Ornithine alpha-ketoglutarate

Other Names

2-Oxopentanedioic Acid-L-OrnithineACOAlpha-Cétoglutarate d'Ornithinealpha-cetoglutarate d'ornithineAlpha-Cétoglutarate de L-OrnithineCétoglutarate d'OrnithineL'alpha-cétoglutarate d'ornithineL-Ornithine 2-oxoglutarateL-Ornithine alpha-ketoglutarateL-Ornithine alpha-ketoglutarate(1:1)L-Ornithine alpha-ketoglutarate(1:1) dihydrateL-Ornithine-a-ketoglutarateL-Ornithine-α-ketoglutarateOAKGOKGOrnithine ketoglutarateOrnithine oxoglutarateOrnithine α-ketoglutarateOrnithine-a-ketoglutarateOrnitina Cetoglutaratooxoglutarate d'ornithine

Synopsis

Ornithine Alpha-Ketoglutarate (OKG)

1. Identity, Chemical Nature, and Physical Properties

Ornithine alpha-ketoglutarate (abbreviated OKG) is a salt formed by the ionic combination of the amino acid L-ornithine and the organic acid alpha-ketoglutarate (also called 2-oxoglutarate). OKG is a salt formed of two molecules of ornithine and one molecule of alpha-ketoglutarate. The canonical, clinically studied form of the molecule follows this 2:1 stoichiometric ratio, and it is this specific ratio that is considered biologically important. A 1:1 (monoornithine) variant also exists but has been studied less extensively.

L-Ornithine-α-ketoglutarate is a salt formed by the combination of ornithine and α-ketoglutarate, both of which are important intermediates in the urea cycle and the citric acid cycle, respectively. The parent compound in its monohydrate 1:1 form carries CAS number 5191-97-9, molecular formula C₅H₁₂N₂O₂·C₅H₆O₅, and molecular weight of approximately 278.26 g/mol. Its physical appearance is a white crystalline solid, soluble in water and alcohol and insoluble in non-polar solvents, with an odorless, slightly bitter taste. A dihydrate form (L-Ornithine alpha-ketoglutarate (1:1) dihydrate, CID 91873690 in PubChem) with molecular formula C₁₀H₂₂N₂O₉ also appears in the scientific literature.

Synonyms and trade names used in research and clinical settings include: ACO, Alpha-Cétoglutarate de L-Ornithine, Alpha-Cétoglutarate de L(+)-ornithine, Alpha-Cétoglutarate d'Ornithine, Cétoglutarate d'Ornithine, L-Ornithine Alpha-Ketoglutarate, L(+)-ornithine alpha-ketoglutarate, OKG, Ornicetil, and Ornitina Cetoglutarato. In France, OKG has been marketed as Cétornan® (CHIESI Pharmaceutical). Ornithine alpha-ketoglutarate (Cétornan®) has been developed in France as a drug, granted a Marketing Authorization, and holds the status of a reimbursed drug, indicated as an adjuvant treatment in undernourished elderly patients or in patients with hypercatabolism states.

Natural source: Although the amino acids that comprise OKG are present in protein foods such as meat, poultry, and fish, the OKG compound itself is found only in supplements. The individual moieties — ornithine and alpha-ketoglutarate — occur naturally in mammalian metabolism, but OKG as a defined salt compound is produced synthetically via a controlled chemical reaction. OKG is a synthetic compound and does not have traditional or ancient use in herbal or folk medicine; its development stems from 20th-century advancements in biochemistry and nutritional science.

Commercial forms and preparations: OKG is available as oral powder, oral solution, tablets, and capsules for dietary supplement use. In clinical and hospital settings it has been administered via enteral feeding (tube feeding) and parenterally (intravenous infusion). OKG has been used successfully via oral, enteral, and parenteral routes to improve protein status in patients with chronic and acute protein depletion.

2. Historical and Clinical Development

OKG has no traditional use in folk medicine, herbalism, or pre-modern healing systems. Its history is entirely situated within 20th-century clinical biochemistry and hospital nutrition. OKG was introduced in the 1970s and 1980s as a potential agent for promoting protein synthesis and reducing muscle catabolism. It gained considerable attention in clinical nutrition, particularly for patients experiencing muscle wasting, trauma, or surgery, where it was found to promote nitrogen retention and enhance wound healing.

Its use began to gain traction in the 1980s and 1990s when researchers began looking for ways to reduce catabolism and improve recovery outcomes in hospitalized patients. OKG was identified as a potent anabolic and anticatabolic agent, and several clinical trials supported its effectiveness in improving outcomes in patients with trauma, surgery, and severe infections. Early studies — some published as early as the late 1970s — examined the compound's effects on insulin and glucagon secretion in alcoholic cirrhosis, and on hyperammonemia management. A landmark early report examined the effect of ornicetil (ornithine alpha-ketoglutarate) on encephalopathy in patients with acute and chronic liver disease, published in Acta Hepatogastroenterol in 1977.

OKG has been successfully used by the enteral and parenteral route in burn, traumatized, and surgical patients and in chronically malnourished subjects. Its profile as a clinical nutrition compound — rather than a folk remedy — is consistent and uniform across the research literature. The compound belongs to what has been termed the "immunopharmaconutrient" family of nutritional agents. OKG is part of the immunopharmaconutrient family: a salt formed of 2 molecules of ornithine and 1 molecule of α-ketoglutarate, used successfully via oral, enteral, and parenteral routes to improve protein status in chronically and acutely protein-depleted patients.

3. Constituent Moieties and Biochemical Role

3.1 L-Ornithine

L-Ornithine is a non-proteinogenic amino acid — it does not appear in protein chains but is a critical intermediate in the urea cycle, the pathway by which the body converts toxic ammonia to urea for renal excretion. L-Ornithine-α-ketoglutarate plays a role in the metabolism of amino acids and the detoxification of ammonia; it is involved in the production of urea for the excretion of nitrogenous waste products. Ornithine is also a biosynthetic precursor to polyamines (spermine, spermidine, putrescine) and, under appropriate metabolic conditions, to arginine and proline.

3.2 Alpha-Ketoglutarate (2-Oxoglutarate)

Alpha-ketoglutarate is an intermediate of the citric acid (Krebs) cycle, occupying a central node in energy metabolism, amino acid interconversion, and redox chemistry. Through the common metabolic pathway of OKG, the urea cycle (via the ornithine moiety) and the Krebs cycle (via the alpha-ketoglutarate moiety) are linked, with ornithine leading to alpha-ketoglutarate generation and alpha-ketoglutarate leading to ornithine synthesis. Alpha-ketoglutarate is a key acceptor in transamination reactions and is a direct precursor to glutamine and glutamate.

3.3 The Synergistic Salt: More Than the Sum of Its Parts

A central and well-documented observation in the OKG literature is that the compound cannot be reduced pharmacologically to the simple co-administration of its two constituent parts. There is evidence that OKG activity is not the simple addition of the effects of ornithine and alpha-ketoglutarate, because the presence of both moieties is required to induce the generation of key metabolites such as glutamine, proline, and arginine, whereas this does not occur when one or the other is given separately.

This observation is related to the fact that the main feature of ornithine at the whole-body level is to be metabolized through the ornithine aminotransferase-dependent pathway, whereas the simultaneous administration of ornithine and alpha-ketoglutarate saturates this pathway, diverting ornithine toward metabolism into arginine. Animal and human studies have confirmed that the mechanism of OKG action may be associated with increases in growth hormone and insulin, as well as the production of metabolites of ornithine and alpha-ketoglutarate, and OKG has better metabolic benefits than its two components given separately in the nutritional support of injured subjects.

4. Mechanisms of Action

The mechanisms of action of OKG are multifactorial and, as is explicitly acknowledged in the peer-reviewed literature, not fully understood. The mechanism of action of OKG is not fully understood, but the secretion of anabolic hormones (insulin, human growth hormone) and the synthesis of metabolites (glutamine, polyamines, arginine, ketoacids) may be involved. Research has progressively elaborated several overlapping, potentially synergistic pathways:

Anabolic hormone secretion: OKG acts as a potent stimulator of the secretion of anabolic hormones such as insulin, growth hormone, and IGF-1/Sm-C, and this effect has been implicated in OKG anabolic activity in infants receiving long-term total parenteral nutrition and trauma patients.
Glutamine generation: Glutamine is produced from both alpha-ketoglutarate and ornithine via glutamate. The key role of glutamine in the control of protein metabolism, particularly in muscle, and as energy substrate in cell turnover has been previously reported.
Arginine and nitric oxide pathway: Recent studies using chemical inhibitors of nitric oxide synthase suggest that nitric oxide derived from arginine could be partly involved in OKG activity. Polyamines, branched-chain keto acids, and glutamine have all been suggested as being involved in OKG mechanisms of action, and they probably are, because OKG seems to have different mechanisms depending on the underlying pathology, or even different overlapping mechanisms in a given situation.
Polyamine and proline synthesis: L-Ornithine-α-ketoglutarate is a precursor for the synthesis of polyamines, which are important for cell growth and proliferation. In addition to its stimulating role on growth hormone and insulin secretion, arginine accelerates healing and stimulates, directly or indirectly through the formation of nitric oxide, the immune system including macrophage and polymorphonuclear neutrophil function.
Anticatabolic effect on muscle protein: According to the metabolic situation, OKG treatment decreases muscle protein catabolism and/or increases synthesis.
Immune modulation: The actions of these amino acids are mediated in part through their metabolism (into nitric oxide, glutathione, polyamines), through increased hormone secretions (insulin, growth hormone), and through cell swelling. These amino acids modulate protein turnover and are contributive to gut trophicity and immune cell functionality.
Urea cycle and ammonia detoxification: The ornithine component plays a vital role in the urea cycle, assisting with ammonia detoxification and supporting liver function, while alpha-ketoglutarate supports energy production and the synthesis of glutamine and other amino acids.

The requirement for both molecular components for full biological activity is well established. It is well established that the presence of ornithine and alpha-ketoglutarate is required for OKG to be effective. Additionally, the molar ratio of 2:1 (ornithine to alpha-ketoglutarate) matters: studies examining whether a 1:1 monoornithine salt produces equivalent effects have found the canonical 2:1 form to be superior in its metabolic actions, though the precise biochemical reasons for this remain under investigation.

5. Scientific Evidence by Area of Use

5.1 Burns and Acute Trauma (Strongest Evidence)

The area with the most robust clinical evidence for OKG is the treatment of severe burn injuries and other acute catabolic states. Multiple prospective randomized controlled trials have been conducted in this population.

A landmark prospective, randomized, double-blind trial by Donati and colleagues (published in Clinical Nutrition, 1999) examined OKG in severe burn injury. In this prospective, randomized and double-blind study, 60 patients who had undergone severe burns (20–60% of body surface area) received either ornithine α-ketoglutarate (20 g/day) or an isocaloric placebo for 21 days, starting a mean 4 days after injury. In the OKG group, nitrogen balance reached positive values at day 5 and stabilized at higher levels versus controls (P < 0.05 or less from day 3 to day 21), resulting in a strongly positive cumulated nitrogen balance at day 21. Transthyretin and retinol-binding protein levels were higher in the OKG group, body weight loss was counteracted at day 21 (−2.6% vs −6.3%, P < 0.001), and assessment of wound healing using objective scoring showed better performances in the OKG group (P < 0.05).

A separate randomized controlled trial by De Bandt and colleagues, published in The Journal of Nutrition (1998), investigated dose and mode of administration. 54 burn patients (total burn surface area: 20–50%) were included and assigned to receive either a supplement of OKG (10, 20 or 30 g/d) as bolus or continuous infusion, or a continuous infusion of an isonitrogenous amount of a soy protein mixture. OKG administration significantly improved nitrogen balance and reduced 3-methylhistidine and hydroxyproline urinary elimination, and this was associated with a gradual rise in plasma glutamine over time. Given as a bolus, OKG significantly improved wound healing, assessed both clinically (day of last graft: OKG bolus 23.7 ± 2.1 d versus control 39.9 ± 9.9 d; P < 0.05). Data indicated a benefit of 30 g OKG/d administration over 10 g/d, and this trial was the first based on objective data to favor bolus over continuous infusion of OKG in critically ill patients.

An important caveat from this dose-ranging trial is that large doses of OKG (>10 g/d) given as bolus induce diarrhea, which precludes its use under that mode; however, fractionation into several separate 10-g boluses enabled increased dosage without adverse side effects.

In clinical nutrition, OKG has been successfully used in the treatment of catabolic diseases (severe burn) and in malnourished elderly patients. Several studies also provide evidence that OKG enhances wound healing. Overall evidence assessment: The evidence for OKG in severe burns is the strongest in this literature, deriving from multiple RCTs with consistent findings on nitrogen balance, visceral protein markers, and wound healing outcomes.

5.2 Wound Healing: Post-Surgical and Pressure Ulcers

Beyond burns, clinical evidence exists for OKG in post-surgical wound healing and pressure ulcers. A controlled double-blind clinical study comparing OKG to a placebo was carried out in patients after severe plastic surgery. Statistical analysis of the two groups was largely in favor of the OKG group in terms of healing period and rate of skin complications. The same data were reported in patients receiving 10 to 15 g of OKG per day after cervicofacial reconstructive surgery.

For pressure ulcers in elderly patients, a multi-centre, international, randomized, comparative, double-blind, parallel-group, placebo-controlled trial was conducted. 160 patients (ITT population) aged over 60 years with a heel pressure ulcer at stage II or III participated. Patients received OKG (n=85) or placebo (n=75) once a day for 6 weeks, and ulcer area was measured each week. The primary endpoint was the percentage reduction in ulcer surface area. When closure rate was considered, a significant difference in favor of the OKG group was observed (−0.07 cm²/day in the OKG group and −0.04 cm²/day in the placebo group, respectively; p=0.007, Mann-Whitney test). However, the results had an important limitation: at inclusion, ulcer area distribution deviated from normal distribution (median ulcer area OKG 6.6 cm², placebo 3.9 cm², p=0.044), and as healing is strongly related to baseline ulcer area, this abnormal distribution was a major bias. The investigators concluded that this clinical trial supports a potential benefit of OKG 10 g daily in the subgroup of patients with pressure ulcers ≤8 cm² surface area in the elderly population when associated with debridement; however, this study highlights methodological difficulties in performing clinical trials in old-old patients that may affect the robustness of the results.

Overall evidence assessment for wound healing and post-surgical recovery: Moderate, based on multiple small-to-moderate trials. The biological rationale (arginine, proline, polyamine generation) is well-supported; clinical trials are generally positive but often involve small samples, and methodological limitations (such as baseline imbalances) temper firm conclusions.

5.3 Malnutrition in Elderly and Convalescent Patients

OKG has been studied in chronically malnourished elderly populations, both ambulatory and institutionalized. A two-centre, randomized, double-blind trial by Brocker et al. (1994, Age and Ageing, referenced in multiple review papers) enrolled 194 elderly, ambulatory, convalescent subjects. This trial is consistently cited as a landmark study supporting OKG use in malnourished elderly.

Administration of OKG improves nutritional status in chronically malnourished (e.g., elderly) and acutely malnourished patients (especially burn and trauma patients). OKG, a precursor of amino acids such as glutamine and arginine, could represent an effective nutritional supplement in sarcopenia because OKG stimulates insulin secretion. A recent study testing the impact of OKG supplementation in malnourished elderly participants found positive effects on weight and body mass index; however, further studies are needed to assess potential effects in elderly individuals without nutritional problems.

OKG is indicated as an adjuvant treatment in undernourished elderly patients or in patients with hypercatabolism states. OKG optimizes the efficiency of nutritional intake and accelerates the improvement in nutritional status.

Overall evidence assessment: Moderate, primarily from RCTs in malnourished or institutionalized elderly. Evidence consistently supports improvements in nutritional markers and anthropometric measures. Whether benefits extend to well-nourished elderly is unknown.

5.4 Sarcopenia and Age-Related Muscle Loss

A dedicated review published in The Journal of Nutrition, Health & Aging (Walrand, 2010) examined whether OKG could serve as a therapeutic option for sarcopenia. OKG is a precursor of amino acids such as glutamine, arginine, and proline, and increases the secretion of anabolic hormones (insulin and growth hormone). A beneficial anabolic action of OKG has been demonstrated in several pathological conditions associated with muscle loss; therefore, OKG may be of potential interest to modulate muscle protein metabolism and to maintain muscle mass during aging.

The review notes, however, that this therapeutic potential is largely theoretical or extrapolated from catabolic-disease models; direct interventional studies in non-malnourished, community-dwelling elderly with sarcopenia are scarce. Overall evidence assessment: Preliminary. The biochemical rationale is strong, but dedicated clinical trials specifically targeting age-related sarcopenia in otherwise healthy populations are lacking as of the date of available literature.

5.5 Pediatric Parenteral Nutrition and Growth

OKG has been added to intravenous nutritional formulas for children requiring long-term total parenteral nutrition (TPN). Ornithine ketoglutarate is added to formulas to prevent abnormally slow growth in children who are receiving long-term intravenous feeding. OKG has been used for treating burns and wounds, to promote the production of muscle protein following trauma, stroke, or surgery, and to promote growth in children who are fed via intravenous tube for the long term (long-term total parenteral nutrition). This growth-promoting effect has been implicated in OKG anabolic activity in infants receiving long-term total parenteral nutrition.

Overall evidence assessment: Limited number of trials; use is clinical-empirical and largely confined to hospital settings. There is insufficient robust evidence for general pediatric supplementation outside of medically supervised parenteral nutrition.

5.6 Liver Disease and Hepatic Encephalopathy

Early studies in the 1970s and subsequent clinical research examined OKG in patients with liver cirrhosis and hepatic encephalopathy, driven by its role in the urea cycle and ammonia metabolism. However, research indicates that giving ornithine ketoglutarate intravenously by IV does not help treat mental changes caused by liver disease. This is an important distinction: while the closely related compound L-ornithine-L-aspartate (LOLA) has accumulated substantial evidence for hepatic encephalopathy, OKG specifically has not demonstrated equivalent efficacy in this indication.

Overall evidence assessment: Weak and negative for OKG specifically in hepatic encephalopathy. The potential in cirrhosis-associated malnutrition has been studied in a limited way, but the evidence does not support OKG as a first-line intervention for liver disease.

5.7 Athletic Performance and Body Composition

OKG is marketed in some countries as a sports supplement, based on its capacity to stimulate insulin and growth hormone secretion and its precursor relationship to arginine and glutamine. However, the clinical evidence for this application is absent. No research has explored the effects of OKG in athletes. While anabolic effects have been found in studies on hospitalized patients and elderly people, no studies on muscle growth in athletes using OKG have been published. Taking ornithine ketoglutarate does not seem to improve athletic performance based on available evidence. While there are anecdotal claims of its benefits in sports supplementation for muscle building, scientific evidence remains limited and primarily centered on its use in clinical recovery settings.

Overall evidence assessment: Very weak to absent. Claims about athletic enhancement in healthy subjects are unsupported by published clinical trials.

5.8 Anti-Emesis in Chemotherapy

An early exploratory double-blind randomized study by Sevin and colleagues (1988, published in SEM HOP) compared the anti-emetic effects of ornithine alpha-ketoglutarate and metoclopramide in patients treated with cisplatin or adriamycin. This remains an isolated, very early-phase finding with no subsequent replication in the current literature.

Overall evidence assessment: Single preliminary study; insufficient evidence to draw conclusions.

6. Body Systems Associated with OKG

Musculoskeletal system: Reduction of muscle protein catabolism; promotion of anabolic protein synthesis; potential relevance in sarcopenia and cachexia.
Integumentary/wound healing: Promotion of collagen synthesis (via proline precursor role), accelerated wound closure in burns, pressure ulcers, and surgical sites.
Endocrine system: Stimulation of insulin and growth hormone secretion; effects on IGF-1/Sm-C.
Hepatic/metabolic: Participation in the urea cycle; ammonia detoxification; role in nitrogen balance regulation.
Immune system: Generation of arginine and downstream nitric oxide; polyamine-mediated macrophage and neutrophil function modulation.
Gastrointestinal: Glutamine generation contributes to intestinal epithelial integrity; OKG has been associated with gut trophicity in catabolic states.
Energy metabolism: Alpha-ketoglutarate participates directly in the citric acid cycle, linking OKG to cellular bioenergetics.

7. Dosage Forms and Dosages Reported in Studies

Dosages used across the clinical research literature vary by indication, patient population, route of administration, and clinical severity.

Severe burns (enteral/parenteral): A prospective, randomized double-blind study used 20 g/day for 21 days. A dose-ranging randomized controlled trial tested 10, 20, or 30 g/day as bolus or continuous infusion. Data indicated a benefit of 30 g OKG/d administration over 10 g/d.
Post-surgical/wound healing: Patients received 10 to 15 g of OKG per day after cervicofacial reconstructive surgery.
Pressure ulcers in elderly patients: Clinical trial support exists for OKG 10 g daily in the subgroup of patients with pressure ulcers ≤8 cm² when associated with debridement.
Clinical trials generally (range): Typical dosages range from 5 to 25 grams daily, though higher amounts may lead to digestive issues.
Sports/dietary supplement context: Optimal levels remain unknown, though 10 grams per day has been used in clinical trials.
Mode of administration: Evidence favors bolus over continuous infusion of OKG in critically ill patients. In the oral/enteral context, fractionated bolus dosing (e.g., multiple 10-g doses per day) has been used to achieve higher total daily doses while avoiding gastrointestinal adverse effects.

8. Safety Considerations and Known Adverse Effects

OKG is generally considered well tolerated within the dose ranges used in clinical trials. Serious adverse events attributable to OKG have not been reported in the reviewed randomized trials.

Gastrointestinal effects: The most commonly documented adverse effect is dose-dependent gastrointestinal disturbance. High doses (over 5 to 10 g) can cause diarrhea and stomach cramps. This threshold is clinically relevant because therapeutic doses of 20–30 g/day have been used in burn patients. The clinical solution to this, as demonstrated in the De Bandt 1998 RCT, was fractionation of the total daily dose into multiple smaller boluses rather than single large doses or continuous administration.

Safety in the pressure ulcer trial: Thirty serious adverse events were reported in 28 patients (15 allocated to OKG and 13 to placebo), and none of them was considered treatment-related. This provides reassurance that OKG at 10 g/day for 6 weeks in elderly patients did not generate drug-attributable serious adverse events beyond rates observed with placebo.

Populations with unestablished safety: The maximum safe dosages for young children, women who are pregnant or nursing, and those with serious liver or kidney disease have not been established.

Theoretical interactions with nitrogen metabolism: Because OKG stimulates insulin secretion, individuals taking antidiabetic medications should be aware of a theoretical additive effect on blood glucose lowering, though this interaction has not been formally studied in published clinical trials.

Differentiation from related compounds: OKG must not be confused with structurally related but distinct compounds: L-ornithine-L-aspartate (LOLA/Ornicetil), L-ornithine HCl, or calcium alpha-ketoglutarate. Ornithine should not be confused with ornithine alpha-ketoglutarate (OKG), and these distinctions carry pharmacological significance since their mechanisms, metabolic fates, and evidence bases differ substantially.

Ammonia and urea cycle consideration: In patients with known urea cycle enzyme deficiencies, supplementation with ornithine-containing compounds should be approached with caution, as urea cycle flux could be altered. This is a theoretical concern extrapolated from the biochemistry of the compound rather than a clinical report from OKG-specific studies.

References

Health Conditions

Health conditions that Ornithine alpha-ketoglutarate may help support.

Athletic PerformanceScientific
Ornithine alpha-ketoglutarate (OAK) is an amino acid-keto acid compound studied for anabolic properties, wound healing, and athletic recovery. The EBSCO Research Starters sports performance database lists it as a proposed ergogenic aid. Clinical evidence is strongest in clinical nutrition contexts; athletic performance RCT evidence is limited but supportive.
Growth HormoneScientific
Ornithine alpha-ketoglutarate (OKG), a salt of two ornithine molecules and one alpha-ketoglutarate molecule, has been associated with GH and insulin secretion in enteral and parenteral nutrition studies. When fed enterally to trauma and burn patients, OKG significantly increased both IGF-1 and GH levels. Its anabolic mechanism involves generating glutamine and arginine, both of which are independent GH secretagogues.
Nitric OxideScientific
Ornithine alpha-ketoglutarate (OKG) is metabolized to citrulline and arginine, supporting eNOS substrate availability and NO production. Clinically studied at 10–30 g/day in post-surgical and trauma patients, with arginine elevation and NO production proposed as contributing mechanisms to its documented wound healing and muscle metabolism benefits.

Body Systems

Body systems that Ornithine alpha-ketoglutarate may help support.

No body systems available.