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  • N&PD Moderators: Skorpio

N,N-DMT is an endogenous sigma receptor regulator

Interesting! Now just to get rid of the pesky DA antagonism, the anticholinergic and whatever other reasons it has such terrible effect.
 
Carbolines responsible for aftereffects?

I think, it’s the haloperidole’s similarity to the pyrovalerones or MDPV.

Anyway I always asked myself whether ß-Carbolines, which are metabolites of DMT or 5-MeODMT, could contribute to the long lasting afterglow. Pinoline, which is a metabolite of 5-MeODMT is described as inhibitor of MAO and SERT. Additionally it is a naturally occurring compound in the brain.
Besides the fact, that MAOI and SERTI is a dangerous combo, has anybody speculations how a low single dose would feel?
 
I tried finding reference of serotonin syndrome induced by it in animals, but it either doesn't occur or they're using doses where it doesn't happen (I've seen as high as 8mg/kg)
 
Thanks for the note, maybe it would be the best to try it. Can you imagine that it could feel like the afterglow tranquility and clarity?
 
how is it that no one has synthed and played around with Pinoline to date at least as per any anecdotal reports?

or even tried very large dose melatonin?
 
Well, I've had up to 70mg (in powder, not pills!) orally and it didn't really do anything. I slept okay that night, but I didn't get tired or anything.

I suspect oral melatonin is either rapidly destroyed by MAO or has terrible oral BA for some other reason. Is this known? I imagine it is, but my son's in a terrible mood. I'll have to look later.
 
yes very poor bioavailability orally and hence by VERY large dose I am thinkingl one may need to be at 500-1000mg to engender Pinoline thresholds of worth

far less elegant than using Pin itself, but it is obviously readily at hand and cheap enough for someone to give a go to such levels or even higher as i do not think there is any danger
 
Is it destroyed by MAO though? I don't feel like going into A inhibition range, but that'd make it active if it was.
 
i believe it is largely destroyed by MAO-A, but with a high enough threshold some gets through

some people seem to feel some of the sleep aid effects at lowish doses, though that may be placebo largely and again indeed I believe the molecule has very poor bioavailability so a dose of 500mg+ would need to be tried to elicit thresholds that would engender significant pinoline levels
 
Garfinkel, Lauden, Nof and Zisapel (1995) did a randomized, double bind, crossover study in which they regulated the sleep quality of 12 elderly people. The melatonin used in the study was controlled release melatonin. Some of the participants were given 2 mg of melatonin for three weeks. Others were given a placebo for three weeks. There was a great improvement in the sleep of those who took the melatonin in comparison to those who took the placebo.
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About bioavailability: using 80 mg in a study this is said:
Peak serum melatonin levels, ranging from 350 to 10,000 times those occurring physiologically at nighttime, were observed 60-150 min after its administration, remaining stable for approximately 1.5 h.
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So even though BA may be 'a bit poor', relatively it is still enough to produce significant modulation.

This means I think that while pinoline levels may not be easily affected by administered melatonin, bioavailability per say is not the issue but the ineffective mechanism linking the two compounds.
 
PsychedelicPeptide said:
I wouldn't say they focused only on the sigma receptor because they wanted to "make their work seem cooler" though. The most important conclusion the paper comes to (as I, an unbiased observer, reads it) is that DMT is the likely endogenous regulator of sigma receptors in vivo. Although I don't think they directly show this despite their firm conclusion that it is indeed the case. DMT certainly has detectable activity at the sigma-1R, but whether it is the true endogenous agonist is not shown definitively (unless I missed something and just need to read it again...).
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Unfortunately, researchers in most academic disciplines are routinely forced to hype data in the unending fight to acquire more funding for research. Claiming DMT is the endogenous ligand for the Sigma-1 receptor seems like a bold claim given that:

Wikipedia said:
However, the concentrations of about 10 mg/l (50 µM) that is needed for sigma-1 activation is many orders of magnitude higher than physiologically observed concentrations and is also about two orders of magnitude higher than that needed to activate the 5-HT2A receptor
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Well perhaps we should reserve judgment until more is known about the workings of the sigma-1 receptors? Or how about this new Science Signaling paper that addresses a lot? =P

So my take home thinking is that we just don't know enough about the workings of the sigma-1 system to declare why the higher doses are needed for the activities. Is there any work published examining what concentrations of specifically DMT can get into the brain when you take MAOIs? Or what concentrations are achievable with the small DMT molecule when you take a big fat vaporizer hit of the stuff? This could be particularly important.

Another question could be, does the physical location of the sigma-1 receptor also play a role here-- that is, the neurons could be primarily located in a more readily accessible area of the brain. Hence this could also help achieve high concentration DMT in particular places. I should probably look up some more info on it... Additionally there is a possibility that a serotonin receptor itself could be what allows DMT to first enter the right cell type (rather than just through diffusion or non-specific uptake) and then accumulate to a higher local concentration and allow sigma-1 activity? It takes what a few seconds for a vaporizer hit to really kick in... is that long enough for 5-HTR-mediated uptake and then sigma-1 activity to start? Maybe not, but we can't disregard possibilities until the right mechanism is defined. Finally, with all the proteins involved in the system, there could be some serious allostery going on that definitely complicates the way molecules work with respect to each other.

:-)

http://stke.sciencemag.org/cgi/reprint/sigtrans;2/61/pe12.pdf -- if you have journal access. If not:

Sci Signal. 2009 Mar 10;2(61).
When the endogenous hallucinogenic trace amine N,N-dimethyltryptamine meets the sigma-1 receptor.
Su TP, Hayashi T, Vaupel DB.

Cellular Pathobiology Section, Cellular Neurobiology Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA.

N,N-dimethyltryptamine (DMT) is a hallucinogen found endogenously in human brain that is commonly recognized to target the 5-hydroxytryptamine 2A receptor or the trace amine-associated receptor to exert its psychedelic effect. DMT has been recently shown to bind sigma-1 receptors, which are ligand-regulated molecular chaperones whose function includes inhibiting various voltage-sensitive ion channels. Thus, it is possible that the psychedelic action of DMT might be mediated in part through sigma-1 receptors. Here, we present a hypothetical signaling scheme that might be triggered by the binding of DMT to sigma-1 receptors.
 
Does this imply that a whole slew of related tryptamines may also be sigma ligands? Wouldn't most 4-substituted tryptamines fit the pharmacophore as well?
 
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Are you talking about the same receptors DXM psychosis (plateau sigma) activates? That would explain some weird stuff.
 
plateau sigma??? you mean the 5th plateau???

Macropsia, in looking at the Science paper's structure-activity data, I find myself questioning why a compound like N-ethyltyramine is 10-fold more potent at sigma-1 binding, yet N-ethyltyramine is not a powerful psychedelic (correct me if I am wrong please?!) like DMT. Similarly a few other molecules they tested are very close in potency to DMT itself, yet they are also not known as powerful psychedelics and if anything just weak stimulants.

To me this raises a major red flag, and I am kind of surprised I just noticed this. It signals to me that something else besides sigma-1 activity is what permits DMT to have its psychedelic action; although it may be that action that permits DMT to exert the sigma-1 activity inside the cell that causes the psychedelia.

Actually at this point I am very confused to say the least. However I will reference my original idea that either another receptor or special diffusion property of DMT could be what allows it to get inside the right cells at high concentration to achieve the sigma-1 response. An alternative hypothesis is also that an allosteric property of DMT at the sigma-1 receptor causes a highly specific interaction to occur that allows the psychedelic response. I doubt that though, those other ligands are just so close in bindng potency (and one 10X better) and structure that this should be unlikely.

Then again the possibility that it could just all be a function of the serotonin receptors still exists... which would not bode well for these guy's reputations. I'm sure in a few years time we will know much more about this though.

The moral of the story: science is tricky sometimes. =)
 
I've got some articles on 1a/2a anatagonists (back before we had such selectivity) attenuating DMT's effect, but my understanding was that 2a was of minor significance (if any at all).
 
Are the antagonists true antagonists, as in 0% receptor activation? One must be careful in declaring that one molecule is a true full antagonist if they are not running a sufficiently sensitive bioassay. And this could skew their results & interpretations.

Do you have a title I can search for or anything? I'd be interested to see... I don't know much about 5-HTR antagonists unfortunately, or what little I've read has been since removed from memory in favor of information regarding larger GPCR modulators like peptides. =P
 
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