The oral activity of tryptamines that are degraded by MAO can be enhanced by chemicals called monoamine oxidase inhibitors (MAOI). This synergism serves as the basis for the Amazonian entheogenic brew, ayahuasca (which means “vine of the souls”), where DMT is rendered orally active by the presence of MAOI harmala alkaloids from the plant Banisteriopsis caapi (Metzner 1999). Another botanical source of the MAOI harmala alkaloids harmaline and harmine is the seed of the Syrian rue, Peganum harmala, a bush related to the creosote, native to Asia and Africa. There are anecdotal reports that the potency of psilocybin mushrooms can be increased by perhaps a factor of two by ingestion of 1 to 3 grams of ground Peganum harmala seeds 30 minutes prior to ingestion of the mushrooms (DeKorne 1994).
Figure 11B. A space-filling representation of the framework drawing of psilocin depicted in Figure 11A. The molecular structures depicted in the figures in this chapter are two-dimensional, line-drawing representations of the molecules that show how the atoms are connected and allow for ready comparison of similarity between molecules. Molecules actually have three-dimensional shapes in which each of the constituent atoms occupies a volume defined by its cloud of electrons. Linus Pauling and two of his colleagues, Robert Corey and Walter Koltun, first developed a form of molecular models to depict the 3-dimensional space-filling aspect of molecules in the way shown in this figure.
Note: MAO inhibitors can have a profound impact on the metabolism of the monoamine neurotransmitters, serotonin, dopamine, and norepinephrine. Phenethylamines such as amphetamine and MDMA (3,4-methylenedioxymethamphetamine, “ecstasy”) cause the release from axon terminals of monoamine neurotransmitters. Normally these amines are rapidly degraded by MAO and have little physiological effect. In the presence of an MAOI, however, these transmitters can accumulate and lead to severe and potentially fatal consequences. Thus, it is essential to avoid using MAOIs together with any amine that might stress the cardiovascular system (such as amphetamine or MDMA). One must also avoid the ingestion of MAOIs if one is using any of the antidepressant medications that block the uptake of serotonin into neurons, such as SSRIs (like Prozac, Paxil, Zoloft, or celexa) and certain tricyclic antidepressants. Such a combination could result in toxic overactivity of serotonergic neurotransmission and produce what is called a serotonin syndrome. This potentially life-threatening condition may include symptoms such as mental confusion, anxiety, hypomania, hallucinations, hyperthermia, tachycardia, muscle rigidity, and tremor. Your physician will counsel you that it is best (and sometimes essential) to avoid MAOIs whenever any antidepressant medications are being used.
CROSSING THE BLOOD-BRAIN BARRIER
The particular way in which the walls of the blood vessels in the central nervous system are constructed results in their being impermeable to many substances, thereby limiting the ability of molecules to pass from the blood into the brain. This phenomenon is called the “blood-brain barrier.” Molecules may cross the blood-brain barrier by mechanisms of active transport, or by being sufficiently lipid soluble that they can diffuse through the hydrophobic core of the lipid membranes that form the boundaries of the cells composing the blood-brain barrier. Most psychoactive drugs are sufficiently lipid soluble that they can pass from the blood into the brain by passive diffusion.
It was noted earlier that psilocin is less basic than bufotenin by a factor of more than ten-fold. The consequence of this is that there is less of the protonated form of psilocin in the blood, and therefore more of the free base, which is the more lipid-soluble species that actually crosses the blood-brain barrier. In that earlier cited study (Migliaccio et al. 1981), it was shown that even after one considers the reduced ionization of psilocin, this molecule still has greater lipid solubility than would be predicted. Again, it appears that some interaction between the 4-hydroxy and the amino group of the side chain may be responsible, perhaps a hydrogen bond between the 4-hydroxy and the amine (fig. 11A). The same effects are not seen in bufotenin, 5-hydroxy-DMT, which has much lower lipid solubility than psilocin, and also is a substrate for MAO. The atomic distances would preclude such an intramolecular hydrogen bond in bufotenin. Thus, not only does the 4-oxygen substituent of psilocin appear to confer resistance to degradation by MAO, but it also enhances lipid solubility, making the molecule enter the brain more readily.
NEUROCHEMISTRY
Entheogens pharmacologically related to psilocin produce profound changes in thought, feeling, perception, and conscious awareness. They produce alterations in some very basic brain neurochemical processes and many entheogenic chemicals share at least some common neurochemical mechanisms. Interaction with brain circuitry employing the neurotransmitter serotonin is believed to be central to the brain mechanism of entheogens, including the tryptamine entheogens found in psilocybin mushrooms.
Serotonin has many different types of receptors, characterized by differences in the amino-acid sequences of the protein that folds across the nerve cell membrane to form the receptor. All known serotonin receptors except one belong to a large family of receptors called G-protein (GTP-binding protein) coupled receptors. (The exception is the 5-HT3 receptor, which is a cation channel.) G-protein coupled receptor proteins are thought to be comprised of seven alpha-helical segments that span the neuronal membrane, with external and internal connecting loops. Different types of G-protein coupled receptors have certain key amino acids that appear in all such receptors, but also have differences that give them their unique properties of recognizing a specific neurotransmitter and producing a particular type of intracellular signaling message (fig. 12).
Molecules that activate G-protein coupled receptors and cause an intracellular signal to be generated are called agonists. Other molecules can occupy the receptor binding site and prevent the neurotransmitter from gaining access and generating a signal. Those drugs are called antagonists. Interaction of the neurotransmitter with a specific extracellular binding site on the receptor causes a change in the shape of the receptor that leads to the binding and activation of a G-protein on the side of the receptor that is within the neuronal cell. The activated G-protein then goes on to initiate various intracellular biochemical processes that may result in alterations of the activities of various enzymes, changes in cyclic nucleotide levels, and cleavage of membrane phospholipids. Such processes may cause the opening or closing of ion channels, which will alter membrane electric potential with resulting excitation or inhibition of neuronal activity.
Figure 12. Schematic representation of the human serotonin 5-HT2A receptor. Each small circle represents one of the 471 amino acids that comprise the receptor and the alphabetic characters are the standard abbreviations for amino acids (e.g., alanine=A, glycine=G, tyrosine=Y, etc.). The protein structure is believed to be comprised of seven alpha-helices packed together and spanning the neuronal cell membrane; these are represented by the cylindrical segments. Although these helical segments are shown here arranged in a linear fashion for ease of visualization, in the actual receptor they adopt a more barrel-like packing arrangement, with a central cavity for binding serotonin. The connecting loops between the helical segments inside the cell membrane (at the bottom of the figure) also are arranged in specific shapes but are less well understood. Activating ligands (e.g., serotonin or psilocin) approach the receptor from the extracellular side of the receptor, which is at the top of the figure. After the agonist binds to the receptor, the bundle of helical segments rearranges, causing the connecting chains on the interior of the cell membrane (at the bottom in the figure) to change their 3-dimensional shape. This latter effect leads to the generation of a signal inside the cell by way of the association of the intracellular loops with the binding of a G-protein. When the intracellular loops change shape, a process is initiated within the associated G-protein that leads it to bind GTP (guanosine triphosphate), dissociate from the receptor, and become “activated.” These activated G-proteins then interact with other enzymes within the cell that, in turn, increase or decrease in activity, leading to vari
ous changes in the cellular biochemistry that constitute the intracellular “signal” that ultimately derives from the agonist molecule. Amino acids of importance for maintaining structure/function are shown in black, and those thought necessary to recognize and interact with the agonist ligand are shown in gray. (Figure provided courtesy of Dr. James Chambers)
Still other changes may be induced by activating transcription factors within the cell nucleus, leading to alterations in gene expression and subsequent protein synthesis. In short, many things may happen following the activation of a G-protein coupled receptor by a neurotransmitter or other agonist, some things relatively quickly, and some over longer periods of time.
Although serotonin activates all subtypes of serotonin receptors, tryptamine entheogens interact predominantly with the type-2 serotonin receptors. In this subfamily, comprised of three members: 5-HT2A, 5-HT2B, and 5-HT2C, it is currently believed that the key receptor is the one designated as the 5-HT2A (Aghajanian and Marek 1999). Although other receptors could be involved, this is the one site that has been consistently implicated as most important. Antagonists that block this receptor appear to block the major psychoactive effects of psilocybin in humans (Vollenweider et al. 1998).
The 5-HT2A receptor has been the focus of increased interest in recent years for a variety of reasons. It has been implicated in a number of psychiatric disorders, consistent with its important role in the regulation of cognition and mood states. Furthermore, it is found in highest density throughout the cerebral cortex of the mammalian brain (Willins et al. 1997; Jakab and Goldman-Rakic 1998). This finding is significant because the cerebral cortex is the most recent and largest evolutionary addition to the brain. The frontal cortex of the human brain is very involved in judgment, planning, and complex reasoning (so-called “executive functions”), emotional processing, and language, while more posterior regions of the cortex (temporal, parietal, and occipital lobes) are responsible for the analysis and interpretation of sensory information. Jakab and Goldman-Rakic (1998) indicate that 5-HT2A receptors are highest in density in regions of the frontal cortex, temporal cortex, and occipital cortex, as well as the cingulate cortex of the limbic system. These workers also note that 5-HT2A receptors are often located on promixal dendritic regions rather than on more distal dendritic spines, the former location resulting in a greater impact on modulation of cell activity. More recently, Williams et al. (2002) have found that prefrontal cortical 5-HT2A receptors have a previously unrecognized role in the cognitive function of working memory.
These studies all indicate that the site that is believed to be essential to the action of entheogens, the serotonin 5-HT2A receptor, is located in key areas of the brain that are responsible for memory, sensory processing, and a variety of functions that make us uniquely human. There is great research interest today in the neuroscience community in these receptors. As they are studied further, we shall no doubt learn more about how they modulate our awareness, and how they are affected by entheogens. Indeed, one might suppose that continued study along these lines will result in increasing understanding of the cellular and molecular aspects of entheogenic experiences!
OTHER PSYCHOACTIVE FUNGI, BRIEFLY NOTED
Although psilocybin-containing fungi are the most well understood, there are other fungi with psychoactive properties, although their neurochemistry is completely different. Amanita muscaria is found throughout the world and is known as a picturesque mushroom with a bright red cap. In the decade following his work with the Psilocybe mushrooms of Mexico, R. Gordon Wasson (1968, 1971) proposed that Amanita muscaria might be the sacred intoxicant “Soma” mentioned in the ancient Asian texts of the Rig Veda. Ott (1993) reviews many reports of psychoactive and entheogenic effects from ingestion of Amanita muscaria. Physiologically active chemicals in this mushroom include muscarine, isolated from Amanita muscaria in 1869 by German chemists. Muscarine affects the peripheral nervous system by activating muscarinic acetylcholine receptors in the parasympathetic branch of the autonomic nervous system. It is a quaternary amine carrying a fixed positive charge and, as such, does not cross the blood-brain barrier. Thus, there are no effects of muscarine on the brain. In addition, it is found only in small quantities in the mushroom.
The psychoactive effects of Amanita muscaria are believed to be due to the chemicals ibotenic acid (fig. 13) and muscimol (fig. 14). Ott (1993) summarizes reports that there are entheogenic (hallucinogenic) effects in humans following oral doses of 50–100 mg of ibotenic acid or 10–15 mg of muscimol. Once in the blood circulation, muscimol would cross the blood-brain barrier by inefficient diffusion. Ibotenic acid would cross the blood-brain barrier using the transporter protein for certain amino acids. Ibotenic acid can be decarboxylated by the enzyme aromatic amino acid decarboxylase, found both within the brain and in the periphery, to form muscimol. Ibotenic acid is known to be an agonist at the NMDA-type glutamate receptor, one of the primary excitatory neurotransmitter receptors in the brain, and can lead to the so-called excitotoxic cell death of neurons. Muscimol is an agonist at the GABA-A receptor, the primary inhibitory neurotransmitter receptor in the brain. How these various receptor interactions may lead to hallucinogenic effects is unknown. What is clear, however, is that these effects are behaviorally and neurochemically very different from those of the tryptamine entheogens that occur in Psilocybe mushrooms.
Figure 13. Ibotenic Acid.
Figure 14. Muscimol.
It also should be noted that within the genus Amanita there exist several species of deadly mushrooms. They are among the small number of mushroom species the ingestion of which can prove fatal. These species include Amanita phalloides and Amanita viA, both of which contain small peptides called amanitins that inactivate RNA polymerase and cause irreversible damage to liver function.
A final example of a psychoactive fungus is the ergot Claviceps purpurea, which grows on grains such as rye and wheat, and from which Hofmann isolated the ergot-alkaloid precursor for his synthesis of LSD (lysergic acid diethylamide) (Hofmann 1980). Hofmann (in Wasson et al. 1998) has also established that the Claviceps purpurea fungus itself contains pharmacologically-active alkaloids in the form of ergonovine (lysergic acid propanolamide) and lysergic acid amide (fig. 15). The ergot alkaloids, in general, act at many different types of receptors, and the overall alkaloidal composition of ergot fungus makes it quite toxic. Nevertheless, there are a variety of strains of Claviceps, with differing alkaloid content, some of which likely are more toxic than others. Wasson, Hofmann, and Ruck (1998) further proposed that ingestion of Claviceps purpurea or related fungi growing on cultivated grains or wild grasses may have been the basis for an entheogenic ritual of ancient Greece called the Eleusinian Mysteries. The neurochemistry of these molecules, closely related to LSD in structure, would largely be through serotonin-receptor mechanisms similar to those described above for psilocin.
Figure 15. Lysergic Acid Amide.
CODA
The serotonergic neurons of the raphe nuclei in the brainstem innervate the entire brain and likely exert substantial modulatory effects on our perceptions, emotions, thought processes, and conscious awareness—the mental states that may collectively be called “the mind.” Psilocybin and related tryptamines from Psilocybe fungi are believed to produce their profound effects on the brain and mind by way of interacting with 5-HT2A receptors in the cerebral cortex, limbic system, and elsewhere. As chemical probes that might lead to a better understanding of how the neural circuitry of the brain is related to the nature of mind, they offer unprecedented opportunities!
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