St. Anthony’s Fire

1. St. Anthony’s Fire By Nickerson: Kristina Haagsma, Mark Hnatiuk, Jan Kozicky, Justin Ma, Jessica Ng, Josh Plante, Jana Rieger

2. Introduction • Caused by ergot • A filamentous fungus • Genus Claviceps • Parasitic • Found in grains • corn, wheat, barley, oats, rice, and rye • Spread via spores • Transported by wind, rain, insects and other animals, or by plant-to-plant contact

3. Introduction • Infection of plants can be easily overlooked • Mimics the shape of grains • Fungal form is the most dangerous • Causes ergotism • Infection usually follows oral consumption of contaminated food ie/ rye bread

4. Overview • History • Signs & Symptoms • Mechanism of Action • Drug Interactions • Treatment • Therapeutic Uses • LSD

5. History Eleusinian Mysteries • Greek religious cult promising pleasant afterlife • Lasted for almost 200 years, between 1500BC and 396AD • Cult of Demeter and Persephone • Drank ritual drink kykeon before having visions of afterlife, hallucinations • Kykeon likely contained ergotized barley • Extremely secretive, death penalty for revealing secrets and visions

6. Tollund Man • Perfectly preserved body found in Danish peat bog, from 400BC • Rope around neck, likely drowned as ritual sacrifice to earth goddess • Stomach contained porridge with very high levels of ergot in the barley • Ergotised porridge likely taken to induce hallucinations before ritual sacrifice

7. Tollund Man

8. Medieval Ergot Epidemics • Rhine Valley had many ergotism outbreaks recorded between 7th and 17th centuries, rye bread was staple food • Became known as St. Anthony’s Fire as monks of St. Anthony specialized in treatment • Also called Ignis Sacer and Holy Fire • 40 000 deaths in southern France in 944AD

9. Convulsive ergotism called Dancing Mania, St. Vitus’s Dance, as people screamed, babbled, convulsed, and ‘danced’ in streets • shut down Strasbourg in 1418 • Often attributed to demons and madness or divine intervention • Scientific breakthroughs in 1670s • ergotism was connected bread and later to ergotized rye • ergot life cycle identified in 1853

10. Salem Witch Trials • 1692 Salem, Massachusetts had wet harvest, rye bread likely contaminated with ergot • 8 girls in Salem experienced hallucinations, convulsions, burning skin sensations • Pastor’s daughters affected • Immediately accused other women of bewitching them

11. Those accused of witchcraft were mostly unpopular, poor, and non-churchgoing • Over 150 people imprisoned for witchcraft that year • 20 people executed, 5 died in prison

12. Salem Witch Trials

13. Russia • Ergotism very common until 1945 as rye bread was staple food • After 1945, potatoes were planted instead and pesticides/fungicides introduced • 1926, there were 10,000 confirmed cases of ergotism in Russia • Government statistics show that areas with wet weather and rye crops had outbreaks of trembling, confusion, hysteria, and hallucinations

14. Signs and Symptoms • Ergotism can be caused by • Acute ingestion of large amounts of fungus • Chronic ingestion, usually via contaminated food • 2 main categories of symptoms • Gangrenous • Convulsive

15. Gangrenous Symptoms • Dry gangrene caused by tissue necrosis • Fingers and toes are affected first • Followed by arms and legs • Infection may result and can lead to death • Amputation is often the only solution • Happens in livestock as well as in humans

16. Convulsive Symptoms • Includes tingling sensation in the fingers, tinnitus, dizziness, hallucinations, seizures, nausea and vomiting • Mental disturbances such as mania, psychoses and delirium may also be present

17. Kinetics • Many compounds; absorbed to varying degrees from GI tract • Absorption increased in the presence of caffeine (ergotamine) • Extensively metabolized by CYP450 • Cinx in liver failure • Certain drugs inhibit metabolism • Protease inhibitors • Macrolide antibiotics

18. Mechanism of Action • Ergot compounds are structurally similar to the biogenic amines • Dopamine • Serotonin (tryptophan) • Norepinephrine • Serotonergic system particularly affected • Accounts for many of the convulsive symptoms • Similar to symptoms of schizophrenia and epilepsy

19. Mechanism of Action • N/V/D • stimulated serotonin receptors of the GI tract and emetic centres of the brain • LSD • a weak partial agonist at 5HT-2 receptors in the brain • Results in many of the convulsive symptoms

20. Mechanism of Action • All ergot compounds exhibit some vasospastic properties • Effects on serotonin and alpha adrenergic receptors in blood vessels • St. Anthony’s Fire • Body feels extremely warm due to constriction of peripheral vessels

21. Mechanism of Action • Results in myocardial or peripheral ischemia • Gangrene, infection, amputation, death • Cinx in CAD, PAD, uncontrolled HTN • Uterine smooth muscle is also affected by serotonergic and alpha adrenergic effects • Contractions may lead to miscarriage or preterm birth

22. Treatment • 16th and 17th century folk remedies • “green ointment of herbs,  earthworms stamped in vinegar, swan or goose dung stamped with the white or yolk of the egg, or doves dung in salad oil” • Later remedies • “British Oil” originally containing bitumen, • later preparations with oil of turpentine, oil of rosemary and Barbados tar

23. Treatment • Modern-Day Treatment • Early detection and immediate discontinuation of exposure vital • Severe ischemia may be irreversible • If overdose is detected early • Gastric lavage if patient is conscious • Activated charcoal

24. Treatment • Treatment of hallucinations • Stopping exposure to toxin usually effective • Intracranial injection of combination serotonin and cholinergic drugs successful treatment in mice

25. Treatment • Treatment for ischemia • Vasodilators • Nitroprusside, nifedipine, captopril, prostaglandins • Anticoagulants • Dextrin, heparin • In extreme cases of ischemia • Regional sympathectomy • Hyperbaric oxygen chamber • Hydrostatic dilation with balloon catheters

26. Medicinal Uses • Bromocriptine • Stimulates D2 receptors in the brain • Treatment for Parkinson’s • female infertility, abnormal lactation, amenorrhea, hypogonadism, and acromegaly • Effective in cocaine withdrawal • Diabetes and Obesity

27. Medicinal Uses • Pergolide • Anti-Parkinson • 1000x more potent than Bromocriptine • Inhibits Prolactin Release • Effects on Leutinizing and Growth Hormone

28. Medicinal Uses • Methysergide • Prophylactic migraine treatment • Activation of 5HT-1D receptors in cranial blood vessels • vasoconstriction • Linked to retroperitoneal fibrosis

29. Medicinal Uses • Ergotamine • Intermittent treatment of migraines • Similar MOA as Methysergide • Cinx in pregnant women • Migraine treatments are non-selective • Overdose or drug interaction may result in ergotism • Replaced by safer -triptans

30. Medicinal Uses • Methylergonovine • Used after delivery • Initiates strong contractions of uterine smooth muscle • Contract the uterus, prevent hemorrhage, promote placental passage

31. Drug-Drug Interactions • SSRI’s will potentiate the effects of ergot derivatives which are partial 5-HT agonists • Ex. Fluoxetine • LSD has sympathomimetic effects; therefore, stimulants will worsen adverse effects like tachycardia and hypertension

32. Drug-Drug Interactions • Since LSD is metabolized by CYP enzymes, CYP inhibitors may lead to toxicity • Ex. Antiretrovirals (ritonavir), Macroglide antibiotics (erythromycin), Grapefruit juice • LSD should not be combined with other hallucinogens • Ex. Psilocybin, Mescaline

33. LSD • Synthesized by Albert Hoffman in 1938 • Accidentally dosed himself • Had the first ‘acid trip’ • Hallucinations, synesthesias, emotionality, body distortions • Used as a psychoanalytic drug • Was thought to elicit repressed memories • Given to alcoholics as part of counselling process

34. LSD • Believed to be helpful in treating schizophrenia • Tried to map out a ‘model psychoses’ using animals • Later realized that schizophrenia and acid trips are very different • Therapeutic use discontinued in the ’60s

35. LSD • CIA • Attempted to use it for mind control • Cold War, Russian spies • Tested it on unsuspecting civilian and military ‘volunteers’ • Caused mental trauma and suicides in subjects • No real use was found for it

36. LSD • Eventually became accessible to the public • Counterculture committed to social change and cultural liberation • Timothy Leary’s League of Spiritual Discovery was a church in the ’70s based on LSD use

37. LSD Widespread stories of bad trips and flashbacks decreased its use Legislation was imposed prohibiting LSD Today it is part of the ‘party drug’ scene Along with ecstasy and mushrooms

38. LSD Video evidence of why you SHOULD NOT give your cat LSD

39. LSD LSD Military Experiments with LSD

40. References • BAADER, W., HERMAN, C., JOHANSEN, K. (Date?). St. Anthony’s Fire: successful reversal of ergotamine induced peripheral vasospasm by hydrostatic dilation. Annals of Vascular Surgery. 4(6): 597-9. • Banhidy F, Acs N, Puho E, Czeizel AE. Ergotamine treatment during pregnancy and a higher rate of low birthweight and preterm birth. British Journal of Clinical Pharmacology (2007). 64(4):510-516. • BROWN, P.S., (1976). Medicines advertised in eighteenth-century Bath newspapers. Med Hist. 20(2): 152-168 • CAPORAEL, L. (1976). Ergotism: the Satan loosed in Salem? Science,192, 21-6. • EADIE, M. (1983). Ergotamine Pharmacokinetics in Man: An Editorial. Cephalalgia. 3(3):135-8 • EDWARDS, R.J., FULDE, G.W., MCGRATH, M.A. (1991). Successful limb salvage with prostaglandin infusion: a review of ergotamine toxicity. Medical Journal of Australia. 155, 825-7 • FREDERICKSON, A. (1998). Mechanisms of LSD: a Glimpse into the Serotonergic System. Neurobiology and Behaviour (http://serendip.brynmawr.edu/bb/neuro/neuro98/202s98-paper3/Frederickson3.html) • Golan DE, et al. Principles of Pharmacology, The Pharmacological Bases of Drug Therapy. Lippincott Williams & Wilkins. (2005) • HART, C. (1999). Drugs for Migraine. Modern Drug Discovery. 2 (2), 20-21, 23-24, 28, 31 • HOMER. (unknown date) The Iliad. http://www.mala.bc.ca/~johnstoi/homer/iliad_title.htm • KATZUNG, B. (2004). Chapter 16: Histamine, Serotonin and the Ergot Alkaloids. Basic and Clinical Pharmacology, 9th Edition • MATOSSIAN, M. (1989). Poisons of the Past: Molds, Epidemics, and History. New Haven: Yale University Press. • MECHEM, C. (2007). Antipsychotics and LSD lowering of seizure potential, sypathomimetics. http://www.emedicine.com/emerg/topic911.htm • MERRICK, J., GUFLER, K., JACOBSEN, E. (1978). Ergotism treated with hyperbaric oxygen and continuous epideral analgesia. Acta Anaesthesiologica Scandinavica. 67: 87-90 • NAZ, I., SOPHIE, Z., (2006) Acute limb ischemia due to ergotism. Journal of the College of Physicians and Surgeons. 16(8): 553-5. • Nestler EJ, Hyman SE, Malenka RC. Molecular Neuropharmacology. McGraw Hill. (2001)

41. References • PANACCIONE, D., COYLE, C. (2005). Abundant respirable ergot alkaloids from the common airborne fungus Aspergillus fumigatus. Applied and Environmental Microbiology, 71, 3106-11. • ROBERTS, T., HRUBY, P. (2001). Religion and Psychoactive Sacraments: An Entheogen Chrestomathy. Council on Spiritual Practices. http://www.csp.org/chrestomathy/ergot_and.html • SCHIFF, P. (2006). Ergot and its alkaloids. American Journal of Pharmaceutical Education, 70. • SCHMIDT, R., ERASMI, H., WALTER, M., WOLF, M., GROSS-FENGELS, W. (1992). Ergotism and ischemia of the limbs. Annales de Cardiologie et d’Angeiologie., 41, 489-95. • SOLOGUK, S. (2005). Diseases Can Bewitch Durum Millers. Milling Journal. Second Quarter 2005, 44-45. • STANGE, K., POHLMEIER, H., LUBBESMEYER, A., GUMBINGER, G., SCHMITZ, W., BAUMGART, P (1998). Vascular ergotism through inhalation of grain dust. Deutsche Medizinische Wochenschrift. 123, 1547-50. • UNKNOWN (1960). St. Anthony’s fire rekindled. Can Med Assoc Journal, 83, 658-9. • WONG, G. (2004). Ergot of Rye: History. University of Hawaii Department of Botany. http://www.botany.hawaii.edu/faculty/wong/BOT135/LECT12.HTM • Zanettini R, et al. Valvular heart disease and the use of dopamine agonists for Parkinson's disease. New England Journal of Medicine (2007). 4;356(1):39-46.

42. References • Pijl H, et al. Bromocriptine: a novel approach to the treatment of type 2 diabetes. Diabetes Care (2000). 23(8):1154-1161. • Lexi-Comp Online • Drugbank • http://redpoll.pharmacy.ualberta.ca/drugbank/index.html • KSIR, C., HART, C. and Oakley, R. (2004). Drugs, Society, and Human Behavior. 11th Edition. Toronto: McGraw Hill, 338-347 • PREPELICZAY, S. (2002) Socio-cultural and Psychological Aspects of Contemporary LSD in Germany. Journal of Drug Issues. Spring2002, Vol. 32 Issue 2, 431-458 • SCHNELL, B. et al. (2007) Compendium of Pharmaceuticals and Specialties • WINTER, J., HELSLEY, S., FIORELLA, D., RABIN, R. (1999). The acute effects of monoamine reuptake inhibitors on the stimulus effects of hallucinogens. Pharmacol. Biochem. Behav., 63, 507-13. • TACITUS (unknown date). Germania. • http://www.fordham.edu/halsall/source/tacitus1.html • WONG, G. (2004). Ergot of Rye: History. University of Hawaii Department of Botany. • http://www.botany.hawaii.edu/faculty/wong/BOT135/LECT12.HTM • WOOLLEY, D.W. (1955).Production of abnormal (psychotic?) behavior in mice with lysergic acid diethylamide, and its partial prevention with cholinergic drugs and serotonin. Proc Natl Acad Sci, 41(6): 338-344. • WOOLTORTON, E. (2003). Risk of stroke, gangrene from ergot drug interactions. CMAJ, 168. • http://www.bmed.com/images/cydg1.jpg • http://www.buyemp.com/tmp_image.php?item_id=1122956&width=150&height=150 • http://www.cartoonstock.com/lowres/rni0036l.jpg • http://www.fda.gov/centennial/this_week/images/38-06/img-01.jpg • http://www.grahamazon.com/pics/plaguephysician.jpg • http://www.neurosurgery.pitt.edu/spine/images/endosymp.jpg

43. References • http://www.pathology.vcu.edu/education/dental2/images/sc1-2.jpg • http://www.shropshiretourism.info/ironbridge/gorge-museum/the-tar-tunnel/images/TAR-TUNNEL.jpg • http://www.skinandaging.com/article/..%5CSA%5CHTML%5Cimages%5Cthumbs%5CSA09CME_fig9tif.jpg • http://www.worksofheartinc.org/images/projects/boh/HeparinLockFlushLg.jpg • WYNN, G., COZZA, K., ZAPOR, M., WORTMANN, G., ARMSTRONG, S. (2005). • Med-psych drug-drug interactions update. Antiretrovirals, part III: antiretrovirals and drugs of abuse. Psychosomatics, 46, 79-87. • ZIMRAN, A., OFEK, B., HERSHKO, C. (1984). Treatment with captopril for peripheral ischaemia induced by ergotamine. British Medical Journal. 288(6414): 364.