A group has very recently published a paper in Science dempnstrating dmt as a agonist ligand for the elusive sigma receptors. I haven't read through the paper yet, but it sounds quite intriguing. To be honest I had never heard about sigma receptors before, gotta do some homework to understand the implications of this finding.

Enjoy!

Hey this is nice find...the implications of this research are potentially understanding the role DMT plays physiologically such as why is it present in our bodies, what is its function, and possible insight into the DMT altered state that we all find intriguing. Thanks for the link

Sigma was initially thought to be an opiate receptor. A variety of compounds bind to and activate Sigma-1. Sigma-1 is not a g-coupled protein receptor, it is found intracellularly in the ER. This is a very interesting find.
The paper does show that DMT binds to and has activity at Sigma-1 however it does not show that endogenous DMT interacts with Sigma-1 in vivo. This is an important and necessary step towards understanding the function(s) of endogenous DMT. The information is good and Sigma-1 likely plays a role in the subjective effects of administered DMT what its role is with endogenous DMT only time will tell.

Also the authors ignored the fact that 5-MeO-DMT and Bufotenine are also dimethylated amines found in the mammalian CNS. Additionaly TAAR activty was down played as DMT has only been evaluated for binding at TAAR1, there are several other TAAR sites which DMT and other endogenous HA likely interact with. Hopefully these sites will also be evaluated, and endogenous DMT can be co-localized with these receptors.

The fact that sigma receptors are intracellular instead of membrane bound/asociated is indeed intriguing. This basically means these things to me:

1)dmt can be synthecised AND used within the cell, i.e. in cells may never actually secrete it.

2)dmt may actually enter the cell actively (via some tryptamine transporter similar to the reuptake of serotonin) to modify the actions of the cell(s) that uptake it. Would be nice to identify a membrane protein transporter that is "dedicated" to the dmt intake.

3)dmt passively gets inside the cell and acts on the sigma receptors by virtue of its lipophilicity. Something analogous is happening with the lipophilic hormones estrogen and progesterone; they diffuse through the plasma membrane and bind to their cognate intracellular receptors.

The latter may be able to explain some of the effects, (especially bodily effects) of smoked dmt. The freebased dmt should be able to cross cell membranes easily and interact with the sigma receptors.

All DMT is converted to the freebase form once absorbed. The form it takes at the receptor depends on the microenvironment of the protein.

It is indeed interesting Sigma-1 is found intracellularly, TAAR1 is also found intracellularly. Other TAAR sites are likely also. Many hallucinogens are known substrates for re-uptake transporters including DMT. Transport is most likely. Some would likely diffuse but the rapid rate of onset and intensity of effects would imply direct entry into the cells, if the effects do indeed result from binding at intracellular receptors. (Hormones have slow onset of action and exert effects over time).

It is important to realize that the authors did not prove that DMT is an endogenous transmitter at the Sigma-1 receptor. They merely showed that administered DMT binds to, activates, and mediates behavioral effects in mice via Sigma-1. Other research needs to be done to show endogenous interaction.

well, they haven't proved that endogenous dmt is a neurotransmitter either...they just showed evidence for it


scientists still don't know the specific function of sigma-1. they've merely observed that it's involved with NMDA signaling downstream, via ion-channel modulation.

excellent find, Infundibulum. this likely explains some of the dissociative feeling of the dmt experience (i had been wondering if some sigma binding was occurring...some of the sensations are reminiscent of my bouts with 'wet'

There is strong evidence to suggest DMT is a neurotransmitter. Look at Steve Barkers Endogenous Hallucinogen paper. It fits all of the known criteria for Neurotransmitter.

However the authors of the sigma paper in no way showed that endogenous DMT interacts with the sigma-1 receptor. They showed that administered DMT does. This is important, however it does not mean that endogenous DMT interacts with Sigma. .
Many other endogenous molecules have been shown to interact with Sigma-1, however more work will need to be performed to show what interaction are occurring in normal physiology.

Don't get to hyped on Sigma-1. The largest levels of expression are in the brainstem associated motor cortices. It is more likely involved in side effects of hallucinogens than desirable effects.

it makes me beyond happy to know that i have such intelligent "family" on this board....truly....although my degree is in kinesiology, brain chemistry was only shallowly and briefly skimmed over. i had no aptitude for it. i enjoy beyond measure, however, reading you guys batting this stuff around. rock on!

love and gratitude!

Regarding the effects of PCP, Sigma-1 is not likely to play a role in the subjective effects at all. Haloperidol (A sigma-1 antagonist) has been evaluated with ketamine. While it attenuates some effects the psychological effects are not effected. Thus NMDA activity or some other downstream affect are likely for the subjective effects of PCP (Wet) and ketamine but not Sigma-1.
Sigma-1 is likely only minorly involved in the subjective effects of any drugs. Many different psychoactive drugs with very different subjective effects bind to Sigma-1. Cocaine, opiates, DMT, progesterone and many other different drugs with different effects bind and activate this receptor.

http://www.springerlink....ntent/r7xm21flu9pvq97d/

http://www.physorg.com/news153670865.html

"Ruoho speculates that the hallucinogen's involvement may mean that the sigma-1 receptor is connected in some fashion to psychoactive behavior."

"addictive drug action" ? lol

and all this 'we injected dmt on mice and they became hyperactive, and hyperactive action is related to drug use and psychiatric problems', lol again

and what about ". Elevated levels of DMT and a related molecule have been found in the urine of schizophrenics. " . Wasnt this refuted already as any kind of significant generalizable relationship?


I love any research and more info on dmt.. But I really dislike that they always have use this 'drugs are bad we have to find out how to cure this problem' kind of justification for the research, and always generalize and put a negative spin to it.

I believe Straussman used a similar ruse to get his studies going as well...

probably because the funding comes from NIDA.

filter out the implications, and you see other correlations
*edit* oh shit...didn't realize that link refers to this paper should've known by the date

well, i'm still in favor of the chaperon/folding theory of sigma receptors; there's more to them than we know

Nice paper but yes as bufoman pointed out no in-vivo implications can be drawn yet.

nonsense.

the verdict still isn't in

Now I am a layment when it comes to scientific papers, but I'm 99.9999% they were directly asking all of us to smoke a lot more Spice.

recent relevant abstract
http://www.ncbi.nlm.nih.gov/pubmed/19278957

here you go:

yeah, that.

these studies suggest doing up fat rails of spice, st8 to the dome