IngredientsPyridoxal alpha-ketoglutarate represents a unique combination of pyridoxal (the active aldehyde form of vitamin B6) and alpha-ketoglutarate (a key intermediate in the Krebs cycle). The compound is also found in the scientific literature under the name pyridoxine alpha-ketoglutarate (reflecting broader usage of the term "pyridoxine" to denote the B6 family) and is widely abbreviated as PAK. Synonyms encountered in the literature and product labeling include: pyridoxal alphaketoglutarate, pyridoxal-alpha-ketoglutarate, and pyridoxine-alpha-ketoglutarate (PAK).
Vitamin B6 is composed of three compounds — pyridoxine, pyridoxal, and pyridoxamine — where pyridoxine contains a methylhydroxyl group (–CH₃OH), pyridoxal an aldehyde (–CHO), and pyridoxamine an aminomethyl group (–CH₃NH₂). The phosphorylated forms can be interconverted to the active, or the cofactor form of vitamin B6, pyridoxal phosphate (PLP). In the context of PAK, the "pyridoxal" component specifically refers to this aldehyde B6 vitamer, the direct precursor to PLP.
Alpha-ketoglutarate (AKG) is a molecule that has a central role in the Krebs cycle, determining the overall rate of the citric acid cycle of the organism, and is also a nitrogen scavenger in the body. Alpha-ketoglutarate is an intermediate metabolite in the tricarboxylic acid cycle and transamination of amino acids, which is generated from isocitrate via isocitrate dehydrogenase and amino acids metabolism.
PAK and its derivatives correspond to a molecular formula in which X may be a hydrogen atom or an alkali metal or alkaline-earth metal, or an organic base. According to German patent application DE-OS No. 1,958,226 of 1969, PAK and its derivatives are therapeutically useful drugs, since they combine within a single molecule both the pyridoxine and alpha-ketoglutarate, resulting in the increase of the useful activities of these two compounds and in the reduction, in certain cases, of the toxicity thereof.
Common commercial preparations of PAK include:
One patented application provides compositions having synergistic effects by administration of L-glutamine in conjunction with pyridoxal-alpha-ketoglutarate (PAK), with compositions containing PAK:L-glutamine at a ratio (w/w) of from 1:1 to 1:10 proposed as effective for providing beneficial effects of L-glutamine at nontoxic levels.
PAK as a single, pre-formed molecular entity is not found naturally in significant amounts in foods. Rather, its two constituent components occur naturally and abundantly in living organisms:
AKG is one of the nutritional ingredients in sports drinks, and a component of liver function test kits. Its use as a supplement precedes the emergence of PAK as a distinct combination compound, and AKG salts — notably the calcium (CaAKG), ornithine (OKG), and arginine salts (AAKG) — are widely encountered independently.
PAK as a defined compound does not have a documented history of use in classical herbal or folk medicine traditions, as it is a synthetic salt created by combining two metabolic intermediates. Its history is therefore primarily one of pharmaceutical and nutritional research rather than traditional botanical or ethnopharmacological use. The historical record that does exist is rooted in the mid-to-late 20th century:
The component molecules have deeper histories. Pyridoxal, as vitamin B6, has long been celebrated for its role in amino acid metabolism, neurotransmitter synthesis, and immune function support. Alpha-ketoglutarate has been recognized for its central role in cellular energy production and as a nitrogen scavenger, supporting detoxification and healthy metabolic processes. Clinical investigation of PAK specifically as a liver-protecting and lactate-reducing agent in hospital patients with cirrhosis dates primarily to the early 1980s in Italy, and exercise physiology researchers at the University of Geneva evaluated the compound in the same period.
Pyridoxal-5-phosphate (PLP), the active component of vitamin B6, functions as a coenzyme in approximately 150 different enzymatic reactions, primarily involved in the processing of carbohydrates, lipids, and proteins, in addition to participating in neural functions that are modulated by the synthesis and degradation of vitamin B6.
The PLP molecule serves as a mediator by inhibiting the formation of reactive oxygen species (ROS), and it impedes the generation of advanced glycation end products (AGEs), which are believed to be linked to aging and diabetes and are known to possess genotoxic properties.
The body uses vitamin B6 in numerous enzymatic reactions, including neurotransmitter production, amino acid metabolism, glucose metabolism, lipid metabolism, hemoglobin synthesis and function, and gene expression.
AKG can be rapidly converted into glutamate through transamination by glutamate dehydrogenase, and further into glutamine through amination by glutamine synthase. This conversion is central to its role as a nitrogen scavenger — AKG can accept and detoxify excess nitrogen (including ammonia), converting it into glutamate and ultimately glutamine.
AKG has a great effect on suppressing the production of oxygen free radicals and preventing peroxidative damage of lipids by participating in nonenzymatic oxidative decarboxylation during the decomposition of hydrogen peroxide.
Dietary supplementation with AKG improves energy status by modulating the AMP-activated protein kinase (AMPK) signaling pathway in the small intestine.
Collectively, evidence from Drosophila studies indicates that AKG extends lifespan by activating AMPK signaling and inhibiting the mTOR pathway.
The reaction in which the nitrogen group from an amino acid is transferred to alpha-ketoglutarate is accomplished by PLP-dependent enzymes called transaminases. This biochemical intimacy — pyridoxal/PLP acting as the coenzyme for transaminases that operate on alpha-ketoglutarate as the nitrogen acceptor — provides a strong theoretical basis for combining the two molecules. When bound as a salt, PAK may deliver both reaction partners to the same enzymatic site simultaneously.
The increase in VO₂ max and the corresponding decrease in blood lactate are not found after separate administration of either of the components of the complex — a finding from a published clinical study suggesting that the combined molecule may have pharmacological properties distinct from the sum of its parts, although this requires corroboration.
AKG has potent effects in inhibiting the NF-κB-mediated inflammatory pathway, suppressing TNF-α, and in regulating PXR and its downstream targets (CYP3As and CYP2Bs) in vivo and in vitro.
This is the area with the strongest and most specific clinical evidence for the PAK compound as a single entity.
Cirrhosis and ammonia: Administration of PAK to patients with hepatic cirrhosis significantly reduced hyperammonaemia and plasma levels of pyruvic and lactic acid. No significant changes in glycaemia were found. PAK treatment increased plasma levels of glutamic acid and decreased plasma levels of glutamine. This double-blind placebo-controlled trial showed that PAK administration has a positive effect on some metabolic disturbances in cirrhotic patients. This was published by Salerno, Abbiati, and Fici in the International Journal of Clinical Pharmacology Research (1983, 3(1):21–25) and is indexed on PubMed (PMID: 6679504).
Hyperlactacidaemia in cirrhosis: Belvisi, Matergi, and Fici published a study titled "Treatment of hyperlactacidemia in cirrhotic patients with pyridoxine-alpha-ketoglutarate (PAK)" in the International Journal of Clinical Pharmacology and Therapeutics and Toxicology, March 1982 (20(3):142–6; PMID: 7068288).
Advanced cirrhosis: Salerno, Lorenzini, Conti, Abbiati, and Fici published "Effect of pyridoxine-2-oxoglutarate administration in patients with advanced cirrhosis: control of ammonia pyruvate and lactate high plasma concentrations" in Advances in Experimental Medicine and Biology (1982;153:479–85), classified by PubMed as a clinical trial (PMID: 6762055).
Prophylaxis of hyperlacticacidaemia: A US patent (no. 4,361,570) specifically claims the use of pyridoxine alpha-ketoglutarate in the prophylaxis of hyperlacticacidaemia, drawing on the Italian clinical evidence base.
Evidence strength: The cirrhosis/ammonia area has multiple small clinical trials (double-blind, placebo-controlled) from the early 1980s. The sample sizes were small, the studies are now decades old, and they have not been replicated in large modern trials. Evidence is preliminary but consistent across the studies available.
VO₂ max and blood lactate in trained individuals: The administration of 30 mg/kg of body weight of an alpha-ketoglutarate-pyridoxine complex (stoichiometric ratio alpha-KG:pyridoxine 46.35 to 53.65) to trained non-athletic individuals increased VO₂ max by 6% (p < 0.005). Peak blood lactate concentration following two supramaximal running work loads lasting 60 s and 132 ± 4 s was significantly (p < 0.05 and p < 0.005) lower after the alpha-KG complex treatment (Δ[La]b = −1.1 and −2.7 mmol/L, respectively) than in a control group. This study by Marconi, Sassi, and Cerretelli was published in European Journal of Applied Physiology (1982; 49:307–317; PMID: 6890446).
Short-term maximal exercise in cyclists: A study determined the effects of the simultaneous use of pyridoxine-alpha-ketoglutarate (PAK) and sodium bicarbonate (NaHCO₃) on short-term maximal exercise capacity in eight well-trained male cyclists. Oral tablets of NaHCO₃ and PAK were given in doses of 200 mg/kg and 50 mg/kg respectively. There were no significant differences between treatments in the ability to sustain maximal power during the test. The subjects were able to sustain maximal power for 7.6 ± 4.3 min with PAK + bicarbonate, 6.7 ± 2.9 min with PAK alone, 7.3 ± 4.9 min with bicarbonate alone, and 6.9 ± 2.7 min with placebo. This study by Linderman et al. was published in Journal of Sports Sciences (1992, 10(3):243–253; PMID: 1318390).
Another study found no significant differences in maximal power output during a short-term maximal exercise test between groups receiving PAK (50 mg/kg body mass), NaHCO₃, both, or a placebo, suggesting that PAK, in the dosage used, did not enhance short-term maximal exercise performance.
Evidence strength: Results are mixed. The Marconi et al. (1982) study reported significant improvements in VO₂ max and reduced blood lactate, but the Linderman et al. (1992) study in cyclists found no performance benefit. Sample sizes in both studies were small (fewer than 15 subjects). No large, definitive RCTs exist specifically for the PAK combination on exercise performance.
PubMed-indexed research includes a study titled "The effect of pyridoxine-alpha-ketoglutarate (PAK) on exercise-induced increase of blood lactate in patients with type I diabetes." Additional PubMed-indexed research includes "Effects of pyridoxine alpha-ketoglutarate on blood glucose and lactate in type I and II diabetics." These studies, referenced by their PubMed citations (PMID: 7068289), are from the same early-1980s Italian research cluster. Full abstracts are not available in open access, limiting evaluation of their methodology.
The B6 component of PAK has separately attracted attention in diabetes research. Despite incomplete comprehension of the underlying cellular and molecular mechanisms responsible for the beneficial impact on diabetes pathology and its related consequences, various studies have reported beneficial effects of B6 therapy. PLP deficiency can affect diabetes through multiple mechanisms, and pyridoxal-5-phosphate is a crucial component of various enzymes that aid this process.
Evidence strength: Very preliminary. The PAK-specific diabetes studies are from the early 1980s, have limited available methodology detail, and have not been replicated in modern, large-scale trials.
Research on AKG-containing supplements in surgical patients has examined the parent compound, alpha-ketoglutarate, as a component of alpha-ketoglutarate salts (e.g., ornithine-alpha-ketoglutarate, or OKG). Ornithine alpha-ketoglutarate (OKG) is used as an adjuvant treatment in undernourished elderly patients or in patients with hypercatabolism states, and is a precursor of different amino acids which play a role in the process of healing. While this evidence pertains to OKG rather than PAK specifically, the AKG moiety is shared. A reference in the PAK literature cites: "Wernerman J, Hammarqvist F, Vinnars E. Alpha-ketoglutarate and postoperative muscle catabolism. Lancet 1990;335:701–703" — indicating AKG's studied role in reducing post-surgical muscle breakdown.
Evidence strength: The post-operative catabolism data pertains primarily to OKG (ornithine-AKG) rather than PAK itself. Extrapolation to PAK requires caution.
This area of research applies specifically to alpha-ketoglutarate (AKG) as a component — not to PAK as the combined molecule.
Alpha-Ketoglutarate (AKG) has been studied widely in model animals, but there are few studies testing its geroprotective properties in humans.
In Drosophila, AKG significantly upregulated mRNA expression of genes including cry, FoxO, HNF4, p300, Sirt1, and AMPKα, and downregulated expression of HDAC4, PI3K, TORC, PGC, and SREBP. The metabolic effects included reduction in the ATP/ADP ratio and increased autophagy, collectively indicating that AKG extends Drosophila lifespan by activating AMPK signaling and inhibiting the mTOR pathway.
Alpha-ketoglutarate (delivered in the form of a calcium salt, CaAKG) can significantly extend lifespan and healthspan in mice. AKG is involved in various fundamental processes, including central metabolism, collagen synthesis, and epigenetic regulation.
The ongoing ABLE trial is a double-blinded placebo-controlled randomized trial of 1 g sustained release Ca-AKG versus placebo for 6 months of intervention and 3 months follow-up, including 120 individuals aged 40–60 years with a higher DNA methylation age compared to their chronological age; the primary outcome is the decrease in DNA methylation age from baseline to end of intervention.
Evidence strength: Preclinical and preliminary for aging/longevity applications. Animal data (worms, flies, mice) are promising, but robust human RCT data are lacking. The ABLE trial and similar efforts represent early-phase human investigation.
Dietary AKG supplementation reversed the adverse effects induced by lipopolysaccharide (LPS). A strong inhibitory effect was found on the NF-κB-mediated inflammatory pathway; specifically, in AKG-treated intestinal tissues, LPS-induced NF-κB phosphorylation was inhibited and TNF-α was suppressed. This evidence is from animal (piglet) and cell-line models; no human clinical trials have specifically evaluated PAK's anti-inflammatory properties.
Evidence strength: Preclinical only (animal and in vitro).
In a piglet study, AKG supplementation improved bone mineral density, length, weight, and geometrical and strength properties of the femur and tibia, and increased apparent ileal and total tract digestibility of phosphorus. Colonic microbiota analysis showed that AKG supplementation increased α-diversity and beneficial bacteria, including Lactobacillus and Clostridium butyricum. This animal evidence is not directly transferable to PAK supplementation in humans.
Evidence strength: Animal data only for the bone application of AKG.
RxList cites: "Alpha-ketoglutarate stimulates procollagen production in cultured human dermal fibroblasts, and decreases UVB-induced wrinkle formation following topical application on the dorsal skin of hairless mice." (Son et al., Biol Pharm Bull 2007;30(8):1395–1399). This is cell/animal data for AKG alone, not PAK.
Evidence strength: In vitro and animal models only.
Alpha-ketoglutarate is a multifunctional intermediate of the Krebs cycle and is one of the central metabolic regulators of tumor fate, playing an important role in carcinogenesis and tumor progression. There is growing evidence suggesting that AKG may represent a novel adjuvant therapeutic opportunity in anti-cancer therapy. In osteosarcoma cell lines, AKG inhibited proliferation in a concentration-dependent manner and blocked cell cycle progression at the G₁ stage, which was accompanied by induction of apoptotic cell death and caspase-3 activation in both cell lines.
Evidence strength: In vitro only; no human or animal in vivo cancer data for PAK specifically.
The following dosages are reported as used in cited studies and sources; they are not recommendations.
Scientific studies specifically examining the combined form, pyridoxine/pyridoxal alpha-ketoglutarate, are limited. There is no established consensus daily dosage for PAK as a dietary supplement.
According to patent application DE-OS No. 1,958,226, PAK and its derivatives are therapeutically useful drugs that combine within a single molecule both pyridoxine and alpha-ketoglutarate, resulting in the increase of the useful activities of these two compounds and, in certain cases, the reduction of the toxicity thereof. No specific safety data for chronic PAK supplementation in healthy humans have been identified in the peer-reviewed literature. The safety profile must therefore be assessed based on the known safety profiles of the component molecules.
Intake of food-based sources of pyridoxine will not cause toxicity. The only reported cases of vitamin B6 toxicity are from supratherapeutic dosing of supplements or iatrogenic sources.
Pyridoxine toxicity typically manifests as neurologic symptoms, including paresthesias in the extremities and, in severe cases, difficulty with ambulation. This sensory neuropathy usually develops at doses of pyridoxine above 1,000 mg per day. There are some case reports of sensory neuropathies at doses of less than 500 mg per day in patients taking supplements for months. However, none of the studies had sensory nerve damage at a daily intake below 200 mg of pyridoxine per day.
In 2023, the Panel on Nutrition, Novel Foods and Food Allergens of the European Food Safety Authority (EFSA) released a scientific opinion on the tolerable upper intake levels for vitamin B6. Based on systematic reviews that examined associations between vitamin B6 and peripheral neuropathy, the panel set an upper limit for vitamin B6 of 12 mg/day for all adults, including women who are pregnant or lactating, with lower amounts ranging from 2.2 to 10.7 mg/day for infants and children, depending on age.
Neuropathy observed after taking a relatively high dose of vitamin B6 supplements is due to pyridoxine specifically; the inactive form pyridoxine competitively inhibits the active pyridoxal-5′-phosphate. This is relevant because PAK contains pyridoxal (not pyridoxine), which may have a different neurotoxic threshold, although regulatory upper limits for total B6 intake apply regardless of vitamer form.
Higher vitamin B6 levels, which usually occur following the taking of nutritional supplements, may lead to the development of a predominantly sensory neuropathy of the axonal type. After pyridoxine discontinuation, such patients subjectively report improved symptoms.
A noteworthy finding from recent case series: Three of four pediatric patients who received prolonged high-dose oral pyridoxal-5-phosphate (PLP) therapy developed hepatocellular carcinoma after several years of treatment. The shared exposure to prolonged high-dose PLP across all affected patients, despite differing metabolic conditions, suggests a possible role for PLP toxicity independent of the underlying metabolic disorder. Known toxic mechanisms include mitochondrial dysfunction, Schiff base–mediated protein modification, and accumulation of reactive PLP degradation products. This finding, published in 2025, pertains to long-term, high-dose PLP in patients with rare inborn B6-dependent epilepsies — a context very different from typical supplement use — but it underscores that pyridoxal-form vitamers are not categorically free of risk at pharmacological doses.
AKG is water-soluble, nontoxic, and highly stable in aqueous solutions. However, alpha-ketoglutaric acid has low oral bioavailability, which is one reason the calcium or other salt forms are preferred in supplements.
In at least one clinical trial protocol, the intervention with AKG was described as well tolerated with no adverse reactions found.
Vitamin B6 can interact with certain medications, and several types of medications might adversely affect vitamin B6 levels.
Isoniazid, phenelzine, hydralazine, penicillamine, levodopa, and chemotherapy treatments are medications that might lead to pyridoxine shortages because they interfere with its metabolism.
Toxicological uses of pyridoxine include treatment of isoniazid overdose, false morel (Gyromitra) mushroom poisoning, hydrazine exposure, ethylene glycol toxicity, and crimidine toxicity — situations in which B6 functions as an antidote, relevant because co-administration of PAK with isoniazid would alter the pharmacodynamics of both.
Scientific studies specifically examining the combined form — pyridoxine/pyridoxal alpha-ketoglutarate — are limited. Preliminary in vitro and animal research suggests potential synergistic effects, such as enhanced absorption or effectiveness, but robust clinical trials in humans are lacking.
The existing clinical evidence for PAK as a distinct compound is largely confined to a cluster of small Italian clinical studies from 1982–1983 and two exercise physiology studies from 1982 and 1992. These studies were conducted with small sample sizes, and no large, long-term, multicenter RCTs have been conducted since. The growing body of AKG research in aging biology (ABLE trial and others) focuses on the calcium salt of AKG independently, and does not directly assess PAK.
Additionally, the distinction between "pyridoxal alpha-ketoglutarate" (where pyridoxal — not pyridoxine — is the B6 vitamer) and the more commonly studied "pyridoxine alpha-ketoglutarate" (PAK) is blurred in the supplement literature, and many product labels and commercial databases use the terms interchangeably. Rigorous pharmacokinetic studies comparing the absorption and bioavailability of pyridoxal-AKG versus pyridoxine-AKG as intact molecules versus free components are not available in the open literature.
Health conditions that Pyridoxal alpha-ketoglutarate may help support.
Body systems that Pyridoxal alpha-ketoglutarate may help support.
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