Choline supplements: An update

**Background:** Choline is an essential nutrient critical for liver, muscle, and brain function, serving as a precursor for acetylcholine, membrane phospholipids, and the methyl donor betaine. The US FDA recognized choline as an essential nutrient in 1998, and adequate intake (AI) values have been set by the National Academy of Medicine and the European Food Safety Authority (e.g., 400 mg/day for healthy adults). Choline deficiency can lead to conditions such as premature birth, cystic fibrosis, and hepatic steatosis. Several forms of choline supplementation are available, including choline alfoscerate (alpha-glycerophosphocholine, GPC), choline bitartrate, lecithin, and citicoline. This narrative review summarizes the main preclinical and clinical investigations assessing the effects of these supplements.

**Methods:** The authors conducted a comprehensive review of the literature, examining preclinical studies (in vitro and animal models) and clinical trials (randomized controlled trials, cross-over studies, and observational studies) that investigated various forms of choline supplementation. The review covers studies on GPC, choline bitartrate, lecithin, and citicoline, focusing on their effects on cognitive function, physical performance, endothelial function, and cardio-metabolic health. Key clinical trials are summarized in Table 3 of the paper.

**Key Results:** - **GPC (Choline Alfoscerate):** Preclinical studies show GPC enhances hippocampal neurogenesis, protects against seizure-induced neuronal death, and antagonizes scopolamine-induced amnesia. In vitro, GPC antagonizes neurotoxicity triggered by Aβ(25–35) and attenuates Tau protein phosphorylation. Clinically, a study in male young adults demonstrated that ingestion of 1000 mg GPC significantly increases plasma free choline levels. In a multicenter clinical trial (daily intramuscular dose of 1000 mg for 28 days and oral dose of 800 mg during the following 5 months), GPC showed excellent tolerability and therapeutic role on cognitive recovery in patients with acute stroke or transient ischemic attack (TIA). However, a recent retrospective study found that GPC is associated with a higher 10-year incident stroke risk in a dose-response manner after adjusting for traditional cerebrovascular risk factors. In physical performance, 600 mg GPC increased isometric mid-thigh pull force by 98.8 N in 13 college-aged males, and 250 mg GPC improved maximum velocity and maximum mechanical power. - **Choline Bitartrate:** A randomized cross-over study (DRKS00020454) in 6 healthy adult men compared choline chloride, choline bitartrate, GPC, and egg-PC (550 mg choline equivalent each) and found no difference in area-under-curve of choline plasma concentrations. In a randomized, double-blind, placebo-controlled trial (NCT01149538), 500 mg/day choline bitartrate in 18 children aged 2.5-5 years with fetal alcohol spectrum disorder (FASD) improved processing speed and corpus callosum white matter microstructure after 7-year follow-up. A placebo-controlled double-blind study with 2 g choline bitartrate in 30 healthy individuals enhanced visuomotor performance. - **Lecithin:** A randomized double-blind, placebo-controlled trial (NCT00720343) with 20 g lecithin in 60 women undergoing gynecological surgery found no analgesic benefit. - **Citicoline:** A randomized, double-blind, placebo-controlled clinical trial (NCT03369925) with 500 mg/day citicoline in 100 healthy men and women aged 50-85 years with age-associated memory impairment improved attention and may be beneficial against memory loss due to aging. - **Endothelial Dysfunction:** Citicoline attenuated hypoxia/OGD-induced increase in endothelial permeability via upregulating tight junction proteins (zonula occludens-1, occludin, claudin-5) in HUVECs and bEnd.3 cells. Choline supplementation activated α7 nAChRs and protected against hypoxia-induced endothelial dysfunction. - **Cardio-metabolic Disorders:** Choline exhibits protective effects against cardiovascular disorders including arrhythmias, cardiac hypertrophy, and ischemia/reperfusion injury. However, a choline- or carnitine-rich diet was reported to promote atherosclerosis in mice via increased TMAO production. Dietary lecithin has shown hypocholesterolemic and anti-atherogenic properties. - **Cognitive Dysfunction:** A cross-sectional study on ~2400 elderly patients demonstrated that choline intake correlates with cognitive performance. Lifelong choline supplementation in APP/PS1 mice decreased amyloid-β plaque load and improved spatial memory. Maternal choline supplementation in Ts65Dn mice (Down syndrome model) enhanced emotion regulation and improved spatial learning.

**Clinical Implications:** The review indicates that choline supplements, particularly GPC and citicoline, may offer benefits for cognitive function, physical performance, and endothelial health. However, the association of GPC with increased stroke risk in a dose-response manner raises safety concerns that require further investigation. The contrasting effects of choline on cardiovascular health—protective via direct mechanisms versus potentially harmful via TMAO production—highlight the complexity of choline metabolism and the need for personalized supplementation strategies. The review underscores the importance of considering the form of choline supplement, dosage, duration, and individual patient factors (e.g., gut microbiota composition, genetic polymorphisms) when recommending choline supplementation. Further dedicated studies are warranted to compare the different effects of currently available forms of choline supplementation.