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Endogenous DMT: Facts and Fiction

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endlessness

endlessness

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What do we know about Endogenous DMT?

This thread`s purpose is to sum up what we know so far about the endogenous presence of DMT and other related tryptamines in the human body. This is just a first collection of information, this post can get edited with time. Please feel free to add more information or give constructive criticism to what is posted below.



Presence in the human body

DMT (and other related tryptamines such as 5-MeO-DMT and Bufotenine) are present in normal human metabolism, as described by these papers:

Category:DMT - DMT-Nexus Wiki

wiki.dmt-nexus.me wiki.dmt-nexus.me

Plasma concentration of endogenous DMT is usually <0.001 mg/L. (Callaway et al 1999; Clarke's Second Edition)

A 70kg person ingesting 140ml of Huasca containing 33.6mg DMT, 238mg Harmine, 28mg Harmaline and 149mg THH reached a peak plasma concentration of DMT of 15.8 mg/L, 1:47min after ingestion (Callaway et al 1999)
A 70kg person injecting intramuscularly 49mg reached peak DMT plasma concentration of 0.1 mg/L after 0.17h [Kaplan et al. 1974]

Interestingly enough, the intramuscular dose, even though psychoactive, has resulted in 100x less plasma DMT than ingesting orally with ayahuasca. Why, is it the harmalas? Is it related to pharmacodynamics depending on route of administration? Or some issue with methodology between different papers?


So what is that endogenous DMT doing there? There have been a few theories proposed so far in scientific literature or otherwise. Below are some of the main theories:



Immune system regulation

Facts, hypothesis and reasoning:
DMT's three process active uptake from peripheral sources to neurons suggests an important biological function to DMT. DMT, as a sigma-1 ligand has been demonstrated in vitro to reduce inflammation and boost anti-inflammatory responses, amongst other immune-related effects. Authors suppose this points out to a immune regulating function of endogenous tryptamines.

Questions:
The paper show an anti-inflammatory effect at dosages higher than are present endogenously and even higher than when dmt is consumed for psychoactive purposes, according to Infundibulum' s preliminary review. Do lower doses show same immune modulating effects? Also, is it possible the anti inflammatory effects are secondary effects and that DMT has yet another function (or several?)

Full Paper
www.plosone.org

Psychedelic N,N-Dimethyltryptamine and 5-Methoxy-N,N-Dimethyltryptamine Modulate Innate and Adaptive Inflammatory Responses through the Sigma-1 Receptor of Human Monocyte-Derived Dendritic Cells

The orphan receptor sigma-1 (sigmar-1) is a transmembrane chaperone protein expressed in both the central nervous system and in immune cells. It has been shown to regulate neuronal differentiation and cell survival, and mediates anti-inflammatory responses and immunosuppression in murine in vivo...
www.plosone.org www.plosone.org

Aya2014 Presentation Powerpoint

Dedicated Threads:



DMT' s anxiolytic role

Facts, hypothesis and reasoning:
Jacob and Presti describe how DMT and other tryptamines have been found to interact with G-protein-coupled human trace amine receptor (TAAR), which are a class of receptors discovered in the early 2000's that have been implicated with different important processes in human metabolism. The connection of such receptors with the gut and the amygdala may point out to an important role in relation with emotions, and therefore authors suggest a possible natural anxiolytic role to DMT.

Questions:
Is something being implicated a good enough indication for a defined endogenous role? (correlation/causation etc). What other functions do TAAR have, and have they been considered in regards to these endogenous tryptamines? Can this be just one more of several functions the molecule has?

Full Paper




DMT`s relation to dreams

Facts, hypothesis and reasoning:
Callaway speculates that the presence of endogenous amines may be related to dreams. He argues that the circadian cycles have been shown to be related with the formation of certain compounds such as pinoline and melatonin which are related to dreams, and that it could be tryptamines such as DMT are also involved.

Questions:
Isn't the serotonin signalling inhibited during dreams? (source, benz DMT Secretion During REM Sleep - Welcome discussion - Welcome to the DMT-Nexus )

Also, while there may be some similarities, dream states seem to be more often different rather than similar to tryptamine states. Very few people dream regularly of elves and fractals :D, and if it was mostly tryptamine mediated, one would suppose those types of experiences would be as common as with exogenous tryptamine effects.

Paper:




Other Theories and Speculations

People have speculated wildly about DMT`s connection to birth and death, spontaneous altered state experiences, and others, but so far these are all hypothesis, none of which AFAIK have any evidence behind them.
 
DMT as a neuromodulator
Burchett, Scott A., and T. Philip Hicks. "The mysterious trace amines: protean neuromodulators of synaptic transmission in mammalian brain." Progress in neurobiology 79.5 (2006): 223-246.

DMT as a neurotransmitter
Vitale, Arturo A, et al. "In Vivo Long-Term Kinetics Of Radiolabeled N,N-Dimethyltryptamine And Tryptamine." Journal Of Nuclear Medicine: Official Publication, Society Of Nuclear Medicine 52.6 (2011): 970-977.

Cozzi, N. (2010). Recent Developments in N,N-dimethyltryptamine (DMT) Pharmacology. Paper presented at MAPS Psychedelic Science in the 21st Century Conference, San Jose, CA, April 15-18, 2010.
 

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..thank you for this good summary endlessness..and additions dreamer042..if i find anything more will post here..

i would speculate that it's more likely that DMT has multiple functions, like serotonin..this would be more efficient in an optimised system..
regarding the dream theory, as pinoline is a beta-carboline, the interaction of endogenous harmala-like compounds with tryptamines would result in different possible visual modes, ratio dependant..that there are are a range of endogenous tryptamines suggests a complex system of interactions, ratios, threshold gates, and 'gain controls' ..in other words the compounds interact..

(ps. without wandering too far off-topic, i don't see how a substance can 'produce visions'..surely it can only modulate input/processing or access pattern or memory?)
 
The following post contains speculation, so please keep a level of skepticism.

You really shouldn't try to derive and useful information from the plasma concentrations, not in this situation anyway. The discrepancy between the routes of administration is interesting enough, but trying to compare it to endogenous levels is just going to get you nowhere. The primary reason being that the circulation of exogenous DMT is going to reach every part of the brain. However, there is no reason whatsoever that endogenous DMT would have to do the same.

This is a clunky example, but it's one of the simplest I could make. Say that you could take exogenous dopamine and have it cross the blood-brain barrier (which you cannot). That dopamine would then circulate your brain, causing effects similar to (but not entirely the same as) dopamine releasing agents. However, there are times when your endogenous dopamine might be very high in one part of the brain and very in low in another part. That would be because thinking of an entire effect spectrum as "what dopamine does" is inaccurate. Dopamine in the striatum does one thing, but dopamine in the prefrontal cortex does something entirely different, and your brain could need both of these things to be done either together or opposite of each other depending on the situation. Therefore, it is quite important to remember that saying that you have "more dopamine" does not inherently mean anything; measuring the plasma level of dopamine would tell you nothing about which parts of the brain have more or less.

I have also heard that the serotonin signal is low or mute during regular dreaming. However, serotonin receptor activation is not believed to be the point of endogenous DMT. This paper proposes that the reason DMT could be useful at such small concentrations is because it builds up in neurons to be released on to sigma-1 receptors for its better studied effects. If that is the case, it seems even less likely to me that DMT's serotonin receptor activity would play much of a role under normal conditions. I had personally dismissed DMT a while ago for the serotonergic reason, but lately I have reconsidered at least one plausible (to me) theory....

In the striatum, a part of the brain which has been implicated in psychosis, sigma-1 receptors are known to form heteromers with both D1 and D2 receptors. This study shows that cocaine actually creates D1-dominant dopaminergic effects by activating sigma-1 receptors which form heteromers with D1 receptors in the striatum. Activating the former potentiates the latter. This study, in addition, shows that cocaine inhibits D2 receptor activity through a heteromer formed between sigma-1 and D2, furthering this relationship. It is known that sigma-1 receptor agonists applied exogenously have antidepressant, nootropic, and rewarding properties. The rewarding properties make sense if you consider what the cocaine studies say in that D2 in an aversion learning receptor and D1 is a reward learning receptor, since natural dopamine flow would be shifted toward the latter. The antidepressant effects could probably fall under that explanation as well. The nootropic effects I would think might come from the fact that D2 in the striatum is known to be one of the most important receptors for dopaminergic psychosis based on antipsychotic mechanisms, and D1 agonists have also been shown to have nootropic properties.

A theory of mine based on these D1, D2, and sigma-1 relationships is that D2 causes the feeling of being in a dream, and the declining lucidity that accompanies it. On the other hand, D1 would increase the feeling of alertness. This would make enough sense if you consider that there is a known relationship between D1, D2, and NMDA, wherein D1 potentiates NMDA receptor currents and D2 inhibits them. Therefore, D2 should cause some dissociative-like changes in perception, in addition to other effects. My thought is that in lower levels of dopaminergic stimulation, D1 activity probably overpowers D2 activity. That would be why moderate levels of dopamine release have a nootropic effect. Higher levels would then start to cause the dissociation that twists your mind into a dreamlike delirium. If, however, there is strong sigma-1 receptor activity at the same time, much of this dissociation should be reversed. This is interesting to think about if you consider that not all psychotic D2 activity necessarily has to take place through a D2 and sigma-1 heteromer.

This paper, which I can only link to the abstract of, highlights the importance of the heteromer formed between D2 and 5-HT2A in the striatum. It found that LSD and DOI, but not serotonin, enhanced the signaling of D2 agonists through a mechanism that was blocked by a 5-HT2A antagonist. For all intents and purposes, receptor heteromers should be thought of as serving unique, individual functions, but they of course can still be grouped to a degree by the receptor protomers that they are comprised of. Therefore, all of the D2 activities of heteromers in the striatum could be considered as a potentially important contribution to the totality of the stereotypical psychosis. My guess is that, considering that serotonin does not activate this process, the 5-HT2A/D2 heteromer might be a significant player in psychedelic entity contact. And here's why I think this would work....

If exogenous DMT gets into the striatum and activates the 5-HT2A/D2, sigma-1/D2, and sigma-1/D1 receptor heteromers, a few different things should happen. Affinity of dopamine for D2 binding sites connected to 5-HT2A would improve, the response of D2 binding sites connected to sigma-1 would deteriorate, and the response of D1 binding sites connected to sigma-1 would improve. This is especially important because DMT increases dopamine levels in the striatum as well, likely, like all psychedelics, through various serotonin receptor activities and enhanced firing of glutamate from prefrontal 5-HT2A receptors on to ventral tegmental area dopaminergic neurons. In this case, the dopamine released by dopamine should have a theoretical shift toward the creation of dream-like perceptions like entity interactions and a shift from the abstract dissociation seen with high doses of many psychedelics towards a very intensely aware and connected nootropic state. This could logically mean that the hallucinations caused by the 5-HT2A/D2 heteromers are intensified by cognition-enhancing effects of the sigma-1/D1 heteromer without being held back by sigma-1/D2, and therefore the crispness, complexity, and rationality of the hallucinations would increase in the same was as a dream being enhanced by something like galantamine or nicotine patches, which drive cholinergic and glutamatergic systems similarly to D1 activation.

My theory about how DMT could possibly be involved in natural dream processes is this. In a normal dream state, high dopamine levels in limbic areas of the brain such as the striatum disable feedback neurotransmission to the higher cognitive areas of the brain like the prefrontal cortex, including glutamate signals. If there was going to be a dopamine receptor that created the dreamy, disconnected delirium that exists in any typical dream, wouldn't it make sense that it would be the dissociative D2 receptor? However, this level of cloudiness does vary from one dream to another, and of course, there is a state where it can be very strongly removed: lucid dreams. When you become lucid, those higher cognitive centers of your brain become active again, the fog and some of the randomness clears up, and the dream actually becomes a lot more vivid. It also suddenly feels incredibly rewarding, like a huge rush of euphoria, to the point that most people have to train themselves to not wake themselves up almost immediately. And of course, there is a remarkable feeling of clarity that comes with the whole experience, compared to the dream from before.

So what would this model look like if you proposed that a release of striatal DMT actually played a role in the transition into lucidity? As I said, high dopamine levels would be suppressing the prefrontal cortex. Suddenly, the good old attentional processes trigger some DMT to come flying their way. In normal brain states, DMT is not believed to reach the level of concentration required to reach 5-HT2A activity. So, if this is assumed to be correct, then the activity of dopamine on 5-HT2A/D2 heteromers will not change. Instead, activity of sigma-1 will disable its connected D2 activity and enhance its connected D1 activity. So, if a switch from D1 to D2 dominance at high doses of many typical psychedelics is responsible for the transition from feeling more alert to feeling like you're in a dream, then wouldn't it be logical enough to suppose that a switch from D2 to D1 dominance might cause a sudden feeling of becoming more awake? If this was the case, then striatal DMT could be the reason for this feeling of suddenly increased clarity and alertness when becoming lucid during a dream. At the same time, the increased signaling of D1 would potentiate the hallucinogenic structure of the dream, which of course also happens greatly at the moment of lucidity.

That theory works well with a dream not exactly being all that similar to a DMT trip because it actually suggests that the generation of the dream itself has nothing at all to do with the DMT, but that the clarity, complexity, and reward of a lucid dream may be a direct result of DMT release. This would then become significant when exogenous DMT is ingested, because when taken at a high enough dose it would actually cause its own level of dreamlike activity through intense dopamine release, in addition to enhancing 5-HT2A-linked D2 activity to the point of causing the powerful, mystical hallucinations associated with psychedelic "psychosis", only at that point by this theory it would be like taking your lucidity neurotransmitter in an enormous dose, thereby blocking sigma-1-linked D2-based dissociative psychosis and shifting to an intense nootropic effect instead. That would then power the already quite intense DMT dream-like state to the level of overwhelming realism, complete immersion, feelings of sudden intense clarity, and pure, freeing euphoria of a lucid dream. The result would be taking the same world of abstractions and entity perceptions that you see on high doses of many psychedelics and supercharging it with rocket fuel and switching your perception of it from a dreamy dissociation to an intensely focused experience that makes you feel more "awake" than ever before, considering that you're activating this process very strongly while already awake in the first place. I think that would also be an important part of funneling enough processing power into entities to be able to give them actual intelligence and understanding. Just another theory....

That's my thoughts on the matter for the moment anyway. What do you guys think?
 
^^ That's a very interesting theory. I also agree with you regarding the limits of correlation one can derive from measuring plasma or CSF levels of neurotransmitters and break-down products and conclusions re site of action (and differential effects between sites).

Thankyou for your speculation- I for one get your thinking and am glad to see a new member who clearly has an interest in the neural sciences! :thumb_up:
 
Thanks, I'm glad that you liked it! :) I'm always happy to contribute my ideas. I really do like thinking about these things as well. I would really love to see some sigma-1 binding and intrinsic activity data for a wide array of psychedelics, especially tryptamines. Based on the data from the study which identified DMT as a sigma-1 agonist I'd be willing to bet that many synthetic tryptamines bind to sigma-1 in varying ratios as well, and based on some ligand discovery that I have been reading about lately I wouldn't even be surprised if a handful of them are sigma-1 antagonists. Having that information about a collection of psychedelics sure would make for some interesting opportunities to extrapolate ideas from subjective reports!
 
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