Arwen Podesta

Abstract

Disruptions in one-carbon metabolism, particularly involving the methylenetetrahydrofolate reductase (MTHFR) enzyme, have emerged as critical determinants of vulnerability to mental illness and addiction. The MTHFR gene, especially the C677T polymorphism, regulates conversion of 5,10-methylenetetrahydrofolate to 5-methyl-tetrahydrofolate, a cofactor essential for remethylation of homocysteine to methionine and synthesis of S-adenosylmethionine (SAM), the universal methyl donor. Impaired MTHFR activity has been associated with decreased SAM and altered DNA methylation patterns, leading to dysregulation of neurotransmitter synthesis, oxidative stress, and impaired neural plasticity. Evidence from psychiatric cohorts reveals higher prevalence of MTHFR variants among individuals with depression, anxiety, schizophrenia, and substance use disorders, supporting a shared biological vulnerability through under-methylation and catecholamine imbalance.

Emerging studies link methylation deficits to addiction susceptibility by influencing reward circuitry, stress reactivity, and epigenetic adaptation to repeated drug exposure. For instance, MTHFR polymorphisms and associated folate-cycle inefficiencies alter dopamine and serotonin synthesis, increase oxidative burden, and predispose to maladaptive behavioral regulation—mechanisms observed across alcohol, opioid, and stimulant use disorders. These methylation-related redox imbalances act at the intersection of neuroinflammation, cognitive impairment, and emotional dysregulation, potentiating both psychiatric and addictive pathways.

Intervention through nutrient-based methylation support offers a modifiable target for clinical improvement. Supplementation with L-methylfolate, methylcobalamin (vitamin B12), and pyridoxal-5-phosphate (vitamin B6) restores cofactor availability for one-carbon metabolism and has demonstrated efficacy in augmenting antidepressant response and stabilizing neurochemical function. Personalized approaches integrating MTHFR genotyping, homocysteine monitoring, and targeted nutrient replacement represent a translational model for precision psychiatry—bridging molecular pathophysiology with practical treatment strategies. This presentation will synthesize current evidence linking methylation biology to psychiatric and addictive disorders, highlighting biochemical markers, clinical correlations, and emerging data on methylation-directed nutrient interventions as adjunctive or preventive therapeutic options within integrative mental health care.

Audience take away from presentation:

• Implement evidence-based MTHFR testing and clinical phenotype appearance to identify methylation-related psychiatric vulnerabilities.


• Apply methylation cofactor support (L-methylfolate, methylcobalamin, B6) to improve mental health and addiction outcomes.


• Integrate pharmacogenetic data to personalize psychiatric and addiction treatment protocols.


• Educate clinicians on clinical decision-making for nutrient-based adjunctive therapy.

How will this help the audience in their job? Is this research that other faculty could use to expand their research or teaching? Does this provide a practical solution to a problem that could simplify or make a designer’s job more efficient? Will it improve the accuracy of a design, or provide new information to assist in a design problem? List all other benefits. Enables clinicians to tailor treatments for resistant depression, anxiety, and addiction.

• Expands faculty teaching and research on epigenetics and personalized psychiatry.


• Simplifies clinical decision-making by identifying a biochemical cause of poor response.


• Improves accuracy in treatment design using genetic and metabolic biomarkers.


• Reduces trial-and-error prescribing, enhances safety, and supports preventive care.


• Strengthens integrative care models linking molecular psychiatry and nutrition science.