Albert Hoffman is mostly known for his discovery and synthesis of the famous LSD-25 molecule which made so much impact in the following years after that. There are other feats he performed that are less known (at least to my observation), therefore I think it would be good to have a thread dedicated to Albert Hoffman in general and also to point those less know feats out and bring them into the general awarenes.
These are only selected paragraphs. In the attached book you can find the full text.DISCOVERY OF LSD-25»Looking for a new field of research, I asked Professor Stoll to let me continue the investigations on the alkaloids of ergot, which he had begun in 1917 and which had led directly to the isolation of ergotamine in 1918. Ergotamine, discovered by Stoll, was the first ergot alkaloid obtained in pure chemical form.«
»Professor Stoll granted my request, with some misgivings: "I must warn you of the difficulties you face in working with ergot alkaloids. These are-exceedingly sensitive, easily decomposed substances, less stable than any of the compounds you have investigated in the cardiac glycoside field. But you are welcome to try." And so the switches were thrown, and I found myself engaged in a field of study that would become the main theme of my professional career. I have never forgotten the creative joy, the eager anticipation I felt in embarking on the study of ergot alkaloids, at that time a relatively uncharted field of research.«
»The early 1930s brought a new era in ergot research, beginning with the determination of the chemical structure of ergot alkaloids, as mentioned, in English and American laboratories. By chemical cleavage, W. A. Jacobs and L. C. Craig of the Rockefeller Institute of New York succeeded in isolating and characterizing the nucleus common to all ergot alkaloids. They named it lysergic acid.«
»Lysergic acid proved to be a rather unstable substance, and its rebonding with basic radicals posed difficulties. In the technique known as Curtius' Synthesis, I ultimately found a process that proved useful for combining lysergic acid with amines. With this method I produced a great number of lysergic acid compounds.«
»I further employed my synthetic procedure to produce new lysergic acid compounds for which uterotonic activity was not prominent, but from which, on the basis of their chemical structure, other types of interesting pharmacological properties could be expected. In 1938, I produced the twenty-fifth substance in this series of lysergic acid derivatives: lysergic acid diethylamide, abbreviated LSD-25 (Lyserg-säure-diäthylamid) for laboratory usage.«
»I had planned the synthesis of this compound with the intention of obtaining a circulatory and respiratory stimulant (an analeptic). Such stimulating properties could be expected for lysergic acid diethylamide, because it shows similarity in chemical structure to the analeptic already known at that time, namely nicotinic acid diethylamide (Coramine). During the testing of LSD-25 in the pharmacological department of Sandoz, whose director at the time was Professor Ernst Rothlin, a strong effect on the uterus was established. It amounted to some 70 percent of the activity of ergobasine. The research report also noted, in passing, that the experimental animals became restless during the narcosis. The new substance, however, aroused no special interest in our pharmacologists and physicians; testing was therefore discontinued.«
»For the next five years, nothing more was heard of the substance LSD-25. Meanwhile, my work in the ergot field advanced further in other areas.«
»And yet I could not forget the relatively uninteresting LSD-25. A peculiar presentiment—the feeling that this substance could possess properties other than those established in the first investigations—induced me, five years after the first synthesis, to produce LSD-25 once again so that a sample could be given to the pharmacological department for further tests. This was quite unusual; experimental substances, as a rule, were definitely stricken from the research program if once found to be lacking in pharmacological interest.«
»Nevertheless, in the spring of 1943, I repeated the synthesis of LSD-25. As in the first synthesis, this involved the production of only a few centigrams of the compound.«
»In the final step of the synthesis, during the purification and crystallization of lysergic acid diethylamide in the form of a tartrate (tartaric acid salt), I was interrupted in my work by unusual sensations. The following description of this incident comes from the report that I sent at the time to Professor Stoll:
Last Friday, April 16,1943, I was forced to interrupt my work in the laboratory in the middle of the afternoon and proceed home, being affected by a remarkable restlessness, combined with a slight dizziness. At home I lay down and sank into a not unpleasant intoxicated-like condition, characterized by an extremely stimulated imagination. In a dreamlike state, with eyes closed (I found the daylight to be unpleasantly glaring), I perceived an uninterrupted stream of fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of colors. After some two hours this condition faded away.«
»This was, altogether, a remarkable experience—both in its sudden onset and its extraordinary course. It seemed to have resulted from some external toxic influence; I surmised a connection with the substance I had been working with at the time, lysergic acid diethylamide tartrate. But this led to another question: how had I managed to absorb this material? Because of the known toxicity of ergot substances, I always maintained meticulously neat work habits. Possibly a bit of the LSD solution had contacted my fingertips during crystallization, and a trace of the substance was absorbed through the skin. If LSD-25 had indeed been the cause of this bizarre experience, then it must be a substance of extraordinary potency. There seemed to be only one way of getting to the bottom of this. I decided on a self-experiment. Exercising extreme caution, I began the planned series of experiments with the smallest quantity that could be expected to produce some effect, considering the activity of the ergot alkaloids known at the time: namely, 0.25 mg (mg = milligram = one thousandth of a gram) of lysergic acid diethylamide tartrate. Quoted below is the entry for this experiment in my laboratory journal of April 19, 1943.«
The first self-experiment with LSD-25:»4/19/43 16:20: 0.5 cc of 1/2 promil aqueous solution of diethylamide tartrate orally = 0.25 mg tartrate. Taken diluted with about 10 cc water. Tasteless.
17:00: Beginning dizziness, feeling of anxiety, visual distortions, symptoms of paralysis, desire to laugh.
Supplement of 4/21: Home by bicycle. From 18:00- ca.20:00 most severe crisis.«
»Here the notes in my laboratory journal cease. I was able to write the last words only with great effort. By now it was already clear to me that LSD had been the cause of the remarkable experience of the previous Friday, for the altered perceptions were of the same type as before, only much more intense. I had to struggle to speak intelligibly. I asked my laboratory assistant, who was informed of the self-experiment, to escort me home. We went by bicycle, no automobile being available because of wartime restrictions on their use. On the way home, my condition began to assume threatening forms.«
»Everything in my field of vision wavered and was distorted as if seen in a curved mirror. I also had the sensation of being unable to move from the spot. Nevertheless, my assistant later told me that we had traveled very rapidly. Finally, we arrived at home safe and sound, and I was just barely capable of asking my companion to summon our family doctor and request milk from the neighbors. In spite of my delirious, bewildered condition, I had brief periods of clear and effective thinking—and chose milk as a nonspecific antidote for poisoning. The dizziness and sensation of fainting became so strong at times that I could no longer hold myself erect, and had to lie down on a sofa. My surroundings had now transformed themselves in more terrifying ways. Everything in the room spun around, and the familiar objects and pieces of furniture assumed grotesque, threatening forms. They were in continuous motion, animated, as if driven by an inner restlessness. The lady next door, whom I scarcely recognized, brought me milk—in the course of the evening I drank more than two liters. She was no longer Mrs. R., but rather a malevolent, insidious witch with a colored mask. Even worse than these demonic transformations of the outer world, were the alterations that I perceived in myself, in my inner being. Every exertion of my will, every attempt to put an end to the disintegration of the outer world and the dissolution of my ego, seemed to be wasted effort. A demon had invaded me, had taken possession of my body, mind, and soul. I jumped up and screamed, trying to free myself from him, but then sank down again and lay helpless on the sofa. The substance, with which I had wanted to experiment, had vanquished me. It was the demon that scornfully triumphed over my will. I was seized by the dreadful fear of going insane. I was taken to another world, another place, another time. My body seemed to be without sensation, lifeless, strange. Was I dying? Was this the transition? At times I believed myself to be outside my body, and then perceived clearly, as an outside observer, the complete tragedy of my situation. I had not even taken leave of my family (my wife, with our three children had traveled that day to visit her parents, in Lucerne). Would they ever understand that I had not experimented thoughtlessly, irresponsibly, but rather with the utmost caution, an-d that such a result was in no way foreseeable? My fear and despair intensified, not only because a young family should lose its father, but also because I dreaded leaving my chemical research work, which meant so much to me, unfinished in the midst of fruitful, promising development. Another reflection took shape, an idea full of bitter irony: if I was now forced to leave this world prematurely, it was because of this Iysergic acid diethylamide that I myself had brought forth into the world. By the time the doctor arrived, the climax of my despondent condition had already passed. My laboratory assistant informed him about my self-experiment, as I myself was not yet able to formulate a coherent sentence. He shook his head in perplexity, after my attempts to describe the mortal danger that threatened my body. He could detect no abnormal symptoms other than extremely dilated pupils. Pulse, blood pressure, breathing were all normal. He saw no reason to prescribe any medication. Instead he conveyed me to my bed and stood watch over me. Slowly I came back from a weird, unfamiliar world to reassuring everyday reality. The horror softened and gave way to a feeling of good fortune and gratitude, the more normal perceptions and thoughts returned, and I became more confident that the danger of insanity was conclusively past. Now, little by little I could begin to enjoy the unprecedented colors and plays of shapes that persisted behind my closed eyes. Kaleidoscopic, fantastic images surged in on me, alternating, variegated, opening and then closing themselves in circles and spirals, exploding in colored fountains, rearranging and hybridizing themselves in constant flux. It was particularly remarkable how every acoustic perception, such as the sound of a door handle or a passing automobile, became transformed into optical perceptions. Every sound generated a vividly changing image, with its own consistent form and color.«
»Late in the evening my wife returned from Lucerne. Someone had informed her by telephone that I was suffering a mysterious breakdown. She had returned home at once, leaving the children behind with her parents. By now, I had recovered myself sufficiently to tell her what had happened.«
»Exhausted, I then slept, to awake next morning refreshed, with a clear head, though still somewhat tired physically. A sensation of well-being and renewed life flowed through me. Breakfast tasted delicious and gave me extraordinary pleasure. When I later walked out into the garden, in which the sun shone now after a spring rain, everything glistened and sparkled in a fresh light. The world was as if newly created. All my senses vibrated in a condition of highest sensitivity, which persisted for the entire day.«
SACRED MUSHROOM -- PSILOCYBIN/PSILOCIN»As it later turned out, LSD was the reason that these mushrooms found their way into my laboratory, with out my assistance, at the beginning of the following year.«
»Through the mediation of Dr. Yves Dunant, at the time director of the Paris branch of Sandoz, an inquiry came to the pharmaceutical research management in Basel from Professor Roger Heim, director of the Laboratoire de Cryptogamie of the Museum National d'Histoire Naturelle in Paris, asking whether we were interested in carrying out the chemical investigation of the Mexican hallucinogenic mushrooms. With great joy I declared myself ready to begin this work in my department, in the laboratories for natural product research. That was to be my link to the exciting investigations of the Mexican sacred mushrooms, which were already broadly advanced in the ethnomycological and botanical aspects.«
»As the chemical investigations in Paris and in the United States turned out to be ineffectual, Professor Heim addressed this matter to our firm, as mentioned at the beginning of this chapter, because he felt that our experimental experience with LSD, related to the magic mushrooms by similar activity, could be of use in the isolation attempts. Thus it was LSD that showed teonanácatl the way into our laboratory.«
»As director of the department of natural products of the Sandoz pharmaceutical-chemical research laboratories at that time, I wanted to assign-the investigation of the magic mushrooms to one of my coworkers. However, nobody showed much eagerness to take on this problem because it was known that LSD and everything connected with it were scarcely popular subjects to the top management. Because the enthusiasm necessary for successful endeavors cannot be commanded, and because the enthusiasm was already present in me as far as this problem was concerned, I decided to conduct the investigation myself.«
»Some 100 g of dried mushrooms of the species Psilocybe mexicana, cultivated by Professor Heim in the laboratory, were available for the beginning of the chemical analysis. My laboratory assistant, Hans Tscherter, who during our decade-long collaboration, had developed into a very capable helper, completely familiar with my manner of work, aided me in the extraction and isolation attempts. Since there were no clues at all concerning the chemical properties of the active principle we sought, the isolation attempts had to be conducted on the basis of the effects of the extract fractions. But none of the various extracts showed an unequivocal effect, either in the mouse or the dog, which could have pointed to the presence of hallucinogenic principles. It therefore became doubtful whether the mushrooms cultivated and dried in Paris were still active at all. That could only be determined by experimenting with this mushroom material on a human being. As in the case of LSD, I made this fundamental experiment myself, since it is not appropriate for researchers to ask anyone else to perform self-experiments that they require for their own investigations, especially if they entail, as in this case, a certain risk. In this experiment I ate 32 dried specimens of Psilocybe mexicana, which together weighed 2.4 g. This amount corresponded to an average dose, according to the reports of Wasson and Heim, as it is used by the curanderos. The mushrooms displayed a strong psychic effect.«
»This self-experiment showed once again that human beings react much more sensitively than animals to psychoactive substances. We had already reached the same conclusion in experimenting with LSD on animals, as described in an earlier chapter of this book. It was not inactivity of the mushroom material, but rather the deficient reaction capability of the research animals vis-à-vis such a type of active principle, that explained why our extracts had appeared inactive in the mouse and dog.«
»With the help of this reliable test on human subjects, the active principle could be isolated, concentrated, and transformed into a chemically pure state by means of the newest separation methods. Two new substances, which I named psilocybin and psilocin, were thereby obtained in the form of colorless crystals.«
»These results were published in March 1958 in the journal Experientia, in collaboration with Professor Heim and with my colleagues Dr. A. Brack and Dr. H. Kobel, who had provided greater quantities of mushroom material for these investigations after they had essentially improved the laboratory cultivation of the mushrooms.«
»Some of my coworkers at the time—Drs. A. J. Frey, H. Ott, T. Petrzilka, and F. Troxler—then participated in the next steps of these investigations, the determination of the chemical structure of psilocybin and psilocin and the subsequent synthesis of these compounds, the results of which were published in the November 1958 issue of Experientia. The chemical structures of these mushroom factors deserve special attention in several respects. Psilocybin and psilocin belong, like LSD, to the indole compounds, the biologically important class of substances found in the plant and animal kingdoms. Particular chemical features common to both the mushroom substances and LSD show that psilocybin and psilocin are closely related to LSD, not only with regard to psychic effects but also to their chemical structures. Psilocybin is the phosphoric acid ester of psilocin and, as such, is the first and hitherto only phosphoric-acid-containing indole compound discovered in nature. The phosphoric acid residue does not contribute to the activity, for the phosphoric-acid-free psilocin is just as active as psilocybin, but it makes the molecule more stable. While psilocin is readily decomposed by the oxygen in air, psilocybin is a stable substance.«
»The total synthesis of psilocybin and psilocin, without the aid of the mushrooms, could be developed into a technical process, which would allow these substances to be produced on a large scale. Synthetic production is more rational and cheaper than extraction from the mushrooms.«
»Thus with the isolation and synthesis of the active principles, the demystification of the magic mushrooms was accomplished. The compounds whose wondrous effects led the Indians to believe for millennia that a god was residing in the mushrooms had their chemical structures elucidated and could be produced synthetically in flasks. Just what progress in scientific knowledge was accomplished by natural products research in this case? Essentially, when all is said and done, we can only say that the mystery of the wondrous effects of teonanácatl was reduced to the mystery of the effects of two crystalline substances—since these effects cannot be explained by science either, but can only be describe.«
OLOLIUQUI/MORNING GLORY»After we had managed to solve the riddle of the sacred mushroom teonanácatl in a relatively short time, I also became interested in the problem of another Mexican magic drug not yet chemically elucidated, ololiuhqui. Ololiuhqui is the Aztec name for the seeds of certain climbing plants (Convolvulaceae) that, like the mescaline cactus peyotl and the teonanácatl mushrooms, were used in pre-Columbian times by the Aztecs and neighboring people in religious ceremonies and magical healing practices. Ololiuhqui is still used even today by certain Indian tribes like the Zapotec, Chinantec, Mazatec, and Mixtec, who until a short time ago still led a genuinely isolated existence, little influenced by Christianity, in the remote mountains of southern Mexico.«
»When I decided in 1959 to attempt the isolation o the active principles of ololiuhqui, only a single report on chemical work with the seeds of Turbina corymbosa was available. It was the work of the pharmacologist C. G. Santesson of Stockholm, from the year 1937. Santesson, however, was not successful in isolating an active substance in pure form.«
»Through the mediation of R. Gordon Wasson, I obtained two samples of ololiuhqui seeds. In his accompanying letter of 6 August 1959 from Mexico City, he wrote of them:
. . . The parcels that I am sending you are the following: . . . A small parcel of seeds that I take to be Rivea corymbosa, otherwise known as ololiuqui well-known narcotic of the Aztecs, called in Huautla "la semilla de la Virgen." This parcel, you will find, consists of two little bottles, which represent two deliveries of seeds made to us in Huautla, and a larger batch of seeds delivered to us by Francisco Ortega "Chico," the Zapotec guide, who himself gathered the seeds from the plants at the Zapotec town of San Bartolo Yautepec....«
»My capable laboratory assistant Hans Tscherter, with whom I had already carried out the isolation of the active principles of the mushrooms, participated in the chemical investigation of the ololiuhqui drug. We advanced the working hypothesis that the active principles of the ololiuhqui seeds could be representatives of the same class of chemical substances, the indole compounds, to which LSD, psilocybin, and psilocin belong. Considering the very great number of other groups of substances that, like the indoles, were under consideration as active principles of ololiuhqui, it was indeed extremely improbable that this assumption would prove true. It could, however, very easily be tested. The presence of indole compounds, of course, may simply and rapidly be determined by colorimetric reactions. Thus even traces of indole substances, with a certain reagent, give an intense blue-colored solution.«
»We had luck with our hypothesis. Extracts of ololiuhqui seeds with the appropriate reagent gave the blue coloration characteristic of indole compounds. With the help of this colorimetric test, we succeeded in a short time in isolating the indole substances from the seeds and in obtaining them in chemically pure form. Their identification led to an astonishing result. What we found appeared at first scarcely believable. Only after repetition and the most careful scrutiny of the operations was our suspicion concerning the peculiar findings eliminated: the active principles from the ancient Mexican magic drug ololiuhqui proved to be identical with substances that were already present in my laboratory. They were identical with alkaloids that had been obtained in the course of the decades-long investigations of ergot; partly isolated as such from ergot, partly obtained through chemical modification of ergot substances.«
»Lysergic acid amide, lysergic acid hydroxyethylamide, and alkaloids closely related to them chemically were established as the main active principles of ololiuhqui. (See formulae in the appendix.) Also present was the alkaloid ergobasine, whose synthesis had constituted the starting point of my investigations on ergot alkaloids. Lysergic acid amide and lysergic acid hydroxyethylamide, active principles of ololiuhqui, are chemically very closely related to lysergic acid diethylamide (LSD), which even for the non-chemist follows from the names.«
»Lysergic acid amide was described for the first time by the English chemists S. Smith and G. M. Timmis as a cleavage product of ergot alkaloids, and I had also produced this substance synthetically in the course of the investigations in which LSD originated. Certainly, nobody at the time could have suspected that this compound synthesized in the flask would be discovered twenty years later as a naturally occurring active principle of an ancient Mexican magic drug.«
»After the discovery of the psychic effects of LSD, I had also tested lysergic acid amide in a self-experiment and established that it likewise evoked a dreamlike condition, but only with about a tenfold to twenty-fold greater dose than LSD. This effect was characterized by a sensation of mental emptiness and the unreality and meaninglessness of the outer world, by enhanced sensitivity of hearing, and by a not unpleasant physical lassitude, which ultimately led to sleep. This picture of the effects of LA-111, as lysergic acid amide was called as a research preparation, was confirmed in a systematic investigation by the psychiatrist Dr. H. Solms.«
»When I presented the findings of our investigations on ololiuhqui at the Natural Products Congress of the International Union for Pure and Applied Chemistry (IUPAC) in Sydney, Australia, in the fall of 1960, my colleagues received my talk with skepticism. In the discussions following my lecture, some persons voiced the suspicion that the ololiuhqui extracts could well have been contaminated with traces of lysergic acid derivatives, with which so much work had been done in my laboratory.«
»There was another reason for the doubt in specialist circles concerning our findings. The occurrence in higher plants (i.e., in the morning glory family) of ergot alkaloids that hitherto had been known only as constituents of lower fungi, contradicted the experience that certain substances are typical of and restricted to respective plant families. It is indeed a very rare exception to find a characteristic group of substances, in this case the ergot alkaloids, occurring in two divisions of the plant kingdom broadly separated in evolutionary history.«
»Our results were confirmed, however, when different laboratories in the United States, Germany, and Holland subsequently verified our investigations on the ololiuhqui seeds. Nevertheless, the skepticism went so far that some persons even considered the possibility that the seeds could have been infected with alkaloid-producing fungi. That suspicion, however, was ruled out experimentally.«
»
My studies in the field of hallucinogenic drugs reached a kind of logical conclusion with the investigations of ololiuhqui. They now formed a circle, one could almost say a magic circle: the starting point had been the synthesis of lysergic acid amides, among them the naturally occurring ergot alkaloid ergobasin. This led to the synthesis of lysergic acid diethylamide, LSD. The hallucinogenic properties of LSD were the reason why the hallucinogenic magic mushroom teonanácatl found its way into my laboratory. The work with teonanácatl, from which psilocybin and psilocin were isolated, proceeded to the investigation of another Mexican magic drug, ololiuhqui, in which hallucinogenic principles in the form of lysergic acid amides were again encountered, including ergobasin—with which the magic circle closed.«
COMPOUNDS USED IN MEDICINEErgometrine/ergonovine/ergobasine »By combining lysergic acid with the amino alcohol propanolamine, I obtained a compound that was identical to the natural ergot alkaloid ergobasine. With that, the first synthesis—that is, artificial production—of an ergot alkaloid was accomplished. This was not only of scientific interest, as confirmation of the chemical structure of ergobasine, but also of practical significance, because ergobasine, the specifically uterotonic, hemostatic principle, is present in ergot only in very trifling quantities. With this synthesis, the other alkaloids existing abundantly in ergot could now be converted to ergobasine, which was valuable in obstetrics.«
Methergine»After this first success in the ergot field, my investigations went forward on two fronts. First, I attempted to improve the pharmacological properties of ergobasine by variations of its amino alcohol radical. My colleague Dr. J. Peyer and I developed a process for the economical production of propanolamine and other amino alcohols. Indeed, by substitution of the propanolamine contained in ergobasine with the amino alcohol butanolamine, an active principle was obtained that even surpassed the natural alkaloid in its therapeutic properties. This improved ergobasine has found worldwide application as a dependable uterotonic, hemostatic remedy under the trade name Methergine, and is today the leading medicament for this indication in obstetrics.«
Hydergine»The solution of the ergotoxine problem was not merely scientifically interesting, but also had great practical significance. A valuable remedy arose from it. The three hydrogenated ergotoxine alkaloids that I produced in the course of these investigations, dihydroergocristine, dihydroergokryptine, and dihydroergocornine, displayed medicinally useful properties during testing by Professor Rothlin in the pharmacological department. From these three substances, the pharmaceutical preparation Hydergine was developed, a medicament for improvement of peripheral circulation and cerebral function in the control of geriatric disorders. Hydergine has proven to be an effective remedy in geriatrics for these indications. Today it is Sandoz's most important pharmaceutical product.«
Dihydergot»Dihydroergotamine, which I likewise produced in the course of these investigations, has also found application in therapeutics as a circulation- and blood-pressure-stabilizing medicament, under the trade name Dihydergot.«
»While today research on important projects is almost exclusively carried out as teamwork, the investigations on ergot alkaloids described above were conducted by myself alone. Even the further chemical steps in the evolution of commercial preparations remained in my hands—that is, the preparation of larger specimens for the clinical trials, and finally the perfection of the first procedures for mass production of Methergine, Hydergine, and Dihydergot. This even included the analytical controls for the development of the first galenical forms of these three preparations: the ampoules, liquid solutions, and tablets. My aides at that time included a laboratory assistant, a laboratory helper, and later in addition a second laboratory assistant and a chemical technician.«