Albert Hofmann. Psychotomimetic Agents (PDF)

CHAPTER 5

PSYCHOTOMIMETIC AGENTS
ALBERT HOFMANN
SANDOZ A. G.
BASEL, SWITZERLAND

5.1. Jntroduction .
169
5.2. The History of Psychotomimetic Drugs
171
A. Hashish
172
B. Magie Plants of Mcxico
173
C. Magie Plants of South America
180
D . The Discovery of LSD-25
183
5.3. Chemistry and Structure-Activity Relationshipof Psychotomimetic Agents 186
A. Structural Types of Psychotomimetics
186
B. Tryptarnine Derivatives
188
C. Harmine and Derivatives
197
D. d-Lysergic Acid Amides
198
E. Mescaline .
213
F. Tetrahydrocannabinols
218
5.4. Indole Structure and Psychotomimetic Activity
221
5.5. Use of Psychotomimetic Agents in Psychotherapy
223
5.6. Paramedical Use of Psychotomimetic Agents
224
References
226

5.1 . INTRODUCTION

Over the last few decades novel classes of active substances have been
discovered in the field of pharmaceutical research which brought with them
new possibilities of exerting a pharmacological influence on psychic functions.
These were in particular the nonhypnotic sedatives, the so-called tranquilizers, ofwhich chlorpromazine is a prototype, and highly active compounds
of the psychotomimetic group, compounds which produce specific and
dramatic psychic alterations, the most effective representative being LSD.
The discovery ofthese novel psychotropic compounds brought with it a new
medical science, psychopharmacology, a science which is gaining in importance in the general sphere of modern medicobiological research. lt must be
noted, however, that this new medical science does not, in principle, represent
a new line of research. In fact, scientific investigations of the infiuence exerted
by pharmaceuticals on psychic functions were initiated in the latter part ofthe
last century. In this respect mention should be made here of the fundamental
169

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investigations carried out by Emil Kraepelin who, in his monograph Ueber die
Beeinflussung einfacher psychischer Vorgänge durch einige Arzneimittel (1),
which was published in 1892, laid the basis for the science now known as
psychopharmacology.
The psychotomimetics, to which this chapter is dedicated, are the psychopharmaceuticals "par excellence," as the psychic effects of these compounds
are not only unusually profound and specific but also extremely diverse.
Other names, such as hallucinogens, phantastica, eidetics, psychodysleptics (2),
psychedelics, etc., have been suggested for these compounds aside from the
term psychotomimetics (3), depending on which aspect ofthe complex pattern
of effects is first taken into consideration. Priority should be given to the
designation "phantastica," coined by Lewin and used by this author in the
early twenties in his monograph entitled Phantastika (4). Unfortunately this
designation has not been adopted by the English-speaking countries. The lastmentioned term, "psychedelic," meaning "mind manifesting," is often used,
especially in the United States. This designation, suggested by Osmond (5), is
intended to convey the fact that the pattern of effects of these compounds is
determined not so much by the pathological components, as indicated by the
term "psychotomimetic," i.e., mimicking a sort of psychosis, as by a general
activation and manifestation of psychic phenomena, which in no way may be
considered entirely morbid and negative. In fact, the exceptional psychic
states induced by psychotomimetics only partially correspond to the pathological pattern of schizophrenia (6).
Psychotomimetic drugs have been defined as follows (5, 7,8): Psychotomimetic agents are substances which produce changes in thought, perception,
and mood, occurring alone or in conjunction with each other, without causing
major disturbances of the autonomic nervous system, i.e., clouding of consciousness or other serious disability. High doses generally elicit hallucinations.
Disorientation, memory disturbance, hyperexcitation, or stupor and even
narcosis occur only when excess dosages are administered and are therefore
not characteristic.
This definition excludes narcotics such as morphine, cocaine, or atropine,
and their derivatives. lt also excludes anesthetics, analgesics, and hypnotics.
The psychic changes and the accompanying unusual states of consciousness
produced by psychotomimetics differ so greatly from the ordinary experiences
ofthe outer and inner world that they cannot be described with the aid ofwords
customarily used in the normal daily pattern of the outer and inner universe.
One may get an idea of the strangeness of the worlds experienced under the
influence of psychotomimetics by reading the numerous reports written by a
variety of persons from different points of view concerning their excursions
into the unknown continents of the soul. The brilliant descriptions of
A. Huxley of his experiences with mescaline (9) and the experiences reported

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in Cohen's book The Beyond Within (10) deserve special mention in this respect.
The profound transformation of the conception of the universe under the
influence of psychotomimetics, toward either the diabolical sphere or celestial
transfiguration, is explained by changes in perception of space and time, the
two basic elements of our existence. The experience of corporeity and the
spiritual being is also profoundly altered. The subject leaves the familiar world
behind and while retaining full consciousness enters a pseudo-dream world
ruled by other standards, other dimensions, and a different time.
Time often seems to stand completely still. The familiar surroundings appear

in a new light. Forms and colors are changed or have a new significance;
objects lose their symbolic character, they are detached, radiating their own
intense entity. Colors are usually more intense, transparent, radiating from the
inside. The condition elicited by the psychotomimetics is generally accompanied by visual and auditory hypersensitivity, which may even lead to
illusions and hallucinations. However, hallucinations usually occur only after
very high <loses.
Review articles on psychotomimetic agents which appeared during recent
years have been written by Hofmann (1961) (11), (1963) (12), by Crocket et al.
(1963) (13), by Cerletti et al. (1963) (6), by Jacobsen (1963) (14), by Downing
(1964) (15), by Giarman and Freedman (1965) (16), and by Hoffer (1965) (17).
5.2. THE HISTORY OF PSYCHOTOMIMETIC DRUGS

As has been indicated in the introduction, psychotomimetic agents have only
in modern times become the object of scientific research and now occupy an
important position in the field of psychopharmacology. Most psychotomimetics, however, are of plant origin, and the respective plants have been
known since ancient times and have been used as magic or sacred drugs. Their
history is as old as the history of mankind itself.
Aside from spiritual practices, religious and mystic submersion, often
strengthened by physical means such as asceticism, fasting, and isolation,
human beings, in their longing for higher knowledge and a more profound
understanding of the outer and inner world, have at all times used drugs in
order to bring about unusual states of consciousness. The cloak of mystery
has always enveloped this type of drug, owing to its profound and inexplicable
effects. These drugs were worshiped as sacred or magic drugs, and their use
was Iimited to the witch doctor or magician. When one considers the fact that
primitive man, despite being bound to his primitive mythical mind, succeeded
in discovering in the inexhaustible vegetable kingdom the few plant species
containing highly specific psychoactive substances, one cannot help but be
filled with amazement and admiration. Modem psychopharmacological
research is very much indebted to the anonymous discoverers from past ages.
Several thousand years ago a drug named "soma," which according to the

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old Sanskrit manuscripts "made one feel like a God," was of great importance
in lndia. While it is known that the plant was imported into India from Central
Asia, it is no longer known from what plant soma was obtained (18).
lt is very probable that a magic drug was used for the secret cults, famous
in the entire ancient world, which took place in Eleusis in Greece. From there
it is reported that the adepts who ingested a mysterious drink had ineffable
visions.

A. Hashish
A narcotic of the Near East swathed in legends is hashish, obtained from
the hemp plant, Cannabis sativa L. lts use dates back more than 2500 years.
Herodot (5th century before Christ) reports that the Scythians on the
Caspian Sea intoxicated themselves with vapors of Kavvaßi,; (Cannabis)
(quoted from Lewin) (4). The consumption of hashish has spread over wide
areas of Asia and Africa during the course of time. This drug aroused the
interest of certain circles of writers and artists in Europe du ring the latter part
ofthe past century. As an example, mention should be made ofthe "Club des
Hachichins" in Paris, of which Gautier and Baudelaire were members. The
latter described his experiences with hashish in his famous book Les Paradis
arti.ficie/s (19). The consumption of hashish in the form of marihuana smoking
has become a serious problem in America today. A number of preparations
are obtained from the hemp plant for intoxicating purposes (20). Especially
rich in active ingredients is hemp from India, Cannabis sativa L. var. indica.
The most commonly used portion is the resin that is excreted from the female
inflorescence. Hashish is generally assimilated by smoking the resin in combination with Nicotiana leaves. Chewing or swallowing cannabis preparations
is less prevalent. The numerous preparations are known by many different
names in various parts of the world. Some of the more common names are
bhang, dagga, hashish, kif, and marihuana.
Since euphoria and a narcotic component predominate in the pattern of
effects of hashish, its active principles do not fully correspond to the definition
of psychotomimetics. Furthermore, its widespread use as an intoxicant, as
opposed to the predominantly cultic use of psychotomimetics, justifies
classifying hashish in a position between psychotomimetics and narcotics.
The psychotropic effect ofhashish is mainly due to its content oftetrahydrocannabinols, which together with other derivatives of cannabinol constitute
the characteristic constituents of hemp.
The amount of literature on hashish and its active substances is extremely
vast. Here only two of the newer publications are quoted, which summarize
the subjects and in which reference to the original literature may easily be
found (21,22).

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B. Magie Plants of Mexico

The country of origin of the majority and most important of the magic
drugs, however, is Central America. Most of the psychotomimetically active
substances are obtained from Mexican magic plants. Magie drugs were
already of great importance in the old Indian cultures of Mexico. The Spanish
chroniclers and naturalists who came to the country soon after the conquest
of Mexico by Cortez mentioned in their writings a great number ofplants with
intoxicating, stimulating, or narcotic effects; these plants were unknown in the
Old World and were used by the Indians both in their medical practices andin
their religious ceremonies. The cultic use and divine worship given to many of
these drugs met with the disapproval of the Christian missionaries, who
attempted by any means possible to liberate the Indians from this devilry.
They were, however, only partially successful in this respect. The native
population secretly continued using the drugs considered by them as holy
even after having been converted to Christianity.
Three magic drugs were used mainly by the Aztecs and neighboring tribes
in their religious ceremonies and medical practices, which were strongly
influenced by magical concepts; these drugs are still used today for the same
purpose by the witch doctors in remote districts of Mexico. They are: ( l) peyotl,
a cactus species; (2) teonanacatl, certain foliate mushrooms; (3) ololiuqui, the
seeds of bindweeds.
Recent reviews summarizing the research in these Mexican hallucinogenic
drugs have been written by Hofmann (23) and by Cerletti (24).
1. PEYOTL

The first magic drug to be analyzed was peyotl, also named peyote, this
being done at the turn ofthe century. These investigations are tobe considered
as the first scientific studies in the field of psychotomimetics, and the two
pioneer researchers who carried them out, Louis Lewin and Arthur Heffter,
deserve a place of honor in the history of psychotomimetic research.
In the year 1886, during a trip to America, Lewin obtained several samples
of the peyotl cactus from an American pharmaceutical firm. The aboveground parts of the cactus, cut in slices and dried, were also named "mescal
buttons." The plant was classified by Hennings in the botanical museum of
Berlin as belonging to the Anhalonium species and was given the name
Anhalonium Lewinii, Hennings. Among the !arge number of synonyms,
Lophophora Williamsii (Lern.) Coulter is the botanical designation which has
prevailed (25). The cactus grows in the dry northern territories of Mexico and
in the adjacent southwestern districts of the United States. Lewin carried out
the first pharmacological tests on the cactus named after him and on the
alkaloids contained therein (26). Heffter was successful in isolating a number

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of alkaloids in pure form from mescal buttons. He studied the pharmacological
properties of these substances in tests carried out on animals and in heroic
tests on himself, whereby he found that the main alkaloid, mescaline, has the
hallucinogenic properties which are characteristic of peyotl (27,28). Späth
elucidated the chemical structure of mescaline and was able to produce this
alkaloid synthetically (29).
The history ofpeyotl, its ancient cultic use by the Indians ofCentral America
and its present use, as weil as the psychic effects on human beings, were
summarized and described for the first time by Lewin in his monograph
Phantastika (4). This brilliant pharmacologist and toxicologist, who did his
research in Berlin, established the basis for psychotomimetic research with
this standard work in which the psychotomimetics, then named phantastica,
were considered for the first time as forming an independent group within the
psychopharmaceuticals.
Lewin quotes the sources with the first statements on peyotl made by the
Spanish chroniclers in the sixteenth century. The Franciscan friar Bernardino
de Sahagun was the first to report on this drug in his famous historical work
Historia General de las Cosas de Nueva Espana (30) approximately 40 years
after the conquest of Mexico by Cortez. He writes that the Chichimecs ingested
peyotl instead of wine, as weil as the mushrooms nanacatl, and describes their
effects. Even today certain Indian tribes in the northern part of Mexico, for
example, the Huichol Indians, ingest peyotl during religious festivals.
A great deal has been published recently on the peyotl cult. Mention is made
here only of La Barre's Twenty Years of Peyote Studies (31), in which the
different aspects ofthe peyotl problem are dealt with andin which füll reference
to the literature is made.
The extension of the peyotl cult from Mexico to the Indian tribes of the
United States is of interest. Up to approximately 1890 peyotl was used in
North America by only five Indian tribes ; later its use spread like an epidemic
over the remaining Indian reservations. 1n the year 1918 a Christian religious
fellowship was founded in Oklahoma, called the Native American Church, in
which peyotl plays an important role as a sacred drug. This organization
includes the peyotl communities of the individual Indian tri bes. The history
of the peyotl cult of one of the Indian tribes living in the northern United
States, the Menomini Indians, has been written by Slotkin in his brilliant study
on "Menomini-Peyotism" (32). Non-Indian Christians have often protested
against the sacramental use of peyotl. However, when they went so far as to
denounce peyotl as being responsible for moral corruption and as being
habit-forming, five known American ethnologists, in a common declaration
published in Science, stated their opposition to this affirmation (33).
From the vast amount of literature about clinical reports on peyotl or
mescaline intoxication and its possibilities of being used in psychiatry, the

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classical publications of Prentiss and Morgan (34), Mitchell (35), Ellis (36),
and Heffter (37), as weil as the monographs of Beringer (38) and Klüver (39),
should be mentioned. Of the numerous publications dealing with the
philosophic-epistemological aspects of mescaline intoxication, it must suffice
here to refer to Huxley's books (9,40).
2. TEONANACATL

Teonanacatl, a word which could be translated as "sacred mushroom" or
"God's ftesh," was mentioned by the Spanish chroniclers as early as the
sixteenth century, as were peyotl and ololiuqui. The most important source of
information on this drug is de Sahagun's famous chronicle, Historia General
de las Cosas de Nuel'a Espaiia, written in the years 1529-1590. lt contains data
on the use of intoxicating sacred mushrooms which were eaten by the Indians
of Mexico at their feasts and religious ceremonies (41). From de Sahagun's
chronicle and from other reports it can be seen that teonanacatl was not only
ingested at social and festival occasions but also by witch doctors and soothsayers. The mushroom god-which the Christian missionaries called the
devil-endowed them with clairvoyant properties, which enabled them,
besides other things, to identify the causes of diseases and indicate the way in
which they could be treated.
The use and the worship of these mushrooms by the Indians of Central
America must be very ancient. In Guatemala so-called "mushroom stones"
have been found. These are stones carved in the form of a pileate mushroom,
in the stem of which the head or entire figure of a god is depicted . The oldest
specimens found are over three thousand years old. lt can therefore be concluded that the mushroom cult of the Indians dates back to more than thousands ofyears before Christ. More detailed historical data can be found in the
monograph of Wasson and Wasson, Mushrooms, Russia, and History (42).
Although this mushroom cult is very old, our knowledge of it is very recent.
For some centuries the reports in the old chronicles were given surprisingly
little attention, probably because they were regarded as extravagances of a
superstitious age. The last signs of the Indian mushroom cult seemed to be
finally disappearing when in 1915 the American botanist Safford (43,44)
supported the thesis that teonanacatl was not a mushroom but another name
for peyotl, the known mescaline drug. The Spanish chroniclers had obviously
erred and had confused the dried cactus with a mushroom.
However, between 1936 and 1938, American investigators, i.e., Weitlaner,
Reko, Johnson (45), and Schultes (46,47) ascertained that mushrooms are
currently still being eaten for magical purposes by the natives in certain
districts of southern Mexico.
Systematic studies ofthe mushroom cult in its present form were later made
by the amateur investigators R. Gordon Wasson and his wife, Valentina Pav-

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lovna Wasson (42). Between 1953 and 1955 they made several expeditions to
the remote mountainous districts of southern Mexico to study the current use
of the magic mushrooms. In the summer of 1955 R. G . Wasson was for the
first time able to take active part in a secret nocturnal mushroom ceremony in
Huautla de Jimenez, Province ofüaxaca, and probably was the first white man
to ingest the holy mushrooms. This experience, which impressed him profoundly and which convinced him of the hallucinogenic effect of the mushrooms, has been described by him in detail in his monograph. On a further
expedition in 1956 Wasson was accompanied by the mycologist Roger Heim,
director of the Laboratoire de Cryptogamie du Museum National d'Histoire
Naturelle in Paris. Heim succeeded in identifying and classifying the most
important types of mushrooms used for magical purposes by the Indians.
These were foliate mushrooms (agaricales) of the family Strophariaceae,
mostly new types, the greater part belonging to the genus Psilocybe, as weil as
one species ofthe genus Stropharia and one species ofthe genus Conocybe (48).
Subsequently cultures of some of these species were successfully grown in the
laboratory. Artificial cultivation provided a very good yield , especially of one
of these sacred mushrooms, namely, Psilocybe mexicana Heim. The chemical
analysis ofthis mushroom material was effected in the pharmaceutical chemical
research laboratories of Sandoz Ltd. in Basle by A . Hofmann and collaborators (49-52). The pharmacologists of the Sandoz laboratories first tested the
mushroom extracts on animals. Studies were made of pupillary reaction and
of piloerection in mice and of general behavior in dogs. The results were not
clear-cut and led to disagreement in the evaluation of the various extract
fractions. After most of the very rare and valuable material (or rather the
extract) had been given to the animals without effect, there was some doubt as
to whether the mushrooms cultivated and dried in Paris were still active. A
personal trial by Dr. Hofmann settled this fundamental point. He ate thirtytwo dried specimens of Psilocybe mex icana weighing 2.4 g, a medium dose by
Indian Standards. The mushrooms exerted a marked psychotomimetic effect
as described by Hofmann (53):
"Thirty minutes after taking the mushrooms the exterior world began to
undergo a strange transformation. Everything assumed a Mexican character.
As 1 was perfectly weil aware that my knowledge of the Mexican origin of the
mushroom would lead me to imagine only Mexican scenery, 1 tried deliberately
to look on my environment as 1 knew it normally. But all voluntary efforts to
look at things in their customary forms and colors proved ineffective. Whether
my eyes were closed or open 1 saw only Mexican motifs and colors. When the
doctor supervising the experiment bent over me to check my blood pressure,
he was transformed into an Aztec priest and 1 wo uld not have been astonished
if he had drawn an obsidian knife. In spite of the seriousness of the situation
it amused me to see how the Germanic face of my colleague had acquired a

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purely Indian expression. At the peak of the intoxication, about 11 hours after
ingestion of the mushrooms, the rush of interior pictures, mostly abstract
motifs rapidly changing in shape and color, reached such an alarming degree
that 1 feared that 1 would be torn into this whirlpool of form and color and
would dissolve. After about six hours the dream came to an end. Subjectively,
1 had no idea how long this condition had lasted. 1 feit my return to everyday
reality to be a happy return from a strange, fantastic but quite really experienced world into an old and familiar harne."
This personal study showed that the negative results of the tests in animals
were due not to the mushroom material but to the animals used and that
human beings provide a more sensitive index of substances with psychic
effects than do animals.
With the aid of this reliable test in human beings it was then possible to
extract the active principles from the mushroom and to purify and crystallize
them.
The main active component was named psilocybin, and an accompanying
alkaloid, usually present only in small amounts, was named psilocin. The
elucidation of their structures showed that these were novel indole derivatives.
Soon afterwards it was also possible to produce them synthetically. The
synthetic production ofpsilocybin and psilocin is more fruitful than obtaining
them from the mushrooms.
The existence ofthe chemically pure principles ofthe Mexican magic mushrooms made possible the scientific investigation of their pharmacological
properties, in tests carried out on animals, and of the psychic pattern of effects
on human beings. The first study of the effects of psilocybin on the whole
animal and on isolated organs was carried out in the pharmacological department of Sandoz Ltd. in Basle under the direction of Dr. A. Cerletti (54,55).
The first analysis of the effects of psilocybin on human beings was effected in
the psychiatric clinic of the University of Basle by tests on a number of collaborators of the Sandoz research laboratories (56, 57). Since then the active
component of teonamicatl has been used for experimental purposes in a great
number of psychiatric clinics all over the world and has been tested as to the
possibility of its being used as a medicament in psychoanalysis and
psychothera py.
The history ofthe solution ofthe teonanacatl mystery is a very good example
of how modern scientific research, in its efforts to obtain novel compounds
which are valuable in medicine, can revert to ancient knowledge of the
miraculous power hidden in the plant kingdom.
3. OLOLIUQUI

Ololiuqui is the Aztec name for the seeds of certain convolvulaceous plants
which have been used since prehispanic times by the Aztecs and related tribes,

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Albert Hofmann

just as the sacred mushrooms and the cactus peyotl have been used in their
religious ceremonies for magic and religious purposes. Ololiuqui is still used
in our day by certain tribes, such as the Zapotecs, Chinantecs, Mazatecs, and
Mixtecs, who live in the remote mountains of southern Mexico in comparative isolation, little or not at all influenced by Christianity.
An excellent review of the historical, botanical, and ethnological aspects of
ololiuqui was given in 1941 by Schultes in his monograph, A Contribution to
Our Knowledge of Rivea corymbosa: The Narcotic Ololiuqui of the Aztecs (58).
The following information on the history of ololiuqui, its botanical identifications, and its past and present use have been taken mainly from Schultes'
monograph.
One ofthe first descriptions and the first illustration of ololiuqui were given
by Francisco Hernandez, a Spanish physician, who between 1570 and 1575
carried out extensive research on the flora and fauna of Mexico for Philip II.
In his famous Rerum medicarum Novae Hispaniae thesaurus, seu plantarum,
animalium, minera/ium mexicanorum historia, which appeared in 1651 in
Rome, Hernandez described and classified ololiuqui under the heading, "De
Oliliuhqui, seu planta orbicularium foliorum" (59). An extract of a free
translation of the 1651 Latin version reads as follows: "Oliliuhqui, which
some call coaxihuitl, or snake-plant, is a twining herb with thin, green, cordate
leaves, slender, green terete stems, and long white flowers. The seed is round
and very like coriander. Formerly, when the priests wanted to commune with
their gods and to receive a message from them, they ate this plant to induce a
delirium. A thousand visions and satanic hallucinations appeared to
them .... "
lf we are to judge from the many ancient writers quoted in Schultes' monograph, ololiuqui must have been very extensively used in the valleys of Mexico
in prehispanic times. lt seems to have been more important in divinity than
peyotl or teonanacatl. However, the medicinal use was also very extensive.
Ololiuqui served to eure flatulence, to remedy venereal troubles, to deaden
pain, and to remove tumors. Ololiuqui was believed to possess a deity of its
own, which worked miracles if properly propitiated.
In spite of the above relatively good description and characteristic illustrtltion by Hernandez, the botanical identification of ololiuqui caused a great
number of discussions in professional circles. Finally, in 1897, M. Urbina
identified ololiuqui as Rivea corymbosa Hall. f. (syn. lpomoea sidaefolia
(HBK.)). This identification was confirmed by Schultes.
In Mexico, Rivea corymbosa is known and has been known by a number of
different vernacular names, the more important ofwhich are: Aztec: oliliuhqui,
ololiuqui, coaxihuitl, cuexpalli; Chinantec: a-mu-kia, huan-mei, huan-menha-sei; Maya: xtabentum; Mazatec: no-so-le-na; Mixtec: yucu-yaha;
Zapotec: bador, bad oh, bitoo, kwan-la-si, kwan-do-a; Spanish: flor de Ja

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Virgen, Ja sefiorita, manto, pascua, piuJe, semilla de Ja Virgen, yerba de las
serpientes, yerba de Ja Virgen.
OloJiuqui was used by the ancient Aztecs not onJy as a potion but also as an
ingredient of magical ointments. At the present time the crushed seeds are
taken in water or in alcoholic beverages such as puJque, mescal, or aguardiente.
Reko described in detaiJ the present use of oJoliuqui in his monograph
Magische Gifte (60). Usually the professional soothsayers, "piuleros," give
their c!ients advice under the inftuence of the piule drink, another name for
ololiuqui. Sometimes they also give the ololiuqui drink to their dient or

patient, who then replies to the piulero's leading questions in a narcotichypnotic state produced by the drug and thus reveals facts or discovers his
illness, for which the piulero then finds the medicines.
The only report on chemical investigations with the seeds of Rivea corymbosa
mentioned in Schultes' review on ololiuqui is that of the pharmacologist
Santesson in Stockholm in 1937. He was, however, unsuccessful in isolating
definite crystalline compounds. Alcoholic extracts produced a kind of
narcosis or partial narcosis in frogs and mice. Certain chemical reactions
seemed to suggest the presence of a gluco-alkaloid (61, 62).
In 1955, the Canadian psychiatrist Osmond conducted a series of experiments on himself. After taking 60 to 100 Rivea seeds he passed into a state of
apathy and listlessness accompanied by increased visuaJ sensitivity. After
about 4 hours, there followed a period in which he had a relaxed feeling ofwellbeing that lasted for some longer time (63). In contrast to these results,
Kinross-Wright in 1958 published experiments performed on eight male
voJunteers who had taken doses of up to 125 seeds without any ascertainable
effect in a single case (64).
After the chemical investigations of the sacred Mexican mushrooms had
come to a successfuJ end, the writer decided also to tackle the problem of the
third most importantMexican magicdrugafter peyotl and teonanacatl, namely,
oJoliuqui . Through the heJp of R. G. Wasson he was able to obtain authentic
oJoliuqui. He received two different sampJes of ololiuqui seeds, collected by a
Zapotec Indian near Oaxaca in southern Mexico. One sampJe consisted of
brown seeds, which proved on botanicaJ classification to be Rivea corymbosa.
The second sample, black seeds, was identical with lpomoea violacea L. (syn.
Ipomoea tricolor CA V.). These black seeds, ca!led "badoh negro," are used,
especially in the region of the Zapotecs, in conjunction with, or instead of,
"Badoh," the brown seeds of Rivea corymbosa (65).
The chemical investigations in the Sandoz Jaboratories led to the surprising
result that the psychotomimetic principles of oJoliuqui are ergot alkaloids.
The main components are d-lysergic acid amide and d-lysergic acid methylcarbinolamide, accompanied by 5 or 6 minor alkaloids (23, 66-69). From the
phytochemicaJ point of view, this finding was quite unexpected and of

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particular interest because lysergic acid alkaloids, which had hitherto been
isolated only from the lower fungi of the genus Claviceps, Penicillium, or
Rhizopus, were now, for the first time, found in higher plants, in the phanerogamic family Convolvulaceae. Subsequent chemical investigations in various
other laboratories confirmed the occurrence of ergot alkaloids in lpomoea
species (70-75).
The isolation of lysergic acid amides from ololiuqui closed a strange cycle
of research füll of coincidence. lt started with the discovery of the most potent
psychotomimetic drug, d-lysergic acid diethylamide (LSD-25) (see Section
5.2,D), in 1943 by A. Hofmann in the same laboratory where later the active
principles of teonanacatl, psilocybin, and psilocin were isolated and where
finally, again, d-lysergic acid amides were found in the ancient Aztec narcotic
ololiuqui.
C. Magie Plants of South America

A number of magic plants have also been used in South America since
ancient times, but insofar as their role in social history and their effective
compounds are concerned, they do not have the importance ofthe three magic
plants of Mexican origin described above.
1. AYAHUASCA (CAAPI, YAJE)

The magic drink known in the Western Amazonian regions as "ayahuasca"
(Ecuador, Peru, and Bolivia), "caapi" (Brazil and Colombia), and "yaje"
(Colombia) is made basically from the same or closely related plants of the
Malpighiaceae. lt is probable that the Indian names "natema," "nepe," and
"pinde" are synonymous with the three more commonly used names mentioned above. The most widely employed species are members of the genus
Banisteriopsis. The species most frequently used in Brazil, easternmost
Colombia, and much ofthe Amazon basin of Peru and Bolivia is Banisteriopsis
Caapi (Spruce ex. Griseb.) Morton, but B. Rusbyana seems also to be used in
easternmost Colombia. In the westernmost fringe ofthe Amazon basin, along
the Andean foothills of Colombia, Ecuador, and Peru, Banisteriopsis quitensis,
B. inebrians, and B. Rusbyana seem to be the species most preferred. The
closely related genus Tetrapterys is employed in Brazil and possibly in
Colombia. The only species of Tetrapterys definitely identified as a source of
the psychotomimetic "caapi" is T. methystica. Nonmalpighiaceous plants are
known to be added occasionally as admixtures together with Banisteriopsis in
some areas.
Schultes reached this conclusion with regard to the botanical source of the
most important South American psychotomimetic, ayahuasca, on the basis of
a critical examination of older reports but first of all as a result of his own

Psychotomimetic Agents

181

field experience in the northwestern part ofthe Amazon valley. In his publications in this connection (76-78) the vast amount of old literature on ayahuasca
is also mentioned, and therefore these fundamental publications of Schultes
may be used as a reference.
Science is indebted to the botanical explorer Richard Spruce for his discovery and first ethnobotanical study of caapi. In his report, written in 1852 on
his expedition along the upper Rio Negro, he describes how the Tukanoan
Indians of the Rio Uaupes use caapi to induce a trance for prophetic and
divinatory purposes, characterized, among other strange effects, by frighteningly realistic colored visual hallucinations and a feeling of extreme and reckIess bravery. In 1857, while working in the Peruvian Andes, he encountered the
Zaparo Indians using the same preparation under the name "ayahuasca" (79).
The earliest published record of the use of ayahuasca dates from 1858
(Spruce's report was published in 1908), when Manuel Villavicencio reported
that the drug was employed by the Zaparos, Angateros, Mazanes, and other
tribes of the upper Rio Napo in Amazonian Ecuador for sorcery, witchcraft,
prophecy, and divination. Villavicencio's account included a report on selfexperimentation (80).
The numerous later reports made by other investigators confirmed these
statements, although interminable discussions resulted on the botanical
identity of the plants used.
The hallucinating ayahuasca drink is prepared from the stem, sometimes
together with the leaves, of the liana, by pounding the material in a mortar
with the addition of water or by boiling pieces of the trunk together with the
crushed bark of the trunk. In some places cold water infusions of the rasped
bark are prepared.
According to Villavicencio's statements, ayahuasca was used by the natives
"to foresee and to answer accurately in difficult cases, be it to reply opportunely
to ambassadors from tribes in a question of war; to decipher plans of the
enemy through the medium of this magic drink and take proper steps for
attack and defense; to ascertain, when a relative is sick, what sorcerer has put
on the hex; to carry out a friendly visit to other tribes; to welcome foreign
travellers or, at last, to make sure of the love of their womenfolk."
The n10st fantastic descriptions ofthe ayahuasca intoxication were given by
Dr. Rafael Zerda Bayon, a Colombian pharmacist, who put forth extraordinary claims concerning the telepathic properties of the vine; they are
quoted in the monograph by Reko (60).
The ayahuasca-drinking habit is still widely extended in our day among the
Indians of the Amazon region. Mention is made here only of the excellent
report, "Ayahuasca Drinkers among the Chama Indians of Northeast Peru,"
by Kusel, in which the author describes the effects of the ayahuasca drink on
the white man, based on experiments on himself (81).

182

Albert Hofmann

The same confusion as that concerning the botanical identity of ayahuasca
existed in the chemistry of its active principles. The first chemical analyses
suffered from the Jack of a botanical determination of the plant material used.
An alkaloid has been isolated by various workers and named "telepathine"
(82), "yageine," or "banisterine" (83). Further investigations by Elger (84)
and by Wolfes and Rumpf (85) showed that only one alkaloid was concerned
and that it was identical with the already well-known alkaloid harmine.
Aside from the main alkaloid, two minor alkaloids, harmaline and d-tetrahydroharmine, were later also shown to be present in small amounts (86).
Harmine and harmaline had already been known for a long time as components
ofthe steppe plant Peganum harmala (zygophyllaceae), the seeds ofwhich were
used as diaphoretic and anthelmintic in Arabian medicine (87).
The hallucinogenic effects of the main alkaloid of ayahuasca, namely
harmine, are doubtful. No reports on the psychotomimetic activity of the
minor alkaloids harmaline and d-tetrahydroharmine are available (see
Section 5.3,C). The discrepancy between the often described hallucinogenic
and psychotomimetic effects of the crude extracts used by the natives and the
doubtful effect of the pure alkaloid shows that the chemical and medical
aspects of the ayahuasca problem have not yet been completely solved.
2. YOPO (COHOBA)

The first scientific report concerning yopo, a psychotomimetic snuff prepared from the seeds of a leguminous plant, is apparently that ofvon Humboldt
(88), who, in 1801, saw the Otomacs along the Orinoco pulverize the seed of
Piptadenia peregrina (leguminosae), mix the powder with quicklime, and use
it like tobacco snuff. But it was Spruce (79) who gave the earliest detailed
report when he wrote ofthe niopo ofthe quahibos ofthe Orinoco ofColombia.
The principal area of use of yopo lies in the upper Orinoco basin (89), but it is
also known in wide areas of the Amazon. The snuff named cohoba by the
Indians of ancient Hispaniola has been found to be prepared also from the
seeds of Piptadenia peregrina. Another species of Piptadenia, P. macrocarpa,
seems to be the source of a snuff of the Amazonian regions of Peru, where the
plant is called "huilca." But little of a definite nature is known about huilca.
Similarly, little is known in the case of P. colubrina, which is supposed to be
used for preparing the snuff "sebil" in some areas of Argentina (90).
As practiced today in the Orinoco basin of Colombia and Venezuela yoposnuffing is a dangerous habit, which is carried on not by the witch doctors
alone but also by the whole population. The snuff is inhaled or is blown into
the nostrils by means of a forked tube made from chicken bones. The use of
yopo in daily life may be relatively recent, for it was employed in ancient times
only for specific purposes, such as to induce bravery before a battle, to give

Psychotomimetic Agents

183

hunters keener sight, and as an agent for prophesying, clairvoyance, and
divination (90).
Recent chemical work has shown that the major alkaloid of a number of
species of Piptadenia is bufotenine. Other tryptamine derivatives were found,
such as N,N-dimethyltryptamine, N-methyltryptamine, 5-methoxy-N-methyltryptamine, and 5-methoxy-N,N-dimethyltryptamine (91-93).
3. VINHO DE JUREMA

Another South American magic beverage, called vinho de Jurema, is
prepared from the seeds of the leguminous Mimosa hostilis and is used in
magico-religious ceremonies by the Pancaru Indians in Pernambuco, Brazil.
An alkaloid named nigerine was isolated, which was later shown tobe identical
with N,N-dimethyltryptamine, the same constituent as found in species of the
closely related genus Piptadenia (90).
4. YAKEE, PARICA, EPENA

In the Colombian Amazon a particularly intoxicating snuff, which is named
yakee or parica, is used by the witch doctors in several tribes. Schuhes ascertained that this snuff is produced from the resin of various Virola species:
V. calophylla, V. calophylloidea, and possibly V. elongata (94). lt is possible
that a tree named epena-kesi, as yet still unidentified, the bark of which is also
used as an ingredient of a snuff powder, also belongs to this plant family (90).
The question of which plants were used to procure yakee or parica, as well as
the snuff named epena, has not yet been completely answered, because,
besides Virola species, other leguminosae and often various plants are apparently used simultaneously (95). This also explains the contradictory findings
that completely different compounds were isolated from snuff of various
origins; for example, 5-methoxy-N,N-dimethyltryptamine was the main
component, and small amounts of N,N-dimethyltryptamine and bufotenine
were found in epena of the Waicas, who inhabit the region between the
Rio Negro and Rio Branco in northwest Brazil (96), whereas harmine and
( + )tetrahydroharmine were obtained from epena of the Surara tribe (97).

D. The Discovery of LSD-25
While the hitherto discussed psychotomimetic compounds occur in nature
as constituents of ancient magic drugs, LSD-25 is a synthetic compound, a
product of modern pharmaceutical-chemical research. LSD-25 is the laboratory name of d-lysergic acid diethylamide tartrate. As stated in a previous
paragraph (Section 5.2,B,3), it was later found that d-lysergic acid amides,
closely related to LSD, also occur in nature as active principles of the old
Mexican magic plant ololiuqui.

Albert Hofmann

184

The way which led to the discovery of LSD was (mferent in principle from
the process for finding psychotomimetics such as mescaline and psilocybin,
which are produced from the so-called magic plants which have a well-known
psychotomimetic effect, and therefore a brief description of how LSD was
discovered is given here. The history ofthe discovery of LSD is also interesting
because LSD has by far the highest and most specific psychotomimetic effect
and may, therefore, be considered as the genuine prototype of psychotomimetic compounds.
Lysergic acid diethylamide was prepared in the course of investigations on
ergot alkaloids in the Sandoz research laboratories at Basle in Switzerland.
Lysergic acid is the characteristic nucleus of all the alkaloids of ergot and can
be obtained by alkaline hydrolysis of these alkaloids. In 1938 Stoll and
Hofmann succeeded in synthesizing ergometrine (ergonovine) (1), the wellknown oxytocic, by combining d-lysergic acid with L( + )2-aminopropanol
(98,99). This was the first partial synthesis of a natural ergot alkaloid. Using
the same synthetic procedure, Hofmann prepared, among many other derivatives, d-lysergic acid diethylamide (2) with the aim of obtaining an analeptic.
This could be expected, as lysergic acid diethylamide has many structural
features in common with thewell-known analepticnikethamide (Coramine) (3).
/CH20H
CONHCH
H\

"CH3

(1)

Ergomctrine
(crgonovinc)

(2)

d-Lysergic acid
diethylamide
(LSD-25)

(3)

Nicotinic acid
diethylamide
(nikethamide)

A number ofpharmacological experiments were carried out. They revealed
a fairly marked uterotonic action, which was not unexpected in view of the
close chemical relationship between LSD and the oxytocic drug ergometrine.
In addition, striking excitation was observed in some of the animals. In the
course of these investigations an accidental observation led Hofmann to the
discovery of the extraordinary action of LSD on the human psyche. The
following is the translation of an extract from Hofmann's original report (100).
"Last Friday, April 16, 1943, 1 was forced to stop my work in the laboratory
in the middle of the afternoon and to go home, as 1 was seized by a peculiar

Psychotomimetic Agents

185

restlessness associated with a sensation of mild dizziness. Having reached home,
1 lay down and sank in a kind of drunkenness which was not unpleasant and
which was characterized by extreme activity of imagination. As 1 lay in a
dazed condition with my eyes closed (1 experienced daylight as disagreeably
bright) there surged upon me an uninterrupted stream of fantastic images of
extraordinary plasticity and vividness and accompanied by an intense,
kaleidoscope-like play of colors. This condition gradually passed off after
about two hours."
Hofmann suspected some connection between these peculiar phenomena
and the substances with which he had been working that afternoon, i.e.,
d-lysergic acid diethylamide and its isomer, d-isolysergic acid diethylamide.
He had separated the two isomeric forms and prepared the crystalline watersoluble tartrate of d-lysergic acid diethylamide (LSD-25). As he had not
ingested any LSD-25 intentionally, only traces of the substance could at best
have entered his body in some accidental manner. In order to investigate this
problem, he decided to experiment on himself. To begin with, he took only
0.25 mg of LSD-25, which according to experience with other ergot derivatives
might be regarded as a small dose.
"April 19, 1943: Preparation of an 0.5 %aqueous solution of d-lysergic acid
diethylamide tartrate.
"4:20 P.M.: 0.5 cc (0.25 mg LSD) ingested orally. The solution is tasteless.
"4 :50 P.M.: no trace of any effect.
"5.00 P.M.: slight dizziness, unrest, difficulty in concentration, visual
disturbances, marked desire to laugh . .. "
At this poin! the laboratory notes are discontinued:
" The last words could only be written with great difficulty. 1 asked my
laboratory assistant to accompany me home as 1 believed that my condition
would be a repetition ofthe disturbance ofthe previous Friday. While we were
still cycling home, however, it became clear that the symptoms were much
stronger than the first time. 1 had great difficulty in speaking coherently, my
field ofvision swayed before me, and objects appeared distorted like images in
curved mirrors. 1 had the impression of being unable to move from the spot,
although my assistant told me afterwards that we had cycled at a good pace ....
"By the time the doctor arrived, the peak of the crisis had already passed.
As far as 1 remember, the following were the most outstanding symptoms:
vertigo, visual disturbances; the faces of those around me appeared as grotesque, colored masks ; marked motor unrest, alternating with paresis ; an
intermittent heavy feeling in the head, limbs and the entire body, as if they
were filled with metal; cramps in the legs, coldness and loss of feeling in the
hands; a metallic taste on the tongue ; dry, constricted sensation in the throat;
feeling of choking; confusion alternating between clear recognition of my
condition, in which state 1 sometimes observed, in the manner of an

186

Albert Hofmann

independent, neutral observer, that 1 shouted half insanely or babbled incoherent words. Occasionally 1 feit as if 1 were out of my body.
"The doctor found a rather weak pulse but an otherwise normal circulation .
. . . Six hours after ingestion ofthe LSD-25 my condition had already improved
considerably. Only the visual disturbances were still pronounced. Everything
seemed to sway and the proportions were distorted Iike the reftections in the
surface of moving water. Moreover, all objects appeared in unpleasant,
constantly changing colors, the predominant shades being sickly green and
blue. When 1 closed my eyes, an unending series of colorful, very realistic and
fantastic images surged in upon me. A remarkable feature was the manner in
which all acoustic perceptions (e.g., the noise of a passing car) were transformed into optical effects, every sound causing a corresponding colored
hallucination constantly changing in shape and color Iike pictures in a
kaleidoscope. At about 1 o'clock 1 feil asleep and awakened next morning
somewhat tired but otherwise feeling perfectly weil."
This is the history of the discovery of LSD-25. Subsequent experiments on
volunteers of the Sandoz research Iaboratories confirmed the extraordinary
activity of lysergic acid diethylamide on the human psyche. These showed that
the effective oral <lose of LSD in human beings is 0.03-0.05 mg. The amount
of 0.25 mg used by Hofmann in his first planned test on himself, therefore,
already corresponded to a five-fold quantity of an average effective dose. LSD
is by far the most active and most specific psychotomimetic. lt is about 5,000-10,000 times more active than mescaline or about 100-200 times more active
than psilocybin.
The first systematic clinical studies of LSD in normal su bjects and in mental
patients were then carried out by the psychiatrist Stoll ofthe Psychiatrie Clinic
of Zürich University (101) . Since then more than 2000 original papers on
LSD, dealing with the clinical, pharmacological, neurophysiological, and
biochemical aspects of this extraordinary compound, have been published,
the most important of which are mentioned in the corresponding subsequent
sections of this chapter.
5.3. CHEMISTRY AND STRUCTURE-ACTIVITY RELATIONSHIP
OF PSYCHOTOMIMETIC AGENTS

A. Structural Types of Psychotomimetics

Virtually all the older psychotomimetic compounds are of plant origin.
They are the active principles ofthe magic plants discussed above or synthetic
derivatives of these natural compounds. Although there are other natural and
synthetic compounds which also produce profound psychic disturbances,
these derangements occur only after the use of toxic <loses as side effects of an
activity pattern primarily determined by autonomic symptoms. Thus, after

Psychotomimetic Agents

187

toxic doses of anticholinergics, e.g., atropine and scopolamine, symptoms
such as anxious excitation, disorientation, narcotic conditions, deliria,
hallucinations, etc., are observed. Owing to these effects, the plants which
contain these alkaloids have also been used since ancient times for magic and
divinatory purposes; for example, certain Datura species are still used today
under the name of "toloache" in the northern areas of Mexico, as weil as in
certain parts of South America (90). The newly developed synthetic anticholinergics, such as piperidyl glycolates of the type of Ditran, also show this
effect pattern (102, 103). Furthermore, the compounds which stimulate
cholinergic functions, such as phenylcyclidine (Sernyl), also produce psychic
changes (104, 105). As the psychotomimetic effects of these compounds do
not delineate their pharmacological spectrum of activity but are merely toxic
side effects, these compounds cannot be considered specific psychotomimetics
and have therefore not been included in the present survey.
Psychotomimetics in a narrower sense, which are characterized by the effect
pattern described in Section 5.1, fall chemically within the structural groups
listed in Table 5.1.
In the following sections the chemical and pharmacological data of the
individual psychotomimetics and their derivatives are given, and their
structure-activity relationship (SAR) is discussed. As the establishment ofthe
SAR is the main object, no details ofthe chemical constitution and no description of the syntheses are given. Literature references to the corresponding
original chemical studies are made for the reader interested in the chemistry
of the subject.
TABLE S.l
STRUCTURAL TYPES OF PSYCHOTOMIMETICS

a. Tryptamine derivatives

R1

Ri~CH2CH2N(CH3)2

UNJ
H

(a)

R 1 = R 2 = H: N,N-Dimcthyhryptaminc
(constitucnt of yopo, etc.)
(b) R 1 = H; R 2 = OH : Bufotcninc
( constitucnt of yopo, etc.)

(c)

R 1 = OH ;

(d)

Ra = OPO,H ;

Rz = H : Psilocin
R 2 = H : Psilocybin

} (constitucnts
of,
teonanacatl)

(4)

b, Harmine and derivatives
Harminc
}
3,4-Dihydroharminc (harmalinc) (constituents of ayahuasca, etc.)
d-1,2,3.4-Tctrahydroharminc

(5)

Albert Hofmann

188
TABLE 5.1-continued
c. d-Lysergic acid amides

H\

-~---

(a)
(b)
(c)

R 1 = R2= H: d-Lyscrgic acid amidc = crginc } (coristitucnts of
R1=CHOHCH3; R,=H: d-Lyscrgic acid
ololiuqui)
mcthylcarbinolamidc
R 1= R,= C2Hs: d-Lyscrgic acid dicthylamidc = LSD-25 (synthctic)

(6)

d. Phenethylamines
CH30-0CH2CH2NH2
CH 30 - y
OCH3
(7)

3,4,5-Trimcthoxyphcncthylaminc (mcscalinc) (constitucnt of pcyotl)

e. Tetrahydrocannabinols

(8)

B. Tryptamine Derivatives
1. N,N-DIMETHYLTRYPTAMINE (9)

(9)

This simplest indole alkaloid with hallucinogenic properties was found to
be an ingredient of various snuff powders used by the South American Indian
tribes for magic purposes (see Section 5.2,C,2-4).

Psychotomimetic Agents

189

The compound was produced for the first time in 1931 by Manske (106).
Later a number of improved syntheses were described (107-109). The psychotomimetic properties of N,N-dimethyltryptamine were discovered and tested
by Szara (110-1/ 2) and later confirmed by other authors (113, 114). The
effective <lose for man is approximately 1 mg/kg intramuscularly. The psychotomimetic effect sets in rapidly and fades away after 50 to 60 minutes (115).
Higher N,N-dialkyltryptamines which do not occur in nature also show a
psychotomimetic effect. The N,N-diethyl, N,N-dipropyl, and N,N-diallyl
derivatives have approximately the same, but a longer-lasting, effect than the
dimethyl analogue (J 16). When the alkyl radical is extended further the effect
is considerably reduced; e.g., N,N-dihexyltryptamine is practically inactive
(117) .

2. BUFOTENINE (IOa) AND 5-METHOXY-N,N-DIMETHYLTRYPTAMINE (10b)

Bufotenine (5-hydroxy-N,N-dimethyltryptamine) (lOa) is one of the compounds contained in South American leguminosae which are used for the
production of hallucinogenic snuff powder (see Section 5.2,C,2-4). This
compound was first discovered in the skin glands of toads (118) and it is

(a)
(b)

R = H: Bufoteninc
R = CH 3: 5-Mcthoxy-N,N-dimcthyltrypta minc

(10)

widely distributed in higher plants and animals (119). The structure of
bufotenine was elucidated in 1934 by Wieland et al. (J 20). Many syntheses
were developed for bufotenine, the most convenient of which appear to be
those of Speeter and Anthony (109) and of St oll et al. (121).
Bufotenine, when administered by intravenous injection, was reported by
Fabing and Hawkins (122) to produce psychotomimetic effects in man
(2- 16 mg/kg). Other investigators found no hallucinogenic activity after
intravenous injections of up to 20 mg (114), nor after oral administration of
50 mg (12). lt could be that the special application in the form of a snuff
powder modifies in some way the psychotomimetic activity ofthis compound.
The 0-methyl derivative of bufotenine (5-methoxy-N,N-dimethyltryptamine) (tob), which is also a constituent of various hallucinogenic snuff
powders (see Section 5.2,C,2- 4), has been found to be more active in a conditioned avoidance response test than bufotenine or N,N-dimethyltryptamine
(123).

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Albert Hofmann

3. PSILOCYBIN (11) AND PSILOCIN (12)

Psilocybin and psilocin are the active principles of "teonanacatl," the
"sacred mushrooms" of Mexico (see Section 5.2,B,2), psilocybin being the
main component. These compounds were first isolated from Psilocybe mexicana Heim in 1958 by Hofmann et al. (49). Because ofthe inconclusive results
O~ /OH
o/P'-o<-)

(+)
CH2CH2NH(CH3)z
N
H
(II)

(12)

Psilocybin ( 4-phosphoryloxy-N.Ndimethyltryptamine)

Psilocin ( 4-hydroxy-N.Ndimethyltryptamine)

with animal tests in attempts to follow the active principles through the
extraction and chromatographic procedures, human experiments had to be
done at various stages during the concentration ofthe active principles (7,53).
Later other Psilocybe species belonging to the teonanacatl group were also
shown to contain psilocybin, usually together with a small amount of psilocin,
e.g., P. caerulescens Murr. var. Mazatecorum Heim, P. Zapotecorum Heim,
P. Aztecorum Heim, P. semperviva Heim et Cailleux, Stropharia cubensis Earle
(124) . Stropharia cubensis is found not only in Central America but also in
Cambodia and Thailand. Furthermore, psilocybin and psilocin were also
found in North American Psilocybe species which are not known to be used
for magical purposes, namely, in P. pel/iculosa A. H. Smith (125), P. cyanescens
Wakefield, P. baeocystis Singer and Smith, and in the botanically closely
related species Conocybe cyanopus (Atk.) Kuehner (126).
Degradation studies showed psilocybin to be 4-phosphoryloxy-N,Ndimethyltryptamine (11). Hydrolysis of psilocybin gives equimolecular
amounts of phosphoric acid and psilocin, which is 4-hydroxy-N,N-dimethyltryptamine (12). These structures were confirmed by synthesis (50- 52). The
synthetic production of psilocybin is much more rational than obtaining it
from the mushrooms. The dried mushrooms contain 0.2-0.4 % of psilocybin.
Psilocin is present in trace amounts only. Psilocybin is a stable compound
which is readily soluble in water and which is obtained in colorless crystals.
Psilocin on the other band is very sensitive to oxidation and difficultly soluble
in water. Psilocybin is the first and only hitherto known natural indole compound which has a phosphoric acid radical. Psilocybin and psilocin are also
novel in that they are substituted in the 4-position of the indole structure by
a hydroxy radical. All the other indole alkaloids with the exception of

Psychotomimetic Agents

191

Mitragyna alkaloids have hydroxyl functions in the 5, 6, or 7 position (J 27).
Tryptophan seems to be the biogenetic precursor of psilocybin. D,Ltryptophan-[ß-14C] was utilized at a rate of 10-20% by the fungus Psilocybe
semperviva Heim et Cailleux in producing psilocybin (128).

a. Mental Effects
Psilocybin and psilocin produce psychotomimetic effects in man which are
similar to those produced by mescaline or LSD-25. The medium oral dose for
man is 4 to 8 mg; it elicits the same symptoms as the consumption of about 2 g
of dried Psilocybe mexicana fungus (53, 129).
The first analysis ofthe effects ofpsilocybin in man was made at the Psychiatrie Clinic of the University of Basle and was based on personal studies made
by several members of the staff of the Sandoz research Iaboratories (56, 57).
More detailed investigations have been carried out by Delay and his associates
in Paris (130, 131). As a result of these and many further investigations, of
which only a few are mentioned in this article (J 32-138), the effects ofpsilocybin
can be described as follows: Oral doses of a few milligrams lead, after 20 to 30
minutes, to changes in the psychic sphere. The psychic symptoms produced by
small doses, i.e., up to 4 mg, comprise effects on mood and environmental
contact in that there frequently is a subjectively pleasant sensation of intellectual and bodily relaxation and detachment from the environment. Not
infrequently these effects are associated with a pleasant feeling of physical
tiredness and heaviness, but sometimes they are accompanied by a feeling of
extraordinary lightness, a bodi!y hovering. With higher <loses, 6 to 20 mg,
more profound psychic changes are prominent and are associated with
alterations in spatial and temporal perception and with changes in the awareness of the seif and body image. Visual hypersensitivity is present and may lead
to illusions and hallucinations. In this dreamlike state long-forgotten
memories, even some from early childhood, are often recalled.
The psychotomimetic effects of psilocybin, psilocin, LSD, and mescaline
were compared by W olbach et al. (J 39) and found to be qualitatively similar.
The time course of the psilocybin and psilocin reactions is shorter than that
of LSD or mescaline reactions. Psilocin is approximately 1.4 times as potent
as psilocybin . This ratio is the same as that ofthe molecular weights ofthe two
drugs. The development of "cross" tolerance between LSD and psilocybin
supports the idea that these two drugs cause psychic disturbances by acting on
some common mechanisms, or on mechanisms acting through a common
final pathway (140-142) .
The influence of expectations and mood on responses to psilocybin was
studied. lt was found that positive expectations, in general, lead to positive
experiences; anxiety or preoccupation leads to unpleasant experiences. Mood

192

Albert Hofmann

before the session is the best predictor of mood during the session: unpleasant,
depressed, anxious moods are intensified on the whole; pleasant moods lead
to pleasant and varied experiences. Mystical or religious experiences are often
reported after respective expectations and especially when these expectations
are combined with high <loses. A hypothesis was proposed, according to which
the effect of psilocybin is to suspend or deactivate temporarily the cognitiveperceptual screening structures (143).
The influence of psilocybin on the expressive capabilities for drawing were
examined by Roubicek and Drvota (144) and by Volmat and Robert (145).
b. Pharmacological Properties

Psilocybin does not exhibit typical effects on isolated organs (intestine,
uterus, heart), with the exception of a pronounced inhibiting effect towards
serotonin. On the entire animal, however, it has characteristic autonomic
effects, namely, dilatation of the pupils, contraction of the nictitating membrane, piloerection, temperature increase, etc. This is an ergotropic excitation
syndrome, which mainly results from a central stimulation of sympathetic
structures (54,55). In the electroencephalogram an activation may be detected
which is characterized by a practically complete disappearance of the slow
waves. The electroencephalographic "arousal" reaction of rabbits after
psilocybin is not determined by a stimulating effect of the compound on the
formatio reticularis but by an inhibition of thalamic substrates (J 46, 147). As
opposed to this autonomic excitation syndrome produced by the central
nervous system, the motor behavior of the animals in general is strangely
rather damped, which, however, does not exclude the simultaneous existence
of a certain overexcitation towards outer stimuli.
A very characteristic effect of psilocybin is the regular enhancement of
monosynaptic spinal reflexes, e.g., the patellar reflex of cats (148).
The pharmacological effects of psilocin amply correspond to those of
psilocybin qualitatively and quantitatively in studies performed thus far (149).
The phosphoric acid radical, therefore, does not appear to contribute to the
pharmacological activity possessed by psilocybin, but as psilocybin is more
stable towards chemical influences than psilocin, especially towards oxidation,
the phosphoric acid radical could act biologically as a protective group.
The toxicity of psilocybin in animals is very low in comparison to the
effective <lose in man. The LD 50 for the mouse is 280 mg/kg; i.e., psilocybin is
2.5 times less toxic than mescaline in this test, while it has a 50 times higher
psychotomimetic effect in man (7).
c. Biochemical Effects

A simultaneous investigation of blood sugar level and of behavioral and
corticographic changes after administration of psilocybin was carried out on

Psychotomimetic Agents

193

wake rabbits. Significant transient changes in behavior, accompanied by
increases in blood sugar level and corticographic changes, were noted. The
last included decrease of voltage and of cortical potentials and desynchronization of brain activity (150).
Humanserum cholinesterase was inhibited 97 %by 10- 4 M, 68 %by 10- 4 •5 M,
25 %by 10- 5 M, 5 %by 10- 5 •5 M psilocybin solution (151). No correlation was
found between the in vitro anticholinesterase activity ofpsilocybin, bufotenine,
serotonin, and LSD and its derivatives, and the hallucinogenic effect of these
compounds (152) .
Urinary excretion of inorganic phosphorus and total circulating eosinophiles were significantly reduced after administration of psilocybin in man
(135).

Psilocybin is readily dephosphorylated by purified calf intestinal phosphatase to give psilocin and inorganic phosphate (153) . Investigations of the
enzymic dephosphorylation and oxidation of psilocybin and psilocin by
mammalian tissue homogenates showed that the psilocybin-dephosphorylating
activity was highest in the rat and mouse kidney and the mucosa of the small
intestine of the guinea pig and rabbit. Oxidase activity, which transforms
psilocin into a blue-colored product of an o-quinone type of structure, was
highest in the heart of all the animal species and in the kidney of the rat and
mouse (154) . The administration of psilocybin to intact mice resulted in the
accumulation of psilocin in the kidney, liver, and brain. The highest concentration in the kidney and liver was found within 10-20 minutes, and the brain
levels reached a peak 25-30 minutes after administration of psilocybin.
Behavioral effects, characterized by piloerection, exophthalmos, and motor
incoordination, closely followed the increase in brain levels of psilocin. There
is some evidence that the CNS effects of psilocybin are exerted only after its
transformation to psilocin (J 55, 156).
Psilocin and other hydroxyindoles are oxidized by preparations of the gill
plates of Mytilus edulis. This is attributed to the action of a hydroxyindole
oxidase found in this species of mollusc (157, 158).

d. Absorption, Distribution, and Excretion
The absorption, distribution, excretion, and metabolism of psilocin in the
rat were studied quantitatively with labeled compounds ( 159). Psilocin labeled
with 14 C in the 2'-position ofthe side chain or in the N-methyl group was used.
From these experiments it could be concluded that psilocin is absorbed to
about 50 % by the gastrointestinal tract of the rat. lts distribution in the body
is on the whole quite uniform, most of the organs and tissues showing nearly
the same content after 30 minutes. The brain is not an exception, as is the case
when using LSD, where only very Iow brain levels are reached (160) . The

194

Albert Hofmann

activities in the tissues, with the exception ofthe liver and the adrenals, fall off
to low values in the course of 8 hours. Psilocin and its metabolites are excreted
mainly in the urine, approximately 65 % within 24 hours, whereas 15-20 %
appear in the bile and feces. Most ofthe products are excreted during the first
8 hours, but a considerable part (10-20 %) is retained longer, so that even after
7 days significant quantities of metabolites are found in the urine. The side
chain of psilocin seems to be remarkably stable to metabolic transformations.
Oxidative demethylation ofthe dimethylaminoethyl group plays only a minor
role in the metabolism of psilocin, a maximum of 4 % being degraded in this
manner. The resulting secondary and primary amines are metabolized further
to 4-hydroxyindolyl-3-acetic acid. Apart from a considerable quantity of
psilocin excreted unaltered (about 25 %), the main metabolic products seem
to be conjugates with as yet unidentified partners to form highly hydrophilic
substances.
e. Chemical Modifications of Psilocybin and Psilocin
In order to investigate the SAR in the group of hydroxylated tryptamine
derivatives, the molecules of psilocybin and psilocin were modified in various
ways (161). For example, the isomers ofpsilocybin and psilocin were produced
(7) in which the hydroxy or phosphoryloxy group was in the 5-, 6-, or 7-position
instead of the 4-position (see Table 5.2,A). Second, the dimethylamino side
chain was varied, whereby the hydroxyl group was placed in the 4- or 5-position
(see Table 5.2,B). Third, the indole nitrogen atom was substituted by a methyl
or benzyl group (see Table 5.2,C). Finally, the hydroxy or phosphoryloxy
group in the 4 position was replaced by other radicals (see Table 5.2,D).
The testing of these derivatives in man has as yet been effected only to a
limited degree. Most of these compounds, however, have already been compared pharmacologically. In this connection the effect on the knee jerk of
spinal cats was the test used from which a relationship with the psychotomimetic effect ofthe corresponding compounds could be expected. lt has been
observed that psilocybin, like LSD, enhances the sensitivity of spinal reflexes
(148). This could also be verified in man (140, 162). The results ofthe investigation of psilocybin and its derivatives and to their effect on the knee
jerk of spinal cats (163) are listed in Table 5.2. Psilocybin and psilocin already
produce an enhancement of the reflex in <loses of 5-10 y/kg, whereas, for
example, serotonin administered in the same minimal <loses weakens the reflex.
As a result of this examination of the SAR, it may be seen from Table 5.2
that the enhancing effect on spinal reflexes is limited to the tryptamine derivatives which have the hydroxyl function in the 4-position. Substitution of the
indole ring in the 4-position, which psilocybin and psilocin have in common
with lysergic acid and LSD, appears to be a structural condition for high

Psychotomimetic Agents

195

psychotomimetic activity. The structure of the tryptamine side chain also
plays apart in producing a positive effect. The dimethylaminoethyl group gives
an optimum effect, whereas, for example, 4-hydroxytryptamine, in which the
nitro gen atom of the side chain is not methylated, even has a reflex-inhibiting
elfect.
TABLE S.2
EFFECT ON THE KNEE JERK OF SPINAL CATS OF PSILOCYBIN AND RELATED
COMPOUNDSa

Position of R

5

4

R

-

6

7

--- - -- --

t (psilocin)

OH
OP03H2

t

t

5- 10 y
(psilocybin)
5-10 y

t

(bufotenine)
20- 50 y
>50 y

no etfect

no etfect

no etfect

no effect

HOO:J-4

s

1
~

1 R

(B)

N
H

R

OH in position 4
OH in position 5
------- -- - - - - -· - -·· - - ·-··---·- - - ·
t
20-50
y
.j,
(serotonin)
5-10
y
CH2CH2NH2
t 20-50 y
CH2CH2NHCH3
t (psilocin) 5-10 y
CH 2C H2N(CH3)i
t (bufotenine) 20--50 y
t 20- 50 y
CH2CH2NHC2Hs
t 20--50 y
CH2CH2N(C2Hsh
CH2CH2NJ
CH 2CH(CH3)NH2
CH2CH(CH3)N(CH3)i
CH(CH3)CH2NH2
CH(CH3)CH2N(CH3)i
CH(OH)CH2N(CH3)i

t

20-50 y

t

> 50 y

t
t

>50 y
> 50 y

t
t
t

10--20 y
20-50 y
>50 y

t

No effect
> 50 y

196

Albert Hofmann
TABLE S.2-continued

Effect on
kneejerk

R1

R4

CH3
CH3
CH2C6H5

OP03H2
OH
OH

no effect

t 20-50 y
no effect

Effect on
knee jerk
Br
Cl
CH3
OCH3
OS03H
OCH2C6H5
OCOC6H5
OCONHCH3
OS02C6H5CH3-p

t

<50y
no effect
H 20-50 y
tP0-50 y
no effect
t 20-50 y
t 5-10 y
t >50y
no effect

<> Upward arrow means augmentation of the reftex response and the downward arrow,
reftex inhibition. The numbers indicate the minimal intravenous doses in micrograms per kg
which were necessary in the average of experiments to produce alteration of the knee jerk.

Substitution in the 1-position also produces a weakening or complete disappearance ofthe effect. On replacing the 4-hydroxy or phosphoryloxy radical
by other groups, the benzyloxy derivative was found tobe the only compound
which has a reftex-enhancing effect analogous to that ofpsilocin and psilocybin.
With regard to the testing of derivatives of psilocybin and psilocin in man,

Psychotomimetic Agents

197

the only existing report concerns the use of the ethyl analogues, i.e., 4-phosphoryloxy- N,N - diethyltryptamine and 4- hydroxy- N,N- diethyltryptamine
(164). These two compounds do not show any significant quantitative or
qualitative differences in their effect. They differ from psilocybin and psilocin
in that their period of action is somewhat shorter, amounting to an average of
31 hours; these compounds are therefore suitable for ambulant treatment.
C. Harmine and Derivatives
Harmine (13) is the major alkaloid, and harmaline (14) and d-1,2,3,4-tetrahydroharmine (15) are the minor alkaloids of various Banisteriopsis species
which are used by the South American Indian tribes for the preparation of

(13)

(14)

Harminc

Harmalinc

(IS)

d-1 .2,3,4-Tctrahydroharminc

magic beverages (ayahuasca, caapi, yaje, etc.) (see Section 5.2,C, !). Harmine
and harmaline were isolated considerably earlier from Peganum harmala L.
(zygophyllaceae) (165, 166). Harmine could also be detected in Passijfora
incarnata L. (passifloraceae) (167) and in Zygophyllum fubago L. (zygophyllaceae) (168).
The structures (13) and (14) for harmine and harmaline, respectively, were
suggested by Perkin and Robinson in 1919 (169) and confirmed in 1927 by
synthesis by Manske et al. (170). More convenient synthetic routes were
published later by Späthand Lederer (171), by Akabori and Saito (172), by
Harvey and Robson (173), and by Spenser (174). On reduction, harmaline
yields tetrahydroharmine, and on gentle oxidation it is converted into harmine
(175).
1. PHARMACOLOGICAL AND M ENTAL EFFECTS

In !arger doses harmine causes tremors and clonic convulsions, the latter
occurring without marked increase in spinal reflex excitability. With poisonous

198

Albert Hofmann

doses respiration is paralyzed, and in mammals there is a fall in temperature.
Harmine induces a fall in blood pressure, chiefly because of weakening of the
cardiac muscle. Harmaline is about twice as toxic to most laboratory animals
as harmine, the degree of activity rather than its pharmacological character
being different, as is also the case with tetrahydroharmine. The minimum lethal
doses of the three bases for the rabbit are in the following ratio: harmineharmaline-tetrahydroharmine = 2: 1: 3 (176). The course of harmine intoxication in intact cats corresponds to the effect of a centrally excitant spasmogen
(177). The evident excitant etfect of harmine and harmaline in tests with
animals is probably related to their inhibiting etfect toward monoamine
oxidase (MAO) (178). lt is known that this enzyme participates in the decomposition of important biogenic amines, and its inhibition leads to an accumulation .of epinephrine and norepinephrine in the organism. The use of these
alkaloids in the treatment of postencephalitic conditions has been abandoned
(179).

Small doses of harmine (25-75 mg subcutaneously) are reported to produce
euphoria in man (83). Turner and associates (180) doubted whether harmine
was psychotomimetically active, although Gershon and Lang (181) found that
it caused restlessness and apparent hallucinations in dogs. Pennes and Hoch
(182) reported LSD-like etfects in mental patients given 150-200 mg intravenously, whereas oral application (300-400 mg) produced, as the only
perception disturbance, the impression ofa wavelike movement ofthe environment, as well as paresthesia and a lower sensitivity of the skin toward contact
and pain stimuli.
lt is possible that the psychotomimetic, hallucinogenic etfects of the crude
extracts of ayahuasca, etc., are caused by compounds other than harmine.
Unfortunately there still exist no investigations on the psychotomimetic etfects
of the minor alkaloids harmaline and d-tetrahydroharmine. The results
obtained so far with harmine clearly show that this alkaloid does not have
psychotomimetic properties as specific as those of the "classical" psychotomimetics, LSD, psilocybin, and mescaline. For this reason it has not yet been
used suitably in experimental psychiatry, as is the case with these three
compounds.

D. d-Lysergic Acid Amides
Lysergic acid, from which the most etfective psychotomimetics are derived,
is the fundamental component of ergot alkaloids. Natural ergot alkaloids and
ergot alkaloid derivatives are of great significance in medicine. Aside from the
classical use in obstetrics as hemostatic uterotonics, ergot alkaloids or their
derivatives are now being used to a greater extent in internal medicine as
sympatholytics and vessel-contracting agents or as medicaments for the

199

Psychotomimetic Agents

improvement of peripheral blood circulation, and in neurology as CNSdamping medicaments. Certain lysergic acid derivatives, which will be discussed below, are now also gaining in importance in experimental psychiatry
and psychotherapy. In connection with the chemistry of ergot alkaloids in
general, with which several generations of medicinal chemists have been
occupied, the newest monograph of Hofmann may be mentioned (183), in
which a survey is also given on the pharmacology and therapeutic use of this
alkaloid group.
1. d-LYSERGIC ACID AMIDE AND RELATED CONSTITUENTS OF

OLOLIUQUI

d-Lysergic acid amide (16a), which is also named ergine, is the main constituent of the Mexican magic drug ololiuqui, i.e., seeds of Rivea corymbosa
Hall.f. (see Section 5.2,B,3). Furthermore, the following minor alkaloids were
isolated from seeds of Rivea: d-isolysergic acid amide (isoergine) (17a),
0

II

R, C-R
9 8

~ 10

(a) R = N H2 : d-Lysergic acid
amide (Ergine)
1

N
H

(b)

TH'

R=NHCH

bH

d-Lysergic acid
N-(1-hydroxycthyl)amide

(16)

0

II

~~H,

(a) d- lsolysergic acid
amide (lsoerginc)
(b) d-Isolyscrgic acid
N-(1-hydroxycthyl)amidc

H
(17)

&J~'
H
(18)

Elymoclavine

H,

CH2 0H
CH3
H
1

N
H
(19)

Lyscrgol

200

Albert Hofmann

chanoclavine, elymoclavine (18), and lysergol (19). The seeds of the related
convolvulaceous plant !pomoea violacea L. (syn. /. tricolor Cav.) yielded the
same alkaloids, with the difference that lysergol was obtained in place of
ergometrine (ergonovine, d-lysergic acid L-2-propanolamide (66, 68, 69).
Laterit was found that ergine and isoergine were present in the seeds to some
extent as d-lysergic acid N-(1-hydroxyethyl)amide (16b) or d-isolysergic acid
N-(1-hydroxyethyl)amide (17b) (72). The presence of further minor alkaloids,
i.e., ergometrinine and penniclavine, was detected by chromatographic tests.
Investigations on commercially available varieties of Morning Glory seeds
(!pomoea and Convolvulus spp.) showed the presence of ergot alkaloids in a
number of these ornamental plants (71-75).
d-Lysergic acid amide and d-isolysergic acid amide were first obtained as
products of the alkaline hydrolysis of ergot alkaloids (184, 185), then also by
partial synthesis from lysergic acid, and more recently as naturally occurring
alkaloids together with the corresponding N-(1-hydroxyethyl)amides from
ergot of Paspalum grass (186). Chanoclavine has previously been discovered
in ergot of the tropical millet cob Pennisetum typhoideum Rich. ( 187). Elymoclavine was first isolated from ergot of the wild grass Elymus mol/is Trin. ( 188).
Lysergol was produced synthetically by reduction of d-Iysergic acid (189)
before it was discovered to occur in nature as one of the active principles of
ololiuqui. Ergometrine (ergonovine) is the alkaloid which is mainly responsible
for the uterotonic hemostatic action of the ergot drug. lt can also be obtained
synthetically (99).
a. Pharmacological and Mental Effects
d-Lysergic acid amide (LA-111 =designation ofthe experimental drug) was
tested pharmacologically and clinically during the course of investigations on
d-lysergic acid diethylamide (LSD-25) and related compounds long before it
was known tobe a component of ololiuqui.
LA-111 elicited strong autonomic symptoms in rabbits, e.g., mydriasis,
piloerection, and hyperthermia, which were accompanied by a general motor
restlessness. The antiserotonin activity, tested on the isolated rat uterus, has a
value of 4 on a scale on which LSD-25 is 100 (190).
Psychotomimetic activity of LA-111, having a marked narcotic component,
could be ascertained from the first self-experiment by Hofmann, reported as
follows (69):
10.00 h: Intramuscular injection of 0. 5 ml of l part per thousand solution
of LA-111 ( =0.5 mg d-lysergic acid amide).
11 .00 h : Tiredness in the neck, slight nausea.
11.05 h: Tired, dreamy, incapable of clear thoughts; very sensitive to noises
which give an unpleasant sensation.

Psychotomimetic Agents

201

II. I 0 h: Desire to lie down and sleep; genuine physical and mental tiredness,
which is not experienced as an unpleasant sensation. Slept for 3 hours.
15.00 h: Return ofnormal condition with full capacity for performing work.
This action of d-lysergic acid amide was Iater confirmed by comparative
systematic investigations by Solms (19J,192). He describes the action as
follows: LA- I 11 induces indifference, a decrease in psychomotor activity, the
feeling of sinking into nothingness and a desire to sleep ... until finally an
increased clouding of consciousness does produce sleep.
Only little information is available on the activity of d-isolysergic acid amide
(isoergine). After taking 2.0 mg orally Hofmann experienced tiredness, apathy,
a feeling of mental emptiness and of the unreality and complete meaninglessness of the outside world (69).
d-Lysergic acid N-(1-hydroxyethyl)amide (16b), and d-isolysergic acid
N-(1-hydroxyethyl)amide (17b) are hydrolyzed very easily to the corresponding amides and acetaldehyde (186). This could also occur in the organism.
d-Lysergic acid N-(1-hydroxyethyl)amide induces contractions in the isolated
uterus ofthe guinea pig andin the rabbit uterus in situ, showing about 30-50 %
of the activity of ergometrine. In rnice and rabbits it produced the syndrome
of central sympathetic stirnulation, such as piloerection, rnydriasis, and
hypertherrnia, which suggests that it could have an LSD-Iike activity, but this
hypothesis has not yet been verified by experirnents on humans (193).
Elyrnoclavine and lysergol elicit an excitation syndrome in various animals
that is caused by a central stimulation of the sympathetic nerves (194), which
seems to indicate psychotomimetic activity. Results of clinical tests are not as
yet available.
Psychotomirnetic effects are unknown for ergometrine, which is used to a
!arge extent in obstetrics as a uterotonic and hemostatic agent. In small
dosages, which are administered for this purpose, the alkaloid apparently has
no action on the psychic functions . Jts occurrence in the alkaloid mixture of
ololiuqui can thus have no significant effects on its mental action.
Furthermore, chanoclavine, which has no outstanding pharmacological
activity, appea rs to play no part in the occurrence of the psychic effects of
ololiuqui.
According to the results of experirnents performed thus far with pure
alkaloids, it appears that d-lysergic acid arnide, d-lysergic acid N-(1-hydroxyethyl)amide, elymoclavine, and lysergol, and possibly also d-isolysergic acid
amide are rnainly responsible for the psychic effect of ololiuqui.
2. d-LYSERGIC ACID DIETHYLAMIDE (LSD-25) AND ITS STEREOISOMERS

d-Lysergic acid diethylarnide (20) does not occur in nature. lt was produced
by partial synthesis by a process analogous to that used fo r the synthesis of
ergometrine and other acid arnide-Iike derivatives of lysergic acid (99).

Albert Hofmann

202

Racemic isolysergic acid hydrazide, obtained by heating d-lysergic acid methyl
ester or peptide ergot alkaloids with hydrazine, was used as starting material.
H,, CON(C2Hs)2

H

,CON(C2Hs)2
CH3
H

;6NCH3
>----.'--H

c

B

1

N

N
H

H
(20)

d-Lysergic acid diethylamide
(LSD-25)

(21)
d- lsolysergic acid

diethylamide

Racemic isolysergic acid hydrazide was separated into its optical antipodes
with di-(p-toluyl)-L-tartaric acid, and d-isolysergic acid hydrazide was converted with nitrous acid into the corresponding azide, which with diethylamine

&?~~:'

H.

CON(C2Hsh
CH3
H
1

H

N
H

(22)

(23)

/-Lysergic acid
diethylamidc

1-Isolysergic acid
diethylamidc

gave a mixture of d-lysergic acid diethylamide (20) and d-isolysergic acid
diethylamide (21). This mixture could be separated by chromatography into
its pure components. The crystalline d-lysergic acid diethylamide in the form
of the free base is practically insoluble in water. For medicinal use the readily
water-soluble tartrate was produced, which is known by the experimental drug
designation LSD-25. The discovery of the extraordinarily high psychotomimetic activity of LSD has been described in Section 5.2,D. t
As there exist two centers of asymmetry in the molecule of lysergic acid
diethylamide, i.e., at C-5 and C-8, four stereoisomeric forms are theoretically
possible : d-lysergic acid diethylamide (20); d-isolysergic acid diethylamide (21),
which differs from (20) in the spatial arrangement of the substituents at C-8;
/-lysergic acid diethylamide (22), which is the mirror image of (20) and differs

t The drug is available for research purposes from Sandoz Ltd., Basle, under the trade
name "Delysid."

Psychotomimetic Agents

203

from (20) in the spatial arrangement at both C-5 and C-8; /-isolysergic acid
diethylamide (23), which differs from (20) in the configuration ofthe hydrogen
atom at C-5. In order to elucidate the infiuence of steric relationships on the
psychotomimetic activity, all the stereoisomeric forms of LSD-25 were
produced (195).
Besides the azide method, other processes for the production of amides of
lysergic acid, which were likewise suitable for the preparation of LSD, were
discovered later (196-200). Lysergic acid, the starting material for LSD-25,
was first obtained by cleavage of natural ergot alkaloids, but since 1954 it has
also been obtained synthetically (201,202). However, lysergic acid is now
most advantageously obtained by fermentative processes (186,203,204).
3. CHEMICAL MODIFICATIONS OF LSD-25

In order to investigate the SAR, the molecular structure of LSD was
modified in the following ways: (!) variations in the acid amide residue,
(2) variations in the spatial arrangement, (3) saturation of the dou hie bond in
position 9,10, (4) substitutions in the indole ring system at positions 1 and 2.
A series ofhomologues were produced in which the diethylamino group was
replaced by other amino groups, such as dimethylamino, dipropylamino,
dibutylarnino, piperidino, pyrrolidino, and morpholino (195). The preparation
of the stereoisorneric forms of LSD has already been discussed in the preceding
section. The double bond at the 9, 10 position was saturated with hydrogen
(195) or by addition of the elements of water (205). Furthermore, the indole
nitrogen atorn was methylated (206), acetylated or hydroxymethylated (207),
and halogen was introduced in the 2 position (208), or an -S-S bridge was
placed in the 2 position (209).
4. MENTAL EFFECTS OF LSD-25

Since the discovery ofthe extraordinary effect of LSD on the human psyche
in 1943 by Hofmann, an enormous amount of literature dealing with the
infiuence of this compound on normal subjects and mental patients has
accumulated. A large number of papers, review articles, novels, and books
have appeared.
The experience of the LSD psychosis had already been described in such
detail in the first psychiatric investigations that the numerous later pu blications
on the phenomenology of the LSD reaction hardly brought with them any
substantial novelty. Reference is made here therefore only to some of the
earlier authors ofLSD literature: Stoll (101, 210); Condrau (211); Becker (212);
Weyl (213); Rinkel et al. (214); Delay and Benda (215); and furthermore to the
newest survey publications of Cohen (10) and Hoffer (17), in which backreference to the vast amount of original literature is made.

204

Albert Hofmann

About 15 to 30 minutes after oral administration of 30-60 µ.g of LSD, i.e.
µ.g/kg (the minimal effective dose is about 20 µ.g, very high doses are 100500 µ.g), there appear as precursors of the psychic effects autonomic-nervous
physical symptoms, such as dilatation of the pupils, slight intensification of
heart frequency, and rise in blood pressure, which suggest a central sympathetic excitation. Less frequently signs of parasympathetic stimulation
occur, such as salivation, nausea, and, seldom, vomiting. These somatic
changes fade away as the psychic reaction progresses. More and more psychic
changes become evident, e.g., changes in perception, mood, thought, and in
the awareness of the seif (depersonalization).
Alterations in perception are for the most part manifested in the visual
sphere: first, they are elementary hallucinations: spots, damp fog, lights, snow
flakes, geometrical figures, etc., which are usually small and colored and often
wander in groups over the visual field. These optical phenomena, which are at
first perceived only with closed eyes or in the dark but later also with open eyes
and in a light room, are soon accompanied by an illusory deformation of the
environment: objects appear to have colored or unusually well-defined outlines or are strangely unfamiliar, distorted, and sinister. Motionless objects
seem to move. Surfaces move back and forth rhythmically or in wavelike
movements, resembling a rippled water surface. Distances are shortened or
lengthened, and the perspective sometimes changes in quick succession. Faces
ofthose present seem distorted or the facial expression changed. The strongest
form of change in perception is the appearance of figure hallucinations
(visions), in which human beings, animals, houses, even entire cities and
landscapes appear, often of particular beauty, seldom depressing or even
shocking.
Acoustic phenomena are usually present only as an enhancement of the
power of hearing. Abnormal olfactory or taste perceptions play only a
secondary role; abnormalities in the sense oftouch, however, are not unusual.
When the reaction reaches its peak, disorders of the body image develop: one
extremity is feit as abnormally long or short or as not belonging to the body,
or the entire body or part thereof is perceived as unusually heavy or light. lt
may even culminate in an "out-of-the-body experience." A subject becomes so
unaware of his body that he feels he is liberated therefrom and is floating in
space.
The mood is predominantly euphoric, eventually accompanied by compulsive laughter, talkativeness, feelings of ecstasy. Sometimes depression and
fear are present. Moods may change suddenly.
Disturbances in the thought process manifest themselves by lowered
attentiveness, difficulties in the capacity of concentration, and flight of ideas.
In the case of a negative, distrustful mood, hostile paranoid thoughts against
the persons present come up and are often uttered without inhibition. The

t

Psychotomimetic Agents

205

decisive fact is that the test person always knows that all these abnormal
reactions and experiences are produced by the compound ingested. Consciousness is maintained but may undergo dreamlike changes, especially in the case
of a lively hallucinatory activity. The sense of time is very often disturbed,
usually in the sense of an overestimation of time.
In the case of a very intensive reaction to LSD, the normal feeling of the
identity with the own seif is weakened (depersonalization). The test person at
the same time appears to himself as a stranger watching him and judging his
actions coolly and critically. In connection with the loss of the seif, this may
take the form of a feeling of dissolution in the universe ("cosmic consciousness") in the case of predisposed persons, an experience which is later recalled
as pleasant and enriching. Aside from the depersonalization at the peak of the
LSD reaction, there is a feeling of unreality of the environment, which is
naturally determined to a great extent by its illusory change.
The kind of experience under the inftuence of LSD, or of other psychotomimetic agents, depends upon a large number of variables. lt may reach only
the point of trivial changes in the perception sphere, or, especially after high
<loses, the intoxication may advance to the point of ecstatic rapture and
mystical experiences, which may be accompanied by a supernatural feeling of
joy or profound depression. The personality and education of the individual
exert an inftuence on the reaction to LSD. The more differentiated and sensible
a person is, the more profound and rich will his LSD experience be in general.
lt is not possible, however, to make predictions as to the type ofLSD experience
on the basis of the personality structure.
The set or expectations of subjects are extremely important factors. The
volunteer who takes LSD for monetary gain to help in a research project will
respond differently from a Zen mystic who expects to gain religious insight.
lt is impossible to infer from a single test how the same subject will react to
the following test. Each experience has a life of its own and in essence differs
from the previous one and from those which will follow. The initial psychic
condition of the test person is extraordinarily important for the experiences in
the LSD test. Usually the mood before the test is intensified by LSD. An
anxious melancholic mood often leads to profound depressions, with disagreeable visions which are often frightening, whereas a gay mood and cheerful
optimism are requisites for a positive experience during the LSD test, with
pleasant insights and beautiful visions.
The outer surroundings and environment also have a decisive inftuence on
the character and course of the LSD experience. Persons present may be
included as constituting part of the outer surroundings. Especially important
is the personality of the person directing the test and his relationship to the
test person. LSD produces a state ofhypersuggestibility, which is characterized
by an enormous sensitiveness to the inftuence of sensory and cognitive stimuli

206

Albert Hofmann

and which is of decisive importance for the use of LSD as adjuvant in
psychotherapy.
5. PHARMACOLOGICAL PROPERTIES OF LSD-25 AND ITS CONGENERS

a. Toxicological Data (216)
The acute toxicity of LSD differs considerably, depending upon the animal
species utilized. Mice tolerate the highest doses, so that in determining the
LD 50, 50-60 mg/kg must be injected intravenously. In the rat the intravenous
LD 50 drops to 16.5 mg/kg andin the rabbit to 0.3 mg/kg. LSD poisoning is
devoid of any specific features. Ataxia, paralysis, and sometimes increased
reflex response may be seen, in addition to various autonomic symptoms.
Death occurs as a result of respiratory failure. In chronic experiments in rats
2.5 mg/kg ofLSD-25 could be given daily intravenously for a period of 30days
without losing any animals. Rats submitted to chronic LSD treatment exhibit
tremor, increased reflex response, and piloerection. These symptoms decline
in intensity within a few days. Nevertheless, the animals are retarded in weight
increase compared with the control animals. Following chronic administration
in dogs, degenerative changes of ganglionic cells in the brain have been
described (217). Aberrations in human chromosomes (217a) and teratogenic
effects in Jaboratory rodents (217b) have been observed after treatment with
LSD and other psychotomimetics.
b. Absorption, Distribution, and Excretion
LSD is highly active when administered orally. lt is quickly and completely
absorbed in the gastrointestinal tract.
An attempt was made to determine the distribution of LSD in the organism
after intravenous administration in mice. The method for the determination
consisted in testing the antagonism of LSD extracted from the tissues to
serotonin in the isolated rat uterus. The findings showed that LSD disappears
rapidly from the blood, and its presence could be detected in various organs.
The LSD content of the liver is especially high, the ratio for LSD in hepatic
tissue and blood remaining constant. Independent of the blood level, the LSD
content of the brain diminishes more rapidly (218).
The distribution in the body and the excretion were studied in mice and in
rats also with the aid of 14C-labeled LSD (160,219-221). LSD given by
intravenous injection disappears rapidly from the blood. Some radioactivity
is then found in all tissues, particularly liver, spieen, kidney, and adrenals.
Surprisingly enough, the brain concentration is lowest, being only about
0.0 l % of the administered dose. The concentrations in the organs reach peak
values after 10 to 15 minutes and then decrease very rapidly. One exception
is the small intestine, where activity rises to a maximum over a period of
2 hours. Excretion is mainly (about 80 %) through the liver, bile, and the

Psychotomimetic Agents

207

intestinal tract. About 4 % is exhaled as 14C0 2 , and about 8 % appears in the
urine. Extraction studies of various organs made 2 hours after administration
showed that only 1-10 % of the activity is present in the form of unchanged
LSD-25; the remainder consists of water-soluble metabolites. There is little
difference in the distribution pattern after either intravenous or intraperitoneal
administration.
In a third investigation on the fate of LSD in the organism another highly
specific and sensitive method for the estimation of LSD in biological material,
viz., the determination by spectrofluorimetry, was used (222). The LSD
content of extracts was determined by measuring its ftuorescence in a spectroftuorophotometer at 445 mµ. after activation at 325 mµ.. As little as 0.001 µ.g/ml
of LSD could be determined by this procedure. The specificity ofthe measurements for LSD was assayed by means of comparative distribution ratios (223).
Ninetyminutes after administration of 1 mg/kg ofLSDintravenously to the cat,
the drug was found in all tissues in the following order of decreasing concentrations: bile, plasma, Jung, liver, kidney, brain, intestines, spieen, cerebrospinal fluid, muscle, and fat. LSD is almost completely metabolized in the
body, only negligible amounts of the drug being excreted in the urine or the
stools. The liver is the major site of metabolism. The rate of metabolism of
LSD varies considerably from species to species. The biological half-life of
LSD, that is, the time required for the plasma level to fall to half its value, was
found tobe 100 minutes in the monkey (Macaca mulatta), 130 minutes in the
cat, and 7 minutes in the mouse.
In vitro studies with guinea pig liver microsomes showed that LSD is transformed into 2-oxo-2,3-dihydro-LSD (224,225), a metabolite that does not
possess LSD-like activity in the CNS. Chlorpromazine and SKF-525
(ß-diethylaminoethyl 2,2-diphenylvalerate) markedly inhibit the in vitro
metabolism of LSD, while serotonin and reserpine inhibit the metabolism to
only a moderate extent.
In tests for the isolation of the metabolites, 3 mg/kg of LSD were administered intravenously to rats under urethane anesthesia, and the bile was thereafter collected through a tubule. Two metabolites could be isofated from the
bile in crystalline form and were identified as glucuronides of 12-hydroxyLSD and its stereoisomer, 12-hydroxy-d-isolysergic acid diethylamide (226).
As the psychic effects of LSD reach their peak only after 1 to 3 hours, i.e.,
when nearly all of the substance has disappeared from the organs, as shown
by the excretion studies described above, it could be concluded with a great
degree of probability that even minimal <loses of LSD can set off a chain of
reactions culminating in the psychic symptoms.
c. Pharmacodynamic Properties

The principal investigations of the pharmacological properties of LSD and
its derivatives were performed in the pharmacological laboratories of Sandoz

208

Albert Hofmann

Ltd., Basle (216,227-230). The most important pharmacodynamic properties
of LSD-25 have been represented schematically in Figure 5. l.
The effects ofLSD can be divided into three main groups: central, peripheral,
and neurohumoral.
CENTRAL EFFECTS

Stimulation of the synapsis
in the Formatio reticu/aris:
increased sensibility to
sensory stimulation

Stimulation of central
sympathetic structures:
mydriasis
hyperthermia

~

piloerection
hyperglycemia

<im•la<::h:;:~:-

vnaptic reflexes:
e.g., knee jerk

[ataxial

~

""'d-Lysergic acid diethylamide
(LSD-25)

~ L---------'------'

/

-

[bulbomedullary effects:

PERIPHERAL EFFECTS

NEUROHUMORAL EFFECTS

smooth muscle effects:
uterine contraction
slight vasoconstriction

pronounced serotonin antagonism

Fig. 5.1.

Of the peripheral effects special mention must be made of the direct action
on smooth muscle. LSD increases the contractility of the uterine muscle and
in this respect has practically the activity of ergometrine (ergonovine) (99).
This oxytocic effect is characteristic of the ergot alkaloids.
The smooth muscle of the vasculature contracts after ]arge <loses of LSD,
but this effect is manifested only in isolated vessels and spinal animals. In the
presence of intact innervation, the effect of LSD on the CNS predominates
and decreases the vasomotor tone.
As a neurohumoral effect the antagonism of LSD to serotonin (5-HT) is of
importance. In extraordinarily low concentrations, LSD antagonizes the
peripheral effects of serotonin (231,232). But some serotonin effects are
potentiated by LSD, e.g„ the cardiovascular and respiratory reflex actions of
serotonin in the cat (233).
lt has been postulated that the psychic effects of LSD might be due to its

Psychotomimetic Agents

209

blocking brain serotonin, which apparently plays a role in the regulation of
central nervous processes (234-236). However, this hypothesis is far from
being proved because, as will be shown later, there are many derivatives of
LSD which are potent antagonists to serotonin but which do not possess
psychotomimetic activity.
The central effects of LSD are numerous. They may be summarized as
forming a syndrome of ergotropic stimulation. This syndrome comprises:
(a) Activation in the EEG "alert" pattern, increase in the responsiveness of
the alpha rhythm (237).
(b) Stimulation of the synapsis in the reticular formation, leading to
increased sensitivity to sensory stimuli (237-241).
(c) Stimulation of central sympathetic structures, manifested by mydriasis,
tachycardia, hyperthermia, hyperglycemia, piloerection, etc. These ergotropic
symptoms are caused by the CNS, as they are not present in narcosis (227, 242),
in the spinal animal (243), or afterpretreatment with ganglionic blockers (227).
(d) Stimulation of monosynaptic reflexes; e.g„ patellar stretch reflex
(244, 245). The parallelism of the stimulation of the patellar stretch reflex
(knee jerk) to the psychic symptoms could also be ascertained in man (246).
Not all the effects of LSD are stimulant. In certain tests and in certain
animals LSD elicits marked depressant effects. Thus, barbiturate anesthesia
in the mouse and its rate is enhanced by LSD, and body temperature and
oxygen consumption are reduced. Ataxia and bulbomedullary effects, such as
vomiting, occur only after very high, toxic <loses. In general the <loses required
to produce these pharmacological effects in animals are significantly higher
than those which exert psychic effects in human beings. The only exception is
the rabbit, in which certain autonomic effects, e.g„ hyperthermia, can be
elicited by the same minimal doses, i.e„ 0.5-1.0 µ.g/kg body weight.
d. Biochemical Effects (247, 248)
There exist contradictory reports on the influence of LSD on the carbohydrate metabolism. Mayer-Gross et al. (249,250) reported that in subjects
treated with LSD there was a small fall in blood sugar and a concomitant rise
in hexose monophosphate. Experiments in vitro using homogenates of guinea
pig brain showed stimulation of the oxidation of glucose after addition of
LSD and inhibition ofthe utilization ofhexose monophosphate. These results
could not be confirmed by later workers (248, 251).
In patients who were given high doses of LSD no change occurred in nonprotein nitrogen levels, and cephalin-cholesterol flocculation tests were
normal (252).
Chronic schizophrenic patients even after high doses of LSD did not show
observable psychiatric responses or changes in the urinary excretion of

210

Albert Hofmann

epinephrine or norepinephrine, whereas other mental patients gave a strong
response in urinary epinephrine/norepinephrine. A greater resistance of
mental patients, especially schizophrenics, to LSD, in contrast to that of
normal control patients, has been reported by many other workers (211,253,
254). lt has been suggested (255) that the high threshold of responsiveness of
schizophrenics to LSD may result from their production of a possible endogenous metabolite that competes with LSD for enzyme receptors, thus reducing
the effectiveness of LSD in these patients.
After taking LSD, normal men showed a marked reduction in urinary
phosphate excretion. The injection of ACTH during the period of action of
LSD enhanced the phosphate excretion. Thus the behavior ofphosphates both
at rest and under the impact of adrenocorticoids in the LSD-treated normal
person is similar to that found in schizophrenics without LSD (255).
The reports on the action of LSD on cholinesterase are somewhat contradictory. While most investigators report some degree of inhibition, some
failed to find any effect, and a few have observed some increased activity of
the enzyme by LSD. Thompson et al. (256) found a 50 % inhibition of the
pseudocholinesterase from the brain ofthe human at 5 x 10-6 M, a concentration of LSD which had no effect on true cholinesterase of human brain. LSD
and 2-bromo-LSD are potent inhibitors of pseudocholinesterase of human
serum in vitro, whereas they are less potent on true or erythrocytic cholinesterase (257). However, very small amounts of LSD were found to enhance the
activity ofhuman pseudocholinesterase in vitro (258). Similarly it was reported
that LSD increased the activity of cholinesterase in rat brain (259). The
inhibitory effects of LSD on the cholinesterase and monoamine oxidase in the
spinal cord have been suggested to be a possible factor in the mechanism of
hallucination (260). More recent investigations on LSD and cholinesterases
and on interactions with miscellaneous neurochemical substances have been
reviewed by Giarman and Freedman (16).
6. PHARMACOLOGICAL EFFECTS AND PSYCHIC ACTIVITY OF LSD-25
DERIVATIVES

One of the pathways by which psychopharmacological research gains
insight into psychosomatic relationships is provided by making modifications
of the structure of a psychotropic agent and comparing the pharmacological
effects of the various derivatives with their psychic effects in human beings.
This provides correlations between biochemical, peripheral, and central
effects on the one hand and psychic effects on the other.
This procedure was used in the case of LSD and its derivatives. A more or
less comprehensive pharmacological analysis of the many derivatives mentioned in Sections 5.3,D,2 and 3 was carried out (229). Some ofthem were also
studied in human beings. In order to compare the pharmacological effects and

Psychotomimetic Agents

211

psychic activity, Cerletti (230) selected 18 typical modifications of LSD, as
depicted in Figure 5.2.
_

E-syndrome
(P)

Total E-syndrome

100

10

10

100

1000

Fig. 5.2. Correlation between psychotropic and pharmacological activity of lysergic acid
derivatives.
TABLE 5.3
Lysergic acid derivative

No.
-

- - --

1
2
3
4
5
6
7
8
9
10

···-

No.

Lysergic acid derivative

- - - - ------···-- --------·-- ·-- - ·- --

d-Lysergic acid diethylamide (LSD)
d-Lysergic acid dimethylamide
d-Lysergic acid pyrrolidide
d-Lysergic acid morpholide
d-Lysergic acid monoethylamide
/-Lysergic acid diethylamide
d-lsolysergic acid diethylamide
Dihydrolysergic acid-(1) diethylamide
Lumilysergic acid-(1) diethylamide
2-Bromo-LSD

- - - - - -- -

11 1-Methyl-2-bromo-LSD
12 Di-LSD-disulfide
13 !-Methyl-LSD
14 !-Acetyl-LSD
15 1-Hydroxymethyl-LSD
16 1-Methyl-d-lysergic acid monoethylamide
17 1-Acetyl-d-lysergic acid monoethylamide
18 1-Methyl-d-lysergic acid pyrrolidide

On the Ieft-hand side the psychotomimetic activity is indicated in relative
logarithmic value, LSD being taken as 100 (standard). The values are derived
mainly from investigations by lsbell et al. (246), but some were also obtained
from personal studies (261). lt can be seen that when the diethylamide group

212

Albert Hofmann

is replaced by other amide groups psychic effects are still present but to a
lesser degree. Even the closely related dimethylamide is only approximately
one-tenth as active as LSD. The stereoisomers of LSD (see Section 5.3,D,2)
and the derivatives in which the double bond in ring D has been saturated
are practically devoid of psychic activity. Other derivatives that are almost
without effect are those with a substituent group in the 2-position, for instance
2-bromo-LSD (also known as BOL-148), and the bimolecular product with
an S-S bridge in the 2-position. By contrast, the derivatives with substituent
groups at the indole nitrogen include some with considerable psychic activity.
Thus, 1-acetyl-LSD is as potent as LSD. The combination of substitution in
the amide group and in position 1 always led to compounds with weaker
effects, their activity being less than 10% of that of LSD. Of all the many
modifications of LSD none has been found so far which exceeds LSD in
psychic activity.
The right-hand side of Figure 5.2 shows the pharmacological effects ofthese
derivatives expressed in relative logarithmic values. The strong line represents
the syndrome of excitation, which, as already mentioned in the case of LSD,
is caused by stimulation of sympathetic centers and consists of mydriasis,
piloerection, hyperthermia, etc. The hyperthermic effect in rabbits is a good
index of the central autonomic stimulation. With some compounds, e.g.,
(1)-(9), the pyrogenic effect (P) parallels the general syndrome of excitation
(E-syndrome, continuous line). In the case of compounds with substitution in
position 1 the hyperthermic effect is weaker than the other symptoms of
sympathetic stimulation, and therefore an average value is marked with a
dotted line (total E-syndrome). The thinner line of this diagram is an
expression of the antagonism of these agents to serotonin. The antagonism
to serotonin is a characteristic feature of LSD, as has already been mentioned.
A comparison of antiserotonin activity and psychic activity reveals some
interesting findings. When LSD was discovered to be a potent antagonist of
serotonin, it was postulated that the psychic effects of LSD might be due to its
blocking brain serotonin, which apparently plays a role in the regulation of
central nervous processes (236). However, this comparison shows that the
serotonin antagonism does not parallel the psychotomimetic activity. Compounds such as bromo-LSD or, more particularly, l-methyl-2-bromo-LSD,
and 1-methyllysergic acid ethylamide, are far more potent than LSD as
antagonists of serotonin but exert little or no effect on the psyche.
On the other hand, a comparison of the excitation syndrome (strong line)
and psychic effects reveals interesting parallels. The compounds with the most
marked psychic effects, LSD and acetyl-LSD, elicit the most marked syndrome
of excitation. The series of compounds which are devoid of psychotomimetic
activity, (6) to (12), are barely effective in eliciting the syndrome of excitation.
From these investigations it can be concluded that there exists within the

213

Psychotomimetic Agents

group of LSD and related compounds a relationship between psychotomimetic activity on the one hand and the syndrome of a general sympathetic
stimulation on the other.

E. Mescaline
Mescaline (24) is the main active component of the peyotl cactus Lophophora
Williamsii (syn. Anhalonium-Lewinii), one of the magic Mexican plants (see
Section 5.2,B, 1). Heffter (27) isolated this alkaloid in 1896 along with a number
CH300CH2CH2NH2
CHP-y
OCH3
(24)

Mescaline

OH
1

H00CHCH2NHR

HO~

(a)
(b)

R = H: Norepinephrine
R=CH1: Epinephrine

(a)
(b)

R = H: Amphetamine
R=CH1: Methedrine

(25)

CH3
1

o-CH2CHNHR

(26)

of related bases, most of which belong to the structural class of tetrahydroisoquinoline alkaloids (262, 263). Mescaline was also found later in other
Cactaceae, in Gymnocalycium gibbosum (264), in the Argentinian giant cactus
Trichocereus terschekii (265), in the related Peruvian cactus T. pachoni (266),
and in Opuntia cylindrica (267). Derivatives of mescaline such as N-methylmescaline and N-acetylmescaline were isolated from Lophophora Wil!iamsii
(268), and N,N-dimethylmescaline from Trichocereus terschekii (265). But no
hallucinogenic activity of these derivatives has been reported.
The formula for mescaline was proposed by Späth in 1919 and confirmed
by synthesis (29). Many variations of this synthesis have since been described
(269-278). The minor alkaloids of the peyotl cactus may also be obtained by
synthesis (279).
Being a phenethylamine derivative, mescaline is chemically closely related
to the hormone epinephrine (25b) and the neurohormone norepinephrine (25a).

214

Albert Hofmann

A similar relationship exists between the psychotomimetic agent psilocybin,
which is of plant origin, and the neurohormone serotonin, which is produced
in the body, both being derived from tryptamine. The chemical relationship
between mescaline and the two synthetic psychotropic compounds amphetamine (26a) and methedrine (26b), which are potent stimulants of the CNS,
is also noteworthy. lt is not a matter of chance that the most important
representatives of the group of psychotomimetic agents contain either the
tryptamine group (psilocybin, psilocin, harmine, LSD) or the phenethylamine
group (mescaline). Because of this relationship with the neurohormones
serotonin and norepinephrine, it is probable that a mutual inftuence in the
biochemistry ofthe CNS causes the psychotomimetic activity.
1. MENTAL EFFECTS

The effect of mescaline on the human psyche is very analogous to that of
LSD. Except for the assertion that it has a rather stronger hallucinogenic and
somewhat weaker depersonalizing effect, the mescaline effect does not show
any characteristic qualitative differences in comparison with LSD. The most
important difference is quantitative; on a molar basis, mescaline is about
5,000 to 10,000 times less effective than LSD (139,280). An average oral dose
is 0.2 g, whereas 0.6 g constitutes a relatively high dose.
Usually there are unpleasant autonomic symptoms, nausea, tremor,
perspiration, which subside after 1 to 2 hours and are replaced by a dreamlike
hallucinatory state, which lasts 5 to 12 hours. The symptoms typical of a
hangover precede the intoxication.
Many descriptions ofthe mescaline-induced state are available. The older
publications have already been quoted in Section 5.2,B, 1. In addition, mention
is made ofthe newer descriptions of self-experiments by the French writer and
painter Henri Michaux (281-283).
Subjects receiving mescaline daily became tolerant to mescaline and crosstolerant to LSD. Since persons directly tolerant to LSD are cross-tolerant to
psilocybin (141), it seems likely that persons directly tolerant to psilocybin
would be cross-tolerant to mescaline. From this it was concluded that
mescaline, LSD, and psilocybin probably share common mechanisms of
action or some common final pathway (280).
2. PHARMACOLOGICAL PROPERTIES

An excellent review on the pharmacology and metabolism of mescaline
comprising the literature up to 1957 has been given by Fischer (284).
a. Toxicological Data
The toxicity of mescaline (LD 50 ) is 0.5-0.6 g/kg in mice (intraperitoneally)
and 0.5 g/kg in the guinea pig (subcutaneously). lt produces motor paralysis,

Psychotomimetic Agents

215

caused by depression of the CNS, and death from respiratory failure (285).
The LD 50 in rats (intraperitoneally) is said to be in the range 330-410 mg/kg
(15).

b. Absorption, Distribution, and Excretion

Mescaline is readily absorbed from the intestinal tract. lt is concentrated in
the kidney, liver, and spieen. The concentration is lowest in the brain (286, 287).
In white mice some mescaline-oi:- 14 C is bound to the proteins of the liver.
There appears to exist an interrelationship between the onset ofhallucinations
and the mescaline protein (288). In man 60-90 % of a given <lose is excreted
unchanged in the urine, 9-39 % within the first 18 hours (284, 289). An average
of26.2 % ofthe administered <lose is excreted in the urine as 3,4,5-trimethoxyphenylacetic acid. This metabolite administered to humans orally produced
no psychological changes (290, 291). Other workers could not detect this
metabolite (292). Certain minor metabolites have also been identified, i.e.,
3,4-dihydroxy-5-methoxyphenylacetic acid (292) and 3,4-dimethoxy-5hydroxyphenethylamine (293) in human urine and 3,4,5-trimethoxyphenylethanol (294, 295) as a metabolite in rats.
Distribution and metabolism studies of mescaline-a- 14 C in the cat brain
indicated a relatively high concentration of radioactivity in cortical and subcortical gray matter. Only two radioactive components, identified as mescaline
and 3,4,5-trimethoxyphenylacetic acid, were found (296). N-Acetylation and
0-demethylation constitute another metabolic pathway for mescaline (297,
298). In the urine of rats treated with mescaline- 14 C, N-acetyl-3,5-dimethoxy-4hydroxyphenethylamine, N-acetyl-3,4-dimethoxy-5-hydroxyphenethylamine,
and N-acetylmescaline were detected (299).
c. Pharmacodynamic Properties

The action of mescaline on circulation and respiration in animal experiments has been investigated by Raymond-Hamet (300) and by Grace (285).
Mescaline (10 mg/kg) produced in anesthetized cats and rabbits a fall in blood
pressure but no change in heart rate and no depression of respiration. After
vagal sectioning, atropinization, or decapitation, the effect on the blood
pressure was reversed, and respiration was no longer affected. Isolated smooth,
striated, and cardiac muscles were unaffected by moderate concentrations of
mescaline. Given to rats, mescaline caused hypoglycemia and not hyperglycemia (284).
There is a certain inconsistency between thcse results of animal experiments
and the results oftests in man, in whom mescaline produces effects which are
typical ofthe sympathomimetic amines. In man it causes a syndrome of central
sympathetic stimulation similar to that of LSD and psilocybin, characterized

216

Albert Hofmann

by increased pupillary size, increase in pulse rate and blood pressure, and
elevation of body temperature. Mescaline also decreases the threshold for
elicitation of the knee jerk (280).
Mescaline was shown to have no effect on the vasoconstrictive action of
serotonin but to have some vasoconstrictive activity itself (301).
The electrophysiological effects of mescaline have been reviewed by Evarts
(237) and by Smythies (302). Mescaline inhibits the postsynaptic component
of the transcallosal response. lt stimulates the reticular formation (238). The
effects of mescaline on spontaneous electrical activity in the rabbit are almost
identical with those of LSD. Mescaline causes an "alert" EEG pattern.
d. Biochemical Effects

The biochemical effects of mescaline have been reviewed by Hoagland (247),
by Bain (248), and by Giarman and Freedman (16). Mescaline and a number
of other amines strongly inhibit glucose, lactate, and pyruvate oxidation by the
brain enzymes (251,303-305). These amines, including serotonin and
epinephrine, all compete for amine oxidase in the brain. Considering the
structural similarity of mescaline to epinephrine and norepinephrine, the
hypothesis was put forward that aberrant catecholamine metabolism may be
involved in mental disease (306,307). Both epinephrine and mescaline could
serve as precursors of indolic compounds such as adrenochrome and
adrenolutine (308).
3. CHEMICAL MODIFICATIONS OF MESCALINE

Many isomers and derivatives of the simple mescaline structure have been
prepared, and some of them could be of interest to psychopharmacologists.
3,4-Dimethoxyphenethylamine (homoveratrylamine) was found to have no
sympathomimetic action in the cat andin the rabbit, and it depressed the CNS.
3,5-Dimethoxy-4-ethoxyphenethylamine and 3-methoxy-4,5-diethoxyphenethylamine are reported to be somewhat more toxic than mescaline but
pharmacologically very similar to it (285). Benington et al. described the
synthesis of the 2,4,6-trimethoxy isomer of mescaline, of 2,4,6-triethoxyphenethylamine (309), of all the possible ring-substituted tetramethoxyphenethylamines and of pentamethoxyphenethylamine (310). The syntheses of 3,4dimethyl-, 3,4-dichloro-, and 3,5-dimethoxy-4-methylphenethylamine were
also reported by Benington et al. All three compounds induced a strong sham
rage response in cats (311).
Smythies and Levy (312) have investigated mescaline analogues in rats,
using a rope-climbing test. They found that the removal of the 5-methoxy
group from mescaline reduced the activity by one half and that demethylation

Psychotomimetic Agents

217

of the 4-methoxy group caused complete loss of activity. If, however, the
4-methoxy group was replaced by benzyloxy the activity was increased.
An interesting modification of the mescaline molecule consists in substituting a methyl radical in the ex position of the side chain, which leads to
compounds structurally related to amphetamine (26a). Shulgin has synthesized
and tested such types of mescaline derivatives. Both a.-methylmescaline,
3,4,5-trimethoxyamphetamine (27a) (313), and 3-methoxy-4,5-methylenedioxyamphetamine (28) exhibited psychotropic potencies greater than that of
mescaline or cx-ethylmescaline (27b) (314-317). The effective dosage of(28) is
2 mg/kg in man. Both the lengthening of the aliphatic side chain R of (27)
from C 2 H 5 to C 7 H 15 (314) and the enlargement ofthe heterocyclic ring in (28)
R
1

CH30ACH2CHNH2
CH30-y

(a)

(b)

R=CH3
R=CH2CH1

OCH3
(27)

(28)

have resulted in a decreased human effectiveness. An increase in potency
resulted by variation of the position of the methoxy and the methylenedioxy
groups, as shown in formulas (29)-(32).
OCH3

CH 3

lfrcH2tHNH2
CH30-y
OCH3
(30)

(29)

OCH3

CH 3

CH30~CH2tHNH2
CH30v
(31)

(32)

Albert Hofmann

218

Compounds (29), (30), and (32) are reported to be about 20 times as active
as mescaline in humans. Themental effects were qualitatively similar to that of
mescaline, (30) and (32) leading, in general, to a more empathic and pleasant
response, whereas personal anxiety and restlessness were common with (29).
The vicinal analogue (31) demonstrated neither physical nor psychotropic
effects (318).

F. Tetrahydrocannabinols
The chemistry of the active ingredients of Cannabis sativa L. was reviewed
by Schultz in 1964 (319), by Korte and Sieper (320), and by Downing (15).
The euphoric and hallucinogenic action of hemp and its preparations, such
as hashish, bhang, marihuana, etc., is attributed mainly to their content of

CsH11-n

(33)
Isomerie

tctrahydrocannabinols

(35)

Cannabinol

(34)

(a) R = H: Cannabidiol
(b) R=COOH: Cannabidiolic acid

(36)

Cannabigcrol

tetrahydrocannabinols (33) (321). They form an oily mixture consisting of
several isomeric forms. Besides the tetrahydrocannabinols, several compounds
chemically related to (33) have been isolated from C. sativa and its preparations, e.g., cannabidiol (34a), cannabidiolic acid (34b), cannabinol (35), and
cannabigerol (36).
The structures of these compounds have been elucidated mainly by Cahn
(322), by Berge! et al. (323), and by Adams et al. (324). The structure (34a) of
cannabidiol was proposed by Mechoulam and Shvo (325) and by Santavy (326).
Cannabidiolic acid (34b) was isolated by Schultz and Haffner (327,328) and
by Krejci et al. (329). Cannabigerol (36) was isolated only recently from
Oriental hashish by Gaoni and Mechoulam (330).