While pursuing ergot alkaloid medicinal chemistry research, Albert Hofmann synthesized LSD-25 (lysergic acid diethylamide-25), a drug with potent psychogenic properties that were not recognized until 1943.

For thousands of years, human beings have searched for tranquillity, spiritual enlightenment, and guidance in understanding and defining their role in the natural world. Both primitive and modern religions frequently advocate individuals’ use of aids such as meditation, fasting, and ritual ingestion of psychoactive plants to alter perception of the world and to achieve a harmonious state of being. Mescaline, a natural substance occurring in peyote cactus, and psilocybin, found in various species of mushrooms, have been used in religious rituals in Mexico since the Aztec era; these are only two examples of the dozens of psychoactive plants distributed throughout the world. Such plants contain substances that have a profound ability to influence consciousness—the innermost essence of being. [kw]Hofmann Synthesizes the Potent Psychedelic Drug LSD-25 (1938)
[kw]Psychedelic Drug LSD-25, Hofmann Synthesizes the Potent (1938)
[kw]Drug LSD-25, Hofmann Synthesizes the Potent Psychedelic (1938)[Drug LSD 25, Hofmann Synthesizes the Potent Psychedelic (1938)]
[kw]LSD-25, Hofmann Synthesizes the Potent Psychedelic Drug (1938)[LSD 25, Hofmann Synthesizes the Potent Psychedelic Drug (1938)]
Drugs;hallucinogens
LSD-25[LSD twenty five]
Psychedelic drugs
[g]Switzerland;1938: Hofmann Synthesizes the Potent Psychedelic Drug LSD-25[09640]
[c]Science and technology;1938: Hofmann Synthesizes the Potent Psychedelic Drug LSD-25[09640]
[c]Chemistry;1938: Hofmann Synthesizes the Potent Psychedelic Drug LSD-25[09640]
Hofmann, Albert
Stoll, Arthur
Stoll, Werner

Mystical experiences are difficult to express and are often beyond words, thus a number of words have been fashioned to define and describe the psychic effects of such natural substances. Because these compounds often induce visual hallucinations (colors, patterns, objects, flights of imagination) perceived by the taker as either drug-induced fantasy or less often as reality, the term “hallucinogen” is commonly employed. Such compounds also have been called “psychotomimetic” drugs because people suffering from psychoses are often plagued by hallucinations and altered states of reality.

The term “psychedelic” (mind-expanding), coined by British psychiatrist Humphry Osmond, Osmond, Humphry was widely used in the 1960’s. Since then, the hallucinogenic drug lysergic acid diethylamide (LSD) stands alone as having achieved a notoriety matched only by its potency. On the basis of weight, LSD is ten thousand times more active than mescaline.

As told firsthand by the “father” of LSD, Albert Hofmann, in his 1980 book LSD, My Problem Child, the discovery of LSD began not as a quest for a drug with fantastic properties but as a disappointment to the chemist working in a research laboratory that was investigating derivatives of natural products for use as medicines. After completing his dissertation research at the University of Zurich, in which he determined the chemical constituents of chitin (the structural material of wings, shells, and claws of insects and crustaceans) in only three months, Hofmann joined the pharmaceutical research group at Sandoz Limited in Basel, Switzerland, in 1929. Hired by Arthur Stoll, director of the laboratory, Hofmann spent several years working with ergot alkaloids. These natural compounds are produced by a parasitic fungus of rye and were an area of interest to Stoll. In 1918, Stoll had isolated the pure active principle of ergot, ergotamine, and this natural product was used widely as a treatment for migraine and as a hemostatic remedy in obstetrics to stop uterine bleeding after childbirth. In the early 1930’s, several research groups, including Sandoz, published simultaneous reports that the principal active ingredient of ergotamine was a simple alkaloid, subsequently named ergobasine by Stoll. By chemical degradation, it was determined that ergobasine was composed of two chemical constituents: lysergic acid and the amino alcohol, propanolamine. With this knowledge and further research into the chemistry of these compounds, Hofmann began to synthesize many artificial ergot alkaloids, all derivatives of lysergic acid.

In 1938, Hofmann produced his twenty-fifth substance in a series of lysergic acid derivatives, lysergic acid diethylamide, abbreviated LSD-25 (based on the German name for the compound, Lysergsaure-diathylamid). This synthesis had been planned to produce a compound with properties similar to the drug Coramine, a circulatory and respiratory stimulant. Animal tests with LSD-25, however, aroused no special interest at Sandoz. Further testing was discontinued and LSD was forgotten.

Over the next five years, Hofmann developed several commercially successful drugs including Hydergine, an effective geriatric remedy that was Sandoz’s most successful pharmaceutical product. Despite his obvious successes, Hofmann decided to produce LSD-25 once again to provide samples to the pharmacology department for further testing, an unusual undertaking as the compound had been rejected already for further testing. On April 16, 1943, when Hofmann was performing the final purification step of the synthesis of LSD-25, he was affected by dizziness and a remarkable restlessness. He stopped working and went home, where, as he later reported to Stoll, he “sank into a not unpleasant intoxicatedlike condition, characterized by an . . . uninterrupted stream of fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of colors.”

Hofmann attributed this remarkable experience to working with LSD-25, but he was skeptical. He was a chemist who had worked with very toxic compounds for years and had meticulous work habits. He wondered if a drop of the chemical had touched his fingertips. If so, LSD-25 was a very potent psychogenic compound. With the full knowledge of Stoll and his assistants, Hofmann carefully planned a self-experiment with LSD-25. As recorded in his laboratory notebook, Hofmann took merely 0.25 milligram of the drug dissolved in water at 4:20 p.m. on April 19, 1943. At 5:00 p.m., he recorded that he felt dizzy, anxious, and had visual distortions and an urge to laugh. That was his last entry in the notebook. Hofmann became overwhelmed by the hallucinogenic experience and asked his assistant to escort him home by bicycle.

Hofmann later described the next two hours as a nightmare. He was convinced that he had poisoned himself and that he was going to die, but neither his assistant nor the doctor who was summoned to attend him observed anything out of the ordinary about him physically other than extremely dilated pupils. His respiration and heartbeat were normal, and the assistant said they had bicycled to his home at a good speed. With the constant assurances of his companions, by 8:00 p.m. Hofmann was no longer panic-stricken, although this LSD experience was much stronger than his previous experience a few days earlier. One hallucinogenic feature of the drug that astounded Hofmann was synesthesia, the overflow from one sensory modality to another in which colors are “heard” and sounds may be “seen.” The effects subsided gradually and he was able to sleep.

The next morning, feeling refreshed and without a hangover, Hofmann went to work and reported on the previous day’s experiences to Stoll and Ernst Rothlin, director of the pharmacology laboratory. Both expressed disbelief that the dose of a fraction of a milligram of LSD could have such effects; a psychoactive compound of such potency seemed unbelievable. Several days later, Rothlin and two colleagues repeated Hofmann’s LSD experiment but took only one-third the dose that Hofmann had ingested. The effects they experienced were remarkable, and all doubts about Hofmann’s statements were eliminated.

It was determined later that for his first self-experiment, Hofmann ingested five to eight times the optimal dose of LSD necessary to achieve the psychedelic state. LSD is such a potent substance that experimental doses in humans are calculated in micrograms (one microgram equals one-millionth of a gram) per kilogram body weight.

Laboratory animal studies proved to be of little value in examining the psychic effects of LSD because lower animals do not respond to the drug except at extremely high doses. Animal studies have demonstrated that LSD has an extremely low toxicity potential in comparison to its effective dose in humans. There are no recorded deaths attributed to the direct action (overdose) of LSD, although deaths have been recorded as accidents or as suicides accomplished under the influence of LSD. The danger of the drug lies not in its toxicity, but rather in the unpredictability of its psychic effects.

In 1947, Werner Stoll, a Zurich psychiatrist and the son of Arthur Stoll, was the first to publish reports of self-experiments with LSD and results of experimental studies involving both healthy normal volunteers and psychiatric patients. In 1953, Sandoz applied to the U.S. Food and Drug Administration to study LSD as an investigational new drug and supplied the drug to authorized investigators.

In the 1950’s, hundreds of scientific papers were written that examined the use of LSD as a model for psychosis, as a psychotherapeutic aid to help patients see themselves and their problems from a detached perspective, in the treatment of alcoholism, and as therapy for terminal cancer patients to help them deal with their own mortality.

A darker side of investigations with LSD evolved as well. The U.S. Army and the Central Intelligence Agency both conducted experiments with LSD as a chemical warfare agent and as a sort of “truth serum” for interrogating spies and prisoners of war. Many of the subjects were dosed secretly with LSD. It was later revealed that the Army sponsored LSD experimental research on more than fourteen hundred people between 1956 and 1967 that often blatantly violated ethical codes of conduct established for experiments with human subjects.

In the mid-1950’s, Aldous Huxley, Huxley, Aldous a philosopher and writer, published two books (The Doors of Perception, 1954; Heaven and Hell, 1956) describing his experiences with the peyote cactus hallucinogen, mescaline. Huxley’s concept of “chemical keys” as an alternative to meditation to alter one’s perception attracted the attention of two Harvard University professors, Timothy Leary Leary, Timothy and Richard Alpert. Alpert, Richard These researchers began studies with graduate students using the mushroom hallucinogen psilocybin but later used LSD as the drug of choice. Although the original work was conducted under proper scientific controls and with a physician present, by 1963, the studies apparently had become little more than off-campus LSD parties, with no semblance of scientific method applied. Leary and Alpert were dismissed from the university. Alpert moved to the West Coast and abandoned the drug, but Leary continued to advocate the use of LSD, encouraging people to “turn on, tune in, drop out.”

The LSD movement expanded rapidly to students, writers, and artists who were more interested in the possibilities of self-exploration of the psychedelic experience than in scientific experimentation. By 1967, the “psychedelic age” had arrived and evolved into a distinct subculture with its own language, music, and art forms. LSD came to be known as “acid,” and users were “acid heads.” An LSD experience was a “trip.” Words like “bummer” and “bad trip” were used to describe panic or psychotic reactions to LSD. Bright fluorescent colors appeared in the palettes of psychedelic artists. Many popular music groups of the day recorded songs with veiled references to drugs in their lyrics; the music of several San Francisco-based bands—including Jefferson Airplane and the Grateful Dead—became known as “acid rock.”

The use of LSD declined sharply at the end of the 1960’s because of widely publicized concern over “bad trips,” prolonged psychotic reactions, and personality changes in some people who took the drug. Other publicized adverse effects of LSD (chromosome damage and birth defects), although never validated, contributed to this decline. By 1970, U.S. law included LSD in the same regulatory category as the narcotic heroin, as a drug with no proven, effective use in medicine or scientific investigations. Drugs;hallucinogens
LSD-25[LSD twenty five]
Psychedelic drugs

• Bowman, William C., and Michael J. Rand. Textbook of Pharmacology. 2d ed. Oxford, England: Blackwell Scientific Publications, 1980. Chapter titled “Psychotropic Drugs” offers brief treatment of the history and pharmacology of major hallucinogens. Chapter titled “Social Pharmacology: Drug Use for Nonmedical Purposes” describes the spread of LSD from controlled clinical experiments to street use and discusses adverse psychiatric reactions and social consequences of LSD use; dismisses some of the dangers attributed to LSD.
• Hoffer, A., and Humphry Osmond. The Hallucinogens. New York: Academic Press, 1967. Indispensable resource for any serious student of hallucinogens. Extensive literature review covers the history, pharmacology, and psychiatric uses of LSD, how the drug works, and the psychedelic state of mind induced by the drug.
• Hofmann, Albert. LSD, My Problem Child. Translated by Jonathan Ott. New York: McGraw-Hill, 1980. Excellent firsthand account of the history of LSD. Describes Hofmann’s career as a chemist at Sandoz and conveys the excitement and joys of a scientist immersed in his work. Details his collaboration with Albert Stoll on ergot alkaloids, his self-experiments with LSD, and his later work with other hallucinogens. The last third of the book is devoted to Hofmann’s encounters with people such as Huxley and Leary.
• Jaffe, Jerome H. “Drug Addiction and Drug Abuse.” In Goodman and Gilman’s the Pharmacological Basis of Therapeutics, edited by A. S. Gilman, L. S. Goodman, I. W. Rall, and F. Murad. 7th ed. New York: Macmillan, 1985. Presents a good explanation and description of the altered states of consciousness and the hallucinations induced by LSD as well as standard pharmacology text discussions of the pharmacology and toxicity of LSD.
• Julien, Robert M. A Primer of Drug Action: A Concise, Nontechnical Guide to the Actions, Uses, and Side Effects of Psychoactive Drugs. Rev. ed. New York: Owl Books, 2001. Comprehensive coverage of psychoactive substances for general readers. Chapter 12 discusses psychedelic drugs, including LSD.
• Ray, Oakley, and Charles Ksir. Drugs, Society, and Human Behavior. 10th ed. New York: McGraw-Hill, 2004. Thorough treatment of hallucinogens includes an interesting discourse on the history, use, and politics of LSD during the 1960’s. Suitable for nonscientists.
• Stevens, Jay. Storming Heaven: LSD and the American Dream. New York: Perennial Library, 1987. Looks back at the 1960’s psychedelic movement as part comedy, part tragedy. Presents sketches of many of the advocates of LSD use, including Leary, poet Allen Ginsberg, and novelist Ken Kesey. Describes the CIA’s experiments with LSD and discusses the impact of the era on American life.

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