Muscimol went under clinical trial phase I for epilepsy, but the trial was discontinued.[4]
Muscimol, an agonist for the GABAA receptor, was able to significantly alleviate pain in its peak effect, recent studies from 2023 show. It has since been federally banned in Australia and is pending FDA review in the United States, but scientists believe it may relieve pain as well as some opioids without much of the risk of addiction associated with opioids. [5]
Muscimol is one of the psychoactive compounds responsible for the effects of Amanita muscaria intoxication. Ibotenic acid, a neurotoxicsecondary metaboliteofAmanita muscaria, serves as a prodrug to muscimol when the mushroom is ingested or dried, converting to muscimol via decarboxylation.[6]
Muscimol is produced in the mushrooms Amanita muscaria (fly agaric) and Amanita pantherina, along with muscarine (which is present in trace amounts and it is not active), muscazone, and ibotenic acid.[7][8]A. muscaria and A. pantherina should be eaten with caution and prepared properly to lessen effects of nausea. In A. muscaria, the layer just below the skin of the cap contains the highest amount of muscimol, and is therefore the most psychoactive portion.[9]
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.[8]
Muscimol is a potent GABAAagonist, activating the receptor for the brain's principal inhibitoryneurotransmitter, GABA. Muscimol binds to the same site on the GABAA receptor complex as GABA itself, as opposed to other GABAergic drugs such as barbiturates and benzodiazepines which bind to separate regulatory sites.[10] GABAA receptors are widely distributed in the brain, and so when muscimol is administered, it alters neuronal activity in multiple regions including the cerebral cortex, hippocampus, and cerebellum. While muscimol is normally thought of as a selective GABAA agonist with exceptionally high affinity to GABAA-delta receptors,[11][12][6] it is also a partial agonist at the GABAA-rho receptor, and so its range of effects results from a combined action on more than one GABAA receptor subtype.[13]
Scientific studies have shown that dosing of the active ingredient muscimol is usually not precise as it has to be extracted from dried amanita mushroom. However, a psychoactive dose of muscimol is reported to be between 8 and 15 mg. As little as a gram of dried Amanita muscaria button may contain this amount of muscimol; however, the potency varies greatly among mushrooms. [14]
When consumed, a substantial percentage of muscimol goes un-metabolized and thus excreted in urine, a phenomenon exploited by Siberian practitioners of the traditional entheogenic use of Amanita muscaria.[15]
During a test involving rabbits connected to an EEG, muscimol presented with a distinctly synchronizedEEG tracing. This is substantially different from serotonergic psychedelics, with which brainwave patterns generally show a desynchronization. In higher doses (2 mg/kg via IV), the EEG will show characteristic spikes.[17]
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 thirty minutes.[29]
Muscimol was synthesized in 1965 by Gagneux,[30] who utilized a bromo-isoxazole starting material in a two step reaction. 3-bromo-5-aminomethyl-isoxazole (1) was refluxed in a mixture of methanol and potassium hydroxide for 30 hours, resulting in 3-methoxy-5-aminomethyl-isoxazole (2) with a yield of 60%.
Chemists report having struggled to reproduce these results.[31][32] More dependable and scalable procedures have been developed, two examples being the syntheses of McCarry[33] and Varasi.[26]
McCarry's synthesis is a three step synthesis involving a lithiumacetylide produced from propargyl chloride. The acetylide (3), was dissolved in ether, cooled to -40 °C, and treated with excess ethyl chloroformate to afford ethyl 4-chlorotetrolate (4) in a 70% yield. (4) was then added to a solution of water, methanol and hydroxylamine at -35 °C. At a pH of between 8.5 and 9, the isoxazole (5) was recovered in a 41% yield. Muscimol was formed in a 65% yield when (5) was dissolved in a saturated solution of methanol and anhydrous ammonia and heated from 0 °C to 50 °C. The total yield was 18.7%.[33]
Varasi's synthesis is notable for its inexpensive starting materials and mild conditions. It begins with the combination of 2,3-Dichloro-1-propene (6), potassium bicarbonate, water, and dibromoformaldoxime (7), all dissolved in ethyl acetate. 5-Chloromethyl-3-bromoisoxazole (8) was extracted with an experimental yield of 81%. 5-Aminomethyl-3-bromoisoxazole (9) was formed in 90% yield by the combination of (8) and ammonium hydroxideindioxane.[26]
(9) was then refluxed with potassium hydroxideinmethanol to generate 5-Aminomethyl-3-methoxyisoxazole (10) with a 66% yield. Subsequent reflux of (10) with hydrobromic acid and acetic acid generated muscimol with a yield of 62%. The overall synthetic yield was 30%.[26]
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."[36]
Neither Amanita muscaria nor muscimol is considered a controlled substance by the Federal government of the United States. This means that cultivation, possession, and distribution are unregulated by the United States Federal Government.[37][38] The legality of Amanita muscaria and muscimol as ingredients in food is unclear since neither are approved as food additives by the FDA. However, agriculture regulatorsinFlorida actioned against one seller of Amanita products after the agency had determined such products were considered adulterated under state law. [39]
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.[40]
^Chilton WS, Ott J (1976). "Toxic metabolites of Amanita pantherina, A. cothurnata, A. muscaria and other Amanita species". Lloydia. 39 (2–3): 150–157. PMID985999.
^Chilton WS (1978). "Chemistry and Mode of Action of Mushroom Toxins". In Rumack, BH, Salzman, E (eds.). Mushroom Poisoning: Diagnosis and Treatment. Palm Beach: CRC Press. pp. 87–124. ISBN9780849351853.
^Frølund B, Ebert B, Kristiansen U, Liljefors T, Krogsgaard-Larsen P (August 2002). "GABA(A) receptor ligands and their therapeutic potentials". Current Topics in Medicinal Chemistry. 2 (8): 817–832. doi:10.2174/1568026023393525. PMID12171573.
^Quirk K, Whiting PJ, Ragan CI, McKernan RM (August 1995). "Characterisation of delta-subunit containing GABAA receptors from rat brain". European Journal of Pharmacology. 290 (3): 175–181. doi:10.1016/0922-4106(95)00061-5. PMID7589211.
^Tamminga CA, Neophytides A, Chase TN, Frohman LA (December 1978). "Stimulation of prolactin and growth hormone secretion by muscimol, a gamma-aminobutyric acid agonist". The Journal of Clinical Endocrinology and Metabolism. 47 (6): 1348–1351. doi:10.1210/jcem-47-6-1348. PMID162520.
^Scotti de Carolis A, Lipparini F, Longo VG (1969-01-01). "Neuropharmacological investigations on muscimol, a psychotropic drug extracted from Amanita muscaria". Psychopharmacologia. 15 (3): 186–195. doi:10.1007/BF00411168. PMID5389124. S2CID26824149.
^Takemoto T, Nakajima T, Yokobe T (December 1964). "[Structure of Ibotenic Acid ]". Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan (in Japanese). 84: 1232–3. PMID14266560.
^Eugster CH, Müller GF, Good R (June 1965). "[The active ingredients from Amanita muscaria: ibotenic acid and muscazone]". Tetrahedron Letters (23): 1813–1815. doi:10.1016/S0040-4039(00)90133-3. PMID5891631.
^ abGagneux AR, Häfliger F, Eugster CH, Good R (January 1965). "Synthesis of pantherine (agarin)". Tetrahedron Letters. 6 (25): 2077–2079. doi:10.1016/S0040-4039(00)90157-6.
^Chiarino D, Napoletano M, Sala A (1986). "A convenient synthesis of muscimol by a 1,3-dipolar cycloaddition reaction". Tetrahedron Letters. 27 (27): 3181–3182. doi:10.1016/S0040-4039(00)84748-6.
^Bowden K, Crank G, Ross WJ (1968). "The synthesis of pantherine and related compounds". Journal of the Chemical Society C: Organic: 172. doi:10.1039/j39680000172.
^ abMcCarry BE, Savard M (January 1981). "A facile synthesis of muscimol". Tetrahedron Letters. 22 (51): 5153–5156. doi:10.1016/S0040-4039(01)92445-1.
