Nicotinamide Riboside, Vit B3 Analogue, and Brain Energy Metabolism

The Effects of Nicotinamide Riboside Supplementation on Brain NAD+/NADH Ratio and Bioenergetics

The goal of this clinical trial is to learn how nicotinamide riboside (NR), a form of vitamin B3, affects brain energy metabolism in healthy adults. Researchers want to find out if taking NR by mouth for 2 weeks can raise the balance of two related brain chemicals called NAD+ and NADH, which play a key role in how cells make and use energy. The main questions are: Does short term NR treatment increase the NAD+ to NADH ratio in the brain, and does it change other brain energy measures that we can see with a special type of MRI scan called phosphorus 31 MR spectroscopy.

Adults between 18 and 65 years old who are generally healthy and do not have a personal or close family history of mood or psychotic disorders may be able to take part. People who join the study will first have a screening visit with a psychiatric interview and safety checks to confirm they are eligible and to review the risks and procedures. Eligible participants will then have a baseline visit that includes a blood draw, vital signs, urine drug and pregnancy tests when needed, and a 7 Tesla MRI/MRS scan focused on brain chemistry and structure.

After the baseline visit, participants will take NR capsules by mouth at home, 1500 milligrams in the morning and 1500 milligrams in the early afternoon each day, for about 2 weeks, for a total daily dose of 3000 milligrams. They will be asked to avoid alcohol and other drugs during the study and to complete a short food diary near the end of the dosing period so that researchers can track diet. On the last day of taking NR, participants will return for repeat MRI/MRS scans, blood tests, and vital signs so that researchers can compare brain and blood measures before and after NR treatment.

Researchers will compare each participant's brain NAD+ to NADH ratio and other bioenergetic markers before and after NR to see if NR changes these measures in a consistent way. If NR raises brain NAD+ and improves measures of energy metabolism in healthy adults, this may provide important background information for future studies that test whether NR can help people with psychiatric or neurological disorders linked to mitochondrial dysfunction and oxidative stress. There is no expected direct health benefit for participants, but their involvement may help improve understanding of how NR affects human brain 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.

Inclusion Criteria:

1. Adults (between 18 and 65 years old)
2. Without a current psychiatric diagnosis assessed by a structured psychiatric interview at the screening/consent visit
3. Without a history of a psychotic disorder and/or mood disorder among parents, siblings, or children

Exclusion Criteria:

1. Any current significant medical or neurological illness.
2. Diagnosis of diabetes mellitus (DM), uncontrolled hypertension (HTN), severe hypotension, coronary artery disease (CAD), metabolic syndrome, glaucoma, liver impairment, decreased renal function, respiratory disorders, and uncontrolled peptic ulcer disease.
3. Currently taking any other medications, including over-the-counter supplements except oral contraceptives for women and Tylenol as needed for pain or headache.
4. Currently pregnant or breastfeeding. Females of child-bearing age must be using an effective contraceptive method.
5. History of substance abuse or dependence.
6. Contraindication to MR scan (claustrophobia, cardiac pacemakers, metal clips and stents on blood vessels, artificial heart valves, artificial arms, hands, legs, etc., brain stimulator devices, implanted drug pumps, ear implants, eye implants or known metal fragments in eyes, exposure to shrapnel or metal filings, other metallic surgical hardware in vital areas, certain tattoos with metallic ink, certain transdermal patches, metal- containing IUDs)
7. Medical condition that would prevent blood draws, including current anti-coagulant or anti-aggregant therapy, tendency for abnormal scarring (e.g., keloids).
8. Difficulty in swallowing capsules.