Editing Amanita muscaria (section)

==Toxicity==
[[File:Amanita muscaria After Rain.jpg|thumb|upright|Mature. The white spots may wash off with heavy rainfall.|alt=a tall red mushroom with a few white spots on the cap]]
''A. muscaria'' poisoning has occurred in young children and in people who ingested the mushrooms for a [[hallucinogenic]] experience,<ref name = "Michelot03"/><ref name="Benjamin 1992 Mushroom Poisoning in Infants"/><ref name="Hoegberg">{{cite news |author1=Hoegberg LC |author2=Larsen L |author3=Sonne L |author4=Bang J |author5=Skanning PG |title=Three cases of ''Amanita muscaria'' ingestion in children: two severe courses |pages=407–408 }} In: {{cite journal |title=Abstracts of the XXVIII International Congress of the European Association of Poison Centres and Clinical Toxicologists, May 6–9, 2008, Seville, Spain |journal=Clinical Toxicology |date=January 2008 |volume=46 |issue=5 |pages=351–421 |doi=10.1080/15563650802071703 |pmid=18568796 }}</ref> or who confused it with an edible species.

''A. muscaria'' contains several biologically active agents, at least one of which, [[muscimol]], is known to be [[psychoactive]]. [[Ibotenic acid]], a [[neurotoxin]], serves as a [[prodrug]] to muscimol, with a small amount likely converting to muscimol after ingestion. An active dose in adults is approximately 6&nbsp;mg muscimol or 30 to 60&nbsp;mg ibotenic acid;<ref>{{cite journal |last1=Theobald |first1=W |last2=Büch |first2=O |last3=Kunz |first3=HA |last4=Krupp |first4=P |last5=Stenger |first5=EG |last6=Heimann |first6=H |title=Pharmakologische und experimental psychologische Untersuchungen mit 2 Inhaltsstoffen des Fliegenpilzes (''Amanita muscaria'') |trans-title=Pharmacological and experimental psychological studies with 2 components of fly agaric (''Amanita muscaria'') |language=de |journal=Arzneimittel-Forschung |date=March 1968 |volume=18 |issue=3 |pages=311–315 |pmid=5696006 }}</ref><ref name=chilton>{{cite journal |author=Chilton WS|title=The course of an intentional poisoning|journal=MacIlvanea |volume=2 |page=17 |year=1975 }}</ref> this is typically about the amount found in one cap of ''Amanita muscaria''.<ref name="Satora05"/> The amount and ratio of chemical compounds per mushroom varies widely from region to region and season to season, which can further confuse the issue. Spring and summer mushrooms have been reported to contain up to 10 times more ibotenic acid and muscimol than autumn fruitings.<ref name="Benjamin 1992 Mushroom Poisoning in Infants"/>

Deaths from ''A. muscaria'' have been reported in historical journal articles and newspaper reports,<ref>{{cite journal |author=Cagliari GE|title=Mushroom poisoning|journal=Medical Record |volume=52 |page=298 |year=1897}}</ref><ref name="Buck63"/><ref>{{cite news |title=THE STUDY OF MYCOLOGY: Vecchi's Death Said to be Due to a Deliberate Experiment with Poisonous Mushrooms. GROWING POPULAR INTEREST Clubs Formed in This City, Boston, Philadelphia, and Washington -- Views of Prof. Underwood of Columbia University |newspaper=[[The New York Times]] |date=19 December 1897 |page=12 |id={{ProQuest|95504145}} |url=https://www.nytimes.com/1897/12/19/archives/the-study-of-mycology-vecchis-death-said-to-be-due-to-a-deliberate.html }}</ref> but with modern medical treatment, fatal poisoning from ingesting this mushroom is extremely rare.<ref name="Tupalska-Wilczyńska"/> Many books list ''A.&nbsp;muscaria'' as deadly,<ref>{{cite book |last=Phillips |first=Roger |title=Mushrooms and Other Fungi of North America |date=2010 |publisher=Firefly Books |location=Buffalo, NY |isbn=978-1-55407-651-2 |page=16}}</ref> but according to [[David Arora]], this is an error that implies the mushroom is far more toxic than it is.<ref name="arora894">Arora, ''Mushrooms demystified'', p. 894.</ref> Furthermore, The [[North American Mycological Association]] has stated that there were "no reliably documented cases of death from toxins in these mushrooms in the past 100 years".<ref>{{cite web|url=http://www.namyco.org/toxicology/poison_syndromes.html|title=Mushroom poisoning syndromes|work=North American Mycological Association (NAMA) website|publisher=NAMA|access-date=2009-03-22| archive-url= https://web.archive.org/web/20090404122352/http://www.namyco.org/toxicology/poison_syndromes.html| archive-date= 4 April 2009 | url-status= live}}</ref>

The active constituents of this species are water-soluble, and boiling and then discarding the cooking water at least partly detoxifies ''A.&nbsp;muscaria''.<ref name="INTOX"/> Drying may increase potency, as the process facilitates the conversion of ibotenic acid to the more potent muscimol.{{sfn|Benjamin|1995|p=310}} According to some sources, once detoxified, the mushroom becomes edible.<ref name="RubArora"/><ref>{{cite web |last=Shaw |first=Hank |url=http://honest-food.net/2011/12/24/eating-santas-shroom/ |title=How to Safely Eat Amanita Muscaia |date=2011-12-24 |work=honest-food.net |url-status=live |archive-url=https://web.archive.org/web/20160304191941/http://honest-food.net/2011/12/24/eating-santas-shroom/ |archive-date=2016-03-04}}</ref> Patrick Harding describes the Sami custom of processing the fly agaric through reindeer.<ref>{{youTube|GIB5umwbJwE|Dr. Patrick Harding - Unwrapping the Mysteries of Christmas}}</ref>

===Pharmacology===
[[File:Muscimol chemical structure.svg|right|thumb|[[Muscimol]], the principal psychoactive constituent of ''A.&nbsp;muscaria'']]
[[File:ibotenic acid2.png|right|thumb|[[Ibotenic acid]], a [[prodrug]] to muscimol found in ''A.&nbsp;muscaria'']]
[[Muscarine]], discovered in 1869,<ref>{{cite book|author=Schmiedeberg O.|author2=Koppe R.|title=Das Muscarin, das giftige Alkaloid des Fliegenpilzes|publisher=F.C.W. Vogel|location=Leipzig|year=1869|oclc=6699630|language=de}}</ref> was long thought to be the active hallucinogenic agent in ''A.&nbsp;muscaria''. Muscarine binds with [[muscarinic acetylcholine receptor]]s leading to the excitation of neurons bearing these receptors. The levels of muscarine in ''Amanita muscaria'' are minute when compared with other poisonous fungi<ref>{{cite journal |last1=Eugster |first1=Conrad Hans |title=Wirkstoffe aus dem Fliegenpilz |trans-title=Active substances from the toadstool |language=de |journal=Die Naturwissenschaften |date=July 1968 |volume=55 |issue=7 |pages=305–313 |doi=10.1007/BF00600445 |pmid=4878064 |bibcode=1968NW.....55..305E }}</ref> such as ''[[Inosperma erubescens]]'', the small white ''[[Clitocybe]]'' species ''[[Clitocybe dealbata|C. dealbata]]'' and ''[[Clitocybe rivulosa|C. rivulosa]]''. The level of muscarine in ''A.&nbsp;muscaria'' is too low to play a role in the symptoms of poisoning.{{sfn|Benjamin|1995|p=306}}

The major toxins involved in ''A.&nbsp;muscaria'' poisoning are [[muscimol]] (3-hydroxy-5-aminomethyl-1-isoxazole, an [[Unsaturated compound|unsaturated]] cyclic [[hydroxamic acid]]) and the related amino acid [[ibotenic acid]]. Muscimol is the product of the [[decarboxylation]] (usually by drying) of ibotenic acid. Muscimol and ibotenic acid were discovered in the mid-20th century.<ref name="Bowden K"/><ref name="Eugster"/> Researchers in England,<ref>{{cite journal |author=Bowden, K. |author2= Drysdale, A. C. |title=A novel constituent of ''Amanita muscaria''|journal=Tetrahedron Lett. |volume=6 |issue= 12|pages=727–8 |date=March 1965 |pmid=14291871 |doi= 10.1016/S0040-4039(01)83973-3}}</ref> Japan,<ref>{{cite news |author1=薬 学 雑 誌 |title=イ ボ テ ン 酸 の 構 造 |trans-title=Structure of Ibotenic Acid |language=ja |pages=1232–1233 }} In: {{cite journal |last1=Takemoto |first1=Tsunematsu |last2=Nakajima |first2=Tadashi |last3=Yokobe |first3=Tetsuro |last4=Sakuma |first4=Reiko |last5=Fujitani |first5=Kazuyoshi |last6=Aoyagi |first6=Yoshiaki |last7=Masaki |first7=Yukio |title=Communication to the Editor |journal=Yakugaku Zasshi |date=December 1964 |volume=84 |issue=12 |pages=1230–1236 |doi=10.1248/yakushi1947.84.12_1230 }}</ref> and Switzerland<ref name="Eugster">{{cite journal |author=Eugster, C. H. |author2= Müller, G. F.|author3= Good, R. |title=[The active ingredients from Amanita muscaria: ibotenic acid and muscazone] |language=de |journal=Tetrahedron Lett. |volume=6 |issue= 23|pages=1813–5 |date=June 1965 |pmid=5891631 |doi=10.1016/S0040-4039(00)90133-3}}</ref> showed that the effects produced were due mainly to ibotenic acid and muscimol, not muscarine.{{sfn|Benjamin|1995|pp=306–307}}<ref name="Bowden K">{{cite journal |author=Bowden, K. |author2= Drysdale, A. C.|author3= Mogey, G. A. |title=Constituents of ''Amanita muscaria'' |journal=Nature |volume=206 |issue=991 |pages=1359–60 |date=June 1965 |pmid=5891274 |doi=10.1038/2061359a0 |bibcode=1965Natur.206.1359B }}</ref> These toxins are not distributed uniformly in the mushroom. Most are detected in the cap of the fruit, a moderate amount in the base, with the smallest amount in the stalk.<ref>Lampe, K.F., 1978. "Pharmacology and therapy of mushroom intoxications". In: Rumack, B.H., Salzman, E. (Eds.), ''Mushroom Poisoning: Diagnosis and Treatment''. CRC Press, Boca Raton, FL, pp. 125–169</ref><ref>{{cite journal |last1=Tsunoda |first1=Koujun |last2=Inoue |first2=Noriko |last3=Aoyagi |first3=Yasuo |last4=Sugahara |first4=Tatsuyuki |title=Changes in Concentration of Ibotenic Acid and Muscimol in the Fruit Body of Amanita muscaria during the Reproduction Stage |journal=Food Hygiene and Safety Science (Shokuhin Eiseigaku Zasshi) |date=1993 |volume=34 |issue=1 |pages=18–24_1 |doi=10.3358/shokueishi.34.18 |doi-access=free }}</ref> Quite rapidly, between 20 and 90 minutes after ingestion, a substantial fraction of ibotenic acid is excreted unmetabolised in the urine of the consumer. Almost no muscimol is excreted when pure ibotenic acid is eaten, but muscimol is detectable in the urine after eating ''A.&nbsp;muscaria'', which contains both ibotenic acid and muscimol.<ref name=chilton/>

Ibotenic acid and muscimol are structurally related to each other and to two major [[neurotransmitter]]s of the central nervous system: [[glutamic acid]] and [[GABA]] respectively. Ibotenic acid and muscimol act like these neurotransmitters, muscimol being a potent [[GABA A receptor|GABA<sub>A</sub>]] [[agonist]], while ibotenic acid is an agonist of [[NMDA receptor|NMDA glutamate receptors]] and certain [[metabotropic glutamate receptor]]s<ref>{{cite journal |author=Jørgensen, C. G. |author2= Bräuner-Osborne, H.|author3=Nielsen, B. |title=Novel 5-substituted 1-pyrazolol analogues of ibotenic acid: synthesis and pharmacology at glutamate receptors |journal=Bioorganic & Medicinal Chemistry |volume=15 |issue=10 |pages=3524–38 |date=May 2007 |pmid=17376693 |doi=10.1016/j.bmc.2007.02.047 |display-authors=etal}}</ref> which are involved in the control of neuronal activity. It is these interactions which are thought to cause the psychoactive effects found in intoxication.<ref name = "Michelot03"/><ref name="Satora05">{{cite journal |author=Satora, L. |author2=Pach, D.|author3= Butryn, B.|author4= Hydzik, P.|author5= Balicka-Slusarczyk, B. |title=Fly agaric (''Amanita muscaria'') poisoning, case report and review |journal=Toxicon |volume=45 |issue=7 |pages=941–3 |date=June 2005 |pmid=15904689 |doi=10.1016/j.toxicon.2005.01.005 |bibcode=2005Txcn...45..941S }}</ref>

[[Muscazone]] is another compound that has more recently been isolated from European specimens of the fly agaric. It is a product of the breakdown of ibotenic acid by [[ultraviolet radiation]].<ref>{{cite journal |last1=Fritz |first1=H. |last2=Gagneux |first2=A.R. |last3=Zbinden |first3=R. |last4=Geigy |first4=J.R. |last5=Basle |first5=S.A. |last6=Eugster |first6=C.H. |title=The structure of muscazone |journal=Tetrahedron Letters |date=January 1965 |volume=6 |issue=25 |pages=2075–2076 |doi=10.1016/S0040-4039(00)90156-4 }}</ref> Muscazone is of minor [[Biological activity|pharmacological activity]] compared with the other agents.<ref name = "Michelot03"/> ''Amanita muscaria'' and related species are known as effective [[bioaccumulation|bioaccumulators]] of [[vanadium]]; some species concentrate vanadium to levels of up to 400 times those typically found in plants.<ref name="Garner"/> Vanadium is present in fruit-bodies as an [[Organometallic chemistry#Organometallic compounds|organometallic]] compound called [[amavadine]].<ref name="Garner">{{cite journal |last1=Garner |first1=C.David |last2=Armstrong |first2=Elaine M |last3=Berry |first3=Rober E |last4=Beddoes |first4=Roy L |last5=Collison |first5=David |last6=Cooney |first6=J.Jon A |last7=Ertok |first7=S.Nigar |last8=Helliwell |first8=Madeleine |title=Investigations of Amavadin |journal=Journal of Inorganic Biochemistry |date=May 2000 |volume=80 |issue=1–2 |pages=17–20 |doi=10.1016/s0162-0134(00)00034-9 |pmid=10885458 }}</ref> The biological importance of the accumulation process is unknown.<ref>{{cite journal |last1=Hubregtse |first1=Ton |last2=Neeleman |first2=Ernst |last3=Maschmeyer |first3=Thomas |last4=Sheldon |first4=Roger A. |last5=Hanefeld |first5=Ulf |last6=Arends |first6=Isabel W.C.E. |title=The first enantioselective synthesis of the amavadin ligand and its complexation to vanadium |journal=Journal of Inorganic Biochemistry |date=May 2005 |volume=99 |issue=5 |pages=1264–1267 |doi=10.1016/j.jinorgbio.2005.02.004 |pmid=15833352 }}</ref>

===Symptoms===
Fly agarics are best known for the unpredictability of their effects. Depending on habitat and the amount ingested per body weight, effects can range from mild [[nausea]] and twitching to drowsiness, [[cholinergic crisis]]-like effects (low [[blood pressure]], [[sweat]]ing and [[saliva]]tion), auditory and visual distortions, mood changes, [[Euphoria (emotion)|euphoria]], relaxation, [[ataxia]], and [[Vertigo (medical)|loss of equilibrium]] (like with [[tetanus]].)<ref name="Benjamin 1992 Mushroom Poisoning in Infants">{{cite journal |last1=Benjamin |first1=Denis R. |title=Mushroom Poisoning in Infants and Children: The ''Amanita Pantherina''/''Muscaria'' Group |journal=Journal of Toxicology: Clinical Toxicology |date=January 1992 |volume=30 |issue=1 |pages=13–22 |doi=10.3109/15563659208994442 |pmid=1347320 }}</ref><ref name="Hoegberg"/><ref name="Satora05"/><ref name="Buck63">{{cite journal |author=Buck, R. W. |title=Toxicity of ''Amanita muscaria'' |journal=JAMA |volume=185 |issue= 8|pages=663–4 |date=August 1963 |pmid=14016551 |doi=10.1001/jama.1963.03060080059020}}</ref>

In cases of serious poisoning the mushroom causes [[delirium]], somewhat similar in effect to [[anticholinergic]] poisoning (such as that caused by ''[[Datura stramonium]]''), characterised by bouts of marked [[Psychomotor agitation|agitation]] with confusion, hallucinations, and irritability followed by periods of [[central nervous system]] depression. [[Seizures]] and [[coma]] may also occur in severe poisonings.<ref name="Hoegberg"/><ref name="Satora05"/> Symptoms typically appear after around 30 to 90 minutes and peak within three hours, but certain effects can last for several days.<ref name="Brvar06">{{cite journal |author=Brvar, M. |author2= Mozina, M.|author3= Bunc, M. |title=Prolonged psychosis after ''Amanita muscaria'' ingestion |journal=Wien. Klin. Wochenschr. |volume=118 |issue=9–10 |pages=294–7 |date=May 2006 |pmid=16810488 |doi=10.1007/s00508-006-0581-6 }}</ref><ref name=chilton/> In the majority of cases recovery is complete within 12 to 24&nbsp;hours.<ref name="INTOX">{{cite web | author = Piqueras, J.| title = Amanita muscaria, Amanita pantherina and others | publisher = IPCS INTOX Databank | date = 10 January 1990 | url = http://www.intox.org/databank/documents/fungi/aminita/pimg026.htm | access-date = 2008-12-08}}</ref> The effect is highly variable between individuals, with similar doses potentially causing quite different reactions.<ref name="Benjamin 1992 Mushroom Poisoning in Infants"/><ref name="chilton" /><ref name="Ott76">{{cite book|author=Ott, J. |title=Hallucinogenic Plants of North America|publisher=Wingbow Press|location=Berkeley, CA|year=1976|isbn=978-0-914728-15-3}}</ref> Some people suffering intoxication have exhibited headaches up to ten hours afterwards.<ref name=chilton/> [[Retrograde amnesia]] and [[somnolence]] can result following recovery.<ref name="Satora05"/>

===Treatment===
Medical attention should be sought in cases of suspected poisoning. If the delay between ingestion and treatment is less than four hours, [[activated charcoal]] is given. [[Gastric lavage]] can be considered if the patient presents within one hour of ingestion.<ref>{{cite journal | author=Vale, J. A. |author2= Kulig, K.|author3= American Academy of Clinical Toxicology|others= European Association of Poisons Centres and Clinical Toxicologists | title=Position paper: gastric lavage | journal=Journal of Toxicology: Clinical Toxicology | year=2004 | pages=933–43 | volume=42 | issue=7 | pmid=15641639 | doi=10.1081/CLT-200045006 }}</ref> Inducing vomiting with [[syrup of ipecac]] is no longer recommended in any poisoning situation.<ref>{{cite journal | author=American Academy Of Clinical Toxico | author2=European Association Of Poisons Cen | title=Position paper: Ipecac syrup | journal=Journal of Toxicology: Clinical Toxicology | year=2004 | pages=133–43 | volume=42 | issue=2 | pmid=15214617 | doi=10.1081/CLT-120037421 }}</ref>[[File:Amanita muscaria-Portland.jpg|thumb|Found in a parking lot, Portland Oregon US.]]

There is no antidote, and supportive care is the mainstay of further treatment for intoxication. Though sometimes referred to as a [[deliriant]] and while muscarine was first isolated from ''A. muscaria'' and as such is its namesake, [[muscimol]] does not have action, either as an [[agonist]] or [[Receptor antagonist|antagonist]], at the [[muscarinic acetylcholine receptor]] site, and therefore [[atropine]] or [[physostigmine]] as an antidote is not recommended.<ref>{{cite book | author = Dart, R. C.|title = Medical toxicology | publisher = Lippincott Williams & Wilkins | year = 2004 | location = Philadelphia, PA | pages = 1719–35 | isbn = 978-0-7817-2845-4}}</ref> If a patient is [[Delirium|delirious]] or agitated, this can usually be treated by reassurance and, if necessary, physical restraints. A [[benzodiazepine]] such as [[diazepam]] or [[lorazepam]] can be used to control combativeness, agitation, muscular overactivity, and seizures.<ref name="Benjamin 1992 Mushroom Poisoning in Infants"/> Only small doses should be used, as they may worsen the [[Respiratory depression|respiratory depressant]] effects of muscimol.<ref>{{cite book | author = Brent, J.|author2= Wallace, K. L.|author3= Burkhart, K. K.|author4= Phillips, S. D.|author5= Donovan, J. W. | title = Critical care toxicology: diagnosis and management of the critically poisoned patient | publisher = Elsevier Mosby | year = 2005 | location = Philadelphia, PA | pages = 1263–75 | isbn = 978-0-8151-4387-1}}</ref> Recurrent vomiting is rare, but if present may lead to fluid and electrolyte imbalances; intravenous rehydration or electrolyte replacement may be required.<ref name="Satora05"/>{{sfn|Benjamin|1995|p=313}} Serious cases may develop loss of [[consciousness]] or [[coma]], and may need [[intubation]] and [[artificial ventilation]].<ref name="Hoegberg"/><ref>{{cite journal |author=Bosman, C. K.|author2= Berman, L.|author3= Isaacson, M.|author4= Wolfowitz, B.|author5= Parkes, J. |title=Mushroom poisoning caused by ''Amanita pantherina''. Report of 4 cases |journal=South African Medical Journal |volume=39 |issue=39 |pages=983–86 |date=October 1965 |pmid=5892794}}</ref> [[Hemodialysis]] can remove the toxins, although this intervention is generally considered unnecessary.<ref name="INTOX"/> With modern medical treatment the prognosis is typically good following supportive treatment.<ref name="Tupalska-Wilczyńska">{{cite journal |last1=Tupalska-Wilczyńska |first1=Krystyna |last2=Ignatowicz |first2=Roman |last3=Poziemski |first3=Andrzej |last4=Wójcik |first4=Halina |last5=Wilczyński |first5=Grzegorz |title=Zatrucia muchomorami plamistym i czerwonym—patogeneza, objawy, leczenie |trans-title=Poisoning with spotted and red mushrooms—pathogenesis, symptoms, treatment |language=pl |journal=Wiadomosci Lekarskie |volume=49 |issue=1–6 |pages=66–71 |year=1996 |pmid=9173659 }}</ref><ref name="INTOX"/>