Nicotinamide riboside (NR) is
a newly discovered form of Vitamin B3. In the first controlled clinical trial of nicotinamide riboside, researchers have shown that the
compound is safe for humans and increases levels of a cell metabolite
that is critical for cellular energy production and protection against
stress and DNA damage.
Studies in mice have shown that boosting the levels of this cell
metabolite - known as NAD+ - can produce multiple health benefits,
including resistance to weight gain, improved control of blood sugar and
cholesterol, reduced nerve damage, and longer lifespan. Levels of NAD+
diminish with age, and it has been suggested that loss of this
metabolite may play a role in age-related health decline.
‘Nicotinamide riboside, a form of Vitamin B3, safely boosts levels of important cell metabolite linked to multiple health benefits.’
These findings in animal studies have spurred people to take
commercially available NR supplements designed to boost NAD+. However,
these over-the-counter supplements have not undergone clinical trials to
see if they work in people.
The new research, reported in the journal Nature Communications
was led by Charles Brenner, professor and Roy J. Carver Chair of
Biochemistry at the University of Iowa Carver College of Medicine in
collaboration with colleagues at Queens University Belfast and ChromaDex
Corp. (NASDAQ: CDXC),
which supplied the NR used in the trial. Brenner is a consultant for
ChromaDex. He also is co-founder and Chief Scientific Adviser of
ProHealthspan, which sells NR supplements under the trade name Tru
The human trial involved six men and six women, all healthy. Each
participant received single oral doses of 100 mg, 300 mg, or 1,000 mg of
NR in a different sequence with a seven-day gap between doses. After
each dose, blood and urine samples were collected and analyzed by
Brenner's lab to measure various NAD+ metabolites in a process called
metabolomics. The trial showed that the NR vitamin increased NAD+
metabolism by amounts directly related to the dose, and there were no
serious side effects with any of the doses.
"This trial shows that oral NR safely boosts human NAD+ metabolism,"
Brenner says. "We are excited because everything we are learning from
animal systems indicates that the effectiveness of NR depends on
preserving and/or boosting NAD+ and related compounds in the face of
metabolic stresses. Because the levels of supplementation in mice that
produce beneficial effects are achievable in people, it appears than
health benefits of NR will be translatable to humans safely."
The next step will be to study the effect of longer duration NR
supplementation on NAD+ metabolism in healthy adults, but Brenner also
has plans to test the effects of NR in people with diseases and health
conditions, including elevated cholesterol, obesity and diabetes, and
people at risk for chemotherapeutic peripheral neuropathy.
Self-study precedes clinical trial
Prior to the formal clinical trial, Brenner conducted a pilot human
study - on himself. In 2004, he had discovered that NR is a natural
product found in milk and that there is pathway to convert NR to NAD+ in
people. More than a decade of research on NR metabolic pathways and
health effects in mice and rats had convinced him that NR
supplementation had real promise to improve human health and wellness.
After consulting with UI's institutional review board, he conducted an
experiment in which he took one gram of NR once a day for seven days, and
his team analyzed blood and urine samples using mass spectrometry. The
experiment showed that Brenner's blood NAD+ increased by about 2.7
times. In addition, though he reported immediate sensitivity to flushing
with the related compound niacin, he did not experience any side
effects taking NR.
The biggest surprise from his metabolomic analysis was an increase
in a metabolite called NAAD, which was multiplied by 45 times, from
trace levels to amounts in the micromolar range that were easily
"While this was unexpected, I thought it might be useful," Brenner
says. "NAD+ is an abundant metabolite and it is sometimes hard to see
the needle move on levels of abundant metabolites. But when you can look
at a low-abundance metabolite that goes from undetectable to easily
detectable, there is a great signal to noise ratio, meaning that NAAD
levels could be a useful biomarker for tracking increases in NAD+ in
Brenner notes this was a case of bidirectional translational
science; having learned something from the initial human experiment, his
team was able to return to laboratory mice to explore the unexpected
NAAD finding in more detail.
First mice, then men and women
Brenner's mouse study showed that NAAD is formed from NR and
confirmed that NAAD levels are a strong biomarker for increased NAD+
metabolism. The experiments also revealed more detail about NAD+
In particular, the researchers compared the ability of all three
NAD+ precursor vitamins - NR, niacin, and nicotinamide - to boost NAD+
metabolism and stimulate the activity of certain enzymes, which have
been linked to longevity and health benefits. The study showed for the
first time that oral NR is superior to nicotinamide, which is better
than niacin in terms of the total amount of NAD+ produced at an
equivalent dose. NR was also the best of the three in stimulating the
activity of sirtuin enzymes. However, in this case, NR was the best at
stimulating sirtuin-like activities, followed by niacin, followed by
The information from the mouse study subsequently helped Brenner's
team design the formal clinical trial. In addition to showing that NR
boosts NAD+ in humans without adverse effects, the trial confirmed that
NAAD is a highly sensitive biomarker of NR supplementation in people.
"Now that we have demonstrated safety in this small clinical trial,
we are in a position to find out if the health benefits that we have
seen in animals can be reproduced in people," says Brenner, who also is
co-director of the Obesity Research and Education Initiative, professor
of internal medicine, and a member of the Fraternal Order of Eagles
Diabetes Research Center at the UI.