Pharmacia 67(4): 317–323

DOI 10.3897/pharmacia.67.e56112

Review Article

Toxicological and pharmacological profile of

Amanita muscaria (L.) Lam. – a new rising
opportunity for biomedicine
Maria Voynova1, Aleksandar Shkondrov2, Magdalena Kondeva-Burdina1, Ilina Krasteva2
1 Laboratory of Drug metabolism and drug toxicity, Department “Pharmacology, Pharmacotherapy and Toxicology”, Faculty of Pharmacy, Medical
University of Sofia, Bulgaria
2 Department of Pharmacognosy, Faculty of Pharmacy, Medical University of Sofia, Bulgaria

Corresponding author: Magdalena Kondeva-Burdina (magdalenakondeva@gmail.com)

Received 2 July 2020  ♦  Accepted 19 August 2020  ♦  Published 26 November 2020

Citation: Voynova M, Shkondrov A, Kondeva-Burdina M, Krasteva I (2020) Toxicological and pharmacological profile of Amanita
muscaria (L.) Lam. – a new rising opportunity for biomedicine. Pharmacia 67(4): 317–323. https://doi.org/10.3897/pharmacia.67.
e56112

Abstract
Amanita muscaria, commonly known as fly agaric, is a basidiomycete. Its main psychoactive constituents are ibotenic acid and mus-
cimol, both involved in ‘pantherina-muscaria’ poisoning syndrome. The rising pharmacological and toxicological interest based on
lots of contradictive opinions concerning the use of Amanita muscaria extracts’ neuroprotective role against some neurodegenerative
diseases such as Parkinson’s and Alzheimer’s, its potent role in the treatment of cerebral ischaemia and other socially significant
health conditions gave the basis for this review. Facts about Amanita muscaria’s morphology, chemical content, toxicological and
pharmacological characteristics and usage from ancient times to present-day’s opportunities in modern medicine are presented.

Keywords
Amanita muscaria, muscimol, ibotenic acid

Introduction rica, the genus had an ancestral origin in the Siberian-Be-

ringian region in the Tertiary period (Geml et al. 2008).
Amanita mushrooms belong to divis. Basidiomycota, class The cap of A. muscaria may be orange or yellow (or
Agaricomycetes, ord. Agaricales, fam. Amanitaceae (Bas rarely, with red and yellow alternating sectors) at first.
1969; Persoon 1801). Species of the genus Amanita are Some populations in North America and Europe may
distributed worldwide and are generally easy to recognize. have consistently yellow or white caps (Geml et al. 2008).
Native to conifer and deciduous woodlands throughout the According to Tulloss (2005) the cap is orange-red, 90–
temperate and boreal regions of the Northern Hemisphere, 145  mm wide; the volva is distributed over the cap as
including regions such as Hindu Kush, the Mediterranean, white or yellow warts that are easily removed by rain; the
and also Central America (Tulloss 2005). There are around gills are free to narrowly adnate, crowded to sub-crowded,
1000 species of Amanita worldwide (Tulloss 2005). About and white or whitish; the short gills are truncate; the stipe
100 species of the genus are considered poisonous and is 60–210 × 8–22 mm and has a skirt-like annulus and no-
about 50 are edible. Some recent molecular studies propose table bulb of a rather variable shape (up to 46 × 45 mm).
that before spreading across Asia, Europe, and North Ame- Rings of volval material commonly encircle the top of the
bulb and the base of the stipe. The spores measure (7.4)8.5

Copyright Voynova M et al. This is an open access article distributed under the terms of the Creative Commons Attribution License
(CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source
are credited.
318 Voynova M et al.: Toxicological and pharmacological profile of Amanita muscaria

uble substances by heat. For instance, Mexican people

ate the carpophore of A. muscaria without the cuticle
and also discarded the cooking water. (Perez-Silva and
Herrera-Suarez 1991) In Italy, after boiling and discard-
ing the water, A. muscaria is preserved in brine prior to
consumption. In North America, the mushroom is dried
and then smoked after the red cuticle is peeled (Rubel
and Arora 2008). Apart from intoxication in people who
voluntarily ate the mushroom for a hallucinogenic expe-
rience, A. muscaria poisoning has been reported in chil-
dren (Benjamin 1992) and in adults who ingested it by
mistake. This is a case of misscollection because the white
spots on the cap sometimes wash away during heavy rain
Figure 1. A. muscaria (L.) Lam. in Belasitsa Mountain, Bulgaria. and the mushrooms may resemble the edible A. caesarea.
Death from this kind of mushroom is rare or rarely re-
ported. If so, it is due to complications.
–11.5(13.1) × (5.6)6.5 – 8.5(9.8) µm and are broadly ellip-
soid and inamyloid.  Clamps are very common at bases of
basidia (Fig. 1). Chemical compounds in
A. muscaria  forms symbiotic ectomycorrhizal associ- A. muscaria
ations with a broad range of hosts from the families Bet-
ulaceae, Cistaceae, Cupressaceae, Pinaceae, Rosaceae and The chemical composition of the mushroom depends on
Salicaceae, though associates most frequently with tree the substrates, atmospheric conditions, age, and develop-
members of genera Betula, Pinus, Pice and Eucalyptus ment stage. Mushrooms are rich in proteins, fats, carbo-
(Dunk et al. 2011). hydrates, vitamins of group B (thiamine, riboflavin, py-
There is a vast amount of literature on the poisonous ridoxine, pantothenic acid, nicotinic acid, nicotinamide,
agents in Amanita species. Some produce alkaloids with folic acid and cobalamin), but also in ergosterol, biotin,
hallucinogenic properties. A. muscaria  as a widespread phytochinone, and tocopherols.
fungus containing ibotenic acid and muscimol (Takemoto According to FDA classification (2012) there are four
et al. 1964, Eugster et al. 1965) has been used to catch flies main categories of mycotoxins:
for centuries due to the exclusive presence of glutamate-gat-
ed chloride channels in invertebrates where glutamate and • protoplasmic poisons (that result in generalized de-
ibotenic acid serve as excitatory and inhibitory neurotrans- struction of cells, followed by organ failure);
mitters in insects (Stebelska 2013). Some simple prepara- • neurotoxins (that cause neurological symptoms
tion methods were soaking the fungus in milk or water or such as profuse sweating, coma, convulsions, hallu-
sprinkling milk directly on the cap, while others were more cinations, excitement, depression, spastic colon);
complex and included a combination of heat or mechanical • gastrointestinal irritants (that produce rapid, tran-
processing and soaking (Rubel and Arora 2008). The re- sient nausea, vomiting, abdominal cramping, and
lease of ibotenic acid was time-dependent, with the extract- diarrhoea);
ed amount increasing over time (Lumpert and Kreft 2016). • disulfiram-like toxins (which are generally non-tox-
Thousands of years before this usage began, the psycho- ic and produce no symptoms unless alcohol is con-
tropic effects of the mushroom were widely used by the in- sumed within 72 h after ingestion);
habitants of Siberia, Kamchatka, and the Vikings. The ‘fairy’ • external intoxicants as heavy metals and radioactive
mushrooms as well as A. muscaria appeared on rock paint- contaminants (due to polluting environmental con-
ings, dated back to 3500 BC, in a cave in present Algeria, de- ditions where the mushrooms are harvested).
picting dancing figures, holding mushrooms in their hands
(Wieczorek 2014). Similar findings from Central America The pharmacology of Amanita muscaria is not en-
suggest that hallucinogenic mushrooms were used in the tirely understood. Two primary compounds, ibotenic
Aztecs’ and the Mayas’ religious rituals (Feeney 2010). acid and muscimol, are known to be responsible for its
The main psychoactive substances of the mushroom psychoactive effects. Ibotenic acid, a neurotoxin, serves
are muscimol, ibotenic acid and mukazon. When in- as a pro-drug to muscimol, with approximately 10–20%
gested the mushroom leads to a state resembling alco- converting to muscimol after decarboxylation). Only
holic intoxication (Meyer and Quenzer 2005) known as 53 mg of muscimol are sufficient to produce psychoac-
‘pantherina-muscaria’ poisoning syndrome. The custom tive effects when ingested, while a dose of 93 mg pro-
of peeling the cuticule before mushroom consumption duces a strong inebriation, including vomiting (Chil-
aims to eliminate the highest content of psychoactive ton and Ott 1975). In human volunteers, effects were
substances (Catalfomo and Eugster 1970). Cooking measurable about 1 h after ingestion of 7.5 to 10 mg of
would eliminate the greater part of the active water-sol- muscimol, or 50 to 90 mg of ibotenic acid. These effects
Pharmacia 67(4): 317–323 319

continue for 3 to 4 h with some residual effects lasting

as much as 10 to 24 h in some subjects. (Chilton and Ott
1975). Waser (1979) reported flushing, lassitude, and
sleepness after ingestion of 20 mg of ibotenic acid and
5 mg of muscimol. The LD50 of muscimol in rats ranges
from 4.5 mg/kg administered intravenously to 45 mg/
kg, oral gavage (p.o.) (Ott 1976). Experiments in dogs
suggest that the effects of 20 mg/kg/day, p.o., are not
cumulative (Waser 1979). Probably its psychoactivity is
caused purely by the decarboxylation product of ibo-
tenic acid, muscimol (Ott 1976).
According to Stebelska (2013), psychedelic effects in
Figure 2. Structure of muscarine.
adults occur after an oral intake of approx. 6 mg of mus-
cimol or 30 to 60 mg ibotenic acid (one fruit body of A.
muscaria, 50–70 g, may contain up to 70 mg of ibotenic Izoxazoles
acid). The symptoms such as dizziness, nausea, tiredness,
a feeling of weightlessness, visual and auditory hypersen- Muscazone (Fig. 3) (2-Amino-2-(2-oxo-3H-1,3-oxazol-5-
sitivity, space distortion, unawareness of time, and colour- yl)acetic acid) is another compound that has been isola-
ed hallucinations start 20–30 min after ingestion and usu- ted from European specimens of the fly agaric (Fritz et
ally end within 2  to 8 h to full recovery in 24 h (Satora al. 1965). It is a product of ibotenic acid breakdown by
et al. 2005). There is no specific antidote or therapy. The UV radiation. Muscazone has a minor pharmacological
treatment is mainly supportive and symptomatic. Only activity compared with the other agents (Catalfomo and
in the first 2 h activated charcoal may be given or urgent Eugster 1970).
gastric lavage can be applied. Sedation is urgently needed. Ibotenic acid and muscimol are structurally related.
Atropine is not recommended but may be administered Muscimol, being structurally similar to GABA is a potent
subcutaneously. Special attention must be given to medi- GABAA receptor agonist, while ibotenic acid is an ago-
cations for seizure control with precaution, because GAB- nist of NMDA glutamate receptors interactions causing
Aergic anticonvulsants such as benzodiazepines or barbi- the hallucinogenic effects observed during intoxication
turates may contribute to respiratory or central nervous (Johnston, 2009).
system depression (Michelot and Melendez-Howell 2003; Ibotenic acid, (S)-2-Amino-2-(3-hydroxyisoxazol-5-yl)
Benjamin 1992). acetic acid, is a colourless, crystalline substance soluble
Тhe main toxins in A. muscaria are muscarine, iboten- in water (Fig. 3). It is metabolized by decarboxylation in
ic acid, muscimol and muscazone (Eugster and Takemoto the stomach, liver, and brain (Nielsen et al. 1985) to equal
1967). The mushroom is known as an effective bio accu- amount of muscimol which pass the blood-brain barrier
mulator of vanadium (in an organometallic compound (Michelot and Melendez-Howell 2003). Both substances
called amavadine) and other toxic metals (Berry et al. can be detected in urine within 1 h of exposure (Mero-
1999). Stizolobic acid, stizolobinic acid and tricholomic va et al. 2008). Ibotenic acid, unlike muscimol, is much
acid are also present as derivatives of ibotenic acid. These more dangerous, causing ibotenate-induced seizures and
three compounds are related to L-DOPA oxidation prod- lesions in specific brain regions, similar to Alzheimer’s
ucts, which are known to cause anticholinergic activity. disease for which it is used in animal test models (Stebel-
These three amino acids can activate excitatory amino ska 2013). Stereotactic intrahippocampal administration
acid receptors, but there are probably not enough of these of ibotenic acid (5µg/µl) lesioned rats impairs cholinergic
compounds to have an effect, at least in most Amanita transmission, learning and memory performance (related
muscaria poisonings (Chilton et al. 1974). to Alzheimer’s disease) and thus chosen as a suitable mod-
el to understand drug efficacy in preventing Alzheimer’s
Muscarine disease pathophysiology (Patocka et al. 2017).
Exposure to chronic stress in young male rats increases
In 1869, muscarine (Fig. 2) was isolated from European A. hippocampal glutaminergic receptor density or affinity, thus
muscaria and was for decades believed to be the main ac- making cornus ammonis neurons more vulnerable to ibo-
tive principle (Eugster 1979), from which the compound tenic acid (Conrad et al. 2007). In Alzheimer’s disease (AD),
derives its name. Muscarine is a selective cholinergic ago- where HPA (hypothalamic-pituitary-adrenal) activity is
nist  suspected to contribute to the overall activity of A. elevated, hippocampal NMDA receptor number does not
muscaria. Muscarine is both water soluble and thermo- generally decrease. The results on the presence of NMDA
stable (does not degrade with cooking). It is known to sites in the majority of AD cases indicate that receptor den-
be responsible for reduced heart rate, lowering of blood sity is preserved except in cases where there is extremely se-
pressure, vomiting, diarrhoea, bradycardia, bronchorrhea, vere cell loss. Rats exposed to the same paradigm of chronic
tearing, bronchospasm (asthmatic-like breathing), saliva- restraint do not show increase in hippocampal NMDA or
tion, pupil contraction and blurred vision. non-NMDA receptor binding (Geddes et al. 1986).
320 Voynova M et al.: Toxicological and pharmacological profile of Amanita muscaria

Figure 3. Chemical changes of ibotenic acid to muscazone and muscimol.

Muscimol (5-(Aminomethyl)-isoxazol-3-ol) was iso- cause a decrease of the catecholamines, as on the contrary
lated from A. muscaria in the early 1960’s (Takemoto et ibotenic acid increases the catecholamine concentration
al. 1964; Eugster, Muller and Good 1965) as a colourless, (Konig-Bersin et al. 1970).
crystalline substance, readily soluble in cold water (Fig. A low dose of muscimol injected at doses of 0.5–1 mg/
3). It appears to be the essential principle of Amanita kg i.p. affects the EEG of cats and rabbits (De Carolis et al.
muscaria since it is present in very high concentration 1969). These observations further support a localization
(0.03–0.1%) of fresh mushroom (DeFeudis 1980). Oral, of action of muscimol in the brain rather than in the pe-
systemic, or intracerebral administration of muscimol ripheral nervous system.
undoubtedly affects certain CNS functions and behaviour. Recently it has been suggested that GABA is involved
Muscimol is a non-selective GABAA receptor agonist ac- in morphine analgesia. The injection of 0.15 to 0.2 mg/kg
tivating both pre- and postsynaptic receptors and partial of muscimol i.v., lowered ED50 dose of morphine in mice
agonist of GABAc receptors devoid of effects on the GA- and rats. Muscimol given alone, at doses up to 2.0 mg/kg
BA-metabolizing enzyme, GABAA transaminase, and the (i.v.) failed to cause analgesia in mice or rats. However,
GABAA uptake systems which also enters the brain after when injected intravenously 10 min before morphine at
peripheral injection (Snodgrass 1978). It is reported to be a dose of 0.15 mg for morphine analgesia in mice from
a potent agonist at bicuculline-sensitive, strychnine-in- 4.1 mg/kg (s.c.) to 1.6 mg/ ED50 is highly significant (Big-
sensitive postsynaptic receptors of the mammalian central gio et al. 1977).
nervous system. For example, muscimol (3 mg/kg, i.p.) Reversible inactivation of brain areas is an useful meth-
evokes serotonin rise and decreases catecholamine levels od for inferring brain-behaviour relationships. Infusion of
in the brain. The compound binds to GABAA  receptors GABA or of the GABA receptor agonist muscimol is con-
mainly in the areas of the forebrain, including the caudate sidered one interesting reversible inactivation method be-
nucleus and putamen, the thalamus and the hippocampal cause it may not affect fibres of passage and may therefore
formation leading to the opening of the receptor associ- be compared to axon-sparing types of lesions (Majchrzak
ated with the chloride ion channel, which in turn leads to et al. 2000). Concluding that reversible inactivation tech-
inhibition of neuronal activity, where these receptors are niques significantly contribute to the knowledge of “where
located (Stebelska 2013). Muscimol high-affinity binding and when” neuronal events for learning and memory take
in forebrain regions such as caudate – putamen, thalamus, place in the brain.
and hippocampus was dependent on distinct population of In concern to affecting memory, intra-hippocampal
GABAA receptors possibly containing subunit 6 and lack- infusion of muscimol increased the percent of neurons
ing subunit 1 as shown in knockout study in mice (Chan- active in cornus amonius (CA3) significantly, improving
dra et al. 2009). rats’ learning and memory abilities in both normal and
AD-type rats suggesting that intensification of GABAe-
Central nervous system activity rgic processes may be an useful pharmacotherapeutic
strategy in early memory decline in AD (Pilipenko et al.
Like LSD, muscimol and ibotenic acid induce a genera- 2015). Infusions of muscimol into the dorsal hippocam-
lized increase of serotonin but only muscimol keeps the pus in male rats produce impairments in fear learning
serotonin concentration increased in midbrain and hypo- (at a dose of 0.5 mg of muscimol per hemisphere) (Cor-
thalamus after pre-treatment with p-ehlorophenylalani- coran and Maren 2001) and working memory (at a dose
ne (a serotonin synthesis inhibitor). Muscimol and LSD of 0.03–0.06 µg of muscimol) (Mao and Robinson 1998).
Pharmacia 67(4): 317–323 321

These findings suggest that because muscimol is a potent al. 1992) was again connected with GABA agonists acti-
GABAA agonist, it is likely that hippocampal infusions of vity over the control of anterior pituitary hormones; the
muscimol modulate learning through increased neural sympathetic and parasympathetic nervous system. Using
inhibition of the hippocampus. muscimol as a GABAA receptors agonist proved its pro-
Тhe activation of the GABAA receptor by muscimol tective role in treatment of oral squamous cell carcinoma
modulates the hypothalamic–pituitary–gonadal (HPG) (Jing Ma et al. 2016).
axis increasing kisspeptin expression through stimulating
KiSS-1 mRNA expression, in the hypothalamic neurons.
Kisspeptin is a neuropeptide closely linked to the repro- Other bioactive compounds
ductive function of multiple species. Surprisingly, the
natural GABA compound had no effect on KiSS-1 gene
Antioxidants
expression, in contrast to muscimol (Kanasaki et al. 2017).
Muscimol was also used as a prototype substance for Last but not least A. muscaria, like the other mushrooms
the design of THIP (Gaboxazole, 4,5,6,7-tetrahydroi- from the genus, contain a vast amount of biologically ac-
soxazolo[5,4-c]pyridin-3-ol hydrochloride,) an izoxaz- tive compounds with proven antioxidant activity: proteins
ole investigated as insomnia and seizure medication but and peptides (glutathione and ergothioneine), phenolic
withdrawn from phase 3 clinical trials, due to efficacy and compounds (flavonoids, lignans, oxidized polyphenols,
side effects problems (Johnston et al. 2009). The GABA re- phenolic acids, stilbenes and tannins), vitamins and de-
ceptors agonist used in a double-blind study administered rivatives (ascorbic acid, ergosterol, tocopherols, carote-
orally (5–10 mg per day) to ten patients with Huntington’s noids), and minerals (zinc and selenium). Their antioxi-
disease did not result in improvement of motor or cogni- dant properties and ability to scavenge free radicals have
tive functions but significantly ameliorated chorea in the been further demonstrated in studies using rodent mo-
most severely hyperkinetic patient, and it was associated dels with hepatic injury, induced by either streptozotocin
with the appearance of dystonic features, electroencepha- (STZ), carbon tetrachloride (CCl4), or D-galactosamine
lographic changes, and behavioural alterations in five pa- (D-GalN). For example, the activation of GABAA receptor
tients. Moreover, adverse effects as increased irritability, inhibits stem cell proliferation but protects differentiated
agitation and lethargy, lack of attention, loss of appetite, cells from injures (Wang et al. 2017). Muscimol treatment
and insomnia occurred in five patients and appeared to be decreases the formation of pseudo bile ductiles and the
dose related in each instance (Shoulson et al. 1978). How- enlargement of hepatocytic canaliculi in GalN-treated rats
ever, the constant failure to prove muscimol’s potential revealing that a complex GABA signalling system exists in
effect as an anticonvulsant only indicates that the GABA the rat liver. Its activation protects the liver against toxic
disturbances connected with motor deficits does not alone injury (Wang et al. 2017).
account for the clinical features of the ongoing disorders.
Potentiation of inhibitory mechanisms may be impor- Pigments
tant to neuronal protection from the effects of ischaemia.
The GABAA agonist effects of muscimol showed protec- The colouring of A. muscaria is due to a complicated mix-
tive role in a dose-dependent manner in both rat and rab- ture of pigments. Muscarufin and muscaflavin are terphe-
bit microsphere embolism model of ischaemia (Lyden and nylquinone derivatives which give the yellow colouring.
Hedges 1992). In a model of forebrain ischaemia, musci- The betalain group composed of numerous betalamic acid
mol given 7 days before the onset, protected the cortex, condensates (muscapurpurin and muscaaurins) with dif-
hippocampus, substantia nigra, striatum and thalamus ferent amino acids, ibotenic or stizolobic acid are responsi-
(Sternau et al. 1989), suggesting that the damaging effects ble for the typical red-orange colour of the caps of A. mus-
from forebrain ischemia may be a result of excessive excit- caria (Michelot & Melendez-Howell, 2003). By repeated
ability or loss of inhibitory influence. chromatography the pigment mixture has been fractiona-
ted into at least ten components, i. e. the orange muscaau-
Anticarcinogenic effects rins, the yellow muscaflavin, the red-violet muscapurpurin
and the red muscarubrin (Stintzing et al. 2007).
Sonnenberg (1988) found that gastric cancer occurred
more frequently in patients who had ischaemic heart Polysaccharides
disease or cerebrovascular disease, and concluded that
gastric cancer and diseases related to hypertension share Among polysaccharides, glucans are the most abundant
a common etiologic factor. Prolonged administration of and widely distributed carbohydrates in the fungal cell
the GABAA receptor-agonist muscimol (i.p. injections of wall. A fucomannogalactan (Ruthes et al. 2013) and a
0.5 mg/kg body weight) attenuated the enhancement of (1→3),(1→6)-linked β-D-glucan (Kiho et al. 1994) were
N-methyl-N-nitro-N-nitrosoguanidine (MNNG)-indu- isolated from A. muscaria fruiting bodies and their bio-
ced gastric carcinogenesis in spontaneously hypertensi- logical activities were further studied against pain and
ve rats (SHR) on the 52th week, resulting in a significant inflammation as well as antitumor activity. All of these
reduction in the incidence of gastric cancer (Tatsuta et activities are a subject of further studies.
322 Voynova M et al.: Toxicological and pharmacological profile of Amanita muscaria

Conclusion also call for supervised and cautious designed studies with
precautious administration of its active compounds es­
The findings suggest that A. muscaria offers а great versa- pecially muscimol. Still, mycotherapy turns to be a very
tility of beneficial effects in cell protection and especially promising territory for future investigations, but a lot of
in neuroprotection, cardio protection, hepatoprotec­tion, experiments, would be needed to validate the usefulness
inflammation process, oxidative stress, and may even con- of A. muscaria and its compounds, either alone or in com-
tribute to development of new drugs. The adverse effects bination with existing therapies.

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