Threonic acid

Threonic Acid: A Comprehensive Reference

1. Identity, Chemistry, and Natural Sources

1.1 Chemical Identity

Threonic acid is a four-carbon sugar acid (aldonic acid) with the molecular formula C₄H₈O₅, derived from the oxidation of the aldose sugar threose, and it exists primarily as the L-enantiomer in biological contexts as a metabolite of L-ascorbic acid (vitamin C). Chemically, L-threonic acid is (2S,3R)-2,3,4-trihydroxybutanoic acid, a weak organic acid with a pKa around 3.5–4.0, high water solubility (approximately 53 mg/mL at neutral pH), and a molecular weight of 136.1 g/mol.

Synonyms recorded in pharmacological databases include 2,3,4-trihydroxy-(threo)-butanoic acid, DL-threonic acid, and threo-2,3,4-trihydroxybutyric acid. Its chemical formula is C₄H₈O₅. L-threonic acid exists in two enantiomeric forms, with the L-form being biologically relevant. The compound's CAS registry number is 7306-96-9 for the L-form (CID 5460407 on PubChem).

1.2 Natural Occurrence and Biosynthetic Origin

L-threonic acid is a normal, endogenous component of human plasma, and its presence is intrinsically linked to the metabolism of L-ascorbic acid (vitamin C), of which it is a primary degradation product. It is produced endogenously through the oxidative degradation of vitamin C, involving initial oxidation by enzymes such as L-ascorbate oxidase followed by non-enzymatic breakdown, and it can also arise from the breakdown of glycated proteins or during microbial fermentation.

Ascorbic acid (vitamin C) is sequentially metabolized to dehydroascorbic acid (DHA), 2,3-diketogulonic acid (DKGA), oxalic acid, and threonic acid. Dehydroascorbate has an unstable lactone ring that can be hydrolyzed to 2,3-diketogulonate in aqueous solution; 2,3-diketogulonate further degrades to various carbonate products, including CO₂, oxalate, glyoxalate, glycerate, and threonate.

In some Geraniaceae plants, ascorbic acid is cleaved at the C2/C3 bond, producing oxalic acid and L-threonic acid as discrete products. L-threonate and D-erythronate, the four-carbon acid sugars, are metabolites of ascorbic acid and are widely distributed in food and present in human biofluids and excretions; moreover, these two acid sugars are components of aqueous humour in the eye.

Threonic acid can be derived from glycated proteins or from degradation of ascorbic acid; it is a normal component of aqueous humour and blood. Threonic acid is a substrate of L-threonate 3-dehydrogenase in the ascorbate and aldarate metabolism pathway, and it has also been found to be a microbial metabolite.

In human and animal physiology, L-threonic acid participates in the ascorbate and aldarate metabolism pathway, acting as a substrate for L-threonate 3-dehydrogenase (EC 1.1.1.129), which converts it to 3-dehydro-L-threonate. The compound is typically found in various fruits and vegetables, and it can also be synthesized in the laboratory.

1.3 Common Forms and Preparations

Threonic acid itself is not commonly formulated as a standalone supplement. Its primary commercial and scientific relevance comes from two mineral salt forms:

• Magnesium L-threonate (MgT / Magtein®): In nutritional and neuropharmacological science, the most notable application of threonic acid is its salt form, magnesium L-threonate, which has been studied for its ability to cross the blood-brain barrier and elevate magnesium levels in the cerebrospinal fluid. The 2010 Neuron paper by Slutsky and colleagues at MIT became the scientific foundation for the product category, and the compound was subsequently licensed and commercialized as Magtein® by Magceutics and later AIDP.
• Calcium L-threonate: Calcium threonate is a calcium salt of threonic acid and a novel drug developed for the treatment of osteoporosis and as a calcium supplement.

The organic salt structure of magnesium L-threonate is composed of the L-threonate anion and magnesium ion, verified by Fourier transform infrared spectroscopy showing the stretching vibration of the carboxylate group of L-threonate and lacking the signal corresponding to the protonated carboxyl group. According to information from manufacturers, the novel food is produced in line with current Good Manufacturing Practice (GMP) and Hazard Analysis Critical Control Points (HACCP) principles.

2. Traditional and Historical Use

Threonic acid was not identified or used in traditional herbal or medical systems, as it is a relatively modern discovery tied to vitamin C metabolism and organic chemistry. Its origins in ascorbic acid link it indirectly to the long-standing use of vitamin C-rich plants; structurally, it is a four-carbon polyhydroxy acid that typically exists in the form of L-threonic acid in biological systems.

There is therefore no documented use of threonic acid in Ayurvedic, Traditional Chinese Medicine, European herbal, or any other pre-modern medical tradition. The compound was not isolable or identifiable without modern analytical chemistry. Its characterization as a discrete metabolite of vitamin C emerged from twentieth-century biochemical research. Any association with "traditional use" in contemporary marketing should be understood as an indirect reference to the broader traditions of using ascorbic acid–rich foods, not to threonic acid itself as a recognized therapeutic entity.

Threonic acid is a major breakdown product of ascorbic acid; when studied as a food additive in guinea pigs at 100 mg/kg body weight for periods of 4 or 28 days, it produced a significant fall in ascorbic acid concentration in certain organs. This early animal study from the 1980s represents one of the first systematic investigations into threonic acid's biological activity and its relationship with vitamin C metabolism, establishing it as a pharmacologically relevant entity distinct from its parent compound.

3. Key Constituents and Mechanisms of Action

3.1 The Threonate Ligand and Mineral Transport

The L-threonate ligand in magnesium L-threonate (Magtein®) plays an important functional and mechanistic role, as preclinical research has demonstrated that the effect of threonate is mediated through glucose transporters, which enhances magnesium bioavailability and enables significant increases in brain magnesium concentrations.

The proposed mechanism suggests that L-threonate itself may enhance magnesium transport across the blood-brain barrier, possibly by utilizing specific transporters (like glucose transporters) or by altering membrane dynamics in a way that facilitates magnesium entry. While the exact transport mechanism is still under investigation, animal data strongly indicates superior brain bioavailability for magnesium L-threonate compared to conventional magnesium salts.

3.2 NMDA Receptor Modulation and Synaptic Plasticity

The proposed downstream mechanism runs through NMDA-receptor function. Magnesium acts as a voltage-dependent blocker of NMDA receptors; intracellular magnesium concentration shapes how efficiently those receptors support long-term potentiation. Recent work confirms intracellular magnesium enhances hippocampal plasticity.

Coupled with concurrent upregulation of NR2B-containing NMDA receptors and its downstream signaling, synaptic plasticity induced by correlated inputs is enhanced; an increase in brain magnesium enhances both short-term synaptic facilitation and long-term potentiation and improves learning and memory functions.

The possible mechanisms of action of magnesium L-threonate on cognitive functions are via the activation of the NMDA receptors, which leads to increased synaptic density and improved memory. In intact animals, elevation of brain magnesium increased NMDA receptor signaling, BDNF expression, density of presynaptic puncta, and synaptic plasticity in the prefrontal cortex.

3.3 Glucose Transporter Competition (Hypothalamic Effects)

The anorexigenic effects of threonic acid are associated with its role in reversing fasting-induced upregulation of the hypothalamic orexigenic neuropeptides NPY and AGRP. In the hypothalamus, threonic acid competed with glucose for uptake via glucose transporter 3 (GLUT3), while intermittent fasting boosted threonic acid uptake through both glucose depletion and upregulation of GLUT3, resulting in more robust suppression of NPY and AGRP expression.

3.4 Osteoblast and Collagen Synthesis Pathways

Cell pharmacodynamics tests demonstrated that calcium L-threonate can facilitate proliferation, differentiation, and mineralization functions of osteoblasts. Studies found that calcium L-threonate upregulated the level of α-COL I mRNA in osteoblasts cultured in vitro, which was correlated with an enhanced bone-forming function of osteoblasts. This suggested that calcium L-threonate might enhance bone-forming function by enhancing the expression of certain genes in osteoblasts.

Threonic acid's research applications extend to bone health, where it demonstrates a stimulatory action on vitamin C uptake in cells, a process crucial for collagen synthesis and the mineralization process in osteoblast formation.

4. Scientific Evidence by Area of Use

4.1 Cognitive Function and Memory

4.1.1 Foundational Preclinical Research

The landmark 2010 study by Slutsky, Abumaria, Wu, and colleagues (published in Neuron) showed that increasing brain magnesium using magnesium L-threonate (MgT) leads to the enhancement of learning abilities, working memory, and short- and long-term memory in rats. This research demonstrated that MgT uniquely elevated cerebrospinal fluid magnesium, produced significant increases in synaptic density in hippocampal neurons, significantly enhanced hippocampal long-term potentiation (LTP), and produced substantial improvements in both short-term and long-term memory performance. Oral delivery of magnesium L-threonate to rats achieved significantly higher brain magnesium levels than control feed, whereas magnesium chloride, magnesium orotate, or magnesium gluconate did not; this report also demonstrated increases in synaptic density in hippocampal regions and reversed task impairment in Alzheimer's-model rodents.

These rodent findings are foundational but must be interpreted carefully: rodent pharmacokinetics and cognitive paradigms do not always translate directly to human outcomes.

4.1.2 Older Adults with Cognitive Complaints (RCT, 2016)

A randomized, double-blind, placebo-controlled trial performed in Miami enrolled 51 adults (36 women, 15 men), aged up to 70 years, who received a daily dose of 1.5 or 2 g/day to study the effects of 12 weeks of dietary supplementation with magnesium L-threonate. The subjects had self-reported complaints of cognition (memory and concentration) but were otherwise generally healthy. In this 12-week randomized controlled trial on older adults with mild cognitive impairment, Magtein® supplementation was associated with a significant improvement in the total cognitive score, equivalent to an approximate 9-year cognitive improvement, suggesting a meaningful reversal of age-related cognitive decline.

4.1.3 Healthy Chinese Adults (RCT, 2022)

In a double-blind, placebo-controlled study, Magtein®PS — a magnesium L-threonate and phosphatidylserine-based formulation additionally containing vitamins C and D — was tested for its cognitive benefits in 109 healthy Chinese adults aged 18–65 years. Subjects were randomly assigned to receive either Magtein®PS or placebo (starch) capsules at a dose of 2 g/day. "The Clinical Memory Test," the standard test commonly used in Chinese hospitals and academic institutes for cognitive evaluation, was administered before and 30 days after subjects received the supplement. Subjects receiving Magtein®PS showed significant improvements over the control group in all five subcategories of "The Clinical Memory Test" as well as the overall memory quotient scores. The older participants showed more improvement than younger participants.

Important limitation: This study used a multi-ingredient formula (also containing phosphatidylserine and vitamins C, D, and B6), making it impossible to attribute the observed effects solely to magnesium L-threonate or to the threonate ligand specifically.

4.1.4 Young-to-Middle-Aged Adults (RCT, 2025/2026)

In a two-arm, 6-week, parallel-group, randomised, double-blind, placebo-controlled trial (Lopresti & Smith, published January 2026 in Frontiers in Nutrition), researchers examined the effects of magnesium L-threonate supplementation on cognitive performance, cognitive age, sleep quality, and physiological indicators in adults. Results demonstrated that magnesium L-threonate supplementation for 6 weeks was associated with improvements in cognitive performance in young-to-middle-aged adults. Moreover, improvements in hand-eye coordination and reaction time were observed. Improvements in subjective sleep were demonstrated, confirmed with a subjective sleep questionnaire (PROMIS Sleep). No changes in sleep parameters as measured by the Oura Ring were demonstrated, although a reduction in resting heart rate and an increase in heart rate variability during sleep were demonstrated, suggesting Magtein® may increase parasympathetic activity.

4.1.5 Open-Label Trial in Dementia (2017–2018)

An open-label trial explored the effects of magnesium L-threonate in patients with mild to moderate dementia. Fifteen patients underwent 18F-FDG-PET imaging, cognitive testing, and blood draws at baseline and at 12 weeks of treatment in order to assess the acute effect of magnesium L-threonate supplementation on hippocampal- and prefrontal-cortex-mediated cognitive abilities including executive function, attention, processing speed, verbal fluency, and memory. As an open-label trial with only 15 participants, this study provides preliminary, hypothesis-generating data rather than confirmatory evidence.

4.1.6 Overall Strength of Cognitive Evidence

The evidence for cognitive benefits of magnesium L-threonate is preliminary to moderate. The foundational mechanistic work is from animal models. Human trials are limited in number, sample size, and often involve multi-ingredient formulas or lack placebo controls. Proponents suggest that by potentially influencing brain magnesium levels, the supplement may affect synaptic density and neuronal signalling, though these mechanisms are largely based on laboratory and animal studies rather than confirmed in humans. Evidence for L-threonate's superiority over other magnesium forms remains limited, based largely on animal studies.

4.2 Sleep Quality

In a randomized, double-blind, placebo-controlled, parallel-arm study, 80 adults aged 35–55 years with self-assessed sleep problems participated, taking 1 g/day of magnesium L-threonate or placebo for 21 days. Magnesium L-threonate showed significant (p < 0.05) improvements over placebo for Leeds Sleep Questionnaire subcategory behavior following awakening, and Restorative Sleep Questionnaire subcategories including mood and mental alertness.

In the Lopresti & Smith 2026 trial, improvements in subjective sleep were demonstrated and confirmed with a subjective sleep questionnaire (PROMIS Sleep), though no changes in sleep parameters as objectively measured by the Oura Ring were demonstrated. Taken together, sleep evidence is preliminary; self-reported sleep improvements are recorded across two RCTs, but objective polysomnographic data are absent. Replication with larger samples and objective endpoints is needed.

4.3 Bone Health and Osteoporosis

4.3.1 In Vitro and Animal Evidence

In vitro, the resorption area and CTx concentration in calcium L-threonate–treated groups were reduced significantly as compared with control and with calcium gluconate groups. This study found that L-threonate, especially calcium L-threonate, inhibited the bone resorption of osteoclasts in vitro; however, the reductive effects on the CTx level and resorptive area were not as significant as alendronate and 17β-estradiol at the same concentration.

In animal studies, the bone mineral density of rats fed calcium L-threonate chronically was significantly higher than that of the model group, wherein the beneficial effect of calcium L-threonate on increase of bone mineral density was dose-related. Animal tests showed that calcium L-threonate could not only promote proliferation, differentiation, and mineralization functions of osteoblasts, but also promote the expression of mRNA procollagen I in osteoblasts cultured in vitro; through these functions, calcium L-threonate could facilitate bone fracture healing and increase bone density and mechanical performance.

In vitro treatment with ascorbate containing vitamin C metabolites enhanced the formation of mineralized nodules and collagenous proteins, and calcium threonate may be one of the metabolites influencing the mineralization process.

4.3.2 Human Pharmacokinetic Evidence

Phase I clinical trials of calcium L-threonate, including tolerance, pharmacokinetics, and calcium absorption evaluation, were performed in Peking Union Medical College Hospital. In a calcium bioavailability study, fourteen healthy Chinese subjects were enrolled and given 300 mg calcium L-threonate tablets containing 40 mg ⁴⁴Ca after an intravenous injection of 4 mg ⁴²Ca solution (as calcium chloride), with fractional urine samples collected across defined time intervals. The bioavailability of calcium L-threonate in humans was successfully determined using a double-label stable isotope method, providing a useful approach for the evaluation of bioavailability of calcium formulations.

The bone health evidence for calcium L-threonate is preclinical (in vitro and animal data) with human studies limited to pharmacokinetics and safety. Randomized clinical trials demonstrating fracture reduction or significant bone density improvement in humans are not yet available in the peer-reviewed literature.

4.4 Attention-Deficit/Hyperactivity Disorder (ADHD)

In an open-label study on adults with attention-deficit hyperactivity disorder (ADHD), 12 weeks of Magtein® supplementation was associated with improvements in self-reported and clinician-rated measures of attention, and objective measures of cognitive performance and intelligence. In the open-label trial by Surman et al. (2021), 15 patients of an average age of 36.4 ± 14.0 years with ADHD were given 1.5–2 g/day of an anhydrous form of magnesium L-threonate for 12 weeks; no serious adverse events were observed.

This evidence is very preliminary: the single open-label study has no placebo group, a small sample (n=15), and substantial risk of expectation bias. No controlled trials of magnesium L-threonate specifically for ADHD have been published as of 2026.

4.5 Obesity and Metabolic Health

A 2025 study reported that combining intermittent fasting with threonic acid — an ascorbic acid metabolite — led to more pronounced reductions in body weight and food intake, as well as improvements in energy expenditure and glycemic control, compared with either intervention alone in diet-induced obese mice. The combination therapy significantly improved glucose tolerance, insulin sensitivity, and energy expenditure while increasing thermogenesis in brown adipose tissue, leading the authors to conclude that, when combined, threonic acid and intermittent fasting appear to synergistically support weight loss and improve markers of insulin sensitivity.

This research is currently animal data only (diet-induced obese mouse model). No human clinical trials have tested threonic acid for obesity or metabolic endpoints. The metabolic evidence must therefore be considered highly preliminary.

4.6 Parkinson's Disease Biomarker Association

A GC-MS metabolomics study conducted in early-stage Parkinson's disease showed that dehydroascorbic acid, urea, and glyceric acid were significantly decreased, while fructose, mannose, threonic acid, hydroxybutyric acid, and lauric acid were significantly increased. This study had two important strengths: all Parkinson's disease patients were drug-naïve, eliminating treatment influence, and findings were validated by an independent cohort.

This metabolomics finding establishes threonic acid as an associated biomarker in early Parkinson's disease, not as a therapy. Its mechanistic role, if any, in Parkinson's disease pathology is currently unexplained.

5. Body Systems and Health Areas of Association

• Central Nervous System: The most notable application of threonic acid is its salt form, magnesium L-threonate, which has been studied for its ability to cross the blood-brain barrier and elevate magnesium levels in the cerebrospinal fluid; increased brain magnesium has been associated with improved synaptic plasticity, learning, and memory in animal studies.
• Skeletal System: The calcium salt of threonic acid is investigated for its potential in osteoporosis and as a calcium supplement, with studies indicating it can inhibit bone resorption of osteoclasts in vitro.
• Metabolic/Endocrine System: In preclinical research, combining intermittent fasting with threonic acid led to more pronounced reductions in body weight and food intake, as well as improvements in energy expenditure and glycemic control, compared with either intervention alone in diet-induced obese mice.
• Hypothalamic Appetite Regulation: Threonic acid was identified as the metabolite responsible for suppressing orexigenic neuropeptides (NPY and AGRP), leading to reduced hunger signals during fasting.
• Ascorbate Metabolism: In scorbutic guinea pigs, dietary threonic acid significantly reduced lifespan; these results indicate that threonic acid may modify the metabolism of ascorbic acid.
• Ocular System: L-threonate and D-erythronate are components of aqueous humour in the eye.
• Cardiovascular / Autonomic: In the 2026 Lopresti & Smith RCT, a reduction in resting heart rate and an increase in heart rate variability during sleep were demonstrated with Magtein® supplementation, suggesting it may increase parasympathetic activity.

6. Dosage Forms and Doses Reported in Studies

Threonic acid itself is not formulated as a standalone supplement in clinical studies. All human dosage data come from its mineral salt derivatives.

6.1 Magnesium L-Threonate

• In the 2016 randomized, double-blind, placebo-controlled trial (Liu et al.), 51 adults received a daily dose of 1.5 or 2 g/day for 12 weeks.
• In the 2024 sleep RCT (Hausenblaus et al.), 80 adults aged 35–55 years took 1 g/day of magnesium L-threonate for 21 days.
• In the ADHD open-label study (Surman et al., 2021), 15 patients received 1.5–2 g/day of magnesium L-threonate for 12 weeks.
• In the Lopresti & Smith 2026 RCT, the study used Magtein® for 6 weeks in healthy adults with dissatisfied sleep, with the compound administered as capsules. For the purposes of EU regulatory assessment, the novel food was intended to be used at a maximum intake level of 3,000 mg per day by adults, which corresponds to approximately 2,730 mg L-threonate and 250 mg magnesium, also corresponding to the upper limit (UL) for supplemental magnesium from readily dissociable magnesium salts.

6.2 Calcium L-Threonate

• In the human calcium bioavailability study at Peking Union Medical College Hospital, 14 healthy Chinese subjects received 300 mg calcium L-threonate tablets containing 40 mg ⁴⁴Ca.
• In 2008, EFSA's ANS Panel assessed calcium L-threonate and concluded that up to 4 tablets per day, each providing 100 mg calcium and 675 mg L-threonate, corresponding to a daily intake of 400 mg calcium and 2,700 mg L-threonate, are not of safety concern.

7. Safety Considerations and Interactions

7.1 Regulatory Status

On October 18, 2024, the European Commission published Commission Implementing Regulation (EU) 2024/2694, officially authorizing the use of magnesium L-threonate as a novel food ingredient in food supplements intended exclusively for adults. In its scientific opinion, the EFSA Authority concluded that the novel food, magnesium L-threonate, is safe under the proposed conditions of use. AIDP Inc., the applicant company, holds exclusive rights to market magnesium L-threonate in the EU for five years starting November 7, 2024.

Based on results obtained from a dissociation study, two rat studies, and one human trial, the EFSA Panel considers that magnesium is bioavailable from the novel food. The Panel concludes that the novel food is a source from which magnesium is bioavailable.

7.2 Oxalic Acid Co-Impurity

Analytical data on one production batch showed the composition as oxalic acid 0.155%, magnesium 7.80%, and threonic acid 89.3%. The range for oxalic acid in three other batches used for stability testing was 0.2%–0.5%. The EFSA Panel considers that an additional exposure to oxalic acid of up to 30 mg daily from the novel food is not of safety concern.

7.3 Tolerated Doses and Absence of Serious Adverse Events in Trials

In the ADHD open-label trial (Surman et al., 2021), the authors reported that no serious adverse events were observed. The EFSA Panel concludes that the novel food (magnesium L-threonate) is not nutritionally disadvantageous.

7.4 Interaction with Ascorbic Acid Metabolism

When threonic acid was administered orally to guinea pigs at 100 mg/kg body weight for periods of 4 or 28 days, it produced a significant fall in the ascorbic acid concentration in certain organs but was without effect on other physiological and biochemical characteristics. The lifespan of scorbutic guinea pigs was significantly reduced by dietary threonic acid at 100 mg/kg body weight. This finding, from a 1983 study in a species unable to synthesize its own vitamin C, raises the theoretical concern that very high exogenous doses of threonic acid could interfere with ascorbic acid homeostasis, though there are no equivalent data in healthy adult humans receiving normal supplemental doses.

7.5 Exclusion from Infant Supplements

The European Commission's request to EFSA explicitly excluded food supplements for infants and young children from the novel food assessment scope for magnesium L-threonate. This regulatory exclusion is relevant: the safety profile established by EFSA applies only to adult populations.

7.6 Magnesium Upper Intake Level

The novel food is intended to be used as a source of magnesium in food supplements at a maximum intake level of 3,000 mg magnesium L-threonate per day by adults, except for pregnant and lactating women; this dose corresponds to approximately 2,730 mg L-threonate and 250 mg magnesium, which also corresponds to the established upper limit (UL) for supplemental magnesium from readily dissociable magnesium salts. Exceeding this UL for supplemental magnesium from any source — including threonate salts — is associated with gastrointestinal effects (diarrhea, nausea) characteristic of excess magnesium supplementation.

7.7 Limitations of the Safety Data

The EFSA assessment concerns only the risks that might be associated with the consumption of the novel food under the proposed conditions of use, and is not an assessment of the efficacy of the novel food with regard to any claimed benefit. The bulk of formal safety data for threonate salts comes from short-term trials (up to 12 weeks) in adults. Long-term safety data beyond 12 weeks in humans remain limited.

References

• PubChem: L-Threonic Acid (CID 5460407)
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