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Anxiety. Although there has been interest in using oral GABA for anxiety, there is insufficient reliable information about the clinical effects of GABA for this condition.
Athletic performance. Although there has been interest in using sublingual GABA for athletic performance, there is insufficient reliable information about the clinical effects of GABA for this purpose.
Attention deficit-hyperactivity disorder (ADHD). Although there has been interest in using oral GABA for ADHD, there is insufficient reliable information about the clinical effects of GABA for this condition.
Cerebral palsy. It is unclear if oral GABA is beneficial for cerebral palsy in children. Details: Preliminary clinical research in children with cerebral palsy shows that taking a specific product containing GABA (Gammalon) one to four tablets daily (depending on age) for 2 months, in addition to standard therapy for cerebral palsy, improves mental development, learning, vocabulary, physical function, motor strength and activity, and motor hyperactivity in a greater percentage of children when compared with standard therapy alone (19362). These findings are limited by poor study design.
Chronic bronchitis. It is unclear if oral GABA is beneficial for chronic bronchitis. Details: Preliminary clinical research in adults with chronic bronchitis shows that taking a specific GABA product (Aminalon) 1.5-3 grams daily for 18-20 days, along with conventional treatment for acute exacerbations of bronchitis, increases the duration of subsequent remission by about 3 months when compared with conventional treatment alone (19361).
Cushing syndrome. It is unclear if oral GABA is beneficial for Cushing syndrome. Details: Preliminary clinical research shows that taking a specific GABA product (Aminalon) 1-3 grams daily for one month decreases plasma levels of adrenocorticotropic hormone (ACTH) 60 minutes after administration, as well as cortisol and ACTH levels up to 2 days after GABA discontinuation, when compared with baseline (19363). The validity of these findings is limited by the lack of a comparator group.
Depression. Although there has been interest in using oral GABA for depression, there is insufficient reliable information about the clinical effects of GABA for this condition.
Epilepsy. It is unclear if oral GABA is beneficial for epilepsy. Details: Preliminary clinical research shows that taking a combination of GABA 2.5-3 grams and phosphatidylserine 500 mg daily for 3-8 months reduces seizure frequency when compared with placebo in patients with absence seizures, but not in those with focal aware or focal impaired awareness seizures (19364). Other preliminary clinical research suggests that taking GABA 3 grams with phosphatidylserine 600-1200 mg daily for 2 days does not affect the seizure photosensitivity range in people with photoconvulsive responses (5113).
Hypertension. Preliminary clinical research suggests that oral GABA may modestly reduce blood pressure in patients with mild or borderline hypertension. Details: Preliminary clinical research in adults with hypertension shows that drinking 100 mL of fermented milk containing GABA 10-12 mg daily at breakfast for 12 weeks reduces systolic and diastolic blood pressure by about 17 mmHg and 7 mmHg, respectively, when compared with baseline. Compared with patients treated with a placebo milk, these reductions were significant. However, it is unclear if the placebo milk also differed from the fermented milk in other ways (19367). Other preliminary clinical research in patients with borderline hypertension shows that taking a chlorella supplement containing GABA 20 mg twice daily for 12 weeks reduces systolic blood pressure when compared with placebo (19368). However, these findings are limited by poor study design.
Insomnia. It is unclear if oral GABA is beneficial for insomnia. Details: Two small clinical studies in adults with insomnia show that taking fermented rice germ extract, standardized to provide GABA 75 mg or 300 mg, one hour before bedtime for 4 weeks modestly decreases sleep latency when compared with placebo, but does not improve sleep efficacy or reduce episodes of waking after sleep onset (110134,110135). As these doses were evaluated in separate studies, no direct comparison between GABA 75 mg and 300 mg has been conducted.
Meningitis. It is unclear if oral GABA is beneficial for meningitis. Details: Preliminary clinical research in children aged 7 months to 16 years with meningitis shows that taking a specific GABA product (Aminalon) 0.5-1.5 grams daily, starting within 2-4 weeks of illness and continuing for one month thereafter, decreases the incidence of residual disease manifestations and prevents the development of cerebrospinal syndrome when compared with control (19369). However, this study was conducted prior to the development of current treatment guidelines for meningitis; it is unclear if GABA is beneficial when used in conjunction with current standard care.
Menopausal symptoms. Although there has been interest in using oral GABA for menopausal symptoms, there is insufficient reliable information about the clinical effects of GABA for this purpose.
Motion sickness. It is unclear if oral GABA is beneficial for motion sickness. Details: Preliminary clinical research shows that taking a specific GABA product (Aminalon) 0.5 grams as a single dose 40-50 minutes before induced motion sickness or three times daily for 4 days significantly delays onset of motion sickness when compared with placebo. GABA also decreases the occurrence of motion sickness symptoms including chills, cold sweats, and pallor when compared with placebo (19370).
Obesity. Although there has been interest in using oral and sublingual GABA for weight loss, there is insufficient reliable information about the clinical effects of GABA for this purpose.
Pain (acute). Although there has been interest in using oral and sublingual GABA for acute pain, there is insufficient reliable information about the clinical effects of GABA for this purpose.
Post-traumatic stress disorder (PTSD). Although there has been interest in using oral GABA for PTSD, there is insufficient reliable information about the clinical effects of GABA for this condition.
Premenstrual syndrome (PMS). Although there has been interest in using oral GABA for PMS, there is insufficient reliable information about the clinical effects of GABA for this condition.
Psychological well-being. Although there has been interest in using oral and sublingual GABA to improve well-being, there is insufficient reliable information about the clinical effects of GABA for this purpose.
Stress. It is unclear if oral GABA is beneficial for stress. Details: Preliminary clinical research shows that taking a single dose of GABA 100-200 mg by mouth 10-70 minutes prior to completing a mentally stressful task does not appear to reduce subjective measure of stress when compared with placebo (90568). However, it does attenuate alpha wave reduction and reduces beta wave upsurge on the EEG during testing when compared with placebo (19373,90568). More evidence is needed to rate GABA for these uses.

EFFECTIVE

Sickle cell disease. A specific oral glutamine powder (Endari, Emmaus Medical, Inc) is approved by the US Food and Drug Administration (FDA) to reduce acute complications of sickle cell disease. Details: Clinical research in adults and children 5 years of age and older shows that taking glutamine 5-15 grams (0.3 grams/kg body weight) orally twice daily for 48 weeks, either with or without hydroxyurea, delays the median time to first crisis by 30 days, and reduces the incidence of acute chest syndrome by 15%, number of hospitalizations by 33%, and the number of hospitalized days by 40%, when compared with placebo (96519,99414).

Burns. Oral glutamine seems to improve healing in patients with severe burns and may also reduce the risk for burn wound infections; however, it is unclear if glutamine improves hospitalization length or mortality. Details: Some clinical research shows that administering enteral nutrition supplemented with glutamine 0.35-0.5 grams/kg daily for 12-14 days, beginning within 24-48 hours of hospitalization for severe burn injury (excluding inhalation injury), decreases the length of hospital stay by 6-9 days and may shorten wound healing when compared to control enteral nutrition (52307,52337). A clinical study in adults with moderate to severe burns (including inhalation injury) shows that administering enteral nutrition supplemented with intravenous alanyl glutamine 0.5 grams/kg daily, beginning within 24 hours of burn injury and continued for 14 days, may improve burn-induced organ damage, particularly intestinal mucosal injury, but does not improve mortality or length of hospitalization, when compared with standard nutritional support (108027). Another study in the same population shows that administering enteral nutrition supplemented with glutamine 4.3 grams every 4 hours, beginning within 24 hours of burn injury, decreases the risk of mortality by 83% and the risk of Pseudomonas wound infections; however, it does not decrease the duration of hospitalization (52311). A meta-analysis of these trials and one additional trial shows that administering glutamine enterally reduces the risk of Gram-negative bacterial wound infections by 73% and reduces the risk of mortality by 87% when compared to a control group. However, there was no difference in length of stay or overall wound infection rate (97363). Results were based on a small number of patients within each outcome evaluation. Intravenous glutamine has also been evaluated. One small clinical study shows that intravenous glutamine 0.57 grams/kg daily decreases the incidence of Gram-negative bacteremia by 35% when compared with control in patients with severe burns. However, it does not appear to decrease the incidence of Gram-positive bacteremia, the need to use antibiotics, or risk of mortality (52272).
Critical illness (trauma). Oral and intravenous glutamine seem to reduce infectious complications in critically ill adults. However, glutamine does not seem to reduce mortality in this population. Details: Some studies show that glutamine reduces the risk of infectious complications in critically ill, multiple-trauma, or postoperative adult patients (5449,5450,7309,7731,8184,52288,52359). However, other studies show no benefit (52308,52360,97362). Meta-analyses of these and other clinical trials suggest that glutamine supplementation reduces the risk of nosocomial infections in critically ill patients by 15% to 18% and the risk of nosocomial infections in surgical patients by 30% to 41%. This benefit was seen only with parenteral glutamine; enteral glutamine does not appear to reduce the risk for nosocomial infection (91355,91358). The role of glutamine for reducing mortality in critically ill adults is conflicting. Some clinical trials suggest that glutamine-enriched enteral and parenteral nutrition reduces mortality in critically ill patients (52283,52289,52408). However, other studies show no benefit (52288,52308,52354,52359,97362). Meta-analyses of results from these and other clinical trials show that, overall, taking glutamine does not reduce the risk of mortality in critically ill patients (91355,91358). However, the dose and dosage form may affect outcomes. One meta-analysis shows that glutamine does not affect the risk of mortality when administered at doses up to 0.5 grams/kg daily, although doses greater than 0.5 grams/kg daily may INCREASE mortality by 18% (91355). Another meta-analysis shows that glutamine decreases short-term mortality in critically ill patients by 25% when administered parenterally, but not enterally (91358). Neither parenteral nor enteral glutamine appears to decrease the risk of long-term mortality in critically ill patients (91358). Research evaluating glutamine in critically ill children is limited. One clinical study in children ages 1-17 admitted to an intensive care unit (ICU) shows that enteral administration of glutamine along with zinc, selenium, and intravenous metoclopramide does not reduce nosocomial infections when compared with whey supplementation (86095).
HIV/AIDS-related wasting. Oral glutamine seems to attenuate weight loss related to HIV/AIDS. Details: Very small clinical studies show that taking glutamine orally seems to enhance intestinal absorption of nutrients, decrease intestinal permeability, and increase weight gain in adults with HIV/AIDS when compared with placebo. Doses of 40 grams daily seem to produce the greatest effect (2337,2702). Lower doses of 14 grams daily might also be effective when used in combination with arginine and hydroxymethylbutyrate (a leucine metabolite) (7310).
Postoperative recovery. Oral or intravenous glutamine seems to reduce the duration of hospitalization and improve postoperative nutritional status in adults. However, it does not seem to reduce postoperative mortality. Details: Although some conflicting evidence exists (52316), most clinical research shows that receiving free glutamine or glutamine-containing dipeptide intravenously decreases the duration of hospitalization after surgery, particularly after major abdominal surgery (2363,5448,7300,7732,52275,52341). A meta-analysis of this research and other studies shows that IV supplementation with glutamine-containing dipeptides reduces the length of hospital stay by 3 days when compared with no supplementation (96507). Other meta-analyses of clinical research also show that glutamine supplementation, as free glutamine or glutamine-containing dipeptides, reduces the risk of hospital-acquired infections by 30% in surgical intensive care unit (ICU) patients and by 41% in elective surgical patients (91355,91358). In cancer patients undergoing abdominal surgery, glutamine-supplemented parenteral nutrition seems to improve nutritional status and gastrointestinal function (100943). Glutamine-containing dipeptides also appear to help to preserve intestinal integrity (7299,7300,7732,52306). One small study has evaluated oral glutamine 10 grams, in combination with arginine 4.5 grams, in patients undergoing surgery for enterocutaneous fistulas. This study shows that taking this combination daily for 7 days prior to surgery reduces recurrence of fistulas by 35%, and also reduces postoperative infections (103837). Although glutamine seems to decrease length of stay and reduce infection rate, it does not appear to reduce the risk of mortality in either surgical ICU or elective surgical patients (91355,91358,96509,103834), including those receiving major abdominal surgery (5448,52316,91355,96507). Additionally, most research shows that glutamine supplementation does not reduce the incidence of infectious complications following abdominal surgery (52306,52316,52341,5448,7300,96507). The effects of glutamine on reducing infection rate might be related to patient population, modes of nutrition, or dose of glutamine. Taking a combination of glutamine 7 grams, arginine 7 grams, and hydroxymethylbutyrate 1.2 grams (Abound, Abbott) orally daily for 3 days before and 7 days after abdominal surgery does not reduce the incidence of wound infections or other complications (99413). Most of the research evaluating glutamine in surgical patients has been conducted in adults. Information in children is limited. Existing clinical research shows that glutamine-fortified parenteral nutrition does not improve intestinal permeability, nitrogen balance, duration of hospitalization, incidence of infectious complications, or risk of mortality in newborns and infants undergoing digestive-tract surgery (52338,96508).

POSSIBLY INEFFECTIVE

Athletic performance. Oral glutamine does not seem to improve athletic performance. Details: Small studies in trained athletes or healthy adults show that taking glutamine orally does not seem to enhance performance or immune response during intense acute or prolonged exercise when compared with placebo (2341,2342,5455,5456).
Crohn disease. Oral glutamine does not seem to improve symptoms of this condition. Details: Small clinical studies in adults and children with Crohn disease show that taking glutamine 7 grams three times daily or following a glutamine-enriched diet for 4 weeks does not seem to improve intestinal permeability or disease activity, and might even worsen disease activity, when compared with placebo or a low-glutamine diet (2338,6256).
Cystinuria. Oral glutamine does not seem to improve cystinuria. Details: According to case reports, taking glutamine orally does not seem to reduce the excretion of cysteine in the urine in patients with homozygous cystinuria (2339).
Low birth weight. Oral glutamine does not seem to reduce adverse consequences of low birth weight in infants. Details: Most clinical studies show that glutamine supplementation does not improve the time to full enteral feeding, infant growth rate, or length of hospital stay in low birth weight infants (52305,52312,52325,52342,52362,52410). One follow-up study also shows that neonatal glutamine supplementation is not associated with improvements in cognitive function, motor skills, or behavior outcomes by school age when corrected for neonatal infection rate (52342,97365).
Muscular dystrophy. Oral glutamine does not seem to improve symptoms of Duchenne muscular dystrophy. Details: Clinical studies show that taking glutamine 0.5-0.6 grams/kg orally does not significantly improve muscle strength or whole body protein degradation in children with Duchenne muscular dystrophy when compared with placebo or a nonspecific amino acid mixture (46657,52363).
Prematurity. Oral glutamine does not seem to reduce morbidity or mortality associated with prematurity. Details: A meta-analysis of clinical trials in preterm infants, including infants with low to very low birth weight, shows that use of enteral or parenteral glutamine does not reduce the risk of mortality or morbidities, such as necrotizing enterocolitis, when compared with control. However, limited evidence from a sub-group analysis suggests that enteral glutamine might modestly reduce the risk of invasive infection when compared with control (105015). These findings are limited by the selection bias and heterogeneity of the included trials.
Radiation-induced diarrhea. Oral glutamine does not seem to improve diarrhea due to radiation therapy. Details: One meta-analysis of five randomized, controlled trials shows that taking oral glutamine during radiotherapy for pelvic cancers does not prevent or reduce the severity of diarrhea when compared with placebo (97367).

Antiretroviral-associated diarrhea. It is unclear if oral glutamine improves diarrhea caused by antiretroviral agents. Details: A small crossover clinical study in HIV patients shows that oral glutamine 30 grams daily for 10 days seems to reduce the severity of nelfinavir-associated diarrhea when compared with placebo (52313).
Alcohol use disorder. Although there is interest in using oral glutamine for alcohol use disorder, there is insufficient reliable information about the clinical effects of glutamine for this condition.
Attention deficit-hyperactivity disorder (ADHD). Although there is interest in using oral glutamine for ADHD, there is insufficient reliable information about the clinical effects of glutamine for this condition.
Chemotherapy-induced diarrhea. It is unclear if oral glutamine improves diarrhea caused by chemotherapy. Details: Although preliminary clinical studies show that glutamine might reduce the occurrence of chemotherapy-induced diarrhea (7235,7285), a meta-analysis of this research and others shows no difference in the severity of diarrhea (7233,7295,96516). Despite results showing a significant 1-day reduction in the duration of diarrhea, this might not be considered clinically significant (96516).
Chemotherapy-induced lymphocytopenia. It is unclear if oral glutamine reduces lymphocytopenia caused by chemotherapy. Details: One small clinical study in patients with esophageal cancer receiving chemo-radiotherapy shows that taking glutamine 30 grams daily for 28 days seems to prevent a reduction in lymphocytes when compared with placebo (2705). However, another small clinical trial in patients with leukemia or lymphoma receiving intensive chemotherapy shows that adding glutamine 26 grams to total parenteral nutrition (TPN), in place of other amino acids, does not affect duration of neutropenia when compared with receiving an isonitrogenous standard TPN (7295).
Coronavirus disease 2019 (COVID-19). It is unclear if oral glutamine is beneficial in patients hospitalized with COVID-19 pneumonia. Details: A very small, nonblinded, non-randomized evaluation of otherwise healthy patients over 50 years of age who were hospitalized with mild COVID-19 pneumonia shows that taking glutamine 10 grams three times daily orally with meals is associated with a 1-day decrease in hospital stay (from 10 days to 9) when compared with patients not taking glutamine. In the latter group, 4 patients required transfer to the ICU, compared with no patients in the glutamine group (103839). A similar, non-randomized evaluation of adults hospitalized with COVID-19 pneumonia shows that adding the same dose of glutamine to other therapies for 5 days is associated with a 3-day decrease in hospital stay (from 14 days to 11) when compared with patients not taking glutamine. At the end of treatment, 0% of patients in the glutamine group required ICU services, compared with 54% of patients who did not receive glutamine. This study also shows that taking glutamine may increase appetite (108035). The validity of these findings is limited by short duration of treatment and use of non-standardized treatments.
Cystic fibrosis. It is unclear if oral glutamine improves growth and development in children with cystic fibrosis. Details: A small clinical study in undernourished or stunted children with cystic fibrosis shows that taking glutamine 0.7 grams/kg daily orally for 4 weeks with or without recombinant human growth hormone (rhGH) does not promote protein gain when compared with rhGH alone (52321).
Diabetic foot ulcers. Oral glutamine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a specific nutritional supplement drink containing glutamine 7 grams, arginine 7 grams, and hydroxymethylbutyrate 1.5 grams (Abound, Abbott) twice daily for 16 weeks does not improve total wound closure or reduce the time to complete healing when compared with a control drink in patients with diabetic foot ulcers (96637). It is unclear if this effect is due to glutamine, other ingredients, or the combination.
Diarrhea. It is unclear if oral glutamine improves diarrhea in children and infants. Details: One preliminary clinical study in 6-24 month-old otherwise healthy children with acute diarrhea shows that taking capsules prepared with a specific glutamine powder (Power Glutamine, Champion Nutrition) 0.3 grams/kg daily for 7 days reduces the duration of diarrhea by about one day when compared with placebo (52323). However, other clinical research in male infants 1-12 months old with acute diarrhea and dehydration shows that adding glutamine 90 mmol/L along with the standard World Health Organization oral rehydration salts (ORS) does not decrease the duration of diarrhea, stool output, or the volume of oral rehydration solution required to achieve and maintain hydration when compared with standard ORS alone (7298).
Hematopoietic stem cell transplant (HSCT). It is unclear whether oral glutamine or glutamine added to parenteral nutrition improves morbidity and mortality in patients undergoing HSCT. Some research has suggested that intravenous glutamine may actually worsen outcomes. Details: Some research suggests that patients receiving glutamine-supplemented parenteral nutrition (PN) after HSCT primarily to treat hematologic malignancies have a diminished incidence of clinical infections, lower rates of microbial colonization, and decreased length of hospital stay when compared to control (2366,52381). However, not all patients seem to benefit. Some research shows that oral glutamine or PN with glutamine does not reduce the risk of mortality or infections in patients with hematologic malignancies and/or solid tumors (5451,52385). Also, a small clinical study in patients undergoing HSCT shows that PN with glutamine dipeptide may increase the duration of hospital stay (52292). Furthermore, one small study has found that receiving PN with glutamine was associated with lower disease-free survival and event-free survival over 3 years when compared with standard PN in patients receiving HSCT for hematologic malignancies (52355).
Irritable bowel syndrome (IBS). There is limited evidence on the oral use of glutamine in patients with IBS. Details: A clinical trial in adults with IBS (diarrhea-predominant, constipation-predominant, mixed, or alternating bowel habits) shows that following a low FODMAP diet supplemented with oral glutamine 15 grams three times daily for 6 weeks improves IBS-Severity Scoring System (IBS-SSS) scores, with 88% of patients in the glutamine group reporting a 45% improvement in severity scores, compared with 60% of patients following the low FODMAP diet alone (108037). The validity of this finding is limited by short duration of treatment and lack of follow-up. Preliminary clinical research in patients with postinfectious, diarrhea-predominant IBS shows that taking glutamine 5 grams three times daily for 8 weeks leads to a nearly 14-fold greater likelihood of symptom improvement, defined as a reduction of 50 points or more on the IBS-SSS, and decreases stool frequency by 2.45 stools daily when compared with placebo. Taking glutamine also seems to reduce abdominal pain ratings by 55% and improve quality of life scores by 53% when compared to baseline in these patients (100944). The validity of these findings is limited by the lack of a comparator group.
Lung cancer. It is unclear if oral glutamine improves survival in patients with advanced lung cancer. Details: One small clinical study in patients with advanced non-small cell lung cancer shows that taking glutamine 10 grams three times daily for 12 months along with palliative chemoradiotherapy prevents weight loss, which is an important predictor of survival, but does not increase the likelihood of progression-free survival when compared with palliative chemoradiotherapy alone (100942). It is unclear if this study was adequately powered to detect a difference in survival between groups.
Malnutrition. It is unclear if oral alanyl-glutamine improves height and weight in children at risk for malnutrition. Details: Preliminary clinical research in children aged 2 months to 5 years from a low-income area of Brazil and at risk for malnutrition, shows that taking 3-12 grams of alanyl-glutamine orally daily for 10 days improves gut integrity and is associated with a modest, short-term increase in weight when compared with a glycine placebo (103838).
Exercise-induced muscle damage. It is unclear if oral glutamine is beneficial for exercise-induced muscle damage. Details: A very small clinical crossover trial in professional athletes undergoing rigorous training shows that taking oral glutamine 6 grams daily for 20 days reduces serum levels of creatine kinase and myoglobin when compared with placebo (108031). The validity of these findings is limited due to the small size and short duration of treatment.
Obesity. It is unclear if oral glutamine is beneficial for weight loss. Details: A preliminary clinical study in 36 overweight or obese adults shows that taking glutamine 30 grams daily for 2 weeks reduces waist circumference by 1.8 cm, but does not improve body weight, body mass index, or glycemic indices, when compared to baseline. None of these outcomes were improved over baseline in an alanine control group (100941). Given the small study size and short duration of therapy, the long-term effects of glutamine on anthropometric measures is unclear.
Opioid withdrawal. Oral glutamine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in Chinese patients undergoing detoxification from heroin shows that taking a combination of tyrosine, lecithin, 5-HTP, and glutamine 50 mg/kg orally daily for 6 days might reduce mood-related withdrawal symptoms when compared with placebo (88178). It is unclear if this effect is due to glutamine, other ingredients, or the combination.
Oral mucositis. There is contradictory evidence about the effects of glutamine in patients with, or at risk of developing, oral mucositis from chemotherapy or radiotherapy. Details: Small clinical studies suggest that taking glutamine orally or swishing and swallowing a glutamine solution can decrease the incidence, severity, and duration of oral mucositis in some patients undergoing chemotherapy and/or radiation therapy for cancer or hematopoietic stem cell transplant (HSCT) (2336,2368,2704,5029). Additionally, three meta-analyses of highly heterogeneous clinical trials in patients with cancer receiving chemotherapy and/or radiation therapy suggests that glutamine reduces the incidence of severe (grade ≥3) oral mucositis when compared with control (105014,108028,108036). These analyses are limited for several reasons, including reporting bias, lack of sensitivity analysis, and population heterogeneity. Some small clinical studies included in these meta-analyses suggest that supplementation with glutamine may reduce the need for feeding tubes and opioid analgesics (108028,108036). However, not all research has been positive. Some small clinical studies in patients receiving chemotherapy with 5-fluorouracil for cancer or HSCT suggest that oral or intravenous glutamine does not reduce the incidence of oral mucositis when compared with control (2365,5451,5462,7296,52349,52350). Furthermore, a meta-analysis of 5 clinical trials in patients with head or neck cancers shows that oral glutamine does not reduce the overall incidence or the incidence of moderate to severe radiation-induced oral mucositis when compared with control (103836). The Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology (MASCC/ISOO) cautiously recommends the use of oral glutamine to prevent oral mucositis in patients with head and neck cancer receiving chemoradiotherapy. However, due to some evidence suggesting that intravenous glutamine may actually worsen outcomes in HSCT patients, the MASCC/ISOO recommends against its use for the prevention of oral mucositis in patients receiving high-dose chemotherapy, with or without total body irradiation, for HSCT (105004).
Paclitaxel-induced myalgia and arthralgia. It is unclear if oral glutamine reduces the risk for myalgias and arthralgias due to paclitaxel. Details: One small clinical study shows that taking glutamine 10 grams three times daily for 5 days, starting on the day of chemotherapy and repeated over 2 cycles of chemotherapy, does not reduce the rate or severity of paclitaxel-induced myalgias or arthralgias when compared with placebo (52331).
Pancreatitis. It is unclear if oral glutamine improves outcomes in patients with acute pancreatitis. Details: Two meta-analyses of the available clinical research in patients with pancreatitis show that enteral or parenteral supplementation with glutamine increases albumin, decreases C-reactive protein, and might reduce mortality, multiple organ dysfunction syndrome, hospital length of stay, and infections. Results are difficult to interpret due to the significant heterogeneity of the included trials and limited generalizability of the results (96513,103835).
Peptic ulcers. Although there is interest in using oral glutamine for peptic ulcers, there is insufficient reliable information about the clinical effects of glutamine for this condition.
Postoperative infection. It is unclear if oral or intravenous glutamine is beneficial for the prevention of postoperative infection in patients with colorectal cancer who are recovering from surgery. Details: A meta-analysis of nonblinded clinical research in adults with colorectal or colon cancer who recently underwent radical surgery shows that daily supplementation with glutamine 0.3-1 grams/kg, administered either orally or parenterally, improves the rate of surgical site infections and anastomotic leakage when compared with control (108033). These findings are limited by the high heterogeneity of the included studies and unclear reporting.
Postoperative recovery. It is unclear if oral or intravenous glutamine is beneficial in patients with colorectal cancer who are recovering from surgery. Details: A meta-analysis of nonblinded clinical research in adults with colorectal or colon cancer who recently underwent radical surgery shows that taking either oral or parenteral glutamine 0.3-1 grams/kg daily may reduce the length of hospital stay when compared with control (108033). These findings are limited by the high heterogeneity of the included studies and unclear reporting.
Pressure ulcers. Oral glutamine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in patients with stages II-IV pressure ulcers shows that taking a specific nutritional supplement drink containing glutamine 7 grams, arginine 7 grams, and hydroxymethylbutyrate 1.5 grams per packet (Abound, Abbott Nutrition) as two packets twice daily by mouth for 2 weeks has no effect on wound area or healing scores by the Pressure Ulcer Scale for Healing (PUSH) measurement when compared with standard nutritional care (96506).
Radiation dermatitis. It is unclear if oral glutamine reduces the risk of developing dermatitis from radiation therapy. Details: One small clinical study in patients with head and neck cancers receiving cisplatin shows that taking a specific supplement containing glutamine 7 grams, arginine 7 grams, and hydroxymethylbutyrate 1.5 grams (Abound, Abbott) orally twice daily, starting on day 1 of radiation and continuing until 1 week after radiation therapy, does not reduce the incidence of severe radiation-induced dermatitis when compared with no supplementation (96639). However, another small clinical study in patients with breast cancer who have had both chemotherapy and surgery shows that taking oral glutamine 5 grams three times daily, starting 1 week before radiation and continuing until 1 week after radiation, is associated with a reduction in grade 1 and grade 2 radiation dermatitis when compared with placebo (97366).
Radiation-induced esophagitis. It is unclear if oral glutamine reduces the risk of developing esophagitis from radiation therapy. Details: A small clinical study in patients with advanced non-small cell lung cancer shows that taking glutamine 10 grams three times daily for 12 months along with a palliative dose of chemoradiotherapy (total 30 Gy) results in a 7% incidence of symptomatic (grade 2 or higher) radiation-induced esophagitis, compared with a 53% incidence with palliative chemoradiotherapy alone. The glutamine group also had a 5.8-day delay in the onset of esophagitis (100942). However, a lower dose of glutamine in patients receiving higher doses of radiotherapy might not be beneficial. A small clinical study in patients with advanced thoracic malignancies shows that taking glutamine 4 grams mixed in water twice daily for 4 weeks along with radiotherapy (total dose of at least 45 Gy) to the esophagus, with or without chemotherapy, does not slow the onset of radiation-induced esophagitis or reduce its severity when compared with a glycine placebo (105011).
Short bowel syndrome. It is unclear if oral glutamine improves symptoms of short bowel syndrome. Details: Although small clinical studies suggest that glutamine plus growth hormone can decrease dependence on parenteral nutrition in some patients (2334,2361,2362,2703), it has not shown benefit for improving intestinal absorption of energy in all studies (8185). Additionally, glutamine alone doesn't appear to be beneficial (7730).
Traumatic Brain injury (TBI). It is unclear if intravenous glutamine is beneficial in patients hospitalized with severe TBI. Details: A clinical trial in patients hospitalized for a severe TBI shows that adherence to a hypocaloric, low-protein diet supplemented with daily intravenous glutamine 0.3 g/kg for 7 days does not improve 28-day mortality when compared with standard nutritional support alone. However, it may reduce the length of ventilator use, hospitalization, and duration of intensive care unit stay (108034).
Vincristine-induced neuropathy. It is unclear if oral glutamine reduces the risk of developing neuropathy from treatment with vincristine in children. Details: Preliminary clinical research in children ages 1-21 years receiving vincristine for various cancer types shows that taking glutamine 6 grams/m2 twice daily orally for 21 days reduces sensory neuropathy when compared with placebo. There was a significant improvement in self-reported, but not parent-reported, quality of life scores as measured by the PedsQL scale. However, there was no effect on motor neuropathy with the use of glutamine (96517).
Wound healing. It is unclear if oral glutamine improves wound healing. Details: Preliminary clinical research in trauma patients with wound healing disorders shows that taking glutamine 20 grams orally daily in combination with ascorbic acid 500 mg, vitamin E 166 mg, beta-carotene 3.2 mg, selenium 100 mcg, and zinc 6.6 mg (Glutamine Plus, Fresenius Kabi) for 14 days reduces the time to wound closure by 29 days when compared with placebo. However, there is no difference in length of stay (97364). More evidence is needed to rate glutamine for these uses.

Schizophrenia. Oral glycine may improve negative, but not positive, symptoms of schizophrenia when used as adjunct to therapy with typical antipsychotics in patients resistant to monotherapy. However, glycine does not seem to provide additional benefit when used with clozapine. Details: Some small clinical trials show that taking glycine 0.4-0.8 grams/kg daily in divided doses along with conventional treatment seems to reduce negative symptoms of schizophrenia in patients that are resistant to monotherapy with typical antipsychotics such as thioridazine, haloperidol, and perphenazine (10250,10251,10252,98591). However, when used with the atypical antipsychotic clozapine, glycine appears to have a negligible effect on or worsen symptoms of schizophrenia (10253,11321). Additionally, glycine does not seem to improve positive symptoms of schizophrenia (10250,10251,10252,98591).

3-phosphoglycerate dehydrogenase (3-PGDH) deficiency. It is unclear if oral glycine is beneficial in patients with 3-PGDH deficiency. Details: A case series describing two patients with 3-PGDH deficiency who did not respond to serine supplementation suggests that taking oral glycine 0.2 grams/kg daily along with serine might reduce seizure frequency. 3-PGDH deficiency is a rare condition in which serine is not synthesized properly (10254).
Aging. Oral glycine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in adults aged 61-80 years with overweight or obesity shows that taking a specific combination product (GlyNAC), providing glycine 100 mg/kg and N-acetyl cysteine 100 mg/kg, daily for 16 weeks improves some markers associated with aging, including glutathione levels, oxidative stress, mitochondrial impairment, genomic damage, inflammation, and endothelial dysfunction, when compared to baseline. Improvements in these measures were lacking in the placebo group (110624). The validity of these findings is limited by a lack of statistical comparison between groups. Also, it is unclear if these effects are due to glycine, N-acetyl cysteine, or the combination.
Attention deficit-hyperactivity disorder (ADHD). Although there has been interest in using oral glycine for ADHD, there is insufficient reliable information about the clinical effects of glycine for this purpose.
Benign prostatic hyperplasia (BPH). Although there has been interest in using oral glycine for BPH, there is insufficient reliable information about the clinical effects of glycine for this purpose.
Cognitive function. Small clinical studies suggest that oral glycine may modestly improve memory and cognitive function in some patients. Details: Two small clinical studies in healthy young adults and adults with psychosis risk syndrome show that taking glycine 0.2-0.4 grams/kg once or twice daily for up to 24 weeks may improve some measures of memory and cognitive performance when compared with baseline or placebo (11322,92321).
Cystic fibrosis. It is unclear if oral glycine is beneficial in patients with cystic fibrosis. Details: A small clinical trial in patients 6-23 years of age with cystic fibrosis shows that taking glycine 0.5 grams/kg daily for 8 weeks modestly improves some measures of lung function and reduces sputum and dyspnea by 15% and 23%, respectively, when compared with placebo. However, taking glycine does not improve appetite or energy (98583).
Gout. Oral glycine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in patients with mild hyperuricemia shows that taking a powder containing glycine 3 grams and L-tryptophan 0.2 grams nightly at bedtime for 6 weeks reduces serum uric acid levels by 0.3 mg/dL when compared with placebo. Improvements also occurred in the subgroup of patients with uric acid levels greater than 7 mg/dL, the point at which symptoms of gout can occur (99883). However, it is unclear if this combination improves gout-related pain. Also, it is not clear if these findings are due to glycine, L-tryptophan, or the combination.
Insomnia. Small clinical studies suggest that oral glycine may modestly improve sleep quality and daytime feelings of fatigue in patients with poor sleep quality or a restricted sleep duration. Details: Two very small studies in patients who have reported a subjective reduction in sleep quality show that taking glycine 3 grams one hour before bedtime for 2-4 days improves overall sleep quality and sleep efficacy when compared with placebo (92318,92320). Another very small clinical study in healthy males shows that taking glycine 3 grams 30 minutes before bedtime for 3 nights, during which time sleep duration is restricted by 25%, modestly reduces feelings of fatigue after the first night, but not after the third night, when compared with placebo (92316). The effects of glycine on sleep measures have also been evaluated in combination with other ingredients. A very small crossover study in healthy adults without documented sleep disorders shows that taking a combination product containing glycine 3000 mg, tryptophan 1000 mg, magnesium 300 mg, tart cherry powder 220 mg, and L-theanine 200 mg before bed for 3 nights reduces sleep onset latency, increases total sleep time, increases sleep efficiency, and reduces morning sleepiness when compared with placebo (111184). It is unclear if these effects are due to glycine, other ingredients, or the combination.
Isovaleric acidemia. Although there has been interest in using oral glycine for isovaleric acidemia, there is insufficient reliable information about the clinical effects of glycine for this purpose.
Metabolic syndrome. Although there has been interest in using oral glycine for metabolic syndrome, there is insufficient reliable information about the clinical effects of glycine for this purpose.
Obesity. Oral glycine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in adults aged 61-80 years with overweight or obesity shows that taking a specific combination product (GlyNAC), providing glycine 100 mg/kg and N-acetyl cysteine 100 mg/kg, daily for 16 weeks reduces waist circumference but does not improve body weight or body mass index (BMI) when compared to baseline. None of these outcomes were improved in individuals taking placebo (110624). The validity of these findings is limited by a lack of statistical comparison between groups. Also, it is unclear if these effects are due to glycine, N-acetyl cysteine, or the combination.
Overactive bladder. It is unclear if oral glycine is beneficial in patients with overactive bladder. Details: One very small, non-randomized, crossover trial in patients with overactive bladder shows that taking glycine 3 grams twice daily for 4 weeks reduces urinary urgency, urinary incontinence, and nighttime urinary frequency and improves quality of life scores when compared with placebo (106497). The validity of these findings is limited by a lack of randomization.
Physical performance. Oral glycine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in adults aged 61-80 years with overweight or obesity shows that taking a specific combination product (GlyNAC), providing glycine 100 mg/kg and N-acetyl cysteine 100 mg/kg, daily for 16 weeks improves upper and lower extremity strength and gait speed, but not walking distance, when compared to baseline. None of these outcomes were improved in individuals taking placebo (110624). The validity of these findings is limited by a lack of statistical comparison between groups. Also, it is unclear if these effects are due to glycine, N-acetyl cysteine, or the combination.
Stroke. It is unclear if sublingual glycine is beneficial in patients with acute ischemic stroke. Details: One small clinical study in patients with acute ischemic stroke in the carotid artery territory shows that taking glycine 1-2 grams sublingually daily for 5 days, starting within 6 hours after the onset of stroke, modestly improves clinical outcomes on the Orgogozo Stroke Scale, the Scandinavian Stroke Scale, and the Barthel index when compared with placebo (11320).
Venous leg ulcers. Topical glycine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study shows that applying a cream containing glycine, L-cysteine, and DL-threonine to leg ulcers reduces pain and modestly improves healing when compared with a placebo cream (10255). It is unclear if these effects are due to glycine, other ingredients, or the combination.
Wound healing. Although there has been interest in using topical glycine for wound healing, there is insufficient reliable information about the clinical effects of glycine for this purpose. More evidence is needed to rate glycine for these uses.

L-ARGININE

Angina. Oral L-arginine seems to improve symptoms and exercise tolerance in patients with angina. Details: Clinical research shows that taking L-arginine orally seems to decrease symptoms and improve exercise tolerance and quality of life in patients with mild to severe angina (3593,7815,7816,31866,31923). Some patients with severe angina who have frequent attacks at rest despite treatment with standard antianginal agents might also benefit from L-arginine (3593). However, L-arginine does not seem to improve objective measures of blood vessel dilation or increase circulating concentrations of nitric oxide (7817,99262). Also, when used in combination with ten 200 mcg injections of vascular endothelial growth factor (VEGF)-165 plasmid DNA, L-arginine 6 grams daily orally for 3 months does not improve angina severity in patients with coronary artery disease who underwent surgical angiogenesis compared to patients who did not receive this combination (32001). In addition, intravenous infusion of arginine 10% solution does not improve exercise capacity in patients with stable angina when compared with placebo (31843,32293).
Erectile dysfunction (ED). Oral L-arginine might improve symptoms of ED. When taken with phosphodiesterase type 5 (PDE5) inhibitors, L-arginine seems to provide a small additional benefit. Details: Taking L-arginine orally in high doses, 5 grams daily, improves subjective assessment of sexual function in males with organic ED when compared with placebo (222,102586). Additionally, a meta-analysis of 4 small clinical studies in patients with ED, including those with diabetes and/or cardiovascular disease risk factors, shows that although PDE5 inhibitors improve sexual function better than L-arginine, the combination of PDE5 inhibitors and L-arginine may be more effective than either treatment alone (105065). In most clinical trials, doses of L-arginine 2.5-5 mg daily for 6-12 weeks were used alone or in addition to PDE5 inhibitors such as sildenafil 50 mg or tadalafil 5-10 mg daily (102586,102587,102592,104222). Higher doses have also been investigated. One clinical trial shows that taking L-arginine (Bioarginina, Farmaceutici Damor S.p.A., Napoli, Italy), 2 grams three times daily for 3 months improves sexual function compared with placebo (110387). However, taking lower doses, 1.5 grams daily, might not be effective in patients with mixed-type ED (2038). L-arginine has also been examined in combination with other ingredients. Some preliminary clinical evidence suggests that taking L-arginine orally in low doses, 1.7 grams daily in combination with maritime pine bark extract (Pycnogenol) or taking 0.69 grams daily along with maritime pine bark extract and aspartic acid (Edicare, Kobayashi Pharmaceutical Co. Ltd.) modestly improves symptoms of ED (10416,50924). Another preliminary clinical trial has investigated the effects of a combination of L-arginine 2.5 grams daily for 6 months and tadalafil 5 mg daily for 3 months, both starting with the initiation of weekly extracorporeal shock wave (ESW) therapy. When compared with ESW alone, this combination modestly improves sexual function for up to 12 months (110388). The effect of L-arginine alone is not clear from these studies.
Hypertension. Oral L-arginine can modestly reduce systolic and diastolic blood pressure. Details: Oral L-arginine seems to have additive vasodilating effects when used with angiotensin converting enzyme (ACE) inhibitors or nitrate vasodilators such as isosorbide mononitrate (7822,20192,31916). A meta-analysis of clinical research in a variety of populations shows that taking L-arginine reduces systolic and diastolic blood pressure (SBP; DPB) by an average of 6.40 mmHg and 2.64 mmHg, respectively. Sub-analyses show that these reductions occur in both normotensive and hypertensive individuals. Beneficial effects were limited to adults with a body mass index (BMI) of 18.5 to 19.9 kg/m² (110384). The effect of L-arginine on blood pressure levels in adults exposed to traffic-related air pollution (TRAP) has also been investigated. Clinical research in adults with hypertension shows that taking L-arginine 3 grams three times daily for 2 weeks modestly reduces SBP and DBP elevations following a 2-hour exposure to TRAP during an outdoor walk compared with taking placebo (110383). Doses have included 4-24 grams daily, with the best evidence of benefit for doses of less than 9 grams daily, for 2-24 weeks (7818,10636,31871,31923,32167,32201,110383,110384).
Necrotizing enterocolitis (NEC). Oral L-arginine may help prevent NEC in premature infants. Details: In a meta-analysis of 3 clinical trials, L-arginine 260 mg/kg orally in a single dose or two divided doses daily reduces the absolute risk of NEC in premature infants by about 62% when compared with placebo. To prevent one case of NEC, 6 infants would need to be treated with L-arginine (8474,91194,96803).
Peripheral arterial disease (PAD). Short-term use of intravenous or oral L-arginine may improve symptoms of PAD, but long-term use does not seem to be beneficial. Details: Clinical research shows that using L-arginine intravenously or orally for up to 8 weeks increases flow-mediated dilation and improves symptoms of intermittent claudication associated with PAD (3465,31857,31905). However, long-term administration of L-arginine orally for up to 6 months does not improve walking speed, walking distance, or absolute claudication distance in patients with PAD and intermittent claudication (31957,31985).
Pre-eclampsia. Intravenous L-arginine may have beneficial effects in pre-eclampsia. However, it is unclear if oral L-arginine is effective. Details: One small clinical study shows that intravenous L-arginine 30 grams as a one-time dose decreases systolic blood pressure (SBP) by 5 mmHg and diastolic blood pressure by 11 mmHg when compared to baseline in pregnant patients with hypertension or pre-eclampsia (31847), while intravenous L-arginine 20 grams daily for 5 days decreases SBP and DBP by about 2% when compared with placebo (31978). Another small clinical study shows that oral use of L-arginine 3 grams daily for 3 weeks reduces SBP and DBP by around 7 and 5 mmHg, respectively, when compared with placebo (31938); however, taking L-arginine 12 grams daily by mouth for 5 days does not seem to improve blood pressure in these patients (11828). Another preliminary clinical trial allowing for both oral and intravenous dosing shows that taking L-arginine 3.5 grams by mouth every 6 hours or 10 grams via intravenous infusion every 8 hours shortly before or immediately after delivery and continuing until postpartum day 3 does not improve blood pressure when compared with placebo (31959). The reasons for the disparate findings are unclear, but the small study sizes, as well as variations in the dose, duration, and timing of therapy before and/or after delivery, may explain some of the differences. Oral L-arginine has also been evaluated for the prevention of pre-eclampsia. One clinical study in patients at high risk for pre-eclampsia shows that taking L-arginine 3 grams daily starting the 20th week of gestation reduces the risk of pre-eclampsia by about 74% when compared with placebo (96811). Based on these results, one case of pre-eclampsia is prevented for every 6 high-risk pregnant patients treated with L-arginine 3 grams daily. Another clinical study also shows that taking two bars of a specific medical food (Heart Bars, Nellson Nutraceutical) containing L-arginine 6.6 grams and antioxidant vitamins daily starting at 14-32 weeks gestation and continuing until delivery reduces the risk of pre-eclampsia by 44% when compared with a bar containing antioxidant vitamins alone in patients at high risk of pre-eclampsia (91197). Based on these results, one case of pre-eclampsia is prevented for every 11 high risk patients treated with this L-arginine-containing medical food.
Pregnancy-induced hypertension. Intravenous L-arginine may have beneficial effects in pregnancy-induced hypertension. Details: Some clinical research in patients with pregnancy-induced hypertension shows that intravenous infusion of L-arginine 20 grams daily for up to 5 days decreases systolic blood pressure by 2% to 3% and diastolic blood pressure by about 3% when compared with placebo (31933,31961,31978). Clinical research in patients with pre-existing hypertension has also been conducted. One clinical trial shows that taking L-arginine 4 grams by mouth daily for 10-12 weeks does not seem to reduce blood pressure in those with pre-existing hypertension or mild gestational hypertension. However, these results are confounded by the fact that more patients taking placebo needed to be placed on antihypertensive therapy during the study. L-arginine reduced the risk of being placed on antihypertensive drug therapy during the pregnancy by 47% when compared with placebo (32191). Based on this study, for every 5 patients with pregnancy-induced hypertension treated with L-arginine over placebo, antihypertensive drug therapy is avoided in one additional patient. L-arginine has also been investigated in combination with other ingredients in patients with pre-existing hypertension. Preliminary clinical research in patients with pre-existing hypertension and a previous history of pre-eclampsia, stillbirth, intrauterine growth restriction (IUGR), or other placenta vascular disorder shows that taking L-arginine and other ingredients starting at 14 weeks gestation prevents an increase in blood pressure and reduces the percentage of patients requiring new antihypertensive medication by about 73% compared with 24.5% of those not taking this combination. In this study, L-arginine 3 grams daily was taken with magnesium 350 mg and salicylate 100 mg. Therefore, the effect of L-arginine alone is unclear. All patients in the study were taking low dose aspirin 100 mg daily (110382).

POSSIBLY INEFFECTIVE

Chronic kidney disease (CKD). Oral or intravenous L-arginine does not seem to improve CKD. Details: Most preliminary clinical research shows that taking L-arginine, either orally for up to 6 months or intravenously short-term, does not improve kidney function, glomerular filtration rate, or renal plasma flow in patients with CKD, although proteinuria may be reduced in some patients (31844,31904,32235,32303).
Hypercholesterolemia. Oral L-arginine does not seem to reduce cholesterol levels. Details: Preliminary clinical research in patients with hypercholesterolemia shows that taking L-arginine 21 grams daily for 4 weeks does not reduce plasma lipids (1363). Furthermore, meta-analyses of clinical research show that taking L-arginine for up to about 6 months does not reduce total or low-density lipoprotein (LDL) cholesterol levels in populations of healthy individuals or those with cardiovascular disease risk factors. However, there was a very small effect on fasting triglyceride levels (102590,102591).
Myocardial infarction (MI). Oral L-arginine does not seem to improve outcomes after MI. Details: Patients who have had an ST-segment MI who take L-arginine within 24 hours to 21 days, titrated up to a dose of 3 grams three times a day for up to 6 months, do not seem to have reduced vascular stiffness or increased ejection fraction (13221,32137). Also, there is some concern that long-term use of L-arginine might actually worsen outcomes and increase mortality in these patients (13221). Population studies also suggest that intake of L-arginine does not reduce the risk of experiencing an acute coronary event such as MI or coronary heart disease-related mortality (3332,6896,7821,10637).
Tuberculosis. Oral L-arginine does not seem to improve symptoms or the clearance of tuberculosis infection. Details: Clinical research shows that taking L-arginine (ArgimaxH) 6 grams daily orally for 8 weeks, with or without vitamin D, does not improve symptoms of tuberculosis or the clearance of tuberculosis infection when used with standard treatment (91196).
Wound healing. Oral L-arginine does not seem to improve wound healing. Details: Clinical research shows that taking L-arginine (as arginine aspartate) 17 grams orally in three divided doses daily for 2 weeks does not improve epithelialization in healthy, elderly patients with catheter wounds, although it may improve collagen deposition (32247). Also, taking L-arginine (as L-arginine hydrochloride) 26 grams daily for 5 days perioperatively does not improve angiogenesis, re-epithelialization, or neutrophil count in patients undergoing skin graft donation when compared with placebo (20692). In addition, taking a wound-specific oral nutrition supplement containing L-arginine 4.5 grams, zinc, and vitamin C twice daily for 4 weeks, along with standard wound care for 8 weeks, is no more effective for wound healing than a standard oral nutrition supplement along with standard wound care (90198). L-arginine has also been studied in combination with other ingredients. Taking L-arginine enterally or orally, before or after surgery, in combination with ribonucleic acid (RNA) and either eicosapentaenoic acid (EPA) or fish oil, seems to improve wound healing when compared with a control group (5531,32174). However, due to the lack of benefit seen with the use of L-arginine alone, it is possible that this effect is due to the other ingredients or the combination of ingredients.

Acute respiratory distress syndrome (ARDS). Small clinical studies suggest that oral L-arginine may prevent ARDS. Details: A meta-analysis of three small studies shows that taking L-arginine 3 grams daily, starting in the second or third trimester usually until delivery, reduces the risk of ARDS in the infant by about 54% when compared to control, including placebo or no treatment (110379).
Altitude sickness. It is unclear if oral L-arginine is beneficial in patients with altitude sickness. Details: Preliminary clinical research shows that taking L-arginine 4 grams orally three times daily for 2 days while ascending to a high altitude and for 24 hours while at high altitude does not reduce altitude sickness when compared with placebo (31955).
Anthracycline cardiotoxicity. Although there is interest in using oral L-arginine for anthracycline cardiotoxicity, there is insufficient reliable information about the clinical effects of L-arginine for this purpose.
Anemia of chronic disease. It is unclear if oral L-arginine is beneficial for anemia in patients with chronic kidney disease. Details: One very small clinical study in elderly adults with chronic kidney disease and anemia shows that taking L-arginine orally 1.3 grams daily might increase hemoglobin and erythropoietin levels in some patients when compared to baseline (31988). The validity of these findings is limited by the small study size and the lack of a comparator group.
Asthma. It is unclear if oral L-arginine is beneficial in patients with asthma. Details: Preliminary clinical research in adults with severe asthma shows that taking L-arginine 0.05 gram/kg ideal body weight twice daily does not reduce asthma exacerbations when compared with placebo (104223). This study may have been inadequately powered to detect a difference in exacerbation rates between groups. While other studies have shown adverse airway effects in patients with asthma (121,31849), this study demonstrated no change in exacerbations and reported no adverse airway effects.
Athletic performance. Small clinical studies suggest that oral L-arginine may improve measures of athletic performance. Details: A meta-analysis of 5 small clinical trials shows that taking L-arginine seems to modestly improve measures of cardiorespiratory fitness, as measured by a 0.07 L/minute increase in maximal oxygen uptake, when compared with control (105064). L-arginine has also been examined for its effects on athletic performance. Most research suggests that taking L-arginine does not improve athletic performance. However, clinical trials are small and may not be adequately powered to detect a difference in these outcomes Taking L-arginine as a single dose of 5 or 6 grams or as 5-10 grams daily for 2-4 weeks does not improve grip strength, strength during resistance exercise, power output during cycling, or muscle function during recovery from intense resistance exercise in healthy adults (91190,97393,99265,110381,110389). Also, taking L-arginine 5 grams daily for 4 weeks (Bioarginina Farmaceutici Damor) or 8 grams daily for 8 days does not increase swim speed (110381,110386). In contrast, some research suggests that drinking a single beverage containing the same dose of L-arginine 6 grams increases the time to exhaustion during high-intensity exercise when compared with placebo (32180). Also, a meta-analysis of small clinical trials shows that supplementation with L-arginine has a large beneficial effect on aerobic performance and a small beneficial effect on anaerobic performance. However, publication bias was evident in the aerobic performance data, limiting these conclusions. Doses found to be beneficial in this analysis included an acute dose of L-arginine 0.15 gram/kg 60-90 minutes before performance or chronic dosing of 1.5 grams to 2 grams daily for 4-7 weeks for aerobic performance. The chronic dose of L-arginine most likely to be beneficial for anaerobic performance is unclear from this analysis due to inclusion of studies using arginine alpha-ketoglutarate (110395). With the exception of a few studies which include a very small number of healthy females (99265,110395,110386), research on the use of L-arginine for athletic performance has focused almost exclusively on healthy males. Also, studies are heterogeneous with respect to sport and endpoints. Therefore, whether results can be applied to females or specific athletes is unclear. L-arginine has also been evaluated in overweight males. One small clinical study shows that taking a single dose of L-arginine 6 grams 90 minutes prior to high-intensity interval training seems to improve exercise tolerance by improving ventilation, heart rate, and oxygen uptake when compared with placebo (105060). L-arginine has also been evaluated in combination with other ingredients. Research in male soccer players shows that taking L-arginine 1.2 grams and L-citrulline 1.2 grams daily for 7 days increases total power output over a 10-minute cycling test and improves subjective perceptions of exertion when compared with placebo (100956). Another study shows that taking L-arginine 1.5 or 3 grams daily, in combination with grape seed extract, increases physical working capacity at fatigue threshold when compared with pretreatment in untrained, college-aged males (32164).
Beta-thalassemia. It is unclear if oral L-arginine is beneficial in children with beta-thalassemia. Details:Preliminary clinical research in children aged 6-18 years treated conventionally for pulmonary hypertension related to beta-thalassemia shows that taking L-arginine 0.1 mg/kg daily for 60 days reduces Doppler echocardiography pulmonary arterial pressure by 35% compared with baseline. This measurement was increased by up to 15% in children given conventional treatments only; however, a statistical comparison between these treatment groups was lacking (110391).
Breast cancer. It is unclear if oral L-arginine is beneficial in patients with breast cancer. Details: Preliminary clinical research shows that taking L-arginine 30 grams daily for 3 days prior to chemotherapy does not improve the clinical response rate in breast cancer patients when compared with placebo (32282).
Cognitive impairment. It is unclear if oral L-arginine is beneficial in patients with cognitive impairment. Details: A small clinical trial in frail adults aged 65 years of age and up with hypertension shows that taking L-arginine (Bioarginina) 1.66 grams twice daily for 4 weeks modestly improves cognitive function when compared to placebo (110385).
Congestive heart failure (CHF). It is unclear if oral L-arginine is beneficial in patients with CHF. Details: One small clinical study in patients with CHF stage 2-3 shows that taking L-arginine 15 grams daily for 5 days, in combination with conventional treatment, seems to improve glomerular filtration rate (GFR), creatinine clearance, and sodium and water elimination after saline loading, indicating an improvement in kidney function (3596).
Coronavirus disease 2019 (COVID-19). It is unclear if oral L-arginine is beneficial in patients with severe COVID-19 infection. Details: A small clinical trial in patients with severe COVID-19 shows that receiving oral L-arginine (Argin, Nutrigrow, India) 3 grams daily for a maximum of 10 days while on oxygen support does not affect the percentage of patients weaned off oxygen support after 10 days, the length of time requiring oxygen support, the duration of hospitalization, or the incidence of adverse thrombotic events, compared with placebo (110392). This study may not have been adequately powered to detect differences between groups. An interim analysis of a small clinical trial in patients hospitalized with severe COVID-19 shows that adding oral L-arginine (Bioarginina, Farmaceutici Damor) 1.66 grams twice daily to standard therapy throughout hospitalization increases the rate of respiratory support reduction by 60% after 10 days of therapy, but not after 20 days of therapy, when compared with placebo. L-arginine also significantly reduced the length of hospital stay. The median hospital stay was 25 days and 46 days, respectively, for L-arginine and placebo (106500). L-arginine has also been investigated in combination with other ingredients for post-acute COVID symptoms. Preliminary clinical research in adults with persistent fatigue following a COVID infection shows that taking L-arginine 1.66 grams plus vitamin C 500 mg (Bioarginina C, Farmaceutici Damor) twice daily for 28 days increases the distance walked in 6 minutes by 30 meters and reduces the percentage of patients with fatigue by about 89%, when compared with placebo. Grip strength was also increased (110390).
Coronary artery bypass graft (CABG) surgery. It is unclear if oral L-arginine is beneficial for preventing complications after CABG surgery. Details: Preliminary clinical research shows that venous infusion of L-arginine hydrochloride 30 grams as a 10% solution over 15 minutes helps maintain mean arterial pressure, coronary vascular resistance, and graft blood flow when compared with a placebo infusion in patients that have undergone CABG (31840). Administering L-arginine 7.5 grams in 500 mL of cardioplegic solution also seems to reduce wedge pressure and intensive care unit stay in patients undergoing CABG; however, it does not reduce hospital stay duration or postoperative complications when compared with cardioplegic solution alone (31958,31886).
Critical illness (trauma). Oral L-arginine has only been evaluated in combination with other ingredients; its effects when used alone are unclear. Details: A meta-analysis of clinical research shows that taking L-arginine orally with glutamine, nucleotides, and omega-3 fatty acids reduces the recovery time, the need for ventilation, and infection rates in critically ill patients, but does not reduce the risk of mortality (31853).
Cyclosporine-induced nephrotoxicity. Although there is interest in using oral L-arginine for cyclosporine-induced nephrotoxicity, there is insufficient reliable information about the clinical effects of L-arginine for this purpose.
Cystic fibrosis. It is unclear if oral L-arginine is beneficial in patients with cystic fibrosis. Details: Preliminary clinical research in teens and adults with cystic fibrosis shows that twice daily inhalation with L-arginine 500 mg for 2 weeks does not improve lung function when compared with inhaling 2.6% hypertonic saline twice daily (96807).
Dental caries. Small clinical studies suggest that using a dentifrice containing L-arginine might prevent dental caries. Details: A meta-analysis of small studies shows that use of a dentifrice containing L-arginine 1.5% w/w in combination with calcium base (Dical or calcium carbonate) and fluoride 1450 ppm 2-3 times daily for up to 2 years reduces the risk of developing dental caries by a small to moderate amount when compared with a dentifrice containing only fluoride in children and adults (96806). Also, preliminary clinical research shows that using a confection containing an L-arginine complex (CaviStat) for one year reduces the number of dental caries in molars of children when compared with a sugarless mint control (32011).
Dental hypersensitivity. Oral L-arginine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that using a toothpaste containing L-arginine, calcium, and fluoride twice daily reduces dentin hypersensitivity when compared with pretreatment or control (32130,32131,32132,32177).
Diabetes. Small, low-quality studies suggest that oral L-arginine does not improve glycemic control in people with type 2 diabetes. Details: A meta-analysis of small, low-quality studies shows that taking L-arginine 2-20 grams daily for up to 77 weeks decreases fasting blood glucose and serum insulin levels in adults without diabetes. However, no improvements occurred in adults WITH type 2 diabetes. This may be explained by previous studies which suggest L-arginine affects glucose control only in the early steps of beta-cell dysfunction. L-arginine did not improve insulin resistance or glycated hemoglobin (HbA1c) in patients with or without diabetes (104225). Also, a prospective observational study in patients with type 1 or type 2 diabetes has found that taking a specific product (Flebotrofine, AMNOL Chimica Biologica) containing L-arginine for 3 months is not associated with improvements in HbA1c, cholesterol, or triglyceride levels when compared with baseline. Other ingredients in this product included diosmin, troxerutin, hesperidin, black currant extract, and gotu kola extract (108151). The validity of these findings is limited by the lack of a comparator group.
Diabetic foot ulcers. It is unclear if oral or subcutaneous L-arginine is beneficial in patients with diabetic foot ulcers. Details: A very small clinical study shows that administering L-arginine subcutaneously at the site of diabetic foot ulcers does not decrease healing time or rate of amputation when combined with conventional therapies (14914). Also, taking a specific drink containing L-arginine 7 grams, L-glutamine 7 grams, and calcium hydroxymethylbutyrate (HMB) 1.5 grams (Juven/Abound, Abbott Nutrition) orally twice daily for 16 weeks does not improve diabetic foot ulcer healing when compared with a control drink in non-ischemic patients or those with normal albumin levels. However, in specific populations with low albumin and/or poor limb perfusion, up to 74% more patients had total wound healing when compared with the control drink (96637).
Diabetic neuropathy. It is unclear if oral L-arginine is beneficial in patients with diabetic neuropathy. Details: Preliminary clinical research shows that taking L-arginine 3 grams daily for 3 months does not improve circulation, disability, or nerve function in patients with diabetic neuropathy when compared with placebo (32145).
Head and neck cancer. It is unclear if oral L-arginine is beneficial in patients with head and neck cancer. Details: Small clinical studies suggest that enteral nutrition supplemented with L-arginine does not seem to have any beneficial effects on markers of immune function such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), length of postoperative hospital stay, or fistula rates; however, it seems to reduce wounds and general infections after surgery in patients with head and neck cancer when compared with control (10160,32008).
Heart failure. It is unclear if oral L-arginine is beneficial in patients with heart failure. Details: Preliminary clinical research in adults with heart failure shows that taking L-arginine 3.0-12.6 grams orally daily for 6-12 weeks does not consistently improve exercise tolerance or peripheral vascular resistance (3595,6028,32138). However, some research shows that taking L-arginine 1000 mg three times daily for 10 weeks modestly improves measures of cardiac function compared with placebo (110380). Although some research disagrees (32138), most research shows that taking L-arginine modestly improves quality of life (3595,110380).
Heart transplant complications. It is unclear if oral L-arginine is beneficial in patients that have received a heart transplant. Details: Preliminary clinical research shows that taking L-arginine 6 grams orally twice daily for 6 weeks increases walking distance and oxygen uptake and delays the ventilatory threshold in heart transplant patients when compared with baseline (32150).
HIV/AIDS-related wasting. Oral L-arginine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One clinical study in patients with HIV/AIDS shows that taking L-arginine orally, in combination with hydroxymethylbutyrate (HMB) and glutamine for 8 weeks, increases body weight, particularly lean body mass, and positively affects immune status when compared with placebo (1909). However, other clinical research in HIV-positive patients shows that taking L-arginine 7.4 grams daily orally, in combination with omega-3 fatty acids and a balanced oral nutritional supplement for 6 months, does not improve body weight or fat mass, total energy intake, or immune status when compared to taking the nutritional supplement alone (113).
Impaired glucose tolerance (prediabetes). It is unclear if oral L-arginine can prevent the development of type 2 diabetes in adults with prediabetes. Details: Clinical research shows that taking L-arginine (Bioarginine, Farmaceutici Damor) 3.2 grams orally twice daily for 18 months does not reduce the incidence of diabetes in patients with impaired glucose tolerance (prediabetes). However, when assessed one year after treatment discontinuation, patients who took L-arginine had a 58% lower risk of developing diabetes when compared with placebo (91195).
Infertility. It is unclear if oral L-arginine improves outcomes in people undergoing an assisted reproductive technology (ART) program. Details: Some preliminary clinical research shows that taking L-arginine 16 grams daily decreases the cancellation rate of in vitro fertilization (IVF) and increases the number of oocytes collected in females undergoing an ART program when compared with control. However, taking L-arginine does not seem to improve the number of viable pregnancies (31842). A small clinical study of females undergoing an ART program shows that taking a combination product containing L-arginine 1 gram with folate 200 mcg or L-arginine 2 grams, folate 400 mcg, and vitamin E 10 mg daily for 12 weeks does not affect the hCG-positive rate or clinical pregnancy rate when compared with placebo. A subgroup analysis suggests that taking these combination products might improve HCG-positive and clinical pregnancy rates in females who are undergoing ART due to male infertility (104224). However, this small study was not adequately powered to detect a difference in these outcomes, limiting the validity of these findings.
Interstitial cystitis. Small clinical studies suggest that oral L-arginine may improve pain in interstitial cystitis. Details: Taking L-arginine orally seems to reduce some symptoms, especially pain, that are associated with interstitial cystitis (107,114,3460,31855,32267). Research shows that patients with interstitial cystitis having a bladder capacity greater than 800 mL and/or a history of recurrent genitourinary infections might respond more favorably to L-arginine than patients with bladder capacity less than 800 mL and/or no history of recurrent genitourinary infections. Three months of treatment may be necessary before significant symptom improvement occurs (3460). However, L-arginine does not seem to reduce the need to urinate at night or improve urgency or frequency of urination (3460,31855).
Intrauterine growth restriction (IUGR). Small clinical studies suggest that oral or intravenous L-arginine may increase birthweight in IUGR. Details: A meta-analysis of mainly small studies shows that L-arginine given orally or intravenously in the third trimester for a time period of 7 days or until delivery increases the birthweight by up to 650 grams in patients with an IUGR pregnancy. Furthermore, there is evidence from a small number of these studies that L-arginine supplementation decreases the risk of neonatal respiratory distress syndrome and fetal intracranial hemorrhage (96804). A more recent meta-analysis of small studies also shows that taking L-arginine 3 grams daily, starting in the second or third trimester usually until delivery, reduces the risk of an IUGR infant by about 32% when compared to control, including placebo or no treatment (110379). Doses used in clinical research have usually been 3 grams daily orally, although some studies have used up to 20 grams intravenously (31930,31937,96804,110379). However, supplementation with L-arginine does not seem to increase birthweight or reduce neonatal mortality or morbidity when compared with placebo in patients with severe IUGR (32083).
Kidney transplant. Small clinical studies suggest that oral L-arginine may not improve kidney function in patients after kidney transplantation. Details: Although preliminary clinical research showed some benefit, evidence from other clinical research shows that infusion with L-arginine does not increase renal plasma flow or glomerular filtration rate in kidney transplant patients treated with cyclosporine, including those experiencing transplant dysfunction (112,31876,32229). Other evidence suggests that intravenous L-arginine improves kidney function only in transplant patients receiving organs with a short cold ischemia time or those receiving kidneys from young donors (31887).
Male infertility. It is unclear if oral L-arginine is beneficial in males with infertility. Details: Preliminary clinical research shows that taking L-arginine 4 grams daily for 12 weeks does not improve semen quality in males with oligospermia when compared with placebo (32209). However, one small clinical study shows that a specific formulation of L-arginine aspartate and maritime pine bark extract (Prelox), taken for 6 months, improves sperm quality in males with idiopathic male infertility when compared to baseline (32061). The validity of this finding is limited by the lack of a comparator group. Additionally, it is unclear if this effect is due to L-arginine, maritime pine bark, or the combination.
Mitochondrial myopathies. Small clinical studies suggest that intravenous L-arginine may modestly improve symptoms in patients with MELAS (myoclonic epilepsy with lactic acidosis and stroke-like episodes syndrome). Details: Preliminary clinical research shows that infusions of L-arginine, 0.5 grams/kg administered within one hour of stroke-like symptoms, improves headaches, nausea, vomiting, transient blindness, and the appearance of bright spots when compared to pretreatment in patients with MELAS (31943,99263). Also, taking oral L-arginine 4-24 grams daily for 18 months seems to reduce the frequency and severity of stroke-like symptoms associated with MELAS when compared to baseline (31943). However, other preliminary clinical research shows that taking oral L-arginine 0.3-0.5 grams/kg daily in three divided doses for 2 years does not reduce the severity of MELAS symptoms, including migraine and stroke-like episodes. If a stroke-like episode did occur, administration of intravenous L-arginine 0.5 grams/kg improved headache, nausea, vomiting, and visual disturbance (99263). The validity of this research is limited by the small study sizes and the absence of comparator groups.
Migraine headache. Although there is interest in using oral L-arginine for migraine, there is insufficient reliable information about the clinical effects of L-arginine for this condition.
Muscular dystrophy. There is limited evidence on the oral use of L-arginine in patients with Duchenne muscular dystrophy. Details: A very small study in five children with Duchenne muscular dystrophy, shows that drinking a beverage containing L-arginine hydrochloride (L-Arginine Hydrochloride, Selectchemie) 2.5 grams three times daily, in addition to metformin 250 mg twice daily, for 16 weeks improves motor function by 4% and increases distance walked in two minutes by 9.6 meters when compared to baseline (96805). The validity of these findings is limited by the very small study size and lack of a comparator group.
Nitrate tolerance. It is unclear if oral L-arginine is beneficial for nitrate tolerance. Details: A very small crossover study in adults with stable angina shows that taking L-arginine orally 700 mg four times daily for up to 10 days seems to prevent tolerance to transdermal nitrate when compared with placebo (8475).
Obesity. Small clinical studies suggest that oral L-arginine may be beneficial for weight loss. Details: A meta-analysis of mainly small clinical trials shows that taking L-arginine daily for at least 8 weeks modestly reduces body weight, body mass index (BMI), and waist circumference when compared with placebo. However, when taking L-arginine for less than 8 weeks, BMI and body weight were not affected. The optimal dose of L-arginine was 2-6 grams (110398). An additional small clinical study suggests that taking a specific arginine supplement (NOW Foods) 3 grams by mouth three times daily for 12 weeks, in addition to receiving dietary counseling, reduces waist circumference by 4-6 cm and reduces body weight by 1.8-2.9 kg when compared to baseline in obese females 18-40 years of age (91193). The validity of these findings is limited by the lack of a comparator group.
Oral mucositis. Oral L-arginine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study shows that taking a specific combination of L-arginine 7 grams, L-glutamine 7 grams, and hydroxymethylbutyrate (HMB) 1.2 grams (Abound; Abbott) in water twice daily during chemoradiotherapy treatment for head and neck cancer does not reduce the incidence of severe oral mucositis when compared with a historical control (99243). The validity of this finding is limited by the lack of a placebo control.
Periodontitis. It is unclear if oral L-arginine is beneficial in patients with periodontitis. Details: Preliminary clinical research in patients with chronic periodontitis shows that using L-arginine aspartate (Yuria-Pharm, Ukraine) 1 gram three times daily orally for 10 days after scaling and root planing, modestly reduces bleeding on probing but not periodontal pocket depth, when compared with untreated controls (108926).
Physical performance. It is unclear if oral L-arginine is beneficial for improving physical performance in older adults. Details: A small study in physically active females 65 years of age and older shows that taking L-arginine 8 grams as a single dose does not improve lower body strength, measured by knee flexion and extension tests, or functional performance, measured by sit-stand, tandem gait, and timed up-and-go tests, when compared with placebo (96812).
Polycystic ovary syndrome (PCOS). Oral L-arginine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a combination of N-acetylcysteine 1200 mg daily plus L-arginine 1600 mg daily for 6 months modestly improves menstrual function and decreases insulin resistance in patients with PCOS when compared to baseline (32094). The validity of these findings is limited by the lack of a comparator group.
Postoperative infection. Oral L-arginine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Small clinical studies show that taking L-arginine, enterally or orally, either before or after surgery, in combination with fish oil, or with ribonucleic acid (RNA) and eicosapentaenoic acid (EPA), seems to reduce the rate of perioperative infection when compared with a control group. The risk of infection was 41% lower when compared to taking no arginine-based formulations. However, there is no good evidence to support the use of L-arginine alone for this purpose, and it is possible that this effect is due to the other ingredients or the combination of ingredients (5531,32174,32196).
Postoperative recovery. Oral L-arginine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Small clinical studies show that taking L-arginine, enterally or orally, either before or after surgery, in combination with fish oil, or with ribonucleic acid (RNA) and eicosapentaenoic acid (EPA), seems to reduce the recovery time after surgery or serious illness when compared with a control group. This seems to be related to a reduced number of perioperative infections and improved wound healing. However, there is no good evidence to support the use of L-arginine alone for this purpose, and it is possible that this effect is due to the other ingredients or the combination of ingredients (5531,32174,32196). The effect of another combination product containing L-arginine is unclear. In one clinical study, taking a combination product (Abound, Abbott) containing L-arginine 7 grams, glutamine 7 grams, and hydroxymethylbutyrate 1.2 grams orally daily for 3 days before and 7 days after abdominal surgery did not reduce the incidence of wound infection or other complications when compared with placebo (99413). However, when a similar combination of L-arginine 14 grams, glutamine 14 grams, and hydroxymethylbutyrate 3 grams (Heallagen) was taken orally daily for one month before heart surgery, the length of hospital and ICU stay were reduced by about one day. Recovery, based on some but not all biochemical or other measurements, was also improved. However, there was no difference in risk of overall postoperative complications (110394). The discrepancies between these two studies may be related to differences in the dose or duration of the combination product and/or the type of surgery.
Pressure ulcers. Oral L-arginine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Oral L-arginine has been evaluated in combination with other ingredients for the treatment of grade II-IV pressure ulcers. Two small clinical studies in hospitalized patients show that administering an oral nutritional supplement enriched with L-arginine, zinc, and vitamin C improves ulcer healing when compared with a standard diet (31953,87173). A small preliminary clinical study in sedentary older adults in care facilities shows that giving an oral or enteral combination of L-arginine 7.4 grams, L-glutamine 7.4 grams, and hydroxymethylbutyrate (HMB) 1.3 grams (Abound, Abbott) daily for 20 weeks reduces median time to healing by 48 days when compared with standard care only (110396). Also, preliminary clinical research in patients living in long-term care facilities with grade II-IV pressure ulcers shows that taking an oral nutritional supplement enriched in protein, energy, L-arginine, vitamin C, and zinc daily for 9 weeks reduces ulcer area and decreases oozing when compared to baseline (32045). The validity of this finding is limited by the lack of a comparator group.
Preterm labor. Small clinical studies suggest that oral L-arginine may prevent preterm labor. Details: A meta-analysis of three small studies shows that taking L-arginine 3-6.6 grams daily, starting in the second or third trimester usually until delivery, reduces the risk of preterm labor by about 50% when compared to control, usually placebo (110379).
Pulmonary hypertension. It is unclear if oral L-arginine is beneficial in children with pulmonary hypertension related to beta-thalassemia. Details: Preliminary clinical research in children aged 6-18 years treated conventionally for pulmonary hypertension related to beta-thalassemia shows that taking L-arginine 0.1 mg/kg daily for 60 days reduces Doppler echocardiography pulmonary arterial pressure by 35% compared with baseline. This measurement was increased by up to 15% in children given conventional treatments only; however, a statistical comparison between these treatment groups was lacking (110391).
Radiation dermatitis. Oral L-arginine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with head and neck cancer shows that taking a combination of L-arginine 7 grams, L-glutamine 7 grams, and hydroxymethylbutyrate (HMB) 1.2 grams (Abound, Abbott) in water twice daily from the first day of radiation to approximately 1 week after completion does not reduce the number of patients with severe dermatitis when compared with taking no supplement. However, there was a 34% reduction in the incidence of moderate dermatitis and the overall duration of dermatitis was reduced (96639).
Restenosis. It is unclear if intravenous L-arginine helps to prevent restenosis after stent implantation. Details: Some clinical research suggests that intravenous and intracoronary infusion of L-arginine during stent implantation followed by oral L-arginine for 2 weeks does not reduce the risk of restenosis when compared with placebo (31925). However, local delivery of 6 mL of L-arginine 100 mg/mL for 15 minutes after stent deployment seems to reduce neointimal formation at 6 months after stent placement when compared with placebo (31883).
Respiratory tract infections. Although there is interest in using oral L-arginine for respiratory tract infections, there is insufficient reliable information about the clinical effects of L-arginine for these conditions.
Schizophrenia. It is unclear if oral L-arginine is beneficial in patients with schizophrenia. Details: A small clinical study shows that taking L-arginine 3 grams twice daily for 3 weeks, in conjunction with an individualized medication regimen, does not improve positive, negative, or depressive symptoms associated with schizophrenia when compared with taking the medication regimen alone (99264).
Sexual dysfunction. Oral L-arginine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in females with sexual dysfunction who are taking oral contraceptives shows that taking a specific combination product (Lady Prelox, Horphag Research) containing L-arginine, maritime pine bark extract, L-citrulline, and rose hip extract daily for 8 weeks improves symptoms of sexual dysfunction by 18% when compared with a control group (91963). Taking the same product in a dose of 2 tablets twice daily for 8 weeks, in addition to the lifestyle management program, improves vaginal dryness in pre- and post-menopausal patients when compared with lifestyle management alone (103611). It is unclear if this effect is due to L-arginine, the other ingredients, or the combination.
Sickle cell disease. Small clinical studies suggest that oral or intravenous L-arginine may modestly improve complications in patients with sickle cell disease. Details: Two small clinical studies in hospitalized children aged 3-19 years with sickle cell disease-related veno-occlusive crisis shows that administering L-arginine intravenously or orally 100 mg/kg three times daily for 5 days or until discharge reduces total opioid use by 26% to 54%, pain scores at discharge by 23%, and median length of hospital stay by about 36 hours when compared with placebo (97392,105063). Another very small clinical study in patients aged 13-63 years with sickle cell disease shows that taking L-arginine 0.1 grams/kg orally three times daily for 5 days reduces pulmonary hypertension when compared to baseline (11428).
Stress. Oral L-arginine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in healthy adults shows that taking a single dose of L-arginine 50 mg plus L-theanine 200 mg modestly reduces stress associated with a stress-loading test when compared with placebo, but was no more effective than taking L-theanine alone (110393).
Valproic acid-induced toxicities. Although there is interest in using intravenous L-arginine for valproic acid toxicity, there is insufficient reliable information about the clinical effects of L-arginine for this purpose. More evidence is needed to rate L-arginine for these uses.

Herpes labialis (cold sores). Most clinical research shows that oral lysine can prevent and treat herpes labialis. The benefits of topical lysine are unclear. Details: Despite one small clinical study that found no benefit (1116), most clinical research shows that taking oral lysine monohydrochloride 1000-1248 mg daily or 1000 mg three times daily reduces the recurrence of herpes labialis infections when compared with placebo (1114,1115,1118,1120,19390,19391). Also, small clinical studies show that taking oral lysine 1000 mg daily in up to two divided doses for up to 12 months or 1000 mg three times daily for 6 months reduces the severity and healing time of herpes labialis infections when compared with placebo (1119,1120). Topical lysine has also been studied in combination with other ingredients. A small, open-label study shows that applying a specific combination product containing lysine and zinc oxide plus 14 other ingredients (Super Lysine Plus +) topically every 2 hours for 11 days seems to decrease symptoms and duration of herpes lesions when compared with baseline (11051). The validity of this finding is limited by the lack of a comparator group. Also, it is unclear if any benefit is due to lysine, other ingredients, or the combination.

Athletic performance. Although there is interest in using oral lysine for improving athletic performance, there is insufficient reliable information about the clinical effects of lysine for this purpose.
Canker sores. It is unclear if oral lysine is beneficial in patients with canker sores. Details: Preliminary clinical research shows that taking oral lysine 500 mg daily may be beneficial for preventing canker sores, and taking oral lysine 4000 mg daily may be beneficial for decreasing the duration of canker sores (19390).
Child growth. Oral lysine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in children aged 4-9 years old with idiopathic short stature shows that taking a combination oral solution containing lysine, inositol, and vitamin B12 10 mL twice daily along with moderate stretching exercises for 12 months increases height, growth velocity, and serum growth indicators and reduces height standard deviation scores when compared with control. However, the combination product does not impact body mass index or the ratio of bone age to chronological age when compared with control (112280). It is unclear if these findings are due to lysine, other ingredients, or the combination.
Diabetes. It is unclear if oral lysine is beneficial in patients with diabetes. Details: One small clinical study shows that taking lysine hydrochloride 500 mg twice daily for 2 months does not affect fasting or postprandial blood glucose levels or glycated hemoglobin in patients with type 2 diabetes when compared a calcium phosphate control (19395).
Diabetic foot ulcers. It is unclear if topical lysine is beneficial in patients with diabetic foot ulcers. Details: A small clinical study in adults with type 2 diabetes and grade 2 diabetic foot ulcers shows that applying topical lysine 15% cream twice daily with standard treatment for 8 weeks improves the rate of wound healing and skin color surrounding the wound, and also reduces ulcer size, depth, margins, undermining, edema, induration, granulation tissue, necrotic tissue amount and type, exudate type and amount, and epithelialization when compared with control (112279). The validity of the findings is limited by a lack of blinding and small sample size.
Hypertension. Limited clinical research shows that oral lysine can reduce blood pressure in hypertensive patients who have deficient dietary lysine intake. Details: Preliminary clinical research in malnourished people in West Africa with deficient lysine intake shows that taking lysine orally 500 mg twice daily for 16 weeks reduces systolic blood pressure (SBP) when compared with placebo in those with hypertension at baseline. The mean SBP was reduced by 17 mmHg in males and 12 mmHg in females. Lysine supplementation did not affect SBP in people who were normotensive at baseline (104104).
Hypertriglyceridemia. It is unclear if oral lysine is beneficial for patients with hypertriglyceridemia. Details: Preliminary clinical research shows that taking lysine 1 gram daily for 12 weeks, with or without vitamin B6 50 mg daily, does not affect body weight, triglyceride levels, or blood glucose levels when compared with placebo in males with hypertriglyceridemia. Furthermore, this dose of lysine, taken alone or in combination with vitamin B6, appears to slightly decrease high-density lipoprotein (HDL) cholesterol levels after 12 weeks when compared with placebo (90642).
Muscle strength. Higher dietary intake of lysine seems to improve muscle strength in young under- or well-nourished males. Details: Preliminary clinical research in young, under- or well-nourished males shows that consuming lysine 80 mg/kg daily in the diet for 8 weeks improves muscle strength of the forearm by approximately 7.5% when compared with a diet containing lysine 25-40 mg/kg daily (90643).
Pressure ulcers. A small study suggests that topical lysine may be beneficial for pressure ulcers. Details: A small clinical study in hospitalized adults shows that applying a specific cream containing lysine hyaluronate (Lys-HA, Lysial, Fatai-Nyl Srl; Jasper LLC) topically with dressing changes once daily for one week, then once every 2 days for one week, reduces pressure ulcer size when compared with a cream containing sodium hyaluronate. The effect appears to be greater in patients with more advanced (stage 3) ulcers compared to less advanced (stage 1) ulcers (90641).
Schizophrenia. Large doses of oral lysine seem to improve schizophrenia symptoms in patients taking antipsychotic medications. Details: Clinical research in people with schizophrenia not controlled by risperidone shows that taking L-lysine 2 grams three times daily for 8 weeks improves symptoms by approximately 34% when compared with placebo. Negative and psychopathologic symptoms appear to improve the most (90645). In patients stabilized on antipsychotic medications, preliminary clinical research suggests that taking L-lysine 6 grams once daily for 4 weeks improves positive symptoms of schizophrenia, particularly delusions and suspiciousness/persecution, when compared with baseline. However, this improvement was not significant when compared with placebo (90644).
Stress. Limited clinical research in economically disadvantaged populations shows that fortifying wheat with lysine may reduce stress and anxiety. Details: Preliminary clinical research shows that consuming wheat that has been fortified with lysine 4.2 grams/kg reduces stress in females and reduces anxiety in males in economically disadvantaged populations that typically consume cereal-based diets when compared with control (19394). More evidence is needed to rate lysine for these uses.

Athletic performance. Taking ornithine orally, as a single dose or daily for 1 week, may improve some measures of athletic performance, although there is no clear pattern to the effects. Details: A small clinical study in healthy volunteers shows that taking ornithine hydrochloride 1 gram twice daily for 7 days followed by 3 grams with breakfast and lunch immediately before a cycling test seems to reduce fatigue when compared with placebo (67395). Also, small clinical studies show that taking a single dose of ornithine hydrochloride 0.1 gram/kg seems to increase peak cycling speed in active young males, without changing exercise duration, maximal oxygen consumption, or maximal heart rate (67400,67404). A small clinical study in young male weightlifters shows that taking a combination of ornithine 1 gram and arginine 1 gram daily for 30-35 days is associated with increased lean body mass, strength, and peak anaerobic power when compared with placebo (32207,67427).

Dry skin. Oral ornithine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in healthy adults with low skin moisture shows that ingesting a 30 mL drink containing fish scale-derived collagen peptides 10 grams and ornithine 400 mg (FUJIFILM) daily for 8 weeks does not improve skin moisture. However, it seems to improve skin elasticity and reduce water loss from the skin when compared with placebo (101607). This study was limited by its small size.
Insomnia. Although there is interest in using oral ornithine for insomnia, there is insufficient reliable information about the clinical effects of ornithine for this condition.
Periodontitis. It is unclear if oral ornithine is beneficial in patients with periodontitis. Details: Preliminary clinical research in patients with chronic periodontitis shows that using ornithine, 3 grams three times daily orally for 15 days after scaling and root planing, does not improve periodontal pocket depth or bleeding on probing when compared with untreated controls (108926).
Wound healing. Although there is interest in using oral ornithine for wound healing, there is insufficient reliable information about the clinical effects of ornithine for this purpose. More evidence is needed to rate ornithine for for these uses.

Safety view details

Below is general information about the safety of the known ingredients contained in the product Pro GF. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.

GAMMA-AMINOBUTYRIC ACID (GABA) (Gamma-Aminobutyric Acid)

LIKELY SAFE ...when used orally in amounts commonly found in foods.

POSSIBLY SAFE ...when used orally in medicinal amounts, short-term. GABA has been used with apparent safety in doses of 75 mg to 1.5 grams daily for up to one month in small clinical studies (19361,19363,19369,110134,110135). There is insufficient reliable information available about the safety of GABA when used orally for longer than one month or when used sublingually or intravenously.

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

LIKELY SAFE ...when used orally and appropriately. Glutamine has been safely used in clinical research in doses up to 40 grams per day or 1 gram/kg daily (2334,2337,2338,2365,5029,5462,7233,7288,7293), (52288,52307,52308,52311,52313,52337,52349,52350,96516,97366). A specific glutamine product (Endari) is approved by the US Food and Drug Administration (FDA) (96520). ...when used intravenously. Glutamine has been safely incorporated into parenteral nutrition in doses up to 600 mg/kg daily in clinical trials (2363,2366,5448,5452,5453,5454,5458,7293,52272,52275), (52283,52289,52304,52306,52316,52341), (52359,52360,52371,52377,52381,52284,52385,52408,96637,96507,96516).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Glutamine has been shown to be safe in clinical research when used in amounts that do not exceed 0.7 grams/kg daily in children 1-18 years old (11364,46657,52321,52323,52363,86095,96517). A specific glutamine product (Endari) is approved by the US Food and Drug Administration for certain patients 5 years of age and older (96520). ...when used intravenously. Glutamine has been safely incorporated into parenteral nutrition in doses up to 0.4 grams/kg daily in clinical research (52338,96508). There is insufficient reliable information available about the safety of glutamine when used in larger amounts in children.

PREGNANCY AND LACTATION: LIKELY SAFE
when consumed in amounts commonly found in foods. There is insufficient reliable information available about the safety of glutamine when used in larger amounts as medicine during pregnancy or lactation.

POSSIBLY SAFE ...when used orally and appropriately. Glycine has been used safely at doses up to 6 grams daily for 4 weeks (106497) and doses up to 9 grams daily for 3 days (10250,10251,10252,92319). There is insufficient reliable information available about the safety of glycine when used topically.

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

L-ARGININE

POSSIBLY SAFE ...when used orally and appropriately. L-arginine has been used safely in clinical studies at doses of up to 24 grams daily for up to 18 months (3331,3460,3595,3596,5531,5532,5533,6028,7815,7816)(8014,8473,13709,31943,91195,91196,91963,99264,99267,110380)(110387). A tolerable upper intake level (UL) for arginine has not been established, but the observed safe level (OSL) of arginine intake established in clinical research is 20 grams (31996). ...when used intravenously and appropriately. Parenteral L-arginine is an FDA-approved prescription product (15). ...when used topically and appropriately. L-arginine appears to be safe when 5 grams is applied as a topical cream twice daily for 2 weeks or when a dentifrice is used at a dose of 1.5% w/w for up to 2 years (14913,96806). ...when inhaled, short-term. L-arginine appears to be safe when inhaled twice daily at a dose of 500 mg for up to 2 weeks (96807).

CHILDREN: POSSIBLY SAFE
when used orally in premature infants and children (8474,32286,96803,97392,110391). ...when used intravenously and appropriately (97392). Parenteral L-arginine is an FDA-approved prescription product (15). ...when used topically, short-term. A dentifrice containing L-arginine appears to be safe when used at a dose of 1.5% w/w for up to 2 years in children at least 3.7 years of age (96806). ...when inhaled, short-term. L-arginine appears to be safe when inhaled twice daily at a dose of 500 mg for up to 2 weeks in children at least 13 years of age (96807).

CHILDREN: POSSIBLY UNSAFE
when used intravenously in high doses. Parenteral L-arginine is an FDA-approved prescription product (15). However, when higher than recommended doses are used, injection site reactions, hypersensitivity reactions, hematuria, and death have occurred in children (16817).

PREGNANCY: POSSIBLY SAFE
when used orally and appropriately, short-term. L-arginine 12 grams daily for 2 days has been used with apparent safety in pregnancy during the third trimester (11828). L-arginine 3 grams daily has been taken safely during the second and/or third trimesters (31938,110379,110382). ...when used intravenously and appropriately, short-term. Intravenous L-arginine 20-30 grams daily has been used safely in pregnancy for up to 5 days (31847,31933,31961,31978).

LACTATION:
Insufficient reliable information available; avoid using.

POSSIBLY SAFE ...when used orally in doses up to 3000 mg daily for up to one year (1114,1119,1120,90642,104104), or up to 6000 mg daily for up to 8 weeks (90644,90645). ...when used topically and appropriately, short-term (11051).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

POSSIBLY SAFE ...when used orally and appropriately, short-term. Ornithine hydrochloride has been used with apparent safety at doses up to 500 mg daily for up to 8 weeks and at doses up to 12 grams daily for up to 4 weeks (95226,110717).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

Interactions with Drugs view details

Below is general information about the interactions of the known ingredients contained in the product Pro GF. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.

GAMMA-AMINOBUTYRIC ACID (GABA) (Gamma-Aminobutyric Acid)

ANTIHYPERTENSIVE DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = B

Theoretically, taking GABA with antihypertensive drugs might increase the risk of hypotension.

Details

Some clinical research shows that GABA can decrease blood pressure in patients with hypertension (19367).

CNS DEPRESSANTS

Interaction Rating = Minor Be watchful with this combination.

Severity = Moderate • Occurrence = Unlikely • Level of Evidence = D

Theoretically, GABA might have additive sedative effects when used in conjunction with CNS depressants. However, it is unclear if this concern is clinically relevant.

Details

Endogenous GABA has well-established relaxant effects (51152) and GABA(A) receptors have an established physiological role in sleep (51143). However, the effects of GABA supplements are unclear, as it is unknown whether exogenous GABA crosses the blood-brain barrier (51120,51153,90570). Although there have been limited reports of drowsiness or tiredness with GABA supplements (5115,19364), these effects have not been widely reported in clinical studies. Additionally, intravenous GABA 0.1-1 mg/kg has been shown to induce anxiety in a dose-dependent manner (5116).

ANTICONVULSANTS

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Theoretically, glutamine might antagonize the effects of anticonvulsant medications.

Details

Glutamine is metabolized to the excitatory neurotransmitter glutamate. Glutamate might have antagonistic effects with anticonvulsant drugs (7292,7293,7294). However, this interaction has not yet been reported in humans.

CLOZAPINE (Clozaril)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Mild • Occurrence = Probable • Level of Evidence = B

Theoretically, glycine might decrease the effectiveness of clozapine.

Details

One small clinical study in patients with schizophrenia shows that adding glycine to clozapine therapy worsens symptoms of schizophrenia when compared with clozapine alone (10253). The mechanism of this interaction is unclear.

L-ARGININE

ACE INHIBITORS (ACEIs)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Probable • Level of Evidence = D

Theoretically, concomitant use of L-arginine and ACE inhibitors may increase the risk for hypotension and hyperkalemia.

Details

Combining L-arginine with some antihypertensive drugs, especially ACE inhibitors, seems to have additive vasodilating and blood pressure-lowering effects (7822,20192,31854,31916). Furthermore, ACE inhibitors can increase potassium levels. Use of L-arginine has been associated with hyperkalemia in some patients (32213,32218). Theoretically, concomitant use of ACE inhibitors with L-arginine may increases the risk of hyperkalemia.

ANGIOTENSIN RECEPTOR BLOCKERS (ARBs)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Probable • Level of Evidence = D

Theoretically, concomitant use of L-arginine and ARBs may increase the risk of hypotension and hyperkalemia.

Details

L-arginine increases nitric oxide, which causes vasodilation (7822). Combining L-arginine with ARBs seems to increase L-arginine-induced vasodilation (31854). Furthermore, ARBs can increase potassium levels. Use of L-arginine has been associated with hyperkalemia in some patients (32213,32218). Theoretically, concomitant use of ARBs with L-arginine may increases the risk of hyperkalemia.

ANTICOAGULANT/ANTIPLATELET DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Theoretically, concomitant use of L-arginine with anticoagulant and antiplatelet drugs might have additive effects and increase the risk of bleeding.

Details

Preliminary research suggests that L-arginine infusions reduce platelet aggregation in humans (32260,31864,32239,32220,32257,32263,32276,32188). The clinical significance of this effect is unclear.

ANTIDIABETES DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, concomitant use of L-arginine might have additive effects with antidiabetes drugs.

Details

Preliminary clinical research shows that L-arginine decreases blood glucose levels in patients with type 2 diabetes (31964,32085,31964,104225).

ANTIHYPERTENSIVE DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Probable • Level of Evidence = D

Theoretically, concomitant use of L-arginine and antihypertensive drugs may increase the risk of hypotension.

Details

L-arginine increases nitric oxide, which causes vasodilation (7822). Clinical evidence shows that L-arginine can reduce blood pressure in some individuals with hypertension (7818,10636,31871,32201,32167,32225,31923,32232,110383,110384). Furthermore, combining L-arginine with some antihypertensive drugs seems to have additive vasodilating and blood pressure-lowering effects (7822,20192,31854,31916).

ISOPROTERENOL (Isuprel)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Probable • Level of Evidence = D

Theoretically, concurrent use of isoproterenol and L-arginine might result in additive effects and hypotension.

Details

Preliminary clinical evidence suggests that L-arginine enhances isoproterenol-induced vasodilation in patients with essential hypertension or a family history of essential hypertension (31932).

POTASSIUM-SPARING DIURETICS

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Theoretically concomitant use of potassium-sparing diuretics with L-arginine may increases the risk of hyperkalemia.

Details

Potassium-sparing diuretics can increase potassium levels. Use of L-arginine has been associated with hyperkalemia in some patients (32213,32218).

SILDENAFIL (Viagra)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, concurrent use of sildenafil and L-arginine might increase the risk for hypotension.

Details

In vivo, concurrent use of L-arginine and sildenafil has resulted in increased vasodilation (7822,8015,10636). Theoretically, concurrent use might have additive vasodilatory and hypotensive effects. However, in studies evaluating the combined use of L-arginine and sildenafil for erectile dysfunction, hypotension was not reported (105065).

TESTOSTERONE

Interaction Rating = Minor Be watchful with this combination.

Severity = Mild • Occurrence = Possible • Level of Evidence = D

Theoretically, concomitant use of L-arginine and testosterone might have additive effects.

Details

In clinical research, L-arginine increases the level of testosterone in male patients with erectile dysfunction (102586,104222). The clinical significance of this finding is unclear.

5-HT4 AGONISTS

Interaction Rating = Minor Be watchful with this combination.

Severity = Mild • Occurrence = Unlikely • Level of Evidence = D

Theoretically, lysine may reduce the effects of 5-HT4 agonists.

Details

Animal research suggests that L-lysine is a partial serotonin receptor 4 (5-HT4) antagonist and inhibits diarrhea induced by the 5-HT4 agonist, 5-hydroxytryptophane (19400).

None known.

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Adverse Effects view details

Below is general information about the adverse effects of the known ingredients contained in the product Pro GF. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.

GAMMA-AMINOBUTYRIC ACID (GABA) (Gamma-Aminobutyric Acid)

General ...Orally, GABA seems to be generally well tolerated. Sublingually, no adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Orally: Drowsiness, gastric upset, minor throat burning, muscle weakness, and nausea.

Cardiovascular ...Intravenously, GABA can cause dose-related increases in blood pressure and pulse (5116).

Gastrointestinal ...Orally, minor throat burning has been associated with GABA in one study (5115). In another study in which GABA was administered with phosphatidylserine, one patient experienced severe gastric distress, two patients reported moderate nausea, and one reported constipation (19364). Children with cerebral palsy taking GABA experienced nausea and decreased appetite (19362).

Genitourinary ...In one study, one patient treated with oral GABA and phosphatidylserine reported transient amenorrhea (19364).

Musculoskeletal ...Orally, minor adverse effects associated with GABA included muscle weakness (5115).

Neurologic/CNS ...Orally, GABA may cause drowsiness or tiredness (5115,19364). Four children with cerebral palsy taking GABA had convulsions, and an unspecified number experienced motor restlessness. However, causality of these adverse effects was not clear, and the dose of GABA was not specified (19362). Intravenously, GABA 50 mg has been associated with a "lack of alertness" in healthy female volunteers (51159).

Psychiatric ...Intravenously, GABA 0. 1-1.0 mg/kg has been shown to induce anxiety, dysphoria, and mood disturbances in a dose-dependent manner (5116).

Other ...In one study, patients taking GABA experienced a slight warming of the body (19370).

General ...Orally and intravenously, glutamine is generally well tolerated.
Most Common Adverse Effects:
Orally: Belching, bloating, constipation, cough, diarrhea, flatulence, gastrointestinal pain, headache, musculoskeletal pain, nausea, and vomiting.

Endocrine ...One case of hot flashes has been reported in a patient taking glutamine 5-15 grams orally twice daily for up to 1 year (96520).

Gastrointestinal ...Orally, glutamine has been associated with belching, bloating, constipation, flatulence, nausea, vomiting, diarrhea, and gastrointestinal (GI) pain. Nausea, vomiting, constipation, diarrhea, and GI pain have been reported in clinical trials using high-dose glutamine 10-30 grams (0.3 grams/kg) in two divided doses daily to treat sickle cell disease (99414). One case of dyspepsia and one case of abdominal pain have been reported in patients taking glutamine 5-15 grams twice daily orally for up to 1 year (96520). In a small trial of healthy males, taking a single dose of about 60 grams (0.9 grams/kg of fat free body mass [FFM]) was associated with a 50% to 79% incidence of GI discomfort, nausea, and belching, compared with a 7% to 28% incidence with a lower dose of about 20 grams (0.3 gram/kg FFM). Flatulence, bloating, lower GI pain, and urge to regurgitate occurred at similar rates regardless of dose, and there were no cases of heartburn, vomiting, or diarrhea/constipation (105013). It is possible that certain GI side effects occur only after multiple doses of glutamine.

Musculoskeletal ...Orally, glutamine 30 grams daily has been associated with cases of musculoskeletal pain and non-cardiac chest pain in clinical trials for patients with sickle cell disease (99414).

Neurologic/CNS ...Orally, glutamine has been associated with dizziness and headache. A single case of dizziness has been reported in a patient treated with oral glutamine 0.5 grams/kg. However, the symptom resolved after reducing the dose to 0.25 grams/kg (91356). Mania and hypomania have been reported in 2 patients with bipolar disorder taking commercially purchased glutamine up to 4 grams daily (7291). Glutamine is metabolized to glutamate and ammonia, both of which might have neurological effects in people with neurological and psychiatric diseases or in people predisposed to hepatic encephalopathy (7293).

Oncologic ...There is some concern that glutamine might be used by rapidly growing tumors and possibly stimulate tumor growth. Although tumors may utilize glutamine and other amino acids, preliminary research shows that glutamine supplementation does not increase tumor growth (5469,7233,7738). In fact, there is preliminary evidence that glutamine might actually reduce tumor growth (5469).

Other ...Orally, glutamine has been associated with cough when a powdered formulation is used. It is unclear if this was due to accidental inhalation. One case of a burning sensation and one case of hypersplenism has been reported in a patient taking glutamine 5-15 grams twice daily orally for up to 1 year (96520).

General ...Orally and topically, glycine seems to be well tolerated.

Gastrointestinal ...Soft stools, nausea, vomiting, and upper gastrointestinal (GI) tract discomfort have occurred rarely with oral use of glycine. These symptoms resolve rapidly with discontinuation of glycine (10252,11320,92319). Dry mouth has also been reported but any association to glycine is unclear (92321).

Neurologic/CNS ...Mild sedation has occurred rarely with oral use of glycine. Symptoms resolve rapidly with discontinuation of glycine (10252,11320,92321). Irritability, insomnia, fatigue, memory impairment, headache, and sensory impairment have been reported, but any association with glycine is unclear (92321).

L-ARGININE

General ...Oral, intravenous, and topical L-arginine are generally well tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, bloating, nausea, diarrhea, headache, insomnia, flushing.
Intravenously: Excessively rapid infusion can cause flushing, headache, nausea and vomiting, numbness, and venous irritation.

Cardiovascular ...L-arginine taken orally by pregnant patients in a nutrition bar containing other antioxidants was associated with a 36% greater risk of palpitations when compared with a placebo bar (91197). It is unclear if this effect was due to L-arginine, other ingredients, or other factors.

Dermatologic ...Orally, arginine can cause flushing, rash, and hives (3460,32138,102587,104223). The skin reactions were likely of allergic etiology as oral L-arginine has been associated with eosinophilia (32138). In one case report, intravenous administration caused allergic reactions including urticaria, periorbital edema, and pruritus (11830). Excessively rapid infusion of L-arginine has caused flushing, local venous irritation, numbness. Extravasation has caused necrosis and superficial phlebitis (3330,16817).

Gastrointestinal ...Orally, L-arginine has been reported to cause nausea, diarrhea, vomiting, dyspepsia, gastrointestinal discomfort, and bloating (1363,31855,31871,31972,31978,32261,90198,91197,96811,99243)(102587,102592).
Orally, L-arginine has been reported to cause esophagitis in at least six adolescents. Symptoms, which included pain and dysphagia, occurred within 1-3 months of treatment in most cases (102588). There are at least two cases of acute pancreatitis possibly associated with oral L-arginine. In one case, a 28-year-old male developed pancreatitis after consuming a shake containing 1.2 grams of L-arginine daily as arginine alpha-ketoglutarate. The shake also contained plant extracts, caffeine, vitamins, and other amino acids. Although there is a known relationship between L-arginine and pancreatitis in animal models, it is not clear if L-arginine was directly responsible for the occurrence of pancreatitis in this case (99266).
Intravenously, excessively rapid infusion of L-arginine has been reported to cause nausea and vomiting (3330,16817).

Musculoskeletal ...Intravenous L-arginine has been associated with lower back pain and leg restlessness (32273). Orally, L-arginine has been associated with asthenia (32138).

Neurologic/CNS ...Orally, L-arginine has been associated with headache (31855,31955,32261,91197,102587,102592), insomnia, fatigue (102587,102592), and vertigo (32150,102592).

Oncologic ...In breast cancer patients, L-arginine stimulated tumor protein synthesis, which suggests stimulated tumor growth (31917).

Pulmonary/Respiratory ...When inhaled, L-arginine can cause airway inflammation and exacerbation of airway inflammation in asthma (121). However, two studies assessing oral L-arginine in patients with asthma did not detect any adverse airway effects (31849,104223).

Renal ...Intravenously, L-arginine has been associated with natriuresis, kaliuresis, chloruresis, and systemic acidosis (32225). Orally, L-arginine can cause gout (3331,3595).

Other ...Orally, L-arginine has been associated with delayed menses, night sweats, and flushing (31855).

General ...Orally and topically, lysine is generally well tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, diarrhea, and dyspepsia.

Gastrointestinal ...Orally, lysine has been reported to cause diarrhea and abdominal pain, including dyspepsia (1114,1115,1116,1118,1120).

Renal ...There is one case report of oral lysine use associated with tubulointerstitial nephritis progressing to chronic renal failure in a 44-year old female (1121).

General ...Orally, ornithine seems to be well-tolerated. However, a thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Orally: Gastrointestinal symptoms (unspecified)

Gastrointestinal ...Orally, ornithine might cause adverse gastrointestinal effects. In a small, uncontrolled trial, gastrointestinal symptoms were reported in around 22% of individuals taking ornithine 3.2-12 grams daily (110717).

Genitourinary ...Orally, ornithine has been associated with one case of hematuria. In a small, uncontrolled trial, hematuria was reported in one individual taking ornithine, which resolved quickly without treatment when ornithine was discontinued. While the researchers suspected the hematuria was not related to ornithine supplementation, no cause could be determined (110717).

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