PQQ

• Mitochondrial biogenesis
• Neuroprotection
• Antioxidant defense
• Cellular energy production

• Cognitive function
• Cardiovascular health
• Anti-inflammatory effects
• Sleep quality
• Metabolic health
• Stress resistance

Pyrroloquinoline quinone (PQQ) exerts its biological effects through multiple interconnected mechanisms. As a redox cofactor, PQQ can undergo thousands of redox cycles before being degraded, allowing it to participate repeatedly in electron transfer reactions and neutralize reactive oxygen species (ROS). This potent antioxidant capacity exceeds that of many traditional antioxidants, with PQQ demonstrating 100-1000 times greater efficiency than vitamin C in some experimental models. One of PQQ’s most significant effects is stimulating mitochondrial biogenesis—the creation of new mitochondria within cells.

PQQ activates the PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha) pathway, a master regulator of mitochondrial biogenesis. This activation occurs through multiple mechanisms, including the phosphorylation of CREB (cAMP response element-binding protein) and the activation of the NAD-dependent deacetylase sirtuin-1 (SIRT1). The increased expression of PGC-1α leads to enhanced expression of nuclear respiratory factors (NRF-1 and NRF-2) and mitochondrial transcription factor A (TFAM), which coordinate the expression of nuclear and mitochondrial genes essential for mitochondrial replication and function. PQQ also interacts with signaling proteins involved in cellular growth and differentiation.

It activates DJ-1 (PARK7), a protein that protects neurons against oxidative stress and cell death. Additionally, PQQ modulates the PINK1/Parkin pathway, which is crucial for mitochondrial quality control through the process of mitophagy—the selective degradation of damaged mitochondria. In the nervous system, PQQ enhances nerve growth factor (NGF) production and protects neurons from excitotoxicity by modulating NMDA receptor activity. It also increases production of brain-derived neurotrophic factor (BDNF), supporting neuronal survival, differentiation, and plasticity.

PQQ influences energy metabolism by enhancing the efficiency of the electron transport chain and potentially acting as an alternative electron carrier. It may also interact with quinoproteins—proteins that use PQQ as a cofactor—though the significance of this in mammals remains under investigation. In the cardiovascular system, PQQ reduces inflammation and oxidative stress in vascular endothelial cells, potentially improving endothelial function and reducing atherosclerosis risk. It also appears to protect cardiac cells from ischemia-reperfusion injury.

PQQ modulates immune function by reducing pro-inflammatory cytokine production through inhibition of the NF-κB pathway. It also enhances macrophage function and may influence adaptive immune responses. At the epigenetic level, PQQ may influence DNA methylation patterns and histone modifications, potentially explaining some of its long-term effects on gene expression. Additionally, PQQ interacts with mitochondrial sirtuins, particularly SIRT3, enhancing their activity and promoting mitochondrial health and cellular longevity.

Recent research suggests PQQ may also influence the gut microbiome composition, potentially contributing to its systemic effects on metabolism and inflammation. Finally, PQQ appears to enhance cellular resistance to various stressors, including oxidative stress, metabolic stress, and environmental toxins, contributing to its potential role in promoting cellular resilience and longevity.

Typical supplemental dosage ranges from 10-20 mg per day. Most clinical studies showing benefits have used doses in this range. For general health maintenance and antioxidant support, 10 mg daily is often recommended. Higher doses of 20 mg daily have been used in studies focusing on cognitive function and mitochondrial biogenesis.

Pyrroloquinoline quinone (PQQ) demonstrates moderate oral bioavailability, with studies suggesting approximately 20-30% of an oral dose is absorbed in the gastrointestinal tract. The disodium salt form (PQQ-Na2), which is most commonly used in supplements, shows improved stability and bioavailability compared to the free form. Peak plasma concentrations are typically reached within 2-3 hours after oral administration, with a plasma half-life of approximately 3-5 hours.

Taking with a meal containing some fat may enhance absorption, Liposomal formulations may increase cellular uptake and bioavailability, PQQ disodium salt form offers better stability and absorption than free PQQ, Micronized formulations may provide greater surface area for absorption, Enteric-coated formulations may protect from stomach acid degradation, Formulations with phospholipids may enhance cellular delivery, Combining with CoQ10 may provide synergistic effects on mitochondrial function, Dividing larger doses (>20 mg) may improve overall absorption, Avoiding high doses of competing antioxidants simultaneously may prevent potential interference

PQQ can be taken at any time of day, though some anecdotal reports suggest taking it in the morning or early afternoon may be optimal for most people. This timing allows its energy-enhancing effects to manifest during waking hours without potentially interfering with sleep. For those using PQQ specifically to support sleep quality, taking it approximately 2-3 hours before bedtime may be beneficial, as some studies suggest it may improve sleep quality. Taking PQQ with a meal containing some fat may enhance absorption due to its moderate fat solubility, though it can also be taken on an empty stomach if well-tolerated.

For maximum mitochondrial support, consistent daily use is more important than specific timing, as the effects on mitochondrial biogenesis develop gradually over weeks of regular supplementation. Some users report combining PQQ with CoQ10 taken at the same time for synergistic effects on mitochondrial function, though research specifically on timing of this combination is limited. For individuals using PQQ for cognitive enhancement, morning administration may align peak blood levels with periods of mental demand. PQQ does not appear to interact significantly with most medications, but as a general precaution, separating PQQ intake from medication administration by 1-2 hours may be advisable when starting a new medication regimen.

The effects of PQQ on mitochondrial biogenesis and function are cumulative and typically require consistent supplementation for 8-12 weeks to reach maximum benefit, making adherence to a regular schedule more important than specific timing within the day.

• Headache (uncommon)
• Fatigue (rare)
• Gastrointestinal discomfort (rare)
• Insomnia (rare, particularly when taken late in the day)
• Increased energy or mild stimulation (can be considered a benefit or side effect)
• Skin rash or allergic reactions (very rare)
• Dizziness (very rare)
• Nausea (very rare)

• Known hypersensitivity to PQQ
• Pregnancy and lactation (due to insufficient safety data)
• Children under 18 years (insufficient safety data)
• Scheduled for surgery within two weeks (theoretical concern, consult physician)
• Severe liver or kidney disease (use with caution due to limited research)
• Autoimmune conditions (theoretical concern due to immune-modulating effects, though clinical significance is unclear)
• Use of immunosuppressive medications (theoretical concern, consult healthcare provider)

• Immunosuppressive medications (theoretical concern due to PQQ’s potential immune-modulating effects)
• Blood thinners (theoretical concern, though no clinical evidence of significant interaction)
• Stimulant medications (potential additive effects on energy levels)
• Medications metabolized by cytochrome P450 enzymes (theoretical concern, though specific interactions not well-documented)
• Sleep medications (PQQ may counteract sedative effects in some individuals)
• Antipsychotic medications (theoretical concern due to PQQ’s effects on dopaminergic systems)
• Diabetes medications (monitor blood glucose, as PQQ may affect glucose metabolism)

No official upper limit has been established for PQQ. Clinical studies have typically used doses up to 20-40 mg per day without serious adverse effects. A 90-day toxicity study in rats established a No Observed Adverse Effect Level (NOAEL) of 100 mg/kg/day, which would translate to a much higher dose than typically used in humans. Based on available research, doses up to 20 mg daily appear to be well-tolerated in most adults.

Higher doses (30-50 mg) have been used in some research settings without reported serious adverse effects, but long-term safety data at these doses is limited. As with any supplement, starting with lower doses and gradually increasing can help identify individual tolerance and optimal dosage. Given the potent effects on mitochondrial function and cellular signaling, conservative dosing is recommended until more long-term human safety data becomes available.

In the United States, PQQ is regulated as a dietary ingredient under the Dietary Supplement Health and Education Act (DSHEA) of 1994. The most common commercial form, BioPQQ® (produced by Mitsubishi Gas Chemical), received self-affirmed GRAS (Generally Recognized as Safe) status in 2008, which was acknowledged by the FDA in 2012. This allows its use in both dietary supplements and conventional foods. As a dietary supplement ingredient, PQQ does not require pre-market approval from the FDA, but manufacturers must ensure the product is safe and that any claims made are not misleading.

The FDA has not approved any specific health claims for PQQ. Manufacturers are limited to making structure/function claims (e.g., ‘supports mitochondrial health’) rather than disease claims (e.g., ‘treats neurodegenerative disease’). PQQ is subject to FDA’s current Good Manufacturing Practices (cGMP) regulations for dietary supplements.

Japan: In Japan, where much of the early research on PQQ was conducted, it is approved as a food additive and dietary supplement ingredient. The Japanese Ministry of Health, Labour and Welfare has recognized PQQ as safe for use in foods and supplements. BioPQQ® received approval from the Japanese Ministry of Health and Welfare in 2007. Japan has been at the forefront of PQQ research and commercial applications.

Eu: In the European Union, PQQ has been approved as a Novel Food ingredient under Regulation (EU) 2015/2283. The European Food Safety Authority (EFSA) evaluated the safety of PQQ disodium salt in 2017 and concluded it was safe for use in food supplements for adults at doses up to 20 mg/day. No approved health claims exist for PQQ under the EU Nutrition and Health Claims Regulation. Some member states may have additional regulations regarding its use.

Canada: Health Canada has approved PQQ as a Natural Health Product (NHP) ingredient. It has been issued a Natural Product Number (NPN) and can be legally sold with appropriate claims related to antioxidant support and mitochondrial function. Health Canada permits doses up to 20 mg per day for adults.

Australia: The Therapeutic Goods Administration (TGA) regulates PQQ as a complementary medicine ingredient in Australia. It is listed in the Australian Register of Therapeutic Goods (ARTG) and can be legally sold with appropriate listing. The TGA permits limited claims related to antioxidant support when supported by evidence.

China: The China Food and Drug Administration (CFDA) has approved certain forms of PQQ for use in health food products. Registration requirements are stringent, and approval is product-specific rather than ingredient-wide.

South Korea: The Korean Ministry of Food and Drug Safety (MFDS) has approved PQQ as a functional ingredient for use in health functional foods, particularly for antioxidant effects.

High. PQQ is among the more expensive dietary supplements on the market, particularly when using the clinically-studied BioPQQ® form at effective doses.

BioPQQ® branded supplements (10 mg): $1.00-2.00 per day. BioPQQ® branded supplements (20 mg): $2.00-4.00 per day. Generic or unbranded PQQ supplements (10 mg): $0.70-1.50 per day. Generic or unbranded PQQ supplements (20 mg): $1.40-3.00 per day. PQQ combined with CoQ10: $2.00-5.00 per day, depending on dosages of both compounds. Bulk PQQ powder (rare): $1.00-2.00 per day, but requires precise measurement equipment.

When evaluating the cost-effectiveness of PQQ supplementation, several factors should be considered beyond the simple price per milligram. The form and quality of PQQ significantly impact both price and value. BioPQQ®, the branded form used in most clinical studies, typically commands a premium price but offers greater assurance of quality, purity, and efficacy compared to generic forms. This may justify the higher cost for those seeking evidence-based benefits.

The effective dose for different applications varies, affecting the overall cost. For general antioxidant support, lower doses (10 mg daily) may be sufficient, while mitochondrial biogenesis and cognitive benefits typically require higher doses (20 mg daily) based on clinical studies. This higher dosage doubles the daily cost. PQQ’s effects on mitochondrial biogenesis appear to be cumulative and long-lasting, with some research suggesting that new mitochondria remain after PQQ supplementation is discontinued.

This potential for persistent benefits may improve the long-term value proposition despite the higher upfront cost. For individuals with specific health concerns related to mitochondrial function, energy production, or cognitive health, the potential quality-of-life improvements may justify the premium cost compared to many other supplements with less specific mechanisms of action. Combination products containing both PQQ and CoQ10 may offer better overall value than taking each supplement separately, as these compounds work synergistically to support mitochondrial function. However, verify that such products contain effective doses of each ingredient.

The stability and bioavailability of different PQQ formulations can affect their real-world value. Higher-quality forms with better stability and absorption may provide more consistent benefits, potentially justifying their higher cost. When comparing PQQ supplements, calculating the cost per effective dose rather than simply the cost per capsule provides a more accurate value assessment, as concentration can vary significantly between products. For preventive use in healthy individuals, the value proposition is more subjective and depends on individual health priorities and budget constraints.

The relatively high cost makes PQQ a significant investment compared to many basic supplements. For those on limited budgets who are interested in mitochondrial support, other less expensive options (like CoQ10 alone) might provide better initial value, with PQQ reserved for more targeted needs or added later to a supplement regimen.

PQQ in its disodium salt form (PQQ-Na2, the most common supplement form) is relatively stable, with a typical shelf life of 2-3 years when properly stored. The free acid form of PQQ is less stable and more susceptible to degradation. Commercial supplements typically have an expiration date of 2-3 years from the manufacturing date, depending on the formulation and packaging. Stability studies have shown minimal degradation under recommended storage conditions during this timeframe.

Store in a cool, dry place away from direct sunlight and excessive heat. Temperatures between 15-25°C (59-77°F) are optimal for maintaining stability. Keep containers tightly sealed to prevent moisture absorption, as PQQ can be sensitive to humidity. While refrigeration is not necessary for most formulations, it may extend shelf life in hot and humid climates.

Avoid storing in bathrooms or other areas with high humidity and temperature fluctuations. Blister-packed formulations may offer better protection against environmental factors than bottles. For powder formulations, ensure the container is tightly sealed after each use to prevent moisture absorption. Some manufacturers use oxygen absorbers or desiccants in packaging to enhance stability; these should be kept in the container but not consumed.

If transferring from original packaging, amber glass containers provide better protection from light than clear containers. PQQ is generally more stable in its disodium salt form than as the free acid, which is why most supplements use the salt form.

Exposure to high humidity (accelerates hydrolysis), Prolonged exposure to high temperatures (above 30°C/86°F), Direct sunlight or UV radiation, Oxidation (exposure to air over extended periods), Extreme pH conditions (highly acidic or alkaline environments), Microbial contamination, Presence of metal ions (particularly iron and copper, which can catalyze oxidation), Repeated freeze-thaw cycles, Exposure to strong oxidizing agents, Prolonged exposure to water (hydrolysis)

Synthesis Methods

Natural Sources

Quality Considerations

Pyrroloquinoline quinone (PQQ) has a relatively short history as a supplement compared to many traditional nutrients, as it was only discovered in 1979. The story of PQQ begins with its identification as a novel cofactor in bacterial dehydrogenases by C. Anthony and L.J. Zatman, who found this unique molecule while studying methanol dehydrogenase in methylotrophic bacteria.

Initially called methoxatin, the compound was later renamed pyrroloquinoline quinone to reflect its chemical structure. Following its discovery, research in the 1980s established PQQ as an essential cofactor for several bacterial enzymes, particularly those involved in the metabolism of alcohols and sugars. During this period, PQQ was classified as a member of the quinone family, related to other redox cofactors like ubiquinone (CoQ10) but with a unique structure and properties. A significant controversy emerged in the 1990s regarding PQQ’s status as a vitamin.

In 1989, researchers reported that PQQ appeared to be an essential nutrient for mice, with deficiency leading to impaired growth, compromised immune function, and reduced reproductive capability. This led to proposals that PQQ should be classified as a B vitamin. However, subsequent research failed to consistently replicate these findings, and the vitamin designation was withdrawn. Despite this setback, research on PQQ’s biological effects continued, with studies in the early 2000s revealing its potent antioxidant properties and effects on cellular signaling.

A breakthrough came in 2010 when researchers at the University of California, Davis, demonstrated that PQQ could stimulate mitochondrial biogenesis through activation of the PGC-1α pathway, a finding that significantly increased scientific and commercial interest in the compound. The first commercial PQQ supplement (BioPQQ®) was developed by Mitsubishi Gas Chemical Company in Japan and introduced to the market in the early 2000s. This proprietary form of PQQ disodium salt received GRAS (Generally Recognized as Safe) status from the FDA in 2008, paving the way for its use in dietary supplements and functional foods in the United States. The first human clinical trials with PQQ supplements began appearing in the scientific literature around 2007-2009, primarily conducted in Japan.

These studies investigated PQQ’s effects on stress, fatigue, sleep quality, and cognitive function. By the 2010s, PQQ had gained popularity in the supplement market, particularly in formulations targeting mitochondrial health, cognitive function, and anti-aging. It began appearing in combination products, especially with CoQ10, based on their complementary effects on mitochondrial function. In recent years, research has expanded to explore PQQ’s potential applications in various health conditions, including neurodegenerative diseases, cardiovascular health, and metabolic disorders.

While not as extensively studied as some longer-established supplements, the scientific literature on PQQ continues to grow, with increasing interest in its mechanisms of action and potential therapeutic applications.

Akagawa M, Nakano M, Ikemoto K. Recent progress in studies on the health benefits of pyrroloquinoline quinone. Biosci Biotechnol Biochem. 2016;80(1):13-22., Rucker R, Chowanadisai W, Nakano M. Potential physiological importance of pyrroloquinoline quinone. Altern Med Rev. 2009;14(3):268-277., Jonscher KR, Stewart MS, Alfonso-Garcia A, et al. Early PQQ supplementation has persistent long-term protective effects on developmental programming of hepatic lipotoxicity and inflammation in obese mice. FASEB J. 2017;31(4):1434-1448., Zhang Q, Zhou J, Shen M, et al. Pyrroloquinoline quinone inhibits rotenone-induced microglia inflammation by enhancing autophagy. Mol Neurobiol. 2020;57(5):2475-2489., Xu F, Yu H, Liu J, Cheng L. Pyrroloquinoline quinone disodium salt improves brain function in patients with mild cognitive impairment: a double-blind, randomized, controlled study. Front Aging Neurosci. 2021;13:650031.

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