Epigenetics in Cortisol Metabolism has Generational Effects on Psychological Normalcy. Can a Drug like St. John's Wort Reverse it or Provide a Therapy? If so Can it be used to Reinstate Genes Silenced in Cancers?2022-08-30 Jorma Jyrkkanen

St John’s Wort and Cortisol Potential for Reversing Epigenetic Methylation Gene Silencing and Potential Anti-Cancer Drug. Jorma Jyrkkanen, Bsc, PDP. Environmental Consultant. 2022-08-30 Introduction It has been discovered that epigenetic changes due to trauma in parents can be transferred to offspring and appear as mental instability and cortisol insufficiency is implicated in this with culprit genes identified (Rachel Yehuda in Scientific American. (1 July 2022). Main Cortisol Functions While it would be difficult to name all of the functions of cortisol, here are some of its prime responsibilities: • Cortisol prepares the body to deal with stress or danger. ⁷ • Cortisol helps control blood sugar and blood pressure. ⁷ • Cortisol regulates how the body uses food and gets energy—your metabolism. ⁷ • Cortisol plays a role in helping the brain form memories. ⁶ • Cortisol helps the body recognize when it is time to sleep and when to wake up. ⁵ Epigenetic Inheritance Could some of these epigenetic changes in trauma survivors also be found in the children of trauma survivors? Finding low cortisol in the 9/11 babies back in 2002 had told us that we'd been thinking about some things all wrong. We'd assumed all along that trauma was behaviorally transmitted: Joseph's problems seemed to result from the stressful, bereaved atmosphere in his childhood home. But now it looked like the uterine environment also played a role. So did the sex of the traumatized parent. In our early studies of Holocaust offspring, we had selected only those people with two parents who were Holocaust survivors. We redid the studies to figure out if the sex of the parent mattered—and it did. Those whose mother (or both parents) had PTSD tended to exhibit lower cortisol levels and showed evidence of more sensitive glucocorticoid receptors. In contrast, those whose fathers, but not mothers, had PTSD showed the opposite effect. Taking a closer look, we again discovered lower methylation within the glucocorticoid receptor gene, NR3C1, in Holocaust offspring whose mothers, or both parents, had PTSD. These changes mirrored what we'd observed in the maternal survivors themselves. But in offspring with only paternal PTSD, we observed more methylation—the opposite effect. These findings raised the possibility that PTSD in mothers and fathers might lead to different epigenetic changes on the glucocorticoid receptor in children. In a second series of studies beginning in 2016, we examined methylation within another gene, FKBP5, which encodes a protein involved in regulating the ability of the glucocorticoid receptor to bind cortisol. The findings showed related methylation patterns within the FKBP5 gene in both Holocaust parents and their children. But because of the small number of participants in that study—by this time it was difficult to find many living Holocaust survivors who could participate with their offspring—we couldn't examine how factors such as the parents' PTSD status might contribute to FKBP5 methylation. We were able to replicate and extend this work in a substantially larger sample of just the Holocaust offspring, however. In 2020 we reported lower levels of FKBP5 methylation in the adult children whose mothers—and not fathers—were exposed to the Holocaust during childhood. This effect was independent of whether the mother had PTSD or not. It suggested that trauma might have affected the mothers' eggs decades before her children were conceived, while she was herself a child. Given the obvious difficulties in studying generations of people, scientists often resort to animal studies to explore epigenetic transmission. In 2014 Brian Dias and Kerry Ressler, both at the Emory University School of Medicine, reported an intergenerational epigenetic pathway that ran through sperm. They gave a male mouse a mild electric shock as it smelled a cherry blossom scent, stimulating a fear response to the odor. The response was accompanied by epigenetic changes in its brain and sperm. Intriguingly, the male offspring of the shocked mice demonstrated a similar fear of cherry blossoms—as well as epigenetic changes in their brain and sperm—without being exposed to the shock. These effects were passed down for two generations. In other words, the lesson the grandfather mouse learned, that the cherry blossom scent means danger, was transmitted to its son and grandson. In a recent study, my colleagues and I experimented with genome-wide gene expression, a tool that can identify links between protein expression and specific conditions across the entire human genome. With this approach, we again observed distinct patterns of gene expression linked with maternal and paternal trauma exposure and PTSD (Sci.Am). Was the low Cortisol due to epigenetic silencing of CpG segments of the genes in question? A Substance that Reverses the Mental Effects of Low Cortisol St John’s Wort Drugs That Affect Cortisol Doctor's answers | Diagnosis, Doctor's Answers Question:  I’ve read that lots of common medicines and treatments can raise or lower cortisol.  There’s not much mention of the quantity of these meds that affect cortisol though.  Xanax and codeine lower, for example, and Zoloft, Ritalin, St. John’s Wort, alcohol, and even marijuana raise cortisol.  Growth and thyroid hormones are reported to lower cortisol.  What the Science Says About the Effectiveness of St.  John’s Wort for  Depression The results of studies on the effectiveness of St. John’s wort for depression are mixed. • In a 12-week, 2011 clinical trial with 73 participants, neither St. John’s wort nor a standard antidepressant medication called citalopram, a selective serotonin reuptake inhibitor (SSRI), decreased symptoms of minor depression better than a placebo. The study was funded by NCCIH and NIMH. • In a 26-week clinical trial with 124 participants, St. John’s wort, a standard antidepressant (sertraline, an SSRI), and a placebo were similarly effective in treating major depression of moderate severity. NCCIH and NIMH funded this 2012 analysis of data collected in 2002. • A 2008 review of 29 international studies suggested that St. John’s wort may be better than a placebo and as effective as different standard prescription antidepressants for major depression of mild to moderate severity. St. John’s wort also appeared to have fewer side effects than standard antidepressants. The studies conducted in German-speaking countries—where St. John’s wort has a long history of use by medical professionals—reported more positive results than those done in other countries, including the United States. • St. John’s wort was no more effective than placebo in treating major depression of moderate severity, an NCCIH- and NIMH-funded study of 340 participants reported in 2002. (NIH Info) Minireview: Stress-related psychiatric disorders with low cortisol levels: a metabolic hypothesis Rachel Yehuda  1 , Jonathan Seckl Affiliations • PMID: 21971152 • DOI: 10.1210/en.2011-1218 Abstract Several stress-associated neuropsychiatric disorders, notably posttraumatic stress disorder and chronic pain and fatigue syndromes, paradoxically exhibit somewhat low plasma levels of the stress hormone cortisol. The effects appear greatest in those initially traumatized in early life, implying a degree of developmental programming, perhaps of both lower cortisol and vulnerability to psychopathology. In these conditions, lowered cortisol is not due to any adrenal or pituitary insufficiency. Instead, two processes appear involved. First, there is increased target cell sensitivity to glucocorticoid action, notably negative feedback upon the hypothalamic-pituitary-adrenal (stress) axis. Altered density of the glucocorticoid receptor is inferred, squaring with much preclinical data showing early life challenges can permanently program glucocorticoid receptors in a tissue-specific manner. These effects involve epigenetic mechanisms. Second, early life trauma/starvation induces long-lasting lowering of glucocorticoid catabolism, specifically by 5α-reductase type 1 (predominantly a liver enzyme) and 11β-hydroxysteroid dehydrogenase type 2 (in kidney), an effect also seen in model systems. These changes reflect a plausible early-life adaptation to increase the persistence of active cortisol in liver (to maximize fuel output) and kidney (to increase salt retention) without elevation of circulating levels, thus avoiding their deleterious effects on brain and muscle. Modestly lowered circulating cortisol and increased vulnerability to stress-associated disorders may be the outcome. This notion implies a vulnerable early-life phenotype may be discernable and indicates potential therapy by modest glucocorticoid replacement. Indeed, early clinical trials with cortisol have shown a modicum of promise. Potential to Explore If St. John's Wort raises Cortisol epigenetically by removing methylation from the CpG regions of genes it may have anti cancer drug potential and possibly heritable anti cancer drug potential. This might be worth more detailed investigation.