Muscimol

Last updated
Muscimol
Muscimol chemical structure.svg
Muscimol3d.png
Muscimol structure ball and stick.png
Names
IUPAC name
5-(Aminomethyl)-1,2-oxazol-3(2H)-one
Other names
Agarin, Pantherine, Agarine, Pantherin
Identifiers
3D model (JSmol)
774694
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.018.574 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 220-430-4
KEGG
PubChem CID
UNII
UN number 2811 3077
  • InChI=1S/C4H6N2O2/c5-2-3-1-4(7)6-8-3/h1H,2,5H2,(H,6,7) Yes check.svgY
    Key: ZJQHPWUVQPJPQT-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C4H6N2O2/c5-2-3-1-4(7)6-8-3/h1H,2,5H2,(H,6,7)
    Key: ZJQHPWUVQPJPQT-UHFFFAOYAI
  • NCc1cc(no1)O
Properties [1]
C4H6N2O2
Molar mass 114.104 g·mol−1
Melting point 184 to 185 °C (363 to 365 °F; 457 to 458 K)
very soluble
Solubility in ethanolslightly soluble
Solubility in methanol very soluble
Pharmacology
Legal status
  • AU: S9 (Prohibited substance)
  • in general, uncontrolled
Hazards
GHS labelling: [2]
GHS-pictogram-skull.svg
Danger
H300
P264, P270, P301+P316, P321, P330, P405, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

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 for the GABAA receptor [3] and displays sedative-hypnotic, depressant and hallucinogenic psychoactivity. This colorless or white solid is classified as an isoxazole.

Contents

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 neurotoxic secondary 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]

Amanita muscaria, which contains muscimol Amanita muscaria 3 vliegenzwammen op rij.jpg
Amanita muscaria , which contains muscimol

Pharmacology

GABA and muscimol molecules can have similar 3D-conformations which are shown superimposed in this image. Because of this similarity, muscimol binds to certain GABA-receptors. Muscimol vs GABA 3D.png
GABA and muscimol molecules can have similar 3D-conformations which are shown superimposed in this image. Because of this similarity, muscimol binds to certain GABA-receptors.

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. [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]

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. [16]

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. [17]

Effects

These include euphoria, dream-like (lucid) state of mind, out-of-body experiences and synesthesia.[ citation needed ] Negative effects include mild to moderate nausea, stomach discomfort, increased salivation and muscle twitching or tremors. In large doses strong dissociation or delirium may be felt.[ citation needed ] 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 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. [18] [19]

Chemistry

Structure

Muscimol was first isolated from Amanita pantherina by Onda in 1964, [20] and thought to be an amino acid or peptide. Structure was then elucidated by Takemoto, [21] Eugster, [22] and Bowden. [23] Muscimol is a semi-rigid isoxazole containing both alcohol and aminomethyl substituents. [24] Muscimol is commonly portrayed as a tautomer, where it adopts an amide-like configuration. [25] It is also commonly shown as a zwitterion. [26]

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. 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. [27] A subsequent elution with ammonium hydroxide and recrystallization from alcohol results in pure muscimol. [28]

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%.

Step 1 Gagneux.png

(2) was then refluxed in concentrated hydrochloric acid to hydrolyze the methoxy group, and the zwitterion crystallized from a solution of methanol and tetrahydrofuran after the addition of triethylamine, resulting in a 50% yield. [30]

Step 2 Gagneux.png

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 lithium acetylide 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]

McCarry Synthesis New Nums.png

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]

Varasi Synthesis New Nums.png

(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]

Varasi Part 2 Synthesis New Nums Fixed.png

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]

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]

See also

Related Research Articles

<i>Amanita muscaria</i> Species of fungus in the genus Amanita

Amanita muscaria, commonly known as the fly agaric or fly amanita, is a basidiomycete of the genus Amanita. It is a large white-gilled, white-spotted, and usually red mushroom.

<span class="mw-page-title-main">Thujone</span> Group of four possible stereoisomers found in various plants: a.o., absinthe and mint

Thujone is a ketone and a monoterpene that occurs predominantly in two diastereomeric (epimeric) forms: (−)-α-thujone and (+)-β-thujone.

<span class="mw-page-title-main">Muscarine</span> Chemical compound

Muscarine, L-(+)-muscarine, or muscarin is a natural product found in certain mushrooms, particularly in Inocybe and Clitocybe species, such as the deadly C. dealbata. Mushrooms in the genera Entoloma and Mycena have also been found to contain levels of muscarine which can be dangerous if ingested. Muscarine has been found in harmless trace amounts in Boletus, Hygrocybe, Lactarius and Russula. Trace concentrations of muscarine are also found in Amanita muscaria, though the pharmacologically more relevant compound from this mushroom is the Z-drug-like alkaloid muscimol. A. muscaria fruitbodies contain a variable dose of muscarine, usually around 0.0003% fresh weight. This is very low and toxicity symptoms occur very rarely. Inocybe and Clitocybe contain muscarine concentrations up to 1.6%.

<i>Amanita</i> Genus of mushrooms including some very deadly species

The genus Amanita contains about 600 species of agarics, including some of the most toxic known mushrooms found worldwide, as well as some well-regarded edible species. The genus is responsible for approximately 95% of fatalities resulting from mushroom poisoning, with the death cap accounting for about 50% on its own. The most potent toxin present in these mushrooms is α-Amanitin.

<i>Amanita pantherina</i> Species of fungus

Amanita pantherina, also known as the panther cap, false blusher, and the panther amanita due to its similarity to the true blusher, is a species of fungus found in Eurasia with poisonous and psychoactive properties.

<span class="mw-page-title-main">Mushroom poisoning</span> Harmful effects from ingestion of toxic substances present in a mushroom

Mushroom poisoning is poisoning resulting from the ingestion of mushrooms that contain toxic substances. Symptoms can vary from slight gastrointestinal discomfort to death in about 10 days. Mushroom toxins are secondary metabolites produced by the fungus.

<span class="mw-page-title-main">Ibotenic acid</span> Chemical compound

Ibotenic acid or (S)-2-amino-2-(3-hydroxyisoxazol-5-yl)acetic acid, also referred to as ibotenate, is a chemical compound and psychoactive drug which occurs naturally in Amanita muscaria and related species of mushrooms typically found in the temperate and boreal regions of the northern hemisphere. It is a prodrug of muscimol, broken down by the liver to that much more stable compound. It is a conformationally-restricted analogue of the neurotransmitter glutamate, and due to its structural similarity to this neurotransmitter, acts as a non-selective glutamate receptor agonist. Because of this, ibotenic acid can be a powerful neurotoxin in high doses, and is employed as a "brain-lesioning agent" through cranial injections in scientific research. The neurotoxic effects appear to be dose-related and risks are unclear through consumption of ibotenic-acid containing fungi, although thought to be negligible in small doses.

<span class="mw-page-title-main">Gaboxadol</span> Chemical compound

Gaboxadol, also known as 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP), is a conformationally constrained derivative of the alkaloid muscimol that was first synthesized in 1977 by the Danish chemist Poul Krogsgaard-Larsen. In the early 1980s gaboxadol was the subject of a series of pilot studies that tested its efficacy as an analgesic and anxiolytic, as well as a treatment for tardive dyskinesia, Huntington's disease, Alzheimer's disease, and spasticity. It was not until 1996 that researchers attempted to harness gaboxadol's frequently reported sedative "adverse effect" for the treatment of insomnia, resulting in a series of clinical trials sponsored by Lundbeck and Merck. In March, 2007, Merck and Lundbeck cancelled work on the drug, citing safety concerns and the failure of an efficacy trial. It acts on the GABA system, but in a different way from benzodiazepines, Z-Drugs, and barbiturates. Lundbeck states that gaboxadol also increases deep sleep. Unlike benzodiazepines, gaboxadol does not demonstrate reinforcement in mice or baboons despite activation of dopaminergic neurons in the ventral tegmental area.

<span class="mw-page-title-main">GABA receptor agonist</span> Category of drug

A GABA receptor agonist is a drug that is an agonist for one or more of the GABA receptors, producing typically sedative effects, and may also cause other effects such as anxiolytic, anticonvulsant, and muscle relaxant effects. There are three receptors of the gamma-aminobutyric acid. The two receptors GABA-α and GABA-ρ are ion channels that are permeable to chloride ions which reduces neuronal excitability. The GABA-β receptor belongs to the class of G-Protein coupled receptors that inhibit adenylyl cyclase, therefore leading to decreased cyclic adenosine monophosphate (cAMP). GABA-α and GABA-ρ receptors produce sedative and hypnotic effects and have anti-convulsion properties. GABA-β receptors also produce sedative effects. Furthermore, they lead to changes in gene transcription.

<span class="mw-page-title-main">Amanita muscaria var. guessowii</span> Variety of fungi

Amanita chrysoblema yellow-orange variant, commonly known as the American yellow fly agaric, is a basidiomycete fungus of the genus Amanita. It is one of several varieties of muscaroid fungi, all commonly known as fly agarics or fly amanitas.

<i>Amanita persicina</i> Species of fungus

Amanita persicina, commonly known as the peach-colored fly agaric, is a basidiomycete fungus of the genus Amanita with a peach-colored center. Until c. 2015, the fungus was believed to be a variety of A. muscaria.

<span class="mw-page-title-main">GABA reuptake inhibitor</span> Drug class

A GABA reuptake inhibitor (GRI) is a type of drug which acts as a reuptake inhibitor for the neurotransmitter gamma-Aminobutyric acid (GABA) by blocking the action of the gamma-Aminobutyric acid transporters (GATs). This in turn leads to increased extracellular concentrations of GABA and therefore an increase in GABAergic neurotransmission. Gamma-aminobutyric acid (GABA) is an amino acid that functions as the predominant inhibitory neurotransmitter within the central nervous system, playing a crucial role in modulating neuronal activity in both the brain and spinal cord. While GABA predominantly exerts inhibitory actions in the adult brain, it has an excitatory role during developmental stages. When the neuron receives the action potential, GABA is released from the pre-synaptic cell to the synaptic cleft. After the action potential transmission, GABA is detected on the dendritic side, where specific receptors collectively contribute to the inhibitory outcome by facilitating GABA transmitter uptake. Facilitated by specific enzymes, GABA binds to post-synaptic receptors, with GABAergic neurons playing a key role in system regulation. The inhibitory effects of GABA diminish when presynaptic neurons reabsorb it from the synaptic cleft for recycling by GABA transporters (GATs). The reuptake mechanism is crucial for maintaining neurotransmitter levels and synaptic functioning. Gamma-aminobutyric acid Reuptake Inhibitors (GRIs) hinder the functioning of GATs, preventing GABA reabsorption in the pre-synaptic cell. This results in increased GABA levels in the extracellular environment, leading to elevated GABA-mediated synaptic activity in the brain.

<i>Amanita regalis</i> Species of fungus

Amanita regalis, commonly known as the royal fly agaric or the king of Sweden Amanita, is a species of fungus in the family Amanitaceae. A. regalis has a scabby liver-brown cap and a stem which is yellow-ochre at the base, with patches or rings of patches. The fruit bodies somewhat resemble the smaller A. muscaria, which it was formerly regarded as a variety of.

<i>Amanita muscaria <span style="font-style:normal;">var.</span> formosa</i> Species of fungus

Amanita muscaria var. formosa, known as the yellow orange fly agaric, is a hallucinogenic and poisonous basidiomycete fungus of the genus Amanita. This variety, which can sometimes be distinguished from most other A. muscaria by its yellow cap, is a European taxon, although several North American field guides have referred A. muscaria var. guessowii to this name. American mycologist Harry D. Thiers described a yellow-capped taxon that he called var. formosa from the United States, but it is not the same as the European variety. The Amanita Muscaria is native to temperate or boreal forest regions of the Northern Hemisphere. However, it has also been introduced in New Zealand, Australia, South America, and South Africa.

<span class="mw-page-title-main">CI-966</span> Chemical compound

CI-966 (developmental code name) is a central nervous system depressant acting as a GABA reuptake inhibitor, specifically a highly potent and selective blocker of the GABA transporter 1 (GAT-1) (IC50 = 0.26 μM), and hence indirect and non-selective GABA receptor full agonist. It was investigated as a potential anticonvulsant, anxiolytic, and neuroprotective therapeutic but was discontinued during clinical development due to the incidence of severe adverse effects at higher doses and hence was never marketed.

<span class="mw-page-title-main">GABA analogue</span> Class of drugs

A GABA analogue is a compound which is an analogue or derivative of the neurotransmitter gamma-Aminobutyric acid (GABA).

<i>Amanita muscaria <span style="font-style:normal;">var.</span> inzengae</i> Species of fungus

Amanita muscaria var. inzengae, commonly known as Inzenga's fly agaric, is a basidiomycete fungus of the genus Amanita. It is one of several varieties of the Amanita muscaria fungi, all commonly known as fly agarics or fly amanitas.

<i>Amanita ibotengutake</i> Species of fungus

Amanita ibotengutake is a species of agaric fungus in the family Amanitaceae native to Japan. It was first described in 2002 as distinct on a genetic level from A. pantherina, and earlier has been classified under that name.

<span class="mw-page-title-main">Acromelic acid A</span> Chemical compound

Acromelic acid A (ACRO A) is a toxic compound that is part of a group known as kainoids, characterized by a structure bearing a pyrrolidine dicarboxylic acid, represented by kainic acid. Acromelic acid A has the molecular formula C13H14N2O7. It has been isolated from a Japanese poisonous mushroom, Clitocybe acromelalga. Acromelic acid is responsible for the poisonous aspects of the mushroom because of its potent neuroexcitatory and neurotoxic properties. Ingestion of the Clitocybe acromelalga, causes allodynia which can continue for over a month. The systemic administration of acromelic acid A in rats results in selective loss of interneurons in the lower spinal cord, without causing neuronal damage in the hippocampus and other regions.

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  34. ↑ "Erowid Psychoactive Amanitas Vault: Chemistry". erowid.org. Retrieved 2018-04-05.
  35. ↑ Spoerke D, ed. (1994). Handbook of mushroom poisoning: diagnosis and treatment. Boca Raton: CRC Press. p. 269. ISBN   978-0-8493-0194-0. OCLC   29913834., Preview Google Books.
  36. ↑ "Poisons Standard". The Government of Australia. October 2015.
  37. ↑ "Controlled Substance Schedules". deadiversion.usdoj.gov. US Department of Justice. Retrieved 6 May 2020.
  38. ↑ Erowid. "Erowid Psychoactive Amanitas Vault: Legal Status". erowid.org. Retrieved 6 May 2020.
  39. ↑ Sam O (May 31, 2023). "Mood-altering mushroom sales bloom despite safety concerns". Health News Florida. Retrieved June 6, 2023.
  40. ↑ "Louisiana Act No 159". legis.la.gov. Louisiana State Legislature. Retrieved 6 May 2020.
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