Tribest 750 [Discontinued] by MRM

POSSIBLY EFFECTIVE

• 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.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• 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 (mitochondrial encephalopathy 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.

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POSSIBLY EFFECTIVE

• Sexual dysfunction. Oral tribulus seems to improve sexual experience in females with hypoactive sexual desire disorder (HSDD) or sexual dysfunction. Some research also shows that oral tribulus improves sexual function in males. Details: Clinical research in premenopausal and postmenopausal patients with HSDD shows that taking tribulus 250 mg three times daily (Androsten, Herbarium) for 3 months improves overall satisfaction and lubrication, as well as pain, desire, sexual arousal, and ability to reach orgasm, when compared with placebo (92027,97331,97332). Other preliminary clinical research in females with HSDD shows that taking tribulus extract 7.5 mg daily for 4 weeks improves sexual desire, arousal, satisfaction, orgasm, pain, and lubrication when compared with placebo (92022). A nonblinded clinical study comparing tribulus dosing regimens shows that taking oral tribulus 280 mg, either once daily or in three divided daily doses, for 90 days results in similar improvements in sexual dysfunction, regardless of menopausal status. However, neither dosing schedule increases clitoral blood flow when compared with baseline (108551). Tribulus has also been studied in males. One clinical study in males with erectile dysfunction, with or without HSDD, shows that taking tribulus (Tribestan, Sopharma AD) 500 mg three times daily for 3 months improves sexual desire and intercourse satisfaction when compared with placebo (97330).

POSSIBLY INEFFECTIVE

• Athletic performance. Oral tribulus does not seem to improve athletic performance. Details: Small clinical studies in athletes show that taking tribulus orally, alone or in combination with other ingredients such as androstenedione, most often as 450-770 mg daily for 5-8 weeks, does not seem to enhance body composition or exercise performance when compared with placebo or a control group (7514,13255,92029,108552).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Angina. It is unclear if oral tribulus is beneficial for angina. Details: Preliminary clinical research shows that taking a tribulus extract orally might reduce symptoms of angina when compared with a control (3931).
• Atopic dermatitis (eczema). Oral tribulus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some preliminary clinical research shows that taking tribulus orally in combination with 9 other herbs (Zemaphyte) daily for 8 weeks reduces redness and skin lesions in adults and children with nonexudative atopic dermatitis (12627,12628). However, other research shows no effect (12630). It is unclear if these effects are due to tribulus, the other ingredients, or the combination.
• Bacterial vaginosis. Topical tribulus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with bacterial vaginosis shows that using a specific vaginal suppository (Forzajeh) containing tribulus, myrtle, fennel, and tamarind daily for 1 week is as effective as metronidazole vaginal suppository for improving vaginal discharge volume and odor, pelvic pain, cervical inflammation, and vaginal pH (100339). It is unclear if these effects are due to tribulus, the other ingredients, or the combination.
• Benign prostatic hyperplasia (BPH). Oral tribulus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with BPH shows that taking a combination supplement (Prostalyn, East India Pharmaceutical Works Ltd.) containing tribulus 600 mg and curry leaf (Murraya koenigii) 600 mg twice daily for 12 weeks improves prostate symptoms when compared to baseline, with no difference when compared to tamsulosin 400 mcg daily. This supplement also seems to reduce prostate volume by around 2 mL (92033).
• Cancer. Although there is interest in using oral tribulus for cancer, there is insufficient reliable information about the clinical effects of tribulus for this condition.
• Chronic fatigue syndrome (CFS). Although there is interest in using oral tribulus for CFS, there is insufficient reliable information about the clinical effects of tribulus for this condition.
• Diabetes. It is unclear if oral tribulus is beneficial for diabetes. Details: Preliminary clinical research in females with type 2 diabetes who are taking oral hypoglycemic agents shows that taking tribulus extract powder 500 mg twice daily for 3 months modestly reduces fasting glucose and postprandial glucose levels, but not glycated hemoglobin, when compared with placebo. However, the validity of these findings is limited by the difference in diabetes severity between groups at baseline (97327).
• Erectile dysfunction (ED). It is unclear if oral tribulus is beneficial for ED. Research is conflicting. Details: Clinical research in patients with ED shows that taking tribulus (Tribestan, Sopharma AD) 500 mg three times daily for 3 months does not provide a clinically beneficial improvement in erectile function when compared with placebo (97330). Other clinical research shows that taking tribulus 400 mg twice daily for 30 days does not improve erectile function when compared with placebo (92031). However, one preliminary clinical study in patients with partial androgen deficiency shows that taking tribulus 250 mg three times daily for 3 months improves erectile function when compared to baseline (92028). Tribulus has also been studied in combination with other ingredients. Preliminary clinical research shows that taking a combination supplement (Tradamix TX1000, Tradapharma Sagl) containing tribulus 450 mg, brown algae 300 mg, and chitosan 250 mg twice daily for 3 months improves sexual satisfaction, desire, ejaculation function, and sexual quality of life when compared with placebo in patients with mild-to-moderate ED (92030). It is unclear if these effects are due to tribulus, the other ingredients, or the combination.
• Exercise-induced muscle damage. It is unclear if oral tribulus is beneficial for exercise-induced muscle damage. Details: Clinical research in a small number of healthy, untrained males shows that taking tribulus 500 mg daily for 2 weeks prior to performing resistance exercise reduces markers of muscle damage, including creatine phosphokinase (CPK) and lactate dehydrogenase (LDH), but does not reduce levels of the inflammatory markers interleukin-6 (IL-6) or C-reactive protein (CRP), when compared with placebo (103236). However, another small clinical study in male CrossFit athletes shows that taking tribulus 770 mg capsules (Quamtrax Pharmaceuticals) daily for 42 days does not reduce CPK but does improve CRP and oxidant status when compared with placebo (111747). However, it is unclear whether any improvements are clinically significant. A very small crossover clinical study in trained male athletes shows that taking 20 mg/kg/day of tribulus in 3 divided doses 30 minutes before meals with 500 mL of water for 4 weeks does not reduce muscle soreness after intensive aerobic exercise when compared with placebo (111746).
• Gonorrhea. Although there is interest in using oral tribulus for gonorrhea, there is insufficient reliable information about the clinical effects of tribulus for this condition.
• Hypercholesterolemia. Although there is interest in using oral tribulus for hypercholesterolemia, there is insufficient reliable information about the clinical effects of tribulus for this condition.
• Hypertension. It is unclear if oral tribulus can lower blood pressure. Details: In patients with pre-hypertension, clinical research shows that taking powdered tribulus fruit 2 grams three times daily for 2 months reduces systolic and diastolic blood pressure by 6 and 5 mmHg, respectively, when compared with placebo (105245). It is unclear what effect Tribulus may have in patients with diagnosed hypertension.
• Kidney stones (nephrolithiasis). Although there is interest in using oral tribulus for kidney stones, there is insufficient reliable information about the clinical effects of tribulus for this purpose.
• Male infertility. It is unclear if oral tribulus is beneficial for male infertility; the available research is conflicting. Details: Case series suggest that taking a specific tribulus product (Tribestan, Sopharma) 250 mg three times daily for 30 days improves ejaculate volume, sperm concentration, and sperm motility in patients with infertility due to oligoasthenozoospermia (78865), and improves libido and erections in patients with primary hypogonadism (78868). Conversely, a small clinical study in patients with oligozoospermia shows that taking tribulus granules 6 grams daily for 60 days does not improve sperm count when compared with placebo (92032). In patients with idiopathic infertility, taking tribulus 250 mg three times daily for 3 months does not increase sperm concentration, sperm motility, serum testosterone levels, or luteinizing hormone levels (97328). The difference in these findings might be due to the small study sizes, as well as the variable etiology of infertility.
• Menopausal symptoms. Oral tribulus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking a combination product containing tribulus 40 mg, ginger, saffron, and Ceylon cinnamon (Aphrodit, Goldaru Company) twice daily for 4 weeks improves mental and physical symptoms during menopause, but not genitourinary symptoms, when compared with placebo (97326). It is not clear if this effect is due to tribulus, the other ingredients, or the combination.
• Osteoporosis. Although there is interest in using oral tribulus for osteoporosis, there is insufficient reliable information about the clinical effects of tribulus for this condition.
• Polycystic ovary syndrome (PCOS). Oral tribulus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One clinical study shows that taking tribulus extract (Tribulus forte, Mediherb, Integra Healthcare Ltd) 245 mg daily along with other ingredients and lifestyle modification during the follicular phase of the menstrual cycle for 3 months improves some symptoms of PCOS, including a 33% reduction in oligomenorrhea or amenorrhea and a 43-day reduction in the duration between menstrual cycles, when compared with lifestyle modification alone. Taking tribulus with other ingredients also improves quality of life by about 30% and reduces body mass index by 1 kg/m2 when compared with placebo. Although the conception rate increased 4-fold in patients taking the combination product, the live birth rate was similar to those taking placebo. (97216). It is unclear if these effects are due to tribulus, the other ingredients, or the combination.
• Premature ejaculation. Oral tribulus 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 product containing tribulus, 5-HTP, winter savory, and chanca piedra (EiacuMev, Farmaceutica Mev) daily for 3 months improves time to ejaculation by 30 seconds and reduces symptoms related to premature ejaculation when compared to control (97016). More evidence is needed to rate tribulus for these uses.

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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.

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LIKELY UNSAFE ...when the spine-covered fruit is used orally. There have been reports of bilateral pneumothorax and bronchial polyp after oral consumption of the spine-covered fruit (818).

PREGNANCY: POSSIBLY UNSAFE
when used orally. Animal research suggests that tribulus might adversely affect fetal development (12674); avoid using.

LACTATION:
Insufficient reliable information available; avoid using.

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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.

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ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Taking tribulus with antidiabetes drugs might increase the risk of hypoglycemia.  Details Clinical research shows that Tribulus can lower blood glucose levels in adults with type 2 diabetes who are taking antidiabetes medications (97327).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking tribulus with antihypertensive drugs might increase the risk of hypotension.  Details Animal research shows that tribulus can lower blood pressure by inhibiting angiotensin-converting enzyme (ACE) (12673). Tribulus has also demonstrated hypotensive effects in pre-hypertensive adults (105245).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, tribulus might increase the levels and clinical effects of lithium.  Details Tribulus is thought to have diuretic properties (12681). Due to these potential diuretic effects, tribulus might reduce excretion and increase levels of lithium. The dose of lithium might need to be decreased.

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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).

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General ...Orally, tribulus seems to be well tolerated.
Serious Adverse Effects (Rare):
Orally: Cases of liver and kidney injury, seizures, and chronic painful erection with impaired sexual function have been reported. Pneumothorax and bronchial polyp after consuming the spine-covered tribulus fruit have been reported.

Gastrointestinal ...Orally, tribulus can cause abdominal pain, cramping, nausea, vomiting, diarrhea, and constipation (92022,92027). However, in one study, the rates of these gastrointestinal complaints were similar for patients taking tribulus and those receiving placebo (92022).

Genitourinary ...In one case report, a patient taking two tribulus tablets (unknown dose) daily for 15 days presented to the local emergency department with a painful erection lasting 72 hours. The priapism was resolved with medical management; however, post-episode sexual function was impaired (92023).

Hepatic ...In one case report, a patient drinking tribulus water 2 liters daily for two days presented with lower limb weakness, seizures, hepatitis, and acute kidney injury. The patient's condition improved after hemodialysis and discontinuation of tribulus water (92069).

Neurologic/CNS ...Orally, tribulus has been reported to cause general excitation and insomnia. These symptoms were reversed upon discontinuation of the drug or decreasing the dose (78867). In one case report, a patient drinking tribulus water 2 liters daily for two days presented with lower limb weakness, seizures, hepatitis, and acute kidney injury. The patient's condition improved after hemodialysis and discontinuation of tribulus water (92069).

Pulmonary/Respiratory ...In one case report, a patient developed a bilateral pneumothorax after consuming the spine-covered fruit of tribulus (818). In another case report, a patient developed a polyp in the lobar bronchus of the right interior lobe due to the presence of a tribulus fruit spine (78852).

Renal ...In one case report, a patient drinking tribulus water 2 liters daily for two days presented with lower limb weakness, seizures, hepatitis, and acute kidney injury. The patient's condition improved after hemodialysis and discontinuation of the tribulus water (92069). In another case report, a healthy male taking one tribulus tablet (unknown dose) daily for a few months for bodybuilding purposes developed hyperbilirubinemia followed by acute kidney failure 2-3 weeks later. The patient was managed with intravenous fluids and a low-salt, low-protein diet (92025).

Other ...In one case report, gynecomastia was observed in a male weightlifter taking an herbal combination product containing tribulus. However, it is not clear if this adverse effect can be attributed to tribulus alone (78859).

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