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From Moldy Bread to DHE: A History of the Ergot Drugs
by Stewart Tepper, MD
Many migraine sufferers rely on ergotamine preparations (e.g., Cafergot, Wigraine or Bellergal) or DHE to stop a migraine attack in progress. Sufferers from severe, frequent migraine or cluster headache are often prescribed methysergide (Sansert) to prevent their headaches. These commonly used headache drugs all belong to the ergot family. Like many other distinguished families, the ergots spring from humble beginningsa fungusand include a disreputable neer-do-wellthe hallucinogen LSD.
The ergots are all derived from a mold called Claviceps purpurea that grows on rye. In the Middle Ages, there were frequent mass outbreaks of an ailment known as St. Anthonys fire, caused by consuming toxic amounts of ergot in bread made from moldy grain. Sufferers experienced hallucinations, panic, convulsions, and painful burning in their limbs that followed a loss of circulation in constricted blood vessels. This vasoconstrictive effect of ergot led to its earliest medical use. Sixteenth-century midwives used the fungus to bring on labor and limit blood loss during childbirth.
In the late 19th century, ergot extracts began to be used for headache. However, since physicians were just liquefying the fungus, there were great variations in potency that made safe, effective use of ergot difficult. In 1918, a Swiss chemist named Arthur Stoll synthesized ergotamine tartrate, which he named Gynergen. As the brand name suggests, ergotamine was originally marketed as a obstetrical/gynecological drug for controlling bleeding after childbirth. In the 1920s ergotamine began to be used for migraine, and formal studies of its efficacy appeared in the 1930s. Harold Wolff and John Graham first showed that ergotamine was vasoconstrictive, and argued that this action accounted for its pain-relieving effects.
In 1943, Stoll synthesized a new ergot drug, dihydroergotamine or DHE. There was a great deal of initial interest in DHE because it had fewer unwanted effects on the uterus and was much less likely to cause nausea compared to ergotamine. Three American physicians published an early report of DHEs effectiveness for migraine. Oddly enough, DHE was ignored in the U.S. for nearly 40 years, though it was used in other countries to treat migraine. In the early 1980s, Neil Raskin published reports that DHE was effective for severe treatment-resistant headaches when administered intravenously. Over the next decade, headache physicians went on to investigate the use of DHE injection and nasal spray formulations, and showed it was effective for relief of migraine, cluster and other severe headaches.
Stoll was working for the Swiss pharmaceutical company Sandoz at the time he synthesized DHE, and the company continued to work on developing new ergot-derived drugs. Ergonovine maleate was introduced in the late 1930s, methysergide (Sansert) in the early 1960s, and bromocriptine (Parlodel) in the 1970s. Bromocriptine is primarily indicated for the treatment of Parkinsons disease and for a tumor of the pituitary gland. Ergonovine is used to bring on labor and stop postpartum bleeding. To date, methysergide is the only drug developed specifically for the prevention of migraine. Other commonly used headache preventives were developed for other uses, such as the beta blockers and antidepressants.
Although quite effective in controlling chronic headache, methysergide has a rare, potentially fatal side effect. Somewhere between 1 in 1500 patients and 1 in 5000 patients will develop scar tissue on the heart or other organs if methysergide is taken daily for more than six months. For this reason, physicians are cautious in prescribing methysergide, and patients must take a "drug holiday" every six months to avoid this complication. A handful of cases have been reported with other ergot drugs. Patients should be aware that overuse of ergotamine can result in a daily rebound headache, in which the pain returns as each dose wears off.
All the ergots contain a common structure called lysergic acid. By the early 1940s, Albert Hofmann, a Sandoz chemist, had synthesized dozens of different lysergic acid compounds, following the trial-and-error process of traditional drug discovery. Most were judged to be duds, including one called LSD-25. But Hofmann had an intuition about this LSD, and synthesized it again in 1943. Feeling dizzy, he went home early and slipped into a strange, dream-like state filled with pleasant visions. Guessing that exposure to LSD might have caused his strange trance, he tried swallowing a tiny amount of the chemical and plunged into what can only be described as a very bad trip. Sandoz sponsored research to see if LSD might have therapeutic uses, but its potential to produce terrifying hallucinations could not be controlled.
Researchers do not fully understand how either the outlaw, LSD, or the respectable members of the ergot family produce their effects. All the ergots interact with the brains serotonin system in one way or another. Serotonin is known to influence mood, sleep, inflammation, pain perception and the constriction and expansion of blood vessels. One theory suggests that LSD binds to serotonin receptors in the brain to turn on dreaming during the waking state. The ergots may act on serotonin receptors to block an inflammatory response in the blood vessels supplying the brain. Their vasoconstrictive effects may also contribute to their effectiveness, since these blood vessels dilate (expand) during a migraine attack. Finally, we now have evidence to suggest that the ergots act directly on a pain center in the lower part of the brain that generates the migraine attack.
--Stewart Tepper, MD. Polyclinic. Seattle, WA
From Headache, the Newsletter of ACHE, Spring 1997, vol. 8, no. 1.
From Moldy Bread to DHE: A History of the Ergot Drugs
by Stewart Tepper, MD
Many migraine sufferers rely on ergotamine preparations (e.g., Cafergot, Wigraine or Bellergal) or DHE to stop a migraine attack in progress. Sufferers from severe, frequent migraine or cluster headache are often prescribed methysergide (Sansert) to prevent their headaches. These commonly used headache drugs all belong to the ergot family. Like many other distinguished families, the ergots spring from humble beginningsa fungusand include a disreputable neer-do-wellthe hallucinogen LSD.
The ergots are all derived from a mold called Claviceps purpurea that grows on rye. In the Middle Ages, there were frequent mass outbreaks of an ailment known as St. Anthonys fire, caused by consuming toxic amounts of ergot in bread made from moldy grain. Sufferers experienced hallucinations, panic, convulsions, and painful burning in their limbs that followed a loss of circulation in constricted blood vessels. This vasoconstrictive effect of ergot led to its earliest medical use. Sixteenth-century midwives used the fungus to bring on labor and limit blood loss during childbirth.
In the late 19th century, ergot extracts began to be used for headache. However, since physicians were just liquefying the fungus, there were great variations in potency that made safe, effective use of ergot difficult. In 1918, a Swiss chemist named Arthur Stoll synthesized ergotamine tartrate, which he named Gynergen. As the brand name suggests, ergotamine was originally marketed as a obstetrical/gynecological drug for controlling bleeding after childbirth. In the 1920s ergotamine began to be used for migraine, and formal studies of its efficacy appeared in the 1930s. Harold Wolff and John Graham first showed that ergotamine was vasoconstrictive, and argued that this action accounted for its pain-relieving effects.
In 1943, Stoll synthesized a new ergot drug, dihydroergotamine or DHE. There was a great deal of initial interest in DHE because it had fewer unwanted effects on the uterus and was much less likely to cause nausea compared to ergotamine. Three American physicians published an early report of DHEs effectiveness for migraine. Oddly enough, DHE was ignored in the U.S. for nearly 40 years, though it was used in other countries to treat migraine. In the early 1980s, Neil Raskin published reports that DHE was effective for severe treatment-resistant headaches when administered intravenously. Over the next decade, headache physicians went on to investigate the use of DHE injection and nasal spray formulations, and showed it was effective for relief of migraine, cluster and other severe headaches.
Stoll was working for the Swiss pharmaceutical company Sandoz at the time he synthesized DHE, and the company continued to work on developing new ergot-derived drugs. Ergonovine maleate was introduced in the late 1930s, methysergide (Sansert) in the early 1960s, and bromocriptine (Parlodel) in the 1970s. Bromocriptine is primarily indicated for the treatment of Parkinsons disease and for a tumor of the pituitary gland. Ergonovine is used to bring on labor and stop postpartum bleeding. To date, methysergide is the only drug developed specifically for the prevention of migraine. Other commonly used headache preventives were developed for other uses, such as the beta blockers and antidepressants.
Although quite effective in controlling chronic headache, methysergide has a rare, potentially fatal side effect. Somewhere between 1 in 1500 patients and 1 in 5000 patients will develop scar tissue on the heart or other organs if methysergide is taken daily for more than six months. For this reason, physicians are cautious in prescribing methysergide, and patients must take a "drug holiday" every six months to avoid this complication. A handful of cases have been reported with other ergot drugs. Patients should be aware that overuse of ergotamine can result in a daily rebound headache, in which the pain returns as each dose wears off.
All the ergots contain a common structure called lysergic acid. By the early 1940s, Albert Hofmann, a Sandoz chemist, had synthesized dozens of different lysergic acid compounds, following the trial-and-error process of traditional drug discovery. Most were judged to be duds, including one called LSD-25. But Hofmann had an intuition about this LSD, and synthesized it again in 1943. Feeling dizzy, he went home early and slipped into a strange, dream-like state filled with pleasant visions. Guessing that exposure to LSD might have caused his strange trance, he tried swallowing a tiny amount of the chemical and plunged into what can only be described as a very bad trip. Sandoz sponsored research to see if LSD might have therapeutic uses, but its potential to produce terrifying hallucinations could not be controlled.
Researchers do not fully understand how either the outlaw, LSD, or the respectable members of the ergot family produce their effects. All the ergots interact with the brains serotonin system in one way or another. Serotonin is known to influence mood, sleep, inflammation, pain perception and the constriction and expansion of blood vessels. One theory suggests that LSD binds to serotonin receptors in the brain to turn on dreaming during the waking state. The ergots may act on serotonin receptors to block an inflammatory response in the blood vessels supplying the brain. Their vasoconstrictive effects may also contribute to their effectiveness, since these blood vessels dilate (expand) during a migraine attack. Finally, we now have evidence to suggest that the ergots act directly on a pain center in the lower part of the brain that generates the migraine attack.
--Stewart Tepper, MD. Polyclinic. Seattle, WA
From Headache, the Newsletter of ACHE, Spring 1997, vol. 8, no. 1.