 -dimethoxy-3,4-methylenedioxyphenyiisopr (31) and 2,3-di-

methoxy-4 ,S-methylenedioxyphenyiisopropylamine (.32). They are active at

30 mg and 70 mg resp. (43) corresponding to twelve times, and five times the

potency of mescaline. The -remaining compound is 3,4-methylenedioxyphenyl

isopropylamine (MDA, 33) which, along with MMDA (25) is the only material

sufficiently well studied to warrant generalizations concerning comparative quali-

tative properties (44). Although this compound is not particularly potent

(typical dosage, some 120 mg or about three times the activity of mescaline)

its easy availability and apparent consistency of action have led to its study in

a number of laboratories. The 2,3-isomer is unknown.

The last group to be discussed consists of compounds that are quite re-

moved from nature. They have evolved quite logically however from the im-

portance that is clearly assignable to the 4-position of the aromatic substitution

pattern. An example is that, of all the several possible ethoxy homologs of the

maximally potent trimethoxy-compound 15, it is only the 4-ethoxy compound

(2,5 -dimethoxy-4-ethoxyphenylisopropylamine, MEM, 3r) that maintains com-

plete central activity at the same potency (45). An argument can be extended

that this positional sensitivity might be associated with a theoretical ease of

metabolic attack at this position. Consistent with this approach, one could

expect that the replacement of an easily attackable group (alkoxy) with one

less amenable to removal (aikyl) might radically affect the pharmacological

properties of the corresponding amine. The simplest such example, 2,5-di-

methoxy-4-mcthylphenylisoptopylamine (DOM, STP, 35) proved to be several

times more potent than 15 as a centrally active psychotomimetic. With an

effective, not threshold, level of activity of 3 mg total dosage, it has over one

hundred times the potency of mescaline. Further, the nature and chronology

of the intoxication is quite changed from that common to most of these chemicals

discussed. Most noteworthy is the unexpected lengthening of the time course

by a factor of three or more. Several clinical studies have appeared in the

medical literature concerning this drug (46, 47). The 4-ethyl homolog (2,5-di-

methoxy-4-ethyiphenylisopropylamine, DOET, 36) appears to be fully as potent

as DOM (35) although at lower clinical levels the psychological changes noted

seem to be somewhat more controllable and thus more constructive (118).

Recently yet another analog of this system has been described. In this, the

4-methyl group has been replaced with a bromo substituent to produce 2,5-

dimethoxy-4-bromophenylisopropylamine (37) (49, 50). This compound has in

man an effective response level of between 0.5 and 1.0 mg, thus it is several

hundred times mote potent than mescaline. Yet in the qualitative sense it

presents more of the clinical picture that has been associated with MDA (33)

(49). A positional isomer has been described (2,4-dimethoxy-5-bromophenyliso-

propylamine, 38) which is much less potent than 37 (100 mg for an effective in-

toxication) but which maintains the MDA-like response is1>. The 2-bromo-

analog of MMDA-2 (2-bromo-4,5-methylenedioxy·phenylisopropolymine) is

less active than mescaline (>350 mg in man) and seems to produce an ampheta-

mine-like response.

A final comment is in order concerning the frequent use of the term "ampheta-

mines" to describe these compounds. With the exception of some of the peyote

components, all of the centrally active substances that have been discussed here

contain the carbon skeleton of the amphetamine molecule. Yet almost none of

them display the sympathomimetic stimulation that is the reputation of am-

phetamine. The popular use of the term "amphetamines" has come to embrace

a large number of currently used drugs that are stimulants, and which call upon

these effects for their effectiveness. Examples of this are amphetamine itself

(and its dextrorotatory isomer, dexedrine), methamphetamine, methylphenidate

(Ritalin), phenmetrazine (Preludin) and mephenteramine (Wyamine). An

excellent demonstration of the separation of these pharmacological areas may be

se,., from the fact that the active isomer of DOM (35) is the R (-) form.

The S (+) form shows only stimulant properties, and this is the same absolute

configuration as that seen in the stimulatively active isomer of amphetamine

itself, S-(+) -dextroamphetamine (52).

This has been an up-to-date presentation of our knowledge of the structural

requirements for hallucinogenesis (or whatever this form of central stimulation

and sensory modification might be called). At this state of chemical evolution,

the structure of the parent compound mescaline might well look quite foreign.

However, its role has been evident as a starting point in this rapidly evolving

area of psychopharmacology.

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