|The Discovery of LSD and Subsequent Investigations on Naturally Occurring Hallucinogens|
|Written by Albert Hofmann|
|Thursday, 07 January 2010 20:40|
The Discovery of LSD and Subsequent Investigations
Fig. 1. Mushroom Stone
Fig. 2. Psilocybe mexicana Heim
Although the 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. It was not until 1936 to 1938 that American investigators, i.e., Weitlander, Reko, Johnson and Schultes, ascertained that mushrooms were still being eaten for magical purposes by the natives in certain remote districts of southern Mexico. Systematic studies of the mushroom cult in its present form were later made by the amateur investigators R. Gordon Wasson and his wife. In the summer of 1955, Wasson was able for the first time to take active part in a secret nocturnal ceremony in Huautla de Jimenez Province of Oaxaca, and was probably the first white man to ingest the holy mushrooms. On a later 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 the sacred mushrooms and classifying them botanically. They belong to the family of Strophariaceae, principally to the genus Psilocybe, though one species belongs to the genus Stropharia and another to the genus Conocybe. Artificial cultivation in the laboratory provided a good yield of especially one of these sacred mushrooms, namely, Psilocybe mexicana Heim.
After unsuccessful attempts in Paris to isolate the active principles, Professor Heim sent the mushrooms to the Sandoz Research Laboratories in Basle, believing that our experience with LSD would enable us to solve this problem. In a sense, therefore, LSD brought the sacred mushrooms to our laboratory.
In the first phase of our isolation studies, we tried to evaluate the extracts by testing them on animals, observing pupillary reaction and piloerection in mice and general behavior in dogs. But the results were not clear-cut and led to discrepancies in the evaluation of the various extract fractions. After most of the very rare and valuable mushroom material had been used for animal testing without definite results, there was some doubt whether the mushrooms cultivated and dried in Paris were still active at all. In order to settle this fundamental point, I decided to test them on myself. I ate 32 dried specimens of Psilocybe mexicana weighing 2.4 g, corresponding to a medium dose by Indian standards. I shall describe my experience by reading the English translation of my original published report of that experiment:
Thirty minutes after my taking the mushrooms, the exterior world began to undergo a strange transformation. Everything assumed a Mexican character. As I was perfectly well aware that my knowledge of the Mexican origin of the mushroom would lead me to imagine only Mexican scenery, I tried deliberately to look on my environment as I 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, I 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 I would 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 purely Indian expression. At the peak of the intoxication, about 1 1/2 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 I feared that I would be torn into this whirlpool of form and color and would dissolve. After about six hours the dream came to an end. Subjectively, I had no idea how long this condition had lasted. I felt my return to everyday reality to be a happy return from a strange, fantastic but quite real world to an old and familiar home.
|Fig. 3. Crystals of psilocybin and psilocin, and formulas.|
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 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, named psilocin.
The elucidation of their structures showed that these were a novel type of indole derivatives. Psilocybin is the first and only hitherto known natural indole compound that contains a phosphoric acid radical. Furthermore, psilocin and psilocybin were the first indole alkaloids with a free or phosphorylated hydroxyl group at the position 4 of the indole ring system, all the other numerous indole alkaloids bearing hydroxyl groups at the positions 5, 6 or 7.
The final proof of the correctness of the proposed structures was provided by the total synthesis of psilocin and psilocybin. The synthetic production of psilocybin and psilocin is now more economical than obtaining them from the mushrooms. My colleagues who participated in these investigations were: Dr. Arthur Brack, Dr. Albert Frey, Dr. Hans Kobel, Dr. Hans Ott, Dr. Theodor Petrzilka and Dr. Franz Troxler.
A review of the historical, ethnological, botanical and chemical aspects of the hallucinogenic Mexican mushrooms is presented in the beautiful volume, Les champignons hallucinogènes, by Roger Heim and R. Gordon Wasson, edited by the Museum National d'Histoire Naturelle in Paris. An average human oral dose of psilocybin is 6 mg to 10 mg. Psilocin possesses similar activity. This means that psilocybin and psilocin are about 100 times more active than mescaline and about 100 times less active than LSD. But there is no significant difference between the two compounds in quality of hallucinogenic activity. The development of cross-tolerance between LSD and psilocybin lends support to the view that these two drugs cause psychic disturbances by acting on some common mechanism, or on mechanisms acting through a common final pathway.
When I was in Mexico on an expedition with my friend Gordon Wasson in 1963, in search of a hallucinogenic plant, we also visited the famous curandera Maria Sabina in Huautla de Jimenez. We were invited to attend a nocturnal mushroom ceremony in her hut, but as it was late in the year and no more mushrooms were available, I supplied her with pills containing synthetic psilocybin. She took a rather strong dose corresponding to the number of mushrooms she usually ingests. It was a gala performance assisted by a number of people of Maria Sabina's clan. At dawn when we left the hut, our Mazateca interpreter told us that Maria Sabina had said there was no difference between the pills and the mushrooms. This was a final proof that our synthetic psilocybin was identical in every respect with the natural product.
That was the story of the second magic Mexican drug of teonanacatl. But there was still the riddle of ololiuqui, the third magic Mexican drug. Ololiuqui is the Aztec name for the seeds of certain convolvulaceous plants that since prehispanic times have been used by the Aztecs and related tribes in their religious ceremonies and magic medicinal practices in the same way as the sacred mushrooms and the cactus peyotl. Ololiuqui is still used in our day by such tribes as the Zapotecs, Chinantecs, Mazatecs, and Mixtecs, who live in the remote mountains of southern Mexico in comparative isolation, little influenced by Christianity. An excellent review of the historical, ethnological and botanical aspects of the ololiuqui question was given in 1941 by R. Evans Schultes of the Botanical Museum at Harvard, in his monograph, A Contribution to our Knowledge of Rivea corymbosa. The Narcotic Ololiuqui of the Aztecs.
The first description and illustration of ololiuqui was published 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 Plantarium, Animalium, Mineralium Mexicanorum Historia, which appeared in 1651 in Rome, Hernandez described ololiuqui under the heading "De Oliliuhqui, seu planta orbicularium foliorum." An extract of the 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 wished 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....
|Fig. 5. Seeds of Ipomoea tricolor and Rivea corymbosa|
The only report of chemical studies on 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.
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 visual sensitivity. After about four hours, there followed a period in which he had a relaxed feeling of well-being that lasted for a rather longer time. In contrast to these results, KinrossWright in 1958 published experiments performed on eight male volunteers who had taken doses of up to 125 seeds without any ascertainable effect.
After the chemical investigations of the sacred Mexican mushrooms had been successfully brought to a close, I decided to tackle the problem of the third Mexican magic drug, ololiuqui. Through the help of R. G. Wasson, I was able to obtain authentic ololiuqui from a Zapotec Indian near Oaxaca in southern Mexico. One sample consisted of brown seeds, which proved on botanical classification to stem from Rivea corymbosa. The black seeds of the second sample were identical with those of Ipomoea violacea L. (syn. Ipomoea tricolor CA V.). These black seeds, called "badoh negro," arc used especially in the region of the Zapotecs, in conjunction with, or instead of "Badoh," the brown seeds of Rivea corymbosa.
The chemical analysis of the ololiuqui seeds gave a quite surprising result. The psychotomimetic principles that we isolated proved to be Iysergic acid derivatives, Iysergic acid amides and other ergot alkaloids. Thus in this strange Mexican drug we met with old friends, since Iysergic acid derivatives and ergot alkaloids had been favorite subjects of research in our laboratory since the time I had first synthesized LSD in the nineteen-thirties.
|Fig. 6. Flowering plants of Rivea corymbosa and Ipomoea tricolor.|
The main constituents of ololiuqui, i.e., the seeds of Rivea corymbosa, are lysergic acid amide and lysergic acid 1-hydroxyethylamide. The active constituents of ololiuqui are very closely related to LSD. The only difference between the main constituent of ololiuqui, Iysergic acid amide, and LSD is that the two hydrogen atoms of the amide are replaced by two ethyl radicals. It is a very significant one with regard to the psychotomimetic activity. The ololiuqui principle, Iysergic acid amide, is much less active than Iysergic acid diethylamide (LSD), and provokes psychic symptoms qualitatively different from those of LSD, as will he shown later.
|Fig. 7. Structural relation between active principles of ololiuqui and LSD-25.|
Furthermore, the following minor alkaloids were isolated: isolysergic acid amide and isolysergic acid 1-hydroxyethylamide, chanoclavine, elymoclavine and lysergol. The seeds of the related convolvulaceous plant Ipomoea violacea yielded the same alkaloids with the difference that ergometrine was present instead of lysergol. The occurrence of ergot alkaloids in higher plants, in the phanerogamic family Convolvulaceae was quite unexpected and is of particular interest from the phytochemical point of view because Iysergic acid alkaloids had hitherto been isolated only from genera of lower fungi: Claviceps, Penicillium and Rhizopus. Lysergic acid amide, the main component of ololiuqui, had been tested pharmacologically and clinically under the experimental drug designation LA-111 during the course of our investigations on LSD and related compounds long before it was known to be a natural component of a magic Mexican drug. Self-experiment and comparative systematic clinical investigations with Iysergic acid amide (laboratory code name: LA-111) revealed psychotomimetic effects significantly different from those of Iysergic acid diethylamide (LSD-25). The symptoms after oral ingestion of 1 mg to 2 mg of LA-111 were: indifference, decrease of psychomotor activity, tiredness, feeling of sinking into nothingness, and desire to sleep. Isolysergic amide produces similar symptoms. After taking 2.0 mg of isolysergic amide orally, I experienced tiredness, apathy, a feeling of mental emptiness and of the unreality and complete meaninglessness of the outside world. These comparative experiments showed that the psychotomimetic constituents of ololiuqui are 20 to 40 times less active than LSD and that the general picture of activity is characterized by a pronounced depressive and narcotic component.
I now come to the last section of my chapter; here I shall discuss very briefly some common features in the chemical structure of the hallucinogens I have discussed. The comparison of these structures reveals an interesting relationship with the structures of important neurohumoral substances. This is certainly no mere coincidence, but of major importance.
Mescaline, being a phenylethylamine derivative, is structurally related to the neurohumoral transmitters norepinephrine and epinephritic. LSD, and the constituents of ololiuqui as well as the active principles of the hallucinogenic mushrooms psilocybin and psilocin, are indoles, more precisely tryptamine derivates, like the neurohumoral factor serotonin. Because of this structural relationship between the hallucinogens and norepinephrine and serotonin, it is probable that the psychotomimetic activity is due to an interaction between these substances in the metabolism of the central nervous system. Investigation of the relationships between endogenous neurohumoral factors and hallucinogens is a rewarding facet of psychopharmacological research.
As I am a chemist, I have mainly discussed the chemical, phytochemical and historical aspects of the discovery of LSD and the investigation of naturally occurring hallucinogens. Needless to say, this audience attaches primary importance to the pharmacological and clinical effects, which make LSD and the other specific hallucinogens a valuable tool in experimental psychiatry and a valuable drug aid in psychoanalysis and psychotherapy. Another aspect of the hallucinogens and especially of LSD with enormous social impact is of course the paramedical use and the misuse of these substances. But this very complex problem would provide material for a special lecture, or indeed for a series of such lectures.
The aim of my chapter is to describe an unusual cycle of chemical research, full of coincidences, a kind of magic circle, which started with the synthesis of various Iysergic acid amides and the discovery of the extraordinary psychotomimetic potency of Iysergic acid diethylamide (LSD), which led to the investigation of the sacred Mexican mushrooms, the isolation of psilocybin, and ended with ololiuqui, where lysergic acid amides were again encountered, thus closing the magic circle.
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