TEACHERS' TOPICS Ergot and Its Alkaloids

American Journal of Pharmaceutical Education 2006; 70 (5) Article 98. TEACHERS’ TOPICS Ergot and Its Alkaloids Paul L. Schiff, Jr., PhD School of Pharmacy, University of Pittsburgh Submitted January 10, 2006; accepted April 4, 2006; published October 15, 2006. This manuscript reviews the history and pharmacognosy of ergot, and describes the isolation/preparation, chemistry, pharmacodynamics, and pharmacotherapeutics of the major ergot alkaloids and their derivatives. A brief discussion of the hallucinogenic properties of lysergic acid diethylamide is also featured. An abbreviated form of the material found in this paper is presented in a 4-hour didactic format to third-professional year PharmD students as part of their study of vascular migraine head- aches, Parkinson’s disease, and naturally occurring hallucinogens/hallucinogen derivatives in the modular course offering Neurology/Psychiatry. Keywords: ergot, ergotism, ergot alkaloids, ergot alkaloid derivatives HISTORY OF ERGOT substance was used in obstetrics. A magic spell found in Students at the University of Pittsburgh receive an a small temple in Mesopotamia dating to 1900-1700 BC introduction to pharmacognosy and natural products dur- referred to abnormally infested grain as mehru, while ing their first-professional year in an introductory course Sumerian clay tablets of the same period described the in Drug Development. The role of natural products as both reddening of damp grain as samona. The Assyrians of this historical and continuing sources of drugs, as well as era were sufficiently knowledgeable to differentiate be- sources of precursors for semisynthetic modification tween different diseases affecting grain and by 600 BC and sources of probes for yet undiscovered drug moieties, writings on an Assyrian tablet alluded to a ‘‘noxious pus- is emphasized. In addition, students are continually ex- tule in the ear of grain.’’ References to grain diseases have posed to the concept that complex natural products are also been found in various books of the Bible in the Old a result of secondary metabolism, and as such are pro- Testament (850-550 BC). In 550 BC the Hearst Papyrus duced via the unique combination of a relatively limited of Egypt described a particular preparation in which number of structurally unsophisticated primary metabo- a mixture of ergot, oil, and honey was recommended as lites. As a consequence, secondary metabolites have a treatment for hair growth. In 370 BC Hippocrates fur- a more limited distribution in nature, and their occurrence nished a description of corn blight and subsequently de- is an expression of the individuality of the parent species. scribed ergot as melanthion, noting its use to halt This curricular dialog with pharmacognosy and various postpartum hemorrhage. Around 350 BC the Parsi wrote bioactive natural products continues in courses in the of ‘‘noxious grasses that cause pregnant women to drop second-professional year [Pharmacotherapy of Infectious the womb and die in childbed,’’ while in 322 BC Aristotle Disease 1 and 2 Cardiology) and third-professional year postulated that grain rust was caused by warm vapors. (Oncology, Pulmonology & Rheumatology, Neurology/ Around 286 BC the Greeks concluded that barley was Psychiatry). more susceptible than wheat to rust infections, and that windy fields had less rust than damp, shady low-lying Early History1-11 ones. Although it has been speculated that the 4,000-year old Eleusinian Mysteries of ancient Greece were con- Middle Ages to Twentieth Century1-11 nected with ergot-induced hallucinations, the earliest The first documented epidemic of ergotism likely authenticated reports of the effects of ergot occurred in occurred in 944-945 AD, when some 20,000 people of Chinese writings in approximately 1100 BC, when the the Aquitane region of France (about half of the popula- Corresponding Author: Paul L. Schiff, Jr, PhD. Professor of tion) died of the effects of ergot poisoning. Some 50 years Pharmaceutical Sciences, Department of Pharmaceutical later, about 40,000 people reportedly died because of the Sciences, School of Pharmacy, University of Pittsburgh, ‘‘holy fire.’’ Pittsburgh, Pennsylvania 15261. Tel: 412-648-8462. Fax: 412- Up through the 18th Century botanists persisted in 383-7436. E-mail: [email protected] considering ergot to be a ‘‘super’’ rye, possessing an 1 American Journal of Pharmaceutical Education 2006; 70 (5) Article 98. limb (usually a foot) at a joint, without pain or loss of blood. St. Anthony’s Fire was so named because the Order of St. Anthony traditionally cared for sufferers in the Mid- dle Ages, and the condition was characterized by severe burning pain (‘‘fire’’). The second form of ergotism, also known as the convulsive form (Ergotismus convulsivus), was particularly common in Germany and was typically characterized by the development of delirium and hallucinations, accompanied by rigid, extremely painful flexed limbs, muscle spasms, convulsions, and severe diarrhea. The term ignis sacer (holy fire) was commonly employed for epidemics of ergotism, but numerous other terms, mainly of Latin derivation, were coined, including: Ignis judicalis, Ignis occultus, Morbus hic tabificus, Mor- tifer ardor, Pestilens ille morbus, Pestis ignaria, Plaga ignis, Plaga illa, and Plaga invisibilis. Many were quite naturally translated into various European languages, including French (Feu sacre´) and German (heilige Feuer). Other terms for ergotism included names of regions (Mal de Cologne) and of saints to whom an appeal for help was made (St. Anthony, St. Martin, St. Martial). In 1597 scientists at Marburg University observed that signs of ergotism often appeared after blighted rye grains were consumed, and that blight was promoted by cold, damp growing seasons. In 1630 it was observed that Figure 1. Chemical structures of ergot alkaloids and related feeding of blighted grain to animals produced an illness important compounds. similar to human ergotism and by the end of the 18th century poisoning was demonstrated in animals. enlarged kernel. Finally, in 1764, ergot was recognized as Although the source of ergotism was linked to the con- a fungus by von Munchhausen. Epidemics of ergot poi- sumption of infected rye by 1676, it was the large out- soning, often termed ergotism, continued to ravage con- breaks of ergotism in Europe in 1770 and 1777 that tinental Europe through the Middle Ages and outbreaks of ergotism occurred in Germany in 1581, 1587, and 1596. These epidemics were due, in part, to the fact that rye was grown in larger quantities in medieval times, and many people (particularly those less wealthy) ingested contaminated rye flour. These outbreaks were characterized by the produc- tion of 2 distinct forms of toxic reactions, with these reactions now being understood to be attributable to the effects of the alkaloids produced by the parasitic ergot fungus which was contained within the ergot fungal body (sclerotium). The fungus-contaminated grain crops along with their fungal metabolites (ergot alkaloids) were ingested with flour prepared from the grain. The first gangrenous form (Ergotismus gangraenosus), commonly known as ‘‘holy fire,’’ ‘‘infernal fire,’’ or ‘‘St. Anthony’s Fire,’’ was more common in France and its effects were characterized by pronounced peripheral vasoconstriction of the extremities (limbs). Hands, feet, and whole limbs would swell, producing a violent, burning pain that ulti- Figure 2. Chemical structures of ergot alkaloids and related mately culminated in the separation of a dry gangrenous important compounds. 2 American Journal of Pharmaceutical Education 2006; 70 (5) Article 98. prompted the introduction of legislation in France and BIOLOGY AND CHEMISTRY3-5,9,13,15,16 elsewhere. Epidemics of gangrenous ergotism were Biology and Lifecycle recorded from the Middle Ages to the nineteenth century, The genus Claviceps is a group of phytopathogenic while that of convulsive ergotism were documented be- ascomycetes that is composed of approximately 36 dif- tween 1581 and 1928. ferent species of filamentous fungi. These species are known to parasitize over 600 monocotyledonous plants Twentieth Century1,12 of the families Poaceae, Juncaceae and Cyperaceae, in- From 1926 to 1927, some 11,319 cases of ergotism cluding forage grasses, corn, wheat, barley, oats, millet, were reported in a population of 506,000 in the vicinity sorghum, rice, and rye. Ergot was first recognized as a fun- of Sarapol, near the Ural mountains. In 1928, 200 Jewish gus in 1711 but its lifecycle was not described in the form refugees in Manchester, England, were sickened when of a general outline until 1853 by Tulasne. The term ergot they consumed rye bread that had been prepared from or Secale cornutum derives from the French word argot (a rye grown in South Yorkshire. In mid-August of 1951, spur) and represents the dark brown, horn-shaped pegs 230 villagers of the popular French tourist town of Pont that project from ripening ears of rye in place of rye Saint-Esprit on the Rhone River were sickened after grains. These tuberous projections are collected before ingesting contaminated goods from a local baker. They and during harvesting or are separated from the threshed became violently ill with symptoms of severe gastroin- rye. In a histologic sense, these bodies consist of com- testinal upset, dramatic reduction in body temperature, pactly interwoven hyphae of the filamentous fungus Clav- hallucinations, euphoria, and suicidal ideation. Within iceps purpurea (Fries) Tulasne

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