VERSA-1 [Discontinued] by USPlabs

There is insufficient reliable information available about the effectiveness of aegeline.

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POSSIBLY EFFECTIVE

• Age-related cognitive decline. Clinical research in elderly patients shows that taking oral or intravenous citicoline daily improves some memory scores, short-term. Details: Several small clinical studies in people 50-85 years of age with age-related cognitive decline shows that taking citicoline 500-2000 mg daily, either orally or by intravenous infusion, for up to 12 weeks moderately improves memory scores when compared with placebo (12130,12131,43284,109016). Citicoline consistently improves short-term recall and verbal memory, but the effects on other domains are less clear (12130,12131,43284). In one clinical study, a specific citicoline product (Cognizin, Kyowa Hakko) 500 mg daily for 12 weeks was used (109016).
• Glaucoma. Clinical research shows that oral, intramuscular, or ophthalmic citicoline may improve vision or slow the rate of vision loss in patients with glaucoma. However, these different routes of administration have not been directly compared. Details: Preliminary clinical research in adults with open-angle glaucoma shows that taking citicoline 1600 mg orally daily for 60 days improves visual evoked potentials, but not intraocular pressure (IOP), when compared with baseline (43256). Other preliminary clinical research in patients with rapidly progressing glaucoma shows that taking a specific citicoline product (Neukron Ofta, Omikron), 500 mg orally daily for 4 four-month cycles over the course of 2 years, reduces the rate of visual field loss when compared with baseline (98448). The validity of both of these studies is limited by the lack of a comparator group. Small clinical studies in adults with open-angle glaucoma also show that treatment with intramuscular citicoline 1000 mg daily for 60 days improves visual evoked potentials, but not IOP, when compared with placebo or baseline (12173,43219,43256). Also, one clinical study shows that using a specific citicoline 2% eye drop (OMK1, Omicron) three times a day for 3 years reduces the loss of retinal nerve fibers and decreases visual field progression rates in patients with open-angle glaucoma and controlled IOP when compared with placebo (104827). Citicoline has also been used as part of a combination product. Preliminary clinical research in adults with primary open-angle glaucoma and controlled IOP shows that taking citicoline 500 mg, homotaurine 50 mg, and vitamin E 12 mg orally once daily for 4 months improves visual contrast sensitivity scores by less than 10% and self-reported quality of life scores by about 10% when compared with no additional interventions (104786). It is unclear if these effects are clinically relevant or if they are due to citicoline, other ingredients, or the combination.

POSSIBLY INEFFECTIVE

• Stroke. Oral or intravenous citicoline, started within 12-24 hours of onset of ischemic stroke symptoms, does not seem to improve outcomes in most patients. However, it may be modestly beneficial in those who are not candidates for recombinant tissue plasminogen activator (rtPA). Details: A meta-analysis of 10 trials shows that treatment with oral or intravenous citicoline 500-2000 mg daily for up to 6 weeks after ischemic stroke does not improve mortality, ability to complete activities of daily living, or neurologic function when compared with placebo or no intervention (104828). A different meta-analysis of 10 trials shows that treatment with oral or intravenous citicoline 250-2000 mg daily for up to 6 weeks after ischemic stroke increases the odds of recovery to independence by 56% and decreases the mortality rate and long-term disability by 10-12% when compared with placebo. However, this second meta-analysis included older, lower-quality trials in which the standard of care with conventional medicines was lower and ischemic stroke diagnoses were not confirmed via imaging (98228). Higher-quality trials have not confirmed these benefits, especially when patients receive early treatment with rtPA (98228,104828). A third meta-analysis of 7 trials with more limited inclusion criteria also did not demonstrate benefit on mortality or functional independence when compared with control (98447). Also, a large clinical trial of patients with moderate to severe acute ischemic stroke who received standard of care stroke management, including rtPA when indicated, shows that citicoline 1000 mg, administered intravenously over 30-60 minutes every 12 hours for 3 days and started within 24 hours of symptom onset, does not increase the rate of recovery at 90 days when compared with placebo (98444).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alzheimer disease. It is unclear if oral citicoline is beneficial in patients with Alzheimer disease. Details: Preliminary clinical research in adults with Alzheimer disease shows that taking citicoline 1000 mg orally daily for 12 weeks modestly improves cognitive function scores when compared with placebo (43222). Observational research in adults with Alzheimer disease has also found that taking citicoline 1000 mg orally in conjunction with memantine and rivastigmine for up to 12 months is associated with clinically non-significant improvements in cognitive function scores when compared with memantine and rivastigmine alone. In addition, taking citicoline was not associated with improvement in depression scores or activities of daily living (105730).
• Amblyopia. It is unclear if oral or intramuscular citicoline is beneficial in patients with amblyopia. Details: Preliminary clinical research in children with amblyopia shows that taking citicoline orally once daily, in combination with covering the affected eye with a patch, for 12 months moderately improves visual acuity when compared with the patch alone. Children aged less than 5 years took 250 mg daily and children aged 5-13 years took 500 mg daily (98442). Retrospective research in children aged 5-6 years with amblyopia has also found that citicoline treatment for up to 8 months is associated with modest improvements in visual acuity when compared with baseline. However, preliminary subgroup analyses suggest that benefits may not last longer than 3-4 months (109017). Preliminary clinical research in older patients with amblyopia, aged 9-37 years, shows that treatment with intramuscular citicoline 1000 mg daily for 15 days improves visual acuity in both eyes for 92% of patients when compared with baseline (43281). The validity of this study is limited by the lack of a comparator group.
• Attention deficit-hyperactivity disorder (ADHD). Although there has been interest in using oral citicoline for ADHD, there is insufficient reliable information about the clinical effects of citicoline for this purpose.
• Bipolar disorder. It is unclear if oral citicoline is beneficial in patients with bipolar disorder. Details: Preliminary clinical research in adults with bipolar disorder and cocaine dependence shows that taking citicoline orally for 12 weeks improves verbal learning scores, but not symptoms of depression or mania, when compared with placebo. Citicoline was titrated from 500 mg daily to 2000 mg daily over the first 6 weeks and then continued at 2000 mg daily for 6 weeks (43248).
• Cardiac arrest. It is unclear if intravenous citicoline can improve outcomes in children with cardiac arrest. Details: A small clinical study in children 1-12 years of age with successful resuscitation from cardiac arrest shows that using citicoline 10 mg/kg intravenously every 12 hours for 6 weeks improves disability and coma scores at 12 weeks when compared with no intervention. This study also suggests that using citicoline reduces mortality by 80% and duration of hospitalization by 12% when compared with no intervention (105729). However, the small size of this study limits the reliability of these findings.
• Cerebrovascular disease. It is unclear if oral, intramuscular, or intravenous citicoline is beneficial in patients with cerebrovascular disease. Details: Several small clinical trials in adults with chronic cerebrovascular disease shows that treatment with citicoline 600-1000 mg orally daily for up to 12 months or 600-1000 mg intramuscularly or intravenously daily for up to 12 weeks moderately improves memory and behavior scores when compared with placebo or no intervention (12131,43240,43288,98443). One of these clinical trials failed to show improvement in activities of daily living, although the study may have been inadequately powered to detect a difference between groups (98443).
• Cocaine dependence. It is unclear if oral citicoline is beneficial in patients with cocaine dependence. Details: Preliminary clinical research in adults with cocaine dependence and bipolar disorder shows that taking citicoline orally for 12 weeks reduces the likelihood of positive urine cocaine test results when compared with placebo. Citicoline was titrated from 500 mg daily to 2000 mg daily over the first 6 weeks and then continued at 2000 mg daily for 6 weeks (43248). However, a post-hoc analysis suggests that the effects of citicoline on abstaining from cocaine use decline over time and were no different than placebo in the last weeks of the study (98230). In addition, other clinical research in adults with cocaine dependence that also received weekly counseling shows that taking citicoline 500 mg orally twice daily for 8 weeks does not reduce cocaine craving or consumption levels when compared with placebo (98445).
• Delirium. Although there has been interest in using oral citicoline for delirium, there is insufficient reliable information about the clinical effects of citicoline for this purpose.
• Depression. It is unclear if oral citicoline is beneficial in patients with depression. Details: Preliminary clinical research in patients with major depressive disorder shows that adding citicoline 100 mg orally twice daily for 6 weeks to citalopram therapy improves symptoms of depression, as measured by the Hamilton Depression Rating Scale, and increases the relative rate of remission by 64% when compared with placebo. These results suggest that for every 4 patients treated with citicoline, remission is expected in one additional patient (98446).
• Diabetic retinopathy. Citicoline eye drops have only been evaluated in combination with other ingredients; the effect of citicoline when used alone is unclear. Details: Preliminary clinical research in patients with mild diabetic retinopathy shows that using a specific ophthalmic solution containing citicoline 2% and cyanocobalamin 0.05% (OMK2, Omikron Italia) three times a day for 3 years decreases visual field progression rates and stabilizes retinal nerve fiber thickness when compared with placebo (104825).
• Intracranial hemorrhage. It is unclear if intravenous citicoline is beneficial in patients with intracranial hemorrhage. Details: Preliminary clinical research in patients with non-traumatic intracerebral hemorrhage shows that using citicoline 250 mg intravenously twice daily for 14 days improves muscular strength by 25% when compared with placebo (43252).
• Ischemic optic neuropathy. It is unclear if oral citicoline is beneficial in patients with ischemic optic neuropathy. Details: Preliminary clinical research in patients with non-arteritic ischemic optic neuropathy shows that taking a specific type of citicoline (Cebrolux-Tubilux) 1600 mg orally daily for 60 days improves visual acuity and visual evoked potentials when compared with no intervention (43250).
• Methamphetamine use disorder. It is unclear if oral citicoline is beneficial in patients with methamphetamine use disorder. Details: Preliminary clinical research in adults with methamphetamine dependence shows that taking citicoline 1000 mg orally twice daily for 8 weeks reduces the severity of cravings when compared with baseline, but not when compared with placebo. Taking citicoline also did not reduce the number of methamphetamine positive urine samples when compared with placebo (109015). This study may have been inadequately powered to detect a difference between groups.
• Parkinson disease. It is unclear if oral or intramuscular citicoline is beneficial in patients with Parkinson disease. Details: Preliminary clinical research shows that taking citicoline 1200 mg orally daily for one month improves Parkinson disease symptom scores when compared with no intervention (43259). Other preliminary clinical research in adults with Parkinson disease shows that treatment with citicoline 500 mg orally daily or citicoline 500-1000 mg intramuscularly daily for 30 days improves rigidity and bradykinesia scores, but not tremor scores, when compared with baseline (43253,43262). The validity of these studies is limited by the lack of a comparator group.
• Schizophrenia. It is unclear if oral citicoline is beneficial in patients with schizophrenia. Details: Preliminary clinical research in patients with chronic, stable schizophrenia shows that taking citicoline 1250 mg twice daily for 8 weeks as an add-on to risperidone therapy modestly reduces negative symptoms, but not positive symptoms, of schizophrenia when compared with placebo plus risperidone (100988). Other preliminary clinical research in patients with chronic, stable schizophrenia shows that taking citicoline 500 mg, 1000 mg, or 2000 mg as a single dose does not improve sensory gating when compared with placebo (100987). However, both studies may have been inadequately powered to detect a difference between groups.
• Traumatic brain injury (TBI). It is unclear if oral citicoline is beneficial in patients with TBI; the available research is conflicting. Details: A meta-analysis of 5 low-quality studies in patients with TBI shows that treatment with oral or intravenous citicoline up to 2000 mg daily for up to 9 days does not improve Glasgow outcome scores or cognitive performance. Additionally, one study included in this analysis showed no improvement in survival with citicoline when compared with placebo (98227). However, a very small clinical study not included in this analysis shows that taking citicoline 1000 mg orally daily improves memory, learning, and verbal ability in patients with TBI (43287). Some observational research has found that continuous intravenous infusion of citicoline 3000 mg over 24 hours for up to 21 days is associated with 6.7-fold greater odds of survival while in the intensive care unit (ICU) when compared with matched controls not receiving citicoline. Citicoline therapy was also linked to 2.6-fold greater odds of having a favorable outcome after 6 months, defined as a score of 5-8 on the extended version of the Glasgow Outcome Scale (100989). The discrepant results may be explained by differences in the severity of TBI at baseline and the doses of citicoline used in these studies.
• Vascular dementia. It is unclear if oral citicoline is beneficial in patients with vascular dementia. Details: Preliminary clinical research in adults with vascular dementia shows that taking citicoline 500 mg orally twice daily for 12 months does not improve neuropsychological symptom scores when compared with placebo (12135). More evidence is needed to rate citicoline for these uses.

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POSSIBLY UNSAFE ...when used orally. A specific product containing synthetic aegeline (Super Thermo OxyELITE Pro) has been associated with numerous case reports of liver toxicity and liver failure, some of which resulted in death (90904,102777,102779,102780). While other ingredients such as caffeine, yohimbine, and higenamine were also included in this product, these other ingredients have not been strongly implicated in hepatotoxicity (102781). Consequently, the liver injury associated with the product was attributed to aegeline. While the aegeline in this product was synthetic and may have included contaminants or toxic chemical derivatives (101520), evidence from feeding studies in rats has shown that the bael plant, which contains aegeline, can cause hepatic lesions (101521).

PREGNANCY AND LACTATION:
Insufficient reliable information is available; avoid using.

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POSSIBLY SAFE ...when used orally and appropriately, short-term (12131). Citicoline 1000-2000 mg daily has been used with apparent safety for up to 12 weeks (12130,43248,98230,104828,109015,109016). Citicoline 2500 mg daily has also been used with apparent safety for up to 7 weeks (100988). ...when citicoline is used intravenously or intramuscularly under medical supervision (12131). Citicoline has been administered intravenously with apparent safety at a dose of 500 mg daily for 7 days, or 2000 mg daily for 3 days (43229,98444,104828). ...when used topically on the eye. Citicoline 2% eye drops have been used with apparent safety for up to 3 years alone or in combination with cyanocobalamin 0.05% (98229,104824,104825,104826,104827).

CHILDREN: POSSIBLY SAFE
when citicoline is used orally and appropriately. Citicoline has been used with apparent safety for up to 1 year at a dose of 250 mg daily in children under 5 years of age and 500 mg daily in children 5-13 years of age (98442). There is insufficient reliable information available about the safety of citicoline when used intravenously in children.

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

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General ...Orally, numerous cases of severe acute hepatitis, occasionally resulting in death, have been associated with use of a specific product containing synthetic aegeline (Super Thermo OxyELITE Pro) (90904,102777,102779,102780,102781).

Hepatic ...There are numerous case reports of severe acute hepatitis with fulminant liver failure associated with use of a specific multi-ingredient product containing aegeline (Super Thermo OxyELITE Pro). Symptoms included elevated liver enzymes, dark urine, jaundice, loss of appetite, nausea, abdominal pain, and fatigue. Onset of liver injury typically occurred in patients 2-20 weeks after beginning regular use of this product. Liver transplant was required in at least five cases, and there were at least two deaths (90904,101520,102777,102779,102780). The aegeline included in this product was synthesized by a Chinese manufacturer; the purity of this ingredient or whether it was identical to the constituent of the bael plant where it is found naturally is unclear (101520,102779). However, there is evidence from feeding trials in rats showing that the bael plant, which contains aegeline, can cause hepatic lesions (101521).

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General ...Orally, intramuscularly, and intravenously, citicoline seems to be well-tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, back pain, blurred vision, constipation, diarrhea, edema, headache, insomnia, nausea, rash.

Cardiovascular ...Orally, citicoline may cause chest pain, palpitations, hypotension, bradycardia, tachycardia, and peripheral edema in some patients, although the incidence is likely similar to placebo (12130,12131,12132,43225).

Dermatologic ...Orally, citicoline may cause skin rash in some patients (12130,12132,43248).

Gastrointestinal ...Orally, citicoline may cause abdominal pain, constipation, diarrhea, and nausea in some patients (12130,12132,98846,100988,105730,109015).

Musculoskeletal ...Orally, citicoline may cause back pain in some patients (43225).

Neurologic/CNS ...Orally, citicoline may cause headache and insomnia in some patients (12130,43230,43273,98846,100988,109015,109016).

Ocular/Otic ...Orally, citicoline may cause blurred vision in some patients (12130,12132).

Other ...Orally, citicoline may cause edema of the extremities in some patients (43225).

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