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Endogenous DMT/5MeO and Pinoline- Where, When, and How Much? Options
 
digitalvygr
#1 Posted : 1/7/2017 5:14:47 AM

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60 years of scientific papers on endogenous DMT make it a virtual certainty that it is produced in the human body... Pinoline has also been found, though the exact endogenous chemistry is less well understood.

The main questions now are:

1. Where is it produced?
2. When/under what (special) circumstances is it produced?
3. How much is produced?
and
4. Based on the above and noted subjective effects, what actions, supplements, etc. can be taken to promote higher levels of endogenous DMT, either for a "microdosed" level, or possibly even for large release and natural trips.

1. A lot of spirited discussion goes on about number 1 here. For my research, and based on recent commentary from Rick Strassman, the most likely answer is that it is *primarily* produced in the lungs (which is also where INMT seems to be most expressed), but that the pineal gland might also be an area of secondary production given the unique substrates and enzymes found there. It seems like 5MeODMT is most likely made there, and it has also been found in the human body. CSF seems to be the highest concentrations found for all these substances.

The discovery of DMT in the rat pineal is promising, but does not prove it was made there. The CSF (Cerebro Spinal Fluid) contains INMT and DMT, and the pineal is bathed in the CSF. This means that DMT could simply accumulate in the pineal because of the CSF, or that INMT could reach there and help it be produced there, etc.

2. Studies on the When are lacking... we can speak of this in many ways...

For example, what time of day is it more likely to find these substances in the human body? An educated guess would be towards the end of the night given breathing patterns of sleep and related compound production of things like melatonin, but again, studies are lacking.

Also, extreme stress is theorized to produce DMT, and indeed the pineal is signaled by Norepinephrine... however stress hormones produced in the adrenals basically never get to the pineal, so here we are talking about a unique kind of stress signal, possibly from the same nerve cells that usually only signal the pineal to produce melatonin using norepinephrine, or possibly some other signal. Or possibly just from the lungs under stress, etc. Here again studies are obviously lacking for ethical reasons, so we have mostly speculation.

DMT has been found to be extremely potent for protecting nerve cells against lack of oxygen, so the stress signals due to lack of oxygen in cardiac arrest and drowning, etc. might be an evolutionary adaptive signal that would cause the release of DMT somehow in order to protect the brain. Anecdotally, this would also correlate with the relatively high rate of DMT-like near death experiences, especially in cardiac arrest cases.

In Pranayama and the Wim Hof methods of breathing, practitioners regularly report DMT like experiences. The Dreamer himself has had profound visionary experiences from Pranayama, and from Wim Hof the Dreamer has also experienced a sharpness of daily vision, especially with regard to plants and an emphasis of their underlying fractal nature that is suggestive of something like an endogenous micro-dose.

Meditative states are also reported to bring about strong visual states. Searches for the videos by Jurgen Ziewe of his 4D fractal experiences from mediation/OBEs are one such anecdotal example that indicates the possibility of endogenous DMT release in relatively large quantities.

The Dreamer himself has also had multiple OBEs that lead to 4D realms filled with fractals and mandalas, and on some occasions, other autonomous entites. The Dreamer has also correlated multiple somatic and visual experiences of his OBEs with Strassman's recordings from the experiments and UNM, and has the agreement of Strassman himself that there is a possibility that endogenous DMT is mediating them. The Dreamer compares direct experience of smoalked DMT and notes somewhat less intensity but also amazing similarities to his deepest, most powerful OBEs.

3. How Much - the gut reaction is to say that is can be nowhere near as much as a smoalked session... however, given the half life of DMT in the blood, and how it is so quickly and ravenously scavenged by MAO and other metabolic processes, it is rather amazing to think that it is found at all in bodily fluids of average people. It is suggestive of either large amounts being produced in sleep states, or constant small amounts being produces on a more regular basis (perhaps DMT is part of waking consciousness).

And as various chemistries are examined, there could be "runaway endogenous production" scenarios.

For example, the pineal has all the chemistry necessary to produce at least both pinoline and 5MeODMT, and adding in INMT if from nowhere else but the CSF, also DMT.

Now pinoline is BOTH an MAO AND a serotonin re-uptake inhibitor. So it could keep normal DMT around much longer. And it would cascade the production of serotonin, which in the pienal is already the highest density anywhere in the body. Again, the chemistry is all there to make 5MeO from the serotonin, so in this scenario you could have a possible bonfire production going on.

The point is that if we intelligently discuss the chemistry and known facts, maybe we can stumble on some ways to potentiate the WHEN-WHERE-HOW MUCH aspects of this proven endogenous production.

It would seem that yogis have done this to some extent... Pranayama and things like Kechari Mudra are examples. And the Tibetans with their Dream Yoga have reported things like "DMT is as far as you can go in the Bardo without actually dying..."

Well, I say here at the Nexus are assembled some of the best minds on the planet, and with the most experience of the direct substance, and if we can all just put aside some differences and speak open mindedly about the "what ifs", then we here can also advance this knowledge Thumbs up

 

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cave paintings
#2 Posted : 1/7/2017 7:51:23 AM

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Yeah, fun stuff to discuss! The whole three-step active uptake of dmt into the soma of neurons proposed is interesting to me, and lends credence to its role as a neuroprotective compound against hypoxic damage. I guess as you mention, what signals prompt endogenous dmt to be released from stored vesicles is interesting, and likely might be stress inputs. Obviously its roles are probably pleiotropic. Its whole role in modulating immune activity is interesting, and it seems to generally downregulate inflammatory action, excepting the upregulation of NK cells (if I remember these things correctly).
The high expression of INMT in the lung may also correlate with its role as a xenobiotic modifying enzyme in a tissue that is exposed to a lot of environmental insults (inmt is pretty promiscuous in what it methylates right?).
The adrenal gland also expresses appreciable INMT, along with some of the other endocrine/reproductive tissues. I think the whole hormonal/glucocorticoid/stress/inflammatory axis and DMT's relationship to it is very interesting and bears further exploration. Potential roles in endocrine/reproductive modulation is also interesting, considering INMT's expression in these tissues.

Sorry, not a very clear or directed post.. A little stoned, but wanted to express interest.
Living to Give
 
downwardsfromzero
#3 Posted : 1/7/2017 2:14:52 PM

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Interesting post. To the "where, when and how much" - regarding pinoline/6-MeO-β-carboline - I would add the question, what subjective effects do we have on record?

There seems to be an intuitive link at the very least between the INMT activity of the lungs and the neuroprotective effects of DMT. To what extent does the biochemical output of the lungs pass into the CSF? The lungs are clearly in close proximity to a fairly significant length of spinal column. Would this provide an additional 'fast track' supply of neuroprotectant compounds in cases of anoxic emergency? Is this part of the way breathing exercises can facilitate profound alterations of consciousness?

What is particularly interesting here is the way that physical actions would appear to be affecting enzyme expression at a molecular level. Thus Pranayama, Kechari Mudra, Dream Yoga, etc. are remarkable physiological technologies all things considered.


Rambling musings, perhaps but it's my bookmark here!




“There is a way of manipulating matter and energy so as to produce what modern scientists call 'a field of force'. The field acts on the observer and puts him in a privileged position vis-à-vis the universe. From this position he has access to the realities which are ordinarily hidden from us by time and space, matter and energy. This is what we call the Great Work."
― Jacques Bergier, quoting Fulcanelli
 
entheogenic-gnosis
#4 Posted : 1/7/2017 3:05:13 PM
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Great topic, I'm going to have to return when I have the time to get into detail here...

Honestly you covered a good deal already, and have obviously done your research, making any quick response impossible.

I'm glad you bring up wim hof, I'm fascinated by what he does. Most have speculated that it's endogenous phenethylamines such as epinephrine and norepinephrine that allow wim to accomplish such feats. (The Buddhist "tummo" meditation fits into this category and may be facilitated by similar neurotransmitters )

As far as where DMT is produced, it's hard to say, as the pathway could potentially occur in many areas of the body, any way, here's the pathway:

L-tryptophan enters the system and is decarboxylated via amino acid decarboxylase (AADC) to tryptamine, this tryptamine is then methylated by indole amine methyl transferase (INMT) which is in interaction with S-Adenosyl methionine (SAM) which becomes S-Adenosyl-L-homocysteine (SAH) as it donates its methyl group giving N-methyl-tryptamine, this N-methyl-tryptamine is then methylated by INMT in conjunction with SAM (which becomes SAH as it donates its methyl group) giving N,N-DMT.

5-meo-DMT has a different pathway which also begins with L-tryptophan.

As for pinoline, it's complicated, however:

Tryptophan enters, and is 5-hydroxylated via tryptophan hydroxylase giving 5-hydroxy-tryptophan, which is then decarboxylated (AADC; amino acid decarboxylase) giving 5-hydroxy-tryptamine (serotonin) which is N-acetylated (5HT-N-acetylase) giving N-acetyl-5-hydroxy-tryptamine, which is then 5-methylated via hydroxy-indole-o-methyl-transferase giving N-acetyl-5-5-methoxy-tryptamine (melatonin)...melatonin is then said to undergo metabolic cyclization to give 6-methoxy-THBC, though this is disputed....

Again, I'll have to return to this when I have more time, I created this post very quickly, I apologize for any errors, please point them out and I will correct them.

Fascinating topic, it's just hard to discuss with brevity, when I have some time I will roll a few joints and really get into This discussion...



Misc. Links

https://www.ncbi.nlm.nih.gov/pubmed/6723809
https://www.ncbi.nlm.nih.../articles/PMC3028383/#R7


-eg
 
digitalvygr
#5 Posted : 1/7/2017 4:43:04 PM

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cave paintings wrote:
Yeah, fun stuff to discuss! The whole three-step active uptake of dmt into the soma of neurons proposed is interesting to me, and lends credence to its role as a neuroprotective compound against hypoxic damage. I guess as you mention, what signals prompt endogenous dmt to be released from stored vesicles is interesting, and likely might be stress inputs. Obviously its roles are probably pleiotropic. Its whole role in modulating immune activity is interesting, and it seems to generally downregulate inflammatory action, excepting the upregulation of NK cells (if I remember these things correctly).
The high expression of INMT in the lung may also correlate with its role as a xenobiotic modifying enzyme in a tissue that is exposed to a lot of environmental insults (inmt is pretty promiscuous in what it methylates right?).
The adrenal gland also expresses appreciable INMT, along with some of the other endocrine/reproductive tissues. I think the whole hormonal/glucocorticoid/stress/inflammatory axis and DMT's relationship to it is very interesting and bears further exploration. Potential roles in endocrine/reproductive modulation is also interesting, considering INMT's expression in these tissues.

Sorry, not a very clear or directed post.. A little stoned, but wanted to express interest.


Yes, my understanding of the proposed 3 step process is as follows (from the paper "A possibly sigma-1 receptor mediated role of DMT"Pleased :

1. DMT crosses Blood Brain Barrier (BBB) by an uptake across the endothelial plasma membrane
(Barker et al 1982, Sitaram et al 1987, Takahashi et al 1985, Yanai et al 1986)
2. uptake via Serotonin Transporter (SERT) on the surface of neurons in the brain
3. sequestration into the vesicles from the cytoplasm by neuronal vesicle monamine transporter 2 (VMAT2) (Cozzi et al 2009)

"After its neuronal uptake, DMT can act at intracellular modulators of signal transduction systems (see below) or remain stored in vesicles for up to at least 1 week and available to be released under appropriate stimuli (Vitale et al 2011)"

This really gets to the whole WHEN and HOW MUCH issue, given that DMT could be stored up to a week per their investigations. Maybe some signal causes mass exocytosis of stored DMT all at once.

Also, I had not thought of that role of INMT as being xenobiotic in the lungs, it makes a lot of sense, thanks Cave Paintings Smile
 
digitalvygr
#6 Posted : 1/7/2017 4:58:05 PM

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downwardsfromzero wrote:
Interesting post. To the "where, when and how much" - regarding pinoline/6-MeO-β-carboline - I would add the question, what subjective effects do we have on record?

There seems to be an intuitive link at the very least between the INMT activity of the lungs and the neuroprotective effects of DMT. To what extent does the biochemical output of the lungs pass into the CSF? The lungs are clearly in close proximity to a fairly significant length of spinal column. Would this provide an additional 'fast track' supply of neuroprotectant compounds in cases of anoxic emergency? Is this part of the way breathing exercises can facilitate profound alterations of consciousness?

What is particularly interesting here is the way that physical actions would appear to be affecting enzyme expression at a molecular level. Thus Pranayama, Kechari Mudra, Dream Yoga, etc. are remarkable physiological technologies all things considered.


Rambling musings, perhaps but it's my bookmark here!


Bancopuma here on the Nexus is probably one of the few humans to dose pure pinoline, but used mostly an oral administration route IIRC. Pinoline I believe crosses the BBB poorly, so in retrospect even he realized that different administration would have been better. It sounded like the effects were mostly melatonin like.

I think your question about how much the lungs pass to the CSF is very important and as of yet I have not gotten a clear answer. I think though that the fast track is simply arterial blood, as that would go straight to the brain in emergencey, whereas CSF is more of a "pulsatitle" system rather than circulatory, so it would rely on diffusion to reach the brain.

That being said, the Dreamer did Pranayama once for the first time, and was relaxing after it was all done. The experience so far had been mildly entertaining, the hands experienced tetany and there was some relaxation. However, after something like 5 minutes of laying there in total darkness with eyes covered, an extremely bright 3D vision of something like the lotus of 1000 petals entered vision. It went away and came back 3 times, and each time it made its presence and beingness more profound and powerful and felt, so much so that the Dreamer was crying from the sheer beauty of it all by the 3rd time. This was only interrupted by the Pranayama instructor asking everyone to sit up and share their experiences.

So it seemed like in that experience, there was indeed a lag, which could well have been a CSF mediated experience. Of course, that is speculation and a n=1 experience but seemed worth relating in this context.
 
digitalvygr
#7 Posted : 1/7/2017 5:19:10 PM

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entheogenic-gnosis wrote:
Great topic, I'm going to have to return when I have the time to get into detail here...

Honestly you covered a good deal already, and have obviously done your research, making any quick response impossible.

I'm glad you bring up wim hof, I'm fascinated by what he does. Most have speculated that it's endogenous phenethylamines such as epinephrine and norepinephrine that allow wim to accomplish such feats. (The Buddhist "tummo" meditation fits into this category and may be facilitated by similar neurotransmitters )

As far as where DMT is produced, it's hard to say, as the pathway could potentially occur in many areas of the body, any way, here's the pathway:

L-tryptophan enters the system and is decarboxylated via amino acid decarboxylase (AADC) to tryptamine, this tryptamine is then methylated by indole amine methyl transferase (INMT) which is in interaction with S-Adenosyl methionine (SAM) which becomes S-Adenosyl-L-homocysteine (SAH) as it donates its methyl group giving N-methyl-tryptamine, this N-methyl-tryptamine is then methylated by INMT in conjunction with SAM (which becomes SAH as it donates its methyl group) giving N,N-DMT.

5-meo-DMT has a different pathway which also begins with L-tryptophan.

As for pinoline, it's complicated, however:

Tryptophan enters, and is 5-hydroxylated via tryptophan hydroxylase giving 5-hydroxy-tryptophan, which is then decarboxylated (AADC; amino acid decarboxylase) giving 5-hydroxy-tryptamine (serotonin) which is N-acetylated (5HT-N-acetylase) giving N-acetyl-5-hydroxy-tryptamine, which is then 5-methylated via hydroxy-indole-o-methyl-transferase giving N-acetyl-5-5-methoxy-tryptamine (melatonin)...melatonin is then said to undergo metabolic cyclization to give 6-methoxy-THBC, though this is disputed....

Again, I'll have to return to this when I have more time, I created this post very quickly, I apologize for any errors, please point them out and I will correct them.

Fascinating topic, it's just hard to discuss with brevity, when I have some time I will roll a few joints and really get into This discussion...



Misc. Links

https://www.ncbi.nlm.nih.gov/pubmed/6723809
https://www.ncbi.nlm.nih.../articles/PMC3028383/#R7


-eg


WRT to Wim Hof, going on the Wim Hof method group on FB yields quite a large number of people discussing DMT specifically and their experiences of lights, etc. And there is a group of people who have gone on his extended retreats in Poland that say they learned some techniques not taught in his online courses that were specifically for inducing such experiences.

And in regard to the immune system effects of DMT, it is intresting to note the Wim has amazing control over his immune system as proven in scientific studies where they inject him with endotoxins, but those studies indicated that the effect was more from his ability to control norepinephrine, etc. That is to say, DMT was clearly not part of the study.

The DMT and 5Meo DMT endogenous pathways are pretty solid, as you noted.

5Meo could be produced from Serotonin + HIOMT, both produced in the pineal

Serotonin + INMT could produce Bufotenin
Bufotenin +HIOMT could in turn also produce 5MeoDMT

Melatonin + Arly Aclamidase --> 5MetTryptamine, which could be twice methylated by INMT to produce 5MeODMT

So, there are MULTIPLE pathways in fact for 5MeO production in the pineal.

Pinoline is actually the least understood in terms of potential endogenous pathway and thus my greatest area of interest as it could add that runaway effect I mentioned in the original post.

From what I can tell, you could take Melatonin and cyclize it as you mentioned to produce pinoline, this would likely involve 5MeOTryptamine as an intermediate and formaldehyde to be involved in closing the ring where the NH2 is on the 5MeOTryptamine.

Barker also shows how Trypamine can get biosynthesized into THBC. There is not much discussion of this, but the Pinoline molecule is of course 6 Methoxy THBC, i.e. is has a methoxy group at the 6 position, so a role for HIOMT here seems not unlikely to me to produce pinline from THBC, and HIOMT is again prevalent in the pineal. So this reaction would actually seem simpler than the melatonin route, but would love it if one of the flask bearer members here like Benzyme or others could chime in.
 
cave paintings
#8 Posted : 1/7/2017 8:27:30 PM

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Look what I found. I've been hot on this sigma-1/ALS/dmt story for a bit, and I think this paper helps round out some of our speculations.



"As indicated previously, several endogenous compounds have been shown to bind to the S1R and thus may provide regulation of S1R activities (16). Although the affinity of these compounds for the S1R varies considerably, activation of the S1R may depend on the cellular environments and the local concentrations in various mammalian tissues. We have shown that N,N-dimethylytrptamine (DMT) is an agonist for the S1R (49). The relationship between DMT and the S1R was further reinforced by the demonstration that the enzyme, Indole(ethyl)amine N-methyltransferase (INMT) that converts the amino acid tryptophan decarboxylation product, tryptamine, into DMT, co-localized with the S1R in C-terminals of the primate MN (81) (Fig. 2). This paradigm shifting observation of co-localization of S1R and INMT to produce DMT, may be functionally very important to provide high local concentrations of the agonist due to the close juxtaposition with the S1R. This co-localization may further be relevant because the affinity of DMT towards S1R as determined by in vitro experiments is relatively low, in the micromolar range (49)."

"Recent data indicate (82) that, in contrast to humans, in mice the primary function of INMT (also known as mouse TEMT) is NOT methylation of tryptamine, but rather methylation of sulfur, selenium and tellurium containing compounds, presumably for detoxification purposes (83) and for reduction of oxidative stress (84,85). In addition to its ability to methylate tryptamine, recombinant; human INMT (hINMT) can also methylate thiol containing compounds (such as the endogenous compound, cysteamine and the synthetic substrate, 2-(methylthio) ethylamine) due to an alternate TEMT enzyme activity (82). This observation reinforces the report (63) that the S1R mutation E102Q that underlies juvenile ALS (4) causes cytoplasmic aggregation of S1R and oxidative stress in Neuro2A cells via mitochondrial disruption of ATP synthesis. The potential oxidative stress reducing properties of the TEMT activity of INMT is also in complete accord with previous demonstrations that the S1R reduces oxidative stress in cells (25,54,86). It is therefore reasonable to conclude that the co-localization of S1R with INMT/TEMT (81) in primate and human MN may provide protection by the S1R through both enzyme activities (i.e. formation of DMT and reduction in oxidative stress via methylation of thiols and trace metals)."


Sorry about the wall of words.

Paper is attached.
Living to Give
 
cave paintings
#9 Posted : 1/7/2017 8:58:33 PM

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Oh man, I found a pretty neat paper.

Here is an excerpt from the abstract:

"Unlike in other cell types in previous reports, in photoreceptor cells S1R was found in the nuclear envelope but not localized in the endoplasmic reticulum (ER), raising a possibility of S1R-mediated modulatory mechanisms different than conventionally thought. While in bipolar cells S1R was detected only in the nuclear envelope, in ganglion cells S1R was identified predominantly in the nuclear envelope and found in the ER as well. A predominant localization of S1R in the nuclear envelope in all three retinal neurons implicates a potential role of S1R in modulating nuclear activities. Moreover, its absence in the plasma membrane and presence in the subsurface ER cisternae that are juxtaposed to the plasma membrane in ganglion cells may lend mechanistic insights generally important for frequently reported S1R modulations of ion channels in neurons."

This once again lends credence to the sigma1's role as ox-stress/neuroprotective mediator, as photoreceptors are subject to such harsh conditions. I haven't actually read the whole paper yet, but its localization at the nuclear envelope is really intriguing to me.

What actually gets me kind of perky is the anecdote shared by someone previously on the nexus that they had their colorblindness atleast temporarily relieved by a DMT experience, which I always found astonishing.
https://www.dmt-nexus.me...aspx?g=posts&t=69185

I definitely don't want to get too ahead of myself here, but it is interesting to speculate on the potential mechanisms of transcriptional modulation or even just the ER stress response and misfolded protein clearance.


Edit: Whoops forgot to add paper.
It was taking forever to upload, so I have attached link. Full access is free.
Subcellular Localization of the Sigma-1 Receptor in Retinal Neurons — an Electron Microscopy Study
http://www.nature.com/articles/srep10689
Living to Give
 
digitalvygr
#10 Posted : 1/7/2017 9:05:53 PM

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cave paintings wrote:
Look what I found. I've been hot on this sigma-1/ALS/dmt story for a bit, and I think this paper helps round out some of our speculations.



"As indicated previously, several endogenous compounds have been shown to bind to the S1R and thus may provide regulation of S1R activities (16). Although the affinity of these compounds for the S1R varies considerably, activation of the S1R may depend on the cellular environments and the local concentrations in various mammalian tissues. We have shown that N,N-dimethylytrptamine (DMT) is an agonist for the S1R (49). The relationship between DMT and the S1R was further reinforced by the demonstration that the enzyme, Indole(ethyl)amine N-methyltransferase (INMT) that converts the amino acid tryptophan decarboxylation product, tryptamine, into DMT, co-localized with the S1R in C-terminals of the primate MN (81) (Fig. 2). This paradigm shifting observation of co-localization of S1R and INMT to produce DMT, may be functionally very important to provide high local concentrations of the agonist due to the close juxtaposition with the S1R. This co-localization may further be relevant because the affinity of DMT towards S1R as determined by in vitro experiments is relatively low, in the micromolar range (49)."

"Recent data indicate (82) that, in contrast to humans, in mice the primary function of INMT (also known as mouse TEMT) is NOT methylation of tryptamine, but rather methylation of sulfur, selenium and tellurium containing compounds, presumably for detoxification purposes (83) and for reduction of oxidative stress (84,85). In addition to its ability to methylate tryptamine, recombinant; human INMT (hINMT) can also methylate thiol containing compounds (such as the endogenous compound, cysteamine and the synthetic substrate, 2-(methylthio) ethylamine) due to an alternate TEMT enzyme activity (82). This observation reinforces the report (63) that the S1R mutation E102Q that underlies juvenile ALS (4) causes cytoplasmic aggregation of S1R and oxidative stress in Neuro2A cells via mitochondrial disruption of ATP synthesis. The potential oxidative stress reducing properties of the TEMT activity of INMT is also in complete accord with previous demonstrations that the S1R reduces oxidative stress in cells (25,54,86). It is therefore reasonable to conclude that the co-localization of S1R with INMT/TEMT (81) in primate and human MN may provide protection by the S1R through both enzyme activities (i.e. formation of DMT and reduction in oxidative stress via methylation of thiols and trace metals)."


Sorry about the wall of words.

Paper is attached.


Great find! I have been somewhat aware of this peripherally and have the following related paper on my "to read list":

Development of the sigma-1 receptor in C-terminals of motoneurons and colocalization with the N,N'-dimethyltryptamine forming enzyme, indole-N-methyl transferase
https://www.ncbi.nlm.nih.gov/pubmed/22265729

INMT is sometimes considered to be an "inducible enzyme", i.e. it seems like it is not necessarily continually produced by the body, or at least tends to be produced in larger quantities under certain circumstances.

So discovering that in some places in the primate (C-terminals/motorneurons) that INMT is colocalized with sigma-1 receptors for which DMT is theorized to be the endogenous ligand, it adds one more piece of evidence for theorizing that endogenously produced DMT may exert large influence because it may be produced locally where needed. (Related to the WHERE and HOW MUCH question).

From the abstract of the above cited paper (mouse data):
"We found that indole-N-methyl transferase (INMT), an enzyme that converts tryptamine into the sigma-1 ligand dimethyltryptamine (DMT), is also localized to postsynaptic sites of C-terminals in close proximity to the S1R. This close association of INMT and S1Rs suggest that DMT is synthesized locally to effectively activate S1R in MN."
 
digitalvygr
#11 Posted : 1/7/2017 10:23:15 PM

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With respect to the WHEN question, as pertains to possible pineal production of endogenous tryptamines and beta carbolines, this paper is a must read (yes, its mouse data, but still very likely correlated to human pineal function and day/night rhythm):

Night/Day Changes in Pineal Expression of >600 Genes
https://www.ncbi.nlm.nih...pmc/articles/PMC2658055/

To say this paper blew my mind would be an understatement. They looked at 604 genes and found that 70% of them had greater expression at night, and 334 of them had up to 8X higher expression (for example many of the ones involved in producing melatonin and photodetection - which is itself interesting given that the eyes are shut during sleep). 2000 genes were found to have differences, which is 50X more genes than previously recognized to have night day differences, according to the authors. Some genes had as much as a 20X to 100X change in expression.

The paper also gives details of the pineal that I did not know before. It is I think very related to any discussion of how DMT/5MeODMT and Pinoline might possibly be produced by it. Considering that many endogenous studies take samples during the day, yet much of the genetic expression involved could be only expressed at 1% of nighttime levels in some cases, this also effects the potential HOW MUCH results...

I could probably go on and on about it, but for now just going to leave it here and likely reference it in subsequent discussion.
 
cave paintings
#12 Posted : 1/7/2017 10:24:06 PM

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Thanks for the paper and thoughts digital!

I think I have spent too long digging around on things today, so I should probably go outside soon haha.

Anyhow, I think you're dead on with identifying the inductive signals for inmt expression. It is also interesting to speculate on what the alternatively spliced transcript variants may do, or how their differential expression could affect things.. but that's a whole 'nother rabbit hole.
I think I saw a paper that talked about inmt induction in response to heat stress. Because of its roles in methylating metals and things, in addition to endogenous substrates, I wonder if it is induced in response to ox-stress much like the metallothioneins.
Do you have any good papers on inmt induction? I'm sure I'm just being lazy and missing them. I know there's some papers on inmt's relation to cancer and its expression I can dig out later.

Transcription factors in INMT gene promoter if interested: HEN1 GATA-3 Tal-1 E47 YY1 GATA-1 HFH-1 MyoD C/EBPbeta p300


Edit: Looks like we posted almost simultaneously! I'll look into the melatonin/photoregulation paper. Thanks Thumbs up
Living to Give
 
digitalvygr
#13 Posted : 1/7/2017 10:30:16 PM

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cave paintings wrote:
Thanks for the paper and thoughts digital!

I think I have spent too long digging around on things today, so I should probably go outside soon haha.

Anyhow, I think you're dead on with identifying the inductive signals for inmt expression. It is also interesting to speculate on what the alternatively spliced transcript variants may do, or how their differential expression could affect things.. but that's a whole 'nother rabbit hole.
I think I saw a paper that talked about inmt induction in response to heat stress. Because of its roles in methylating metals and things, in addition to endogenous substrates, I wonder if it is induced in response to ox-stress much like the metallothioneins.
Do you have any good papers on inmt induction? I'm sure I'm just being lazy and missing them. I know there's some papers on inmt's relation to cancer and its expression I can dig out later.

Transcription factors in INMT gene promoter if interested: HEN1 GATA-3 Tal-1 E47 YY1 GATA-1 HFH-1 MyoD C/EBPbeta p300


Edit: Looks like we posted almost simultaneously! I'll look into the melatonin/photoregulation paper. Thanks Thumbs up


Yeah, I gotta get out too lol. That said, your point about heat stress makes me think about how people in sweat lodges often have visions as well...

I dont know any papers offhand for INMT inducement via stress, but that is percolating now and I will be on the lookout when I get more time. I think there are some that have to do with forced swims with rats though come to think of it, but I dont remember which ones...

This endogenous search sometimes seems like a never ending rabbit hole, but one that I can't seem to resist given what may be found if one digs deep enough!
 
digitalvygr
#14 Posted : 1/11/2017 4:53:41 PM

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cave paintings wrote:
Thanks for the paper and thoughts digital!

I think I have spent too long digging around on things today, so I should probably go outside soon haha.

Anyhow, I think you're dead on with identifying the inductive signals for inmt expression. It is also interesting to speculate on what the alternatively spliced transcript variants may do, or how their differential expression could affect things.. but that's a whole 'nother rabbit hole.
I think I saw a paper that talked about inmt induction in response to heat stress. Because of its roles in methylating metals and things, in addition to endogenous substrates, I wonder if it is induced in response to ox-stress much like the metallothioneins.
Do you have any good papers on inmt induction? I'm sure I'm just being lazy and missing them. I know there's some papers on inmt's relation to cancer and its expression I can dig out later.

Transcription factors in INMT gene promoter if interested: HEN1 GATA-3 Tal-1 E47 YY1 GATA-1 HFH-1 MyoD C/EBPbeta p300


Edit: Looks like we posted almost simultaneously! I'll look into the melatonin/photoregulation paper. Thanks Thumbs up


Actually, there is a hit here about how INMT itself and/or the peptides that inhibit INMT may be stress induced:

https://books.google.ca/...tress%20lung&f=false

International Review of Neurobiology, Volume 22
pg 88

That is basically this paper, which is probably floating around here on the Nexus as well, one of the best papers on endogenous DMT production:

https://www.researchgate..._Endogenous_Hallucinogen
 
entheogenic-gnosis
#15 Posted : 1/11/2017 6:25:19 PM
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This is a bunch of misc. Related information, I was hesitant in posting it, as I do not want to interrupt the currant conversation, but I also had reservations about deleting it as I felt it applies to the topic at hand. I apologize if this post does not fit in with the currant state of the thread.

Sorry for the disorganized nature of this post.

*repeat*L-tryptophan enters the system and is decarboxylated via amino acid decarboxylase (AADC) to tryptamine, this tryptamine is then methylated by indole amine methyl transferase (INMT) which is in interaction with S-Adenosyl methionine (SAM) which becomes S-Adenosyl-L-homocysteine (SAH) as it donates its methyl group giving N-methyl-tryptamine, this N-methyl-tryptamine is then methylated by INMT in conjunction with SAM (which becomes SAH as it donates its methyl group) giving N,N-DMT

INMT catalyzes the addition of methyl groups to trytamine using Using S-adenosyl methionine as the methyl group donor, the S-adenosyl methionine becomes S-adenosyl-L-homocysteine after it has donated it's methyl group. S-adenosyl-methionine is a cofactor with indole amine methyl transferase (INMT) in methylation of tryptamine compounds in the biosynthesis of DMT.

Quote:
S-Adenosylmethionine (SAMe) is a naturally-occurring compound found in almost every tissue and fluid in the body http://umm.edu/health/me...ment/sadenosylmethionine


Quote:
A new finding was the detection of large amounts of bufotenine in stools, which may be an indication of its role in intestinal function. It is suggested that fecal and urinary bufotenine originate from epithelial cells of the intestine and the kidney, respectively, although the possibility of their synthesis by intestinal bacteria cannot be excluded. Only small amounts of the DMIAs were found in somatic or neural tissues and none in blood. This can be explained by rapid catabolism of the DMIAs by mitochondrial monoamino-oxidase or by the fact that the dimethylated products of serotonin and tryptamine are not formed in significant amounts in most mammalian tissues despite the widespread presence of INMT in tissues.
https://www.ncbi.nlm.nih.gov/pubmed/16095048/


http://www.uniprot.org/uniprot/O95050



Quote:
Enzymatic formation of psychotomimetic metabolites from normally occurring compounds.
AXELROD J.
Abstract
An enzyme has been found that N-methylates serotonin and tryptamine to psychotomimetic metabolites, bufotenine and N,N-dimethyltryptamine. This enzyme is highly localized in the rabbit lung and also N-methylates phenylethylamine derivatives such as tyramine, phenylethylamine , mescaline, and dopamine
https://www.ncbi.nlm.nih.gov/pubmed/13685339


Below shulgin speculates about exploiting this enzymatic process in an attempt to produce DMT:
Quote:
Almost forty years ago a researcher in the National institute
of Mental Health, in Maryland, discovered an enzyme in rabbit lung
that could transfer a methyl group to a tryptamine from the amino
acid donor, S-adenosyl-methione. With this system, serotonin gave
N-methylserotonin, N-methylserotonin gave bufotenine, tryptamine gave
N-methyltryptamine, and N-methyltryptamine gave DMT. What a fabulous
black box that would make. Get two enzyme preparations, one that can
methylate S-adenosyl-homocysteine to S-adenosyl-methionine and
another that can regenerate S-adenosyl-homocysteine by transferring
the methyl group to an available amine. Two catalysts in a chamber
heated to 37 C, with a spigot adding tryptamine at the top, and
another releasing DMT out the bottom. That's the science - I'll leave
the details to the engineers.




DMT and the sigmar-1

Quote:
nteractions with sigma receptors have not been determined. Of particular interest is the only known endogenous mammalian N,N-dimethylated trace amine, N,N-dimethyltryptamine (DMT) (8–10). In addition to being one of the active compounds in psychoactive snuffs (yopo, epenáPleased and sacramental teas (ayahuasca, yagéPleased used in native shamanic rituals in South America, DMT can be produced by enzymes in mammalian lung (11) and in rodent brain (12). DMT has been found in human urine, blood, and cerebrospinal fluid (9, 13). Although there are no conclusive quantitative studies measuring the abundance of endogenous DMT because of its rapid metabolism (14), DMT concentrations can be localized and elevated in certain instances. Evidence suggests that DMT can be locally sequestered into brain neurotransmitter storage vesicles and that DMT production increases in rodent brain under environmental stress (Cool. Although a family of heterotrimeric GTP-binding protein (G protein)–coupled receptors (GPCRs) known as the trace amine receptors (TARs) was discovered in 2001 (15), only two members of this family respond to trace amines and have been renamed trace amine-associated receptors (TAARs) (16). Because other binding targets for trace amines and DMT are likely (Cool, we first examined the sigma-1 receptor binding affinities of the trace amines and their N-methylated and N,N-dimethylated counterparts.

The binding, biochemical, physiological, and behavioral studies reported here all support the hypothesis that DMT acts as a ligand for the sigma-1 receptor. On the basis of our binding results and the sigma-1 receptor pharmacophore, endogenous trace amines and their N-methyl and N,N-dimethyl derivatives are likely to serve as endogenous sigma receptor regulators. Moreover, DMT, the only known mammalian N,N-dimethylated trace amine, can activate the sigma-1 receptor to modulate Na+ channels. The recent discovery that the sigma-1 receptor functions as a molecular chaperone (30) may be relevant, because sigma-1 receptors, which are observed in the endoplasmic reticulum, associate with plasma membrane Kv 1.4 channels (22) and may serve as a molecular chaperone for ion channels. Furthermore, the behavioral effect of DMT may be due to activation or inhibition of sigma-1 receptor chaperone activity instead of, or in addition to, DMT/sigma-1 receptor modulation of ion channels. These studies thus suggest that this natural hallucinogen could exert its action by binding to sigma-1 receptors, which are abundant in the brain (1, 27). This discovery may also extend to N,N-dimethylated neurotransmitters such as the psychoactive serotonin derivative N,N-dimethylserotonin (bufotenine), which has been found at elevated concentrations in the urine of schizophrenic patients (10). The finding that DMT and sigma-1 receptors act as a ligand-receptor pair provides a long-awaited connection that will enable researchers to elucidate the biological functions of both of these molecules.
https://www.ncbi.nlm.nih...pmc/articles/PMC2947205/


http://www.neurophys.wisc.edu/~cozzi/Indolethylamine%20N-methyltransferase%20expression%20in%20primate%20nervous%20tissue.pdf


-eg
 
digitalvygr
#16 Posted : 1/11/2017 9:14:12 PM

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Thanks Entheogenic-Gnosis, any and all contributions welcome to this thread and all of what you posted is relevant IMO.

Some important points we can draw from what you shared:

-Very clear biosynthesis pathway in humans
-SAMe is part of that pathway and exists just about everywhere in the human body
-DMT is rapidly metabolized in the human body

(As an aside here, Barker et al have shown that after IV administration of DMT, a peak occurs within 10 to 15 min, and within 1 hr, only about 2% of the injected dose remains in the blood. Thus, when a random study of endogenous levels of DMT is taken and the levels are low in blood, it can be inferred that they were likely MUCH higher at some prior time due to these metabolic factors and likely sequestration into the brain. This is important in regards to the HOW MUCH question as all we are ever measuring is the after effects of whatever endogenous production is happening).

-Stress appears to sequester DMT into rodent brain neurotransmitter storage vesicles
-DMT can activate the Sigma-1 receptor to modulate the Na+ channels
(As an aside, this effect changes the firing time of these neurons, likely shortening it and increasing frequency, and thus is possibly implicated in generation of Gamma brain waves which are a hallmark of the ayahuasca experience.)


 
digitalvygr
#17 Posted : 1/11/2017 9:19:27 PM

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Very interesting article with various ideas about DMT formation in humans:

http://q4lt.com/measuring-dmt-formation-in-humans

Very detailed, and looks at this from many angles, highly recommended, should make for some great debate if nothing else on this subject.
 
dreamer042
#18 Posted : 1/12/2017 12:58:43 AM

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digitalvygr wrote:
Very interesting article with various ideas about DMT formation in humans:

http://q4lt.com/measuring-dmt-formation-in-humans

Very detailed, and looks at this from many angles, highly recommended, should make for some great debate if nothing else on this subject.

This was a fascinating read, thanks for posting it!

I'll need some time to digest the material and review the references, but it appears to to be a pretty thorough compilation of interesting data and correlations worthy of further investigation.

I suspect the author is a on the right track. Though I think his focus is too narrow. He's got it in his head that DMT is the only possible candidate here and is displaying a bit of confirmation bias in his interpretation of the research he cites. I'd expect pairing this data with the research on bufotenine, 5-MeO-DMT, and endogenous tryptolines/tetrahydro-beta-carbolines could yield quite fruitful results.
Row, row, row your boat, Gently down the stream. Merrily, merrily, merrily, merrily...

Visual diagram for the administration of dimethyltryptamine

Visual diagram for the administration of ayahuasca
 
digitalvygr
#19 Posted : 1/12/2017 2:29:10 AM

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dreamer042 wrote:
digitalvygr wrote:
Very interesting article with various ideas about DMT formation in humans:

http://q4lt.com/measuring-dmt-formation-in-humans

Very detailed, and looks at this from many angles, highly recommended, should make for some great debate if nothing else on this subject.

This was a fascinating read, thanks for posting it!

I'll need some time to digest the material and review the references, but it appears to to be a pretty thorough compilation of interesting data and correlations worthy of further investigation.

I suspect the author is a on the right track. Though I think his focus is too narrow. He's got it in his head that DMT is the only possible candidate here and is displaying a bit of confirmation bias in his interpretation of the research he cites. I'd expect pairing this data with the research on bufotenine, 5-MeO-DMT, and endogenous tryptolines/tetrahydro-beta-carbolines could yield quite fruitful results.


His overall site looks at a broader array of things, but in this post he is trying to summarize much of his disparate articles about DMT. But one he is working on right now for example has more to do with MAOIs and he notes that they could be as important as the tryptamines themselves:

http://q4lt.com/endohuasca-magic

 
dreamer042
#20 Posted : 1/12/2017 7:27:00 AM

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Now we are talking! Some of those studies are quite intriguing, especially the one about the 500% increase in melatonin levels in CSF after TBI. Also, the theories about the brain increasing tryptamine levels in the CSF of schizophrenics as a repairative/restorative mechanism from the other article are quite interesting.

I still feel the author is extremely heavily focused on DMT being responsible for dreams without sufficient evidence to support this hypothesis. There is actually a whole series of tryptolines present in the mammalian body that I'd suggest lend themselves better to the complex (inter)personal scenarios we tend to experience in the dreamstate as compared to fractaline hyperspacial scenarios of DMT/Bufo or the god-light space of 5-MeO. I'm particularly interested in the role beta-carboline-3-carboxylates may play in dreaming, for example.

I absolutely do believe that dimethyl-tryptamines are involved in the nighttime dreaming/endohuasca process. I just don't think they are the major player that many people want to believe them to be.

P.S. - The author's use of "irregardless" bugged the hell out of me, that's just bad grammar.
P.P.S. - The use of "interwebz" I support.
Row, row, row your boat, Gently down the stream. Merrily, merrily, merrily, merrily...

Visual diagram for the administration of dimethyltryptamine

Visual diagram for the administration of ayahuasca
 
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