Nicotinamide riboside raised NAD+ by about 60% in older adults. Nothing else clearly changed

In a small randomised, placebo-controlled crossover trial, six weeks of nicotinamide riboside (NR), 500 mg twice a day, raised NAD+ in circulating blood cells by about 60% in healthy adults aged 55 to 79 [1]. It was well tolerated. Blood pressure and arterial stiffness moved in a promising direction, but not by enough to count after the trial's own statistical corrections, and the paper is explicit that those results were exploratory [1].

Why this study matters

NAD+ is a molecule every cell needs for energy metabolism, and levels decline with age in animals and in people, according to the studies the authors review [1]. In animal models, raising NAD+ with precursors such as NR or NMN improves several physiological functions [1]. The obvious next question is whether a pill does anything similar in people.

Earlier work had shown that single doses of NR raise NAD+-related molecules in human blood in a dose-dependent way [2]. What nobody had tested was whether taking it every day for weeks was well tolerated and kept NAD+ raised. This 2018 Nature Communications paper from the University of Colorado Boulder set out to test exactly that [1], and it's the source of the widely quoted “60% increase” figure.

What they did

In a crossover design, each person takes both treatments in turn, so they act as their own comparison. Half took NR first and placebo second; the other half did the reverse [1].

The participants were healthy and lean, with an average BMI of 24 and normal blood pressure, cholesterol and glucose on average. They did have one thing in common: all had some age-related decline in the function of their artery lining, which was an entry requirement [1]. Of 60 people who consented, 30 were randomised and 24 finished [1].

The main outcomes were tolerability and whether NR raised NAD+. NAD+ was measured in peripheral blood mononuclear cells (a type of white blood cell), because earlier work had found NAD+ undetectable in plasma and urine [1]. A long list of physiological measures, including blood pressure, arterial stiffness, metabolism, exercise capacity and motor function, was assessed as exploratory outcomes [1].

What they found

NAD+ went up. NAD+ in blood cells averaged about 60% higher after six weeks of NR than after placebo [1]. Another marker of NAD+ metabolism, NAAD, rose nearly fivefold. People with the lowest NAD+ during placebo tended to have the biggest rises [1].

That result comes with some fine print. It was analysed with a one-sided test, the median values were 7.7 versus 12.2 pmol per mg of protein with wide ranges, and the p value was 0.048, without adjustment [1]. The metabolite analysis covered 21 of the 24 completers [1]. NR itself wasn't detectable in the blood cells [1].

Blood pressure and arteries: a hint, not a finding. Systolic blood pressure averaged 3.9 mmHg lower on NR and diastolic 2.0 mmHg lower, but neither was significant after the correction for multiple comparisons the authors had set in advance [1]. In a post hoc split, people with elevated or stage 1 high blood pressure (13 people) had systolic readings about 9 mmHg lower on NR, while those with normal blood pressure saw no change. The authors say no statistical inference can be drawn from that subgroup [1]. Aortic stiffness showed a similar non-significant trend [1].

Everything else: no change. NR didn't affect artery-lining function, carotid artery flexibility, body weight or fat, energy expenditure, the mix of fat and carbohydrate burned, glucose or insulin, VO2 max, exercise performance or motor function [1].

Side effects

People took more than 95% of their capsules, and no serious adverse events occurred [1]. Seven of the 30 participants reported 14 mild adverse events in total. On NR, the reports were single cases of nausea, flushing, leg cramps, increased bruising and a skin rash. On placebo, there were headaches, a rash, flushing, fainting and drowsiness [1]. The two people who dropped out because of side effects were both taking placebo at the time. Routine blood tests for blood counts, kidney and liver function and lipids stayed within normal ranges in both phases [1].

Caveats

• Very small. 24 completers is enough to detect a large rise in a blood marker, not a modest change in blood pressure.
• Blood cells aren't organs. A rise in NAD+ in circulating white blood cells doesn't show that NAD+ rose in muscle, brain, heart or liver.
• Healthy, lean volunteers. The authors note this may have made improvements harder to see [1].
• Dose. The authors state that 1,000 mg a day was above the label-recommended dose of the supplement used, and should be considered investigational [1].
• Funding. The trial was funded by US National Institutes of Health grants, and the authors declared no competing interests [1]. The NR ingredient's manufacturer supplied the NR [1]. The earlier single-dose human study, by contrast, was sponsored by that manufacturer [2].

How it fits with other NR trials

A separate trial from Denmark gave 40 obese, insulin-resistant men 2,000 mg of NR a day, or placebo, for 12 weeks [3]. It found NR safe over that period but saw no improvement in insulin sensitivity, glucose handling, energy expenditure, fat metabolism or body composition [3]. Together, the two trials tell a consistent story: NR reliably raises NAD+ markers in blood, and short trials haven't shown that this changes the physiology people care about.

What it means in practice

This study supports two claims: NR at 1,000 mg a day for six weeks was well tolerated in 30 healthy older adults, and it raised NAD+ in their blood cells. It doesn't show that NR slows ageing, lowers blood pressure or improves fitness. The blood pressure signal was a reason to run a bigger trial, which is exactly how the authors framed it [1].

What we still don’t know

• Whether raising NAD+ in blood translates to meaningful rises in tissues such as muscle or brain.
• Whether NR lowers blood pressure in people with elevated readings, in a trial designed to test that.
• Long-term safety at doses above those on supplement labels.
• Whether any change in NAD+ leads to outcomes that matter, such as fewer cardiovascular events or better function in later life.

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