Muscimol

'' (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. ==Use and effects==

The properties and effects of muscimol in humans have been limitedly assessed in clinical studies. It has been assessed in these studies at doses of 5 to 15mg orally. According to Jonathan Ott, a 15mg dose is "psychoptic" while a 20mg dose is "visionary". 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. Although muscimol and gaboxadol have similar effects on sleep, muscimol has additionally been found to increase REM sleep unlike gaboxadol. ==Toxicity and overdose==

The German Federal Institute for Risk Assessment warns that muscimol and products containing it pose serious health risks, especially to children. 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 3.8mg/kg s.c, 2.5mg/kg i.p. The LD50 in rats is 4.5mg/kg i.v, 45 mg/kg orally. 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. Muscimol has shown potential as an anticonvulsant, blocking seizures induced by various agents in animal models without causing significant toxicity at therapeutic doses. Muscimol exhibits dose-dependent effects with higher doses leading to significant, but reversible, central nervous system symptoms. The dose of muscimol that is thought to be potentially fatal in humans is 90mg, which is 15times its threshold active dose of 6mg. ==Interactions==

The actions and effects of muscimol may be potentiated by benzodiazepines such as diazepam. ==Pharmacology==

Pharmacodynamics (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. Muscimol shows relatively uniform effects on GABAA receptors of differing subunit compositions. On the other hand, alcohol is known to selectively potentiate δ subunit-containing extrasynaptic GABAA receptors analogously to muscimol. While muscimol is often thought of as a selective GABAA agonist with exceptionally high affinity to δ subunit-containing GABAA receptors, In fact, it is more potent as a partial agonist of the GABAA-ρ receptor than as a GABAA receptor agonist. Muscimol is inactive in terms of affecting GABA transaminase (GABA-T). In rodent drug discrimination studies, muscimol and gaboxadol fully generalize between each other, but generalization between benzodiazepines like diazepam does not occur. These findings suggest that muscimol and gaboxadol have differing interoceptive effects from those of benzodiazepines. Pharmacokinetics The pharmacokinetics of muscimol in humans have been very limitedly studied. Muscimol crosses the blood–brain barrier and hence is centrally active. The elimination half-life of muscimol in humans is unknown. In rodents, the half-life of gaboxadol was about twice as long as that of muscimol. The drug is said to be more resistant to metabolism than muscimol, for instance not being a substrate for GABA-T. ==Chemistry==

Structure Muscimol was first isolated from Amanita pantherina by Onda in 1964, and thought to be an amino acid or peptide. Structure was then elucidated by Takemoto, Eugster, and Bowden. Muscimol is a semi-rigid isoxazole containing both alcohol and aminomethyl substituents. Muscimol is commonly portrayed as a tautomer, where it adopts an amide-like configuration. Properties Muscimol is a zwitterion at physiological pH. The drug's log P is similar to that of γ-aminobutyric acid (GABA). 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. A subsequent elution with ammonium hydroxide and recrystallization from alcohol results in pure muscimol. 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 30minutes. Synthesis Several chemical syntheses of muscimol have been published. The structural requirements for GABAA receptor binding and activation are very strict, so relatively few high-efficacy GABAA receptor agonists are known. ==History==

Amanita muscaria has been used by humans as a psychoactive drug since ancient times. Muscimol was isolated from Amanita muscaria independently by three different research groups in 1964 and 1965. 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. Subsequently, its actions were shown to be reversed by the GABA receptor antagonist bicuculline in 1971. The effects of muscimol in humans were studied and described by Waser in 1967. ==Society and culture==

Legal status Muscimol is not a controlled substance and is unregulated in most of the world. Poland Muscimol and ibotenic acid are both considered as novel psychoactive substances in Poland as of 2024. 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. Agriculture regulators in Florida actioned against one seller of Amanita products after the agency had determined such products were considered adulterated under state law. 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. ==Research==

Muscimol has been clinically studied for a number of potential medical uses. Another study evaluated muscimol in schizophrenics with tardive dyskinesia in 1992. Studies also assessed the biochemical effects of muscimol in humans in the late 1970s and early 1980s. According to Povl Krogsgaard-Larsen, muscimol was too toxic and non-selective and as such was not developed for use as a pharmaceutical drug. It has also been formally investigated for potential treatment of Alzheimer's disease and Parkinson's disease. A 2023 systematic review and meta-analysis of 22preclinical studies found that muscimol reduces neuropathic pain in animals, with effects beginning within 15minutes and lasting up to 3hours. Muscimol has never been approved as a pharmaceutical drug for any use anywhere in the world. ==See also==