Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (40 page)

Some days passed, then the nausea and headache struck again while he was sipping a beer and eating a sandwich at lunch. He left work early and bicycled home, wondering if his family were similarly affected, but they were fine.

Even though the attacks continued at work for several more days, sometimes with heart palpitations, he did not alter his habit of having beer with his lunch. Soon thereafter, he met with a colleague, Jens Hald, with whom he was investigating the effects of a drug on intestinal worms. “We were just chatting,” Jacobsen recalled, “and I mentioned this curious affair that I had been through. Hald smiled and said, ‘That's funny. I have had the same bug!’”
¹

At this very point, Jacobsen and Hald had a flash of insight and immediately recognized the cause of their symptoms. While they had
been continuing other investigations in the laboratory, they had each been testing a chemical, disulfiram (tetraethylthiuramdisulphide), upon themselves. Used for a long time in the rubber industry as an antioxidant, it had recently been employed as an ointment by Swedish researchers in patients with scabies, a parasitic disease of the skin endemic at that period of privation throughout occupied Europe. The disease causes maddening itching that leads to incessant scratching and infections. Hald had come up with the idea based on what was known of the drug's action that it might be used to interfere with the metabolism of intestinal parasites.

Jacobsen and Hald prepared pills of disulfiram as a potential oral drug and were encouraged by preliminary tests in rabbits infected with intestinal worms. Next, they had to see if the pills would be safe for humans. Jacobsen had earlier undergone several self-experiments at Medicinalco with other research studies. “It never occurred to us to ask others to volunteer first. We would have regarded that as unethical.”
²
They both began taking disulfiram daily.

At first there were no apparent ill effects. They had attributed their episodic symptoms of flushing, pulsating headache, palpitations, and nausea to the flu, but when they each learned that the other was experiencing the same symptoms, their trained scientific minds led them to understand that these circumstances were not coincidences. They then began to focus their attention on the drug they were both taking. Realizing that the drug had altered their response to alcohol, they began a series of studies, including some in which Jacobsen volunteered for further self-experiments. As it turned out, disulfiram by itself is innocuous, but combined with alcohol it breaks down to form a highly toxic product. At one point, Jacobsen's blood pressure fell to almost zero and he came close to death.

Studies on alcoholic patients were then undertaken by a psychiatrist specializing in aversion therapy. In other words, patients would take small doses of disulfiram specifically to make themselves feel sick if they consumed alcohol, in the hope that their behavior would be conditioned to avoid alcohol. These studies provided the basis for the use of disulfiram in the treatment of chronic alcoholism.

Disulfiram acts by altering the intermediary metabolism of alcohol,
causing a concentration of acetaldehyde in the body.
³
Ordinarily, this does not accumulate in the tissues, but disulfiram interferes with its breakdown so that the blood acetaldehyde concentration rises to a toxicity level five to ten times higher than normal. Dramatic signs and symptoms accompany this effect, known as the Acetaldehyde Syndrome.

The first paper Jacobsen and Hald published, in 1948, established both Jacobsen's trade name for the drug, Antabuse, and its new usefulness.
⁴

An interesting harbinger of the observations of Jacobsen and Hald had occurred a decade before.
⁵
In 1937 a physician to a chemical company in Connecticut noted that the workers, exposed to a chemical similar to disulfiram, had “become involuntary total abstainers” of alcohol. He even speculated in his report in the
Journal of the American Medical Association
“whether one has discovered the cure for alcoholism.”
⁶
But no one took steps to investigate this further.

Jacobsen and Hald's experience leading to Antabuse is a clear example of a discovery that could have occurred only through the channel of serendipity. Researchers conducting animal experiments with the chemical never would have imagined to test with alcohol.

Antabuse has a highly specific usefulness in chronic alcoholism. It is probably most useful in well-motivated patients whose drinking is triggered largely by recurrent psychological stress and who want to remain in a state of enforced sobriety so that supportive and psychotherapeutic treatment may be applied to best advantage. Importantly, the patient is warned to avoid alcohol in disguised form—in sauces, vinegars, cough mixtures, and even preparations containing alcohol that can be absorbed through the skin, like aftershave lotions and massage oils.

39

LSD

The accidental discovery in 1943 of the hallucinogenic effects of LSD is one of the most dramatic episodes in the modern history of drug development.

Albert Hofmann, a thirty-seven-year-old research chemist at the Sandoz pharmaceutical company in Basel, Switzerland, was investigating ergot alkaloids derived from the fungus
Claviceps purpurea.
Alkaloids are nitrogenous organic compounds found in plants. This was an area of research in which Sandoz had long pioneered under the direction of the distinguished Swiss chemist Arthur Stoll. At Sandoz, Stoll had earlier isolated ergotamine, a widely used product to control bleeding after childbirth, but it took him another thirty-three years before he was able to establish its full complex chemical structure. The characteristic nucleus of the ergot alkaloids is lysergic acid.

Lysergic acid itself is not hallucinogenic. Hofmann's original purpose was to synthesize the basic components of ergot in hopes of developing new compounds that might be useful in other fields of medicine. In 1938 Hofmann had synthesized lysergic acid diethylamide with the chief aim of obtaining a stimulus to the circulatory and respiratory systems.

Lysergic acid diethylamide (in German,
Lysergische-Säure Diäthylamid,
or LSD) was given the laboratory code name LSD-25 because it was the twenty-fifth in a series of ergot derivatives of lysergic acid that he and his colleagues synthesized. Not unexpectedly, it had
the effect of inducing uterine contractions. What was not anticipated was the excitation that was observed in some of the animals, but that was of no interest to Hofmann. He put aside the investigation and did not pick it up again until April 1943, when “a peculiar presentiment” overcame him that perhaps he had missed something five years earlier. He synthesized a new batch of LSD-25 one morning and by noon had a crystalline sample that was easily soluble in water.

Hofmann described his now-famous “accidental observation” in his laboratory notes:

Last Friday, April 16, 1943, I was forced to stop my work in the laboratory in the middle of the afternoon and to go home, as I was seized by a peculiar restlessness associated with a sensation of mild dizziness…. As I lay in a dazed condition… there surged upon me an uninterrupted stream of fantastic images of extraordinary plasticity and vividness and accompanied by an intense, kaleidoscope-like play of colors. This condition gradually passed off after about two hours.

What Hofmann had experienced was the first acid trip.

This bizarre reaction baffled him. Over the weekend, he reviewed his preparation of LSD step by step. How could he have been exposed to the effects of this new compound? The possibility of his having unconsciously licked his fingers after some of the LSD-25 accidentally spilled on them seemed most unlikely. Was it possible that he had absorbed a minute amount of LSD solution through his skin? He had trained himself to be careful and meticulous in the laboratory, knowing full well that even small amounts of ergot preparations can be dangerous. Could he have inhaled and then absorbed some of the LSD-25?

As a scientist, Hofmann was compelled to pursue this serendipitous happening. Did this compound have mind-altering effects of greater potency than any previously seen? “In order to get to the root of this matter, I decided to conduct some experiments on myself.” The following Monday, the nineteenth, using other ergot alkaloids as a
guide, Hofmann took 0.25mg of LSD orally, believing that to be the lowest dose that might be expected to have any effect. In fact, this is five to ten times the average effective dose of LSD! The reaction he had to such a large dose was quite spectacular. After forty minutes, he noted a “slight dizziness, unrest, difficulty in concentration, visual disturbances, and a marked desire to laugh.” At this point, the entries in the laboratory notebook end, and the last words were written only with the greatest difficulty. He was used to bicycling the four miles home from his lab, and on this day he asked his laboratory assistant to accompany him. He continued his accounts later:

While we were cycling home, it became clear that the symptoms were much stronger than the first time. I had great difficulty in speaking coherently, my field of vision swayed before me, and objects appeared distorted like images in curved mirrors. I had the impression of being unable to move from the spot, although my assistant told me afterwards that we had cycled at a good pace….

By the time the doctor arrived, the peak of the crisis had already passed. As far as I remember, the following were the most outstanding symptoms: vertigo, visual disturbances; the faces of those around me appeared as grotesque, colored masks; marked motoric unrest, alternating with paralysis; an intermittent heavy feeling in the head, limbs and the entire body, as if they were filled with lead; dry, constricted sensation in the throat; feeling of choking; clear recognition of my condition, in which state I sometimes observed, in the manner of an independent, neutral observer, that I shouted half insanely or babbled incoherent words. Occasionally I felt as if I were out of my body….

Six hours after ingestion of the LSD my condition had already improved considerably. Only the visual disturbances were still pronounced… all objects appeared in unpleasant, constantly changing colors… fantastic images surged in upon me. A remarkable feature was the manner in which all acoustic perceptions (e.g., the noise of a passing car) were transformed into optical effects, every sound evoking a corresponding colored hallucination constantly changing in shape and color like pictures in a kaleidoscope. At about one o'clock I fell asleep and awoke next morning feeling perfectly well.
¹

Hofmann had been propelled into visual hallucinations, out-of-body experiences, cognitive distortions of time and space, a synesthetic swoon, and elements of paranoia. For a while, he feared he was losing his mind, that the drug had precipitated a psychosis, and this anxiety made his experience quite negative. Remarkably, despite his response to the potent properties of LSD mimicking a psychosis, he could later recall the experience in sharp detail.

Hofmann reported his self-experiment to Dr. Ernst Rothlin, Sandoz's chief pharmacologist, who initially doubted that such a tiny amount of any substance could so affect the mind. Rothlin agreed to try it on himself and two other colleagues, prudently taking only one-quarter of the dose that Hofmann had taken. All had hallucinations and, as Hofmann later ruefully recalled, “Rothlin believed it then.”
²

Dr. Werner Stoll, the son of Arthur Stoll, the Sandoz scientist who had pioneered the investigations on ergot chemistry, also tested on himself one-quarter of the dose that Hofmann had taken. Then in 1947 he reported the results of a systematic investigation of LSD in sixteen normal volunteers and six schizophrenic patients at the Psychiatric Clinic of the University of Zurich, in which Hofmann's original findings were essentially confirmed.
³
LSD could cause profound changes in human perception, reminiscent of those experienced by schizophrenics. Stoll also discovered that in low doses LSD seemed to facilitate the psychotherapeutic process by the release of repressed material into consciousness.

LSD turned out to be about 5,000 to 10,000 times more potent than an equivalent dose of mescaline, the substance it most closely resembled. Mescaline was first synthesized in 1919 and allowed the initiation in the 1920s of psychopharmacological studies of its hallucinogenic effects, but interest in such research lapsed until the discovery of LSD.
⁴

Hofmann's discovery of the high potency of LSD led to the popularization of the concept that a toxic substance or product of metabolism might be a cause of mental illness. Shortly after Werner Stoll's 1947 article, Sandoz made LSD available to select researchers under the trade name Delysid. Its arrival in the United States in 1949 enjoyed particularly propitious timing for a new mind drug. It coincided with the ascent of the neurosciences, an exciting period in which the various brain centers were first mapped and the brain's neurotransmitters, its chemical messengers, discovered.
⁵

It had long been accepted that the course of some mental disorders could be modified by certain drugs, such as barbiturates. Thorazine, the first major tranquilizer, appeared in 1954, the sedative Miltown a year later, and then Librium, Valium, Elavil, Tofranil, transforming psychiatry and Western culture itself. Now the pharmaceutical companies—aware of the accumulating evidence and sensitive to the market potential—actively supported the search for new mind drugs. The course of LSD over the next years followed dramatically disparate elements: scientific research on its psychiatric legitimacy, the flowering of the hippie subculture, and clandestine mind control by governmental agencies.