———. 1959. The hallucinogenic mushrooms of Mexico: An adventure in ethnomycological exploration. Transactions of the New York Academy of Sciences Series II, 24 (4):325–39.
———. 1961. The hallucinogenic fungi of Mexico; an inquiry into the origins of the religious idea among primitive peoples. Harvard University Botanical Museum Leaflets 1 (7):137–62. (Reprinted in Psychedelic Review 1 (1), June 1963, 27–42).
———. 1974. Maria Sabina and her Mazatec Mushroom Velada. New York and London: Harcourt Brace Jovanovich.
———. 1980. The Wondrous Mushroom: Mycolatry in Mesoamerica. New York: McGraw-Hill.
———. 1990. Gordon Wasson’s account of his childhood. In The Sacred Mushroom Seeker: Essays for R. Gordon Wasson, ed. Thomas J. Riedlinger. Portland, Ore.: Dioscorides Press.
Wasson, V. P. and R. G. Wasson. 1957. Mushrooms, Russia and History. New York: Pantheon Books.
Thomas J. Riedlinger has degrees in psychology and theological studies. He has been an Associate in Ethnomycology at Harvard Botanical Museum and currently is a Fellow of the Linnean Society of London. In addition to writing and lecturing, he works as a Licensed Mental Health Counselor in Olympia, Washington. He has published several essays and book chapters on entheogens and edited The Sacred Mushroom Seeker: Essays for R. Gordon Wasson (1990). He can be reached via e-mail at: [email protected].
4
BIOCHEMISTRY AND NEUROPHARMACOLOGY OF PSILOCYBIN MUSHROOMS
DAVID E. PRESTI, PH.D., AND DAVID E. NICHOLS, PH.D.
This chapter will present a discussion of the chemistry of a particular type of psychoactive mushroom, of the genus Psilocybe, often known collectively as psilocybin mushrooms, and sometimes referred to as “magic mushrooms.”
The history of the ritual use of these mushrooms spans millennia, from the contemporary Mazatec Indians of southern Mexico, to the Mayan and Aztec cultures of Mexico and central America six hundred years ago, to the cultures that came many centuries before them. In the sixteenth century the Spanish chronicler de Sahagún described teonanácatl, an Aztec word that can be translated as “sacred mushroom” or “God’s flesh.” We know from Sahagún’s writings that teonanácatl was used for social occasions, festivals, and by the Aztec shamans (Hofmann 1971).
When used in a ritual context by the shaman, teonanácatl provided a bridge between everyday consensus reality and extraordinary states of consciousness that allowed perception of events and situations that were not ordinarily accessible: the weather was forecast, illness was diagnosed, aspects of the future might be seen, such as whether or not the harvest would be good. Thus, his ingestion of the “God’s flesh” made the Aztec shaman seem like a god, able to transcend time and space.
Teonanácatl is classified as an entheogen, a substance that can manifest the god within. Certainly, for the Aztec shaman, the connection with the gods that arose in his mind through the ritual use of teonanácatl was the central purpose of the substance. Within this context, and for the purposes of the discussion, we shall use the term entheogenic to describe the effects produced by psilocybin fungi. This convention seems particularly appropriate because, of all the similar types of psychoactive substances of which we know today, these mushrooms have one of the clearest historical justifications for applying this term. Those readers who are more formally inclined should consider it to be synonymous with the terms psychedelic and hallucinogenic.
The chemical makeup of psychoactive mushrooms is extraordinarily complex, with hundreds of chemicals created by the organism’s metabolic biochemistry. Though any number of these may have effects on human physiology, the psychoactive effects of various entheogenic fungi and plants are usually attributable to a small number of identified compounds. The psychoactive chemicals identified in entheogenic fungi are generally secondary metabolites of the organism’s biosynthetic processes. That is, they are not believed to function as part of the mushroom’s energy-generating or structural biochemistry, their primary metabolism, but are instead products of biochemical syntheses.
Recently it has become increasingly appreciated that so-called secondary metabolites may play any number of important roles for the organism. For some plants, certain secondary metabolites that have psychoactive effects in humans have been demonstrated to function as chemical defenses against insect predators. This observation is usually hypothesized to be the reason why they are present, having been selected over the course of biological evolution for their defensive properties. Examples include noxious effects on insects from cocaine in coca plants, caffeine in coffee and tea plants, and nicotine in tobacco plants. Moreover, the psychoactive effects produced by these plants in humans have resulted in an additional evolutionary advantage for the plants in that they have been spread throughout the world by people who cultivate them to maintain ready availability.
The psychoactive chemicals synthesized by entheogenic fungi have not thus far been demonstrated to play chemical defensive roles for the organism. No experiments have been conducted, for example, to investigate whether entheogenic fungi avoid predation by invertebrates such as slugs and snails because of their peculiar chemical content. The notion that entheogenic substances are present in fungi and plants primarily to foster their consumption by humans is a speculative and interesting hypothesis (McKenna 1992), but one for which there is absolutely no scientific evidence.
PSILOCYBIN AND ITS CHEMICAL RELATIVES
The primary effects of the entheogenic psilocybin mushrooms on human physiology are due to several tryptamine alkaloids synthesized and accumulated by these fungi. The categorical name “tryptamine alkaloids” (or “tryptamines”) designates molecules whose molecular structure contains 3-(2-aminoethyl)indole as a central feature (fig. 1).
Figure 1. Tryptamine, showing numbering of the indole ring.
The identified psychoactive chemical components of psilocybin mushrooms are psilocybin, psilocin, baeocystin, and norbaeocystin (figs. 2–5).
Figure 2. Psilocybin or 4-phosphoryloxy-N,N-dimethyltryptamine.
Figure 3. Psilocin or 4-hydroxy-N,N-dimethyltryptamine.
Figure 4. Baeocystin or 4-phosphoryloxy-N-methyltryptamine.
Figure 5. Norbaeocystin or 4-phosphoryloxytryptamine.
Psilocybin and psilocin were identified as the primary psychoactive components of Psilocybe mushrooms by the renowned Swiss chemist Albert Hofmann in 1958. Hofmann isolated and identified the compounds from samples of Psilocybe mexicana mushrooms collected in Mexico. To identify the compounds that produced the effects on consciousness, he and several of his coworkers ingested fractions obtained from the paper chromatographic separation of the fungal extracts (Hofmann et al. 1958, 1959).
Psilocybin can produce significant psychoactive effects in humans following oral doses of approximately 10 to 20 mg (Shulgin and Shulgin 1997). Taken orally, psilocybin and psilocin produce identical effects when given at equivalent molar doses. That is because following oral ingestion, the phosphoryl group of psilocybin is rapidly lost to generate psilocin, which is the actual active molecule. Alkaline phosphatases located in the digestive system, kidney, and perhaps in the blood probably carry out this enzymatic transformation (Horita and Weber 1961). Early animal studies showed that the behavioral effects of psilocybin paralleled the increase in brain level of psilocin (Horita 1963). After administration of psilocybin, only psilocin is detectable in the blood (Hasler et al. 1997). These same workers found that following oral administration of 10–20 mg of pure psilocybin, peak levels of psilocin in the blood (about 8 ng/ml) occur approximately 105 minutes after ingestion. Effects on the psyche appear when a blood concentration of between 2–6 ng/ml is achieved, about 20–90 minutes after oral administration of pure psilocybin. After intravenous administration of 1 mg of pure psilocybin, the conversion to psilocin occurs rapidly, and peak blood concentrations of psilocin (about 13 ng/ml) are achieved within 2 minutes of injection (Hasler et al. 1997).
In the mushroom, the phosphoryl group of psilocybin confers protec
tion against oxidation. Indeed, crystalline samples of psilocybin have been stored at room temperature for decades with no appreciable degradation. Furthermore, psilocybin can even be recrystallized from boiling water, a treatment that would destroy psilocin itself (Nichols and Frescas 1999). Thus, psilocybin is a remarkably stable molecule, particularly when compared with other tryptamines. This stability provides the basis for the extraction of psilocybin mushrooms with hot water for the preparation of ritual teas.
Psilocin, by contrast, is a fairly unstable molecule. The pure material slowly darkens in air, whereas solutions, particularly at basic pH, decompose rapidly. Many psilocin-containing mushrooms turn a bluish color when bruised. This effect is believed to be due to degradation products of psilocin that have yet to be chemically identified (Stamets 1996). Hydroxyindoles in general are readily oxidized, leading to highly colored products, and it is likely that bruising the mushrooms releases psilocin from a protective matrix so that it is exposed to air oxidation or to the action of enzymes that use oxygen to oxidize aromatic substrates. Although the nature of these colored products has not been elucidated, no doubt some of them are quinoid-type species, which typically have dark colors. Although 5-hydroxytryptamines such as bufotenin also oxidize very readily, they do not generate the blue colors that occur with 4-hydroxytryptamines.
Baeocystin and norbaeocystin were first identified from Psilocybe baeocystis (Leung and Paul 1968). Baeocystin has since been found in at least twenty-six species of mushrooms and there is one report that it is psychoactive in humans at doses of approximately 10 mg, ingested orally (Ott 1993). Unfortunately, sufficient data are not available for these two compounds to assess their clinical properties, but it is very likely that they produce qualitatively different psychopharmacological effects. Based on current neurochemical knowledge, one could reasonably speculate that these two compounds would have different affinities and abilities to activate the various brain receptors relevant to the actions of entheogens. Therefore, the relative proportions of psilocybin and baeocystin in a particular species of mushroom are probably relevant to its effects after ingestion. This idea would be consistent with anecdotal reports that some species of mushroom, for example P. cubensis and P. azurescens, can induce qualitatively different effects.
Several related psychoactive tryptamine molecules, which, although synthesized by a variety of plants, have not yet been detected in fungi, include: N,N-dimethyltryptamine or DMT (fig. 6); 5-hydroxy-N,N-dimethyltryptamine or bufotenin; and 5-methoxy-N,N-dimethyltryptamine or 5-MeO-DMT (fig. 7). Conversely, psilocin and psilocybin have not thus far been found in plants.
Figure 6. N,N-dimethyltryptamine or DMT.
Figure 7. 5-methoxy-N,N-dimethyltryptamine or 5-MeO-DMT.
LEGAL STATUS
The legal status of several of these molecules has been specified by the Federal Controlled Substance Act, passed into law by the United States Congress in 1970. Psilocybin, psilocin, DMT, and bufotenin have been classified as Schedule 1 substances by the U.S. Controlled Substances Act. Psilocybin and psilocin are essentially nontoxic to body organs and do not cause physiological dependence or addictive behaviors (presumably the basis for the dangers of drugs of abuse as this term is used in the Controlled Substances Act). The classification of psilocybin, psilocin, and many other entheogens as dangerous drugs is primarily based on socio-political reasons rather than clinical-scientific evidence. Psilocybin, psilocin, and DMT are also internationally classified as Schedule 1 substances by the 1971 United Nations Convention on Psychotropic Substances.
TRYPTAMINES IN THE HUMAN BODY
Some tryptamine molecules found naturally in the human body include tryptophan, 5-hydroxytryptophan, serotonin, melatonin, and N,N-dimethyltryptamine.
Figure 8. Tryptophan.
Tryptophan (fig. 8) is one of the twenty amino acids used by all of life on Earth to build proteins. Although plants, fungi, bacteria, and some other organisms can biosynthesize tryptophan from smaller carbon molecules, humans cannot and must ingest tryptophan as part of their diet. That is, tryptophan is one of the “essential” amino acids. In fungi and plants, tryptophan is the chemical precursor for the biosynthesis of tryptamines such as DMT and psilocybin. In humans and other animals, tryptophan is the precursor for the synthesis of the neurotransmitter serotonin, 5-hydroxytryptamine (5-HT; fig. 9).
Figure 9. Serotonin or 5-hydroxytryptamine.
The synthesis of 5-HT from tryptophan in serotonergic neurons occurs in two steps. First, the enzyme tryptophan hydroxylase catalyzes the conversion of tryptophan to 5-hydroxytryptophan (5-HTP). Then, the enzyme aromatic amino acid decarboxylase catalyzes the conversion of 5-HTP to serotonin.
In the brain, serotonergic neurons are located in the brainstem in clusters of cells called the raphe nuclei, within which is the reticular network. These serotonergic neurons send their axonal projections throughout the entire brain. As a neurotransmitter, serotonin is involved in the regulation of numerous behavioral and physiological processes, including mood, appetite, sleep, sexual function, blood flow, body temperature, and more. The fact that both tryptophan and 5-HTP are chemical precursors for the synthesis of serotonin is presumably the reason for the claim of their efficacy in the treatment of problems related to mood, sleep, and appetite (Murray 1999).
Figure 10. Melatonin.
Melatonin (fig. 10) is a hormone produced from serotonin in the pineal gland, which is embedded within the brain. It is released into the brain and general blood circulation and is involved in the regulation of the sleep-wake cycle and other circadian biological clock processes.
N,N-dimethyltryptamine (DMT) (fig. 6) has been found to occur endogenously at very low concentrations within the human brain, cerebrospinal fluid, and blood. Its function is unknown, but some have speculated that it plays neurotransmitter-like roles in psychotic mental states and dream-sleep imagery (Barker et al. 1981; Callaway 1988; Strassman 2001). Thus, all humans are, presumably at all times, in possession of a Schedule 1 substance and therefore in violation of United States and international law!
METABOLISM OF TRYPTAMINES BY MONOAMINE OXIDASE
Most tryptamine molecules are metabolized by the enzyme monoamine oxidase (MAO). MAO actually occurs in two different forms, MAO-A and MAO-B, which have preferences for different neurotransmitter molecules. MAO-A oxidizes the terminal amine of the tryptamines to an imine. This imine then undergoes nonenzymatic hydrolysis to an aldehyde that is subsequently converted to a carboxylic acid by a second enzyme, aldehyde dehydrogenase. The result is the conversion of the tryptamine into an acidic molecule, called an indole-3-acetic acid, which lacks psychoactivity. DMT is converted into indole acetic acid, whereas serotonin is converted into 5-hydroxyindole acetic acid (5-HIAA), and psilocin is converted into 4-hydroxyindole acetic acid.
The two forms of MAO are found throughout the body, including in the nervous system, where they function to inactivate monoamine neurotransmitters such as serotonin, dopamine, and norepinephrine. MAO is also found in the liver, where it is involved in the metabolism of amines taken in through the digestive system. MAO in the liver will limit the bioavailability of some tryptamines that are orally ingested. For example, DMT lacks significant oral activity due to breakdown by MAO in the liver. However, psilocybin, psilocin, and baeocystin are orally active. Apparently the presence of the 4-oxygen substituent on these latter tryptamines confers resistance to MAO because tryptamines lacking this substituent, or those with the oxygen moved to the 5-indole position, are readily degraded by MAO.
There may be some unique chemical interaction between the tryptamine side chain and the 4-oxygen substituent. A study by Migliaccio et al. (1981) found that psilocin had much greater lipid solubility than bufotenin (5-hydroxy-DMT), and that the amino group of psilocin was also less basic. The decreased basicity of psilocin results in a larger fraction of this molecule being in an uncharged (unionized) form in the body, which leads to enhanced intestinal absorption and enhanced penetration into the brain,
relative to a tryptamine such as bufotenin. Those workers speculated that hydrogen bonding could occur between the 4-hydroxy group and the amine side chain, as illustrated in figures 11A and 11B. It was noted that such a hydrogen bond, if it indeed formed, need only be a weak one to explain their results on basicity and lipid solubility. Computer modeling shows that because of the particular geometry of the indole ring, the illustrated structure has almost ideal geometry for hydrogen bonding.
Figure 11A. Possible hydrogen bonding interaction in psilocin.
It is not unreasonable to speculate that the interaction between the 4-hydroxy and the side chain amino group also lies at the heart of the resistance of 4-oxygenated tryptamines to attack by MAO. Although still controversial, MAO catalysis is generally thought to proceed by what is called a single-electron-transfer pathway. According to this mechanism, the initial step of this catalytic process involves transfer of one electron from the nitrogen lone pair of the amine group to oxidized flavin adenine dinucleotide (FAD), a necessary cofactor for the reaction, to generate an aminyl radical cation and reduced FAD. The important point to be made here is that the type of intramolecular interaction illustrated between the 4-hydroxy and the side chain amine group (figs. 11A and 11B) would make the nitrogen lone pair of electrons less available for this initial step of the MAO degradation process. Hence, by making the first step of the MAO mechanism less efficient, the whole degradation process is blocked.
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