Background
Nicotinamide riboside (NR) is a patented analog of nicotinamide or Vitamin B3, and is sold as a dietary supplement under the brand name Tru Niagen. Cells use NR to synthesize NAD+, an essential cofactor for many processes including ATP generation and DNA repair, and a key sensor of cellular metabolism. NAD+ becomes depleted as people age, and strategies to increase its concentration are being pursued in attempts to improve metabolic health, slow aging, and treat age-related diseases.
Extensive preclinical research supports the idea that boosting NAD+ levels can increase both an animal's health and life span by ameliorating mitochondrial failure, oxidative stress, and dysfunctional proteostasis, among other deficits. Multiple studies in transgenic mice show benefits of NR on Aβ and tau pathology, oxidative stress, mitochondrial function, DNA repair, and cognition (e.g. Hou et al., 2018; Sorrentino et al., 2017; Gong et al., 2013). NR is active in models of brain aging, amyotrophic lateral sclerosis, Huntington’s disease, and Parkinson’s disease (reviewed in Lautrup et al., 2019).
NR is claimed to have better bioavailability and pharmacokinetics than nicotinic acid or nicotinamide, commonly occurring forms of Vitamin B3 used in many supplements (Trammell et al., 2016).
Findings
Multiple Phase 1 studies have examined the pharmacokinetics, pharmacodynamics, and safety of NR supplements. In one study of 60 healthy men, 1,000 mg daily for six weeks elevated blood NAD+ levels, with most participants reporting no side effects (Martens et al., 2018). A company-sponsored study in 140 healthy adults who took up to 1,000 mg/day for eight weeks noted similar tolerability. Blood NAD+ and other metabolites increased by week two, and stayed elevated for the rest of the study (Conze et al., 2019). The same regimen was reported to boost skeletal muscle NAD+ (Elhassan et al, 2019, and see review of early studies by Conlon and Ford, 2022).
In October 2017, a study began to assess the effects of NR on brain NAD+ and energetics using magnetic resonance spectroscopy in healthy adults. In an open-label design, 60 participants are taking 2,000 mg NR daily for two weeks, followed by MRS determination of NAD+/NADH, phosphocreatine/ATP, and creatine kinase activity in brain and muscle. The study, at McLean Hospital in Massachusetts, will finish in September 2022.
From November 2017 on, a single-center study compared a 10-week course of NR to placebo on cognition and brain blood flow in 46 people with mild cognitive impairment. The study titrated NR dose to a maximum of 1,000 mg daily, against a primary outcome of change on the Montreal Cognitive Assessment. Secondary outcomes included functional MRI measures of blood flow, plasma NAD levels, other cognitive and functional assessments, and blood pressure. The trial, at the University of Texas San Antonio, finished in August 2021.
From June 2018 to July 2019, Chromadex assessed effects of NR on cognitive function, mood, and sleep in healthy adults over 55. The study enrolled 40 people, who took placebo, 300, or 1,000 mg/day for eight weeks each in a crossover design. The cognitive outcome is the CNS Vital Signs computerized neurocognitive test battery (Gualtieri and Johnson, 2006). No results have been made public.
In December 2018, a trial began to test a 12-week regimen of 1,000 mg NR daily or placebo in 58 people with mild cognitive impairment. The primary outcomes are change in one or more domains of cognitive function including memory, attention, processing speed, executive function, and language. Secondary and other endpoints include measures of brain blood flow, blood pressure, functional and structural MRI. Completion of the study, running at the University of Delaware, is slated for March 2023.
In March 2019, a Phase 1 trial began at Haukeland University Hospital in Norway, testing brain entry and metabolic response to nicotinamide riboside in people with Parkinson’s disease. Thirty newly diagnosed and drug-naïve patients with DAT Scan evidence of nigrostriatal degeneration were randomly assigned to 1,000 mg NR twice a day or placebo for 30 days. No dopamine treatment was allowed during the study. Primary outcomes included magnetic resonance spectroscopy, CSF metabolomics, and FDG-PET. The trial was completed in February 2020, and results published after peer review (Brakedal et al., 2022). NR supplementation increased brain NAD+, and CSF metabolites in 10 of 13 patients analyzed. These responders had changes in their brain metabolism by FDG-PET, which were associated with a trend for clinical improvement on the MDS-UPDRS. A transcriptional analysis found changes related to mitochondria, and lysosomal/proteasome function in blood cells and skeletal muscle of responders, as well as reductions in CSF inflammatory cytokines, that were not seen in those taking placebo. Adverse events were minor, and none were judged related to NR.
In May 2020, the same group began a Phase 2 trial in 400 early PD patients. Participants go on stable treatment with selegiline and L-dopa, then add on supplements of 1,000 mg daily NR or placebo for one year. The primary outcome is MDS-UPDRS; secondary measures are NAD metabolites in blood. The study is to run at eight hospitals in Norway through March 2024.
In October 2020, a study began to assess NR supplementation in people with subjective cognitive decline or mild cognitive impairment. The single-center, cross-over study, assigns 40 participants to 1,200 mg NR daily, or placebo, for eight weeks, against a primary outcome of cognitive performance on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), with optional lumbar puncture and MRI sub studies. Between study visits, participants wear a Fitbit activity tracker and play computerized brain games several times a week. The study, at Massachusetts General Hospital, is slated to end in Aug 2022.
In March 2022, an open-label study began at McLean Hospital in Massachusetts to examine the effects of NR on metabolism, oxidative stress, and cognition in people with MCI or mild AD. Fifty participants with a clinical diagnosis and at least one copy of the ApoE4 allele will take NR 1,000 mg daily for 12 weeks. Primary outcomes are MRS changes in brain NAD+; secondary measures include brain casein kinase activity and GSH antioxidant levels, as well as the RBANS and ADCS-ADL. This study will deploy passive sensing devices in the bedrooms of 40 participants. The devices emit low-powered radio signals whose reflections are collected and used to track movement, breathing, and sleep. The study is slated to end in April 2025.
A combination of NR and the resveratrol analog pterostilbene (EH301, by Elysium Health), is in testing for ALS. A four-month pilot study was reported to have positive results (see news and commentary on de la Rubia et al., 2019). A one-year trial with optional extension began enrolling 380 patients in 2020 in Norway, with a primary completion expected in October 2022.
Other ongoing trials are testing NR for frailty in veterans, to improve skeletal muscle and bone metabolic function in healthy elderly, for the inherited neurodegenerative disease Friedreich’s ataxia, premature aging diseases, cardiovascular diseases, hypertension, kidney disease, cancer, SARS-CoV-2 infection, Gulf War Illness, and other indications.
Another vitamin B3 version, nicotinamide, is also in trials for AD and PD. A six-month trial in 50 people with mild to moderate AD at the University of California, Irvine, was claimed to show safety, but was too small to detect cognitive improvement (April 2012 news). A second study at UC Irvine has since enrolled 48 participants with MCI or early AD to test the effects of nicotinamide on CSF tau phosphorylated at residue 231. It will finish in August 2022. In January 2020, the VA Medical Center in Augusta, Georgia, began testing 18 months of nicotinic acid or nicotinamide in 100 people with PD, with a primary completion date of November 2023.
For nicotinamide riboside trials, see clinicialtrials.gov.
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