Muscimol 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 with
anhydrous ammonia for 5 hours in a sealed flask to give muscimol. 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. 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. 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.
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. 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. 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. 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,
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. 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 5-10g 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. The LD50 in rats is 4.5 mg/kg i.v, 45 mg/kg orally.
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. Jonathan Ott describes the effects of
Amanita pantherina below: See also
References = Additional references=
External links Psychoactive Amanitas on Erowid
^ Chen LH, Sun B, Zhang Y, Xu TJ, Xia ZX, Liu JF, Nan FJ. "Discovery of a
Negative Allosteric Modulator of GABAB Receptors". ACS Med Chem Lett 5: 742–7.
doi:10.1021/ml500162z. PMC 4094264. PMID 25050158.