Even mild inhibition of oxidative metabolism may cause szhizophrenia, naicinamide reverses it
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An excellent set of studies, demonstrating that another “mysterious” and “genetically-predisposed” condition can be caused entirely by impaired metabolism. It has been known for a long time that people with low thyroid function have a much rate of mental health conditions, especially depression and psychotic states. Schizophrenia, being a type of psychosis is also observed much more often in hypo thyroid people than in the general population. Ray published a newsletter dedicated to schizophrenia more than decade ago and in that newsletter he made a strong case for this condition being driven by low oxidative metabolism in the brain, and especially with inability to properly metabolize glucose. The first study below corroborates Ray’s arguments with human data. One interesting finding in this new study is that even mild inhibition (18%) of the electron transport chain (ETC) is sufficient to cause the functional and structural phenotype of schizophrenia in cells. Thus, one does not need to be in full-blown clinical hypothyroidism in order to develop this psychotic condition. As such, the notorious chronic unpredictable mild stress (CUMS) method comes to mind, both due to ts established efficacy at inducing virtually any mental health condition in animal models, as well as its wide applicability to humans, considering virtually all people living in “developed” countries are exposed to CUMS throughout most of their lifetimes. The good news is that a relative low concentration of niacinamide (10uM/L) was able to reverse most of the issues caused by ETC inhibition (ETC I, to be precise). The benefit of niacinamide were, predictably, due to its role as a precursor to NAD+. That concentration of niacinamide in humans can be achieved with 50mg-100mg taken 2-3 times daily, which happens to be precisely the dose Ray has been recommending to people throughout the years.
https://pubmed.ncbi.nlm.nih.gov/27845781/
https://pubmed.ncbi.nlm.nih.gov/33608825/
https://pubmed.ncbi.nlm.nih.gov/34089344/
https://pubmed.ncbi.nlm.nih.gov/40287324/
https://www.nature.com/articles/s41598-026-36651-7
“…Mitochondrial function is essential for key neurodevelopmental processes, including cellular proliferation, differentiation, migration, synaptogenesis, and synaptic pruning. Previous research from our group demonstrated that neonatal administration of Rotenone (Rot), a mitochondrial complex I inhibitor, led to mitochondrial dysfunction and schizophrenia-like behavioral phenotypes. In this study, we aimed to identify possible cellular pathways disrupted by Rot exposure that may underlie these behavioral alterations. Thus, primary cortical neurons were treated with 1.325 nM Rot for 24 h, a concentration extrapolated from cortical levels observed in the neonatal Rot model. This treatment impaired mitochondrial complex I activity, decreased superoxide production, disrupted mitochondrial respiration and dynamics, reduced dendritic branching, and decreased synapse formation. Notably, pretreatment with Nicotinamide (NAM), a NAD precursor, improved mitochondrial function, reversing these effects. Altogether, our findings underscore the critical role of mitochondrial integrity in neurodevelopment and its potential contribution to neurodevelopmental disorders such as schizophrenia.”
“…Significantly, despite not inducing cytotoxicity, treatment with 1.325nM Rot for 24 hours reduced mitochondrial complex I (CI) activity by approximately 18% compared to the control group (Vehicle: 100±2.34%; Rot: 81.98±8.38%; p=0.03; Figure SS3).”
“…As conclusion (Figure 6), we propose that treatment with 1.325nM of Rot in primary cortical neurons induces CI inhibition, leading to reduced ETC activity, diminished mitochondrial respiration, and consequent decreases in ATP levels and superoxide production. This mitochondrial dysfunction triggers an adaptive response characterized by increased SIRT3 levels and enhanced mitochondrial fission; however, this response appears insufficient to fully restore mitochondrial function, as both autophagy and mitophagy appear to be impaired. As a result, dysfunctional mitochondria accumulate, compromising synaptic processes. In parallel, reductions in superoxide production and mitochondrial activity affect neuronal morphology, leading to shorter dendrites and fewer dendritic branches. Moreover, NAM 10uM pretreatment likely supports ETC activity, presumably through increased NAD⁺ availability, resulting in a partial recovery of mitochondrial respiration, yet sufficient to restore ATP and superoxide levels. NAM pretreatment also promotes SIRT3 activation, maintaining the reduction in mitochondrial fission while restoring mitochondrial mass through improved autophagic flux. Consequently, we observed an increase in dendritic number and length, along with the reestablishment of synaptic processes.”