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DMT, dopamine and serotonin relationship

autumnsphere

autumnsphere

Rising Star
Hey guys, I apologize for the stupid questions beforehand. My basic knowledge is that the brain synthesizes DMT from serotonin (through melatonin), and that dopamine and serotonin peak during a DMT trip. My question is: are there DMT neurons (i.e. where the DMT molecule latches on) and what happens with serotonin and dopamine during a DMT trip - does the DMT cause a spike in them, how and why?

Thanks for your patience!
 
This analogy might help:

neuron = door
receptor = lock
neurotransmitter = key

dmt is very similar to serotonin in terms of chemical structure, so it can open the same locks that serotonin can.

If you have lots of dmt in your brain then a lot of the locks will get filled up with dmt, leaviing more serotonin roaming free.
 
I have always understood DMT, and most psychs (trypts) to NOT be dopanergic drugs, and therefore with less addictive potential than other drugs that do excite the dopamine system. This is also, in my limited understanding, at least partially responsible for the fact that one returns exactly to baseline when they come down, and do not experience any 'jones' when they do. If there is a dopamine peak, it would be insignificant compared to,say, cocaine, heroin or some other euphoric drug.

I am woefully ignorant of nearly all things neurology though so.... Am I wrong?
 
The serotonergic and dopaminergic systems help regulate activity in each-other, so regardless of the actual receptor affinities, there may be downstream effects. For those interested in DMTs actually binding profile:

Wiki said:
DMT binds non-selectively with affinities < 0.6 μM to the following serotonin receptors: 5-HT1A, 5-HT1B, 5-HT1D,5-HT2A, 5-HT2B, 5-HT2C, 5-HT6, and 5-HT7...It has also been shown to possess affinity for the dopamine D1, α1-adrenergic, α2-adrenergic, imidazoline-1, and sigma-1 (σ1) receptors.
Click to expand...

As far as I know, it has no affinity for D2.

As for DMT in the brain - we don't know what the biosynthetic pathway in mammals looks like, but I'd be surprised if it went via melatonin - my hunch would be synthesis from tryptophan, but no one really knows. I think the melatonin thing was started because everyone's high on pineal glands right now and it fits the whole 'dreaming/3rd eye' mythos.


Blessings
~ND
 
Creo said:
This analogy might help:

neuron = door
receptor = lock
neurotransmitter = key

dmt is very similar to serotonin in terms of chemical structure, so it can open the same locks that serotonin can.

If you have lots of dmt in your brain then a lot of the locks will get filled up with dmt, leaviing more serotonin roaming free.
Click to expand...

Best answer ever.

Thanks so much, everyone!
 
autumnsphere said:
My basic knowledge is that the brain synthesizes DMT from serotonin (through melatonin), and that dopamine and serotonin peak during a DMT trip. My question is: are there DMT neurons (i.e. where the DMT molecule latches on) and what happens with serotonin and dopamine during a DMT trip - does the DMT cause a spike in them, how and why?

Thanks for your patience!
Click to expand...

While there are no "dedicated" "DMT neurons", DMT does bind to some serotonin receptors and some dopamine receptors, but the closest thing to a dedicated receptor may be that some neurons have a "Sigma-1 receptor" which does respond specifically to DMT, and may be partially responsible for the hallucinogenic effects. From Wiki entry on Sigma receptors in general:

"The function of these receptors is poorly understood[4] though an endogenous ligand, dimethyltryptamine, was found to interact with σ1.[5][6] Activation of σ–receptors by an agonist ligand may induce hallucinogenic effects"...

..."A variety of specific physiological functions have been attributed to the σ1 receptor. Chief among these are modulation of Ca2+ release, modulation of cardiac myocyte contractility, and inhibition of voltage gated K+ channels.[13] The reasons for these effects are not well understood, even though σ1 receptors have been linked circumstantially to a wide variety of signal transduction pathways."

These kind of receptors fall into a recently discovered (2001) class of receptors called TAARs, or Trace amine-associated Receptors.


As for a path of biosynthesis for DMT, the only one I know of for sure is via tryptophan. Serotonin is also made from tryptophan, but I have not seen the full pathways for serotonin conversion into DMT (see below).

Usually what happens is that something called AADC catalyzes a "decarboxylation reaction" which turns tryptophan in to Tryptamine. Then an enzyme called INMT catalyzes a methylation
reaction that turns the tryptamine into N-Methyltryptamine. It does it again, adding a second methyl group, and BOOM you have Di-MethylTryptamine produced by the body, in the body.

This INMT enzyme is found in the lungs, cerebral spinal fluid, the eyes, etc. I have experienced powerful visionary states from doing pranayama breathing, so I believe both from a scientific and experiential standpoint that this enzyme in the lungs can be released in larger quantities than normal to produce at least some small amount of DMT. It may be that in conjunction with this the Pineal gland releases beta-carbolines that act as a weak MAO Inhibitor that helps prolong the effect of the DMT. The pineal gland is thought to produce substances like Pinoline that could do this, but this has not been proven conclusively to my knowledge.

There could be a way that Melatonin is decarboxylated directly into DMT, but if there is it is not presently known. That would answer a lot of questions, and would explain the idea of the pineal gland being involved in DMT production, etc., but as of right now even the top organic chemicistry experts on DMT like Steven Barker from The Spirit Molecule movie do know know of any such direct melatonin decarboxylation to DMT pathway.

In terms of less direct pathways, this paper claims that melatonin can be deacetylated to 5-methoxytryptamine which can then be metabolized to things like pinoline, bufotenine, DMT, etc.:


But they did not list the exact pathways, if anyone here knows what they are that would be really helpful. I have seen these pathways also mentioned indirectly in manuals on darkroom retreats by Mantak Chia et. al. but again the exact pathways are not specified.


So that was pretty long and verbose, but hopefully somewhat helpful. I am fascinated by the subject of how and why these chemicals are produced in our bodies! 😁
 
So I spent some time today looking up the pathway above and apparently per Wiki, melatonin undergoes a deacetylation reaction in the pineal gland to produce 5-methoxytryptamine, aka Mexamine. (So far the one study I think they reference was done on a golden hamster, so just pointing that out up front). (Further edit, when I looked up the reference below, it sounds like it is in the LIVER that they found that rat melatonin was deactylated, not the brain. They went on to say say that there is aryl acylamidase in the rat pineal, seemingly to infer that this could perhaps cause the pineal deactylation... sheesh!)

www.ncbi.nlm.nih.gov

Day-night rhythm of 5-methoxytryptamine biosynthesis in the pineal gland of the golden hamster (Mesocricetus auratus) - PubMed

5-Methoxytryptamine is a potent agonist of presynaptic 5-hydroxytryptamine autoreceptors modulating serotonin release in the central nervous system. This methoxyindole can be synthesized in the pineal gland, but its presence in vivo is still controversial, probably because of rapid catabolism by...
www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov

Though the same paper says that Bosin & Beck found 5-methoxytryptamine in the human pineal in 1979... so there is that.

Have not found a scientific paper on this yet, but have found some people claiming that the same two reactions with INMT would methylate it twice to give you 5-MeO DMT. This makes sense given that INMT does this with tryptamine to produce DMT.

Alternatively, the enzyme HIOMT in the pineal can supposedly catalyze the transfer of a methly group to the oxygen at the 5 position on the indole ring of the serotonin molecule, thus turning the 5-hydroxy-indole into a 5-methoxy indole. In short, the HIOMT turns serotonin into 5-methoxytrptamine a.k.a. Mexamine. And again, if you can get some INMT from the lungs, the CSF, or maybe somehow the eyes, to mix with that Mexamine, you are then creating 5MeO DMT endogenously it would seem.
 
As for a path of biosynthesis for DMT, the only one I know of for sure is via tryptophan. Serotonin is also made from tryptophan, but I have not seen the full pathways for serotonin conversion into DMT (see below).

Usually what happens is that something called AADC catalyzes a "decarboxylation reaction" which turns tryptophan in to Tryptamine. Then an enzyme called INMT catalyzes a methylation
reaction that turns the tryptamine into N-Methyltryptamine. It does it again, adding a second methyl group, and BOOM you have Di-MethylTryptamine produced by the body, in the body.
Click to expand...

Source for this pathway being active in humans or other mammals?

Blessings
~ND
 
Nathanial.Dread said:
As for a path of biosynthesis for DMT, the only one I know of for sure is via tryptophan. Serotonin is also made from tryptophan, but I have not seen the full pathways for serotonin conversion into DMT (see below).

Usually what happens is that something called AADC catalyzes a "decarboxylation reaction" which turns tryptophan in to Tryptamine. Then an enzyme called INMT catalyzes a methylation
reaction that turns the tryptamine into N-Methyltryptamine. It does it again, adding a second methyl group, and BOOM you have Di-MethylTryptamine produced by the body, in the body.
Click to expand...

Source for this pathway being active in humans or other mammals?

Blessings
~ND
Click to expand...

Sorry, your question made me realize I probably overstepped available proof in my statement, I have pretty much assumed for awhile this is how it is done based on interviews and papers I have read. But looking back at them I only know for sure that this is the only biosynthesis pathway I have ever seen cited for endogenous DMT, but I do not know if there has been any research done *specifically* to prove that this is how the DMT found in the human body is created. It is being created, and this pathway is the mostly likely candidate, but I have not seen a paper dedicated to proving it.

Here is the clip from the man himself talking about it though (the guy who made the DMT for Rick Strassman's experiments):


If you check the wiki entry on DMT there is also a fair amount of discussion there about this likely pathway in mammals and humans under the biosynthesis discussion. But as for a smoking gun paper dedicated *only* to that exact proof, I have not yet seen it if it exists. The best way to describe it would I guess be "the leading candidate" for how the DMT found in humans is produced.

If there are other pathways anyone knows of though I am all ears, would love to hear them!
 
I have a hunch about melatonin because of its relation to sleep (and dreams). I have absolutely no doubt that dreams are caused by DMT, you need to experiment a bit with it to be sure about this. Pay attention to your visions when you wake up suddenly in the middle of the night.

These guys cause DMT release through a 10-day dark room retreat, the info is here (no idea how fringe sciencey it is):


What arrests my attention is that a lot of darkness causes release of DMT, which leads me to the the conclusion that a saturation of melatonin definitely has something in common.

Also, this talk about melatonin being such a crucial bio clock of the human body relates it in a metaphysical way to DMT:

 
autumnsphere said:
I have a hunch about melatonin because of its relation to sleep (and dreams). I have absolutely no doubt that dreams are caused by DMT, you need to experiment a bit with it to be sure about this. Pay attention to your visions when you wake up suddenly in the middle of the night.

These guys cause DMT release through a 10-day dark room retreat, the info is here (no idea how fringe sciencey it is):


What arrests my attention is that a lot of darkness causes release of DMT, which leads me to the the conclusion that a saturation of melatonin definitely has something in common.

Also, this talk about melatonin being such a crucial bio clock of the human body relates it in a metaphysical way to DMT:

Click to expand...

Based on personal experience, I do not disagree with you, but I would love to find more scientific backing for some of the things in that Mantak Chia paper, which I have read before.

They do not really go into the pathways for some of the reactions they claim, and in other places I think they are just plain wrong.

For example, they talk about inhibiting INMT. This would be the last thing you want to do if you want to produce DMT or 5MEODMT, given that as I mentioned, it is the only biosynthesis pathway I have ever seen cited.

Also, INMT does not seem to be produced in the pineal that we know of despite experiments looking for it there, so where and how do they think it is being inhibited in the first place?

INMT however IS found in the eye, and maybe darkness causes it to migrate to the pineal where it can work magic on serotonin in conjunction with HIOMT to produce 5MeODMT... I have no idea, pure speculation there, it probably comes from the CSF actually... my point is that this paper is confusing to me as inhibiting INMT does not make sense and they do not even say how it is inhibited.

All that said, I have had intense hyper geometric 4D visions of machinery, fractals, mandalas all within some of my OBEs, for which I have no other explanation to say that something like endogenous DMT is at work. But there is also a lot to do with acetylcholine, and simply taking an acetycholinesterase inhibitor like galantamine has at times given me 3 OBEs in a row, so even there I have to wonder... there is probably a whole coctail of things going on.

And I know people who have done the darkroom retreat with Mantak Chia and have had intense visionary experiences as well. So *something* is happening, but I still want to have more solid science in order to replicate and reproduce the experience better.

For example, I am pretty convinced *personally* that Pranayama can release DMT via conversion of tryptophan to tryptamine then DMT catalyzed by INMT, as noted in the Steven Barker video I linked to. The reason for this is that I have had minor entity contact and strong closed eye visuals just from pranayama alone.

That said, it is not a consistent thing. Sometimes I get visuals, sometimes I can spend hours doing the breathing and get nothing. Maybe if I understood the pathways better, I could use diet or other aids to make it more reproduce-able. Or I could have OBEs more often, etc.
 
Looking at the Mantak paper more closely, they seem to indicate that by inhibiting INMT, you would block the production of 5MeODMT, and this would be true.

They then say that by doing this, another "enzyme" could turn the 5MeoTryptophan into DMT.

Since they correctly list all the other enzymes like INMT and HIOMT, it feels like they do not know what this enzyme could be that would turn 5MeOTryptphan into DMT.

Also, they say that Melatonin can be transformed to 5-MeO Tryptophan via HIOMT, but I think they have that wrong, it is Serotonin that would be involved, not Melatonin. From what I could tell, you would need some kind of deacetylating agent to turn melatonin into 5MeOTryptophan, and contrary to what I read on Wiki, this happened in rat livers, not the pineals. In any case, I have not read yet what enzyme this might be. Strassman proposed this change from melatonin to 5MeOTryptophan could be going on in the pineal but did not say how that I know of, he just sketched it with an arrow (I saw this in a paper called Autism Viewed as a Consequence of Pineal Gland Malfunction).

So in summary, the Mantak paper is awesome in that it is probably the single most complete attempt I have seen to figure out the endogenous chains, but there do appear to be some holes in it and also some missing/misleading information.

Big Disclaimer: I am not a biochemist, would love to hear from anyone who actually knows the organic chemistry, I only go by what I can read in papers, etc.!
 
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