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PRIDE AND PREJUDICE: THE STORY OF ERGOT fi W. BENNETT* and RONALD BENTLEYf For thousands of years, healers and physicians relied on plant extracts for curative purposes, unwittingly utilizing the pharmacological properties of the chemical constituents they contained. Belladonna (atropine), digitalis , opium, quinine, and salicylic acid have been used in crude form since antiquity, and their Janus-faced qualities provided the first lessons in the vagaries of drug action. Opium relieved pain but also caused stupor, addiction , and death. Overdoses of digitalis could be lethal. Not surprisingly, supernatural causes were regularly invoked to explain the potent and unpredictable effects of botanical medicináis. Purified natural products (in contrast to crude extracts) have been available for barely a century and a half. Moreover, it is only in the last 50 years, spurred on by the development of penicillin, that scientists have systematically screened microorganisms for metabolites with therapeutic applications . During the Golden Age of antibiotics (approximately 1945 to 1960), pharmaceutical companies searched for antibacterial and antifungal agents based on their ability to inhibit growth of target pathogens in Petri plate assays. Starting in the 1960s, screens were expanded to look for new classes ofdrugs: immunomodulators, psychoactive agents, enzyme inhibitors, anticancer agents, and so forth. These non-antibiotic compounds have been variously labeled as "natural medicinal products" or "biopharmaceutins" [1,2]. This article discusses a historically fascinating group of natural products from fungi—the ergot alkaloids. Arguably the oldest of the microbial biopharmaceutins , they may have played a role in both the Mysteries ofEleusis and the Salem Witch trials. Used by midwives for centuries, they were Correspondence: Department of Cell and Molecular Biology, Tulane University, New Orleans , LA 70118. The authors are grateful to Suzanne Gardon for a translation from French. They also thank Linda Lasure for locating some of the references,JeffKarr for alerting them to the Eleusinian mysteries, andJeff Karr and Paul Bayman for commenting on the manuscript. ?Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118. !Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260.© 1999 by The University of Chicago. All rights reserved. 00Sl-5982/99/4203-1006$01.00 Perspectives in Biology and Medicine, 42, 3 ¦ Spring 1999 333 among the first effective obstetric drugs. Best known for their toxic and psychoactive effects, they also figured prominently in tales of medieval pestilence . Ergot poisoning following the ingestion ofcontaminated grains was characterized by burning sensations caused by the contraction of blood vessels. The pain was likened to a "fire," and the fire was described as divine, sacred, or occult. Sufferers prayed to the Virgin Mary or St. Anthony for intercession. Sometimes ergot poisoning was accompanied by hallucinations and bizarre behavior, symptoms that could be interpreted as bewitchment or possession by the devil. The physiological effects of ergot reflected not only the concentrations and combinations of the ingested ergot metabolites, but also the age and nutritional status of the individual who consumed them. Just as importan üy, the sociological interpretation of the ergot response reflected the cultural milieu in which it was encountered. Sufferers were pitied or persecuted , depending on whether they were perceived as the targets or the perpetrators ofwitchcraft. Eventually an array of pharmacologically potent ergot alkaloids was purified from a single fungal structure, the Sclerotium. Only within the last few decades has it been possible to take pride in the limited and careful use of ergot products in medicine (e.g., for the treatment of migraine and to assuage postpartum hemorrhage) . Research on medicinal alkaloids led to the serendipitous discovery of lysergic acid diethylamide (LSD) , which was followed by a brief era of legitimate research on hallucinogens. Ergot and Ergotism As civilizations developed and records were kept, many catastrophic diseases were described with enough detail to permit retrospective diagnosis. In the Middle Ages, the Black Death (bubonic plague) was among the most famous. Winston Churchill provides a vivid description: "The character of the pestilence was appalling. The disease itself, with its frightful symptoms, the swift onset, the blotches, the hardening of the glands under the armpit or in the groin, these swellings which no poultice could resolve, these tumours which, when lanced, gave no relief, the horde ofvirulent carbuncles which followed the...