In the central nervous system, the dimensions of pleasure-reward and energy-arousal appear to be correlated with the levels and activity of several key neurotransmitters—the chemicals that are released at pre-synaptic junctions, and their associated receptors at the postsynaptic junction. The evidence supporting such correlations comes from animal brain studies of the effects of drugs and the reported subjective effects of psychoactive drugs in humans. (For reviews of the effects of these drugs on the brain and nervous systems, see Grob, 1998; Nichols, 2004; Strassman, 2001; Presti, 2002; Holland, 2001.)
It’s important to remember too, that I am only discussing the possible neurochemistry of these two dimensions. In the case of the entheogens (such as LSD) there are other complexities involved in their effects (such as the multidimensional visions and insights) that go far beyond effects on the energy-arousal and the pleasure-reward system.
I suggest the following correlations as undoubtedly oversimplified first approximations. Upward movement on the energy-arousal dimension is primarily correlated with levels of the excitatory neurotransmitter norepinephrine (or noradrenaline). The stimulants, such as cocaine, the plant extract ephedrine, and the synthetic amphetamines (which include MDMA), function to increase levels of norepinephrine in the synaptic junctions in several key brain circuits. Several classes of anti-depressants function to inhibit the reuptake of norepinephrine, thus prolonging its action at the synapse.
Downward movement on the arousal dimension, toward relaxation and sleep, is induced by the depressant-sedative-hypnotics, including alcohol and the barbiturates. The action of depressants on brain function is mediated via the inhibitory neurotransmitter GABA (gamma-aminobutyric acid), which is found distributed throughout the brain and central nervous system. Antianxiety drugs like Valium work by increasing depleted levels of GABA.
The neurotransmitter primarily associated with the pleasure-reward dimension is dopamine. The stimulant amphetamines (including MDMA), as well as cocaine, involve the release of dopamine at neuronal synapses (or the blockage of its reuptake). The dopaminergic circuits in the limbic system, because they induce short, intense bursts of pleasurable sensation, seem to be particularly involved in addictive patterns of stimulant drug use. However, chronically high levels of dopamine are also found in anxiety states and schizophrenia, and some antipsychotic drugs work by blocking dopamine receptors. This suggests some complex interactions of brain circuits that have not as yet been unraveled, and recent research suggests that disturbances of the excitatory neurotransmitter glutamate may also be involved in producing the symptoms of schizophrenia.
Because of the pain-reducing and euphoric, dreamy state induced by the opiate narcotics, they can move awareness along the hedonic continuum toward pleasure, as well as lowering the arousal level. The opiates, whether plant-based (opium, morphine, codeine) or synthetic (heroin, oxycodone, hydrocodone), exert their sedative and analgesic (pain-reducing) action via endogenous neurotransmitters called endorphins, that are structurally similar to morphine. The opiate drugs work by attaching to the endorphin receptor sites, producing addiction when these receptors are reset to require higher inputs of external (rather than endogenous) opiates to feel normal. Endorphins are also what enable hibernating animals such as bears to survive long periods of time at depressed levels of breathing, heart rate, and metabolism.
In the diagram in chapter 8, I have placed the effects of cannabis (marijuana and hashish) in the lower right quadrant—mildly sedative and relaxing, but also moderately euphoriant; and dilating the subjective sense of time passing, which increases the appreciation of music and sensuality. The neurochemistry of the action of THC (tetrahydrocannabinol), the active ingredient in the various plant preparations, is uniquely different from the other major known neurotransmitters. Specialized cannabinoid receptors are widespread in the brain and body—which may account for the wide variety of medicinal uses, including increasing appetite, that have been identified and documented for cannabis.
I’ve also placed ketamine in the lower right quadrant. It is classified as a dissociative anesthetic, used in surgery (advantageously, since it doesn’t depress respiration). At subclinical doses it produces some psychedelic visual effects, accompanied by a diffusion of and detachment from body consciousness. For this reason, ketamine, like GHB, has generated interest in recreational and mind-exploring circles.
The third major neurotransmitter involved with the two dimensions is serotonin, or 5-hydroxytryptamine (5-HT), which occurs in the brain as a metabolic product of tryptophan, one of the eight essential amino acids found in protein foods such as milk, poultry, eggs, and nuts. Serotonin levels are increased by the stimulant amphetamines and MDMA and, to a lesser extent, by cocaine, and also by the classic psychedelics such as LSD and psilocybin. Tryptophan and 5-HTP (5-hydroxytryptophan), an intermediate step in the biosynthesis of serotonin, are used in the treatment of depression, elevating both mood and energy level. The SSRIs (like Prozac), which inhibit the reuptake of serotonin and thus prolong the action at the synaptic junctions, are also well-known antidepressants.
Serotonin deficiency is associated with depression, and also with anger, irritability, impulsiveness, and insomnia—all conditions that respond well to tryptophan and to 5-HTP. Carbohydrate cravings and obesity are also believed to be caused by serotonin deficiency, with the body trying to make up the deficit by eating carbohydrate-rich foods, which help make tryptophan available in the brain. Hence intake of 5-HTP is one of the most effective ways to reduce weight. (There is also a serious neurological syndrome associated with excessive serotonin levels in the brain. While this can occur with certain drug combinations and is potentially life-threatening, it appears to be much less common than the serotonin deficiency believed to underlie both depression and anger as ongoing conditions.)
My speculative hypothesis is that serotonin functions as a mood modulator, raising the subjective energy-arousal level in states of depression and lowering it in anger and irritability. Adequate levels of serotonin in the brain may be the key to emotional balance and equanimity, allowing individuals to make more reasonable choices and reducing emotional reactivity (Murray, 1998).
In the case of MDMA, for which I coined the term empathogenic (“empathy-generating”) in its subjective effects, the serotonin enhancing effect may be the basis of the calm, non-anxious, emotional balance that is particularly valuable in the therapeutic treatment of interpersonal conflict, trauma, and PTSD. The dopamine-releasing effect, which the other amphetamines also have, probably accounts for its role as Ecstasy, the drug of choice at hours-long dance parties with pulsing music, known as “raves.” In addition, the presence of MDMA in the body triggers the release of prolactin—the hormone released during mother-infant bonding and breastfeeding—the paradigmatic example of non-striving, relaxed, empathic mergence of two beings.
Most of the presently known psychedelic, hallucinogenic, or entheogenic compounds, whether occurring in plants or synthesized, belong to one of two chemical “families”: the phenethylamines (which include mescaline, peyote cactus, San Pedro cactus, MDA, MDMA or Ecstasy, and others) and the tryptamines (which include DMT, psilocybin, ayahuasca, LSD, bufotenine, and others). Of the four main neurotransmitters (norepinephrine, acetylcholine, serotonin, and dopamine), all of the known psychedelics act strongly, though not exclusively, on serotonin receptors. The phenethylamines (e.g., MDMA) in addition affect norepinephrine, which is the neurotransmitter mostly involved with the effects of stimulants such as amphetamine (which is also a phenethylamine). This may account for the more energized, stimulating properties of the phenethylamines as compared to the tryptamines. On the level of subjective experience this can be observed if one compares the extremely rapid, almost percussive beat of the typical peyote chants, with the more sedate, mellow, and melodic spirit healing songs sung by ayahuasqueros and mushroom curanderas like Maria Sabina.
Research in the last couple of decades has extended scientific understanding of the complexity and pervasiveness of serotonin in the human brain and nervous systems. The neural circuits primarily involved in the biosynthesis of serotonin are found in the raphe nuclei of the brain stem, from where serotonergic neurons have projections to all other parts of the brain. The brain stem is called the reptilian brain in Paul MacLean’s triune brain model. Serotonin has also been found to be the main neurotransmitter for the enteric nervous system, a system of 100 million neurons distributed in and around the intestinal tract. This brain system is almost completely independent of the cerebral cortex. It is thought to be evolutionarily the oldest part of our nervous system.
My speculation is that the role of serotonin in this reptilian brain system, and the possible effects of psychedelic drugs in it, may be the basis for experiences of evolutionary remembering, heightened instinctual or “gut-level” knowledge, and the healing of psychosomatic disturbances possible with psychedelics.
Dimethyltryptamine (DMT), an extremely powerful hallucinogen, chemically closely related to serotonin, is found in several shamanic entheogenic plant preparations and endogenously in the human brain. DMT is synthesized in the brain’s pineal gland. Some have speculated that DMT or one of its derivatives might be responsible for the vivid imagery of dreams and spontaneous visions. Rick Strassman, who conducted a psychiatric research project with DMT, which he calls the “Spirit Molecule,” speculates that pineal-produced DMT is released in near-death experiences and other mystical revelations.