Evidence Trace, complete trial record

In plain terms

In plain terms: NAD+ (Direct Oral Supplementation) has not yet been tested in a human trial designed to measure the outcome relevant here. The available human research does not yet answer the question.

NAD+ (Direct Oral Supplementation)

D Not shown: no human trial shows benefit

Route 1 — no qualifying human trial has been conducted

Category Supplements

Evidence No outcome trial; one randomized pharmacokinetic study of a proprietary formulation (D Route 1)

Reviewed July 2026

PMIDs 33888596 · 35479740 · 39044608 · 27721479 · 42530810 · 41655607

The endpoint this grade is based on: Hard clinical endpoint (mortality, major event), No randomized trial has tested oral NAD+ itself on a clinical, functional or validated-scale outcome, and a 2026 systematic review found none for oral or intravenous NAD+. The one randomized trial of oral NAD+ (Kornilov 2026) tested a proprietary formulation for 5 days with blood NAD as its primary endpoint; its authors are linked to the formulation's developer. Route 1. The trials commonly cited for NAD+ supplementation are trials of its precursors, NMN and NR, which are different molecules.

The evidence as the record states it

Evidence record

PMID 33888596 PMID 35479740 PMID 39044608 PMID 27721479 PMID 42530810 PMID 41655607

Not established in humans on any outcome. Kornilov et al. (GeroScience, 2026; PMID 42530810): double-blind randomized placebo-controlled phase 0/1b trial, 60 healthy adults aged 45 to 75 randomized and 50 analyzed, 5 days of a proprietary physicochemically modified oral NAD+ formulation; whole-blood intracellular NAD rose 53 percent against placebo while plasma NAD was unchanged, consistent with gut hydrolysis of ordinary NAD+ to nicotinamide; the authors are linked to the company developing the formulation; no clinical outcome. Gallagher et al. (Aging Res Rev, 2026; PMID 41655607): systematic review of 33 human intervention studies of NAD-related compounds; no eligible outcome trial evaluated oral, intravenous or intramuscular NAD+ itself, and the precursor trials showed biochemical target engagement with heterogeneous and often null functional outcomes. The validated oral route is the precursors: nicotinamide riboside is orally bioavailable in humans, Trammell et al. (Nat Commun, 2016; PMID 27721479). The precursor trials are Yoshino et al. (Science, 2021; PMID 33888596): NMN improved muscle insulin sensitivity in postmenopausal women with prediabetes who were overweight or obese; Okabe et al. (Front Nutr, 2022; PMID 35479740): oral NMN raised blood NAD+ levels in healthy subjects; and Nanga et al. (Magn Reson Med, 2024; PMID 39044608): acute nicotinamide riboside raised cerebral NAD+ measured in vivo. None of them tested intact oral NAD+, which is why this entry is graded D and they are not. See NMN (Grade C) and NR (Grade C). Oral NADH, the reduced form, has small trials in chronic fatigue syndrome mostly combined with coenzyme Q10; it is a different form and a combination, and does not grade this record.

PMID 33888596 PMID 35479740 PMID 39044608 PMID 27721479 PMID 42530810 PMID 41655607

Animal lifespan data and mechanistic plausibility are excluded from EBL grades by rule. They inform the scientific rationale but do not carry the letter.

Why Grade D Route 1 and not Grade C

Grade D Route 1 applies when no qualifying human randomized trial has tested this compound or intervention against the relevant endpoint. Absence confirmed: oral nicotinamide adenine dinucleotide (NAD+) supplementation AND humans[mesh] AND (randomized controlled trial[pt] OR clinical trial[pt]) (PubMed, October 2026)

The first qualifying human RCT with a meaningful endpoint would move this to Grade C or higher, depending on what it shows.

What would move this grade

The first qualifying randomized controlled trial in humans, testing this intervention against a meaningful aging-relevant endpoint, would initiate grading. Depending on the result, it could land at any grade from A to D.

How to track whether this is working For direct oral NAD+, plasma NAD alone should not be used as the response marker. A 2026 randomized trial of a proprietary oral NAD+ formulation increased whole-blood intracellular NAD without increasing plasma NAD. This is formulation-specific and short-term; there is still no validated clinical outcome marker for ordinary oral NAD+ supplements.