Latest / Glaucoma, Vision & Longevity: Supplements & Science / Can High-Dose Vitamin B3 Protect the Optic Nerve? A New Glaucoma Trial Will Test 3 Grams a Day

Transcript

Can High-Dose Vitamin B3 Protect the Optic Nerve? A New Glaucoma Trial Will Test 3 Grams a Day · Glaucoma, Vision & Longevity: Supplements & Science

• 0:00
  SPEAKER_00: Can high-dose vitamin B3 protect the optic nerve?
• 0:03
  SPEAKER_00: A new glaucoma trial will test 3 grams a day.
• 0:08
  SPEAKER_00: Research updated September 13, 2026.
• 0:11
  SPEAKER_00: Introduction.
• 0:12
  SPEAKER_00: Glaucoma treatment has traditionally focused on one target, lowering intraocular pressure.
• 0:17
  SPEAKER_00: That strategy clearly helps, but it does not eliminate risk.
• 0:21
  SPEAKER_00: Some patients continue to lose retinal ganglion cells and visual field sensitivity even when their eye pressure appears well controlled.
• 0:28
  SPEAKER_00: The NADIR trial, NCT0780833, is designed to test a different strategy.
• 0:35
  SPEAKER_00: It will add high-dose oral nicotinamide, the non-flushing form of vitamin B3, to standard glaucoma treatment and measure whether the inner retinal layers thin more slowly.
• 0:45
  SPEAKER_00: The central biological idea is straightforward.
• 0:48
  SPEAKER_00: Retinal ganglion cells may become metabolically fragile before they die.
• 0:53
  SPEAKER_00: If nicotinamide raises cellular nicotinamide adenine dinucleotide availability, it might help stressed but living cells withstand glaucoma-related injury.
• 1:02
  SPEAKER_00: That hypothesis is supported by striking animal research, early human electrophysiology studies, and a plausible link between aging, mitochondrial dysfunction, impaired axonal transport, and retinal ganglion cell degeneration.
• 1:17
  SPEAKER_00: But the human evidence remains preliminary, and 3 grams daily is a pharmacological dose, not an ordinary nutritional supplement dose.
• 1:25
  SPEAKER_00: My overall assessment is that nicotinamide is one of the most credible current candidates for pressure-independent glaucoma neuroprotection, but it is not yet proven to slow glaucoma progression in humans.
• 1:37
  SPEAKER_00: The NADAR trial.
• 1:39
  SPEAKER_00: What is actually being tested?
• 1:41
  SPEAKER_00: As of September 13, 2026, NATOR is listed as not yet recruiting.
• 1:47
  SPEAKER_00: It is a single-center University of Chicago study expected to begin enrollment in June 2027.
• 1:53
  SPEAKER_00: The registry describes it as a phase 2 study, while the protocol title calls it a phase 2A trial.
• 2:01
  SPEAKER_00: Trial Summary.
• 2:02
  SPEAKER_00: For the full table, please open this article on VisualFieldTest.com.
• 2:06
  SPEAKER_00: The trial is important because it is not asking whether nicotinamide lowers eye pressure.
• 2:11
  SPEAKER_00: It is asking whether it protects retinal tissue despite ongoing standard pressure lowering treatment.
• 2:16
  SPEAKER_00: Who can participate?
• 2:18
  SPEAKER_00: Natier is designed for adults with mild to moderate primary open angle glaucoma, not advanced disease.
• 2:24
  SPEAKER_00: Key inclusion requirements include age 40 to 80 years, primary open angle glaucoma in at least one eye, study eye visual field mean deviation between minus 2.9 and minus 12.0 decibels, at least one reliable Humphrey 24-2 visual field test, fixation losses of 33 cent or less, false positive responses of 50 cent or less, best corrected visual acuity of 2040, or better structural damage on optical coherence tomography, and or a reproducible glaucomatous visual field defect, macular ganglion cell interplexiform layer and retinal.
• 2:56
  SPEAKER_00: Nerve fiber layer thickness above the device's measurement floor, stable pressure lowering the rapi for at least four months, screening intraocular pressure of 21 mm of mercury or less.
• 3:08
  SPEAKER_00: The visual field range is strategically chosen.
• 3:11
  SPEAKER_00: Patients with mean deviation between minus 2 and minus 12 decibels still have enough surviving retinal tissue for a protective treatment to be measurable, but they have established disease rather than merely being glaucoma suspects.
• 3:24
  SPEAKER_00: Who is excluded?
• 3:26
  SPEAKER_00: The important exclusions include advanced glaucoma with mean deviation worse than minus 12 decibels, best corrected visual acuity worse than 2040, significant retinal disease, including advanced age-related macular degeneration, or more than mild diabetic retinopathy, non-glaucomatous optic neuropathy, recent eye surgery, liver dysfunction, including alanine aminotransferase or aspartate aminotransferase, greater than twice the upper limit of normal.
• 3:55
  SPEAKER_00: Total bilirubin greater than 1.5 times the upper limit of normal.
• 3:59
  SPEAKER_00: Estimated glomerular filtration rate below 30 milliliters per minute per 1.
• 4:05
  SPEAKER_00: 73 square meters.
• 4:07
  SPEAKER_00: Poorly controlled diabetes, defined as hemoglobin A1C greater than 9%.
• 4:11
  SPEAKER_00: Current use of nicotinamide, high-dose vitamin B3, nicotinamide adenine dinucleotide supplements, ginkgo boloba, coenzyme Q10, or certain drugs that could complicate safety interpretation.
• 4:23
  SPEAKER_00: Pregnancy or breastfeeding, active ocular inflammation, media opacity that prevents reliable imaging.
• 4:30
  SPEAKER_00: Patients with untreated normal tension glaucoma are also excluded.
• 4:34
  SPEAKER_00: Nodir is therefore testing an adjunctive treatment in patients whose glaucoma is being treated conventionally, not a therapy for every glaucoma subtype.
• 4:43
  SPEAKER_00: Nicotinamide dosing, why 1.5 grams, then 3 grams.
• 4:48
  SPEAKER_00: Participants assigned to the treatment arm will take.
• 4:51
  SPEAKER_00: Weeks 1 to 6, 500 mg 3 times daily, totaling 1.5 grams daily.
• 4:57
  SPEAKER_00: Week 7 through month 12, 1,500 mg twice daily, totaling 3 grams daily.
• 5:03
  SPEAKER_00: The tablets are taken with meals.
• 5:05
  SPEAKER_00: Advancement to the full dose requires an early safety review confirming acceptable gastrointestinal tolerance and no significant hepatic adverse event.
• 5:15
  SPEAKER_00: What is the basis for the escalation?
• 5:18
  SPEAKER_00: The publicly available record does not describe a formal human exposure response pharmacokinetic model.
• 5:24
  SPEAKER_00: The dose appears to come from three sources.
• 5:26
  SPEAKER_00: The earlier Australian human glaucoma study, which used 1.5 grams daily for six weeks, followed by 3 grams daily for six weeks.
• 5:35
  SPEAKER_00: Mouse glaucoma studies, in which relatively high nicotinamide exposure produced the strongest protection.
• 5:42
  SPEAKER_00: A mechanistic assumption that substantial nicotinamide availability may be needed to overcome age-related or disease-related limitations in the nicotinamide adenine dinucleotide salvage pathway.
• 5:53
  SPEAKER_00: The 3 gram dose was not selected because it is a standard nutritional requirement.
• 5:59
  SPEAKER_00: The recommended daily amount of vitamin B3 is roughly 14 to 16 milligrams in adults, making 3 grams approximately 150 to 200 times the usual nutritional intake.
• 6:11
  SPEAKER_00: Animal investigators have described 3 grams daily as the lowest human equivalent dose likely to reproduce the effective exposure seen in their mouse model.
• 6:21
  SPEAKER_00: A later RAT study used doses equivalent to approximately 2.1 grams and 6.3 grams daily in a 70 kilogram adult, with the higher dose needed for some intervention settings.
• 6:32
  SPEAKER_00: This is body surface area extrapolation, not proof that humans require the same exposure.
• 6:38
  SPEAKER_00: Natters endpoints, primary endpoint.
• 6:41
  SPEAKER_00: The primary outcome is the annualized rate of macular ganglion cell inner plexiform layer thinning.
• 6:47
  SPEAKER_00: Measurements will occur at baseline month 3, month 6, month 12.
• 6:52
  SPEAKER_00: The statistical analysis will use a linear mixed-effects model with a participant-level random intercept, repeated measurements over time, a treatment arm-by-time interaction.
• 7:04
  SPEAKER_00: The key question is whether the nicotinamide group has a less negative slope than the standard care group.
• 7:09
  SPEAKER_00: Secondary structural and functional endpoints.
• 7:12
  SPEAKER_00: The secondary outcomes include annualized rate of peripapillary retinal nerve fiber layer thinning, visual field mean deviation slope, grade 2 or higher hepatic and gastrointestinal adverse events, nicotinamide adherence, study retention.
• 7:28
  SPEAKER_00: Additional exploratory measures include macular superficial capillary plexus perfusion density by optical coherence tomography and geography, peripapillary radial capillary clysis perfusion density.
• 7:41
  SPEAKER_00: The registry specifies that optical coherence tomography and visual field readers will be masked to treatment assignment through de-identified participant identifiers, even though participants and investigators will know which treatment is being given.
• 7:56
  SPEAKER_00: Statistical strengths and weaknesses, strengths, randomized one-one allocation, active standard care control, stratification by mild versus moderated disease, stratification by race and ethnicity, masked structural and visual field reading, repeated optical coherence tomography measurements, a structural primary endpoint that may be more sensitive than visual field change over only one year.
• 8:17
  SPEAKER_00: Weaknesses.
• 8:18
  SPEAKER_00: The trial is open label.
• 8:20
  SPEAKER_00: There is no placebo, only 96 participants are planned.
• 8:23
  SPEAKER_00: It is being conducted at Twin Center.
• 8:25
  SPEAKER_00: 12 months is short.
• 8:26
  SPEAKER_00: For proving long-term visual field preservation.
• 8:29
  SPEAKER_00: The public registry does not provide a detailed power calculation or a pre-specified minimum clinically important difference.
• 8:36
  SPEAKER_00: A positive NATA result would therefore be important, but it would probably be considered proof of biological activity, not definitive proof that nicotinamide should immediately become routine treatment.
• 8:48
  SPEAKER_00: Why might NAD matter in glaucoma?
• 8:50
  SPEAKER_00: Nicotinamide adenine dinucleotide is an energy and repair molecule.
• 8:55
  SPEAKER_00: Nicotinamide adenine dinucleotide is needed for mitochondrial energy production, transfer of electrons during cellular respiration, maintenance of redox balance, DNA repair, regulation of protein acetylation through sertuan enzymes, calcium handling, axonal transport, cellular responses to oxidative stress.
• 9:14
  SPEAKER_00: Retinal ganglion cells are unusually vulnerable to energy failure.
• 9:18
  SPEAKER_00: They have long axons, high electrical activity, substantial transport demands, and a portion of their axons that remain unmyelinated inside the retina.
• 9:27
  SPEAKER_00: Their energy supply must remain reliable even when pressure-related mechanical stress affects the optic nerve head.
• 9:34
  SPEAKER_00: Mitochondrial dysfunction may occur before obvious cell loss.
• 9:38
  SPEAKER_00: In the DBA2J mouse model of glaucoma, abnormal mitochondrial gene expression, mitochondrial cristae disruption, oxidative phosphorylation changes, synapse loss, and pattern electroretinogram abnormalities appeared before obvious retinal ganglion cell degeneration.
• 9:55
  SPEAKER_00: This suggests that a retinal ganglion cell may pass through a sequence such as mitochondrial stress, reduced energy reserve, impaired axonal transport, dendritic and synaptic remodeling, electrophysiological dysfunction, axonal degeneration, cell body death.
• 10:12
  SPEAKER_00: If that sequence is also present in humans, treatment during the earlier stages could preserve function even if it cannot replace retinal ganglion cells that have already died.
• 10:22
  SPEAKER_00: Energy failure can disrupt axonal transport.
• 10:26
  SPEAKER_00: Retinal ganglion cell axons transport proteins, mitochondria, neurotransmitter components, and survival signals between the retina, optic nerve, and brain.
• 10:36
  SPEAKER_00: Pressure-related deformation at the optic nerve head may obstruct this transport.
• 10:41
  SPEAKER_00: Mitochondrial dysfunction then worsens the problem.
• 10:44
  SPEAKER_00: Less adenosine triphosphate is available to power transport proteins.
• 10:48
  SPEAKER_00: Damaged mitochondria produce more reactive oxygen species.
• 10:52
  SPEAKER_00: Calcium buffering becomes less effective.
• 10:55
  SPEAKER_00: Axons accumulate damaged cargo.
• 10:58
  SPEAKER_00: Synaptic support from the brain may be interrupted.
• 11:01
  SPEAKER_00: Nicotinamide adenine dinucleotide is relevant because it supports both energy production and the machinery involved in axonal survival and degeneration.
• 11:09
  SPEAKER_00: Aging reduces metabolic resilience.
• 11:12
  SPEAKER_00: The animal case is not merely that glaucoma causes low nicotinamide adenine dinucleotide.
• 11:18
  SPEAKER_00: It is that aging appears to reduce the retinal reserve that protects against pressure-related stress.
• 11:23
  SPEAKER_00: In aging mice, retinal nicotinamide adenine dinucleotide levels fall.
• 11:28
  SPEAKER_00: At the same time, retinal ganglion cells become more vulnerable to elevated pressure.
• 11:33
  SPEAKER_00: Restoring nicotinamide availability makes those older cells more resistant.
• 11:38
  SPEAKER_00: Human data are less direct.
• 11:40
  SPEAKER_00: Studies have reported lower circulating nicotinamide levels in people with primary open-angle glaucoma, and postmortem tissue studies show that the nicotinamide adenine dinucleotide salvage machinery is highly represented in the inner retina and optic nerve head.
• 11:56
  SPEAKER_00: Nicotinamide phosphoribosyl transferase, the rate-limiting enzyme in the salvage pathway, appears reduced in portions of glaucomatous optic nerve head tissue.
• 12:06
  SPEAKER_00: However, these human findings are limited and do not prove that low nicotinamide causes glaucoma.
• 12:12
  SPEAKER_00: The salvage pathway, the major pathway is nicotinamide, nicotinamide mononucleotide, nicotinamide adenine dinucleotide.
• 12:21
  SPEAKER_00: The first step is controlled primarily by nicotinamide phosphorobosyl transferase.
• 12:25
  SPEAKER_00: The next steps involve nicotinamide mononucleotide denyl transferase enzymes.
• 12:31
  SPEAKER_00: This creates an important uncertainty.
• 12:33
  SPEAKER_00: Giving more nicotinamide may help if the cell has enough salvage capacity.
• 12:38
  SPEAKER_00: But if glaucoma or aging has substantially reduced the enzymes that process nicotinamide, simply adding more substrate may have diminishing returns.
• 12:47
  SPEAKER_00: This is one reason why nicotinamide riboside and other nicotinamide adenine dinucleotide precursors are being studied.
• 12:54
  SPEAKER_00: They may enter the pathway differently, although there is no convincing human evidence yet that they're here for glaucoma.
• 13:00
  SPEAKER_00: The strongest animal evidence mouse model, prevention and intervention.
• 13:07
  SPEAKER_00: The most influential study used DBA2J mice, which develop an age-related glaucoma resembling some features of human pigmentary glaucoma.
• 13:15
  SPEAKER_00: Researchers found mitochondrial abnormalities before detectable wranglion cell degeneration, NAG-related decline in retinal nicotinamide adenin denucleotide protection from nicotinamide given before disease developed protection when treatment began after elevated pressure and early disease were already present, preservation of retinal ganglion cell bodies, preservation of retinal nerve fiberlayer tissue, preservation of optic nerve axons, preservation of pattern electroretinogram function, preservation of anterograde axonal transport.
• 13:46
  SPEAKER_00: At a lower dose, 550 mg per kilogram per day, nicotinamide protected without substantially changing intraocular pressure.
• 13:55
  SPEAKER_00: At the highest tested dose, 2000 mg per kilogram per day, 93% of eyes had no detectable optic nerve damage.
• 14:03
  SPEAKER_00: The investigators described this as approximately a tenfold reduction in the likelihood of glaucoma.
• 14:09
  SPEAKER_00: The high dose also reduced pressure elevation, so the strongest result was not entirely independent of intraocular pressure.
• 14:17
  SPEAKER_00: RAT model, dose and dendritic preservation.
• 14:20
  SPEAKER_00: A newer RAT study tested nicotinamide in an experimentally induced ocular hypertension model.
• 14:26
  SPEAKER_00: The main findings were dose-dependent protection against retinal ganglion cell loss, preservation of retinal ganglion cell nuclei, preservation of dendritic structure, metabolic normalization in optic nerve tissue, better mitochondrial morphology, increased mitochondrial movement in cultured retinal ganglion cell processes, protection against a severe mitochondrial toxin, preservation of dendrites even when the optic nerve itself could not regenerate.
• 14:54
  SPEAKER_00: The study compared 200 mg per kilogram per day, roughly equivalent to 2.1 grams daily in a 70 kg adult, 600 mg per kilogram per day, roughly equivalent to 6.3 grams daily.
• 15:08
  SPEAKER_00: Both doses were strongly protective when given before injury.
• 15:12
  SPEAKER_00: When given after injury had begun, the higher dose was more consistently protective.
• 15:17
  SPEAKER_00: This pattern supports the idea that treatment timing and disease stage may be critical.
• 15:23
  SPEAKER_00: Is the animal benefit independent of pressure?
• 15:26
  SPEAKER_00: Partly, but not completely.
• 15:28
  SPEAKER_00: Evidence for pressure-independent benefit includes protection in optic nerve axotomy models, where the injury does not depend on elevated intraocular pressure, protection against direct mitochondrial inhibition, low-dose mouse treatment that preserved retinal ganglion cells without lowering intraocular pressure, metabolic protection before measurable cell loss.
• 15:50
  SPEAKER_00: However, the highest mouse dose also reduced intraocular pressure.
• 15:54
  SPEAKER_00: Therefore, nicotinamide may act through both retinal ganglion cell metabolic resilience, possible effects on the trabecular meshwork, vascular biology, or other pressure-regulating tissues.
• 16:06
  SPEAKER_00: Natier is valuable because all participants will already be receiving stable glaucoma treatment, making a pressure-independent retinal effect easier to detect.
• 16:16
  SPEAKER_00: What have human glaucoma studies shown?
• 16:18
  SPEAKER_00: Nicotinamide alone, the Australian crossover trial.
• 16:22
  SPEAKER_00: The first major human study enrolled 57 people with treated glaucoma.
• 16:27
  SPEAKER_00: Participants received placebo or nicotinamide in a crossover design, 1.5 grams daily for six weeks, 3 grams daily for six weeks, crossover to the other treatment without a washout period.
• 16:39
  SPEAKER_00: The main outcome was inner retinal function, measured using the photopic negative response, an electroretinographic signal, influenced substantially by retinal ganglion cell activity.
• 16:50
  SPEAKER_00: Numerical results.
• 16:51
  SPEAKER_00: Photopic negative response saturated amplitude improved by 14.8% with nicotinamide.
• 16:57
  SPEAKER_00: The placebo improvement was 5.2%.
• 17:00
  SPEAKER_00: Photopic negative response improved beyond the 95% repeatability limit in 23% of participants on nicotinamide versus 9% on placebo.
• 17:09
  SPEAKER_00: Mean deviation did not differ significantly between treatments.
• 17:13
  SPEAKER_00: Nicotinamide minus placebo, plus 0.1 decibels.
• 17:16
  SPEAKER_00: 95% confidence interval, minus 0.33 to plus 0.53, p equal 0.63.
• 17:22
  SPEAKER_00: A mean deviation improvement of at least 1 decibel occurred in 27% on nicotinamide versus 16% on placebo.
• 17:29
  SPEAKER_00: Mean deviation worsening of at least 1 decibel occurred in 4% on nicotinamide versus 12% on placebo.
• 17:35
  SPEAKER_00: Retinal nerve fiber layer change.
• 17:37
  SPEAKER_00: Nicotinamide minus 0.3 plus 2.9 micrometers.
• 17:41
  SPEAKER_00: Placebo plus 0.4 2.4 micrometers.
• 17:44
  SPEAKER_00: P equ intraonicular pressure was not meaningfully changed.
• 17:47
  SPEAKER_00: Treatment difference approximately 0.2 mm of mercury.
• 17:51
  SPEAKER_00: P equals 0.59.
• 17:53
  SPEAKER_00: Adverse events.
• 17:54
  SPEAKER_00: The most common symptoms were mild gastrointestinal discomfort, 10.5%, nausea, 5.3%, headache, 3.5%.
• 18:03
  SPEAKER_00: One participant withdrew while taking placebo because of tinnitus.
• 18:06
  SPEAKER_00: These findings suggested short-term tolerability, but the trial was small, short, and not designed to show slower glaucoma progression.
• 18:14
  SPEAKER_00: Nicotinamide plus pyruvate.
• 18:16
  SPEAKER_00: A separate phase two trial studied nicotinamide plus pyruvate, not nicotinamide alone.
• 18:22
  SPEAKER_00: Among the participants who completed the study, 21 received the combination, 11 received placebo.
• 18:27
  SPEAKER_00: Median follow-up was approximately 2.2 months.
• 18:30
  SPEAKER_00: Nicotinamide was increased from 1 to 3 grams daily.
• 18:33
  SPEAKER_00: Pyruvate was increased from 1.5 to 3 grams daily.
• 18:37
  SPEAKER_00: Numerical results.
• 18:38
  SPEAKER_00: The treatment group had median 15 improving visual field locations.
• 18:42
  SPEAKER_00: Placebo group, median 7, p equal 0.005.
• 18:46
  SPEAKER_00: Pattern standard deviation improved more rapidly.
• 18:49
  SPEAKER_00: Combination, minus 0.06 decibels per week.
• 18:53
  SPEAKER_00: Placebo, plus 0.02 decibels per week, p equals 0.02.
• 18:57
  SPEAKER_00: But there was no significant difference in mean deviation, treatment plus 0.04 decibels per week, placebo minus 2 decibels per week, p equal 0.35.
• 19:06
  SPEAKER_00: Visual field index, treatment plus 0.09% per week, placebo my 0.02% per week, p equals 0.71.
• 19:13
  SPEAKER_00: Global retinal nerve fiber layer change, difference approximately 0.18 micrometers, p equals 0.13.
• 19:20
  SPEAKER_00: Mild gastrointestinal symptoms occurred in 7 of 21 treatment participants and 3 of 11 placebo participants.
• 19:28
  SPEAKER_00: One participant discontinued treatment because of gastrointestinal symptoms.
• 19:32
  SPEAKER_00: A later topographical analysis of the same small data set found that improving points clustered along arcuate visual field pathways and produced an odds ratio of 373 for identifying improving locations with the combination compared with placebo.
• 19:47
  SPEAKER_00: The analysis estimated a 98.4% posterior probability of more improving locations.
• 19:54
  SPEAKER_00: This is interesting, but it was a post hoc analysis of a very small sample and should not be treated as definitive proof of visual recovery.
• 20:02
  SPEAKER_00: Normal tension glaucoma trial.
• 20:04
  SPEAKER_00: A 2026 crossover trial enrolled 53 people with normal tension glaucoma and used a lower dose, 1 gram daily for 6 weeks, 2 grams daily for 6 weeks, no washout between treatments.
• 20:18
  SPEAKER_00: After 12 weeks, photopic negative response peak to truff amplitude change, nicotinamide plus 3.121968 microvolts, placebo.9964.190 microvolts p equals 045 B wave amplitude change, nicotinamide plus 2.1120 mais 3.220 microvolts, placebo plus 0.305 mais 3.279 microvolts, P equals 0.032.
• 20:45
  SPEAKER_00: No serious nicotinamide-related adverse events were reported.
• 20:48
  SPEAKER_00: However, this study was also short and primarily demonstrated electrophysiological improvement rather than slower structural loss.
• 20:55
  SPEAKER_00: What could explain short-term visual field improvement?
• 20:58
  SPEAKER_00: The reported visual field findings could reflect several different biological processes.
• 21:03
  SPEAKER_00: Genuine recovery of dysfunctional but living retinal ganglion cells.
• 21:07
  SPEAKER_00: This is biologically plausible.
• 21:09
  SPEAKER_00: A retinal ganglion cell can be metabolically impaired without being dead.
• 21:13
  SPEAKER_00: Its dendrites may be retracted, synapses may be reduced, axonal transport may be slowed, membrane function may be abnormal, electrical responses may be weak.
• 21:24
  SPEAKER_00: Animal studies show that nicotinamide can preserve or restore dendritic structure in stressed retinal ganglion cells.
• 21:31
  SPEAKER_00: If some human cells remain viable but function poorly, improving mitochondrial energy supply could increase their signaling.
• 21:38
  SPEAKER_00: Metabolic enhancement without structural recovery.
• 21:41
  SPEAKER_00: This may be the most likely explanation for the early electrophysiological findings.
• 21:46
  SPEAKER_00: A cell could produce a stronger electrical response while remaining structurally damaged.
• 21:51
  SPEAKER_00: Improved energy availability might increase action potential generation, axonal conduction, synaptic transmission.
• 22:00
  SPEAKER_00: Recovery after light stimulation.
• 22:02
  SPEAKER_00: This would not mean that lost retinal nerve fiber layer tissue had grown back.
• 22:07
  SPEAKER_00: Learning and test-retest variability.
• 22:10
  SPEAKER_00: Visual field testing is highly variable.
• 22:12
  SPEAKER_00: Patients often perform better after becoming familiar with the test.
• 22:16
  SPEAKER_00: Fatigue, attention, false positive responses, fixation, and day-to-day health can all change results.
• 22:23
  SPEAKER_00: The lack of a significant global mean deviation difference in the nicotinamide alone trial is an important warning.
• 22:30
  SPEAKER_00: The finding that more patients improved by at least 1 decibel is encouraging, but a responder analysis can be affected by regression toward the mean.
• 22:39
  SPEAKER_00: Statistical noise and post hoc selection.
• 22:42
  SPEAKER_00: The combination study measured many visual field locations.
• 22:46
  SPEAKER_00: When many locations are analyzed, some will improve by chance.
• 22:50
  SPEAKER_00: The later topographical analysis used sophisticated modeling, but it was still based on only 32 study eyes.
• 22:57
  SPEAKER_00: My interpretation.
• 23:01
  SPEAKER_00: Established evidence, nicotinamide can improve some electrophysiological measures over weeks.
• 23:07
  SPEAKER_00: Strong inference, at least some patients may have metabolically stressed but viable retinal ganglion cells that can function better.
• 23:14
  SPEAKER_00: Plausible speculation, nicotinamide can produce a clinically meaningful visual field improvement in selected early or moderate patients.
• 23:23
  SPEAKER_00: Not demonstrated.
• 23:24
  SPEAKER_00: Regeneration of lost retinal ganglion cells, restoration of lost axons, or long-term visual field preservation.
• 23:31
  SPEAKER_00: Can nicotinamide do more than slow progression?
• 23:34
  SPEAKER_00: Can metabolically stressed cells regain function?
• 23:37
  SPEAKER_00: Possibly.
• 23:38
  SPEAKER_00: This is the most credible form of recovery.
• 23:40
  SPEAKER_00: A surviving retinal ganglion cell may regain some function if its mitochondria, membrane potential, axonal transport, and synaptic connections remain sufficiently intact.
• 23:50
  SPEAKER_00: Can surviving axons recover conduction?
• 23:53
  SPEAKER_00: Possibly, particularly if the problem is energy failure or impaired transport rather than complete axonal degeneration.
• 24:01
  SPEAKER_00: However, an axon that has been destroyed cannot simply be repaired by supplying more nicotinamide.
• 24:07
  SPEAKER_00: Restoring it would require axonal regeneration and reconnection to the correct brain targets.
• 24:13
  SPEAKER_00: Is established axonal loss irreversible?
• 24:16
  SPEAKER_00: For practical clinical purposes, yes.
• 24:18
  SPEAKER_00: Nicotinamide is not expected to replace retinal ganglion cells that have died or rebuild an optic nerve that has been severely destroyed.
• 24:26
  SPEAKER_00: The potential treatment window is the period when cells are dysfunctional, stressed, or structurally altered, but still alive.
• 24:34
  SPEAKER_00: Would advanced glaucoma benefit?
• 24:36
  SPEAKER_00: Probably less.
• 24:38
  SPEAKER_00: Advanced glaucoma contains fewer viable retinal ganglion cells, more tissue below the optical coherence tomography measurement floor, greater irreversible axonal loss, more visual field locations that cannot improve because the relevant cells are absent.
• 24:54
  SPEAKER_00: A metabolic treatment might still protect remaining cells, but its measurable benefit is likely to be greater in early to moderate disease.
• 25:03
  SPEAKER_00: How does nicotinamide compare with other emerging treatments?
• 25:06
  SPEAKER_00: G01 and recombinant human nerve growth factor variant 2 G01 is an experimental eye drop containing a modified form of recombinant human nerve growth factor.
• 25:17
  SPEAKER_00: Its mechanism is trophic rather than metabolic.
• 25:20
  SPEAKER_00: It aims to provide survival and repair signals to retinal ganglion cells.
• 25:25
  SPEAKER_00: A phase 2 trial is testing 100 and 200 micrograms per milliliter twice daily for 24 weeks, with visual field mean deviation as the main efficacy measure and retinal nerve fiber layer, ganglion cell inner plexiform layer, and visual evoked potential measures as secondary outcomes.
• 25:44
  SPEAKER_00: No efficacy results are public yet.
• 25:47
  SPEAKER_00: An earlier phase 1B trial of topical recombinant human nerve growth factor enrolled 60 glaucoma patients.
• 25:54
  SPEAKER_00: It found no statistically significant short-term neuroenhancement, although the treatment was generally tolerated.
• 26:01
  SPEAKER_00: Periocular aching occurred in 52% of treated participants versus 5% of placebo participants, and 7.5% discontinued because of discomfort.
• 26:11
  SPEAKER_00: Comparison, G01 is local and potentially more directly trophic.
• 26:15
  SPEAKER_00: Nicotinamide is systemic and targets cellular metabolism.
• 26:19
  SPEAKER_00: A combination is theoretically attractive but untested.
• 26:22
  SPEAKER_00: AS-2667 ASP2767 is a first-in-human gene therapy program for glaucoma-related optic neuropathy.
• 26:30
  SPEAKER_00: The current phase one-half study includes dose escalation and a randomized, sham-controlled component with an estimated enrollment of 156 participants.
• 26:38
  SPEAKER_00: There are no efficacy results yet.
• 26:41
  SPEAKER_00: Comparison.
• 26:42
  SPEAKER_00: ASP2767 could provide longer-lasting cell-targeted treatment, but carries the uncertainties of viral gene therapy.
• 26:49
  SPEAKER_00: ER-100.
• 26:51
  SPEAKER_00: ER-100 is an experimental adeno-associated virus therapy designed to deliver the OCT4, SOX-2, and KLF-4 proteins, collectively called OSK, to retinal cells.
• 27:03
  SPEAKER_00: The goal is partial epigenetic rejuvenation rather than merely metabolic support.
• 27:08
  SPEAKER_00: The first in human trial is a phase 1 study involving up to 18 participants with open-angle glaucoma or non-arteritic anterior ischemic optic neuropathy.
• 27:17
  SPEAKER_00: It is primarily a safety study with long-term follow-up.
• 27:21
  SPEAKER_00: Comparison.
• 27:22
  SPEAKER_00: ER-100 has greater theoretical regenerative potential, but vastly greater uncertainty and invasiveness than nicotinamide.
• 27:30
  SPEAKER_00: NT501 and ciliary neurotrophic factor NT501 is an encapsulated cell implant intended to release ciliary neurotrophic factor inside the eye over an extended period.
• 27:41
  SPEAKER_00: It represents sustained local trophic support, but glaucoma-specific efficacy remains investigational.
• 27:48
  SPEAKER_00: Comparison.
• 27:49
  SPEAKER_00: NT501 may be more suitable for long-term local delivery, but it requires an ocular procedure and carries implant-related risks.
• 27:57
  SPEAKER_00: Cytocaline.
• 27:59
  SPEAKER_00: Citycline supports membrane phospholipid synthesis, neurotransmitter metabolism, and neuronal repair.
• 28:05
  SPEAKER_00: Small studies have reported improvements in electrophysiology, visual function, or quality of life.
• 28:11
  SPEAKER_00: However, a systematic review concluded that conclusive evidence for slowing glaucoma progression is missing.
• 28:17
  SPEAKER_00: One pilot study reported less retinal nerve fiber layer loss over three years, approximately 1.86 micrometers versus 2.99 micrometers, but the broader evidence remains inconsistent.
• 28:30
  SPEAKER_00: Coenzyme Q10.
• 28:32
  SPEAKER_00: Coenzyme Q10 is a mitochondrial electron transport cofactor and antioxidant.
• 28:37
  SPEAKER_00: It has a reasonable biological rationale, particularly in combination with nicotinamide, but there is no strong human evidence that coenzyme Q10 alone slows glaucoma progression.
• 28:48
  SPEAKER_00: Pyruvate.
• 28:49
  SPEAKER_00: Pyruvate may provide additional metabolic substrate and help maintain the balance between glycolysis, mitochondrial oxidation, and redox recycling.
• 28:58
  SPEAKER_00: The short-term nicotinamide plus pyruvate trial produced the strongest human visual field signals so far, but it cannot determine whether the benefit came from nicotinamide, pyruvate, or the combination.
• 29:10
  SPEAKER_00: A later phase 3 study is evaluating a fixed combination of 3 grams daily of nicotinamide plus 1 gram daily of calcium pyruvate.
• 29:19
  SPEAKER_00: Nicotinamide ribicide and nicotinamide mononucleotide.
• 29:23
  SPEAKER_00: Nicotinamide ribicide is another nicotinamide adenine dinucleotide precursor.
• 29:28
  SPEAKER_00: A 125-person randomized trial protocol plans to test 300 mg daily for 24 months, using retinal nerve fiber layer thinning as the primary structural outcome.
• 29:40
  SPEAKER_00: No definitive glaucoma efficacy results are available.
• 29:43
  SPEAKER_00: Nicotinamide mononucleotide is mechanistically interesting, but there is not yet adequate clinical evidence that it protects the human optic nerve.
• 29:51
  SPEAKER_00: Mitochondrial targeted therapies.
• 29:54
  SPEAKER_00: Mitochondrial antioxidants, membrane stabilizing compounds, electron transport enhancers, and metabolic therapies could eventually be combined with nicotinamide.
• 30:04
  SPEAKER_00: The most logical combinations would be nicotinamide plus pyruvate, NAD restoration plus metabolic substrate, nicotinamide plus coenzyme Q10, NAD restoration plus electron transport support, nicotinamide plus a neurotrophic factor, metabolic resilience plus survival signaling, nicotinamide plus pressure lowering, mechanical stress reduction plus cellular protection.
• 30:28
  SPEAKER_00: These combinations are mechanistically rational.
• 30:30
  SPEAKER_00: Only the nicotinamide plus pyruvate combination currently has meaningful short-term human glaucoma data.
• 30:37
  SPEAKER_00: Safety at 3 grams daily.
• 30:40
  SPEAKER_00: 3 grams daily should be regarded as a drug level exposure.
• 30:43
  SPEAKER_00: Liver injury.
• 30:45
  SPEAKER_00: The most important risk is drug-induced liver injury.
• 30:48
  SPEAKER_00: A serious case occurred in a United States glaucoma trial involving a 73-year-old woman who developed vomiting and substantial liver enzyme elevations after reaching 3 grams daily.
• 30:59
  SPEAKER_00: She required hospitalization and recovered after stopping treatment.
• 31:04
  SPEAKER_00: A second case was reported in Singapore in a 69-year-old woman who developed jaundice, nausea, vomiting, rash, itching, and severe liver enzyme abnormalities while taking 3 grams daily.
• 31:16
  SPEAKER_00: These cases appear rare relative to the number of participants exposed, but they demonstrate that serious toxicity can occur even in people with normal baseline liver tests.
• 31:26
  SPEAKER_00: Gastrointestinal effects.
• 31:28
  SPEAKER_00: Nausea, vomiting, abdominal discomfort, constipation, and loose stools are the most common practical problems.
• 31:35
  SPEAKER_00: In the earlier nicotinamide alone study, mild gastrointestinal symptoms occurred in approximately 10.5%, nausea occurred in 5.3%.
• 31:44
  SPEAKER_00: In the nicotinamide plus pyruvate study, mild gastrointestinal discomfort occurred in approximately 31% of participants overall.
• 31:53
  SPEAKER_00: Glucose and insulin resistance.
• 31:55
  SPEAKER_00: High dose nicotinamide may impair insulin sensitivity in some people, although human evidence is inconsistent.
• 32:01
  SPEAKER_00: The concern is more important in patients with diabetes, obesity, metabolic syndrome, or prediabetes.
• 32:08
  SPEAKER_00: Nadir excludes poorly controlled diabetes, but even controlled diabetes may justify more careful glucose and hemoglobin A1C monitoring.
• 32:18
  SPEAKER_00: Platelets.
• 32:19
  SPEAKER_00: Low platelet counts have been reported mainly in people with kidney failure taking 500 to 1500 milligrams daily.
• 32:26
  SPEAKER_00: It is not established that the same risk applies to otherwise healthy glaucoma patients taking 3 grams daily, but a complete blood count could be reasonable in long-term treatment.
• 32:37
  SPEAKER_00: Uric acid.
• 32:38
  SPEAKER_00: Raised uric acid is a well-known concern with high-dose nicotinic acid, the flushing form of vitamin B3.
• 32:45
  SPEAKER_00: It is not clearly established as a major toxicity of nicotinamide.
• 32:49
  SPEAKER_00: This distinction matters.
• 32:51
  SPEAKER_00: Nicotinic acid and nicotinamide are not interchangeable.
• 32:54
  SPEAKER_00: Niacin should not be substituted for nicotinamide in glaucoma research or treatment.
• 32:59
  SPEAKER_00: Homocysteine and methyl group depletion.
• 33:02
  SPEAKER_00: The liver metabolizes excess nicotinamide through methylation pathways.
• 33:06
  SPEAKER_00: Large exposures could theoretically increase demand for methyl donors and alter metabolites such as homocysteine.
• 33:13
  SPEAKER_00: This is a biologically plausible concern, especially in people with folate or vitamin B12 deficiency, but it has not been established as a clinically important toxicity signal in glaucoma trials.
• 33:26
  SPEAKER_00: It should be classified as a safety hypothesis, not a proven adverse effect.
• 33:31
  SPEAKER_00: Interactions NAR excludes several medications and supplements that could complicate safety interpretation, including isoniazid, pyrazinamide, carbamazepine, phenobarbital primidone, high dose niacin, sustained release niacin or nicotinamide, other nicotinamide adenine dinucleotide supplements.
• 33:51
  SPEAKER_00: Patients taking multiple supplements should disclose them because combining high-dose nicotinamide with other metabolic products could increase pill burden and make adverse effects difficult to identify.
• 34:02
  SPEAKER_00: Is lifelong 3-gram treatment practical?
• 34:04
  SPEAKER_00: At present, probably not.
• 34:06
  SPEAKER_00: Reasons include the dossiers far above nutritional requirements, it may require zix 500 mg tablets daily.
• 34:13
  SPEAKER_00: Long-term safety beyond the durations of existing trials is uncertain.
• 34:17
  SPEAKER_00: Rare livery can be severe.
• 34:19
  SPEAKER_00: Periodic laboratory monitoring would likely be required.
• 34:22
  SPEAKER_00: Gastrointestinal symptoms may reduce adherence.
• 34:25
  SPEAKER_00: The treatment is not approved for glaucoma.
• 34:27
  SPEAKER_00: NA study has yet shown that it produces a large enough long-term visual benefit to justify these C-Risks.
• 34:33
  SPEAKER_00: The 2025 joint position statement from the American Glaucoma Society and American Academy of Ophthalmology recommends against high-dose nicotinamid eater above 3 grams daily outside clinical trials with close liver monitoring.
• 34:47
  SPEAKER_00: My evidence-based probability estimates.
• 34:49
  SPEAKER_00: These are my estimates, not published predictions.
• 34:52
  SPEAKER_00: Probability that Natair shows significantly slower ganglion cell inner plexiform layer thinning.
• 34:58
  SPEAKER_00: Approximately 55%.
• 35:00
  SPEAKER_00: Why?
• 35:01
  SPEAKER_00: The animal structural evidence is strong.
• 35:03
  SPEAKER_00: Nicotinamide has shown metabolic and electrophysiological effects in humans.
• 35:07
  SPEAKER_00: The primary endpoint is more sensitive than visual field mean deviation over one year.
• 35:12
  SPEAKER_00: Participants are selected to retain measurable retinal tissue.
• 35:16
  SPEAKER_00: But the study is small, open label, single center, and only 12 months long.
• 35:22
  SPEAKER_00: Optical coherence tomography measurement variability may dilute a modest treatment effect.
• 35:27
  SPEAKER_00: If positive, I would expect a relative reduction in thinning of approximately 20 to 35% rather than complete stabilization.
• 35:35
  SPEAKER_00: Probability of a clear functional visual field benefit, approximately 30% to 40%.
• 35:42
  SPEAKER_00: The reason this is lower than the structural estimate is that visual fields are noisy.
• 35:47
  SPEAKER_00: The earlier nicotinamide alone trial did not significantly improve global mean deviation.
• 35:53
  SPEAKER_00: The strongest visual field findings came from a small nicotinamide plus pyruvate study.
• 35:58
  SPEAKER_00: One year may be too short to show a reliable difference in mean deviation slopes.
• 36:03
  SPEAKER_00: A modest benefit in selected early or moderate patients is more likely than a large improvement across the entire cohort.
• 36:11
  SPEAKER_00: Probability that nicotinamide eventually becomes part of standard glaucoma treatment, approximately 25% to 35% by the mid-2030s.
• 36:20
  SPEAKER_00: This probability would rise substantially if NATAR is positive.
• 36:24
  SPEAKER_00: The larger glaucoma nicotinamide trial, or United Kingdom Phase III study, confirms slower visual field loss, the effective dose can be reduced below 3 grams daily, or a safer precursor such as nicotinamide ribicide produces similar benefit.
• 36:40
  SPEAKER_00: The main barriers are not only efficacy, they include long-term liver safety, adherence, regulatory approval, manufacturing quality, and whether the treatment improves outcomes enough to matter clinically.
• 36:53
  SPEAKER_00: Earliest plausible year for guideline influence.
• 36:56
  SPEAKER_00: If Nadir is positive and larger ongoing studies also succeed, the earliest plausible year for cautious guideline influence would be 2030 or 2031.
• 37:06
  SPEAKER_00: That might initially mean use only under specialist supervision, treatment limited to mild or moderate progressive glaucoma, baseline and periodic liver testing, continued pressure lowering treatment, avoidance in people with liver disease, or significant metabolic risk.
• 37:23
  SPEAKER_00: Broad, routine recommendation would more likely require evidence available around 2033 to 2035.
• 37:30
  SPEAKER_00: Could vitamin B3 become the first practical neuroprotective treatment for glaucoma?
• 37:36
  SPEAKER_00: Best case scenario Nadir shows significantly slower ganglion cell interplexiform layer thinning with no meaningful difference in intraocular pressure.
• 37:45
  SPEAKER_00: Retinal nerve fiber layer thinning is also reduced, and visual field mean deviation decline trends favor nicotinamide.
• 37:52
  SPEAKER_00: The larger phase 3 studies then confirm that nicotinamide slows visual field loss by approximately 20% to 30%.
• 38:00
  SPEAKER_00: Researchers identify a lower effective dose, perhaps 1 to 2 grams daily, or develop a better tolerated nicotinamide adenine dinucleotide precursor.
• 38:10
  SPEAKER_00: In that scenario, nicotinamide becomes an inexpensive adjunct for patients with early or moderate glaucoma who continue to progress despite pressure control.
• 38:19
  SPEAKER_00: Realistic scenario NADR demonstrates a modest structural benefit but no convincing one-year visual field improvement.
• 38:27
  SPEAKER_00: That would still be important.
• 38:28
  SPEAKER_00: It would support the idea that nicotinamide affects retinal biology, but it would not yet prove that patients see better or retain vision longer.
• 38:37
  SPEAKER_00: Nicotinamide might remain available only through specialist guided use or clinical trials, while larger studies determine whether structural slowing translates into meaningful long-term visual preservation.
• 38:50
  SPEAKER_00: Disappointing scenario Natter shows no significant difference in ganglion cell interplexiform layer thinning.
• 38:57
  SPEAKER_00: Visual field results are neutral, adherence is difficult, and gastrointestinal or hepatic adverse events occur more often than expected.
• 39:06
  SPEAKER_00: Possible explanations would include the human dose does not adequately raise retinal nicotinamide adenine dinucleotide.
• 39:14
  SPEAKER_00: The salvage pathway is too impaired for nicotinamide to work.
• 39:17
  SPEAKER_00: The animal models overestimate human treatment response.
• 39:21
  SPEAKER_00: Only a biologically distinct subgroup benefits.
• 39:24
  SPEAKER_00: The primary endpoint is too noisy.
• 39:27
  SPEAKER_00: Neuroprotection requires combination therapy rather than nicotinamide alone.
• 39:32
  SPEAKER_00: A negative nadater trial would weaken the case for high-dose nicotinamide, but it would not eliminate the broader idea of targeting retinal metabolism.
• 39:41
  SPEAKER_00: What would qualify as a genuine glaucoma breakthrough?
• 39:45
  SPEAKER_00: For naudir itself to represent a genuine breakthrough, I would want to see a statistically significant and clinically meaningful reduction in ganglion cell inner plexiform layer thinning, a similar direction of effect in retinal nerve fiber layer measurements, no important difference in intraocular pressure between groups.
• 40:04
  SPEAKER_00: A pre-specified benefit in visual field mean deviation slope or reliable pointwise sensitivity.
• 40:11
  SPEAKER_00: Evidence that the effect is not driven by visual field learning or regression to the mean.
• 40:16
  SPEAKER_00: Acceptable liver and metabolic safety, good adherence over 12 months.
• 40:21
  SPEAKER_00: Confirmation in a larger masked multi-center trial.
• 40:24
  SPEAKER_00: The most persuasive result would be a convergent structural and functional benefit, slower optical coherence tomography thinning, fewer progressing visual field locations, and a meaningful reduction in visual field decline despite identical pressure treatment.
• 40:40
  SPEAKER_00: Conclusion: Nicotinamide is not simply being tested as a vitamin supplement.
• 40:45
  SPEAKER_00: At 3 grams daily, it is being tested as a metabolic neuroprotective drug.
• 40:50
  SPEAKER_00: The biological case is unusually coherent.
• 40:52
  SPEAKER_00: Aging reduces nicotinamide adenine dinucleotide reserve.
• 40:56
  SPEAKER_00: Retinal ganglion cells are highly energy dependent.
• 40:59
  SPEAKER_00: Mitochondrial abnormalities can precede cell loss.
• 41:02
  SPEAKER_00: Axonal transport failure and oxidative stress contribute to degeneration.
• 41:07
  SPEAKER_00: Nicotinamide protects retinal ganglion cells, dendrites, axons, and electrical function in several animal models.
• 41:14
  SPEAKER_00: Short human studies suggest improvement in retinal electrophysiology and selected visual field measures.
• 41:21
  SPEAKER_00: But the central clinical question remains unanswered.
• 41:24
  SPEAKER_00: Does restoring nicotinamide-addenine dinucleotide availability slow glaucoma progression in humans when intraocular pressure is already treated?
• 41:33
  SPEAKER_00: Notter is a carefully targeted attempt to answer that question.
• 41:37
  SPEAKER_00: Its results will probably not settle the issue by themselves, but they could determine whether high-dose nicotinamide moves from an intriguing metabolic hypothesis toward a genuine glaucoma treatment or remains a promising idea, limited by dose, safety, and uncertain clinical benefit.
• 41:54
  SPEAKER_00: All links to sources are available in the text version of this article.
• 41:58
  SPEAKER_00: You can find the full article at visualfieldtest.com.
• 42:02
  SPEAKER_00: Thanks for listening.
• 42:04
  SPEAKER_00: To check your visual field, click the link at the bottom of this article or visit visualfieldtest.com.