L-Glutamine

• Intestinal health support
• Immune system function
• Muscle recovery and growth
• Antioxidant protection

• Supports gut barrier integrity
• May reduce exercise-induced muscle soreness
• Helps maintain acid-base balance
• Supports liver detoxification
• May improve glucose metabolism
• Potential benefits for inflammatory conditions

L-Glutamine is the most abundant free amino acid in the human body, comprising approximately 60% of the free amino acid pool in skeletal muscle and 20% in plasma. Its multifaceted mechanisms of action span several physiological systems, making it a conditionally essential amino acid during periods of stress, illness, or intense physical activity. In the gastrointestinal system, L-glutamine serves as the primary fuel source for rapidly dividing enterocytes (intestinal epithelial cells). It maintains intestinal barrier integrity through multiple mechanisms: it supports the production of intestinal mucin, enhances the expression and localization of tight junction proteins (including occludin, claudins, and zonula occludens-1), promotes the proliferation of intestinal epithelial cells, and reduces intestinal permeability (‘leaky gut’).

Glutamine also modulates intestinal inflammation by reducing pro-inflammatory cytokine production and oxidative stress in the gut mucosa. In the immune system, glutamine is a critical fuel for lymphocytes, macrophages, and neutrophils. It supports immune cell proliferation, cytokine production, phagocytic activity, and antibody synthesis. During immune activation, glutamine consumption by immune cells increases dramatically, creating a higher demand that may not be met by endogenous production alone.

Glutamine also regulates the balance of T-helper cell subsets and influences the production of secretory immunoglobulin A (sIgA), an important component of mucosal immunity. In skeletal muscle, glutamine plays multiple roles beyond being a structural component of proteins. It contributes to protein synthesis by activating mammalian target of rapamycin (mTOR) signaling, a key pathway in muscle protein synthesis. Glutamine also helps prevent muscle protein breakdown (catabolism) during stress or intense exercise by maintaining positive nitrogen balance and reducing the expression of proteins involved in the ubiquitin-proteasome pathway.

Additionally, glutamine serves as a precursor for the synthesis of other amino acids, including alanine, which participates in the glucose-alanine cycle that helps transport nitrogen from muscle to liver. As an antioxidant precursor, glutamine is a rate-limiting substrate for the synthesis of glutathione, one of the body’s most important endogenous antioxidants. Through glutathione production, glutamine indirectly helps neutralize reactive oxygen species, reduce oxidative stress, and protect cells from damage. This mechanism is particularly important during recovery from intense exercise, illness, or injury when oxidative stress is elevated.

Glutamine contributes to acid-base balance by donating its amide nitrogen for the formation of ammonia in the kidneys, which helps buffer excess acid. This renal glutamine metabolism increases during acidosis, helping to maintain pH homeostasis. In the liver, glutamine participates in the urea cycle, aiding in the detoxification of ammonia. It also supports gluconeogenesis (the production of glucose from non-carbohydrate sources) during periods of metabolic stress or low carbohydrate availability.

At the cellular level, glutamine serves as a precursor for the synthesis of nucleotides (purines, pyrimidines), supporting DNA and RNA production in rapidly dividing cells. This role is particularly important in tissues with high cell turnover rates, such as the intestinal mucosa and immune system. Glutamine also functions as a signaling molecule, influencing gene expression and cellular metabolism through various pathways, including the hexosamine biosynthetic pathway, which affects protein glycosylation and cellular stress responses. In the brain, glutamine participates in the glutamate-glutamine cycle between neurons and astrocytes.

Astrocytes take up glutamate (the primary excitatory neurotransmitter) from synaptic clefts and convert it to glutamine, which is then transported to neurons where it is converted back to glutamate. This cycle is essential for maintaining proper neurotransmission and preventing excitotoxicity. For patients with sickle cell disease, glutamine’s FDA-approved indication, the mechanism appears to involve increasing nicotinamide adenine dinucleotide (NAD) levels in red blood cells. This enhances the redox potential of these cells, reducing oxidative stress that contributes to sickling.

Glutamine also increases the availability of reduced glutathione in red blood cells, further protecting against oxidative damage. In summary, L-glutamine’s diverse mechanisms of action—spanning gut barrier function, immune modulation, muscle metabolism, antioxidant production, acid-base balance, and cellular signaling—explain its wide range of physiological roles and potential therapeutic applications. The relative importance of these mechanisms varies depending on the specific physiological context, health status, and level of physical or metabolic stress.

Standard Range: 5-10 g daily

Maintenance Dose: 5 g daily for general health support

Therapeutic Dose: 10-30 g daily depending on condition

Timing: Divided doses throughout the day for optimal absorption and utilization

Cycling Recommendations: Generally not necessary for most users; may be beneficial to cycle 4-8 weeks on, 1-2 weeks off for long-term high-dose use

Established Ul: No officially established upper limit by regulatory agencies

Research Based Ul: Generally considered safe up to 30-40 g daily in divided doses for healthy adults

Toxicity Threshold: No clear toxicity threshold established; doses up to 0.75 g/kg/day have been used in clinical settings

Notes: Higher doses may increase risk of gastrointestinal side effects; very high doses (>40 g/day) should only be used under medical supervision

Optimal Timing: For general health: divided throughout the day; For athletic performance: post-workout; For gut health: between meals or before bedtime

Meal Effects: Taking on an empty stomach may improve absorption by avoiding competition with other amino acids; however, some individuals experience better tolerance when taken with small amounts of carbohydrates

Circadian Considerations: Evening doses may support overnight recovery and immune function during sleep

Exercise Timing: Most beneficial within 30-60 minutes post-exercise for recovery; may also be taken pre-exercise for endurance events

Multiple Dose Scheduling: For doses >10 g daily, divide into 2-4 servings throughout the day for optimal utilization and tolerance

Typical Dietary Intake: Average adult consumes approximately 3-6 g daily through protein-rich foods

Food Sources Comparison: Dietary sources provide glutamine bound in proteins, which is released gradually during digestion; supplements provide free-form glutamine for more immediate availability

Dietary Vs Supplemental: Dietary sources sufficient for general health in non-stressed states; supplementation may be beneficial during increased demands

Dietary Patterns: Low-protein diets may provide insufficient glutamine; high-stress conditions may increase requirements beyond typical dietary intake

Dosage Research Gaps: Optimal dosing for many conditions still being established; individual response variability not well-characterized

Population Specific Research: Limited research in pediatric populations and pregnant/lactating women

Methodological Challenges: Variations in study designs, populations, and outcome measures make direct comparisons difficult

Future Research Needs: More dose-response studies; better characterization of optimal timing; longer-term safety and efficacy data for chronic supplementation

Absorption Rate: Approximately 70-80% from oral supplements in healthy individuals

Absorption Site: Primarily in the small intestine via specific amino acid transporters

Absorption Mechanism: Transported across the intestinal epithelium via sodium-dependent transporters (primarily B0AT1/SLC6A19) and sodium-independent transporters (LAT1/SLC7A5, LAT2/SLC7A8)

Factors Affecting Absorption: Presence of other amino acids (competitive inhibition), Gastrointestinal health (inflammation may reduce absorption), Dosage (higher single doses may saturate transporters), Form of glutamine (free vs. peptide-bound), Fasting vs. fed state, Individual variations in transporter expression, Stress states (may increase intestinal utilization before systemic absorption)

For General Nutrition: Divided doses throughout the day on an empty stomach

For Athletic Performance: 5-10g within 30-60 minutes post-workout; additional doses throughout the day

For Gut Health: Between meals or before bedtime to maximize direct effects on intestinal cells

With Other Supplements: Separate from other amino acids by 1-2 hours if possible; may be taken with non-competing supplements

Half Life: Approximately 1-2 hours in plasma; tissue utilization extends effective duration

Metabolic Pathways: Conversion to glutamate via glutaminase, Utilization by intestinal cells as energy substrate, Incorporation into proteins, Conversion to other amino acids (alanine, proline, arginine), Utilization for nucleotide synthesis, Conversion to glucose via gluconeogenesis, Utilization for glutathione synthesis

Elimination Routes: Minimal urinary excretion of unchanged glutamine; primarily metabolized

Factors Affecting Clearance: Metabolic demand (stress, illness increases utilization), Exercise (increases muscle uptake), Acid-base status (acidosis increases renal glutamine metabolism), Liver and kidney function, Nutritional status, Age and sex

Degree Of Penetration: Limited – glutamine crosses the blood-brain barrier at a moderate rate

Transport Mechanisms: Specific transporters (primarily sodium-dependent system N transporters)

Factors Affecting Penetration: Blood-brain barrier integrity, Concentration gradient, Competition with other amino acids, Pathological conditions that may compromise barrier function

Notes: Brain largely synthesizes glutamine locally; supplementation has limited direct effects on brain glutamine levels under normal conditions

Highest Concentrations: Skeletal muscle (approximately 60% of free amino acid pool), Lungs, Liver, Brain, Intestinal mucosa

Lowest Concentrations: Blood plasma (tightly regulated), Adipose tissue

Compartmentalization: Primarily intracellular; plasma levels represent only a small fraction of total body glutamine

Tissue Specific Metabolism: Muscle: primary site of glutamine synthesis and storage; Intestine: major site of glutamine utilization; Liver: both synthesis and utilization depending on metabolic state; Kidney: increased glutamine metabolism during acidosis

Diurnal Patterns: Some evidence for diurnal variations in plasma glutamine levels, with potential decreases during overnight fasting

Chronopharmacology: Limited research on time-dependent effects of glutamine supplementation

Implications For Timing: Evening doses may support overnight recovery and prevent morning decreases; post-exercise timing based on workout schedule rather than time of day

With Medications: Anticonvulsants: glutamine may potentially reduce effectiveness of some anticonvulsants, Lactulose: may reduce effectiveness of lactulose in hepatic encephalopathy, Cancer chemotherapy: theoretical concerns about supporting rapidly dividing cells

With Other Supplements: Competing amino acids: reduced specific absorption when taken simultaneously, Probiotics: potential synergistic effects on gut health, Antioxidants: may complement glutamine’s effects on glutathione production

Clinical Significance: Generally low for most drug interactions; theoretical concerns require more research

Rating: 4 out of 5

Interpretation: Generally well-tolerated with minimal risk of serious adverse effects at recommended doses

Context: Extensive clinical use and research support safety for most healthy adults; some caution warranted in specific populations

Common Side Effects:

Rare Side Effects:

Long Term Side Effects:

• No well-established long-term adverse effects from glutamine supplementation at recommended doses
• Potential metabolic adaptations with prolonged high-dose use; possible downregulation of endogenous glutamine synthesis
• No specific monitoring needed for most healthy individuals; periodic assessment of liver and kidney function may be prudent with long-term high-dose use

Absolute Contraindications:

Relative Contraindications:

Major Interactions:

Moderate Interactions:

Minor Interactions:

Acute Toxicity:

• Not established in humans; animal studies suggest very low acute toxicity
• Primarily gastrointestinal symptoms: nausea, vomiting, abdominal discomfort, diarrhea
• Supportive care; symptoms typically resolve within 24-48 hours

Chronic Toxicity:

• No Observed Adverse Effect Level not firmly established; doses up to 0.75 g/kg/day have been used in clinical settings without serious adverse effects
• Metabolic adaptations; potential downregulation of endogenous glutamine synthesis with prolonged high-dose use
• No specific biomarkers established for monitoring; standard liver and kidney function tests may be prudent with long-term high-dose use

Upper Limit:

• No officially established upper limit by regulatory agencies
• Generally considered safe up to 30-40 g daily in divided doses for healthy adults
• Higher doses have been used in clinical settings under medical supervision

Pediatric:

• Limited data outside of clinical settings; generally not recommended without medical supervision
• Developing metabolism; different amino acid requirements than adults
• Avoid supplementation unless specifically recommended by healthcare provider

Geriatric:

• Generally well-tolerated; may be particularly beneficial for maintaining muscle mass and immune function
• Potentially reduced kidney function; altered amino acid metabolism
• Start at lower doses (3-5 g daily); gradually increase as tolerated

Pregnancy:

• Insufficient data for supplementation; classified as FDA Pregnancy Category C
• Potential unknown effects on fetal development
• Avoid supplementation unless specifically recommended by healthcare provider

Lactation:

• Insufficient data for supplementation
• Potential transfer to breast milk; unknown effects on infant
• Avoid supplementation unless specifically recommended by healthcare provider

Renal Impairment:

• Use with caution; altered amino acid clearance and metabolism
• Potential nitrogen load; altered glutamine metabolism
• Lower doses if used; medical supervision required; monitor renal function

Hepatic Impairment:

• Use with caution in mild to moderate impairment; contraindicated in severe impairment with encephalopathy
• Altered amino acid metabolism; potential ammonia accumulation
• Lower doses if used; medical supervision required; monitor liver function and ammonia levels

Allergenicity Rating: Very low

Common Allergic Manifestations: Skin rash, itching, swelling (rare)

Cross Reactivity: Potential sensitivity in individuals with MSG intolerance (limited evidence)

Testing Methods: No standardized allergy testing available; typically diagnosed through elimination and challenge

Recommended Baseline Tests: None specifically required for most healthy individuals; consider liver and kidney function tests for those with pre-existing conditions

Follow Up Monitoring: No specific monitoring required for most healthy individuals using recommended doses

Warning Signs To Watch: Persistent gastrointestinal symptoms, unusual fatigue, changes in urination patterns, signs of allergic reaction

When To Discontinue: If significant side effects occur; if new health conditions develop that contraindicate use; if prescribed medications with potential interactions are started

Free Form L Glutamine Powder:

• Potential for dosing errors with loose powder; bitter taste may lead to poor compliance
• Allows for flexible dosing; typically free from additives
• Use accurate measuring tools; mix thoroughly in liquid

L Glutamine Capsules Tablets:

• May contain fillers, binders, or other additives that could cause sensitivity in some individuals
• Convenient; precise dosing; masks bitter taste
• Check ingredient list for potential allergens or problematic additives

L Alanyl L Glutamine Dipeptide:

• Higher cost; less extensive safety data than free-form glutamine
• Enhanced stability; potentially better tolerated in individuals with sensitive digestive systems
• Consider for those who don’t tolerate free-form glutamine well

Liquid Glutamine Preparations:

• Stability issues; potential for bacterial contamination after opening
• Easy to consume; good for those with difficulty swallowing pills
• Store properly; use within recommended time after opening; check for preservative content

Handling Precautions: Standard precautions for food-grade materials; avoid inhalation of powder

Storage Safety: Store in cool, dry place in sealed containers; keep away from moisture

Disposal Considerations: No special disposal requirements for normal quantities

Hospital Use: Widely used in clinical nutrition for critical illness, burns, trauma, and post-surgical recovery

Documented Adverse Events: Generally low incidence of serious adverse events in clinical settings

Safety In Medical Conditions: Well-established safety profile for specific medical applications under proper supervision

Lessons From Clinical Use: Higher doses (up to 0.5-0.75 g/kg/day) generally well-tolerated in clinical settings with appropriate monitoring

Common Combinations:

• Generally safe; complementary effects for muscle recovery
• Generally safe; potential synergistic benefits for gut health
• Generally safe; complementary effects for immune function
• Generally safe; may enhance glutathione-related benefits

Combinations To Avoid:

• Not unsafe but may reduce specific glutamine effects
• See drug interactions section

Reported Adverse Events: Primarily gastrointestinal complaints; very few serious adverse events reported

Population Level Safety Data: Extensive use in sports nutrition and clinical settings supports general safety profile

Regulatory Actions: No significant regulatory actions or warnings specific to glutamine supplementation

Emerging Safety Concerns: Ongoing research into potential effects on tumor metabolism; currently theoretical rather than established concern

Mhlw Status: Classification: May be used in Foods with Health Claims, including Foods with Nutrient Function Claims (FNFC) and Foods for Specified Health Uses (FOSHU), Specific Regulations: Subject to regulations under the Health Promotion Law, Approved Uses: Array, Restrictions: Specific approved products have defined formulations and claims, Classification: Not approved as a pharmaceutical product, Research Status: Ongoing research for potential pharmaceutical applications

Production Significance: Major global producer of glutamine through companies like Ajinomoto and Kyowa Hakko

Nmpa Status: Classification: May be registered as a Health Food, Specific Regulations: Subject to registration or filing under Health Food regulations, Approved Uses: Array, Restrictions: Specific approved products have defined formulations and claims, Registration Process: Requires extensive safety and efficacy data for registration, Classification: Permitted food ingredient, Specific Regulations: Subject to food safety standards

Production Significance: Major global producer of glutamine; significant manufacturing capacity

Relative Cost Category: Low to Medium

Price Range Comparison: Less expensive than specialized amino acids like L-tryptophan or acetyl-L-carnitine; comparable to common amino acids like glycine; significantly less expensive than specialty supplements

Market Trends: Stable pricing for standard forms; premium pricing for specialized forms like dipeptides and pharmaceutical-grade products

Production Scale Impact: Large-scale industrial production keeps costs relatively low; economies of scale benefit standard glutamine products

L-glutamine represents good to excellent value for specific applications, particularly gut health support and athletic recovery, with standard powder forms offering the best cost-effectiveness. The cost-to-benefit ratio is most favorable for individuals with specific needs such as intestinal barrier support, recovery from intense exercise, or post-illness recovery. The pharmaceutical application for sickle cell disease (Endari) demonstrates strong clinical value but at significantly higher cost, with cost-effectiveness heavily dependent on insurance coverage. The wide range of pricing across different forms and brands creates opportunities for consumer savings through informed purchasing decisions, with bulk powder forms typically offering the best value.

The growing diversity of specialized forms provides options for those prioritizing convenience or specific benefits, though at premium prices. Overall, glutamine supplementation offers reasonable economic value when used strategically for specific purposes rather than as a general supplement, with cost-effectiveness optimized through targeted usage during periods of increased physiological demand.

Appearance: White crystalline powder in pure form; may develop slight clumping if exposed to moisture

Solubility: Moderately soluble in water (approximately 35-36g/L at 20°C); practically insoluble in ethanol and other organic solvents

Hygroscopicity: Moderately hygroscopic; absorbs moisture from humid environments

Particle Characteristics: Typically crystalline powder; particle size affects dissolution rate and mixing properties

Physical Changes Over Time: May cake or clump if exposed to moisture; generally stable in solid form when properly stored

Comparative Stability: L-alanyl-L-glutamine shows significantly enhanced stability compared to free glutamine, particularly in solution

Mechanism Of Enhanced Stability: Peptide bond protects the glutamine amide group from hydrolysis; reduced susceptibility to cyclization

Solution Stability: Hours to days longer than free glutamine under identical conditions

Thermal Stability: Better resistance to degradation at elevated temperatures

Applications: Particularly valuable for liquid formulations, sports drinks, and clinical nutrition products

Temperature Excursions: Generally tolerant of short-term temperature excursions during shipping

Vibration Effects: Minimal impact; may cause some powder compaction

Protective Measures: Standard pharmaceutical shipping practices sufficient; additional moisture protection for international shipping

International Shipping Considerations: Avoid extreme temperature exposure; use moisture-protective packaging for sea freight

Synthesis Methods

Natural Sources

Quality Considerations

Sourcing Recommendations

Market Information

Dietary Considerations

First Isolation: Glutamine was first isolated from wheat gluten in 1883 by German chemist Ernst Schulze and his student E. Bosshard at the University of Zurich.

Naming Origin: The name derives from ‘gluten,’ the protein mixture from which it was first isolated, combined with ‘amine’ to denote its chemical structure containing an amide group.

Structural Determination: Its complete chemical structure was determined in the early 20th century, with its stereochemistry confirmed as part of the broader understanding of amino acid stereochemistry.

Key Researchers: Ernst Schulze (first isolation from wheat gluten), E. Bosshard (worked with Schulze on isolation), Hans Krebs (elucidated glutamine’s role in metabolism in the 1930s-1940s), Philip Randle (contributed to understanding glutamine metabolism in the 1950s-1960s), Eric Newsholme (pioneered research on glutamine’s role in immune function in the 1980s)

Rating: 3 out of 5

Interpretation: Moderate evidence supporting specific applications; mixed results across different conditions

Context: Strong evidence for certain clinical applications (sickle cell disease, critical illness, gut health) but more mixed or limited evidence for other popular uses (general athletic performance, immune enhancement in healthy individuals)

Clinical Applications: Strong consensus supporting use in sickle cell disease, critical illness, and certain gastrointestinal conditions; more divided opinion on use for general athletic performance and healthy individuals

Dosing Recommendations: General agreement on 5-10 g daily for general support; 10-30 g daily for therapeutic applications; divided into multiple doses

Safety Assessment: Broad consensus on safety at recommended doses for most healthy adults; agreement on cautions for specific populations

Research Priorities: Better characterization of mechanisms in sickle cell disease; optimization of protocols for athletic applications; exploration of metabolic health applications; long-term effects of supplementation

Early Research: Initial focus on basic metabolism and nutritional role in 1950s-1970s; recognition as ‘conditionally essential’ amino acid

Middle Period: Expansion into clinical applications in 1980s-1990s, particularly for critical illness, surgery, and trauma

Recent Developments: Growing interest in athletic applications, metabolic health, and specific disease states; FDA approval for sickle cell disease in 2017; increasing focus on mechanisms and optimal protocols

Vs Other Amino Acids: More evidence for gut health benefits than most other amino acids; comparable or slightly less evidence for muscle recovery compared to BCAAs; unique evidence for sickle cell disease

Vs Protein Supplements: More targeted effects on gut health and specific conditions; less comprehensive for general muscle protein synthesis compared to complete protein

Vs Pharmaceutical Approaches: Generally fewer side effects than pharmaceuticals for similar indications; may be complementary to conventional treatments rather than replacement

Cost Effectiveness Analysis: Generally favorable for specific clinical applications; moderate for athletic applications; limited data for general health supplementation