Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (53 page)

2. Considerations of physical causes of mental disorders were given support by the finding in 1907 by Alois Alzheimer in Munich of brain abnormalities—“senile plaques,” he called them—in some cases of premature dementia (Alzheimer's disease).

3. John Mann,
Murder, Magic, and Medicine
(Oxford: Oxford University Press, 1992), 186.

4. Alfred Pletscher, Parkhurst A. Shore, and Bernard B. Brodie, “Serotonin Release as a Possible Mechanism of Reserpine Action,”
Science
122 (1955): 374–75.

5. How this came to be found is replete with instances of unexpected findings. In 1945, Ernest Huant was administering nicotinamide to patients with tumors undergoing radiation therapy to lessen their postradiation nausea and vomiting. He was surprised to find clearing of densities in the chest films of some patients who also had pulmonary tuberculosis. E. Huant, “Note sur l'action de très fortes doses d'amide nicotinique dans les lésions bacillaires,”
Gaz Hôp
118 (1945): 259–60. The same year, Chorine reported that nicotinamide possessed tuberculostatic activity. V. Chorine, “Action de l'amide nicotinique sur les bacilles du genre
Mycobacterium,
”
Comp Ren Acad Sci
220 (1945): 150–51. In 1952, within a period of two weeks, two different pharmaceutical companies announced their independent discovery that isoniazid, a synthetic derivative, was a highly effective antitubercular drug. Yet again, remarkably, it was a serendipitous discovery in each case. Walter Sneader,
Drug Discovery: The Evolution of Modern Medicines
(New York: John Wiley, 1985), 293.

6. J. C. Saunders, D. Z. Rochlin, N. Radinger, et al., “Iproniazid in Depressed and Regressed Patients,” in
Psychopharmacology Frontiers,
ed. Nathan S. Kline (Boston: Little, Brown, 1959), 177–94.

7. H. P. Loomer, J. C. Saunders, and N. S. Kline, “A clinical and pharmacodynamic evaluation of iproniazid as a psychic energizer,”
Psychiatr Res Rep, Am Psychiatr Assoc
8 (1958): 129–41.

8. Nathan S. Kline, “Clinical experience with iproniazid (marsilid),”
J Clin Exp Psychopathol
19, no. 2, suppl. 1 (1958): 72–78.

9. Nathan S. Kline, “Monoamine Oxidase Inhibitors: An Unfinished Picaresque Tale,” in Ayd and Blackwell,
Discoveries in Biological Psychiatry,
194–204.

10. The British psychiatrist Barry Blackwell recalled the “chain of coincidence” that led him to the discovery of hypertensive crises provided by amines in cheese and other foodstuffs in patients prescribed MAO inhibitors; see “The Process of Discovery,” in Ayd and Blackwell,
Discoveries in Biological Psychiatry,
11–29. It is the equal of a Sherlock Holmes mystery. While a resident in psychiatry at the famous Maudsley Hospital, he published an initial letter in the
Lancet
in 1963 citing isolated case reports in the literature regarding the occasional association of hypertension in patients taking MAO inhibitors. The letter was read by a hospital pharmacist in Nottingham who noted that his wife had twice experienced identical symptoms after eating cheese and inquired regarding the possible link with the cheese's amino acids. Blackwell was amused by the suggestion and wrote a brief reply dismissing the notion. When he heard that the pharmaceutical company had received a few similar reports, including one death that occurred during treatment with an MAO inhibitor and an amino acid, he reviewed the dietary record of a previous incident at Maudsley, which revealed that the patient had eaten a cheese pie that evening. Soon another patient developed headache and a hypertensive crisis, and inquiry showed that she had eaten cheese sandwiches for supper. Blackwell tried to provoke the reaction in himself without success. However, the reaction was positive in a carefully monitored patient volunteer. “Coincidence continued to play a part.” Two patients in a ward in the hospital simultaneously complained of headache. Both had recently returned from the hospital cafeteria, where cheese had just made its weekly appearance on the menu. It was at this point that certainty “dawned.” The pharmacology of the reaction is now understood. The amine responsible is tyramine. An average portion of natural or particularly aged cheeses contains enough tyramine to provoke a marked rise in blood pressure and other cardiovascular changes. As a result of monoamine oxidase, tyramine brings this about by releasing catecholamines in nerve endings and the adrenal medulla. Another source of tyramine is yeast products used as food supplements.

11. Roland Kuhn, “The Imipramine Story,” in Ayd and Blackwell,
Discoveries in Biological Psychiatry,
205–17.

12. “The Culture of Prozac,”
Newsweek,
February 7, 1994, 41.

13. E. J. Nestler, “Antidepressant treatments in the 21st century,”
Biol Psychiatry
44 (1998): 526–33.

C
HAPTER
37: Librium and Valium

1. Leo H. Sternbach, “The benzodiazepine story,”
Drug Res
22 (1978): 230.

2. E. Kyburz, “Serendipity in drug discovery: The case of BZR ligands,”
Il Farmaco
44, no. 4 (1989): 345–82.

3. When World War II broke out, Sternbach was working as a research fellow at the Swiss Federal Institute of Technology in Zurich and could not return to Poland. He moved to Basel as a research chemist for Hoffman–La Roche, which, fearing a German invasion and wanting to get its Jewish scientists to safety, sent him to its subsidiary in New Jersey in the early 1940s. He became an American citizen in 1946.

4. Sternbach, “The benzodiazepine story,” 235.

5. Ibid., 236.

6. H. J. Parry, M. B. Balter, G. D. Mellinger, I. H. Cisin, and D. I. Manheimer, “National patterns of psychotherapeutic drug use,”
Arch Gen Psychiatry
28, no. 6 (1973): 18–74.

7. Sternbach sold the patents to Librium and Valium (and some 230 others) for one dollar each to Hoffman–La Roche. When asked if he thought the company should be paying him royalties on the drugs’ staggering sales, he replied, “I don't think that I was not treated appropriately. Yet, sometimes I find myself wondering why I didn't ask for more. I suppose I didn't have the chutzpah. Besides, what would I do with the money?” L. Kent, “Leo Sternbach: The tranquil chemist,”
Sciquest
53 (1980): 22–24.

8. Valium and similar products amplify the effects of the brain neurotransmitter gamma-aminobutyric acid (GABA). GABA is present in neurons that exert an inhibitory effect on other neurons in the central nervous system, and is active at up to 40 percent of brain synapses.

9. With the widespread use of these drugs, circumstances are commonly encountered in which an “antidote” would be helpful to reverse or reduce the drug's effects. These include cases of accidental or intentional overdosage and to shorten their effects when used in anesthesia. In another example of a “truly serendipitous discovery,” the continued search for new improved anxiety-relieving drugs by researchers at Hoffman–La Roche in Basel led to a specific benzodiazepine antagonist. Their candid description of stumbles in the late 1970s and early 1980s leading to an epiphany is a dramatic episode. “In contrast to our expectations” and “to our great surprise,” they had stumbled upon the antagonist flumazenil, marketed as Romazicon in the United States and as Anexate in Europe.

C
HAPTER
38: “That's Funny, I Have the Same Bug!”

1. Lawrence K. Altman,
Who Goes First? The Story of Self-Experimentation in Medicine
(New York: Random House, 1987), 100.

2. Ibid., 99.

3. D. I. Eneanya, J. R. Bianchine, D. O. Duran, and B. D. Andresen, “The actions and metabolic fate of disulfiram,”
Annu Rev Pharmacol Toxicol
21 (1981): 575–96.

4. J. Hald, E. Jacobsen, and V. Larsen, “The sensitizing effect of tetraethylthiuramdisulphide (Antabuse) to ethyl alcohol,”
Acta Pharmacologica et Toxicologica
(Copenhagen) 4 (1948): 285–96.

5. Historically, hypersensitivity to alcohol brought about by other substances had been noted. The first was observed in 1914 from industrial exposure to cyanamide. The French cited
mal rouge
among the workers, referring to the intense facial blushing after consuming alcohol. This was accompanied by headache, accelerated and deepened respiration, accelerated pulse, and a feeling of giddiness. These attacks lasted from half an hour to two hours and were followed by sleepiness. Similar sensitization to alcohol is produced by eating the fungus
Coprinus atramentarius.

6. E. E. Williams, “Effects of alcohol on workers with carbon disulfide,”
JAMA
109 (1937): 1472–73.

C
HAPTER
39: LSD

1. Albert Hofmann, “The Discovery of LSD and Subsequent Investigation on Naturally Occurring Hallucinogens,” in Ayd and Blackwell,
Discoveries in Biological Psychiatry.

2. Quoted in Altman,
Who Goes First?
73.

3. W. A. Stoll, “Lysergsäure-diäthyl-amid, ein Phantastikum aus der Mutterkorngruppe,”
Schweiz Arch Neurol Psychiat
60 (1947): 297–323.

4. Mescaline was isolated as the active ingredient from the peyote cactus in 1897 by the German chemist Arthur Heffter. This small spineless cactus grows in the desert regions of Texas and Mexico, and is used for its psychoactive properties by a number of Native American peoples.

5. In a series of experiments at UCLA, cats and monkeys with electrodes implanted in their brains could press a lever and stimulate their pleasure centers with little electrical discharges. A state of ecstasy must have been reached because some pressed the lever eight thousand times an hour, finally collapsing from exhaustion and lack of food. Observing this, Aldous Huxley wrote to a friend, “We are obviously very close to reproducing the Moslem paradise where every orgasm lasts six hundred years.” Aldous Huxley,
Moksha
(Los Angeles: Tarcher, 1982). On the other hand, with the early discoveries of cerebral chemical neurotransmitters in the mid-1940s, new searching questions were raised: Could psycho-pathologies be due to depletion or overabundance of such chemicals?

6. From an unpublished lecture by Hofmann quoted in Christian Rätsch,
The Dictionary of Sacred and Magical Plants,
trans. John Baker (Bridgeport: Prism Press, 1992).

7. Sidney Cohen,
The Beyond Within: The LSD Story
(New York: Atheneum, 1965).

8. John Marks,
The Search for the “Manchurian Candidate”: The CIA and Mind Control
(New York: Times Books, 1978).

9. Quoted in “Sidney Gottlieb, 80, Dies; Took LSD to CIA,”
New York Times,
March 10, 1999.

10. Albert Hofmann,
LSD, My Problem Child,
trans. Jonathan Ott (New York: McGraw-Hill, 1980).

11. Jay Stevens,
Storming Heaven: LSD and the American Dream
(New York: Atlantic Monthly Press, 1987).

12. George Barger,
Ergot and Ergotism
(London: Gurney and Jackson, 1931).

13. This scenario has been imaginatively illustrated in one of Hieronymus Bosch's bizarre paintings,
St. Anthony Triptych,
from the early sixteenth century. Art historian Laurinda S. Dixon has recently interpreted many of the images; see “Bosch's ‘St. Anthony Triptych’—An Apothecary's Apotheosis,”
Art Journal
44(2) (1984): 119–31. Many of the scenes depicted are as viewed through hallucinating eyes. Yet the image of an amputated and mummified human foot is evident. A strange figure—half human, half vegetable—is painted in the shape of a mandrake root. The mandrake root, with its forked shape resembling two human legs, was carried as a talisman against the “holy fire.” A giant red fruit in the painting is the mandrake berry, the juice of which contains a belladonna-like substance, an alkaloid that has a narcotic effect similar to that of opium. It was effective as an anesthetic and used as an aid in the brutal amputations performed in the Antonine
hôpitals des démembrés.
A building is in the shape of an apothecary's retort, the distillery used to reduce medicinal herbs.

14. Mary Kilbourne Matossian,
Poisons of the Past: Molds, Epidemics, and History
(New Haven: Yale University Press, 1989).

15. P. L. Delgado and P. A. Moreno, “Hallucinogens, serotonin, and obsessive-compulsive disorder,”
J Psychoactive Drugs
30 (1998): 359–66.

16. T. J. Reedlinger and J. E. Reedlinger, “Psychedelic and entactogenic drugs in the treatment of depression,”
J Psychoactive Drugs
26 (1994): 41–55.