Efficacy and Safety of NAD+ Precursors in Clinical Trials

A recent systematic review evaluated ten studies with NAD+ precursors for efficacy and safety.

Key Points

  • NADH (10-20 mg) was found to be safe and effective in chronic fatigue syndrome and Alzheimer’s disease
  • Studies evaluating NR (100-1,000 mg) reported efficacy and overall safety in Parkinson’s disease, healthy adults, and in overweight adults
  • NR (2000 mg) was safe in nondiabetic obese men, but did not have an effect on glucose metabolism
  • No significant effects were seen after L-tryptophan, NA, and NAM  supplementation in physically compromised older adults
  • NMN (250 mg) was safe and showed benefits in older Japanese men and prediabetic women

Nicotinamide adenine dinucleotide (NADH)

Study 1.

In patients with chronic fatigue syndrome (CFS), 31% responded favorably to 4 week supplementation of NADH (10 mg), whereas 8% responded favorably to placebo. Side effects included single cases of being overly stimulated, mild loss of appetite, heartburn, increased incidence of gas, and an odd taste and dryness reported on the first day of taking the drug.

“These events were mild enough that the subjects were able to continue taking the drug without problem”

Study 2.

In a separate study, NADH (20 mg) supplementation for 3 months reduced anxiety in patients with CFS . The study demonstrated the importance of NADH in cellular energy production and dopamine production. An increase in body pain was reported (17.6 to 18.4% after treatment).

Study 3.

NADH (10 mg) supplementation in Alzheimer’s disease patients for 6 months showed variable results. Improvements were seen in verbal fluency, visual-constructional ability and a trend for better performance on a measure of abstract verbal reasoning, whereas no differences between groups were seen for measures of attention, memory, or in clinician ratings of dementia severity (Clinical Dementia Rating). There was no mention of adverse events in the paper.

“Consistent with earlier studies, the present findings support NADH as a treatment for AD.”

Nicotinamide Riboside (NR)

Study 4. 

Supplementation with NR (1000 mg/day for 30 days) significantly increased brain NAD+ levels in patients with Parkinson’s disease. Minor adverse events were reported (7 in the NR group and 3 in the placebo group), and were found to be unrelated to NR.

Study 5.

In nondiabetic men with obesity, supplementation with NR (1000 mg twice daily) for 12 weeks did not have an effect on glucose metabolism.Safety information was published in a separate paper, and reported that NR was well tolerated. (Dollerup et.al, 2018)  Four participants in the NR group and two participants in the placebo group reported minor adverse events. The NR group reported pruritus, excessive sweating, bloating, and transient changes in stool, whereas the placebo group acid refux and periodic loose stools. Each adverse event was minor

Study 6. 

The safety of NR (1000 mg/day) was examined in healthy middle aged and older adults in a 2 x 6 week crossover trial. Adverse events were mild for both placebo and NR. The adverse events reported for each group are listed below, with the number of events in parenthesis:

  • Placebo group: headaches (4), skin rash (1), flushing (2), and drowsiness (1)
  • NR group: nausea (1), skin rash (1), flushing (1), leg cramps (1), and increased bruising (1)

Two people dropped out of the study due an adverse event in the placebo phase (headache and skin rash). There were no dropouts due to adverse events in the NR phase.

Additionally, the exploratory analyses showed NR reduced SBP and aortic stiffness.

Study 7. 

The safety of NR was further demonstrated in a 8 week clinical trial in overweight, but otherwise healthy adults. Consumption of 100, 300 and 1000 mg NR dose-dependently and significantly increased whole blood NAD+.

Overall, they found the NR treatments to be safe:

  • No serious AEs or reports of flushing.
  • The type, incidence and severity of the AEs were similar between placebo and the NR groups, and between different NR dosages
  • AEs reported as being possibly related were as follows:
    • 100 mg NR group: 2 mild-intensity AEs (leg pain and high blood pressure)
    • 300 mg NR group: 2 mild-intensity AEs (nausea and muscle pain)
    • 1000 mg NR group: 3 mild-intensity AEs (sore back, muscle soreness and nausea)
    • Placebo group: 3 mild-intensity AEs (rash, raised liver function tests, nausea) and 1 moderate-intensity (upset stomach)

L-tryptophan, Nicotinic Acid (NA), and Nicotinamide (NAM)

Study 8. 

A crossover trial provided the equivalent of 207.5 mg/day niacin equivalents (NE) of the NAD+ precursors L-tryptophan, Nicotinic Acid, and Nicotinamide (32 days per NAD+ precursor with 5 weeks of washout in between) to 13 physically compromised older adults. No significant effects of the NAD+ precursors were observed and adverse events were not mentioned in the study.

Nicotinamide Mononucleotide (NMN)

Study 9.  

NMN (250 mg) supplementation for 12 weeks in older Japanese adults improved lower limb function and reduced drowsiness. No side effects were reported.

“These findings suggest the potential of NMN in preventing loss of physical performance and improving fatigue in older adults.”

Study 10. 

In overweight or obese pre-diabetic women, NMN (250 mg) for 10 weeks increased muscle insulin sensitivity in prediabetic women. No adverse events were reported.

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