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    Psychedelic pharmacology 
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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.



    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



    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



    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 3.00 3.54 2.60 3.76 4.00 3.38 0.00 1.93 2.77 0.00 2.71 2.91 3.44
    2C-B 2.75 3.11 3.71 3.05 3.69 4.00 3.18 0.00 2.63 2.81 0.00 2.64 2.31 3.12
    LSD 3.73 4.00 3.70 2.62 3.54 3.11 3.11 3.64 3.75 3.77 2.34 2.93 0.00 0.00
    DOI 0.00 2.31 3.00 2.66 3.44 3.13 4.00 0.00 2.34 1.90 1.67 3.79 3.13 2.88
    DMT 0.00 0.00 3.91 3.28 2.58 0.00 3.42 3.16 3.35 4.00 3.51 2.75 3.53 3.53
    Psilocin 2.88 2.19 3.40 3.03 2.14 4.00 2.52 2.83 2.82 2.82 3.37 1.36 1.57 1.03
    5-MeO-DMT 4.00 2.41 3.48 1.72 0.98 0.69 1.55 1.84 2.73 3.69 2.38 0.00 0.86 1.57
    DiPT 4.00 0.00 2.51 0.00 0.00 3.48 0.00 0.00 0.00 0.00 0.00 0.00 2.62 2.68
    Mescaline 3.61 0.00 0.00 3.16 0.00 3.97 0.00 0.00 0.00 0.00 0.00 2.92 0.00 4.00
    MDMA 0.00 0.00 0.00 0.00 0.00 3.64 0.00 0.00 0.00 0.00 0.00 2.94 3.09 3.21
    6-F-DMT 2.81 3.07 3.66 2.74 2.47 3.93 2.58 2.43 4.00 3.80 2.67 0.00 2.99 3.24
    Lisuride 4.00 2.27 0.00 0.00 2.74 3.01 0.00 2.99 2.61 2.64 0.00 3.22 3.78 3.88
    4C-T-2 2.04 0.00 0.00 1.77 3.33 4.00 3.09 2.56 0.00 2.18 0.00 0.00 0.00 0.00

    Table 1: A list of popular psychedelic drugs and receptor targets in order of 5-HT2A receptor affinity. A value of 4.00 indicates high affinity at that target; any value under 2.00 should be considered imperceptible. Non-psychedelic control molecules are listed at the bottom for comparison.

    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-HT2AC 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 psychedelic 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 psychedelics

    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
    Last edited by mr peabody; 09-09-2018 at 03:17.
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    CBD and the psychedelic receptor

    Lex Pelger
    March 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.[1] 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.[2] 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.

    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.”[3]

    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.

    FOOTNOTES

    1. By blocking the reuptake of serotonin, SSRIs (selective serotonin reuptake inhibitors) increase the concentration of 5HT in the synaptic cleft between nerve cells and consequent neuronal activity. But chronic use of certain SSRIs have been shown to lower the baseline level of endogenous serotonin.

    2. Known to regulate behavioral aging and longevity in the primitive nematode, serotonin functions as a neurotransmitter in the nervous system of most animals. Concentrations of serotonin are found in insect venom as well as in various fungi and fruits, including plums, kiwi, banana, pineapple, plantains and tomatoes.

    3. There’s a lot that scientists still don’t understand about how and when the cannabinoids modulate serotonin release. Many variables come into play. Some 5-HT receptor subtypes transmit an inhibitory signal; other 5-HT subtypes convey an excitatory signal. Cannabinoid receptors also function in a bidirectional manner, causing both neuronal excitation and inhibition by acting on glutamate and GABAneurotransmitters, respectively. And the biphasic properties of cannabinoids, whereby low and high dosages result in opposite effects, is another confounding factor. Some research indicates that THCdecreases serotonin production via the CB1 receptor. But several other studies arrive at confusing conclusions about what exactly is happening with CB1 receptors and serotonin in the dorsal raphae nucleus. There’s no simple correlation: the endocannabinoid tone of the area, the strength of the synapse and the density of the CB1 receptors all affect whether CB1 activation will cause serotonergic neurons to fire or be inhibited. As is often true with these nuanced systems, there’s not a simple off-and-on switch but a variable and complex feedback mechanism at work.

    4. Adrian Devitt-Lee adds: “Dimerization, in fact, may be the key to understanding why some of the chemicals that activate 5-HT2A aren’t psychedelic (such as serotonin itself). Some research suggests that hallucinogens like LSD cause 5-HT2A to dimerize with mGlu2, a G-protein coupled receptor which responds to the neurotransmitter glutamate. On the other hand, serotonin and other non-hallucinogenic molecules would activate 5-HT2A without causing it to dimerize. This hypothesis, however, is based on computer simulations and needs more evidence.”

    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

    This article is intended to be a detailed explanation of how hallucinogens affect the brain, via the inhibition and excitation of neurotransmitters in the nervous system. This article is not written by me, but an extremely close friend of mine who is significantly more knowledgeable when it comes to science, and specifically chemistry.



    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).



    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.



    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.





    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.


    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.


    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
    Last edited by mr peabody; 02-09-2018 at 05:03.
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    Sprucing up your brain with potent psychedelics


    This figure shows the effects of three psychedelics and one control (VEH) on cortical neurons.


    … A new study, published June 12 in the journal Cell Reports, found psychedelics, specifically DOI, DMT, and LSD, can change brain cells in rats and flies, making neurons more likely to branch out and connect with one another. The work supports the theory that psychedelics could help to fight depression, anxiety, addiction, and post-traumatic stress disorder.


    … “One of the hallmarks of depression is that the neurites in the prefrontal cortex — a key brain region that regulates emotion, mood, and anxiety — those neurites tend to shrivel up,” says Olson. These brain changes also appear in cases of anxiety, addiction, and post-traumatic stress disorder.

    Psychedelics are not the most popular drugs for treating depression, but as we better understand how they promote the growth of new dendrites and synapses, we should be better able to develop safer and more effective antidepressants to accomplish the same effect.

    More from the Cell report of 12 June 2018:

    Neuropsychiatric diseases, including mood and anxiety disorders, are some of the leading causes of disability worldwide and place an enormous economic burden on society. Approximately one-third of patients will not respond to current antidepressant drugs, and those who do will usually require at least 2–4 weeks of treatment before they experience any beneficial effects. Depression, post-traumatic stress disorder (PTSD), and addiction share common neural circuitry, and have high comorbidity.

    … Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clinical effectiveness of these compounds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chemistry efforts focused on developing plasticity-promoting compounds as safe, effective, and fast-acting treatments for depression and related disorders.

    The neuroplasticity described in the 12 June 2018 paper in Cell consists of “neuritogenesis,” or the growth of dendrites and synaptic buttons — providing a denser connectivity between neurons. Another form of neuroplasticity which may take place under some conditions is “neurogenesis,” or the growth of stem cells which develop into neurons. In adults, this may occur in the hippocampus and along the ventricular lining of the brain. The hippocampus is the region of the medial temporal lobes thought to play a prominent role in the retention of long term memories. More on hippocampal neurogenesis:

    … Here we assessed whole autopsy hippocampi from healthy human individuals ranging from 14 to 79 years of age. We found similar numbers of intermediate neural progenitors and thousands of immature neurons in the DG, comparable numbers of glia and mature granule neurons, and equivalent DG volume across ages. Nevertheless, older individuals have less angiogenesis and neuroplasticity and a smaller quiescent progenitor pool in anterior-mid DG, with no changes in posterior DG. Thus, healthy older subjects without cognitive impairment, neuropsychiatric disease, or treatment display preserved neurogenesis.

    It is possible that some psychedelic mixtures may stimulate the transition of neural stem cells into functioning neurons:

    When grown with ayahuasca compounds, the stem cells in the neurospheres also began to differentiate (change their properties) to resemble neurons more effectively than under control conditions. This means that the stem cells started to lose their stem-cell-like properties, and started making proteins that are found in adult neurons.

    Overall, it seems that exposing neural stem cells to harmine, THH, and harmaline encourages them to grow and change into new neurons more effectively than under control conditions.


    This is all very controversial


    Many neuroscientists still doubt that adult human brains can generate new neurons past adolescence. Proving that psychedelics can promote the growth of new neurons in the brain (eg hippocampus) will take some time, and perhaps a somewhat different perspective on neuropharmaceutical ethics than is dominant at this time.

    It is less controversial to pursue the use of ketamine derivatives to promote new “branching” of existing neurons. But ketamine does not seem to be as effective at neuritogenesis as LSD, DMT, or psilocybin. In other words, some old prejudices may need to fall in order to achieve a better solution to an age-old scourge of the human spirit.

    Here at the Al Fin Institutes of Neuroscience, we prefer the use of occasional treatments for chronic ailments over the everyday medication of persons. As people age, their ailments may tend to accumulate — as do the number of treatments required. Many persons may take as many as 10 to 20 medication doses per day. The use of psychedelics or psychedelic analogs for treating depression would likely be of an intermittent nature, rather than daily, and would help to cut down on the total daily dosage regimen.

    We actually prefer to avoid medication altogether

    If possible, the avoidance of pharmaceuticals is best. Electromagnetic or photic approaches to treating depression are preferred, as are other alternatives such as advanced neurofeedback, mindfulness, and cognitive behavioural therapies.

    Still, some people have experienced relief from depression lasting 6 months or longer from a single psychedelic experience, if well designed and overseen.

    We have barely begun to understand all the productive approaches to functional neuroplasticity in the treatment of neurologic and neuropsychiatric disorders.

    Renewed scientific interest in the use of psychedelics to treat disorders of the spirit can be seen as a positive sign.

    https://alfinnextlevel.wordpress.com...-psychedelics/
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    Neuropharmacology of DMT


    Theresa M. Carbonaro, Michael B. Gatch

    N,N-Dimethyltryptamine (DMT) is an indole alkaloid widely found in plants and animals. It is best known for producing brief and intense psychedelic effects when ingested. Increasing evidence suggests that endogenous DMT plays important roles for a number of processes in the periphery and central nervous system, and may act as a neurotransmitter. This paper reviews the current literature of both the recreational use of DMT and its potential roles as an endogenous neurotransmitter. Pharmacokinetics, mechanisms of action in the periphery and central nervous system, clinical uses and adverse effects are also reviewed. DMT appears to have limited neurotoxicity and other adverse effects except for intense cardiovascular effects when administered intravenously in large doses. Because of its role in nervous system signaling, DMT may be a useful experimental tool in exploring how brain works, and may also be a useful clinical tool for treatment of anxiety and psychosis.

    Introduction

    N,N-dimethyltryptamine (DMT) is an indole alkaloid widely found in nature. It is an endogenous compound in animals and in a wide variety of plants found around the globe. Major plant genera containing DMT include Phalaris, Delosperma, Acacia, Desmodium, Mimosa, Virola, and Psychotria, but DMT has been found even in apparently innocuous sources, such as leaves of citrus plants, and in the leaves, seeds, and inner bark of mimosa tenuiflora, which has become a source of livestock poisoning.

    DMT has become of interest because when ingested, it causes brief, episodic visual hallucinations at high concentrations. DMT is one of the major psychoactive compounds found in various shamanistic compounds (e.g., ayahuasca, hoasca, yage) used in South America for centuries and has, more recently found its way into Europe and North America as a recreational drug.

    Recreational use of DMT

    Most hallucinogens such as lysergic acid diethylamide (LSD) and 2,5-dimethoxy-4-methylamphetamine (DOM) cause sensory distortion, depersonalization at high doses, and at least one (N,N-Diisopropyltryptamine, DiPT) causes auditory distortions, whereas some compounds such as DMT (found in ayahuasca), psilocybin (mushrooms) or mescaline (peyote) cause episodic visual effects. In the late 1990s, Rick Strassman conducted the first human research with hallucinogens in 20 years, examining the physiological effects and self-reports from people receiving DMT in carefully controlled settings. A book describing these results was published in the popular press. Strassman concluded that DMT is a powerful tool for self-discovery and understanding consciousness, which may have helped to drive interest in recreational use of DMT and related tryptamine hallucinogens. In recent years, recreational use of DMT has been increasing; for example, Cakic et al., reported that 31% of recreational DMT users endorse psychotherapeutic benefits as the main reason for consumption. Similar to ayahuasca, recreational users have made similar concoctions referred to as pharmahuasca. These are of capsules containing free-base DMT and some monoamine oxidase inhibitors (MAOI) such as synthetic harmaline or Syrian Rue.

    It is unclear what proportion of users of hallucinogenic tryptamines have adverse events serious enough for hospitalization, but it seems that the synthetic hallucinogenic compounds, such as 25I-NBOMe may be more dangerous than the plant-derived compounds. Databases derived from Poison Control and Emergency Department visits only sparing differentiate between hallucinogenic compounds taken and lack adequate records of DMT-specific cases. Street drugs mostly contain powdered DMT, whereas ayahuasca also contains harmine-related compounds, which limit toxic effects. However, aside from the acute cardiovascular effects there have been no consistent reports of toxic effects of long-term use of DMT in the literature. In fact, there has been a report that DMT is neuroprotective. Without more data on the recreational use of this class of compounds, it is not possible to conclude whether the synthetic hallucinogens are indeed more toxic or whether the social context may contribute to the effects.

    It is likely that most adverse effects of hallucinogens are psychological effects, such as intense fear, paranoia, anxiety, grief, and depression, that can result in putting the user or others in physical harm or danger. Anecdotal reports describe psychologically challenging experiences with DMT and other psychedelic compounds. The rates of occurrence for these effects have not been properly accounted for. However, in the case of psilocybin, about 30% of laboratory experiences include psychologically challenging experiences. Even though DMT may not produce physical toxicity, severe psychological adverse effects can occur.

    Endogenous roles of DMT

    Although widespread biological presence of DMT is acknowledged, the biological function of DMT remains a mystery. DMT is found in low concentrations in brain tissue. DMT concentrations can be localized and elevated in certain instances, for example, DMT production increases in rodent brain under stress. Formerly, endogenous DMT was thought to exist at concentrations too low to produce pharmacological effects, but two discoveries changed that. First, trace amine-associated receptors (TAAR) are activated by DMT and other molecules, and second, DMT can be locally sequestered in neurotransmitter storage vesicles at pharmacologically relevant concentrations, thereby being able to active other pharmacological receptors, e.g. serotonin. These findings suggest that DMT may have a role in normal physiological and/or psychopathology. What that role may be has not yet been established.

    Although the serotonin system has been thought to be the main contributor to the psychedelic effects of DMT, other behavioral effects have been observed which do not involve the serotonin or other monoaminergic systems; such as jerking, retropulsion, and tremors. In addition, molecular effects of DMT have been identified that are not mediated by serotonin receptors. For example, DMT-enhanced phosphatidylinositol production is not blocked by 5-HT2A receptor antagonists. More recent hypotheses for molecular roles of endogenous DMT have developed over the last decade, and include the potential involvement of TAAR and sigma-1 receptors. Interactions of both TAAR and sigma-1 receptors will be discussed in detail in subsequent sections.

    There has been a great deal of speculation about the role of DMT in naturally occurring altered states of consciousness, such as psychosis, dreams, creativity, imagination, religious and/or spiritual phenomena, and near-death experiences. Additionally, DMT may play a role in waking reality. Waking reality is created in a similar way to altered states except that the normal state correlates with event in the “physical” world. Thus, waking reality can be thought of as a tightly regulated psychedelic experience and altered states arise when this regulation is loosened in some fashion. This model predicts that the sensory-altering effects of administered psychedelics are a result of the compound acting directly via neuropharmacological mechanisms in regions of the CNS involved in sensory perception. More simply, DMT may potentially act as a neurotransmitter to exert a signaling function in regions of the CNS, which are involved in sensory perception.

    Other theories propose that DMT may be important in psychiatric disorders. Data from early studies of DMT suggested that DMT may be a schizotoxin, and various authors hypothesized that DMT was a key factor in causing schizophrenia. This hypothesis is no longer accepted, but it is still thought that DMT may play a role in psychotic symptoms. Similarly, DMT was thought to be neurotoxic, but more recent research suggests that DMT may actually be neuroprotective.

    More recently, Jacob and Presti proposed that endogenous DMT may have an anxiolytic role based on the reported subjective effects of DMT administered in low doses, which would result comparable concentrations and biological actions to those of endogenous DMT. Sensory alterations commonly described by people taking DMT occur only when relatively high concentrations of DMT are administered. These high concentrations are similar to those observed in the synapse when endogenous DMT is released.

    The putative roles of DMT will be explored in more detail in subsequent sections of this review. The review will begin by addressing the basic mechanisms of action of DMT, both pharmacokinetic and pharmacodynamic. It will then examine evidence regarding the neuropharmacological effects of DMT, from both behavioral studies of the exogenous effects of DMT, and from molecular studies of sites of action of endogenous DMT. Next, the review will turn to the use of DMT both as a model for various disorders and the use of DMT to treat some of these disorders. The review will conclude with the effects of DMT on other organ systems besides the central nervous system.

    Pharmacokinetics of DMT

    Intravenous administration of radio-labeled DMT in rabbits produces entry into the brain within 10 s and excretion via the kidneys, such that no traces of DMT or metabolite was measured in urine 24 h post administration. However, DMT could still be detected at 2 and 7 days (0.1% of initial dose) post administration. In the same study, tryptamine was eliminated within 10 min. These findings show that even after complete clearance of a dose of DMT from the blood, DMT is still present in the CNS, and imply that DMT is being produced in the CNS. The subjective effects of intravenous administration of DMT peak at about 5 min and are gone by 30 min. Intramuscular effects of DMT hydrochloride or DMT fumarate have a rapid onset within 2 – 5 min and can last 30 - 60 min, and the effects are generally less intense than intravenous or inhalation routes of administration. The hallucinogenic effects of DMT in the formulation of ayahuasca generally appear within 60 min, peak at 90 min and can last for approximately 4 h. Typical doses of smoked or inhaled free-base DMT are 40 - 50 mg, although dose may be as high as 100 mg. The onset of these doses of smoked DMT is rapid, similar to that of i.v. administration, but lasts less than 30 min. Smoked DMT effects are extremely intense. Intranasal free-base DMT was inactive, as was DMT administered rectally.

    To establish that DMT acts as a neurotransmitter rather than merely being a by-product of the metabolism of other bioactive molecules, it is necessary to establish that it is synthesized, stored, and released. It is of interest that DMT can pass through three barriers with the help of three different mechanisms so that it can be compartmentalized and stored with the brain. These three mechanisms may yield high intracellular and vesicular concentrations within neurons, which suggests that DMT may have a biological role. Processes for the transport of glucose and amino acids are given similar biological priority, which may suggest that DMT is present in the body for more than its psychedelic effects, such as an adaptive role in biological processes, or a universal role in cellular protective mechanisms.

    Synthesis

    Endogenous DMT is synthesized from the essential amino acid tryptophan, which is decarboxylated to tryptamine. Tryptamine is then transmethylated by the enzyme indolethylamine-N-methyltransferase (INMT), which catalyzes the addition of methyl groups resulting in the production of NMT and DMT. NMT can also act as a substrate for INMT-dependent DMT biosynthesis. INMT is widely expressed in the body, primarily in peripheral tissue such as the lungs, thyroid and adrenal gland. INMT is located in intermediate levels in placenta, skeletal muscle, heart, small intestine, stomach, retina, pancreas, and lymph nodes. It is densely located in the anterior horn of the spinal cord. Within the human brain, highest INMT activity has been found in uncus, medulla, amygdala, frontal cortex, and in the fronto-parietal and temporal lobes. Cozzi et al. has shown INMT is also located in the pineal gland. Based on rodent brain cellular fractionation studies 70% of INMT activity is found in the supernatant and 20% in the synaptosomal fractions, suggesting the enzyme is located in the soma of cells, which are fractured during the homogenization process. The wide distribution of INMT implies a wide distribution for DMT.

    The enzymatic activity of INMT is closely regulated by endogenous inhibitors. DMT at high concentrations (10-4 M) yields a 90% inhibition of rabbit lung INMT. In addition, the same tissues that contain INMT also contain enzymes that metabolize DMT. Only a small fraction of DMT made intracellularly is actually released into the blood. This process helps explain the inconsistent detection levels assessed in many studies discussed below. DMT production is increased under stress in rodent brain and adrenal gland. Whether the stress-induced mechanism for increasing DMT is due to increasing INMT activity, or a decrease in DMT metabolism remains unknown.

    Accumulation and storage

    As previously mentioned, it has been hypothesized that high, local concentrations of DMT can occur within neurons and potentially widely produced in peripheral organs, especially in the lungs. Frecska and colleagues summarized a three-step process by which DMT is accumulated and stored. In step 1, DMT crosses the blood brain barrier by active transport across the endothelial plasma membrane, which is accomplished via Mg2+ and ATP-dependent uptake. In step 2, uptake of DMT into neuronal cells is accomplished via serotonin uptake transporters (SERT) on neuronal plasma membrane. In step 3, facilitated sequestration of DMT into synaptic vesicles from the cytoplasm is accomplished by the neuronal vesicle monoamine transporter 2). DMT inhibited radiolabeled 5-HT uptake via the serotonin transporter (SERT) and VMAT2 with Ki values of 4 and 93 μM, respectively. DMT that has been taken up and stored within cells via SERT and VMAT2 and exhibit high binding-to-uptake ratios, >11 for SERT and >10 for VMAT2. High binding ratios suggest that there are separate substrate and inhibitor sites for SERT and VMAT2 and further supports that DMT (and other tryptamines) are substrates for both transporters.

    The high levels of DMT concentration found in vesicles are needed for various pharmacological actions including activation of sigma-1 receptors and TAARs as described below. Once uptake and storage of DMT has been completed, it can remained stored in vesicles for at least 1 week and can be released under appropriate stimuli. Through these three steps, peripheral synthesis of DMT, consumption of DMT-containing plant matter, or systemic administration of DMT can influence central nervous system functions.

    Bioavailability of exogenous DMT

    DMT is not orally active. This is likely due to rapid degradation by peripheral monoamine oxidase (MAO), the enzyme responsible for catalyzing the oxidative deamination of endogenous biogenic amines. For hallucinogenic or psychedelic phenomena to occur, plasma concentration must be between 12 – 90 μg/L with an apparent volume of distribution of 36-55 L/kg, which roughly corresponds to a plasma concentration of 0.06 – 0.50 μM. In order for DMT to be bioavailable, oral formulations such as ayahuasca contain Banisteriopsis caapi and other beta-carboline harmala alkaloids that act as MAOIs. MAO-A inhibitors such as iproniazid prolongs the half-life of DMT in rat brain, and can extend the time course effects of DMT in drug discrimination from 30 min to 60 min. Exogenous DMT formulations containing a reversible MAOI (such as ayahuasca) can result in blood levels up to 1.0 mg/ml or higher. On average a 100 mL dose of ayahuasca contains about 24 mg of DMT. Interestingly, DMT is itself a short-acting monoamine oxidase inhibitor at high doses, and is selective for MAO-A. In these studies, DMT decreased serotonin and dopamine deamination in rat striatum concomitantly with rapid onset. Normalization occurred 2 hours later with an ED50 of 25 mg/kg for degradation of both serotonin and dopamine.

    Degradation and elimination

    A small fraction of exogenous DMT is excreted in urine as the parent compound. DMT is primarily metabolized by MAO, although there is evidence that DMT can also be metabolized by peroxidases, leading to a variety of other metabolites. In both human and rodent models, none of the metabolites produced DMT-like effects. From the MAO pathway, several indole compounds are produced: NMT, 6-OH-DMT, 6-OH-DMT-NO, DMT-NO, and IAA. The major metabolites of DMT are DMT-NO, and IAA. In rabbit liver microsomal fractions pretreated with MAOI iproniazid, five indole compounds were found: DMT, NMT, 6-OH-DMT, 6-OH-DMT-NO, and DMT-NO; however, in rabbit brain microsomal preparation again with iproniazid pretreatment, no 6-hydroxy metabolites were identified. These findings suggest that metabolism of DMT is somewhat different in brain and in the periphery.

    Formation of IAA was thought to be likely due to oxidase deamination of NMT, but was later established to be also in part by direct deamination by MAO. Pretreatment with the MAO-I iproniazid in rat whole brain homogenates inhibited IAA formation by 83%, NMT and DMT-NO formation were inhibited by 90%, suggesting that the increase in behavioral half-life of DMT is due to MAO-inhibition and inhibition of the enzymes responsible for demethylation and N-oxidation as well.

    Erspamer first recorded IAA as a metabolite of systemically administered DMT in rodent urine, which represented less than 3% of the injected dose of DMT. In human volunteers, 8.3% of the administered dose of DMT was recovered as IAA. Around 50% was recovered as IAA but also as DMT-NO and other MAO-independent compounds. Neither the Erspamer nor Szara study detected unchanged DMT in urine. Little DMT is found unchanged in the urine of ayahuasca users despite taking it with harmala alkaloids. In another study in humans, 0.16% of DMT was recovered as DMT following a 24-hour urine collection. In both of these studies, DMT concentration peaked in blood within 10-15 minutes and was essentially undetectable by one hour. Approximately only 1.8% of the injected dose was present in blood at any one time.

    Oxidative deamination of DMT by MAO may not be the sole metabolic pathway in humans. A study by Gomes et al. suggests that a different metabolic pathway by which DMT can be oxidized by peroxidases may be responsible for increasing cytotoxic activity of peripheral-blood mononuclear cells. Metabolites in this pathway include hydroxy-DMT, N,N-dimethyl-N-formyl-kynuramine, and N,N-dimethyl-kynuramine. Barker et al. suggest other possible metabolites of DMT include 1,2,3,4-tetrahydro-beta-carboline (THBC) and 2-methyl-THBC.

    Detection of endogenous DMT in blood, urine, and cerebrospinal fluid

    DMT as an endogenous compound can be measured in human body fluids, including blood, urine and cerebral spinal fluid. Levels of endogenous DMT do not appear to be regulated by diet or gut bacteria. Infrequent and inadequate sampling methods used over time make it difficult to determine specific details pertaining to DMT production in the body. For example, we still do not know if DMT is produced in phasic or diurnal cycles. Measureable concentrations seem to only occur intermittently, and exact tissue source or sources of DMT is still unclear. It is commonly thought that the adrenal gland and lungs are the most common places for the highest amount of DMT production, since this is where highest levels of INMT have been reported.

    A review by Barker assessed 69 studies that reported endogenous DMT detection and quantities reported in urine, blood, and cerebrospinal fluid, primarily comparing detection levels within healthy controls and schizophrenic patients. DMT in urine was examined in 861 individuals (635 patients), 276 patients and 145 controls were positive for DMT. Throughout the studies, there were inconsistent sampling methods, including various of amounts of urine used in assays, and a range of techniques and analytical approaches were used. Some studies took dietary influences into consideration, but found no associations with endogenous DMT levels. Inconsistent units of measurement were also used across studies. Concentrations in urine range from 0.02 to 42.98 +/-8.6 (SD) ug/24h, and from 0.16 to 19 ng/ml. In blood, data from 417 (300 patients) individuals were examined, 44 patients and 28 controls were positive for DMT. One study was responsible for 137 of the negative samples. Like detection in urine, extraction methods and analytical approaches were highly inconsistent. Testing procedures included discrepancies of samples coming from plasma, serum and/or whole blood, while others had limit detections of 0.2 DMT/ml. Higher concentrations of DMT are extracted from whole blood compared to plasma, but there is no difference in venous and arterial blood. When concentrations were reported, not just whether it was present or not present, it ranged from 51 pg/ml to 55 ng/ml. DMT was detected in cerebrospinal fluid in 4 studies, which tested 136 individuals (82 patients). Of those, 34 patients and 22 controls were positive for DMT. Concentrations ranged from 0.12 to 100 ng/ml. DMT can be detected as an endogenous compound in urine, blood, and cerebrospinal fluid. Even with inconsistent detection methods, DMT does not appear to be related to the onset of schizophrenia, since it seems to be detected more so in healthy controls compared to patients.

    Clinical effects

    Oral dosing of DMT via ayahuasca produces both behavioral and neurochemical effects, such as decreases in motor activity, impairment of cognitive function, sympathomimetic effects, increased prolactin and cortisol levels, and decreased lymphocytes increased natural killer cells. Doses of ayahuasca 15 or 30-fold higher than commonly used ritual doses increased serotonergic neurotransmission. Long-term use of DMT in ayahuasca produces measurable brain changes. Long-term ayahuasca users show difference in midline brain structures using MRI versus matched controls. Interestingly, whereas ayahuasca produced modest impairment of cognitive function in inexperienced users, little or no impairment was observed in experienced users.

    Tolerance

    Several early studies demonstrated that DMT does not produce tolerance. When DMT was administered to squirrel monkeys for 36-38 days, it failed to elicit tolerance to the disruption of responding maintained on a fixed-ratio schedule of food reinforcement. Similarly in cats, Gillin et al. demonstrated that DMT did not produce tolerance when administered 7-15 days twice daily or every 2 or 24 hours to its effects on EEG, pupil dilation, coordination, posture, and other physical signs. To the contrary, an increase in sensitivity to repeated injections were observed. However, following administration of higher doses of DMT and more frequent injections, partial tolerance to DMT in rats occurred with dose ranges of 3.2 – 10 mg/kg every 2 hours for 21 days. Cross-tolerance to LSD after tolerance to 3.2 mg/kg DMT was established; however, only slight tolerance to LSD was established following 10 mg/kg DMT.

    In humans administered 4 repeated doses of DMT 30 minutes apart, Strassman et al. observed no tolerance to the subjective effects of intravenous DMT as measured by the Hallucinogen Rating Scale. However, tolerance did develop to change in body temperature and other physiological factors. Mild cross-tolerance to DMT was reported in humans made tolerant to LSD. Taken together, these findings suggest that tolerance can develop to the cardiovascular and other peripheral effects of DMT, although little or no tolerance develops to the subjective effects.

    Subjective effects of DMT

    Because the subjective effects of hallucinogens seem to drive their use rather than effects on the reward/reinforcement areas of the brain, drug discrimination is often used as an animal model for testing the behavioral effects of hallucinogens. A compound can be tested for its ability to “substitute”, that is, produce drug-appropriate responding in test subjects trained to discriminate a psychoactive compound from its vehicle or from other psychoactive compounds. Typically, drug-appropriate responding greater than 80% is considered “full substitution”. Conversely, novel compounds can also be trained as discriminative stimuli if they have psychoactive effects, and known compounds can be tested for substitution or antagonism of the novel compound. Asymmetries in cross-substitution can indicate that the two compounds may have overlapping, but not identical mechanisms of action. Drug discrimination can be useful in investigating potential mechanisms of action of the trained discriminative stimulus by utilizing selective agonists and antagonists to either mimic or block the effects. Subsequent paragraphs will examine discrimination studies assessing potential mechanisms of action of DMT.

    DMT produced discriminative stimulus effects similar to those of the classic serotonergic hallucinogens DOM and LSD, as DMT fully substituted in DOM-trained rats and produced full or near-full substitution in LSD-trained rats and pigeons. The effects of DMT seem to be mostly hallucinogen-like, as it produced only 50% drug-appropriate responding in MDMA-trained rats, and produced a maximum of 37% drug-appropriate responding in methamphetamine-trained rats. In rats trained to discriminate between the 5-HT2A antagonist ketanserin and the 5-HT2A agonist DOI, DMT produced DOI lever-responding 80% or more of time, indicating that DMT acted more like a 5-HT2A agonist than a 5-HT2A antagonist.

    Despite its very short duration of action, DMT can be trained as a discriminative stimulus. A wide range of synthetic phenethylamine hallucinogens fully substitute for DMT, including DOM, DOC, LSD, 2C-D, 2C-E and 2C-I, whereas 2C-C and 2C-T-2 produced a maximum of only 75% DMT-appropriate responding. In contrast, other tryptamine hallucinogens produced more equivocal effects, with DiPT and 5-MeO-DET producing full substitution, 4-OH-DiPT and 5-MeO-IMPT producing partial substitution, and 5-MeO-αMT producing little if any DMT-like effects. In addition, although DiPT fully substituted in DMT-trained rats, DMT only produced 65 % DAR in DiPT-trained rats. Taken together, these findings indicate that serotonergic hallucinogens largely produce discriminative stimulus effects similar, but not entirely identical to those of DMT.

    Pharmacological mechanisms

    The mechanisms of action for hallucinogens are currently not well understood. The 5-HT2A receptor is thought to be necessary, but not sufficient for hallucinogenic effects, and 5-HT2C and 5-HT1A receptors may play important roles as well. DMT interacts with a variety of serotonin receptors, but also with ionotropic and metabotropic glutamate receptors, dopamine, acetylcholine, TAAR, and sigma-1 receptors.

    Serotonin

    Most studies to date focus on DMT (and most classic psychedelics) as a partial agonist of serotonin (5-HT) receptors, primarily the 1A, 2A, and 2C receptor subtypes, with predominant interest at 5-HT2A receptors. DMT binds 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5A, 5-HT6 and 5-HT7 receptors with affinities ranging from 39 nM to 2.1 μM. The 5-HT2A receptor is thought to be the primary target of classic serotonergic-mediated psychedelic compounds, such as LSD, DOI, psilocin, and mescaline, although 5-HT1A and 5-HT2C receptors may also play some role. DMT has been reported to bind to all three of these receptors in a variety of studies, including the 5-HT1A, 5-HT2A, and 5-HT2C receptors.

    Agonistic properties and affinities for 5-HT1A receptor vary among the classic psychedelics. Interestingly, agonist activity at the 5-HT1A receptor opposes the subjective effect of 5-HT2AR agonists. DMT's affinity for the 5-HT1A receptor is higher compared to 5-MeO-DMT, 6.5 +/- 1.5 nM and 170 +/- 35 nM, respectively. A 5-HT1A antagonist significantly increased the reported psychological effects of DMT. DMT, like other tryptamine hallucinogens, but not phenethylamines, inhibits dorsal raphe cell firing. This mechanism is hypothesized to be an underlying basis of psychedelic-like effects, which may be mediated by stimulation of 5HT1A somatodendritic receptors.

    DMT does bind to 5-HT1D receptor and 5-HT3 receptor, however little has been investigated to follow these results up. Delgado shows that 5-HT1 and 5-HT3 receptors exert anxiolytic effects, which does correspond to some reports of DMT use. DMT is an agonist at 5-HT2C receptors. In drug discrimination, the DMT-like effects were partially blocked by a selective 5-HT2C antagonist, SB242084. The 5-HT2C receptor is likely less significant in the psychedelic effects since tolerance develops to the 5-HT2C receptor. Little or no tolerance is developed to the subjective effects of DMT in clinical studies.

    DMT binds to the 5-HT2A receptor with relative high affinity, yet other psychedelics that lack visual effects have a higher affinity for the 5-HT2A receptor. The 5-HT2A receptor seems to be necessary, but is not sufficient to account for the visual phenomenon common of the classic hallucinogens. Psychedelics and psychedelic-like compounds including MDMA, 5-MeO-DMT, DET, and DiPT are 5-HT2A receptor agonists. Subjective effects for these compounds are reported to be solely emotional, devoid of visual phenomenon common in other psychedelics such as DMT, except in rare circumstances where individual differences in biology seem to be the regulating factor.

    Head twitch response in rodents is thought to be a 5-HT2A receptor-mediated behavior produced primarily by psychedelics, although it is likely that other receptors play a role in this behavior, including 5-HT2C and glutamatergic receptors. Like other classic psychedelics, DMT does induce this head twitch response in C57Bl/6 mice, which is blocked by 5-HT2A inverse agonist, MDL100907. However, the overall number of head twitches induced by DMT is much smaller compared to most other psychedelic compounds. DMT failed to produce this head twitch response in Swiss Webster mice. These discrepancies may be due to the rapid degradation of DMT or other peculiarities specific to DMT.

    Functional selectivity on how psychedelic compounds modulate the 5-HT2 receptor family is not well understood. The 5-HT2 family of receptors are Gq/11 mediated and primarily use the phospholipase C second messenger system pathway, but also an phospholipase A2. Phospholipase C hydrolyzes phosphatidylinositol membrane lipids generating inositol-1,4,5-triphosphate (IP3) and diacylglycerate. Diacylglycerate remains bound to the membrane and leads downstream activation of protein kinase C and increases the release of calcium from intracellular stores. In particular, protein kinase C can mediate desensitization of 5-HT2A receptors during drug exposure. Phospholipase A2 stimulation can lead to formation of arachidonic acid. DMT stimulates arachidonic acid release, and less inositol phosphate formation via the 5-HT2A receptor. Whereas inositol phosphate formation via the 5-HT2C receptor seems to be more efficacious and more potent. Stimulation of phospholipase A2 does not seem to directly related to the subjective effects of psychedelic compounds. Other pathways such as the phospholipase D may play a role, but DMT-mediated effects had not been thoroughly investigated. The importance of each second messenger pathway is an important area of future investigation.

    DMT, like other classic hallucinogens increase 5-HT levels and/or decrease the turnover of 5-HT. DMT increases excretion of IAA and 5-hydroxy IAA in humans. Other studies have reported an increase in 5-HT and a decrease in 5-hydroxy IAA after DMT administration. DMT seems to have no effect on tryptophan hydroxylase, but produces a main effect on the rate of 5-HT turnover. DMT inhibited SERT transport and VMAT2, acting as a substrate and not as an uptake blocker.

    Glutamate and 5-HT/glutamate interactions

    An approach gaining increasing interest within the last decade is to examine interacting roles of serotonin and glutamate in mediating the effects of DMT. Of particular interest are the roles of group II metabotropic glutamate receptors, the NMDA receptor, and 5-HT2A receptors in modulating the levels of glutamate in the synapse. These group II glutamate receptors may also be potential target sites for mediating hallucinogenic effects.

    mGlu2/3 receptor agonists can act presynaptically to suppress glutamate release, although the significance of this effect in mediating the effects of DMT has not been systematically studied. In contrast, mGluR2/3 antagonist increases the amount of glutamate in the synapse, creating a potentiation of hallucinogenic or psychedelic effects. The 5-HT2A receptor inverse agonist, MDL100907, fully blocked the discriminative stimulus effects and head twitched produced by DMT, whereas the 5-HT2C receptor antagonist produced little or no effect on the discriminative stimulus effects of DMT. A mGlu2/3 receptor agonist produced modest decreases in the discriminative stimulus effects of DMT, whereas a mGlu2/3 receptor antagonist facilitated the effects of low doses of DMT. Comparatively, a mGluR2 agonist blocked the discriminative stimulus effects of LSD, whereas a mGluR2 antagonist facilitated the discriminative stimulus effects of LSD. Further, mGluR2 knockout mice showed little or no head twitch following DOI, and some signaling was disrupted, which may mean that mGlu2 receptors are necessary for hallucinogenic activity. Systematic administration of DOI increases glutamate efflux in ventral tegmental area.

    Electrophysiological studies suggest that stimulation of 5HT2A receptors in the medial prefrontal cortex increases pyramidal cell activity and may stimulate corticotegmental glutamatergic projection neurons. A possible explanation for these effects is that mGlu2 receptors co-localize with 5-HT2A receptors to form heteroreceptor complexes. It has been suggested that the heteroreceptors induce a psychedelic-specific second messenger cascade, although this has not been definitively established.

    There has been some evidence that NMDA receptors may also play a role in mediating the effects of DMT. DMT partially blocked the discriminative stimulus effects of phencyclidine, which produces hallucinations through its actions at NMDA receptors. In addition, activation of sigma-1 receptor by DMT may lead to potentiation of NMDA receptors.

    Dopamine

    DMT lacks direct dopaminergic properties, since it did not stimulate dopamine (DA)-sensitive adenylate cyclase. This finding is in agreement with data from a behavioral technique often used to assess direct dopamine agonist effects, which records turning behavior in unilateral nigro-striatal lesioned rats. If a compound stimulates dopamine receptors directly, the animal will rotate toward the intact side, otherwise if a compound induces dopamine release in the striatum from the nerve terminals of the intact side induces a rotation toward the lesion side. As reviewed by Barker, Pieri et al. suggest that DMT appears to have no dopamine receptor agonist effects, although higher doses of DMT does produce ipsilateral turning, although were not indicative of a very potent dopamine releasing effect. Another indication that DMT does not act directly at dopamine receptors is the lack of adenylate cyclase activity in the dorsal striatum of rats.

    DMT-induced EEG activation in rabbits can be antagonized by neuroleptics (DA receptor blocking compounds. This may be due to blockade of downstream sequela. For example, DMT releases dopamine from presynaptic stores. This release of dopamine in combination with the effects of MAO causes an indirect dopaminergic stimulant activity. DMT caused 42% decrease in concentration of dopamine in rat forebrain, while norepinephrine was not affected, no change in the levels of the dopamine metabolite homovanillic acid was observed in corpus striatum. This decrease in concentration of dopamine may be caused by a stimulation of the release of dopamine or by inhibition of its synthesis. This decrease in dopamine levels is likely not related to change in synthesis, because no change in norepinephrine levels or turnover rate in the diencephalon were observed. It appears as if DMT increases central dopamine turnover and enhances striatal dopamine synthesis in rats.

    Acute and chronic administration of DMT significantly increased endogenous levels of striatal 3-MT. Dopamine steady state concentrations remained unchanged. Further, DMT increased accumulation of 3HDA and 3H3MT newly formed from 3HDOPA. DOPAC, a major metabolite of dopamine more efficiently lowered by DMT rather than HVA in the striatum and whole brain. This is distinct from the effects of classic MAOIs, which decrease both DOPAC and HVA. After acute administration striatal dopamine synthesis was increased, yet there was no effect on steady state conditions. Dopamine degradation must be enhanced proportionally and is likely done so extraneuronally, due to the increase in 3-MT. No change in the increase of DA turnover over one month treatment, with consistent rises in 3-MT is observed.

    Acetylcholine

    Little investigation has occurred in reference to DMT's effect on acetylcholine. DMT significantly decreases concentration of acetylcholine in corpus striatum, which may be due to a direct release of acetylcholine, thus reducing concentration of striatal acetylcholine. Generally, acetylcholine levels in brain are reduced when its rate of release or turnover are increased. DMT had no effect on the level of acetylcholine in the cortex.

    Trace amine-associated receptors

    Trace amine-associated receptors (TAARs) are a more recently discovered class of receptors which may play a role in mediating DMT and other psychedelic drug effects. The rat trace amine-associated receptor – 1 (rTAAR1) is a G protein-coupled receptor with homology with members of the catecholamine receptor family. Trace amines p-tyramine, and p-PEA stimulate cAMP production, are commonly measured to assess activation of the TAAR. DMT binds to the rTAAR-1 with high affinity and acts as an agonist, causing activation of adenylyl cyclase and resultant cAMP accumulation in HEK293 cells transfected with rTAAR1. Other psychedelics such as (+/-)DOI, d-LSD, and 5-MeO-DMT, and non-psychedelics such as R(+)lisuride, (+/-)MDMA and amphetamine also stimulate cAMP production through their effects at rTAAR1. This second-messenger cascade does not seem to be selective for any of these compounds as these effects occurred at approximately 1 μM concentration (no other concentrations tested). rTAAR1 seems to be located in the intracellular puncta, and not at the plasma membrane in vitro; it is not known if this is the case in vivo.

    Because TAARs were discovered long after research had on DMT (and other psychedelic compounds) had been initiated at the 5HT2AR, there is a paucity of research on the role of TAAR, which makes it difficult to discern what role this class of receptor may play in mediating the effects of endogenous and exogenously administered DMT. It is unknown whether the typically used 5-HT2AR antagonists ketanserin and/or risperidone have any antagonist effects of TAAR as well. This is an area where more research needs to be done to fully understand the importance of TAARs and psychedelic effects.

    Sigma-1 receptor

    The sigma-1 receptor was once thought to be a subtype of an opioid receptor. It has been implicated to have a role in several neurobiological diseases and conditions such as addiction, depression, amnesia, pain, stroke, and cancer. It is found widely distributed though out the body including in the CNS, liver, heart, lung, adrenal gland, spleen, and pancreas. They are localized between endoplasmic reticulum and mitochondrion. Sigma-1 receptor agonists signal the receptor to disassociate itself form other endoplasmic reticulum chaperones, which allows the receptor to act as a molecule chaperone to IP3 receptors. This enhances calcium signaling from the ER to mitochondria, activates TCA cycle and increase ATP production. Sigma-1 receptors can translocate to plasma membrane or sub plasma membrane area when stimulated with higher concentrations of agonists or when sigma-1 receptors are over-expressed. Once sigma-1 receptors translocate to the plasma membrane they can interact with and inhibit several ion channels. Sigma-1 receptor activation can also lead to potentiation of NMDA receptors.

    Psychedelics and non-psychedelics bind promiscuously to sigma-1 receptors. DMT binds to sigma-1 receptors at low micromolar concentrations, and appears to have agonist-like effects. DMT inhibits cardiac voltage-activated sodium ion channels at higher concentration (100 M) in HEK293 cells, and neonatal mouse cardiac myocytes, induces hypermobility in wild-type mice, which is blocked in sigma-1 receptor knock-out mice. DMT modulated current in sigma-receptor-mediated Na+ channels, which was reduced by sigma-1 receptor knockdown and by progesterone. In addition, DMT synthesizing enzyme indolethylamine-N-methyltransferase is co-localized with sigma-1 receptor in C-terminals of motor neurons, which suggests that there may be adequate levels of endogenous DMT to activate sigma-1 receptors.

    The main problem with the theory that DMT is an endogenous sigma-1 receptor agonist is that it requires concentrations in the micromolar range, whereas selective sigma-1R agonists such as (+)-pentazocine have affinities in the nanomolar range. If DMT is only available in trace amount in humans and is rapidly metabolized, how can DMT levels rise enough to account for sigma-1 receptor-mediated effects? One possible explanation for this is the three step process of accumulation and storage discussed earlier, which includes active transport across the blood brain barrier, and DMT may be a substrate for transporters at the cell surface and at the neuron level. Supporting the role of sigma-1 receptor is that the SSRI fluvoxamine, has sigma-1 receptor agonist properties with higher affinity than DMT. Fluvoxamine works better with patients suffering from psychotic depression compared to antidepressants without sigma-1 receptor agonist properties. Selective sigma-1 receptor agonists do not cause psychotomimetic effects in animals. At best, sigma-1 receptors may partially mediate the subjective effects of DMT.

    Whether or not the sigma-1 receptor plays a significant role in the psychedelic effects of DMT, it may still play an important role in other physiological mechanisms. Sigma-1 receptors agonists are potentially neuroprotective via several mechanisms. DMT reduced inflammation ostensibly via sigma-1 receptor, and can induce neuronal plasticity, which is a long-term recuperative process that goes beyond neuroprotection. Sigma-1 receptors can regulate cell survival and proliferation, thus if DMT is an endogenous agonist, this may explain physiological relevance and importance of why DMT has 3-step uptake process.

    Regulation of intracellular calcium overload, proapoptotic gene expression via Sigma-1 receptors, can result in neuroprotection during and after ischemia and acidosis. There would be further benefit through sigma-1 receptor dependent plasticity changes. Along these lines Frecska colleagues suggest that DMT may be protective during cardiac arrest, beneficial during perinatal development, immunoregulation, and aid in reducing cancer progression.

    Immediate early gene stimulation

    Through second messenger systems, DMT can affect the rate of genetic transcription, such that DMT encodes the transcription factors c-fos, egr-1 and egr-2, which are associated with synaptic plasticity. Increases in expression of brain-derived neurotrophic factor (BDNF) are also observed after DMT administration. BDNF expression is associated with synaptic plasticity, cognitive process such as memory and attention, and modulation of efficacy and plasticity of synapses.

    Summary

    As previously mentioned, DMT interacts with a variety of ionotropic and metabotropic receptors. The subjective effects of large doses of exogenous DMT are most likely mediated primarily by 5-HT2A receptors, with 5-HT2C receptors playing little or no role. mGlu2/3 receptors have significant modulatory effects, and the interaction of serotonergic and glutaminergic receptors may play a central role. DMT does not have direct effects on DA receptors, but indirectly alters the levels of dopamine, with resulting neurochemical and behavioral effects. Similarly, DMT also alters levels of acetylcholine. Finally, DMT may be an endogenous ligand at TAAR and sigma-1 receptors, but at the least, the effects of DMT at these receptors may play important physiological roles.

    DMT as a model of psychiatric disorders

    There has been a revival of interest in clinical uses of hallucinogens. Among the first were a series of controlled clinical studies on DMT. Those studies reported that pure DMT had rapid and extremely strong cardiovascular effects as well as profound psychological effects. The cardiovascular effects preclude the use of pure DMT; however, ayahuasca and other DMT-containing ritual beverages seem to be less toxic while retaining the psychological effects. Based on studies of the health status of ayahuasca users, the use of ayahuasca may be safe and even beneficial.

    Recently, a series of studies examined the long-term personal and spiritual significance of exposure to psilocybin have suggested that psilocybin may be useful for anxiety-related disorders. Similarly, ayahuasca and similar DMT-containing mixtures have been proposed as treatments for a variety of psychiatric disorders and ayahuasca is mostly well-tolerated. For example, long-term ayahuasca users showed less psychopathology, and better performance on neuropsychological tests compared to matched controls and less substance abuse and fewer psychiatric/psychosocial problems than matched controls.

    Schizophrenia

    The classic positive symptoms of schizophrenia include delusions and hallucinogens, so hallucinogenic compounds seem an obvious tool for modeling schizophrenia. Given that hallucinogens produce their effects primarily through activation of the 5-HT2A receptor, the serotonin system provides an alternative to the dopamine model of schizophrenia. The dopamine model has produced a wide range of treatment medications which are very useful, but do not fully treat the range of symptoms experienced during psychotic episodes and produce substantial adverse effects. Discovery that DMT exists as an endogenous compound led to research focusing on DMT as a model of schizophrenia in the 1960s and 1970s. Reviews of this early research concluded that the data was suggestive but not conclusive. These early studies are not reviewed in the present manuscript.

    Subsequent research reported that levels of endogenous DMT increased in schizophrenic patients during psychotic episodes, which declined as their state improved. However, no changes in DMT levels were observed in rapidly cycling states (manic-depressive). These findings renewed interest in the transmethylation hypothesis, which states that schizophrenia may be due to stress-induced production of psychotomimetic methylated derivatives of catecholamines or indolealkylamines in the brain. DMT seems to fits the bill as it is an indolealkylamine, is an endogenous compound, and is linked to stress reactivity.

    In addition, DMT was identified as the active ingredient in ayahuasca, which produces effects similar to a psychotic episode, including thought disorders, delusions, and hallucinations. When given to human subjects, DMT produces complex visual and auditory hallucinations and increases cortisol levels, which supports its possible role as a possible mediator of schizophrenia.

    More recent studies have examined the effects of DMT on various experimental models of changes in cognition in schizophrenic patients. Normal subjects are administered DMT and given various cognitive tasks to perform during fMRI scans. DMT slowed reaction time in tests of inhibition of return, decreased alertness, but produced less mismatch negativity than did the NMDA glutamate channel blocker ketamine, which commonly serves as a tool for investigating the glutaminergic hypothesis of schizophrenia.

    In summary, DMT is still an interesting model of the serotonergic aspects of schizophrenia, but there is no conclusive evidence that endogenous DMT is a primary player. In fact, it has been argued that DMT is anti-anxiety/anti-psychotic via actions at the trace amino acid receptor (TAAR). Jacob and Presti, and others have suggested that the effects of endogenous DMT are mediated via sigma receptor roles.

    Depression

    Few studies have investigated the effects of DMT-containing compounds on depression. One study investigated the effects of ayahuasca in the forced-swim test, a common animal model of depression. In female Wistar rats, ayahuasca increased swimming, which is considered a sign of potential antidepressant effects. In a human experimental study, long-term ayahuasca users showed reduced ratings of hopelessness while under the influence. Finally, in an open-label clinical trial in in-patients suffering from depression, ayahuasca produced marked improvement in depressive symptoms with no mania or hypomania for up to up to 21 days after a single dose. Convergent evidence from three different experimental approaches provides stronger evidence for potential antidepressant effects of DMT. However, replication of these findings will be necessary to confirm whether DMT-containing compounds will be useful for treatment of depression.

    Anxiety/aggression

    It has been proposed that DMT is an endogenous anxiolytic compound through its actions at the trace amino acid receptor. To date, this hypothesis has generated little interest and DMT has been mostly investigated for its hallucinogenic effects. One early study did examine the effects of DMT in an animal model of anxiety/aggression in which pairs of rats receive shocks while in a test chamber. The shocks produce fighting and anti-anxiety compounds reduce the shock-induced fighting. LSD increased the amount of fighting, whereas DMT suppressed fighting. However, the effective doses also produce sedation and reduced locomotor activity, which could also account for the effects.

    In a case study of a homeless male with multiple convictions for manslaughter and diagnosed with antisocial disorder, ayahuasca sessions reportedly produced significant moral insights and allowed completion of a rehabilitation program in which the subject had been highly resistant. No follow up was conducted, so no data is available on whether incidences of violent behavior decreased. In two larger scale studies, ayahuasca decreased ratings of anxiety in depressive-disorder patients and reduced ratings of panic but not state- or trait-anxiety, in long-term users. Taken together, these findings do not provide support that DMT is useful for treatment of anxiety and/or aggression. It is possible that DMT may be useful in specific settings, similar to the successful use of psilocybin to treat anxiety in cancer patients, but careful experimental research will be necessary before a strong conclusion can be make about DMT's efficacy as an anxiolytic medication.

    Effects on cardiovascular system

    Single doses of DMT produced rapid onset of marked sympathomimetic effects including increased heart rate and blood pressure. When a 5-HT1A antagonist, pindolol, was co-administered with DMT, the increase in heart rate was diminished whereas the increase in blood pressure was enhanced. Tolerance to the effects of DMT was tested by administration of DMT to human volunteers four times at 30-min intervals. A progressive decrease in heart rate was observed over the four doses, but not in blood pressure. In contrast, two repeated doses of ayahuasca 4-h apart reduced systolic blood pressure and heart rate. Long-term use of DMT-containing beverages may be of more concern as 14-day exposure to ayahuasca in rats altered the structure of the aorta, leading to a thickening of the walls of the aorta relative to the lumen diameter.

    Cardiac arrest

    DMT has been speculated to aid in extending the survival of brain. A review by Frecska and colleagues suggests that during physical signals of agony, lungs synthesize large amount of DMT and can release DMT into arterial blood within seconds. Once in blood circulation DMT is safe from degradation as extracellular, circulating MAO enzymes deaminate only primary amines. DMT is a tertiary amine, thus reaching the brain with minimal degradation. Through the use of active transport mechanisms already discussed for taking DMT from blood into the brain, could potentially keep brain alive longer without the brain having to produce DMT on its own. Exogenous DMT-like psychedelic effects are in essence similar to subjective reports provided after clinical death and near death experiences. Strassman believes DMT to be very likely involved in the dying process.

    Endocrine system

    DMT increased levels of corticotropin, cortisol, prolactin, and growth hormone when administered to human volunteers. When DMT was given repeatedly to human volunteers, tolerance to the increases in various endocrine levels was observed, including corticotropin, prolactin and cortisol. Similarly, ayahuasca increased prolactin and cortisol levels in human volunteers, whereas repeated doses resulted in lower levels of GH secretion.

    Immune system and neurotoxicity

    Ayahuasca has been reported to decrease the percentage of CD3 and CD4 lymphocytes, but to increase the number of natural killer cells. It has been hypothesized that DMT might increase activity of the immune system and could prove useful as a treatment for cancer. Evidence for this hypothesis is equivocal. DMT increased the cytotoxic activity of peripheral blood mononuclear cells in the A172 human glioma cell line. However, in another study, DMT did not exhibit cytotoxicity of KB or HepG2 carcinoma cells. In addition, others have proposed that DMT and related compounds are anti-inflammatory and reported that DMT inhibited production of pro-inflammatory compounds IL-1β, IL-6, IL-8 and TNFα and increased levels of the anti-inflammatory compound IL-10 through actions at the sigma-1 receptor.

    Immunoregulation

    Serotonin plays an important role with immunoregulation. And on cellular immune functions critical in the elimination of pathogens or cancer cells. It is possible that DMT may also play a role in immunoregulation via its Sigma-1 and 5-HT2A receptor activation. Sigma receptors are also expressed on many cells of the immune system. In particular, Dorocq showed that sigma-1 receptors can reduce pro-inflammatory cytokines and enhance the production of anti-inflammatory cytokine IL-10. DMT through the formulation of ayahuasca increased levels of blood circulating natural killer (NK) cells with concentrations as low as 1 mg DMT/kg body weight. In vitro DMT administration has shown an increase of secreted interferons in vitro in NK cell and dendritic cell cultures. Interferons are potent anticancer factors. If DMT does increase interferon secretion, it may be beneficial in contributing to or aid in better elimination of malignant and/or infected cells.

    Perinatal INMT activity

    Levels of INMT in the placenta are higher than in adults. It is speculated that activity in fetal lungs compensates for difference. INMT activity in rabbit lung is relatively high in fetus, increases rapidly after birth and peaks at 15 days of age. It then declines to mature levels and remains constant through life. If INMT levels are paralleled with increased DMT synthesis, it could be possible that DMT-mediated sigma-1 receptor activity induces neuronal plasticity changes that can be expected for newborns. Selective sigma-1 receptor agonists have shown to be protective against excitotoxic perinatal brain injury and ischemic neurodegeneration in neonatal striatum. Expression of INMT seems to be important for pregnancy success. Whether DMT, a product of INMT plays any role in these protective and beneficial effects, is unknown.

    INMT and cancer

    Down regulation of the expression for the gene responsible for INMT production has been associated with cancer. It is believe to be a potential candidate gene in prevention of cancer progression. INMT expression has been associated with a dramatic decrease in recurrence of malignant prostate and lung cancers. It is possible that the regulating roles of INMT via its product DMT could potentially have a direct tumor suppression effect, but this is highly speculative.

    Summary and conclusions

    DMT is a compound found widely across the plant and animal kingdoms. In mammals, the psychoactive effects produced by DMT seem to be largely mediated by the 5-HT2AR, although the complex subjective effects reported by DMT users are likely modulated by other receptor systems such as the metabotropic glutamate receptors.

    The wide use of DMT in the form of ayahuasca for many years has led to a number of studies focusing on adverse health effects or potential benefits of ayahuasca use. There have been few reports of adverse health consequences. Ayahuasca did produce modest impairment of cognitive function in inexperienced users; however, little or no impairment was observed in experienced users. Ayahuasca decreased markers of sleep quality and sleep disturbances are common on the night following administration, but the users reported no perception of deterioration of quality. As mentioned previously, there is little sign of tolerance or dependence to DMT except to the cardiovascular and endocrine effects, which actually could be viewed as the primary adverse effects. Diminution of these effects would preferred by long-term users. The greatest concern appears to the possibility of teratogenicity. Large doses of ayahuasca 50-fold higher than typical ritual doses were fed to pregnant rats. No lethality was observed, but increased incidence of cleft palate and skeletal malformations was observed in their pups.

    DMT may be an agent of significant adaptive mechanisms that can also serve as a promising tool in the development of future medical therapies. There have been proposals that DMT might be a useful treatment of anxiety, substance abuse, inflammation, or for cancer. Experimental studies have been few and it is premature to conclude that DMT may have clinically relevant uses.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5048497/
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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 systems 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? Osmonds 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 Osmonds 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. Huxleys 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.

    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 Freuds 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.

    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 Huxleys 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 Huxleys 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 Freuds ego, and Huxleys 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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    N, N-Dimethyltryptamine (DMT), an Endogenous Psychedelic: Past, Present, and Future Research to Determine Its Role and Function


    Steven A. Barker

    Abstract

    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.





    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.




    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.





    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.

    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/
    Last edited by mr peabody; 19-09-2018 at 10:55.
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