Bitartrate: A Comprehensive Encyclopedic Reference
1. Identity and Chemical Characterization
1.1 The Bitartrate Anion: Chemical Definition
Bitartrate is an anion that is the conjugate base of tartaric acid; the term may also refer to any salt or monoester of tartaric acid. More precisely, in chemical usage, a bitartrate is a tartrate in which only one of the two acidic hydrogen atoms of tartaric acid is replaced by a metal or positive group; it is also called a hydrogen tartrate or acid tartrate. The term "bitartrate," therefore, is not the name of a single compound but rather describes a class of salts sharing this half-neutralization chemistry. The most pharmacologically and nutritionally significant bitartrate salts encountered in dietary supplementation are choline bitartrate and potassium bitartrate, each with distinct chemistry, history, and biological activity.
Tartaric acid itself is a white, crystalline organic acid that occurs naturally in many fruits, most notably in grapes but also in tamarinds, bananas, avocados, and citrus. It is an alpha-hydroxy-carboxylic acid, diprotic and aldaric in character, and is a dihydroxyl derivative of succinic acid. When one of its two acidic protons is replaced by a cation, the resulting compound is a bitartrate salt.
1.2 Choline Bitartrate
Choline bitartrate is an organic compound with the chemical formula [(CH3)3NCH2CH2OH]+HOOC−CH(OH)−CH(OH)−COO−. It is a white crystalline powder with an acid taste and is hygroscopic when exposed to air. Modern texts refer to the choline salt of the natural form of tartaric acid, specifically the salt called choline dextrobitartrate, choline (2R,3R)-bitartrate, or choline L-(+)-bitartrate.
Structurally, choline (C5H14NO+) is a quaternary ammonium compound characterized by a positively charged nitrogen atom bonded to three methyl groups and an ethanol group. Choline bitartrate contains quaternary ammonium cations ((2-hydroxyethyl)trimethylammonium) paired with the bitartrate anion; a quaternary ammonium cation is one in which all four hydrogen atoms of ammonium are replaced with organyl groups.
Choline bitartrate is a small molecular weight quaternary amine salt that readily dissociates in water; a benefit of choline salts is their rapid dissolution and availability in the body as free choline, as opposed to bound forms that require enzymatic liberation. Choline chloride and choline bitartrate deliver a greater bioavailable cation content (74% and 40%, respectively) than naturally occurring forms such as phosphatidylcholine and soybean meal, and they exhibit excellent stability and high bioavailability in virtually all applications.
1.3 Potassium Bitartrate
Potassium bitartrate, also known as potassium hydrogen tartrate, with formula KC4H5O6, is the potassium acid salt of tartaric acid — specifically, L-(+)-tartaric acid. Especially in cooking, it is also known as cream of tartar. It crystallizes naturally in wine casks during the fermentation of grape juice, where the tartaric acid in grapes reacts with potassium, one of the most abundant minerals in grapes, to form this crystalline compound.
1.4 Other Clinically Notable Bitartrate Salts
Beyond choline and potassium bitartrate, the bitartrate anion is widely used in pharmaceutical salt forms to modify the solubility, stability, and pH compatibility of drugs. Hydrocodone bitartrate, for instance, is a key component in opioid analgesics, where the bitartrate anion aids in achieving the desired solubility and pH compatibility in syrups and tablets. Potassium bitartrate itself acts as a buffering agent and stabilizer in some pharmaceutical preparations, including laxatives and diuretics, helping to maintain formulation integrity.
2. Natural Sources and Occurrence
The bitartrate anion occurs naturally as salts such as potassium bitartrate in various plant sources, primarily fruits where tartaric acid is a key organic acid. The most abundant natural source is grapes (Vitis vinifera), where tartaric acid constitutes a major component of the fruit's acidity, typically comprising 40–70% of total organic acids in mature berries. In grape metabolism, tartaric acid is biosynthesized from L-ascorbic acid (vitamin C) during early berry development, accumulating in vacuoles to maintain pH balance and contribute to fruit firmness and organoleptic properties.
Potassium bitartrate is defined as a salt that precipitates from supersaturated solutions of potassium and tartaric acid, typically found in wine, where its crystallization is influenced by factors such as temperature and the presence of protective colloids. The L-(+)-tartaric acid isomer is industrially produced in the largest amounts; it is obtained from lees, a solid byproduct of fermentations, which consist predominantly of potassium bitartrate (KHC4H4O6).
Choline, the cationic moiety of choline bitartrate, is found endogenously across mammalian tissues. Choline is found in a wide variety of foods; eggs and meats are rich sources in the North American diet, providing up to 430 milligrams per 100 grams. As a supplement ingredient, choline bitartrate is a synthetic salt prepared by combining choline with tartaric acid; it is not isolated directly from any single plant or animal tissue.
3. Common Forms and Preparations
Bitartrate compounds appear in several commercial and pharmaceutical forms:
- Choline bitartrate: CDP-choline (citicoline) and choline salts, such as choline chloride and choline bitartrate, are available as supplements. Water-soluble choline salts such as choline chloride and choline bitartrate are very easily added to virtually any processed food or feed product, liquid, tablet, or capsule.
- Potassium bitartrate (cream of tartar): Approved by the FDA as a direct food substance, cream of tartar is used as an additive, stabilizer, pH control agent, antimicrobial agent, processing aid, and thickener in various food products.
- Lecithin-associated choline: Although the term "lecithin" is synonymous with phosphatidylcholine when used in chemistry, commercial lecithins are usually prepared from soybean, sunflower, and rapeseed and may contain anywhere from 20% to 90% of phosphatidylcholine.
- Pharmaceutical salt forms: The bitartrate anion is used in pharmaceutical manufacturing to improve the solubility, crystallinity, and shelf-stability of active drug substances including opioid analgesics and other alkaloid drugs.
Choline chloride and bitartrate are mentioned in the US Code of Federal Regulations as nutrition/dietary supplements that have been accorded GRAS (Generally Recognized as Safe) status.
4. Historical and Traditional Use
4.1 Potassium Bitartrate: Ancient and Pre-Modern Medicine
Tartaric acid has been known to winemakers for centuries; its crude crystalline form as found on top of wine barrels was called tartarum (rendered tartre by Chaucer) or "wine stone." The recorded medicinal employment of bitartrate compounds is among the oldest for any naturally derived mineral salt.
Potassium bitartrate was used as a diuretic and laxative in ancient Greece and Rome; it also found applications in treating arthritis, heartburn, and acne-prone skin. Historical records indicate that ancient healers and herbalists employed bitartrate for its gentle laxative effects, using it to support digestive health and alleviate constipation naturally; additionally, it was often included in remedies aimed at reducing edema and promoting urinary health, given its mild diuretic action.
Cream of tartar has a long history as a medicinal purgative; for instance, included among Lewis and Clark's medicinal supplies was two pounds of cream of tartar, and in his diary Clark describes treating a "dangerously ill" child with cream of tartar. Other historical publications extolled the usefulness of cream of tartar as a diuretic for the treatment of edema and as a cathartic and laxative.
Potassium bitartrate was first formally characterized by Swedish chemist Carl Wilhelm Scheele (1742–1786) as a result of his work studying fluorite and hydrofluoric acid. Use of potassium bitartrate has been reported to date back 7,000 years to ancient viticulture.
The Smithsonian's National Museum of American History preserves a Squibb pharmaceutical-grade preparation of cream of tartar from the 19th century, described as "an exceptionally clean and extremely pure product, specially intended for medicinal use"; it was directed to "act as a laxative, aperient, and diuretic," with a dose of "1 to 3 teaspoonfuls dissolved in water."
4.2 Choline: Recognition as an Essential Nutrient
The history of choline as a nutrient differs from the ancient use of potassium bitartrate. Choline's nutritional importance was not recognized until the 1930s, when deficiency was demonstrated to cause fatty liver disease in dogs and rats, which resolved when choline was reintroduced to the diet. Over the following decade, consensus emerged around the general essentiality of choline to prevent liver damage in several mammalian species, including the rat, dog, chicken, pig, rhesus monkey, and baboon; recognition that choline is an essential nutrient for humans was further advanced in the 1980s by studies in men and women on parenteral nutrition who developed liver damage in its absence.
The definitive proof that choline was an essential nutrient for humans awaited a 1991 rigorous clinical study by Zeisel et al., who placed a group of healthy men on a low-choline diet and found they developed liver damage that could be reversed with a standard dose of dietary choline; this landmark discovery served as the initial basis for the classification of choline as an essential nutrient in 1998 when the Food and Nutrition Board (FNB) of the Institute of Medicine issued guidelines on its daily intake.
Choline was officially recognized as an essential nutrient by the Institute of Medicine (IOM) in 1998; there is significant variation in the dietary requirement for choline that can be explained by common genetic polymorphisms. Choline bitartrate as a supplement form became prominent after this recognition, as manufacturers sought a stable, water-soluble salt form of choline for use in dietary supplement products.
5. Key Constituents and Mechanisms of Action
5.1 Choline as an Active Moiety
When choline bitartrate is ingested, it dissociates in aqueous solution, releasing free choline, which is the biologically active component. Choline has several roles in the body: it is an important component of phospholipids, affects mobilization of fat from the liver (lipotropic action), acts as a methyl donor, and is essential for formation of the neurotransmitter acetylcholine.
Choline is an important nutrient essential for proper functioning of liver, muscle, and brain; it is a main constituent of cell and organelle membranes and plays a vital role in numerous physiological processes including signal transduction, DNA and histone methylation, and nerve myelination.
5.2 Acetylcholine Synthesis
Animal studies have shown that choline is a precursor of the major neurotransmitter acetylcholine, a neurotransmitter crucial for cholinergic memory functioning; choline is chemically very similar to acetylcholine, and the synthesis of acetylcholine largely depends on dietary choline intake. Choline serves as a precursor for acetylcholine, a key neurotransmitter important for functions such as memory, muscle control, and mood regulation.
5.3 Phospholipid and Membrane Biosynthesis
By serving as a precursor for acetylcholine and phospholipids, choline is important for cholinergic transmission and the structural integrity of cell membranes. Phosphatidylcholine — synthesized from choline — is one of the most abundant phospholipids in eukaryotic cell membranes and is essential for membrane fluidity and the structural integrity of cells throughout the body.
5.4 Methyl Donor Function and Epigenetic Regulation
Choline is involved in lipid and cholesterol transport and serves as a methyl donor after oxidation to betaine. The epigenetic mechanism has also been proposed, demonstrating the essential role of choline as an epigenetic modifier; as a critical methyl donor that involves DNA and histone methylation, choline may alter brain function by modulating neuronal gene expression, such as influencing the availability of S-adenosylmethionine.
Furthermore, choline supports methyl group metabolism, serving as a precursor for S-adenosylmethionine, a critical methyl donor in the body.
5.5 Lipotropic Action and Hepatic Fat Transport
Choline is essential for transporting lipids from the liver via phosphatidylcholine-dependent VLDL (very low-density lipoprotein) assembly; when choline is deficient, fat accumulates in the liver, resulting in nonalcoholic fatty liver disease. By virtue of its fundamental functions in membrane structure, a choline deficiency causes a whole range of phospholipid abnormalities that express themselves clinically as fatty liver, kidney lesions (hemorrhagic renal necrosis), and impairment of lipoprotein metabolism; with a diet deficient in choline, cholesterol esters and fats accumulate in the liver.
5.6 Choline Signaling Beyond Neurotransmission
Choline has important roles in neurodevelopment, cognition, liver function, lipid metabolism, and cardiovascular health; while its signaling role has been considered mostly indirect via acetylcholine and phosphatidylcholine, which are synthesized from choline, emerging evidence supports a role for choline as an intracellular messenger acting on Sigma-1R, a non-opioid intracellular receptor.
5.7 Potassium Bitartrate: Mechanism of Laxative Action
Potassium bitartrate is a carbon dioxide-releasing laxative that works by forming carbon dioxide gas, which creates mechanical distension against the intestinal wall and induces bowel contractions. Combined with sodium bicarbonate in a poly(ethylene glycol)-based suppository, it is a useful and safe treatment for patients at risk of electrolyte, renal, or cardiovascular disorders.
6. Scientific Evidence by Area of Use
6.1 Cognitive Function and Memory in Healthy Adults
The most commercially prominent claim for choline bitartrate supplementation is cognitive enhancement in healthy subjects. The clinical evidence on this specific point is, however, mixed and largely negative in the short term.
A 2016 published study at Leiden University investigated whether the food supplement choline bitartrate improved declarative memory and working memory in healthy, young students one to two hours after supplementation, using two double-blind, placebo-controlled cross-over experiments. The study found no acute effect of choline bitartrate on either declarative or working memory in this healthy, well-nourished population. The authors noted that the lack of effect may reflect a ceiling effect in individuals with adequate baseline choline status.
One study measured plasma and brain choline levels with 1H-MRS after a single dose of choline bitartrate equal to a free choline dose of 50 mg/kg body weight in young and aged healthy subjects; despite a similar choline increase in plasma in both groups, brain levels of choline measured by MRS were lower in the aged group, suggesting a decrease in choline uptake into the brain with age, interpreted as a sign of reduced uptake that may be involved in age-dependent altered memory function.
A comprehensive review of preclinical and clinical investigations assessing the effects of different forms of choline supplementation — including choline bitartrate, choline alfoscerate (α-GPC), lecithin, and citicoline — noted these cholinergic compounds and precursors of acetylcholine have been shown to represent an effective strategy for boosting memory and enhancing cognitive function. However, the review also noted that effects differ substantially by form: choline supplements in the form of lecithin and choline chloride did not significantly improve memory performance in humans, although some papers have reported positive outcomes in animal models; citicoline, choline bitartrate, and α-GPC appear to be very promising in the treatment of elderly patients suffering from dementia.
A clinical study combining choline bitartrate and vitamin B12 demonstrated amelioration of cognitive impairment in hypertensive elderly patients with cognitive frailty, though this was a combination study, making it difficult to isolate the specific contribution of choline bitartrate alone.
Evidence quality: Evidence for acute cognitive enhancement from choline bitartrate in healthy, well-nourished young adults is currently negative or inconclusive from RCT data. Observational and clinical data suggest benefits may be more relevant in populations with deficiency, cognitive decline, or aging-related reduced choline uptake.
6.2 Cognitive Function and Choline Intake in Aging Populations
Studies have shown a link between cognitive performance in adults with higher choline intakes and plasma concentrations; observational studies suggest that higher intakes of choline are associated with higher cognitive function and improved memory in both males and females.
In a large cross-sectional study of elderly Americans, choline intake of 187.6–399.5 mg/day indicated a beneficial effect, but no change in cognitive performance was observed when choline intake reached greater than 399.5 mg/day, and the relationship assembled a "U" shape as choline consumption increased, implying there might be an optimal level of choline consumption to attenuate age-related cognitive declines.
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; a systematic review of rodent studies indicates that cognitive improvement induced by choline supplementation has mainly been attributed to enhanced cholinergic neurotransmission in the hippocampal system.
The underlying mechanism of choline influencing cognition has been investigated in previous studies; patients with Alzheimer's disease display a reduced level of acetylcholine, which activates microglia in the hippocampus and leads to cascade reactions of brain inflammation and neuronal death.
Evidence quality: Observational associations between choline intake and cognitive performance in aging populations are consistent and plausible, but RCT evidence isolating choline bitartrate as a form in aging humans is limited. Human RCT data are stronger for other forms of choline (citicoline, α-GPC) than for bitartrate specifically.
6.3 Prenatal and Neurodevelopmental Applications
This area has the strongest and most consistent body of evidence linking choline status (and supplementation) to health outcomes, and choline bitartrate is explicitly used as the supplement form in several trials.
Choline is indispensable for neural tube formation, brain development, and the overall well-being of expectant mothers; inadequate choline intake is associated with neural tube defects, cognitive deficits in offspring, and maternal health complications.
Different forms of choline — including phosphatidylcholine, choline chloride, choline bitartrate, and glycerophosphocholine — and doses (≤1 g/day) have been used on top of the diet in RCTs; choline intake in the available RCTs was higher than the average intake that women could achieve through the usual diet and exceeded the adequate intake of 450 mg/day or 480 mg/day for pregnant women as set by the IOM or EFSA; thus, maternal choline intake above the present adequate intake appears to be necessary to influence neurocognition of the child.
A 2022 systematic review and meta-analysis of human studies found that low maternal choline intake/circulating choline concentrations were associated with a higher odds ratio for neural tube defects in the offspring. Results on choline supplementation in pregnancies exposed to alcohol provided supportive evidence that choline could impact brain functions; choline supplementation versus placebo in pregnant women exposed to alcohol from the second trimester to birth had positive effects on learning and memory of the infants.
However, the overall RCT picture for prenatal supplementation with choline in otherwise healthy pregnancies is less definitive: findings support conclusions of previous reviews showing some suggestions of a benefit from increased prenatal choline for neurodevelopment, but mainly null effects and insufficient quality evidence to allow confidence in results; one previous meta-analysis found an increased risk of neural tube defects with lower levels of circulating choline, but did not deem it appropriate to attempt a meta-analysis of measures of child development; the lack of strong or consistent benefits of prenatal choline in humans may be attributable to the body's ability to synthesize choline precursors.
Evidence quality: There is moderate to strong epidemiological and mechanistic evidence linking adequate choline intake during pregnancy to reduced neural tube defect risk and improved infant brain development. Multiple forms of choline, including choline bitartrate, have been used in relevant RCTs. The evidence base is strongest for populations at risk of deficiency; confirmation in well-nourished populations by well-powered, form-specific RCTs remains incomplete.
6.4 Liver Health and Non-Alcoholic Fatty Liver Disease (NAFLD)
Research on humans and other mammals has suggested that choline is necessary to maintain the liver's normal function; scientists in the 1930s demonstrated that choline deficiency caused fatty liver disease in dogs and rats.
Evidence that consuming a choline-deficient diet for three weeks led to a 30% reduction in plasma choline and a significant rise in serum alanine aminotransferase (ALT) activity, indicating liver injury, provided the initial basis for the classification of choline as an essential nutrient.
While a choline-deficient diet results in organ dysfunction and nonalcoholic fatty liver disease (NAFLD), it is not known whether suboptimal dietary choline intakes in healthy subjects may contribute to an increased risk for NAFLD.
A preliminary clinical study examined the use of supplemental choline in patients on total parenteral nutrition (TPN): fifteen patients who had required TPN for ≥80% of their nutritional needs were randomized to receive their usual TPN or TPN to which 2 g choline chloride had been added for 24 weeks. This preliminary pilot study suggested choline-supplemented TPN may be useful in reversal of hepatic abnormalities.
Evidence quality: The connection between choline deficiency and fatty liver disease is well-established in animal models and in humans on TPN-induced deficiency. Evidence that supplemental choline bitartrate specifically can reverse or prevent NAFLD in humans with adequate dietary intake is preliminary and limited; data from TPN studies cannot be directly extrapolated to general supplementation.
6.5 Cardiovascular Health and TMAO Risk
The available evidence regarding the nexus between dietary choline intake and health outcomes encompassing cardiovascular disease (CVD), cancer, and all-cause mortality is limited and inconclusive. One NHANES-based cross-sectional analysis demonstrated a significant nonlinear association between choline intake and all-cause mortality; the overall cancer prevalence association was nonsignificant, except for colon cancer, where each 100 mg increase in choline intake indicated a 23% reduced risk; elevated choline intake was associated with an inverse association with CVD and colon cancer, while moderate consumption exhibited a correlated reduction in mortality.
On the other side of the cardiovascular risk ledger, a critical concern has emerged around the gut-microbiome metabolism of free choline to trimethylamine N-oxide (TMAO): certain bacteria in the colon break down choline using a specific enzyme system, releasing trimethylamine (TMA), which travels to the liver where it is converted into trimethylamine N-oxide (TMAO), a molecule consistently linked to atherosclerosis and cardiovascular disease.
A key randomized, controlled, double-blinded crossover study examined this in detail: healthy men (n = 37) were provided meals containing 600 mg choline either as choline bitartrate or phosphatidylcholine, or no choline control; choline bitartrate yielded three-times greater plasma TMAO AUC and 2.5-times greater urinary TMAO change from baseline compared to no choline and phosphatidylcholine. Gut microbiota composition differed between high-TMAO producers (with ≥40% increase in urinary TMAO response to choline bitartrate) and low-TMAO producers.
A Cleveland Clinic study found that choline bitartrate supplementation (411 mg/day total choline) for one month increased fasting TMAO levels by about 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.
More recent studies suggest that the blood concentration of TMAO, generated from trimethylamine-containing nutrients like dietary choline, rather than that of choline itself, might influence the risk of cardiovascular events; it is not yet clear whether concentrations of choline, betaine, and/or TMAO in the blood can predict the risk for cardiovascular disease.
Emerging research has raised questions about the cardiovascular implications of elevated TMAO levels, which have been associated with increased atherosclerosis risk in some observational studies; however, there is no official link established between choline supplementation at recommended doses and adverse cardiovascular outcomes.
Evidence quality: The TMAO signal from choline bitartrate supplementation in clinical studies is robust and specific to the free-choline salt forms (bitartrate and chloride) as compared to phosphatidylcholine. The long-term cardiovascular implications of sustained TMAO elevation from supplementation, compared with food-source choline, remain under investigation. Epidemiological data on choline intake and CVD outcomes are inconsistent.
6.6 Potassium Bitartrate as a Laxative
Potassium bitartrate has a long history of medical and veterinary use as a laxative administered as a rectal suppository, and is used also as a cathartic and as a diuretic. It is an approved third-class OTC drug in Japan.
In medical studies, potassium bitartrate was shown to be an effective treatment for chronic constipation when combined with sodium bicarbonate in a polyethylene glycol-based suppository. The carbon dioxide it releases causes mechanical distension against the intestinal wall, inducing bowel movements; combined with sodium bicarbonate in a poly(ethylene glycol)-based suppository, it is a useful and safe treatment for patients at risk of electrolyte, renal, or cardiovascular disorders.
Potassium bitartrate is also one of the active ingredients in Phexxi, a non-hormonal contraceptive agent approved by the FDA in May 2020.
Evidence quality: Clinical evidence for the efficacy of potassium bitartrate as a suppository laxative is supported by formal clinical use and pharmacological mechanism. Evidence for oral use as a medicinal agent in humans at modern standards of RCT rigor is limited.
7. Body Systems and Health Areas Associated with Bitartrate
- Central nervous system: The brain and nervous system need choline to regulate memory, mood, muscle control, and other functions.
- Hepatic system: An adequate dietary intake of choline during pregnancy supports proper fetal development, and throughout life supports brain, liver, and muscle functions, while choline deficiency is linked to disease states like fatty liver.
- Cardiovascular system: There is currently no convincing evidence that high choline intakes benefit cardiovascular health by lowering blood homocysteine; moreover, elevated blood concentrations of TMAO, generated from choline, have been associated with an increased risk of cardiovascular events in some observational studies.
- Reproductive and developmental biology: During pregnancy, the demand for choline significantly increases as it is involved in vital processes such as neural tube formation, brain development, and the synthesis of lipoproteins.
- Musculoskeletal system: 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.
- Gastrointestinal system (potassium bitartrate): Potassium bitartrate acts on the bowel via mechanical CO2-induced distension when delivered as a suppository.
- Epigenetic regulation: Choline programs brain development via DNA and histone methylation.
8. Dosage Forms and Doses Reported in Studies
8.1 Established Adequate Intakes (AI) for Choline
Choline was recognized as an essential nutrient for humans in 1998 by the National Academy of Medicine; adequate intakes (AI) were established at 550 mg/day for adult men, 425 mg/day for adult women, 450 mg/day for pregnant women, and 550 mg/day during lactation.
The choline AI increases with age: from 125 mg/day for infants (0–6 months) to 150 mg/day (6–12 months), 200 mg/day in children (1–3 years), and 250 mg/day (4–8 years); boys and girls (9–13 years) have the same choline AI of 375 mg/day, while during adolescence (14–18 years), boys have a higher AI (550 mg/day) compared with girls (400 mg/day).
8.2 Doses Used in Clinical Studies
- Two double-blind, placebo-controlled cross-over experiments examined choline bitartrate supplementation in healthy, young university students, one to two hours after supplementation. The specific doses were in the range used in commercially available food supplements, evaluated for effects on declarative and working memory.
- A randomized, controlled, double-blinded, crossover study provided healthy men (n = 37) meals containing 600 mg choline as choline bitartrate or phosphatidylcholine, or no choline control.
- A Cleveland Clinic study supplemented subjects with choline bitartrate at 411 mg/day total choline for one month.
- Another study used 450 mg of choline from choline bitartrate twice daily (i.e., 900 mg/day) in vegans/vegetarians and omnivores over 1–2 months.
- One pharmacokinetic study used a single dose of choline bitartrate equal to a free choline dose of 50 mg/kg body weight.
- A clinical trial protocol used 1,200 mg of choline bitartrate per 24-hour period administered as a single oral vial.
- RCTs in pregnancy have used doses up to 1 g/day of various choline forms, generally exceeding the adequate intake of 450–480 mg/day.
- A TPN study added 2 g choline chloride per day over 24 weeks to TPN in patients requiring parenteral nutrition.
- For potassium bitartrate as a laxative: historical pharmaceutical directions instructed "1 to 3 teaspoonfuls dissolved in water."
8.3 Supplement Formulation Context
When supplements are indicated, typical doses range from 250–550 mg daily, often provided as choline bitartrate, phosphatidylcholine, or CDP-choline (citicoline). Choline is available as a dietary supplement such as choline chloride or choline bitartrate, and lecithin, which usually contains approximately 25% phosphatidylcholine or 3–4% choline by weight.
9. Safety Considerations and Interactions
9.1 Tolerable Upper Intake Level and Adverse Effects
The EFSA has established a Tolerable Upper Intake Level of 3,500 mg/day for adults based on adverse effects including fishy body odour, hypotension, and increased sweating and salivation observed at high doses.
Getting too much choline can cause a fishy body odor, vomiting, heavy sweating and salivation, low blood pressure, and liver damage; some research also suggests that high amounts of choline may increase the risk of heart disease.
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.
9.2 TMAO and Cardiovascular Risk: A Form-Specific Safety Signal
A rigorous crossover study established that 600 mg of choline as choline bitartrate yielded three-times greater plasma TMAO and 2.5-times greater urinary TMAO change from baseline compared to the same dose delivered as phosphatidylcholine. This finding is of direct clinical relevance: the free-salt form of choline (bitartrate, chloride) appears to generate substantially more TMAO than the phospholipid-bound form. 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.
Daily aspirin (81 mg) was able to reduce but not eliminate the increase in platelet aggregation associated with choline bitartrate supplementation.
9.3 GRAS Status and General Safety Profile
Choline chloride and bitartrate are mentioned in the US Code of Federal Regulations as nutrition/dietary supplements that have been accorded GRAS status. Since it is very difficult to consume excessively high amounts of choline from food, most health concerns related to toxicity are linked to supplementation.
9.4 Potassium Bitartrate: Hyperkalemia Risk
Large oral ingestions of potassium bitartrate carry a specific and serious risk. Cream of tartar (potassium bitartrate) has a long history as a cooking aid and medicinal purgative; despite containing large amounts of potassium, there had been no well-documented cases of it causing toxicity until the reporting of two cases in which intentional ingestions resulted in life-threatening hyperkalemia. In both cases, individuals ingested a large quantity of cream of tartar in an effort to "clean themselves out"; they manifested initial vomiting, abnormal serum potassium (>8.0 mmol/L), and EKGs with peaked T waves; both patients were treated for hyperkalemia and recovered without complication.
Cream of tartar can interact with certain medications, particularly those that affect potassium levels in the body such as some heart medications and diuretics.
9.5 Individual Variability in Response
There is significant variation in the dietary requirement for choline that can be explained by common genetic polymorphisms. Similarly, gut microbiota composition differs significantly between high-TMAO producers and low-TMAO producers in response to choline bitartrate, suggesting that individual cardiovascular risk from supplementation is highly variable.
9.6 Pregnancy-Specific Considerations
Men have a higher requirement than postmenopausal women, who in turn need more than premenopausal women; pregnancy and lactation are periods when maternal reserves of choline are depleted, and the availability of choline for normal development of the brain during this period is critical.
References
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