NAD+

NAD+ is a redox coenzyme central to glycolysis, the citric acid cycle, and oxidative phosphorylation, cycling between NAD+ and NADH.

Separately it is consumed as a substrate — not merely used as a cofactor — by sirtuins (which regulate metabolism and stress responses) and PARPs (DNA repair). This consumption is why NAD+ can become depleted under conditions of DNA damage or metabolic stress.

The age-related decline is documented across tissues, and restoring it is the premise of the whole NAD+ field.

Direct NAD+ is a large charged molecule and does not cross cell membranes efficiently, which is why precursors that cells can salvage into NAD+ are the pharmacologically sensible approach.

Nicotinamide riboside and NMN trials reliably increase blood NAD+ levels — that part works and is well replicated.

What has not followed is the clinical benefit: trials have generally not demonstrated meaningful improvements in metabolic parameters, physical function, or ageing markers in healthy adults.

Intravenous NAD+ has essentially no controlled trial evidence for the indications it is marketed for, despite widespread commercial availability.

The honest summary is that the biomarker moves and the outcomes largely have not.

Oral precursors (nicotinamide riboside, NMN, or plain niacinamide) are the best-studied route and the most practical.

Intravenous infusion requires clinical administration and is typically given slowly over hours specifically because faster rates are poorly tolerated.

Subcutaneous NAD+ is used in community practice and is commonly reported to sting considerably.

Oral precursors are well tolerated in trials, with mild gastrointestinal effects most common. Plain niacinamide avoids the flushing associated with nicotinic acid.

Intravenous NAD+ infusion reliably produces chest tightness, nausea, abdominal discomfort, and flushing when run quickly. These are rate-dependent and resolve on slowing, which is why infusions are given over hours.

Subcutaneous injection is reported as painful.

The theoretical long-term concern is that sirtuin and PARP activity intersects with cell survival pathways, and the consequences of chronically elevated NAD+ have not been characterised in humans.

Commonly combined with resveratrol on the sirtuin-activation rationale, which has weakened considerably as the sirtuin-activator literature has been re-examined.

No significant interaction concerns are documented for the precursors.

The underlying NAD+ biology is excellent and mainstream — this is real biochemistry published in leading journals.

The intervention literature is where it thins out: precursor trials raise the biomarker consistently and have repeatedly failed to show the functional benefits the field predicted. Intravenous NAD+ is commercially popular and scientifically almost unstudied.

Nicotinamide riboside and niacinamide are permitted dietary supplements. NMN's US status became contested after the FDA took the position that it is excluded from the supplement definition owing to prior drug investigation. Intravenous NAD+ is administered through clinics and compounding, outside any approval.

Not on the WADA Prohibited List. Sold as a dietary supplement rather than a drug, so the S0 unapproved-substance clause does not apply. Note that supplement contamination is a recognised source of inadvertent doping violations, and third-party batch testing is the only real mitigation.

NAD+ is a case where excellent fundamental biology has not translated into demonstrated benefit. The decline with age is real, the precursors do raise levels, and the outcomes trials have largely disappointed.

If you are going to engage with this, oral precursors have the evidence and the economics. IV infusions have neither, plus several hours of discomfort.