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

Amanita muscaria (fly agaric) is presented as a culturally prominent and readily recognisable mushroom in Europe and the UK, notable for its scarlet cap with white scales and association with birch forests. Earlier research and ethnographic reports established its long-standing use as an inebriant and hallucinogen among Siberian shamans, while 19th- and 20th-century pharmacological work identified multiple bioactive alkaloids; nonetheless, the mushroom's precise contribution to understanding parasympathetic pharmacology and the identity of the endogenous parasympathetic transmitter remained a historically important puzzle. This paper traces that historical and pharmacological trajectory. It aims to recount the ethnographic accounts of shamanistic use, summarise the isolation and characterisation of the mushroom's active constituents (including muscarine, ibotenic acid, muscimol and muscazone), and to describe how those findings, together with work on other alkaloids such as pilocarpine and physostigmine, contributed to the discovery of acetylcholine and to the development of therapeutics for glaucoma and respiratory disease. The article is framed as a narrative historical review rather than an empirical study with a formal experimental protocol.

The extracted text contains a descriptive, historical narrative rather than a methods section typical of empirical research. No explicit search strategy, inclusion criteria, databases searched, or systematic review methods are reported in the extracted material. Instead, the paper synthesises ethnographic accounts (notably early 20th-century descriptions of Siberian reindeer-herding tribes), classical pharmacological experiments from the 19th and early 20th centuries, and later chemical analyses from the mid-20th century onward. Because no formal methodology is given in the extracted text, it is not possible to state whether the authors used a systematic literature search, archival work, or selective citation. The account therefore should be read as a narrative synthesis of historical and pharmacological sources rather than as a systematic review with reproducible methods.

The paper opens with a concise natural history of A. muscaria: the cap may reach about 20 cm, the stipe up to 23 cm with a bulbous base, and the species favours acidic soils, often in birch woodland, appearing in late summer and autumn. The Amanita genus also includes other medically important species such as A. phalloides (death cap) and A. pantherina (panther cap). Ethnographic material summarises the use of A. muscaria among Eastern Siberian peoples, particularly the Koryak and related groups. The shamanic rituals are linked to a creation myth (the Big Raven), and reported effects include an initial drunken stupor followed by a phase of frantic activity, auditory hallucinations and altered colour vision. A culturally specific practice was the retention and reuse of urine from intoxicated individuals, which still contained active hallucinogens and could intoxicate reindeer that consumed it. The text emphasises that fatal poisonings from A. muscaria are rare and that the mushroom had economic value in some communities. Pharmacological history is reviewed through key figures and discoveries. Oswald Schmiedeberg and Richard Kloppe isolated muscarine in 1869 and observed its parasympathetic (muscarinic) effects, including bradycardia mediated via vagal stimulation and blockade by atropine. Subsequent chemical work established that muscarine is actually a minor constituent of A. muscaria (reported as perhaps 1-3% by weight). The principal active compound in many fly agaric specimens appears to be ibotenic acid (reported concentrations about 0.3–1.0 g per kg dry weight), which is decarboxylated in the body to muscimol; muscimol and related compounds (including muscazone) act as gamma-aminobutyric acid (GABA) receptor agonists and are implicated in the central nervous system effects (stupor followed by frenzy). Variability in alkaloid content and seasonal changes in the ibotenic acid/muscimol ratio are noted as likely explanations for differing intoxication profiles. The paper contrasts species and genera that produce predominantly peripheral muscarinic syndromes (for example A. pantherina, Inocybe and Clitocybe) with those, like A. muscaria, whose central effects derive from ibotenic acid/muscimol. Typical muscarinic signs described include vomiting, diarrhoea, salivation, bronchoconstriction and bradycardia; these are usually short-lived and responsive to supportive care (intravenous fluids) and atropine administration. A broader pharmacological narrative connects these natural products to therapeutics. Pilocarpine, an imidazole alkaloid isolated from Pilocarpus species in the 19th century, produced strong parasympathetic effects (sweating, salivation, miosis) and led to ophthalmic use for lowering intraocular pressure and treating glaucoma; it remains in use for xerostomia. Physostigmine, isolated from the Calabar bean, acted as an anticholinesterase and facilitated the detection of the endogenous parasympathetic transmitter by preserving it from enzymatic destruction. Historical experiments and reasoning by Henry Dale and Otto Loewi are summarised: Dale hypothesised a muscarine-like endogenous transmitter and, with Loewi's complementary work, physostigmine enabled the isolation and identification of acetylcholine as the parasympathetic neurotransmitter. The role of acetylcholinesterase in terminating acetylcholine action and the classification of muscarinic and nicotinic effects are described. Finally, the text reviews the development of antimuscarinic drugs for respiratory disease. Ipratropium, a synthetic quaternary ammonium compound introduced in the 1980s, has limited systemic absorption but blocks multiple muscarinic receptor subtypes (M1–M3) with roughly equal affinity. Tiotropium is presented as a functionally selective M3 antagonist with a longer duration of effect permitting once-daily inhalation and improved efficacy in some trials for asthma and COPD. The existence of five muscarinic receptor subtypes (M1–M5) and ongoing development of selective M3 antagonists are noted, as is the potential for combination inhaler therapies that pair an M3 antagonist with a β2-agonist and steroid.

Lee and colleagues present the historical narrative as an exemplar of how ethnobotanical/ethnomycological observation can seed pharmacological discovery. They interpret the story of A. muscaria as moving from shamanistic ritual use through 19th-century pharmacological isolation of muscarine to mid-20th-century chemical characterisation of ibotenic acid and muscimol, culminating in the biochemical work that identified acetylcholine and the development of clinically useful cholinergic and anticholinergic drugs. The paper situates these developments relative to earlier research by highlighting key turning points: Schmiedeberg's isolation of muscarine and demonstration of vagal-like effects, the later identification of ibotenic acid/muscimol as central nervous system actives, and the pivotal use of physostigmine to permit isolation of acetylcholine by Dale and Loewi. The authors emphasise the medical consequences of this chain of discovery, naming pilocarpine, physostigmine and modern antimuscarinics such as tiotropium as therapeutic outcomes. The extracted text acknowledges variability in alkaloid content between species and across seasons as a source of differing toxicological and psychoactive profiles. It does not, however, present a formal limitations section or methodological caveats typical of empirical studies; the account remains a narrative synthesis of historical and pharmacological sources. The authors draw implications for drug discovery more broadly: identification of natural sources, isolation of active principles and subsequent pharmacological characterisation can lead to useful therapeutics.

The authors conclude that the history of Amanita muscaria is striking: a fungus once central to shamanistic rites contributed, via a sequence of ethnographic observation and biochemical investigation, to the identification of acetylcholine and to the development of drugs such as pilocarpine, physostigmine and tiotropium. They present this arc as illustrative of the broader scientific process—discover the organism, isolate active compounds and evaluate therapeutic activity—and close by noting the ambivalent cultural status of the mushroom while emphasising the practical benefits that emerged from its study.