Pantherine, Agarin

Muscimol is a psychoactive compound found in the mushroom Amanita muscaria. Another compound in this mushroom, ibotenic acid, is a prodrug of muscimol via decarboxylation.1

The Chemistry of Muscimol

Muscimol is a heterocyclic isostere of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA).2 It was first isolated from a mushroom in the Amanita genera in 1964 by Onda.3 One year later, Gagneux et al. published the first synthesis of the compound.4

The Pharmacology of Muscimol

Muscimol works as a potent agonist of GABAA receptors in the brain.5 Activation of GABAA causes an inhibitory effect, meaning it reduces the transmission of neuronal signals. Muscimol can displace GABA and other GABA agonists from GABA receptor sites in nanomolar concentrations.

Unlike GABA, muscimol can penetrate the blood-brain barrier.6 This characteristic makes muscimol an attractive candidate for developing drugs that act on GABA receptors. Also, GABA receptors and their transport mechanisms are often used as targets for drug development.7

Muscimol is metabolized primarily by transamination8 and research indicates that its metabolites penetrate the blood brain barrier.9

As a GABA agonist, muscimol is implicated in the toxic effects of Amanita muscaria.10 The effects of muscimol are similar to those of diazepam (Valium). At low doses it decreases motor activity and larger doses cause ataxia.

The Applications and Potential of Muscimol

In 1978, Tamminga et al. suggested that muscimol may be a therapeutic treatment for schizophrenia.11 In clinical studies, muscimol has been shown to have a variety of effects including analgesic, antispastic, anxiolytic, and a muscle relaxant (see review in Krogsgaard-Larsen et al. 1985).2

  1. Stebelska K. Fungal hallucinogens psilocin, ibotenic acid, and muscimol: analytical methods and biologic activities. Therapeutic Drug Monitoring. 2013;35(4):420-442. doi:10.1097/FTD.0b013e31828741a5
  2. Krogsgaard-Larsen P, Falch E, Hjeds H. 2 Heterocyclic Analogues of GAB A: Chemistry, Molecular Pharmacology and Therapeutic Aspects. In: Ellis GP, West GB, eds. Progress in Medicinal Chemistry. Vol 22. ; 1985:67-120. doi:10.1016/S0079-6468(08)70229-7
  3. Onda M, Fukushima H, Akagawa M. A flycidal constituent of Amanita pantherina (DC.) FR. Chemical and Pharmaceutical Bulletin (Tokyo). 1964;12:751. doi:10.1248/cpb.12.751
  4. Gagneux AR, Häfliger F, Eugster CH, Good R. Synthesis of pantherine (agarin). Tetrahedron Letters. 1965;6(25):2077-2079. doi:10.1016/S0040-4039(00)90157-6
  5. Ebert B, Thompson SA, Saounatsou K, Mckernan R, Krogsgaard-Larsen P, Wafford KA. Differences in agonist/antagonist binding affinity and receptor transduction using recombinant human gammaaminobutyric acid Type A receptors. Molecular Pharmacology. 1997;52(6):1150-1156. doi:10.1124/mol.52.6.1150
  6. Moroni F, Forchetti MC, Krogsgaard‐Larsen P, Guidotti A. Relative disposition of the GABA agonists THIP and muscimol in the brain of the rat. Journal of Pharmacy and Pharmacology. 1982;34(10):676-678. doi:10.1111/j.2042-7158.1982.tb04702.x
  7. Krogsgaard-Larsen P, Frolund B, Frydenvang K. GABA uptake inhibitors. Design, molecular pharmacology and therapeutic aspects. Current Pharmaceutical Design. 2000;6(12):1193-1209. doi:10.2174/1381612003399608
  8. Baraldi M, Grandison L, Guidotti A. Distribution and metabolism of muscimol in the brain and other tissues of the rat. Neuropharmacology. 1979;18(1):57-62. doi:10.1016/0028-3908(79)90009-1
  9. Maggi A, Enna SJ. Characteristics of muscimol accumulation in mouse brain after systemic administration. Neuropharmacology. 1979;18(4):361-366. doi:10.1016/0028-3908(79)90143-6
  10. Rumack BH, Spoerke DG. Handbook of Mushroom Poisoning: Diagnosis and Treatment. CRC Press; 1994.
  11. Tamminga CA, Crayton JW, Chase TN. Muscimol: GABA agonist therapy in schizophrenia. The American Journal of Psychiatry. 1978;135(6):746-747. doi:10.1176/ajp.135.6.746