Nicotinamide Riboside Side Effects: What Studies Report

Nicotinamide riboside (NR) is an oral NAD⁺ precursor that has been tested in a series of small, mostly short-duration randomised trials. Much of that literature was designed primarily to record safety and tolerability rather than to demonstrate clinical benefit. This page summarises what those published reports stated about adverse events, dose exposure and the limits of the evidence. This page is for educational purposes only and is not medical advice; consult a licensed physician about any question concerning supplements, medications or symptoms.

How Safety Was Measured in Nicotinamide Riboside Trials

Most published NR studies collected adverse events as a secondary or co-primary outcome alongside blood NAD⁺ measurement. A 2023 review in Science Advances examined what is actually known about NR supplementation in humans and reported that while trials consistently raise NAD⁺ and related metabolites, the human evidence base for clinical effects remains small and inconsistent (PMID 37478182). That review is useful context for interpreting side-effect data: when trials enrol a few dozen participants for a few weeks, they can detect common, mild events but are not sized to detect rare ones.

Three features recur across the trials described below. First, sample sizes were generally in the tens rather than the hundreds. Second, exposure durations ranged from a single acute dose to several weeks or months. Third, several studies tested NR as one component of a multi-ingredient formulation, which complicates attribution of any event to NR itself.

Tolerability in Healthy Adults: What Studies Report

The most frequently referenced safety dataset in healthy volunteers is an 8-week randomised, double-blind, placebo-controlled trial of nicotinamide riboside chloride in healthy overweight adults, in which researchers administered 100, 300 or 1000 mg per day and reported dose-dependent increases in whole blood NAD⁺ without serious adverse events attributed to the supplement (PMID 31278280). The study also examined metabolic parameters over that period, and its authors framed the results as supporting tolerability of long-term administration at those daily amounts (PMID 31278280).

Acute exposure has also been characterised. In a study comparing NAD⁺ precursors included in combined metabolic activators, researchers reported on the acute plasma response after administration, providing pharmacological rather than long-term safety information (PMID 37271226).

High-Dose Exposure: What Studies Report

The dedicated high-dose safety trial in the published record is NR-SAFE, a randomised, double-blind trial in Parkinson's disease in which researchers administered 3000 mg of nicotinamide riboside per day for four weeks and reported that this high dose was safe and well tolerated in the participants studied (PMID 38016950). Because that trial was explicitly a safety study, its adverse-event reporting is more granular than in efficacy-oriented work, but the study population was small and the exposure period short (PMID 38016950).

The 2023 Science Advances review cautioned that extrapolating from such trials to broader populations or longer timeframes is not supported by the current human literature (PMID 37478182).

Clinical Populations: What Studies Report

Heart failure

In patients with heart failure with reduced ejection fraction, a clinical study assessed safety and tolerability of nicotinamide riboside and reported that administration was tolerated in that population while blood NAD⁺ levels rose (PMID 36644285). Interest in NAD⁺ precursors in cardiology is discussed mechanistically in a review of how systemic aging contributes to heart failure, which described NAD⁺ biology as one of several therapeutic avenues under investigation rather than an established treatment (PMID 39034866).

Cognition and neurological conditions

A randomised placebo-controlled trial of nicotinamide riboside in older adults with mild cognitive impairment reported on tolerability alongside NAD⁺ and cognitive outcomes in that group (PMID 37994989). In long-COVID, a randomised controlled trial examined the effects of nicotinamide riboside on NAD⁺ levels, cognition and symptom recovery (PMID 41357333). In ataxia telangiectasia, researchers reported that long-term nicotinamide riboside use improved coordination and eye movements in the patients followed (PMID 37899683). None of these reports was designed as a large-scale safety study, so their adverse-event information is descriptive.

Rare disease crossover data

A double-blind randomised crossover placebo-controlled trial in patients with Werner syndrome reported benefits of nicotinamide riboside supplementation in that rare genetic condition (PMID 40459998). Crossover designs allow each participant to serve as their own control, which can help separate background symptom fluctuation from treatment-period events, although the total number of participants in rare-disease trials is typically very small (PMID 40459998).

Animal Ototoxicity Findings: What Studies Report

Not every signal in the literature is reassuring. An experimental study published in 2024 reported an ototoxic effect of nicotinamide riboside in laboratory animals (PMID 39340621). Preclinical findings of this kind do not translate automatically to humans — species, exposure route and concentration all differ from oral supplementation studies — but the report illustrates that adverse-event profiles remain an active research question rather than a settled matter (PMID 39340621). Human NR trials summarised above focused on general tolerability and did not report audiometric outcomes as a primary endpoint (PMID 37478182).

Multi-Ingredient Formulations and Attribution: What Studies Report

Several trials tested NR inside a combination product. In a randomised, double-blinded, placebo-controlled phase-II trial, researchers reported that combined metabolic activators — a formulation that includes nicotinamide riboside among other components — improved cognitive functions in patients with Alzheimer's disease (PMID 36703196). A related study characterised the acute effect of different NAD⁺ precursors used within those combined metabolic activators (PMID 37271226). Because multiple actives were given together, any tolerability observation from those trials describes the formulation rather than NR in isolation (PMID 36703196).

Study-by-Study Overview

What the Literature Does Not Establish

Several questions remain open in the published record, and the 2023 review of human NR data made this explicit when it reported that firm conclusions about clinical effects are not yet supported (PMID 37478182). Specific gaps visible across the trials cited here include:

• Duration. The longest controlled tolerability dataset in healthy volunteers covered eight weeks (PMID 31278280), and the dedicated high-dose trial covered four weeks (PMID 38016950).
• Population breadth. Trials were conducted in defined groups such as Parkinson's disease, heart failure, mild cognitive impairment, long-COVID and Werner syndrome rather than in the general population (PMID 36644285, PMID 41357333).
• Organ-specific endpoints. The preclinical ototoxicity report was an animal study, and comparable human audiometric data are not part of the trials summarised here (PMID 39340621).
• Attribution in combinations. Combined metabolic activator trials evaluated a multi-component formulation containing NR, not NR alone (PMID 36703196).

Reading Side-Effect Data Critically

Adverse-event tables in small trials describe what happened to a specific group under specific conditions. Mild events are common in both active and placebo arms of supplement trials, which is why placebo-controlled designs such as those used in the healthy-volunteer study and NR-SAFE matter for interpretation (PMID 31278280, PMID 38016950). Mechanistic reviews add biological plausibility to why NAD⁺ precursors are being studied at all, as in the discussion of systemic aging pathways in heart failure, but reviews do not generate safety data themselves (PMID 39034866).

Readers comparing sources will notice that promotional summaries often emphasise benefit findings while trial publications emphasise uncertainty; the 2023 review was written specifically to separate those two registers (PMID 37478182). Again, this page is educational only and is not medical advice; questions about personal health, interactions or symptoms belong with a licensed physician.

References

• Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-controlled Clinical Trial of Healthy Overweight Adults (Scientific Reports, 2019)
• NR-SAFE: a randomized, double-blind safety trial of high dose nicotinamide riboside in Parkinson's disease (Nature Communications, 2023)
• What is really known about the effects of nicotinamide riboside supplementation in humans (Science Advances, 2023)
• Safety and Tolerability of Nicotinamide Riboside in Heart Failure With Reduced Ejection Fraction (JACC: Basic to Translational Science, 2022)
• A randomized placebo-controlled trial of nicotinamide riboside in older adults with mild cognitive impairment (GeroScience, 2024)
• Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial (eClinicalMedicine, 2025)
• Nicotinamide Riboside Supplementation Benefits in Patients With Werner Syndrome: A Double-Blind Randomized Crossover Placebo-Controlled Trial (Aging Cell, 2025)
• Long-Term Nicotinamide Riboside Use Improves Coordination and Eye Movements in Ataxia Telangiectasia (Movement Disorders, 2024)
• Ototoxic Effect of Nicotinamide Riboside (Bulletin of Experimental Biology and Medicine, 2024)
• Combined metabolic activators improve cognitive functions in Alzheimer's disease patients: a randomised, double-blinded, placebo-controlled phase-II trial (Translational Neurodegeneration, 2023)
• The acute effect of different NAD+ precursors included in the combined metabolic activators (Free Radical Biology & Medicine, 2023)
• Systemic aging fuels heart failure: Molecular mechanisms and therapeutic avenues (ESC Heart Failure, 2025)