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]
Biochemistry
Muscimol is one of the psychoactive compounds responsible for the effects of Amanita muscaria intoxication.
Ibotenic acid, a
neurotoxicsecondary metabolite of Amanita 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]
Pharmacology
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]
Chemical synthesis
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 hydroxide in
dioxane.[26]
(9) was then refluxed with
potassium hydroxide in
methanol 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]
Toxicity
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.[34]
Human deaths are rare, mainly occurring in young children, the elderly, or those with serious chronic illnesses.[35]
Legal status
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."[36]
United States
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 regulators in
Florida 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.