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 stabler 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. Pharmacology Ibotenic acid acts as a potent agonist of the NMDA and group I (mGluR1 and mGluR5) and II (mGluR2 and mGluR3) metabotropic glutamate receptors. It is inactive at group III mGluRs. Ibotenic acid also acts as a weak agonist of the AMPA and kainate receptors. In addition, due to in vivo decarboxylation into muscimol, it acts indirectly as a potent GABAA and GABAA-ρ receptor agonist. Unlike muscimol—the principal psychoactive constituent of Amanita muscaria that is understood to cause sedation and delirium—ibotenic acid's psychoactive effects are not known independent of its serving as a prodrug to muscimol, however it may be speculated that it would act as a stimulant. Biological properties Mechanism of action Ibotenic acid is an agonist of glutamate receptors, specifically at both the N-methyl-D-aspartate, or NMDA, and trans-ACPD receptor sites in multiple systems in the central nervous system. Ibotenic neurotoxicity can be enhanced by glycine and blocked by dizocilpine. Dizocilpine acts as an uncompetitive antagonist at NMDA receptors. Ibotenic acid toxicity comes from activation of the NMDA receptors. NMDA receptors are related to synaptic plasticity and work with metabotropic glutamate receptors to establish long term potentiation or LTP. The process of long term potentiation is believed to be related to the acquisition of information. The NMDA receptor functions properly by allowing Ca2+ ions to pass through after activation at the receptor site. The binding of ibotenic acid allows excess Ca2+ into the system which results in neuronal cell death. Ca2+ also activates CaM-KII or Ca2+/Calmodulin Kinase which phosphorylates multiple enzymes. The activated enzymes then begin producing reactive oxygen species which damages surrounding tissue. The excess