Amanita muscaria (fly agaric): from a shamanistic hallucinogen to the search for acetylcholine

This historical review (2018) examines the cultural context of the Amanita Muscaria (Fly Agaric) mushroom, from its early shamanistic use in Siberia and the investigation of its pharmacology. The identification of its hallucinogenic alkaloids, muscarine, muscazole, muscazone, and ibotenic acid/muscimole led to the identification of acetylcholine as the mediator of their parasympathetic activity, and the development of anticholinergic medicines for treating asthma and COPD.

Abstract

“The mushroom Amanita muscaria (fly agaric) is widely distributed throughout continental Europe and the UK. Its common name suggests that it had been used to kill flies, until superseded by arsenic. The bioactive compounds occurring in the mushroom remained a mystery for long periods of time, but eventually four hallucinogens were isolated from the fungus: muscarine, muscimol, muscazone and ibotenic acid.”

Authors: M. R. Lee, E. Dukan & I. Milne

Summary

Introduction

Amanita muscaria is a scarlet mushroom with conical white fl eecy scales, which grows in acidic environments, especially in birch forests, and is most prevalent in late summer or autumn.

The Siberian shamans

Siberia’s Eastern part was isolated from the rest of Russia for millennia, and its Stone Age culture depended totally on reindeer for its economy. Its shamans used A. muscaria, a hallucinogenic fungus, in their religious rites.

The Big Raven ate a fungus that made him feel gay and started dancing. He then developed special muscular power and lifted a whale and released it into the ocean.

The Koryak tribe of Kamchatka ate fl y agaric mushrooms and experienced hallucinations. The reindeer would follow the drunken individual around and eat his urine, which was valued for its psychedelic activity, and the Koryaks traded fl y agaric mushrooms with other communities.

Oswald Schmiedeberg and muscarine

Oswald Schmiedeberg4 was one of the great pharmacologists of his generation and his institute at Strasbourg played host to many young research workers. His main work concerns muscarine, one of the alkaloids present in A. muscaria.

When the vagus nerve to the heart was stimulated electrically, the heart slowed and a substance that mimicked muscarine was released. This substance was called the Vagusstoff and kept its identity secret until Henry Dale.

The chemical constitution of Amanita muscaria

The active alkaloids in Amanita muscaria are ibotenic acid, muscazole and muscazone, which act as gamma-aminobutyric acid receptor agonists and induce stupor followed by frenzy. Ibotenic acid is decarboxylated in the body to form muscimole, which is readily passed into the urine.

Other mushroom species such as Amanita pantherina contain a higher concentration of muscarine than A. muscaria, and produce a pure muscarinic syndrome when an overdose is taken. These species produce a short lived but dramatic constellation of symptoms, fortunately easily treated with saline and atropine.

Pilocarpine: a muscarine-like alkaloid derived from the jaborandi shrub

The Guarani Indians used Jaborandi to treat a variety of conditions, including mouth ulcers, epilepsy, and diphtheria. French physicians found that the leaves increased sweating and salivation, and caused a less degree secretion from the mucous membranes of the nose, the bronchial tubes, the stomach, and the intestines.

The Jaborandi shrub is a small shrub, 3 – 7.5 metres tall, that grows as an individual or in stands. Its most active alkaloid, pilocarpine, was isolated in 1875.

Pilocarpine7 is an imidazole alkaloid found in the leaves of the Jaborandi tree. It was used to treat oedema in cardiac failure and later led to the successful use of the alkaloid in the treatment of glaucoma.

Physostigmine from the Calabar bean

A novel alkaloid, physostigmine, was isolated from the Calabar bean in the 1860s. It had similar properties to pilocarpine and lowered intraocular pressure, and was used together with pilocarpine to treat glaucoma until the 1960s, when -adrenergic blocker drugs began to supplant them.

Early investigators noted that the belladonna alkaloid atropine could reverse the action of three alkaloids, and this was tantalising. Henry Dale and Otto Loewi would jointly receive the Nobel Prize in 1936 for their discovery.

The search for the elusive parasympathetic transmitter succeeds: acetylcholine is isolated

Henry Dale, director of The Wellcome Laboratory for Medical Research in London, was puzzled by the parasympathetic nervous system and called the unknown transmitter the ‘true’ muscarine.

A parasympathetic transmitter was suspected to be an ester of choline, perhaps the acetyl derivative, but physostigmine preserved the parasympathetic transmitter from destruction and allowed acetylcholine to accumulate in the heart and sympathetic ganglion, where it could be more easily detected.

Lee has described the development of physostigmine as a treatment for myasthenia gravis, but the greatest advance has come with the discovery of muscarinic receptors in the bronchioles and lung tissue.

The use of antimuscarinic drugs in lung disease

Muscarinic blockade is one of the most ancient treatments for asthma, but atropine has severe side effects and crosses the blood-brain barrier. Ipratropium and tiotropium were developed as alternative treatments, but are now less well-absorbed and have limited serious toxic effects.

Ipratropium is a synthetic quaternary ammonium compound that blocks all three muscarine receptors with equal affi nity. However, blocking the M2 receptors can potentiate vagally induced bronchoconstriction.

Tiotropium bromide is the fi rst anticholinergic to be effective in treating poorly controlled asthma. It has several other effects in respiratory disease, including inhibition of neutrophil migration into the lung.

Several other active selective M3 antagonists are under development, but it remains to be seen whether they will challenge tiotropium as an effective drug for the long term treatment of lung disease.

Conclusion

Amanita muscaria’s contribution to modern medicine is barely credible: from shamanistic cults in Eastern Siberia to Dale’s serendipitous suggestion that acetylcholine was the muscarine-like compound, to the development of useful drugs.

Shakespeare’s Romeo and Juliet concludes with a quotation from the Friar’s speech: “O mickle is the powerful grace that has.”

The history of Amanita muscaria is summarized in this speech. It was regarded as dangerous, devilish and deadly by the Russian authorities, but eventually proved useful in the treatment of glaucoma, asthma and COPD.