The fungus Amanita muscaria has been the object of intensive investigations for many years, and two of its constituents, muscarine and acetylcholine, are of fundamental importance in pharmacology. The elucidation of the structure of muscarine in the classical researches has overshadowed the existence in the plant of other interesting substances. The fungus has long had a reputation for insecticidal properties in folk-lore as the names ‘muscaria’, ‘fly agaric’ and ‘fliegenpilz’ imply. Ramsbottom6 describes its use—broken up in milk or sprinkled with sugar—as a fly trap in various parts of Europe.
The fly agaric contains compounds that individually exhibit various biological activities, mainly the muscarine, the ibotenic acid, and the muscimol. The combination of all these compounds can trigger a wide range of symptoms depending on the ingested quantities, the relative amounts of compounds in the mushroom, and the overall physical condition of the patient. These symptoms involve a state of inebriation, hallucinations, restlessness, increased psychomotor drive, central nervous system depression, and gastrointestinal disturbance. The usual clinical course after ingestion of a fly agaric usually starts after 30 min with nausea, vomiting, diarrhea, cramps, tremor, ataxia, and incoordination. After 60 min, there is an apparition of an altered mental status characterized by declining senses, alternating between agitation and obtundation, and bizarre behaviors, involving disorientation and depersonalization. Hallucinations under the form of visual and auditory distortions are also common. Finally, later effects imply lethargy, followed by deep sleep. There is no existing antidote, as symptoms are both cholinergic and anticholinergic. Treatments after ingestion usually involve gastric lavage, use of activated charcoal, and symptomatic supportive care. However, the ingestion of a cap is very unlikely to lead to death, and fatal cases are very scarce. Still, a lethal dose for a human adult was calculated to be equivalent to ingesting 15 caps. In addition to acute toxicity, and as previously mentioned, the mushroom is also consumed after detoxification as edible and the caps can accumulate contaminants. Therefore, the repeated consumption of mushroom harvested in contaminated areas may result in chronic toxicity related to long-term exposure to heavy metals.
The name of this alkaloid derives directly from the Amanita muscaria from which it was first isolated. As a nonselective acetylcholine agonist, it acts directly on muscarinic acetylcholine receptors in the parasympathetic nervous system—one of the three divisions of the autonomous peripheral nervous system. Once fixated to a cholinergic receptor, it is not degraded by cholinesterase; hence, it has a larger duration of action on neurons than that of acetylcholine and the subsequent toxicity. The nerves of this system encompass smooth muscles and glands; it has a direct influence on a variety of organs. Its action is tied to the “rest and digest” system, encompassing sexual arousal, salivation, lacrimation, urination, digestion, and defecation. This compound is unable to cross the blood–brain and blood–cerebrospinal fluid barriers, preventing potential effects on the acetylcholine receptors of the central nervous system. Although it is present as trace amounts (0.02% dry weight) in the basidiocarps, muscarine is notably responsible for the autonomic aspects of the symptoms and, particularly, the gastrointestinal ones—upon mushroom consumption, involving perspiration, hypersalivation, lachrymation, bradycardia, diarrhea, and fatigue. Higher concentrations of muscarine are reported in mushrooms belonging to the genera Inocybe, Inosperma and Pseudosperma.
Regarding biological activities, with muscarine being a neurotransmitter agonist, it exhibits a large range of actions on various neurons and endocrine cells.
Amanita muscaria contains isoxazoles compounds, mainly ibotenic acid and muscimol, but some derivatives have also been reported, such as muscazone, which is a product of ibotenic acid breakdown by UV radiation; it has a minor pharmacological activity compared with the other agents.
Unlike muscarine, ibotenic acid and muscimol readily cross the blood–brain barrier via an active transport system and exert their effects primarily on the central nervous system, where they act as neurotransmitter agonists. Ibotenic acid acts as an agonist of the glutamate at the N-methyl-d-aspartate (NMDA) glutamate receptors, while muscimol is a gamma-aminobutyric acid (GABA) agonist, targeting GABAA receptor. These two compounds are the main cause of the psychotropic effects after mushroom ingestion, with muscimol accounting for the greater part, because its psychoactive dose is 10 times lower than that of ibotenic acid. One fruit body of Amanita muscaria weighing 50–70 g (fresh weight) may contain around 6 mg of muscimol and up to 70 mg of ibotenic acid. Therefore, sufficient levels of alkaloids are contained in one basidiocarp of a mushroom to trigger psychoactive effects in a human adult. Ibotenic acid was also detected in the spores of the mushroom. After ingestion, ibotenic acid is partly metabolized to muscimol in the organism during an acidic decarboxylation step in the gastrointestinal tract. Afterwards, a part of the two compounds is carried to the brain and another part passes through the organism quickly and unmetabolized via the systemic circulation. They are then excreted by the kidneys and, thus, both ibotenic acid and muscimol can be detected in human urine collected a few hours after ingestion of mushrooms. In the brain, the same way muscarine is not degraded by cholinesterases, ibotenic acid and muscimol are not effectively removed from the neuronal synapse by the enzymatic systems that remove glutamate and GABA. They are then naturally excreted and almost all the ingested ibotenic acid and muscimol can be recovered in urine.
Regarding the biosynthetic pathway, seven genes belonging to the same ibo biosynthetic gene cluster and, hence, presenting in physical vicinity in the genome of A. muscaria are involved in the synthesis of muscimol. The synthesis is initiated with the hydroxylation of glutamate and six enzymes are required to form ibotenic acid from glutamate. One decarboxylase then catalyzes the formation of muscimol from ibotenic acid, with a yield of around 20%
Although they have related structures, ibotenic acid and muscimol have different effects on the central nervous system. As mentioned before, muscimol is an orthosteric agonist of the GABA, the main inhibitory neurotransmitter of the mammalian central nervous system; it is, therefore, responsible for central depressant effects. These psychotropic effects may be sedative, inebriant, and hallucinogenic, along with a somatic reaction involving nausea and vomiting.
On the other hand, ibotenic acid is an agonist of glutamate, thus inducing an excitatory effect on the central nervous system. These different actions are supported by the different syndromes observed in patients after the intoxication with Amanita muscaria and Amanita pantherina. Confusion, agitation, and euphoria are the main tendencies in the case of Amanita muscaria, in which ibotenic acid is present in higher concentrations than muscimol, and somnolence and comatose in the case of Amanita pantherina, in which muscimol is the major compound. Currently, the symptoms following intoxication with these two mushrooms share the same name: the so-called ibotenic or pantherina-muscaria syndrome; some authors suggest making a distinction to underline the specificity of each mushroom and, therefore, of each compound. However, because a portion of ibotenic acid is decarboxylated into muscimol in the stomach, the complete distinction regarding the effects of each compound is difficult.
Regarding the biological activities, infusion of low doses of muscimol in various brain areas—ventral hippocampus, prefrontal cortex, and amygdale—involved in the emotional processes and, notably, the anxiety state participated in the disruption of Pavlovian fear memory in rats.Gaba, through its interaction with Gabaa receptors, is known to negatively regulate the cellular proliferation in the nervous system, peripheral organs, and in tumor tissues. This way, muscimol also revealed an interesting effect in the attenuation of gastric carcinogenesis progression in rats.
Fly agaric extract containing a high concentration of muscimol showed an interesting neuroprotection effect on rat brain synaptosomes exposed to neurotoxin 6-hydroxydopamine, significantly preserving the synaptosomal viability in comparison with control, in which the toxin led to the formation of reactive oxygen species (ROS) and reactive quinones in the cells (a process occurring in Parkinson’s disease). As suggested by its name, the fly agaric is a natural insecticide. Due to the exclusive presence of glutamate-gated chloride channels in invertebrates, ibotenic acid exhibits insecticidal properties against the fly Musca domestica.
The presence of tropane alkaloids is unclear, as some studies highlighted the presence of these compounds in minor quantities in some mushrooms, while their occurrence is rejected by others. Those compounds include atropine, hyoscyamine, and scopolamine, which are acetylcholine antagonists; they bind to muscarinic acetylcholine receptors, blocking the action of the neurotransmitter, thus exerting a parasympatholytic action on the organism, including excitation, pupil dilatation, and repression of salivary, sweat, and gastric secretions. On the central nervous system, hyoscyamine has an excitatory effect, whereas scopolamine has a depressant action; both are classified as deliriant, meaning that the hallucinations are not recognized as unreal. The presence of traces of the highly lethal amatoxins and phallotoxins—typical from Amanita phalloides—have also been reported in some fly agaric.Bufotenine (5-hydroxy-N,N-dimethyltryptamine) has also been reported in various studies. Structurally, this compound is closely related to the psilocin (the active form of psilocybin), a fungal hallucinogenic tryptamine. Bufotenine is an agonist of serotonin on 5-HT receptors.
In addition, fly agaric extracts exhibit powerful antioxidant properties thanks to its high level of tocopherols—mainly γ-tocopherol and δ-tocopherol—and ascorbic acid. These antioxidant effects are also reported in vivo, exhibiting protection effects on human neuroblastoma cell line exposed to oxidant agents.
During the classical era, the fly agaric was consumed as an entheogenic substance during ceremonies of mystery cults, such as the Dionysian Mysteries in Greece and the Mithraic Mysteries in Rome. Fly agaric has also been consumed for millennia in Siberian societies for whom hunter–gatherer culture stems directly from the Stone Age for religious and recreational purposes, as it was the only inebriant in the area before the availability of alcohol brought by Slavic travelers, especially in the eastern part of Siberia.The religious practices in Eurasia involve the Siberian shaman, through mycophagy and aided by percussive rhythm, attaining a trance state of consciousness that allows him to connect his mind with spirits.As stated previously, an important part of both ibotenic acid and muscimol is excreted almost intact in urine; therefore, the tradition of drinking the urine of the shaman or of a reindeer who consumed fly agarics in order to get a second-hand stimulus was observed in some Siberian tribes.Drinking a reindeer’s urine after it had ingested mushrooms would also help to attenuate the unpleasant side effects.The Koryaks—indigenous people from the Kamchatka Peninsula—were known to carry flasks on their sleighs for that purpose.
Ancient Romans believed that some mushrooms emerged from the soil in locations that were stricken by a thunderbolt. Similar beliefs regarding the lightning strike origin of the fly agaric have also been reported amongst indigenous people from Guatemala and Southern Mexico.This tie is also explored in the theory established by Wasson (1971). Indeed, the author states that the fly agaric could be one of the candidates to be the Soma mentioned in the Rig Veda one of the four Vedas, religious scriptures of Hinduism and written in Indo-Aryan language.The Soma, like the Ambrosia in Greek mythology, is an elixir that gave immortality to the gods and, when consumed by the priests, had healing properties. Soma is both a god and a divine ritual drink, the god, being a personification of the drink, is himself the son of Parjanya, the Vedic Indo-Aryan god of thunder. Wasson (1968) also based his theory, supported by geographic and linguistic evidence, on the Northern Eurasiatic origins of the Indo-Aryan tribes, a region where the fly agaric shamanic rituals were common, as mentioned previously. The original text from the Rig Veda also details the preparation of the drink, including different steps of pressing and filtering. These purification steps could be a way to mitigate the toxicity of the mushroom, reducing the autonomic aspect of the symptoms, such as nausea and vomiting, to provide only the psychoactive effects. The debate on the identity of Soma is, however, far from being over, as there is still no consensus.
Another well-known theory regarding Amanita muscaria, formulated in the 18th century by the Swedish naturalist Samuel Ödman, stated that Viking warriors called berserkers could undergo a state of murderous rage, the berserkergang, during battle after the ingestion of fly agaric. Nowadays, this theory is rejected, notably because of the effects induced by the ingestion of fly agaric resulting in incapacitation for the fight. The henbane (Hyoscyamus niger), a plant rich in hyoscyamine and scopolamine, amongst other compounds, is a more serious candidate, as the substance is able to trigger the berserkergang.
During the Winter Solstice, the rebirth of the Sun was celebrated in all pre-Christian Europe through religious rituals and feasts to conjure luck and fertility for the new coming cycle. In a syncretic approach, because of the shared attributes between Jesus Christ and the Solar Deity, the church established the birth of Christ around the Winter Solstice during the 4th century. Some remnants of the pagan admixtures to Christian celebrations are still vivid. Under its obvious phallic shape, Amanita muscaria, along with mistletoe, was a symbol of luck and fertility, especially in the Germanic traditions. A reason that may explain the omnipresence of fly agaric on Christmas representations cards, decorations in Germany and Austria. The modern figure of Santa Claus results in the mixing of various Christian and Northern pagan traditions (most notably, Finnish and Scandinavian). Details ranging from the white and red colors to the flying reindeers pulling his sleigh are reminders of the shamanic tradition of fly agaric ingestion. Interestingly, just like Amanita muscaria that, through ectomycorrhizal interactions with pines, emerge and are harvested by the shaman under these trees, gifts are placed by Santa Claus under the green fir tree during Christmas Eve.
The toxins in Amanita muscaria are water-soluble: parboiling Amanita muscaria fruit bodies can detoxify them and render them edible, although consumption of the mushroom as a food has never been widespread. The consumption of detoxified Amanita muscaria has been practiced in some parts of Europe (notably by Russian settlers in Siberia) since at least the 19th century, and likely earlier. The German physician and naturalist Georg Heinrich von Langsdorff wrote the earliest published account on how to detoxify this mushroom in 1823. In the late 19th century, the French physician Félix Archimède Pouchet was a populariser and advocate of Amanita muscaria consumption, comparing it to manioc, an important food source in tropical South America that must be detoxified before consumption.
Use of this mushroom as a food source also seems to have existed in North America. A classic description of this use of Amanita muscaria by an African-American mushroom seller in Washington, D.C., in the late 19th century is described by American botanist Frederick Vernon Coville. In this case, the mushroom, after parboiling, and soaking in vinegar, is made into a mushroom sauce for steak. It is also consumed as a food in parts of Japan. The most well-known current use as an edible mushroom is in Nagano Prefecture, Japan. There, it is primarily salted and pickled.
A 2008 paper by food historian William Rubel and mycologist David Arora gives a history of consumption of Amanita muscaria as a food and describes detoxification methods. They advocate that Amanita muscaria be described in field guides as an edible mushroom, though accompanied by a description on how to detoxify it. The authors state that the widespread descriptions in field guides of this mushroom as poisonous is a reflection of cultural bias, as several other popular edible species, notably morels, are toxic unless properly cooked.
The red-and-white spotted toadstool is a common image in many aspects of popular culture. Garden ornaments and children's picture books depicting gnomes and fairies, such as the Smurfs, often show fly agarics used as seats, or homes. Fly agarics have been featured in paintings since the Renaissance, albeit in a subtle manner. For instance, in Hieronymus Bosch's painting, The Garden of Earthly Delights, the mushroom can be seen on the left-hand panel of the work. In the Victorian era they became more visible, becoming the main topic of some fairy paintings. Two of the most famous uses of the mushroom are in the Mario franchise (specifically two of the Super Mushroom power-up items and the platforms in several stages which are based on a fly agaric), and the dancing mushroom sequence in the 1940 Disney film Fantasia.
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