To coincide with the Nature Science Blogging 2008 conference this weekend in London, we present this guest post from Coracle, the away-from-the-bench scientist who writes the Science and Progress blog. I’ve long been a fan of Science and Progress and Coracle shares my love of natural products pharmacology and skeptical eye for alternative medicine.

If you’re in London and see Coracle at the conference, please buy him a pint and send me the bill.

“Last Friday, April 16th, 1943, I was forced to interrupt my work in the laboratory in the middle of the afternoon, being affected with a remarkable restlessness, combined with a slight dizziness.”

The invention and serendipitous discovery of the psychoactive properties of Lysergic acid diethylamine (LSD) are, of course, well known. However, the curious history and biology of its parent compound are perhaps less well known. For those that are not familiar with the story, LSD is a semisynthetic compound produced from a metabolite found in the fungal parasite ergot. When Albert Hofmann was screening ergot derivatives for oxytocic activity, he happened to become intoxicated by LSD. How this happened, either by ingestion or absorption, is not clear. However, the compounds effects were severe enough to force him to stop working. To confirm the effect Hofmann experimented on himself, ingesting 0.25 mg of each product he had been working on that Friday. Shortly after consuming LSD he again suffered hallucinations. The ingestion of 0.25 mg seems to be a rather high dose. Current opinion has it that the threshold dose for mental effects is 20 – 30 microgrammes.

However fascinating, LSD is only part of the story.

Ergot has a rich and varied history in medicine and in disease. It grows on a range of cereal and grass plants, preferring damp conditions. In rye, ergot forms dark horns which project from the ear of the plant. These growths give ergot its name, from the French argot, or cock’s spur.

Its growth on cereal crops has resulted in many historical outbreaks of disease, at its height it is thought to have resulted in 40,000 deaths. Ergot poisoning takes two forms: the gangrenous and the convulsive and neither sound particularly pleasant. Gangrenous ergotism results from the vasoconstrictive actions of ergot alkaloids, and causes swelling of the extremities and limbs. This swelling was said to be extremely painful, and could result in the loss of a hand or foot at a joint. Because of the vasoconstriction this loss was both painless and bloodless. The order of St Anthony, whose members traditionally cared for the victims, also contributes to one of the justifiably dramatic names for the disease, St Anthony’s Fire.

The second form, the convulsive, sounds barely preferable. A number of symptoms occur, including painful muscle spasms, convulsions and diarrhoea, as well as the mental manifestations of hallucinations and delirium. Although the worst of the epidemics occurred in the middle ages, there were still some out-breaks in the twentieth century, in both the UK and in France.

Along with its history of disease, ergot has a history of medicinal use. Its earliest use was in obstetrics in ancient China, in around 1100 BC. The effect of ergot alkaloids on smooth muscle meant that it had applications as an abortificant or to induce labour. The oxytocic effect of ergot was rediscovered in 1582 in Germany, when the physician and botanist Lonitzer described its use by midwives as a means of quickening labour.

Ergot derivatives still find use in modern obstetrics. Ergonovine, a naturally occurring ergot alkaloid, is somewhat pharmacologically promiscuous. It is a weak antagonist to dopamine in blood vessels, and a partial agonist on a-adrenergic receptors in the same tissues. However, its primary effect is believed to be as an agonist on 5-HT₂ receptors in uterine smooth muscle, enhancing contractions. This stimulant effect has lead to ergonovine being approved for the treatment of spontaneous abortion complicated by haemorrhage, or for the treatment and prophylaxis of haemorrhage following delivery.

Thanks their effects on blood vessels, ergot alkaloids also find uses outside obstetrics. Although they have fallen out of favour somewhat, ergotamine, dihydroergotamine and methysergide have found use in migraine therapy. Ergotamine tends to be used in a preventative manner, whereas dihydroergotamine is used in the management of acute symptoms. Understandably, due to their vasocontrictive actions, these compounds are contraindicated in vascular diseases.

The progressive loss of dopaminergic neurons in the substantia nigra results in the movement disorder known as Parkinson’s disease, and is characterised by tremor, muscle rigidity and the slowing of movements. The standard therapy is to replace missing dopamine using the pro-drug L-dopa, which is converted to dopamine by L-amino acid decarboxylase. However, as treatment with L-dopa continues, the body becomes tolerant and the therapeutic effect is abrogated. Fortunately, a number of ergot derivatives exhibit selective dopaminergic agonism. Bromocryptine, pergolide and cabergoline may be used on their own, or as adjuncts, in the treatment of Parkinson’s disease.

So, ergot alkaloids act on a number of pharmacological targets. We have seen them as agonists to serotonin receptors, to dopamine receptors and to adrenergic receptors, but which of these are responsible for the remarkable psychic effects of LSD? That LSD is antagonistic to serotonin in peripheral tissues was established in the 1950s. This lead to the hypothesis that a similar activity in the CNS and, indeed, LSD was found to be inhibitory to 5-HT neurons within the dorsal raphe nucleus through an agonistic activity on 5-HT_1A receptors. However, other hallucinogens with structural similarities, such as psilocin or mescaline, don’t share this activity, suggesting that this activity is not responsible for the hallucinatory effects of LSD. One shared affinity of these compounds is for agonism at 5-HT_2A receptors. Activation of these receptors increases the activity of neurons in a range of structures within the brain. However, LSD is also an agonist at dopamine D₂ receptors and the the role this activity may play is not clear. Although many applications for LSD have been tried, none have stuck, and these tribulations contributed to Hofmann considering LSD his ‘troubled child’.

Back in April we had a discussion as to whether Terra Sig should become a co-blog given my decreased posting frequency due to changes in my offline life. Based on your feedback, we’ll stay solo but will gladly offer you guest posts like these on occasion.