DMT, Sigma Receptor Ligand?

[Ernestrome]

Society for Neuroscience Abstracts, 34, 660.10 (2008)


N,N-dimethyltryptamine (DMT) as an endogenous ligand candidate for the sigma receptor.


Dominique Fontanilla,1 Molly Johannessen,2 Abdol R. Hajipour,3 Arindam Pal,1 Nicholas V. Cozzi,1 Meyer B. Jackson,2 Arnold E. Ruoho1



1Department of Pharmacology, University of Wisconsin School of Medicine and Public Health, 1300 University Avenue, Madison, WI 53706
2Department of Physiology, University of Wisconsin School of Medicine and Public Health, 1300 University Avenue, Madison, WI 53706
3Pharmaceutical Research Laboratory, College of Chemistry, Isfahan University of Technology, Isfahan 84156, IR Iran



Abstract

Sigma-1 receptor involvement in higher brain function and in the pathology of neurological and psychiatric disorders has made it a potential therapeutic target. Therefore, since the discovery of the sigma-1 receptor, much of the focus has involved sigma-1 ligands, which include cocaine, (+)-pentazocine, (+)-N-allylnormetazocine ((+)SKF-10047), and haloperidol. Endogenous ligands for the sigma receptor are currently unknown. Interestingly, endogenous N,N‑dimethylated trace amines closely resemble a pharmacophore modeled after the chemical structures of known sigma‑1 ligands. N,N-dimethyltryptamine (DMT), the N,N-dimethylated trace amine derived from decarboxylated tryptophan, was first reported to exist naturally in brain tissue by Julius Axelrod (1972) and is of particular interest as it is hallucinogenic and is found at elevated levels in the urine of patients with psychiatric disorders. Along with other non‑methylated, mono-methylated, and di-methylated trace amines, we tested binding affinities for the sigma-1 receptor by competitive displacement of [3H]-(+)-pentazocine. Binding was further verified by DMT protection of photolabeling of the sigma-1 receptor by 1‑N‑(2',6'‑dimethylmorpholino)-3-(4-azido-3-[125I]iodophenyl)propane ([125I]IAF). Functional studies include DMT inhibition of sodium hNav1.5 channels in HEK-293 cells, COS-7 cells, and wildtype and sigma-1 receptor knockout neonatal mouse cardiac myocytes. Additionally, we examined the effects of DMT-induced hypermobility in wildtype (WT) mice as compared to sigma-1 receptor knockout (KO) mice. Our results indicate that DMT has a sigma-1 KD of 14.8 mM and a sigma-2 KD of 21.7 mM. N,N-dimethylphenethylamine and N,N-dimethyltyramine were also found to inhibit [3H]-(+)-pentazocine at low micromolar concentrations. In addition, these ligands were able to specifically protect photolabeling in a manner parallel to their binding affinities. DMT (100 mM) significantly inhibited sodium hNav1.5 channels in HEK-293 cells (62 ± 3%) and in COS-7 cells (22 ± 4%). In WT mouse neonatal cardiac myocytes, DMT (100 mM) inhibited hNav1.5 channel current 29 ± 3%, which was reduced to 7 ± 2% inhibition in sigma-1 KO mouse neonatal cardiac myocytes. DMT (4 mg/kg, i.p.) also induced a hypermobility response in WT mice that was completely absent in sigma-1 KO mice. Our binding, physiological, and behavioral data support the hypothesis that DMT acts as an endogenous ligand at sigma receptors.

http://www.neurophys.wisc.edu/~cozzi/sfnabs34b.html

 

[Limpet_Chicken]

Its about time we discovered an endogenous ligand for sigma.

Its interesting that sigma knockout mice don't display any overt phenotype.

 

[Tsukasa]

I believe DHEA could also be a ligand for the sigma 1 receptor.

 

[Riemann Zeta]

I spoke with the investigators at Neuroscience 08 in some length about this work. The assays were fairly solid, but my concern (or critique) was the extremely high Ki values for DMT at the receptor. Binding in the 100 uM - 10 mM range is an extremely weak affinity, extremely. I have a very hard time believing that endogenous DMT concentrations would ever shoot up into the mM range in vivo. DHEA and pregnenelone have much better sigma affinities--like <100nM. So while a taking a shitload of smoked/IV DMT might tickle those sigma receptors, I doubt the mystery of the endogenous ligand has been solved.

 

[crOOk]

I spoke with the investigators at Neuroscience 08 in some length about this work. The assays were fairly solid, but my concern (or critique) was the extremely high Ki values for DMT at the receptor. Binding in the 100 uM - 10 mM range is an extremely weak affinity, extremely. I have a very hard time believing that endogenous DMT concentrations would ever shoot up into the mM range in vivo. DHEA and pregnenelone have much better sigma affinities--like <100nM. So while a taking a shitload of smoked/IV DMT might tickle those sigma receptors, I doubt the mystery of the endogenous ligand has been solved.

The Kd's of DMT for the two known sigma receptors do not really allow conclusions about it's significance as an endogenous sigma receptor ligand and I am surprised the investigators haven't specifically mentioned that.

Let's do a calculation here without any additional data. Assuming the endogenously produced dmt stays considerably below the dosage level needed to induce the mystical experience, we can calculate the plasma concentration, that can be reached by administering 25mg DMT through whichever method, but generously assuming 100% bioavailability.
Using a representative blood volume of 5 liters for the calculation and using dmt's molar mass of 188,27g/mol we end up with the following plasma concentration:
50mg / 188,27g/mol / 5l = 2,7umol/l.

DMT has a dissociation constant (Kd) of 14.8 uM for s1r, meaning a concentration of 14.8uM/l in direct proximity to the receptors will result in 50% of the DMT being bound to the receptor, while the other 50% are still floating around freely. Now a plasma concentration of 2,7umol/l is about 20% of the amount needed for 50% of the transmitter to be s1r bound. Quite low you say for dmt to act as a sigma receptor ligand, but not unrealistically low for dmt to still have a high significance as one...

Let's consider the following:
-The sigma receptor is found within the cell, specifically on the ER membrane. We could therefore safely assume that IF it's primary function within the human body IS sigma activation, there would be mechanisms to transport it into neurons/other cells. This could guarantee very high local peak activities, rendering the Kd value almost useless for our understanding of dmt's physiological significance. It would merely represent an orientation of the minimum plasma concetrations needed assuming even distribution throughout the body and a receptor located on the plasma membranes.
-Let's also assume DMT is NOT secreted through endocrine mechanisms, meaning it will not have to spread out over a whopping 5 liters of blood. Even with endocrine secretion mechanisms we could still assume that the substance is not distributed evenly in the body, but is instead through whatever mechanism transported to specific organ systems. I will later get to the specific pharmacokinetics of dmt in our organism, these are still just considerations, nothing more.
-Some transmitters are stored in vesicles after endocytosis and can be released at specific target sites, guaranteeing a huuuuge difference between activities in direct proximity to it's proteine target vs. plasma activity.
-Taking all these possibilities (and some more I haven't mentioned) into consideration, we can easily imagine that dmt can in fact very well be an endogenous ligand for sigma receptors and one of significance at that.


Now... Let's get to the newest findings regarding this issue. For fairness sake I'll post the abstracts in this thread and not in my own (which was created 2yrs later :D).

The pharmacodynamics of DMT are discussed in detail in the following study. They have been deducted from marking of DMT with radioactive iodine prior to intravenous administration into the organism of a rabbit. Rabbits are not able to metabolise alpha-substituted monoamines like humans and there are a few more tiny holes in this study I will spare to mention. Nonetheless it is an excellent article demonstrating that
A) 87,5% of plasma DMT is in fact taken up by the bunny brain within seconds time;
B) SERT transports DMT into neuronal cells;
C) Monoamine transporter 2 stores dmt in vesicles once it reached the intracellular space.

Impressed? I surely am. Here comes the quoted abstract:

In Vivo Long-Term Kinetics of Radiolabeled N,N-Dimethyltryptamine and Tryptamine
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: 131I-labeled DMT and tryptamine were injected into rabbits. g-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

Source: Arturo A. Vitale, Alicia B. Pomilio, Carlos O. Canellas, Martín G. Vitale, Eva Maria Putz and Jorge Ciprian-Ollivier
DOI: 10.2967/jnumed.110.083246

Here comes another study which doesn't really add that much proof to the question at hand, but is nonetheless an excellent article to say the least! I'll let it speak for itself

The Hallucinogen N,N-Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor Regulator
Abstract:
The sigma-1 receptor is widely distributed in the central nervous system and periphery. Originally mischaracterized as an opioid receptor, the sigma-1 receptor binds a vast number of synthetic compounds but does not bind opioid peptides; it is currently considered an orphan receptor. The sigma-1 receptor pharmacophore includes an alkylamine core, also found in the endogenous compound N,N-dimethyltryptamine (DMT). DMT acts as a hallucinogen, but its receptor target has been unclear. DMT bound to sigma-1 receptors and inhibited voltage-gated sodium ion (Na+) channels in both native cardiac myocytes and heterologous cells that express sigma-1 receptors.
DMT induced hypermobility in wild-type mice but not in sigma-1 receptor knockout mice. These biochemical, physiological, and behavioral experiments indicate that DMT is an endogenous agonist for the sigma-1 receptor.

Source: Dominique Fontanilla, Molly Johannessen, Abdol R. Hajipour, Nicholas V. Cozzi, Meyer B. Jackson, Arnold E. Ruoho
DOI: 10.1126/science.1166127

If anyone needs help on acquiring the full versions of these articles or additional information on the pharmacology of sigma receptors or their clinical significance write me a private message and I will try to do my best. I've got a shitload more for those interested, it is a very promising and (to me personally) one of the most fascinating research fields of today. I personally assume (mere hunch/opinions) a role of high importance of sigma receptors in what human kind often most ignorantly describes as an isolated phenomenom called "placebo effect", but which more open minded, observing people will view as an aspect of our bodies' ability to heal itself to a much more efficient degree (though much less reliably) than many therapeutic interventions of modern western medicine can.

I have abstained from posting any information regarding the receptor's currently presumed role in pathological processes, but let's just say that selective sigma agonists are currently being investigated for their potential use in heart failure, depression (s1r) and all types of cancer (s2r). While there aren't any placebo controlled double blind randomised trials being conducted as of yet there have been case control studies on readily prescribed pharmaceuticals that have sigma activity additionally to their primary mode of action, specifically in 'broken heart' - patients. With promising results to say the least.

 

[crOOk]

On a sidenote: You gotta love the fact that this thread on dmt has less than 400 views while the designer opioid thread has 12k views lol. :D Humanity will never ever get things right I guess! (Not saying I don't love opioids and have to fight my urge to use them every single day for the rest of my life, so please don't feel insulted by that remark, fellow opiophiles).

 

[yoyoman]

Your back! (crOOk). Yer not on aim miss our chats lot of crazy life shit has happened. yeah opiates are the worst to get into, if your going to get into drugs..

 

[freedstar]

On a sidenote: You gotta love the fact that this thread on dmt has less than 400 views while the designer opioid thread has 12k views lol. :D Humanity will never ever get things right I guess! (Not saying I don't love opioids and have to fight my urge to use them every single day for the rest of my life, so please don't feel insulted by that remark, fellow opiophiles).

You got that right!!

@crOOk Very interested in this, do you have any links to share?