Muscimol

"Pantherine" redirects here. For the big cat subfamily, see Pantherinae.
Muscimol
Names
IUPAC name
5-(Aminomethyl)-isoxazol-3-ol
Identifiers
2763-96-4 N
3D model (Jmol) Interactive image
ChEBI CHEBI:7035 N
ChEMBL ChEMBL273481 YesY
ChemSpider 4116 YesY
ECHA InfoCard 100.018.574
4259
PubChem 4266
Properties[1]
C4H6N2O2
Molar mass 114.10 g·mol−1
Melting point 184 to 185 °C (363 to 365 °F; 457 to 458 K)
very soluble
Solubility in ethanol slightly soluble
Solubility in methanol very soluble
Pharmacology
Legal status
  • AU: S9 (Prohibited)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YesYN ?)
Infobox references

Muscimol (also known as agarin or pantherine) is the principal psychoactive constituent of Amanita muscaria and related species of mushroom. Muscimol acts as a potent, selective agonist for the GABAA receptors and displays sedative-hypnotic and dissociative psychoactivity.

Chemistry

Muscimol is the psychoactive compound responsible for the effects of Amanita muscaria intoxication. Ibotenic acid, a neurotoxic secondary metabolite of Amanita muscaria, serves as a prodrug to muscimol when the mushroom is ingested or dried, converting to muscimol via decarboxylation.

It can be produced synthetically from propargyl chloride. The lithium acetylide is produced by reaction with BuLi. Remaining at -40 °C this is treated with a two-fold excess of ethyl chloroformate to afford ethyl 4-chlorotetrolate. This is added to an aqueous methanolic solution of basic hydroxylamine at -35 °C followed 15 min later by a pH 7 aqueous buffer so as to give a final pH between 8.5 and 9 for optimum cyclisation. The resulting chloromethylisoxazole is heated to 50 °C in a solution of methanol saturated (at 0 °C) with anhydrous ammonia for 5 hours in a sealed flask to give muscimol.[2] The overall yield achieved in the literature was 18.7%.

Biology

Muscimol is produced naturally in the mushrooms Amanita muscaria and Amanita pantherina, along with muscarine, muscazone, and ibotenic acid.[3][4] A. muscaria and A. pantherina should be eaten with caution and prepared properly to lessen effects of nausea; no official deaths from poisoning have been recorded from A. muscaria and A. pantherina.[5] 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.[6]

Amanita muscaria, which contains muscimol

Pharmacology

Muscimol is a potent GABAA agonist, activating the receptor for the brain's principal inhibitory neurotransmitter, 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.[7] 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 conventionally thought of as a selective GABAA agonist, it is also a partial agonist at the GABAA-rho receptor, and so its range of effects results from a combined action at both targets.[8]

In patients with Huntington's disease and chronic schizophrenia, oral doses of muscimol have been found to cause a rise of both prolactin and growth hormone.[9]

During a test involving rabbits connected to an EEG, muscimol presented with a distinctly synchronized EEG tracing. This is substantially different from serotonergic psychedelics, with which brainwave patterns generally show a desynchronization. In higher doses (2 mg/kg), the EEG will show characteristic spikes.

When consumed, some percentage of muscimol goes un-metabolized and thus excreted in urine, a phenomenon exploited by practitioners of the traditional entheogenic use of Amanita muscaria.[10]

The psychoactive dose of muscimol is around 10–15 mg for a normal person.[11] 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 5-10g is necessary. A correct dose may be difficult to determine because potency varies dramatically from one mushroom to the next.

Toxicity

The LD50 in mice is 3.8 mg/kg s.c, 2.5 mg/kg i.p.[12] The LD50 in rats is 4.5 mg/kg i.v, 45 mg/kg orally.[12]

Effects

Many of muscimol's effects are consistent with its pharmacology as a GABAA receptor agonist, presenting many depressant or sedative-hypnotic effects. Atypical of the effect profile of sedative drugs generally however, muscimol, like Z-drugs, can cause dissociative changes in perception.[13] Jonathan Ott describes the effects of Amanita pantherina below:

About 90 minutes after ingestion ... I noticed that I was experiencing changes in visual perception. These effects became stronger over the next hour or some, and were characterized by sensing an 'alive quality' in inanimate objects, wavy motion in the visual field like a Van Gogh canvas ... and mild distortion of size, distance and depth perception. Auditory hallucination were also prominent -- especially the effect, called 'anahata sounds' of yoga, of hearing fine high-pitched sounds like bells and violin strings.[14]

Australia

Muscimol is considered a Schedule 9 prohibited substance in Australia under the Poisons Standard (October 2015).[15] 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.[15]

See also

References

  1. ↑ The Merck Index, 12th Edition
  2. ↑ McCarry, Brian E.; Savard, Marc (1981). "A facile synthesis of muscimol" (PDF). Tetrahedron Letters. 22 (51): 5153–5156. doi:10.1016/S0040-4039(01)92445-1.
  3. ↑ Chilton, WS; Ott, J (1976). "Toxic metabolites of Amanita pantherina, A. Cothurnata, A. Muscaria and other Amanita species". Lloydia. 39 (2–3): 150–7. PMID 985999.
  4. ↑ Michelot, D; Melendez-Howell, LM (2003). "Amanita muscaria: chemistry, biology, toxicology, and ethnomycology". Mycological Research. 107 (Pt 2): 131–46. doi:10.1017/S0953756203007305. PMID 12747324.
  5. ↑ Tupalska-Wilczyńska, K; Ignatowicz, R; Poziemski, A; Wójcik, H; Wilczyński, G (1996). "Poisoning with spotted and red mushrooms--pathogenesis, symptoms, treatment". Wiadomości Lekarskie (in Polish). 49 (1–6): 66–71. PMID 9173659.
  6. ↑ Chilton, WS (1978). "Chemistry and Mode of Action of Mushroom Toxins". In Rumack, BH; Salzman, E. Mushroom Poisoning: Diagnosis and Treatment. Palm Beach: CRC Press. pp. 87–124. ISBN 9780849351853.
  7. ↑ 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. PMID 12171573.
  8. ↑ Woodward, RM; Polenzani, L; Miledi, R (1993). "Characterization of bicuculline/baclofen-insensitive (rho-like) gamma-aminobutyric acid receptors expressed in Xenopus oocytes. II. Pharmacology of gamma-aminobutyric acidA and gamma-aminobutyric acidB receptor agonists and antagonists". Molecular Pharmacology. 43 (4): 609–25. PMID 8386310.
  9. ↑ 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. PMID 162520.
  10. ↑ Goldstein A. (2001). Addiction: From Biology to Drug Policy. Oxford University Press. p. 228. ISBN 978-0-19-514664-6.
  11. ↑ "Erowid Psychoactive Amanitas Vault : Dosage".
  12. 1 2 "Erowid Psychoactive Amanitas Vault : Chemistry".
  13. ↑ "Erowid Psychoactive Amanitas Vault : Effects".
  14. ↑ Ott, Jonathan (June 11, 2000). "Studies of Amanita: experience with Amanita muscaria (ID 366)". Erowid.org.
  15. 1 2 Poisons Standard October 2015 https://www.comlaw.gov.au/Details/F2015L01534

Additional references

  • Ito Y, Segawa K, Fukuda H; Segawa; Fukuda (1995). "Functional diversity of GABAA receptor ligand-gated chloride channels in rat synaptoneurosomes". Synapse. 19 (3): 188–96. doi:10.1002/syn.890190306. PMID 7784959. 
  • Rätsch, Christian. (1998). The Encyclopedia of Psychoactive Plants. Rochester, VT: Park Street Press.
  • Beaumont K, Chilton W. S., Yamamura H. I., Enna S. J.; Chilton; Yamamura; Enna (1978). "Muscimol binding in rat brain: association with synaptic GABA receptors". Brain Res. 148 (1): 153–62. doi:10.1016/0006-8993(78)90385-2. PMID 207386. 
  • S. R. Snodgrass (1978). "Use of 3H-muscimol for GABA receptor studies". Nature. 273 (1): 392–394. doi:10.1038/273392a0. 
  • G. A. R. Johnston; D. R. Curtis; W. C. de Groat; A. W. Duggan (1968). "Central actions of ibotenic acid and muscimol". Biochemical Pharmacology. 17 (12): 2488–2489. doi:10.1016/0006-2952(68)90141-X. PMID 5752907. 
  • Tamminga CA, Neophytides A, Chase TN, Frohman LA; Neophytides; Chase; Frohman (December 1978). "Stimulation of prolactin and growth hormone secretion by muscimol, a gamma-aminobutyric acid agonist". J. Clin. Endocrinol. Metab. 47 (6): 1348–51. doi:10.1210/jcem-47-6-1348. PMID 162520. 
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