Muscimol

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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]
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 [ citation needed ] psychoactivity. This colorless or white solid is classified as an isoxazole.

Muscimol underwent a phase I clinical trial 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

The main natural sources of muscimol are fungi of the genus Amanita, such as Amanita muscaria (fly agaric) and Amanita pantherina (panther amanita). It is produced in the mushrooms along with muscarine (which is present in trace amounts and it is not active), muscazone, and ibotenic acid. [6] [7] 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. [8]

Muscimol is recognized as a potent agonist for ionotropic GABA-A receptors. By mimicking the inhibitory neurotransmitter GABA, muscimol activates these receptors, leading to the opening of chloride channels and subsequent hyperpolarization of neurons. This results in decreased neuronal excitability, which is crucial for maintaining the balance between excitation and inhibition in the central nervous system. [9]

The biochemical properties of muscimol make it a valuable tool for investigating GABAergic mechanisms. Its high affinity and specificity for GABA-A receptors allow researchers to study synaptic transmission, neural circuit dynamics, and the overall role of GABAergic inhibition in various physiological and pathological states. [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] [13] 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. [14]

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. [15]

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 . [16]

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. [17]

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. [18]

Mechanism of action

Muscimol primarily functions as a GABA-A receptor agonist, mimicking the action of GABA, the main inhibitory neurotransmitter, in the central nervous system.

Effects

Muscimol, as a GABA-A receptor agonist, has shown diverse pharmacological effects, spanning neuroprotective, anti-nociceptive, and anti-epileptic activity. [19]


Recent research has highlighted the following effects of muscimol:

Clinical research

Muscimol underwent a phase I clinical trial for epilepsy in 2012, but this trial was discontinued. [4]

A handful of exploratory clinical trials (n≤10) probing the utility of muscimol in the treatment of schizophrenia, Huntington's disease, and tardive dyskinesia occurred between 1977-1982. [28] [29] [30] The clinical investigation of muscimol in these conditions was superseded by gaboxadol, a conformationally constrained derivative of muscimol. [31] Neither drug appeared to be efficacious in the treatment of Huntington's disease or L-dopa/neuroleptic induced dyskinesia. [32] [33]

Muscimol-based products

Muscimol, a psychoactive compound derived from the ibotenic acid found in certain mushrooms, particularly Amanita muscaria , has garnered significant interest due to its unique effects on the nervous system. Muscimol binds to GABA receptors in the brain, resulting in its sedative and hallucinogenic properties.[ citation needed ] Muscimol-based products are currently being investigated for their potential therapeutic applications, especially in the treatment of anxiety, insomnia, and other neurological disorders. [34] [35] The psychoactive nature of muscimol necessitates stringent regulation and cautious usage to ensure safety. [36] However, ongoing research aims to harness its medicinal benefits in a controlled context, highlighting the broader scientific interest in natural compounds as potential sources for novel medical treatments.[ citation needed ]

Chemistry

Structure

Muscimol was first isolated from Amanita pantherina by Onda in 1964, [37] and thought to be an amino acid or peptide. Structure was then elucidated by Takemoto, [38] Eugster, [39] and Bowden. [40] Muscimol is a semi-rigid isoxazole containing both alcohol and aminomethyl substituents. [41] Muscimol is commonly portrayed as a tautomer, where it adopts an amide-like configuration. [2] It is also commonly shown as a zwitterion. [42]

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. [43] A subsequent elution with ammonium hydroxide and recrystallization from alcohol results in pure muscimol. [44]

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. [45]

Chemical synthesis

Muscimol was synthesized in 1965 by Gagneux, [46] 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. [46]

Step 2 Gagneux.png

Chemists report having struggled to reproduce these results. [47] [48] More dependable and scalable procedures have been developed, two examples being the syntheses of McCarry [49] and Varasi. [42]

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%. [49]

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) (which is a well known precursor of bromo nitriloxyde, a reactive dipole for regioselective Diels-Alder cycloadditions, which forms in alkali), 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. [42]

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%. [42]

Varasi Part 2 Synthesis New Nums Fixed.png

Toxicity

The toxicity and safety profile of Muscimol have been studied in various contexts, both experimental and clinical.

Dose-Dependent Effects in Primates

A study on nonhuman primates indicated that muscimol, when administered in escalating doses, caused reversible hyperkinesia and dyskinesias at higher doses (up to 88.8 mM), but no long-term toxicity was observed on histological examination. [50]

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. [51]

Anticonvulsant Properties

Muscimol has shown potential as an anticonvulsant, blocking seizures induced by various agents in animal models without causing significant toxicity at therapeutic doses. [52]

Human Poisoning Cases

A retrospective review of muscimol poisoning cases from Amanita mushrooms indicated that symptoms included gastrointestinal upset, CNS excitation, but no deaths were reported. Most symptoms resolved within 24 hours. [53]

Distribution and Metabolism

Studies on muscimol's distribution in rats showed it enters the brain and is metabolized rapidly, suggesting that its toxicity is low when used in controlled doses.[ citation needed ]

Muscimol exhibits dose-dependent effects with higher doses leading to significant, but reversible, CNS symptoms. [54] Its toxicity appears to be low when used in controlled environments, with no long-term damage observed in animal studies and human cases resolving without severe outcomes. However, caution is advised with its use due to its potent effects on the central nervous system.[ citation needed ]

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." [55]

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. [56] [57] 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. [58]

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. [59]

See also

Related Research Articles

<i>Amanita muscaria</i> Species of mushroom

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.

<i>Amanita</i> Genus of mushrooms including some 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">Ibotenic acid</span> Glutamate receptor agonist and neurotoxin

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.

GABA<sub>A</sub> receptor Ionotropic receptor and ligand-gated ion channel

The GABAA receptor (GABAAR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Accurate regulation of GABAergic transmission through appropriate developmental processes, specificity to neural cell types, and responsiveness to activity is crucial for the proper functioning of nearly all aspects of the central nervous system (CNS). Upon opening, the GABAA receptor on the postsynaptic cell is selectively permeable to chloride ions and, to a lesser extent, bicarbonate ions.

<span class="mw-page-title-main">Progabide</span> Pharmaceutical drug

Progabide is an analogue and prodrug of γ-aminobutyric acid (GABA) used in the treatment of epilepsy. Via conversion into GABA, progabide behaves as an agonist of the GABAA, GABAB, and GABAA-ρ receptors.

<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 similar effects. Furthermore, they lead to changes in gene transcription, and are mainly found in autonomic nervous system centers.

A convulsant is a drug which induces convulsions and/or epileptic seizures, the opposite of an anticonvulsant. These drugs generally act as stimulants at low doses, but are not used for this purpose due to the risk of convulsions and consequent excitotoxicity. Most convulsants are antagonists at either the GABAA or glycine receptors, or ionotropic glutamate receptor agonists. Many other drugs may cause convulsions as a side effect at high doses but only drugs whose primary action is to cause convulsions are known as convulsants. Nerve agents such as sarin, which were developed as chemical weapons, produce convulsions as a major part of their toxidrome, but also produce a number of other effects in the body and are usually classified separately. Dieldrin which was developed as an insecticide blocks chloride influx into the neurons causing hyperexcitability of the CNS and convulsions. The Irwin observation test and other studies that record clinical signs are used to test the potential for a drug to induce convulsions. Camphor, and other terpenes given to children with colds can act as convulsants in children who have had febrile seizures.

<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.

<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.

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

Isoguvacine is a GABAA receptor agonist used in scientific research.

<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">Rostral ventromedial medulla</span> Group of neurons in medulla of brain

The rostral ventromedial medulla (RVM), or ventromedial nucleus of the spinal cord, is a group of neurons located close to the midline on the floor of the medulla oblongata. The rostral ventromedial medulla sends descending inhibitory and excitatory fibers to the dorsal horn spinal cord neurons. There are 3 categories of neurons in the RVM: on-cells, off-cells, and neutral cells. They are characterized by their response to nociceptive input. Off-cells show a transitory decrease in firing rate right before a nociceptive reflex, and are theorized to be inhibitory. Activation of off-cells, either by morphine or by any other means, results in antinociception. On-cells show a burst of activity immediately preceding nociceptive input, and are theorized to be contributing to the excitatory drive. Neutral cells show no response to nociceptive input.

<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.

GABA<sub>A</sub> receptor positive allosteric modulator GABAA receptor positive modulators

In pharmacology, GABAA receptor positive allosteric modulators, also known as GABAkines or GABAA receptor potentiators, are positive allosteric modulator (PAM) molecules that increase the activity of the GABAA receptor protein in the vertebrate central nervous system.

<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).

This is a list of the legality of psychoactive Amanita mushrooms by country. In addition to muscimol and ibotenic acid, some species of Amanita mushrooms, including Amanita muscaria and Amanita citrina, may contain bufotenine which is illegal in many countries and is not included on this list.

<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.

References

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