NAD+ and Depression: What a Randomized Trial Actually Found

Written by the Nuvirox Research Team

Short answer: the one randomized, placebo-controlled trial that measured depression symptoms directly did not find a significant benefit from an NAD+ precursor over placebo — though an exploratory secondary analysis in the same study left the door open for further research. If you're dealing with low mood and searching for a supplement answer, the responsible thing to say is that this isn't where the strongest evidence currently points, and depression deserves an evaluation from someone qualified to treat it.

A note before going further

This article discusses research on NAD+ precursors and depressive symptoms in a general population studied for other reasons. It is not a treatment guide, and depression is a medical condition that ranges widely in severity — some presentations are life-threatening. If you are having thoughts of harming yourself, please reach out to a crisis line or emergency services in your area right away; in the US, you can call or text 988 for the Suicide & Crisis Lifeline. The rest of this article is written for people who want an honest look at the supplement research, alongside a serious recommendation to talk to a doctor or therapist about depression itself.

Why NAD+ gets connected to mood at all

NAD+ is essential for mitochondrial energy production in neurons, and some research has linked reduced brain energy metabolism to depressive symptoms. NAD+ is also a co-substrate for sirtuins, enzymes involved in stress-response regulation, and for enzymes in the kynurenine pathway, which links tryptophan metabolism (a precursor to serotonin) to inflammation and mood. These are legitimate areas of neuroscience research. The open question, as always, is whether raising NAD+ levels with an oral supplement translates into a measurable mood benefit in real people — and that's exactly what one 2025 trial tried to find out.

What the trial actually measured

Researchers ran a 24-week, double-blind, randomized, placebo-controlled trial of nicotinamide riboside (2000 mg/day) in 58 adults with long-COVID, a condition where depressive symptoms are common. Depression was assessed using the Beck Depression Inventory (BDI), a validated clinical scale, as a pre-specified secondary outcome. NAD+ levels rose substantially in the treatment group, confirming the supplement worked as intended metabolically. But the primary, controlled comparison between the NR group and the placebo group showed no significant difference in depression scores (p = 0.20).

The honest counterweight built into this trial

This is a case where the honest counterweight isn't a separate negative study — it's baked directly into the trial's own design. The controlled, between-group result (the one that actually rules out placebo effect) was null. But in a post-hoc, exploratory analysis, the researchers also looked at how the NR group's symptoms changed relative to their own baseline over 10 weeks, and found significant within-group improvement in depression scores that wasn't seen during the placebo phase. That's a genuinely interesting signal — but it's a weaker form of evidence than the primary comparison, prone to regression-to-the-mean and other biases, and the study authors explicitly framed it as something that needs to be tested in a larger, purpose-built trial before it means much. Reporting only the exploratory finding and leaving out the null primary result would be a misleading way to cover this study.

What this doesn't tell us

The trial studied people with long-COVID, not people with a primary diagnosis of major depressive disorder — so even the exploratory signal, if real, might not generalize to depression that isn't tied to post-viral illness. No trial has directly tested an NAD+ precursor in people with clinically diagnosed depression as the primary population. That's a real evidence gap, and it means claims about NAD+ "treating" or "improving" depression go well beyond what's actually been shown.

What actually has strong evidence for depression

Depression has some of the best-studied treatments in all of medicine. Cognitive behavioral therapy and other structured psychotherapies have decades of randomized trial support. Several classes of antidepressant medication (SSRIs, SNRIs, and others) are well studied and, for many people, effective — though finding the right one can take some trial and adjustment with a prescriber. Regular exercise has moderate trial support as an adjunct. None of these are a supplement, and that's the point: depression is a condition where the evidence-based path runs through mental health professionals, not through a bottle.

What NAD+ supplementation won't do

Based on the available evidence, an NAD+ precursor should not be expected to reliably improve clinical depression on its own, and it's not a substitute for therapy or medication where those are indicated. It may still support general cellular energy metabolism, which is a legitimate reason to take it — just not with a depression claim attached to that reasoning.

Frequently asked questions

Did the 2025 trial prove NAD+ doesn't help depression at all?

Not quite — it showed no significant benefit over placebo in the primary comparison, in a specific population (long-COVID patients) over 24 weeks. That's meaningful evidence against a benefit, but it isn't a final, universal answer, and the exploratory within-group finding leaves some genuine uncertainty.

Is it safe to combine an NAD+ supplement with antidepressant medication?

This should be discussed with your prescribing doctor or a pharmacist, since it depends on your specific medication and health history. Don't stop or adjust a prescribed antidepressant based on supplement research.

What should I do if I think I might be depressed?

Talk to a doctor or mental health professional, who can properly evaluate your symptoms and discuss evidence-based options. If you're in crisis or having thoughts of self-harm, contact a crisis line immediately — in the US, that's 988.

Could a larger trial show a real benefit?

It's possible — the study authors themselves called for larger, confirmatory trials based on their exploratory finding. Until that research exists, the fair conclusion is "not yet demonstrated," not "proven to help."

The bottom line

The most direct evidence available — a randomized, placebo-controlled trial that measured depression symptoms with a validated scale — did not find a significant benefit from an NAD+ precursor. An exploratory finding in the same trial hints at a possible effect worth studying further, but it isn't strong enough to build a claim on. If low mood is something you're navigating, the more productive next step is a conversation with a doctor or therapist, not a supplement search. See our related coverage of NAD+ and anxiety and NAD+ and stress resilience for adjacent evidence.

References

1. Wu CY, Reynolds WC, Abril I, et al. Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial. eClinicalMedicine. 2025. PMID: 41357333.
2. Cui L, Yang G, Ye J, et al. Nicotinamide adenine dinucleotide homeostasis and depression: mechanisms and therapeutic potential. Prog Neuropsychopharmacol Biol Psychiatry. 2023. PMID: 36646365.
3. Cuijpers P, Karyotaki E, Weitz E, et al. The effects of psychotherapies for major depression in adults on remission, recovery and improvement: a meta-analysis. J Affect Disord. 2014;159:118-126. PMID: 24679399.

*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease. This article is for informational purposes only and is not a substitute for professional medical advice.