Muscimol
Muscimol, also known as agarin, pantherine, or pyroibotenic acid, is a GABAA receptor agonist with sedative and hallucinogenic effects and the principal psychoactive constituent of Amanita mushrooms such as Amanita muscaria and Amanita pantherina. It is a 3-hydroxyisoxazole alkaloid and is closely related structurally to the neurotransmitter γ-aminobutyric acid. The compound is widely used as a ligand and agonist of the GABAA receptor in scientific research. Muscimol is typically taken orally, but may also be smoked. Peak effects occur after 1 to 3hours orally and its duration is 4 to 8hours but up to 24hours.
The effects of muscimol in humans include central depression, sedation, sleep, cognitive and motor impairment, hallucinations, perceptual distortion, and muscle twitching, among others. Muscimol acts as a potent GABAA receptor full agonist. It is also a potent GABAA-ρ receptor partial agonist and a weak GABA reuptake inhibitor. The drug is inactive at the GABAB receptor but is a substrate of GABA transaminase. Muscimol mostly exerts its effects via GABAA receptor activation. It is very different from drugs like benzodiazepines and barbiturates as it is an orthosteric agonist of the GABAA receptor rather than an allosteric modulator. Unlike GABA, muscimol crosses the blood–brain barrier and hence is centrally active. Muscimol, which is also known chemically as 5-aminomethylisoxazol-3-ol, is a conformationally restrained analogue of GABA. The related compound and Amanita spp. constituent ibotenic acid is a prodrug of muscimol.
Muscimol was first isolated from Amanita muscaria and hence was discovered in 1964. It has been limitedly clinically studied as a potential pharmaceutical drug for a number of uses, such as treatment of epilepsy. In addition, analogues and derivatives of muscimol, such as the selective GABAA receptor agonist gaboxadol and the selective GABA reuptake inhibitor tiagabine, have been developed as pharmaceutical drugs. Muscimol and Amanita muscaria mushrooms have rarely been used as recreational drugs historically. By the mid-2020s however, use of these substances, including recreational use for hallucinogenic effects and microdosing for claimed therapeutic benefits, has become increasingly prominent. The most commonly cited therapeutic reason for their use is to improve sleep. Muscimol is not a controlled substance and is unregulated in most of the world, including in most of the United States and Europe.
Natural occurrence
The main natural sources of muscimol are fungi of the genus Amanita, such as Amanita muscaria and Amanita pantherina. It is produced in the mushrooms along with muscarine, muscazone, and ibotenic acid. In Amanita muscaria, the layer just below the skin of the cap contains the highest amount of muscimol, and is therefore the most psychoactive portion.Use and effects
The properties and effects of muscimol in humans have been limitedly assessed in clinical studies. It has been assessed in these studies at doses of 5 to 15mg orally. The oral threshold dose of muscimol is approximately 6mg, while the psychoactive dose range has been said to range from approximately 8 to 15mg. As little as 1g of dried Amanita muscaria button may contain this amount of muscimol, although the potency varies greatly among mushrooms. According to Jonathan Ott, a 15mg dose is "psychoptic" while a 20mg dose is "visionary". The onset of action of muscimol, via isolated muscimol or Amanita muscaria consumption orally, is between 30minutes and 2hours, with peak effects occurring after 1 to 3hours. The duration is 4 to 8hours, but some effects may persist for up to 24hours. In one publication, the effects of muscimol were described as follows:The effects of muscimol in humans in different studies have been found to include sedation, dizziness, incoordination, relaxation, reduced anxiety, mood improvement, sleep, rich dreaming, difficulty speaking, impaired attention, focus, and concentration, impaired learning, confusion, loss of appetite, stimulation, agitation, hallucinogenic effects, echo-like pseudohallucinations. In humans, gaboxadol decreases sleep onset latency, increases sleep duration, increases slow wave sleep and slow wave activity, and does not suppress REM sleep. The effects of muscimol and gaboxadol on sleep differ from those of widely used GABAA receptor positive allosteric modulators like benzodiazepines and Z-drugs, which can instead disrupt SWS and SWA despite improving sleep onset and duration. Although muscimol and gaboxadol have similar effects on sleep, muscimol has additionally been found to increase REM sleep unlike gaboxadol.
Ibotenic acid, a prodrug of muscimol, is active at doses of approximately 20 to 100mg orally in humans. About 10 to 20% of ibotenic acid is said to be converted into muscimol following decarboxylation.
Toxicity and overdose
The toxicity and safety profile of muscimol has been studied in various contexts, both experimental and clinical. The median lethal dose in mice is 3.8mg/kg s.c, 2.5mg/kg i.p. The LD50 in rats is 4.5mg/kg i.v, 45 mg/kg orally. A study on non-human primates indicated that muscimol, when administered in escalating doses, caused reversible hyperkinesia and dyskinesias at higher doses, but no long-term toxicity was observed on histological examination. Muscimol has shown potential as an anticonvulsant, blocking seizures induced by various agents in animal models without causing significant toxicity at therapeutic doses. Muscimol exhibits dose-dependent effects with higher doses leading to significant, but reversible, central nervous system symptoms. The dose of muscimol that is thought to be potentially fatal in humans is 90mg, which is 15times its threshold active dose of 6mg.Interactions
The actions and effects of muscimol may be potentiated by benzodiazepines such as diazepam.Pharmacology
Pharmacodynamics
Muscimol is a potent GABAA receptor full agonist, activating the receptor for the brain's principal inhibitory neurotransmitter, γ-aminobutyric acid. Muscimol binds to the same site on the GABAA receptor complex as GABA itself, unlike other GABAergic drugs such as barbiturates, benzodiazepines, and Z-drugs, which interact with separate allosteric sites. GABAA receptors are widely distributed in the brain, so when muscimol is administered, it alters neuronal activity in multiple regions including the cerebral cortex, hippocampus, and cerebellum. By mimicking 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.Muscimol shows relatively uniform effects on GABAA receptors of differing subunit compositions. However, it was found to act as a superagonist of extrasynaptic α4β3δ subunit-containing GABAA receptors. This was found to be due to reduced receptor desensitization with muscimol compared to GABA. Subsequent research has found that muscimol is a preferential agonist of the relatively small population of δ subunit-containing GABAA receptors and that these receptors have a substantial contribution to its effects. In contrast to muscimol, benzodiazepines and Z-drugs do not activate δ subunit-containing GABAA receptors. On the other hand, alcohol is known to selectively potentiate δ subunit-containing extrasynaptic GABAA receptors analogously to muscimol.
While muscimol is often thought of as a selective GABAA agonist with exceptionally high affinity to δ subunit-containing GABAA receptors, it is also a potent partial agonist of the GABAA-ρ receptor, and so its range of effects results from a combined action on more than one GABAA receptor subtype. In fact, it is more potent as a partial agonist of the GABAA-ρ receptor than as a GABAA receptor agonist. Muscimol has been said to be inactive at the GABAB receptor. However, a subsequent study reported that muscimol may have GABAB receptor-mediated inhibitory activity, although more research is needed to further characterize this activity. Muscimol is inactive in terms of affecting GABA transaminase. There is little evidence that muscimol interacts with other biological targets besides the GABA receptors and the GABA transporters.
In animals, muscimol produces central depression, sedation, analgesia, anxiolysis, anticonvulsant effects, neuroprotective effects, and anesthesia, among other effects. In rodent drug discrimination studies, muscimol and gaboxadol fully generalize between each other, but generalization between benzodiazepines like diazepam does not occur. These findings suggest that muscimol and gaboxadol have differing interoceptive effects from those of benzodiazepines. During a test involving rabbits connected to an EEG, muscimol presented with a distinctly synchronized EEG tracing. This is substantially different from serotonergic psychedelics like psilocybin, with which brainwave patterns generally show a desynchronization. In higher doses, the EEG will show characteristic spikes.