{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T10:14:47Z","timestamp":1788430487475,"version":"build-2803163510"},"reference-count":43,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: Nicotinamide (NAM), a form of vitamin B3 and precursor of nicotinamide adenine dinucleotide (NAD), has emerged as a potential metabolic and neuroprotective strategy in glaucoma. This systematic review aimed to evaluate the available human evidence on NAM-containing and NAD-targeted strategies in glaucoma, integrating interventional, observational, and mechanistic evidence with particular attention to clinical outcomes, methodological quality, and safety. Methods: A systematic literature search was conducted in PubMed, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL), with the search updated through 22 August 2026. Eligible studies included randomized and non-randomized interventional studies evaluating NAM-containing or NAD-targeted supplementation strategies, as well as observational human studies investigating NAM\/NAD-related biomarkers or mitochondrial metabolic alterations in relation to glaucoma. Risk of bias was assessed according to study design using RoB 2 for randomized trials, ROBINS-I for non-randomized interventional studies, and a domain-based assessment for observational exposure and biomarker studies. Owing to substantial clinical and methodological heterogeneity, findings were synthesized narratively without quantitative pooling. Results: Thirteen eligible reports representing eight unique human studies were included. Randomized trials provided preliminary evidence that NAM-containing interventions may produce short-term functional and electrophysiological effects. NAM supplementation was associated with improvement in inner retinal electrophysiological function in randomized crossover studies, whereas effects on visual field outcomes were inconsistent. A trial combining NAM with pyruvate reported favorable short-term visual field changes, although the specific contribution of NAM could not be isolated. Non-randomized studies provided complementary evidence on vascular, metabolic, structural, electrophysiological, and patient-reported outcomes but were limited by potential confounding and uncontrolled study designs. Observational studies reported associations between glaucoma and altered circulating NAM concentrations and systemic mitochondrial dysfunction. Available studies were generally small and of limited duration, and the evidence was insufficient to establish sustained neuroprotection or modification of glaucoma progression. Conclusions: Human evidence supports the biological plausibility of targeting NAM\/NAD metabolism in glaucoma and provides preliminary signals of short-term biological and functional effects. However, current evidence remains insufficient to support routine high-dose NAM supplementation in clinical practice. Larger, adequately powered, long-term randomized controlled trials are required to establish sustained efficacy, optimal dosing, patient selection, and long-term safety.<\/jats:p>","DOI":"10.3390\/nu18172885","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T09:20:43Z","timestamp":1788427243000},"page":"2885","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Nicotinamide Supplementation in Glaucoma: A Systematic Review of Human Studies"],"prefix":"10.3390","volume":"18","author":[{"given":"Andrea","family":"Giudiceandrea","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"},{"name":"Faculty of Medicine and Surgery, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2826-3625","authenticated-orcid":false,"given":"Martina","family":"Cocuzza","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"},{"name":"Faculty of Medicine and Surgery, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianni","family":"Gravina","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Policlinico San Matteo, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8451-8901","authenticated-orcid":false,"given":"Valeria","family":"Silvestri","sequence":"additional","affiliation":[{"name":"National Centre of Services and Research for the Prevention of Blindness and Rehabilitation of Low Vision Patients-IAPB ETS, Fondazione Policlinico Universitario A. 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Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3089-7696","authenticated-orcid":false,"given":"Francesco","family":"De Dominicis","sequence":"additional","affiliation":[{"name":"National Centre of Services and Research for the Prevention of Blindness and Rehabilitation of Low Vision Patients-IAPB ETS, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Bruzio","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Epifanio","family":"Giudiceandrea","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Azienda Ospedaliera San Paolo, 20142 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Salgarello","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Surgery, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2803-5550","authenticated-orcid":false,"given":"Grazia Maria","family":"Cozzupoli","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Ospedale dei Castelli, 00040 Ariccia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Cristina","family":"Savastano","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"},{"name":"Faculty of Medicine and Surgery, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1694-1062","authenticated-orcid":false,"given":"Benedetto","family":"Falsini","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Surgery, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanislao","family":"Rizzo","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Fondazione Policlinico Universitario A. 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Gemelli IRCCS, 00168 Rome, Italy"},{"name":"Faculty of Medicine and Surgery, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1016\/j.ophtha.2014.05.013","article-title":"Global prevalence of glaucoma and projections of glaucoma burden through 2040: A systematic review and meta-analysis","volume":"121","author":"Tham","year":"2014","journal-title":"Ophthalmology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1001\/jama.2014.3192","article-title":"The pathophysiology and treatment of glaucoma: A review","volume":"311","author":"Weinreb","year":"2014","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1016\/S0140-6736(14)62111-5","article-title":"Latanoprost for open-angle glaucoma (UKGTS): A randomised, multicentre, placebo-controlled trial","volume":"385","author":"Crabb","year":"2015","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Tezel, G. 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