Muscimol

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| _other_data=5-(aminomethyl)-1,2-oxazol-3-one

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| _countSecondIDs={{#invoke:ParameterCount |main |CAS_number2 |ATC_prefix2 |PubChem2 |PubChemStructure2 |IUPHAR_ligand2 |DrugBank2 |ChemSpiderID2 |UNII2 |KEGG2 |ChEBI2 |ChEMBL2 |PDB_ligand2 |NIAID_ChemDB2 |SMILES2 |smiles2 |StdInChI2 |StdInChIKey2 |DTXCID2}} | _countIndexlabels={{#invoke:ParameterCount |main |index_label |index2_label}} | _trackListSortletter= |QID = |QID2 = |Verifiedfields=verified |Watchedfields=verified |verifiedrevid=410573320}} Muscimol, also known as agarin, pantherine, or pyroibotenic acid, is a GABA_A receptor agonist with sedative and hallucinogenic effects and the principal psychoactive constituent of Amanita mushrooms such as Amanita muscaria (fly agaric) and Amanita pantherina (panther cap).<ref name="Elks_2014">Template:Cite book</ref><ref name="RiveraIllanes_2024">Template:Cite journal</ref><ref name="Johnston_2014">Template:Cite journal</ref><ref name="Michelot_2003">Template:Cite journal</ref><ref name="KrogsgaardLarsen_1981">Template:Cite journal</ref> It is a 3-hydroxyisoxazole alkaloid and is closely related structurally to the neurotransmitter γ-aminobutyric acid (GABA).<ref name="Johnston_2014" /><ref name="RiveraIllanes_2024" /><ref name="Okhovat_2023" /> The compound is widely used as a ligand and agonist of the GABA_A receptor in scientific research.<ref name="Johnston_2014" /><ref name="RiveraIllanes_2024" /> Muscimol is typically taken orally, but may also be smoked.<ref name="RiveraIllanes_2024" /><ref name="Stebelska_2013" /><ref name="Okhovat_2023" /><ref name="Ott_1996" /> Peak effects occur after 1 to 3Template:Nbsphours orally<ref name="Ott_1996" /><ref name="Hollister_1990" /><ref name="Tamminga_1978" /> and its duration is 4 to 8Template:Nbsphours but up to 24Template:Nbsphours.<ref name="Ott_1996" /><ref name="Okhovat_2023" /><ref name="Trachsel_2000" />

The effects of muscimol in humans include central depression, sedation, sleep, cognitive and motor impairment, hallucinations, perceptual distortion, and muscle twitching, among others.<ref name="HallHall1994" /><ref name="Stebelska_2013" /><ref name="Brimblecombe_1975" /><ref name="Waser_1967" /> Muscimol acts as a potent GABA_A receptor full agonist.<ref name="Johnston_2014" /><ref name="RiveraIllanes_2024" /><ref name="KrogsgaardLarsen_1997">Template:Cite journal</ref> It is also a potent GABA_A-ρ receptor partial agonist and a weak GABA reuptake inhibitor.<ref name="Johnston_2014" /><ref name="RiveraIllanes_2024" /><ref name="Okhovat_2023" /> The drug is inactive at the GABA_B receptor but is a substrate of GABA transaminase (GABA-T).<ref name="Johnston_2014" /><ref name="Stebelska_2013" /><ref name="Okhovat_2023" /> Muscimol mostly exerts its effects via GABA_A receptor activation.<ref name="Stebelska_2013" /> It is very different from drugs like benzodiazepines and barbiturates as it is an orthosteric agonist of the GABA_A receptor rather than an allosteric modulator.<ref name="RiveraIllanes_2024" /><ref name="Frlund_2002" /> Unlike GABA, muscimol crosses the blood–brain barrier and hence is centrally active.<ref name="Frlund_2002">Template:Cite journal</ref><ref name="Michelot_2003" /><ref name="Stebelska_2013" /> Muscimol, which is also known chemically as 5-aminomethylisoxazol-3-ol, is a conformationally restrained analogue of GABA.<ref name="Johnston_2014" /><ref name="Okhovat_2023" /> The related compound and Amanita spp. constituent ibotenic acid is a prodrug of muscimol.<ref name="RiveraIllanes_2024" /><ref name="Michelot_2003" /><ref name="Okhovat_2023" />

Muscimol was first isolated from Amanita muscaria and hence was discovered in 1964.<ref name="Johnston_2014" /><ref name="RiveraIllanes_2024" /><ref name="KrogsgaardLarsen_1981" /> It has been limitedly clinically studied as a potential pharmaceutical drug for a number of uses, such as treatment of epilepsy.<ref name="RiveraIllanes_2024" /><ref name="DeFeudis_1980" /><ref name="Ramawad_2023" /><ref name="Heiss_2019" /> In addition, analogues and derivatives of muscimol, such as the selective GABA_A receptor agonist gaboxadol (THIP; LU-2-030) and the selective GABA reuptake inhibitor tiagabine (Gabitril), have been developed as pharmaceutical drugs.<ref name="Johnston_2014" /><ref name="KrogsgaardLarsen_2004">Template:Cite journal</ref><ref name="Okhovat_2023" /><ref name="Morris_2013">Template:Cite magazine</ref> Muscimol and Amanita muscaria mushrooms have rarely been used as recreational drugs historically.<ref name="Ott_1996" /> By the mid-2020s however, use of these substances, including recreational use for hallucinogenic effects and microdosing for claimed therapeutic benefits, has become increasingly prominent.<ref name="RiveraIllanes_2024" /><ref name="Hartwig_2025" /><ref name="Savickaite_2025">Template:Cite journal</ref><ref name="Ordak_2023">Template:Cite journal</ref> The most commonly cited therapeutic reason for their use is to improve sleep.<ref name="Hartwig_2025" /> Muscimol is not a controlled substance and is unregulated in most of the world, including in most of the United States and Europe.<ref name="RiveraIllanes_2024" /><ref name="Leas_2024">Template:Cite journal</ref><ref name="Savickaite_2025" />

Natural occurrence

Amanita muscaria (fly agaric) mushrooms, which contain muscimol.

The main natural sources of muscimol are fungi of the genus Amanita, such as Amanita muscaria (fly agaric) and Amanita pantherina (panther cap). It is produced in the mushrooms along with muscarine (which is present in trace amounts and it is not active), muscazone, and ibotenic acid.<ref name="Chilton_1976">Template:Cite journal</ref><ref name="Michelot_2003" /> In Amanita muscaria, the layer just below the skin of the cap contains the highest amount of muscimol, and is therefore the most psychoactive portion.<ref name="Chilton_1978">Template:Cite book</ref>

Use and effects

The properties and effects of muscimol in humans have been limitedly assessed in clinical studies.<ref name="Stebelska_2013" /><ref name="Hollister_1990" /><ref name="Brimblecombe_1975">Template:Cite book</ref><ref name="Waser_1967">Template:Cite book</ref> It has been assessed in these studies at doses of 5 to 15Template:Nbspmg orally.<ref name="Stebelska_2013" /> The oral threshold dose of muscimol is approximately 6Template:Nbspmg,<ref name="Stebelska_2013">Template:Cite journal</ref><ref name="Ott_1976" /> while the psychoactive dose range has been said to range from approximately 8 to 15Template:Nbspmg.<ref name="RiveraIllanes_2024" /><ref name="Okhovat_2023">Template:Cite journal</ref><ref name="Trachsel_2000" /> As little as 1Template:Nbspg of dried Amanita muscaria button may contain this amount of muscimol, although the potency varies greatly among mushrooms.<ref name="Peredy_2014">Template:Cite book</ref> According to Jonathan Ott, a 15Template:Nbspmg dose is "psychoptic" while a 20Template:Nbspmg dose is "visionary".<ref name="Ott_1996" /> The onset of action of muscimol, via isolated muscimol or Amanita muscaria consumption orally, is between 30Template:Nbspminutes and 2Template:Nbsphours,<ref name="Okhovat_2023" /><ref name="Waser_1967" /> with peak effects occurring after 1 to 3Template:Nbsphours.<ref name="Ott_1996" /><ref name="Hollister_1990">Template:Cite journal</ref><ref name="Tamminga_1978" /> The duration is 4 to 8Template:Nbsphours, but some effects may persist for up to 24Template:Nbsphours.<ref name="Ott_1996" /><ref name="Okhovat_2023" /><ref name="Satora_2005" /><ref name="Trachsel_2000" /><ref name="Hollister_1990" /><ref name="Tamminga_1978" /> In one publication, the effects of muscimol were described as follows:<ref name="Brimblecombe_1975" /><ref name="Waser_1967" />

"Waser (1967) describes the effects of self-administration of 10–15 mg. of muscimol as '. . . intense hallucinations as with LSD were missing . . . there resulted considerable disturbances of psychic functions, such as orientation in space and time, visual perception, process of thinking, speech, and some new psychic phenomena of illusions and echo pictures'. Higher doses tended to produce severe intoxication in man, with painful muscular twitching, considerable agitation, and vivid hallucinations."<ref name="Brimblecombe_1975" /><ref name="Waser_1967" />

The effects of muscimol in humans in different studies have been found to include sedation, dizziness, incoordination, relaxation, reduced anxiety, mood improvement, sleep, rich dreaming, difficulty speaking, impaired attention, focus, and concentration, impaired learning, confusion, loss of appetite, stimulation, agitation, hallucinogenic effects, echo-like pseudohallucinations (visual and auditory, vivid hallucinations, psychosis, and delirium.<ref name="Stebelska_2013" /><ref name="RiveraIllanes_2024" /><ref name="Okhovat_2023" /><ref name="Brimblecombe_1975" /> At higher doses, coma, seizures, and death can occur.<ref name="Okhovat_2023" /><ref name="RiveraIllanes_2024" /> Physical effects of muscimol can include muscle twitching, flushing, slightly increased blood pressure, nausea, vomiting, abdominal pain, and diarrhea, among others.<ref name="Stebelska_2013" /><ref name="Okhovat_2023" /><ref name="RiveraIllanes_2024" /><ref name="HallHall1994" /> After-effects have been reported to include fatigue, inactivity, and headache and migraine.<ref name="Stebelska_2013" /> Muscimol can increase prolactin and growth hormone levels.<ref name="Tamminga_1978a" /><ref name="Durso_1983" />

Muscimol is said to have similar effects on sleep in rodents as the related experimental pharmaceutical drug gaboxadol (THIP).<ref name="KrogsgaardLarsen_2004" /><ref name="Johnston_2014" /><ref name="Wafford_2006">Template:Cite journal</ref><ref name="McDonaldSheppardStaveley2007">Template:Cite journal</ref> In humans, gaboxadol decreases sleep onset latency, increases sleep duration, increases slow wave sleep (SWS) and slow wave activity (SWA), and does not suppress REM sleep.<ref name="Wafford_2006" /> The effects of muscimol and gaboxadol on sleep differ from those of widely used GABA_A receptor positive allosteric modulators like benzodiazepines and Z-drugs, which can instead disrupt SWS and SWA despite improving sleep onset and duration.<ref name="KrogsgaardLarsen_2004" /><ref name="Johnston_2014" /><ref name="Wafford_2006" /><ref name="Dijk_2010">Template:Cite journal</ref> Although muscimol and gaboxadol have similar effects on sleep, muscimol has additionally been found to increase REM sleep unlike gaboxadol.<ref name="McDonaldSheppardStaveley2007" />

Ibotenic acid, a prodrug of muscimol, is active at doses of approximately 20 to 100Template:Nbspmg orally in humans.<ref name="Ott_1996">Template:Cite book</ref><ref name="Stebelska_2013" /><ref name="Okhovat_2023" /><ref name="RiveraIllanes_2024" /> About 10 to 20% of ibotenic acid is said to be converted into muscimol following decarboxylation.<ref name="Hartwig_2025">Template:Cite journal</ref><ref name="Ott_1996" />

Toxicity and overdose

The toxicity and safety profile of muscimol has been studied in various contexts, both experimental and clinical. The median lethal dose (LD₅₀) in mice is 3.8Template:Nbspmg/kg s.c, 2.5Template:Nbspmg/kg i.p. The LD₅₀ in rats is 4.5Template:Nbspmg/kg i.v, 45 mg/kg orally.<ref name="Erowid">Template:Cite webTemplate:Rs</ref> A study on non-human primates indicated that muscimol, when administered in escalating doses, caused reversible hyperkinesia and dyskinesias at higher doses (up to 88.8 mM), but no long-term toxicity was observed on histological examination.<ref>Template:Cite journal</ref> Muscimol has shown potential as an anticonvulsant, blocking seizures induced by various agents in animal models without causing significant toxicity at therapeutic doses.<ref>Template:Cite journal</ref> Muscimol exhibits dose-dependent effects with higher doses leading to significant, but reversible, central nervous system symptoms.<ref>Template:Cite journal</ref> The dose of muscimol that is thought to be potentially fatal in humans is 90Template:Nbspmg, which is 15Template:Nbsptimes its threshold active dose of 6Template:Nbspmg.<ref name="Peredy_2014" />

Interactions

The actions and effects of muscimol may be potentiated by benzodiazepines such as diazepam.<ref name="Michelot_2003" /><ref name="Johnston_2014" />

Pharmacology

Pharmacodynamics

γ-Aminobutyric acid (GABA) and muscimol molecules can have similar 3D conformations which are shown superimposed in this image. Because of this similarity, muscimol binds to certain GABA receptors.<ref name="Michelot_2003" />

Muscimol is a potent GABA_A receptor full agonist, activating the receptor for the brain's principal inhibitory neurotransmitter, γ-aminobutyric acid (GABA).<ref name="Johnston_2014" /> Muscimol binds to the same site on the GABA_A receptor complex as GABA itself, unlike other GABAergic drugs such as barbiturates, benzodiazepines, and Z-drugs, which interact with separate allosteric sites.<ref name="Frlund_2002" /><ref name="Johnston_2014" /> GABA_A receptors are widely distributed in the brain, so when muscimol is administered, it alters neuronal activity in multiple regions including the cerebral cortex, hippocampus, and cerebellum. By mimicking GABA, muscimol activates these receptors, leading to the opening of chloride channels and subsequent hyperpolarization of neurons. This results in decreased neuronal excitability, which is crucial for maintaining the balance between excitation and inhibition in the central nervous system.<ref name="Chebib_1999">Template:Cite encyclopedia</ref>

Muscimol shows relatively uniform effects on GABA_A receptors of differing subunit compositions.<ref name="Johnston_2014" /><ref name="RiveraIllanes_2024" /> However, it was found to act as a superagonist of extrasynaptic α₄β₃δ subunit-containing GABA_A receptors (Template:Abbrlink = 120 to 140% relative to GABA).<ref name="Johnston_2014" /><ref name="RiveraIllanes_2024" /> This was found to be due to reduced receptor desensitization with muscimol compared to GABA.<ref name="Johnston_2014" /> Subsequent research has found that muscimol is a preferential agonist of the relatively small population of δ subunit-containing GABA_A receptors and that these receptors have a substantial contribution to its effects.<ref name="Benkherouf_2019">Template:Cite journal</ref><ref name="RiveraIllanes_2024" /> In contrast to muscimol, benzodiazepines and Z-drugs do not activate δ subunit-containing GABA_A receptors.<ref name="DeaconStanerStaner2007">Template:Cite journal</ref> On the other hand, alcohol is known to selectively potentiate δ subunit-containing extrasynaptic GABA_A receptors analogously to muscimol.<ref name="LoboHarris2008">Template:Cite journal</ref><ref name="SanthakumarWallnerOtis2007">Template:Cite journal</ref><ref name="WallnerOlsen2008">Template:Cite journal</ref>

While muscimol is often thought of as a selective GABA_A agonist with exceptionally high affinity to δ subunit-containing GABA_A receptors,<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="Benkherouf_2019" /> it is also a potentpartial agonist of the GABA_A-ρ receptor, and so its range of effects results from a combined action on more than one GABA_A receptor subtype.<ref>Template:Cite journal</ref> In fact, it is more potent as a partial agonist of the GABA_A-ρ receptor than as a GABA_A receptor agonist.<ref name="Johnston_2014" /><ref name="Okhovat_2023" /> Muscimol has been said to be inactive at the GABA_B receptor.<ref name="Johnston_2014" /><ref name="Okhovat_2023" /> However, a subsequent study reported that muscimol may have GABA_B receptor-mediated inhibitory activity, although more research is needed to further characterize this activity.<ref name="RiveraIllanes_2024" /><ref name="Yamauchi_2000">Template:Cite journal</ref> Muscimol is inactive in terms of affecting GABA transaminase (GABA-T).<ref name="Okhovat_2023" /> There is little evidence that muscimol interacts with other biological targets besides the GABA receptors and the GABA transporters.<ref name="Johnston_2014" />

In animals, muscimol produces central depression, sedation, analgesia, anxiolysis, anticonvulsant effects, neuroprotective effects, and anesthesia, among other effects.<ref name="Stebelska_2013" /><ref name="KaurSinghArora2020">Template:Cite book</ref> In rodent drug discrimination studies, muscimol and gaboxadol fully generalize between each other, but generalization between benzodiazepines like diazepam does not occur.<ref name="Wafford_2006" /><ref name="McDonaldSheppardStaveley2007" /><ref name="Sanger_1985">Template:Cite journal</ref> These findings suggest that muscimol and gaboxadol have differing interoceptive effects from those of benzodiazepines.<ref name="Wafford_2006" /><ref name="Sanger_1985" /> During a test involving rabbits connected to an EEG, muscimol presented with a distinctly synchronized EEG tracing.<ref name="De_Carolis_1969" /> This is substantially different from serotonergic psychedelics like psilocybin, with which brainwave patterns generally show a desynchronization.<ref name="De_Carolis_1969" /> In higher doses (2Template:Nbspmg/kg via IV), the EEG will show characteristic spikes.<ref name="De_Carolis_1969">Template:Cite journal</ref>

Pharmacokinetics

The pharmacokinetics of muscimol in humans have been very limitedly studied.<ref name="RiveraIllanes_2024" /> Pharmacokinetic parameters such as bioavailability, volume of distribution, plasma protein binding, and elimination half-life are unavailable.<ref name="RiveraIllanes_2024" /><ref name="DrugBank" />

Absorption

Muscimol is readily absorbed in the gastrointestinal tract when taken orally.<ref name="Okhovat_2023" />

Distribution

The brain tissue distribution of muscimol in rats has been studied.<ref name="RiveraIllanes_2024" /><ref name="Baraldi_1979" /> Muscimol rapidly enters and unevenly distributes in rat brain, especially in the substantia nigra, colliculi, and hypothalamus.<ref name="RiveraIllanes_2024" /><ref name="Baraldi_1979">Template:Cite journal</ref> Muscimol crosses the blood–brain barrier and hence is centrally active.<ref name="Frlund_2002" /><ref name="Michelot_2003" /><ref name="Stebelska_2013" /> This has been said to likely be mediated by active transport via the high-affinity GABA uptake system and other amino acid transporters.<ref name="RiveraIllanes_2024" /><ref name="Michelot_2003" /><ref name="Stebelska_2013" /> Although muscimol crosses the blood–brain barrier, it does so relatively poorly and far less readily than gaboxadol.<ref name="Wafford_2006" /><ref name="MoroniForchettiKrogsgaard-Larsen1982" />

Metabolism

Muscimol is known to be metabolized via transamination by GABA transaminase (GABA-T).<ref name="RiveraIllanes_2024" /><ref name="Stebelska_2013" /><ref name="Baraldi_1979" /> Ibotenic acid is a prodrug of muscimol via decarboxylation.<ref name="RiveraIllanes_2024" /><ref name="Michelot_2003" /><ref name="Okhovat_2023" /> However, it has been said that muscimol can also be converted back into ibotenic acid via glutamate decarboxylase.<ref name="Okhovat_2023" /> The metabolites of muscimol have not been identified, but might contribute to the toxicity of muscimol.<ref name="KrogsgaardLarsen_1981" />

Elimination

Muscimol is excreted by the kidneys into urine.<ref name="Stebelska_2013" /> It is excreted partially unmetabolized.<ref name="Stebelska_2013" /> This has been taken advantage of by Siberian practitioners of the traditional entheogenic use of Amanita muscaria via recycling of muscimol in urine.<ref>"[[[:Template:GBurl]] Another Magic Mushroom]" p. 228 in: Template:Cite book</ref>

The elimination half-life of muscimol in humans is unknown.<ref name="RiveraIllanes_2024" /><ref name="DrugBank" /> The closely related drug gaboxadol (THIP), which is a cyclized derivative of muscimol, has an elimination half-life in humans of 1.5 to 2Template:Nbsphours.<ref name="HoehnSaric_1983">Template:Cite journal</ref> In rodents, the half-life of gaboxadol was about twice as long as that of muscimol.<ref name="MoroniForchettiKrogsgaard-Larsen1982">Template:Cite journal</ref> The drug is said to be more resistant to metabolism than muscimol, for instance not being a substrate for GABA-T.<ref name="Frlund_2002" /><ref name="KrogsgaardLarsen_1981" />

Chemistry

Structure

Muscimol was first isolated from Amanita pantherina by Onda in 1964,<ref>Template:Cite journal</ref> and thought to be an amino acid or peptide. Structure was then elucidated by Takemoto,<ref>Template:Cite report in: Template:Cite journal</ref> Eugster,<ref>Template:Cite journal</ref> and Bowden.<ref>Template:Cite journal</ref> Muscimol is a semi-rigid isoxazole containing both alcohol and aminomethyl substituents.<ref>Template:Cite journal</ref> Muscimol is commonly portrayed as a tautomer, where it adopts an amide-like configuration.<ref name="PubChem" /> It is also commonly shown as a zwitterion.<ref name="Pevarello_1992">Template:Cite journal</ref>

Properties

Muscimol is a zwitterion at physiological pH.<ref name="RiveraIllanes_2024" /> Its predicted log P of –1.4 to –2.2.<ref name="DrugBank" /><ref name="PubChem">Template:Cite web</ref> The drug's log P is similar to that of γ-aminobutyric acid (GABA).<ref name="Paleologos_1990">Template:Cite journal</ref>

Isolation

Muscimol can be extracted from the flesh of the Amanita muscaria by treatment with boiling water, followed by rapid cooling, and further treatment with a basic resin. This is washed with water, and eluted with acetic acid using column chromatography. The eluate is freeze dried, dissolved in water, and passed down a column of cellulose phosphate.<ref>Template:Cite web</ref> A subsequent elution with ammonium hydroxide and recrystallization from alcohol results in pure muscimol.<ref>Template:Cite journal</ref>

In instances where pure muscimol is not required, such as recreational or spiritual use, a crude extract is often prepared by simmering dried Amanita muscaria in water for 30Template:Nbspminutes.<ref>Template:Cite webTemplate:Self-published inline</ref>

Synthesis

Several chemical syntheses of muscimol have been published.<ref name="Michelot_2003" /><ref name="RiveraIllanes_2024" /><ref name="Okhovat_2023" /><ref name="Gagneux_1965">Template:Cite journal</ref><ref name="ChiarinoNapoletanoSala1986">Template:Cite journal</ref><ref name="BowdenCrankRoss1968">Template:Cite journal</ref><ref name="McCarrySavard1981">Template:Cite journal</ref><ref name="Pevarello_1992" />

Analogues

Analogues of muscimol include γ-aminobutyric acid (GABA), ibotenic acid, dihydromuscimol, thiomuscimol, piperidine-4-sulphonic acid (P4S), gaboxadol (THIP), 4-AHP, 4-PIOL, isonipecotic acid, guvacine, isoguvacine, THPO, nipecotic acid, and tiagabine, among others.<ref name="Okhovat_2023" /><ref name="KrogsgaardLarsen_1981" /><ref name="KrogsgaardLarsen_2004" /><ref name="GrinbergaDamgaardAndersen2016">Template:Cite conference</ref> The structural requirements for GABA_A receptor binding and activation are very strict, so relatively few high-efficacy GABA_A receptor agonists are known.<ref name="Krogsgaard-LarsenFrølundLiljefors2006">Template:Cite book</ref><ref name="Krogsgaard-Larsen2018">Template:Cite book</ref>

History

Amanita muscaria has been used by humans as a psychoactive drug since ancient times.<ref name="RiveraIllanes_2024" /><ref name="KrogsgaardLarsen_1981" /><ref name="HallHall1994">Hall, A. H., & Hall, P. K. (1994). Ibotenic acid/muscimol-containing mushrooms. In Handbook of Mushroom Poisoning—Diagnosis and Treatment (pp. 265-278). CRC Press, Boca Raton. https://books.google.com/books?id=WPWsZNvOqVAC&pg=PA265</ref> Muscimol was isolated from Amanita muscaria independently by three different research groups in 1964 and 1965.<ref name="Johnston_2014" /><ref name="RiveraIllanes_2024" /><ref name="KrogsgaardLarsen_1981" /> It was synthesized by Gagneux and colleagues in 1965.<ref name="Johnston_2014" /><ref name="RiveraIllanes_2024" /><ref name="Okhovat_2023" /><ref name="Gagneux_1965" /> The chemical structure of muscimol, along with that of ibotenic acid, was published by Conrad Eugster at the University of Zurich in 1967.<ref name="Johnston_2014" /><ref name="Eugster_1967">Template:Cite journal</ref><ref name="UZH-Eugster">Template:Cite web</ref>

Its structural similarity to the neurotransmitter γ-aminobutyric acid (GABA) was quickly recognized and muscimol was shown to have GABA-like actions by Graham Johnston and colleagues in 1968.<ref name="Johnston_2014" /><ref name="Johnston_1968">Template:Cite journal</ref> Subsequently, its actions were shown to be reversed by the GABA receptor antagonist bicuculline in 1971.<ref name="Johnston_2014" /><ref name="Curtis_1971">Template:Cite journal</ref>

The effects of muscimol in humans were studied and described by Waser in 1967.<ref name="Brimblecombe_1975" /><ref name="Ott_1976">Template:Cite journal</ref><ref name="Waser_1967" /> Later, ethnobotanist Jonathan Ott further described the effects of muscimol, via Amanita pantherina consumption, in 1976.<ref name="RiveraIllanes_2024" /><ref name="Ott_1976" />

Danish medicinal chemist Povl Krogsgaard-Larsen and colleagues studied muscimol and synthetic analogues over several decades starting in the 1970s.<ref name="Johnston_2014" /><ref name="RiveraIllanes_2024" /> Other GABA_A receptor ligands, such as gaboxadol (THIP) and 4-PIOL, and GABA transporter modulators, such as nipecotic acid and tiagabine, have been derived from muscimol.<ref name="Johnston_2014" /><ref name="RiveraIllanes_2024" /><ref name="KrogsgaardLarsen_2004" /> Many muscimol analogues were developed by Krogsgaard-Larsen and colleagues.<ref name="Johnston_2014" /><ref name="RiveraIllanes_2024" /><ref name="KrogsgaardLarsen_2004" />

Society and culture

Legal status

Muscimol is not a controlled substance and is unregulated in most of the world.<ref name="RiveraIllanes_2024" /><ref name="Leas_2024" /><ref name="Savickaite_2025" />

Australia

Muscimol is considered a Schedule 9 prohibited substance in Australia under the Poisons Standard (October 2015). A Schedule 9 substance is a substance "which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical, teaching or training purposes with approval of Commonwealth and/or State or Territory Health Authorities."<ref name="Poisons Standard">Template:Cite web</ref>

Poland

Muscimol and ibotenic acid are both considered as novel psychoactive substances in Poland as of 2024.<ref name="SEJM" /> Possessing or selling them is illegal.<ref name="SEJM">Template:Cite web</ref>

United States

Neither Amanita muscaria nor muscimol is considered a controlled substance by the Federal government of the United States. The United States Food and Drug Administration (FDA) has deemed Amanita muscaria and its constituents, including muscimol, unapproved for conventional foods and is also evaluating their use in dietary supplements.<ref>Template:Cite web</ref> Agriculture regulators in Florida actioned against one seller of Amanita products after the agency had determined such products were considered adulterated under state law.<ref>Template:Cite web</ref>

Muscimol may be regulated on a state level. Louisiana State Act 159 banned the possession and cultivation of the Amanita muscaria except for ornamental or aesthetic purposes. Except as a constituent of lawfully manufactured food or dietary supplements, the act outlaws preparations of the Amanita muscaria intended for human consumption, including muscimol.<ref>Template:Cite web</ref>

Research

Muscimol has been clinically studied for a number of potential medical uses.<ref name="RiveraIllanes_2024" /><ref name="DeFeudis_1980" /><ref name="Ramawad_2023" /><ref name="Heiss_2019" /> It was assessed in small clinical studies in the treatment of Huntington's disease, tardive dyskinesia, and schizophrenia in the 1970s but was not found to be useful for these indications.<ref name="DeFeudis_1980">Template:Cite journal</ref><ref name="Stebelska_2013" /><ref name="Shoulson_1977">Template:Cite journal</ref><ref name="Shoulson_1978">Template:Cite journal</ref><ref name="Tamminga_1978">Template:Cite journal</ref><ref name="Tamminga_1979">Template:Cite journal</ref><ref name="ChaseTamminga1979">Chase, N., & Tamminga, C. A. (1979). Muscimol therapy of hyperkinetic extpapyramidal disorders Thomas. Brain Research Bulletin, 4(5), 700. https://scholar.google.com/scholar?cluster=11103420926788228270</ref><ref name="TammingaChase1979">Tamminga, C. A., & Chase, T. N. (1979). GABA agonist effect on cognitive dysfunction in schizophrenic subjects. Brain Research Bulletin, 4(5), 708. https://scholar.google.com/scholar?cluster=12333477908462637709</ref> Another study evaluated muscimol in schizophrenics with tardive dyskinesia in 1992.<ref name="Cassady_1992">Template:Cite journal</ref> Studies also assessed the biochemical effects of muscimol in humans in the late 1970s and early 1980s.<ref name="Tamminga_1978a">Template:Cite journal</ref><ref name="Cavagnini_1982">Template:Cite journal</ref><ref name="Durso_1983">Template:Cite journal</ref>

According to Povl Krogsgaard-Larsen, muscimol was too toxic and non-selective and as such was not developed for use as a pharmaceutical drug.<ref name="Frlund_2002" /><ref name="Morris2018-S02E07">Template:Cite episode</ref><ref name="Morris_2013" /> Instead, the synthetic analogue gaboxadol (THIP), which was more selective and less toxic, was developed.<ref name="Johnston_2014" /><ref name="KrogsgaardLarsen_2004" /><ref name="Morris_2013" />

In 2019, a phase 1 clinical trial of muscimol for drug-resistant epilepsy was published.<ref name="Kaur_2016">Template:Cite journal</ref><ref name="Heiss_2019">Template:Cite journal</ref> It has also been formally investigated for potential treatment of Alzheimer's disease and Parkinson's disease.<ref name="Synapse">Template:Cite web</ref><ref name="Kaur_2020">Template:Cite book</ref> A 2023 systematic review and meta-analysis of 22Template:Nbsppreclinical studies found that muscimol reduces neuropathic pain in animals, with effects beginning within 15Template:Nbspminutes and lasting up to 3Template:Nbsphours.<ref name="Ramawad_2023">Template:Cite journal</ref><ref name="RiveraIllanes_2024" />

Muscimol has never been approved as a pharmaceutical drug for any use anywhere in the world.<ref name="RiveraIllanes_2024" /><ref name="DrugBank" />

See also

• List of hallucinogens
• Mushroom edible

External links

• Muscimol - Isomer Design
• Psychoactive Amanitas - Erowid
• Amanita muscaria - PsychonautWiki
• r/AmanitaMuscaria - Reddit