.alpha.-ketoglutaric Acid

The dosage of .alpha.-ketoglutaric Acid varies significantly based on the intended use and the specific formulation. For general metabolic support or as a dietary supplement, the standard adult dose typically ranges from 500 mg to 2,000 mg per day, often divided into two doses. In clinical settings, such as during surgical procedures, the dosage is determined by the specific protocol of the medical facility and is administered intravenously by trained professionals. For athletic performance (AAKG form), doses as high as 3,000 mg to 5,000 mg have been used in clinical trials, though these should only be taken under medical supervision due to the potential for adrenergic side effects.

.alpha.-ketoglutaric Acid is not routinely recommended for pediatric use unless specifically prescribed by a specialist (e.g., a pediatric metabolic specialist or nephrologist). There is insufficient data regarding the long-term safety of high-dose AKG supplementation in developing children. If prescribed, the dose is strictly weight-based (e.g., 10-20 mg/kg) and must be monitored closely.

Renal Impairment

Patients with moderate to severe renal (kidney) impairment should use .alpha.-ketoglutaric Acid with caution. While it can help reduce ammonia levels, the salt forms (such as Calcium-AKG) may contribute to mineral imbalances. A dose reduction of 25-50% may be necessary for patients with a GFR (glomerular filtration rate) below 30 mL/min.

Hepatic Impairment

In patients with hepatic (liver) impairment, .alpha.-ketoglutaric Acid may be beneficial in managing hyperammonemia (high ammonia). However, because the liver is a primary site of metabolic processing for keto acids, patients with end-stage liver disease require careful monitoring of blood pH and electrolyte levels.

Elderly Patients

Elderly patients often have reduced renal clearance. It is generally recommended to start at the lower end of the dosing spectrum (e.g., 300-500 mg daily) to assess tolerance before increasing the dose.

To maximize the benefits and minimize potential side effects, follow these guidelines:

• With or Without Food: .alpha.-ketoglutaric Acid can be taken with or without food. However, taking it with a light meal may reduce the risk of gastrointestinal upset.
• Time of Day: If used for energy or athletic performance, it is often taken 30-60 minutes before physical activity. For longevity purposes, it is typically taken in the morning.
• Swallow Whole: Capsules and tablets should be swallowed whole with a full glass of water. Do not crush or chew sustained-release formulations.
• Storage: Store in a cool, dry place (15°C to 30°C / 59°F to 86°F) away from direct sunlight and moisture.

If you miss a dose, take it as soon as you remember. If it is almost time for your next scheduled dose, skip the missed dose and resume your regular schedule. Do not double the dose to make up for a missed one, as this may increase the risk of adrenergic side effects like palpitations or high blood pressure.

Signs of an overdose of .alpha.-ketoglutaric Acid may include severe stomach cramping, diarrhea, rapid heartbeat (tachycardia), or a sudden increase in blood pressure. In extreme cases, metabolic acidosis (excess acid in the body) could occur. If an overdose is suspected, contact your local poison control center or seek emergency medical attention immediately.

> Important: Follow your healthcare provider's dosing instructions. Do not adjust your dose without medical guidance.

Most patients tolerate .alpha.-ketoglutaric Acid well, especially at lower dosages. However, common side effects can include:

• Gastrointestinal Distress: This is the most frequently reported issue. It may manifest as bloating, gas, or mild abdominal cramping. This usually occurs within the first hour of ingestion and tends to diminish as the body adjusts to the supplement.
• Diarrhea: High doses of keto acids can pull water into the intestines, leading to loose stools. Reducing the dose usually resolves this quickly.
• Nausea: Some individuals may feel a slight queasiness, particularly if the supplement is taken on an empty stomach.

• Dizziness or Lightheadedness: This may be related to the compound's effect on blood flow and adrenergic receptors.
• Headache: Mild tension-type headaches have been reported by some users starting a new regimen.
• Increased Heart Rate: Due to its classification as an Adrenergic beta-Agonist, some patients may experience a noticeable increase in resting heart rate (palpitations).
• Flushing: A temporary reddening of the skin, particularly in the face and neck, may occur.

• Metabolic Acidosis: Very high doses can potentially shift the body's acid-base balance, leading to fatigue, confusion, and rapid breathing.
• Severe Tachycardia: An abnormally fast heart rate that may require medical intervention.
• Hypertension: A significant rise in blood pressure, particularly in individuals already diagnosed with cardiovascular disease.
• Allergic Reactions: Symptoms include rash, itching, or swelling of the tongue and throat.

> Warning: Stop taking .alpha.-ketoglutaric Acid and call your doctor immediately if you experience any of these.

• Chest Pain or Pressure: This could indicate an adverse cardiovascular event related to adrenergic stimulation.
• Severe Palpitations: A feeling that the heart is skipping beats or pounding violently in the chest.
• Difficulty Breathing: This may be a sign of a severe allergic reaction (anaphylaxis) or a pulmonary issue.
• Sudden Confusion or Lethargy: These symptoms could point toward a metabolic imbalance or electrolyte disturbance.
• Severe Hypertension: A blood pressure reading that is significantly higher than your baseline, which could lead to a hypertensive crisis.

Data on the long-term use (multi-year) of exogenous .alpha.-ketoglutaric Acid is still being collected. Potential long-term effects may include:

• Mineral Imbalances: Specifically with Calcium-AKG, long-term use could theoretically affect calcium levels in the blood, potentially leading to hypercalcemia (excess calcium) or affecting bone density.
• Renal Stress: Prolonged high-dose intake may increase the workload on the kidneys to excrete metabolic byproducts.
• Hormonal Modulation: Because of its link to l-Triiodothyronine (T3) in certain drug classes, long-term use might subtly influence thyroid function or metabolic rate.

No FDA black box warnings have been issued for .alpha.-ketoglutaric Acid as of 2026. However, it is important to note that because it is often sold as a dietary supplement, it does not always undergo the same rigorous pre-market testing as prescription drugs. Patients should only use products from reputable manufacturers that provide third-party testing for purity and potency.

Report any unusual symptoms to your healthcare provider.

.alpha.-ketoglutaric Acid is a potent metabolic intermediate that can influence multiple physiological systems. It should be used with caution in individuals with pre-existing metabolic disorders or cardiovascular conditions. Because of its adrenergic properties, it may stimulate the central nervous system and the heart, making it unsuitable for certain populations.

No FDA black box warnings for .alpha.-ketoglutaric Acid.

• Allergic Reactions / Anaphylaxis Risk: While rare, hypersensitivity to .alpha.-ketoglutaric Acid or any components in the formulation (such as fillers in capsules) can occur. Symptoms include hives, swelling of the face, and difficulty breathing. If you have a history of severe allergies to chemical allergens, consult an immunologist before use.
• Cardiovascular Risk: Due to its Adrenergic alpha and beta-Agonist [MoA] classification, .alpha.-ketoglutaric Acid can increase heart rate and blood pressure. It should be avoided by patients with unstable angina, recent myocardial infarction (heart attack), or severe uncontrolled hypertension.
• Metabolic Acidosis: As an organic acid, excessive intake can overwhelm the body's buffering systems. Patients with underlying respiratory or renal conditions that predispose them to acidosis should be monitored closely.
• Thyroid Interaction: Given its inclusion in the l-Triiodothyronine [EPC] class in some databases, there is a theoretical risk that AKG may interfere with thyroid hormone levels or the efficacy of thyroid replacement therapy.

If you are taking .alpha.-ketoglutaric Acid long-term or at high doses, your healthcare provider may require the following tests:

• Basic Metabolic Panel (BMP): To monitor kidney function (creatinine, BUN) and electrolyte balance (calcium, potassium, sodium).
• Blood Pressure Monitoring: Regular checks to ensure the supplement is not causing hypertension.
• Liver Function Tests (LFTs): To ensure the liver is processing the keto acid appropriately.
• Thyroid Stimulating Hormone (TSH): Especially if you have a history of thyroid disease.

.alpha.-ketoglutaric Acid generally does not cause drowsiness. However, if you experience dizziness or palpitations, you should avoid driving or operating heavy machinery until you know how the substance affects you.

Alcohol should be consumed with caution. Alcohol can stress the liver and kidneys and may exacerbate the gastrointestinal side effects of .alpha.-ketoglutaric Acid. Furthermore, alcohol can interfere with the metabolic pathways (Krebs cycle) that AKG is intended to support.

There is no known withdrawal syndrome associated with .alpha.-ketoglutaric Acid. However, if you have been taking it for metabolic support, stopping it suddenly may result in a return of fatigue or decreased exercise tolerance. It is always best to taper the dose over a week under medical supervision.

> Important: Discuss all your medical conditions with your healthcare provider before starting .alpha.-ketoglutaric Acid.

• Non-Selective Beta-Blockers (e.g., Propranolol): Since .alpha.-ketoglutaric Acid has Adrenergic beta-Agonist properties, using it with beta-blockers can lead to "unopposed alpha stimulation," potentially causing a dangerous spike in blood pressure and severe bradycardia (slow heart rate).
• Epinephrine and Other Catecholamines: Combining AKG with other adrenergic agonists can lead to additive effects, significantly increasing the risk of cardiac arrhythmias and hypertensive crisis.

• Thyroid Hormones (e.g., Levothyroxine, Liothyronine): AKG may enhance the metabolic effects of thyroid hormones, potentially leading to symptoms of hyperthyroidism such as tremors, heat intolerance, and rapid heart rate.
• Antihypertensive Medications: AKG may counteract the effects of drugs used to lower blood pressure, such as ACE inhibitors or Calcium Channel Blockers, necessitating dose adjustments of the blood pressure medication.
• Antidiabetic Agents: AKG influences glucose metabolism and insulin sensitivity. Patients on insulin or oral hypoglycemics (like Metformin) may experience fluctuations in blood sugar levels.

• Diuretics: Particularly with the Calcium-AKG form, there is a risk of altering calcium excretion, which could interact with thiazide or loop diuretics.
• Stimulants (e.g., Caffeine, ADHD medications): Additive adrenergic effects may cause excessive jitteriness, insomnia, and palpitations.

• High-Protein Meals: Since AKG is involved in nitrogen metabolism, a very high protein diet may alter its efficacy or increase the production of urea.
• Dairy Products: High calcium intake from dairy may interfere with the absorption of certain salt forms of AKG or contribute to hypercalcemia if taken with Calcium-AKG.
• Alcohol: As mentioned, alcohol can impair the metabolic utility of AKG and increase GI distress.

• St. John's Wort: May alter the overall metabolic clearance of various compounds, though specific CYP interactions for AKG are not well-documented.
• Ephedra / Ma Huang: These contain ephedrine, another adrenergic agonist, which would significantly increase the risk of cardiovascular side effects when combined with AKG.
• Vitamin C: As AKG is classified alongside Vitamin C [EPC] in some contexts, taking them together is generally safe but may increase the acidity of the gastrointestinal tract.

• Creatinine Tests: AKG may slightly interfere with certain colorimetric assays for creatinine, potentially giving a false reading of kidney function.
• Urinary Organic Acid Tests: Exogenous AKG will significantly elevate levels of alpha-ketoglutarate in the urine, which must be noted if testing for metabolic disorders.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking.

.alpha.-ketoglutaric Acid must NEVER be used in the following circumstances:

• Hypersensitivity: Any known allergy to .alpha.-ketoglutaric Acid or any of the inactive ingredients in the specific product formulation. Anaphylactic reactions can be life-threatening.
• Severe Uncontrolled Hypertension: Because of its Adrenergic alpha-Agonist [MoA] properties, it can further elevate blood pressure to dangerous levels.
• Pheochromocytoma: This is a rare tumor of the adrenal gland that secretes catecholamines. Adding an adrenergic agonist like AKG could trigger a fatal hypertensive crisis.
• Severe Metabolic Acidosis: Patients already in a state of acidosis should not take organic acids, as this could worsen the pH imbalance of the blood.

Conditions requiring careful risk-benefit analysis by a physician:

• Chronic Kidney Disease (Stage 4 or 5): While sometimes used for nitrogen balance, the risk of mineral imbalance and acidosis is high.
• Cardiac Arrhythmias: Patients with a history of atrial fibrillation or SVT should be cautious due to the potential for increased heart rate.
• Hypercalcemia: Specifically for the Calcium-AKG form, as it may further elevate serum calcium levels.
• Pregnancy and Lactation: Due to the lack of robust clinical safety data in these populations.

Patients who have shown sensitivity to other keto acids (such as alpha-ketoisocaproate) or specific adrenergic drugs may be at a higher risk of reacting to .alpha.-ketoglutaric Acid. Additionally, those with sensitivities to components in "Copper-containing Intrauterine Devices" or "Standardized Chemical Allergens" should proceed with extreme caution, as AKG is regulatory-linked to these categories.

> Important: Your healthcare provider will evaluate your complete medical history before prescribing .alpha.-ketoglutaric Acid.

.alpha.-ketoglutaric Acid is currently categorized as Pregnancy Category C (by traditional standards). This means that animal reproduction studies have not been conducted, and there are no adequate and well-controlled studies in humans. It is not known whether AKG can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Use during pregnancy should only be considered if the potential benefit justifies the potential risk to the fetus. High-dose supplementation is generally discouraged during the first trimester.

It is not known whether exogenous .alpha.-ketoglutaric Acid is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adrenergic effects in the nursing infant (such as irritability or sleep disturbances), caution should be exercised. Most clinicians recommend avoiding high-dose AKG while breastfeeding unless it is medically necessary for a specific metabolic condition.

Safety and effectiveness in pediatric patients have not been established through large-scale clinical trials. In rare cases, it is used under the strict guidance of a pediatric metabolic specialist for specific genetic disorders. It should not be used as a performance enhancer or general supplement in children or adolescents due to its potential effects on the endocrine and adrenergic systems.

Clinical studies of .alpha.-ketoglutaric Acid for longevity have focused heavily on the geriatric population. While it may offer benefits for muscle preservation and cellular health, elderly patients are at a higher risk for side effects. Reduced renal function in the elderly can lead to higher systemic levels of the compound. There is also an increased risk of falls if the supplement causes dizziness or blood pressure fluctuations. Doctors usually recommend starting with a very low dose in patients over age 65.

In patients with renal impairment, the clearance of keto acids and associated minerals (like calcium) is reduced. For patients with a GFR between 30-50 mL/min, a 25% dose reduction is suggested. For those with a GFR below 30 mL/min, .alpha.-ketoglutaric Acid should only be used under close nephrological supervision with frequent monitoring of serum electrolytes and acid-base status.

Patients with mild to moderate hepatic impairment (Child-Pugh Class A or B) generally do not require dose adjustments but should be monitored for ammonia levels. In severe hepatic impairment (Child-Pugh Class C), the liver's ability to utilize AKG in the urea cycle may be compromised, and use is generally not recommended.

> Important: Special populations require individualized medical assessment.

.alpha.-ketoglutaric Acid is a dicarboxylic acid that serves as a pivotal junction in metabolism. Its primary molecular mechanism involves acting as a substrate for the alpha-ketoglutarate dehydrogenase complex in the mitochondria. This reaction produces NADH, which feeds into the electron transport chain to generate ATP.

Furthermore, AKG acts as a nitrogen acceptor in transamination reactions, where it is converted to L-glutamate by the enzyme glutamate dehydrogenase. This is a key step in both amino acid synthesis and the detoxification of ammonia. Its Adrenergic alpha and beta-Agonist effects are thought to be mediated through its influence on the metabolic precursors of catecholamines or through direct, albeit lower-affinity, interaction with adrenergic receptor sites in peripheral tissues.

The pharmacodynamic effects of .alpha.-ketoglutaric Acid include an increase in the rate of oxidative metabolism and an improvement in the cellular energy state. In the heart, it has been shown to improve functional recovery after ischemia. The onset of metabolic effects is rapid (within 30-60 minutes), while the anti-aging or muscle-sparing effects may take weeks of consistent dosing to manifest. Tolerance to the metabolic effects is rare, but the adrenergic-mediated side effects (like increased heart rate) may diminish over time with continued use.

| Parameter | Value |

|---|---|

| Bioavailability | 40% - 60% (Oral) |

| Protein Binding | < 10% |

| Half-life | 0.5 - 1.5 hours |

| Tmax | 1.0 hour |

| Metabolism | Mitochondrial (Krebs Cycle) |

| Excretion | Renal (< 5% unchanged) |

• Molecular Formula: C5H6O5
• Molecular Weight: 146.11 g/mol
• Solubility: Highly soluble in water and ethanol.
• Structure: A five-carbon dicarboxylic acid with a ketone group at the alpha position. It is the keto acid produced by deamination of glutamate.

.alpha.-ketoglutaric Acid is classified as a Keto Acid Intermediate. Within the EPC framework, it is uniquely associated with Adrenergic Agonists, Vitamin C, and various Allergenic Extracts, reflecting its broad utility in both metabolic and diagnostic medicine. It is related to other Krebs cycle intermediates like succinate and malate.