Nicotinamide Riboside, Vitamin B3 Form Taken in Trial, Aids Cell Energy

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by Steve Bryson, PhD |

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A modified form of vitamin B3 called nicotinamide riboside (NR), taken as an oral supplement, increased levels of an energy production molecule in the brain and altered brain metabolism over one month in a small group of newly diagnosed Parkinson’s disease patients, according to results of a Phase 1 trial.

Mild clinical improvements were seen in participants whose brain levels of NAD, the molecule involved in cellular energy production, rose more than 10% with treatment.

These findings supported an ongoing, one-year Phase 2 study (NCT03568968) in Norway to further investigate the supplement’s effects on disease severity in up to 400 recently diagnosed Parkinson’s patients, ages 18 and older. The trial, currently recruiting at sites across that country, will run through 2023, ChromaDex, the therapy’s developer, said in a press release.

“The results of this [Phase 1] study in humans are an encouraging step forward for Parkinson’s research and a potentially promising alternative … therapy,” said Andrew Shao, PhD, senior vice president of Global Scientific & Regulatory Affairs at ChromaDex. “We look forward to further research aimed at understanding the role of NR supplementation in Parkinson’s patients.”

Trial findings are detailed in “The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson’s disease,” published in the journal Cell Metabolism.

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Abnormal energy metabolism due to problems in the workings of mitochondria, the organelles that serve as a cell’s power source, is thought to play a role in both Parkinson’s initiation and progression.

Nicotinamide adenine dinucleotide (NAD) is a molecule essential for proper mitochondria function, and emerging evidence suggests that boosting cellular levels of NAD may have protective effects in neurodegenerative diseases.

NAD can be replenished by supplementing with nicotinamide riboside — a modified form of vitamin B3 (niacin) and a precursor of NAD. Cell and animal studies suggest that NR supplements were neuroprotective in models of amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease.

Nicotinamide riboside is also the active ingredient in Niagen, a dietary supplement for “healthy aging” marketed ChromaDex.

A Norwegian research team led by Charalampos Tzoulis, MD, PhD, at Haukeland University Hospital and the University of Bergen, conducted a Phase 1 study called NADPARK (NCT03816020) to evaluate whether NR can alter NAD levels and affect metabolism in the brains of people newly diagnosed with Parkinson’s and not yet under dopamine-replacing treatment.

“We believe that augmenting the brain’s NAD metabolism will not only target and rectify disease-related processes specific to [Parkinson’s] but may also optimize neuronal metabolism and fortify neurons, rendering them more resilient against age-related stress and neurodegenerative diseases,” Tzoulis said.

NADPARK enrolled 30 adults newly diagnosed with Parkinson’s and not yet under treatments to replace dopamine, the nerve cell signaling molecule that is abnormally low in these patients. Half were randomly assigned 1000 mg daily of nicotinamide riboside, and the other half to placebo capsules. Clinical and brain imaging tests were used to assess patients at the study’s start (baseline) and after 30 days of NR treatment.

Using an imaging technique called magnetic resonance spectroscopy (MRS), NAD levels were found to be significantly higher in the brains of NR-treated patients, but not among those in the placebo group. Specifically, 10 of 13 treated patients who underwent MRS showed higher NAD levels in the brain, with nine of them exceeding 10% of baseline levels, the researchers reported.

Positron emission tomography (PET) scan showed altered metabolic activity in the 10 people with higher NAD levels after daily supplement use. This NR-related metabolic pattern was not evident in those with no NAD rise or in placebo patients. No significant correlations were observed between treatment-related changes in brain NAD levels and the NR-related metabolic pattern in either group.

Disease severity, as measured by the Movement Disorder Society Unified Parkinson’s disease rating scale (MDS-UPDRS), showed no overall differences between NR treatment and placebo, or in subsections part 1 (behavior and mood), part 2 (activities of daily living), or part 3 (motor function).

However, the nine patients whose brain NAD levels exceeded 10% with NR treatment showed significant improvements in MDS-UPDRS scores for mood and behavior (part 1) and motor function (part 3).

“NR recipients showing increased brain NAD levels exhibited altered cerebral metabolism … and this was associated with mild clinical improvement,” the researchers wrote.

NR supplements substantially increased a NAD breakdown product called Me-2-PY in the cerebrospinal fluid (CSF), the liquid that surrounds the brain and spinal cord. No other NAD metabolites were found in treated patients’ CSF, which “further corroborated that oral NR therapy increases brain NAD levels,” they added.

Several NAD-related metabolites were elevated in muscle tissue, and in immune cells to a lesser extent. NR supplementation was associated with changes in the activity of 58 genes in muscles, and the activity of 13 genes in immune cells.

A mild but significant decrease was seen in the blood levels of GDF15 in patients given NR supplements, but not in the CSF. GDF15 is a mitochondrial marker, and this change “could be indicative of improved mitochondrial function,” the researchers wrote.

Several pro-inflammatory immune signaling proteins were also lower in the bloodstream and/or CSF in the NR treatment group. Some of these proteins were also lower in placebo patients.

“These findings, particularly the effects on pro-inflammatory cytokines and clinical symptoms, are clearly supportive of carrying out larger trials in Parkinson disease patients,” said Rudolph Tanzi, PhD, vice-chair of neurology and co-director of McCance Center for Brain Health at Massachusetts General Hospital, a professor of neurology at Harvard Medical School, and a member of the ChromaDex scientific advisory board.

Levels of neurofilament light chain, a marker of nerve damage, were unchanged with NR treatment in both the blood and CSF.

“The results of the trial are highly encouraging and nominate NR as a potential neuroprotective therapy for [Parkinson’s disease], warranting further investigation in larger trials,” Tzoulis said.