Choline: A Comprehensive Reference Article
1. Identity: Chemical Nature, Nomenclature, and Forms
Choline is a quaternary ammonium compound that was first discovered in pig bile in 1849 by German chemist Adolph Strecker, but was not analyzed in detail by him until 1862, when it was first named choline (after the Greek word "chole" for bile). Choline is a quaternary saturated amine with the chemical formula (CH₃)₃N⁺CH₂CH₂OH X⁻, where X⁻ is a counterion such as chloride (choline chloride), hydroxide, or tartrate.
It occurs in water-soluble and lipid-soluble forms in the body and diet. The principal forms encountered in foods and supplements include:
- Free choline — the unesterified, water-soluble base form.
- Phosphatidylcholine (PC, lecithin) — the most abundant lipid-soluble dietary form; lecithin was eventually characterized chemically as being phosphatidylcholine.
- Glycerophosphocholine (GPC / Alpha-GPC) — a water-soluble glycerophospholipid metabolite.
- Phosphocholine — an intermediate in phospholipid biosynthesis.
- Sphingomyelin — a lipid-soluble choline-containing sphingolipid.
- CDP-choline (citicoline) — cytidine diphosphocholine, a nucleotide form used in phosphatidylcholine biosynthesis.
In dietary studies, phosphatidylcholine accounts for approximately 42.5% of total choline intake, followed by free choline (25.8%), glycerophosphocholine (21.2%), sphingomyelin (4.5%), and phosphocholine (4.2%).
In the supplement market, the forms of choline in dietary supplements include choline bitartrate, phosphatidylcholine, and lecithin. Alpha-GPC (alpha-glycerophosphocholine) and CDP-choline (citicoline) are also widely used. Choline chloride is sometimes preferred as a supplement because phosphatidylcholine can have gastrointestinal side effects.
2. Historical and Scientific Discovery
In 1850, Theodore Gobley (1811–1876), a member of the Académie Nationale de Pharmacie and a pharmacist in Paris, isolated a molecule from brain tissue and carp fish eggs that he described as "matière phosphorée," which he named "lecithine" from the Greek "lekithos" (egg yolk). In 1862, Adolph Strecker (1822–1871), recently having moved to the University of Tübingen as a Professor, was characterizing the composition of bile from pig and ox, and found that lecithin from bile, when boiled, generated a new nitrogenous chemical that Strecker named "choline."
Three years later, Oscar Liebreich identified a new substance, "neurine," in the brain. After a period of confusion, neurine and choline were found to be the same molecule, and the name choline was adopted. Determination of the chemical structure of choline and its first chemical synthesis was performed shortly thereafter, and in 1868 Strecker found that choline was a part of the molecule of phosphatidylcholine.
In 1954, Eugene Kennedy described the cytidine 5-diphosphocholine pathway by which choline is incorporated into phosphatidylcholine. A second route, the phosphatidylethanolamine-N-methyltransferase (PEMT) pathway, was identified by Jon Bremer and David Greenberg in 1960.
Originally categorized as vitamin B4, choline lost its vitamin status in the years following its vitamin categorization due to the fact that it can also be synthesized endogenously in the human organism to a certain extent. In 1998, the Institute of Medicine officially recognized choline as an essential nutrient, setting recommended daily intake levels to better guide dietary practices.
3. Natural Sources
Rich dietary sources of choline and choline phospholipids include liver, egg yolks, dairy products, peanuts, certain beans, nuts, and seeds. Foods with a known high choline content are eggs, beef, chicken, milk, fish, and selected plant foods. Choline content is particularly high in liver, eggs, and wheat germ, although it is present in a variety of foods.
The main dietary choline sources in European populations studied were eggs, milk, fresh vegetables, lean fish, and bread. In general, animal food sources were the most important contributors to choline intake. Current and rapidly spreading dietary shifts toward plant-based and vegan diets — characterized by a lower proportion of animal foods, the main sources of choline — increase the risk of suboptimal intake in broad segments of the population.
4. Endogenous Synthesis
Besides dietary intake, choline in the body can be generated de novo via the hepatic PEMT pathway. Choline from both dietary and endogenous sources is incorporated into phosphatidylcholine (PC). Yet, de novo choline synthesis in humans is not sufficient to meet their metabolic needs such that healthy humans fed choline-deficient diets develop fatty liver, liver damage, and other organ dysfunction. Therefore, the endogenous synthesis of choline is not sufficient, and dietary sources of choline are necessary to maintain health, making choline an essential nutrient for humans.
Premenopausal women developed signs of choline deficiency less commonly than postmenopausal women or men, possibly as a consequence of upregulation of hepatic PEMT by oestrogen, leading to an increase in the endogenous synthesis of PC. Genetic variants that reduce PEMT efficiency can increase dietary choline requirements, as insufficient phosphatidylcholine synthesis may strain liver function, impair lipid metabolism, and weaken membrane integrity.
5. Key Constituents and Active Compounds
Choline itself is both the key active compound and a precursor to several important biological molecules. Choline and its metabolites are needed for three main physiological purposes: structural integrity and signaling roles for cell membranes; cholinergic neurotransmission (acetylcholine synthesis); and as a major source for methyl groups via its metabolite trimethylglycine (betaine), which participates in the S-adenosylmethionine synthesis pathways.
Major Metabolic Derivatives
- Phosphatidylcholine (PC): Choline is transformed into diverse phospholipids, like phosphatidylcholines and sphingomyelins. These are found in all cell membranes and the membranes of most cell organelles. Phosphatidylcholines are a structurally important part of the cell membranes. In humans, 40–50% of phospholipids are phosphatidylcholines.
- Acetylcholine: Choline promotes the synthesis of acetylcholine, a neurotransmitter intimately associated with cognition. As an information-transmitting molecule, acetylcholine is necessary for proper memory function, and is especially important for aging brains.
- Betaine (trimethylglycine): In one route, choline is irreversibly oxidized to betaine via choline dehydrogenase (CHDH) and betaine aldehyde dehydrogenase. Betaine then donates a methyl group to homocysteine to form methionine via betaine:homocysteine methyltransferase (BHMT), and, in turn, is converted to dimethylglycine. Methionine is used for the biosynthesis of S-adenosylmethionine, a universal methyl donor for various acceptor molecules, including DNA, phospholipids, and proteins.
- CDP-Choline: Phosphocholine reacts with cytidine triphosphate (CTP) to form cytidine 5-diphosphate choline (CDP-choline) by phosphocholine cytidyltransferase (CCT). CDP-choline is esterified with diacylglycerol by choline phosphotransferase (CPT) or choline/ethanolaminephosphotransferase (CEPT) to form PC.
6. Mechanisms of Action
As a precursor for several biomolecules, choline exerts a wide range of biological effects, such as cholinergic neurotransmission, cell membrane composition and signaling, lipid transport, and the provision of methyl groups within the interconnected biochemical network of pathways called one-carbon metabolism.
Cell Membrane Integrity
Choline phospholipids also form lipid rafts in the cell membranes along with cholesterol. These rafts are centers, for example, for cholinergic receptors and receptor signal transduction enzymes.
Cholinergic Neurotransmission
By serving as a precursor for acetylcholine and phospholipids, choline is important for cholinergic transmission and the structural integrity of cell membranes. Acetylcholine plays an important role as a neurotransmitter in the central, peripheral, autonomic, and enteric nervous system. Particularly in the neuromuscular junction, ACh is released by an action potential from a motor neuron, causing the ion channels of muscle fiber to open, which is one of the important sequential steps to finally contract muscle.
Methyl Group Donation and One-Carbon Metabolism
Following oxidation to betaine, choline functions as a methyl group donor in a pathway that produces S-adenosylmethionine. As a methyl donor, choline influences DNA and histone methylation — two central epigenomic processes that regulate gene expression.
Lipid Transport
Phosphatidylcholine synthesis by the phosphatidylethanolamine N-methyltransferase (PEMT) pathway is required for VLDL assembly and secretion from the liver. Polymorphisms of the PEMT gene increase the dietary requirements of choline. Without adequate phosphatidylcholine, fat and cholesterol accumulate in the liver.
Epigenetic Regulation
Zeisel (2012) reviewed the potential effects of choline deficiency on gene expression via epigenetic marks and DNA integrity that could result in increased mutation rates and thereby increased risks of certain cancers.
7. Recommended Intakes and Dietary Reference Values
Insufficient data were available to establish an Estimated Average Requirement (EAR) for choline, so the Food and Nutrition Board (FNB) established Adequate Intakes (AIs) for all ages, based on the prevention of liver damage as measured by serum alanine aminotransferase levels. Adequate daily intake of choline has been established by the US National Academy of Medicine in 1998, considering choline requirements for different ages, sex differences, and physiological states (e.g., pregnancy).
The amount of choline that individuals need is influenced by the amount of methionine, betaine, and folate in the diet; gender; pregnancy; lactation; stage of development; ability to produce choline endogenously; and genetic mutations that affect choline needs.
Key AI benchmarks established by the US National Academy of Medicine include:
- Adult men (19+ years): 550 mg/day
- Adult women (19+ years): 425 mg/day
- An adequate choline intake is 450 mg daily during pregnancy and 550 mg daily while breastfeeding.
Most people in the United States consume less than the AI for choline. An analysis of data from the 2013–2014 National Health and Nutrition Examination Survey (NHANES) found that the average daily choline intake from foods and beverages among children and teens is 256 mg for ages 2–19. In adults, the average daily choline intake from foods and beverages is 402 mg in men and 278 mg in women.
8. Scientific Evidence by Area of Health
8.1 Liver Health and Non-Alcoholic Fatty Liver Disease (NAFLD)
If a person's choline levels drop too low, they can experience muscle and liver damage as well as deposits of fat in the liver (a condition called nonalcoholic fatty liver disease [NAFLD] that can damage the liver). A diet that is devoid of choline causes liver and muscle dysfunction within 3 weeks.
The mechanistic basis for this is well established: phosphatidylcholine synthesis by the PEMT pathway is required for VLDL assembly and secretion from the liver. Adequate choline intake is needed for proper liver function and to prevent NAFLD, but more research is needed to further clarify the role of choline in preventing or treating NAFLD.
Epidemiological data provide supporting but not conclusive evidence. A cross-sectional analysis of two large prospective studies conducted in China — the Shanghai Women's Health Study and the Shanghai Men's Health Study — including 56,195 people (ages 40–75 years) found that the highest versus lowest quintile of choline intake (412 mg/day vs. 179 mg/day) was associated with a 28% lower risk of fatty liver disease in normal-weight women, but no association was found in overweight or obese women or in men.
Evidence strength: The causal link between choline deficiency and NAFLD is strongly supported by controlled depletion-repletion studies in humans. The role of supplemental choline in treating established NAFLD in those who are not formally deficient is less well characterized.
8.2 Neurodevelopment and Pregnancy
Choline is indispensable for neural tube formation, brain development, and the overall well-being of expectant mothers, rendering it a cornerstone of prenatal care. As a methyl donor choline influences DNA and histone methylation — two central epigenomic processes that regulate gene expression. Because the fetus and neonate have high demands for choline, its dietary intake during pregnancy and lactation is particularly important for normal development of the offspring.
Inadequate choline intake during pregnancy poses a heightened risk of neural tube defects (NTDs) in the developing fetus. Choline is a critical factor in early neural tube formation, and its insufficiency can result in NTDs such as spina bifida. These debilitating congenital conditions affect the spinal cord and brain development.
The demand for choline increases markedly during pregnancy, indicated by a pronounced depletion of maternal choline pools even when women consume the Adequate Intake (AI) level. It is a concern that fewer than 10% of reproductive age women achieve the recommended AI level, and that choline is not included in standard prenatal vitamin regimens.
Although no randomized controlled trials are available, observational studies in humans, supported by coherence from interventional studies with neurodevelopmental outcomes and experimental studies in animals, strongly suggest that sufficient intake of choline during pregnancy is necessary for normal brain development and function in the child.
Studies in rodents have shown that high choline intake during gestation improves cognitive function in adulthood and prevents memory decline associated with old age. Research investigators have predicted that cognitive performance of children born to women consuming 480 mg/day (approximately the AI) during the last trimester of pregnancy will be poorer than children born to women consuming 930 mg/day. The predicted results would strongly indicate that the low choline intake of most pregnant women impedes the lifelong cognitive functioning of their children.
Evidence strength: Mechanistic and animal evidence for choline's role in fetal neurodevelopment is robust. Human observational data are consistent with beneficial effects. Large, well-controlled RCTs in humans are limited; the evidence base draws heavily on epidemiological associations and animal models.
8.3 Cognitive Function and Neurological Health in Adults
The effect of dietary choline availability on brain development and function is widely accepted since animal and human research has provided evidence supporting the neuroprotective and cognitive-enhancing effects of choline dietary supplementation at different developmental stages.
Observational studies in adults have shown associations between choline status and cognition. In one observational study involving 2,195 adults aged 70–74 years in Norway, participants with plasma-free choline concentrations below 8.4 mcmol/L (20th percentile) had poorer sensorimotor speed, perceptual speed, executive function, and global cognition than those above that threshold. In another study involving 1,391 participants (aged 36–83) from the Framingham Offspring study, those with higher choline intake, as reported by food frequency questionnaires, demonstrated enhanced verbal and visual memory.
Regarding Alzheimer's disease specifically, choline's effects on Alzheimer's disease (AD) in humans remain unclear. Predominantly preclinical evidence demonstrated that PC enhances neuroplasticity by activating intracellular neuronal signalling pathways or through neuron membrane function. Molecular dynamic simulation methods provided a mechanistic understanding of the interconnection between neuronal PC content and the potential behaviour and trajectory of amyloid-β peptide aggregation. The results indicate that the neuronal membrane composition of PC is critical to inhibiting Aβ aggregation and neuronal damage, protecting the neuron from Aβ toxicity. This might provide a foundation for optimising cellular PC which may prove beneficial in the treatment or prevention of neurodegenerative disease.
Regarding choline alphoscerate (alpha-GPC), a specific pharmaceutical-grade choline form, choline alphoscerate has demonstrated improved cognitive function in patients with mild cognitive impairment (MCI) or dementia and reduced progression of cognitive deterioration in patients with Alzheimer's disease, when administered as monotherapy or in combination with donepezil.
Despite the lack of randomised controlled trials (RCTs) assessing the efficacy of lecithin/PC to improve cognition in AD patients, there exists promising evidence supporting its neuroprotective and neurotrophic role. There is growing evidence suggesting choline intake might have beneficial effects on cognitive function in the elderly. However, some studies report no relationship between choline intake and cognitive function or improvement in Alzheimer's disease patients.
Evidence strength: For general adult cognition, evidence is mixed; some observational studies are supportive but are subject to confounding. For Alzheimer's disease, preclinical evidence is promising, and alpha-GPC has shown clinical benefits in some trials. However, large, well-controlled RCTs for standard choline forms are lacking.
8.4 Cardiovascular Health
The relationship between choline and cardiovascular health is complex and bidirectional. On one hand, choline-derived betaine can reduce homocysteine — an established cardiovascular risk marker — through methylation pathways. On the other, gut bacteria convert dietary choline to trimethylamine (TMA), which is then oxidized to TMAO in the liver.
Choline consumption has been shown to increase production of TMAO, a substance that has been linked to a higher risk of cardiovascular disease, in a dose-dependent manner in adults. Certain bacteria in the colon break down choline using a specific enzyme system, releasing a compound called trimethylamine (TMA). That TMA travels to the liver, where it gets converted into trimethylamine N-oxide (TMAO), a molecule consistently linked to atherosclerosis and cardiovascular disease.
High choline intake can increase levels of TMAO, a metabolite produced by gut bacteria; higher TMAO levels have been associated with cardiovascular disease risk in observational studies, though a causal relationship has not been established. Earlier, large epidemiological studies found no association of high choline intakes with a higher risk of cardiovascular diseases, though these studies also did not specifically measure TMAO blood levels.
There appears to be an association with diets high in choline-rich foods and cardiovascular disease, but the reasons for this link need further study. It is not yet clear whether concentrations of choline, betaine, and/or TMAO in the blood can predict the risk for cardiovascular disease.
Evidence strength: The cardiovascular picture is genuinely uncertain. The TMAO pathway provides a plausible mechanism for harm; observational studies on TMAO and cardiovascular events are concerning but do not establish causation. The net cardiovascular effect of choline from dietary whole foods versus supplemental free choline may differ importantly.
8.5 Muscle Function and Athletic Performance
Plasma choline levels drop during strenuous (above 70% VO₂max) and prolonged (more than 2 hours) exercise, as shown in endurance athletes such as runners and cyclists. The theoretical basis for supplementation in athletes is that choline supplements have been advocated as a means of preventing the decline in acetylcholine production purported to occur during exercise; this decline may reduce the transmission of contraction-generating impulses across the skeletal muscle, an effect that could impair one's ability to perform muscular work.
In one study, the act of taking in 2 grams of choline before exercise totally prevented the fall in choline normally associated with prolonged activity. However, the simple maintenance of choline levels does not automatically mean that performance will be enhanced.
Controlled intervention studies have yielded mixed results. No significant effects were seen with choline supplementation on any outcome performance measure in one study. Consequently, soldiers conditioned to carry heavy loads over long distances did not deplete plasma choline as a result of prolonged exhaustive exercise. Previous studies regarding choline supplementation and exercise generally reported that choline intake exceeding the AI, sufficient to increase blood concentrations of choline, does not positively affect exercise performance.
Attention has been drawn to the need for more research on the clinical consequences of choline supplementation in human skeletal muscle structure and function, given that evidence supporting its relevance comes mainly from basic research.
Evidence strength: Preliminary and inconsistent. While choline depletion during prolonged exercise is documented, controlled supplementation trials have generally not shown significant performance benefits. Evidence base is small and methodologically heterogeneous.
8.6 One-Carbon Metabolism and Homocysteine
The conversion of homocysteine to methionine may utilize methyl groups from betaine (choline's metabolite), which is important health-wise since elevated levels of homocysteine in the blood are associated with increased risk of cardiovascular disease. In addition, choline is involved in lipid and cholesterol transport and serves as a methyl donor after oxidation to betaine. This interaction ties choline metabolism to folate and vitamin B12 pathways; the amount of choline that individuals need is influenced by the amount of methionine, betaine, and folate in the diet.
8.7 Epigenetics and Gene Expression
Following oxidation to betaine, choline functions as a methyl group donor in a pathway that produces S-adenosylmethionine. As a methyl donor, choline influences DNA and histone methylation — two central epigenomic processes that regulate gene expression. This mechanism is of particular importance during fetal development. A systematic review of rodent studies performed during the last two decades indicates that cognitive improvement induced by choline supplementation has mainly been attributed to enhanced cholinergic neurotransmission in the hippocampal system.
9. Dosage Forms and Study Dosages
Dietary supplement dosages range from 10 mg to 250 mg. The forms of choline in dietary supplements include choline bitartrate, phosphatidylcholine, and lecithin. When supplements are indicated, typical doses range from 250–550 mg daily, often provided as choline bitartrate, phosphatidylcholine, or CDP-choline (citicoline).
The following dosages were reported in specific studies:
- A Cleveland Clinic study used choline bitartrate supplementation delivering 411 mg/day total choline for one month, which increased fasting TMAO levels by approximately 71% and increased platelet aggregation.
- Another study found that 450 mg of choline from choline bitartrate twice daily increased TMAO levels more than 10-fold in vegans/vegetarians and 14-fold in omnivores over 1–2 months.
- In an athletic performance study, researchers asked 10 trained runners to run 20 miles as fast as possible after taking 2.8 grams of choline citrate one hour before the run and the same amount at the half-way (10-mile) point (totaling 5.6 grams of choline).
- Choline supplementation of approximately 970 mg (~200% of the AI) was studied in relation to resistance exercise training programs for older adults.
- Clinical research has compared 480 mg/day (approximately the AI) versus 930 mg/day in pregnant women during the last trimester to assess offspring cognitive outcomes.
10. Body Systems and Health Areas
Based on established mechanisms and evidence reviewed, choline is associated with the following body systems:
- Central Nervous System: Acetylcholine synthesis, hippocampal neurogenesis, brain development, and cognitive function.
- Hepatic System: VLDL synthesis, lipid export, NAFLD prevention, and liver cell membrane integrity.
- Cardiovascular System: Homocysteine reduction via betaine; TMAO production and associated cardiovascular risk.
- Skeletal Muscle: Neuromuscular junction function via acetylcholine; muscle lipid metabolism.
- Reproductive and Fetal Development: Neural tube formation, fetal brain development, epigenetic programming.
- Cellular Biology: Membrane phospholipid composition, lipid raft formation, and cell signaling.
- Metabolic Pathways: One-carbon metabolism, methyl group donation, interaction with folate and B-vitamin cycles.
11. Deficiency
Although most people in the United States don't get recommended amounts of choline, few people have symptoms of choline deficiency. One reason might be that our bodies can make some choline. However, if a person's choline levels drop too low, they can experience muscle and liver damage as well as deposits of fat in the liver (NAFLD).
Depletion-repletion studies have provided evidence that dietary restriction of choline in humans causes liver and muscle damage, while feeding choline can avert these symptoms.
Groups at elevated risk for inadequate intake include:
- Pregnant and lactating women — most pregnant women in the United States do not consume the recommended amount of choline.
- Postmenopausal women — due to lower estrogen-mediated PEMT activity.
- Individuals with PEMT gene variants — genetic variants that reduce PEMT efficiency can increase dietary choline requirements.
- Individuals receiving total parenteral nutrition — choline is not typically included in TPN formulas unless specified, and NAFLD has been observed in long-term TPN patients.
- Those following strict vegan or plant-based diets.
12. Safety Considerations
Tolerable Upper Intake Level (UL)
In 1998, the Food and Nutrition Board (FNB) of the Institute of Medicine (now the National Academy of Medicine) established the tolerable upper intake level (UL) for choline at 3,500 mg/day for adults. This recommendation was based primarily on preventing hypotension (low blood pressure). and secondarily, on preventing the fishy body odor due to increased excretion of trimethylamine.
High intakes of choline are associated with a fishy body odor, vomiting, excessive sweating and salivation, hypotension, and liver toxicity. Excessive consumption of choline (greater than 7.5 grams per day) can cause low blood pressure, sweating, diarrhea, and fish-like body smell due to trimethylamine, which forms in the metabolism of choline.
The UL was established for generally healthy people, and the FNB noted that individuals with liver or kidney disease, Parkinson's disease, depression, or inherited trimethylaminuria might be at increased risk of adverse effects when consuming choline at levels near the UL.
TMAO and Cardiovascular Risk: An Emerging Safety Concern
Many studies suggest that trimethylamine-N-oxide (TMAO), a gut-flora-dependent metabolite of choline, contributes to the risk of cardiovascular diseases. TMA is subsequently oxidized by hepatic flavin-containing monooxygenases in the liver, forming trimethylamine-N-oxide (TMAO), which is then released into circulation.
A daily supplement of 500 mg is unlikely to cause acute side effects, but it can significantly raise TMAO levels within weeks. The long-term cardiovascular implications of sustained TMAO elevation from supplementation, as opposed to from food sources, are still being studied.
There is no official link established between choline supplementation at recommended doses and adverse cardiovascular outcomes. Nonetheless, the possibility that free choline supplements raise TMAO more substantially than choline from whole food sources is an active area of investigation.
Differential Risk by Supplement Form
Not all forms of choline appear to raise TMAO equally. Research cited in the literature suggests that phosphatidylcholine does not raise TMAO to the same degree as free choline forms such as choline bitartrate, which appear to be more readily converted by gut bacteria to TMA.
Trimethylaminuria
A characteristic adverse effect of excessive choline intake is a fishy body odour, resulting from the bacterial conversion of choline to trimethylamine (TMA) in the gut. TMA is normally oxidised to TMAO by hepatic enzymes, but this capacity can be overwhelmed at high intakes. Some individuals have genetic variations affecting TMA metabolism, making them more susceptible to this effect even at moderate doses.
Drug Interactions
Choline is not known to have any clinically relevant interactions with medications. However, the interaction with gut microbiota composition is recognized as a variable that modifies the metabolic fate of dietary choline, including TMAO production.
UL for Children and Infants
The FNB has established ULs for choline from food and supplements based on the amounts of choline that are associated with hypotension and fishy body odor. The ULs apply to healthy children and adults but not to those taking high doses of choline under medical supervision. The FNB was unable to establish ULs for infants due to the lack of data on adverse effects in this age group.
References
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