Muscimol was first isolated fromAmanita muscaria and hence was discovered in 1964.[14][1][16] It has been limitedly clinically studied as a potentialpharmaceutical drug for a number of uses, such as treatment ofepilepsy.[1][21][22][23] In addition,analogues andderivatives of muscimol, such as theselective GABAA receptor agonistgaboxadol (THIP; LU-2-030) and the selective GABA reuptake inhibitortiagabine (Gabitril), have been developed as pharmaceutical drugs.[14][24][2][25] Muscimol andAmanita muscaria mushrooms have rarely been used asrecreational drugs historically.[3] By the mid-2020s however, use of these substances, including recreational use for hallucinogenic effects andmicrodosing for claimed therapeutic benefits, has become increasingly prominent.[1][26][5][27] The most commonly cited therapeutic reason for their use is to improve sleep.[26] Muscimol is not acontrolled substance and is unregulated in most of the world, including in most of theUnited States andEurope.[1][4][5]
Amanita muscaria (fly agaric) mushrooms, which contain muscimol.
The main natural sources of muscimol are fungi of the genusAmanita, such asAmanita muscaria (fly agaric) andAmanita pantherina (panther cap). It is produced in the mushrooms along withmuscarine (which is present in trace amounts and it is not active),muscazone, andibotenic acid.[28][15] InAmanita muscaria, the layer just below the skin of the cap contains the highest amount of muscimol, and is therefore the mostpsychoactive portion.[29]
The properties and effects of muscimol in humans have been limitedly assessed inclinical studies.[12][7][18][8] It has been assessed in these studies at doses of 5 to 15mg orally.[12] Theoral threshold dose of muscimol is approximately 6mg,[12][30] while thepsychoactive dose range has been said to range from approximately 8 to 15mg.[1][2][11] As little as 1g of driedAmanita muscaria button may contain this amount of muscimol, although thepotency varies greatly among mushrooms.[31] According toJonathan Ott, a 15mg dose is "psychoptic" while a 20mg dose is "visionary".[3] Theonset of action of muscimol, via isolated muscimol orAmanita muscaria consumption orally, is between 30minutes and 2hours,[2][8] with peak effects occurring after 1 to 3hours.[3][7][9] Theduration is 4 to 8hours, but some effects may persist for up to 24hours.[3][2][10][11][7][9] In one publication, the effects of muscimol were described as follows:[18][8]
"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."[18][8]
Thetoxicity andsafety profile of muscimol has been studied in various contexts, both experimental and clinical. Themedian 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.[37] A study on non-human primates indicated that muscimol, when administered in escalating doses, caused reversiblehyperkinesia anddyskinesias at higher doses (up to 88.8 mM), but no long-term toxicity was observed on histological examination.[38] Muscimol has shown potential as ananticonvulsant, blockingseizures induced by various agents inanimal models without causing significant toxicity attherapeutic doses.[39] Muscimol exhibitsdose-dependenteffects with higher doses leading to significant, but reversible, central nervous systemsymptoms.[40] The dose of muscimol that is thought to be potentially fatal in humans is 90mg, which is 15times its threshold active dose of 6mg.[31]
γ-Aminobutyric acid (GABA) and muscimol molecules can have similar 3Dconformations which are shown superimposed in this image. Because of this similarity, muscimol binds to certain GABA receptors.[15]
Muscimol shows relatively uniform effects on GABAA receptors of differingsubunit compositions.[14][1] However, it was found to act as asuperagonist ofextrasynaptic α4β3δ subunit-containing GABAA receptors (EmaxTooltip maximal efficacy = 120 to 140% relative to GABA).[14][1] This was found to be due to reducedreceptor desensitization with muscimol compared to GABA.[14] Subsequent research has found that muscimol is a preferential agonist of the relatively small population of δ subunit-containing GABAA receptors and that these receptors have a substantial contribution to its effects.[42][1] In contrast to muscimol, benzodiazepines and Z-drugs do not activate δ subunit-containing GABAA receptors.[43] On the other hand,alcohol is known to selectively potentiate δ subunit-containing extrasynaptic GABAA receptors analogously to muscimol.[44][45][46]
While muscimol is often thought of as aselective GABAA agonist with exceptionally highaffinity to δ subunit-containing GABAA receptors,[47][48][42] it is also a potentpartial agonist of theGABAA-ρ receptor, and so its range of effects results from a combined action on more than one GABAA receptor subtype.[49] In fact, it is more potent as a partial agonist of the GABAA-ρ receptor than as a GABAA receptor agonist.[14][2] Muscimol has been said to be inactive at theGABAB receptor.[14][2] However, a subsequent study reported that muscimol may have GABAB receptor-mediated inhibitory activity, although more research is needed to further characterize this activity.[1][50] Muscimol is inactive in terms of affectingGABA transaminase (GABA-T).[2] There is little evidence that muscimol interacts with otherbiological targets besides theGABA receptors and theGABA transporters.[14]
Theelimination half-life of muscimol in humans is unknown.[1][6] The closely related druggaboxadol (THIP), which is acyclizedderivative of muscimol, has an elimination half-life in humans of 1.5 to 2hours.[57] In rodents, the half-life of gaboxadol was about twice as long as that of muscimol.[55] The drug is said to be more resistant tometabolism than muscimol, for instance not being asubstrate for GABA-T.[20][16]
In instances where pure muscimol is not required, such as recreational or spiritual use, a crude extract is often prepared by simmering driedAmanita muscaria in water for 30minutes.[68]
Muscimol is considered aSchedule 9prohibited substance in Australia under thePoisons 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."[81]
NeitherAmanita muscaria nor muscimol is considered a controlled substance by theFederal government of the United States. The United StatesFood and Drug Administration (FDA) has deemedAmanita muscaria and its constituents, including muscimol, unapproved for conventional foods and is also evaluating their use in dietary supplements.[83]Agriculture regulators inFlorida actioned against one seller ofAmanita products after the agency had determined such products were considered adulterated under state law.[84]
Muscimol may be regulated on a state level.Louisiana State Act 159 banned the possession and cultivation of theAmanita muscaria except for ornamental or aesthetic purposes. Except as a constituent of lawfully manufactured food or dietary supplements, the act outlaws preparations of theAmanita muscaria intended for human consumption, including muscimol.[85]
^abcdefghijklmnopqrstuvwxyzaaOkhovat A, Cruces W, Docampo-Palacios ML, Ray KP, Ramirez GA (2023). "Psychoactive Isoxazoles, Muscimol, and Isoxazole Derivatives from the Amanita (Agaricomycetes) Species: Review of New Trends in Synthesis, Dosage, and Biological Properties".Int J Med Mushrooms.25 (9):1–10.doi:10.1615/IntJMedMushrooms.2023049458.PMID37824402.
^abcdefghijklmnopqrstuvwxyzaaabacJohnston GA (October 2014)."Muscimol as an ionotropic GABA receptor agonist"(PDF).Neurochem Res.39 (10):1942–1947.doi:10.1007/s11064-014-1245-y.PMID24473816.We now know that muscimol is a potent agonist at GABAA receptors, a potent partial agonist at GABAC receptors and inactive at GABAB receptors. Unlike bicuculline and TPMPA, it does not distinguish between GABAA and GABAC receptors. It is a weak inhibitor/substrate of GABA uptake and not a substrate for GABA transaminase [18–21].
^abcHall, 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
^abcdefBrimblecombe RW, Pinder RM (1975). "Miscellaneous Hallucinogens".Hallucinogenic Agents. Bristol: Wright-Scientechnica. pp. 196–216.ISBN978-0-85608-011-1.OCLC2176880.OL4850660M.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. Similar doses of ibotenic acid or muscazone were virtually without hallucinogenic activity but showed only some unpleasant effects on the peripheral circulation. [...] WASER, P. G. (1967), in Ethnopharmacologic Search for Psychoactive Drugs (see BREKHMAN and SAM), pp. 419--439.
^abcdefFrølund B, Ebert B, Kristiansen U, Liljefors T, Krogsgaard-Larsen P (August 2002). "GABA(A) receptor ligands and their therapeutic potentials".Curr Top Med Chem.2 (8):817–832.doi:10.2174/1568026023393525.PMID12171573.The fact that muscimol is a non-specific GABAA receptor agonist [38, 39], a substrate for the GABA-metabolizing enzyme, GABA transaminase [40], and moreover a neurotoxin, makes the compound therapeutically less valuable. [...] Further conformational restriction of the GABA structural element in muscimol has been achieved by incorporating the amino group into a piperidine ring leading to the bicyclic analogue, THIP, a specific GABAA agonist [11]. THIP has been shown to be devoid of the neurotoxic properties of muscimol and, in contrast to muscimol, is metabolically stable.
^abcDeFeudis FV (October 1980). "Physiological and behavioral studies with muscimol".Neurochem Res.5 (10):1047–1068.doi:10.1007/BF00966163.PMID6258091.Muscimol will likely not be very useful in human therapy (e.g., as an anticonvulsant or antiparkinson agent). Clinical trials have already revealed that muscimol is of no practical value for treatment of Huntington's chorea, tardive dyskinesia, or schizophrenia (14, 103).
^abcdefgKrogsgaard-Larsen P, Frølund B, Liljefors T, Ebert B (October 2004). "GABA(A) agonists and partial agonists: THIP (Gaboxadol) as a non-opioid analgesic and a novel type of hypnotic".Biochem Pharmacol.68 (8):1573–1580.doi:10.1016/j.bcp.2004.06.040.PMID15451401.
^abcHartwig J, Kendrick J, Ahmad G, Cook J, Matthews DB, Sharma P (2025). "Exploring User Experiences with Amanita muscaria: A Thematic Analysis of Reddit Online Forum Discussions".Subst Use Misuse.60 (7):952–961.doi:10.1080/10826084.2025.2476141.PMID40057818.The commonly reported reason for Amanita muscaria use was to improve sleep.
^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. CRC Press. pp. 87–124.ISBN978-0-8493-5185-3.
^abTamminga CA, Neophytides A, Chase TN, Frohman LA (December 1978). "Stimulation of prolactin and growth hormone secretion by muscimol, a gamma-aminobutyric acid agonist".J Clin Endocrinol Metab.47 (6):1348–1351.doi:10.1210/jcem-47-6-1348.PMID162520.
^abDurso R, Tamminga CA, Denaro A, Ruggeri S, Chase TN (September 1983). "Plasma growth hormone and prolactin response to dopaminergic GABAmimetic and cholinergic stimulation in Huntington's disease".Neurology.33 (9):1229–1232.doi:10.1212/wnl.33.9.1299.PMID6225034.
^abcMcDonald LM, Sheppard WF, Staveley SM, Sohal B, Tattersall FD, Hutson PH (March 2007). "Gaboxadol, a selective extrasynaptic GABA(A) agonist, does not generalise to other sleep-enhancing drugs: a rat drug discrimination study".Neuropharmacology.52 (3):844–853.doi:10.1016/j.neuropharm.2006.10.009.PMID17196996.For example, zolpidem, indiplon, RS-zopiclone and S-zopiclone were all reported to enhance sleep onset and increase the total duration of sleep (Nakajima et al., 2000; Zammit et al., 2004; Swainston Harrison and Keating, 2005; Thomson Scientific, 2006). Gaboxadol did not affect sleep onset and had no effect on rapid eye movement (REM) sleep, but increased the total duration of slow-wave sleep in rats (Lancel and Faulhaber, 1996), which resembled the changes it induces in human sleep (Faulhaber et al., 1997). Muscimol had similar effects to gaboxadol on sleep in rats, although it also increased REM sleep (Lancel et al., 1996).
^Dijk DJ (June 2010). "Slow-wave sleep deficiency and enhancement: implications for insomnia and its management".World J Biol Psychiatry.11 (Suppl 1):22–28.doi:10.3109/15622971003637645.PMID20509829.
^Farber NB, Jiang X, Dikranian K, Nemmers B (December 2003). "Muscimol prevents NMDA antagonist neurotoxicity by activating GABAA receptors in several brain regions".Brain Research.993 (1–2):90–100.doi:10.1016/j.brainres.2003.09.002.PMID14642834.
^Chebib M, Johnston GA (1999). "Muscimol". In Heldman, Dennis R. (ed.).Encyclopedia of Agricultural, Food, and Biological Engineering. CRC Press. pp. 1234–1238.
^Deacon S, Staner L, Staner C, Legters A, Loft H, Lundahl J (March 2007). "Effect of short-term treatment with gaboxadol on sleep maintenance and initiation in patients with primary insomnia".Sleep.30 (3):281–287.doi:10.1093/sleep/30.3.281.PMID17425224.When given orally in healthy subjects, gaboxadol is rapidly absorbed (tmax of 30-60 min) and eliminated (t½ of 1.5 h). More than 95% of the dose is excreted in the urine, mostly unchanged. A glucoronide conjugate is the only metabolite formed in significant amounts. Hence the CYP450 system does not have significant involvement in the metabolism of gaboxadol.
^Yamauchi T, Hori T, Takahashi T (September 2000). "Presynaptic inhibition by muscimol through GABAB receptors".Eur J Neurosci.12 (9):3433–3436.doi:10.1046/j.1460-9568.2000.00248.x.PMID10998126.
^Kaur S, Singh S, Arora A, Ram P, Kumar S, Kumar P, et al. (2020). "Pharmacology of GABA and Its Receptors".Frontiers in Pharmacology of Neurotransmitters. pp. 241–292.doi:10.1007/978-981-15-3556-7_8.ISBN978-981-15-3555-0.
^abcDe Carolis AS, Lipparini F, Longo VG (January 1969). "Neuropharmacological investigations on muscimol, a psychotropic drug extracted from Amanita muscaria".Psychopharmacologia.15 (3):186–195.doi:10.1007/BF00411168.PMID5389124.S2CID26824149.
^abMoroni F, Forchetti MC, Krogsgaard-Larsen P, Guidotti A (October 1982). "Relative disposition of the GABA agonists THIP and muscimol in the brain of the rat".J Pharm Pharmacol.34 (10):676–678.doi:10.1111/j.2042-7158.1982.tb04702.x.PMID6128395.
^Hoehn-Saric R (1983). "Effects of THIP on chronic anxiety".Psychopharmacology (Berl).80 (4):338–341.doi:10.1007/BF00432116.PMID6414002.THIP, a 4,5,6,7-tetrahydroisoxazolo(5,4-C)pyridin-3-ol, is a muscimol analog which exhibits specific GABA-agonists properties without affecting enzymes involved in the synthesis or the catabolism of the neurotransmitter. It is 5–15-times weaker than muscimol and substantially less toxic. THIP penetrates the blood–brain barrier and has a half-life of 1.5–2 h (H Lundbeck and Company 1981).
^イボテン酸の構造 [Structure of Ibotenic Acid] (in Japanese). pp. 1232–1233. in:Takemoto T, Nakajima T, Yokobe T, Sakuma R, Fujitani K, Aoyagi Y, et al. (1964)."寄書" [Communication to the Editor].Yakugaku Zasshi (in Japanese).84 (12):1230–1236.doi:10.1248/yakushi1947.84.12_1230.
^Eugster C, Müller G, Good R (January 1965). "Wirkstoffe aus amanita muscaria: ibotensaeure und muscazon" [The active ingredients from Amanita muscaria: ibotenic acid and muscazone].Tetrahedron Letters (in German).6 (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.
^McCarry BE, Savard M (January 1981). "A facile synthesis of muscimol".Tetrahedron Letters.22 (51):5153–5156.doi:10.1016/S0040-4039(01)92445-1.
^Krogsgaard-Larsen P, Frølund B, Liljefors T (2006). "GABAA Agonists and Partial Agonists: THIP (Gaboxadol) as a Non-Opioid Analgesic and a Novel Type of Hypnotic1".GABA(A) agonists and partial agonists: THIP (Gaboxadol) as a non-opioid analgesic and a novel type of hypnotic. Adv Pharmacol. Vol. 54. pp. 53–71.doi:10.1016/s1054-3589(06)54003-7.ISBN978-0-12-032957-1.PMID17175810.
^Johnston GA, Curtis DR, De Groat WC, Duggan AW (December 1968). "Central actions of ibotenic acid and muscimol".Biochem Pharmacol.17 (12):2488–2489.doi:10.1016/0006-2952(68)90141-x.PMID5752907.
^Curtis DR, Duggan AW, Felix D, Johnston GA (September 1971). "Bicuculline, an antagonist of GABA and synaptic inhibition in the spinal cord of the cat".Brain Res.32 (1):69–96.doi:10.1016/0006-8993(71)90156-9.PMID4398801.
^Shoulson I, Goldblatt D, Charlton M, Joynt RJ (1977). "Huntington's disease: treatment with muscimol, a GABA-mimetic drug".Trans Am Neurol Assoc.102 (3):124–125.doi:10.1002/ana.410040316.PMID150672.
^Shoulson I, Goldblatt D, Charlton M, Joynt RJ (September 1978). "Huntington's disease: treatment with muscimol, a GABA-mimetic drug".Ann Neurol.4 (3):279–284.doi:10.1002/ana.410040316.PMID152602.
^Cassady SL, Thaker GK, Moran M, Birt A, Tamminga CA (August 1992). "GABA agonist-induced changes in motor, oculomotor, and attention measures correlate in schizophrenics with tardive dyskinesia".Biol Psychiatry.32 (4):302–311.doi:10.1016/0006-3223(92)90035-x.PMID1358231.
^Cavagnini F, Pinto M, Dubini A, Invitti C, Cappelletti G, Polli EE (January 1982). "Effects of gamma aminobutyric acid (GABA) and muscimol on endocrine pancreatic function in man".Metabolism.31 (1):73–77.doi:10.1016/0026-0495(82)90029-4.PMID7043162.
