Mycopharmacological Outline and Personal Experiences
from PM&E Volume Five
- Part One: Mycological, Chemical and Neuropharmacological Aspects
- Part II. Personal Experience with Amanita muscaria.
Amanita muscaria, also known as Fly Agaric, is a yellow-to-orange capped wild mushroom. It grows in symbiosis with arboreal trees such as Birch, Pine or Fir, in both Europe and the Americas. Its history has it associated with both shamanic and magical practices for at least the last 2,000 years, and it is probably the Soma intoxicant spoken of in the Indian Rig-Vedas. The following piece details both the generic as well as the esoteric history and pharmacological profiles of the Amanita muscaria. It also introduces research which shows that psychoactivity related to this species is seasonally determinant. This determinant can mean the difference between poisoning and pleasant, healing applications, which include psychedelic experiences. Connections between the physiology of sleep and the plant's inner chemistry is also outlined.
This study is divided into two parts, reflecting two complementary but different approaches to the same topic. The first study, presented by Francesco Festi, presents a critical overview of the mycological, ethnobotanical, chemical and pharmacological data which are referred to the Amanita muscaria (through 1986). In the second part, also Italian author and mycologist Antonio Bianchi reports on personal experiences with the Amanita muscaria taken from European samples. The following experimental data --far from constituting any final answers --are only a proposal and (hopefully) an excitement for further investigations.
Part I: Mycological, Chemical and Neuropharmacological Aspects
1) Mycological Outline
Amanita muscaria (L. ex Fr.) Pers. ex Hooker -- The Fly Agaric -- is one of the oldest classifications of fungi known. It has consistently appeared in all the naturalistic fields throughout history. Linnaeus identified it as Agaricus muscarius and originally introduced it into the genus. He included it along with other gill fungi he classified and which were classified by most Northern European botanists. These same botanists were traditionally mycophobic. This, unfortunately, led to the bypassing of other important mushrooms and fungi in their studies.
The generic name, coined by Persoon, derives from the Greek amanitai, means "fungi without any details" (or from Amanos, a mountain place between Cicilia and Syria). The specific epithet re-proposes a connection for which we will spend some words later. One will be able to recognize these in the popular names of the fungus: Fliegenpilz or Fliegenschwamm in German; Mukhomor in Russian; Amanite tue-Mouche in French, and The FIy Agaric in English.
The typus of the species has a cap of between 5-25 cm. It is at first globe-shaped (in the embryonic stage it is bred from the cloth of the universal veil in typical egg-shape that is characteristic of the genus Amanita) It retains this shape more completely until reaching an applanate or lightly depressed area around the center form, with the margin more or less streaked. The skin of the cap is peelable, bright red or leaning to orange (sometimes with yellow colors, especially near the margin). It is shiny and viscous when moist, strewn with white (or whitish) warts (sometimes absent in mature specimens because of washing away). The flesh is white into the cap and stripe, but yellow or yellowish in the stripe just under the cuticle, having no special taste or smell to humans. After drying it puts on a darker color (from dark cream to pale brown) and an acrid, nauseating taste. The stalk is white, cylindrical and discontinuous (easily discemable from the cap), with a bulbous base and a volva typically fragmented in warts arranged in a concentric circle; white (to whitish), broad and membranaceous, in a more or less streaked ring. The spore print is white, with the spore 9-11 X 6-9 microns, elliptical-ovate, smooth and not amyloid (Ricken, 1915; Gilbert, 1918; Bresadola, 1927-41; Kuhner & Romagnesi, 1953; Moser, 1967; Wasson, 1967b; Cetto, 1970-87; Heim, 1969, 1978; Flammer and Horak, 1983; Roth, et al., 1984; Bresinsky and Besl Regensburg, 1985, and many others). Amanita muscaria is a typical species of the septentrional latitudes. At lesser latitudes it is present particularly in the mountain areas. It is broadly spread throughout Europe, North (in a different form) and Central America, North Africa, Asia and Australia. The Amanita has a preference for acidic soil, and a condition for sprouting includes the presence of arboreal species such as Pine, Fir or, infrequently, Larch and other trees. This inter-plant bond comes from the mycorrhizic relation (a commensalistic symbiosis shared with many other species of fungi. This is very important, among other things, for the ecology) between trees and fungi.
Strictly tied to muscaria are other similar species (A. emilii Riel., A. aureola Kalch., A. regalis Fries, etc.) These, however, probably don't go beyond the subspecific rankings of fungi. Probably the most interesting in this context would be A. americana Helm, typical of Canada and the U.S. It's different from A. muscaria with its slender stalk with fibril becoming brown at the end and the lighter cap (being pale to yellow- orange (ibid.).
Another species of genus Amanita also worth remembering here is A. pantherina (DC ex Fr.) Seer., which is certain to contain the same psychotropic agents as A. muscaria [see following references]. A. pantherina produces a more toxic than hallucinogenic syndrome, however, when ingested. A predominance of nonspecific confusional effects, psychomotor excitement and serious anxious (or anxiety-laden) states generally occur [John, 1935; Bosman, et al., 1965; Gerault & Girre, 1977; Lincoff & Mitchel, 1977; Helm, 1978; Rumack and Saltman, 1978; Flammer, 1980; Gelfand and Harris, 1982; Flammer & Horak, 1983; Roth et al., 1984; Bresinsky & Besl Regensburg, 1985]. A. pantherina has a cap of 6-12 cm. wide at first, then globe-shaped. It is then slightly flattened or depressed near the center. The colors are from chestnut brown to gray-olive green, with a striated margin and a cuticle which is peelable. This is strewn with white or greyish warts which are easily removed through washing. The stalk is discontinuous at 6-15 cm. X 2-20 mm. It is white, stuffed and then hollow. It is fibrillose or glabrous, bulbose at the base where it is ornamented with a volva of 2-3 membranaceous girdles which are superimposed. These are white and narrow, with annules slightly (or not at all) streaked. The flesh has a sweetish taste without special smell (to humans). This is white or brownish so far as the subcuticule layers. The gills are free or just adnexed. These are white or mealy at the margin. The spore print is white, the spores measuring 8-12 X 7.8 microns. They are elliptical-ovate, smooth and not amyloid (see the references for Amanita muscaria, etc.) . It grows with conifers trees, in the wood, in Europe, North America, North Africa and Asia.(1)
2. A Short Ethnomycological Account
A review of the anthropological and historical data on the Fly agaric is impossible herein due to the tremendous bulk of work on this very subject. Nevertheless, it is possible to try to build a hypothesis which connects traditions and the roles of hallucinogenic fungi in man's history. This starts from the fascinating proposals of R. G. Wasson [Wasson & Wasson, 1957; Wasson, 1967a, 1967b, 1978] and those who, simultaneously also contributed to the growth of the subject of ethnomycology [La Barre, 1970; Harner, 1973; Furst, 1976; Ott, 1976; Schultes & Hofmann, 1979, and many others].
One can begin by supposing that primitive man, in his activities as food gatherer, had discovered plants (and fungi) with useful properties but not directly connected with hunger and eating and alimentary use.(2) It's likely that, in this way, man had his first contacts with hallucinogenic plants. Mushrooms, no doubt, had a very particular role herein.
The fact that they apparently are born "from nothing" with rapid development, the beautiful strangeness of their shapes, and all the other characteristics which distinguish them from other plants surely struck the hunter-gatherer man. This surely led him to discover the mushroom's amazing properties. The structure of the Mesolithic-Neolithic society -- surely one of the shamanic type (3) -- had no doubt a catalyptic effect in developing these theme characteristics. Such societal characteristics represent(ed) the ideal support for consciousness alteration -- including hallucinogenic plant use. This made connections with an animistic conception of the world stronger and more widespread.
Let's suppose proto-Indoeuropean man had already discovered the psychotropic properties of Amanita muscaria (and other plants) while these people were still living in the original region of the plants. This supposition is under discussion in order to revise the hypothesis accepted so far. This probably also included the lowlands of central Siberia. During this period the linguistic roots connected with the A. muscaria were transferred cross-culturally to the proto-Uralic people, maybe with the use(s) of the mushroom itself (which later were carried on to the Siberian peoples, at least until the beginnings of this century). Along with Amanita might have come Fomes fomentarius, used as tinder for fire.
A few millennia before this, man's migrations through the Bering Straits had come to an end. These were the peoples who would eventually originate the American peoples. These original explorers took with them the traditions connected with the original uses of cultural planning, the shamanism, etc. They did not, however, openly carry the traditions connected with use(s) of hallucinogens. It was because of the presence of societies originally based on the shamanic structure (including fungi) that the use of hallucinogens developed and continued in the Americas.
In Eurasia, when the Indo-Europeans moved towards Iran and India, they took with them the cult of the sacred fungus. This later became the Indian Soma (the God-plant of the Rig-Veda) and the Persian Haoma. Also carried were the fungi's relation to the Birch tree, sealed by the ancient shamanic religion. It's not impossible that the Tree of Divine Knowledge named in Genesis in the Bible was an echo of the original Tree of life (the Birch). The serpent might have been a metaphor for the sacred Mushroom, bestower of divine knowledge and wisdom. Also, the Indo-European fringe which spread over Europe took with them at least a part of the religious-social structure, characterizing the life in their original lands. The fusion between their animistic totemism and those of the preexisting peoples produced a religion with a shamanistic background. The train of elements include the following which are most interesting: the ritual ingestion of the Amanita muscaria (and maybe other psychotropic vegetables), the deep spiritual ties with nature, the consequent worship of nature spirits (among which were terrestrial ones, such as the toad and the serpent), and the magic interpretation of many events. The links between the many natural-supernatural fusion penetrated into the life of these ancient Europeans, cementing deep connections with their "cultural unconscious."
A particular element of this social structure, also present in the Siberian and Mexican peoples, was the taboo that only the shaman (or the one who took his place as mediator with the divine world) could use with impunity the sacred elements. All the other peoples were prevented from doing this because of the dread of the supernatural. In other religions this tie also involved the name of the sacred plant, and in this way some metaphorical, but self-referential, epithets could have been originated. These words contained reference to some more or less obvious characteristics of the fungus. These included fusion with other animals such as the fly, other insects, the serpent or toads, etc.
Among the characteristics of the West (as opposed to the Test of the globe -- like America, where shamanism has persisted to the present) was the speed of socio-economic development and the relatively sudden changes in lifestyle. This historical evolution contained a base mode of property ownership and rigid role divisions, and class distinctions. The old religions, no longer functional to the powers-that-be, were replaced by new models of worship. These were modeled with ritual symbolism rather than direct share of the divine world. As a consequence, the ancient usages of the psychoactive plants able to modify consciousness was hampered and in some cases forsaken. This is the core of Wasson's hypothesis. He supposed that not all the Gods of these old religions were completely obscured when new religions (and new Gods) took over.
In the traditions fused with Amanita muscaria use, a connection with these natural, totemic forces remained. These remained alive, above and beyond the new taboos. These elements were, at first, only connected to the sacred uses of the mushroom, however. As time went on, this melting together of ideas, both terrifying and divine, lost all the connections with their original source. It soon spread on to the whole of the fungi's' world (and also to the original entities connected with the mushroom). Only the fear truly retained its potency, staying alive through our unconscious as maleficient and inexplicable. In this way we might understand our culture's connections between the evil or harmful and the fly, the serpent and the toad. Mycophobia and its corollaries are thusly explained.
This dichotomic division between mycophilia and mycophobia proposed by Wasson seems to complete itself in a convincing way with the hypothesis of J. Ott (1976). According to this author, the malefic character attributed to the mushroom the survivor of the old animistic religion -- was not the result of the survival of the taboo. Rather it was derived from the events linked to the establishment of a new cult. In fact, when a new religion replaces preexisting ones, consequences occur. One is the change of the social orders which restrict or hamper the previous cults (usually by any means possible). In this way, things not willing to adapt to the new creed become, by neces sity, malefic or demonic.
In our opinion, therefore, and after taking for granted the close bonds between shamanism and the use of hallucinogenic mushrooms, different cultural attitudes relating to fungi can be explained.
Speaking of the European peoples, and taking into account several variables, we propose: the substitutive dynamic referred to the religions after its inception within shamanism; its impacts on the preexisting cultural heritages; the more-or-less distant age in which the passing from cults with shamanistic qualities to those of a dogmatic-fideistic kind occurred; the geographical proximity with people for whom this passing occurred; the geographical proximity for which this passing occurred in relatively recent times (for example, the Slavs); the kind of economic-social development and its bonds with the natural world.
It's certainly true that checks on these matters would request ethnological data newer and more precise than the ones we possess. We think, however, that it is correct to attempt it, with the serene objectivity that this subject deserves.
3. Chemistry and Pharmacology
Even from the point of view of the chemical and pharmacological research, the Amanita muscaria takes up a place which distinguishes it from the many other hallucinogenic mushrooms. In fact, in the species of the Psilocybian group (up until now including parts of the genus Psilocybe, Conocybe, Stropharia, Panaeolus, Gymnopilus and Pluteus [Helm, 1978; Schultes and Hofmann, 1980; Bresinsky and Besl Regensburg, 1985; Festi, 1985]), the isolation of the psilocybin and ingestion experiments led to the belief that this substance (or, more exactly, to Psilocin, its active metabolite) were responsible for all the hallucinogenic effects. For the Amanita muscaria it's not the same.
On different occasions several different compounds have been isolated -- each having psychotropic Properties concurrent with the hallucinogenic properties of the Amanita in toto. Apart from the large number of principal chemicals, the view of the whole is obscured by other factors.
Some reports actually seem to be the result of methodological mistakes (e.g., the ones concerning tropane alkaloids and Bufotenine). The substances at issue would be, in any case, too minimal in the species mentioned in the tropane/Bufotenine references to produce the described effects.
Other compounds, which certainly are of the metabolic store of the Amanita muscaria, have not been submitted, as yet, to any pharmacological studies (i.e.., the indolic substances isolated by Eugster and others, etc.). Or they have turned out to be inactive at the quantities actually contained in the mushroom itself (i.e.., the Muscarine). Though Ibotenic Acid and Muscimol, finally, are at the center of the present hypothesis (so far as the active principal of the Amanita), they don t quite explain all of the psychoactivity. In this context, in order to see our way clear through the mine of substances making up the Amanita muscaria, we prefer to consider all the different compounds within. Thus, we will be able to determine exactly what contributes to the psychoactive nature of the Amanita, what does not, and the relationship of everything to the main psychoactive constituent, Muscimol.
3a. Miscellaneous Chemical Compounds
Muscarine (or 4-hydroxy-5- methyl-tetrahydro- furfuryl-trimethyl-ammonium salt) was isolated from Amanita muscaria, from which the mushroom took its name. This occurred in the nineteenth century [Salemink et al., 1963; Waser, 1967; Eugster, 1968; Waser, 1958, 1961; Helm, 1978; Bresinsky and Besl Regensburg, 1985]. The actual concentration of this compound (on the average) is very low (0.0002- 0.0003% with reference to the fresh weight [Eugster, 1968; Helm, 1978; Schultes and Hofmann, 1980], and in any case much lower than in other species (i.e., Inocybe mixtilis Sacc, with 1.33% of dry weight). Although the activity of muscarine on the central nervous system is demonstrated(4) [Waser, 1967; Bloom, 1980], its resorption through the intestinal wall is very slow and it is almost completely blocked by the blood- brain barrier (the passage is possible only with the combination of an amino acid or Lecithin [Waser, 1967]). Furthermore, the psychological effects shown after poisoning with Muscarine fungi are different from the effects of Amanita muscaria [Festi, 1985].
It is impossible to demonstrate any direct action of Muscarine. Its low concentration in the mushroom itself is enough to leave it out of the origin of psychic (or hallucinatory) effects. Only some of the somatic disturbances caused by the mushroom's ingestion can be attributed to the action of the Muscarine, probably combined with the one of Muscimole.
Other Quaternary Ammonium Bases:
In the Fly Agaric was found, several times over, Choline, Acetylcholine, and buten- (I)-yl-(4)-trimethylammonium and "muscaridine." While the first substance is psychotropically inactive and the second is contained in very low quantity in the Amanita muscaria, the last two (even those found with little concentration) are compIetely lacking in pharmacological data [Waser, 1967; Eugster, 1968; Helm, 1978; Bresinsky and Besl Regensburg, 1985; Festi, 1985].
Tropane Alkaloids and Bufotenine:
In investigating a compound named Pilzatropine by Kolbert in 1881 because of pharmacological similarities, some authors (Lewis in 1955 and Manikowsky & Niezdodzki in 1962) reported the presence of hyoscyamine, atropine and scopolamine in the Amanita muscaria, (Salemink et al., 1963, Tyler and Groger, 1964). This suggests a mistake due to substances with the same chromategraphic behaviors as the tropane alkaloids. Furthermore, the percentage of content reported by Lewis would be, in any way, too low to contribute to the psychoactive activity of the fungus (Waser, 1965,1968)(5).
As well, so far as Bufotenine goes, there is a report by Wieland and Motzel (1953) pertaining to Amanita muscaria, pantherina, and citrina. The presence of Bufotenine was then verified only for the species citrina, porphyria, and tomentelIa [Catalfolmo and Tyler, 1961; Tyler, 1961; Tyler and Groger, 1964b; Hoffer and Osmond, 1967; Eugster, 1968; Andary et al., 1978a, 1978b; Stijve, 1979; Perez-Silva and Aroche Alfonso, 1983; Bresinsky and Besl Regensburg, 1985]. There is probably a mistake due to contamination caused by carpophores of Amanita citrina. Bufotenine should be left out any way because it is not orally active [Fabing and Hawkins, 1956; Hoffer and Osmond, 1967; Schultes and Hofmann, 1980], and, according to some authors, not active at all.
Other Compounds. We list here some substances isolated from the Amanita muscaria, to which accurate pharmacological data are missing. Only the first two (respectively based on the narcotic-antagonist activity and the indolic structure), we suppose could contribute to the psychoactivity of the mushroom.
R4-hydroxy-pyrrolidone-(2): Isolated from butanolic extract of non-isoxazolic fractions during the isolation of Muscimol [Eugester 1968; Theobald, et al., 1968; Matsumoto et al., 1969; Schultes and Hofmann, 1980].
1,2,3,4-tetrahydro-I -methyl-B-carboline-carboxylic acid: Extracted from the same fractions [Eugster, 1968; Matsumoto et al., 1969] and chemically related to the hallucinogenic P-carboline. Such are active compounds within the psychotropic species of the genus Banisteriopsis [Schultes and Hofmann, 1980]. Chilton and Ott , nevertheless, didn't find MTC in Amanita muscaria samples from America.
B-N-Butyl-D-glucopyranosid [Matsumoto et al., 1969].
Stizolobic and Stizolobinic Acid, so far found in Amanita muscaria, pantherina and corthunata [Chilton et al., 1974; Chilton and Ott, 1976].
3b Muscimol and Isoxazoles
In the early sixties a remarkable contribution to our knowledge of Amanita muscaria was brought forth. This dealt with the isolation of three substances, independently carried on by Swiss and Japanese authors and researchers. At least one of these would turn out to be the main psychotropic agent within the mushroom itself.(6) Muscimol or enoI-betaine of 5-amino-methyl3- hydroxy- isoxazole [Gagneux et al., 1965a; Miiller and Eugster, 1965; Eugster, 1967, 1968; Eugster and Takemoto,1967; Theobald et al., 1968; Brehm et al., 1972; Lund, 1979; Schultes and Hofmann, 1980; Stijve, 1982]. Ibotenic Acid or the zwitterion of amino- (3-hydroxy- isoxazolil-(5)-acetic acid monohydrate [Eugster et al., 1965; Gagneux et al., 1956b; Good ER al., 1965; Sirakawa et al., 1966; Eugster, 1967; Eugster & Takemoto, 1967; Eugster, 1968; Lund, 1979; Schultes & Hofmann, 1980]. Muscazone or (a)-amino -(2, 3H)-oxazolonyl-(5)-acetic acid [Eugster et al., 1965; Fritz et al., 1965; Good et al., 1965; Eugster, 1967; Reiner & Eugster, 1967; Eugster, 1968; Schultes and Hofmann, 1980].
In the Swiss specimens, Ibotenic Acid was found in a percentages ranging from 0.08 to 0.1%. Greater concentrations were in the ripe mushrooms grown in the summer. These concentrations focused in the cap more than the stalk.(7) Takemoto isolated it in small quantities also from Amanita pantherina and Amanita strobiliformis. This sample was from Japan [Eugster, 1968]. The compound easily transforms itself through decarboxylation into the most active Muscimol. Because of this, some authors have preferred to give the cumulative percentage of the two compounds together. Benedict and others  found this to be 0.17-0.18% (both for the typus and for the varieties formosa and alba of American origin). In an American pantherina sample, this percentage was 0.46% [Benedict et al., 1966; Chilton and Ott, 1976].
Muscazone, finally, is found in all the species in very small quantities. The data available to estimate how much these compounds contribute to the psychoactive syndromes and psychological effects inducted by the Amanita muscaria are focused in two main research studies. The first one was carried on by Waser  with 20 mg. of Ibotenic Acid and 5, 10, and 15 mg. of Muscimol; the second from Theobald and others  with 7.5-10 mg. of Muscimol and 75 mg. of Ibotenic Acid on ten (10) normal subjects. If we can consider the result of these studies, the following emphasis is shown:
To the Isoxazoles, and in particular to Muscimol, it is possible to attribute most of the effects by the fungus in tote. Almost all the somatic symptoms (for which we have seen the possible contribution of Muscarine) coincide, as do several psychological symptoms. Regarding these last symptoms: It's nevertheless noticeable that the lack of "structured" hallucinations occurs. Such are usually reported after usage of Amanita muscaria. This fact suggests that a collateral action exists with other compounds (some of these already considered) contained in the mushroom. They could act (in respect to the Isoxazoles) by strengthening, modifying or acting directly on the structure responsible for the psychotropic effects, or, perhaps, by modulating some of their pharmacological variables tied to the resorption or distribution. It might be interesting, so far as this idea, to study the ingestion, in controlled conditions, of Muscimol, Ibotenic Acid and Muscazone. These would be studied in varying proportions or in combination. In this way, the Isoxazoles and those other more recently isolated substances could be studied synergistically.
Ibotenic Acid is far less active than Muscimol (the activity of Muscazone is practically negligible). At the average concentration found in the mushroom, it would produce barely perceptible effects.
Estimating content for an Amanita muscaria specimen of autumnal growth, Muscimol can be found at around 0.05%. This is based on an estimate of a mushroom with a cap 10-15 cm. broad and which weighs approximately 60-70 g. There is a good correspondence between an effective dose of the mushroom (1-10 caps of medium size) and the ones of the isolated compound.
In summary, therefore, it seems correct to focus attention on the Muscimol. This is the only compound in the Amanita muscaria that has proven not to be irrelevant so far as psychotropic activity. Also, there is a plethora of solid psychopharmacological data and neurophysiological studies surrounding this compound.
3.c The Pharmacology of Muscimol
Even without considering all the pharmacological studies with animals concerning (see the following: Waser, 1967; Theobald et al., 1968; Scotti de Carolis et al., 1969; Biggio et al., 1977; Kulcsar et al., 1977; Jobert et al., 1979; Worms et al., 1979; Festi, 1985 and the references below), other interesting aspects are worth considering.
If we compare Muscimol with other psychotropic substances, we can observe that its electroencephalographic effects are considerably different from those induced by indolic compounds (psilocybin, psilocin, LSD, etc.), These usually produce effects characterized by EEG desynchronization. In rabbits, the EEG tracings (with Muscimol) are synchronized. It contains a dramatic reduction of the desynchronizing response to acoustical or electrical stimulation of the midbrain reticular substance. This effect is elicited with 0.25 mg./kg. i.v. With 1 mg./kg. the EEG awakening is totally blocked. With higher (2 mg./kg.) doses, characteristic spikes (in the EEG) appear. A further injection of 1 mg./kg. of Diazepam makes the EEG tracing practically isoelectric, even though some spikes are still present.
This EEG syndrome is also the same in rats and cats [Theobald et al., 1968; Scotti de Carolis et al., 1969]. It seems to be closer to readings caused by anticholinergic deliriants than by indolic hallucinogens. However, Physiostigmine (an acetylcholinesterase inhibitor) produced a slight effect on the EEG pattern of Muscimol. This suggests a secondary involvement of the acetylcholinergic system [Scotti de Carolis et al., 1969].
Also interesting, but difficult to understand, are the EEG spikes which appear also after the administration of hallucinogens such as Dimethoxy-Methyl-Amphetamine (DOM) [Florio et al., 1969], Harmine, /\-8 and d-9-transtetra-hydrocannabinol (active principles of Cannabis indica) [Lipparini et al., 1969]. These spikes have turned out to be the most resistant to the depressant action of Diazepam.(8) As well, the relationships between Muscimol and desynchronized sleep appear interesting. In cats, doses (of Muscimol) 0.3 and 1 mg i.p. cause 20% and 40% reductions, respectively, in the whole length of paradoxical sleep. One mg./kg. i.p. increases by 30% the incidence of non-REM PGO (Ponto-Genilo-Occipital) waves [Kulcsar et al., 1977].(9) From a biochemical-pharmacological point of view, it was shown in 1968 that Muscimol had an antagonism towards GABA (Y-aminobutyric acid -- one of the main CNS neurotransmitter amino acids). This was determined right after Muscimol had first been isolated. Muscimol has been shown to be particularly effective on Bicuculline -sensitive receptors. This was discovered by Johnston et al. (1968). In effect, Muscimol is chemically very close to GABA, both in its chemical conformation [Curtis et al., 1970; Kier and Truitt, 1970; Johnston, 1971; Brehm et al., 1972; Curds and Johnston, 1974; Andrews and Johnston, 1979], and for the distributions of the charged molecule regions [Kier and Truitt, 1970]. It differs from the latter in its greater rigidity due to the Isoxazole ring [Snodgrass, 1983].
Many studies with radioactive Muscimol have shown several binding sites (in the nervous system). It is very active in displacing Bicuculline or GABA [Iverson, 1978; Mao and Costa, 1978; Andrew and Johnston, 1979; Wang et al., 1979; Schaeffer, 1980; Snodgrass, 1983].
Furthermore, as a GABA-agonist, it stimulates the binding of benzodiazepines and the reinforcement of its effects by Diazepam may be explained with this stimulation. The slighter strengthening (of its effects) by barbiturates (Penthobarbital and others) is probably due to synergistic actions at the ionophore level [Snodgrass, 1983]. Muscimol is subject to metabolic degradation after systemic administration. However, none of its metabolites has GABAergic activity, or the ability to replace Muscimol itself at receptor sites. Further evidence of this includes the fact that only the active agent itself -- not any transaminated molecule -- correlates with Bicuculline- induced seizures as an antagonist. This has been correlated with the Muscimol concentrations in the brain [ibid.; Baraldi et al., 1979; Maggi and Enna, 1979; Matthews et al., 1981]. In summary, we can say that the oral administration, as well as administration through other routes, activates most GABAergic receptors in the CNS [Johnston et al., 1968; Curtis et al., 1970; Johnston, 1971; Curtis and Johnston, 1974; Kulcsar et al., 1977; Chan-Palay, 1978a, 1978b; Iversen, 1978; Johnston et al., 1978; Mao and Costa, 1978; Olpe and Koella, 1978; Snodgrass, 1978; Amt et al., 1979; Andrew and Johnston, 1979; Matsui and Kamioka, 1979; Waddington and Cross, 1979; Wang et al., 1979; Worms et al., 1979; DeFeudis, 1980; De Feudis et al.; Schaefer, 1980; Snodgrass, 1983; Festi, 1985]. However, the syndrome produced by Muscimol can be slightly different from the one produced by other GABA- agonists. In particular, it causes myoclonic jerks and seizures. From this it is possible to suppose the restriction of inhibitory pathways [Menon and Vivovia, 1981; Snodgrass, 1983] could involve a non-uniform activity on some cerebral area or process [Snodgrass, 1983].
Also, the administration of Muscimol induces metabolic modifications for other neurotransmitters. The level of 5- Hydroxytriptamine (Serotonin) [Konig-Bersin et al., 1970], Dopamine [ibid.; Biggio et al., 1977; Iverson, 1978; Gundlach and Beart, 1980] and Acetylcholine [Scatton and Bartholini, 1982] is increased, while Noradrenaline is decreased [Kunig- Bersin, et al., 1970]. In some cases the concentration is especially changed in particular zones. In others the changes are uniform in the whole brain. Several pharmacological researches suggest, however, that these effects are indirect and pass through the GABAergic system rather than directly on the respective neurotransmitter systems.
3d Possible Mode of Action of Muscimol
It seems clear, therefore, that the main activity (maybe the only one) of Muscimol is as GABA-agonist. However, the broad distribution and the complexity of the GABAergic system don't make it easy to interpret so far as its mechanisms of action. It may be possible to attribute ataxia, dizziness and other vestibular symptoms to the GABA-mimetic action on cerebrovestibular pathways. The decrease of motor activity and catalepsy can be tied to the interface with the GABAergic control of dopaminergic (and probably also acetylcholinergic) neurons in the nigro-strio-pallidal complex.
Nevertheless, the matter is far more difficult when we try to analyze typical psychic symptoms such as hallucinations, mood changes, etc. This is because specific studies on these topics are lacking. After discovering the strong GABA-agonist activity of Muscimol, neurophysiologists and pharmacologists preferred using it in classic researches on GABA itself rather than investigate its mechanisms as a psychotropic agent. The hypothesis that we can produce on this possible mode of action are therefore necessarily reduced and partially speculative, while awaiting further studies on this subject.
It seems possible, however, to try an approach between the available data on Muscimol and an attempt at an integrative hypothesis that one of us [Francesco Festi, 1985] has developed. This is in reference to the hallucinogens of the indole group (psilocybin, psilocin, LSD, DMT, etc.) and other compounds with similar neurophysiological actions (such as mescaline). This proposal takes inspiration from the connections between hallucinations and dreams (suggested by Jacobs and Trulson, 1979). This is founded on the similarity between some physiological states tied to the oneiric process and to the action of indole hallucinogens. These parallel situations can be gauged as follows (see Festi, 1985 for a review of the neuropharmacological data on this topic).
- Decrease or inhibition of the rate in the serotoninergic midbrain raphe neurons.
- Increase of the discharge rate in the neurons of the nearby reticular formations.
- Tendency to cortical and subcortical activation.
- Increase, as compared to the normal state of active waking, in the number of rapid-eye movements (REM) both in humans and monkeys.
Therefore, taking as a reference frame the convincing hypothesis of Hobson and McCarley [1982; McCarley and Hobson, 1975; Hobson, 1977; McCarley, 1978] relating to the oneiric mechanism, we can suppose certain actions. These are that under the effects of hallucinogenic drugs, the brain is in an anomalous situation so far as the "normal" consciousness states and the oneiric one. Disorganized information reaches the encephalic structures, superimposed over the sensorial ones. These inputs can be either of bulbar origin (and thus, according to Hobson and McCarley's model, tied to eye movements) or due to false interpretation of exogenous information, maybe for interference derived from the fall of serotoninergic inhibi tion (or from the complementary facilitation of excitation) on some elaborating or leading structures.
The anomalous data can't be analyzed as normal sensations, because the temporal-spatial coordinates are lacking. Nor can they follow the oneiric iter, because the whole situation is different from desynchronized Sleep and requires coordination with motor activities, which are not blocked out and indeed are even more sensitive! However, like activities during dreams, the proencephalon tries to make what Hobson and McCarley have defined as "the best of bad work." The disorganized inputs are structured by deriving information from mnemonic engrams to which the access is facilitated either by disinhibition by the "normal" pathways, or by the opening of some alternative ones. These also would be under the influence of our postulated serotoninergic inhibition resulting in direct facilitatory actions, etc.
The results of such cortex processings are felt as hallucinations. The subcortical structures, and particularly the limbic system (this also being activated by the fall of tonic inhibibtion) could be responsible for the concurrent emotional experiences.
The hallucinations, therefore, could be produced by a lack of balance among the connections of the neurotransmitter system. These connections are not completely responsible for and superimposable for what occurs during REM sleep. In considering only the interrelation between serotonin and noradrenaline, it is possible that the action of this latter system (more marked, e.g., for psilocin than for LSD, being the second most powerful hallucinogen) counterbalances the alterations on the raphe nuclei (and surely on other parts of the brain), and modulates the strength of the described psychetropic agent.
In attempting to relate this model to aspects of the Muscimol action, it is worth noting that there are pharmacological references which point to Muscimol's ability to depress the rate of serotoninergic raphe neurons. It has been demonstrated that there is a picrotoxin-sensitive inhibition of these neurons after iontophoretic application of GABA. It seems, furthermore, that the afferent adrenergic pathways to the dorsal raphe are mediated by GABAergic interneurons [Gallager and Aghajanian, 1976; Wang et al., 1976; Aghajanian and Wang, 1978; Sulser, 1978; Aghajanian, 1982; Aghajanian, 1984; Hamon, 1984]. Another very significant fact is that Muscimol, in non-toxic doses, can produce interferences on physiological processes tied to oneiric events [Kulcsar et al., 1977; vide supra].
According to this hypothesis we can also assume that the strengthening of action following the soporific effect of the Amanita muscaria (reported so far as the Siberian peoples and sometimes also verified after auto-experience of ingestion [Waser, 1967; Wasson and Wasson, 1957; Doanlies and Volt, 1460; Wasson, 1967a, 1967b; Arietti and Tomasi, 1975; Lincoff and Mitchel, 1977; Helm, 1978; Rumack and Saltman, 1978; Flammer, 1980; Schultes and Hofmann, 1980; Bresinsky and Besl Regensburg, 1985; see also below]) are due to a greater interferencial power when the CNS is in the sleeping biochemical-physiological states. In fact, because this is the natural background for "endogenous" dreams, the state of sleep may produce an amplifying action on the effectiveness of the compound. This possibly may act just on the structures active during the oneiric process [Festi, 1985].
However, the same mode of action for indole hallucinogens and Muscimol are not proposable, not even on a hypothetical basis.(11) The active principle of Amanita certainly has broad activity. This is as broad as the spreading of the GABAergic system itself. It could have possible interferences on several levels. So far as this subject, it is worth considering also the non-identity of the symptomatological complexes, the first being the practically opposite effects on EEG readings. The future of our knowledge about Muscimol is indissolubly tied to the development of the acquisition of information on the GABAergic systems in man. The Muscimol/GABA system interactions must certainly give favorable results. This is in regard to the mechanisms of actions of psychoactive drugs, and also in connection with our knowledge about higher nervous system processes in man.
Part II. Personal Experience with Amanita muscaria.
Speaking about experience with Amanita muscaria is very difficult because it depends on the mushroom, on the person who is undergoing the experience, and on the environment where the experience takes place. We have had a very small number of experiments (six times) with a small group (five people). At the beginning there were six but one withdrew after the first experience because it was too unpleasant for him. We have found, according to the data reported in many texts, that the most important variable is the time of the season when the mushroom is picked. The most powerful mushrooms were picked in the middle of August when the season was beginning. In the mushroom picked in September the narcotic and physical effects were predominant whereas in August the "visionary" and psychedelic effects were more highlighted. Obviously the personality of the single person, his motivation, attitude, mood and past experience are important in all psychedelic experiences. In fact, people who are interested in "meditative" or introspective experiences have found the Amanita muscaria closer to this feeling, while people interested only in a "trip" have found it "too unpleasant." Group interaction has been found to be meaningless because the effect of the drug is very individual and each person wants to be alone with himself. Perhaps this is determined by the absence of a guide, a person with some familiarity with the drug, and this lack has been underlined by all. We haven't analyzed the importance of the expectations and beliefs but it's important that the experience closer to religious or transpersonal "insight" has been experienced by people with stronger expectations of a "religious vision" and with some knowledge of "shamanic belief." Another very important aspect of this mushroom is diet (fasting before taking it): light food two or three days before and a day of fasting help to reduce the nausea in the first stage and to permit a "relaxed" course.
The experience with Amanita muscaria can be split into three stages: a first stage when the physical symptoms of nausea and vomiting predominate (vomiting is very rare while a strong sense of nausea is always present); a second stage when the narcotic effect predominates, and a third when there could be visions and hallucinations. The amount of the drug changes from 1-2 mushrooms in August to 4-5 mushrooms in the middie of September. This is because the August mushrooms are more powerful, so you have to increase the quantity. But even with the higher amount the experience is not the same: in September the physical symptom of nausea is more marked and the narcotic and visionary experience is less. The most particular trait of the Amanita experience is the second stage. In this stage you can have different levels of narcotic effect, including sleep with normal or "particular" dreams.
"Like a stag, come here to drink!
Drink Soma, as much as you like.
Pissing it out day by day, O generous one,
You have assumed your most mighty force."
--VIII 4.10, Rig Veda
"Soma, storm cloud filled with life,
Milked with mild and butter,
Navel of the Path; immortal Concept,
Which springs to life far from here
In unison those charged with the task,
The blessed do honor to Soma.
In flowing movements swollen men piss
-- IX 74.4, Rig Veda
"In the belly of India
Intoxicating Soma is filtered."
--IX 80.3, Rig Veda
The Vedic poets speak of three filters involved in the preparation of Soma:
- The filtering of sunlight into the mushroom, bearing its magical powers from the heavens,
- The woolen cloth through which the juices were strained,
- The human body.
"The Indian Rig Vedas speak extensively about Soma. believed to be the Amanita muscaria. `There are over one hundred (out of one thousand) devoted to this sacrament." (from the Magical & Ritual Use of Herbs by Richard A. Miller (Destiny, 1983).
In the third stage we experience a more typical altered state of consciousness. One person in the first session reported in the passage between stage 1 and stage 2 a "profound sense of spiritual insight with a dreamlike feeling of a religious identity with my deep self." This is the only religious feeling which has been reported. More common were changes in body perspective with a feeling of being split in two, with a part of himself remaining on the left side of his body. Dizziness and a sense of being disoriented, with some difficulty in motor coordination, were very common in the third stage. In all cases this experience occurred in a dreamlike state, which is the most important aspect of stage 3: a state in which a person is experiencing reality as an inner world with a strong feeling of introspection.
Sometimes there was a sense of a change in objects with perceptive and sensorial distortion, a sense of bodily expansion into the environment or of an extraordinary sensory change. All the people were fully aware of being in an unusual state of consciousness but the sense of ego was maintained throughout the experience. The imagery increased at the height of the experience (interface between stages 1 and 2), with a greater distinctness and vividness: people experienced a particular kind of imagination where thoughts were immediately transformed into images. This has happened to six people. During the Amanita experience people complained of a lack of attention with a high involvement in inner images and sensations and great difficulty in directing concentration. No effects were reported on memory, which was unimpaired in all throughout the experience. Nobody has reported feelings of irritation, anger, shame, guilt or other negative feelings. Sexual feelings and also sensations of love, joy and bliss were absent. Some people remember a marked sense of detachment and no emotional involvement. Control of the experience, thought and image was very reduced because of the absence of volition: the person accepted this situation with detachment and absence of any criticism. I think that the most powerful quality of Amanita muscaria is this sense of silent talking to oneself; the kind of internal dialogue where a person has the feeling of important revelations about his life, a feeling which is maintained for a long time after the experience. More research into this is needed, particularly with selected groups of people: I think this mushroom could have a lot to teach us about ourselves.
1 Even without entering into the subject, it's worth mentioning the other three species of the genus Amanita which are somehow connected to the hallucinogenic substances: A. tomentelIa Kromb., A. citrina (Scheff.) S.F. Gray (= A. mappa (Batsch. ex Fr.) Quulet) and A. porphyria (A. & S. ex Fr.) Seer. (= A. recutita (Fr.) Gillet). In this species were found bufotenine and other compounds such as the psychotropic dimethyl-byptamine (DMT) [Catalfolmo & Tyler, 1961; Tyler, 1961; Hofmann, 1964; Tyler and Gr6ger, 1964; Eugster, 1968; Perez-Silva and Aroche Alfonso, 1983]. [Return to Text]
2 Traces of plants with known therapeutical value but without alimentary usefulness are found in caves and burial places more than 60,000 years old [Furst, 1976].[Return to Text]
3 Already Neanderthal men might have had a proto-religion with shaman characters [Furst, 1976].[Return to Text]
4 Well enough known to give the name to cholinergic receptors tied to the effecters (and its parasympathomimetic activity at post-ganglionic levels).[Return to Text]
5 The tropane alkaloids, typical of deliriants of the family Solanaceae, are generally active after ingestion of higher than 10-30 mg. of pure substance [Hoffer and Osmond, 1967; Waser, 1967; Schultes and Hofmann, 1980].[Return to Text]
6 It's worth remembering here the report of a compound, named Agarin, found in the mushroom by Bowden and Drysdale [1965; Bowden et al., 1965] and whose structure is then shown exactly alike Muscimol.[Return to Text]
7 This difference of concentration for different parts of the mushroom, different picking seasons and different growing stages can give partial scientific support to the "rules" of Amanita muscaria gathering among the Siberian people using it as an inebriant [Wasson, 1967a, 1967b].[Return to Text]
8 A benzodiazepine which, as we will see below, potentiates the effects of Muscimol and, in general, of GABA-agonists.[Return to Text]
9 In order to be exhaustive, we can say that the behavioral and EEG effects of ibotenic acid are practically the same as muscimol, yet 5-10 times less powerful.[Return to Text]
10 One among GABA-antagonists at the CNS level.[Return to Text]
11 On the other hand, the lack of neurobiological relationship between hallucinogenic drugs of different psychotropic families demonstrates the baselessness of one among the hypotheses proposed in the early 1970s, which supposed a common final way for the actions of hallucinogens [Brawley and Duffield, 1972; Grinspoon and Bakalar, 1979; Jacobs, 1984].[Return to Text]