recent times as to whether the use of

marihuana is "good" or "bad" should

remind us of some of the phrases used
by different generations in other lands
to describe the plant or, rather, its ef-
Hallucinogenic Plants fects. In the pre-Christian era, the Chi-
nese often referred to marihuana as the
"Liberator of Sin," whereas, in a later
Various chemical substances are known to be the period, these same people named the
plant "Delight Giver." Hindus have
active hallucinogenic principles in many plants. long termed it "The Heavenly Guide"
and the "Soother of Grief."
Norman R. Farnsworth The nature of the descriptive phrases
has, undoubtedly, depended on whether
a society was interested in using the
plant or interested in preventing its use.
Giving valid scientific evidence against
The so-called hallucinogenic drugs, pharmacologists, psychologists, and marihuana has always been difficult, for
many of which are widely used today, others. a number of reasons. A brief descrip-
all seem to have in common the power The hallucinogenic plants can be tion of the plant, its growth character-
to induce visual or other hallucinations divided conveniently into two groups istics, and its chemical constituents
and to divorce the subject from reality. according to whether their activity is should show the reason for many of
The hallucinogens have a long history. due to nonnitrogenous or nitrogenous these difficulties.
Virtually all of them are derived from principles, when this is known. The two The plant Cannabis sativa L. (family
plants (1). Ancient man knew many of representatives of the nonnitrogenous Cannabinaceae), the source of marihu-
these plants, and, because of their ef- group discussed here are marihuana ana, is a tall, annual weed, sometimes
fects, ascribed magical or mystical (Cannabis sativa), which contains sev- reaching a height of 15 feet (41/2 me-
relevance to them, using them as sacra- eral dibenz-a-pyrans (Fig. 1), and ters). It will grow in almost any waste or
ments in religious rites. In more recent nutmeg (Myristica fragrans), which fertile area. It is important to note that
times the hallucinogens (2) have been contains phenylpropenes (Fig. 1). The this weed is dioecious-that is, it has
used by individuals who believe that representatives of the nitrogenous group male and female plants. The male (stami-
they promote spiritual growth, enhance discussed here can be divided into the nate) plant usually grows taller than the
perception, stimulate personal develop- following subgroups: (i) 8-phenethyla- female (pistillate) plant. The staminate
ment, and open up reality. mines [peyote (Lophophora williamsii, flowers are axillary and borne in
It is not known with certainty just family Cactaceae)]; (ii) simple indoles panicles, whereas the axillary pistillate
how many plants have been used for (Piptadenia and Mimosa, family Legu- flowers are long catkins. Differentiation
hallucinogenic purposes, or even how minosae; Virola, family Myristicaceae); of the male and female plants is im-
many of those alleged to induce hal- (iii) "teonanacatyl" (Psilocybe, Cono- portant because the chemical com-
lucinations actually do so (see 3). Most cybe, and Stropharia species, family pounds responsible for the euphoric ef-
of our definitive chemical knowledge of Agaricaceae); (iv) ,B-carbolines (Peg- fect of marihuana are found primarily
hallucinogenic plants has evolved only anum harmala, family Zygophyllaceae); in a sticky resin that covers the female
during the past decade or so. Three (v) isoquinuclides (Tabernanthe iboga, flowers and adjacent leaves. Of im-
important factors have been responsible family Apocynaceae); (vi) ergolines portance in identifying both the male
for this. First, valid botanical authenti- [the morning glories (Rivea corymbosa and female plants are the leaves, which
cation of many hallucinogenic plants and Ipomoea species, family Convolvul- are large and palmately compound,
has been accomplished only during this aceae)]; (vii) tropanes (Methysticoden- each having five to seven linear-lance-
period. Prior to this, chemical reports dron amesianum and Datura species, olate leaflets, with serrate (toothed or
on these plants were, to say the least, family Solanaceae); and (viii} the isox- notched) leaf margins. Although the
chaotic. Second, the isolation and iden- azoles [fly agaric (Amanita muscaria, literature invariably refers to the resin
tification of active principles has been family Agaricaceae) (Fig. 1)]. covering the female flower parts as the
enhanced by the introduction of mod- In addition to the plants from these only portion of the plant containing the
ern research techniques which require two major groups, selected members of euphoric principles, very few data are
only small amounts of plant material. a group of plants which are known to available to support this statement. It is
Finally, there has been an acute need be hallucinogenic but in which the ac- altogether possible that other parts of
for the active principles present in hal- tive principles are unknown are dis- the female plant-and the male plant
lucinogenic plants, either as potentially cussed. as well-may also contain active sub-
useful drugs in the treatment of mental stances. Detailed phytochemical studies
disease or as new tools for the phar- of all parts of both male and female
macologist in his attempts to shed some Plants Having Nonnitrogenous plants, collected in different areas of
light on the biochemical causes of Active Principles the world, seem to be in order.
mental illness. These needs have accel- The seed, seed oil, seed oil cake, and
erated the research, in which workers Marihiana. Marihuana has been pre-
from many disciplines have partici- senting a perplexing problem to various The author is professor of pharmacognosy and
cultures and societies of the world for chairman of the department of pharmacognosy,
pated: botanists, ethnobotanists, ethnol- School of Pharmacy, University of Pittsburgh,
ogists, chemists, pharmacognosists, centuries. The controversy arising in Pittsburgh, Pennsylvania.
10.86 SCIENCE, VOL. 162
fiber (hemp) from Cannabis sativa L. CH3 H
are all important and useful economic
products; other parts of the plant, those
that contain the euphoric principles,
constitute a legal as well as a social PHENYLPROPENES DIBENZ-GL-PYRANS
problem.
Although the layman may not always
use the proper terminology in speaking
of marihuana or its derivatives, the NNH2 ' RR
meaning of certain words associated H H
with this drug is quite clear. "Hashish" ,B-PHENETHYLAMINES 0i-CARBOLINES ISOQUINUCLIDES
and "charas" are the unadulterated R2-
resin from the flowering tops of culti-
vated female C. sativa plants. "Bhang"
is prepared from uncultivated female
plants; the tops are cut from these O LjR
}R
plants, and a decoction in water or milk
is made. The decoction is either drunk ERGOLINES TROPANES ISOXAZOLES
or dried and smoked. "Ganja" is pre- Fig. 1. Chemical structures of various types of hallucinogens.
pared by harvesting the tops from very
carefully selected cultivated female
plants. This preparation is taken in the nabichromene is said to have euphoric biological effects in humans. Of course,
same way that bhang is. Ganja is su- activity (5). Cannabinol and cannabi- other factors, ecological and geograph-
perior to bhang but inferior to hashish. diol are inactive. Cannabigerol and can- ical, are also important, since the active
"Majun" is ganja that has been in- nabidiolic acid are sedative principles, constituents are presumably mainly con-
corporated into sweetmeats. and cannabidiolic acid is a potent anti- tained in the resin, and plants grow-
Most of these terms are seldom en- microbial agent (4). ing in hot climates produce a great deal
countered in the United States, with the The variation in the chemical com- more resin than plants growing in the
exception of "hashish," a term that is position and biological activity of Can- temperate zones (8).
generally used incorrectly, since most nabis sativa results primarily from the One of the chief problems confront-
of the Cannabis sativa used in this fact that some of the constituents are ing legislators with regard to marihuana
country is in the form of dried flow- unstable and change form. It has been has been the conflict of opinion on the
ering tops of the plants (probably explained that, on aging, cannabidiolic exact physical and mental effects of the
a mixture of male and female plants in acid (inactive) is gradually converted active principles from this plant. This
most cases). This mixture is admixed to cannabidiol (inactive), then to tetra- uncertainty has been due to lack of
with considerable leaf material and hydrocannabinols (active), and finally valid, controlled, scientific experiments.
ordinarily goes more correctly under to cannabinol (inactive) (8). These bio- Many of the available biological data,
the names of marihuana, pot, or grass. logical conversions proceed at a more which are indeed scanty, have been ob-
Cigarettes containing marihuana are re- rapid rate in tropical areas than in more tained from experiments made with
ferred to as "reefers," "mooters," "mug- temperate zones. As a result, samples crude plant preparations having un-
gles," "greeters," or "gates." A large of varying age give rise to different known chemical constituents. Even in
quantity of marihuana that finds its way
into the United States is smuggled
across the border from Mexico and is
often referred to as "Acapulco Gold" CH3 OH CH3 OH CH3 OH COOH
by its users.
A number of chemical compounds / /\C5Hn(N) C51-1 I l(N) C5H1- (N)
have been isolated from the resin of
Cannabis sativa (4-6). Among these are
cannabinol, cannabidiol, cannabidiolic CANNABINOL(CBN) AI -TETRAHYDROCANNABINOL ZS-TETRAHYDROCANNABINOL
acid, tetrahydrocannabinol-carboxylic CAREBOXYLIC ACID
acid, cannabigerol, cannabichromene, CH3 OH CH3 OH CH3 OH
and a mixture of stereoisomers known - C5H(N) / H
collectively as tetrahydrocannabinols. C5H11(N1) 5
Some of the tetrahydrocannabinol mix- - OH OOH H\ OH
tures examined show considerable vari-
ation in their pharmacologic activity, CANNABIDIOLIC ACID CANNABIDIOL(CBD) CANNABIGEROL
but most exhibit euphoric activity of (CBDA) OH
varying degrees. Recently it was estab-
lished (7) that AW-tetrahydrocannabinol / \ C5 HI(N)
is, in fact, the major active euphoric I-
principle in C. sativa resin. These com- S/ \0
pounds and their close relationship are
shown in Fig. 2. CANNABICHROMENE
Like the tetrahydrocannabinols, can- Fig. 2. Structures of major constituents of hashish.
6 DECEMBER 1968 1087
 Table 1. 3-Phenethylamines in certain South American halucinatory snuffs (17). to variations in the content of one or
p8-Phenethylammne content more of these three substances. A recent
comparison involving the analysis of
Species Plant 5 DMT 5 5-OH- eight lots of nutmeg oil from various
part MMT MeO- DMT N- MeO- DMT N-
sources showed that the safrole content
MMT oxide DMT oxideN varied from 0.53 to 3.42 percent; the
Piptadenia peregrina Benth. Seed - - + + + + + myristicin content, from 3.86 to 12.78
Paptadenia peregrina Benth. Bark + + + - + - - percent; and the elemicin content, from
Piptadenia macrocarpa Benth. Seed - + + + - + + 0.02 to 2.36 percent (12). However, in
Piptadenia excelsa (Gris.) Lillo Seed - - + - - + + all samples analyzed, these three com-
Piptadenia colubrina Benth. Seed - - - - - + pounds always accounted for from 84
Mimosa hostilis Benth. Root - + - - - -
Virola calophylla Warburg Bark + - + - + to 95 percent of the total aromatic frac-
tion of the volatile oil (12). The struc-
tures of known components of the aro-
matic fraction of nutmeg oil are given
experiments made with so-called tetra- tions after a delay of 2 to 5 or more in Fig. 3.
hydrocannabinol, the experimental ma- hours. The reactions to nutmeg vary To date, no psychopharmacologic in-
terial was, in reality, probably a mixture from none, in some individuals, to those vestigations on pure safrole or on ele-
of stereoisomers having different de- typical of lysergic acid diethylamide micin have been reported. The reports
grees of biological activity. Thus, it has (LSD). These symptoms frequently in- available show that early studies on
proved almost impossible to correlate clude distortion of time and space per- myristicin were made with a product
published data on effects of marihuana. ception, and feelings of unreality. obtained by distillation from oil of nut-
Recently, Rafael Mechoulan and Visual hallucinations are infrequent. meg, and it is known that elemicin-free
Yehiel Gaoni, of the Hebrew University Concomitant side effects such as myristicin cannot be obtained in this
in Israel, announced that they had suc- malaise, headache, dry mouth, tachy- manner. Thus, unless the oil of nutmeg
ceeded in synthesizing pure Al-tetra- cardia, and dizziness are frequent (10, was relatively free of elemicin, this lat-
hydrocannabinol in large-scale labora- 11). ter compound may have been re-
tory experiments (9). This, then, should It seems clear that the active psycho- sponsible for at least some of the psy-
be considered a major breakthrough in tomimetic substances of nutmeg are chotomimetic responses observed in
our understanding of marihuana, since present in the volatile oil fraction of these tests. In any event, elemicin may
a single pure entity is now available for the seeds (11). This volatile oil con- be a major contributor of activity, but
studying the biological effects. tains fatty acids, terpenes, and aro- this substance is not available in pure
Nutmeg. The nutmeg of commerce matics (12). Analyses reported by form for testing.
consists of the dried seed of Myristica several investigators (12) offer real evi- Safrole is probably not an active psy-
fragrans (family Myristicaceae), pro- dence of chemical variability (both chotropic substance; sassafras oil has a
duced from trees grown in either the qualitative and quantitative) of nutmeg- safrole content of some 80 percent, and
East Indies or the West Indies. Weil, oil samples. this oil has never had a reputation of
who has studied the nutmeg problem Safrole, myristicin, and elemicin are being a psychotomimetic substance.
extensively, has arrived at the following most frequently judged to be the active Myristicin has been tested in humans
conclusions with regard to its use as a agents- in nutmeg. If this judgment is at a dose equivalent to twice the dose
psychotomimetic drug. Nutmeg, ad- correct, there is reason to believe that which would be obtained through ad-
ministered orally in doses larger than differences in the psychotomimetic ef- ministration of 20 grams of typical nut-
one teaspoonful, can produce hallucina- fect of various lots of nutmeg are due meg. The symptoms suggested psycho-

I CH3
C-3
R3N(
1

3 4 R R2
HCH H3
SAFROLE MYR ISTICIN ELEM ICIN
R-1 R-2 R-3 R-4 R-5 ALKALOID

CHCH3 H H H OH H TYRAMINE
H CH3 H OH H N-METHYLTYRAMINE
: C3 OCH3
3 E H3 HN3 CH3 CH3 H OH H HORDENINE
H H OCH3 OCH3 OCH3 MESCALINE
?4METHYLEUGENOL EUGENOL METHOXYEUGENOL
H CH3 OCH3 OCH3 OCH3 N-METHYLMESCALINE
H AC OCH3 OCH3 OCH3 N-ACETYLMESCALINE
(CH3)3 +33
H H OH CANDICINE

HH3;~I CH
3 H3
3 H
CH3 Fig. 3 (left). Structures of certain constituents of nutmeg oil.
Fig. 4 (above). Structure of 3-phenethylamine alkaloids from
ISOELEMICIN METHYLISOEUGENOL ISOEUGENOL peyote.
\ 1088 SCIENCE, VOL. 162
tropic effects only in six of ten subjects OPO(OH)O compared with a high lipid solubility for
(12). Thus it appears, from the ab- DMT and 5-MeO-DMT. Because of the
sence of marked effects, that myristicin higher lipid solubility, DMT and 5-
is not the major contributor of psycho- MeO-DMT more readily penetrate the
tomimetic activity in nutmeg. H H-NCH3 nervous system and exert their effects
PSILOCYBINE (17).
It is truly amazing that the South
Plants Having Nitrogenous American Indians found that these
Active Principles OH plant materials were effective hallucino-
Peyote. Peyote, or mescal button, is gens only when they were used as snuff;
the tryptamines are not active when the
derived from the cactus Lophophora N v-CH3 material is ingested orally.
williamsii (Anhalonium lewinii) and H CH3
has been used for hallucinatory pur- PSILOCINE Hallucinogenic mushrooms. The
poses for centuries (13). It is most Fig. 5. Hallucinogenic principles of Psil- mushroom-worshipping Indians of
Mexico have long used "teonanacatl"
commonly used in the southwestern ocybe mexicana. ("Flesh of the Gods") as a sacrament
part of the United States, but in recent in Aztec religious rites, and the fungi
years its use has spread throughout this have indeed been shown to elicit psy-
country. In 1918, the Native American series of substituted /3-phenethylamines: chotomimetic effects (1, 18). The
Church was formed, and part of its N,N-dimethyltryptamine (DMT), N- sacred mushrooms are of several differ-
ceremonial rites involve the use of monomethyltryptamine (MMT), 5- ent genera: Psilocybe, Conocybe, and
peyote. This church, which now has an methoxy-N,N-dimethyltryptamine (5- Stropharia (1).
estimated membership of some 225,000, MeO-DMT), 5-methoxy-N-monometh- The most important of the
preaches family responsibility, brotherly yltryptamine (5-MeO-MMT), 5-hy- tropic mushrooms is Psilocybepsycho-mexi-
love, and abstinence from alcohol. Re- droxy-N,N-dimethyltryptamine (bu- cana, which was chemically analyzed
cently the courts ruled that peyote could fotenine) (5-OH-DMT), N,N-dimeth- by Hofmann and his co-workers (19)
be legally used as part of its ritual, thus yltryptamine-N-oxide (DMT-N-oxide), and found to contain the 4-hydroxydi-
making it a simple matter for persons and 5-hydroxy-N,N-dimethyltrypta- methyltryptamines psilocybine and
to use this plant without fear of legal mine-N-oxide (5-OH-DMT-N-oxide).
complications. For a comparison of the lifferent sub-
psilocine (Fig. 5), which are the active
Although some 15 B-phenethylamine stituted tryptamines in cl rtain South
principles (1, 20). Psilocybine is the
first example of a phosphorus-contain-
and simple isoquinoline alkaloids (Fig. American snuffs, see Table 1 (17).
4) have been isolated from Lophophora It is assumed that the atctive trypta-ing indole found in nature and, unlike
most other substituted tryptamines,
williamsii (14), it is well established mines reach the brain by way of absorp- elicits psychotomimetic effects when
that the major hallucinogenic principle tion from the vascular nasal mucosa taken orally.
is mescaline. into the bloodstream, or that they act
The psychotomimetic effects of mes- Peganum harmala. The seeds of P.
directly on the brain without having harmala (family Zygophyllaceae) have
caline are induced with doses of 0.3 to been transported through the general been used as a spice and as an in-
0.5 gram. After ingestion, mescaline circulation (17). Although not all of
first induces nausea, tremor, and per- the tryptamines known to be present in
toxicant, and psychotropic effects have
been attributed to them in India (21).
spiration. Then, in 1 to 2 hours, these these snuffs have been pharmacolog- In addition to the major 8?-carboline
unpleasant effects subside and a dream- ically investigated, it is reasonably cer- base harmine, the seeds of this plant
like intoxicating phase follows in which tain that 5-OH-DMT does not account contain harmaline, harmalol, and har-
the user has vivid kaleidoscopic visions for the psychotomimetic action (17). man (Fig. 6). Harmine and harmaline
before falling into a deep sleep (14, DMT and 5-MeO-DMT, on the other have both been shown to elicit hallu-
15). hand, have been shown to be potent cinogenic effects in humans when ad-
South American snuffs. A number of psychotomimetic agents (17). This dif- ministered orally at doses above 4 milli-
Piptadenia and Mimosa species (family ference has been explained as reflecting
Leguminosae) and Virola species (fam- a low lipid solubility of 5-OH-DMT, as
grams per kilogram (21). Of interest
is the recent discovery that 6-methoxy-
ily Myristicaceae) have been used in
South America by Indians to induce tetrahydroharman is a natural hormone
of the pineal body (21), and that it is
psychotomimetic effects (16). The
Table 2. Alkaloids in the seeds of Rivea
plant material is prepared as a snuff corymbosa closely related to the harmala bases
and Ipomoea violacea (27). (Fig. 6).
and is blown into the nasal cavity in any
one of several ways. Although some Alkaloid content (%) It has been shown that harmaline is
Alkaloid more hallucinogenic than mescaline is
chemical work has been done on these Rivea Ipomoea
snuffs, in much of it plant material that corymbosa violacea (21) and that tetrahydroharmine is
was not properly identified was used. d-Lysergic acid three times less active than harmaline.
0.0065 0.035 Synthetic 6-methoxyharmalan is active
Recently several studies on botanically amide (ergine)
at oral doses of 1.5 milligrams per
authenticated materials have been d-Isolysergic acid .0020 .005
amide (isoergine)
made, and the major chemical com- Chanoclavine kilogram; 6-methoxytetrahydroharman
.0005 .005 from the pineal body is also a hallucino-
pounds responsible for the psycho- Elymoclavine .0005 .005 at these doses (21).
tomimetic effects of these snuffs, or Lysergol gen
.0005 Banistereopsis species. Natives of the
compounds related to the active prin- Ergometrine .005 Rio Negro of Brazil and adjacent
ciples, have been identified as a (ergonovine) upper
parts of Colombia, as well as Indians in
6 DECEMBER 1968
1089
 Table 3. Major hallucinogenic plants and their active principles. Mexico are known to have used smaller
Plant Family Active principle(s)
quantities of 1. violacea than of R.
corymbosa to produce hallucinogenic
Cannabis sativa Cannabinaceae AW-Tetrahydrocannabinol effects (25, 26); Hofmann has pointed
Lophophora williamsii Cactaceae Mescaline out that seeds from 1. violacea contain
Piptadenia species Leguminosae Substituted tryptamines larger quantities of the active ergoline
Mimosa species Leguminosae Substituted tryptamines principles than seeds of R. corymbosa
Virola species Myristicaceae Substituted tryptamines do, and has thus demonstrated that
Banistereopsis species Malpighiaceae Harmaline, harmine there was a good reason for this prac-
Peganum harmala Zygophyllaceae Harmaline, harmine tice. He subsequently was able to iso-
Tabernanthe iboga Apocynaceae Ibogaine late, in pure form, several indole alka-
Ipomoea violacea Convolvulaceae d-Lysergic acid amide
d-Isolysergic acid amide loids from the seeds of these two plants
Rivea corymbosa Convolvulaceae d-Lysergic acid amide (27). Interestingly enough, the major
d-Isolysergic acid amide active constituent of each proved to be
Datura species Solanaceae Scopolamine d-lysergic acid amide (ergine); a sec-
Methysticodendron ond important alkaloid was d-isolysergic
amesianum Solanaceae Scopolamine
Amanita muscaria Agaricaceae Pantherine, ibotenic acid acid amide (isoergine). In addition, the
Psilocybe mexicana Agaricaceae Psilocybine alkaloids chanoclavine and elymocla-
vine were isolated from each of the two
species, but these had no psychotomi-
metic effects. Ergometrine (ergonovine),
Amazonian Peru and Bolivia, use nar- iboga; an intoxication follows that is a well-known uterotonic and hemostatic
cotic beverages known as "ayahuasca," characterized by excitement, mental alkaloid found in ergot, was isolated
caapi," and "yaje" for purposes of confusion, and possibly hallucinations from 1. violacea but not from R. corym-
prophecy and divination and to prepare (23). The major alkaloid responsible bosa. On the other hand, lysergol was
the male adolescent for the painful rites for these activities is the 5-methoxy- found in R. corymbosa but not in 1.
of initiation into manhood (1, 20). indole ibogaine (23). violacea. The structural relationships
These three beverages are prepared Ibogaine has recently been placed in and the similarities of these active com-
from any one of several species of the same category as LSD by the U.S. pounds from Ipomoea and Rivea to the
Banisteriopsis (B. caapi, B. inebrians, Food and Drug Administration, since synthetic and highly active LSD may
B. rusbyana) (family Malpighiaceae), it has been shown to be a true hallu- be seen in Fig. 7. The alkaloid content
either alone, together, or mixed with cinogen (21). of these seeds is given in Table 2.
other plants (1, 20). Morning glories. The seeds of the Seeds from other convolvulaceous
It is generally agreed that the psycho- morning glory Ipomoea violacea L., plants have been shown to contain erg-
tomimetic principles in these Banisteri- known as "badoh negra," and of Rivea oline derivatives; to date, the following
opsis species are 3-carboline alkaloids, corymbosa (L.) Hall. f., known as have been detected: ergine, isoergine,
represented by harmine, harmaline, and "ololiuqui," have been used since Aztec ergosine, ergosinine, chanoclavine, ely-
(+)-tetrahydroharmine (Fig. 6) (22); times in the uplands of southern Oaxaca moclavine, lysergol, ergometrine, ergo-
exhaustive chemical studies on Ban- for divinatory and hallucinogenic pur- metrinine, agroclavine, penniclavine,
isteriopsis species are lacking, and a poses (24, 25). It has been firmly es- and lysergic acid-a-hydroxyethylamide
closer look might well yield additional tablished that the active psychotomi- (25, 28).
hallucinogens. metic agents in these seeds are ergoline When it was first announced that
Iboga. Natives of certain sections of (lysergic acid) derivatives, closely re- some common morning glory seeds con-
Africa chew the root of Tabernanthe lated to LSD (24, 25). The natives of tained these active alkaloids, seed sup-

CH3CH2N, H
CH3CH NCH
4
CH30 aN
H CH3
HARMINE HARMALINE H
D-LYSERGIC ACID DIETHYLAMIDE
(LSD)

CH3 NNCH3
HO -N': N
H CH3 H CH3
HARMALOL HARMAN H
N
H
Fig. 6 (above). Major p-carboline alkaloids of Peganum
harmala. Fig. 7 (right). Hallucinogenic ergoline deriva- D-LYSERGIC ACID O-ISOLYSERGIC ACID
tives from Rivea and Ipomoea and their relationship to LSD. AMIDE AMIDE
1090 SCIENCE, VOL. 162
 CH20H Fr. (fly agaric) has an interesting his-
tory in Eurasian culture as a psychot- °'UNH2
o1CHII oc-C omimetic agent (34). Ingestion of the
mushroom produces psychotomimetic
effects after about 15 to 20 minutes.
H-N7' jIJ
SCOPOLAMINE Initially sleep is induced, of about 2 OXAMYCIN
hours' duration. At times, the subject Fig. 10. Oxamycin, an antibiotic closely
Fig. 8. Scopolamine, the hallucinogenic has colored visions. Some subjects have related to the hallucinogenic isoxazoles.
agent from solanaceous plants. enjoyed a feeling of elation that lasted
for 3 to 4 hours after they awakened
pliers soon reported a depletion of their from a sound sleep. Often these individ- have been reported as isolated from or
stocks, and a serious public health prob- uals perform extraordinary physical detected in Amanita muscaria; mus-
lem arose from misuse of the seeds. In feats during this period, with great en- carine, acetylcholine, choline, ibotenic
addition to the expected psychic phe- joyment (34). acid (priamuscimol), pantherine (mus-
nomena, serious physical effects and The hallucinogenic properties of fly cimole, agarin), muscazone, muscari-
deaths resulted (25, 29). Some reports agaric pass into the urine and, for this dine, bufotenine, atropine, scopolamine,
have indicated that ingestion of reason, reportedly during times when and hyoscyamine (35) (Fig. 9). Recent
Ipomoea violacea seeds produced no ef- Amanita muscaria was not available in studies, however, have revealed that per-
fects. The reason, in most cases, was abundance, the urine from an individual haps earlier reports of the presence of
that the seeds were not pulverized be- who had consumed the mushroom was tropane alkaloids (tropine, scopolamine,
fore ingestion; the hard impervious drunk to produce the psychotomimetic hyoscyamine) in the fungus were due to
seed coats allow them to pass through effects (34). misinterpretation of chromatographic
the alimentary tract intact, and the To date, the following substances data (36). Further, the report of the
active alkaloids are not absorbed (25). isolation of bufotenine from A. mus-
At present there is no specific legisla- caria has been shown to be incorrect. In
tion prohibiting the sale of morning all probability the error resulted from
glory seeds, and they continue to be
HO-CH2CH2-N-(CH3)3 the fact that the A. muscaria examined
used for psychotomimetic purposes. In CHOLINE was contaminated with A. citrina or A.
England a proposal to ban the sale of porphyria (36), both of which contain
these seeds is under consideration (30). bufotenine.
Enforcement of such a ban would ap- CH300CH2CH2-N-(CH3)3 Ibotenic acid is the zwitterion of at-
pear to be impossible. amine-a-[hydroxyisoxazoylyl- (5) ]-acetic
Solanaceous plants. The seeds of the ACETYLCHOLINE acid monohydrate (see Fig. 9) and
common jimsonweed (Datura stramo- is considered to be the major psycho-
nium) and of other Datura species have HO tropic constituent of Amanita muscaria
been used to produce psychotomimetic (35). Pantherine, also an active prin-
effects (1, 31). Almost all Datura
C 3H CH2N(Cq3 ciple, is the enolbetaine of 5-amino-
species contain tropane alkaloids, MUSCARIDINE methyl-3-hydroxy-isoxazole (Fig. 9)
usually atropine, hyoscyamine, and and is easily formed from ibotenic acid
scopolamine (Fig. 8). The hallucino- by decarboxylation and loss of water
genic effects of scopolamine are well (35) (Fig. 9). The pharmacologically
known (32, p. 544). H CH2-N(CH3)3 less active muscazone (Fig. 9) is
The leaves and stems of the South thought to be formed from ibotenic
American plant Methysticodendron MUSCARINE acid (35). Thus, one would expect to
amesianum have been used by Indians find varying ratios of ibotenic acid and
in their witchcraft rites (1). Scopola- muscazone in A. muscaria, which could
mine constitutes over 80 percent of the well account for the variations in the
alkaloid content of this plant (33). The 43CH2-N% biological effects induced by eating this
natives consider M. amesianum to be fungus that have been reported in the
more potent than the related Datura PANTHERINE literature (35). The chemistry of A.
species, which they also use in their muscaria constituents has recently been
ceremonies to produce frenzy and nar- HO reviewed (37).
cosis. Undoubtedly it is more potent, H1-COO The antibiotic oxamycin (D-4-amino-
since the scopolamine-atropine ratio is 3-isoxazolidone) (Fig. 10) is structur-
higher in Methysticodendron than in + 113 ally related to the active isoxazoles
Datura (33). Even at therapeutic doses IBOTENIC ACID present in Amanita muscaria; in hu-
scopolamine may produce excitement, mans, side effects of this useful drug
hallucinations, and delirium, whereas, N involve the central nervous system and
in the case of atropine, doses bordering <Qt CH-COO include mental confusion, acute psy-
on the toxic are generally required be- chotic episodes, convulsions, and other
fore hallucinations and central nervous abnormal behavial l states (32, p.
system effects are experienced (32, p. MUSCAZONE 1326). Therefore, it is to be expected
544). Fig. 9. Chemical compounds from fly that the isoxazoles of A. muscaria, when
Amanita muscaria. Amanita muscaria agaric. ingested, will have similar effects.
6 DECEMBER 1968 1091
 udogenic Plants hallucinogenic effects are different for N. S. Kie, Eds., "Esthnopharmacologic
Search for Psychoactive Drugs," U.S. Public
Not Yet Invesgated eight of the ten families. Or, put Health Serv. Pub. No. 1645 (Government
another way, when different genera of Printing Office, Washington, D.C., 1967).
4. G. E. W. Wolstenholme and J. Knight, Eds.
In the southern Mexican state of species of a particular plant family con- Hashish: Its Chemistry and Pharmacology
tain true psychotogens, these substances (Little, Brown, Boston, 1965).
Oaxaca, Mazatec Indians utilize the 5. Y. Gaoni and R. Mechoulam, Chem. Com-
leaves of Salvia divinorum (family are always chemically similar, if not mun. 1966, 20 (1966).
6. F. Korte, H. Haag, U. Claussen, Angew.
Labiatae), known as "pipilzintzintle," identical. This is a remarkable finding; Chem. 77, 862 (1965).
chemotaxonomic relationships are not 7. K Mechoulam and Y. Gaoni, J. Amer. Chem.
in divination and as a hallucinogen (24, Soc. 87, 3273 (1965).
38, 39). Wasson, after drinking the always so clear-cut. 8. L. Grlic, Bull. Narcotics 16, 29 (1964).
We are not certain at present of the 9. F, Mechoulam, P. Braun, Y. Gaoni, J. Amer.
juice expressed by hand from 68 leaves Chem. Soc. 89, 4552 (1967)..
of this plant, experienced dancing colors active psychotomimetic principle of 10. A. T. Well, Econ. Botany 19, 194 (1965).
Myristica fragrans, but it appears to be 11.-, In "Ethnopharmacologic Search for
in elaborate three-dimensional designs Psychoactive Drugs," U.S. Public Health
(39). No chemical substances that either elemicin or myristicin. Several Serv. Pub. No. 1645 (Government Printing
Office, Washington, D.C., 1967), p. 188.
would explain these effects have been other minor psychotomimetic plants 12. A. T. Shulgin, T. Sargeant, C. Naranjo, Ibid.,
(for example, Salvia divinorum and p. 202.
isolated from S. divinorum, and prelim- 13. W. LaBarre, The Peyote Cult (Shoestring
inary attempts, by Hofmann, to isolate Olmedioperebea sclerophylla) remain a Press, Hamden, Conn., 1959).
mystery, whereas we do not even know 14. A. DerMarderosian, Amer. J. Pharm. 138, 204
the active principles (or principle) have (1966).
been unsuccessful, due to their apparent the botanical identity of soma. A num- 15. H. Kulver, Mescal and Mechanlsms of Hallu-
cination (Univ. of Chicago Press, Chicago,
instability (23). ber of additional hallucinogenic plants 1966).
Natives living in the central part of are alleged to exist, but in some cases 16. R. E. Schultes, in "Ethnopharmacologic
Search for Psychoactive Drugs," U.S. Public
the Brazilian Amazon prepare a psy- there is a need for verifying the effects, Health Serv. Pub. No. 1645 (Government
whereas in others the plants are not Printing Office, Washington, D.C., 1967), p.
chotomimetic snuff from the fruit of 291; S. von Reis Altschul, ibid., p. 307; G.
Olmedioperebea sclerophylla Ducke botanically authenticated. J. Seitz, ibid., p. 316.
Our present state of knowledge con- 17. B. Holmstedt and J. E. Lindgren, Ibid., p. 339.
(family Moraceae) (40). Nothing is 18. R. E. Schultes, Botan. Museum Leaflet Har-
known of the active principles of this cerning the identity of the active psy- vard Univ. 7, No. 3, 37 (1939).
19. A. Hofmann, J. Exp. Med, Sd. 5, 31 (1961).
plant. chotomimetic principles of the well- 20. R. E. Schultes, Botan. Museum Leaflet Har-
known hallucinogenic plants is now vard Univ. 18, 1 (1957).
More than 144 hymns of the 21. C. Naranjo, in "Ethnopharmacologic Search
Rigveda, the oldest holy scripture of the relatively well established. However, for Psychoactive Drugs," U.S. Public Health
much remains to 'be discovered regard- Serv. Pub. No. 1645 (Government Printing
Aryan settlers of the Indus basin, glorify Office, Washington, D.C., 1967), p. 385.
a divine plant and an intoxicating bev- ing the biological effects of these sub- 22. V. Deulofeu, ibid., p. 393.
stances, with respect to their action not 23. V. E. Tyler, Jr., Lloydla 29, 275 (1966).
erage prepared from it, both of which 24. R. G. Wasson, Botan. Museum Leaflet Har-
are known as "soma." Scientists have only on the mind but on various bio- vard Univ. 20, 161 (1963).
25. A. DerMarderosian, Amer. I. Pharm. 139, 19
not been able to trace the identity of chemical systems of the body, and on (1967).
this plant with any degree of certainty. the total organism. Continued interdis- 26. R. E. Schultes, A Contribution to Our Knowl-
edge of Rivea corymbosa, the Narcotic Olo-
The plants which have been suggested, ciplinary research should provide the IYuqul of the Aztecs (Botanical Museum,
answers to those questions that remain Harvard Univ., Cambridge, Mass., 1941), p.
but which are discounted on specific 45.
points, are Sarcostemma viminale, Peri- concerning these plants and their active 27. A. Hoffmnann, Botan. Museum Leaflet Har-
vard Univ. 21, 194 (1963).
ploca aphylla, Rheum sp., Ephedra sp., principles, and should uncover new hal- 28. D. Stauffacher, H. Tscherter, A. Hofmann,
Peganum harmala, and Amanita mus- lucinatory substances used in primitive Helv. Chim. Acta 48, 1379 (1965).
29. A. L. Ingram, Jr., J. Amer. Med. Ass. 194,
caria (1, 23). Wasson has been investi- cultures. 1133 (1964); W. B. Rice and K. Genest,
Nature 207, 302 (1965).
gating this problem for several years 30. M. Wellendorf, Amer. Soc. Pharmacog.
and still has not reached a definite con- References and Notes -Newsletter 3, 3 (1966).
31. C. E. Johnson, Intern. J. Neuropsychiat. 3,
clusion as to the identity of the elusive 1. Although the most common hallucinogen is 268 (1967).
and mysterious soma. probably lysergic acid diethylamide (LSD), 32. L S. Goodman and A. Gilman, The Pharma-
this is a purely synthetic chemical compound, cological Basis of Therapeutics (Macmillan,
which is not known to occur in nature, and New York, ed. 2, 1955).
therefore has not been included in this dis- 33. I. J. Pachter and A. F. Hopkinson, J. Amer.
cussion. Pharm. Ass. Sci. Ed. 49, 621 (1960).
Remarks 2. A number of terms have been applied to the 34. R. 0. Wasson, in "Ethnopharmacologic Search
so-called hallucinogenic drugs: phantasticants, for Psychoactive Drugs," U.S. Public Health
psychoticants, psychotomimetics, psychotogens, Serv. Pub. No. 1645 (Government Printing
The chemical principles responsible hallucinogens, and schizogens. No attempt has Office, Washington, D.C., 1967>, p. 405.
been made here to distinguish between these 35. C. H. Eugster, Ibid., p. 416; P. G. Waser,
for the effects elicited by the major hal- synonyms.
3. E. von Bibra, Die narkotschen Genussmittel
ibid., p. 419.
36. V. E. Tyler, Jr., in Beltrage zur Biochemie
lucinogenic plants are summarized in und der Mensch (1855); L. Lewin, Phantas- und Physiologle von Naturstoffen (Fischer,
Table 3. It is interesting to note that tica-die betaubenden und erregenden Genuss-
mittel (1924); R. Heim, Actualities Phar-
Jena, 1965), p. 501.
37. T. Wieland, Science 159, 946 (1968).
the genera of Table 3 are distributed in macol. 12, 171 (1959); R. E. Schultes, Lloyd- 38. C. Epling and C. D. Jativa, Botan. Museum
ten different plant families, and that the ia 29, 293 (1966); - , Psychedelic Rev. Leaflet Harvard Univ. 20, 75 (1962).
1, 145 (1963); - , Harvard Rev. 1, No. 39. R. G. Wasson, ibid., p. 77.
chemical substances responsible for the 4, 18 (1963); D. H. Efron, B. Holmstead, 40. R. E. Schultes, Planta Med. 13, 125 (1965).

1092 SCIENCE, VOL. 162