Ergot: an abortifacient for migraine

Toxic toast

For at least the last 1000 years grain crops (and rye in particular) have been prone to infection by the fungus Claviceps purpurea, or ergot.  Outbreaks were particularly common during wet growing seasons in France, Southern Germany and Russia.  Bread made from ergot-contaminated grain caused a characteristic profile of poisoning - ergotism - that came to be known as St Anthony's fire (after the monastery famed for treating victims). Ergotism produces profound constriction of blood vessels (vasoconstriction) in the extremities, leading to a failure of tissue perfusion by blood.  If prolonged, the result is agonising pain (thus the reference to fire) followed by tissue necrosis and gangrene.  Victims 'danced' (or, more likely writhed) in pain.  In some outbreaks central nervous system effects such as hallucination and convulsions occurred, possibly to due different strains of C. purpurea containing different mixtures of biologically-active molecules.  From this description of ergot toxicity, it may be unclear just how this nasty mould found its way into medical use. It's another interesting story.

Lingering parturition

Having noted that ergot poisoning tended to causes miscarriage by producing strong and persistent contractions of the uterus, midwifes and "wise women" began using ergot to treat cases of prolonged, or otherwise difficult, labour.  It is uncertain just when this practice became common.  The first written account the use of ergot during labour appears in Adam Lonicer's Krauterbush (Book of Herbs) in 1582.  From this time onwards pulvis ad partum (powder of birth) appears to have been used in continental Europe.  The English-speaking medical world doesn't appear to have caught up until 1808 when the New York physician John Stearns reported the effects of ergot in "expiditing lingering partuition" - an idea he borrowed from an "ignorant Scottish midwife".  By 1824 Stearns had enough experience with the unpredictable nature of ergot (the powerful contractions it produced often caused asphyxia of the foetus and stillbirth) that he advised its use with caution.  Indeed, two years earlier David Hosack had dubbed ergot pulvis ad mortem (powder of death).  Over the course of the next 50 years or more, the obstetric use of ergot slowly shifted from inducing uterine contractions during labour, towards inducing them post-partum (after birth) to control bleeding.

Living ligatures

The muscles of the uterus are arranged in a mesh-like pattern, through which blood vessels must pass to reach the placenta.  During birth when the the placenta breaks free from the uterine wall, these vessels snap and are prone to bleeding.  The contraction of the mesh of uterine muscles through which these vessels course usually pinches them shut to prevent such post-partum bleeding.  Scottish-born and -educated physician William Smellie was probably the most influential early thinker on post-partum bleeding and recognised the role of reduced uterine contractions as the underlying problem in this potentially lethal complication well before (1752) the adoption of ergot for this purpose by the medical profession. During the course of the nineteenth century, the clinical observation that ergot could produce a beneficial effect by inducing uterine contractions post-partum became more apparent:

'It [ergot] is most frequently employed to cause contraction of the uterus in cases of labour, and the contractions induced by it differ from the natural ones in being continued, instead of alternating with relaxation.  In haemorrage after delivery it is especially indicated.'

- The essentials of materia medica and therapeutics (Garrod, 1874)

(Notice that 50 years after Stearns advised against using ergot to induce uterine contractions during child birth, some physicians still avocated its use.)

Haemorrage

Despite the quite unique anatomical arrangement of muscles and blood vessels that prevents post-partum bleeding when the uterus contracts, ergot gained the reputation for being useful in treating bleeding more generally.  Garrod (1874) continues:

"Moreover, it is a valuable means of checking haemorrhage, whether from the lungs or bowels."

In addition to causing the uterus to contract, ergot contracts most blood vessels (see introduction).  It was probably assumed that this would help to stop bleeding where it occurred, which may, indeed, have contributed partly to its efficacy in post-partum haemorrhage.  However, contracting all the blood vessels in your body increases blood pressure - exactly the opposite effect that you want to stop blood spurting out.  Hale White's Materia Medica of 1903 summarises the general view of the use of ergot for treating haemorrage 30 years later:

"Some authors claim great success.  Frequently it fails, and may, by the general rise of blood-pressure, do more harm than good.  It is difficult to gauge its value, for so many haemorrhages will stop even if no drugs are given."

It wasn't until the 1930s that the use of ergot in treating haemorrhage was considered "historical".  Around that time, another use for ergot had been found.

Migraine

During the mid to late nineteenth century a great number of drugs were administered without much evidence that they worked, often based on strange ideas about how drugs acted, and how the physiology of the body was altered in disease.  Any single drug was often used in several diseases, for reasons that seem alien to us now.  Robert Bartholow, in his A practical treatise on materia medica and therapeutics (1884) noted that ergot was useful in treating a variety of diseases including:

• dysentery and chronic diarrhea
• gonorrhea
• acne
• vertigo
• headache and migraine
• mania
• diabetes insipidus
• spermatorrhoea ("wet dreams")

For most of these indications, Bartholow provides his own anecdotal evidence, or that of his colleagues and correspondents.  Today, we'd consider them all quite unusual uses of a substance that contracts the uterus and blood vessels, and any positive medical outcome a likely placebo effect.

Edward Woakes appears to have made the first reference to the use of ergot in treating migraine in 1862.  Woakes held that pain was due to the swelling of nerves and that by reducing blood supply to nerves, this swelling (and pain) could be abated.  He reported a single case of migraine who had apparently benefited from the treatment.  Over the course of the next 50 years, several physicians reported some successes with treating migraine with ergot, often explaining the therapeutic effect using contrary physiological arguments.  The treament was never embraced with any enthusiasm during this period, possibly because of the risks of overdosing with herbal preparations of ergot, which contained several biologically-active compounds in varying proportions.

Active ingredients

In 1918, the compound ergotamine was isolated from ergot and chemically defined by the chemist Arthur Stoll at (what was then) the drug company Sandoz. Ergotamine was marketed as the specific compound that was responsible for the the useful pro-contractile effect of ergot on the uterus; the effect that could abort post-partum haemorrhage.  Later, the effect of ergotamine on migraine was investigated, based on the earlier, more vague literature.  From 1925 onwards, trials of ergotamine for the treatment for migraine were reported in the medical literature.  Importantly, these were trials of a specific compound - much better than anecdotal reports of a variable herbal extract. By the 1930s, ergotamine was considered a useful treatment for migraine. It remains a treatment - albiet as a bit of a last resort - to this day.  Some of the drugs that have surpassed ergotamine for migraine treatment are synthetic modifications of ergot alkaloids (see for example methysergide), or drugs that act at similar receptors (e.g. the triptan class of anti-migraine drugs).

Nearly 20 years after the identification of ergotamine, another ergot-derived alkaloid - dubbed ergometrine - was described by four independent laboratories, including those at Sandoz run by Arthur Stoll.  Ergometrine was found to be the more uterine-specific component of ergot and has beed used for post-partum haemorrhage since its identification.  More selective agents, such as the unrelated hormone oxytocin have surpassed ergometrine in recent decades, but it remains a second-line drug in first world countries, and the only affodable option in the developing world, when and where it is available.