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Psychedelic Pharmacology

by James Kent

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, 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.

monoamine-structure.jpg


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

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, 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.

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 Parkinsons 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 bodys 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

Diagram-depicting-the-dopamine-blue-and-serotonin-pathways-red-in-the-brain-along.png


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 dont 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 psychedelics, DMT is classified as a selective 5-HT2A 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-HT2A and 5-HT2C 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

affinity.jpg


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-HT2A 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). 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. 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.

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. 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​
3.54​
2.6​
3.76​
4​
3.38​
0​
1.93​
2.77​
0​
2.71​
2.91​
3.44​
2C-B​
2.75​
3.11​
3.71​
3.05​
3.69​
4​
3.18​
0​
2.63​
2.81​
0​
2.64​
2.31​
3.12​
LSD​
3.73​
4​
3.7​
2.62​
3.54​
3.11​
3.11​
3.64​
3.75​
3.77​
2.34​
2.93​
0​
0​
DOI​
0​
2.31​
3​
2.66​
3.44​
3.13​
4​
0​
2.34​
1.9​
1.67​
3.79​
3.13​
2.88​
DMT​
0​
0​
3.91​
3.28​
2.58​
0​
3.42​
3.16​
3.35​
4​
3.51​
2.75​
3.53​
3.53​
Psilocin​
2.88​
2.19​
3.4​
3.03​
2.14​
4​
2.52​
2.83​
2.82​
2.82​
3.37​
1.36​
1.57​
1.03​
5-MeO-DMT​
4​
2.41​
3.48​
1.72​
0.98​
0.69​
1.55​
1.84​
2.73​
3.69​
2.38​
0​
0.86​
1.57​
DiPT​
4​
0​
2.51​
0​
0​
3.48​
0​
0​
0​
0​
0​
0​
2.62​
2.68​
Mescaline​
3.61​
0​
0​
3.16​
0​
3.97​
0​
0​
0​
0​
0​
2.92​
0​
4​
MDMA​
0​
0​
0​
0​
0​
3.64​
0​
0​
0​
0​
0​
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​
3.8​
2.67​
0​
2.99​
3.24​
Lisuride​
4​
2.27​
0​
0​
2.74​
3.01​
0​
2.99​
2.61​
2.64​
0​
3.22​
3.78​
3.88​
4C-T-2​
2.04​
0​
0​
1.77​
3.33​
4​
3.09​
2.56​
0​
2.18​
0​
0​
0​
0​
Table 1 lists the binding strength of popular psychedelic drugs at many 5-HT receptor sites listed in order of 5-HT2A affinity. 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-HT2C affinity, which is also implicated in hallucination, we can see that all substances at the top of the list also have high 5-HT2C affinity, with DMT and DOI having slightly higher affinity than the rest. 5-HT7 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-HT2A,C affinity but oddly the bottom three all have a high 5-HT2B 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-HT1A affinity, which is generally thought to work in contrast to 5-HT2A 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 (N20) 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 at high enough doses, this is why so many different types of plants and chemicals can be uniquely hallucinogenic across many different receptor targets.

http://psychedelic-information-theor...c-Pharmacology
 
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CBD and the Psychedelic Receptor

by Lex Pelger | Reality Sandwich | Mar 29 2018

In a shorthand that drives scientists mad, serotonin is often called ‘the neurotransmitter of happiness.’ This tag is especially troublesome as more and more flaws become apparent in the ‘serotonin hypothesis’ of depression' – the idea that depression is caused by a serotonin deficit, which a pill (a serotonin reuptake inhibitor) could correct. Serotonin is a complex molecule in the brain and the periphery with a vast and intricate receptor system classified into seven main subtypes that regulate a wide array of physiological functions. Calling serotonin the happiness molecule is short shrift.

The importance of serotonin transcends happy mind states. Conserved as an evolutionary through-line in all bilateral animals, including worms and insects, the serotonin molecule modulates the release of a swathe of other neurotransmitters. Serotonin (which is often abbreviated as 5-HT because of its proper chemical name 5-hydroxytryptamine) is involved in behaviors as diverse as aggression, learning, appetite, sleep, cognition, and reward activity. The receptors for serotonin have become pharmaceutical targets for a range of neuropsychiatric disorders and gut-related conditions. Ninety percent of 5-HT is located in the GI tract, where it regulates intestinal motility.

Biochemist Maurice Rapport isolated serotonin and elucidated its molecular structure in the late 1940s. Two distinct serotonin receptor binding sites – 5-HT1 and 5-HT2 (later renamed 5-HT1A and 5-HT2A) – were identified in the rat brain in 1979. It turns out that cannabidiol (CBD), a promiscuous, non-intoxicating cannabis compound, binds directly to both of these receptors.

Whereas CBD has little binding affinity for the classical cannabinoid receptors, CB1 and CB2, several serotonin receptor subtypes are key docking sites for CBD. The 5HT2A receptor also mediates the actions of LSD, mescaline and other hallucinogenic drugs. But CBD and LSD act at 5-HT2A, the psychedelic receptor, in different ways, resulting in markedly different effects.

Receptor complexes

Reported initially in 2005, the discovery that CBDinteracts directly with these (and other) 5-HTreceptors hints at a broader relationship between the endocannabinoid and serotonergic systems that scientists are still uncovering.

Endogenous cannabinoids and serotonin are both well-conserved across animal taxa and both link to an extensive “super family” of G-protein coupled receptors in the brain and the periphery. Furthermore, there is considerable communication between these two neurotransmitter systems, which are involved in similar physiological functions throughout the body, such as the relief of anxiety, the reduction of pain, the alleviation of nausea and headaches, and the regulation of internal temperature.

Embedded on the surface of cells, G-protein coupled receptors are so complicated that the study of their signaling pathways has already yielded a half dozen Nobel Prizes for figuring out various parts of the picture. The activation of a G-protein coupled receptor from a signal outside the cell releases a second messenger molecule into the cell’s interior. These intracellular molecules act as Western Union messengers that telegraph signals all over the cell. Their primacy in human health is demonstrated by the fact that roughly half of all modern pharmaceuticals target a G-protein coupled receptor.

It used to be thought that G-protein coupled receptors worked as solo actors – until scientists learned that these transmembrane-bound proteins can link up and “dimerize” into receptor complexes with novel signaling. (A “dimer” is a chemical structure formed when two of those receptors floating around the lipid membrane join together into a functional unit.) The first breakthrough came in 2002 when researchers at the University of Washington in Seattle reported that CB1 cannabinoid receptors sometimes become entangled and form “homomeric” complexes with themselves.

We still don’t fully understand the physiological consequences of receptor dimerization, but this much is evident: Different types of receptors can intertwine and dimerize with each other. According to a 2013 study by Spanish scientists investigating ischemia (an injury that causes interrupted blood flow) in newborn piglets, neuroprotective effects were mediated by a 5-HT1A serotonin receptor conjoined to CB2cannabinoid receptor in a “heteromer” complex. That’s where two different receptor types meld together and often perform actions that neither of them do on their own.

dat-consciousness-neurosciennwes.jpg


Cross-talk

There is extensive cross-talk and feedback between the endocannabinoid and serotonergic systems. Anandamide, an endogenous cannabinoid compound, shows activity at 5-HT1A. So does CBD, which has been described as “a modest affinity agonist at the human 5-HT1A receptor.”

An agonist activates a receptor; an antagonist blocks a receptor. CBDA, the unheated “acid” version of cannabidiol that exists in the raw plant, is a more potent 5-HT1A agonist than CBD. CBDA shows great promise as an anti-emetic and as a treatment for anticipatory nausea.

When injected into several brain structures, CBDfacilitates 5-HT1A-mediated neurotransmission. CBD activation of the 5-HT1A receptor has been shown to decrease blood pressure, lower body temperature, slow the heart rate, and lessen pain. In 2013, the British Journal of Pharmacology reported that 5HT1A mediates CBD’s helpful effects in animal models of liver damage, anxiety, depression, pain and nausea.

CB1 cannabinoid receptors – which are activated by THC, not CBD – are the most prevalent G-protein coupled receptors in the central nervous system. CB1 receptors are found in many brain regions, including the dorsal raphe nucleus, which is also the primary source of serotonin in the forebrain. In animal models, stimulating these serotonergic neurons lowers anxiety and fights depression. Inhibiting them causes depressive states.

Mice genetically engineered to not express CB1 in this serotonin-producing region of the brain were found to be more anxious than their wild type counterparts.

Long-term cannabinoid activation downregulates 5-HT1A receptors, according to a 2006 article by Matthew Hill, et al, in the International Journal of Neuropsychopharmacology. Another study listed several conditions where by blocking the serotonin receptors, a reduction occurred in various cannabinoids effects such “as the conditioning of fear memory, emotional memory consolidation, antinociception [painkilling], catalepsy, hypothermia [and] the activation of the hypothalamic-pituitary-adrenal axis in rodents.”

5-HT2A: tripping and forgetting

CBD is also active at the 5-HT2A receptor, but apparently less so compared to CBD’s binding affinity for 5-HT1A. Whereas CBD stimulates the 5-HT1A receptor, cannabidiol apparently acts as an antagonist at 5-HT2A.

5-HT2A activity has been linked to various phenomena, such as headaches, mood disorders, and hallucinations. This serotonin receptor subtype is known for its importance to the psychedelic experience. LSD, mescaline, and components of the psilocybin mushroom are potent agonists that bind to 5-HT2A – and when that happens get ready for the magical mystery tour.

It’s worth noting that oral consumption of a high dose of cannabis resin (hashish) can trigger LSD-like effects, including vivid, kaleidoscopic hallucinations. Indeed, there “is an outstanding body of experimental evidence,” according to Dr. Ethan Russo, “to suggest that THC is hallucinogenic while the closely related cannabinoid, cannabidiol (CBD) opposes such activity.”

Could it be that the 5-HT2A receptor mediates the hallucinogenic properties of THC? Unlike CBD, THC does not bind directly to 5-HT2A. But, as noted earlier, THC directly activates the CB1 cannabinoid receptor. And we know from a remarkable paper published by PLoS Biology in 2015 that CB1 receptors form heterodimer complexes with 5-HT2A receptors. This means that CB1 and 5-HT2A receptors can entwine and function as a combined entity.

Intriguingly, these receptors working together activate signaling pathways that neither of them cause on their own. Whether this can account for the hallucinogenic effects of high-dose cannabis concentrates remains a matter of speculation. But we know from behavioral studies on mice that CB1/5-HT2A heteromer complexes mediate both the positive painkilling benefits of THC, as well as THC’s amnesiac effects. [4]

Specifically, the PLOS Biology study found these cannabinoid/serotonin heteromers are “expressed and functionally active in specific brain regions involved in memory impairment.” A subsequent report in Molecular Neurobiology attributed the upregulation of CB1/5-HT2A heteromer complexes in human olfactory cells to chronic cannabis consumption.

Some cannabis proponents might bristle at the allegation that chronic use of their favorite herb causes short-term memory loss, but it’s hard to argue with the scientific evidence: In mice and in humans, cannabis generally makes it more difficult to remember, for example, the details of a movie quite as well or, with respect to rodents, to navigate a maze quite as quickly.

But THC’s impact on memory isn’t necessarily detrimental. In fact, far from being an impairment, forgetting can be one of marijuana’s most important therapeutic aspects. Cannabinoids might be just the thing to help a veteran forget a triggering event or at least lower the stranglehold of that memory.

It seems that these heteromer complexes mediate some of the cognitive deficits attributed to THC as well as its benefits.

CBD, THC and 5-HT3A

The 5-HT3A receptor warrants at least a brief mention because it is unique among serotonin receptors. Unlike all the other serotonin receptor subtypes, 5-HT3A is not a G-protein coupled receptor. Instead, 5-HT3A functions as an ion channel.

An ion channel regulates the flow of ions across the cell membrane and thus helps to regulate the rapid electrical signals used by the brain.

Located in the periphery as well as the central nervous system, 5-HT3A receptors are involved in mood disorders, as well as the transmission of pain signals. Antagonistic drugs that block the 5-HT3A receptor are used for treating chemotherapy-induced nausea and vomiting.

Both THC and CBD are potent negative allosteric modulators of 5-HT3A receptors. This means that THC and CBD interact with the 5-HT3A receptor in a way that changes its conformation, or shape, so that the receptor is less likely to bind efficiently with and be activated by its native ligand, serotonin.

This might account for some of the anti-nausea effects of THC and CBD. Intriguingly, anandamide, the native cannabinoid, also causes this kind of inhibition. Plant cannabinoids and endogenous cannabinoids work in tandem with the serotonin system to help ease yet another human ailment.

http://realitysandwich.com/322794/cb...elic-receptor/
 
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An explanation of the effect of psychedelics on the nervous system at the level of the neurone

Following is a detailed explanation of how hallucinogens affect the brain, via the inhibition and excitation of neurotransmitters in the nervous system.

mRuueFj.png


A neurone is a cell that carries electrical impulses. Information is processed and transmitted by the nervous system in the form of electrical and chemical signals. The neurone primarily comprises of a cell body, an axon and dendrites. The axon is a nerve fibre that carries electrical signals away from the cell body, to the end of the neurone. The end of the neurone then connects to the dendrites on the cell body of the next neurone, via a synapse. Drugs cause their effects due to their action on the neurones in the nervous system.

A nerve impulse is a self-propagating wave of electrical disturbance that travels along the surface of the axon membrane. This electrical disturbance comprises of a temporary reversal of the electrical potential difference; not an electrical current. The axon is usually negatively charged compared to the outside of the axon, and this is known as the resting potential, the value of which is usually around -65mV. When a stimulus is received, a reversal in electrical potential difference is caused, and this is known as the action potential (normally around +40mV).

tumblr_inline_mi0jjoLMZw1qz4rgp.png


To begin, the inside of the axon is negatively charged, compared with the outside of the axon. The change in potential difference, that is needed to fire off an action potential, is controlled by the movement of sodium and potassium ions in and out of the axon. An ion is a positively or negatively charged molecule. This movement occurs via the action of ion pumps and channels. The ions cannot just diffuse in and out of the axon uncontrollably; this diffusion is prevented by a membrane around the axon. Periodically placed along the membrane are proteins that act as channels for ions to pass through. Sodium gated channels and potassium gated channels open and close to allow the ions to pass through only at specific times. Sodium-potassium pumps transport Na+ and K+ in and out of the axon.

The inside of the axon starts at around -65mV compared to the outside of the axon. An action potential is reached when the axon is at +40mV compared to the outside of the axon. This value of +40mV is reached by the movement of sodium and potassium ions in and out of the axon. Sodium-potassium pumps transport 2K+ into the axon for every 3Na+ transported out of the axon. Both sodium and potassium are in the forms of positive ions here. However, more sodium is removed from the axon compared to the potassium brought. This means the overall electro negativity is decreasing in the axon, and the axon is getting closer to reaching the potential difference of +40mV. Sodium ions then begin to diffuse back into the axon naturally, and potassium ions diffuse back out. At this stage however, potassium gated channels are open, whereas sodium gated channels are closed. This means the K+ can diffuse out faster than the Na+ can diffuse back into the axon. This increases the potential difference further between the inside and the outside of the axon.

Once an action potential has been established, it “moves” along the axon in a neurone. The action potential doesn’t move in a physical sense of the word; the reversal of electrical charge is instead reproduced at different points along the axon, in a “Mexican wave” effect. One point in an axon will become depolarised (depolarisation is a change in a cell’s membrane potential, making it more positive, or less negative), and this depolarisation is a stimulus for the next region of the axon to depolarise. As the next region depolarises, the previous region returns to normal and repolarises.

Eventually, the action potential will reach the end of an axon, known as a synaptic knob. A synapse occurs at a point where the axon of one neurone meets the dendrite of another neurone.

VhNgB43.png


When an action potential reaches the synaptic knob, the calcium ion channels open, and Ca2+ enters the synaptic knob. As the Ca2+ enters, the vesicles containing the neurotransmitters fuse with the membrane of the pre-synaptic neurone, and the neurotransmitters are released into the synapse. The neurotransmitter molecules attach to the receptors on the sodium ion channels, which allow Na+ ions to diffuse into the post-synaptic neurone. This influx of Na+ generates a new action potential in the post-synaptic neurone. An enzyme is then released into the synapse that breaks the neurotransmitters down into small, precursor molecules. These fragments are reabsorbed by receptors on the pre-synaptic neurone, and they are then used to remake the neurotransmitters. The neurotransmitters are then ready to release when a new action potential reaches the pre-synaptic neurone. This reabsorbing prevents the neurotransmitters from continuously binding with the sodium ion channels on the post-synaptic neurone, and firing off repeated new action potentials.

Neurotransmitters can have one of two effects. Excitatory neurotransmitters/receptors make it more likely that a new action potential will fire off. Inhibitory neurotransmitters/receptors make it less likely that a new action potential will fire off. Many drugs work by affecting the way neurotransmitters work. There’s a handy table listing the effects of different neurotransmitters here.

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Drugs can stimulate the nervous system by creating more action potentials in the post-synaptic neurone. They can do this by mimicking a neurotransmitter, stimulating the release of more neurotransmitter, inhibiting the re-uptake receptor on the pre-synaptic neurone or by inhibiting the enzyme that breaks down the neurotransmitter. Agonists are chemicals that bind to a receptor and trigger a response, often by mimicking the neurotransmitter.

Drugs are also capable of inhibiting the nervous system by creating fewer action potentials in the post-synaptic neurone. This can be done by inhibiting the release of neurotransmitter, or blocking receptors on the sodium/potassium ion channels. This reduces the body’s response to impulses. Antagonists work by blocking or dampening signals of agonist drugs/neurotransmitters.

The action of different drugs on the nervous system

Psychedelics mostly act on serotonin receptors, and act as full or partial agonists. LSD, LSA, psilocin, DMT, mescaline and the 2Cx family all work as partial agonists. The table below shows a few of the commonly known psychedelics, and their action on receptors. The 5HT receptor system acts via the neurotransmitter of serotonin, D1 acts via dopamine, and the A-2 system acts via noradrenaline.

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The scale is from 0 to 4, with 4 being the highest affinity. The chart above is colour coded with a traffic light system. Green refers to an affinity of 3.5-4, representing a very high affinity. Yellow is 2-3.5, representing medium affinity. Orange is below 2. Any value that is orange/below 2 should be disregarded, as the affinity isn’t high enough to cause any great effect. Grey is 0, meaning no affinity at all to the receptor.

The current scientific consensus is that the 5HT-2A receptor is the one targeted by drugs responsible for psychedelic experiences. However, drugs like mescaline and MDMA are both capable of inducing psychedelic experiences on par with that of psilocin and LSD, but show no affinity to the 5HT-2A receptor.

LSD, for example, works by fitting into the receptors on the post-synaptic neurone. It has a higher affinity than serotonin itself for the serotonin receptors, specifically 5HT receptors,
and therefore prevents serotonin binding to the receptors by competing with it.

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The diagram above shows the structural similarities between the psychedelics. The three classes (phenethylamines, lysergamides and tryptamines) all contain the same chemical rings, which have been labelled. A represents the benzene ring, which all three classes contain. B represents the pyrrole ring, in both tryptamines and lysergamides. A and B together form the indole ring. C (cyclohexane) and D are only contained in the lysergamides, possibly contributing to its potency.

Dissociatives
act as non-competitive NMDA receptor antagonists, meaning they inhibit glutamate molecules. Glutamate is the neurotransmitter responsible for telling the body when it’s “awake”, for building up memories and for regulating awareness, mood and movement. NMDA receptors allow for electrical signals to pass between neurones in the brain and spinal column; for the signals to pass, the receptor must be open. NMDA receptor antagonists close the NMDA receptors, by preventing the glutamate from binding to it. This disconnection of neurones leads to loss of feeling, difficulty moving,and eventually the k-hole. It is also this disconnection that causes the anaesthetic properties of dissociatives.

PCP, MXE and ketamine fall into the arylcyclohexylamine class of chemicals, which possess NMDA receptor antagonist properties. DXM/DXO fall into the morphinan class of chemicals. Nitrous oxide, however, is unique, due to being an inorganic molecule. Another inorganic dissociative is xenon, which is also an NMDA receptor antagonist. However, information on recreational use is limited.

Deliriants are antagonists towards the cholinergic receptors, blocking the neurotransmitter acetylcholine. Acetylcholine is the neurotransmitter responsible for regulating the sleep cycle, dreaming alertness, and for building memory. The prolonged suppression of cholinergic activity and REM sleep due to deprivation or amphetamine abuse creates psychotic episodes which may be defined as bursts of dream activity erupting spontaneously into waking states. Deliriants could therefore be considered to trigger a similar state by blocking acetylcholine and suppressing cholinergic system activity. Causing trippers to begin dreaming whilst maintaining full conscious awareness. Deliriants are known for causing people to have no memory of their experience, tying in with their anticholinergic effects. Anticholinergics are split into two class; anti-muscarinic (act on muscarinic acetylcholine receptors) and anti-nicotinic (act on nicotinic acetylcholine receptors). Anti-muscarinic drugs include DPH, scopolamine and atropine. They are all competitive antagonists, meaning they bind to the receptor, but do not activate it.

Atypical drugs don’t fit into the three basic hallucinogen categories, and act in a number of different ways. MDMA is an entactogenic drug that works as a re-uptake inhibitor targeting serotonin receptors. This leads to the prevention of the re-uptake of the serotonin. More serotonin in then in the synapse, so the receptors on the post-synaptic neurone continue to be fired off. Serotonin is known for its control of mood, often being referred to as “the happy chemical”, along with dopamine. Muscimol is a GABA agonist. Salvia is a k-opioid receptor agonist. The k-opioid receptor is responsible for altering the perception of pain, consciousness, gravity, fear, mood and motor control. This explains the sensations of intense gravity, painful tingling and paranoia during Salvia trips. Ibogaine is 5HT-2A agonist, an NMDA antagonist and the k-opioid receptor agonist. The tryptamine core of ibogaine causes the affinity to the 5HT system.

This section has described the chemistry and neuroscience at the basic level of the neurone. However, I intend to write a second part to this article, which describes in detail the effects of hallucinogens, and specifically psychedelics, on specific parts of the brain, and how this translates into the subjective components of the psychedelic experience.

http://disregardeverythingisay.com/p...ucinogens-upon
 
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Unifying theories of psychedelic drug effects

by Link Swanson

How do psychedelic drugs produce their characteristic range of acute effects in perception, emotion, cognition, and sense of self? How do these effects relate to the clinical efficacy of psychedelic-assisted therapies? Efforts to understand psychedelic phenomena date back more than a century in Western science. In this article I review theories of psychedelic drug effects and highlight key concepts which have endured over the last 125 years of psychedelic science. First, I describe the subjective phenomenology of acute psychedelic effects using the best available data. Next, I review late 19th-century and early 20th-century theories, model psychoses theory, filtration theory, and psychoanalytic theory, and highlight their shared features. I then briefly review recent findings on the neuropharmacology and neurophysiology of psychedelic drugs in humans. Finally, I describe recent theories of psychedelic drug effects which leverage 21st-century cognitive neuroscience frameworks, entropic brain theory, integrated information theory, and predictive processing, and point out key shared features that link back to earlier theories. I identify an abstract principle which cuts across many theories past and present: psychedelic drugs perturb universal brain processes that normally serve to constrain neural system central to perception, emotion, cognition, and sense of self. I conclude that making an explicit effort to investigate the principles and mechanisms of psychedelic drug effects is a uniquely powerful way to iteratively develop and test unifying theories of brain function.

Introduction

Lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), psilocybin, and mescaline, the classic psychedelic drugs, can produce a broad range of effects in perception, emotion, cognition, and sense of self. How do they do this? Western science began its first wave of systematic investigations into the unique effects of mescaline 125 years ago. By the 1950s, rising interest in mescaline research was expanded to include drugs like DMT, LSD, and psilocybin in a second wave of psychedelic science. Because of their dramatic effect on the character and contents of subjective awareness, psychedelic drugs magnified the gaps in our scientific understanding of how brain chemistry relates to subjective experience. Huxley commented that our understanding circa 1954 was "absurdly inadequate" and amounted to a mere clue that he hoped would soon develop into a more robust understanding. "Meanwhile the clue is being systematically followed; the sleuths, biochemists, psychiatrists, psychologists, are on the trail." A third wave of psychedelic science has recently emerged with its own set of sleuths on the trail, sleuths who now wield an arsenal of 21st-century scientific methodologies and are uncovering new sets of clues.

Existing theoretical hurdles span five major gaps in understanding. The first gap is that we do not have an account of how psychedelic drugs can produce such a broad diversity of subjective effects. LSD, for example, can produce subtle intensifications in perception, or it can completely dissolve all sense of space, time, and self. What accounts for this atypical diversity?

The second gap is that we do not understand how pharmacological interactions at neuronal receptors and resulting physiological changes in the neuron lead to large-scale changes in the activity of neural populations, or changes in brain network connectivity, or at the systems-level of global brain dynamics. What are the causal links in the multi-level pharmaco-neurophysiological chain?

The third gap is that we do not know how psychedelic drug-induced changes in brain activity, at any level of description. map onto the acute subjective phenomenological changes in perception, emotion, cognition, and sense of self. This kind of question is not unique to psychedelic drugs but our current understanding of psychedelic drug effects clearly magnifies the disconnect between brain science and subjective experience.

Fourth, there is a gap in our understanding of the relationships between psychedelic effects and symptoms of psychoses, such as perceptual distortion, hallucination, or altered self-reference. What is the relationship between psychedelic effects and symptoms of chronic psychotic disorders?

Fifth and finally, there is a gap in our clinical understanding of the process by which psychedelic-assisted therapies improve mental health. Which psychedelic drug effects (in the brain or in subjective experience) enable clinical improvement? How?

Scientific efforts to understand diverse natural phenomena aim to produce a single theory that can account for many phenomena using a minimal set of principles. Such theories are sometimes called unifying theories. Not everyone agrees on the meaning of unification or unifying theory in science. Morrison observed that, although theory unification is a messy process which may not have discernible universal characteristics, historically successful unifying scientific theories tend to have two common features: (1) a formalized framework (quantitative mathematical descriptions of the phenomena) and (2) unifying principles (abstract concepts that unite diverse phenomena). On this conception, then, a unifying theory of psychedelic drug effects would offer a single formalized (mathematical or computational) framework capable of describing diverse psychedelic phenomena using a minimal set of unifying principles. Unfortunately, the survey of literature in this review does not locate an existing unifying theory of psychedelic drug effects. It does, however, highlight enduring abstract principles that recur across more than a century of theoretical efforts. Furthermore, it reviews recent formalized frameworks which, although currently heterogeneous and divergent, hint at the possibility of a quantitative groundwork for a future unifying theory.

The field of cognitive neuroscience offers formalized frameworks and general principles designed to track and model the neural correlates of perception, emotion, cognition, and consciousness. These broad frameworks span major levels of description in the brain and attempt to map them onto behavioral and phenomenological data. Corlett et al. argue that until this is done "our understanding of how the pharmacology links to the symptoms will remain incomplete. Montague et al. argue that computational psychiatry" can remedy the "lack of appropriate intermediate levels of description that bind ideas articulated at the molecular level to those expressed at the level of descriptive clinical entities." Seth argues that computational and theoretical approaches can facilitate a transition from correlation to explanation in consciousness science, and explains how a recent LSD, psilocybin, and ketamine study was motivated by a need to elucidate descriptions at intermediate levels somewhere between pharmacology and phenomenology: We know there is a pharmacological link, we know there is a change in experience, and we know there is a clinical impact. But the middle bit... what are these drugs doing to the global activity of the brain..., that is the gap we are trying to fill with this study. Taken together, the above quotations point to an emerging sense that cognitive neuroscience frameworks can address gaps in our understanding of psychedelic drug effects.

In this article I review theories of psychedelic drug effects. First, making an effort to clearly define the target explananda, I review the acute subjective phenomenological properties of psychedelic effects as well as long-term clinical outcomes from psychedelic-assisted therapies. Second, I review theories from first-wave and second-wave psychedelic science, model psychoses theory, filtration theory, and psychoanalytic theory, and identify core features of these theories. Third, I review findings from recent neurophysiological research in humans under psychedelic drugs. Finally, I review select 21st-century theories of psychedelic effects that have been developed within cognitive neuroscience frameworks; namely, entropic brain theory, integrated information theory, and predictive processing. My analysis of recent theoretical efforts highlights certain features, first conceptualized in 19th- and 20th-century theories, which remain relevant in their ability to capture both the phenomenological and neurophysiological dynamics of psychedelic effects. I describe how these enduring theoretical features are now being operationalized into formalized frameworks and could serve as potential unifying principles for describing diverse psychedelic phenomena.

Psychedelic drug effects

There are dozens of molecules known to cause psychedelic-like effects. This review focuses only on a limited set of drugs dubbed classical hallucinogens or classic psychedelics which are: LSD, DMT, psilocybin, and mescaline. Importantly, there are qualitative inter-drug differences between the effects of the four classic psychedelic drugs. Drug dosage is a primary factor in predicting the types of effects that will occur. Effects unfold temporally over a drug session; onset effects are distinct from peak effects and some effects have a higher probability of occurring at specific timepoints over the total duration of drug effects. Furthermore, effects are influenced by non-drug factors traditionally referred to as set and setting, such as personality, pre-dose mood, drug session environment, and external stimuli.

The above variables, while crucial, do not completely prohibit meaningful characterization of general psychedelic effects, as numerous regularities, patterns, and structure can still be identified. Indeed, common psychedelic effects can be reliably measured using validated psychometric instruments consisting of self-report questionnaires and rating scales though some of these rating scales may be in need of further validation using modern statistical techniques. Items from these rating scales are wrapped in scare quotes in the following discussion in an effort to characterize the subjective phenomenology of psychedelic effects from a first-person perspective. An example of rating scale results is given in.

Perceptual effects

Perceptual effects occur along a dose-dependent range from subtle to drastic. The range of different perceptual effects includes perceptual intensification, distortion, illusion, mental imagery, elementary hallucination, and complex hallucination. Intensifications of color saturation, texture definition, contours, light intensity, sound intensity, timbre variation, and other perceptual characteristics are common. The external world is experienced as if in higher resolution, seemingly more crisp and detailed, often accompanied by a distinct sense of clarity or freshness in the environment. Sense of meaning in percepts is altered, e.g. "Things around me had a new strange meaning for me, or, Objects around me engaged me emotionally much more than usual."

Perceptual distortions and illusions are extremely common, e.g. "Things looked strange or My sense of size and space was distorted, or, Edges appeared warped or I saw movement in things that were not actually moving." Textures undulate in rhythmic movements, object boundaries warp and pulsate, and the apparent sizes and shapes of objects can shift rapidly. Controlled psychophysical studies have measured various alterations in motion perception, object completion, and binocular rivalry.

In what are known as elementary hallucinations, e.g. I saw geometric patterns, the visual field can become permeated with intricate tapestries of brightly colored, flowing latticework and other geometric visuospatial form constants. In complex hallucinations visual scenes can present elaborate structural motifs, landscapes, cities, galaxies, plants, animals, and human (and non-human) beings. Complex hallucinations typically succeed elementary hallucinations and are more likely at higher doses, especially under DMT. Both elementary and complex hallucinations are more commonly reported behind closed eyelids (closed eye visuals, or CEVs) but can dose-dependently occur in full light with eyes open (open eye visuals; OEVs). CEVs are often described as vivid mental imagery. Under psychedelic drugs, mental imagery becomes augmented and intensified, e.g. My imagination was extremely vivid, and is intimately linked with emotional and cognitive effects. Sometimes sensible film-like scenes appear, but very often the visions consist of scenes quite indescribable in ordinary language, and bearing a close resemblance to the paintings and sculptures of the surrealistic school. Psychedelic mental imagery can be modulated by both verbal and musical auditory stimuli. Synaesthesia has been reported, especially visual phenomena driven by auditory stimuli, e.g. "Sounds influenced the things I saw," but classification of these effects as true synaesthesia is actively debated.

Somatosensory perception can be drastically altered, e.g. I felt unusual bodily sensations including body image, size, shape, and location. Sense of time and causal sequence can lose their usual linear cause-effect structure making it difficult to track the transitions between moments.

Overall the perceptual effects of psychedelics are extremely varied, multimodal, and easily modulated by external stimuli. Perceptual effects are tightly linked with emotional and cognitive effects.

Emotional effects

Emotional psychedelic effects are characterized by a general intensification of feelings, increased (conscious) access to emotions, and a broadening in the overall range of emotions felt over the duration of the drug session. Psychedelics can induce unique states of euphoria characterized by involuntary grinning, uncontrollable laughter, silliness, giddiness, playfulness, and exuberance. Negatively experience emotions, e.g. "I felt afraid or I felt suspicious and paranoid," are often accompanied by a general sense of losing control, e.g. "I feared losing control of my mind." However, the majority of emotional psychedelic effects in supportive contexts are experienced as positive. Both LSD and psilocybin can bias emotion toward positive responses to social and environmental stimuli. Spontaneous feelings of awe, wonder, bliss, joy, fun, excitement (and yes, peace and love) are also consistent themes across experimental and anecdotal reports. In supportive environments, classic psychedelic drugs can promote feelings of trust, empathy, bonding, closeness, tenderness, forgiveness, acceptance, and connectedness. Emotional effects can be modulated by all types of external stimuli, especially music.

Cognitive effects

Precise characterization of cognitive psychedelic effects has proven enigmatic and paradoxical. Acute changes in the normal flow of linear thinking, e.g. "My thinking was muddled or My thoughts wandered freely," are extremely common. This is reflected in reduced performance on standardized measures of working memory and directed attention; however, reductions in performance have been shown to occur less often in individuals with extensive past experience with the drugs effects. Crucially, cognitive impairments related to acute psychedelic effects are dose-dependent. Extremely low doses, known as microdoses, have been anecdotally associated with improvements in cognitive performance, a claim that urgently requires empirical verification through controlled research. Theoretical attempts to account for the reported effects of microdosing have yet to emerge in the literature and therefore present an important opportunity to future theoretical endeavors.

Certain cognitive traits associated with creativity can increase under psychedelics such as divergent thinking use of unlikely language patterns or word associations, expansion of semantic activation, and attribution of meaning to perceptual stimuli, especially musical stimuli. Primary-process thinking, a widely validated psychological construct associated with creativity, is characterized phenomenologically by image fusion; unlikely combinations or events; sudden shifts or transformations of images; and contradictory or illogical actions, feelings, or thoughts. Psilocybin and LSD have been shown to increase primary-process thinking as well as the subjective bizarreness and dreamlike nature of mental imagery associated with verbal stimuli. Cognitive flexibility (or loosening of cognition) and optimism can remain for up to 2 weeks after the main acute drug effects have dissipated. Furthermore, long-term increases in creative problem-solving ability and personality trait openness have been measured after just one psychedelic experience.

Ego effects and ego dissolution experiences

Kluever observed that under peyote "the line of demarcation drawn between object and subject in normal state seemed to be changed. The body, the ego, became objective in a certain way, and the objects became subjective." Similar observations continued throughout first-wave and second-wave psychedelic science. Importantly, effects on sense of self and ego occur along a dose-dependent range spanning from subtle to drastic. Subtle effects are described as a softening of ego with increased insight into ones own habitual patterns of thought, behavior, personal problems, and past experiences; effects which were utilized in psycholytic psychotherapy. Drastic ego-effects, known as ego dissolution, are described as the dissolution of the sense of self and the loss of boundaries between self and world, e.g. "I felt like I was merging with my surroundings, or All notion of self and identity dissolved away, or I lost all sense of ego or I experienced a loss of separation from my environment, or I felt at one with the universe." These descriptions resemble non-drug mystical-type experiences; however, the extent of overlap here remains an open question. Ego dissolution is more likely to occur at higher doses. Furthermore, certain psychedelic drugs cause ego dissolution experience more reliably than others; psilocybin, for example, was found to produce full ego dissolution more reliably compared with LSD. Ego dissolution experiences can be driven and modulated by external stimuli, most notably music. Interestingly, subjects who experienced complete ego dissolution in psychedelic-assisted therapy were more likely to evidence positive clinical outcomes as well as long-term changes in life outlook and the personality trait openness.

Clinical efficacy and long-term effects

Mescaline-assisted therapies showed promising results during first-wave psychedelic science, and this trend continued through second-wave psychedelic research on LSD-assisted therapies. Recent studies have produced significant evidence for the therapeutic utility of psychedelic drugs in treating a wide range of mental health issues, including anxiety and depression, obsessive-compulsive disorder, and addiction to alcohol and tobacco. In many clinical studies, ego-dissolution experience has correlated with positive clinical outcomes.

Remarkably, as mentioned above, a single psychedelic experience can increase optimism for at least 2 weeks after the session and can produce lasting changes in personality trait openness. A study of regular (weekly) ayahuasca users showed improved cognitive functioning and increased positive personality traits compared with matched controls. Interestingly, these outcomes may expand beyond sanctioned clinical use, as illicit users of classic psychedelic drugs within the general population self-report positive long-term benefits from their psychedelic experiences, are statistically less likely to evidence psychological distress and suicidality, and show an overall lower occurrence of mental health problems in general.

Summary

The above evidence demonstrates the broad diversity of acute subjective effects that classic psychedelic drugs can produce in perceptual, emotional, and cognitive domains. Unique changes in sense of self, ego, body image, and personal meaning are particularly salient themes. How do these molecules produce such dramatic effects? What are the relationships between acute perceptual, emotional, cognitive, and self-related effects? What is the link between acute effects and long-term changes in mental health, personality, and behavior? Theories addressing these questions emerged as soon as Western science recognized the need for a scientific understanding of psychedelic drug effects beginning in the late 19th century.

19th and 20th century theories of psychedelic drug effects

The effects described above are what captured the interest of first-wave and second-wave psychedelic scientists, and the theories they developed in their investigations have two central themes. The first theme is the observation that psychedelic effects share descriptive elements with symptoms of psychoses, such as hallucination, altered self-reference, and perceptual distortions. This theme forms the basis of model psychoses theory and is what motivated the adoption of the term psychotomimetic drugs. The second theme is the observation that psychedelic drugs seem to expand the total range of contents presented subjectively in our perceptual, emotional, cognitive, and self-referential experience. This theme forms the basis of filtration theory and is what motivated the adoption of the term psychedelic drugs. A third theoretical account uses psychoanalytic theory to address the expanded range of mental phenomena produced by psychedelic drugs as well as the shared descriptive elements with symptoms of psychoses. The next section reviews these themes along with their historically associated theories before tracing their evolution into third-wave (21st-century) psychedelic science.

Model psychoses theory

When Lewin discovered the peyote cactus, his reports caught the attention of adventurous 19th-century scientists like Prentiss and Morgan, Mitchell, and Ellis, who promptly obtained samples and began consuming the cactus and observing its effects on themselves. When Heffter isolated mescaline from the peyote cactus and Spaeth paved the way for laboratory synthesis, scientists began systematically dosing themselves with mescaline and publishing their findings in medical journals. Kluever, intrigued by the approach of Knauer and Maloney, ingested peyote at the University of Minnesota Psychological Laboratory and, after the effects had taken hold, completed standard psychophysical measures. Kluever argued that systematic investigations into the neural mechanisms of mescaline effects would help neurology "elucidate more general questions of the psychology and pathology of perception." However, it was the pathology aspect, not the general psychology questions, which became the dominant focus of ensuing mescaline research paradigms.

Model psychoses theory began long before any of the classic psychedelic drugs became known to Western science. Moreau (1845) linked hashish effects with mental illness, and Kraepelin founded pharmacopsychology by dosing himself and his students with various psychoactive drugs in the laboratory of Wilhelm Wundt. These scientists hoped to study psychotic symptoms using drugs to induce model psychoses (1) in themselves, to gain first-person knowledge of the phenomenology of psychotic symptoms by "administering to one another such substances as will produce in us transitory psychoses," and (2) in normal research subjects, allowing for laboratory behavioral observations on how the symptoms emerge and dissipate. Kraepelin and colleagues attempted to model psychoses using many drugs, e.g. "tea, alcohol, morphine, trional, bromide, and other drugs," yet Kraepelins pupils Knauer and Maloney argued that these drugs unfortunately produce mental states which have little similarities to actual insanities and argued instead that mescaline was unique in its ability to truly model psychoses. The dramatic subjective effects of mescaline invigorated the model psychoses paradigm. Growing demand for the ideal chemical agent for model psychoses eventually motivated Sandoz Pharmaceuticals to bring LSD to market in the 1940s.

Importantly, model psychoses theory was not initially a theory of drug effects; it was an idealistic paradigm for researching psychoses that was already in use before Western science discovered classic psychedelic drugs. Nonetheless, it seeded the idea that psychedelic effects themselves could be explained in terms of psychopathology and motivated a search for common neural correlates. The founding figures of neuropharmacology were driven by questions regarding the relationship between psychoactive drugs and endogenous neurochemicals. The putative psychoses-mimicking effects of LSD and mescaline inspired the idea that psychotic symptoms might be caused by a hypothetical endotoxin or some yet-unknown endogenous neurochemical gone out of balance. The discovery that LSD can antagonize serotonin led to the hypothesis that the effects of LSD are serotonergic and simultaneously to the historic hypothesis6 that serotonin might play a role in regulating mental function.

At the 1955 Second Conference on Neuropharmacology, the whole class of drugs was dubbed psychotomimetic. Interestingly, the word mimetic means to imitate, mimic, or exhibit mimicry, which is the act of appearing as something else, for example, when one species mimics the appearance or behavior of another. Psychotomimetic drug effects, on this literal reading of the term, would merely mimic or imitate, appear as if they are, psychoses. However, to mimic is not to model. A model intends to capture important structural or functional principles of the entity or phenomena that it models. A mimic, by contrast, merely creates the illusion that it possesses the properties it mimics. Thus, the term psychotomimetic implies that the effects of these drugs merely resemble psychoses but do not share functional or structural properties in their underlying biology or phenomenology. Nonetheless, LSD and mescaline were used as models to investigate psychotic symptoms. Yet the scientific utility of drug models hinges on our understanding of the mechanisms underpinning the drugs effects; we still need a theory of how psychotomimetic drugs work. A subtle explanation, explananda circularity can come into play here, in which psychoses are explained using drug models yet the drug effects are explained using theories of psychoses. Further complicating the matter is the clear difference between acutely induced drug effects and the gradual development of a chronic mental illness. This cluster of conceptual challenges poured fuel on the flaming debates about the merits of drug-induced model psychoses, which in 1957 had already "smoldered for nearly 50 years." An additional conceptual challenge was the fact that mescaline had for years shown promise in treating psychopathologies, and LSD was gaining popularity for pharmaceutically enhanced psychotherapy. Model psychoses theory needed to explain how it was the case that drugs putatively capable of inducing psychotic symptoms could simultaneously be capable of treating them, what Osmond termed, the hair of the dog problem. In fact, to this day, "the apparent paradox by which the same compound can be both a model of, and yet a treatment for, psychopathology has never been properly addressed." Taken together, the above cluster of conceptual challenges drove Osmond to doubt his own prior work on model psychoses, and he declared psychotomimetic an outmoded term, arguing that the effects of these drugs could not be captured wholly in terms of psychopathology. "If mimicking mental illness were the main characteristic of these agents, psychotomimetics would indeed be a suitable generic term. It is true that they do so, but they do much more."

Filtration theory

Osmond argued that the psychotomimetic class of drugs needed a more appropriate name. "My choice, because it is clear, euphonious, and uncontaminated by other associations, is psychedelic, mind-manifesting." But how exactly should we understand psychedelic effects as mind-manifesting? Osmond's nomenclature legacy was directly influenced by his friend Aldous Huxley, who described the core idea to Osmond in the following personal letter dated April 10, 1953:

"Dear Dr. Osmond,

It looks as though the most satisfactory working hypothesis about the human mind must follow, to some extent, the Bergsonian model, in which the brain with its associated normal self, acts as a utilitarian device for limiting, and making selections from, the enormous possible world of consciousness, and for canalizing experience into biologically profitable channels. Disease, mescaline, emotional shock, aesthetic experience and mystical enlightenment have the power, each in its different way and in varying degrees, to inhibit the function of the normal self and its ordinary brain activity, thus permitting the other world to rise into consciousness.

Yours sincerely,

Aldous Huxley"


Huxleys letter can help unpack the intended mind-manifesting etymology of Osmond's new term psychedelic. Huxley saw the biological function of the brain as a device engaged in a continuous process of elimination and inhibition to sustain the normal self of everyday waking experience to maximize adaptive fit. Huxley's choice metaphor for visualizing this was the cerebral reducing valve.

"What I have called the cerebral reducing valve is a normal brain function that limits our mental processes to an awareness, most of the time, of what is biologically useful. Huxley argued that this normal brain function emerges developmentally during the course of psychological maturity, so for a period during childhood, before the cerebral reducing valve has fully developed, there is this capacity to live in a kind of visionary world. Once the valve is fully developed, however, normal waking life becomes restricted to a world fabricated by our everyday, biologically useful and socially conditioned perceptions, thoughts and feelings."

Huxley borrowed the core idea from 19th-century filtration theory accounts of various mental phenomena: According to filtration theorists, consciousness is ordinarily kept narrow by biological and psychological selection processes that exclude a great deal of subconscious material. Filtration theorists include founding figures of psychopharmacology, psychology, and parapsychology, along with early 20th-century philosophers Bergson. Bergson applied his own filtration framework to drug effects in his brief response to James, glowing descriptions of what it is like to inhale nitrous oxide. James peculiar state of mind, explained Bergson, should be thought of as a latent potential of the brain/mind, which nitrous oxide simply "brought about materially, by an inhibition of what inhibited it, by the removing of an obstacle; and this effect was the wholly negative one produced by the drug." Huxley picked up Bergsons line of thinking and eventually convinced Osmond that it was important to reflect this principle in scientific descriptions of the effects of LSD and mescaline. Smythies also subscribed to this idea, stating that "mescaline may be supposed to inhibit that function in the brain which specifically inhibits the mescaline phenomena from developing in the sensory fields."

Thus, Osmonds proposed name-change, psychedelic, was intended to capture the spirit of filtration theory. In this new descriptive model, psyche (mind) delic (manifesting) drugs manifest the mind by inhibiting certain brain processes which normally maintain their own inhibitory constraints on our perceptions, emotions, thoughts, and sense of self. Osmond and Huxley both found this principle highly applicable to their own direct first-person knowledge of what it is like to experience the effects of mescaline and LSD, the expanded range of feelings, intensification of perceptual stimuli, vivid vision-like mental imagery, unusual thoughts, and expanding (or dissolving) sense of self and identity.

Osmond argued that his "mind-manifesting" description had further theoretical virtues that could address the conceptual challenges of model psychoses theory and improve our understanding of (1) the diverse range of psychedelic effects, (2) their relationship to psychotic symptoms, and (3) their role in psychedelic-assisted therapies. First, the pharmacological disruption of hypothetical inhibitory brain mechanisms that normally attenuate internal and external stimuli suggested that the kinds of effects produced by the drug would depend on the kinds of stimuli in the system, which is consistent with the diverse range of effects on multiple perceptual modalities, emotional experience, and cognition.

Second, the brains selective filtration mechanisms, while evolutionarily adaptive and biologically useful, could develop pathological characteristics in two fundamentally distinct ways. First, a chronically overactive filter limits too much of the mind, causing a rigid, dull, neurotic life in which mental contents become overly restricted to those enumerated in the Sears-Roebuck catalog which constitutes the conventionally real world. Second, a chronically underactive or leaky filter places too few constraints on the mind and allows too much Mind at Large to enter conscious awareness, potentially resulting in perceptual instability, cognitive confusion, or hallucination. This picture helped Huxley and Osmond understand the relationship between psychedelic phenomena and psychotic phenomena: temporarily opening the cerebral reducing valve with psychedelics could produce mental phenomena that resembled symptoms of chronic natural psychoses precisely because both were the result of (acute or chronic) reductions in brain filtration mechanisms.

Third and finally, filtration theory addressed the paradoxical hair of the dog issue, e.g. why drugs that mimic psychoses can aid psychotherapy, which, as described in the previous section, was a conceptual challenge for model psychoses theory. The solution to the paradox was in the filtration theory idea that psychedelic drugs temporarily disable brain filtration mechanisms, which could allow patients and therapists to work outside of the patients everyday (pathological) inhibitory mechanisms. Thus, filtration theory offered a way to understand psychedelic effects that was consistent with both their psychotomimetic properties and their therapeutic utility.

Osmond and Huxley argued that filtration theory concepts were fully consistent with the subjective phenomenology, psychotomimetic capability, and therapeutic efficacy of psychedelic drugs. However, it remains unclear exactly what it is that the brain is filtering and consequently what it is that emerges when the filter is pharmacologically perturbed by a psychedelic drug. According to Huxley, LSD and mescaline inhibit the function of the normal self and its ordinary brain activity, thus permitting the other world to rise into consciousness. Huxley spoke of the brain as a device that filters the world and when the filter is removed we experience more of reality. Osmonds mind-manifesting (psyche) (delic) name, by contrast, suggests that these drugs permit latent aspects of mind to rise into conscious awareness. So which is it? Do psychedelic drugs manifest latent aspects of mind or of world? How we answer this question will crucially determine our ontological and epistemological conclusions regarding the nature of psychedelic experience. Huxley and Osmond did not make this clear. Huxley seems to favor the position that psychedelic experience reveals a wider ontological reality and grants epistemic access to greater truth. Osmonds view, on which these drugs reveal normally hidden aspects of mind, seems less radical, more compatible with materialist science, and less epistemically and ontologically committed. Still, if mind provides us with access to world, then lifting restrictions on mind could in principle expand our access to world. This important point resurfaces in section Predictive Processing below.

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Psychoanalytic theory

Freud developed an elaborate theoretical account of mental phenomena which, like filtration theory, placed great emphasis on inhibition mechanisms in the nervous system. Freud divided the psyche into two fundamentally distinct modes of activity: the primary process and the secondary process. In the primary process, the exchange of neuronal energy is freely mobile and its psychological dynamics are characterized by disorder, vagueness, conceptual paradox, symbolic imagery, intense emotions, and animistic thinking. In the secondary process, by contrast, the exchange of neuronal energy is bound and its psychological dynamics are characterized by order, precision, conceptual consistency, controlled emotions, and rational thinking. Freud hypothesized that the secondary process is maintained by an organizing neural mass called the ego which contains and exerts control over the primary process by binding primary process activity into its own pattern of activity. Freud hypothesized that secondary process neural organization, sustained by the ego, is required for certain aspects of perceptual processing, directed attention, reality-testing, sense of linear time, and higher cognitive processes. When Freuds ego is suppressed, such as during dream sleep, wider worlds of experience can emerge, but secondary process functions are lost. The secondary process and its supporting neural organizing pattern, the ego, emerges during ontogenetic development and solidifies with adult maturity: A unity comparable to the ego cannot exist from the start; the ego has to be developed. Furthermore, pathological characteristics can emerge when Freuds ego restricts either too much or too little of the primary process.

Freud himself was apparently uninterested in psychedelic drugs and instead emphasized dreams as the royal road to a knowledge of the unconscious activities of the mind. Nonetheless, psychedelic drugs produce dreamlike visions and modes of cognition that feature symbolic imagery, conceptual paradox, and other hallmark characteristics of the primary process. How did other psychoanalytic theorists describe psychedelic drug effects? The core idea is that psychedelic drugs interfere with the structural integrity of the ego and thereby reduce its ability to suppress the primary process and support the secondary process. This frees the primary process which then spills into conscious awareness, resulting in perceptual instability, wildly vivid imagination, emotional intensity, conceptual paradox, and loss of usual self-boundaries. Due in part to the close resemblance between psychedelic effects and primary process phenomena, psychoanalytic theory became the framework of choice during the mid 20th-century boom in psychedelic therapy. Psychedelic ego effects, which range from a subtle loosening to a complete dissolution of ego boundaries, were found to be great tools in psychotherapy because of their capacity to perturb ego and allow primary process phenomena to emerge.

But how do psychedelic drugs disrupt the structure of the ego? Freud hypothesized that the organizational structure of ego rests upon a basic perceptual schematic of the body and its surrounding environment. Perceptual signals are continuously bound and integrated into the somatic boundaries of the ego. Savage speculated that the LSDs perceptual effects and ego effects are tightly linked. LSD acts by altering perception. Continuous correct perception is necessary to maintain ego feeling and ego boundaries. Perception determines our ego boundaries. Disturbances in perception caused by LSD make it impossible for the ego to integrate the evidence of the senses and to coordinate its activities... Klee expanded Savages insights into a set of hypotheses aimed at elucidating the neurobiological mechanisms of a Freudian stimulus barrier and its dissolution under LSD:

"Such barriers would presumably consist of processes limiting the spread of excitation between different functional areas of the brain. The indications are that LSD, in some manner, breaks down these stimulus barriers of which Freud spoke. Nor is this merely a figure of speech. There is some reason to suspect that integrative mechanisms within the central nervous system (CNS) which handle inflowing stimuli are no longer able to limit the spread of excitation in the usual ways. We might speculate that LSD allows greater energy exchanges between certain systems than normally occurs, without necessarily raising the general level of excitation of all cortical and subcortical structures."

Freud hypothesized that ego is sustained by a delicate balance of neuronal energy which critically depends on integrative mechanisms to process inflowing sensory stimuli and to bind neural excitation into functional structures within the brain. Psychedelic drugs, according to Savage and Klee, perturb integrative mechanisms that normally bind and shape endogenous and exogenous excitation into the structure of the ego. As we will see below, Klee?s ideas strongly anticipate many neurophysiological findings and theoretical themes from 21st-century psychedelic science.

Summary

From the above analysis of first-wave and second-wave theories I have identified four recurring theoretical features which could potentially serve as unifying principles. One feature is the hypothesis that psychedelic drugs inhibit a core brain mechanism that normally functions to "reduce or filter or constrain" mental phenomena into an evolutionarily adaptive container. A second feature is the hypothesis that this core brain mechanism can behave pathologically, either in the direction of too much, or too little, constraint imposed on perception, emotion, cognition, and sense of self. A third feature is the hypothesis that psychedelic phenomena and symptoms of chronic psychoses share descriptive elements because they both involve situations of relatively unconstrained mental processes. A fourth feature is the hypothesis that psychedelic drugs have therapeutic utility via their ability to temporarily inhibit these inhibitory brain mechanisms. But how are these inhibitory mechanisms realized in the brain?

Neuropharmacology and neurophysiological correlates of psychedelic drug effects

Klee recognized that his above hypotheses, inspired by psychoanalytic theory and LSD effects, required neurophysiological evidence. "As far as I am aware, however, adequate neurophysiological evidence is lacking. The long awaited millennium in which biochemical, physiological, and psychological processes can be freely correlated still seems a great distance off." What clues have recent investigations uncovered?

A psychedelic drug molecule impacts a neuron by binding to and altering the conformation of receptors on the surface of the neuron. The receptor interaction most implicated in producing classic psychedelic drug effects is agonist or partial agonist activity at serotonin (5-HT) receptor type 2A (5-HT2A). A molecules propensity for 5-HT2A affinity and agonist activity predicts its potential for (and potency of) subjective psychedelic effects. When a psychedelic drugs 5-HT2A agonist activity is intentionally blocked using 5-HT2A antagonist drugs, e.g. ketanserin, the subjective effects are blocked or attenuated in humans under psilocybin, LSD, and ayahuasca. Importantly, while the above evidence makes it clear that 5-HT2A activation is a necessary mediator of the hallmark subjective effects of classic psychedelic drugs, this does not entail that 5-HT2A activation is the sole neurochemical cause of all subjective effects. For example, 5-HT2A activation might trigger neurochemical modulations downstream, e.g. changes in glutamate transmission, which could also play causal roles in producing psychedelic effects. Moreover, most psychedelic drug molecules activate other receptors in addition to 5-HT2A, and these activations may importantly contribute to the overall profile of subjective effects even if 5-HT2A activation is required for their effects to occur.

How does psychedelic drug-induced 5-HT2A receptor agonism change the behavior of the host neuron? Generally, 5-HT2A activation has a depolarizing effect on the neuron, making it more excitable (more likely to fire). Importantly, this does not necessarily entail that 5-HT2A activation will have an overall excitatory effect throughout the brain, particularly if the excitation occurs in inhibitory neurons. This important consideration (captured by the adage one neurons excitation is another neurons inhibition) should be kept in mind when tracing causal links in the pharmaco-neurophysiology of psychedelic drug effects.

In mammalian brains, neurons tend to fire together in synchronized rhythms known as temporal oscillations (brain waves). MEG and EEG equipment measure the electromagnetic disturbances produced by the temporal oscillations of large neural populations and these measurements can be quantified according to their amplitude (power) and frequency (timing). Specific combinations of frequency and amplitude can be correlated with distinct brain states, including waking resting state, various attentional tasks, anesthesia, REM sleep, and deep sleep. In what ways do temporal oscillations change under psychedelic drugs? MEG and EEG studies consistently show reductions in oscillatory power across a broad frequency range under ayahuasca, psilocybin, and LSD. Reductions in the power of alpha-band oscillations, localized mainly to parietal and occipital cortex, have been correlated with intensity of subjective visual effects, e.g. "I saw geometric patterns, or, My imagination was extremely vivid," under psilocybin and ayahuasca. Under LSD, reductions in alpha power still correlated with intensity of subjective visual effects but associated alpha reductions were more widely distributed throughout the brain. Furthermore, ego-dissolution effects and mystical-type experiences, e.g. "I experienced a disintegration of my self, or ego, or, The experience had a supernatural quality," have been correlated with reductions in alpha power localized to anterior and posterior cingulate cortices and the parahippocampal regions under psilocybin and throughout the brain under LSD.

The concept of functional connectivity rests upon fMRI brain imaging observations that reveal temporal correlations of activity occurring in spatially remote regions of the brain which form highly structured patterns (brain networks). Imaging of brains during perceptual or cognitive task performance reveals patterns of functional connectivity known as functional networks, e.g. control network, dorsal attention network, ventral attention network, visual network, auditory network, and so on. Imaging brains in taskless resting conditions reveals resting-state functional connectivity (RSFC) and structured patterns of RSFC known as resting state networks. One particular RSN, the default mode network, increases activity in the absence of tasks and decreases activity during task performance. DMN activity is strong during internally directed cognition and a variety of other metacognitive functions. DMN activation in normal waking states exhibits inverse coupling or anticorrelation with the activation of task-positive functional networks, meaning that DMN and functional networks are often mutually exclusive; one deactivates as the other activates and vice versa.

In what ways does brain network connectivity change under psychedelic drugs? First, functional connectivity between key hub areas, mPFC and PCC, is reduced. Second, the strength or oscillatory power of the DMN is weakened and its intrinsic functional connectivity becomes disintegrated as its component nodes become decoupled under psilocybin, ayahuasca, and LSD. Third, brain networks that normally show anticorrelation become active simultaneously under psychedelic drugs. This situation, which can be described as increased between-network functional connectivity, occurs under psilocybin, ayahuasca and especially LSD. Fourth and finally, the overall repertoire of explored functional connectivity motifs is substantially expanded and its informational dynamics become more diverse and entropic compared with normal waking states. Notably, the magnitude of occurrence of the above four neurodynamical themes correlates with subjective intensity of psychedelic effects during the drug session. Furthermore, visual cortex is activated during eyes-closed psychedelic visual imagery and under LSD, the early visual system behaves as if it were receiving spatially localized visual information, as V1-V3 RSFC is activated in a retinotopic fashion.

Taken together, the recently discovered neurophysiological correlates of subjective psychedelic effects present an important puzzle for 21st-century neuroscience. A key clue is that 5-HT2A receptor agonism leads to desynchronization of oscillatory activity, disintegration of intrinsic integrity in the DMN and related brain networks, and an overall brain dynamic characterized by increased between-network global functional connectivity, expanded signal diversity, and a larger repertoire of structured neurophysiological activation patterns. Crucially, these characteristic traits of psychedelic brain activity have been correlated with the phenomenological dynamics and intensity of subjective psychedelic effects.

21st-century theories of psychedelic drug effects

How should we understand the growing body of clues emerging from investigations into the neurodynamics of psychedelic effects? What are the principles that link these thematic patterns of psychedelic brain activity (or inactivity) to their associated phenomenological effects? Recent theoretical efforts to understand psychedelic drug effects have taken advantage of existing frameworks from cognitive neuroscience designed to track the key neurodynamic principles of human perception, emotion, cognition, and consciousness. The overall picture that emerges from these efforts shares core principles with filtration and psychoanalytic accounts of the late 19th and early 20th century. Briefly, normal waking perception and cognition are hypothesized to rest upon brain mechanisms which serve to suppress entropy and uncertainty by placing various constraints on perceptual and cognitive systems. In a selecting and limiting fashion, neurobiological constraint mechanisms support stability and predictability in the contents of conscious awareness in the interest of adaptability, survival, and evolutionary fitness. The core hypothesis of recent cognitive neuroscience theories of psychedelic effects is that these drugs interfere with the integrity of neurobiological information-processing constraint mechanisms. The net effect of this is that the range of possibilities in perception, emotion, and cognition is dose-dependently expanded. From this core hypothesis, cognitive neuroscience frameworks are utilized to describe and operationalize the quantitative neurodynamics of key psychedelic phenomena; namely, the diversity of effects across many mental processes, the elements in common with symptoms of psychoses, and the way in which temporarily removing neurobiological
constraints is therapeutically beneficial.

This section is organized according to the broad theoretical frameworks informing recent theoretical neuroscience of psychedelic effects: entropic brain theory, integrated information theory, and predictive processing.

Entropic brain theory

Entropic Brain Theory links the phenomenology and neurophysiology of psychedelic effects by characterizing both in terms of the quantitative notions of entropy and uncertainty. Entropy is a quantitative index of a systems (physical) disorder or randomness which can simultaneously describe its (informational) uncertainty. EBT proposes that "the quality of any conscious state depends on the systems entropy measured via key parameters of brain function." Their hypothesis states that hallmark psychedelic effects, e.g. perceptual destabilization, cognitive flexibility, ego dissolution) can be mapped directly onto elevated levels of entropy/uncertainty measured in brain activity, e.g. widened repertoire of functional connectivity patterns, reduced anticorrelation of brain networks, and desynchronization of RSN activity. More specifically, EBT characterizes the difference between psychedelic states and normal waking states in terms of how the underlying brain dynamics are positioned on a scale between the two extremes of order and disorder, a concept known as self-organized criticality. A system with high order (low entropy) exhibits dynamics that resemble petrification and are relatively inflexible but more stable, while a system with low order (high entropy) exhibits dynamics that resemble formlessness and are more flexible but less stable. The notion of criticality describes the transition zone in which the brain remains poised between order and disorder. Physical systems at criticality exhibit increased transient metastable states, increased sensitivity to perturbation, and increased propensity for cascading avalanches of metastable activity. Importantly, EBT points out that these characteristics are consistent with psychedelic phenomenology, e.g. hypersensitivity to external stimuli, broadened range of experiences, or rapidly shifting perceptual and mental contents. Furthermore, EBT uses the notion of criticality to characterize the difference between psychedelic states and normal waking states as it describes cognition in adult modern humans as near critical but sub-critical, meaning that its dynamics are poised in a position between the two extremes of formlessness and petrification where there is an optimal balance between order and flexibility. EBT hypothesizes that "psychedelic drugs interfere with entropy-suppression brain mechanisms which normally sustain sub-critical brain dynamics, thus bringing the brain, closer to criticality in the psychedelic state."

Entropic Brain Theory further characterizes psychedelic neurodynamics using a neo-psychoanalytic framework proposed in an earlier paper by Carhart-Harris and Friston where they recast some central Freudian ideas in a mechanistic and biologically informed fashion. Freuds primary process (renamed primary consciousness) is hypothesized to be a high-entropy brain dynamic which operates at criticality, while Freud's secondary process (renamed secondary consciousness) is hypothesized to involve a lower-entropy brain state which sustains a sub-critical dynamic via a key neurobiological entropy-suppression mechanism, the ego, which exerts an organizing influence in order to constrain the criticality-like dynamic of primary consciousness. EBT argues that these ego functions have a signature neural footprint; namely, the DMNs intrinsic functional connectivity and DMN coupling of medial temporal lobes (MTLs) in particular. Furthermore, EBT argues that DMN/ego develops ontogenetically in adult humans and plays an adaptive role in which it sustains secondary consciousness and associated metacognitive abilities along with an integrated sense of self.

Importantly, this hypothesis maps onto the subjective phenomenology of psychedelic effects, particularly ego dissolution. As psychedelics weaken the oscillatory power and intrinsic functional connectivity of the DMN, the normally constrained activity of subordinate DMN nodes, MTLs in particular, becomes freely mobile, allowing the emergence of more uncertain (higher entropy) primary consciousness. This view, based on Freudian metapsychology, is also consistent with filtration accounts, like those of Bergson and Huxley, who hypothesized that psychedelic drug effects are the result of a pharmacological inhibition of inhibitory brain mechanisms. EBT recasts these theoretical features using the quantitative terms of physical entropy and informational uncertainty as measured via the repertoire of functional connectivity motifs that form and fragment across time. In normal waking states, the DMN constrains the activity of its cortical and subcortical nodes and prohibits simultaneous co-activation with TPNs. By interfering with DMN integration, psychedelics permit a larger repertoire of brain activity, a wider variety of explored functional connectivity motifs, co-activation of normally mutually exclusive brain networks, increased levels of between-network functional connectivity, and an overall more diverse set of neural interactions.

Carhart-Harris et al. point out a number of implications of EBT. First, they map the feelings of uncertainty that often accompany psychedelic effects onto the fact that a more entropic brain dynamic is the information-theoretic equivalent to a more uncertain brain dynamic. Thus, according to the entropic brain hypothesis, just as normally robust principles about the brain lose definition in primary states, so confidence is lost in how the world is and who one is as a personality.

Second, like Huxleys cerebral reducing valve and Freuds ego, EBT argues that the DMNs organizational stronghold over brain activity can be both an evolutionary advantage and a source of pathology. It is argued that this entropy-suppressing function of the human brain serves to promote realism, foresight, careful reflection and an ability to recognize and overcome wishful and paranoid fantasies. Equally however, it could be seen as exerting a limiting or narrowing influence on consciousness. Carhart-Harris et al. point out that neuroimaging studies have implicated increased DMN activity and RSFC with various aspects of depressive rumination, trait neuroticism, and depression. The suggestion is that increased DMN activity and connectivity in mild depression promotes concerted introspection and an especially diligent style of reality-testing. However, what may be gained in mild depression (i.e., accurate reality testing) may be offset by a reciprocal decrease in flexible or divergent thinking (and positive mood).

Third, consistent with both psychoanalytic and filtration theory, is the notion that psychedelic drugs capacity to temporarily weaken, collapse, or disintegrate the normal ego/DMN stronghold underpins their therapeutic utility. Specifically, it is proposed that psychedelics work by dismantling reinforced patterns of negative thought and behavior by breaking down the stable spatiotemporal patterns of brain activity upon which they rest.

Fourth and finally, EBT sheds light on the shared descriptive elements between psychedelic effects and psychotic symptoms by characterizing both in terms of elevated levels of entropy and uncertainty in brain activity which lead to a regression into primary consciousness. The collapse of the organizing effect of DMN coupling and anticorrelation patterns, according to EBT, point to system-level mechanics of the psychedelic state as an exemplar of a regressive style of cognition that can also be observed in REM sleep and early psychosis.

Thus, EBT formulates all four of the theoretical features identified in filtration and psychoanalytic accounts, but does so using 21st-century empirical data plugged into the quantitative concepts of entropy, uncertainty, criticality, and functional connectivity. EBT hints at possible ways to close the gaps in understanding by offering quantitative concepts that link phenomenology to brain activity and pathogenesis to therapeutic mechanisms.

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Integrated information theory

Integrated Information Theory (IIT) is a general theoretical framework which describes the relationship between consciousness and its physical substrates. While EBT is already loosely consistent with the core principles of IIT, Gallimore demonstrates how EBTs hypotheses can be operationalized using the technical concepts of the IIT framework. Using EBT and recent neuroimaging data as a foundation, Gallimore develops an IIT-based model of psychedelic effects. Consistent with EBT, this IIT-based model describes the brains continual challenge of minimizing entropy while retaining flexibility. Gallimore formally restates this problem using IIT parameters: brains attempt to optimize the give-and-take dynamic between cause-effect information and cognitive flexibility. In IIT, a (neural) system generates cause-effect information when the mechanisms which make up its current state constrain the set of states which could casually precede or follow the current state. In other words, each mechanistic state of the brain: (1) limits the set of past states which could have causally given rise to it, and (2) limits the set of future states which can causally follow from it. Thus, each current state of the mechanisms within a neural system (or subsystem) has an associated cause-effect repertoire which specifies a certain amount of cause-effect information as a function of how stringently it constrains the unconstrained state repertoire of all possible system states. Increasing the entropy within a cause-effect repertoire will in effect constrain the system less stringently as the causal possibilities are expanded in both temporal directions as the system moves closer to its unconstrained repertoire of all possible states. Moreover, increasing the entropy within a cause-effect repertoire equivalently increases the uncertainty associated with its past (and future) causal interactions. Using this IIT-based framework, Gallimore argues that, compared with normal waking states, psychedelic brain states exhibit higher entropy, higher cognitive flexibility, but lower cause-effect information.

Neuroimaging data suggests that human brains exhibit a larger overall repertoire of neurophysiological states under psychedelic drugs, exploring a greater diversity of states in a more random fashion. For example, in normal waking states, DMN activity rules out the activity of TPNs, and vice versa, due to their relatively strict anticorrelation patterns. Brain network anticorrelation generates cause-effect information because it places constraints on the possible causal interactions within and between brain mechanisms; for example, DMN-TPN anticorrelation patterns rule out the DMN activity in the presence of activated TPNs. However, psychedelic drugs dissolve DMN-TPN (and other) network anticorrelation patterns, which permits simultaneous activation of brain networks which are normally mutually exclusive. The cause-effect repertoire of brain mechanisms thus shifts closer to the unconstrained repertoire of all possible past and future states. This has the effect of increasing the probability of certain states from zero or, at least, from a very low probability. Therefore the subjective contents perception and cognition become more diverse, more unusual, and less predictable. This increases flexibility but decreases precision and control as the subjective boundaries which normally demarcate distinct cognitive concepts and perceptual objects dissolve. Gallimore leverages IIT in an attempt unify these phenomena under a formalized framework.

However, as Gallimore notes, "this model does not explain how neural entropy is increased by (psychedelic drugs), but predicts consequences of the entropy increase revealed by functional imaging data." How do psychedelic drugs increase neural entropy?

Predictive processing

The first modern brain imaging measurements in humans under psilocybin yielded somewhat unexpected results: reductions in oscillatory power (MEG) and cerebral blood flow (fMRI) correlated with the intensity of subjective psychedelic effects. In their discussion, the authors suggest that their findings, although surprising through the lens of commonly held beliefs about how brain activity maps to subjective phenomenology, may actually be consistent with a theory of brain function known as the free energy principle.

In one model of global brain function based on the free-energy principle, activity in deep-layer projection neurons encodes top-down inferences about the world. Speculatively, if deep-layer pyramidal cells were to become hyperexcitable during the psychedelic state, information processing would be biased in the direction of inference, such that implicit models of the world become spontaneously manifest, intruding into consciousness without prior invitation from sensory data. This could explain many of the subjective effects of psychedelics.

What is FEP? In this view, the brain is an inference machine that actively predicts and explains its sensations. Central to this hypothesis is a probabilistic model that can generate predictions, against which sensory samples are tested to update beliefs about their causes. FEP is a formulation of a broader conceptual framework emerging in cognitive neuroscience known as predictive processing. PP has links to bayesian brain hypothesis, predictive coding, and earlier theories of perception and cognition dating back to Helmholtz, who was inspired by Kant. At the turn of the 21st century, the ideas of Helmholtz catalyzed innovations in machine learning, new understandings of cortical organization, and theories of how perception works.

PP subsumes key elements from these efforts to describe a universal principle of brain function captured by the idea of prediction error minimization. What does it mean to say that the brain works to minimize its own prediction error? Higher-level areas of the nervous system (i.e., higher-order cortical structures) generate top-down synaptic predictions aimed at matching the expected bottom-up synaptic activity at lower-level areas, all the way down to input activity at sense organs. Top-down signals encode a kind of best guess about the most likely (hidden) causes of bodily sensations. In this multi-level hierarchical cascade of neural activity, high-level areas attempt to explain the states of levels below via synaptic attempts to inhibit lower-level activity, high-level areas tell lower levels to shut up. But lower levels will not shut up until they receive top-down feedback (inference) signals that adequately fit (explain) the bottom-up (evidence) signals. Mismatches between synaptic expectation and synaptic evidence generate prediction error signals which carry the news by propagating the surprise upward to be explained away by yet higher levels of hierarchical cortical processing anatomy. This recurrent neural processing scheme approximates (empirical) Bayesian inference as the brain continually maps measured bodily effects to different sets of possible causes and attempts to select the set of possible causes that can best explain away the measured bodily effects.

Crucially, the sets of possible causes must be narrowed in order for the system to settle on an explanation). Prior constraints which allow the system to narrow the hypothesis space are known as inductive biases or priors. Efforts in Bayesian statistics and machine learning have demonstrated that improvements in inductive capabilities occur when priors are linked in a multi-level hierarchy, with not just a single level of hypotheses to explain the data, but multiple levels: hypothesis spaces of hypothesis spaces, with priors on priors. Certain priors in the hierarchy, known as hyperpriors or overhypotheses are more abstract and allow the system to rule out large swaths of possibilities, drastically narrowing the hypothesis space, making explanation more tractable. For example, the brute constraints of space and time act as hyperpriors, e.g. prior knowledge that there is only one object (one cause of sensory input) in one place, at a given scale, at a given moment, or the fact that we can only perform one action at a time, choosing the left turn or the right but never both at once.

Thus, PP states that brains are neural generative models built from linked hierarchies of priors where higher levels continuously attempt to guess and explain activity at lower levels. The entire process can be characterized as the agents attempt to optimize its own internal model of the sensorium (and the world) over multiple spatial and temporal scales. Interestingly, PP holds that our perceptions of external objects recruit the same synaptic pathways that enable our capacity for mental imagery, dreaming, and hallucination. The brains ability to simulate its own virtual reality using internal (generative) models of the worlds causal structure is thus crucial to its ability to perceive the external world. A fruitful way of looking at the human brain, therefore, is as a system which, even in ordinary waking states, constantly hallucinates at the world, as a system that constantly lets its internal autonomous simulational dynamics collide with the ongoing flow of sensory input, vigorously dreaming at the world and thereby generating the content of phenomenal experience.

How do psychedelic molecules perturb predictive processing? If normal perception is a kind of controlled hallucination where top-down simulation is constrained by bottom-up sensory input colliding with priors upon priors, then, as the above quotation from Muthukumaraswamy et al. suggests, psychedelic drugs essentially cause perception to be less controlled hallucination. The idea is that psychedelic drugs perturb the (learned and innate) prior constraints on internal generative models. Via their 5-HT2A agonism, psychedelic drugs cause hyperexcitation in layer V pyramidal neurons, which might cause endogenous simulations to run wild so that awareness becomes more imaginative, dreamlike, and hallucinatory. This hypothesis could in principle still be consistent with observed reductions in brain activity under psychedelics; recall from above that, in PP schemes, the higher-level areas explain away lower-level excitation by suppressing it with top-down inhibitory signals. Here, explaining away just means countering excitatory bottom-up inputs to a prediction error neuron with inhibitory synaptic inputs that are driven by top-down predictions.

How does PP tie into filtration theories and psychoanalytic accounts? Carhart-Harris et al. link Huxley with Friston to interpret their initially surprising fMRI scans of humans under psilocybin. One objection to this linkage might be that Huxley often describes psychedelic opening of the cerebral reducing valve as revealing more of the world. At first glance this seems at odds with the above PP account of psychedelic effects, which describes psychedelic drugs causing rampant internal simulations of reality, not revealing more of the external world. However, this apparent tension might be resolved in light of active inference, a key principle of FEP. Active inference shows how internal models do not merely generate top-down (inference) signals but also shape the sampling and accumulation of bottom-up sensory (evidence) signals. In short, the agent will selectively sample the sensory inputs that it expects. This is known as active inference. An intuitive example of this process (when it is raised into consciousness) would be feeling our way in darkness: we anticipate what we might touch next and then try to confirm those expectations. The principle of active inference hints at a resolution to the apparent tensions between Osmonds mind-manifesting model and Huxley's world-manifesting model. Psychedelics manifest mind by perturbing prior constraints on internal generative models, thereby expanding the possibilities in our inner world of feelings, thoughts, and mental imagery. Importantly, this could also manifest normally ignored aspects of world by altering active inference, which would in effect expand the sampling of sensory data to include samples that are normally routinely explained away. Potentially, this understanding goes some way in explaining the perception-hallucination continuum of psychedelic drug effects, as it shows how perceptual intensifications, on the one hand, and distortions and hallucinations, on the other hand, could both be caused by a synaptic disruption of hierarchically linked priors in internal generative models.

The brief speculative remark by Muthukumaraswamy et al. is not the only PP-based account of psychedelic drug effects. The PP framework describes a recurrent back-and-forth give-and-take between colliding top-down and bottom-up signals, where internal models serve to shape experience and experience serves to build internal models, so this leaves room for rival PP-based accounts that diverge regarding where exactly the psychedelic drug perturbs the system. For example, increased top-down activity could be the result of pharmacological hyperactivation of top-down synaptic transmission; yet equally plausible is the hypothesis that increased top-down activity is a compensatory response to pharmacological attenuations or distortions of bottom-up signal.

For example, Corlett et al. hypothesize that LSD hallucinations result from noisy, unpredictable bottom-up signaling in the context of preserved and perhaps enhanced top-down processing. In contrast to the PP-based account outlined above, which focuses on changes to top-down signals, the strategy of Corlett et al. is to map various psychedelic effects to disturbances of top-down and/or bottom-up signals. The issue of what is primary and what is compensatory illustrates the vast possibilities in the hypothesis space of PP-based accounts.

While most PP-based accounts point to changes in top-down signaling, even within this hypothesis space there are contrasting conceptions of exactly how psychedelic molecules perturb top-down processing. Briefly, these differing hypotheses include: (1) hyperactivation or heavier weighting of top-down signaling, (2) reduced influence of signals from higher cortical areas, (3) interference with multisensory integration processes and PP-based binding of sensory signals, and (4) changes in the composition and level of detail specified by top-down signals.

Carhart-Harris and Friston argue that the Freudian conception of ego, with its organizing influence over the primary process, is consistent with PP descriptions of higher-level cortical structures predicting and suppressing the excitation in lower levels in the hierarchy (i.e., limbic regions). Freud hypothesized that the secondary process binds, integrates, and organizes the lower and more chaotic neural activity of the primary process into the broader and more cohesive composite structure of the ego.

Carhart-Harris and Friston argue that when large-scale intrinsic networks become dis-integrated, the activity at lower levels can no longer be explained away (suppressed) by certain higher-level systems, causing conscious awareness to take on hallmark characteristics of the primary process. In normal adult waking states, networks based in higher-level areas can successfully predict and explain (suppress and control) the activity of lower level areas. "In non-ordinary states, this function may be perturbed, e.g. in the case of hallucinogenic drugs, through actions at modulatory post-synaptic receptors), compromising the hierarchical organization and suppressive capacity of the intrinsic networks."

Similar PP-based theories of psychedelic ego dissolution have been proposed without invoking Freud. PP posits that the brain explains self-generated stimuli by attributing its causes to a coherent and persisting entity (i.e., the self), much like how it predicts and explains external stimuli by attributing their causes to coherent and persisting external objects. Letheby and Gerrans use the PP framework to recast the psychoanalysis-based theories of LSD ego effects proposed by Savage and Klee described in Section Psychoanalytic Theory. The core idea is that psychedelic drugs interfere with processes that bind and integrate stimuli according to probabilistic estimates of how relevant the stimuli are to the organisms (self) goals. Letheby and Gerrans point out that ego dissolution under psychedelic drugs is correlated with the desynchronization (reductions in intrinsic functional connectivity) of brain networks implicated in one aspect or another of self-representation, specifically the salience network (SLN) and the DMN. This causes an unbinding of stimuli that are normally processed according to self-binding multisensory integration mechanisms. Attention is no longer guided exclusively by adaptive and egocentric goals and agendas; salience attribution is no longer bound to personal concern. This description echoes Huxley's cerebral reducing valve in which the brain with its associated normal self, acts as a utilitarian device for limiting, and making selections from, the enormous possible world of consciousness, and for canalizing experience into biologically profitable channels. Letheby and Gerrans PP-based account elucidates how psychedelic drugs could perturb the brains associated normal self preventing the usual self-binding of internal and external stimuli.

Pink-Hashkes et al. argue that under psychedelic drugs top-down predictions in affected brain areas break up and decompose into many more overly detailed predictions due to hyper activation of 5-HT2A receptors in layer V pyramidal neurons. Pink-Hashkes et al. state that when internal generative models are described as categorical probability distributions rather than Gaussian densities, the state space granularity (how detailed are the generative models and the predictions that follow from them) is crucial. Categorical predictions that are less detailed will explain more bottom-up data (because they cover more ground) and thus produce less prediction error. Categorical predictions that are more detailed, by contrast, will carry less precision and thus potentially generate more prediction error. Pink-Hashkes et al. propose that psychedelic drugs cause brain structures at certain levels of the cortical hierarchy to issue more detailed decomposed predictions that fit less data than the usual broad prediction. They argue that many psychedelic effects stem from the brains attempts to compensate for these decomposed top-down predictions as it responds to the increase in prediction errors that result from overly detailed predictions.

In summary, the current state of PP-based theories of psychedelic effects reveals a divergent mix of heterogeneous ideas and conflicting hypotheses. Do psychedelic molecules perturb top-down (feedback) signaling, or bottom-up (feedforward) signaling, or both? Do the subjective phenomenological effects result from direct neuropharmacological changes or compensatory mechanisms responding to pharmacological perturbations? Yet there seems to be a core intuition that transcends the conceptual variance here: psychedelic drugs somehow interfere with established priors that normally constrain the brain?s internal generative models.

Predictive processing-based accounts, consistent with EBT and IIT (and filtration and psychoanalytic accounts), propose that psychedelic drugs disrupt neural mechanisms (priors on internal generative models) which normally constrain perception and cognition. Perturbing priors causes subjective phenomenology to present a wider range of experiences with increased risk of perceptual instability and excessive cognitive flexibility. As prior constraints on self and world are loosened, the likelihood of psychosis-like phenomena increases. At the same time, novel thinking is increased and the brain becomes more malleable and conducive to therapeutic cognitive and behavioral change.

Conclusion

The four key features identified in filtration and psychoanalytic accounts from the late 19th and early 20th century continue to operate in 21st-century cognitive neuroscience:

(1) psychedelic drugs produce their characteristic diversity of effects because they perturb adaptive mechanisms which normally constrain perception, emotion, cognition, and self-reference,

(2) these adaptive mechanisms can develop pathologies rooted in either too much or too little constraint,

(3) psychedelic effects appear to share elements with psychotic symptoms because both involve weakened constraints, and

(4) psychedelic drugs are therapeutically useful precisely because they offer a way to temporarily inhibit these adaptive constraints.

It is on these four points that EBT, IIT, and PP seem consistent with each other and with earlier filtration and psychoanalytic accounts. EBT and IIT describe psychedelic brain dynamics and link them to phenomenological dynamics, while PP describes informational principles and plausible neural information exchanges which might underlie the larger-scale dynamics described by EBT and IIT. Certain descriptions of neural entropy-suppression mechanisms (EBT), cause-effect information constraints (IIT), or prediction-error minimization strategies (PP, FEP) are loosely consistent with Freud's ego, and Huxley's cerebral reducing valve.

In surveying the literature for this review I can confidently conclude that 21st-century psychedelic science has yet to approach a unifying theory linking the diverse range of phenomenological effects with pharmacology and neurophysiology while tying these to clinical efficacy. However, the historically necessary ingredients for successful theory unification, formalized frameworks and unifying principles, seem to be taking shape. Formal models are an integral part of 21st-century neuroscience where they help to describe natural principles in the brain and aid explanation and understanding. Here I have reviewed a handful of formalized frameworks, EBT, IIT, PP, which are just beginning to be used to account for psychedelic effects. I have also highlighted the fact that all of the accounts reviewed here, from the 19th-century to the 21st-century, propose that psychedelic drugs inhibit neurophysiological constraints in order to produce their diverse phenomenological, psychotomimetic, and therapeutic effects.

Why should we pursue a unified theory of psychedelic drug effects at all? To date, theories of brain function and mind in general have resisted the kind of unification that has occurred in other areas of science. Because the human brain has evolved disparate and complex layers under diverse environmental circumstances, many doubt the possibility of and debate the merits of seeking grand unified theories (GUTs) of brain function. "There is every reason to think that there can be no grand unified theory of brain function because there is every reason to think that an organ as complex as the brain functions according to diverse principles." Indeed, Anderson and Chemero caution that "we should be skeptical of any GUT of brain function, and charge that PP in particular, when taken as a unified theory as outlined by Clark, threatens metaphysical disaster."

Given these understandable critical reservations about seeking after GUTs of brain function (and therefore any truly unifying theory of psychedelic drug effects), it is perhaps safer to aspire for theories that feature broad explanatory frameworks and offer conceptual breadth allowing us to paint the big picture. PP and FEP, at the very least, offer a broad explanatory framework that emcompasses a large swath of perceptual and cognitive phenomena. Psychedelic drugs offer a unique way to iteratively develop and test such big-picture explanatory frameworks: these molecules can be used to probe the links between neurochemistry and neural computation across multiple layers of neuroanatomy and phenomenology. Meeting the challenge of predicting and explaining psychedelic drug effects is the ultimate acid test for any unified theory of brain function.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5853825/
 
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Ann and Alexander Shulgin

DMT, the endogenous psychedelic

Steven A. Barker

This report provides a historical overview of research concerning the endogenous psychedelic N, N-dimethyltryptamine (DMT), focusing on data regarding its biosynthesis and metabolism in the brain and peripheral tissues, methods and results for DMT detection in body fluids and brain, new sites of action for DMT, and new data regarding its possible physiological and therapeutic roles. Research that further elaborates its consideration as a putative neurotransmitter is also addressed. Taking these studies together, the report proposes several new directions and experiments to ascertain the role of DMT in the brain, including brain mapping of enzymes responsible for the biosynthesis of DMT, further studies to elaborate its presence and role in the pineal gland, a reconsideration of binding site data, and new administration and imaging studies. The need to resolve the “natural” role of an endogenous psychedelic from the effects observed from peripheral administration are also emphasized.

Introduction

Despite their presence in the human pharmacopeia for millennia, we have yet to resolve the biochemical mechanisms by which psychedelics so dramatically alter perception and consciousness. It is the only class of compounds that efficiently and specifically does so. For that matter, we do not fully understand the biochemistry of perception itself or how we live such a vivid and complex internal life in the absence of external stimulation. We do not understand the basic biochemical mechanisms of some of our most common experiences, such as the many human aspects of creativity, imagination or dream states. This is also true for extraordinary states of consciousness such as “visions” or spontaneous hallucinations or phenomena such as near-death experiences (NDE). And it is troubling that we have not sufficiently turned the scientific method on these latter subjects despite the profound role they have played in the evolution of our science, philosophy, psychology and culture.

The experiences derived from the administration of psychedelics are often compared to dream states. However, the experience of administered psychedelic substances is far more intense, robust and overwhelming than the subtlety of mere dreams. By comparison, the natural biochemical processes for our related psychedelic experiences are obviously far more highly regulated, occurring as an orchestrated and inherent function of the “normal” brain. Nonetheless, it is conceivable that attaining an explanation for these related natural human phenomena may lie in resolving the biochemical mechanisms involved in the more dramatic pharmacology of psychedelics, recognizing that the complexities and intensity of the “administered” experience are, essentially, an overdose relative to corresponding natural regulatory controls. Given their status, increased study of psychedelics, particularly with advanced brain imaging and molecular biology approaches, may provide a better understanding of the “common” biochemistry that creates mind.

Perhaps the science behind the discovery of endogenous opioids offers us a corollary. We came to better understand the common human experience of pain through examining the pharmacology of administered opiates and the subsequent discovery of endogenous opioid ligands, receptors and pathways that are predominantly responsible for and regulate the experience and perception of pain. Such may also be the case for understanding perception and consciousness. With the discovery of the endogenous DMT, perhaps, as with the endogenous opioids, we have a similar opportunity to understand perception and consciousness. Recent research has stimulated a renewed interest in further study of this compound as a neuro-regulatory substance and, thus, a potential neuro-pharmacological target. Taking results from these and more classical studies of DMT biochemistry and pharmacology together, this report examines some of the past and current data in the field and proposes several new directions and experiments to ascertain the role of endogenous DMT.

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A brief history of DMT

In terms of Western culture, DMT was first synthesized by a Canadian chemist, Richard Manske, in 1931 but was, at the time, not assessed for human pharmacological effects. In 1946 the microbiologist Oswaldo Gonsalves de Lima discovered DMT's natural occurrence in plants. DMT's psychedelic properties were not discovered until 1956 when Stephen Szara, a pioneering Hungarian chemist and psychiatrist, extracted DMT from the Mimosa hostilis plant and administered the extract to himself intramuscularly. This sequence of events formed the link between modern science and the historical use of many DMT-containing plants as a cultural and religious ritual sacrament, their effect on the psyche and the chemical structure of DMT.

The discovery of a number of psychedelics in the 1950's and observations of their effects on perception, affect and behavior prompted hypotheses that the syndrome known as schizophrenia might be caused by an error in metabolism that produced such psychedelics in the human brain, forming a schizo- or psycho-toxin. The presence of endogenous psycedelic compounds, related mainly to those resembling dopamine (mescaline) or serotonin (DMT), were subsequently sought. Although several interesting new compounds were found, the only known psychedelics isolated were those derived from tryptophan (DMT, and 5-methoxy-DMT). Data were subsequently developed illustrating pathways for their endogenous synthesis in mammalian species, including humans. Over 60 studies were eventually undertaken in an attempt to correlate the presence or concentration of these compounds in blood and/or urine with a particular psychiatric diagnosis. However, there has yet to be any clear-cut or repeatable correlation of the presence or level of DMT in peripheral body fluids with any psychiatric diagnosis. Nonetheless, the discovery of endogenous psychedelics and the possibilities rendered in various hypotheses surrounding their role and function in mental illness, normal and “extraordinary” brain function spurred further research into the mechanisms for their biosynthesis, metabolism and mode of action as well as for their known and profound effects on consciousness.

DMT biosynthesis

After the discovery of an indole-N-methyl transferase in rat brain, researchers were soon examining whether the conversion of tryptophan to tryptamine could be converted to DMT in the brain and other tissues from several mammalian species. Numerous studies subsequently demonstrated the biosynthesis of DMT in mammalian tissue preparations in vitro and in vivo. In 1972, Juan Saavedra and Julius Axelrod reported that intracisternally administered TA was converted to N-methyltryptamine and DMT in the rat, the first demonstration of DMT's formation by brain tissue in vivo. Using dialyzed, centrifuged whole-brain homogenate supernatant from rats and humans, these same researchers determined that the rate of synthesis of DMT from TA was 350 and 450 pmol/g/hr, and 250 and 360 pmol/g/h, using NMT as substrate, in these tissues, respectively.

In 1973, Saavedra et al. characterized a nonspecific N-methyltransferase in rat and human brain, reporting a Km for the enzyme of 28 uM for TA as the substrate in rat brain. The highest enzyme activity in human brain was found in the subcortical layers of the fronto-parietal and temporal lobes and the cortical layers of the frontal parietal lobe. However, an INMT found in rabbit lung was shown to have a much higher Km than the brain enzyme in rats. This suggested that INMT may exist in several isoenzyme forms between species and possibly even within the same animal, each having different Km's and substrate affinities. INMT activity has subsequently been described in a variety of tissues and species. There have also been several reports of an endogenous inhibitor of INMT in vivo that may help regulate its activity and, thus, DMT biosynthesis.

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Pathways for the biosynthesis and metabolism of DMT, 1. Biosynthesis: Tryptophan (2) is converted to tryptamine (TA, 3) by aromatic amino acid decarboxylase (AADC). TA is dimethylated to first yield N-methyltryptamine (NMT, 4) and then DMT (1) by indole-N-methyltransferase (INMT), using S-adenosyl-methionine (SAM) as the methyl source. Metabolism: TA, NMT and DMT are all substrates for monoamine oxidase, yielding indole-3-acetic acid (5, IAA) as both a common precursor metabolite and the most abundant metabolite of DMT itself. DMT is also converted to DMT-N-oxide (6) as the second-most abundant metabolite. Two 1,2,3,4-tetrahydro-beta-carbolines (THBCs) have also been identified as metabolites; 2-methyl-THBC (7, MTHBC) and THBC (8).

The combined data demonstrate that DMT is formed from tryptophan, a common dietary amino acid, via the enzyme aromatic L-amino acid decarboxylase (AADC) formation of TA and its subsequent N, N-dimethylation. The enzyme indolethylamine-N-methyltransferase (INMT) uses S-adenosyl-l-methionine as the methyl source to produce N-methyltryptamine and then DMT. Both AADC and INMT act on other substrates as well. As a historical and research note regarding DMT, there was initial confusion and misidentification of the products formed when using 5-methyltetrahydrofolate (5-MTHF) as the methyl source in INMT studies due to formation of indole-ethylamine condensation products with formaldehyde.

There has also been interest in the role of INMT and DMT biosynthesis in maturation and development. Relatively elevated levels of INMT activity have been found in the placenta from a variety of species, including humans. INMT activity in rabbit lung was reported to be elevated in the fetus and to increase rapidly after birth, peaking at 15 days of age. It then declined to mature levels and remained constant through life. In this regard, Beaton and Morris have examined the ontogeny of DMT biosynthesis in the brain of neonatal rats and rats of various ages. Using gas chromatography-mass spectrometry with isotope dilution for their analyses, DMT was detected in the brain of neonatal rats from birth. DMT levels remained low until days 12 and 17 at which time they increased significantly and then returned to the initial low levels for all subsequent ages. There has yet to be any follow-on research as to the significance of this change in DMT concentrations during rat brain neurodevelopment or correlation with possible changes of INMT activity in other developing tissues, specifically during days 12–17. Nonetheless, these findings correlate well with the Lin et al. data for INMT changes in rabbits and deserve further inquiry.

There is a significant literature concerning INMT, particularly in peripheral tissues. INMT and its gene have been sequenced, commercial antibodies for its detection have been developed and commercial probes exist for monitoring its mRNA and gene expression. A study using Northern blot detection of the INMT mRNA conducted by Thompson et al. in the rabbit suggested that INMT was present in significant quantities in the periphery, and particularly the lung, but that it was almost non-existent (low to absent) in the brain. These data became the foundation for several hypotheses that any neuropharmacological effects of endogenous DMT must lie in its formation in the periphery and its subsequent transport into the brain. This idea was strengthened by the fact that DMT has been shown to be readily, and perhaps actively, transported into the brain. However, the data concerning the apparent absence of INMT in brain would appear to be in conflict with the many earlier studies that demonstrated both in vivo and in vitro biosynthesis of DMT in the brain. Indeed, several studies had identified INMT activity or the enzyme itself in the central nervous system (CNS) including the medulla, the amygdala, uncus, and frontal cortex, the fronto-parietal and temporal lobes and, more recently, the anterior horn of the spinal cord as well as the pineal gland.

Thus, in 2011, Cozzi et al. sought to determine why earlier studies had not detected significant INMT in brain using Northern blots despite several reports that brain tissue had been shown to synthesize DMT from TA. One possibility was that INMT was “expressed in nervous tissue but that in some situations, INMT mRNA is not detectable by Northern analysis.” Examining primate nervous system tissues (Rhesus macaque spinal cord, pineal gland, and retina) probed with rabbit polyclonal antibodies to human INMT, all three tissues tested positive. INMT immunoreactivity in spinal cord was found to be localized in ventral horn motoneurons. The study also showed that INMT response was “robust and punctuate” in the pineal gland. Further, intense INMT immuno-reactivity was detected in retinal ganglion neurons and at synapses in the inner and outer plexiform layers. In 2012, Mavlyutov et al. reported that INMT is also localized in postsynaptic sites of C-terminals of rat motoneurons in close proximity to sigma-1 receptors, which have been linked to control of the activities of ion channels and G-protein-coupled receptors. It was proposed that the close association of INMT and sigma-1 receptors suggests that DMT is synthesized locally to effectively activate sigma-1 in motoneurons. It has been further proposed that DMT is an endogenous sigma-1 receptor regulator.

Taking these newer data together with historical in vitro and in vivo results regarding INMT enzyme activity in the brain and CNS, it is now clear that the work of Thompson and Weinshilboum is not the final word on DMT biosynthesis in the brain.

Future research on the biosynthesis of DMT

Considering that tryptamine formation, itself a trace biogenic amine, is essential for the formation of DMT and given its own rapid metabolism by monoamine oxidase (MAO) as well, demonstrating its availability for the biosynthesis of DMT is also relevant to a complete elucidation of the overall pathway. Indeed, demonstrating the co-localization of AADC and INMT should be a necessary endeavor in any future research regarding DMT biosynthesis in both the brain and periphery. The co-localization of AADC in discreet brain cells and areas with INMT permits TA and, subsequently, DMT formation locally. With demonstration of co-localization of the necessary biosynthetic machinery in the brain, both AADC and INMT, mechanisms for a rapid biochemical response to signaling and DMT formation may be shown to exist. Furthermore, the demonstration of mechanisms for the protection, storage, release and re-uptake of DMT would demonstrate that higher concentrations of DMT could be reached in the synaptic cleft and at neuronal receptors than would have to occur from, based on previous thought, formation and transport from the periphery. Pursuit of research of these mechanisms, as well as detailed mapping of INMT-AADC in the brain, is needed. We should not rule out the possibility that the biosynthesis and transport of DMT can and does occur from the periphery, however.

Peripheral DMT, especially if synthesized in tissues that bypass liver metabolism on first pass, may also serve as a signaling compound from the periphery to the brain. Such signaling may occur in maintaining homeostasis or in response to extreme changes in physiology. However, the immediate availability of TA for the biosynthesis of DMT in the periphery should also be demonstrated and studies examining the co-localization of AADC and INMT in the periphery should also be performed. This will require using highly sensitive and well validated antibodies and probes for detection of INMT and/or its mRNA in brain and/or peripheral tissues as well as those for aromatic-L-amino acid decarboxylase (AADC). Demonstration of co-localization with AADC has not been previously conducted in any other study seeking to identify INMT's presence or to demonstrate INMT activity. Such a determination may prove fruitful since a preliminary examination for the possible co-localization of INMT and AADC in the brain is supported by the data provided in the Allen Brain Atlas, mapping INMT and AADC gene expression.

A thorough re-examination of possible peripheral DMT biosynthesis is needed. Indeed, INMT actually methylates other substrates, such as histamine. Thus, much of the INMT in the periphery may be involved to a greater degree with methylation of other substances than TA alone. In this regard, in vitro studies of INMT as it relates to DMT biosynthesis necessarily added TA to their incubations, making TA “artificially” available in regions where natural levels may be absent or at significantly lower levels. Without a source for TA, the hypotheses regarding the formation of DMT in the periphery and its transport to the brain as a mechanism of action/function of endogenous DMT may be seen to be based on a less significant pathway than previously thought. Failure to demonstrate co-localization of INMT and AADC in the periphery would alter, to some degree, the focus of studies of peripheral synthesis and detection for understanding the role of endogenous DMT.

At least one study has now shown that the pineal gland has high concentrations of INMT. These data are underscored by the findings of Barker et al. demonstrating the presence of DMT in pineal perfusates from free-moving rats. Clearly, further research into the biosynthesis and role of DMT in the pineal is needed, as is a further assessment of our current knowledge of pineal function.

We will also need to examine protein and gene arrays to determine the factors that assist or work in concert with the up and down regulation of the INMT system in brain and how it responds to selected physiological changes. Such analyses will be essential in examining the possible role of DMT biosynthesis in changing biochemical and physiological events. We will also need to create brain-specific INMT KO animals, to further understand DMT biosynthesis and the “normal” role of DMT in vivo. It would also be of interest to better understand the possible role of DMT in neurodevelopment as suggested by the work of Beaton and Morris and Lin et al. in rats and rabbits, respectively. While DMT appears to clearly be biosynthesized in the pineal, mechanisms for its biosynthesis and release may exist in other brain areas as well and research into these other possibilities will also need to proceed.

DMT metabolism

The metabolism of DMT has been thoroughly studied, with a great deal of newer data being provided from studies of ayahuasca administration. All of the in vivo metabolism studies have shown that exogenously administered (IV, IM, smoking, etc). DMT is rapidly metabolized and cleared, with only a small fraction of IV or IM administered DMT subsequently being found in urine. For example, 0.16% of an intramuscular dose of DMT was recovered as the parent compound following a 24 h urine collection. DMT administered in this manner reached a peak concentration in blood within 10–15 min and was below the limits of detection within 1 h. It was estimated that only 1.8% of an injected dose was present in blood at any one time. Due to rapid metabolism in the periphery, DMT is not orally active, being converted to inactive metabolites before sufficient penetration to the brain can occur. DMT is only orally active if co-administered with a monoamine oxidase inhibitor (MAOI). DMT is pharmacologically active following administration by injection or smoking, pathways which can avoid first-pass metabolism by the liver to some degree. The time to onset of effects is rapid (seconds to minutes) by these routes and short lived.

The primary route of metabolism for DMT is via monoamine oxidase A (MAO-A), yielding indoleacetic acid. The other metabolites formed include DMT-N-oxide, the second most abundant metabolite, and lesser amounts of N-methyltryptamine, which, along with TA, is also a substrate for MAO-A, with both yielding IAA. Inhibition of MAO leads to a shift in favor of the amounts of DMT-NO and NMT formed. Other metabolites have been reported, such as 6-hydroxy-DMT (6-OH-DMT), as well as products from a peroxidase pathway, reported to yield N, N-dimethyl-N-formyl-kynuramine, and N, N-dimethyl-kynuramine. However, these latter metabolites have yet to be identified in vivo. Metabolites also result from the cyclization of an intermediate iminium ion that forms during demethylation of DMT, yielding 2-methyl- 1,2,3,4- tetrahydro-beta-carboline and THBC.

The primary role of MAO-A in the metabolism of DMT has been further confirmed by pre-treatment of experimental subjects with the MAO inhibitor (MAOI) iproniazid as well as other MAOIs, the ability of the MAO-inhibiting harmala alkaloids of ayahuasca to make DMT orally active and the increased half-life and extended effects of an α, α, B, B-tetradeutero-DMT, which is less susceptible to MAO-A metabolism due to the kinetic isotope effect.

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Future research on the metabolism of DMT


While the metabolism of DMT has been thoroughly studied and a number of metabolites have been identified, one of the complications in understanding the role and function of endogenous DMT has been the fact that, to date, no study examining body fluids (blood, urine, saliva) has ever been conducted to correlate such data with human physiological events, such as circadian changes, sex differences, etc. Of greater impact is the fact that, despite DMT's rapid metabolism and multiple metabolites, no study has fully assessed all of these compounds simultaneously to better understand DMT's overall occurrence or rate of endogenous synthesis, release, clearance and/or the overall assessment of the relevance of endogenous levels in the brain or periphery. All of these factors need to be examined. Given that peripherally administered DMT, at what must be considered as much higher doses than would be expected to occur naturally in the entire organism, is rapidly metabolized and cleared, measuring endogenous DMT alone in an attempt to assess its role and function is probably doomed to failure. This is particularly true if endogenous DMT is mainly produced, stored and metabolized in discreet brain areas and that DMT and its metabolites so produced never attain measurable levels in peripheral fluids.

To the degree that DMT is produced peripherally, measurement of IAA, DMT-NO, N-methyltryptamine and the precursor for the synthesis of both DMT and NMT, tryptamine, would be advantageous. These compounds have been variously reported in tissue, blood and urine samples. However, this approach is complicated by the fact that the major MAO metabolite of all three of these latter compounds, IAA, is also derived from dietary sources and is produced from the action of bacteria in the gut. It is not unreasonable to question whether measurement of DMT and its metabolites, and thus the role and function of endogenous DMT, can be understood by simply trying to measure these compounds in the periphery. This is particularly true in understanding DMT production in the CNS. Peripheral measurements may not be the way to determine the central role of DMT and DMT produced in the brain may never be available for measurement in the periphery. Nonetheless, additional studies should determine if there is validity in such measurements and examine possible circadian, ultradian or diurnal variations in DMT synthesis as well as the changes that may occur due to alterations in other physiological parameters.

DMT detection in blood, urine, and cerebrospinal fluid

Barker et al. have published a thorough overview of the 69 published studies examining blood, urine and cerebrospinal fluid detection of endogenous N, N-dimethylated tryptamines [N, N-dimethyltryptamine (DMT), 5-hydroxy-DMT (bufotenine, HDMT), and 5-methoxy-DMT (MDMT)]. Nearly all of the studies were directed at establishing a relationship between the presence and/or level of these compounds and a psychiatric diagnosis. In total, the 69 studies examined DMT in thousands of subjects. A critical review of these data determined, however, that most early studies reporting rather high concentrations of these compounds in blood and/or urine were most likely in error and any correlations based on these data were likewise probably incorrect. The reasons for this conclusion were: (1) Based on current analytical requirements for unequivocal structure identification, it is highly probable that many of these studies misidentified the target analyte. (2) If properly identified, the studies showed that a psychiatric diagnosis was not a necessary or sufficient criterion for finding one or more of these psychedelics in various body fluids; “normal” controls were also positive (and sometimes higher) for these compounds. Nevertheless, it was also concluded that, particularly where mass spectral evidence was provided, DMT and HDMT are endogenous and can often be successfully measured in human body fluids. The evidence was less compelling for MDMT where the only two MS-based positive studies—in CSF—were performed by the same research group. There was no mass spectral data demonstrating detection of MDMT in blood or urine. There was also no study that attempted a determination of HDMT in CSF.

In conducting studies to determine the natural occurrence of a compound as being endogenous, it is also necessary to eliminate other possible dietary or environmental sources. Of the 69 studies reviewed, many addressed the possible source of DMT as being from diet or gut bacteria by using special diets. Of those conducted, it was determined that neither was a source but additional research in this area using more modern technology and a more standard diet across studies is a necessity. There have also been only a few efforts to examine the many variables that may influence the levels of these compounds, such as circadian or diurnal variations, sleep stages and gender-age-related differences. Indeed, most of the studies collected only a single time point or were from 24 h collections (urine). Such infrequent sampling makes it impossible to assess central DMT production from peripheral measurements and suggests, perhaps incorrectly, that DMT only appears intermittently or not at all. In trying to compare the results, interpretations and correlation of the data were hampered by variability in sampling methods, amount of sample assayed, type of sample (plasma, serum and/or whole blood), divergent techniques and analytical methodology that also had highly variable or unspecified limits of detection.

Future research measuring DMT in the blood, urine, and/or cerebrospinal fluid

In terms of pursuing future research on the presence of the endogenous indolealkylethylamines, further studies are necessary to determine whether MDMT actually exists in humans. Similarly, there are no data on the possible presence of HDMT in CSF although it has been routinely identified in urine. Future analyses to determine endogenous N, N-dimethyl-indolethylamines should also include a search for their major metabolites. The methodology applied in such analyses must include rigorous validated protocols for sample collection, storage, extraction and analyte stability and appropriate criteria for unequivocal detection and confirmation of the analytes using validated methods. Modern exact-mass liquid chromatography-mass spectrometry instrumentation should be the analytical method of choice. Such capabilities may then be applied to address the many variables that may influence the ability to measure DMT and/or its precursors and metabolites in the periphery.

Measurement of DMT in the brain

Many studies have been conducted to detect and/or quantitate DMT in blood and urine and only a few in the CSF of humans. However, the CSF studies made no effort to quantitate the DMT detected. In fact, there have been no efforts to quantify the actual levels of endogenous DMT and its metabolites in human brain and only a few have attempted to address the issue in rats. Barker et al. described the presence of DMT in pineal gland perfusates from free-moving rats but no quantitation was conducted since the perfusates were essentially dilutions of the surrounding tissue effluent and were collected at a single point-in-time. As noted, no circadian studies of DMT production or release from the pineal as a function of time have ever been conducted. In Karkkainen et al., using multiple extraction and clean-up steps and an LC/MS method for analysis, reported the level of DMT in whole rat brain (n = 2) taken from animals pre-treated with a MAOI as being 10 and 15 ng/kg. This study's information is unfortunately quite limited in terms of sample number and did not address extraction recoveries, method validation or brain distribution of DMT.

As noted earlier, one study, using rat pups of different ages and conducted using a validated extraction/gas chromatographic-mass spectrometric analysis of whole-brain extracts, examined the ontogeny of DMT in rat brain and found significant changes in the concentrations of DMT as a function of age. The highest levels were 17.5 +/- 4.18 ng/g of brain (wet weight) at day 17. Values for other days ranged from undetected to 1, 2 or as high as 11 ng/g. A n = 6 and a total of 4–6 brains were pooled for each day-post-birth analysis. Since pooled whole brain was used for the analysis, it is still not known how the DMT was distributed in the brain or if the DMT observed actually arose from a discrete brain area or areas alone. The data necessarily expressed the DMT concentration as if it was homogeneously distributed. Rats were also sacrificed at constant times during the study and no accounting was made for possible circadian or ultradian variations.

Given these facts, any speculation that attempts to dismiss the relevance of DMT in vivo because the concentrations in brain are too low necessarily ignores the fact that data concerning the actual levels of DMT in brain, particularly humans and levels that may be observed in different brain areas, simply does not exist.

Future research to determine the concentration of DMT in brain tissues

While more research into the brain concentrations and distribution of DMT is obviously warranted, it is possible, as with many other substances, that it may only be found in specific brain areas or cell types. For example, the pineal gland of an adult rat weighs between 0.9 and 1.56 mg and the total brain weight is approximately 2.0 g. If all of the DMT found, on average, at day 17 in the Beaton and Morris study were to be located solely in the pineal, the tissue concentration would range between 18.9 and 10.9 ug/g or, converting ug to moles and gram to liter, the concentrations would be about 0.1 umoles/g or 0.1 mmoles/L to 0.06 umoles/g or 0.06 mmoles/L. While converting g to ml regarding tissue is by no means exact, the point to be made is that DMT in brain could have significant concentrations in discrete brain areas and exist in sufficient concentrations in such areas to readily affect various receptors and neuronal functions. Lower concentrations could occur in other brain areas as well with their concentrations being enhanced by mechanisms for DMT uptake and vesicular storage. What is obvious from these speculative calculations is the fact that more research into DMT brain distribution and concentrations is needed, recognizing its rapid metabolism and possible sequestration. It is quite clear that we have no good estimates at present concerning brain/neuronal distribution or concentration of endogenous DMT, particularly in humans, that will permit informed decisions or conclusions to be drawn regarding its function or the relevance of in vitro binding studies and relative Km's to endogenous levels. As with measurements in other matrices, well validated and sensitive methods for such quantitative analyses will be required.

Receptor binding of DMT: 5-HT2A, TAARs, and sigma-1 receptors

There is a significant literature correlating the binding affinity of DMT and related psychedelics for the 5HT2A receptor and its subset of receptors with other psychedelics and their subsequent behavioral effects. However, DMT has been shown to interact with a variety of ionotropic and metabotropic receptors. While the subjective behavioral effects of exogenously administered DMT appear to be primarily acting via 5-HT2A receptors, the interaction of other receptors, such as other serotonergic and glutaminergic receptors, may also play a synergistic and confounding role. Indeed, the activation of frontocortical glutamate receptors, secondary to serotonin 5-HT2A receptor-mediated glutamate release, appears to be a controlling mechanism of serotonergic psychedelics. However, although this type of receptor research is quite mature, these findings have yet to define and accurately correlate what makes a compound psychedelic vs. compounds that have similar binding characteristics that are not psychedelic. Clearly, we are missing some pieces to the psychedelic receptor/mode-of-action puzzle.

For example, Keiser et al. have shown that DMT binds to a variety of 5-HT receptors and that such binding does have physiological relevance. In their study, the role of 5-HT2A agonism in DMT-induced cellular and behavioral effects was examined in both cell-based and 5-HT2A knock-out mouse models. It was reported that “DMT binds to 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5A, 5-HT6, and 5-HT7 receptors with affinities from 39 nM to 2.1 uM.” Nonetheless, it was observed that DMT was not only a potent partial agonist at 5-HT2A but also that the DMT-induced head twitch response, a common measure of psychedelic activity, occurred only in wild-type mice but not in 5-HT2A knockout mice. However, it has been shown that the mixed 5-HT1A/1B antagonist pindolol markedly potentiates the subjective effects of DMT in humans. Furthermore, DMT-enhanced inositol trisphosphate production has been shown to persist even in the presence of the 5-HT2A antagonist ketanserin, suggesting other receptor sites for DMT's effects. Of interest is the finding of Urban et al. that receptors, such as the 5-HT family, can couple to multiple effectors, which allows receptor agonists to produce different pharmacological endpoints. Thus, certain compounds may selectively activate a specific subset of effectors producing a functional selectivity that complicates the interpretation of observed psychopharmacological or biochemical effects. In this regard, Carhart-Harris and Nutt have recently offered a novel bipartite model of serotonin neurotransmission involving co-modulation of the 5-HT1A and 5-HT2A receptors. This bipartite model purports to explain how different serotonergic drugs (including psychedelics) modulate the serotonergic system in different ways to achieve their observed pharmacology.

Clearly the 5-HT2A receptor is involved in the mode of action of DMT and other psychedelics, but is it also clear that this is not the sole receptor on which we should rely for an overall explanation.

Despite the failure of serotonin receptor binding theory to completely explain psychedelic activity, these observations support the 5-HT2A receptor as being a possible primary target for DMT's psychedelic effects. While DMT has been shown to bind to the 5-HT2A receptor with relative high affinity, many other compounds that lack DMT's visual effects have a higher affinity for the 5-HT2A receptor.

In examining the possible complex interaction of multiple systems that may be necessary to explain the effects of compounds such as DMT, attention has also turned toward additional possible binding sites. Another set of functionally relevant binding sites for DMT is the family of trace amine-associated receptors (TAARs). DMT has been shown to be an agonist in binding to TAAR-1 with high affinity, causing activation of adenylyl cyclase and cAMP accumulation in TAAR1 transfected HEK293 cells. However, as is the case with the 5-HT2A receptor, other psychedelics and non-psychedelics also stimulate cAMP production following binding at TAAR1. There has yet to be sufficient research of TAAR to determine what role, if any, this class of receptors plays in the pharmacology or endogenous function of DMT. Thus, the research to date regarding the role of TAAR receptors suffers from the same lack of explanation for the mode of action of the psychedelics as the 5-HT2A but may comprise a piece of what is obviously a complex set of interactions.

Another receptor family has also been implicated; the sigma-1 receptor. One of the possible roles of the sigma-1 receptor appears to be to act as an intracellular chaperone between the endoplasmic reticulum (ER) and mitochondria. In this role, it is involved in the transmission of ER stress to the nucleus. This process would be expected to result in the enhanced production of anti-stress and antioxidant proteins, with the activation of sigma-1 mitigating the possible damage done by hypoxia or oxidative stress. Using in vitro cultured human cortical neurons (derived from induced pluripotent stem cells), monocyte-derived macrophages, and dendritic cells, Szabo et al. have shown that DMT greatly increases the survival of these cell types in severe hypoxia, apparently via its interaction with sigma-1 receptors. A decreased expression and function of the alpha subunit of the hypoxia-inducible factor (HIF-1) was also observed, suggesting that DMT-mediated sigma-1 activation may alleviate hypoxia-induced cellular stress and increase survival via decreased expression and function of the stress factor HIF-1α in severe hypoxia. Such a mechanism has relevance to stroke, myocardial infarct or similar arterial occlusive disorders, cardiac arrest, and perinatal asphyxia, all conditions associated with hypoxic consequences. Szabo et al. and Szabo and Frecska have speculated that DMT may also contribute to neuroregenerative and neurorestorative processes by modulating the survival of microglia-like cells.

These sigma-1 associated effects may also be related to findings that DMT affects the rate of genetic transcription associated with synaptic plasticity, increased expression of brain-derived neurotrophic factor (BDNF) expression associated with synaptic plasticity, cognitive processes such as memory and attention, and modulation of efficacy and plasticity of synapses.

The sigma-1 receptor has been implicated in several neurobiological disorders and conditions and is found widely distributed though out the body, including in the CNS. However, both psychedelics and non-psychedelics bind to sigma-1 receptors, again complicating an attribution to this receptor as the primary site of DMT's action. Further, DMT binds to sigma-1 receptors at what should be considered as a high concentration but does, nonetheless, have agonist activity. INMT has been shown to be co-localized with sigma-1 receptors in C-terminals of motor neurons and such intracellular synthesis would allow for DMT accumulation and storage, producing the necessary μM concentrations for its action. It is also important to consider that the role of endogenous DMT is not necessarily to produce the same effects as observed from exogenous administration and such a “normal” role may be one of its biological assets.

It has also been observed that sigma-1 receptor agonists are potentially neuroprotective. DMT has been shown to reduce neuronal inflammation via the sigma-1 receptor and can also induce neuronal plasticity, a long-term recuperative process that goes beyond neuroprotection. Sigma-1 receptors can also influence cell survival and proliferation, and Frecska et al. have suggested that DMT is protective during cardiac arrest and perinatal development. With respect to the ontogeny of DMT, Lin et al. and Beaton and Morris have examined changes in INMT activity and DMT biosynthesis, respectively, with age in the rat. Taken together, changes in INMT levels consequently yielded increased DMT synthesis. It is possible that DMT-mediated sigma-1 receptor activity is also increased during this period to induce neuronal changes in newborns. Several selective sigma-1 receptor agonists have been shown to be protective against excitotoxic perinatal brain injury and ischemic neurodegeneration in neonatal striatum. In addition, it has been suggested that adequate expression of placental INMT may be necessary for pregnancy success.

Future DMT receptor binding studies

Studies examining non-serotonergic receptors for DMT, such as TAAR and sigma-1, have begun to bear useful and insightful evidence for the possible “normal” roles of endogenous DMT and should be extended and expanded. Molecular biological studies of DMT's effects on these receptors and DMT's effects on their up-or-down regulation will also prove informative. Mapping of these receptors in brain tissues, with a determination of the nature and degree of colocalization of DMT's enzymes for synthesis in mind, will also add impetus to the growing recognition of DMT's possible “normal” functions in brain. This understanding may also lead to new therapeutic applications for regulating and altering endogenous DMT levels and function, providing new avenues for understanding psychedelic pharmacology and their possible therapeutic use. The data suggest that the 5-HT2A receptor is only part of the story. The data further suggest there may well remain a psychedelic receptor or receptor complex that has yet to be discovered. A more integrative mechanism to explain psychedelic activity is also intriguing and requires further inquiry.

Perhaps the true psychedelic receptor has already been discovered and is simply mislabeled as being one of the many 5-HT receptors. Perhaps it is their interaction with many receptors and their complex functional connectivity that produces the observed effects. Indeed, the data suggest that DMT is both endogenous and possesses the properties of a neurotransmitter. Studies have clearly shown that it binds with respectable affinity to the 5-HT2A receptor as well as other members of the serotonin family of receptors and elicits biochemical and physiological activity that can be correlated, to some degree, with such binding. These data support the idea that it is, therefore, an endogenous ligand for such receptors and intrinsically involved in serotonergic function. This being the case, there is already a significant body of work regarding DMT's binding and effects, especially relative to effects on serotonin, acting as a serotonergic modulator. Additional work in this area, while acknowledging DMT as an endogenous ligand, will prove essential. It is also unlikely that DMT acts alone in exerting it effects. Changes in relevant metabolomic and array profiles following DMT administration will further add to our understanding of its endogenous role.

Administration of DMT

Szara originally reported that the effects of a medium dose of DMT, given intramuscularly, were similar to those of mescaline and LSD, including visual illusions, distortion of body image, speech disturbances, mood changes and euphoria or anxiety (dependent on set and setting). Several other studies have replicated these findings using either IV or IM administrations. Intramuscular effects of DMT at a reported dose of 0.2–1 mg/kg generally had a rapid onset (2–5 min) and lasted 30–60 min. The IM effects are usually less intense than intravenous or inhalation-of-vapor routes of administration.

The subjective effects of DMT from ayahuasca administration usually appear within 60 min, peak at 90 min and can last for approximately 4 h. The prolongation of effect is attributed to the MAOI effects of the constituent harmala alkaloids. Riba et al. have also reported the effects of oral and vaporized DMT alone. As expected, oral ingestion of pure DMT produced no psychotropic effects. Vaporized DMT was found to be quite psychoactive. This study also showed that smoked DMT caused a shift from the MAO-dependent route to the less active CYP-dependent route for DMT metabolism. Commonly used doses for vaporized or inhaled free-base DMT are 40–50 mg, although a dose may be as much as 100 mg. The onset of vaporized DMT is rapid, similar to that of i.v. administration, but lasts less than 30 min. It is of interest to note that intranasal free-base DMT is inactive as is DMT administered rectally.

There is also additional significant literature concerning the administration of DMT via consumption of ayahuasca. While of great scientific interest, this subject is not reviewed here. This is mainly due to the complexity of composition of ayahuasca, especially the presence of significant MAOI effects.

Strassman et al. have reported dose-response data for intravenously administered DMT fumarate's neuroendocrine, cardiovascular, autonomic, and subjective effects in a group of experienced psychedelic users. DMT was administered to 11 experienced psychedelic users. The results of these studies showed peak DMT blood levels and subjective effects were attained within 2 min after drug administration and were negligible at 30 min. DMT was also shown to dose-dependently elevate blood pressure, heart rate, pupil diameter, and rectal temperature, in addition to elevating blood concentrations of B-endorphin, corticotropin and cortisol. Prolactin and growth hormone levels rose equally at all doses of DMT. Levels of melatonin were unaffected. The lowest dose that produced statistically significant effects relative to placebo and that was also psychedelic was 0.2 mg/kg.

The effects observed and the biochemical and physiological parameters measured in these studies add needed insight into the role and function of endogenous DMT. However, we must distinguish the effects of exogenously administered DMT from that which may be observed from its natural role as an endogenous substance. Exogenous administration of a bolus of DMT represents an “overdose” of a naturally occurring compound that may, when administered in this manner, exert a more complex pharmacology. However, this could also be true of any physiological change that produced a “normal” elevation in endogenous DMT, such as a response to stress or hypoxia, but with the entire process still remaining under a greater degree of biochemical control and response and the elevation possibly occurring in only certain brain areas or systems. For exogenously administered DMT we know plasma concentrations between 12 and 90 ng/ml must be attained in order to produce psychedelic effects. The concentrations actually attained in whole brain or in specific areas required to produce psychedelic effects from such administrations are unknown.

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Future DMT administration studies

While these “overdoses” have given us valuable data regarding DMT's pharmacology and hints as to DMT's normal role and function, it will be necessary to lower the doses and expose the brain only to more “natural” levels or ranges to more fully ascertain why DMT is in the brain and what it is doing there. Part of that research will require the renewal of drug administration studies to assess the many prospects that have been raised by recent and current research. Gallimore and Strassman have offered an interesting proposal regarding the future conduct of DMT administration research; a target-controlled continuous, low-dose, IV infusion. This approach would be conducted to better discern the physiology and pharmacology of DMT and to produce a “prolonged and immersive psychedelic state.” The short duration of DMT's effects prevents the use of single dose administration as the research model for such studies. Target-controlled continuous IV infusion is a technology developed to maintain a stable brain concentration of anesthetic drugs during surgery. The rationale for this approach and the conduct of such research lies in the fact that DMT users have consistently reported “the complete replacement of normal subjective experience with a novel ‘alternate universe,’ often densely populated with a variety of strange objects and other highly complex visual content, including what appears to be sentient ‘beings.”' A further stated purpose of this approach, and one that would be quite informative, is to allow greater functional neuroimaging of the DMT experience, with subjects remaining under the influence of DMT for the extended periods necessary to collect the best data.

The administration of DMT by the IV route will require determination of an effective continuous dose, such that the desired level of experience is both attained and maintained. The lower the dose necessary the less likely volunteers will be to experience some of DMT's other peripheral and central “side-effects” and will establish a threshold above which further higher dose administrations may be examined. Concomitant administration of a MAOI would assist in attaining this goal but has the drawback of affecting levels of many other amine neurotransmitters as well, complicating the effects and subsequent data interpretation.

However, one alternative method of administration may be to use analogs of DMT that are structurally altered as so to inhibit the ability of the molecule to be metabolized by MAO-A, such as an alpha methyl or 2-N, N-dimethyl-propyl sidechain structure. However, such molecules may not bind in the same manner as DMT itself and may have other untoward effects. Another alternative that may assist in the ability to use lower doses and to prolong the effect of the DMT administered, however, may be the use of a deuterated analog.

In 1982, Beaton et al., reported on the behavioral effects of DMT administered interperitoneally to rats. The D4DMT was observed to produce, at equivalent doses to DMT itself, a significantly greater disruption of behavior, a longer duration of action and a shorter time to onset than non-deuterated DMT. This potentiation was apparently due to the kinetic isotope effect which, in theory, makes it harder for the MAO enzyme to extract a deuterium (vs. a hydrogen) from the alpha position, thus inhibiting degradation by MAO. In a companion study, Barker et al. also showed that, at the same dose, D4DMT attained a significantly higher brain concentration than DMT itself and that the elevation in brain level lasted for a longer period of time. Similar data have recently been presented for a tetra deutero-5-MeO-DMT and the authors reached a similar conclusion; these results demonstrate that deuterated tryptamines may be useful in behavioral and pharmacological studies to mimic the effects of tryptamine/MAOI combinations, but without the MAOI. While the synthesis of deuterated analogs may be more expensive initially, newer methods for such synthesis may overcome these concerns. Furthermore, the pharmacological properties of D4DMT may render it orally active. Such a possibility has yet to be explored. It is also possible that oral administration and kinetic isotope effect inhibition of metabolism may prolong the effects of a deuterated analog sufficiently to also be of use in imaging studies.

It would be of interest to determine if the proposal of Gallimore and Strassman, using a continuous infusion of DMT, would also be of use in in an animal model for the treatment of severe brain injury and trauma or in conditions resulting from a hypoxic insult, such as arterial occlusive disorders, cardiac arrest, and perinatal asphyxia, promoting the possible neuroprotective and neuroregenerative effects of DMT that have been recently described. Such studies will also allow validation or refutation of the recent data in this area.

Imaging research

While there have been several studies reporting neuroimaging data from volunteers consuming ayahuasca, there is minimal neuroimaging data for the administration of DMT alone. Using functional magnetic resonance imagining (fMRI) techniques, administration of DMT “caused a decreased blood oxygenation level-dependent response during performance of an alertness task, particularly in the extrastriate regions during visual alerting and in temporal regions during auditory alerting.” It was concluded that the effects for the visual modality were more pronounced. Imaging data for other psychedelics, such as psilocybin and LSD, have been generated. dos Santos et al. have concluded that “the acute effects of psychedelic administration, as interpreted from imaging studies, included excitation of frontolateral/frontomedial cortex, medial temporal lobe, and occipital cortex, and inhibition of the default mode network.” For long-term use, the administration of psychedelics was associated with “thinning of the posterior cingulate cortex, thickening of the anterior cingulate cortex, and decreased neocortical 5-HT2A receptor binding.” It was also suggested that psychedelics “increase introspection and a positive mood by modulating brain activity in the fronto-temporo-parieto-occipital cortex.”

Future imaging research

The data to be derived in such imaging studies are highly dependent on the instrumentation and methods used, and the interpretation of the data can often be somewhat subjective. However, any such data may provide the necessary roadmaps to understand brain distribution of administered and endogenous DMT and the activation-deactivation profiles created naturally or artificially in various states of consciousness. Indeed, recent imaging data and pharmacological studies of 5-HT2A receptor activation suggest that psychedelics create a brain-image patterning that resembles dream states. Such studies of DMT have yet to be reported and should be undertaken. The involvement of DMT in various dream states has been hypothesized. One possible mechanism is the possibility that endogenous DMT is the signaling molecule responsible for the up-and-down regulation of specific brain areas that occurs during different dream states. Understanding the DMT-related functional connectivity or connectome, either from administration and/or from endogenous production stimulation, will expand our research frontiers in this field. Administration studies, such as proposed by Gallimore and Strassman, could provide imaging data that will permit interpretation of the neural pathways relevant to DMT's effects, particularly in eliciting hallucinations, but also as part of its “normal” function.

DMT as a neurotransmitter, neurohormone, or neuroregulatory substance

In 1976, Christian et al., published the accumulated evidence that DMT was a naturally occurring transmitter in mammalian brain, having met the criteria for such a designation at the time; “1) the synthetic enzymes and substrates are present in the CNS for the production of DMT, 2) a binding site is present to react with the compound and 3) the compound is found in human CSF and isolated synaptic vesicles from rat brain tissue.” Additional criteria have been added over the years, such as demonstration of electrophysiological activity. Indeed, DMT had also been shown to change the transepithelial and intracellular potentials of the blow-fly salivary gland and to increase the production of cyclic AMP early on. Another added criterion is that a pathway for DMT's metabolism and removal must be demonstrated. Pathways of DMT metabolism in the brain are well understood and newer data offers other mechanisms, such as uptake into synaptic vesicles and neurons, for controlling its synaptic levels. Like any neurotransmitter, uptake and storage can allow a reservoir of DMT to remain stored in vesicles, ready for release, and provide a mechanism for protecting and concentrating the compound.

Christian et al. subsequently described a specific high-affinity binding site for DMT on purified rat synaptosomal membranes that was also sensitive to LSD but not to serotonin. DMT was also shown to lead to the production of cAMP in synaptosomal membrane preparations as well as in rat brainstem slices and rat cerebrum in vivo. Unfortunately, no additional research on these findings has been reported. Other studies have also demonstrated that administered DMT becomes localized in the synaptosomal fraction of rat brain following administration and is detected in the vesicular fraction of such preparations. Further, the Mg2+ and ATP dependent uptake of DMT into rat brain vesicles has also been demonstrated as has apparent high and low affinity uptake sites for active transport of DMT in rat brain cortical slices.

The supporting data for DMT as a neurotransmitter have continued to accumulate. DMT has also been shown to be taken up into neuronal cells via serotonin uptake transporters (SERT) on neuronal plasma membrane and Cozzi et al. have shown sequestration of DMT into synaptic vesicles from the cytoplasm by the neuronal vesicle monoamine transporter 2 (VMAT2). Blough et al. have also shown that DMT releases 5-HT via SERT with an EC50 in the low nM range. This indicates that DMT is a substrate for the SERT transporter and provides a further mechanism for the neuronal accumulation of DMT. Newer data concerning INMT in specific brain areas and its presence in perfusates of the pineal gland of living rats add additional evidence for DMT's potential role as a neurotransmitter. At a minimum, the anatomy, pharmacology and physiology of DMT have been sufficiently characterized and demonstrated to afford DMT the classification as a putative neurotransmitter.

The concentration of DMT into vesicles and its release at the synaptic cleft would permit elevated concentrations of DMT, perhaps sufficient to elicit its known pharmacological actions as well as other effects. It would also be protected from MAO degradation. Peripheral production of DMT would not be required. It may also be the case that brain DMT biosynthesis is inducible in response to specific physiological effects, causing an increase in concentration in specific cell types and areas. This being the case, the idea that a pharmacologically relevant blood level of DMT must be attained before such effects are observed from endogenous production of DMT would not be relevant.

Future studies characterizing DMT as a neurotransmitter

Setting aside speculation in favor of what has been scientifically proven, the effects of administered psychedelics must be recognized as acting via existing, naturally occurring, neuropharmacological pathways and mechanisms. Perhaps we should first consider research into the possible role of endogenous DMT in explaining the elusive mode of action of the varied class of compounds possessing psychedelic properties. There is no doubt that DMT acts on the serotonergic system as well as other known neurotransmitter systems. Nonetheless, if DMT is a neurotransmitter, neurohormone and/or neuroregulatory substance then we should consider all of the more well understood properties of agonists and antagonists acting on such a system. While many psychedelics have been shown to act on many different neurotransmitters and receptors, we may now add the need to examine their effects on the synthesis, binding, release, reuptake, storage, degradation, etc. of an “endogenous psychedelic,” DMT. This is especially true in relation to serotonin regulation. As with our more recent understanding of the mode of action of opiates, finding new endogenous ligands and receptors can actually lead to a more complete understanding of the effect of what often appear to be divergent substances.

Hypothetically, the mode of action of psychedelics may be via their effects on an endogenous psychedelic neuronal system. Establishing DMT as a neurotransmitter makes such research not only somewhat obvious and relevant but necessary. If such a system is found to be responsible for these phenomena it may lead to more discoveries explaining other normal or pathological conditions such as, for example, delirium, certain symptoms of psychoses, spontaneous hallucinations and sleep disorders, autism and other perceptual anomalies. Perhaps it may yet be shown to be involved in schizophrenia, just not necessarily by previously expressed mechanisms. Certainly, it could give us insight into the proposals of its involvement in our more human attributes of creativity, imagination and dream states and of our less common experiences of visions, NDEs and extraordinary states of consciousness occurring without exogenous administration of a psychedelic substance. Thus, we need to better understand the molecular biology, physiology and anatomy surrounding endogenous DMT and its potential regulatory role.

Taken together, the evidence for DMT as a neurotransmitter is compelling. Recent research and more classical data have established that it is synthesized, stored, and released in the brain and mechanisms for its uptake, metabolism and removal have all been established. While more work remains to establish DMT as a neurotransmitter, such as more electrophysiological and iontophoretic data, it appears to be following the same path to recognition as other neurotransmitters have followed before final acceptance.

DMT as a therapeutic

There has been a renewed interest in using psychedelic drugs as therapeutics in clinical research to address depression, obsessive-compulsive disorder, the psychological impacts of terminal illness, prisoner recidivism, and substance abuse disorders, including alcohol and tobacco. Most studies have examined the use of LSD, psilocybin or ayahuasca instead of DMT alone.

In the history of use of DMT-containing “remedies,” ayahuasca has perhaps the longest record. Long-term use of ayahuasca has been shown to produce measurable changes in the brain itself, such as differences in midline brain structures as determined from MRI studies. While such effects may not appear to be of therapeutic value, long-term ayahuasca users have shown reduced ratings of hopelessness. Long-term ayahuasca use has also produced marked improvement in depressive symptoms with no concomitant mania or hypomania for up to 21 days after a single dose. These data suggest evidence for a potential antidepressant effect for DMT. However, ayahuasca is a complex mixture containing MAOIs (harmala alkaloids) which, as a class of drugs, have also been used alone to treat depression. Thus, it is impossible to say from such studies that DMT itself or the elevation of other brain neurotransmitters in combination is responsible for the perceived positive clinical effects or even if the hallucinations produced by DMT consumed under these conditions are themselves somehow cathartic.

While other classic psychedelics (LSD, psilocybin, etc.) are beginning to show promise in the treatment of addiction, PTSD and other mental disorders, there has yet to be generated conclusive evidence regarding the efficacy of DMT in any of them. DMT has been shown to exert anti-anxiety/anti-psychotic properties at the trace amino acid receptor (TAAR) and others have suggested that the possible positive symptoms observed in schizophrenia may be mediated by the effects of endogenous DMT. These findings do not necessarily support the conclusion that DMT is useful for treatment of anxiety or mental illness, however. The possible use of DMT as an adjunct to psychiatric therapy has been proposed by numerous investigators, a proposal that contravenes the tenets of the transmethylation hypothesis.

Frecska et al. have suggested that DMT may be involved in significant adaptive mechanisms that can also serve as a promising tool in the development of future medical therapies and there have been proposals that DMT might be useful to treat substance abuse, inflammation, or even cancer. However, at this point, the necessary data to support such proposals have not been presented and it would be premature to propose that DMT will become commonly used for clinical purposes. If it is a neurotransmitter, then understanding its role and function in normal or disease states could provide pharmacological targets to alter these functions, however.

Future study of DMT as a therapeutic

At present, the data arguing for the use of DMT as a therapeutic, particularly via administration, is thin. The claimed therapeutic effects for DMT in combination with harmala MAOIs as in ayahuasca or pharmahuasca is of interest but presents a complex data set that prevents an understanding of the contribution of each component. To further study DMT without the effects of an MAOI, research should pursue whether or not D4DMT is orally active, as previously noted, which would enhance the opportunities to examine its potential as a therapeutic. The use of psychedelics in psychotherapy is gaining renewed interest and certainly DMT should be among the drugs in the psychiatric pharmacopeia. Any proposal to pursue this avenue will require more than the current combined body of scientific evidence. Both Federal and State laws will have to change in order to make the manufacture and use of such compounds easier and to make conducting the necessary research feasible.

However, if DMT is a neurotransmitter and is responsible for modulation of serotonergic or other neurotransmitter systems, it may well be that many existing pharmaceuticals already exert their pharmacology via DMT-related-effect mechanisms. This may be the case for the other psychedelics, as noted, but may also be true for part of the mode of action of certain serotonergic drugs, such as antidepressants. Further characterization of DMT cellular distribution, receptors and general biochemistry may lead to new targets for more effective pharmaceutical substances and interventions.

Conclusions

It has been 86 years since DMT's first synthesis by Manske and 61 years since Szara discovered its psychedelic properties. It has been 41 years since Christian et al. characterized DMT as a neurotransmitter. Further research has better defined the latter's characteristics such that a compelling case can be made to consider DMT as a putative neurotransmitter.

Over time, the observations of the psychedelic phenomena experienced following the administration of DMT have led to speculation that endogenous DMT is possibly involved in psychosis, normal attributes and experiences such as creativity, imagination and dream states, maintenance of waking reality, altered states of consciousness including religious and/or spiritual phenomena, and NDEs. Even more far reaching and “other worldly” hypotheses have also been offered, suggesting that DMT, as well as other psychedelics, may provide actual proof of and/or philosophical insights into many of our unanswered questions regarding extraordinary states of consciousness. Regardless of the level and cause of such speculation and hypotheses, it is only scientific research that can inform or refute such thinking. There is no doubt that psychedelic research has been a forbidden fruit long ripening on the tree of knowledge.

Recent research has demonstrated that DMT is present in and is released from the pineal gland of live, freely-moving rodents. Although older data suggested that DMT might not be synthesized to any great extent in brain, studies have now shown that the necessary enzymatic components for the biosynthesis of DMT are present in discreet brain cell types and areas as well as other tissues not previously examined. New receptors for DMT have been identified and a potential role for DMT as a neuroprotectant and/or neuroregenerative agent has been suggested. Psychedelics have been shown to produce brain patterning resembling dream states, apparently mediated through 5-HT2A receptor activation. DMT's effect in this regard has yet to be examined, but raises speculation as to one of the possible roles of endogenous DMT.

As discussed above, more research is needed on DMT's natural role and function and interaction with other neurotransmitter systems. This will require the recommended future research into DMT biosynthesis, metabolism and binding, new methods for peripheral and central detection and data from administration, imaging and therapeutic trial studies. The data derived from the areas of research addressed above will no doubt suggest several possible new avenues for additional future research on DMT. In order to advance, however, regulatory blockades to psychedelic research must be removed. Progress in psychedelic research in these areas has been slowed due to over-regulation. For at least the last 50 years, research on DMT and other psychedelics has been impeded in the United States by passage of the Congressional Amendment of 1965 and the Controlled Substances Act of 1970 by the United States Congress that classified DMT and other major psychedelics as Schedule-I substances. Given the endogenous nature of DMT, it deserves a special status for future research.

It is evident that we have too long ignored the field of psychedelic research. This is especially true if continuing research demonstrates a clear role for DMT as an endogenous regulator of brain function. It is my opinion that these and many other possible approaches and hypotheses regarding DMT and other psychedelics are research endeavors that have great potential and are worthy of attention and support. Turning the newest technologies to this work, in genetics, analytical chemistry, molecular biology, imaging and others, we will no doubt acquire both new knowledge and ask new questions. If the politics of any one nation forbid it, perhaps others will take up the challenge to further the knowledge of our own potential and the further development and understanding of what we prize as our most unique human characteristic; the untapped possibilities of the mind.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6088236/
 
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Treating addiction: Cryo-EM technology enables the 'impossible'

Oregon Health & Science University | April 24, 2019

Scientists have used a compound found in the shrub iboga to reveal the three shapes of the serotonin transporter, a protein in the brain linked to anxiety and depression.

Using cryo-electron microscopy, the scientists examined the protein binding to ibogaine, an alkaloid that alters brain function and occurs naturally in the shrub iboga. Using ibogaine, researchers reveal the structure of the serotonin transporter in its outward-open, closed and inward-open shapes.

The discovery published today in the journal Nature.

"It means we can target different states of the transporter to modulate its activity," said senior author Eric Gouaux, Ph.D., senior scientist at the OHSU Vollum Institute in Portland, Oregon, and an investigator with the Howard Hughes Medical Institute. "It opens up new thinking as to how you might come up with novel molecules to bind to the transporter."

In describing the mechanism of how the protein works with ibogaine, co-authors said they expect the finding may open the door to developing medications that stop addiction without the hallucinogenic and other dangerous properties of ibogaine.

"There's a real need to develop molecules that have these anti-addictive properties," said co-lead author Jonathan Coleman, Ph.D., a researcher in the OHSU Vollum Institute.

In 2016, Gouaux led a team that first revealed the structure of the serotonin transporter, which provided new insight about how the antidepressants citalopram and paroxetine, two of the most widely prescribed selective serotonin reuptake inhibitors, or SSRIs, interact with and inhibit the transport of serotonin.

Influencing virtually all human behaviors, serotonin regulates the activity of the central nervous system as well as processes throughout the body, from cardiovascular function to digestion, body temperature, endocrinology and reproduction. The serotonin transporter acts as a molecular pump for serotonin, recycling the neurotransmitter following neuronal signaling. Serotonin shapes neurological processes including sleep, mood, cognition, pain, hunger and aggression.

The new study extends that groundbreaking work by showing the transporter's major conformations, or shapes. The National Institute for Drug Abuse of the National Institutes of Health provided the researchers with ibogaine, which is a Schedule 1 controlled substance that's tightly regulated under U.S. law.

"Most antidepressant drugs bind to the outward-open conformation, and our study shows ibogaine can bind to the inward state," said co-lead author Dongxue Yang, Ph.D., a researcher in Gouaux's lab.

"It provides many more avenues to design small molecules with anti-addictive properties," Coleman added.

Cryo-EM enables scientists to visualize molecules in near-atomic detail, however previous work has focused on relatively large proteins. This is one of the smallest molecules to be so clearly revealed through cryo-EM.

"That's a huge development for biomedical science," Gouaux said. "Five years ago, people would have said this was impossible."

 
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Faan Rossouw

An introduction to psychedelic tryptamine chemistry

by Faan Rossouw

This paper is intended for the general reader that has an appreciation for the beauty of chemistry, and/or desire to learn more about it. I am going to be pedantic throughout the paper, deconstructing technical terms and “dirty pictures” with the assumption that you do not know what they mean. That way we can learn them as we go along. If you are already fluent in Chemistrian, it goes without saying that you are free to skip over these and peruse selectively. This first section is an introductory exploration of the tryptamine class, and will be followed by further forays into other interesting aspects related specifically to this class before I move on.

The three main classes of psychedelics

There are three classes to which most psychedelic compounds belong – tryptamines, phenethylamines, and ergolines. The tryptamines include most of the well-known naturally-occurring psychedelics, including compounds derived from entheogenic fungi (psilocybin and psilocin), DMT, 5-MeO-DMT, bufotenin, and ibogaine. Mescaline is the only common naturally-occurring phenylethylamine, yet the class includes numerous well-known synthetic compounds such as MDMA and the 2-C’s. Ergolines most notable representatives include the naturally-occurring LSA and the semi-synthetic compound that turned on a generation, LSD.

Tryptamines

Psychedelics of this class are all derived from tryptamine, a ubiquitous endogenous ligand and agonist of the human trace amine-associated receptor 1 (TAAR1). The name tryptamine is derived from its structural similarity to l-tryptophan, an essential amino acid and the precursor to both serotonin and melatonin.

Substituted tryptamines

Although the “template” for psychedelics tryptamines is the molecule with all the various positions presented in Figure 2, in actuality there are limitations to how this manifests in psychedelic compounds. This is either because certain modifications are either difficult to impossible, or they lead to inactive compounds. An example of this is if something is attached to position 2 (Figure 2) the compound becomes a serotonin-2A receptor antagonist therefor losing its psychoactivity. Based on these restrictions we can simplify the template presented in Figure 2 to Figure 4, which is called the ‘substituted tryptamine’. The three main changes that synthetic chemists can make to derive psychedelic analogs is derived from this figure.

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First, one can add side chains to either position 4 or 5, and those side chains have to contain an oxygen molecule. We can confirm this by looking at all the well known psychedelic compounds that have side chains attached to the ring – bufotenine has a hydroxyl (OH) group at position 5, 5-MeO-DMT has a methoxy (O-CH3) at position 5, psilocin has a hydroxyl (OH) group at position 4, and psilocybin has a phosphoryloxy (OPO3H2) at position 4. All at position 4 or 5, all with an oxygen included.

The second major change that can be made is a substitution at the α-position. Chemists can methylate (add a methyl group) the alpha-position to change a non-orally active species into one with orally active. We will explore this in full detail in the next article.

The final feasible change is adding sidechains to positions N1 or N2. All five of the major naturally-occurring species we have discussed thus far possess methyls at both positions (hence “dimethyl” from which the DM in DMT is derived – more below). These methyls may be substituted with more complex alkyls, another way in which chemists can turn non-orally active tryptamines into orally active species.

Tryptamine psychedelics

Now that we have an idea of the chemical “archetype” of tryptamine psychedelics and the possible changes chemists can make, let’s have a look at the five most well-known naturally-occurring examples: DMT, 5-MeO-DMT, bufotenin, psilocybin, and psilocin.

DMT

The substitutive name for DMT is N,N-dimethyltryptamine. One of the most magical parts of learning chemical language is that from it one can deduce what they actual molecule looks like, and vice-versa. Let’s explore that using DMT as an example. Starting from the back we have tryptamine, so we know that is the foundation of our molecule – the indole ring with an ethyl in position 3 attaching to an amine. Then we have “dimethyl,” meaning two methyls. Okay so now we know it’s the tryptamine molecule that has two methyls added to it. And where are these two methyls? They’re both positioned on the nitrogen of the amine, hence ‘N,N’.

What’s interesting about N,N-dimethyltryptamine is that it forms the foundation for all four other compounds we are going to discuss. In other words, all four of them are N,N-DMT with a little something extra. We can see that because the term is contained within the substitutive name of all four other molecules. Let’s have a look.

5-MeO-DMT

The substitutive name for 5-MeO-DMT is 5-methoxy-N,N-dimethyltryptamine (Figure 6). We can see that it has the whole name of DMT in it, so when we draw it we know we can start with that molecule – a tryptamine with two methyls on the amine (red and blue). What’s left is ‘5-methoxy’, which means that at position 5 we have a methoxy (green). A methoxy is a combination of a methyl and an oxygen – hence the name.

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Bufotenin

The substitutive name for bufotenin is 5-hydroxy-N,N-dimethyltryptamine. As with 5-MeO-DMT, the molecule has DMT. But this time, instead of a methoxy at position five, we have the hydroxy, -OH.

Psilocin

The substitutive name for psilocin is 4-hydroxy-N,N-dimethyltryptamine. Same story, it starts with the structure of DMT (red and blue). If we compare them, we can see the psilocin is extremely similar to bufotenin, the only difference being where bufotenin had the hydroxy at position 5, here it is at position 4 (green). Later in this paper we learn why this small change is crucial to ensure that psilocin, unlike bufotenin, is an orally active species.

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Psilocybin

The substitutive name for psilocybin is 4-phosphoryloxy-N,N-dimethyltryptamine (Figure 9). By now I’m sure you’ve grokked it – it’s a DMT molecule (red and blue) with a little something extra. As with it’s cousin psilocin, that something extra is at position 4, but here instead of a hydroxy, it’s a phosphoryloxy with the composition OPO3H2 (green).

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The art of appetizing aromatics

In the previous section, I introduced the tryptamine class of psychedelics, and we discussed five well-known examples: DMT, 5-MeO-DMT, bufotenine, psilocybin, and psilocin. While the latter two, primary psychedelic constituents of Psilocybe mushrooms, are orally active, neither DMT, 5-MeO-DMT, nor bufotenine are. In this section we will explore two types of alterations that synthetic chemists can make to those molecules to bestow oral activity upon them. These alterations lead to the psychedelic tryptamine analogs (“research chemicals”): AMT (Indopan), MiPT, DiPT, 5-MeO-aMT (Alpha-O), 5-MeO-MiPT (Moxy), and 5-MeO-DiPT (Foxy Methoxy).

L-monoamine oxidase (MAO) are a family of enzymes that catalyze the oxidation of monoamines. Monoamines contain a single amine connected to an aromatic ring via a 2-carbon chain, and include neurotransmitters such as serotonin and norepinephrine, as well tryptamines such as DMT, 5-MeO-DMT, and bufotenin. The reason therefor that these compounds are not active after being consuming orally is because once they enter one’s gut they are inactivated by MAO.

If you want to experience the psychedelic effects of these compounds there are two basic strategies. The first is to use a route of administration that bypasses the gut. Smoking and vaporizing are by far the most common ways to achieve this, but are also the most intense (rapid onset) and shortest-lasting methods. Accordingly, some people favour other non-oral routes such as sublingual (under the tongue), insufflation (in the nasal passage), and rectal administration. Each of these administration routes has its own set of unique pharmacokinetic properties that may be favoured by certain people depending on the context and/or intention. Different strokes for different folks.

But that applies equally to oral delivery, which is unsurpassed in terms of its simplicity (swallow and then you’re done), ease and duration. Except for transdermal delivery, which is technologically complex and has severe restrictions on what can be administered, oral delivery is the longest lasting. Hence its popularity for journeyers that wish to go in deep. So even with a number of non-oral administration routes available, there is still good reason to utilize the oral route.

How to do so if we all walk around with an enzyme in our belly that will deactivate the psychedelic? Simple – consume another compound, called a monoamine oxidase inhibitor (MAOI), that will deactivate that enzyme. Ayahuasca is a prime example of this, though there are a number idiosyncratic formulas of the brew, in essence it is based on two core ingredients. One contains DMT, the most common being chacruna (Psychotria viridis), and the other contains the MAOI, which is always the ayahuasca vine (Banisteriopsis caapi).

Synthetic chemists love to ask “what if” questions. Like “what if” I make this simple change to the molecular nature of the compound, how does that then affect its properties? These type of questions are explored not only in the name of scientific curiosity, but also because studying how simple changes affect the properties of compounds informs us about its structure-activity relationship, as well provide intimations of what the target receptor looks and behaves like. To the specific question of whether or not a simple alteration to DMT/5-MeO-DMT can actuate oral activity chemists have thus far provided two answers – α-methylation and N-alkylation.

As we covered previously, DMT is a tryptamine molecule with two methyls at the N-position. So what would happen if, instead of adding two methyls to the N-position of the tryptamine, we added a single methyl to the alpha-position? This yields AMT (alpha-methyltryptamine), a molecule originally developed in the ‘60s by a Michigan-based pharmaceutical company called Upjohn and which was prescribed in the USSR as an antidepressant. It is at once psychedelic, entactogenic (like MDA/MDMA), and a stimulant with an oral dose typically lasting upwards of 12 hours.

The same goes for 5-MeO-tryptamine (mexamine) – if instead of adding two methyls to the N-position to form 5-MeO-DMT we add a single methyl to the alpha-position, we get 5-MeO-AMT – 5-methoxy-alpha-methyltryptamine (Figure 5). This orally-active and potent psychedelic, commonly known as ‘Alpha-O’, is sometimes peddled as faux-LSD. This is problematic as, unlike LSD with no known lethal toxicity, 5-MeO-AMT has lead to deaths at fairly low doses. It’s not a War on Drugs, it’s a War on People.

With both AMT and 5-MeO-AMT there is a chiral centre at the alpha-position. Attaching a single methyl to the alpha position potentially yields either an S- or R-configuration. Both are psychoactive, both orally active, but work by Dr. David Nichols lab has found that the S-enantiomer is more potent.

N-Alkylation

With N-alkylation we manipulate DMT and 5-MeO-DMT as the departure point to realize oral activity. Both these molecules possess two methyls on the amine nitrogen. Work again by Dr. Nichols’ lab has found that if you replace one, or both, these methyls with isopropyl, the molecule becomes orally active.

In the case of DMT, if a single methyl is replaced by an isopropyl it results in MiPT (N-methyl-N-isopropyltryptamine), an obscure psychedelic with indistinct effects first introduced to the world in TiHKAL. In the case of 5-MeO-DMT, the same single substitution results in 5-MeO-MiPT (5-methoxy-N-methyl-N-isopropyltryptamine). Commonly known as “Moxy”, it is an extremely potent (4 to 6 mg p.o.) psychedelic with stimulating properties.

As my articles on chemistry are intended for the general reader, I just want to take a brief moment here to remind you that the reason I always write out the substitutive name of each compound is because it describes the actual molecule. If we know the substitutive name, we can draw the molecule, and vice-versa. Let’s briefly review this by using Moxy as an example, but please feel free to skip over to the next paragraph if this is old news for you by now. Starting from back we have tryptamine, so our “foundational” structure is an indole ring with an ethyl chain at 3 which connects to an amine group. Then we start from the front – at position 5 we have a methoxy group, at N1 we have a methyl (fuschia), and then at N2 we have an isopropyl.

If both methyls are substituted by isopropyl, in the case of DMT the result is DiPT (N,N-diisopropyltryptamine), another bizarre creation of Sasha that primarily produces audial distortions. With 5-MeO-DMT the double substitution leads to 5-MeO-DiPT (5-methoxy-N,N-diisopropyltryptamine) which likely has the most endearing street name of any psychedelic – “foxy methoxy”. Note that in both cases, though making the additional isopropyl substitution retains oral activity, it decreases potency.

What’s Going On Here?

So why is it that in both the case of DMT and 5-MeO-DMT replacing a methyl with a slightly larger and more complex compound makes it impervious to deamination by MAO thereby giving it oral activity? To give us a clue we need to look at the nitrogen in the amine group – Figure 9. In order for MAO to deaminate a molecule it needs to access the lone electron pair of electrons (blue) on the nitrogen. A change in the molecule, such as substituting functional groups, changes its 3D-conformation. In the case of substituting a methyl with an isopropyl group on the amine, it changes the molecule’s 3D shape in such a way that shields the lone pair of electrons from MAO, thus giving it oral activity.

How do we know this is the case that it’s the molecule’s 3D shape that protects the lone pair from attack by the MAO and thus allows it to retain oral activity? Earlier in this article I said that MAO break down tryptamines. We then spoke about DMT and 5-MeO-DMT, but what about psilocybin and psilocin? They are naturally-occurring tryptamines, yet they are also orally active – how so? Pioneering work by Dr. David Nichols in the ‘80s using NMR spectroscopy showed that the fact that psilocin has a substitution at position 4 and not 5 (as with DMT/5-MeO-DMT) causes a critical change in the molecule’s 3D structure which ensures the compound is orally active. This study and all the profound implications for psychedelic chemistry gleamed from it will be the topic of the next section.

Afterword:

If it is your intention to consume DMT, and especially 5-MeO-DMT, orally by combining it with an MAOI please do your homework. And once you’ve done your calculations, double-check them. Terence McKenna used to quip that the only real danger with DMT is “death by astonishment.” Though that is the case for smoking it, overdoing orally-administered DMT/5-MeO-DMT can lead to serotonin shock, convulsions, and in some cases, death. The Psychedelic Ship is leaving the harbour, please don’t drop any cannonballs on the deck.

Why is psilocin orally active?

In the previous section we learned that though DMT and 5-MeO-DMT lack oral activity, chemistry wizards are able to change that. By making one of a variety of simple alterations to their structure they may be changed into analogs (“research chemicals”, or RCs), each possessing their own unique subset of characteristics including oral activity. That’s because the chemists changed the three-dimensional configuration of the molecules in such a way that the lone pair of electrons situated on the amine’s nitrogen became shielded, thereby preventing their degradation by MAO. To recap, if one consumes monoamines (such as certain tryptamines) orally, MAO transforms them in the gut and by the time they enter the bloodstream they are no longer psychoactive.

This section is going to unpack a study that showed, by comparing the structures of the naturally-occuring molecules psilocin and bufotenin why the former is orally active while the latter is not. This is another pioneering study from the lab of Dr. David Nichols, who is, along with Albert Hoffman and Sasha Shulgin, in my estimation one of the three true giants of psychedelic chemistry. Its his work and excellent lectures from ESPD50, Psychedelic Science (2013 and 2017), and Breaking Convention that restoked my appreciation for chemistry and inspired me to not only deepened my knowledge, but also to start this series of articles. The outpourings from his majestic mind has fundamentally shaped the topics and content of these articles… Shout out Big D, whut-whut!

The structure and atomic composition of a chemical is obviously critical to our understanding, and the progression of, chemistry and pharmacology. The problem with that is that molecules are small – really small. Even with today’s stupefying repertoire of advanced scientific analytical instruments there is still no practical way for us to observe their structure directly. So instead we have devised sophisticated methods in which to do so indirectly. One of these methods is called Nuclear Magnetic Resonance (NMR) Spectroscopy, which uses information about the spin of atomic nuclei to determine what a compound’s structure looks like.

In 1980 the team at Purdue University used NMR spectroscopy to investigate how the three-dimensional structures of bufotenin and psilocybin differ from one another. Even though these two compounds are constitutional isomers, there is a critical difference in their activity – psilocin is orally active, whereas bufotenin is not. This tiny change, moving the hydroxyl group from position 5 to 4 made this critical difference in the way they are absorbed by a human body. Though 2D-representations of the respective molecules are too low resolution to allude to the reason for the disparity, the researchers (correctly) suspected that by looking at their 3D-structures they would be able to understand why one molecule could resist deamination by MAO, while the other could not.

NMR spectroscopy revealed that the ethyl sidechain of bufotenin is able to rotate freely, meaning it can spin around on its own axis (Figure 5). That is however not the case for psilocin, something locks it in place, preventing it from rotating freely. The ethyl sidechains of the molecules are identical, which means that whatever is preventing the free rotation of psilocin’s ethyl sidechain is related to the hydroxyl group being situated at position 4, and not 5. To find out exactly what that was, the researchers used specialized software called LAOCN3. Before we explore what they found it would be useful to our interpretation of the results if we brushed up on a couple of elementary concepts in chemistry.

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There are two basic types of bonds that atoms can form with one another. The first, called an ionic bond, forms when atoms exchange electrons with one another. This happens if the encountering atoms possess large differences in their respective affinities for electrons (called electronegativity), one atom really wants to lose an electron, while the other really wants to gain it. So an electron (or electrons) are exchanged, and because it is negatively charged the transfer changes the charge of the each atom. The atom that gains the electron gains a negative charge and thus becomes negative, while the atom that loses the electron loses a negative charge and thus becomes positive. And as the old adage goes, opposites attract – the oppositely-charged atoms come together and form a stable bond with one another.

The other type of bond that can unite atoms is a covalent bond. This happens when atoms with similar affinity for electrons encounter one another, neither really wants to lose/gain an electron so they reach a compromise – they share their electrons among each other. Both atoms pretend that the electron that it shares, as well as the electron shared by the other atom, belongs to it. It’s this overlap of shared electrons that connects the atoms together into a single molecule.

Because there are no electrons that are transferred in the covalent bond the atoms don’t assume a charge as was the case with ionic bonds. However, that’s only partially true… In certain cases the atoms that take part in a covalent bond do have some difference in their affinity – not enough for them to exchange electrons and form an ionic bond, but enough so that when they form a covalent bond and share electrons those shared electrons are closer to one atom than the other. This is known as a polar covalent bond. The atom to which the shared electrons are in closer proximity has a higher electronegativity and thus becomes partially negative (δ-). Conversely, the atoms with lower electronegativity is further from the shared electrons and is partially positive (δ+). Because of this asymmetrical charge, polar molecules are able to form weak bonds with other polar molecules, or with compounds that have a net charge. Now that we’ve covered some basic concepts let’s get back to the results of the study and apply what we’ve learned by taking a closer look at psilocin.

Taken together: psilocin has hydroxyl group at position 4 with a partially negative oxygen and a partially positive hydrogen, and an amine with a nitrogen that is partially negative and carbons that are partially positive. Because of these partial charges something interesting happens – the partially positive hydrogen from the hydroxyl group and the partially negative nitrogen from the amine attract one another.

But what has this to do with the difference in oral activity between the two molecules? Turns out, everything. It’s this hydrogen bond and closed loop formation in psilocin which shields the lone pair of electrons situated on the nitrogen. Because MAO cannot access the electrons it cannot deaminate the molecule – this is why it can pass through the gastrointestinal system unchanged.

The hydrogen bond and resulting closed loop formation also lead to several other important changes in the property of the molecule which further accentuates its efficacy and potency as an orally-active psychedelic tryptamine. After generating 3D-models of the respective molecules, the researchers went on to compare their pKa, and Log P values.

When they measured the pKa and the Log P for both psilocin and bufotenin they found the following:

The pKa for Bufotenin is 9.67, meaning that at that specific pH-value equal amounts of the the molecule will be present in both the ionized (water soluble) and protonated forms (lipid soluble). When the molecule is in the blood, which has a pH of about 7.4, almost all of it (99.5 percent) is in the ionized form. In contrast, psilocin has a pKa of 8.47, closer to the pH of blood. So for psilocin, only about 52% is in the ionized form. That means that in the blood, 48% of psilocin will be in its unionized form versus only about 0.5% when it comes to bufotenin. As it is only the unionized form of the drug that can cross cell-membranes, this has profound implications for the potency of these two drugs – psilocin is not only able to better withstand degradation by MAO, but once it is in the blood there is also much more of it available in a form that can cross cellular membranes and thus can reach the target receptors and exert an effect.

The difference in pKa is also related to the shielding of the electron lone pair by the hydrogen bond. Amines possess a nitrogen with a lone pair of electrons. These free electrons, which carry a negative charge, are all too happy to snap up positively-charged protons (H+) from a solution they are in. This is, according to the Bronsted-Lowry acid-base theory, the very definition of a base – something that accepts protons. When it comes to psilocin the lone pair of electrons are shielded and are thus much less likely to accept protons. As a consequence, psilocin is less basic that is bufotenin.

The researchers also detected a difference in the Log P values – 1.19 for bufotenin, and 1.45 for psilocin. In the Log P scale a negative value indicates a compound which is hydrophilic, whereas a positive value indicates one that is lipophilic. Both these compounds are thus lipophilic, and psilocin, with the higher value, is more lipophilic. For drugs in general it is preferable for them to be lipophilic so as to be able to cross cell membranes, but not too lipophilic because then they immediately migrate to, and are stored in, the body fat. Research indicates that a Log P value of about 3.0 is the “sweet spot”, so psilocin is closer to this number, again indicating that its properties are more favourable once it enters the body.

The researchers started with a simple question: how is it that two isomeric compounds with such a small difference have such widely different properties when they are consumed orally? With NMR Spectroscopy we learned that it all has to do with the fact that because the hydroxyl group of psilocin is a little bit closer to the amine it was able to form a hydrogen bond between the two groups. This hydrogen bond shields the electron lone pair from deamination by MAO, which means that, unlike bufotenin, psilocin is orally active. The hydrogen bond also decreases the molecule’s proton-accepting capacity thereby decreasing its pKa value which means that at blood pH there is more of psilocin in the non-ionized (lipid soluble) form which is able to cross cell membranes and thus enter the central nervous system (CNS). Finally, we saw that it also affected the Log P value, and that psilocin is a more lipophilic compound, closer to an ideal value for drugs to effectively enter and bind to the appropriate receptors in the CNS.

http://altdotmind.com/an-introduction-to-psychedelic-tryptamine-chemistry/
 

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Towards an integration of psychotherapy and pharmacology: Using psychedelic drug-assisted psychotherapy
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by Dr Ben Sessa | Psychedelic Press | 22 Nov 2017

The fields of psychology and psychopharmacology have developed along surprisingly divergent historical trajectories, given their shared clinical endpoint. The subsequent schism between drug and psychotherapeutic treatments is artificial, and exaggerated by continued ignorance on both sides of the debate. In fact, such distinctions are relatively contemporary. There exists a rich history of shared psychotherapeutic-drug assisted clinical practices in pre-history and non-Western cultures using the psychedelic (hallucinogenic) drugs. These practices were re-invented in the 1950s and 1960s in Western medicine and are now enjoying a renaissance in contemporary research. It is postulated in this article that further development of psychedelic drug-assisted psychotherapy offers a bright future for the fields of psychology and psychiatry alike.

There exists in psychiatry a fundamental rift between our understanding of mental states (psychological processes) and brain states (organic or neurobiological processes). The Cartesian model drives both professionals and the general public to erect an immovable barrier between the mental and the physical. Despite decades of research into the neurophysiology of the brain, modern psychiatry’s continued pursuit of the pharmacological quick fix maintains this dualistic schism.

This essay will postulate a resolution of these contrasting models through the use of discrete, targeted, drug-assisted psychotherapy using specific pharmaceutical agents (the psychedelic drugs) that directly enhance the psychotherapeutic experience. A brief history of these drugs, their usefulness, their limitations and the state of modern research with psychedelics will be discussed in this paper.

The trouble with pharmacology

Despite their limitations, many of the drugs available to today’s psychiatrist are effective at relieving some of the symptoms of mental disorder. This is well-documented by scientific studies and supported by regulatory bodies such as the National Institute for Clinical Evidence (NICE) that make evidence-based recommendations for doctors to use as part of their clinical practice.

Nevertheless, the multiple factors (from genetics and the environment) that cause mental illnesses shape the vast range of treatment options available. Although drugs may have a role, they alone are insufficient to resolve problems. Combination therapies (psychotherapy alongside medication) are often the most effective. And there are always risks when prescribing medication. The incidence of iatrogenic illness increases year on year and is illustrated particularly in psychiatry. Despite the efforts of the NICE, there are sceptical voices about the ethics of drug trials that are financed and run by the pharmaceutical industry - who clearly have a product to sell.

Dissenting voices are growing within the medical profession, with professional bodies becoming progressively more cynical about drug company influences. It is not only the financing of research that is concerning, but also the insidious induction of doctors’ confidences through the sponsorship of conferences, gift offerings and—of course—the endless supply of office stationary.

It is clear that purely academic institutions, such as universities, could never compete with the budgets offered by drug companies. Objective research that potentially challenges the drug-treatments, therefore, does not get a fair chance at being developed. There are areas of medicine with important potential that are going un-researched. Examples include the ‘alternative therapies’, psychotherapy in general and, of course, psychedelic psychotherapy.

What is psychotherapy anyway?

Like drugs, psychotherapy is effective at reducing symptoms and improving the quality of life for patients. And clinical trials—whilst less numerous than those that champion drugs—robustly demonstrate these effects. Psychotherapy is therefore recommended, often in combination with drugs, by the NICE. In some cases psychotherapy has been shown to be more effective and better tolerated than drug treatments.

The term ‘psychotherapy’ has come a long way since Freud’s conception of psychoanalysis. There is little provision for this kind of lengthy treatment in today’s NHS. And attempts have been made to shorten psychoanalytical psychotherapy into more clinically manageable packages, such as Psychodynamic Psychotherapy. Driven partly by economics, the last 50 years has seen the development of increasingly brief and structured therapies. Some, e.g. Interpersonal Therapy and Cognitive Analytic Therapy bear some resemblance to their analytical roots. Whereas others, particularly in terms of structure and method, seem very far removed, e.g. Cognitive Behavioral Therapy and Dialectical Behavioral Therapy.

There are newer versions of psychotherapy appearing all the time. Their effectiveness is often dependent upon the skill and training of the therapist delivering the model and evaluating the different types can be difficult. Frequently no such differences can be observed. It has also been postulated that the ‘psychological mindedness’, personality traits and intellectual level of the patient can have effects on the efficacy of the treatment.

Despite the proven efficacy of psychotherapy, doctors are still over-prescribing medication for many mental disorders because of the relative ease and cheapness of doing so.

From schism to stigma

Both Descartes, and more recently Ken Kesey, author of ‘One Flew Over the Cuckoo’s Nest’, have a lot to answer for. Their works have had a lasting effect on how the public understand mental illness and psychiatry. The negative attitudes towards psychiatric patients and their doctors appear early in the medical training. Many people see such patients as lazy and weak-willed-frequently having brought problems upon themselves, and many see psychiatrists as eccentric and not quite ‘proper’ doctors. Much work has been done in recent years both from within the profession and from external, user-lead pressure groups to tackle this problem. Central to stigmatisation is the schism between mind and body, and how we, ‘the well’, justify our own mental health through polarising ourselves against those we label as unwell.

What has psychiatry become?

We are at the point now in the evolution of psychiatry that general medicine reached over a hundred years ago. At the turn of the 20th century our skills as doctors in recognising and categorising the epidemiology of physical illnesses was finely tuned. But we still had no idea how to defeat the great killers, the infectious diseases. We thought these diseases could never be beaten, but in fact the invention of antibiotics was just around the corner.

Similarly in mental health today we have become experts at skilful diagnosis and identification of the problems our patients have. But how effective are we really at treating disabling conditions like anxiety and depression?

Flattered and seduced by the possibility of a chemical quick fix we pursue the idea of a simple solution. This is the ultimate act of repression; blaming our psychological experiences on our hapless biology. This situation is analogous to our attribution of obesity to our ‘metabolism’, ignoring our gluttonous lifestyles and looking for a pharmaceutical wonder drug—the illusive ‘slimming pill’—that will allow us to continue our greedy way of life.

It is only through demanding re-visitation of those memories that we can reprogram the psychological processes into their appropriate pigeonholes. There is no easy and non-toxic solution. It was the chronic, relentless experience of human relationships that gave us these neuroses - and only through careful examination and re-visiting of these memories with psychotherapy can we begin to untangle the mess. No, there are no wonder pills. And there are no stomach staples or frontal lobotomies either.

Partial resolution of this schism with drug-assisted psychotherapy

In relation to the division between biological and psychological models of mental illness and treatment, a necessary shift could perhaps come from combining the psycho?therapeutic experience with an acute drug experience designed to enhance the psychotherapy. This differs, of course, from the current practice of using a course of drugs (such as SSRIs), taken daily over many months or years, to improve somatic and psychological factors—either alongside a course of psychotherapy or (as more often occurs), without any added psychological input.

Drug-assisted psychotherapy, as will be described here, involves the patient undergoing a short, time-limited course of psychotherapy, during which some of the sessions (perhaps as few as just two) are enhanced by the acute action of a drug that has specific properties conducive to improving the efficacy of the psychotherapy. There is a class of powerful psychoactive substances—the psychedelic, drugs—that characteristically boost important factors present in the psychotherapeutic experience.

What are psychedelic drugs?

There are several ways in which to define these substances. Many psychiatrists may define them as psychotropic agents that produce profound alterations in consciousness, and may induce perceptual distortions as part of an organic psychosis. However, the psychedelic experience has significant differences from the psychotic episode. Firstly, in the psychedelic experience the perceptual distortions and the changes in thinking are extremely fleeting and dynamic, abnormal beliefs are rarely held with the rigid and unshakable quality of psychotic delusions. And secondly, crucially, in almost every case the informed user of a psychedelic drug has full insight into their experience as being secondary to intoxication with a drug.

Some different types of psychedelic drugs:

The ‘Classical’ psychedelics:

- LSD-25 (Lysergic Acid Diethylamide)
- Mescaline (3,4,5-trimethoxyphenylathylamine)
- Psilocybin (4-hydroxy-N,N-dimethyltryptamine)
- DMT (dimethyltryptamine)

The Entactogens or empathogens:

MDMA - ‘Ecstasy’ (3,4-Methylenedioxymethamphetamine). There are many other drugs in this group - mostly based around the structure of phenethylamine

The Dissociative Anesthetics:

- Ketamine
- Phencyclidine

Some researchers may also class the psychological effects of cannabis (tetrahydrocannabinol) as psychedelic at high doses.

Characteristics of the Psychedelic Experience that may enhance the Psychotherapeutic Experience

Psychedelic drugs produce a variety of mental phenomena. The effects on perceptions are particularly well recognized. But perhaps the most interesting effects of the psychedelic experience are those that can facilitate psychotherapy. It is postulated these drugs can improve the depth and speed of psychotherapy, through making therapeutic use of regression, abreaction, transference and symbolic drama. And the newer drug MDMA is often credited with the ability to increase empathy and shared understanding between the patient and therapist.

Another feature of the experience is the presence of eidetic images, which are seen ‘in the mind’s eye’, with the eyes shut. They range from simple geometric shapes to complex figures involved in scenarios that have an intense personal meaning. These images often have an archetypal element and may represent relevant material from the patient’s unconscious. In the therapeutic environment offered by a skilled psychedelic therapist, the meaning of the images can be interpreted and explored to reveal otherwise inaccessible parts of the psyche. If Freud called dreaming ‘the royal road to the unconscious’ then this internal visual element of the psychedelic experience is more like a Technicolor super-highway to the unconscious.

The nature and the quality of the hallucinatory experiences are identical with the dreams of some patients during the course of analysis. But like dream-work analysis in traditional psychotherapy, one must be cautious to not interpret all the content of such experiences in its entirety - the real value lies in using these images as a springboard with which to free-associate and access repressed parts of the unconscious.

This can be particularly helpful in the recall of painful memories that, unlike dreams, can then be worked through with the therapist in real, waking time. The patient under the influence of a psychedelic drug, accompanied by an experienced guide, may therefore revisit past traumatic experiences with great clarity. Many patients, who had previously been disabled by unremitting neuroses were able to benefit from this approach.

The therapeutic effects of a drug like LSD do not come entirely from the drug’s pharmacological properties. The drug acts as a catalyst that, in combination with extra-pharmacological factors, such as the patient’s pre-existing attitudes, personality and expectations (mindset), together with the structure of the environment in which the drug is taken (including the quality of the relationship between the user and their guide) - the setting - determines the quality and nature of the experience. This accounts for the extreme variability of the experience. But when taken in a clinical setting, the material revealed is of such personal relevance to the patient that if interpreted wisely, it can be of significant value.

*From the article here: https://psychedelicpress.co.uk/blog...herapy-pharmacology-psychedelic-therapy-sessa
 
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LSD and the serotonin receptor

UNC School of Medicine

For the first time, UNC School of Medicine researchers crystalized the structure of LSD attached to a human serotonin receptor of a brain cell, and they may have discovered why an LSD trip lasts so long.

CHAPEL HILL, NC – A tiny tab of acid on the tongue. A daylong trip through hallucinations and assorted other psychedelic experiences. For the first time, researchers at the UNC School of Medicine have discovered precisely what the drug LSD looks like in its active state when attached to a human serotonin receptor of a brain cell, and their first-ever crystal structure revealed a major clue for why the psychoactive effects of LSD last so long.

Bryan L. Roth, MD, PhD, the Michael Hooker Distinguished Professor of Protein Therapeutics and Translational Proteomics in the UNC School of Medicine, led the research, which was published today in Cell.

“There are different levels of understanding for how drugs like LSD work,” Roth said. “The most fundamental level is to find out how the drug binds to a receptor on a cell. The only way to do that is to solve the structure. And to do that, you need x-ray crystallography, the gold standard.”

That is what Roth’s lab accomplished – essentially “freezing” LSD attached to a receptor so his team could capture crystallography images. As it turns out, when LSD latches onto a brain cell’s serotonin receptor, the LSD molecule is locked into place because part of the receptor folds over the drug molecule, like a lid. And then it stays put.

“We think this lid is likely why the effects of LSD can last so long,” said Roth, who holds a joint appointment at the UNC Eshelman School of Pharmacy. “LSD takes a long time to get onto the receptor, and then once it’s on, it doesn’t come off. And the reason is this lid.”

Eventually, though, an acid trip ends. Some LSD molecules pop off their receptors as the lid moves around. Also, brain cells eventually respond to this strange molecule by sucking the receptor into the cell, where it – along with the LSD – is degraded or disassembled for recycling.

Postdoctoral researchers Daniel Wacker, PhD, and Sheng Wang, PhD, led the experiments to crystallize LSD bound to a serotonin receptor and discover why it stays bound so long. “Serotonin, obviously, hits this receptor on brain cells,” Wacker said. “But our experiments show that serotonin does not interact with this lid in the same way LSD does.”

Although other labs have reported that LSD “washes” out of the brain’s fluid within four hours, such experiments could not determine what was happening on or inside brain cells. Roth’s lab has shown for the first time that LSD is very much not washed out of the serotonin receptors located within the membrane of brain cells in a few hours.

How this popular drug causes such powerful effects has remained a mystery ever since Swiss scientist Albert Hofmann first accidently synthesized and dosed LSD to report its effects in 1938. Now, because of the work of Roth’s lab, scientists can begin to parse how the drug sparks such a dramatic reaction in the brain, just as the scientific and medical communities renew interest in the drug as a potential treatment for a number of conditions, such as cluster headaches, substance abuse, and anxiety associated with life-threatening conditions.

For two decades, Roth’s lab – first at Case Western Research University and then upon his arrival at UNC in 2005 – had been trying to crystalize LSD attached to its receptor through a series of tedious and unsuccessful experiments. Others, too, have been trying. Without crystals, no one would be able to see what LSD bound to a receptor would look like.

“To get crystals of a known compound bound to its receptor is incredibly difficult,” said Roth, who is also director of the National Institute of Mental Health's Psychoactive Drug Screening Program housed at UNC. “In some cases, it’s nearly impossible.”

There are a few reasons why crystallizing LSD bound to a receptor is difficult. The first is lack of material; the receptors need to be produced in the lab using a number of tricks such as generating a virus that than infects cells and generates the receptor. Second, the receptors are incredibly flexible, even when compounds such as LSD are bound to them; the receptors do not want to sit still. Third, unlike, say, a molecule of water, a serotonin receptor is highly complex and composed of thousands of atoms.

Wacker explains: “We need a lot of receptors to generate an image because of their small size – much smaller than the wavelength of visible light. Instead we use x-rays, but for that to work we need all of these receptors to sit perfectly still, and they all need to sit still in the same exact way, and that’s what happens in crystals. So, even if you create a lot of serotonin receptors and attempt to crystallize them, one receptor might twitch in one direction, another receptor might twitch in another direction, a third receptor might not be bound to the LSD, and a fourth receptor might have a lid that moves a little more than the other receptors. So, we need to dissolve all these receptors in water and then slowly take away the water. The temperature needs to be just right. And then we need to employ all kinds of experimental tricks to continue to draw out the water and convince the molecules to sit still so that they will want to crystallize.”

"It’s sort of like letting soup sit out overnight,"
Wacker says. "You’ll notice salt crystals at the bottom. That’s because the salt in the soup is dissolved in water, but then as water slowly evaporated over time, salt molecules latch onto each other to stay stable. The result: crystals."

But serotonin receptors are not soup. Getting serotonin-LSD crystals took Wacker and colleagues two years, but once they got crystals, the serotonin receptors with LSD were packed tightly together. And that allowed them to shoot x-rays at the receptors, which allowed them to create images of atomic resolution.

Then UNC postdoctoral researcher John McCorvy, PhD, discovered that the lid was the key to LSD being bound to its serotonin receptor. McCorvy and colleagues created mutant receptors with floppier lids, and they found that LSD bound more quickly and also detached from the receptor more easily. They also noticed that the shorter binding times led to different signaling patterns inside cells. These different patterns likely means that the effects of LSD would have been different than the typical effects with the lid tightly secured.

Ron Dror, PhD, and his team at Stanford used computer simulations to confirm that this is what might happen when LSD engages its receptor protein in a human brain.

“There is a headache drug that binds to the same receptor as LSD,” Dror said. “The two drugs bind in the same receptor pocket, but the shape of that binding pocket is different when one drug or the other is bound. We used computer simulations to help explain why the two drugs favor different binding pocket shapes."

Another aspect of this computational work focused on the fact that the receptor site is not static—the receptor and the drug are both highly dynamic. “They wiggle around all the time," Dror said. “It has long been observed that LSD trips are long. The simulations helped explain why the receptor holds onto LSD for so long despite the fact that they have such a dynamic connection.”

https://www.med.unc.edu/pharm/news/...d-attached-to-a-brain-cell-serotonin-receptor
 
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Neuroendocrine associations underlying the persistent therapeutic effects of classic serotonergic psychedelics

Emmanuelle A. D. Schindler, Ryan M. Wallace, Jordan A. Sloshower & Deepak C. D’Souza

Recent reports on the effects of psychedelic-assisted therapies for mood disorders and addiction, as well as the effects of psychedelics in the treatment of cluster headache, have demonstrated promising therapeutic results. In addition, the beneficial effects appear to persist well after limited exposure to the drugs, making them particularly appealing as treatments for chronic neuropsychiatric and headache disorders. Understanding the basis of the long-lasting effects, however, will be critical for the continued use and development of this drug class. Several mechanisms, including biological and psychological ones, have been suggested to explain the long-lasting effects of psychedelics. Actions on the neuroendocrine system are some such mechanisms that warrant further investigation in the study of persisting psychedelic effects. In this report, we review certain structural and functional neuroendocrinological pathologies associated with neuropsychiatric disorders and cluster headache. We then review the effects that psychedelic drugs have on those systems and provide preliminary support for potential long-term effects. The circadian biology of cluster headache is of particular relevance in this area. We also discuss methodologic considerations for future investigations of neuroendocrine system involvement in the therapeutic benefits of psychedelic drugs.

Introduction

There has been a resurgence of interest in the therapeutic potential of classic serotonergic psychedelic drugs, such as psilocybin, LSD, and DMT, all compounds that bind and activate serotonin 2A receptors. Psilocybin has been reported to treat depression and anxiety in cancer patients, obsessive-compulsive symptoms, and alcohol and tobacco addictions, as well as enhance attitude, mood, and behavior. In early studies, LSD has been shown to be effective in the treatment of alcoholism, and it improved affect and sleep while reducing pain in cancer patients. More recently, LSD has been shown to improve quality of life in patients with life-threatening disease. Surveys have also described relief from cluster headache with LSD and psilocybin. Ayahuasca, the botanical brew containing DMT and a monoamine oxidase A inhibitor, produces an antidepressant effect and reduces symptoms of panic and hopelessness. There are ongoing studies investigating the effects of psychedelics in depression, drug and alcohol addiction, and headache disorders. One of the most intriguing features of psychedelics’ therapeutic profile is the apparent persistence of therapeutic effects after limited exposure, such measures as antidepressant effects, cigarette smoking reduction/cessation, and termination of cluster headache attacks. While the mechanisms of this ability to produce long-term effects are not fully understood, neuroplastic, genetic, and psychological, processes are some of those postulated to be involved. The neuroendocrine system is another potential player in the lasting effects of psychedelics after limited exposure, particularly as the conditions shown to benefit from psychedelic therapy have demonstrable neuroendocrine aberrations. In this review, we describe certain structural and functional aspects of the neuroendocrine pathologies in neuropsychiatric disorders and cluster headache, as well as the effects that classic serotonergic psychedelics have on these systems. Where applicable, those associations with the most supportive evidence for a persisting therapeutic effect will be discussed. This review will also serve to unify existing theories for the persisting effects of classic serotonergic psychedelics and highlight methodological strategies for future research in this area.

Theories for the persisting effects of classic sertogeneric psychedelics

Classic serotonergic psychedelics are those compounds that bind and activate the 5-HT2A receptor and cause significant alterations in sensorium and consciousness. While other drugs, such as MDMA, THC, and ketamine, are often included in the category of psychedelic drugs and may have indirect effects on 5-HT2A receptors, their pharmacology is nevertheless distinct. For the purposes of this discussion, the pharmacologic definition of a 5-HT2A receptor agonist with psychotropic effects will be used when discussing psychedelics. The terms psychedelic and hallucinogen will also be used interchangeably.

The pharmacology of psychedelics has long been considered in their unique effects. The primary focus has involved the 5-HT2A receptor, as the binding affinity of psychedelics at this receptor is strongly correlated to the typical human dose for hallucinogenesis. The roles of specific intracellular 5-HT2A receptor components and scaffolding proteins, such as B-arrestin, have been considered in identifying a marker for hallucinogenesis. The relative potencies and efficacies at activating 5-HT2A-mediated phosphatidylinositol hydrolysis and arachidonic acid release have also been investigated, but were not found to predict psychedelic potency or discriminate psychedelic from non-psychedelic drugs.

The density of 5-HT2A receptors can be manipulated to measure changes in the response to psychedelics. For instance, repeated daily administration of the psychedelic DOI in rats and rabbits leads to a reduction in cortical 5-HT2A receptor density by about 50%. Serotonin2A receptor reduction is accompanied by significant attenuations in 5-HT-elicited PI hydrolysis signaling, as well as psychedelic-elicited behaviors, such as head movements in rodents and rabbits. In rats, chronic administration of either LSD or DOI attenuated the locomotor inhibition induced by either drug. Similarly in rabbits, chronic administration of DOI significantly decreased the head bob response to either DOI or LSD. Such cross-tolerance was also shown in cats when a single dose of the psychedelics DOM, LSD, or mescaline attenuated DOM-elicited behaviors 24 h later. In humans, tolerance, or tachyphylaxis, to a psychedelic’s effects occurs within about 3 days of daily exposure; sensitivity returns in about as many days. Unlike other psychedelics, however, DMT does not readily induce tolerance, which may be due to its short half-life or other yet unidentified factors. For instance, human subjects who received closely spaced repeated administrations of intravenous DMT failed to demonstrate tolerance to the psychedelic effects of the drug. The ability of psychedelics to induce tolerance is relevant in the consideration of their use as therapeutic agents.

The pharmacologic effects of limited or infrequent exposure to a psychedelic have not been extensively investigated, though they are sometimes reported in chronic administration studies. One group found that single administrations of LSD or DOI in rats did not affect cortical 5-HT2A receptor density at low doses, but did so at high doses. DOM reduced cortical 5-HT2A receptor density in rats after 2 doses spaced 8 h apart. In mice, a single dose of DOI resulted in a significant increase in DOI-elicited head twitches out to 6 days, suggesting a super-sensitivity of the behavior. Species differences are important to consider here. For one, genetic differences between mouse and human 5-HT2A receptor genes distinguish pharmacologic interactions with ligands. Furthermore, the binding properties of a number of serotonergic drugs in rabbits is more similar to those in humans than rats. Additional studies examining the effects of single or intermittent dosing of psychedelics that include multiple measures taken at extended time points could help identify the pharmacologic substrate for persisting therapeutic effects.

In addition to the 5-HT2A receptor, psychedelics have appreciable activity at other serotonergic receptors, such as 5-HT2C and 5-HT1A receptors. The 5-HT2C receptor is involved in anxiety, dopaminergic neurotransmission, regulation of body weight, and addiction. Importantly, 5-HT2C receptors have been implicated in the lack of addictive properties of the psychedelic drug class. The serotonin1A receptor has been associated with neurogenesis, neuroprotection, depression, anxiety, dopaminergic neurotransmission, thermoregulation, and endocrine function. In animal studies, 5-HT1A receptor inhibition has been found to block various effects of psychedelics, such as drug stimulus cues and locomotor activity reduction. Across drugs, the importance of 5-HT1A receptor activation may differ, however. For example, in rats, the drug stimulus cue of psilocybin was not affected by 5-HT1A receptor blockade, though the LSD cue was found to be modulated by 5-HT1A receptor activation. In humans, 5-HT1A receptor blockade with pindolol enhanced the effects of a sub-psychedelic dose of DMT in humans. In addition to its 5-HT1A receptor inhibition, pindolol may enhance the effects of drugs through adrenergic inhibition. The role of 5-HT1A receptor activation in neurogenesis has been associated with the therapeutic effects of antidepressants. In mice, a single low dose injection of psilocybin tended to stimulate hippocampal neurogenesis 2 weeks after injection, though a high dose inhibited it. This dose effect may stem from counteractions mediated by 5-HT2A receptors. Another receptor involved in hippocampal neurogenesis is sigma-1. Activation of sigma-1 receptors is similarly associated with a reduction in depressive behaviors in mice. The sigma-1 receptor has also been associated with psychotropic drug effects. Ultimately, the actions at any one receptor cannot explain either the acute or persisting effects of these drugs. Additional systems associated with the action of psychedelics are dopaminergic, glutamatergic, and GABAergic systems.

Genetics

Single doses of LSD and DOI induce a number of immediate early genes in various regions of rodent brain, including cortex, amygdala, nucleus accumbens, and striatum. These various genes have been implicated in memory and synaptic plasticity and most remain active for several hours following drug treatment, which may initiate the processes involved with longer term phenotypic changes. The induction of some genes, such as c-fos and Arc, is non-specific and seen with other serotonergic drug groups, such as antidepressants and 5-HT2A receptor antagonist antipsychotics. The induction of egr-1, egr-2, and period 1 genes was previously described as hallucinogen-specific as the effect was seen in mouse somatosensory cortex 1 h after LSD and DOI injection, but not lisuride injection. Gene induction likely depends on the model being used, however. For example, egr-2 expression was increased in rat cortical tissue cultures after LSD, but not lisuride, treatment, though in a human study, LSD failed to alter expression of egr-1, -2, or -3 in peripheral blood at 1.5 or 24 h after ingestion. Thus, while gene activation studies offer a valuable means to identifying long-term effects, results should be interpreted with careful consideration.

Epigenetics

Another possibility is that psychedelics may produce long lasting changes through epigenetic mechanisms. Decades ago, psychoactive doses of intravenously administered LSD were shown to rapidly increase histone acetylation in rabbit brain tissue. In contrast, another early experiment showed that neither LSD nor the phenethylamine psychedelic, mescaline, inhibited interactions between nucleic acids and histone. Although studies of the epigenetic effects of psychedelic drugs are extremely limited, future investigations may seek to focus on those components identified in related conditions. For instance, animal models of anxiety and depression have implicated methylation of the promoter in the serotonin transporter gene, SLC64A, and activity of histone deacetylase 6. Epigenetic modification of the glucocorticoid receptor gene, NR3C1, has also been associated with conditions of stress.


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Nick and Usha Sand

Psychological processes

The psychedelic experience itself has been suggested as a potentially beneficial or transformative therapeutic force with lasting effects. When administered under supportive conditions, psilocybin and LSD have been shown to result in peak experiences with substantial and sustained personal meaning and spiritual significance. Recent clinical trials of psychedelic drugs in the treatment of psychiatric disorders have demonstrated a correlation between the occurrence of such peak experiences and therapeutic benefits. The mechanisms by which peak experiences lead to these benefits are currently not well understood. If traumatic events are capable of causing epigenetic modifications within brain regions that influence behavior, as well as persistent structural and functional changes in limbic and neuroendocrine systems as observed in PTSD, then it is plausible that powerful positive or cathartic experiences, such as some psychedelic-occasioned peak experiences, “may function as a salient, discrete event producing inverse PTSD-like effects – that is, persisting changes in behavior associated with lasting benefit.” While admittedly speculative, a powerful event holding significant salience could lead to epigenetic changes or have effects on limbic circuitry that in turn alter neuroendocrine function, potentially reversing previously dysregulated systems caused by acute or chronic stress. This could help explain how psychedelic-assisted therapies not only have persisting effects, but why they may have therapeutic potential across a range of neuropsychiatric disorders.

Psychedelics have also been described as “meaning-response magnifiers," serving to enhance the effects of placebo and set and setting. Indeed, LSD was found to enhance suggestibility in human subjects as measured by the creative imagery scale. The subjective effects of LSD have also been equated to those produced by hypnotic therapy, the combination resulting in more pronounced alterations in consciousness. The significance of such factors as intention, expectancy, preparation, and social setting in treatment outcomes is well recognized. The placebo effect has also been discussed in the context of pain and reward circuitry. A role for oxytocin has also been proposed. As reviewed elsewhere, set and setting are well-known to influence the response to psychedelics. Studerus et al. studied the influence of several predictor variables on the acute response to psilocybin in pooled data from 23 controlled experimental studies involving 261 healthy volunteers who had participated in 409 psilocybin administrations. They confirmed that non-pharmacological factors play an important role in the effects of psilocybin. Thus, high emotional excitability and the experimental situation of undergoing positron emission tomography imaging most strongly predicted unpleasant and/or anxious reactions to psilocybin. The interplay of psychedelics with a subject’s and the environment’s influence adds another facet to their potential therapeutic repertoire.

Neuroendocrine anatomy and functional imaging

The hypothalamus produces neuropeptides that regulate various biologic functions. The posterior hypothalamus, comprised of the paraventricular and supraoptic nuclei, produces oxytocin and vasopressin, which are transported via the infundibulum to the posterior pituitary to be released into the blood. The anterior and lateral portions of the hypothalamus, comprised of several nuclei, produce such neuropeptides as corticotropin releasing hormone and thyrotropin releasing hormone, which are released into the anterior pituitary to stimulate release of their respective hormones. Some such anterior pituitary hormones include adrenocorticotropic hormone, thyroid stimulating hormone, prolactin, and orexin. Many biological functions are influenced by the neuroendocrine system and consequently, altered neuroendocrine function has association with a broad range of disorders.

The hypothalamus contains those receptors activated by psychedelics, including 5-HT2A, 5-HT1A, dopamine, and sigma-1. An early study demonstrated that acute injection of LSD in rats increased “neurosecretory materials” in the excised posterior pituitary. More recently, DOI has been shown to induce serum increases of oxytocin, prolactin, ACTH, and corticosterone in rats, an effect blocked by either subcutaneous or intraparaventricular injection of 5-HT2A antagonist MDL100,907. Serotonin2A receptor binding in the paraventricular nucleus of rats was decreased after repeated daily injections of DOI, an effect accompanied by reduced DOI-induced serum oxytocin and ACTH levels. Interneurons and afferent fibers are likely to be involved with the neuroendocrine effects of psychedelics as well. Indeed, cortical, subcortical, limbic, and brainstem inputs are involved with neuroendocrine regulation. For example, serum cortisol increases in rhesus monkeys exposed to stress were associated with increased subgenual prefrontal cortex metabolism as measured by F-18-fluorodeoxyglucose PET imaging. In Vietnam combat veterans undergoing trauma recall, serum ACTH increases were associated with increased cerebral blood flow in the right insula and decreased activation of medial prefrontal cortex measured by H2O PET. In contrast, the so-called ACTH non-responders in this study activated medial prefrontal cortex and deactivated amygdala and hippocampus. Increased hypothalamic glucose metabolism has also been identified in depressed patients presented negative stimuli.

Functional brain imaging has shown that the inferior region of the posterior hypothalamus is activated during cluster attacks. Cluster attacks are the paroxysms of cluster headache, a disorder characterized by episodes of unilateral retro-orbital pain so severe the disorder is coined “suicide headache.” In addition to activation, the volume of posterior hypothalamic gray matter is increased in cluster headache patients compared to healthy controls and appears slightly lateralized to the side of attacks. The posterior hypothalamus is also the target of deep brain stimulation in the most refractory cases of cluster headache. It has been proposed that chronic stimulation of the posterior hypothalamus prevents activation, thus modulating activation of the trigeminal complex, resulting in pain relief. Indeed, after 1 month of posterior hypothalamic DBS activation in refractory cluster headache patients, sublingual nitroglycerin failed to trigger a cluster attack. Imaging has also served to identify pituitary lesions manifesting as a cluster headache syndrome, that improves or resolves with treatment of the particular lesion.

Psychedelics produce measurable effects in the brain that may speak to their role in treating disease. In a review of neuroimaging studies, psychedelics are understood to generally increase prefrontal and limbic activity and decrease amygdala and default mode network activity, a combination that could serve to enhance interoception and cognition while blunting anxiety, fear, and rumination. Vollenweider et al. reported that psilocybin increased glucose metabolism in the brains of healthy human volunteers, increases in cortical regions being greater than those in subcortical regions. Similarly, in another human PET imaging study, psilocybin increased the cortical/subcortical ratio of metabolism. This study specifically found decreased metabolism in subcortical regions relative to placebo. Another group found decreased amygdalar reactivity in healthy volunteers after oral psilocybin ingestion. As measured by single photon emission tomography, oral ayahuasca increased cerebral blood flow in the left nucleus accumbens, right insula, and left subgenual area, regions associated with mood regulation. Intravenous LSD increased connectivity in frontal, parietal, and temporal cortices and bilateral thalami. Taken together, these investigations may inform the neurobiological underpinnings of the therapeutic potential of psychedelics to treat depression, anxiety, and drug addiction. One study specifically described decreased hypothalamic blood flow, as measured by arterial spin labeling and blood-oxygen level-dependent methods, after intravenous administration of psilocybin in healthy humans, which may hold relevance for treatment in cluster headache, although all brain regions of interest were found to have decreased blood flow in this particular study.

Regarding cluster headache, it remains unknown how brief psychedelic exposure could affect the activation threshold of the hypothalamus or other relevant brain regions. The traditional dosing regimen for terminating cluster periods or inducing remission in chronic cluster headache is two to three doses, approximately 5 days apart, of psilocybin, LSD, or other psychedelics. How this traditional dosing regimen affects posterior hypothalamic anatomy and function is unknown, but could be investigated further with functional imaging, including a challenge of nitroglycerin or another attack trigger, such as ethanol.

Hypothalamus–Pituitary–Adrenal axis

In the well-described hypothalamus–pituitary–adrenal axis, CRH from the anterior hypothalamus stimulates the release of ACTH from the anterior pituitary, which in turn acts in the adrenal gland to stimulate the release of such hormones as cortisol, aldosterone, and adrenaline. With widespread actions, the HPA axis is best known for its roles in stress, metabolism, and inflammation. Manipulation of this system, even short-term, can have lasting effects. For instance, antenatal glucocorticoid exposure in humans has been associated with structural brain abnormalities, behavioral disturbances, and affective disorders from infancy to adulthood. Childhood trauma and repeated stressful life events in adulthood also increase the risk for metabolic syndrome. Epigenetic modification of the glucocorticoid receptor gene, NR3C1, has been documented in such conditions as maternal stress, childhood maltreatment, and war trauma. Moreover, these epigenetic, as well as behavioral and physiologic changes are reported to persist into subsequent generations.

In otherwise healthy individuals with depressive symptoms, HPA axis abnormalities have also been identified, such as elevated basal cortisol levels and abnormal responses to the dexamethasone suppression test, which normalize with treatment. Long-term exposure to prednisone, which mimics the biological effects of hypercortisolism in depression, is also associated with depressive symptoms. In contrast to depression, individuals with PTSD show lowered baseline cortisol levels and greater cortisol suppression following a dexamethasone challenge. This is hypothesized to be secondary to the persistent intrusion of prior trauma leading to a repetition of the physiological stress response, thus altering HPA functioning. In alcoholic patients, basal cortisol levels may vary depending on the amount of alcohol consumed. In abstinence, serum cortisol and serum and cerebrospinal fluid levels of ACTH did not differ among controls and alcoholics, though ACTH release induced by ovine CRH was suppressed in early abstinence. In cluster headache, cortisol levels are increased during cluster periods, an effect that appears to be independent of headache pain or lack of sleep. Short term systemic glucocorticoid therapy is used in the treatment of cluster headache. There is also evidence for lasting effectiveness after suboccipital steroid injection in cluster headache.

Serotonin, as well as DOI, has been reported to stimulate CRH release from explanted rat hypothalami, containing the PVN, in a dose-dependent, inverted-U manner, DOI and the related phenethylamine psychedelic DOB both dose-dependently raised serum levels of ACTH and corticosterone in rats. ACTH and cortisol increases have also been found in humans after oral ingestion of LSD, psilocybin, and ayahuasca, as well as intravenous administration of DMT. Hormone increases are not specific to serotonergic psychedelics, however. Other psychotropic agents, such as MDMA and THC, also stimulate hormone production and release. Investigating functional outcomes and epigenetic effects after treatment may reveal additional therapeutic actions that are more specific to serotonergic psychedelics.

Oxytocin

Oxytocin is a neuropeptide that plays a central role in social functions, particularly the attachment process, but also sexual behavior, maternal behavior, affiliation, and social memory. Administration of oxytocin has anxiolytic and anti-depressive effects in rodents. While there have been mixed results about oxytocin levels in depression, certain oxytocin receptor single nucleotide polymorphisms have been associated with unipolar depression and could be a mediator of selective serotonin reuptake inhibitor response. Oxytocin is also likely involved in the pathophysiology of PTSD and there is reason to believe it could be helpful in its treatment, particularly given its role in stress responsiveness, fear conditioning, and social functioning, all of which are impacted by PTSD. Post-mortem examination of patients with alcohol disorder showed reduced oxytocin mRNA levels as compared to controls. In turn, intranasal oxytocin has been shown to reduce withdrawal symptoms in alcoholic patients. Oxytocin is further implicated in pain processing; oxytocin receptors are localized on trigeminal ganglion neurons, which directly implicates headache and facial pain disorders. There is also support for therapeutic activity of oxytocin in migraine headache, which theoretically could extend to cluster and other headache types.

DOI acutely increased oxytocin levels in rats, an effect shown to be 5-HT2A receptor mediated. LSD also raised serum oxytocin levels in humans at 3 h. This stimulation of oxytocin by psychedelics could have implications for psychotherapy, as the administration of oxytocin during psychotherapy leads to changes in individual and dynamic factors in depressed patients and in patients with PTSD. The proposed role of oxytocin in generating those elements required for placebo response supports the hormone’s potential function in a broad range of conditions; cluster headache is included in this consideration, given the placebo effect of approximately 15% in prophylactic medication trials.

Melatonin

Melatonin, a metabolite of serotonin, is produced in and secreted from the pineal gland, which receives modulatory input from the suprachiasmatic nucleus of the anterior hypothalamus. Melatonin is secreted in times of darkness and has been extensively studied in circadian biology, serving as both a marker for and modulator of biologic rhythms. The role of melatonin in affective disorders has also been discussed in light of circadian disruption. Serum melatonin levels and diurnal variation are aberrant in subjects with active depression and treatment with antidepressants modulate serum melatonin levels. A post-mortem study also showed reduced melatonin receptor 1 immunoreactivity in the SCN of depressed patients. In abstinent alcoholics, the nocturnal rise in melatonin was reported to be delayed. Melatonin levels are also low in cluster headache, including times outside of cluster attack periods, and the timing of melatonin release was found to be phase advanced. Nightly melatonin has been shown to reduce the mean number of cluster attacks and terminate the cluster period in some patients. In addition, intravenous methylprednisolone reduced cluster attack burden, while also raising aberrantly low levels of the melatonin metabolite, 6-sulfatoxymelatonin.

In vitro, mescaline and to a lesser extent, LSD and psilocybin, stimulated melatonin release from rat pineal tissue, dose-dependently increased pineal melatonin content in rats, an effect blocked by pre-treatment with 5-HT2C antagonist, but not 5-HT2A antagonist, ketanserin. In addition to serotonergic receptors, dopaminergic and sigma-1 receptors have been identified in the pineal gland. Psychedelics and melatonin have some opposing effects—psychedelics induce arterial hypertension, hyperthermia, anorexia, and HPA axis activation, whereas melatonin induces arterial hypotension, hypothermia, hyperphagia, and HPA axis suppression. Serving perhaps as a form of feedback, DOI blocked melatonin-induced hypothermia, as well as serotonin release from the hypothalamus, in rats. In turn, the suppression of food intake in rats induced by DOI was blocked by melatonin in a dose-dependent manner. Understanding the normal rhythm of melatonin production and release is crucial for in vivo studies. For instance, intravenous DMT did not acutely alter daytime serum melatonin levels in humans, but DOI delayed the time of onset of urinary 6-sulfatoxymelatonin excretion by approximately 2.5 h in rats. Furthermore, the delay in 6-sulfatoxymelatonin excretion induced by a single dose of DOI was sustained for 8 days, illustrating the potential for long-term effects and the value of taking extended measures. Given that melatonin release was shown to be phase advanced in cluster headache, this effect of DOI in rats may reveal part of mechanism by which psychedelics provide relief for patients with the disorder. In healthy human subjects, a single dose of the SSRI fluvoxamine also delayed melatonin release by approximately 2 h. The norepinephrine reuptake inhibitor, desipramine, phase advanced melatonin release by 2–3 h, but it also increased 6-sulfatoxymelatonin excretion over a 48-h period. In another human study, the SSRI paroxetine and the anxiolytic, ipsapirone, failed to alter serum melatonin levels over a 12-h period. Antidepressants and anxiolytics are not effective in treating cluster headache and unlike psychedelics, single doses are not expected to have therapeutic effect. Be it melatonin or another hormone or marker, these studies do demonstrate that importance of collecting data at multiple time points for extended periods in order to best characterize the effects.

Circadian rhythm/sleep

The SCN is the primary regulator of the circadian rhythm and receives afferent signals from retinal ganglion cells, highlighting the role of the environment in the daily rhythm. The role of serotonin in SCN entrainment has also been described. Disruption of the circadian rhythm through environmental stress, toxic exposures, or genetic mutation have been associated with various health repercussions. As an example, mice raised for the first 3 weeks of life in 24-h light conditions were shown to have increased CRH mRNA in the PVN and a depressive phenotype. Maternal mouse exposure to a disrupted light-dark cycle led to signs of metabolic and affective abnormalities, as well as genetic changes, out to second and some third generation subjects. In these second generation mice, a reduction in mRNA transcript levels of circadian clock genes in the SCN were also identified. Numerous animal studies have also shown that manipulation of clock genes results in behavioral and metabolic disturbances. For instance, the manipulation of the clock genes, CLOCK and PER2, affected self-administration of addictive substances in rodents, though some gene associations are drug-specific. Affective and addictive conditions in humans have also been associated with clock gene SNPs. The disrupted circadian rhythm is further supported clinically, as symptoms of depression show diurnal variation and sleep disturbance is common in depressed individuals and those with alcohol use disorders.

The role of clock genes in cluster headache is also under investigation, though varying results are found. Cluster headache is a particularly valuable model for studying biological rhythms. Circadian disruption, such as seasonal changes, shift work, and jet lag can trigger headache attacks. There is also a tendency for cluster periods to initiate or symptoms to worsen in spring and fall. Cluster attacks have the propensity to occur at predictable times of day as well, particularly during sleep and often during rapid eye movement sleep. Interestingly, the polysomnogram of cluster headache patients may show decreased number and frequency of REM sleep periods, though REM sleep abnormalities are not always reported. The alleviation of cluster headache symptoms after posterior hypothalamic DBS implantation may also be accompanied by changes in sleep quality and architecture, though these changes are not always pleasant.

In rats, LSD postponed REM sleep onset. In cats, this delay of REM onset after LSD was shown to occur in a dose-dependent manner. Total REM sleep duration was also reduced after LSD in both rats and cats. This reduction in REM sleep duration after LSD was shown to occur in a dose-dependent manner in cats. The non-psychedelic congener of LSD, 2-bromo-LSD, also delayed REM sleep onset and reduced REM duration in rats, though to a lesser degree than LSD at the dose tested. In healthy humans, low doses of LSD given approximately at bedtime increased the duration of the first or second REM period, abbreviated subsequent REM periods, and induced REM bursts during slow wave sleep. Another low dose of LSD administered in a healthy subject at bedtime advanced the first REM period and increased the ratio of REM to slow wave sleep. In one human subject under treatment for alcoholism, a high dose of LSD given mid-day led to a delay in the first REM period, an effect that persisted the following night. Total duration of REM, isolated bursts of REM, gross body movements, and vocalizations, were increased in this patient the night of LSD exposure and the following two nights. In another early study, sleep disturbances were reduced for approximately 10 days after cancer patients took a single dose of LSD after breakfast. While it is not possible to generalize effects of LSD from this small number of subjects, the persisting effects are particularly noted. Furthermore, that psychedelics may delay the onset and reduce total duration of REM sleep might suggest that one of their therapeutic benefits in cluster headache stems from manipulation of the sleep period during which attacks often occur. REM sleep duration may already be reduced in some cluster headache patients, however, and thus, psychedelics may not simply correct abnormal sleep patterns, but act on other related systems. In addition, REM sleep suppression is not unique to psychedelics; SSRI and tricyclic antidepressants, for instance, also acutely reduce REM sleep duration. Distinctions in the effects of classic serotonergic psychedelics and other drugs may, again, be appreciated with longer-term monitoring of subjects.

In addition to taking repeated measures for an extended period, future studies examining sleep, circadian cycle, or other aspects of neuroendocrine function must also carefully consider timing of drug administration. For instance, melatonin administered at the end of the light phase, advanced the timing of peak water and ethanol drinking in alcohol-treated rats, but this shift was absent when melatonin was administered at the beginning of the light phase. In humans, low doses of oral melatonin taken for 3 weeks led to decreased measures of depression in patients with seasonal affective disorder when peak melatonin levels were achieved in the afternoon/evening as opposed to the morning. Given that most SAD patients are phase-delayed in their circadian rhythm, administering melatonin in the afternoon/evening is conceptually favorable. Light therapy was also found to reduce depressed symptoms in SAD when administered in the morning as opposed to the evening. Of note, this morning light therapy also advanced the onset of melatonin production. Time of day is also relevant in the consideration of neuroimaging studies. For example, between morning and evening, functional connectivity of the medial temporal lobe in humans was shown to expand to involve neocortical areas, suggesting a representation of memory consolidation. In other human subjects, between morning and afternoon, default mode network connectivity decreased, an effect that also correlated with diurnal decreases in salivary cortisol levels. In depressed patients, evening mood improvements were associated with increased metabolism in parietal and temporal cortices, basal ganglia, and the cerebellum, possibly reflecting a normalization required to preserve “emotional homeostasis."

Given the desire to monitor subjects through the duration of psychotropic effects, studies investigating psychedelics in humans often administer drug early in the day. Though limited, early human studies showed that LSD produced differing effects on REM sleep, though doses and times of drug administration were quite variable. Animal models have further demonstrated the significance of the timing of administration of psychedelic compounds, however. For instance, disruption of the locomotor activity of house crickets was seen when LSD was administered early in the light phase, but not when administered late in the light phase. In addition, LSD had no acute effects the day of injection, but reversed the locomotor rhythm of the house crickets the following day. The psychedelic 5-MeO-DMT dose-dependently elicited head twitches in mice, an effect that was maximal in the middle of the light phase. In contrast, another group reported that 5-MeO-DMT elicited maximal head twitches in mice at the end of the dark period. In rats, DOI dose-dependently induced wet dog shakes, a response that peaked late in the light phase after either subcutaneous or intracerebroventricular injection. In addition to differences among species and routes of administration, the methods of measuring time points must be considered in the effects of psychedelics. For instance, as discussed previously, a single subject dosed multiple times may develop tolerance to a drug, whereas different subjects each dosed at a time point of interest would better reflect the effects of a single administration.

Discriminating the effects of psychedelics

Psychedelics are best known for their ability to alter one’s consciousness. There are actions of classic serotonergic psychedelics unrelated to hallucinogenesis, however. Indeed,
various systemic targets of psychedelics, such as heart rate and blood pressure, are commonly measured alongside psychotropic effects. Anti-inflammatory and anti-cancer effects of psychedelics have also been described. Regarding the topic of this report, psychedelic drugs target the anatomical and biochemical substrates of neuroendocrine function. Both central and peripheral actions are involved. For example, psychedelic-induced increases in corticosterone have been shown to involve both peripheral and central mechanisms. While the peak psychotropic effects of oral LSD, psilocybin, and ayahuasca in humans approximately coincide with maximal serum hormone increases, a separation between these measures can also be shown. For instance, low, though still psychoactive, doses of psilocybin—did not significantly change the levels of various hormones, including ACTH, cortisol, prolactin, thyroid stimulating hormone, and growth hormone, at multiple time points out to 300 min. Furthermore, when administered intravenously, DMT-induced psychological effects peaked at 5 min, the approximate time of peak ACTH and prolactin elevation, but well preceding maximum cortisol levels. Four closely spaced doses of intravenous DMT in humans led to tolerance of ACTH, cortisol, and prolactin stimulation, but not the psychedelic effects of the drug. This separation between psychotropic and endocrine effects underscores the multiple actions of psychedelics.

The delayed and/or sustained effects on sleep and melatonin measured in both human and non-human animals are also examples of the separation between psychotropic and other effects. That BOL, as well as low doses of LSD, can affect sleep architecture in a similar manner to psychoactive LSD doses lends further support to actions independent of psychotropic effects. To be precise, oral BOL ingestion in humans does not induce psychedelic effects, although “flabby” or “light drunk” feelings have been described. In one early case report, BOL induced sensory perceptual changes, panic, and cardiovascular and gastrointestinal activation in one subject. The source and purity of BOL in this case was not identified, however. Of note, the subject in this early report had ingested BOL after the development of a pounding headache, which was reduced in intensity from moderate to mild. Anecdotally, patients have reported lasting relief from cluster headache after ingesting BOL. In a case series, BOL was shown to reduce cluster attack burden in the same 3-dose regimen as for hallucinogenic psychedelics. While the pharmacologic effects of BOL have not been fully examined, the general consensus that it has greatly reduced psychedelic properties, raises the question as to the necessity of psychotropic effects in treatment with classic serotonergic psychedelics. Indeed, sub-psychedelic doses of psilocybin and LSD are also reported to provide relief from cluster headache in some patients. There are widespread anecdotal reports of sub-psychedelic doses being beneficial in a range of psychiatric illnesses via microdosing protocols as well, though clinical trials are lacking. The persisting effects of psychedelics in cluster headache may be independent in origin from those in neuropsychiatric disorders.

Conclusion

There is ongoing interest in the study of classical serotonergic psychedelics in the fields of pharmacology, epi/genetics, neuroimaging, and psychology. The neuroendocrine system should be considered among the many potential targets for lasting therapeutic benefit. In mood and substance use disorders, HPA axis function is widely studied. The manipulation of this system can have demonstrable long-term effects and should be of interest in considering the additional non-psychological effects of psychedelics in the treatment of neuropsychiatric disease. In cluster headache, aberrations in melatonin and circadian rhythm are topics of value in examining the effects of psychedelics. With advancing understanding of circadian biology, psychedelics should be actively considered in this process. Importantly, given the associations with the neuroendocrine system, future studies examining the effects of psychedelics must take into account the timing and pattern of drug administration, as well as frequency and duration of outcome measures. Finally, though incomplete, existing evidence raises the intriguing possibility that as a class, psychedelics could have therapeutic effects independent from their psychedelic effects. Pharmacologically similar, but non-psychedelic compounds, such as BOL, should also be utilized in examining the role of hallucinogenesis in the therapeutic effects of this drug class.

https://www.frontiersin.org/articles/10.3389/fphar.2018.00177/full
 
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Comparing the effects of 4-AcO-DMT and psilocybin mushrooms

by Barb Bauer | PSR | May 02 2019

According to experience reports, magic mushrooms elicit more emotions and visual effects than 4-AcO-DMT (psilacetin).

Many experienced psychonauts and newcomers alike believe that the subjective effects of 4-AcO-DMT (psilacetin) and psilocybin “magic” mushrooms are effectively the same. Granted, this may be true for some because of the metabolic differences between individuals. But, the current knowledge base in chemistry and biology confirms that different chemicals cause different effects on the human body, whether perceived by the user or not. By examining experience reports and through an understanding of molecules versus mushrooms, it is easier to understand why they are different.

Psilocybin-assisted therapy is showing promise for treating conditions such as treatment-resistant depression, anxiety in terminal cancer patients, alcohol addiction, and tobacco dependence. Historically, psilocybin is difficult and expensive to make in the lab and on a larger scale. The original synthesis method designed by Albert Hofmann has a yield of less than 20%.

Dr. David Nichols, Professor Emeritus of Pharmacology at Purdue University has suggested that 4-AcO-DMT (also known as psilacetin, O-acetylpsilocin, psilocetin, 4-acetoxy-DMT, and 4-acetoxy-N,N-dimethyltryptamine) is a prodrug of psilocin in the body just like psilocybin.

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Figure 1: The chemical structure of psilocybin.

When a person ingests psilocybin (Figure 1) the body readily converts it to psilocin (Figure 2) through the process of dephosphorylation.

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Figure 2: The chemical structure of psilocin.

The body also converts 4-AcO-DMT (Figure 3) to psilocin via removal of the acetyl group by deacetylase and acetyltransferase enzymes. Scientists don’t know if 4-AcO-DMT is biologically active on its own. Interestingly, in their 1963 patent, Albert Hofmann and Franz Troxler described indole acetate esters like 4-AcO-DMT as serotonin receptor antagonists. However, over the years, scientists have come to classify them as prodrugs that are inactive on their own by way of analogy to psilocybin.

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Figure 3: The chemical structure of 4-AcO-DMT.

In 1999, Dr. Nichols published an improved synthesis method for psilocybin. In the same paper, he also explains a simple method for preparing 4-AcO-DMT which readily crystallizes as the fumarate salt and is more stable than psilocin. Dr. Nichols puts forth the idea that 4-AcO-DMT is an easy and cost-effective alternative for studying the psychopharmacology of psilocin. 4-AcO-DMT is called a semi-synthetic drug meaning it is made synthetically from a naturally-occurring compound.

Those wishing to use 4-AcO-DMT on their own but don’t have a lab can find it available for purchase from websites such as The Indole Shop. 4-AcO-DMT is receiving increased attention in the psychonaut world recently because of the similarity of its effects to those of psilocin without nausea that often accompanies eating magic mushrooms. But how similar are the effects of these compounds?

Comparing the effects of psilocin and 4-AcO-DMT

It’s important to understand that ingesting pure psilocybin by itself is very different from the cocktail of chemicals a person receives after eating magic mushrooms. All the psychoactive compounds in magic mushrooms (like baeocystin, norbaeocystin, norpsilocin, and aeruginascin) work together to produce the overall psychedelic experience for the user. For example, researchers have noted that aeruginascin has a synergistic effect on the pharmacological action of psilocybin in magic mushrooms. Specifically, Jochen Gartz says, “Aeruginascin seems to modify the pharmacological action of psilocybin to give an always euphoric mood during ingestion of the mushrooms.” In the world of medical cannabis, this synergy is known as the entourage effect.

Notably, psilocybin experience reports come from people who have ingested magic mushrooms, not pure psilocybin (and the dose is not always the same). The types and amount of psychoactive chemicals in magic mushrooms vary from species to species, batch to batch, and even in different parts of the mushroom. Experience reports for 4-AcO-DMT reflect the effects of the pure compound (again, the dosage may not be the same for all users). Also, set and setting (context) are known to be critical components affecting the psychedelic experience. This environment varies from user to user and is another reason it can be difficult to draw objective conclusions from experience reports.

The Urban Dictionary describes the effects of magic mushrooms versus 4-AcO-DMT this way:

“The effects are VERY similar to a mushroom trip, except it lasts a little longer than mushrooms (around 7 hours). Its effects, however, differ somewhat from mushrooms. It seems to have a much more relaxing quality to it, which makes it harder to have a bad trip. Several available reports of 4-ACO-DMT compare it favorably to psilocybin, describing it as more euphoric, gentle, warm, and colorful. It has also been described as less jarring/scary, and less likely to produce nausea.”

PsychonautWiki says:

“Users frequently describe 4-AcO-DMT as being extremely similar to psilocybin mushrooms. It is generally described as euphoric, gentle, warm, and colorful. Visuals are reported by some users to be brighter and more neon in a manner reminiscent of DMT. It is also reported to be less nauseating than psilocybin mushrooms, which may be due to the fact that it does not require digesting mushroom matter.”

And, from Tripsit Wiki:

“Its effects and duration are similar to those of Psilocybin/Psilocin although it is sometimes described as ‘warmer’ or ‘more euphoric’ than psilocybin-containing mushrooms. Ingesting mushrooms often creates feelings of nausea for the user due to the flesh of the fungi containing chitin, and for this reason it seems that 4-AcO-DMT has far fewer reports of feelings of nausea or vomiting.”

Below are excerpts taken from individual experience reports on the websites Reddit, Erowid, and BlueLight comparing the effects of 4-AcO-DMT and psilocybin mushrooms. There are people who report no difference in effects between the compounds. This may be due to the dosage, context, individual metabolic differences or a combination thereof as mentioned earlier. For those that did notice a difference, this compilation represents some of the most frequently mentioned similarities and differences between the compounds.

- “I find 4-Aco-Dmt to be more introspective/introverted without any magic feeling to it. While on shrooms I feel like happy child again. Also realizations on shrooms are better, more positive.”

- “I find 4aco to be a lot less emotional and ‘spiritual’ than psilocybin mushrooms- it’s a more clear headed ‘space age mushroom’ great for introspection but a bit more cerebral than the mushrooms.”

- “Amazing visions and teachings as much or more then [sic] mushrooms. It was very sad in parts but also very euphoric. I even had more visions with this medicine then [sic] mushrooms.”

- “I found that the lower doses (8-15 mg) of this compound [4-AcO-DMT] we’re [sic] almost identical to a low dose of psilocybe cubensis (1-1.5 grams). I find it interesting that this chemical doesn’t produce as many visuals as psilocybe mushrooms. Maybe because of the lack of baeocystin, norbaeocystin and other compounds that produce an entourage effect of sorts.”

- “It’s [4-AcO-DMT] almost identical to shrooms but more DMT-ish.”

- “Space age shrooms without the nausea. I was also really euphoric in a silly kinda way. Mushrooms make me euphoric in a wow this is so beautiful kinda way.”

- “I’ve always found the two to be very similar. Mushrooms of course produce nausea and discomfort on the come up that I never feel from 4-AcO-DMT. Mushrooms are also a bit more unpredictable emotionally in my experience, whereas 4-AcO-DMT has almost always felt peaceful and serene at doses under 30 mg.”

- “Very similar, but I find 4-aco-dmt to not be as lucid as mushrooms.”

- “In my experience I find shrooms more emotional and psychologically intense. perhaps just more intense in general.”

- “I find 4-AcO-DMT is able to produce a more DMT like experience in higher doses. Especially when snorted after the initial oral dose.”

- “The differences for me were just the duration and bodyload. Shrooms have a heavier bodyload and make me salivate much more and is a bit more stoning. 4-aco also comes on a lil [sic] quicker.”

- “Visuals are definitely different from my experience, 4 aco dmt visuals seemed as a cross between psilocybin and n-n dmt. Shrooms showed me a new world, 4 aco dmt put me in a new world.”

- “Within 30 minutes I was feeling a significant body high, similar to the come up of mushrooms. Within 60 minutes, I was experiencing a very comfortable mental headspace with mild visuals. The visuals were certainly similar to some of the mushroom trips I’ve had, with somewhat less distortion. 4-aco-DMT definitely has a lot going for it. I virtually no nausea or stomach upset. Duration lasted for a good 6 hours, but with a much more gradual come-down than mushrooms had (at least another 2 hours).”

- “4-ACO-DMT feels much more ‘digital’ and has an easier head-space. While mushrooms feel more natural, much more earthy, and have a much heavier headspace. 4-aco feels ‘cleaner’ but mushrooms feel more ‘natural'”

- “In my experience, AcO tends to be less mystical/magical, and more “electric” somehow…They feel like different animals to me.”

- “I find that the 4-AcO trip provides a ‘cleaner’ headspace, gives me better visuals, and keeps nausea to a minimum. Shrooms, on the other hand, gives me more of a body load that can be uncomfortable, and almost always gives me bad nausea.”

- “In my experience 4-AcO-DMT feels like a mix of shrooms and DMT. The comeup feels exactly like mushrooms but once I reach the peak it’s more clearheaded, more digital, and more stimulating than mushrooms.”

- “In my experience (I have experienced both dozens of times) 4-AcO-DMT is no replacement for psilocybin mushrooms. 4-AcO feels more synthetic to me, and doesn’t make me analyze important things in my life like mushrooms. It also doesn’t give me the giggles or euphoria like mushrooms do. I’ve learned a multitude of lessons, spiritual and emotional, with psilocybe mushrooms. However 4-AcO usually just makes me throw up on the come up, trip really hard for 4 hours (I like 60+mg) and then come down with a headache. No lessons or revelations. It sucks because I figured, as a literal prodrug to psilocin, it should be mushrooms in a pill. But it’s just not the same.”

- “I find 4-AcO-DMT to be more sedentary than magic mushrooms. Mushrooms are pretty chill too, but 4-AcO-DMT especially makes me especially inclined to recline and vegetate.”

- “On mushrooms I tend to feel more crazed, but the emotional rollercoaster often left me refreshed afterwards… on 4-AcO-DMT it was more sneaky and I could be deep without fully realizing it, less obvious and less of a guided journey but a similar / generic effect on wellbeing.”


Conclusion

Despite the uncontrolled variables between users like the set, setting, and dose, the anecdotal evidence indicates that the effects of pure 4-AcO-DMT are different from the mixtures provided by naturally-occurring mushrooms. In general, 4-AcO-DMT appears to give a more colorful experience and imparts more feelings of warmth, relaxation, and euphoria than psilocybin mushrooms. Also, there is little or no nausea reported like magic mushroom users often experience. In contrast, magic mushrooms elicit more emotions and more visuals than 4-AcO-DMT. These differences make sense because they are 100% consistent with current scientific understanding—including how G-protein coupled receptors work, different chemicals causing different effects, and using multiple drugs to treat diseases and conditions (polypharmacy).

The different effects of these two compounds could also be due to the entourage effect caused by the other psychoactive chemicals present in magic mushrooms. The increased emotions and visuals experienced with psilocybin mushrooms could be evidence of allosteric modulation of receptors, enzymes, molecular transporters or a combination of these factors in the brain. This is a wide-open research area for studying and starting to unravel the mysteries of how psilocybin and its derivatives interact with each other and the brain to produce the overall psychedelic experience.

 
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Albert Hofmann

5-HT2A agonism and multisensory binding

by James L. Kent | Psychedelic Information Theory

Most visual hallucinogens are active as full or partial agonists at the 5-HT2A receptor subtype, and all produce similar visual hallucinations that are immediately recognizable as psychedelic.1 Although the 5-HT2A receptor subtype is not the only receptor implicated in hallucinogenesis, it is one of the most studied hallucinogenic targets and offers some insights into the quality of classical psychedelic interaction. 5-HT2A receptors are ubiquitous throughout the nervous system, found in the sensory cortex, the frontal cortex, the olfactory cortex, the basal ganglia, the cerebellum, the hippocampus, thalamic nuclei, brainstem nuclei, sensory neurons, platelets, fibroblasts, intestines, smooth muscles, and cardiovascular systems. By following the pathways of 5-HT2A modulated signal transduction through the human organism it is possible to extrapolate that psychedelic experience is not limited to mere hallucination, but is instead a complex multi-layered experience integrated throughout all biological signaling systems. The layering of cellular signaling systems mediated by 5-HT provides a framework for viewing the 5-HT2A pathway as a primary modulator for homeostatic feedback regulation of multisensory awareness, behavior, and learning. 5-HT2A receptor agonists (hallucinogens) promote disinhibition and excitability in 5-HT mediated pathways, indicating that psychedelic action is the product of spontaneous nonlinear feedback excitation in the recurrent circuits responsible for real-time binding of sensation to multisensory perception, affective behavior, and the process of consciousness.

5-HT2A receptor mechanics

The 5-HT2A receptor is a G protein-coupled receptor (GPCR), which means it does not activate ion channels or directly alter cell polarity, but instead sets off a chain reaction of intracellular signaling systems involving phosphatidylinositol (PI) hydrolysis, the production of inositol trisphosphate (IP3), the release of calcium (Ca2+), and the activation of protein kinase C (PKC) and various mitogen-activated protein kinases (MAPK). PKC regulates a variety of cellular functions at the membrane, including signal transduction, receptor desensitization, and synaptic formation and strengthening responsible for learning and memory.10 MAPK regulates fundamental intracellular functions such as gene expression, proliferation, cell growth, and survival. It is interesting to note that Salvinorin A, another potent hallucinogen not active at the 5-HT receptor, also stimulates PKC and MAPK signaling pathways via Kappa Opioid receptors. These receptor-mediated secondary pathways undoubtedly play a role in psychedelic neuroplasticity and cellular regeneration, but these secondary messengers are not necessarily directly responsible for hallucination and psychedelic effect. Hallucinogenesis is more likely related to tonic disinhibition of neural assemblies normally stabilized by tonic feedback inhibition. In other words, 5-HT2A agonism does not cause neurons to fire, it activates cellular signaling pathways for learning and growth in the wake of stimulus, which, over time, promotes hypersensitivity and uninhibited network cross-excitability.

Layer V pyramidal cells and perceptual binding

In the human brain the highest density of 5-HT2A receptors are expressed on the dendrites of cortical layer V pyramidal cells, and the highest density of layer V dendrites project upward into the arbors of cortical layer I, the very outward surface of the brain. 5-HT2A receptors in the dendritic arbors of pyramid cells are primarily responsible for modulating asynchronous (late) glutamate release in the wake of incoming sensory spike trains, presumably for enhanced top-down aliasing (reconstruction and rendering) of salient sensory data. Sensory signal rising to the dendrites of the cortical surface encodes a highly detailed reconstruction of external perception for latent real-time analysis and progressive perceptual filling. Multiple layers of the neocortex have descending columnar dendrites or ascending recurrent axon collaterals to provide real-time sensory feedback to apical rendering layers, allowing a seamless representation of perception to be shared across the cortex. Cortical layer V neurons receiving input through apical dendrites are one of the primary conduits for binding coherent sensory perception across the entire cortical surface of the brain.

Layer V pyramidal cells are unique in that they mediate multiple pathways of perceptual feedback analysis. For example, in the visual cortex layer V pyramidal cells are responsible for synchronizing corticothalamic activity with the thalamic nuclei via descending axons; they mediate feedback discrimination in columnar circuits via recurrent collaterals ascending through Layers I-IV; they mediate reciprocal interareal connections via laterally branching arboreal and basilar dendrites; and they mediate afferent cortico-cortical signal flow to the pre-frontal cortex (PFC) along both dorsal and ventral processing streams. Through lateral, vertical, elliptical, and recurrent feedback connections, layer V pyramidal cells bind multisensory frame data across the cortex with a functional refresh rate of roughly 15 to 30 frames-per-second (FPS), which means these neurons must process and neutralize incoming sensory spike trains at roughly every 30-60 milliseconds. Loss of precise synchrony and coupling in these circuits would necessarily lead to loss of temporal fidelity in multisensory frame binding. Agonism, disinhibition, excitation, and destabilization in layer V recurrent circuits would necessarily lead to global multisensory frame aliasing errors, feedback synesthesia, and eventual perceptual overload.

Nonlinear destabilization in thalamocortical feedback loops

The most potent psychedelics are 5-HT2A receptor agonists; the highest density of 5-HT2A receptors are in the dendrites of layer V pyramidal cells; layer V pyramidal cells bind information in feedback projections throughout the brain. Taking these factors into account it is reasonable to assume that psychedelic hallucinogenic activity is due to nonlinear signal destabilization and amplification via recurrent layer V feedback projections. Psychedelic hallucination is achieved by partial or full agonism along recurrent layer V binding pathways; the introduction of a competing agonist in the 5-HT2A modulatory system leads directly to loss of localized inhibition and self-sustaining excitation of autonomic sensory binding complexes. Destabilization of layer V projections is most acute where signal travels in recurrent loops or feedback circuits that resolve incoming multisensory data in real time. The primary circuits for binding real-time frame data include the cortico-striato-thalamo-cortical (CSTC) loops, and the more distributed cortico-thalamo-cortical feedback loops (or thalmocortical loops) which pass information from the cortex through the basal ganglia and back into the thalamus for discrimination and gating of incoming signal flow to the cortex. These loops can be described as attention-controlled feedback filters which drive and stabilize external perception and behavior. CSTC loops provide real-time sensory feedback for fine-tuning eye movements, motor reflexes, emotional responses, and cognitive value placed on stimulus. Destabilization in signal coupling along thalamocortical feedback pathways will necessarily lead to problems with sensory gating, multisensory frame resolution, and fast temporal aliasing.

There are specific perceptual effects one would expect to see as a result of instability in thalamocortical feedback loops between the thalamus to the visual cortex, such as a subtle flickering or pulsing of light intensity; geometric grids and matrices; the perception of halos or auras around light sources; increased luminosity of reflective objects; the softening of line and texture resolution; and the inability to hold sharp focal contrast between foreground and background in depth perception. Sensory filling in the visual periphery relies on fast temporal aliasing of visual signal for real-time results, and this temporal aliasing can be subverted by optical illusions which create a sense of movement in the periphery. A competing 5-HT2A agonist would necessarily disrupt the precise inhibitory timing in the cortical columns needed for peripheral edge detection and sensory filling, leading to shifting line and depth ambiguities. If the rate of multisensory frame saturation or neutralization was slowed or interrupted by even a few milliseconds, incoming sensation would begin to layer over itself with increasing levels of smoothing, liquidity, and phantom frame echo decaying in the wake of sensation.

5-HT2A receptor agonists can destabilize multisensory perception in a number of ways. The most general explanation is that 5-HT2A agonists introduce a competing excitatory impulse that disrupts the precise timing of sensory binding in the apical dendrites and recurrent circuits of the thalamus and cortex. Evidence indicates that 5-HT2A agonists promote a late release of glutamate from layer V pyramidal cells following strong incoming spike trains, resulting in the generation of asynchronous excitatory postsynaptic currents (EPSCs). Asynchronous EPSCs in recurrent sensory circuits are normally helpful for resolving important perceptual data, but if the subject is unable to inhibit evoked ESPCs caused by exogenous modulators (hallucinogens), this late signaling action can lead to glutamate flooding and tonic sensory saturation in perceptual neural assemblies, which is consistent with manic states of hallucinogenesis. There is evidence that 5-HT2A agonists lead to lateral disinhibition in the cortex by blocking presynaptic uptake of 5-HT at the lateral inhibitory synapse, or by overriding tonic GABAB inhibitory postsynaptic potentials (IPSPs) with asynchronous ESPCs at the lateral-inhibitory synapse. Loss of inhibition at the lateral synapses in columns of the visual cortex would lead directly to shifting and wiggling in peripheral line, texture, and contrast resolution. As thalamocortical feedback circuits become increasingly disinhibited they may fall into coherent self-sustaining states of underconstrained perception, promoting phantom sensory activity such as hallucination and spontaneous dream imagery. In the disinhibited state mild stimulus may not provoke hallucinogenic response, but intense stimulation would drive sudden localized feedback coherence, nonlinear signal amplification, and frame latency errors. The sudden shift from stabilized brain focus to states of elicited thalamocortical feedback excitation can be described in terms of a nonlinear, non-equilibrium phase transition in response to energetic sensory drivers.

5-HT2A cross-agonism and holistic organism re-modulation

Looking beyond the cortex, it is worth mentioning that 5-HT2A receptors are also found in the midbrain, olfactory systems, the brainstem, intestines, and all over the body in smooth muscles and cardiovascular systems. There is some evidence that 5-HT2 agonists have a secondary effect at the locus ceruleans in the brainstem (LC), promoting adrenal activity in the presence of strong sensory drivers. Sensory driving of adrenal release may promote a synesthetic burst of emotional intensity accompanying any strong multisensory experience. There is evidence that 5-HT agonist hallucinogens inhibit sensory gating in the thalamus, allowing more raw sensation to flood the cortex; this is consistent with decreased gating and nonlinear feedback amplification in thalamocortical loops. A common early side-effect of hallucinogen use is stomach tightening and intestinal cramping; this is undoubtedly due to 5-HT2A agonism interfering with serotonergic modulation of smooth muscle contraction in the gut. 5-HT2A cross-agonism in the intestines can lead to nausea and purgation, and reports of intense hallucinations and peak psychedelic experiences typically increase immediately following release of intestinal discomfort. This indicates that radical interruption and re-modulation of all 5-HT2A pathways, from the intestines to the cortex, may be a common precursor to peak psychedelic experiences and states of bodily transcendence.

Because of the multiple systems affected by 5-HT2A receptor agonism, it would be overly reductive to point to a single pathway as being responsible for full psychedelic activation. The synergistic effect of multi-layered 5-HT2A agonism is felt subjectively as a throbbing or pulsation of energy which suffuses the entire body, builds in strength and complexity, and culminates in a cathartic multisensory release of highly charged transformative content. At the sensory level glutamate flooding saturates perception. At the emotional level adrenal response drives sensual intensity. At the frame level aminergic destabilization leads to disorientation and loss of temporal ego cohesion. At the cognitive level aminergic destabilization drives irrationality, depersonalization, and hallucinogenic dream states. At the circulatory level 5-HT2A agonism promotes vasoconstriction and increases blood pressure. At the somatic level an interruption of digestive functioning drives metabolic destabilization and energetic intracellular signaling. At the organism level the holistic effects of prolonged 5-HT2A agonism become nonlinear, meaning they begin to generate complex energetic output in response to sensory input over time. This multi-layered organism activation can be formally described as a runaway biological feedback process, or a nonlinear cellular signaling loop which drives increasing cellular coupling complexity over the duration of synergistic agonism.

 
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Deconstructing the iboga alkaloid skeleton

Ibogaine Foundation

An interesting new scientific paper has been published today. Ibogaine is probably a Neurotrophin (Nerve growth factor) rather than a typical psychedelic:

Isolated from the West African shrub Tabernanthe iboga, the natural product ibogaine and the other members of the ibogamine alkaloid family have traditionally been used in religious ceremonies, likely due to their dissociative effects observed at high doses.

In recent decades, however, ibogaine has been investigated as an experimental therapeutic for treating substance use disorders (SUDs), with evidence for suppression of craving and self-administration of diverse drugs of abuse in humans (e.g., alcohol, opioids, and3cocaine) for extended periods of time (weeks to months), as well as reduction of acute opioid withdrawal symptoms. These clinical findings (mostly uncontrolled clinical studies and anecdotal reports)3 have been recapitulated in animal models.

Unfortunately, despite decades of ongoing interest, ibogaine’s molecular mechanism of action remains undefined. Ibogaine has been reported to bind to, and/or show functional activity at, many central nervous system (CNS) receptors with micromolar potency, including the N-methyl-D-aspartate receptor (NMDAR), the dopamine and serotonin transporters, mu-opioid receptor, sigma 2 receptor, 5-HT2a, acetylcholine receptors, ERG channels, and others, 8-11 which, combined with its hallucinogenic effects, makes ibogaine a controversial treatment option.

The complex pharmacology of ibogaine (and its metabolite noribogaine) continues to be studied: while ibogaine has been shown to block NMDA receptors in different brain tissues in the range of 3−10 μM, 14−16 it does not appear to activate the mu-opioid receptor, suggesting an indirect mechanism of action for ibogaine’s effects on opioid withdrawal. In addition, the inhibition of human ERG channels by ibogaine at ∼4 μM may account for the heart arrhythmias associated with ibogaine usage.

Therefore, there have been efforts to isolate the key therapeutic mechanism(s) from the dissociative and other potentially dangerous side effects. Most notably, the ibogaine analog 18- methoxycoronaridine (18-MC) was developed in this spirit as an antagonist of α3β4 nicotinic receptor with much improved selectivity for this molecular target over other CNS receptors when compared to ibogaine. 18-MC is effective at reducing self-administration in rodents of several addictive substances, including morphine, cocaine, ethanol, and nicotine, and thus α3β4 nicotinic receptor antagonism is considered an important mechanism of action of ibogaine and 18-MC. However, clinical efficacy of 18-MC has not yet been reported. Others have also developed acyclic ibogaine analogs that show binding to some of the same targets, including dopamine and serotonin transporters, the kappa-opioid receptor, and the NMDA receptor; however, these compounds have apparently not been pursued further.

We were inspired by an intriguing mechanistic hypothesis that links iboga alkaloids to modulation of neurotrophic factor signaling systems. Namely, ibogaine was shown to induce glial cell line-derived neurotrophic factor (GDNF) expression in the ventral tegmental area (VTA) of rats, and it was suggested that GDNF activates an autocrine loop, leading to the increased and long-term synthesis and release of GDNF, which in turn repairs the function of the VTA-ventral striatum reward system.

http://ibogainefoundation.org/deconstructing-the-iboga-alkaloid-skeleton/
 
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Decoding the tripping brain

by Diana Kwon

Scientists are beginning to unravel the mechanisms behind the therapeutic effects of psychedelic drugs.

Lying in a room at Imperial College London, surrounded by low lighting and music, Kirk experienced a vivid recollection of visiting his sick mother before she passed away. “I used to go and see my mum in the hospital quite a lot,” recalls Kirk, a middle-aged computer technician who lives in London (he requested we use only his first name). “And a lot of the time she’d be asleep . . . [but] she’d always sense I was there, and after about five minutes she’d wake up, and we’d interact. I kind of went through that again—but it was a kind of letting go.”

Kirk choked up slightly while retelling his experience. “It’s still a little bit emotional,” he says. “The thing I realized [was that] I didn’t want to let go. I wanted to hold on to the grief, because that was the only connection I had with my mum.”

While this may sound like an ordinary therapy session, it was not what you would typically expect. Kirk was experiencing the effects of a 25-mg dose of psilocybin—the active ingredient in psychedelic “magic” mushrooms—which he had ingested as part of a 2015 clinical trial investigating the drug’s therapeutic potential.

After his mother died, Kirk says, he fell into a “deep, dark pit of grief.” Despite antidepressants and regular sessions with a therapist, his condition was not improving. “I was stuck in it for years,” he recalls. So when he heard Imperial College London was recruiting participants for an upcoming trial studying the impact of psilocybin on depression, Kirk decided to sign up.

The study, led by psychologist and neuroscientist Robin Carhart-Harris as part of the Beckley/Imperial Research Program, enrolled 12 patients with varying stages of treatment-resistant depression. Each participant took part in two guided treatment sessions, first with a low dose (10 mg) of psilocybin in pill form, then a high dose (25 mg) one week later. During each psychedelic session, subjects were closely monitored by at least one psychiatrist and an accompanying counselor or psychologist. “The guides [help] provide a safe space for the patient to have their experience,” Carhart-Harris explains.

In addition to the deeply emotional encounter with his deceased mother, Kirk also recalls moments of “absolute joy and pleasure” during his sessions. He remembers having a vision of the Hindu deity Ganesh (the “remover of obstacles”) and feeling an altered sense of self and his surroundings. “Your mind is always chattering and observing things,” Kirk says. “And that was all shut down. For me, there was a feeling of new space.”

Experiences like Kirk’s are common among people who have participated in a psychedelic session (or “trip,” as it was allegedly first called by US Army scientists in the 1950s). Reports consistently include feeling intense emotions, having mystical experiences, and entering a dreamlike state. Many also articulate a dissolving sense of a bounded self, coupled with a feeling of increased connectedness with others and the rest of the world.

When Carhart-Harris and his team assessed their study’s participants three months after treatment, they found that most of the participants showed reduced depressive symptoms, with 5 of the 12 in complete remission1—including Kirk. It’s now been two years since he received psilocybin therapy, and he says that he has not needed antidepressants or therapy since. “I got a new positivity that I didn’t have for some time,” he says.

These results are preliminary—the study tested a small sample size with no control group. But other recent trials, including some that were larger and included controls, have revealed additional therapeutic benefits. Last December, for example, two randomized placebo-controlled clinical trials of psilocybin in terminal cancer patients (51 and 29 patients, respectively) found that giving participants psilocybin in guided sessions could substantially decrease depression and anxiety—an improvement that persisted for at least six months after treatment. In smaller pilot studies, psilocybin has also shown success in treating addiction. In two small trials, one involving smokers and the other alcoholics,5 most participants remained abstinent for months after treatment with the psychedelic.

A number of early studies have also reported evidence that other psychedelics, primarily LSD, have similar effects. Roland Griffiths, a psychiatry professor at Johns Hopkins University, describes the effects of psychedelics as a sort of “reverse PTSD.” With PTSD, there is “some discrete, traumatic event that produces some alteration in neurology and perception that produces [psychological] dysregulation going forward,” he says. In a similar but opposite way, treatment with hallucinogenic substances is a “discrete event that occurs to which people attribute positive changes that endure into the future.” While scientists are only beginning to understand the mechanisms behind these effects, what they’ve found so far already tells quite a compelling story.

Most psychedelics researchers believe that the session itself—the profound experiences individuals have during a trip—is key to the drugs’ therapeutic effects. But whether this is a cause or consequence of underlying neurobiological effects is still unclear. Studies show that psychedelics disrupt established networks in the brain, potentially allowing new connections to form. Recent work has also begun to reveal that these drugs’ effects—such as promoting neuroplasticity and reducing inflammation—are exerted through the serotonin 2A receptor.

“It’s very exciting that we seem to be at a threshold of establishing the neurobiological basis for the range of effects that hallucinogens have, and specifically, the therapeutic range of action,” says Charles Grob, a psychiatry professor at Harbor-UCLA Medical Center who conducted a pilot study of psilocybin for terminal cancer patients that was published in 2011. “I think there is growing knowledge and appreciation that this work can be conducted responsibly and safely, and that it has the quite compelling potential to offer us very new and exciting treatment models.”

The tripping brain

While on psychedelics, people commonly experience ego dissolution, a loss of the sense of a separate self, and an enhanced feeling of connectedness with the outside world. Recent neuroimaging studies have revealed that the intensity of this experience correlates with changes in brain activity, primarily in the default mode network (DMN)—a system of brain regions that is more active at rest than during tasks, and that is thought to be involved in, among other things, processing information related to the self.

To understand what happens in the brain during a trip, Carhart-Harris and colleagues have been dosing healthy participants with psychedelics and scanning their brains using functional magnetic resonance imaging (fMRI) to measure cerebral blood flow, a proxy measure of neural activity. In 2012, for example, the researchers found that, following an intravenous injection of 2 mg of psilocybin, 15 subjects displayed an overall decrease in cerebral blood flow as well as decreased connectivity between the posterior cingulate cortex and the medial prefrontal cortex, two hubs of the default mode network.

Follow-up studies using both fMRI and magnetoencephalography (MEG)—a technique to detect the tiny magnetic fields generated by electrical activity in the brain—on subjects dosed with LSD have revealed similar effects. This work also revealed a correlation between decreased connectivity in the default mode network and subjective ratings of ego dissolution.

But while the two psychedelic drugs “share signature psychological effects,” Carhart-Harris notes, “they differ in the potency [and] in their kinetics. The psilocybin trip is shorter, and for that reason is more manageable than an LSD trip.”

Researchers have found similar neurological effects during meditation—another altered state of mind associated with psychological well-being. Expert meditators also show an acute reduction in the activity of the default mode network. Conversely, an increase in activity and connectivity in this network has been found in some individuals with depression. “In some ways, it kind of makes sense that psilocybin, which brings people very powerfully into the present moment, would be more similar to meditation than it would be to depression,” says Griffiths. “In other words, people are riveted with interest in the present moment and what’s happening here and now, rather than in the future or in the past.” Griffiths and his colleagues at Johns Hopkins are currently conducting a neuroimaging experiment probing the brains of expert meditators on psychedelic trips.

Using MEG, Carhart-Harris and colleagues have also discovered that psilocybin and LSD alter neural oscillations, rhythmic brain activity linked to various perceptual and cognitive functions, across the default mode network. Individuals under the influence of these drugs experience a drop in so-called alpha rhythms, oscillations in the range of around 8 to 13 hertz, that correlate with their reports of ego dissolution. “When you plot out what rhythms contribute to the brain’s overall oscillatory activity, you get this huge peak in the alpha band—this really prominent frequency that, in some ways, sort of dominates the rhythmicity of the brain,” Carhart-Harris explains. “It’s a really curious rhythm, because it’s more prominent in humans than in any other species, and its prominence increases as we develop into adulthood. I see it as a kind of signature of high-level consciousness that adult humans have.”

In contrast to the decrease in activity and connectivity within the DMN, imaging studies have revealed an increase in functional links between normally discrete brain networks during a trip, and such activity also correlates with reports of ego-dissolution. Together with findings of changes in the default mode network and reduced alpha rhythms, these results are contributing to a hypothesis that the brain becomes “entropic”—more disordered, fluid, and unpredictable—during psychedelic use, disrupting certain pathways while allowing for new connections to be made. “What’s been consistently found is that the brain or the mind during psychedelic states is in a different state of consciousness, and this is also reflected in how the brain is behaving,” says Rainer Kraehenmann, a psychiatrist and researcher at the University of Zurich. But, he adds, more research is needed to understand just what these changes mean. “I would not say that we can reduce it to certain areas or certain mechanisms,” Kraehenmann says. “The brain is still too complex to really understand what’s going on.”

And of course, the biggest question that remains is how these neurological changes might be therapeutic. In a soon-to-be published study, Carhart-Harris and his colleagues found that changes in the connectivity of the default mode network predicted how well patients would do after psilocybin treatment, but the results are preliminary. “We know that there’s fascinating things happening acutely in terms of these changes in the synchronization across brain areas,” says Matthew Johnson, a behavioral pharmacologist at Johns Hopkins. “But the really tantalizing possibilities that a number of groups, including ours, are looking at is whether those types of changes persist and are related to long-standing clinical benefits.”

Mind-bending molecules

All the classic psychedelic drugs—psilocybin, LSD, and N,N-dimethyltryptamine (DMT), the active component in ayahuasca—activate serotonin 2A (5-HT2A) receptors, which are distributed throughout the brain. In all likelihood, this receptor plays a key role in the drugs’ effects. Kraehenmann and his colleagues in Zurich have discovered that ketanserin, a 5-HT2A receptor antagonist, blocks LSD’s hallucinogenic properties and prevents individuals from entering a dreamlike state or attributing personal relevance to the experience.

Other research groups have found that, in rodent brains, 2,5-dimethoxy-4-iodoamphetamine (DOI), a highly potent and selective 5-HT2A receptor agonist, can modify the expression of brain-derived neurotrophic factor (BDNF)—a protein that, among other things, regulates neuronal survival, differentiation, and synaptic plasticity. This has led some scientists to hypothesize that, through this pathway, psychedelics may enhance neuroplasticity, the ability to form new neuronal connections in the brain. “We’re still working on that and trying to figure out what is so special about the receptor and where it is involved,” says Katrin Preller, a postdoc studying psychedelics at the University of Zurich. “But it seems like this combination of serotonin 2A receptors and BDNF leads to a kind of different organizational state in the brain that leads to what people experience under the influence of psychedelics.”

This serotonin receptor isn’t limited to the central nervous system. Work by Charles Nichols, a pharmacology professor at Louisiana State University, has revealed that 5-HT2A receptor agonists can reduce inflammation throughout the body. Nichols and his former postdoc Bangning Yu stumbled upon this discovery by accident, while testing the effects of DOI on smooth muscle cells from rat aortas. When they added this drug to the rodent cells in culture, it blocked the effects of tumor necrosis factor-alpha (TNF-α), a key inflammatory cytokine.

“It was completely unexpected,” Nichols recalls. The effects were so bewildering, he says, that they repeated the experiment twice to convince themselves that the results were correct. Before publishing the findings in 2008,15 they tested a few other 5-HT2A receptor agonists, including LSD, and found consistent anti-inflammatory effects, though none of the drugs’ effects were as strong as DOI’s. “Most of the psychedelics I have tested are about as potent as a corticosteroid at their target, but there’s something very unique about DOI that makes it much more potent,” Nichols says. “That’s one of the mysteries I’m trying to solve.”

After seeing the effect these drugs could have in cells, Nichols and his team moved on to whole animals. When they treated mouse models of system-wide inflammation with DOI, they found potent anti-inflammatory effects throughout the rodents’ bodies, with the strongest effects in the small intestine and a section of the main cardiac artery known as the aortic arch. “I think that’s really when it felt that we were onto something big, when we saw it in the whole animal,” Nichols says.

The group is now focused on testing DOI as a potential therapeutic for inflammatory diseases. In a 2015 study, they reported that DOI could block the development of asthma in a mouse model of the condition, and last December, the team received a patent to use DOI for four indications: asthma, Crohn’s disease, rheumatoid arthritis, and irritable bowel syndrome. They are now working to move the treatment into clinical trials. "The benefit of using DOI for these conditions," Nichols says, "is that because of its potency, only small amounts will be required—far below the amounts required to produce hallucinogenic effects."

In addition to opening the door to a new class of diseases that could benefit from psychedelics-inspired therapy, Nichols’s work suggests “that there may be some enduring changes that are mediated through anti-inflammatory effects,” Griffiths says. Recent studies suggest that inflammation may play a role in a number of psychological disorders, including depression and addiction.

“If somebody has neuroinflammation and that’s causing depression, and something like psilocybin makes it better through the subjective experience but the brain is still inflamed, it’s going to fall back into the depressed rut,” Nichols says. But if psilocybin is also treating the inflammation, he adds, “it won’t have that rut to fall back into.”

If it turns out that psychedelics do have anti-inflammatory effects in the brain, the drugs’ therapeutic uses could be even broader than scientists now envision. “In terms of neurodegenerative disease, every one of these disorders is mediated by inflammatory cytokines,” says Juan Sanchez-Ramos, a neuroscientist at the University of South Florida who in 2013 reported that small doses of psilocybin could promote neurogenesis in the mouse hippocampus. “That’s why I think, with Alzheimer’s, for example, if you attenuate the inflammation, it could help slow the progression of the disease.”

Research revival

Although researchers have only recently started to test psychedelics’ effects in controlled clinical trials, evidence that these drugs could help treat conditions such as depression and terminal cancer–related anxiety has existed since the middle of the 20th century. (See table below.) Despite promising results, the counterculture that emerged around LSD use led to the criminalization of it and other psychedelics in 1966. Since 1970, almost all of these compounds have been Schedule I controlled substances, which imposes strict prohibitions on their use, even in research.

“If the drug war hadn’t started, and we didn’t have this demonization [of psychedelics], we’d know a lot more about what makes people happy, sad, depressed,” says David Nichols, a professor emeritus of pharmacology at Purdue University and a pioneering psychedelics researcher (also the father of Charles Nichols). “That’s the tragedy—that none of that has happened because [the research] basically died in 1970.”

Now, psychedelics research is slowly starting to regain ground, though it’s still not easy to win federal funding for these studies. But with support from private organizations such the Heffter Research Institute and the Multidisciplinary Association for Psychedelic Studies (MAPS), scientists have begun to probe the mechanisms underlying the drugs’ psychological effects and the enduring changes they can bring about. The answers to these mysteries may help scientists gain insight into what happens to the brain in disease, and perhaps learn more about the nature of consciousness itself.

“There are many different questions to ask, and in some ways, the therapeutic ones are among the most mundane,” says Griffiths. “Our understanding is so primitive that I think it’s important that we not be so naive as to think that our current technologies are going to be able to unravel the many, many subtleties that account for some of these kinds of sustained effects. That’s why [the study of psychedelics is] such an interesting, important, and rich field of investigation for neuroscience.”

https://www.the-scientist.com/features/decoding-the-tripping-brain-30240
 
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The brain on psychedelics

by Diana Kwon

Understanding how hallucinogenic drugs affect different neural networks could shed light on their therapeutic potential.

Key brain areas involved in the effects of psychedelic drugs are located in the default mode network (DMN), which is more active at rest than when attention is focused on the external environment. Neuroscientists first discovered this network while scanning participants’ brains at rest: rather than a decrease in activity across the brain, they found that activity in some regions was actually higher when people were not engaged in a goal-directed task. Over the years, researchers have linked the DMN to a variety of functions, including autobiographical recollection, mind wandering, and processing self-related information.

Key hubs of the DMN include the posterior cingulate cortex (PCC), the medial prefrontal cortex (mPFC), and the posterior inferior parietal lobule (pIPL). Through neuroimaging, researchers have discovered that psychedelic drug use decreases activity in some of these brain areas, and also reduces connectivity within the DMN.

Neuroimaging studies have also shown that connectivity between brain networks is increased when psychedelics are administered. For example, the DMN; the salience network, which helps identify behaviorally relevant information; and the frontoparietal network, known to be involved in attentional control and conscious awareness, all show stronger connections to each other. Researchers believe that this increased crosstalk throughout the brain may play a key role in the drugs’ effects.

https://www.the-scientist.com/multimedia/infographic-the-brain-on-psychedelics-30994

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“During my LSD sessions, I would learn a great deal” said Cary Grant about the 100 LSD trips he did in search of his true self. “And the result was a rebirth. I finally got where I wanted to go.” Steve Jobs described taking LSD as “a profound experience, one of the most important things in my life.”

What is it about psychedelics that has the power to change lives for the better? The answer might lie in the unique ways that psychedelics interact with the brain.

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The experiences of Cary Grant and Steve Jobs are in no way isolated cases. In a recent experiment at Johns Hopkins University School of Medicine, 36 healthy volunteers were given a high dose of psilocybin. Most participants rated their experience amongst “the five most meaningful and spiritually significant events of my life.” They reported increased well-being and positive behavior changes, even 14 months after the psychedelic experience.

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'Higher’ state of consciousness?


In this post, when I say ‘psychedelic drugs’ I’m referring to the classic psychedelics namely LSD, psilocybin, DMT, ayahuasca and peyote. Users of these drugs often report experiencing a ‘higher state of consciousness’ in which their perception seems enriched.

When researchers first scanned a human brain under the influence of these drugs, they expected to measure an increase in brain activity. To their surprise, most of the brain remained at the same level of activity except for a few areas. In those few areas the activity didn’t increase as expected, but rather decreased. What’s more, the participants experiencing the most intense psychedelic effects also showed the strongest decreases of activity in those particular areas. In other words, the lesser the activity, the stronger the trip.

Now, how does that make sense? Psychedelic drugs leave your brain’s executive functions intact: you can move, think, speak, know when to use the bathroom and other useful things. What they shut down however are certain connector hubs in the brain.

To understand the role of these connector hubs, think of traffic in a big city. When you shut down a major highway, drivers have to deviate from their normal routes and often find themselves in unfamiliar territory. Because a big city has an abundance of streets, drivers can still get to their destination, but only after a more lengthy and perhaps interesting ‘trip’.

Something similar happens when psychedelics shut down certain connector hubs in the brain. All of a sudden, there is a lot more cross-talk between areas which usually wouldn’t communicate.

The visualization below compares the brain’s communication pathways during (a) a regular state, with all the connector hubs intact. And (b) the psychedelic state, with the connector hubs shut down, leading to an abundance of novel communication pathways between brain areas.

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Communication pathways after (a) placebo and (b) psilocybin

By this time, you may be asking yourself ‘What are these mysterious connector hubs and what do they do in the first place?’ The following section is all about these hubs and how they make up the so-called default mode network in your brain. This network is a relatively new discovery and turns out to play a key role in understanding the effects of psychedelics.

The Default Mode Network

Whenever your mind is not engaged in a specific task, it switches into a kind of “autopilot” mode referred to as the default mode network or DMN for short. One way to think about the DMN is as an integration center, where information is collected and organized in ways that makes it coherent with regard to the rest of your cognition. The DMN is like a librarian who—when not handling immediate customer requests—indexes and categorizes books to keep the library neatly organized.

Another way to think about the DMN is as the center of the self. It’s engaged in self-reflection and metacognition, i.e. thinking about thinking. It allows you to mentally travel back and forth in time, pondering autobiographical events or future problems.

These important functions make the DMN a vital connector hub in the human brain and part of what distinguishes us from other species. However, an overactive DMN is associated with people being neurotic, depressed or anxious.

Disrupting the default mode network

When psychedelic drugs shut off certain connector hubs, they also reduce the stability of the networks that exist on top of these hubs, in our case: the default mode network. So, if you were to disrupt your DMN—for example through the use of psychedelic drugs—how would it change the way you think and act?

When the usual DMN connectivity is not available and signals therefore travel on different routes, you experience reality in a different way. This is why the psychedelic state is often called an altered state of consciousness. ‘Seeing with your eyes shut’ and a disintegration of the self as you know it are two typical characteristics of such a state. To learn more, check out The Psychedelic Experience post with a side-by-side comparison of how different drugs change your perception.

Particularly in people suffering from mood disorders, psychedelics frequently show another interesting effect: their condition improves. Mental disorders such as depression, anxiety and obsessive compulsive disorders (OCD) are often associated with a hyperactive DMN. If you disrupt the DMN, you often see substantial and long-lasting reductions in symptoms. We’ll talk more about concrete study results in a follow-up article next week.

Psychedelics are unique in how they can modulate the DMN. How they work in the brain is endlessly fascinating—and unfortunately—pretty complicated. And yet, I’ll have a try in explaining it in simple terms:

Your brain on psychedelic drugs

Right. Let’s break that down into normal language:

I. Receptor binding

Psychedelics interact with the serotonergic system in the brain, meaning they can bind to serotonin receptors. Why? Because serotonin, LSD and psilocin—the psychoactive metabolite of psilocybin—look very similar on a molecular basis.

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But whereas serotonin binds to about a dozen different subtypes of serotonin receptors, psychedelic drugs bind to a very specific subtype, the so-called serotonin 2A receptor. LSD additionally binds to a few other subtypes of serotonin and dopamine receptors, but to a lesser degree. Most relevant for the psychedelic experience is the serotonin 2A receptor.

II. Long axons

Serotonin 2A receptors sit on specific types of neurons which have long axons that span across the brain, as opposed to neurons with short axons that only connect to other cells in their close vicinity. These large neurons have axons that leave the cortex and run down into areas below the prefrontal cortex. Doing so, they have top-down control over the regions they connect to, and in this case it’s areas associated with emotions and stress responses.

III. Excitatory neurons

Neurons can be either excitatory or inhibitory. Think of training a dog.

Both, “speak” and “quiet” are signals that produce a certain reaction. An excitatory signal tells the neuron to “fire”, whereas an inhibitory signal says “don’t fire”. Remember, psychedelics stimulate serotonin 2A receptors, and those are located on excitatory neurons, meaning causing the neuron to fire. Logically, one would think that taking a psychedelic drug would lead to more firing in the brain. Paradoxically, the opposite is the case. How does that make sense?

When activation leads to inaction

LSD binds to the serotonin 2A receptor and causes the neuron to fire off an excitatory signal. When these neurons fire, they also stimulate nearby, inhibitory neurons called fast spiking interneurons, which have serotonin 2A receptors as well. So what happens is a massive firing and an even greater inhibition at the same time. Eventually, the inhibitory signaling is stronger than the excitatory and you’re left with a net decrease in activity.

Unique signaling

Just because serotonin and psychedelic drugs bind to the same serotonin 2A receptor doesn’t mean that they produce the same signal. For a long time, scientists believed that receptors worked like light switches, meaning that they are either on or off. According to this theory, psychedelics and serotonin must have had the exact same effect: either binding to the receptor and activating it, or clearing the receptor and deactivating it. But today we know that each molecule interacts with a receptor in its own unique way, causing a unique signal within the cell. How does that work? When a molecule binds to a receptor, the receptor has to physically accommodate the molecule’s unique shape. And by doing so it activates certain signaling pathways within the neuron. The jargon for this principle is functional selectivity, in case you wish to go deeper.

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Ok, so an LSD molecule doesn’t actually look like a rainbow. Rather, it’s a big, rigid molecule which takes up a lot more space within the receptor than the smaller, more flexible serotonin molecule. And receptors don’t look like sticks but more like funny party streamers being tied together at the ends with a thin thread. So, when LSD binds to a receptor, it looks a little something like this:

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You can see how the party streamers give way to the big LSD molecule and thereby trigger a distinct signaling pathway within the cell. Tip: if you ever talk to a biochemist about this, don’t call it a party streamer—call it a helix.

As of today, it remains unknown which signaling pathway is most relevant for the psychedelic experience. What we do know is that it’s a different pathway than the one activated by serotonin.

Why an LSD trip lasts so long

Serotonin molecules clear receptors a split second after binding to them. In contrast, when LSD binds to a receptor, the receptor collapses over the molecule and forms a lid, preventing the LSD from clearing.

As long as the LSD molecule is trapped within the receptor, it causes the receptor to send off signals—for a few hours and sometimes longer. That’s why mere micrograms of LSD can make users ‘trip’ for 6-15 hours.

Drugs as tools

You can probably see now that psychedelics work like no other molecule in the brain. Fossil evidence supports that humans have made use of psychoactive plants for as much as 10,000 years during ritual ceremonies. Ancient societies regarded psychedelic drugs as tools; will modern society adopt this perspective once again?

https://sapiensoup.com/brain-on-psychedelic-drugs
 
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How psychedelic drugs influenced the growth and development of psychopharmacology

by Nicholas Cozzi

IN THE MID-20TH CENTURY, the prevailing views in psychology and psychiatry were that mood, desires, feelings, memories, behaviors, and personalities were determined by environmental histories, childhood experiences, the interplay among reward, punishment, repression, and reinforcement, the unconscious mind, and psychosexual mechanisms, among others. Brain activity was believed to be essentially electrical in nature. Before the 1940s and early 1950s, the notion that consciousness was influenced, if not determined, by the actions of chemicals produced in the brain, was completely foreign. Important events that transformed the existing paradigms and birthed the fields of neurochemistry and neuropharmacology, leading directly to the development of psychopharmacology as a scientific discipline, are in fact centered around the discovery and investigation of the psychoactive effects of LSD, DMT, psilocybin, and other psychedelic substances.

One of the most important discoveries springing from psychedelic drug research was the elucidation of the role of serotonin in mental processes. Serotonin, whose chemical structure was determined in 1949, was known to be present in clotted blood since the late 1800s. Here, it has a hemostatic role: It helps prevent bleeding when tissues are damaged. Upon injury, serotonin is released from blood platelets, producing local vasoconstriction and stimulating further platelet aggregation, helping to form a clot and stanch bleeding. The discovery of serotonin in brain tissues in the early 1950s then hinted a potential role for serotonin in brain function and consciousness. The discovery of serotonin in the brain was made independently and simultaneously by a team in the United States and another team in Edinburgh, Scotland, led by John Gaddum. But it was Gaddum’s self-experiments with LSD that were especially important in shaping early theories of the involvement of serotonin in consciousness.

John Gaddum was a British pharmacologist who was involved in early serotonin research. On four separate occasions in 1953, Gaddum ingested LSD to learn of its effects in him. Thanks, no doubt, in part to these self-experiments and in part to observations from his in vitro laboratory experiments with LSD and serotonin, Gaddum became the "first person to propose a relationship between LSD and serotonin and to then suggest that the effects of LSD on serotonin function were responsible for LSD’s psychedelic effects." His handwritten notes from a self-experiment with 86 micrograms of LSD on June 1, 1953 read as follows:

9:48: "My hand looks queer, like a monstrous picture of a hand—that writhes about until I fix it with a look. It has interesting contrasts in its colours. I see it like an overreal picture - with a rather strange feel to it - as if it was someone elses [sic]. Everything in the room is rather unstable. Methedrine has not abolished the effect on sensations."

He went on to write: “The evidence for the presence of HT [serotonin] in certain parts of the brain may be used to support the theory that the mental effects of lysergic acid diethylamide are due to interference with the normal action of this HT.” Thus, in John Gaddum, there is a confluence of first-hand LSD experience and a "fledgling chemical neuroscience."

Independently, D.W. Woolley and E. Shaw in New York proposed “...that the mental disturbances caused by lysergic acid diethylamide were to be attributed to an interference with the action of serotonin in the brain.” They further state that “Gaddum also was cognizant of the mental effects of lysergic acid diethylamide and of the occurrence of serotonin in the brain. We have surmised that he has been thinking, just as we have, about the relationship of serotonin to the mental disturbances induced by the drug.” Unlike in the case of Gaddum, however, there is no evidence that Woolley or Shaw ingested LSD themselves. Later, they wrote:

"The thesis of this paper is that these pharmacological findings indicate that serotonin has an important role to play in mental processes and that the suppression of its action results in a mental disorder. In other words, it is the lack of serotonin which is the cause of the disorder. If now a deficiency of serotonin in the central nervous system were to result from metabolic rather than from pharmacologically induced disturbances, these same mental aberrations would be expected to become manifest. Perhaps such a deficiency is responsible for the natural occurrence of the diseases... In summary, the suggestions we wish to make are the following: (1) serotonin probably plays a role in maintaining normal mental processes; (2) metabolically induced deficiency of serotonin may contribute to the production of some mental disorders; (3) serotonin or a long-acting derivative of it may prove capable of alleviating disorders similar to schizophrenia."

In these early reports, one finds the seeds of ongoing re-search and development of modern psychotherapeutic drugs, which has produced a multi-billion-dollar-a-year pharmaceutical industry aimed at modifying the actions of serotonin and other neurotransmitters in the brain to treat mental diseases.

DMT has also had an important influence in the evolution of our thinking on normal and extraordinary states of consciousness. In 1961, Nobel laureate Julius Axelrod made the remarkable discovery that mammalian tissue (rabbit lung) had the ability to synthesize DMT. This finding was extended in the early 1970s when it was reported that biopsied human brain tissue could carry out this same biotransformation. The discovery that human brain tissue could produce, at least in vitro, small amounts of DMT, led to much speculation regarding the possible role of DMT in human consciousness. However, the analytical technology at that time was not as sensitive or robust as current methods. While some investigators were able to confirm the presence of DMT in human tissues and fluids, others failed to do so. Some scientists at the time believed that the in vitro observations of Axelrod and other researchers were experimental artifacts.

The issue was unresolved for almost 30 years. Then, in 1999, Michael Thompson and coworkers at the Mayo Medical School in Rochester, Minnesota, using cloning and sequencing techniques of molecular biology, discovered the human gene that codes for the enzyme (INMT) that synthesizes DMT from tryptamine. The Thompson discovery renewed discussion in, and significantly strengthened hypotheses about, a role for endogenous DMT in states of consciousness such as spiritual exaltation, dreams, creativity, near-death experiences, and other possible physiological roles. The view that the presence of DMT in mammalian tissues is only an artifact now seems untenable.

More recently, our group at the University of Wisconsin School of Medicine and Public Health in Madison, Wisconsin, using immunohistochemical techniques, has extended the original work of Thompson et al. by identifying the INMT protein itself in several primate central nervous system tissues. To couple the presence of the INMT protein in brain tissues with the biosynthesis of DMT within these tissues, in realtime, remains a challenging research objective. For interested readers, a critical review of the scientific literature of the past 55 years regarding the presence of DMT and other tryptamines in human tissues and fluids was recently published by Steven Barker, Ethan McIlhenny, and Rick Strassman.

Since the time of Gaddum, research into psychedelics, serotonin, and other neurotransmitters and receptors has continued apace. Building upon the early theories of Gaddum, Wooley, and Shaw regarding the role of serotonin in the pharmacology of LSD, in the 1980s Richard Glennon and colleagues at the Medical College of Virginia at Virginia Commonwealth University were the first to name the serotonin 2 receptor (now called the 5-HT2A receptor) as a major binding target for lysergamide, phenylalkylamine, and indolealkylamine psychedelic agents. Over the following two decades, additional binding sites have been discovered and now 40 or more additional psychedelic drug receptor sites have been identified. While the 5-HT2A receptor is still widely considered to be a common receptor for psychedelic drug action, it is increasingly becoming recognized that activity at this receptor alone is not sufficient to explain the effects of psychedelic drugs. For example, other serotonin receptors, at least have been implicated in the behavioral effects produced by indolealkylamine psychedelics in animals. There is also evidence for the direct or indirect involvement of dopamine, glutamate, norepinephrine, gamma-aminobutyric acid, and other neurotransmitters and their receptors in the actions of these drugs. The 5-HT2A receptor may therefore serve as a “gateway” receptor, activation of which is necessary, but not sufficient, for psychedelic drug activity.

Apparently, the simultaneous actions of psychedelic drugs on many or all of the 40+ currently identifed receptor sites, with each psychedelic agent having a unique receptor binding and activation profile (a pharmacological “fingerprint”), shapes the variety of subjective experiences produced by these substances. Thus, although the term “psychedelic” is often used as a simplifying term, psychedelic drugs, while producing some similar subjective effects in humans, do not produce identical subjective effects, as people who have ingested these agents will readily testify. LSD is experienced differently from mescaline, which is different from DMT, which is di$erent from TMA-2, which is different from psilocybin, which is different from 2C-B, etc. In fact, while in vitro data and animal behavioral models are commonly used to study these materials, these approaches are limited in that they tend to blur the qualitative, experiential differences among psychedelic drugs, differences which human beings can easily distinguish. In vitro and animal data can supplement, but in no way substitute for, human experience, which of course is the sine qua non of psychedelic drug effects.

The problem of choosing uniform criteria to define psychedelic drugs and the experiences they produce is certainly not new. One approach put forth in the 1970s was to define psychedelic drugs to the extent that they mimic the effects of LSD. Although this definition is rather circular, it does put the psychedelic experience itself squarely at the center of the discussion. According to Grinspoon and Bakalar, “Whether a drug should be regarded as psychedelic or not can be said to depend on how closely and in what ways it resembles LSD; the resemblance must be judged by the drug’s cultural role as well as by its range of psychopharmacological effects. From this point of view, the group of psychedelic drugs has a clearly defined center and a vague periphery...” Linking molecular binding events to animal behavior to human experiences remains a tantalizing but incompletely realized goal.

It is apparent from the literature reviewed above and other sources that much present-day research into neurotransmitters and drugs that affect their function in the brain is directly traceable to the experiments and writings of scientists investigating the mechanisms of action of LSD, DMT, and other psychedelic compounds.

In light of these discoveries in neurochemistry, the suppositions of psychology and psychiatry with respect to the origin and nature of consciousness and psychological diseases were required to undergo significant revision. It became necessary for psychology and psychiatry to incorporate observations from neurobiology into models of mental functioning. Neuro-chemistry and neuropharmacology began to assume dominant roles in consciousness research and in the medical treatment of mental illness by the late 1950s and into the 1960s. In particular, it became obligatory for psychotherapeutic practices to employ psychoactive drug treatments, which were rationally derived from the experimental discoveries of neuropharmacology, as a major approach to psychological healing. Although there remains much that could be improved, the effectiveness of these drugs has undoubtedly benefited countless lives.

Interest in neurotransmitters and drugs that modulate their activity continues to motivate much current research in academia, the pharmaceutical and biotechnology industries, and government institutes. For a person seriously interested in such research - especially if it involves psychedelic drugs - Ph.D. or M.D. level academic study or clinical training, at least, is usually necessary. Several years of post-doctoral training may eventually lead to a role as a principal investigator directing basic science research or as a clinical study director supervising human studies. In any case, post-baccalaureate graduate study at any level will lead to more opportunities to be involved, perhaps as a team member, in doing research at a university, a pharmaceutical company, the National Institutes of Health, or a private research foundation. The long line of consciousness researchers seeking to develop tools to study the mind and improve mental health awaits you as a participant!

http://www.maps.org/news-letters/v23n1/v23n1_p16-19.pdf
 
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4-AcO-DMT

by Psychedelic Science Review

In 1963, German chemists Albert Hofmann and Franz Troxler patented their discovery of 4-AcO-DMT along with other indole esters they had synthesized. Just as Hofmann put LSD aside for five years after synthesizing it in 1938, unaware of its psychedelic properties, psilacetin was patented but shelved. According to the United Nations Office on Drugs and Crime, synthetic tryptamines like psilacetin began appearing in illicit drug markets throughout the 1990s.

The chemistry of 4-AcO-DMT

Psilacetin is a structural analog of the psychedelic mushroom (aka psilocybin mushroom or magic mushroom) compound psilocybin. Psilocybin is a prodrug of psilocin, and psilocin is an analog of the neurotransmitter of serotonin. Chemically, psilacetin is O-acetylated psilocin, whereas psilocybin is O-phosphorylated.

The pharmacology of 4-AcO-DMT

In their 1963 patent, Hofmann and Troxler described indole acetate esters like 4-AcO-DMT as serotonin receptor antagonists. However, over the years, scientists have come to classify them as prodrugs that are inactive on their own by way of analogy to psilocybin.

The way psilacetin is metabolized in the human body is unknown. However, based on the chemistry and metabolism of similar tryptamine compounds,3 it is reasonable to assume that psilacetin undergoes deacetylation to form psilocin. From that point, psilocin would follow the accepted theory of binding to the serotonin 5-HT2A receptor, causing a psychedelic effect.

There are no published scientific studies specifically addressing whether psilacetin is metabolically active on its own. The possibility exists that when ingested, psilacetin may bind to serotonin receptors, including 5-HT2A, and elicit a psychedelic effect, perhaps one that is unique from psilocin. According to anecdotal reports, the psychoactivity of psilacetin is immediate when in injected, bypassing the first-pass metabolism in the stomach and liver.

A 2017 substance abuse study using rodents suggests a single administration of 4-AcO-DMT prevents and reverses heroin and nicotine addictions. The authors of the study theorize the mechanism involves preventing the up-regulation of brain-derived neurotrophic factor via serotonin 5-HT2A receptor signaling.

The renowned psychedelic researcher Dr. David Nichols has suggested that psilacetin, like psilocybin, is a prodrug of psilocin. In their 1999 work, Dr. Nichols and Dr. Stewart Frescas synthesized the fumarate salt of psilacetin.

Recent scientific studies on 4-AcO-DMT

Following 20 years of inactivity, the chemical community recently published new data about psilacetin. Building on the work Nichols and Frescas did in 1999 scientists solved the crystal structure of 4-AcO-DMT fumarate in March 2019. Chadeayne, et al. demonstrated that the solid-state structure is an asymmetric unit containing one 4-acetoxy-N,N-dimethyltryptammonium cation, and one 3-carboxyacrylate anion. Despite its use as a research chemical in the illicit drug market, this work was the first conclusive structural characterization of the molecule.

In a follow-up to this study, the same research team defined the crystal structure of a new solvate form of 4-AcO-DMT fumarate, bis(4-acetoxy-N,N-dimethyltryptammonium) fumarate. The crystal structure consists of two protonated psilacetin molecules that are charge-balanced by one fumarate dianion. This new solvate form of psilacetin is an important discovery because it opens the door to more options for drug development.

 
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A new category of medications: Psychoplastogens


by Eugene Rubin M.D., Ph.D. | Psychology Today | 11 Jul 2018

In an article published recently in the journal Cell Reports, David Olson, Calvin Ly, and colleagues investigate the biologic actions of a class of drugs that they have named psychoplastogens. The authors provide the following description of drugs that fall into this new class: “To classify the growing number of compounds capable of rapidly promoting induced plasticity, we introduce the term ‘psychoplastogen’ from the Greek roots psych- (mind), -plast (molded), and -gen (producing).” These drugs cause nerve cells in the brain to form new neurites, i.e., projections that extend out from the cell body and have the potential to become axons and dendrites. In addition, these agents enhance the ability of nerve cells to interact with other nerve cells by increasing the number of synapses — the regions where nerve cells connect with one another.

Ketamine appears to be an example of one such drug. Ketamine has been shown to have rapid antidepressant and anti-suicidal properties. Ketamine-like drugs are likely to be approved by the Food and Drug Administration (FDA) for the treatment of depression in the future. Ketamine works by influencing brain receptor systems that respond to the neurotransmitter glutamate. The glutamatergic system then stimulates a variety of chemical pathways in nerve cells that control cell growth and cell connections.

Ly, Olson, and colleagues elegantly demonstrate that another group of drugs are as powerful, or even more powerful, than ketamine in causing cellular changes in brain cells. Whereas ketamine exerts its effect through glutamate-related systems, these drugs work through serotonergic systems. Although they involve different neurotransmitters, the effects of both groups of drugs lead to similar influences on the chemical systems inside neurons that are involved in growth and development.

The group of serotonergic drugs that the authors studied include psilocybin, LSD, ayahuasca, and ecstasy. They note that there is preliminary clinical evidence that these drugs may be helpful in treating several psychiatric conditions, including depression, anxiety states, and possibly addictive states. These drugs are currently undergoing formal clinical trials.

The authors note that while ketamine can be addictive, these non-ketamine drugs are not. However, they have psychedelic properties and have long been abused for their mind-altering effects, including perceptual changes that some people find enjoyable and others terrifying. Thus, continued development of these drugs as therapeutic agents will have to consider risks, potential benefits, and methods of administration carefully in well-designed clinical trials. Olson and colleagues are hopeful that new medications can be derived from the existing drugs that retain the psychoplastogen properties while eliminating the psychedelic effects.

The next decade will be a very interesting time for the development of truly unique pharmacologic approaches for the treatment of psychiatric disorders such as depression, anxiety, and addiction — disorders that are among the most impairing of all illnesses.

https://www.psychologytoday.com/us/...ble-new-category-medications-psychoplastogens
 
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Cambridge

Neuromodulators and Global Brain States*

Psychedelic Information Theory

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. 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-HT2A 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-HT2A and 5-HT2C 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.

*From the article here :
 
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New LSD research may help explain the brain chemistry of depression and schizophrenia

by Ed Cara | 20 Mar 2018

A small new study published in the Journal of Neuroscience seems to offer some insight into what’s happening in the brain on LSD. And it might even provide a hint as to how certain mental disorders develop.

German researchers asked 24 healthy volunteers to lay down in a MRI machine and play a little game. They were told to interact, via eye movements, with a virtual human avatar on a computer screen across five different scenarios (the avatar was controlled by the researchers). Scientists have used this exercise as a way to test how well people can socially interact with someone else.

The researchers found that when the volunteers were on LSD (as opposed to a placebo), they were less able to pay attention to the avatar and recognize it as another person while they completed their tasks. And the MRIs found they had less brain activity in the posterior cingulate cortex and the temporal gyrus. These regions are known to help with our self-perception, autobiographical memory, and our ability to communicate with others.

The study—not for the first time—shows how LSD can create “temporary alterations in self-experience” that make it hard for us to distinguish ourselves from others, lead author Katrin Preller, a researcher at the University of Zurich, told Gizmodo via email. This blurring, Preller added, can then hamper our ability to interact socially.

“We showed that alterations in self-experience are not independent from alterations in social cognition,” Preller said.

Preller and her team used the experiment to try to better understand mental disorders like depression, anxiety, and schizophrenia. The same sort of alterations we see with LSD can be found in these disorders, though they manifest in different ways.

“While schizophrenia patients suffer from an incoherent self-experience, depressed patients show an increased self-focus, i.e. ruminating about the own person/personality,” she explained. "In both cases, our ability to interact with others in a healthy way can be impaired."

Preller and her team theorized, based on animal research, that a specific version of the neurotransmitter serotonin, called serotonin 2A, plays a major role in how LSD affects the brain.

And in fact, when the volunteers were given both LSD and a drug that blocks serotonin 2A receptors, they performed just as well on the game and had similar brain activity as they did on placebos. That finding in particular highlights the potential applications of drugs that directly interact with and stabilize a person’s level of serotonin 2A, Preller said.

“When developing new medication we should therefore consider blocking the serotonin 2A receptor in patients with, for example, schizophrenia, which might lead to symptom improvement regarding self-experience but also social processing,” she said. And as some researchers and adventurous volunteers have speculated, both in the past and even today, these treatments could even include LSD.

“For disorders with increased self-focus such as depression or anxiety disorders, stimulating serotonin 2A receptors with psychedelics might indeed be beneficial,” Preller noted.

Recent, studies have shown that the active ingredient in psychedelic mushrooms can help alleviate depression and anxiety, even in low doses. And there is a similar trial of low-dose LSD in the works over in the UK. In the US, meanwhile, research involving LSD remains much more difficult to get off the ground, given its status as a Schedule I controlled substance.

The team next plans to explore other receptors in the brain that can help explain the psychedelic effects of drugs like LSD, as well as their influence on social cognition.

https://gizmodo.com/new-lsd-research...y-o-1823901901
 
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