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 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. 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, 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.
The psychoactive dose of muscimol is around 10-15 mg for a normal person.A Guide to British Psilocybin Mushrooms by Richard Cooper published in 1977 recommends a smaller dose, 8.5 mg, and suggests that it is possible for this amount to be present in as little as 1 g of dried A. muscaria but this is not consistent with most other reports which suggest 5-10 mg is necessary. A correct dose may be difficult to determine because potency varies dramatically from one mushroom to the next.
When consumed, a substantial percentage of muscimol goes un-metabolized and thus excreted in urine, a phenomenon exploited by practitioners of the traditional entheogenic use of Amanita muscaria.
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.
Many of muscimol's effects are consistent with its pharmacology as a GABAA receptoragonist, presenting many depressant or sedative-hypnotic effects. Atypical of the effect profile of sedative drugs generally however, muscimol, like Z-drugs, can cause hallucinogenic changes in perception. The hallucinogenic effect produced by muscimol is most closely comparable to the hallucinogenic side effects produced by some other GABAergic drugs such as zolpidem.
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.
Muscimol was synthesized in 1965 by Gagneux, 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. More dependable and scalable procedures have been developed, two examples being the syntheses of McCarry and Varasi.
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 propargyl chloride 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%.
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 hydroxide in dioxane.
The median lethal dose in mice is 3.8 mg/kg s.c, 2.5 mg/kg i.p. The LD50 in rats is 4.5 mg/kg i.v, 45 mg/kg orally.
Human deaths are rare, mainly occurring in young children, the elderly, or those with serious chronic illnesses.
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."
^Lonser, Russell R.; Oldfield, Edward H.; Sato, Susumu; Rene' Smith, R. N.; Walbridge, Stuart; Heiss, John D. (2012-08-01). "174 Convection-Enhanced Delivery of Muscimol to the Epileptic FocusPreclinical and Clinical Research". Neurosurgery. 71 (2): E568. doi:10.1227/01.neu.0000417764.02569.dc. ISSN0148-396X.
^Chilton, WS; Ott, J (1976). "Toxic metabolites of Amanita pantherina, A. Cothurnata, A. Muscaria and other Amanita species". Lloydia. 39 (2-3): 150-7. 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 (2002). "GABA-A receptor ligands and their therapeutic potentials". Current Topics in Medicinal Chemistry. 2 (8): 817-32. doi:10.2174/1568026023393525. PMID12171573.
^Tamminga, CA; Neophytides, A; Chase, TN; Frohman, LA (1978). "Stimulation of prolactin and growth hormone secretion by muscimol, a gamma-aminobutyric acid agonist". The Journal of Clinical Endocrinology and Metabolism. 47 (6): 1348-51. doi:10.1210/jcem-47-6-1348. PMID162520.
^Carolis, A. Scotti De; Lipparini, F.; Longo, V. G. (1969-01-01). "Neuropharmacological investigations on muscimol, a psychotropic drug extracted from Amanita muscaria". Psychopharmacologia. 15 (3): 186-195. doi:10.1007/BF00411168. ISSN0033-3158. PMID5389124.
^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, W. J. (1968). "The synthesis of pantherine and related compounds". Journal of the Chemical Society C: Organic: 172. doi:10.1039/j39680000172.