From Problem Child to Wonder Child: LSD turns 50

Spring 1993 Vol. 04, No. 1 Remembrance and Renewal

Download this article.

Sunbeams danced across meadows of the Jura mountains, capturing my gaze from Rittimatte’s living room window. I quickly sensed what Albert Hofmann meant as he recounted the mystical experiences of his youth: "As I was strolling through freshly greening woods illuminated by the morning sun and filled with bird-song, everything suddenly appeared in an unusually clear light. It radiated in a glow of eloquent beauty, touching the heart in a singular manner, as though it wanted to include me in its glory. I was filled with an indescribably blissful feeling of belonging and a blessed security." That mystical state awakened in young Albert a longing for deeper understanding of nature and the mysteries of life. Mystical experiences play an important role in our everyday lives, and they occur more often than we may realize, because most of us do not recognize their characteristics nor comprehend their meaning. Yet, we also strongly desire to relate our experiences to other people, but we usually cannot find meaningful words to describe them; in essence, they are ineffable.

Albert decided to study chemistry because he was attracted by the miracles of physical matter and the plant world. As he learned more about the chemical composition of plants, his respect and admiration grew for the wonders of nature. He eventually became most interested in those psychoactive compounds that under certain circumstances seemed to produce visionary experiences, similar to the spontaneous, mystical states of his youth.

After receiving his doctorate in chemistry from the University of Zurich in spring of 1929, he faced choosing a research position at one of the pharmaceutical companies, Ciba, Hofmann-LaRoche, or Sandoz, in Basle, Switzerland. Completing his dissertation on the chemical structure of chitin (it comprises the shells and skeletal parts of insects and crustaceans and is related to cellulose, the basic material of plants), he was interested in a position at a company with a plant chemistry program, so he joined Sandoz that year.

His early research at Sandoz focused on Mediterranean squill (Scilla maritima) and woolly foxglove (Digitalis lanata) glycosides for treatment of heart conditions, and ergot (Claviceps purpurea) alkaloids for use in obstetrics. He retired from Sandoz in 1971 as director of research for the department of natural products. With the business of pharmaceutical development behind him, and the tranquil surroundings of Rittimatte for comfort and inspiration, he began to reflect fully on his important discoveries. [Photograph of Rittimatte here] I.

Birth of a Wondrous Molecule

"A personal, childlike perception of nature, to be equated with the mystical experience, as the one source, and natural scientific insights as the other, form the basis of the following work."

I had the great honor of meeting Albert Hofmann, and his charmingly elegant wife Anita, at their home, Rittimate, this past autumn. I was seeking his reflections for a book I am writing on psychoactive fungi. He kindly consented to describe life experiences that led to his discoveries and to share new insight into his work.

Albert thought many people received a particular insight from their use of LSD; through it, they perceived the existence of a Creator. The LSD experience provides a sense of wonder that creation does not seem possible by accident alone, something spiritual is behind it, something we call God. I thought of Albert as a creator, the father of the very molecule he was describing, lysergic acid diethylamide. That discovery has been chronicled by Albert and others (see background reading list). But today, many people cannot image the social and scientific environment in which the synthesis and subsequent uses of LSD occurred.

Albert’s amazing discovery was based on work begun early this century at Sandoz, when a series of compounds were isolated from ergot (Claviceps purpurea, a fungus that grows on rye and other grains). There was great interest in the "mystery of ergot," because of its traditional use in childbirth by midwives, and a long history of epidemic outbreaks of ergot poisoning (ergotism, also known as St. Anthony’s fire), especially during the Middle Ages in Europe.

An amorphous alkaloidal substance, called ergotoxine, had been prepared from ergot by English researchers Barger and Carr in 1906, the year of Albert’s birth. But the first pure crystalline alkaloid, ergotamine, was isolated in 1918 by Arthur Stoll, later the director of Albert’s laboratory. After the discovery of ergotamine (Gynergen ), and its application in obstetrics to treat postpartum bleeding, it seemed that the mystery of ergot had been solved. Sandoz decided not to pursue further research with these compounds.

In the early 1930s, however, English an d American laboratories renewed research activity on ergot alkaloids, and Albert felt that Sandoz should resume its earlier work in this area too. He had finished his studies elucidating the chemical structure of scilla glycosides and was looking for a new project. Stoll told him that "ergot alkaloids are exceedingly sensitive, easily decomposed substances," and he warned him of the many difficulties in working with these unstable compounds. But Stoll let him proceed, and in 1937, Albert eagerly embarked on his investigations of ergot derivatives.

The chemical nucleus, common to all ergot alkaloids, had been identified by Jacobs and Craig at the Rockefeller Institute and named lysergic acid. Albert began his research by developing a procedure which allowed for the synthesis of ergot alkaloids and related compounds, starting with naturally occurring lysergic acid. By chemically bonding aminopropanol to the lysergic acid nucleus, he succeeded in synthesizing ergobasine, later called ergonovine (lysergic acid propanolamide). Ergonovine, the first naturally occurring ergot alkaloid to be synthesized in a laboratory, became an important medicine in obstetric therapeutics.

He continued working on lysergic acid derivatives with hopes of producing an analeptic (a respiratory and circulatory stimulant), analogous to the well known drug nicotinic acid diethylamide (Coramine). In November 1938, he synthesized the twenty-fifth compound in that speculative series, lysergsaure diathylamid (German for lysergic acid diethylamide), and it was given the lab code, LSD-25.

LSD-25 was tested (in animals) by the Sandoz pharmacology unit that same year (1938), but results were not that impressive. The report indicated LSD-25 showed strong activity on the uterus, about 70% that of ergonovine, and it also noted that the research animals became restless during anesthesia. These preliminary results did not arouse enough interest to encourage further investigation, and LSD-25 was all but forgotten, except by one person, for almost five years.

In the spring of 1943, Albert felt a "a peculiar presentiment, the feeling that this substance could possess properties other than those established in the first investigation, induced me, five years after the first synthesis, to produce LSD-25 again." This premonition compelled him to repeat the synthesis to obtain sufficient amounts for renewed pharmacological testing. It was an unusual course of action because experimental substances that produced inconclusive results in pharmacological testing usually were dropped from further investigation in the company’s research program.

During the purification and crystallization steps in the synthesis process, Albert’s work was interrupted by unusual physical and mental sensations:

"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."

That experience intrigued him greatly. He decided to engage in a self-experiment with the compound he had synthesized, and thus began his adventures into the chemistry of phantastica drugs and into his inner self.

Albert Hofmann’s Adventures

"It is impossible to predict the biological activity of a substance in man from the pattern of activity demonstrated in laboratory animals."

Our adventure with Albert Hofmann began in his orchards and took us up the ridge to an early 19th century stone marker at the border. Imbued with history, this boundary marker serves Albert and his guests well as a nutcracker. I watched as he placed a nut from a nearby tree in the groove on top, Switzerland was on one side and France on the other, and brought a small stone down on it; image became metaphor as I contemplated how he solved another mystery of ergot in a daring exploration through self-administration of LSD.

Self-experimentation, in which the researcher serves as his or her own subject, has led traditionally to major drug discoveries in pharmacy and medicine. It allows for direct personal contact with the empirical world and for gathering useful scientific information, and it also provides a moral justification for using specific therapies in patients. Drug researchers have self-administered pharmacologically active compounds in order to assess short and long term effects, dose-response relationships, toxic reactions, and therapeutic applications.

Albert Hofmann enhanced that great tradition when he engaged in the first planned self-experiment with a synthetic psychedelic compound. He reflected upon his strange and mystifying first experience, that previous Friday, with the lysergic acid derivative he had created. The nature of its effects did not coincide with what he knew to be symptoms associated with ergotism.

On Monday, the 19th of April, 1943, at twenty minutes past four in the afternoon, with his assistant in attendance, Albert dissolved in water a dose of 250 millionths of a gram (0.25 milligrams) of the LSD-25 he had prepared the previous week and drank it. He used what he thought was a very small amount, showing extreme caution for the compound’s potential effects he felt sure were responsible for his first phantastic experience. But it was still a high dose, and it produced more intense emotional states than before.

By 4:50 p.m., he had noticed no effects, but by 5:00 p.m., forty minutes into the experiment, he noted the following symptoms in his laboratory journal: "beginning dizziness, feeling of anxiety, unrest, difficulty in concentration, visual disturbances, desire to laugh." His last written words were barely legible.

"I requested my laboratory technician to accompany me home; we went by bicycle. This journey is about 4 miles and I had the feeling of not getting ahead, whereas my escort stated that we were rolling along at a good speed. I lost all count of time. I noticed with dismay that my environment was undergoing progressive changes. Space and time became more and more disorganized and I was overcome by a fear that I was going out of my mind. The worst part of it being that I was clearly aware of my condition. I was not, however, capable by any act of will, of preventing the breakdown of the world around me."

That intensely complex psychedelic experience developed into a terrifying state for him. He knew nothing of mescaline’s pharmacology, and he knew little of hallucinations and nervous disorders associated with ergotism. Nothing he had read or knew prepared him for what he actually did experience that day. It was a profound psychic experience that lasted for about twelve hours. He had no idea if he would return to everyday reality and be restored to a normal state of consciousness.

The correct chemical structure of the lysergic acid, the nucleus common to all ergot alkaloids, was elucidated in 1949 by Hofmann and his colleagues, and the total synthesis of lysergic acid was accomplished in 1954 by Kornfeld and his associates. More than thirty alkaloids have been isolated from ergot, and hundreds of chemical modifications of those natural compounds have been synthesized and analyzed. Yet even with the many alterations of the lysergic acid nucleus, as far as psychedelic properties, no molecule has been produced that is as active as lysergic acid diethylamide.

Albert’s work on LSD brought Roger Heim and Gordon Wasson, who had rediscovered teonanacatl, the magic mushroom of Mesoamerica (Psilocybe mexicana), to his laboratory early in 1957. They thought that his experiences with LSD, which produced effects qualitatively similar to those of the mushroom, prepared him to find active compounds that produced the mushroom’s effects. None of his colleagues, however, showed any enthusiasm for investigating the mushrooms. At that time, anything in anyway connected with LSD was becoming unpopular with the senior management of Sandoz, so he undertook the isolation experiments himself together with his trusty laboratory assistant, Hans Tscherter.

Tests of the mushroom material in mice and dogs produced insignificant results. Albert realized that the animal results were not due to inactivity of the mushroom, but to insensitivity of the animal assay. Only human beings could evaluate, specifically and emotionally, substances with psychic effects, a lesson Albert learned from LSD. He decided to test a precious sample of the mushrooms on himself. On the first of July, 1957:

"Thirty minutes after taking the mushrooms, the exterior world began to undergo a strange transformation. At the peak of the intoxication, about 1 1/2 hours after ingestion, the rush of interior pictures, mostly abstract motifs rapidly changing in shape and color, reached such an alarming degree that I feared being torn into this whirlpool of form and color and would dissolve. After about six hours, the dream came to an end. I felt my return to everyday reality to be a happy return from a strange, fantastic but quite real world to an old familiar home."

Additional self-experiments, eventually involving his co-workers and some of his colleagues as ‘guinea pigs’, allowed Albert and his research group to extract and isolate the active molecules, psilocybin and psilocin. Psilocybin was distributed in limited circles for psychiatric research, under the trade name Indocybin , but it never was released to the pharmaceutical market.

Wasson and Hofmann followed that discovery with an exploration of the Mexican magic drug, ololiuhqui, the seeds of morning glories (Rivea corymbosa and Ipomoea violacea), in the early 1960s. Extraction, isolation, and identification of these compounds led to an astonishing, almost unbelievable result. The active compounds of ololiuhqui proved to be very similar to molecules that had been isolated or synthesized in Albert’s lab. In fact, they were identical to substances obtained from decades of research with ergot, such as ergonovine and lysergic acid amides.

Albert continued his self-experimental approach in later years, during his inquiry into the role of ergot in the Eleusinian mysteries, and self-administered ergonovine to determine its psychoactivity. Even after decades of use in obstetrics, there had been no mention of hallucinogenic activity, probably due to the extremely low dosages that were used. His self-experiment, in April, 1976, showed that ergonovine possesses psychotropic, mood-altering, slightly hallucinogenic activity when taken in the same dosages as an effective dose of lysergic acid amide.

Albert Hofmann isolated and synthesized many oth er therapeutically beneficial molecules from ergot alkaloids, such as: methylergonovine (Methergine) for use in obstetrics, dihydroergotamine (Dihydergot) for treatment of postural hypotension and vascular headaches, l-methyl-lysergic acid (Sansert) for prophylactic treatment of migraine, and ergoloid mesylates – a combination of three hydrogenated ergotoxine alkaloids (Hydergine ) for use as a nootropic or memory enhancer, mostly in geriatric medicine. Hydergine has become a multi-million dollar success for Sandoz.

The wondrous discovery of LSD truly exemplifies the scientific method and the process of pharmaceutical discovery, intertwined with a personal modification of that method in order to explore new mindscapes. Albert’s discovery involved; 1) making a new compound based on speculation of what effects it might produce, but not really knowing what its pharmacological activity would be; 2) testing the compound, and experiencing effects, at dosages much lower than was known pharmaceutically for most drugs; 3) dealing with a profile of pharmacological activity that was impossible to measure in animals, and highly variable in humans, thus necessitating experimentation on himself; and 4) having difficulty comprehending, once the basic activity was known, its potential therapeutic applications, and even its very nature and meaning.

Nature & Meaning of LSD

"There are experiences that most people avoid talking about because they do not fit into the reality of everyday life and defy rational explanation."

Entranced by the expansive view of the Alsatian mountainside, relaxing in the cool alpine air with my traveling companion and Albert on his "meditation" bench near the border marker, we listened as he quoted Hegel ( Phenomenology of Spirit , 1807): "For one who is initiated into these [Eleusinian] mysteries not only comes to doubt the being of things of sense, but to despair of it; in part he brings about the nothingness of such things himself in his dealings with them, and in part he sees them reduce themselves to nothingness." Contemplating on the nature and meaning of the psychedelic experience, Albert pointed out that Hegel again is a relevant source of inspiration: "In the actual attempt to say it, it would therefore crumble away; those who started to describe it would not be able to complete the description, but would be compelled to leave it to others, who would themselves finally have to admit to speaking about something which is not."

Describing these ineffable drug experiences is quite a difficult task, and semantics become very important. Albert believes that psychedelic experiences are very complex, emotionally moving and even enigmatic on occasion, varying greatly from person to person and situation to situation. It is almost impossible to arrive at a generic listing of effects, a pharmacological description, that would apply to most users. In addition, as many users know, in attempting to describe a psychedelic experience, the ineffable becomes more so, and symbolic notions crystallizing to portray the whole phenomenon melt into a too complex swirl of bedazzling imagery and spiritual insight.

Louis Lewin’s ideas about psychoactive compounds helped Albert understand his discoveries; they are still among the best descriptions of the pharmacology of psychedelics. Albert emphasized Lewin’s concept of phantastica drugs "exercising their chemical power on all the senses, but they influence particularly the visual and auditory spheres as well as the general sensibility." These drugs of illusion bring about cerebral excitation in the form of hallucinations and related altered perceptions.

Our western perspective on the world, and thus our attempts to understand psychedelics, is based on scientific naturalism of 17th century Europe. It developed with the creation of an ego that was capable of contrasting itself with the surrounding world; that regarded the world as an entity, an object; essentially, a mind that could objectify the world around it. From this foundation, scientific research of our century has concentrated more and more on the quantitative, measurable aspects of nature, employing increasingly complicated techniques and advanced technology to measure components of any phenomenon.

But this approach reduces experience, the various aspects of our living world, to a few chemical elements or atoms, thus expressing an incredibly exaggerated role for physical matter in our lives.

Yet, contemporary science continues to amass formidable amounts of information on mechanisms of drug action, thanks to technology, but Albert strikes a discordant note:

"Today we can say of many drugs that we know they act and in what way, but we are still quite unable to say they act as they do. There are no known laws defining the relation between chemical constitution and pharmacological effects. All knowledge of the relations between chemical structure and pharmacological action is ultimately based on empirical data."

He began to recognize the meaningful connection between LSD experiences and spontaneous visionary states only after more self-experiments at lower doses and under different conditions broadened his psychedelic repertoire. LSD changed him, got him interested in mysticism, and enhanced his conception of reality and the workings of the mind. Experiences with LSD gave him insight into the borderland between mind and matter. He said that "if there were not something of mind in matter, how could matter change the mind?" The fundamental question that occupied him was whether use of psychedelic drugs "could not indeed represent a forbidden transgression of limits."

It also was difficult early on to realize fully the therapeutic and social benefits of LSD and related psychedelic drugs. These substances affect our perceptual systems and states of consciousness, the inner most essence of our being. They can produce intensely profound experiences. Experience can be interpreted in different ways, and there is no such thing as an objective reality. As a result, those interested in probing the mind and investigating consciousness had to practice care and prepare responsibly for the explorations they sought.

Phantastica Lost

"Deliberate provocation of mystical experience, particularly by LSD and related psychedelics, in contrast to spontaneous, visionary experience, entails dangers that must not be underestimated."

Walking among the colchicum and eating fruit from Albert’s famous plum trees, I began to reflect on the difficult times that repressed psychedelic inquiry. During the early years after his discovery, Albert was happy and gratified that LSD and other compounds were finding very useful therapeutic applications.

Psychiatric research with LSD-25 began in Switzerland in 1947. Sandoz supplied it to selected researchers under the tradename Delysid (lysergsaure-diathylamid). The company’s drug product literature indicated two possible medical uses: 1) analytical, to elicit release of repressed material and provide mental relaxation, particularly in anxiety states and obsessional neuroses, and 2) to assist the psychiatrist, who self-experiments with it, to gain insight into the world of ideas and sensations of mental patients.

In 1949, LSD was introduced in the U.S. Its use in American clinics involved psychedelic therapy, the administration of one single high dose (0.3-0.6 mg.) after extensive psychological preparation. LSD use in European clinics, in the form of psycholytic therapy, employed moderate doses administered over successive sessions at regular intervals. LSD also was used in research on normal subjects to induce "model psychosis." It had evolved into a major adjunct to psychotherapy and meditation, an important pharmacological tool in brain research, and a valuable medicinal agent in treatments for people with terminal illnesses and drug addictions.

The joy of having fathered LSD was tarnished for Albert when recreational use began to occur after more than ten years of uninterrupted scientific research and medical use. He held these events in disbelief, "since my self-experiment had revealed LSD in its terrifying, demonic aspect, the last thing I could have expected was that this substance could ever find application as anything approaching a pleasure drug."

As more and more LSD was disseminated and used, in careless and unsupervised ways, the untoward reactions began to occur with greater frequency. Accidents, poisonings, and criminal acts resulting from misuse of LSD escalated, and Sandoz became inundated with requests for information by a wide range of health professionals and governmental authorities. These enormous, unprofitable difficulties upset the business management of Sandoz. In fact, Arthur Stoll, the managing director of pharmaceutical research, reproached Albert during those troubled times, saying, "I would rather you had not discovered LSD."

The last of the Sandoz patents for the production of LSD expired in 1963, and none of the international drug control laws included LSD, so many people began to manufacture it. The hysteria of publicity, both about LSD’s wondrous effects and its potential for dangerous misuse, reached its zenith between 1964 and 1966. Many people began to use it primarily as a tool in the exploration of consciousness, and others applied it in religious ceremonies. Inappropriate use, LSD’s relationship with the emerging counterculture, and the social and political implications of mystical experiences and consciousness research led to repressive laws and withdrawal of permission to perform further research on it. These events hindered greatly basic scientific research and clinical studies on LSD and related compounds for over 25 years.

On the 23rd of August, 1965, the management of Sandoz decided and announced publicly that LSD, as well as psilocybin, psilocin, and all of their derivatives, would no longer be produced and distributed by Sandoz. Was this the end for a phantastically therapeutic chemical substance?

The Magic Circle Closes

"The investigation of ancient magical and religious plants by means of modern scientific methods led to the discovery of potent drugs with a specific action on the psyche."

Our professional conversation and Albert’s reflections ended with the setting sun. Enveloped by the familiarity of his library, he encapsulated for us the knowledge and wisdom that came with his psychedelic inquiries and experiences.

He regards his research on psychedelic drugs as having the symmetry and characteristics of a magic circle. Beginning with the extraction and isolation of ergot alkaloids and the synthesis of various lysergic acid amides, such as ergonovine, he then followed a logical sequence: synthesis of lysergic acid diethylamide as he searched for an analeptic; isolation and identification of psilocybin and psilocin from magic mushrooms, sent to his lab after he reported the hallucinogenic properties of LSD; and finally, investigations of another magical Mexican plant, ololuihqui, from which lysergic acid amides, ergonovine, and lysergic acid hydroxyethylamide were isolated; thus, closing the magic circle.

Albert views the 1960s as a cultural experiment with LSD and he wanted to observe and reflect upon it fully before writing about it. His professional autobiography (LSD: My Problem Child ) was not published until 1979. He does not feel sad nor does he regret his discoveries just because his molecules have been misused. His original intention was to produce useful medicinal substances for applications in psychiatry and psychopharmacological research. In his opinion, "the last word has not yet been said about the possible medical applications of this drug."

What does the future hold for LSD and its pharmaceutical cousins? Is the world rediscovering this wondrous molecule with celebrations of its birth fifty years later?

In the realms of psychedelic research and experience, Albert feels that "the scientific view of life contains truth, but it only represents half of reality, only its material, quantifiable parts. All of the personal, social, and spiritual dimensions that cannot be described in physical or chemical terms, which include the most important characteristics of that which is living, are absent." The future understanding of psychedelic compounds rests on augmenting rational knowledge with emotional experience.

After years of struggle with regulatory authorities and public misconceptions, scientific researchers and health professionals are beginning to rturn to these valuable drugs. Revitalization of psychedelic research for therapeutic utility is occurring around the world (as reported in these pages). It is exciting to see and hear of the use of LSD, psilocybin and other compounds in therapies for cancer patients and in research on human brain mechanisms and psychic activity.

New clinical trials are being initiated in a number of countries. A group of Swiss psychiatrists formed the Swiss Medical Society for Psycholtic Therapy in 1985, and they have been granted permission by their government ot use psychedelics in psychotherapy. The U.S. Food and Drug Administration’s Drug Abuse Advisory Committee recommended, in July 1992, that medical research on psychedelics be expanded, that new therapeutic applications be considered, following recent approval of protocols for new clinical testing.

A grand celebration will take place in Lugano-Agno, Switzerland on October 21-22, 1993, when the Swiss Academy of Medical Sciences will hold an international symposium to commemorate the 50th anniversay of Albert’s discovery. They have invited 15 presenters and 70 participants to discuss "50 Years of LSD: State of the Art and Perspectives on Hallucinogens." These are very positive signs of new, exciting inquiries into a class of drugs that almost were forgotten.

The time certainly has come for a full appreciation of the beneficial uses that LSD has to offer. With renewed interest, it becomes necessary to understand better this chemical substance, its origins, effects, and dangers to guard against misuse and to allow for therapeutic and spiritual applications that are compatible with its uniquely characteristic actions. Let the 50th anniversary of the discovery of LSD realize and celebrate Albert Hofmann’s dream that "if people would learn to use LSD’s vision-inducing capability more wisely, under suitable conditions, in medical practice and in conjunction with meditation, then this problem child could become a wonder child."