FancyPants Posted March 4, 2015 Sorry can't copy paste the abstract (fucking ipad)... http://www.researchgate.net/profile/Ede_Frecska/publication/236339046_A_possibly_sigma-1_receptor_mediated_role_of_dimethyltryptamine_in_tissue_protection_regeneration_and_immunity/links/02e7e52c6816e599bd000000.pdf Very interesting stuff as I've had a lot of health issues regarding immune response (allergies/asthma); spinal cord injury from ischaemia on the anterior horn; severe hypoxia (medically induced opiate overdose). The latter inducing an event which could be explained by endogenous dmt release. Share this post Link to post Share on other sites
doxneed2c-me Posted March 5, 2015 Sigma receptors have always interested me greatly seems a number of nootropics hit these sites too and hence why I have always pondered about what other things might target them. Share this post Link to post Share on other sites
satyr Posted March 5, 2015 Abstract (full article available for free download)N,N-dimethyltryptamine (DMT) is classified as a naturally occurring serotonergic hallucinogen of plant origin. It has also been found in animal tissues and regarded as an endogenous trace amine transmitter. The vast majority of research on DMT has targeted its psychotropic/ psychedelic properties with less focus on its effects beyond the nervous system. The recent discovery that DMT is an endogenous ligand of the sigma-1 receptor may shed light on yet undiscovered physiological mechanisms of DMT activity and reveal some of its putative biological functions. A three-step active uptake process of DMT from peripheral sources to neurons underscores a presumed physiological significance of this endogenous hallucinogen. In this paper, we overview the literature on the effects of sigma-1 receptor ligands on cellular bioenergetics, the role of serotonin, and serotoninergic analogues in immunoregulation and the data regarding gene expression of the DMT synthesizing enzyme indolethylamine-Nmethyltransferase in carcinogenesis. We conclude that the function of DMT may extend central nervous activity and involve a more universal role in cellular protective mechanisms. Suggestions are offered for future directions of indole alkaloid research in the general medical field. We provide converging evidence that while DMT is a substance which produces powerful psychedelic experiences, it is better understood not as a hallucinogenic drug of abuse, but rather an agent of significant adaptive mechanisms that can also serve as a promising tool in the development of future medical therapies Share this post Link to post Share on other sites
Alchemica Posted March 7, 2015 (edited) Other psychoactive σ-1R agonists have been studied, too [1]: “…sigma-1 receptor ligands inhibited the production of pro-inflammatory cytokines IL-1β, IL-6, TNFα and the chemokine IL-8, while increased the secretion of the anti-inflammatory cytokine IL-10.” The study concluded that σ-1R ligands may act as “systemic endogenous regulators of inflammation and immune homeostasis through the sigma-1 receptors” and could be “harnessed for the pharmacological treatment of autoimmune diseases and chronic inflammatory conditions of the CNS or peripheral tissues” I'd much prefer using a less psychoactive, higher affinity, longer half-life and more therapeutically accessible sigma-1 agonist... Sure, the following aren't specific for the σ-1R but they still show promise. Something like DXM (Ki = 50-142 nM), fluvoxamine (Ki = 17 nM) or even donepezil (IC50 = 29.12 nM). DHEA is also another option (Ki = 706 nM), as is afobazole (IC50 = 7.1 μM) One study found that 60mg/day dextromethorphan (doses low enough for insignificant NMDA antagonism via the parent compound [dextromethorphan binds to several neurotransmitter receptors, notably and in rank order, to the serotonin transporter > sigma-1 receptor = norepinephrine transporter > NMDA receptor = mu opiate receptor [2]]) improved immunological parameters such as TNF-α, IL-6 and IL-1β and markers of inflammation in schizophrenic patients treated with an antipsychotic. There were significant reductions in schizophrenia symptoms, too. I'd guess similar doses could be used in other conditions...On the contrary, others would suggest a combination with quinidine "As dextromethorphan is a substrate of the cytochrome P450 enzyme 2D6 and is rapidly metabolized, oral administration of dextromethorphan by itself leads to rapid and unsustained peak levels of drug with a short duration of action. Oral administration of dextromethorphan alone is fully adequate for rapid- onset, short-duration antitussive actions and that is how it is dosed in various cough suppressants. However, oral administration of dextromethorphan alone does not lead to the sustained levels needed to substantially occupy neurotransmitter receptors in the brain without the need for frequent administration and high-peak doses associated with dissociative side effects. To solve this problem, dextromethorphan was reformulated in combination with a low dose of the cytochrome P450 2D6 inhibitor quinidine" See a review on σ-1Rs here One thing that should be mentioned is that some 5-HT2 receptor ligands also potently reduce inflammation, potentially at non-psychoactive doses [link]. "A highly selective agonist at serotonin 5-HT2 receptors super-potently inhibits tumor necrosis factor alpha (TNF-α) induced inflammation" Edited March 7, 2015 by Alchemica Share this post Link to post Share on other sites
FancyPants Posted March 9, 2015 (edited) Would something like quinidine be bad news for those with opiate dependancy? Given the P450 inhibition? I seriously have NO real understanding, and the more I think I'm vaguely getting something, the more I realise I know shit about squat. And if dextromethorphan were administered with an inhibitor which allowed it more therapeutic applicable levels, would that mean the risks associated with NMDA overstimulation (eg olney's lesions) were still as high? Also thanks heaps to all for the input Edited March 9, 2015 by FancyPants Share this post Link to post Share on other sites
Alchemica Posted March 9, 2015 (edited) I did have a nicely typed reply but managed to lose that... In general, avoid inhibiting CYP2D6 (or any other CYPs) while there are other substances in one's blood stream to worry about. Combining an inhibitor with a substrate [see here] will cause substrate levels to increase while some substrates (codeine, tramadol, oxycodone etc), as an example, are dependent on CYP2D6 mediated O-demethylation to form more active metabolites (so you'll get the side-effects of increased levels of parent compounds and the decreased efficacy due to decreased levels of the more active metabolite). There can be significant inter-individual differences in metabolism to consider, too. The use of DXM + quinidine is more aimed towards treatment-resistant depression where getting the therapeutic levels high enough for (some) NMDA antagonism along with the synergy of hitting a broad spectrum of other depression-related targets is likely to be beneficial. It's also promising for things like pseudobulbar affect. Seeing that study got beneficial results @60mg/day DXM without quinidine, it's likely that keeping it simple would be the way to go DM at a high dose (10 mg/kg) is an NMDA receptor antagonist (Ribeiro Do Couto, Aguilar et al. 2004; Ribeiro Do Couto, Aguilar et al. 2005). However, in the present study, patients took 60 mg/day (about 1 mg/kg), and their plasma DM concentrations ranged from 10–100 ng/ml (28–280 nM) (data not shown). Because DM is a weak NMDA receptor antagonist (ED50: 5–50 µM) (Church, Sawyer et al. 1994), DM in such low doses might be insufficient to block NMDA receptors. However, because low dose DM has an alternative mechanism of anti-inflammation and neurotrophic effects, using low-dose DM seems to be an ideal adjuvant strategy While there are distinctions between different NMDA antagonists; with regard to Olney's lesions, I'll stick with the most neutral statement and say:"based on some fundamental differences between rat biology and human biology and because there have only been very few studies done on the occurrence of Olney's lesions, no connection can currently be proved or disproved" [wiki] would that mean the risks associated with NMDA overstimulation (eg olney's lesions) were still as high Not sure. Seeing DXM is a pretty poor affinity NMDA antagonist and the CYP2D6-dependent metabolite DXO is more potent, maybe not? Nonetheless, many can attest to the side-effects of heavy dissociative use, so I'm not saying it's safe Sub-chronic/chronic NMDA antagonism is a good animal model for schizophrenia if nothing else... While 60mg/day DXM is unlikely to pose any problems (unless one is on a MAOI), it's worth considering other σ-1R agonists for long-term use.Fluvoxamine has issues with regard to CYP1A2 inhibition so similar drug-drug interaction considerations need to be made Edited March 9, 2015 by Alchemica 1 Share this post Link to post Share on other sites
