‘Apparently Useless’: The Accidental Discovery of LSD

Acid Test author Tom Shroder writes for The Atlantic about psychedelic chemist Albert Hofmann’s discovery of LSD. The article details the experiments leading up to Hofmann’s first synthesis of LSD, recounts the first-ever human experiences with LSD, and shares how Hofmann’s LSD experiences helped influence his perspective about the potential of psychedelics.

Originally appearing here.

All that 32-year-old Albert Hoffman wanted to do in 1938 was synthesize a chemical compound that would stimulate the respiratory and circulatory systems. He had gone to work for Sandoz, a Swiss chemical company, in 1929, after graduation from the University of Zurich. Sandoz, founded in 1886, had started out manufacturing dyes and, later, saccharin. There wasn’t even a formal pharmaceutical department until 1917, when professor Arthur Stoll isolated an active substance called ergotamine from ergot, a fungus found in tainted rye that had been used as a folk medicine for generations.

In its natural form and in quantity, ergot was a deadly poison and a scourge responsible for the deaths of hundreds of thousands of people over many centuries. In 857 in what is now Germany, a contemporary accounting of the events of the year recorded that “a great plague of swollen blisters consumed the people by a loathsome rot, so that their limbs were loosened and fell off before death.”

Historians now attribute this and similar events throughout early history to long-term exposure to infected grains, a condition known as St. Anthony’s fire, after the French monastic order that devoted itself to caring for the plague’s victims. Ergot was not suspected as the cause until the late 17th century. Eventually, ergotism’s toxic effects were classified into two categories: gangrenous ergotism and convulsive ergotism. The description of the symptoms on a University of Hawaii botany website is enough to permanently put a person off rye bread:

"Convulsive ergotism is characterized by nervous dysfunction, where the victim is twisting and contorting their body in pain, trembling and shaking, and wryneck, more or less fixed twisting of the neck, which seems to simulate convulsions or fits. In some cases, this is accompanied by muscle spasms, confusions, delusions and hallucinations …"

Some believe that the advent of these gruesome symptoms without a known cause, especially the convulsive symptoms—which, along with hallucinations, sometimes included mania and psychosis—led to accusations of witchcraft, followed by witch-hunting hysterias such as the famous Salem witch trials in 1692 and 1693. Studies have even correlated years of rye scarcity—suggesting an increased willingness to consume tainted rye—with years of abundant witchcraft accusations.

But in small doses, the muscle- and blood vessel-constricting properties of ergot could be useful to hasten childbirth and staunch bleeding after delivery, capabilities that had somehow been divined by alchemists and midwives and made use of for generations.

Arthur Stoll’s accomplishment was to isolate the compounds in ergot that caused the constrictions: ergatomine and ergobasine. In its refined form, the compound could be precisely dosed to avoid a host of side effects from other unhelpful compounds in ergot—properties that made Sandoz a lot of money and launched the pharmaceutical research and development department that hired Hofmann to teach 12 years later.

Within a few years researchers had determined the chemical structure of the various biologically active compounds in ergot, all of which shared a common nucleus. This chemical starting point was called lysergic acid, or, in German, Lysergsaure.

Hofmann developed a synthetic process to build the ergot compounds from their component chemicals. Using this method, he recreated ergot’s active ingredients as well as novel but similar compounds that, based on the potency of the ergot compounds, could reasonably be expected to have medical uses.

In a sense Hofmann was playing God, combining lysergic acid with various other organic molecules just to see what happened. He created 24 of these lysergic acid combinations. Then he created the 25th, reacting lysergic acid with diethylamine, a derivative of ammonia. The compound was abbreviated as LSD-25 for the purposes of laboratory testing.

He had hoped for something that could stimulate circulation and respiration. But his hopes were dashed, though the research report noted in passing that the experimental animals became highly excited during testing. “The new substance, however, aroused no special interest in our pharmacologists and physicians; testing was therefore discontinued.”

Hofmann went on with his ergot research. But for some reason, even as the years passed, he couldn’t stop thinking about the apparently useless LSD-25. Maybe it was the memory of all those oddly excited animals in the test pens. Hofmann never said, beyond calling it “a peculiar presentiment—the feeling that this substance could possess properties other than those established in the first investigations.”

So, five years after lysergic acid diethylamide was tossed on the ash heap of pharmaceutical history, based on nothing but his odd presentiment, Hofmann decided to synthesize it again. He would later tell intimates, “I did not choose LSD; LSD found and called me.”

It was a Friday in the middle of a world war, April 16, 1943. Hofmann was in the final stage of synthesis of just a few centigrams of the material, the part where the LSD crystallized into a salt, when he suddenly felt very strange to the point that he had to leave work and go home. When he returned to the lab the following Monday, he wrote a memo to his boss, Stoll, explaining what had happened:

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 dream-like state, with eyes closed (I found the daylight to be unpleasantly glaring), I perceived an uninterrupted steam of fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of colors.
When he recovered, Hofmann set about trying to figure out what had so strongly affected him. In a 2006 New York Times interview, Hofmann said that he first suspected the fumes of a chloroform-like solvent he had been using. Now he intentionally breathed in its fumes, to no effect. It was only then that he was forced to the conclusion that he must have somehow ingested a trace of LSD, an idea he discounted at first because he had been very careful to avoid contamination, knowing the potential toxicity of any ergot-related compounds. The only point of access would have been through the skin of his fingertips, and the amount involved would have been so tiny that he could not imagine it could produce such a significant reaction.

Now that his intuition about LSD was showing tantalizing signs of proving justified, Hofmann decided there was only one course of action: self-experimentation.

At 4:20 in the afternoon of April 19, without informing anyone at Sandoz except his lab assistant, Hofmann dissolved 250 millionths of a gram of lysergic acid diethylamide tartrate—the crystallized salt form of the compound—and drank it. He expected it to do absolutely nothing.

Hofmann was dealing with the LSD as if it might be deadly poison. That’s why he had begun his tests with such an infinitesimal dose, a thousand times less than the active dose of any other physically active compound he knew of. He
had planned to increase the dosage by tiny increments until he got the first inkling of a reaction, expecting it to take many dose increases before that happened.

But just 40 minutes after that initial dose, he wrote the one and only entry in his lab journal:

17:00: Beginning dizziness, feeling of anxiety, visual distortions, symptoms of paralysis, desire to laugh.
“I was able to write the last words only with great effort,” he wrote in his memoir, LSD: My Problem Child. “I had to struggle to speak intelligibly.”

Hofmann asked his lab assistant to escort him home, which wasn’t as easy as it might have been. Because of wartime restriction on automobile use, both men were on bicycles. On what must have been an extraordinarily adventurous bike ride, Hofmann felt his condition take a threatening turn.

“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.”

The powerful effects were as frightening as they had been unexpected. Hofmann had no idea how the experience might play out in the next few hours, and beyond. For all he knew, the drug might permanently damage his psyche. Perhaps it might even physically injure or kill him. These fears were what prompted him to request the milk, a nonspecific palliative for a range of toxic substances. The hubris of what he had done in testing this potent drug on himself filled him with anxiety and regret. He would only realize later how important that fearful mind-set would be in shaping the nature of his experience, which he described compellingly in his book:

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 … 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 relentlessness. 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 … 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 a wasted effort. A demon had invaded me, had taken possession of my body, mind, and soul … 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?
Hofmann wasn’t dying. In fact, when the doctor arrived, he detected nothing more alarming that dilated pupils. Blood pressure, respiration, pulse were all completely normal. The doctor left his bag shut: No medications were required. He simply put Hofmann to bed and waited by his side. Hofmann began to come to himself.

His account continued:

"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 …
By the time his wife arrived home, Hofmann was able to speak coherently about what happened to him. The next morning he wrote:

"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."

It was clear that a remarkable discovery had been made. First the drug had to be tested extensively on animals to determine any acutely toxic effects that Hofmann had merely been lucky to survive. Animal tests would eventually provide some curious results. Mice given LSD moved erratically and showed “alterations in licking behavior.” Cats’ hair stood on end and they salivated—indications they were having hallucinations that were threatening or enticing. When researchers introduced mice into the cats’ cages, instead of attacking, the felines would ignore the rodents’ intrusion or sometimes even appear frightened by them. Dosed chimpanzees did not show any obvious signs of being affected, but the normal chimps around them tended to become extremely upset, which Hofmann attributed to the test animals’ failure to maintain social norms perceptible only to the chimps.

Aquarium fish swam oddly, and spiders altered web-building patterns. At low doses, Hofmann noted, “the webs were even better proportioned and more exactly built than normally. However, with higher doses, the webs were badly and rudimentarily made.”

The salient fact was this: None of the animals in the tests seemed to suffer acute harm at the active dose, and the lethal dose was a hundred times higher than what was necessary for psychic effect, leaving a wide safety margin.

Now that he was reassured that LSD wouldn’t kill him or destroy his brain, Hofmann’s curiosity about his own experience only intensified. He decided to continue his LSD research informally, “in the friendly and private company of two good friends of mine.”

“I did this,” he later wrote, “in order to investigate the influence of the surroundings, of the outer and inner conditions on the LSD experience. These experiments showed me the enormous impact of—to use modern terms—set and setting on the content and character of the experience.”

“In some of my psychedelic experiences I had a feeling of ecstatic love and unity with all creatures in the universe,” he later said in a High Times interview. “To have had such an experience of absolute beatitude means an enrichment of our life.”

But he also learned something else: Controlling for set and setting had its limits. “In spite of a good mood at the beginning of a session—positive expectations, beautiful surroundings, and sympathetic company—I once fell into a terrible depression. The unpredictability of effects is the major danger of LSD.”