review: endogenous N,N-dimethyltryptamines

[crOOk]

http://www.ncbi.nlm.nih.gov/pubmed/22371425

Abstract

Three indole alkaloids that possess differing degrees of psychotropic/psychedelic activity have been reported as endogenous substances in humans; N,N-dimethyltryptamine (DMT), 5-hydroxy-DMT (bufotenine, HDMT), and 5-methoxy-DMT (MDMT). We have undertaken a critical review of 69 published studies reporting the detection or detection and quantitation of these compounds in human body fluids. In reviewing this literature, we address the methods applied and the criteria used in the determination of the presence of DMT, MDMT, and HDMT. The review provides a historical perspective of the research conducted from 1955 to 2010, summarizing the findings for the individual compounds in blood, urine, and/or cerebrospinal fluid. A critique of the data is offered that addresses the strengths and weaknesses of the methods and approaches to date. The review also discusses the shortcomings of the existing data in light of more recent findings and how these may be overcome. Suggestions for the future directions of endogenous psychedelics research are offered. Copyright © 2012 John Wiley & Sons, Ltd.


Unfortunately, I don't have access to the journal (Drug Testing and Analysis). If anyone else does, I urge you to please let me have this article. Please please please please.

 

[alkap555]

Sorry man, my University doesn't subscribe to that particular journal...it's kinda obscure not to mention this study was performed at a school of VETERINARY medicine lol!

Testing doggy-derived tryptamines I guess.

 

[crOOk]

ye, mine neither. kinda hesitant to ask our head of physiology about it. he loves me and we have talked about sigma receptors and ceremonial dmt use before, but still its crystallizing out what my real interests are. the other day my physiology teacher asked me in front of the class why i am trying to find an answer to a particular question and he went "well since its you, i assume its drugs right?". he did so with a smile on his face, but still...

i wish we could have a sticky somewhere in add where every one lists what jounrals he has access too. i usually asked a prof, but not if its an overly sensitive subject (like a meta analysis of cutting agents in street drugs lol), i am naturally hesitant.

theres an EXCELLENT radioimaging study about how dmt is distritbuted within the rabbit after iv administration of dmt. seems it takes around ten seconds till over 90% of it has reached the brain. funnily excretion rates went on for 10 day or so. nobody knows exactly what happens after serotonergic receptors internelize the dimi. it has to reach our dear beloeved and yet so mysterious s1r's somehow, the study found some evidence that it gets packed up byvMAT2 (vesicular monoamine transporter 2) which might there be producted from even monoamino oxidases and maby evenn more relevant incontributing to it dmt's s breakdown. s1r translocated over from ER to cell membrare released to bind to sigma1r's, which then externalize to the cell membrane and do their magic ion channel modifications there. its still not entirely clear, but at least iv administration of dmt would suggest that somethiing similar could be going on in humans. itdsurely account for the rapid onset.

i hate that mckenna guy since he simply isnt working scientififally, bases his theories on wild spculations and does seem to enjoy building out-of-ass-truthes here and there. it just seems that hes been so damn right about so many thing already. zthe more i see the guy though, thr more im stsrting to rellay rellay want to find out more about both phyrmacodynamics, and -hidtppgy kinetics, that review wold be a good strting point.

same goes for that radioimaging rabbit study, ill see if i can dig it up eventhough ive posted it before. please write me whenever yoyu stumnle imnho. accoress a free

sometimes i have a feeling that whatever comes after sigma behinding, that thats were the real magic happens. its so far upstream from ion channels actualy opening that quite a few steps are still not very clear. we need a proper meta study and here it was (despide including the hot fidning in late 2011 whih arent included.) DMT is just so very different from all other psychedelics out there, id loce to believe that sr1 is playing a major role in self healing ("placebo") and tons of pyhsiatric problems. so curious of thge neea future.

hopefully we will see some work on this subject in the past ypl years.


if anyone DOES have access please let m have the article or ill have to get a one day pass or even by the whole boock

peace, fab

 

[alkap555]

You do know that Terence McKenna has been dead for 12 years right? Or are you referring to some other McKenna?

funnily excretion rates went on for 10 day or so

Excretion persists up to 10 days?! That I did not know. Can you post a link to that specific study? I just find that incredibly hard to believe for many reasons. First, its subjective effects are so damn short, and we all know that it's a substrate for MAO. Even if it were taken up by the VMAT2 and stored in vesicles (before MAO-A can catabolize it), I find it hard to believe that any vesicular contents wouldn't be "exocytosed" back into the cleft and chewed up by successive cycles of reuptake, vesicular packaging and release.

I'm not familiar with the time-course of vesicular release (or how long a filled vesicle could actually hang around without fusing), but the 10 days thing just seems crazy. The combined losses of DMT due to MAO-A, diffusion and who knows what else would lead me to believe that DMT is metabolized and excreted pretty damn quickly.

After all the effects only last ~15 min via intranasal, inhalation or parenteral. If I am incorrect in any of this please let me know...seems quite interesting

Okay after reading this paper (http://www.ncbi.nlm.nih.gov/pubmed/19278957) the proposed alternative theory for the activity of DMT goes something like this:

High cytosolic DMT concentrations associate with the sigma1R on the ER, causing it to dissociate from its chaperone. Then sigma1Rs are translocated to the plasma membrane, inhibiting ion channels (voltage-gated K+, Na+, Ca++ channel) and potentiating NMDARs, and via some currently unknown mechanism induces hallucinogenic effects.

This is all very interesting. Honestly, I hadn't really ever given much thought to the sigma1Rs. Unfortunately the type of pharmacology research I currently do is related to developing/characterizing radioligands selective for beta-amyloids plaques and Tau neurofibrillary tangles in Alzheimers.

I would LOVE to get into some medicinal chemistry/pharmacology related to the psychedelics. That's always been my goal. Unfortunately there isn't much research interest/funding in the psychedelic realm these days in the US, although hopefully that will change.

 

[bluedolphin]

Sniffing DMT lasts about an hour not 15 minutes.

 

[alkap555]

aight my bad, never had the opportunity to try it.

 

[crOOk]

You do know that Terence McKenna has been dead for 12 years right? Or are you referring to some other McKenna?

Yo I was very very high last night and deleted large parts of that post. I did not know he was dead, may he rest in hyperspace.

Excretion persists up to 10 days?! That I did not know. Can you post a link to that specific study? I just find that incredibly hard to believe for many reasons. First, its subjective effects are so damn short, and we all know that it's a substrate for MAO. Even if it were taken up by the VMAT2 and stored in vesicles (before MAO-A can catabolize it), I find it hard to believe that any vesicular contents wouldn't be "exocytosed" back into the cleft and chewed up by successive cycles of reuptake, vesicular packaging and release.

Or 14 days even? Not sure. I'll dig it up for you sure. pm me your email address, would you? Thing is, you do know sigma1 receptors are located in the ER right? That's where it seems the dimi binds and when that happens the proteine tranlocates to the cell membrane where it modifies the functions of other ion channels. I'm no expert on sigma physiology and little seems to be known about it though, so don't take everything I say for granted (which I'm sure you wouldn't anyway).

I'm not familiar with the time-course of vesicular release (or how long a filled vesicle could actually hang around without fusing), but the 10 days thing just seems crazy. The combined losses of DMT due to MAO-A, diffusion and who knows what else would lead me to believe that DMT is metabolized and excreted pretty damn quickly.

After all the effects only last ~15 min via intranasal, inhalation or parenteral. If I am incorrect in any of this please let me know...seems quite interesting

Okay after reading this paper (http://www.ncbi.nlm.nih.gov/pubmed/19278957) the proposed alternative theory for the activity of DMT goes something like this:

High cytosolic DMT concentrations associate with the sigma1R on the ER, causing it to dissociate from its chaperone. Then sigma1Rs are translocated to the plasma membrane, inhibiting ion channels (voltage-gated K+, Na+, Ca++ channel) and potentiating NMDARs, and via some currently unknown mechanism induces hallucinogenic effects.

This is all very interesting. Honestly, I hadn't really ever given much thought to the sigma1Rs. Unfortunately the type of pharmacology research I currently do is related to developing/characterizing radioligands selective for beta-amyloids plaques and Tau neurofibrillary tangles in Alzheimers.

I would LOVE to get into some medicinal chemistry/pharmacology related to the psychedelics. That's always been my goal. Unfortunately there isn't much research interest/funding in the psychedelic realm these days in the US, although hopefully that will change.

I don't know man. Cytosolic DMT concentrations should never get really high and it's dissociation constant is in the nanomolar range if I remember right. I've written more about this in another dmt thread. The vMAT2 thing is making a lot of sense.

Note: Serotonergic receptor activity seems to be very low during REM sleep. I find this a little ironic since McKenna suggested DMT to induce dreams and current evidence shows that dmt enters the cell through 5HT receptors. I'm not denying he could've been right there, but I'm really curious still where exactly the stuff is being pumped out or how individual neurons are signalled to produce it. I'll look for that radioimaging study now.


...Hehe 5 seconds later...

http://www.ncbi.nlm.nih.gov/pubmed/21622895

Abstract

N,N-dimethyltryptamine (DMT), a strong psychodysleptic drug, has been found in higher plants, shamanic hallucinogenic beverages, and the urine of schizophrenic patients. The aim of this work was to gain better knowledge on the relationship between this drug and hallucinogenic processes by studying DMT behavior in comparison with tryptamine.
METHODS:

(131)I-labeled DMT and tryptamine were injected into rabbits. γ-Camera and biodistribution studies were performed. Brain uptake, plasma clearance, and renal excretion were assessed for each indolealkylamine.
RESULTS:

DMT and tryptamine showed different behavior when brain uptake, residence time, and excretion were compared. Labeled DMT entered the brain 10 s after injection, crossed the blood-brain barrier, and bound to receptors; then it was partially renally excreted. It was detected in urine within 24 h after injection and remained in the brain, even after urine excretion ceased; up to 0.1% of the injected dose was detected at 7 d after injection in the olfactory bulb. In contrast, tryptamine was rapidly taken up in the brain and fully excreted 10 min after injection.
CONCLUSION:

To our knowledge, this is the first demonstration that exogenous DMT remains in the brain for at least 7 d after injection. Although labeled DMT and tryptamine behave as agonists for at least 5-hydroxytryptamine 2A receptor, 5-hydroxytryptamine 2C receptor, trace amine-associated receptor, and σ-1 putative receptor targets, binding to the latter can explain the different behavior of labeled DMT and tryptamine in the brain. The persistence in the brain can be further explained on the basis that DMT and other N,N-dialkyltryptamines are transporter substrates for both the plasma membrane serotonin transporter and the vesicle monoamine transporter 2. Furthermore, storage in vesicles prevents DMT degradation by monoamine oxidase. At high concentrations, DMT is taken up by the serotonin transporter and further stored in vesicles by the vesicle monoamine transporter 2, to be released under appropriate stimuli. Moreover, the (131)I-labeling proved to be a useful tool to perform long-term in vivo studies.

Gets into the cell through SERT (and maybe that other serotonin reuptake transporter) which would explain dmt's ridiculous effects when the subject has taken SSRI's. not sure if that has been looked at in rem sleep studies.

btw does the s1r dissociate when it translocates? i thought the whole proteine complex would translocate. not sure about the s1r structure and which subunits it even has... i relly need to read into sigma physiology.

Here's another for you
http://www.ncbi.nlm.nih.gov/pubmed/19756361



and this is kinda off topic (cancer and s2r's), but ill still post it in case someone is interested:
http://www.ncbi.nlm.nih.gov/pubmed/21050178
http://www.ncbi.nlm.nih.gov/pubmed/22065721
http://www.ncbi.nlm.nih.gov/pubmed/22551149

 

[endotropic]

To our knowledge, this is the first demonstration that exogenous DMT remains in the brain for at least 7 d after injection.

To me this conclusion seems like a bit of a jump. I don't think it's fair to generalize findings from 2-I-DMT to proper DMT, but maybe someone has done a comparison and found them identical, seems unlikely though.

 

[nuke]

I think it's unlikely too, the 2-I substituent is huge. If it were 2-2H then maybe, but the activity of the iodinated compound is probably very different from N,N-DMT

In fact I'm surprised that made it into the abstract of a journal with an impact factor of ~7, I guess that's what happens when pharmacists and not biochemists conduct and review these studies

 

[crOOk]

To me this conclusion seems like a bit of a jump. I don't think it's fair to generalize findings from 2-I-DMT to proper DMT, but maybe someone has done a comparison and found them identical, seems unlikely though.

Good point, I hadn't thought of that. It is at least plausible assuming DMT is packed into vesicles and stored intracellularly. I don't know too much about radiolabelling and I'm no chemist, but I guess labelling the DMT internally with some isotope wouldn't be all that difficult would it? What atom would be chosen by convention, one of the carbons? Isn't radiolabeled indole commercially available? I wonder why they chose to modify the molecule at position 2. Why use 2-I-DMT?
-Either they were trying to prove a point and knew the results would be different from what they'd have been if actual DMT had been used (gonna have to read into earlier publications of the team)
-or they lacked the financial means to acquire properly radiolabeled dmt (unlikely)
-or they didn't give it any thought (near impossible )

Would you even expect halogenation at c2 to have any effect on metabolism? Iodine is pretty bulky and electronegative, it should somehow modify protein binding, right? I'm really a noob on the subject, so some clearing up of this would be much appreciated.

Considering the small size of dmt and the relatively large modification, I am at a loss what to think about this study now... :/

 

[endotropic]

I'm really not sure how modifications at c2 will modify its metabolism/effects/localization, but I'm guessing they used [131]I because as I understand it can be detected at much lower concentrations than [14]C, and [3]H is much more liable to exchange making it harder to separate the signal (labeled DMT) from the noise (whatever it exchanged with).

 

[sekio]

This is all pharmacology. These are answers to the question, what does the drug do? A second point must be loudly mentioned here, one that concerns the questions, “How does it do what it does, and where does it go to do it?” Allow me to tell a tale based on an old, made up, Sufi legend.

The master asked the student, “How do you follow a guide who cannot be seen, who walks through a dark forest in the middle of the night?”

The student answers, “It is simple. Let him carry a light.”

“But then, ” answers the teacher, “He is no longer the guide who cannot be seen.”

“True, but at least I can now follow him, and I know where he goes.”

“You must be aware you are following a different guide?”

The student thinks for a minute, and then says, “Yes, of course I know that, but what else can I do?”

This is the sad plight of the research pharmacologist, who is trying to plot the in vivo course of a biochemical that cannot be followed. It must be labeled somehow, with a radioactive element, but nature demands that it is one that is not a normal part of its makeup. So he says, I would like to follow melatonin through the darkness of the body but I cannot see it as there is no light. I will attach a brilliant radioactive label to it, something like an iodine 125, so I can follow it as it goes here and there. The iodine is the light that the melatonin molecule is carrying, and the light can indeed be followed, but it is a different molecule. It is no longer melatonin, it is now 2-iodomelatonin. It is a completely different guide.

It is a sad story to tell, but this subtle shape-shifting is all too often invisible to the researcher. We will learn what melatonin does, by studying its radio-iodinated derivative. We will determine the quality of our synthetic analogs by measuring the displacement they make of iodinated melatonin from the melatonin receptor. Iodomelatonin is not melatonin. It is a different compound. It has a different biochemistry and a different pharmacology. It is used in melatonin studies only because it can be seen. Melatonin itself is, by its nature, a dark traveler in a dark forest, and we still do not know how to study it directly.

I think the reason they're using 2-I-DMT and not anything 'fancier' is because such methods were not in widespread use when the paper was authored. And I have a feeling that it is relatively easy to add a halogen at the 2' position. But the point still stands that 2-I-DMT is going to be a wildly more heavy and bulkier molecule than 'plain' DMT and by no means is a 1:1 substitution...

I would suggest 14C labeled DMT

 

[skillet]

Uh, it's from 2011

 

[sekio]

Woopsy

 

[alkap555]

Yea we use [125]I, [14]C and [3]H on our radioligands but only because they all demonstrate similar binding affinities. And we aren't tracking uptake or metabolism...ours are in the pipeline for clinical PET radioligands for imaging protein deposits. So these compounds aren't active, they just kinda stick to protein aggregates.

 

[crOOk]

Yea we use [125]I, [14]C and [3]H on our radioligands but only because they all demonstrate similar binding affinities. And we aren't tracking uptake or metabolism...ours are in the pipeline for clinical PET radioligands for imaging protein deposits. So these compounds aren't active, they just kinda stick to protein aggregates.

Well that would kinda confirm the theory proposed, the 7 day excretion interval might have been due to the modification of the molecule.

I would suggest 14C labeled DMT

Thanks for the info! Now I just need a rabbit and a lab.

Thymacetine.] EXPERIMENTAL THERAPEUTICS. B-55

Thymacetine. — An experimental research of the action of
thymacetine upon man has been instituted by E. Marandon de
Montyel,jfj3ofrom wliich the investigator draws the following inter-
esting conclusions : 1. Tliymacetine does not seem to exercise an
action on sleep, the intellect, the va^somotor system, the genital or-
gans, tlie secretions, or the intestines. 2. Thymacetine, without
influencing any of the other reflexes, produces in a few instances a
marked double dilatation of the pupil, but without disturbances of
vision, the symptom appearing during the first liour, and lasting
from thirty to forty minutes. 3. Tliymacetine sometimes produces
immediately after its administration, but only for a short time, how-
ever, dizziness, associated with a slight degree of intoxication. 4.
In three-fourths of the cases thymacetine causes a slight headache,
this lasting several hours, appearing usually at bed-time, and, rarely,
next morning on awakening. 5. Tliymacetine always increases,
for about two hours, muscular force, as measured by the dynamom-
eter, 6, Thymacetine increases the bodily temperature to about
one degree, the elevation, like the decline of the same, occurring
gradually, and returning to the normal point in about two hours.
7, Thymacetine, during a period of two hours, increases the niun-
ber of inspirations without modifying their rhythm. 8. The drug
also causes, during the same period of two hours, a rise of the arte-
rial pressure and an increase in the number of pulsations, but with-
out producing cardiac palpitations. 9. Thymacetine, in two-tliirds
of the cases, causes great lassitude toward the afternoon, which
often persists till the following day, even after awaking ; but there
are no concomitant physiological or psychological disturbances pro-
duced. 10. Thymacetine, in all cases, modifies micturition in three
ways : {a) it accelerates or delays the desire of urinating ; (Jj) it
causes a urethro-vesical spasm, a momentary retention, and dysu-
ria, but these disturbances soon disappear; (c) occasionally during
the passage of lu'ine a scalding sensation is felt, which also soon
disappears; these occur singly or in combination. 11. Exception-
ally before micturition thymacetine produces shooting urethral
pains. 12. Thymacetine, in two-thirds of the cases, causes a bitter
taste, accom[)anied with a sore mouth and a coated tongue, but no
special odor of the breath. 13. In most individuals thymacetine
produces, during an hour or more, a burning gastric pain, more
often localized, but sometimes felt all over the body ; rarely, a
scalding sensation is felt along the oesophagus. 14. Tliymacetine
is capable of producing marked thirst, anorexia, and also gastric
disturbances, wliich disa])pear on the suspension of the drug. 15.
In a general way the organs become rapidly accustomed to the
action of thymacetine, especially the bhidder and the urethra ; the
stomach, however, is the only organ to become more susceptible to
the in-tiuence of the remedy. 16. All tlie preceding physiological
actions are produced by small doses ; still, the sensation of dizzi-
ness, the temperature, digestion, and micturition are influenced in
direct proportion to the amount of the drug ingested.

I wasn't saying it would kick ass...