Nicotinamide Riboside, Vit B3 Analogue, and Brain Energy Metabolism

This is a single arm, open label interventional study that evaluates the effects of high dose nicotinamide riboside (NR) on in vivo brain NAD+ and NADH levels and bioenergetic function in healthy adults using phosphorus 31 magnetization transfer MR spectroscopy at 7 Tesla. The study is designed as a within subject, before and after comparison, with each participant serving as their own control to maximize sensitivity to NR related changes in brain energy metabolism. The planned sample size is up to 40 participants, which provides approximately 80 percent power to detect a moderate effect size difference in the primary outcome, the NAD+ to NADH ratio, between baseline and post treatment assessments. Participants are medically and psychiatrically healthy adults aged 18 to 65 years without a current or past DSM defined psychiatric disorder and without a first degree family history of psychotic or mood disorders. Key exclusion criteria include significant medical or neurological illness, diabetes, uncontrolled hypertension, coronary artery disease, metabolic syndrome, glaucoma, liver or renal impairment, respiratory disease, peptic ulcer disease, pregnancy, current substance use disorder, and any contraindication to MRI such as ferromagnetic implants, certain tattoos, or severe claustrophobia. Use of prescription medications and dietary supplements is generally not allowed, with the exception of oral contraceptives and occasional acetaminophen, to minimize pharmacologic confounding of NAD related measures. The study procedures include a screening visit, a baseline imaging visit, a 14 day home dosing phase, and a final imaging visit. At screening, a licensed clinician or trained research staff member obtains written informed consent, conducts a structured psychiatric interview, and reviews medical history to determine eligibility and to ensure that participants can safely receive NR and undergo MRI. At the baseline visit, participants undergo urine toxicology and pregnancy testing when applicable, a blood draw for NAD related metabolites and other exploratory markers, measurement of vital signs, and a 7 Tesla MRI/MRS session focused on the medial prefrontal and parietal cortices and whole brain measures where technically feasible. The MR protocol includes phosphorus 31 magnetization transfer spectroscopy to quantify NAD+, NADH, and related metabolites, as well as structural, functional, and diffusion imaging to characterize gray matter, white matter, and resting state connectivity. Following baseline assessments, participants take oral NR at a total daily dose of 3000 milligrams, administered as 1500 milligrams twice daily for 14 consecutive days, with dosing initiated on a weekday to facilitate monitoring. Participants receive a supply of study capsules and written instructions, are advised to avoid alcohol and other substances during the study, and are asked to complete a four day food diary near the end of the dosing period to document dietary intake that could influence NAD+ metabolism. Adherence is monitored through pill counts and self report, and participants who miss more than three doses or who miss doses during the last three days of treatment are discontinued from the protocol because incomplete exposure could bias within subject comparisons. On day 15, participants return for repeat safety and imaging assessments that mirror the baseline visit. Procedures include urine toxicology and pregnancy testing when indicated, vital signs, a 30 ml blood draw for NAD related metabolites and kynurenine pathway markers, and a 7 Tesla MRI/MRS scan using the same acquisition parameters as at baseline. The primary outcome is the change in brain NAD+ to NADH ratio from baseline to post treatment in predefined regions of interest, particularly medial prefrontal and parietal cortex, quantified from phosphorus 31 MR spectra using validated methods. Secondary outcomes include changes in other bioenergetic indices such as phosphocreatine, inorganic phosphate, ATP related peaks, and enzyme kinetic measures derived from magnetization transfer, as well as exploratory associations between brain changes and blood NAD metabolite profiles. Data will be analyzed using paired statistical tests that compare within subject pre and post NR measures for the primary and secondary endpoints. The study is powered to detect moderate changes in the NAD+ to NADH ratio, based on prior work demonstrating redox and bioenergetic abnormalities in psychiatric populations and on pilot NR trials in other medical and neurological conditions. Although NR has shown a favorable safety profile across numerous human studies, participants are closely monitored for adverse events throughout the dosing and imaging phases, with predefined criteria for discontinuation in the event of clinically significant side effects or abnormal vital signs. All imaging and clinical data are coded and stored in secure, HIPAA compliant systems, and only authorized study personnel have access to the linkage between identifiers and research data. This study does not aim to test clinical efficacy in a patient population and does not offer direct therapeutic benefit, but it addresses an important mechanistic question in human brain metabolism. By defining the extent to which NR can modulate brain NAD+, NADH, and downstream bioenergetic markers in healthy adults, the results will inform dose selection, target engagement expectations, and feasibility for future trials in mood disorders characterized by mitochondrial dysfunction, oxidative stress, and neuroinflammation.