Psychedelic Information Theory : Chapter 06

Psychedelic Pharmacology

Figure 1 : Psychedelic amines look very much like the transmitters serotonin, norepinephrine, and dopamine.

Most psychedelic molecules are structurally similar to neurotransmitters that modulate signal flow in the brain. If we take a close look at the structure of common neurotransmitters (Fig. 1) the transmitters most closely related to the classic psychedelics are serotonin (5-HT), adrenaline (epinephrine), norepinephrine, and dopamine (DA), and all of these chemicals are classified as amines, meaning that they have a nitrogen (N+) containing amino group hanging off a root carbon ring. This nitrogen structure is the key element in any amino acid, carrying the energy needed for metabolic processes which do work. Since these transmitter chemicals have only one nitrogen group they are called monoamines, and they are the essential messengers of the aminergic neuromodulatory system.

Monoamines entering the bloodstream are normally kept out of the brain by the blood-brain-barrier, but psychedelic molecules have a neutral charge so they are able to pass. When these amine crystals pass through the blood-brain barrier they brush against neural receptor sites; if the receptors are a good fit then the crystals get stuck for a short period of time. The bonding of amine ligands to serotonin and dopamine receptors is where psychedelic action begins.1,2

Serotonin and the Tryptamines

Because of depressive mood disorders and pharmaceuticals like Prozac, the most well known neuromodulator is serotonin, or 5-HT (5-hydroxytryptamine). 5-HT is essential to many basic brain functions, linked to mood, depression, contentment, anxiety, sleep, appetite, and the regulation of involuntary smooth muscles that control blood pressure and digestive functions. Serotonin is an indoleamine and a variant of tryptamine, which is the most basic of all the indoleamines and the structural starting point for DMT (N,N-dimethyltryptamine), 5-MeO-DMT, psilocin, psilocybin, DPT, AMT, and most psychedelic drugs with acronyms ending in T (which stands for Tryptamine). LSD is also a tryptamine, but it is larger and more complex than the other tryptamines, and is in many ways structurally unique.

Dopamine and the Phenethylamines

Working in concert with serotonin is the neuromodulator dopamine (3-hydroxytyramine). Dopamine is synthesized from L-DOPA and is instrumental in modulating salient attention, motivational response, and fine motor control. Dopamine is central to the reward system, and dopamine release is stimulated by recreational drugs, food, gambling, sex, and physical risk taking. Dopamine imbalances are linked Parkinsons disease, ADD, compulsive risk behavior, and psychosis. The role of dopamine interruption is relevant to psychedelic activity in many aspects; psychedelics may affect sensuality and motor control, and may facilitate psychosis, mania, and compulsive behaviors.

Amphetamines and the phenethylamine group of psychedelics (mescaline, 2-CB, MDA, MDMA, and so on) are more structurally similar to dopamine, epinephrine, and norepinephrine, which are also monoamines but sometimes referred to as catecholamines since they are based on the single catechol ring structure. Epinephrine and norepinephrine are referred to as stress hormones because they prime the bodys energy production in response to stress and danger. The phenethylamines and catecholamines all have the six-carbon benzene ring backbone, simpler than the dual-ring tryptamine structure, with at least one amine group. The simplest form of this molecule is called phenethylamine, and is structurally similar to amphetamine.

In very general terms, the phenethylamine psychedelics are said to be more energetic, sensual, empathogenic, or entactogenic, while tryptamine psychedelics are thought to be more hallucinogenic, disorienting, and somatically heavy. These descriptions are very broad, but this is the popular distinction made between the two major classes of psychedelics.

Neuromodulators and Global Brain States

Figure 2 : Serotonin and dopamine pathways ascend from the brainstem and midbrain and synchronize global changes in mood and behavior.

Serotonin, dopamine, and the other monoamines dont cause neurons to fire, they instead tune the spiking rate of neurons, which means they adjust global network polarity over time to make neural assemblies more or less responsive to stimulus. Serotonin and dopamine are projected into higher areas of the brain from nuclei in the brainstem and middle brain, meaning they are primal signaling mechanisms for modulating many areas of the brain simultaneously. (Fig. 2) The axons from these aminergic clusters reach upward to many areas of the cortex, affecting the thalamus (sensory filter), amygdala (fear and survival), hypothalamus (homeostatic regulator), hippocampus (memory and learning), and neocortex (sensory and logic processing). Neuromodulators synchronize the neural response to incoming stimulus and keep local competing brain circuits functioning smoothly and in unison. These neuromodulators produce a one-way bottom-up effect, which means they are switched on and off reflexively and unconsciously by glands in the brainstem and basal forebrain in direct response to internal conditions or external stimulus. Using neuromodulators the brainstem can exert global homeostatic control over organism mood and behavior. The effect of the aminergic modulators projected upward by the brainstem are tonic, which means their signaling effects are sticky and persist over the duration of many incoming spike trains.

Generally serotonin is thought to have a polarizing effect on neurons, making them less likely to fire and thus having an overall relaxing effect on the brain. This is why many depression and anxiety remedies focus on increasing the supply of serotonin; to decrease anxiety and increase satisfaction. If we assume psychedelics are mimics for neurotransmitters and apply this analogy to DMT, we would expect DMT to have a calming effect on the brain because it looks similar to serotonin. But a flood of DMT does not calm the brain, it makes it hallucinate. Psychedelics act on the same receptors as serotonin and dopamine, but as partial agonists. Since DMT binds to the same receptor sites as serotonin but does not produce a relaxing effect, it would be logical to assume that DMT is a 5-HT antagonist, meaning it blocks serotonin and depolarizes neurons, making them more excitable. This is not the case. There are many different types of 5-HT receptors, some inhibit neural activity and some promote neural activity. Like most hallucinogens, DMT is classified as a selective 5-HT 2A partial or full agonist; also active at other 5-HT subtypes, at adrenal receptors, at Sigma-1 receptors, and at tertiary amine receptors. This means that DMT is active at many 5-HT sites and can mimic some of the agonistic functions of serotonin with varying frequency and efficacy.

5-HT partial agonism can be described as a subtle form of aminergic modulatory signal interference. In the most general case it can be assumed that psychedelic activity is due to interference at 5-HT receptor subtypes. In more specific cases we can assume that visual hallucinogenic effect is associated with 5-HT 2A and 5-HT 2C receptor interaction. Somatic heaviness and dreaminess is associated with broader aminergic interaction; and more sensual, entactogenic, or compulsive effects are associated with DA and adrenergic receptor interaction. Psychedelics can have a wide affinity and interact as partial or full agonists at multiple receptor subtypes to produce a wide range of effects. Because psychedelics are full or partial agonists acting on the same modulatory pathways as 5-HT, the synergistic interaction between these competing agonists can be described in terms of a modulatory wave interference pattern. Agonistic interference at 5-HT subtypes promotes disinhibition and extreme excitability between feedback-coupled autonomic neural assemblies in the cortex, midbrain, and brainstem. Excitation in the autonomic neural assemblies which process sensation and memory lead to spontaneous hallucination; excitation in autonomic assemblies which process thought and self-awareness lead to expanded states of psychedelic consciousness.

Molecular Shape and Receptor Affinity

Figure 3 : 5-HT2 affinity correlates to hallucinogenic potency.

The strength and duration of the bond a ligand forms with a receptor is referred to as receptor affinity or potency, and is described in terms of pharmacodynamics. The higher the affinity the stronger and longer the ligand bonds with a receptor and influences charge moving across the neural membrane. Research has shown that 5-HT 2A receptor affinity is an accurate measure of the potency of any psychedelic compound; the higher the affinity the higher the potency and psychedelic effect (Fig 3.).4,5 Another thing we know is that the conformational shape of the amine determines how long the molecule takes to metabolize and how sticky it will be at 5-HT receptor types.6 For instance, the amine tail of LSD is different from other tryptamines; it is long, complex, and connects back to the benzene ring, keeping it rigid instead of flexible like most amino groups or substitutions. Designer amines with a similarly rigid molecular structure have also shown a marked increase in psychedelic potency.7

Using this information it can be assumed that the unique structure of LSD is what makes it so potent; giving it a high affinity across a wider range of receptor types; making it more difficult to metabolize; and giving it a broader range of effect over a longer duration. DMT also binds to a wide variety of 5-HT receptor types, but it is smaller and metabolizes very quickly. When DMT is taken with a monoamine-oxidase inhibitor (MAOi) in an ayahuasca mixture, the enzymes which metabolize DMT are blocked making the hallucinogenic effects of DMT orally active and longer lasting. Adding an MAOi to any tryptamine psychedelic will make it nearly twice as hallucinogenic.8 These few pieces of pharmacology tell us that the efficacy of modulatory interruption, or psychedelic potency, can be somewhat predicted by molecular shape, the rigidity of the molecular structure, and speed of metabolic pathways.

Breadth of Psychedelic Receptor Binding

Mol/Target 5ht1a 5ht1b 5ht1d 5ht1e 5ht2a 5ht2b 5ht2c 5ht5a 5ht6 5ht7 D1 A-2A A-2B A-2C 2C-E 2.91 3.00 3.54 2.60 3.76 4.00 3.38 0.00 1.93 2.77 0.00 2.71 2.91 3.44 2C-B 2.75 3.11 3.71 3.05 3.69 4.00 3.18 0.00 2.63 2.81 0.00 2.64 2.31 3.12 LSD 3.73 4.00 3.70 2.62 3.54 3.11 3.11 3.64 3.75 3.77 2.34 2.93 0.00 0.00 DOI 0.00 2.31 3.00 2.66 3.44 3.13 4.00 0.00 2.34 1.90 1.67 3.79 3.13 2.88 DMT 0.00 0.00 3.91 3.28 2.58 0.00 3.42 3.16 3.35 4.00 3.51 2.75 3.53 3.53 Psilocin 2.88 2.19 3.40 3.03 2.14 4.00 2.52 2.83 2.82 2.82 3.37 1.36 1.57 1.03 5-MeO-DMT 4.00 2.41 3.48 1.72 0.98 0.69 1.55 1.84 2.73 3.69 2.38 0.00 0.86 1.57 DiPT 4.00 0.00 2.51 0.00 0.00 3.48 0.00 0.00 0.00 0.00 0.00 0.00 2.62 2.68 Mescaline 3.61 0.00 0.00 3.16 0.00 3.97 0.00 0.00 0.00 0.00 0.00 2.92 0.00 4.00 MDMA 0.00 0.00 0.00 0.00 0.00 3.64 0.00 0.00 0.00 0.00 0.00 2.94 3.09 3.21 6-F-DMT 2.81 3.07 3.66 2.74 2.47 3.93 2.58 2.43 4.00 3.80 2.67 0.00 2.99 3.24 Lisuride 4.00 2.27 0.00 0.00 2.74 3.01 0.00 2.99 2.61 2.64 0.00 3.22 3.78 3.88 4C-T-2 2.04 0.00 0.00 1.77 3.33 4.00 3.09 2.56 0.00 2.18 0.00 0.00 0.00 0.00 Table 1: A list of popular psychedelic drugs and receptor targets in order of 5-HT 2A receptor affinity. A value of 4.00 indicates high affinity at that target; any value under 2.00 should be considered imperceptible. Non-psychedelic control molecules are listed at the bottom for comparison.3

Table 1 lists the binding strength of popular psychedelic drugs at many 5-HT receptor sites listed in order of 5-HT 2A affinity.3 This table should be an accurate representation of hallucinogenic potency in descending order. From subjective reports all substances at the top of this list are very hallucinogenic, but DMT, which is often considered to be the most hallucinogenic, actually falls somewhere in the middle. If we look at 5-HT 2C affinity, which is also implicated in hallucination, we can see that all substances at the top of the list also have high 5-HT 2C affinity, with DMT and DOI having slightly higher affinity than the rest. 5-HT 7 receptor affinity, which stimulates cAMP activity and the reward system, also seems to be implicated in overall transcendent psychedelic action, with the mystically popular DMT, 5-MeO-DMT, and LSD topping the affinity list. In contrast, there are four non-visual psychedelics at the bottom of the list, 5-MeO-DMT, DiPT, Mescaline, and MDMA. These substances have very poor 5-HT 2A,C affinity but oddly the bottom three all have a high 5-HT 2B and adrenal affinity; this indicates they are effective at stimulating serotonin production, cardiovascular activity, and acute sensuality. It is interesting to note that DiPT, Mescaline, and 5-MeO-DMT all have a high 5-HT 1A affinity, which is generally thought to work in contrast to 5-HT 2A agonism. DiPT is unusual because is produces distinct audio hallucinations and little or no visual hallucinations, and predictably does not bond with targets associated with visual hallucination. By analyzing this affinity table it seems possible to predict the relative potency of any hallucinogen based solely on binding profiles, though the three control molecules at the bottom of the list (6-F-DMT, Lisuride, 4C-T-2) are reportedly non-hallucinogenic despite high 5-HT receptor promiscuity; this is likely because they are not active as agonists, they are antagonists, or their binding profiles somehow cancel each other out.

Dissociatives, Anticholinergics, and Other Hallucinogens

Psychedelic tryptamines and phenethylamines are not the only hallucinogens, but all hallucinogens work by interrupting sensory binding pathways. Hallucinogenic dissociatives like ketamine (special K), phencyclidine (PCP), and dextromethorphan (DXM) interrupt NMDA glutamate sensory signaling pathways; these pathways mediate fast sensory signal projection through the brain. Anticholinergic deliriants like scopolamine and atropine interrupt cholinergic modulation of memory, recall, and dreaming; these pathways mediate the smooth input and output of memory from the hippocampus. Salvia divinorum interrupts Kappa-opioid tactile sensory pathways; these pathways mediate pain, gravity awareness, and feedback for determining physical orientation in space. Depressants like GHB and alcohol interrupt sensory binding via inhibitory GABA pathways, pathways which dampen and slow smooth sensory throughput. Nitrous Oxide (N 2 0) is the simplest and perhaps the most promiscuous of hallucinogens, worming its way in between a number of rudimentary signaling channels to produce novel feelings of dissociation and out-of-body emergence. Although the pharmacological targets of hallucinogens differ, in all cases perceptual distortion is linked directly to interruption of seamless multisensory signaling and binding across the cortex. Any drug which interrupts pathways of multisensory signaling or binding will be considered psychedelic or hallucinogenic at high enough doses, this is why so many different types of plants and chemicals can be uniquely hallucinogenic across many different receptor targets.

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Notes and References

[1] Snyder S, 'Drugs and The Brain'. Scientific American Books, 1986

[2] Cooper JR, Bloom FE, Roth RH, 'The Biochemical Basis of Neuropharmacology'. Oxford University Press, NY, 7th ed., 1996.

[3] Ray TS, 'Psychedelics and the Human Receptorome'. PLoS One. 2010; 5(2): e9019.

[4] Glennon RA, Titeler M, McKenney JD, 'Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents'. Life Sci. 1984 Dec 17;35(25):2505-11

[5] Sadzot B, Baraban JM, et al., 'Hallucinogenic drug interactions at human brain 5-HT2 receptors: implications for treating LSD-induced hallucinogenesis'. Psychopharmacology (Berl). 1989;98(4):495-9

[6] McLean TH, Parrish JC, Braden MR, Marona-Lewicka D, Gallardo-Godoy A, Nichols DE, '1-Aminomethylbenzocycloalkanes: conformationally-restricted hallucinogenic phen­ethylamine analogues as functionally-selective 5 HT2A receptor agonists'. J Med Chem. 2006 Sep 21;49(19):5794-803.

[7] Sattelkau, Tim, 'An Interview with Dave Nichols'. Trip Magazine, Vol 5., Spring 2000, p 42.

[8] Subjective reports of taking an MAO inhibitor with psychedelic tryptamines such as DMT, psilocybin, LSD, and 5-MeO-DMT confirm that the addition of an MAOi increases potency and hallucination by an order of magnitude. MAOi potentiation can come from plant sources, such as the harmala alkaloids found in Peganum harmala seeds and Bandisteriopsis caapi vine, but is particularly intense when derived from a pharmaceutical source like moclobemide.

Citation: Kent, James L. Psychedelic Information Theory: Shamanism in the Age of Reason, Chapter 06, 'Psychedelic Pharmacology'. PIT Press, Seattle, 2010.

Keywords: psychedelics, hallucinogens, serotonin, dopamine, modulators, pharmacology

Copyright: © James L. Kent, 2010. Some Rights Reserved. Please read copyright information before reproducing.