What are the uses and safety of Nicotinamide adenine dinucleotide (NAD) injections?

NAD Injections: Clinical Uses and Safety Profile

Direct Recommendation

NAD injections should not be used for therapeutic medical purposes outside of research protocols, as there are no established clinical guidelines supporting their use, no proven clinical benefits, and concerns about poor pharmacokinetics and potential adverse effects. 1

Evidence-Based Assessment

Lack of Clinical Support

• The American Academy of Physical Medicine and Rehabilitation does not recommend NAD administration (including patches and by extension, injections) due to lack of clinical evidence 1, 2
• FDA labeling for intravenous NAD lists only cosmetic uses, not therapeutic medical indications 1
• No established clinical guidelines recommend NAD injections for any medical condition 2
• Despite decades of investigation, only a small number of randomized and adequately powered clinical trials of NAD upregulation have been conducted 3

Efficacy Concerns

• The efficacy of NAD precursors in humans is lower than expected from preclinical studies 4
• While preclinical studies in rodents show beneficial effects, these results have not been successfully recapitulated in human clinical trials 5
• Most evidence supporting NAD supplementation comes from 113 preclinical studies versus only 34 clinical studies, indicating a significant evidence gap 5

Safety Considerations and Potential Risks

Acute toxicity profile:

• High doses of nicotinic acid (a NAD precursor) can cause flushing, nausea, vomiting, liver toxicity, blurred vision, and impaired glucose tolerance 1, 2
• The upper intake level for nicotinic acid is only 10 mg/day due to flushing effects 1, 2
• Potential gastrointestinal symptoms including nausea, vomiting, and diarrhea may occur 6

Long-term and mechanistic concerns:

• Potential risks include accumulation of putative toxic metabolites, tumorigenesis, and promotion of cellular senescence 5
• NAD(P)H oxidase activity has been implicated in anthracycline-induced cardiotoxicity, raising concerns about NAD supplementation in certain clinical contexts 1
• High-dose nicotinamide may cause epigenetic alterations through effects on DNA and protein methylation, leading to changes in cellular transcriptome and proteome 7
• Nicotinamide inhibits poly(ADP-ribose) polymerases (PARPs), which protect genome integrity 7
• Evidence for long-term safety in humans remains quite limited 5

Clinical Algorithm for Patient Inquiries

Step 1: First-line approach

• Recommend dietary sources of niacin (meat, poultry, red fish such as tuna and salmon, nuts, legumes, and seeds) as the primary method to support NAD levels 6, 1
• Adult males require 16 mg/day and adult females 14 mg/day of niacin 6

Step 2: If deficiency is suspected

• Measure blood or tissue NAD levels in the presence of pellagra symptoms (diarrhea, dermatitis, dementia) 1
• Urinary metabolites (N-methyl-nicotinamide and N-methyl-2-pyridone-carboxamide) can assess niacin status 6

Step 3: If deficiency is confirmed

• Use oral nicotinic acid (15-20 mg/day) or nicotinamide (300 mg/day) for pellagra treatment 1
• The oral/enteral route should be used whenever the gastrointestinal tract is functional 1

Step 4: Avoid NAD injections

• Do not recommend NAD infusion for therapeutic purposes given the lack of guideline support, poor pharmacokinetics, and absence of proven clinical benefit 1

Alternative Evidence-Based Approaches

• Physiological means of raising NAD levels, such as exercise programs and dietary interventions tailored to older individuals, may be more effective than pharmacological supplementation 3
• For patients requiring parenteral nutrition, provide at least 40 mg of niacin per day 6, 1
• When niacin deficiency is suspected in parenteral nutrition patients, higher doses may be required 1

Critical Pitfalls to Avoid

• Do not assume that preclinical benefits in animal models will translate to human efficacy 4, 5
• Avoid recommending NAD injections based solely on marketing claims about "anti-aging" or "energy enhancement" without clinical evidence 1, 2
• Do not overlook the complexity of NAD metabolism, including host-gut microbiota interactions that affect NAD precursor metabolism 4
• Be cautious about chronic high-dose supplementation due to potential epigenetic risks 7