Muscimol (also known as agarin or pantherine) is one of the principal
psychoactive constituents of ''
Amanita muscaria'' and related species of mushroom. Muscimol is a potent and selective orthosteric
agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ag ...
for the
GABAA receptors and displays
sedative-hypnotic,
depressant and
hallucinogenic
psychoactivity. This colorless or white solid is classified as an
isoxazole
Isoxazole is an electron-rich azole with an oxygen atom next to the nitrogen. It is also the class of compounds containing this ring. Isoxazolyl is the univalent radical derived from isoxazole.
Occurrence
Isoxazole rings are found in some natural ...
.
Muscimol went under clinical trial phase I for epilepsy, but the trial was discontinued.
Biochemistry
Muscimol is one of the psychoactive compounds 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.
Muscimol is produced in the mushrooms ''
Amanita muscaria'' (fly agaric) and ''
Amanita pantherina
''Amanita pantherina'', also known as the panther cap, false blusher, and the panther amanita due to its similarity to the true blusher (''Amanita rubescens''), is a species of fungus found in Europe and Western Asia.
Description
*Cap: 5� ...
'', along with
muscarine (which is present in trace amounts and it is not active),
muscazone, and
ibotenic acid.
''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.
Pharmacology
Muscimol is a potent
GABAA agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ag ...
, activating the
receptor
Receptor may refer to:
*Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...
for the brain's principal
inhibitory neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neu ...
,
GABA. Muscimol binds to the same site on the GABA
A receptor complex as GABA itself, as opposed to other GABAergic drugs such as
barbiturates and
benzodiazepines which bind to separate regulatory sites. GABA
A receptors are widely distributed in the brain, and so when muscimol is administered, it alters neuronal activity in multiple regions including the
cerebral cortex
The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consisting o ...
,
hippocampus
The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic syste ...
, and
cerebellum. While muscimol is normally thought of as a selective
GABAA agonist with exceptionally high affinity to GABA
A-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 GABA
A 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 g 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''.
In patients with
Huntington's disease
Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an uns ...
and chronic
schizophrenia
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social w ...
, 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 (2 mg/kg via
IV), the EEG will show characteristic spikes.
Effects
The effects of muscimol begin around one hour after consumption, peaking at 3 hours, and lasting a total of 10-24 hours.
These include
euphoria
Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and d ...
, dream-like (
lucid
LUCID (Langton Ultimate Cosmic ray Intensity Detector) is a cosmic ray detector built by Surrey Satellite Technology Ltd and designed at Simon Langton Grammar School for Boys, in Canterbury, England. Its main purpose is to monitor cosmic rays ...
) state of mind,
out-of-body experiences and
synesthesia
Synesthesia (American English) or synaesthesia (British English) is a perceptual phenomenon in which stimulation of one sensory or cognitive pathway leads to involuntary experiences in a second sensory or cognitive pathway. People who re ...
. Negative effects include mild to moderate
nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of th ...
, stomach discomfort, increased
saliva
Saliva (commonly referred to as spit) is an extracellular fluid produced and secreted by salivary glands in the mouth. In humans, saliva is around 99% water, plus electrolytes, mucus, white blood cells, epithelial cells (from which DNA can ...
tion and muscle twitching or tremors. In large doses strong
dissociation or
delirium may be felt.
Many of muscimol's effects are consistent with its pharmacology as a
GABAA receptor agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ag ...
, presenting many
depressant or
sedative-
hypnotic effects. Atypical of the effect profile of sedative drugs generally however, muscimol, like
Z-drugs
Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive drugs that are very benzodiazepine-like in nature. They are used in the treatment of sleep problem ...
, can cause
hallucinogenic changes in perception. The hallucinogenic effect produced by muscimol is most closely comparable to the hallucinogenic / Lilliputian side effects produced by some other
GABAergic drugs such as
zolpidem.
Chemistry
Structure
Muscimol was first isolated from ''
Amanita pantherina
''Amanita pantherina'', also known as the panther cap, false blusher, and the panther amanita due to its similarity to the true blusher (''Amanita rubescens''), is a species of fungus found in Europe and Western Asia.
Description
*Cap: 5� ...
'' by Onda in 1964, and thought to be an
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
or
peptide
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...
. Structure was then elucidated by Takemoto,
Eugster, and Bowden. Muscimol is a semi-rigid
isoxazole
Isoxazole is an electron-rich azole with an oxygen atom next to the nitrogen. It is also the class of compounds containing this ring. Isoxazolyl is the univalent radical derived from isoxazole.
Occurrence
Isoxazole rings are found in some natural ...
containing both
alcohol and
aminomethyl substituents. Muscimol is commonly portrayed as a
tautomer
Tautomers () are structural isomers (constitutional isomers) of chemical compounds that readily interconvert.
The chemical reaction interconverting the two is called tautomerization. This conversion commonly results from the relocation of a hy ...
, where it adopts an
amide
In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it i ...
-like configuration. It is also commonly shown as a
zwitterion.
Isolation
Muscimol can be extracted from the flesh of the ''
Amanita muscaria'' by treatment with boiling water, followed by rapid cooling, and further treatment with a
basic resin
In polymer chemistry and materials science, resin is a solid or highly viscous substance of plant or synthetic origin that is typically convertible into polymers. Resins are usually mixtures of organic compounds. This article focuses on nat ...
. This is washed with water, and
eluted with
acetic acid using
column chromatography. The
eluate is freeze dried, dissolved in water, and passed down a column of
cellulose phosphate. A subsequent elution with
ammonium hydroxide and
recrystallization from alcohol results in pure muscimol.
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.
Chemical Synthesis
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
Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical and the simplest aliphatic alcohol, with the formula C H3 O H (a methyl group linked to a hydroxyl group, often abbreviated as MeOH). It is ...
and
Potassium Hydroxide
Potassium hydroxide is an inorganic compound with the formula K OH, and is commonly called caustic potash.
Along with sodium hydroxide (NaOH), KOH is a prototypical strong base. It has many industrial and niche applications, most of which exp ...
for 30 hours, resulting in 3-methoxy-5-aminomethyl-isoxazole (2) with a yield of 60%.
(2) was then refluxed in concentrated
hydrochloric acid
Hydrochloric acid, also known as muriatic acid, is an aqueous solution of hydrogen chloride. It is a colorless solution with a distinctive pungent smell. It is classified as a strong acid. It is a component of the gastric acid in the dige ...
to
hydrolyze
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile.
Biological hydrolysis i ...
the
methoxy group
In organic chemistry, a methoxy group is the functional group consisting of a methyl group bound to oxygen. This alkoxy group has the formula .
On a benzene ring, the Hammett equation classifies a methoxy substituent at the ''para'' position ...
, and the
zwitterion crystallized from a solution of
methanol
Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical and the simplest aliphatic alcohol, with the formula C H3 O H (a methyl group linked to a hydroxyl group, often abbreviated as MeOH). It is ...
and
tetrahydrofuran
Tetrahydrofuran (THF), or oxolane, is an organic compound with the formula (CH2)4O. The compound is classified as heterocyclic compound, specifically a cyclic ether. It is a colorless, water- miscible organic liquid with low viscosity. It is ...
after the addition of
triethylamine, resulting in a 50% yield.
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
lithium
Lithium (from el, λίθος, lithos, lit=stone) is a chemical element with the symbol Li and atomic number 3. It is a soft, silvery-white alkali metal. Under standard conditions, it is the least dense metal and the least dense soli ...
acetylide produced from
propargyl chloride. The acetylide (3), was dissolved in
ether
In organic chemistry, ethers are a class of compounds that contain an ether group—an oxygen atom connected to two alkyl or aryl groups. They have the general formula , where R and R′ represent the alkyl or aryl groups. Ethers can again ...
, 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
Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical and the simplest aliphatic alcohol, with the formula C H3 O H (a methyl group linked to a hydroxyl group, often abbreviated as MeOH). It is ...
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
Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical and the simplest aliphatic alcohol, with the formula C H3 O H (a methyl group linked to a hydroxyl group, often abbreviated as MeOH). It is ...
and
anhydrous ammonia
Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous wast ...
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
Water (chemical formula ) is an inorganic, transparent, tasteless, odorless, and nearly colorless chemical substance, which is the main constituent of Earth's hydrosphere and the fluids of all known living organisms (in which it acts as ...
, 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.
(9) was then refluxed with
potassium hydroxide
Potassium hydroxide is an inorganic compound with the formula K OH, and is commonly called caustic potash.
Along with sodium hydroxide (NaOH), KOH is a prototypical strong base. It has many industrial and niche applications, most of which exp ...
in
methanol
Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical and the simplest aliphatic alcohol, with the formula C H3 O H (a methyl group linked to a hydroxyl group, often abbreviated as MeOH). It is ...
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%.
Toxicity
The
median lethal dose in mice is 3.8 mg/kg s.c, 2.5 mg/kg i.p. The LD
50 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.
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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."
United States
Neither ''
Amanita muscaria'' nor muscimol is considered a controlled substance by the
Federal government of the United States
The federal government of the United States (U.S. federal government or U.S. government) is the national government of the United States, a federal republic located primarily in North America, composed of 50 states, a city within a fede ...
. This means that cultivation, possession, and distribution are unregulated by the United States Federal Government.
Muscimol may be regulated on a state level.
Louisiana State Act 159
Signed into law June 28, 2005, and effective August 8, 2005, Louisiana State Act No 159 found in, Louisiana RS 40:989.1, outlawed the cultivation, possession or sale of 40 named plants defined as hallucinogenic in the state of Louisiana, US. House ...
banned the possession and cultivation of the ''
Amanita muscaria'' except for ornamental or aesthetic purposes. This act outlaws preparations of the ''
Amanita muscaria'' intended for human consumption, including muscimol.
See also
*
Ibotenic acid
*
Gaboxadol
*
Thiomuscimol
*
CI-966
*
Z-drugs
Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive drugs that are very benzodiazepine-like in nature. They are used in the treatment of sleep problem ...
References
External links
Psychoactive ''Amanitas'' on Erowid
{{Glutamate receptor modulators
Entheogens
GABAA receptor agonists
GABAA-rho receptor agonists
Isoxazoles
Mycotoxins
Oneirogens
Sedatives
Amines
Alkaloids
Anticonvulsants