Toxic Fungi of Western North America

by Thomas J. Duffy, MD

Toxins of the ibotenic acid/muscimol group (pantherine poisoning)

Amanita muscaria derives its name from the ability of its juice to stun and sometimes kill house flies (Musca domestica). The fly attractant is 1-3 diolein. (98) and the “flycidal” agents are ibotenic acid and erythro-DL-tricholomic acid. (99,100)

The major toxins present in the mushrooms are ibotenic acid (an acidic amino acid in the form of an isoxazole ring) and muscimol, its decarboxylation product. Unfortunately muscarine was the first toxin to be identified in Amanita muscaria, albeit in minute, non-physiologic amounts: about 0.00025% was extracted from this mushroom by Holmstedt and Liljestrand in 1863. (106) It took years to rid American textbooks of the idea that muscarine was the major toxin in Amanita muscaria, rather than ibotenic acid and muscimol. The result was treatment with useless and mildly toxic atropine, generally increasing the patients' misery if not worsening the toxic effects. Even if muscarine were the effective toxin in Amanita muscaria, it would take over 100 pounds of that amanita to cause major muscarinic symptoms and roughly 250 pounds to cause death. [calculation in Lincoff/Mitchell]

In 1964, Takemoto and colleagues isolated the true toxins. An international agreement in 1967 named these toxins ibotenic acid and muscimol. Muscimol, supposedly the more important toxin, structurally resembles GABA (g-amino-butyric acid), the brain's most important inhibitory neurotransmitter. (49a) Competing with GABA, the toxin attaches itself to GABA receptor sites. There, muscimol may in part stimulate GABA receptors, at least initially, thus first producing an inhibitory effect similar to that of GABA itself with transient drowsiness and sleep. The major effects, however, are a loss of GABA’s suppressive effect on neuronal activity and a marked increase in the synthesis of glutamate and other excitatory amino acids. Thus the illusions and other fragmentations of thought suggest an over-all inhibition of GABA by muscimol’s competition for its receptor site.

Ibotenic acid & Muscimol
Figures 5,6. Ibotenic acid and muscimol

It has been shown in monkeys that loss of GABA inhibition allows an increase of the constant stream of of stray neuronal signals (“cerebral static”). The result is interference with the main path of thought. The suppression of “garbage” signals is a paramount necessity where concentration holds sway: memory, decision-making, calculation and inference. By 2005 GABA treatment was found to markedly help these activities in Alzheimer’s and similar disorders.

Both muscimol and ibotenic acid pass the blood-brain barrier better than GABA or glutamic acid. Within rat brain slices, isoxazole compounds do inhibit GABA uptake. (102) Benjamin notes, however, that ibotenic acid appears to have an excitatory effect closer to glutamic acid. (101) Presumably ibotenic acid binds and also stimulates glutamate receptors. The further clinical course suggests activation of a series of glutamate excitatory effects, which would be severe when accompanied with partial loss of GABA inhibition.

Scott Chilton in 1978 was among the first to propose a possible role for glutamic acid and glutamate in isoxazole poisoning. (50a) Although glutamic acid and glutamate do not readily cross the blood-brain barrier and are quickly destroyed at that interface, ibotenic acid easily crosses and once entering brain cells, is able to stimulate glutamate receptors.

A number of intermediate compounds have been found to be part of an excitatory aspartate/glutamate "hierarchical system". This system transports unintegrated “information” from areas of the brain stem to the higher centers of consciousness in the cerebrum. The "glutamate cascade” is now thought so important that it may be a common pathway for many CNS disease states. (103) Presumably, it is muscimol stimulation of the glutamate cascade in these amanitas that produces the illusion of time change, the increased perception of strength, the changes in vision and even seizures.

Muscazone, an ultraviolet radiation product, is found in minute and variable quantities in most European specimens, but is not present in North American specimens. (104) Stizolobic acid, stizolobinic acid and tricholomic acid are also present as derivatives of ibotenic acid. (105) These three amino acids can activate excitatory amino acid receptors, but there is probably not enough of these compounds to have an effect, at least in most Amanita muscaria poisonings. The first two—stizolobic acid and stizolobinic acid—are present in Amanita pantherina in amounts that might be clinically significant. These three compounds are related to L-DOPA oxidation products, which are known to cause anticholinergic activity.