Pyrroloquinoline Quinone Disodium Salt (PQQ·2Na): A Comprehensive Reference
1. Identity, Chemical Characterization, and Common Forms
1.1 Names and Chemical Identity
Pyrroloquinoline disodium salt is the stabilized, water-soluble form of pyrroloquinoline quinone (PQQ), a redox-active compound and antioxidant found naturally in soil, certain foods, and breast milk. The compound is also known by the synonyms methoxatin disodium salt, PQQ disodium salt, and PQQ-Na₂. The free-acid form of PQQ carries the systematic chemical structure 4,5-dihydro-4,5-dioxo-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid. The disodium salt form, assigned CAS registry number 122628-50-6, replaces two of PQQ's acidic protons with sodium cations. Pyrroloquinoline quinone disodium salt (PQQ-Na₂) is a water-soluble quinone compound that has a strong antioxidant capacity.
Pyrroloquinoline quinone disodium salt (PQQ) is a red trihydrate crystal. The PQQ disodium crystal exists in the crystalline pentahydrate form, and single crystal analysis has revealed the structure of the disodium crystal. PQQ has the molecular formula C₁₄H₆N₂O₈, and is a new cogroup with similar physiological functions to vitamins, widely existing in prokaryotes, plants and mammals, but at very low content.
1.2 Relationship Between PQQ Free Acid and the Disodium Salt
PQQ in nature exists as a free acid, as salts (e.g., the sodium salt of PQQ), or as a complex derivative of an amino acid, imidazolopyrroloquinoline. PQQ can also be found in the form of PQQ disodium salt; while these are technically chemically different compounds, their physiological metabolism and effect are thought to be similar. The organic acid form of PQQ is quickly converted into a salt during the process of digestion, or merely by dissolving PQQ into a complex mixture. The disodium salt form enhances its solubility, stability, and bioavailability in supplements.
1.3 Natural Sources
PQQ is produced exclusively by certain bacteria, not by plants, animals, or fungi. It enters the food chain through soil bacteria and rhizobacteria that synthesize PQQ via the pqq operon biosynthetic pathway. It is isolated from cultures of methylotrophic bacteria and tissues of mammals.
PQQ has been detected from microorganisms and from edible plants, such as soybeans, broad beans, green pepper, potatoes, parsley, and spinach, and processed food products, such as vinegar, tea, cocoa, natto, and tofu. It is found in fruits and vegetables at 7–34 μg/kg, in legume seeds at 18.24 μg/kg, in fermented products at 60–800 μg/kg, in human milk at 140–180 μg/kg, in cow milk at 3.4 μg/kg, and in chicken egg yolk at 7 μg/kg.
Fermented foods, including tofu, miso, and natto, contain high concentrations of PQQ (up to 61 ng/g in natto). Despite its prevalence, typical dietary PQQ concentrations remain relatively low (around 1–30 ng/g across most foods). Fermented foods like natto have higher PQQ content because fermentation involves PQQ-producing bacteria. Human milk has a very high concentration of PQQ (140–180 ng/mL), which is approximately 4 to 5 times higher than that in cow milk (Mitchell AE et al., Analytical Biochemistry 1999; 269:317–325).
1.4 Supplement Production and Forms
PQQ is produced commercially by fermentation using Hyphomicrobium denitrificans CK-275 and a purification process, achieving a minimum purity of 99.0%. PQQ can be produced by methodologies such as organic chemical syntheses and fermentation processes and is often provided in the form of an alkali metal salt crystal, in particular a disodium salt crystal. The Hyphomicrobium sp. TK0441 was selected by Mitsubishi during a broad survey for PQQ-producing bacteria, and cultivation conditions were developed for high PQQ excretion. Upon cultivation under iron-limited conditions, PQQ accumulated up to 1 g/L during a protracted 15-day fermentation run.
The principal branded ingredient derived from this process is BioPQQ® (also marketed as MGCPQQ®). MGCPQQ® (BioPQQ®) was successfully filed as a New Dietary Ingredient (NDI) with the U.S. Food & Drug Administration (FDA) in 2008, and Mitsubishi Gas Chemical became the first company to utilize PQQ in food applications; MGCPQQ® (BioPQQ®) remains the only ingredient of its kind with NDI notification. In 2018, the European Commission approved PQQ (marketed as MGCPQQ®) as a novel food ingredient, following a favourable safety assessment by the European Food Safety Authority (EFSA).
2. Historical Discovery and Scientific Backstory
2.1 Initial Discovery
Pyrroloquinoline quinone (PQQ, also known as methoxatin) was discovered in 1964 by Hauge, and its structure was determined by Kennard 15 years later. In addition to flavins and nicotinamides, PQQ acts as the third redox cofactor in bacteria. Its structure was later determined by derivatized crystallography (Salisbury et al., 1979). This placed PQQ alongside NAD and FAD as one of only three known redox cofactors in prokaryotes at that time.
In the 1980s, Mitsubishi Gas Chemical began supplying PQQ disodium salt. In 2003, a research group in Japan suggested that the ingredient has the potential to become a new vitamin. The scientific journal Nature published a 2003 paper by Kasahara and Kato that essentially stated that PQQ was a new vitamin, a cofactor required for the activity of an enzyme they believe to be involved in lysine metabolism (U26). In 2005, an article by Anthony and Felton stated that the 2003 Kasahara–Kato paper drew incorrect and unsubstantiated conclusions, specifically that the databases used by the paper inappropriately labeled β-propeller sequences as PQQ-binding motifs. The vitamin status of PQQ therefore remains scientifically contested.
An article by Bruce Ames in The Proceedings of the National Academy of Sciences in 2018 identified pyrroloquinoline quinone as a "longevity vitamin" — not essential for immediate survival, but necessary for long-term health.
2.2 Traditional Use
PQQ has no documented history of isolated traditional or folk medicinal use as a distinct compound. This is consistent with its scientific nature: PQQ was not identified as a discrete molecular entity until 1964, and its structure was not characterized until 1979. Traditional cultures consuming foods such as natto, fermented soy products, parsley, green tea, and other PQQ-containing foods would have received dietary PQQ incidentally. PQQ is present in small amounts of everyday food, including fruits, vegetables, fermented foods, and breast milk. No traditional medical system has historically attributed therapeutic properties to this compound as an identifiable ingredient; its existence as a supplement ingredient is entirely a product of modern biochemistry and nutritional science.
3. Key Constituents, Chemical Properties, and Mechanisms of Action
3.1 Redox Chemistry and Antioxidant Mechanism
PQQ is an aromatic tricyclic orthoquinone with redox cycling that has 7.4 times the aroxyl radical-scavenging capacity of vitamin C in its reduced form, making it one of the most potent water-soluble antioxidants. It is water- and heat-stable, and is capable of catalyzing continuous redox cycling as well as oxidative deamination. PQQ has been reported to act as a free radical scavenger, capable of carrying out thousands of electron transfers without undergoing molecular breakdown. In particular, PQQ has been reported to be effective in neutralizing superoxide and hydroxyl radicals.
It is important to note, however, that the antioxidant and redox functions are form-dependent. The reduced form of PQQ has extremely high antioxidant properties, but PQQ itself (in its oxidized form) does not inherently have antioxidant properties.
3.2 Mitochondrial Biogenesis
Perhaps the most studied mechanistic effect of PQQ is its capacity to stimulate the formation of new mitochondria (mitochondrial biogenesis). Studies have shown that mice and rats fed diets lacking in pyrroloquinoline quinone have reduced mitochondrial content. Exposure of mouse Hepa1-6 cells to 10–30 µM PQQ for 24–48 hours resulted in increased citrate synthase and cytochrome c oxidase activity, Mitotracker staining, mitochondrial DNA content, and cellular oxygen respiration.
The induction of this process occurred through the activation of cAMP response element-binding protein (CREB) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a pathway known to regulate mitochondrial biogenesis. PQQ exposure stimulated phosphorylation of CREB at serine 133, activated the promoter of PGC-1α, and increased PGC-1α mRNA and protein expression. PQQ did not stimulate mitochondrial biogenesis after small interfering RNA-mediated reduction in either PGC-1α or CREB expression, confirming that these transcription factors are obligate mediators of PQQ's mitochondriogenic effect. Consistent with activation of the PGC-1α pathway, PQQ increased nuclear respiratory factor activation (NRF-1 and NRF-2) and Tfam, TFB1M, and TFB2M mRNA expression.
The ability of PQQ to stimulate mitochondrial biogenesis accounts in part for its action and suggests that PQQ may be beneficial in diseases associated with mitochondrial dysfunction. It must be noted that this mechanistic work derives primarily from in vitro cell culture and rodent studies; direct confirmation of robust mitochondrial biogenesis in supplemented humans is limited.
3.3 Cell Signaling Pathways
A small amount of hydrogen peroxide is generated in the PQQ conversion process, which causes the oxidation of protein thiols. This results in the inhibition of protein tyrosine phosphatase 1B (PTP1B), a direct negative regulator of insulin receptors, insulin-like receptors, epidermal growth factor receptors (EGFR), and nerve growth factor receptors. Inhibition of PTP1B by PQQ causes a ligand-independent activation of insulin receptors and EGFRs, suggesting that PQQ may function as a growth factor.
PQQ has been reported to depress NMDA-induced electrical responses and is neuroprotective in vitro against NMDA-mediated neurotoxic injury. Combined with other studies, PQQ has been shown to regulate several intracellular signaling pathways, including Ras-related ERK1/2 activation, CREB-dependent mitochondriogenesis, and JAK/STAT activation.
PQQ also stimulates enzyme activities, such as glutathione peroxidase and glutathione reductase, and prevents lipid peroxidation of human serum. Pyrroloquinoline quinone disodium salt (PQQ-Na₂) protects cells from oxidative damage and increases the mitochondrial membrane potential, which is essential for the production of ATP.
3.4 Bacterial Cofactor Role
PQQ is a redox cofactor utilized by a number of prokaryotic dehydrogenases. Redox reactions are essential to PQQ given their quinone structure. PQQ can be reduced by various substances and converted back to its oxidized state by oxygen. This reaction describes how PQQ functions as the active site of glucose dehydrogenase and can be used as a glucose sensor to manage diabetes. In 2016, PQQ was reported to be a new mammalian lactate dehydrogenase (LDH) coenzyme.
3.5 Anti-Inflammatory Mechanisms
PQQ is associated with biological processes such as mitochondriogenesis, reproduction, growth, and aging, and attenuates clinically relevant dysfunctions such as those associated with ischemia, inflammation, and lipotoxicity. At the molecular level, in animal studies, PQQ has been shown to inhibit neuroinflammatory signaling. In cell and rodent models, these anti-inflammatory effects have been attributed to downregulation of NF-κB and p38/JNK pathways, though this work has not been confirmed in controlled human trials.
4. Scientific Evidence by Health Area
4.1 Cognitive Function and Brain Health
Evidence strength: Moderate for some cognitive parameters (short-term); limited by small sample sizes and few independent replications.
In the field of cognitive function, double-blind, placebo-controlled trials have been conducted. Various improvements have been reported regarding general memory, verbal memory, working memory, and attention.
A key 2023 study published in Food & Function (RSC Publishing) examined PQQ's effects across a wider age range than prior trials. In this double-blind, placebo-controlled study, the effects of PQQ on cognitive function were investigated in adults aged between 20 and 65 years. PQQ (20 mg per day) was administered for 12 weeks to the participants. After 12 weeks, the participants showed improvements in composite memory and verbal memory. A further age-stratified analysis was performed. In younger adults (aged 20–40 years), PQQ improved cognitive function (cognitive flexibility, processing speed, and execution speed) after 8 weeks. Only older adults (aged 41–65 years) showed improvements in complex and verbal memory after 12 weeks.
A stratified analysis of a population with a wide range of ages revealed unique effects in young people (20–40 years old) that were not observed in older adults (41–65 years old). Specifically, cognitive flexibility and executive speed improved more rapidly in young people at 8 weeks.
A further clinical investigation by Koikeda et al. (2011), described in published literature, used a placebo-controlled, double-blind, three-group parallel design. Subjects took PQQ alone, PQQ with CoQ10, or placebo for 24 weeks. They were evaluated using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Co-administration of PQQ and coenzyme Q10 further enhanced these cognitive effects.
A 2024 randomized controlled trial examined the combination of dihydrogen and PQQ in a more vulnerable population. Thirty-four elderly individuals with mild cognitive impairment (mean age 71.9 ± 3.8 years; 28 females) were assigned in a double-blind parallel-group design to receive either a dihydrogen-PQQ mixture or placebo twice daily for a 6-week intervention period. Dihydrogen-PQQ resulted in a significant elevation in serum BDNF levels at the six-week follow-up (P = 0.01); conversely, no changes in BDNF levels were observed in the placebo group. A significant interaction effect was observed for the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) scores in the orientation domain (P = 0.03), indicating the superiority of dihydrogen-PQQ over placebo. A limitation of this trial is that PQQ was co-administered with dihydrogen-producing minerals, making it difficult to attribute effects solely to PQQ.
Prior trials involved only elderly individuals, targeting people over 45 years of age. Therefore, the effects of PQQ on young people had remained largely elusive until the 2023 study was conducted. Overall, while the clinical evidence points toward modest, real effects on certain cognitive parameters, human trials remain few in number, generally small in scale, and not yet independently replicated by groups unconnected to the ingredient's commercial developers.
4.2 Oxidative Stress and Antioxidant Activity in Humans
Evidence strength: Preliminary; supported by one small crossover human study and consistent animal/mechanistic data.
Harris et al. (2013) published the first study directly linking PQQ effects in animals to human subjects. Using a crossover study design, 10 subjects (5 females, 5 males) ingested PQQ added to a fruit-flavored drink in two separate studies. In Study 1, PQQ was given in a single dose (0.2 mg PQQ/kg). Multiple measurements of plasma and urine PQQ levels and changes in antioxidant potential were made throughout the period of 48 hours. In Study 2, PQQ was administered as a daily dose (0.3 mg PQQ/kg). After 76 hours, measurements included indices of inflammation. The standard clinical indices were normal and not altered by PQQ supplementation. However, dietary PQQ exposure (Study 1) resulted in apparent changes in antioxidant potential based on malonaldehyde-related TBAR assessments. In Study 2, PQQ supplementation resulted in significant decreases in the levels of plasma C-reactive protein, IL-6, and urinary methylated amines such as trimethylamine N-oxide, and changes in urinary metabolites consistent with enhanced mitochondria-related functions. PQQ ingestion lowers blood lipid peroxide levels in humans, suggesting antioxidant activity. The crossover design and very small sample size (n=10) are significant limitations of this study.
4.3 Sleep and Mood
Evidence strength: Very preliminary; open-label data only.
In an open-label trial, PQQ was shown to improve sleep and mood. Open-label trials lack placebo controls and are highly susceptible to bias; this finding requires confirmation in randomized controlled trials before conclusions can be drawn.
4.4 Cardiovascular Protection
Evidence strength: Preclinical only in humans; mechanistic and animal evidence is substantial.
The potential role of PQQ in cardiovascular health is evidenced by studies which indicate its ability to modulate endothelial function, mitigate inflammation, and provide protection against ischemic injury. Non-toxic dosages of PQQ drugs have been found useful as cardioprotective agents, potentially valuable in the treatment of various heart-related conditions such as ischemia-reperfusion injury, congestive heart failure, cardiac arrest, and myocardial infarction. PQQ has been found to modulate cardioprotective signaling pathways such as the regulation of the mitochondrial channel mitoKATP, the nitric oxide-protein kinase C pathway, and the angiotensin-converting enzyme pathway. These findings are based on animal and patent literature; well-controlled clinical trials in human cardiac populations have not been reported in peer-reviewed literature as of the time of this writing.
4.5 Neuroprotection
Evidence strength: Preclinical/mechanistic; limited human translation data.
Given its potent antioxidant properties, including free radical scavenging and reduction of oxidative stress, PQQ holds promise for potential applications in both the treatment and prevention of aging-associated neurodegenerative diseases. The expression of superoxide dismutase 2 (SOD-2) at the transcriptional level was significantly improved by exposure to PQQ. By binding with excess glutamate, PQQ may alleviate memory impairments and neurotoxicity caused by D-galactose. PQQ is a potent neuroprotective nutrient against 6-hydroxydopamine-induced neurotoxicity, methyl mercury-induced neurotoxicity, and N-methyl-D-aspartate-mediated neurotoxicity in preclinical models. Translation of these findings into human therapeutic contexts has not yet been established through large-scale clinical trials.
4.6 Mitochondrial Function, Energy Metabolism, and Obesity
Evidence strength: Preclinical (animal/cell); limited direct human metabolic trial data.
The potential health benefits of PQQ have been studied considering its antioxidant and anti-inflammatory properties. Furthermore, PQQ has been demonstrated to significantly influence the functions of mitochondria, the organelles responsible for energy production within cells, and their dysfunction is associated with various health conditions, including obesity complications. The absence of PQQ in diets produces a response like a vitamin-related deficiency, with recovery upon PQQ repletion in a dose-dependent manner. PQQ deficiency results in a wide variety of systemic responses, including compromised immune function, growth impairment, and abnormal reproductive performance in mice and rats. Human metabolic studies examining these endpoints specifically are limited and mostly confined to a small exploratory crossover study (Harris et al., 2013, described above).
4.7 Skin Health
Evidence strength: Preliminary human observation; requires replication.
PQQ was found to suppress skin moisture loss and increase PGC-1α expression in an observational study context, suggesting potential relevance to skin barrier function. The mechanistic link via PGC-1α is consistent with PQQ's mitochondrial effects, but the clinical evidence base is sparse.
5. Body Systems and Health Areas Associated with PQQ
- Central Nervous System: PQQ has redox properties and exerts antioxidant, neuroprotective, and mitochondrial biogenesis effects. Clinical evidence supports modest improvements in select cognitive parameters.
- Mitochondrial / Cellular Energy System: PQQ functions as a redox cofactor involved in cellular energy production and is known for its role in supporting mitochondrial function, brain health, and cellular longevity.
- Immune System: PQQ is vital for mammals, playing a crucial role in enhancing immune function.
- Cardiovascular System: Preclinical evidence for cardioprotection and anti-ischemic effects, mediated by mitochondrial and redox pathways.
- Endocrine/Metabolic System: PQQ has shown potential health benefits owing to its growth-promoting, anti-diabetic, anti-obesity, and neuroprotective functions. These findings are based largely on animal data.
- Reproductive System: PQQ is associated with biological processes such as mitochondriogenesis, reproduction, growth, and aging. Animal deficiency models show abnormal reproductive performance.
- Skin: Preliminary human evidence for effects on skin moisture retention and PGC-1α-mediated activity.
6. Dosage Forms and Dosages Reported in Studies
Clinical trials in humans have generally used PQQ doses ranging from 10 mg to 20 mg per day. The following specific dosages are reported in the cited literature:
- 20 mg per day for 12 weeks (double-blind, placebo-controlled cognitive trial in adults aged 20–65 years).
- Single dose of 0.2 mg PQQ/kg (Study 1) and daily dose of 0.3 mg PQQ/kg (Study 2), administered in a fruit-flavored drink in a crossover human metabolic study of 10 subjects.
- PQQ alone or PQQ with CoQ10 taken for 24 weeks in a placebo-controlled, double-blind trial of older adults with memory concerns (Koikeda et al., 2011).
- Twelve clinical studies were conducted on PQQ with doses up to 100 mg/day for up to 24 weeks, and these studies did not raise safety concerns, according to the EFSA Panel assessment.
- The applicant for EFSA novel food authorization intended to market PQQ at a maximum proposed level of consumption of 20 mg/day (corresponding to 0.29 mg/kg bw per day for a 70-kg person).
- The baseline intake level of PQQ considered for supplementation is 20 mg/day.
- In a registered clinical trial of non-endurance-trained athletes, the PQQ content per capsule was 10 mg, and the indication was to take two capsules every evening for 6 weeks (20 mg/day total).
In both humans and animal models, endogenous PQQ concentrations in biological fluids and tissues typically range from 3 to 54 nM, depending on dietary intake, tissue type, and physiological conditions. The proposed supplemental level of consumption (20 mg/day) is at least 250 times higher than the estimated background intake of PQQ occurring naturally in foods.
7. Safety, Toxicology, and Notable Considerations
7.1 Regulatory Safety Status
Pyrroloquinoline quinone disodium salt (PQQ) was approved as a new food ingredient by FDA in 2008. It is now also approved as a food in Japan and the EU. In 2012, Health Canada approved PQQ as a natural health food. In accordance with Regulation (EU) 2015/2283, the European Commission amended the annex to apply pyrroloquinoline quinone sodium salts to dietary supplements for adults, excluding pregnant and lactating women. The maximum dosage is 20 mg/day.
7.2 Toxicological Studies and NOAEL
The no-observed-adverse-effect-level (NOAEL) of 100 mg/kg bw per day was established from a 90-day repeated dose oral toxicity study with BioPQQ™. The margin of exposure relative to the proposed 20 mg/day human supplemental dose is 344. The EFSA Panel concludes that the novel food, pyrroloquinoline quinone disodium salt (BioPQQ™), is safe under the intended conditions of use as specified by the applicant.
A 14-day dose-range finding study, a 90-day repeated-dose toxicity study, and a 28-day renal toxicity study have been conducted in rats using BioPQQ™. A 90-day repeated-dose toxicity study was also conducted using a PQQ product from another manufacturer with 98% purity.
7.3 Genotoxicity
An in vitro bacterial reverse mutation assay, three in vitro chromosomal aberration tests, and one in vivo micronucleus test were conducted with PQQ. Based on these studies, the Panel concludes that there is no concern with regard to potential genotoxicity of PQQ. PQQ disodium was concluded to have no genotoxic activity in vivo. The weak responses in the in vitro test in CHL cells were considered of little relevance under conditions of likely human exposure.
7.4 Pro-Oxidant Potential
PQQ exhibits context-dependent redox behavior. In vitro evidence at high concentrations shows pro-oxidant activity through hydrogen peroxide generation. However, given the low plasma concentrations reached at the proposed use levels (i.e., nM), the EFSA Panel does not consider that there is a safety concern with respect to a pro-oxidant activity of the novel food. It was highlighted that the antioxidant–pro-oxidant functions are greatly dose-dependent and the antioxidant–pro-oxidant system is in a very sensitive balance.
7.5 Renal Considerations
Functional and morphologic changes of kidneys were observed when PQQ was intraperitoneally injected into rats at a dose of 11.5 mg/kg (Watanabe et al., 1989). This observation was obtained via an intraperitoneal route—not the oral route used in humans—and at doses considerably higher than supplemental use levels. Twelve clinical studies conducted by the applicant do not raise safety concerns. The EFSA Panel notes, however, that these studies were not designed to assess renal function and are of limited value for the safety assessment. EFSA identified renal function monitoring as a gap in the safety dossier and recommended further long-term chronic and carcinogenicity studies.
7.6 Populations Excluded from Regulatory Approval
The intended use is for food supplements for healthy adults, except pregnant and lactating women. Food supplements containing PQQ are not intended for use by children. These exclusions are based on absence of data rather than demonstrated harm.
7.7 Absorption, Distribution, and Metabolism
Information on the absorption, distribution, metabolism, and excretion of PQQ in animals and humans is limited. Information on the absorption, distribution, metabolism, and excretion of PQQ in animals and humans is limited. This is an explicitly recognized data gap by both EFSA and FDA reviewers. Since PQQ levels in human tissues and body fluids are 5–10 times lower than those found in foods, it is probable that PQQ existing in human tissues is derived, at least partly, from the diet.
7.8 Potential for Long-Term Chronic Use Data Gaps
Considering the low background intake of PQQ in comparison with the proposed intake of the highly purified compound via food supplements and the possible long-term consumption of such food supplements by some consumers, a full toxicological assessment, including studies aimed at examining potential chronic toxicity and carcinogenicity, was considered necessary by EFSA reviewers. This remains an ongoing data gap in the compound's regulatory file as of the most recent publicly available assessments.
References
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