Introduction

Citicoline, also known as CDP-choline, is a naturally occurring compound that supports nerve cell function. It serves as a key precursor for phospholipids — essential components of cell membranes — and boosts levels of important neurotransmitters in the brain. In the visual system, citicoline has drawn attention as a possible neuroprotective agent for retinal ganglion cells (RGCs) affected by glaucoma and other optic neuropathies (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Likewise, in the aging brain, citicoline’s membrane-repair and neurochemical effects have been investigated for preserving memory and cognition with age (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This article reviews clinical and experimental evidence that citicoline can improve RGC function (often measured by visual fields and electrophysiologic tests) and explores how its cellular mechanisms (membrane repair and dopaminergic modulation) may also benefit age-related cognitive decline. We also consider practical issues of dosing, safety, adherence, and how long any benefits last once treatment stops.

How Citicoline Works in Nerve Cells

Citicoline (cytidine-5′-diphosphocholine) is metabolized into cytidine and choline in the body. Choline feeds into the synthesis of phosphatidylcholine, a major membrane lipid, and of the neurotransmitter acetylcholine (pmc.ncbi.nlm.nih.gov). By supplying these building blocks, citicoline helps repair and maintain cell membranes. It can prevent loss of cardiolipin (a key membrane lipid in mitochondria) and accelerate membrane phospholipid resynthesis (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). These actions support overall cell integrity and energy production, which are crucial for high-energy neurons like RGCs and aging brain cells.

Citicoline also boosts neurotransmission. It provides choline for acetylcholine, raising levels in the hippocampus and cortex. It has been shown to increase dopamine levels by enhancing tyrosine hydroxylase (the enzyme that makes dopamine) and by slowing dopamine reuptake (pmc.ncbi.nlm.nih.gov). In animal models, retinal dopamine was specifically elevated after citicoline treatment (pmc.ncbi.nlm.nih.gov). Citicoline likewise raises noradrenaline and serotonin levels in various brain regions (pmc.ncbi.nlm.nih.gov). Because dopamine is especially important in the retina (for visual signal modulation) and in brain circuits for attention and memory, these effects may underlie improved neural function. Relatedly, citicoline may attenuate glutamate excitotoxicity by upregulating the EAAT2 glutamate transporter (pmc.ncbi.nlm.nih.gov), and it has been shown to reduce β-amyloid plaque formation in experimental models (pmc.ncbi.nlm.nih.gov). All these mechanisms – membrane repair, energy support, and modulation of neurotransmitters – contribute to citicoline’s broad neuroprotective profile (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

Citicoline in Glaucoma and RGC Protection

Glaucoma is characterized by the loss of RGCs and their fibers, leading to progressive vision loss (peripheral visual field defects). Elevated eye pressure (IOP) is the main treatable factor, but many patients continue to show RGC degeneration despite good pressure control. Citicoline has been extensively studied as an adjunct therapy aimed at slowing RGC loss.

Laboratory and Animal Studies

In laboratory models of optic nerve injury or glaucoma, citicoline consistently showed neuroprotective effects on RGCs. For example, rabbit studies found that citicoline reduced retinal cell death and increased retinal dopamine levels (pmc.ncbi.nlm.nih.gov). In a model of optic nerve crush, citicoline not only preserved RGCs but upregulated the anti-apoptotic protein Bcl-2 (pmc.ncbi.nlm.nih.gov). Cultured retinal neurons exposed to toxic stress had ~50% less cell death when treated with citicoline. And in diabetic retina models, citicoline-rich eye drops helped protect the inner retinal layers from degeneration. These findings indicate citicoline counteracts the biochemical stressors (oxidative damage, glutamate toxicity, ischemia) that drive RGC apoptosis.

Electrophysiological Measures (PERG and VEP)

Because RGCs form the innermost retinal layer, their function can be assessed noninvasively by Pattern Electroretinogram (PERG). PERG measures the electrical response of the retina to patterned visual stimuli and selectively reflects RGC activity. Similarly, Visual Evoked Potentials (VEP) record electrical responses in the visual cortex to visual stimuli, reflecting the integrity of the entire visual pathway from eye to brain. Improvements in PERG and VEP parameters indicate better RGC function and faster neural conduction.

Clinical studies in glaucoma patients have repeatedly shown that citicoline improves these electrophysiological endpoints. For instance, in one trial of open-angle glaucoma patients, intramuscular citicoline significantly increased the PERG P50-N95 amplitude (an index of RGC signal strength) and shortened the PERG P50 and VEP P100 implicit times (indexes of faster nerve conduction) (pmc.ncbi.nlm.nih.gov). These changes were statistically significant compared to untreated controls, and they correlated with better visual field performance. After a washout period (no citicoline), PERG measures began to decline back toward baseline, but remained better than untreated eyes (pmc.ncbi.nlm.nih.gov). Subsequent re-treatment with citicoline produced further gains in PERG and VEP, showing a clear treatment-dependent improvement in retinal signaling (pmc.ncbi.nlm.nih.gov). Other controlled studies found similar results: two-month courses of intramuscular citicoline led to improved PERG/VEP responses, and repeated yearly cycles preserved these enhancements over as long as 8 years of follow-up (pmc.ncbi.nlm.nih.gov).

Notably, a comparison of oral versus injectible routes found no significant differences in electrophysiological outcomes (pmc.ncbi.nlm.nih.gov). In one analysis, patients treated with intramuscular citicoline and those given equivalent doses orally showed nearly identical PERG and VEP improvements (pmc.ncbi.nlm.nih.gov). This suggests that the neuroenhancement is largely driven by citicoline itself, regardless of administration route, as long as adequate systemic levels are achieved.

Visual Field Outcomes

Improvements in electrophysiology often translate to better visual function. Small clinical trials reported that citicoline reduced visual field defects in glaucoma. In a classic study from the 1990s, short-term intramuscular citicoline (1 g/day for 10 days) improved visual field scotomas in most treated eyes, with effects lasting about 3 months (pmc.ncbi.nlm.nih.gov). In a long-term follow-up extending over 10 years, repeating 15-day courses of intramuscular citicoline every 6 months kept visual field loss from progressing: only 10% of treated patients had significant field worsening versus ≥50% in untreated controls (p=0.007) (pmc.ncbi.nlm.nih.gov).

More recently, an observational study of 41 glaucoma patients with documented progression showed that two years of daily oral citicoline (in addition to regular glaucoma therapy) dramatically slowed the rate of field loss (pmc.ncbi.nlm.nih.gov). Prior to treatment their mean field loss was about –1.1 dB/year; after starting citicoline it fell to about –0.15 dB/year by the end of two years (p=0.01) (pmc.ncbi.nlm.nih.gov). In other words, citicoline largely stabilized the fields. The study noted that these effects accumulated gradually and were most apparent after nearly a year of continuous treatment (pmc.ncbi.nlm.nih.gov).

Structural data echo these functional gains. Over several years, glaucoma patients on citicoline showed slower thinning of the retinal nerve fiber layer (RNFL) and inner macular layers on OCT, compared to expected decline. For example, one long-term trial (two 120-day on/60-day off cycles per year for 2 years) found significantly less RNFL and ganglion cell complex thinning in treated eyes, with corresponding clinical stability of visual fields (pmc.ncbi.nlm.nih.gov). Likewise, daily citicoline eye drops (containing 1–2% citicoline) used in glaucoma led to preservation of nerve fiber layer thickness over 3 years, again aligning with steadier fields (pmc.ncbi.nlm.nih.gov). These morphological findings support the idea that citicoline can protect or even “rescue” RGCs under chronic stress (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

Citicoline in Cognitive Aging and Neurodegeneration

The benefits of citicoline on neurones extend beyond the eye. Many parallels exist between RGC degeneration and brain aging. Like RGCs, neurons in the aging brain suffer from membrane breakdown, reduced neurotransmitter levels, and energy deficits.

In older adults, choline availability becomes a limiting factor: brain uptake of choline declines with age, potentially impairing acetylcholine production (pmc.ncbi.nlm.nih.gov). Dietary choline (from eggs, meat, etc.) tends to correlate with better memory performance in the elderly. Citicoline offers a way to boost choline and cytidine without the cardiovascular byproducts (TMAO) seen with some other sources (pmc.ncbi.nlm.nih.gov). Indeed, a 2021 study of healthy older adults with mild memory complaints found that adding 500 mg/day of citicoline for 12 weeks significantly improved episodic memory and overall cognitive scores compared to placebo (pmc.ncbi.nlm.nih.gov). Compliance was excellent (99/100 completed), and analytes (vitals, labs) stayed normal, suggesting the 12-week supplementation was well-tolerated (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

These findings fit into a broader picture. Trials in people with mild cognitive impairment or early dementia have also generally reported cognitive benefits from citicoline. A recent meta-analysis covering patients with vascular cognitive impairment, Alzheimer’s disease, or post-stroke cognitive decline found that all included studies showed positive effects on memory or mental status (pmc.ncbi.nlm.nih.gov). Pooled analysis yielded a moderate improvement in global cognitive scores (effect sizes roughly 0.5 to 1.6 standard deviations) favoring citicoline (pmc.ncbi.nlm.nih.gov). The authors caution that study quality varied, but the consistency of improvement across trials illustrates a real potential for citicoline to slow cognitive decline.

Mechanistically, these cognitive results are plausible. Citicoline’s membrane-repair and neurotransmitter-enhancing roles are just as relevant in brain neurons as in RGCs. By bolstering acetylcholine and dopamine – key players in learning and attention – and by mitigating excitotoxic and inflammatory damage, citicoline can support neural circuits that underlie memory and executive function. In fact, citicoline has been shown in very healthy volunteers (young adults) to improve psychomotor vigilance, arousal and working memory even after only two weeks of use (pmc.ncbi.nlm.nih.gov). And benefits appear greater with longer use, consistent with a gradual restoration of cellular health (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

Dosage, Duration, and Safety

Typical dosages of citicoline in studies range from 500 mg to 2000 mg per day, given either orally or by intramuscular injection (brief cycles of 10–60 days). Importantly, citicoline is well-absorbed: more than 90% bioavailable even orally (pmc.ncbi.nlm.nih.gov). Its animal toxicity is extremely low (mouse LD50 >4000 mg/kg), and human therapeutic doses (7–28 mg/kg) are far below harmful levels (pmc.ncbi.nlm.nih.gov). Accordingly, clinical trials report very few side effects. In the muscle, nasal, or eye-drop formulations tested, no significant differences in blood tests or adverse events appeared between citicoline and placebo groups (pmc.ncbi.nlm.nih.gov). The most common complaints (if any) are minor stomach discomfort or local injection-site soreness, and these are infrequent.

Adherence in the published studies tended to be high, especially for oral regimens. For example, one large trial of older adults with memory complaints found virtually 100% completion of the 12-week supplement course (pmc.ncbi.nlm.nih.gov). Intramuscular or subcutaneous routes may be less convenient, so long-term use is often by pill or solution. Eye-drop formulations (1–2% citicoline) were also tested successfully in glaucoma and diabetic patients, offering a non-oral alternative.

Regarding duration and persistence of effect, evidence suggests that citicoline’s benefits generally fade if treatment is stopped. In glaucoma studies, the functional improvements (PERG amplitudes, visual fields) tended to regress toward baseline after a washout period (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). The positive effects re-emerged only when a new course of citicoline was given (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This “required repeating” pattern indicates the drug has more of a neuroenhancement than a permanent structural rescue. Similarly, cognitive trials have primarily measured outcomes at end of active treatment, so it’s unclear how long gains last off therapy. Given citicoline’s role as a metabolic precursor, it is likely most effective when taken regularly. In practice, clinicians who use citicoline for glaucoma often administer it in extended cycles (e.g. 2 months on, 3–4 months off) repeated indefinitely. Cognitive health studies suggest longer-term supplementation (months to years) may be needed to see durable effects on neurodegeneration (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

Conclusion

Citicoline (CDP-choline) represents a well-studied, low-risk neuroprotective strategy for both the eye and aging brain. In glaucoma and other optic nerve diseases, it consistently improves objective measures of retinal ganglion cell function (PERG, VEP) and slows visual field loss, when used as an adjunct to pressure-lowering therapy (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Its mechanisms – supplying membrane phospholipids, supporting mitochondria, and enhancing dopamine/acetylcholine signaling – directly combat the metabolic deficits seen in RGC degeneration (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Parallels in the brain explain why citicoline also favors memory and cognition in older adults: it repairs neuronal membranes and boosts neurotransmitters implicated in learning (cholinergic, catecholaminergic) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). The clinical evidence, though sometimes from small trials, is consistent: most studies find cognitive scores improve with citicoline, including healthy older subjects and those with mild impairment (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

Available data suggest that for both eye and brain, continuous or repeated dosing of citicoline is needed to maintain benefit. Trials show gains appearing after weeks to months of use, and fading when stopped (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Importantly, citicoline is very safe even at gram-level daily doses (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Patients generally tolerate it well, whether taken by mouth or by periodic injection.

In summary, citicoline offers a dual advantage: it is biologically suited to repair damaged neural membranes and it has a track record of improving functional endpoints in degenerating visual and cognitive systems. For glaucoma patients experiencing continued visual loss, citicoline may be a useful neuroenhancement. In aging individuals, citicoline could be part of a nutritional approach to preserve memory. Future larger trials will clarify optimal regimens and long-term benefits, but the existing evidence supports citicoline as a promising supplement for visual pathway support and cognitive aging (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).