L-Homocysteine

• None – elevated levels are associated with health risks

• None – primarily monitored as a biomarker rather than used as a supplement

L-Homocysteine is not a typical supplement but rather a sulfur-containing non-proteinogenic amino acid that functions as an intermediate in methionine metabolism. Unlike most supplements that are taken to produce beneficial effects, homocysteine is primarily monitored as a biomarker because elevated levels (hyperhomocysteinemia) are associated with various pathological conditions, particularly cardiovascular disease. The mechanisms by which elevated homocysteine levels may contribute to disease processes include: 1) Endothelial dysfunction: Homocysteine can impair endothelial function by reducing nitric oxide (NO) bioavailability through multiple mechanisms. It increases oxidative stress by promoting the formation of reactive oxygen species (ROS), which directly inactivate NO.

It also reduces the expression and activity of endothelial nitric oxide synthase (eNOS), further decreasing NO production. Additionally, homocysteine can inhibit the activity of dimethylarginine dimethylaminohydrolase (DDAH), leading to accumulation of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of eNOS. 2) Vascular inflammation: Homocysteine activates nuclear factor-kappa B (NF-κB), a key transcription factor that regulates the expression of pro-inflammatory cytokines, adhesion molecules, and chemokines. This promotes the recruitment and adhesion of inflammatory cells to the vascular wall, contributing to atherosclerotic plaque formation.

3) Oxidative stress: Homocysteine undergoes auto-oxidation to form homocystine, generating hydrogen peroxide and other reactive oxygen species in the process. This oxidative stress damages cellular components, including lipids, proteins, and DNA, and contributes to endothelial dysfunction and vascular damage. 4) Prothrombotic effects: Elevated homocysteine levels promote thrombosis through multiple mechanisms, including increased tissue factor expression, enhanced platelet aggregation, reduced thrombomodulin expression, and impaired fibrinolysis. These effects collectively create a prothrombotic state that increases the risk of thromboembolic events.

5) Protein homocysteinylation: Homocysteine can modify proteins through a process called homocysteinylation, where it forms disulfide bonds with protein cysteine residues or incorporates into proteins via acylation. This can alter protein structure and function, potentially contributing to cellular dysfunction. 6) Epigenetic modifications: Homocysteine metabolism is closely linked to one-carbon metabolism, which provides methyl groups for DNA and histone methylation. Elevated homocysteine levels can disrupt these methylation processes, leading to alterations in gene expression that may contribute to disease development.

7) Endoplasmic reticulum (ER) stress: Homocysteine can induce ER stress by disrupting disulfide bond formation in proteins, leading to the accumulation of misfolded proteins and activation of the unfolded protein response (UPR). Chronic ER stress can ultimately lead to cell apoptosis. Rather than supplementing with homocysteine, the clinical focus is on reducing elevated homocysteine levels through supplementation with B vitamins (particularly folate, vitamin B6, and vitamin B12) that serve as cofactors in homocysteine metabolism, promoting its conversion to methionine or cysteine.

L-Homocysteine is not used as a supplement and has no established optimal dosage for supplementation. In fact, elevated homocysteine levels in the blood (hyperhomocysteinemia) are associated with increased risk of cardiovascular disease, neurodegenerative disorders, and other health conditions. The clinical focus is on maintaining normal homocysteine levels or reducing elevated levels rather than supplementing with homocysteine. Normal blood homocysteine levels are generally considered to be between 5-15 μmol/L, with levels above 15 μmol/L classified as hyperhomocysteinemia.

Mild hyperhomocysteinemia is defined as levels between 15-30 μmol/L, moderate as 30-100 μmol/L, and severe as >100 μmol/L.

L-Homocysteine is not typically administered as a supplement, so traditional bioavailability parameters like absorption rate are not directly applicable in a supplementation context. Instead, homocysteine is an endogenous amino acid produced as an intermediate in methionine metabolism. Plasma homocysteine exists in several forms: approximately 70-80% is bound to proteins (primarily albumin) through disulfide bonds, 15-25% exists as homocysteine dimers (homocystine) or mixed disulfides with other thiols, and only about 1-2% exists as free reduced homocysteine. The distribution between these forms is dynamic and depends on the overall redox state.

Homocysteine can cross cell membranes through specific amino acid transporters, though the efficiency varies by tissue type. It can also cross the blood-brain barrier, which is significant for its potential effects on neurological function. The half-life of homocysteine in plasma is approximately 3-4 hours, though this can be influenced by various factors including renal function, vitamin status, and genetic factors affecting homocysteine metabolism.

Not applicable – The clinical goal is to reduce rather than enhance homocysteine levels, Strategies focus on promoting homocysteine metabolism through adequate intake of B vitamins (folate, B6, B12) that serve as cofactors in homocysteine metabolic pathways, Betaine (trimethylglycine) supplementation can enhance the conversion of homocysteine to methionine through the betaine-homocysteine methyltransferase pathway, particularly in the liver, N-acetylcysteine (NAC) may help reduce homocysteine levels by promoting glutathione synthesis and improving redox status

Since L-Homocysteine is not used as a supplement, timing recommendations for its administration are not applicable. Instead, the focus is on the timing of interventions to reduce elevated homocysteine levels. For individuals with hyperhomocysteinemia who are supplementing with B vitamins to reduce homocysteine levels, consistent daily supplementation is typically recommended rather than timing around specific activities or meals. Folate supplements may be better absorbed on an empty stomach, while vitamin B12 is often better absorbed with meals.

For monitoring purposes, blood homocysteine levels are typically measured in the fasting state (after at least 8-12 hours of fasting) to minimize the influence of recent dietary intake on the results. Homocysteine levels can increase transiently after methionine-rich meals. For individuals with methylenetetrahydrofolate reductase (MTHFR) gene variants that affect homocysteine metabolism, the active form of folate (methylfolate) may be more effective than folic acid for reducing homocysteine levels. In these cases, consistent daily supplementation is still recommended.

• Not applicable as a supplement – L-Homocysteine is not used as a dietary supplement
• Elevated endogenous homocysteine levels (hyperhomocysteinemia) are associated with increased risk of cardiovascular disease
• Hyperhomocysteinemia is associated with endothelial dysfunction
• Elevated homocysteine levels may contribute to oxidative stress
• High homocysteine levels are linked to increased inflammation
• Elevated homocysteine may promote thrombosis and impair fibrinolysis
• Hyperhomocysteinemia is associated with cognitive decline and neurodegenerative disorders

• Not applicable as a supplement – L-Homocysteine is not used as a dietary supplement
• Individuals should focus on maintaining normal homocysteine levels through adequate B vitamin intake rather than considering homocysteine supplementation
• Those with existing cardiovascular disease should particularly avoid any theoretical homocysteine supplementation due to established links between elevated homocysteine and cardiovascular risk
• Individuals with genetic disorders affecting homocysteine metabolism (e.g., homocystinuria, MTHFR mutations) should be under medical supervision for management of homocysteine levels

• Not applicable as a supplement – L-Homocysteine is not used as a dietary supplement
• Several medications can affect endogenous homocysteine levels:
• Methotrexate depletes folate and can increase homocysteine levels
• Anticonvulsants (phenytoin, carbamazepine) may increase homocysteine by interfering with folate metabolism
• Nitrous oxide inactivates vitamin B12 and can elevate homocysteine levels
• Lipid-lowering drugs like fibrates and niacin may increase homocysteine levels
• Some antidiabetic medications like metformin may lower homocysteine levels by improving insulin sensitivity
• Oral contraceptives may affect homocysteine levels through their impact on B vitamin metabolism

Not applicable as a supplement – L-Homocysteine is not used as a dietary supplement. Instead, the focus is on maintaining normal blood homocysteine levels, which are generally considered to be between 5-15 μmol/L. Levels above 15 μmol/L are classified as hyperhomocysteinemia, with mild hyperhomocysteinemia defined as 15-30 μmol/L, moderate as 30-100 μmol/L, and severe as >100 μmol/L. Elevated homocysteine levels are associated with increased risk of various health conditions, particularly cardiovascular disease.

Some research suggests that even levels in the upper range of normal (10-15 μmol/L) may be associated with increased cardiovascular risk compared to lower levels (<10 μmol/L). The focus of clinical intervention is on reducing elevated homocysteine levels through adequate intake of B vitamins (particularly folate, vitamin B6, and vitamin B12) that serve as cofactors in homocysteine metabolism, promoting its conversion to methionine or cysteine. Genetic factors, particularly variants in the methylenetetrahydrofolate reductase (MTHFR) gene, can affect homocysteine metabolism and may require personalized approaches to maintaining optimal levels.

L-Homocysteine is not approved by the FDA as a dietary supplement ingredient or drug. It is not marketed or sold as a supplement in the United States, as elevated homocysteine levels are associated with increased health risks rather than benefits. The FDA has not established a recommended daily allowance (RDA) or tolerable upper intake level (UL) for homocysteine, as it is not a nutrient but rather an endogenous metabolite. The FDA has approved various laboratory tests for measuring homocysteine levels in blood as diagnostic tools.

These tests are regulated as medical devices and must meet certain performance standards. The FDA has not approved any specific health claims related to homocysteine levels or homocysteine-lowering interventions. However, the agency has approved health claims for folate regarding its role in reducing the risk of neural tube defects, which indirectly relates to homocysteine metabolism since folate is a key factor in homocysteine remethylation.

The European Food Safety Authority (EFSA) has not approved L-homocysteine as a food or supplement ingredient. Like the FDA, EFSA recognizes homocysteine as an endogenous metabolite rather than a nutrient or supplement ingredient. EFSA has evaluated and rejected health claims related to homocysteine-lowering effects of various nutrients and their relationship to cardiovascular health. Specifically, in 2012, EFSA’s Panel on Dietetic Products, Nutrition and Allergies concluded that a cause-and-effect relationship had not been established between the consumption of various B vitamins and maintenance of normal homocysteine metabolism in the context of cardiovascular health.

EFSA has, however, approved certain health claims related to folate, vitamin B6, and vitamin B12 regarding their contribution to normal homocysteine metabolism, without making claims about the subsequent health effects of lowered homocysteine levels. European regulatory bodies authorize clinical laboratories to perform homocysteine testing as a diagnostic tool, subject to quality control standards.

Health Canada has not approved L-homocysteine as a Natural Health Product (NHP) ingredient. It is not listed in the Natural Health Products Ingredients Database (NHPID) as an acceptable medicinal or non-medicinal ingredient. Health Canada, like other regulatory agencies, recognizes homocysteine as an endogenous metabolite rather than a supplement ingredient. Health Canada has authorized laboratory tests for measuring homocysteine levels for clinical use.

The agency acknowledges the role of B vitamins in homocysteine metabolism but has not approved specific health claims linking homocysteine-lowering interventions to reduced disease risk. Health Canada’s position aligns with other major regulatory bodies in focusing on maintaining normal homocysteine metabolism through adequate B vitamin intake rather than direct intervention with homocysteine itself.

The Therapeutic Goods Administration (TGA) of Australia has not approved L-homocysteine as an ingredient in listed or registered complementary medicines. It is not included in the TGA’s list of permissible ingredients for use in listed medicines. The TGA, consistent with other regulatory bodies, recognizes homocysteine as an endogenous metabolite rather than a supplement ingredient. The TGA has approved various laboratory tests for measuring homocysteine levels for clinical use in Australia.

The TGA permits certain claims about the role of B vitamins in maintaining normal homocysteine metabolism but has not approved claims directly linking homocysteine levels to specific health outcomes.

Globally, there is consistency among regulatory bodies in not approving L-homocysteine as a supplement ingredient. No major jurisdiction permits the marketing of homocysteine as a supplement or therapeutic agent. There are some variations in how different countries regulate claims related to homocysteine metabolism and the nutrients that influence it. For example, some jurisdictions may permit more specific claims about the relationship between B vitamins, homocysteine levels, and health outcomes than others.

The regulation of homocysteine testing as a diagnostic tool varies somewhat between countries, with different standards for laboratory certification and quality control. In some countries, particularly those with high rates of cardiovascular disease, health authorities may place greater emphasis on homocysteine as a risk factor and provide more specific guidelines for testing and management. In regions with mandatory folate fortification programs (such as the United States, Canada, and Australia), there may be less regulatory focus on homocysteine as a public health concern due to the population-wide reduction in homocysteine levels achieved through fortification.

L-Homocysteine is not available as a prescription medication in any jurisdiction. It is not used therapeutically due to its association with adverse health effects. Laboratory testing for homocysteine levels typically requires a prescription or order from a healthcare provider in most jurisdictions, though specific requirements vary by country and healthcare system. The medications and supplements used to address elevated homocysteine levels (primarily B vitamins) have varying prescription requirements depending on the jurisdiction and dosage.

High-dose folate (e.g., 5 mg) is prescription-only in some countries but available over-the-counter in others. Vitamin B12 injections typically require a prescription, while oral B12 supplements are generally available without prescription. Specialized treatments for genetic disorders affecting homocysteine metabolism (such as homocystinuria) are typically available only by prescription and often require management by specialists.

L-Homocysteine is not available or marketed as a dietary supplement, so there is no consumer price range for supplementation. Instead, the cost considerations related to homocysteine are primarily focused on: 1) Laboratory testing costs for measuring blood homocysteine levels, which typically range from $50-$150 per test in the United States, though this can vary significantly based on laboratory, insurance coverage, and geographic location. 2) Costs of interventions to address elevated homocysteine levels, primarily B vitamin supplements. These costs are generally modest, with basic B vitamin supplements ranging from $5-$30 per month depending on formulation, dosage, and brand.

Specialized methylated forms of B vitamins, which may be recommended for individuals with certain genetic variants affecting homocysteine metabolism, typically cost $20-$60 per month. 3) For research purposes, L-homocysteine is available as a chemical reagent at prices ranging from approximately $50-$200 per gram, depending on purity and quantity purchased. However, this is relevant only for laboratory research, not for supplementation.

Since L-Homocysteine is not used as a supplement, traditional value comparisons are not applicable. Instead, the value considerations relate to the cost-effectiveness of homocysteine testing and interventions to address elevated levels. Routine homocysteine testing for the general population has not been shown to be cost-effective for cardiovascular risk assessment, as most major guidelines do not recommend it for primary prevention screening. Targeted homocysteine testing may be cost-effective in specific populations, such as individuals with premature cardiovascular disease, unexplained venous thrombosis, or family history of homocystinuria.

B vitamin supplementation to lower homocysteine levels has not consistently demonstrated cost-effectiveness for cardiovascular disease prevention in the general population, based on the results of large randomized controlled trials. However, B vitamin supplementation may be cost-effective in specific high-risk populations or in regions without mandatory folate fortification. For individuals with genetic disorders affecting homocysteine metabolism (e.g., homocystinuria), specialized interventions to lower homocysteine levels are highly cost-effective despite their higher cost, as they prevent serious complications including life-threatening thromboembolism and developmental abnormalities.

Not applicable for L-Homocysteine itself, as

it is not used as a supplement. For B vitamins used to manage homocysteine levels, bulk purchasing can provide cost savings: B complex supplements are often more economical

when purchased in larger quantities (3-6 month supply) or through subscription services, potentially reducing costs by 10-30%. Some online retailers and membership-based stores offer significant discounts on larger quantities of B vitamin supplements. For individuals requiring ongoing B vitamin supplementation to manage homocysteine levels,

these bulk purchasing options can improve cost-efficiency.

L-Homocysteine itself is not covered by insurance as it is not used therapeutically. However, several related aspects may be covered: Homocysteine blood testing is often covered by health insurance when medically indicated (e.g., for evaluation of unexplained thrombosis, premature cardiovascular disease, or suspected genetic disorders), though coverage policies vary by insurer. Prescription-strength B vitamins (e.g., high-dose folate, B12 injections) used to treat elevated homocysteine levels are frequently covered by prescription drug plans when medically necessary. Over-the-counter B vitamin supplements are generally not covered by conventional insurance but may be eligible expenses for Health Savings Accounts (HSAs) or Flexible Spending Accounts (FSAs) with a physician’s recommendation.

For individuals with diagnosed genetic disorders affecting homocysteine metabolism, specialized medical foods and treatments are often covered by insurance, though coverage may require prior authorization and documentation of medical necessity.

L-Homocysteine is not used as a dietary supplement, so shelf life information is primarily relevant for research applications rather than supplementation. In its pure form, L-homocysteine is highly unstable in the presence of oxygen, rapidly oxidizing to form homocystine (the disulfide dimer) and mixed disulfides with other thiols. For research purposes, L-homocysteine is typically stored as a stable precursor (such as homocysteine thiolactone) or as homocystine, which can be reduced to homocysteine immediately before use. When stored as a solid under inert gas (nitrogen or argon) at -20°C or below, homocysteine precursors can remain stable for 1-2 years.

In biological samples (such as blood) collected for homocysteine measurement, stability is a significant concern. Without proper handling, homocysteine levels can increase artificially due to ongoing production from erythrocytes. For clinical testing, blood samples should be placed on ice immediately after collection and plasma or serum should be separated within 1 hour.

Not applicable for supplementation – L-Homocysteine is not used as a dietary supplement, For research applications:, Store as homocystine or homocysteine thiolactone rather than reduced homocysteine when possible, Store under inert gas (nitrogen or argon) to prevent oxidation, Keep in tightly sealed containers with minimal headspace, Store at -20°C or below for long-term storage, Protect from light, as UV radiation can accelerate oxidation, For clinical samples collected for homocysteine measurement:, Place blood samples on ice immediately after collection, Separate plasma or serum within 1 hour of collection, If analysis is delayed, store samples at -70°C for optimal stability

Oxidation: The free thiol group of homocysteine is highly susceptible to oxidation, forming disulfide bonds with other homocysteine molecules (homocystine) or with other thiols, Temperature: Higher temperatures accelerate oxidation and other degradation processes, pH extremes: Homocysteine is most stable at slightly acidic to neutral pH (pH 4-7), Metal ions: Certain metal ions, particularly copper and iron, catalyze the oxidation of homocysteine, Light exposure: UV radiation can accelerate oxidation reactions, Enzymatic degradation: In biological samples, enzymes can continue to metabolize homocysteine if samples are not properly processed, Freeze-thaw cycles: Repeated freezing and thawing can affect stability in stored samples

L-Homocysteine is highly unstable in aqueous solution, particularly under aerobic conditions. In oxygenated solutions at physiological pH, the half-life of free reduced homocysteine can be as short as minutes to hours, depending on temperature, pH, and the presence of other compounds. For research applications requiring homocysteine solutions, they should be prepared fresh immediately before use, preferably under inert gas. The addition of reducing agents such as dithiothreitol (DTT) or tris(2-carboxyethyl)phosphine (TCEP) can temporarily maintain homocysteine in its reduced form, but these solutions still have limited stability.

In biological fluids like plasma, homocysteine exists primarily in protein-bound and oxidized forms, with only about 1-2% present as free reduced homocysteine. This distribution helps stabilize homocysteine in vivo. For clinical measurements, acidification of plasma samples can help prevent artifactual increases in homocysteine levels during storage. In some research protocols, homocysteine is deliberately oxidized to homocystine for analysis, as the disulfide form is more stable for chromatographic separation.

Natural Sources

Synthetic Production Methods

Quality Indicators

Sustainability Considerations

L-Homocysteine has no history of traditional medicinal or nutritional applications. Unlike many other amino acids that have been used in traditional medicine systems or as nutritional supplements, homocysteine was not identified until the 20th century and has never been used as a therapeutic agent or supplement. In fact, once its role in metabolism was understood, the focus has been on maintaining normal homocysteine levels rather than supplementing with it. There are no known traditional cultures or medical systems that utilized homocysteine or specifically targeted its metabolism.

However, many traditional diets rich in folate and other B vitamins (such as Mediterranean and traditional Asian diets) likely helped maintain healthy homocysteine metabolism, though this would not have been recognized as such historically. Some traditional foods now known to support healthy homocysteine metabolism include leafy greens, legumes, and fermented foods, which provide folate and other B vitamins that help convert homocysteine back to methionine or forward to cysteine.

Homocysteine was first isolated and characterized in 1932 by Vincent du Vigneaud, who later received the Nobel Prize in Chemistry for his work on sulfur-containing compounds. Initially, homocysteine was primarily of interest to biochemists studying amino acid metabolism rather than clinicians. The medical significance of homocysteine was first recognized in 1962 when children with homocystinuria, a rare genetic disorder causing severely elevated homocysteine levels, were found to develop premature vascular disease and thromboembolism. In 1969, Dr.

Kilmer McCully made the seminal observation that vascular disease was common in individuals with different genetic disorders that all shared the feature of elevated homocysteine levels. This led to his ‘homocysteine theory of atherosclerosis,’ proposing that elevated homocysteine might be a causal factor in cardiovascular disease even in the general population. Initially controversial, McCully’s hypothesis gained support in the 1970s and 1980s as epidemiological studies began to show associations between moderately elevated homocysteine levels and cardiovascular risk. By the 1990s, homocysteine had become established as an independent risk factor for cardiovascular disease, with numerous observational studies showing that even mild elevations in homocysteine levels were associated with increased risk.

The discovery of common genetic variants, particularly in the methylenetetrahydrofolate reductase (MTHFR) gene, that affect homocysteine metabolism further advanced understanding of the factors influencing homocysteine levels. The implementation of folate fortification programs in several countries in the late 1990s, primarily aimed at reducing neural tube defects, provided a natural experiment that also demonstrated population-wide reductions in homocysteine levels.

Unlike most compounds covered in this database, L-homocysteine has never evolved into use as a supplement or therapeutic agent. Instead, its significance has been as a biomarker and potential causal factor in disease processes. The evolution of homocysteine’s role in medicine has primarily been in how it is measured, interpreted, and managed. In the 1980s and early 1990s, homocysteine testing was primarily a specialized research tool.

By the late 1990s and early 2000s, as evidence for its role in cardiovascular disease accumulated, homocysteine testing became more widely available in clinical settings. During this period, some clinicians began routinely measuring homocysteine levels in patients with cardiovascular disease or risk factors, and treating elevated levels with B vitamin supplementation. The early 2000s saw the initiation of several large randomized controlled trials testing whether lowering homocysteine levels with B vitamin supplementation would reduce cardiovascular events. Contrary to expectations based on observational studies, most of these trials failed to show significant benefits of homocysteine-lowering therapy on cardiovascular outcomes, leading to a reevaluation of the causal role of homocysteine in cardiovascular disease.

As a result, enthusiasm for routine homocysteine testing and treatment declined somewhat in general cardiovascular practice. However, homocysteine remains an important biomarker in specific clinical contexts, including the evaluation of certain genetic disorders, nutritional deficiencies, and unexplained thrombosis or premature atherosclerosis. In recent years, interest in homocysteine has expanded beyond cardiovascular disease to include potential roles in neurodegenerative disorders, pregnancy complications, and other conditions. The focus has shifted from simply lowering homocysteine levels to understanding the complex mechanisms by which homocysteine may contribute to disease processes and identifying specific populations who might benefit from interventions targeting homocysteine metabolism.

Throughout this evolution, the consistent theme has been that homocysteine itself is not used therapeutically; rather, the goal has been to maintain normal homocysteine metabolism through adequate B vitamin status and addressing underlying causes of hyperhomocysteinemia.

VITACOG follow-up studies: Examining the long-term effects of B vitamin supplementation on cognitive function and brain atrophy in elderly with elevated homocysteine levels, Genetic studies using Mendelian randomization approaches to further clarify the causal relationship between homocysteine and various disease outcomes, Trials investigating the potential benefits of homocysteine-lowering interventions in specific high-risk populations, such as those with genetic variants affecting homocysteine metabolism, Studies exploring the interaction between homocysteine-lowering interventions and other cardiovascular risk reduction strategies, Research on novel biomarkers related to one-carbon metabolism that may provide better risk prediction than homocysteine alone