Citicoline (CDP-Choline) | Supplementopedia

Overview

Citicoline (also known as CDP‑choline or cytidine‑5′‑diphosphocholine) is a naturally occurring nucleotide that serves as an intermediate in the biosynthesis of phosphatidylcholine, a major phospholipid of cell membranes. When taken as a dietary supplement, its primary purpose is to support neuronal membrane integrity and support the synthesis of the neurotransmitter acetylcholine, thereby influencing cognitive and neuro‑protective functions.

Benefits

Cognitive performance: Randomized controlled trials (RCTs) in healthy adults and in patients with mild cognitive impairment show modest improvements in attention, memory recall, and executive function (e.g., 500 mg/day for 12 weeks).
Neuro‑protection after stroke/brain injury: Meta‑analyses of acute stroke trials report reduced infarct size and better functional recovery when 1–2 g/day is administered within 24 h of onset.
Age‑related brain decline: Long‑term supplementation (up to 24 months) has been linked to slower brain atrophy rates measured by MRI.
Vision and retinal health: Small clinical studies suggest benefit in glaucoma and retinal disease by supporting retinal cell membranes.
Physical performance: In athletes, 500‑1000 mg/day has been associated with reduced perceived fatigue and improved reaction time in high‑intensity tasks.
Metabolic support: Preliminary data indicate modest improvement in hepatic lipid metabolism and decreased serum homocysteine, especially when combined with B‑vitamin therapy.

How It Works

Process: Citicoline is hydrolyzed to cytidine and choline after oral absorption.
Pathway:
- Cytidine crosses the blood–brain barrier and is phosphorylated to cytidine‑triphosphate (CTP), while choline is phosphorylated to phosphocholine.
- These two intermediates combine via CDP‑choline synthase to regenerate phosphatidylcholine (PC) in neuronal membranes, enhancing membrane fluidity and signaling.
- The choline portion also fuels acetylcholine synthesis via choline acetyltransferase, thereby boosting cholinergic neurotransmission.
- In addition, citicoline increases the expression of brain‑derived neurotrophic factor (BDNF) and up-regulates phosphatidylinositol‑dependent signaling pathways, which support synaptic plasticity.
- Cytidine also serves as a precursor for nucleic acids, supporting DNA/RNA repair.
Combined Effects: The combined effects improve neuronal energy metabolism, reduce excitotoxic glutamate release, and attenuate oxidative stress, underpinning its neuro‑protective and cognitive-enhancing actions.

Dosage

Standard adult dose: 250–500 mg taken 1–2 times daily (total 500–1000 mg/day) for cognitive support or general brain health.
Acute neuro‑protective use (stroke, TBI): 1–2 g/day divided into 2 doses, initiated as early as possible (within 24 h) and continued for 7–14 days.
Older adults/clinical impairment: 500 mg twice daily (1 g/day) for 12–24 weeks, often monitored for efficacy.
Timing: Split dosing (morning and early afternoon) maintains steady plasma levels; taking with food improves tolerability but is not mandatory.
Special populations: Lower starting dose (250 mg) may be used in those with renal impairment or who are medication‑sensitive; increase gradually if needed.
Loading: Some protocols start with 1000 mg on day 1 then 500 mg twice daily for 7 days, but evidence is limited.

Safety & Side Effects

Citicoline is generally well tolerated.
Adverse Events: Reported adverse events are mild and include headache, gastrointestinal upset (nausea, diarrhea), insomnia, and mild insomnia.
Serious Adverse Events: No serious adverse events have been recorded in doses up to 2 g/day in clinical trials.
Contra‑indications:
- Known hypersensitivity to citicoline.
- Severe hepatic or renal failure (dose reduction recommended).
- Pregnant or lactating women (lack of robust safety data).
Potential drug interactions:
- Anticholinergic agents (may blunt cognitive benefits).
- Anticoagulants (theoretical additive effect on bleeding due to reduced platelet aggregation).
- Dopaminergic agents (possible amplification of dopaminergic signaling).
Caution: Caution is advised in patients with seizure disorders, as high-dose choline may theoretically reduce seizure threshold, although clinical evidence is limited.

Chemistry

Citicoline is chemically known as cytidine 5′‑diphosphate choline (IUPAC: (2‑R‑hydroxy‑3‑(phosphonooxy)propyl) 5‑(2‑deoxy‑β‑D‑ribofuranosyl)‑1‑phosphoryl‑4‑hydroxy‑5‑(phosphonooxy)‑diphosphate).
Molecular formula: C₁₄H₃₅N₃O₁₄P₂, molecular weight ≈ 489.98 g/mol.
Structure: The molecule consists of a cytidine nucleoside linked via a diphosphate bridge to a choline moiety.
Properties:
- Highly water‑soluble.
- Stable at neutral pH.
- Exists as a sodium or calcium salt in most commercial preparations.
- The phosphodiester bond (phosphoryl‑choline) is the key functional group enabling its conversion into phosphatidylcholine and CTP.
- The compound is a zwitterion at physiological pH, conferring high bioavailability (≈ 90 % oral absorption) and rapid plasma clearance (half‑life ~ 6–8 h).

Sources & Quality

Production: Commercial citicoline is produced primarily by synthetic chemical routes: condensation of cytidine monophosphate (CMP) with choline chloride under controlled pH, followed by purification and conversion to the sodium or calcium salt.
Cytidine Source: Some manufacturers obtain cytidine from biotechnological fermentation of Saccharomyces or E. coli cultures, then chemically couple the choline component.
Natural Sources: Natural dietary sources contain only trace amounts (e.g., liver, egg yolk, fish) and are not practical for supplementation.
Quality Considerations:
- GMP‑certified manufacturing.
- Verification of > 95 % purity by HPLC.
- Absence of heavy metals and residual solvents.
- Third‑party testing (e.g., USP, NSF).
- Consistent particle size and stable salt form (Na or Ca) ensure reproducible bioavailability.