. A growing number of studies indicate that the psychotherapeutic potential of ayahuasca is based mostly on the strong serotonergic effects, whereas the sigma-1 receptor (Sig-1R) agonist effect of its active ingredient dimethyltryptamine raises the possibility that the ethnomedical observations on the diversity of treated conditions can be scientifically verified. Moreover, in the right therapeutic or ritual setting with proper preparation and mindset of the user, followed by subsequent integration of the experience, ayahuasca has proven effective in the treatment of substance dependence. This article has two important take-home messages: (1) the therapeutic effects of ayahuasca are best understood from a bio-psycho-socio-spiritual model, and (2) on the biological level ayahuasca may act against chronic low grade inflammation and oxidative stress via the Sig-1R which can explain its widespread therapeutic indications. http://www.ncbi.nlm.nih.gov/pubmed/26973523

A variety of specific physiological functions have been attributed to the σ1 receptor. Chief among these are modulation of Ca2+ release, modulation of cardiac myocyte contractility, and inhibition of voltage gated K+ channels.[13] The reasons for these effects are not well understood, even though σ1 receptors have been linked circumstantially to a wide variety of signal transduction pathways. Links between σ1 receptors and G-proteins have been suggested such as σ1 receptor antagonists showing GTP-sensitive high affinity binding,[14] there is also, however, some evidence against a G-protein coupled hypothesis.[15] The σ1 receptor has been shown to appear in a complex with voltage gated K+ channels (Kv1.4 and Kv1.5), leading to the idea that σ1 receptors are auxiliary subunits.[16] σ1 receptors apparently co-localize with IP3 receptors on the endoplasmic reticulum.[17] Also, σ1 receptors have been shown to appear in galactoceramide enriched domains at the endoplasmic reticulum of mature oligodendrocytes.[18] The wide scope and effect of ligand binding on σ1 receptors has led some to believe that σ1 receptors are intracellular signal transduction amplifiers.[9] -wikipedia

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. http://www.ncbi.nlm.nih.gov/pubmed/19213917

An endogenous ligand for the σ1 receptor has yet to be conclusively identified, but tryptaminergic trace amines, as well as neuroactive steroids such as dehydroepiandrosterone (DHEA) and pregnenolone all activate the receptor. -Wikipedia

In recent years, knowledge of the storage, receptors and metabolism of DMT has increased. Riba et al. [37] measured DMT metabolites in volunteers who received DMT orally and concluded that oxidative deamination of DMT by MAO may not be the sole metabolic pathway in humans. In vitro and animal studies have found endogenous psychedelic tryptamines in humans [38] and also found tryptamine metabolites in the pineal gland [39]. In addition to DMT, 5-hydroxy-DMT (bufotenin, HDMT) and 5-methoxy-DMT (MDMT) have been reported as endogenous substances in humans. Mcllhenny et al. [40] described N-oxidation, N-demethylation and cyclization as alternative DMT metabolic routes. Full characterization of DMT metabolites is required for cell biochemical and biology studies and also from pharmacological and toxicological points of view given the increasing interest in the potential medical applications of Ayahuasca

Full characterization of DMT metabolites is required for cell biochemical and biology studies and also from pharmacological and toxicological points of view given the increasing interest in the potential medical applications of Ayahuasca

Although direct causation cannot be established, these data suggest that regular use of psychedelic drugs could potentially lead to structural changes in brain areas supporting attentional processes, self-referential thought, and internal mentation. These changes could underlie the previously reported personality changes in long-term users and highlight the involvement of the PCC in the effects of psychedelics.

Bouso JC, Palhano-Fontes F, Rodríguez-Fornells A, Ribeiro S, Sanches R, Crippa JA, Hallak JE, de Araujo DB, Riba J.
“Long-term use of psychedelic drugs is associated with differences in brain structure and personality in humans”.
Eur Neuropsychopharmacol. 2015 Jan 31;.

Psychedelic agents have a long history of use by humans for their capacity to induce profound modifications in perception, emotion and cognitive processes. Despite increasing knowledge of the neural mechanisms involved in the acute effects of these drugs, the impact of sustained psychedelic use on the human brain remains largely unknown. Molecular pharmacology studies have shown that psychedelic 5-hydroxytryptamine (5HT)2A agonists stimulate neurotrophic and transcription factors associated with synaptic plasticity. These data suggest that psychedelics could potentially induce structural changes in brain tissue. Here we looked for differences in cortical thickness (CT) in regular users of psychedelics. We obtained magnetic resonance imaging (MRI) images of the brains of 22 regular users of ayahuasca (a preparation whose active principle is the psychedelic 5HT2A agonist N,N-dimethyltryptamine (DMT)) and 22 controls matched for age, sex, years of education, verbal IQ and fluid IQ. Ayahuasca users showed significant CT differences in midline structures of the brain, with thinning in the posterior cingulate cortex (PCC), a key node of the default mode network. CT values in the PCC were inversely correlated with the intensity and duration of prior use of ayahuasca and with scores on self-transcendence, a personality trait measuring religiousness, transpersonal feelings and spirituality. Although direct causation cannot be established, these data suggest that regular use of psychedelic drugs could potentially lead to structural changes in brain areas supporting attentional processes, self-referential thought, and internal mentation. These changes could underlie the previously reported personality changes in long-term users and highlight the involvement of the PCC in the effects of psychedelics.

Understanding the brain's function properly would require widening the search beyond the physical. Evidence for non-physical existence - OBEs, NDEs, that sort of thing - is there, but how do non-physical mind and physical brain interact? Or is that something that may be a bit too tricky for science with its current materialist paradigm?

Is sigma-1 receptor agonism the meat of Ayahuasca's healing potential? Or does it play a role in liberating consciousness from its limitations? Life is weirder than it seems... seems so simple, that we can know that poking this receptor or that can cause certain effects... but one thing we still don't understand, scientifically, is why and how these receptors intrinsically work. Fascinating stuff, but I feel that the answers lie beyond the physical.

Just some mumbling thoughts... I hope it's relevant.

Although direct causation cannot be established, these data suggest that regular use of psychedelic drugs could potentially lead to structural changes in brain areas supporting attentional processes, self-referential thought, and internal mentation. These changes could underlie the previously reported personality changes in long-term users and highlight the involvement of the PCC in the effects of psychedelics.

Bouso JC, Palhano-Fontes F, Rodríguez-Fornells A, Ribeiro S, Sanches R, Crippa JA, Hallak JE, de Araujo DB, Riba J.
“Long-term use of psychedelic drugs is associated with differences in brain structure and personality in humans”.
Eur Neuropsychopharmacol. 2015 Jan 31;.

read this study on the sigma-1 receptor agonism as well several months ago, still don't know what this receptor is or what it does, fascinating stuff though.

The orphan receptor sigma-1 (sigmar-1) is a transmembrane chaperone protein expressed in both the central nervous system and in immune cells. It has been shown to regulate neuronal differentiation and cell survival, and mediates anti-inflammatory responses and immunosuppression in murine in vivo models.
http://journals.plos.org...371/journal.pone.0106533

Here we demonstrate for the first time the immunomodulatory potential of NN-DMT and 5-MeO-DMT on human moDC functions via sigmar-1 that could be harnessed for the pharmacological treatment of autoimmune diseases and chronic inflammatory conditions of the CNS or peripheral tissues. Our findings also point out a new biological role for dimethyltryptamines, which may act as systemic endogenous regulators of inflammation and immune homeostasis through the sigma-1 receptor.

Since the details of these findings have not been elucidated so far, we studied the effects of the endogenous sigmar-1 ligands N,N-dimethyltryptamine (NN-DMT), its derivative 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and the synthetic high affinity sigmar-1 agonist PRE-084 hydrochloride on human primary monocyte-derived dendritic cell (moDCs) activation provoked by LPS, polyI:C or pathogen-derived stimuli to induce inflammatory responses. Co-treatment of moDC with these activators and 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 T-cell activating capacity of moDCs was also inhibited, and dimethyltryptamines used in combination with E. coli or influenza virus as stimulators decreased the differentiation of moDC-induced Th1 and Th17 inflammatory effector T-cells in a sigmar-1 specific manner as confirmed by gene silencing. Here we demonstrate for the first time the immunomodulatory potential of NN-DMT and 5-MeO-DMT on human moDC functions via sigmar-1 that could be harnessed for the pharmacological treatment of autoimmune diseases and chronic inflammatory conditions of the CNS or peripheral tissues.

The ability of sigma receptor antagonism to mitigate the actions of many drugs of abuse suggests that these receptors represent a common medication development target for a variety of classes of abused substances. The modulatory role of sigma receptors, particularly the σ1-subtype, in the body and their tendency to normalize cellular functions makes them an attractive medication development lead. The modulatory role allows σ1-receptor ligands to intervene in a wide variety of situations and functional states, including in the presence of drugs of abuse. At the same time, they produce few effects under normal conditions and have a low side-effect liability, resulting in a class of drugs that would be expected to have a favorable therapeutic and safety margin. The existing preclinical data indicate that sigma receptor ligands have the potential to treat various aspects of drug abuse, including the reversal of acute toxic overdoses, prevention of relapse and compensation for pathological neuroadaptations and behaviors that result from repeated drug exposures.
http://www.ncbi.nlm.nih....C3662539/?report=classic

Sigma receptors (sigma-1 and sigma-2) represent two independent classes of proteins. Their endogenous ligands may include the hallucinogen N,N-dimethyltryptamine (DMT) and sphingolipid-derived amines which interact with sigma-1 receptors, besides steroid hormones (e.g., progesterone) which bind to both sigma receptor subpopulations. The sigma-1 receptor is a ligand-regulated molecular chaperone with various ion channels and G-protein-coupled membrane receptors as clients. The sigma-2 receptor was identified as the progesterone receptor membrane component 1 (PGRMC1). Although sigma receptors are over-expressed in tumors and up-regulated in rapidly dividing normal tissue, their ligands induce significant cell death only in tumor tissue. Sigma ligands may therefore be used to selectively eradicate tumors. Multiple mechanisms appear to underlie cell killing after administration of sigma ligands, and the signaling pathways are dependent both on the type of ligand and the type of tumor cell. Recent evidence suggests that the sigma-2 receptor is a potential tumor and serum biomarker for human lung cancer and an important target for inhibiting tumor invasion and cancer progression. Current radiochemical efforts are focused on the development of subtype-selective radioligands for positron emission tomography (PET) imaging. Right now, the mostpromising tracers are [18F]fluspidine and [18F]FTC-146 for sigma-1 receptors and [11C]RHM-1 and [18F]ISO-1 for the sigma-2 subtype. Nanoparticles coupled to sigma ligands have shown considerable potential for targeted delivery of antitumor drugs in animal models of cancer, but clinical studies exploring this strategy in cancer patients have not yet been reported. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.
Copyright © 2014 Elsevier B.V. All rights reserved.
http://www.ncbi.nlm.nih.gov/pubmed/25173780

http://www.ncbi.nlm.nih.gov/pubmed/25510962
The sigma-1 receptors are present in monomeric and oligomeric forms in living cells in the presence and absence of ligands.

Based on the current understanding of the cell biological actions of Sig-1Rs (34, 35, 38 ), we propose a hypothetical scheme for the molecular mechanism by which DMT signals through sigma-1 receptors (Fig. 1). Like other Sig-1R agonists (34), DMT at affinity concentrations (14 μM) (24) might cause the dissociation of Sig-1Rs from the Sig-1R-BiP complex (34, 35) (Fig. 1A), and at higher concentrations (100 μM) (24) might cause Sig-1Rs to translocate from the MAM to the plasma membrane (36, 37) (Fig. 1B). By doing so, DMT might first unleash the chaperone activity of the free form of Sig-1Rs at the MAM (34) and then cause the receptors to translocate (36, 37) to the plasma membrane to inhibit voltage-gated ion channels (24, 38–42). We do not know at present whether the chaperone activity of Sig-1Rs contributes to ion channel inhibition or whether Sig-1Rs associate with ion channels at the subplasma ER membrane or at the plasma membrane. Nor do we know whether the chaperone-unleashing action seen at affinity concentrations of DMT or the ion channel–inhibiting action caused by high concentration of DMT relate to the psychedelic effect induced by DMT. More studies are needed to provide answers to these questions.

http://www.ncbi.nlm.nih....C3155724/?report=classic

The following is a detailed functional analysis:
“DMT binds to the sigma-1 receptor, which provides new opportunities for understanding how ayahuasca may produce its marked effects on the body and mind and what might be the role of endogenous DMT and how ayahuasca may have effects on cancer.
The human sigma-1 receptor has been cloned and shows no homology with other mammalian proteins. Single-photon emission tomography (SPET) analysis in humans revealed that these receptors are present in organs such as the lung and liver and most concentrated in the brain. Sigma-1 receptor activity has been implicated in a variety of diseases, including cancer, depression, and anxiety. Sigma-1 receptors are found in high densities in many human cancer cell lines, including lung, prostate, colon, ovaries, breast, and brain; thus, sigma ligands are regarded as potential novel antineoplastic tools.”

“DMT binds sigma-1 receptors with moderate affinity (KD = 14.75 µM, approximately half the affinity for 5-HT1A and 5-HT2A receptors) and, at high concentrations, is also capable of inhibiting voltage-gated sodium channels. Thus, DMT may exert two types of effects through sigma-1 receptors: at low concentrations, it regulates calcium flow from the ER to the mitochondria, whereas at higher concentrations, it exerts diverse effects at the plasma membrane region. The effect on calcium influx into the mitochondria may be extremely important for cancer treatment given that an energetic imbalance between excessive cytosolic aerobic glycolysis and reduced mitochondrial oxidative phosphorylation (the Warburg effect) was recently suggested as the seventh hallmark of cancer. This metabolic profile of cancer cells is accompanied by a hyperpolarization of the mitochondrial membrane potential that may be reduced by the calcium influx triggered by DMT binding to the sigma-1 receptor at the MAM. This effect may facilitate the electrochemical processes at the electron transport chain inside the mitochondria, thus increasing the production of reactive oxygen species (ROS) and leading these cells to apoptotic pathways. When high DMT concentrations induce sigma-1 receptor translocation to the plasma membrane, many cellular effects would occur due to the receptor’s interaction with different ion channels. At high concentrations of DMT, a calcium influx and mitochondrial membrane depolarization might be enough to also activate the permeability transition pore (PTP), inducing mitochondria swelling, rupture, and apoptosis.

For all these effects to help explain the available case reports of ayahuasca on cancer treatment, DMT’s physiological degradation by enteric monoamine oxidase (primarily MAO-A) after oral consumption should be inhibited, thus allowing the DMT to pass into circulation. The pharmacological activity of β-carbolines (primarily harmine) in ayahuasca inhibits MAO, with a high affinity for MAO-A. Therefore, the specific effects of ayahuasca on the different types of cancer could also vary depending on the predominant MAO subtype, given that the ratio of MAO-A to MAO-B varies, for example, from 1:3 in the brain to 4:1 in the intestine, and the placenta has only MAO-A and blood platelets have only MAO-B. Another consequence of inhibiting MAO in different tissues is interference with apoptotic pathways, thus strengthening the synergistic action of β-carbolines and DMT.

In addition to allowing DMT to exert its effects on cancer tissues and cells, β-carbolines may have other important roles. It was recently demonstrated that harmine activates pathways of apoptosis in B16F-10 melanoma cells; it inhibits tumor-specific neo-vessel formation, both in vitro and in vivo in mice, through a series of mechanisms involving decreased serum levels of pro-angiogenic factors and an increase in antitumor factors and displays an inhibitory effect on cell proliferation against human carcinoma cells. Harmine and harmaline were also shown to reduce cell proliferation in the human leukemia cell line HL60. Harmine was also shown to induce apoptosis in the human hepatocellular carcinoma cell line HepG2. Harmine may also be beneficial in cancer treatment due to its inhibitory effect on the DYRK1A kinase. This kinase is implicated in the resistance of many cancerous tissues to pro-apoptotic stimuli and the enhancement of proliferation, migration, and reduced cell death. Another pharmacological effect of harmine that may be important in brain cancer is its role on the EAAT2 glial glutamate reuptake transporter. Harmine was identified as one the most efficient molecules to upregulate this transporter in glial cells among a library of 1040 Food and Drug Administration (FDA)-approved substances. This fact may be of importance because most brain tumors are of glial origin and involve excessive glutamate release, causing neurotoxicity. Also important for gliomas may be the binding of harmine to imidazoline I2 receptors. These receptors are highly expressed in gliomas, and their density increases with malignancy in human cells. However, their physiological role in these tissues remains unclear.

A recent study has shown that DMT inhibits the indoleamine 2,3 dioxygenase enzyme. This enzyme, when upregulated, is associated with malignant cells escaping immune surveillance, and thus DMT may help increase immune functions against malignant cells.”

In summary, it is hypothesized that the combined actions of β-carbolines and DMT present in ayahuasca may diminish tumor blood supply, activate apoptotic pathways, diminish cell proliferation, and change the energetic metabolic imbalance of cancer cells, which is known as the Warburg effect. Therefore, ayahuasca may act on cancer hallmarks such as angiogenesis, apoptosis, and cell metabolism.”
http://www.munaymedicine.com/pages/ayahuasca.aspx

has been known for decades that immunomodulation through serotonin/5-hydroxytryptamine receptors (5-HTRs) has the potential to regulate inflammation and prevent dam-age of the nervous tissue (Shajib and Khan, 2015). Recently another receptor has been added to the greater picture: the orphan receptor sigma-1 (Sig-1R). 5-HTRs and Sig-1R have been shown to be expressed ubiquitously in higher verte-brate tissues and mediate various processes, including the regulation of cognition and behavior, body temperature, as well as immune functions (Szabo, 2015). Both 5-HTRs and the Sig-1R use G protein-coupled (GPCR) pathways thereby modulating a plethora of cellular functions, such as cyto-kine/neurotransmitter release, proliferation, differentiation, and apoptosis. The molecular chaperone Sig-1R is located at the endoplasmic reticulum-mitochondrion interface and has an important role in the fine-tuning of cellular metabolism and energetics under stressful conditions (Hayashi, 2015). At the MAM, Sig-1Rs are involved in the regulation and mobilization of calcium from endoplasmic reticulum stores. Neuroprotection by Sig-1R activation can be attained by preventing elevations of intracellular calcium-mediated cell death signaling (Ruscher and Wieloch, 2015). Based on its central localization and function, pivotal physiological activ-ities of the Sig-1R have been described such as indispensable role in neuronal differentiation, neuronal signaling, cellular survival in hypoxia, resistance against oxidative stress, and mitigating unfolded protein response (Pal et al., 2012).Tryptaminergic trace amines (e.g ., N,N-dimethyltrypt-amine; DMT) as well as neurosteroids (e.g ., dehydroepi-androsterone) are endogenous ligands of the Sig-1R (Fon-tanilla et al., 2009). Tryptamines are naturally occurring monoamine alkaloids sharing a common biochemical –tryptamine– backbone. DMT was shown to be endogenous-ly present in the human brain and in other tissues of the body, however the exact physiological role of this tryptamine has not been identified yet (Frecska et al., 2013). It has been shown that, besides its affinity for the Sig-1R, DMT also acts as an agonist at numerous serotonin receptors, such as 5-HT1A, 5-HT2A, and 5-HT2C (Keiser et al., 2009; Ray, 2010). This wide-spectrum agonist activity may allow DMT to modulate several physiological processes and regulate in-flammation through the Sig-1R and 5-HTRs. Indeed, DMT has been found to modulate immune responses through the Sig-1R under various conditions. These include the suppres-sion of inflammation by blocking inflammatory cytokine and chemokine release of dendritic cells, as well as inhibiting the activation of Th1 and Th17 subsets (Szabo et al., 2014). The biochemical background of this extensive ability lies in the possible cross-talk of the GPCR-coupled downstream signaling of 5-HTRs/Sig-1R and other inflammatory path-ways in immune cells, as well as the fine-tuning of cytokine feedback loops in peripheral tissues. Thus, in neuroinflam-mation, two major scenarios are possible: i) the modulation of cytokine production by brain resident microglia that implies a negative feedback regulation of inflammation via the induction of the release of anti-inflammatory IL-10 and TGF β
occurring subsequent of both 5-HTR and Sig-1R ac-tivation; ii) the direct/indirect control of NF-κB signaling and possibly other pathways (e.g ., MAPKs) involved in in-flammation through intracellular kinases, adaptor proteins, etc (reviewed by Szabo, 2015). This way, the activation of 5-HTRs and Sig-1R may also interfere with the chemokine, inflammatory cytokine signaling of immune cells through intracellular mechanisms. Most of the receptors that are involved in psychedelic effects belong to the GPCR family or interact with GPCRs (Rogers, 2012). The role of 5-HTR/Sig-1R GPCR-coupled signals in the intracellular regulation and orchestration of NF-κB and MAPK pathways may be of particular importance regarding the complex neuroimmuno-logical effects of DMT.

http://www.academia.edu/...tion_and_neuroprotection

From: Dimethyltryptamine (DMT): a biochemical Swiss Army knife in neuroinflammation and neuroprotection?

In the last two decades several clinicalstudies demonstrated the importance of sigmar-1 in many diseasesranging from cancer, pain and addiction to different psychiatricand neurological disorders among them Major depression, Alzheimer’s disease, schizophrenia, and stroke [2].Early studies showed that sigmar-1 is expressed not only indistinct regions of the CNS but also in immune cells [4,6]. It wasshown to regulate cell differentiation and survival by acting as achaperone at the mitochondria-associated endoplasmic reticulummembrane [7,8]. Murine studies also demonstrated that thespecific activation of sigmar-1 resulted in immunosuppression [9],and
in vivo decreased lymphocyte activation and proliferation[10]. Sigma-1 receptor ligands possess potent immunoregulatoryproperties via increasing the secretion level of anti-inflammatoryIL-10 [11], and suppressing IFNc and GM-CSF expression [10].These important studies showed that sigmar-1 may cause significant alterations in immune function