El Mecanismo de la Medicina
Is sigma-1 the key to cellular metabolism?
I live in a city and country with lots of humidity and very poor building standards. In this and similar environments, I’ve found myself with a high reactivity to indoor mold. Given my longstanding interest in unorthodox, but legit health solutions, I’ve been working though various options to save my brain from the short term and long term consequences of neuroinflammation.
I’ve had both my physical and cosmic eyes on the metabolic effects of psychedelics for some time now. So I was recently surprised when I found that some psychedelics activate a receptor located on the membrane between endoplasmic reticulum and the mitochondria called the sigma-1 receptor (SIR). While there is a lot of work trying to decipher the full effects and nuance of the receptor, the therapeutic potential seems large.
Here are some paper titles to give a sense of the potential with sigma-1 agonism:
Sigma-1 Receptor in Retina: Neuroprotective Effects and Potential Mechanisms
Targeting Sigma-1 Receptor: A Promising Strategy in the Treatment of Parkinson's Disease
Mitochondria-associated endoplasmic reticulum membrane: Overview and inextricable link with cancer
Revisiting the sigma-1 receptor as a biological target to treat affective and cognitive disorders
A number of substances activate this receptor and many seem to have positive physical and behavioral effects. Of those N,N-Dimethyltryptamine (DMT) seems to have some of the most clear evidence behind its effects.
The sigma-1 receptor is expressed in a variety of known tissues: the nervous system, retina, kidney, liver, lung and heart (source). The sigma-1 receptor membrane is critical to energy regulation of the cell.
Sigma-1 activation stabilizes critical components of cells including the mitochondria and mitochondria-associated membrane while improving intracellular calcium status and reducing excitotoxicity. The reduction of excitotoxicity is another way of saying that the cell is more energized. It might seem paradoxical, but more energized cells are relaxed. A fully energized cell is full of potential chemical energy, somewhat like a battery waiting to discharge. “Deficiencies in energy supply are particularly damaging to neurons, which have a high energy demand” (source). Conversely, a well energized cell is relaxed and ready to execute its primary function as required.
Activating the sigma receptor shows promise for a wide range of central nervous system disorders and injuries. Some studies call it neurorestorative and neuroprotective (source) and others have found promise in treating animal models of PTSD (source). The form or vehicle of DMT in the later study was the ayahuasca brew which is often a drink of leaves containing DMT and vine containing a variety of harmala alkaloids that inhibit the breakdown of dopamine and serotonin as well as having their own psychotropic effects. While psychedelics as “drugs” have long been demonized in the west, the consideration of plant medicines as medicine is being revalidated in academia. Based on the studies presented here they are quite broad in their applicability.
“Neuroprotection appears to be due to inhibition of cellular Ca2+ toxicity and/or inflammation, and neurorestoration may include balancing aberrant neurotransmission or stimulation of synaptogenesis, thus remodelling brain connectivity. The Sig-1R is therefore a strong therapeutic target for the development of new treatments for neurodegenerative diseases and stroke.” (source).
All the above said, we cannot expect the existing regulatory framework to evaluate DMT or ayahuasca coherently for a variety of reasons, the lack funding and lack of profit incentives chief among them. Despite that, we can deduce that safety is well established by the pre-existing epochs of human use. In that light, and with the basic physiological research linked to in this essay, it seems the risk-to-benefit ratio runs in complete contradisctinction to the fears conjured by our culture.
For the times, places, and persons not suitable for psychedelics there are a number of known molecules that activate the sigma-1 receptor while not facilitating a psychedelic experience:
Fluvoxamine
DHEA
Pregnenalone
Estrogen
Berberine
An odd and potentially relevant curiosity is that berberine (typically considered a glucose regulation drug) and DHEA (a steroid/neurosteroid) are both monoamine oxidase inhibitors while not typically being considered as such.
The sigma-1 receptor plays several roles related to energy metabolism at the organism level. It both protects beta cells and promotes their proliferation. Beta cells are pancreatic cells critically related to the regulation of glucose and insulin. The overexpression of sigma-1 receptors in model animals (a proxy for receptor activation), also demonstrates a reduction in insulin secretion under stress (source). This is inline with the fact that sigma-1 receptor activation seems to make all affected cells simply work more efficiently. In turn, that efficiency reduces inflammation and neuroinflammation.
Most relevant to my mold journey is that DMT and 5-MEO-DMT have both been shown to play roles as immune regulatory molecules in both innate and adaptive immune systems: “Here we demonstrate for the first time the immunomodulatory potential of NN-DMT and 5-MeO-DMT on human moDC functions via sigma-1 ... 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.” The question remains as to whether other SIR agonists also modulate the immune system.
APPENDIX (further supporting evidence and related curiosities)
DMT:
The hallucinogen N,N-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator
When the endogenous hallucinogenic trace amine N,N-dimethyltryptamine meets the sigma-1 receptor
According to these data, DMT may be considered as adjuvant pharmacological therapy in the management of acute cerebral ischemia.
“DMT-mediated Sig-1R activation may alleviate hypoxia-induced cellular stress and increase survival in a HIF-1-independent manner. Our results reveal a novel and important role of DMT in human cellular physiology. We postulate that this compound may be endogenously generated in situations of stress, ameliorating the adverse effects of hypoxic/ischemic insult to the brain.”
Ayahuasca:
This study concludes the anxiolytic and antidepressant potential of ayahuasca in an animal model of neuroinflammation, possibly due to the antineuroinflammatory effects already reported of the compound.
“Patients treated with ayahuasca showed a significant correlation (rho = + 0.57) between larger reductions of C-reactive protein and lower depressive symptoms at 48 hours after substance ingestion”
“Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial”
“Ayahuasca's components also seem to modulate levels of inflammatory and neurotrophic factors beneficially. On a biological level, this translates into neuroprotective and neuroplastic effects.”
“ratings of depression and stress significantly decreased after the ayahuasca ceremony and these changes persisted for 4 weeks”
AutoImmunity:
Potentially by their immunomodulatory activity and in part through the mobilization of cell-intrinsic neuroprotective mechanisms, psychedelics may represent a promising intervention for autoimmune-related depression and other mental illness.
Psychedelics as a novel approach to treating autoimmune conditions - ScienceDirect
Regulation of the hypothalamic-pituitary-adrenocortical stress response - PMC
Environmental Factor - March 2021: Autoimmunity origins may lie in defective mitochondria
Active duty military personnel with PTSD may have an elevated risk of a range of autoimmune diseases, regardless of combat experience or prior trauma.
Neurosteroids & Mental Health:
“In clinical studies, some sigma-1 receptor agonists, including fluvoxamine, donepezil and neurosteroids, improve cognitive impairment and clinical symptoms in neuropsychiatric diseases.”
SIGMAR1 Confers Innate Resilience against Neurodegeneration - PMC
Neurosteroids Ameliorate Conditioned Fear Stress: An Association with Sigma 1 Receptors
Sigma-1 receptor agonists as therapeutic drugs for cognitive impairment in neuropsychiatric diseases
Neurosteroids and sigma1 receptors, biochemical and behavioral relevance - PubMed (nih.gov)
“Blockade of sigma-1 receptor significantly inhibited the generation of ROS and activation of the MAPK and Akt pathways. These findings underscore the critical role of the sigma-1 receptor in methamphetamine-induced microglial activation.”
The sigma-1 receptor (Sig-1R) is a chaperone receptor that primarily resides at the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) and acts as a dynamic pluripotent modulator regulating cellular pathophysiological processes. Multiple pharmacological studies have confirmed the beneficial effects of Sig-1R activation on cellular calcium homeostasis, excitotoxicity modulation, reactive oxygen species (ROS) clearance, and the structural and functional stability of the ER, mitochondria, and MAM.
Allosteric Modulation of the Sigma-1 Receptor Elicits Antipsychotic-like Effects - PMC
Sigma-1 Receptor Agonists and Their Clinical Implications in Neuropsychiatric Disorders
Sigma-1 Receptor in Retina: Neuroprotective Effects and Potential Mechanisms - PMC
Sigma-1 Receptors in Depression: Mechanism and Therapeutic Development
Roles of sigma-1 receptors on mitochondrial functions relevant to neurodegenerative diseases - PMC
Other SIR-1:
“Sig-1R ligands in preclinical models have significantly beneficial effects associated with improved cardiac function, ventricular remodeling, hypertrophy reduction, and, in the kidney, reduced ischemic damage.”
Knocking out sigma-1 receptors reveals diverse health problems. - PMC
Repurposing of CNS drugs to treat COVID-19 infection: targeting the sigma-1 receptor
Serotonergic Psychedelic - an overview | ScienceDirect Topics
Sigma 1 Receptor, Cholesterol and Endoplasmic Reticulum Contact Sites
The Sigma-1 Receptor as a Pluripotent Modulator in Living Systems
SIR-1 & Retina
“Sigma1R may be a novel retinal stress modulator, and targeting it even after disease onset may afford retinal neuroprotection.”
Sig‑1R overexpression was found to promote β‑cell proliferation by accelerating cell cycle progression. Furthermore, Sig‑1R overexpression ameliorated the apoptosis rate whilst impairing insulin secretion induced by palmitic acid by relieving ER stress and mitochondrial dysfunction in MIN6 cells. Sig‑1R overexpression also promoted Ca2+ transport between mitochondria and ER by increasing the quantity of ER adjacent to mitochondria in the 50‑nm range. It was concluded that Sig‑1R overexpression conferred protective effects on β‑cells against lipotoxicity as a result of the promotion of cell proliferation and inhibition of ER stress and oxidative stress, by regulating the structure of MAM.
Psychedelics & Personality:
Neuroticism scores significantly decreased while Extraversion increased following psilocybin therapy. These changes were in the direction of the normative NEO-PI-R data and were both predicted, in an exploratory analysis, by the degree of insightfulness experienced during the psilocybin session. Openness scores also significantly increased following psilocybin, whereas Conscientiousness showed trend-level increases, and Agreeableness did not change.
degree of insightfulness during the psychedelic experience predicted changes in Neuroticism and Extraversion.
“reduced connectivity between the left amygdala and ACC may impair extinction of the amygdala response to anxiety-eliciting stimuli. Second, the neural evidence matches the psychological findings, which associate N with a negative bias in attention, interpretation and recall of information, increased reactivity, and ineffective coping, and is consistent with findings of decreased cardiovascular flexibility. Third, current studies suggest that HPA-axis influences mood independently of N”
“that personality traits were mostly unrelated to resting metabolic rate and energy expenditure at normal walking pace. However, those who scored lower on neuroticism (r = −0.12) and higher on extraversion (r = 0.11), openness (r = 0.13), and conscientiousness (r = 0.09) had significantly higher energy expenditure at peak walking pace. In addition to greater aerobic capacity, individuals with a more resilient personality profile walked faster and were more efficient in that they required less energy per meter walked. The associations between personality and energy expenditure were not moderated by age or sex, but were in part explained by the proportion of fat mass.”
In conclusion, the findings suggest that high neuroticism is related to elevated levels of plasma leptin/adiponectin ratio, leptin and IL-6 in young adults.
Results: Neuroticism correlated positively with frontolimbic serotonin 2A receptor binding [r(79) = .24, p = .028]. Post hoc analysis of the contributions from the six constituent traits of neuroticism showed that the correlation was primarily driven by two of them: vulnerability and anxiety. Indeed, vulnerability, defined as a person's difficulties in coping with stress, displayed the strongest positive correlation, which remained significant after correction for multiple comparisons (r = .35, p = .009).
Berberine:
“Berberine can be used to treat many diseases, such as cancer and digestive, metabolic, cardiovascular, and neurological diseases. Berberine has protective capacities in digestive diseases. It can inhibit toxins and bacteria, including Helicobacter pylori, protect the intestinal epithelial barrier from injury, and ameliorate liver injury. Berberine also inhibits the proliferation of various types of cancer cells and impedes invasion and metastasis....Berberine also improves cardiovascular hemodynamics, suppresses ischemic arrhythmias, attenuates the development of atherosclerosis, and reduces hypertension. Berberine shows potent neuroprotective effects, including antioxidative, antiapoptotic, and anti-ischemic. Furthermore, berberine exerts protective effects against other diseases.” (source)
Biological properties and clinical applications of berberine
On the mechanism of antidepressant-like action of berberine chloride
Improvement of adjunctive berberine treatment on negative symptoms in patients with schizophrenia
Berberine in Cardiovascular and Metabolic Diseases: From Mechanisms to Therapeutics
Berberine as a Potential Anticancer Agent: A Comprehensive Review