NAD and the Ageing Brain: Part Five: Two Trials, Two Standards

Abstract

Two trials of nicotinamide riboside are recruiting in the United States. Both concern the ageing brain, both were registered in advance, and both will eventually be described in consumer material with the same four words: a clinical trial showed.

One has 50 participants, single masking and a questionnaire as its primary outcome. The other has 214, triple masking, and four objective physiological measures of one process.

This part closes the series by setting them side by side, because the distance between them is the most useful thing in this whole file.

1.Buffalo: Sleep in Older Veterans

Registry entry NCT05500170 is titled "The Benefits of Nicotinamide Riboside Upon Cognition and Sleep in Older Veterans", sponsored by the State University of New York at Buffalo with no listed collaborators. It has been recruiting since April 2023 and is scheduled to complete in August 2027.

Fifty participants are randomised to nicotinamide riboside or a microcellulose placebo. Entry requires a Pittsburgh Sleep Quality Index global score above 5 — established poor sleep — and dementia is excluded by a screening cut-off. The primary outcome is sleep quality at twelve weeks; cognitive function is secondary.

Two design features will shape what its result can mean. The masking is single, not double. And the primary outcome is a sleep quality assessment rather than a physiological recording — the same combination our L-theanine series found producing movement in questionnaires while devices recorded nothing.

The title deserves a sentence of its own. "The Benefits of" states a conclusion in the name of the study that exists to test whether the conclusion holds. Registry titles are written by investigators, and they occasionally reveal a prior.

This is also the trial cited among the registered studies in the circadian review from Part Four, which makes it the nearest thing the field has to a direct test of that hypothesis.

2.Oklahoma: Blood Flow in Community-Dwelling Adults

Registry entry NCT05483465, "Effects of NAD Restoration on Neurovascular Coupling in Community Dwelling Older Adults", is sponsored by the University of Oklahoma with the University of Pennsylvania, the Oklahoma Medical Research Foundation and Elysium Health as collaborators. Elysium Health sells nicotinamide riboside commercially — a disclosure to carry into the results.

It is a phase 4 trial: 214 participants aged 60 to 85 with a Mini-Mental State Examination score of at least 24, randomised under triple masking to 1 gram of nicotinamide riboside daily or a visually identical placebo, for eight weeks. Recruiting since May 2023, completing June 2027.

The dose matches the 1 gram at which Part One documented a 60 per cent rise in cellular NAD+. Target engagement is expected rather than hoped for.

The primary outcomes are the reason to watch it. Neurovascular coupling — the mechanism Part Three described in mice — is measured by functional near-infrared spectroscopy, by transcranial Doppler, and by dynamic retinal vessel analysis, with neuronal activity as a fourth measure.

Three independent techniques applied to one construct is convergent measurement, and it is rare outside pharmacology. A positive result cannot easily be an artefact of one instrument; a null cannot easily be blamed on insensitive equipment. Both directions become interpretable, which is the entire purpose of designing a trial well.

3.What Separates Them

Neither trial is dishonest. Both were registered before recruitment, both state their outcomes in advance, and the smaller one has no commercial collaborator at all while the larger one does.

What separates them is how much each invested in being able to believe its own answer. Fifty participants against 214. One party unblinded against four. A questionnaire against three physiological instruments measuring the same thing.

This is the practical case for reading registry entries at all. By the time both reach publication, the difference will be invisible in any summary a consumer encounters, and the weaker result will travel just as far as the stronger one — possibly further, since sleep quality is easier to write a headline about than neurovascular coupling.

4.How We Will Read Them

For Oklahoma: do the three techniques agree? Concordance across near-infrared spectroscopy, Doppler and retinal analysis would be a strong signal. Divergence would be a finding about the methods, and worth knowing separately.

For Buffalo: was anything objective recorded, and was NAD+ measured? The registry names a sleep quality assessment without specifying the instrument, and does not state the dose. A paper reporting outcomes without reporting NAD+ has omitted the one number that makes the rest interpretable.

For both: does anything cognitive accompany the physiology? Restoring neurovascular coupling over eight weeks would be biologically interesting and would still not establish that anyone thinks or remembers better. Those are separate claims needing separate, longer trials.

And one note on timing. Buffalo opened recruitment in April 2023 for 50 participants and has moved its completion to August 2027. A four-year enrolment for a fifty-person trial usually means recruitment is difficult.

5.Where Five Parts Leave the Question

The molecule reaches its target: NAD+ rises by roughly 60 per cent at 1 gram a day, documented in a crossover trial. In the same trial, nothing functional followed.

Where the question has been tested most thoroughly, in muscle, the pooled randomised evidence is null across every outcome, with one subgroup result running the wrong way in people with mild cognitive impairment.

The mechanism in the brain is well described and it is described in mice, using a different molecule from the one humans are given.

The most specific remaining hypothesis is circadian, and on its own authors' account the best-supported interventions within that framework are light timing, activity and meals.

Two trials will report in 2027. One of them is built well enough that its answer will mean something either way.

Editorial Comment

MindHeaven® does not use nicotinamide riboside or nicotinamide mononucleotide, and makes no claim about NAD+ restoration, sleep, cerebral blood flow or cognition.

Boost contains niacinamide at 20 mg, which is 125 per cent of the nutrient reference value, and niacinamide is itself an NAD+ precursor from the same vitamin family. A reader could reasonably ask whether this series describes our own ingredient's neighbourhood, so here is the distinction precisely.

Niacin contributes to the reduction of tiredness and fatigue. That is an authorised health claim under Reg. (EU) 432/2012, it attaches to the vitamin rather than to our product, and that wording is the entire extent of what may be said. Correcting a vitamin intake so that ordinary energy metabolism runs normally is a different proposition from raising NAD+ above normal to change an ageing brain — the first has a regulatory basis and a nutritional rationale, the second is what these five parts have been about, and nothing above establishes it.

When the Oklahoma trial reports, we will cover it here, including if it is positive and including if it is null. Committing to that now, while the answer is unknown, is the only reason writing this series in advance is worth anything.

Cerebral blood flow and sleep are both affected by things with far stronger evidence than any supplement: blood pressure control, physical activity, sleep-disordered breathing, alcohol, and the timing of light. If brain health at 60 is the concern, those are the conversation to have with a doctor now rather than a trial to wait for.