The Champion Stack - Blox by BPI Sports

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Benign prostatic hyperplasia (BPH). Although there has been interest in using oral alanine for BPH, there is insufficient reliable information about the clinical effects of alanine for this purpose.
• Cognitive function. Oral alanine 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 fatigue shows that taking alanine 1 gram, along with serine, glutamate, aspartate, and tyrosine daily for 4 weeks improves some measures of cognitive function including attention, spatial cognition, orientation, motivation, and time management when compared with placebo (111249). It is unclear if these effects are due to alanine, other ingredients, or the combination.
• Diabetes. Although there has been interest in using oral alanine for diabetes, there is insufficient reliable information about the clinical effects of alanine for this purpose.
• Diarrhea-related dehydration. It is unclear if oral alanine is beneficial in children or adults with diarrhea-related dehydration. Details: One preliminary clinical trial in males age 6-59 years with severe secretory diarrhea primarily related to cholera or enterotoxigenic Escherichia coli shows that an oral rehydration solution fortified with L-alpha-alanine 90 mmol/L, along with a reduced glucose concentration, is significantly more effective for reducing stool output than the standard WHO solution (16028). However, other clinical research in males age 3-48 months of age with diarrhea primarily related to viral infections shows that an oral rehydration solution fortified with L-alpha-alanine 30-90 mmol/L along with a reduced glucose concentration is not significantly more effective at reducing stool output than the standard WHO oral rehydration solution (16021).
• Fatigue. Oral alanine 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 fatigue shows that taking alanine 1 gram, along with serine, glutamate, aspartate, and tyrosine daily for 4 weeks does not improve subjective or objective measures of fatigue when compared with placebo (111249).
• Glycogen storage disease type II (Pompe disease). It is unclear if oral alanine is beneficial in patients with Pompe disease. Details: A case series of 5 patients aged 15-47 years with late-onset glycogen storage disease type II shows that taking L-alpha-alanine 0.14 grams/kg daily, divided into 3 doses, for 4 weeks decreased resting energy expenditure, protein turnover, and catabolism when compared with baseline. However, measures of Pompe disease-associated myopathy were not reported. The validity of this study is limited by its small size and the lack of a comparator group (16444).
• Hypoglycemia. Small clinical studies suggest that oral alanine may modestly reduce iatrogenic hypoglycemia in patients with type 1 diabetes. Details: Preliminary clinical research shows that taking 20-40 grams of L-alpha-alanine orally produces a sustained rise in blood glucose levels after insulin-induced hypoglycemia in people with type 1 diabetes (14612,16020). The rise is more prolonged than after 20 grams of oral glucose or 1 mg of subcutaneous glucagon (14612). Other preliminary clinical research also shows that patients with type 1 diabetes had more consistent and prolonged protection against nocturnal hypoglycemia after taking 40 grams of L-alpha-alanine plus 10 grams of glucose orally with a bedtime dose of NPH insulin than when they consumed a snack with the insulin dose (16019).
• Schizophrenia. It is unclear if oral alanine is beneficial in patients with schizophrenia. Details: Preliminary clinical research shows that taking D-alpha-alanine orally 100 mg/kg daily for 6 weeks improves positive and negative symptom scores in patients with schizophrenia that were also on a stable antipsychotic regimen when compared with placebo (16027).
• Stress. Although there has been interest in using oral alanine for stress, there is insufficient reliable information about the clinical effects of alanine for this purpose. More evidence is needed to rate alanine for these uses.

(Read more about ALANINE)

POSSIBLY EFFECTIVE

• Hepatic encephalopathy. Oral and intravenous BCAAs improve symptoms and nutritional status in patients with hepatic encephalopathy, especially in those not tolerating protein supplementation. Details: Taking BCAAs 240 mg/kg (up to 25 grams) daily in 3 divided doses for up to 3 months can improve symptoms, liver function tests, and nitrogen balance in patients with chronic hepatic encephalopathy (68,69,82,690,92643,97531). Oral BCAAs are recommended for malnourished patients with chronic hepatic encephalopathy who cannot tolerate protein supplementation (69,4274). When the enteral route is unavailable and when patients cannot tolerate general purpose amino acid solutions, intravenous solutions with BCAAs can be used for nutritional support; however, most patients can tolerate standard amino acid mixtures (4274). Some clinical research also suggests that taking BCAAs orally improves psychomotor function, attention, intelligence, and driving ability in patients with latent hepatic encephalopathy (684,685,37131,97531). However, not all studies show a positive effect of BCAAs on psychometric outcomes (37135). There is also some preliminary evidence that intravenous BCAAs might be helpful for reversing coma in acute hepatic encephalopathy, although findings are conflicting (66,81,686,687,688,689,4274,37134). BCAAs do not appear to reduce the risk of mortality or improve quality of life in patients with hepatic encephalopathy (92643,97531).
• Tardive dyskinesia. Oral BCAAs might reduce symptoms of tardive dyskinesia precipitated by antipsychotic drugs. Details: Taking BCAAs orally seems to reduce symptoms of tardive dyskinesia (72,10146,13307). Clinical research in adult and pediatric patients who are taking antipsychotic drugs shows that taking a drink containing BCAAs 222 mg/kg three times daily for 3 weeks reduces tardive dyskinesia movements by 30% to 60% when compared with placebo (10146,13307).

POSSIBLY INEFFECTIVE

• Liver cancer. Oral BCAAs do not seem to improve outcomes or reduce the risk for recurrence in patients with liver cancer. Details: A meta-analysis of the available clinical research, as well as individual clinical studies, in patients with hepatocellular carcinoma show that consuming up to 50 grams of BCAAs twice daily for up to 4 years does not improve survival, reduce tumor recurrence, or reduce the risk of complications such as ascites following liver resection when compared with a control group receiving no intervention (37143,92646,97532,105578). However, one small clinical study suggests that BCAAs may be beneficial in patients recently diagnosed with hepatocellular carcinoma that does not require surgery. Taking two packets of a specific supplement (Aminoleban EN) daily containing a total of L-leucine 4 grams, L-isoleucine 3.8 grams, and L-valine 3.2 grams, starting two weeks before receiving transcatheter arterial chemoembolization and radiofrequency ablation and continuing for up to 5 years, reduces recurrence of liver cancer and increases event-free survival when compared with placebo (97533). However, the validity of these findings is limited by the high withdrawal rate in this study.

LIKELY INEFFECTIVE

• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). Overall, oral BCAAs are not beneficial and might even lead to worsened outcomes in patients with ALS. Details: Although early studies have indicated that taking BCAAs might be beneficial in ALS, more recent studies show no benefit and a possible increased loss of pulmonary function and higher rate of mortality among patients using BCAAs (678,679,680,681,37154).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alzheimer disease. It is unclear if dietary BCAAs prevent Alzheimer disease. Details: Observational research has found that higher blood levels of BCAAs are associated with an 11% to 13% lower risk of Alzheimer disease; however, when research was adjusted for mortality, body mass index, and concomitant cholesterol-lowering medications, the association was no longer significant (100469).
• Athletic performance. Small clinical trials suggest that although oral BCAAs may not enhance athletic performance, they may modestly reduce perceived exertion and fatigue with some forms of exercise. Details: In most studies, taking BCAAs orally does not enhance athletic performance (692,1135,37080,37094,37106,37123,37141,37142,37151,92641). For instance, BCAAs do not appear to improve strength or work power or to reduce completion times for long-distance running or cycling trials (692,37106,37112,37141,37142,92641). However, most research shows that BCAAs are beneficial for reducing exercise-induced fatigue and perceived exertion after prolonged or intense exercise, exercise in the heat, or exercise following glycogen depletion (692,37112,37124,37144,92642,92644,92645,92648,97529,97530)(97535,105582). In many cases, this improvement is observed when BCAAs are taken in combination with arginine, citrulline, or green tea powder (37124,92642,92645,92648,97529,100462). However, some conflicting evidence exists (1135,37080,37094). Overall, the validity of these findings is limited because most studies differ widely in the amount and type of product consumed. For example, studied doses included BCAAs 0.17-0.3 mg/kg daily; or valine 0.5-1.7 grams, leucine 1-3.5 grams, and isoleucine 0.48-2.1 grams given before and/or after exercise (37108,37123,92642,92644,92645). Other limitations include variability in the studied endpoints and control comparisons used.
• Bipolar disorder. It is unclear if oral BCAAs are beneficial in patients with bipolar disorder. Details: One small clinical study shows that consuming a tyrosine-free amino acid drink containing 60 grams of the BCAAs leucine, isoleucine, and valine in a ratio of 3:3:4, reduces acute manic symptoms within 6 hours when compared with placebo. When taken daily for 7 days, it seems to continue to improve symptoms over a 2-week period (10117).
• Cachexia. Small clinical studies suggest that oral BCAAs are beneficial in patients with cachexia from various causes. Details: Preliminary clinical research in elderly malnourished patients receiving hemodialysis shows that taking a combination of BCAAs 4 grams three times daily improves appetite and caloric intake and increases plasma albumin levels and anthropometric measurements when compared with placebo (10147). Also, small clinical studies in adults with cachexia due to cancer or cirrhosis show that taking oral BCAAs 2.4 grams twice daily for 1 year or 4.8 grams 3 times daily for 1 week might be helpful when compared to baseline (71,37090). This finding is limited by the lack of a comparator group. A small clinical study in adults with congestive heart failure who have lost at least 7.5% of dry weight over the past 6 months or have a body mass index below 20 kg/m² shows that taking BCAAs 10 grams every evening at bedtime for 8 weeks improves physical and emotional quality of life scores, appetite, and fatigue when compared with placebo. Patients taking melatonin 20 mg nightly in addition to BCAA supplementation observed greater improvements in appetite and fatigue when compared with placebo (108478). However, a statistical comparison of outcomes between the groups taking BCAA alone or BCAA with melatonin was not provided.
• Cancer. It is unclear if dietary BCAA consumption improves cancer-related mortality. Details: Observational research in adults has found that consuming BCAAs 19 grams or more daily as part of the diet is not associated with a reduced risk of cancer-related mortality when compared with a lower dietary BCAA intake of less than 7.8 grams daily (108467). The validity of this finding is limited due to unclear reporting; additionally, dietary intake was recorded from a single survey.
• Cardiovascular disease (CVD). It is unclear if dietary BCAA consumption reduces the risk of CVD-related mortality. Details: Observational research in adults has found that CVD-related mortality is not associated with dietary BCAA intake or with individual leucine, isoleucine, or valine intake (108467). The validity of this meta-analysis is limited due to unclear reporting; additionally dietary intake was recorded from a single survey.
• Chronic obstructive pulmonary disease (COPD). It is unclear if oral BCAAs can improve physical performance in adults with COPD. Details: A clinical study in adults with stable, stage 2 or 3 COPD undergoing a pulmonary rehabilitation program shows that taking a BCAA powder 4.3 grams, diluted in water and consumed once daily for 4 weeks, may improve recovery after exercise, but does not impact maximal exercise capacity, functional and muscular performance, or quality of life when compared with placebo (108464). The validity of these findings is limited due to the short duration of treatment.
• Cirrhosis. Most small studies suggest that BCAAs may modestly improve certain measures in some patients with liver cirrhosis. Details: One small clinical study shows that although taking BCAAs 14.4 grams daily for 12 months does not improve survival or liver function in patients with advanced liver cirrhosis, the number of hospitalizations and prevalence of cachexia are reduced and quality of life is improved when compared with control or whey protein (37090). A clinical study in patients with sarcopenia and liver cirrhosis shows that taking BCAAs 7.2 grams for 6 months decreases bilirubin levels and improves Child-Turcotte-Pugh and model for end-stage liver disease (MELD) scores when compared with baseline (108468). Although the study enrolled a control group (whey protein), the investigators did not provide a statistical comparison of outcomes between groups. In addition, a small study in Japanese patients with cirrhosis shows that taking BCAAs 12.45 grams daily for at least 12 months improves liver function and reduces liver complications by 50% to 60% over 3-5 years when compared with control (37120). Also, taking a specific product (Livact, Samil Pharmaceutical) providing the same dose for 11-22 months improves liver function by a small to moderate amount over a 24-month period when compared with not taking BCAAs. There was also a moderate reduction in the rate of developing or worsening major complications such as ascites or hepatic encephalopathy (103351). However, some research providing BCAAs as part of a late evening snack has found no benefit. In one small study, consuming BCAAs as part of a late evening snack in an undefined dose for 3 months does not seem to improve quality of life when compared with a late evening snack without BCAAs (37101). Also, a very small clinical study in patients with abnormal glucose metabolism related to cirrhosis shows that consuming BCAAs in an undefined dose as part of a late evening snack for 1 week does not improve glycemic control when compared with baseline. Instead, glucose levels increased in some patients (103348). It is possible that the doses provided in these latter studies were lower than those used in the studies showing benefit. Additionally, these very small studies may not have been adequately powered to detect a difference between groups.
• Colorectal cancer. It is unclear if dietary BCAAs are beneficial or harmful in patients with colorectal cancer. Details: An observational study in Italy has found that increased dietary intake of BCAAs is associated with a lower risk of developing sigmoid colon cancer, but not overall colorectal cancer risk, when compared with lower intake (105584). However, there's some concern that increased dietary BCAAs may have negative effects in patients who have been diagnosed with colorectal cancer. Observational research in patients living in the US has found that higher dietary intake of BCAAs is associated with a slightly higher risk of all-cause mortality when compared with lower intake (105581).
• Dementia. It is unclear if dietary BCAAs help to prevent dementia. Details: Observational research has found that higher blood levels of BCAAs are associated with a 13% to 17% lower risk of dementia. The lowered risk was maintained when research was adjusted for mortality, body mass index, and concomitant cholesterol-lowering medications (100469).
• Diabetes. It is unclear if dietary BCAAs reduce the risk for developing diabetes. Details: Some population research in Japanese females has found a decreased risk of diabetes associated with higher intake of BCAAs (97543). However, other observational research in people from the US has found that increased dietary intake of BCAAs is associated with an increased risk of diabetes (97536). Reasons for the conflicting finding are not entirely clear. Some evidence suggests that the dietary pattern of BCAA intake, rather than the total intake, may influence the risk of diabetes. Also, there is some speculation that differences in gut microbiota may attribute to the observed differences in diabetes risk associated with BCAA intake (100465). Prospective clinical research is needed to determine whether this association is causal or correlative.
• Exercise-induced muscle damage. Small studies suggest that BCAAs might reduce some, but not all, markers of muscle damage caused by exercise. Details: A meta-analysis of small clinical studies shows that supplementation with BCAAs reduces creatine kinase (CK) levels 24 hours post-exercise, but not 48 hours post-exercise. Additionally, this analysis shows that lactate dehydrogenase (LDH) levels are not affected by BCAA supplementation (97534). The validity of this analysis was limited because baseline dietary protein consumption was not taken into consideration as a potential confounder. A separate meta-analysis of clinical research in trained male athletes performing various resistance exercises shows that taking BCAAs 0.2-1.76 grams/kg for 1-28 days improves CK levels immediately following exercise, and at 24 and 48 hours post-exercise, but does not reduce LDH levels at any timepoint, when compared with placebo or control (108469). Most doses of BCAAs studied consisted of a 2:1:1 ratio of leucine, isoleucine, and valine, respectively. The validity of these findings is limited due to the short duration of treatment and various doses studied. Small individual clinical trials show that taking BCAAs does not affect urinary myoglobin after a marathon nor plasma myoglobin or CK levels after isotonic muscular exercise (37123,92641,100471). The benefits of BCAAs might depend on baseline protein consumption. A small clinical study in resistance trained males shows that adding BCAAs 0.22 grams/kg (MusclePharm BCAA) daily for 8 days to a high daily protein consumption of 1.2 grams/kg does not attenuate muscle damage or improve muscle recovery when compared with placebo (100471). Conversely, a meta-analysis of clinical research in adults completing various exercises shows that taking BCAAs consisting of any combination of valine, leucine, and isoleucine ratios modestly reduces CK, LDH, and myoglobin 24 and 48 hours post-exercise, but does not improve muscle recovery or muscle force after exercise, when compared with placebo (108471). The validity of these findings is limited due to unclear reporting.
• Exercise-induced muscle soreness. Limited evidence suggests that oral BCAAs may modestly attenuate exercise-induced muscle soreness. Details: One meta-analysis shows that taking BCAAs does not reduce delayed-onset muscle soreness after exercise when assessed at the individual time points of 24, 48, or 72 hours (97534). However, when results of all time points are pooled together in two separate meta-analyses, supplementation modestly reduces soreness after exercise (97534,103353). Most, but not all, individual trials also show that taking BCAAs in various doses, such as 0.087 grams/kg or 5-10 grams before and/or after exercise, modestly reduces muscle soreness after exercise (37108,37123,37124,92648,97530,97535,100467,100471,103346,108471). The validity of these individual trials is limited by their small sample sizes, variable dosing regimens, and enrolled populations, which were mainly limited to young untrained adult males (97534,103353). A separate meta-analysis of clinical research in trained male athletes performing various resistance exercises shows that taking BCAAs 0.2-1.76 grams/kg for 1-28 days may improve muscle soreness during the first 24 hours after exercise, but not at 24 or 48 hours post-exercise, when compared with placebo or control (108469). The validity of these findings is limited due to the short duration of treatment and various doses studied. Also, it is not clear whether taking BCAAs before or after a workout may be more beneficial. Some research found a nonsignificant trend toward reduced muscle soreness when consuming a specific product (Aminofeel, Seikatsu Bunkasya Co. Ltd.) containing BCAAs 3.2 grams three times daily starting 3 days before working out and continuing 3 days after, when compared to control (100467). More research is needed to determine the best dosing regimen and which populations, if any, may benefit.
• Heart failure. It is unclear if oral BCAAs are beneficial in patients with heart failure. Details: A small clinical study in patients with heart failure and hypoalbuminemia shows that taking a specific packet of BCAA granules (LIVACT, Ajinomoto Co) containing L-valine 1144 mg, L-leucine 1904 mg, and L-isoleucine 952 mg, three times daily for at least 7 days and stopping after discharge from the hospital, does not affect serum albumin or cardiothoracic ratio (CTR) when compared with placebo (100470). It is possible that this study was underpowered to detect differences between groups. Another small clinical study in adults with chronic heart failure participating in a cardiac rehabilitation program shows that taking a specific oral supplement (Meiji Mei Balance Rehasupport Mini; Meiji Group) containing BCAAs 2.5 grams and various vitamins, minerals, and whey protein, twice daily for 12 weeks increases fat mass, but has no effect on peak oxygen uptake, 6-minute walking distance, or strength parameters, when compared with no supplementation (108470). It is unclear if these effects are due to BCAAs, the other ingredients, or the combination.
• Hepatitis. It is unclear if oral BCAAs are beneficial in patients with hepatitis. Details: Preliminary clinical research in patients with alcoholic hepatitis shows that taking BCAAs 20 grams daily orally or enterally for 3 weeks or until discharge, in combination with a controlled diet, does not reduce the risk of mortality when compared with conventional protein or a controlled diet alone (37133).
• Inflammatory myopathies. It is unclear if oral BCAAs are beneficial in patients with polymyositis and dermatomyositis. Details: A small clinical study in adults with suspected or confirmed polymyositis or dermatomyositis who are receiving standard corticosteroid therapy shows that a BCAA-specific product containing L-isoleucine 952 mg, L-leucine 1904 mg, and L-valine 1144 mg for 12-28 weeks, taken as two packages three times daily for a total daily dose of 24 grams, does not improve manual muscle test scores or clinical response at 12 and 28 weeks when compared with placebo (108477).
• Obesity. It is unclear of oral BCAAs can reduce the likelihood of developing obesity or improve weight loss in adults with overweight or obesity. Details: Some observational research has found that higher dietary intake of BCAAs is associated with lower odds of obesity when compared with a lower intake (100466). Conversely, a large observational study in adults in Iran, including those who are overweight or obese, has found that the highest dietary intake of BCAAs is associated with a 24% higher likelihood of general obesity in males, but not in females, when compared with the lowest dietary BCAA intake (108465). This study did not report ranges for highest and lowest BCAA intake, limiting the validity of this study. BCAAs have also been evaluated in adults with overweight or obesity. A small clinical study in obese females that underwent a 4-week calorie-restricted diet shows that taking 6 caplets daily containing a total of L-leucine 3 grams, L-isoleucine 1.5 grams, and L-valine 1.5 grams in addition to vitamin B6 40 mg daily for 4 weeks does not further reduce weight, but may slightly preserve lean body mass, when compared with placebo (100464). Another small clinical study in overweight and obese adults shows that taking BCAAs 0.1 gram/kg daily in addition to starting a low-calorie diet for 16 weeks does not improve weight loss, but may preserve lean muscle mass, when compared with taking placebo while following the low-calorie diet (105583).
• Overall mortality. It is unclear if dietary BCAA consumption reduces the risk of all-cause mortality. Details: Observational research in adults has found that total BCAA intake, as well as isoleucine intake, is associated with a reduced risk of all-cause mortality, particularly in those with higher serum triglyceride concentrations (108467). However, this association was not present for leucine or valine intake. The validity of this meta-analysis is limited due to unclear reporting; additionally dietary intake was recorded from a single survey.
• Pancreatic cancer. The association between dietary BCAA intake and pancreatic cancer risk is unclear. Details: Observational research in adults in Italy has found that consuming BCAAs as part of the diet in quantities greater than 18 grams daily is associated with a 2-fold increased risk of pancreatic cancer when compared with less than 12 grams daily. This relationship was stronger in younger males, those with higher body mass indexes, and in those who smoke or have high alcohol intake (108476). Dietary information was recorded from a single, weekly consumption questionnaire.
• Phenylketonuria (PKU). It is unclear if oral BCAAs are beneficial in patients with PKU. Details: A small clinical trial in adolescents and young adults with PKU shows that taking BCAAs, consisting of valine 150 mg/kg, isoleucine 150 mg/kg, and leucine 200 mg/kg, with meals and at bedtime for up to 6 months seems to improve attention and processing when compared with a control group (37127).
• Physical performance. It is unclear if oral BCAAs are beneficial for improving physical function and muscle strength in older adults. Details: In malnourished elderly individuals, preliminary clinical research shows that taking a supplement providing BCAAs 5000 mg daily, in addition to other amino acids, vitamin B6, and vitamin B1 (Aminotrofic) for 2 months, does not improve muscle mass, muscle strength, or physical function to a greater extent than dietary advice intended to maximize nutritional intake from food and drink (103349). Similarly, a clinical study in middle aged and elderly adults shows that a specific product (Sarcojoint; Orient Euro Pharma, Inc) containing leucine 1 gram, arginine, vitamin D3, glucosamine, chondroitin, and calcium, taken twice daily in addition to regular resistance exercise for 12 weeks, does not improve muscle strength, muscle mass, or physical performance when compared with taking an unspecified vitamin B supplement twice daily with regular exercise (108472). Conversely, one small clinical study in older adults who have had a hip replacement shows that taking BCAAs 1.2 grams and lysine 1.8 grams (Amino-aile, Ajinomoto Co., Inc.) daily for one month after undergoing exercise therapy sessions modestly increases the strength of both legs and arms when compared with taking starch. However, there was no effect on hip abductor strength of the operated leg or on grip strength or measures of independence (103347).
• Postoperative infection. There is limited evidence on the intravenous and oral use of BCAAs for reducing infection after oncologic surgery. Details: A meta-analysis of 6 small heterogeneous clinical trials in patients after oncologic surgery, mostly for liver cancer, suggests that receiving oral or intravenous BCAAs reduces the risk of postoperative infection by 38% when compared with control (105577).
• Postoperative recovery. There is limited evidence on the intravenous and oral use of BCAAs for improving postoperative recovery after oncologic surgery. Details: A meta-analysis of small heterogeneous clinical trials in patients after oncologic surgery, mostly for liver cancer, suggests that receiving oral or intravenous BCAAs reduces hospital stay by about 2 days, but does not reduce mortality or post-operative complications, when compared with control (105577).
• Psychological well-being. It is unclear if oral BCAAs are beneficial for psychological well-being. Details: A cross-sectional observational study has found that higher dietary consumption of BCAAs is associated with a lower risk of anxiety and depression when compared with lower consumption (105579).
• Sarcopenia. It is unclear if oral BCAAs are beneficial in patients with primary sarcopenia or in those with sarcopenia related to liver cirrhosis. Details: A small clinical study in postmenopausal adults at risk for sarcopenia shows that consuming BCAAs 9 grams daily for 8 weeks in addition to resistance training increases strength and muscle mass when compared with baseline, but is no different than resistance training plus a placebo (105576). Another small clinical study in adults 65 years or older with sarcopenia shows that taking a supplement containing BCAAs 2500 mg, vitamin D 500 IU, protein, and other vitamins daily for 8 weeks in addition to resistance training does not improve physical function when compared with resistance training alone. The supplement did seem to slightly improve handgrip strength and body mass when compared with no supplementation (100468). However, overall the study was inadequately powered to detect smaller effects on physical function and muscle mass. There is also interest in using BCCAs in patients with sarcopenia and liver cirrhosis. A clinical study in this population shows that taking BCAAs 7.2 grams (containing 1.2 grams of L-leucine, 600 mg of L-isoleucine, and 600 mg of L-valine) daily for 6 months improves handgrip strength, gait speed, and muscle mass when compared with baseline (108468). Although the study enrolled a control group (whey protein), the investigators did not provide a statistical comparison of outcomes between groups. A separate meta-analysis of low-quality clinical research in this population shows that taking BCAAs has no effect on handgrip strength when compared with no supplementation (108473). Although other outcomes were evaluated, results are inconclusive due to the limited number of studies available for each outcome.
• Spinocerebellar ataxia (SCA). It is unclear if oral BCAAs are beneficial in patients with SCA. Details: Although there is some preliminary clinical evidence that oral BCAAs might have a beneficial effect on symptoms of SCA (73), a small clinical crossover study shows that taking a particular BCAA compound (Livact) 4.5-18 grams daily for 4 weeks does not improve ataxia in patients with SCA when compared with placebo (37088).
• Stroke. It is unclear if oral BCAAs are beneficial in patients recovering from stroke. Details:A small nonblinded, clinical study in elderly patients with subacute stroke and sarcopenia currently undergoing intensive inpatient rehabilitation therapy shows that administering a specific product (Seniup; Enterogenomics Co) containing BCAAs 6 grams, given twice daily orally or by feeding tube for 1 month, modestly improves skeletal muscle index, dysphagia, gait, balance, and handgrip strength, and may attenuate muscle loss in affected upper and lower extremities, when compared with rehabilitation alone (108474). The validity of these findings is limited by the short duration of treatment. Other research has compared BCAA dosing regimens. A small study in stroke patients taking part in exercise sessions shows that taking BCAAs 3.5 grams (Hepas, Clinico Co. Ltd) daily for 2 months with breakfast is more effective for improving leg strength and balance than when taken post-exercise in the mid-afternoon. However, there were no differences in most measures of strength or in skeletal muscle mass (103352). More evidence is needed to rate BCAAs for these uses.

(Read more about BRANCHED-CHAIN AMINO ACIDS (BCAA))

POSSIBLY EFFECTIVE

• 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).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• 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.

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POSSIBLY EFFECTIVE

• Schizophrenia. Meta-analyses of small clinical studies suggest that oral D-serine, taken with standard antipsychotic therapy, may improve positive and negative symptoms in patients with schizophrenia. Details: Observational research has found that patients with schizophrenia have lower serum D-serine levels when compared with healthy controls (102201). Results from several small clinical trials assessing the impact of oral D-serine supplements on symptoms of schizophrenia are mixed (102202,102208,102214,102215,102216,102217,102237). However, meta-analyses of these and other small clinical studies in patients with schizophrenia show that taking D-serine as adjunct to antipsychotic therapy modestly improves negative symptoms when compared with placebo (102201,102214,102224). Some analyses have also found an improvement in positive symptoms (102201). Doses of D-serine assessed in clinical studies include 30 mg/kg daily for 4-12 weeks (102202,102208,102215), 60-120 mg/kg daily for 4 weeks (102215), and 2 grams daily for 6-16 weeks (102214,102216,102217,102237). Limited research shows that serine supplementation alone is inferior to antipsychotic treatment. A small clinical study in patients with treatment-resistant schizophrenia shows that taking D-serine 3 grams daily for 10 weeks is less effective for improving symptoms than olanzapine 30 mg (102203).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). It is unclear if oral L-serine is beneficial in patients with ALS. Details: Observational research in patients with ALS has found that taking L-serine 0.5-15 grams twice daily for 4 months is associated with a dose-dependent reduction in the rate of disease progression when compared with historical controls (102200).
• Alzheimer disease. It is unclear if oral serine is beneficial for the prevention or treatment of Alzheimer disease. Details: A small observational study in a group of patients with Alzheimer disease or mild cognitive impairment has found that increased blood levels of D-serine are associated with improved cognition, especially improved word recall, orientation, comprehension, and word-finding difficulty (102221). However, not all research agrees. Another small observational study in patients with Alzheimer disease found no correlation between levels of D-serine in cerebrospinal fluid and Alzheimer disease or level of cognitive function (102198). While clinical trials on the use of serine alone for improving cognitive function in patients with Alzheimer disease are lacking, serine has been evaluated in combination with other ingredients for this purpose. A small clinical study in patients with Alzheimer disease shows that taking a combination of L-serine 12.35 grams, N-acetyl cysteine 2.55 grams, nicotinamide riboside 1 gram, and L-carnitine tartrate 3.73 grams once daily for 4 weeks then twice daily for 8 weeks improves cognitive function, as measured using the ADAS-Cog score, in patients with greater baseline cognitive impairment when compared with placebo. However, taking this combination product did not improve cognitive function in patients with lower cognitive impairment at baseline (110623). It is unclear if these effects are due to serine, other ingredients, or the combination.
• Back pain. Oral L-serine 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 chronic low back pain and knee pain that is primarily neuropathic in nature shows that taking L-serine 594 mg with eicosapentaenoic acid (EPA) 149 mg daily for 8 weeks decreases back pain scores by 50% at week 8, compared with a 30% reduction in those taking placebo. However, there was no difference between groups at 4 weeks, and improvements were not maintained 4 weeks after treatment discontinuation (105831). It is unclear if these effects are due to serine, EPA, or the combination.
• Circadian rhythm sleep disorders. It is unclear if oral serine is beneficial in patients with circadian rhythm sleep disorders. Details: A small clinical study in healthy adults shows that taking L-serine 3 grams at bedtime daily for 2 weeks does not alter sleep habits, including bedtime, wake time, and time in bed, when compared with placebo. However, dim light melatonin onset, used as a marker of the circadian phase, was delayed in the placebo group, but not in the L-serine group, suggesting that L-serine may attenuate circadian phase delay (111267). The validity of these findings is limited by the small study size and short duration. Further, it is unclear if these findings can be generalized to patients with circadian rhythm sleep disorders.
• Cognitive function. Small clinical studies suggest that a single dose of oral D-serine may improve some, but not all, measures of cognitive function in adults. Details: A small clinical study in healthy adults shows that taking a single dose of D-serine 2.1 grams improves attention, vigilance, and verbal memory, but not visual memory, when compared with placebo (102219). Another small clinical study in healthy older adults shows that taking a single dose of D-serine 30 mg/kg improves spatial memory, learning, and problem solving, but does not affect executive function, working memory, or visual attention, when compared with placebo (102197). These studies are limited by small sample size and short duration. Serine has also been evaluated in combination with other ingredients for this purpose. A small clinical study in healthy adults with fatigue shows that taking serine, alanine, glutamate, aspartate, and tyrosine daily for 4 weeks improves measures of cognitive function including attention, spatial cognition, orientation, motivation, and time management when compared with placebo (111249). It is unclear if these effects are due to serine, other ingredients, or the combination.
• Depression. It is unclear if oral serine is beneficial in patients with depression. Details: A small observational study in patients with major depressive disorder has found that lower concentrations of D-serine in the cerebrospinal fluid are associated with greater depression severity. However, when cerebrospinal fluid levels of L-serine or D-serine were compared between healthy controls and patients with major depressive disorder, there was no significant between-group difference (102211).
• Fatigue. Oral serine 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 fatigue shows that taking serine, alanine, glutamate, aspartate, and tyrosine daily for 4 weeks does not improve subjective or objective measures of fatigue when compared with placebo (111249).
• Hereditary motor and sensory neuropathy. It is unclear if oral L-serine is beneficial in patients with hereditary motor and sensory neuropathy. Details: A very small clinical study in patients with hereditary sensory autonomic neuropathy type I (HSAN1) shows that taking L-serine 400 mg/kg daily for one year modestly reduces neuropathy severity when compared with placebo (102204).
• Inflammatory bowel disease (IBD). Although there has been interest in using oral serine for IBD, there is insufficient reliable information about the clinical effects of serine for this purpose.
• Insomnia. It is unclear if oral L-serine is beneficial in patients with insomnia. Details: A small clinical study in healthy patients dissatisfied with their sleep shows that taking L-serine 3 grams 30 minutes before going to bed seems to improve falling asleep, staying asleep, and subjective sleep quality when compared with placebo (102212). It is uncertain if patients with insomnia would also have the same benefits from L-serine.
• Knee pain. Oral L-serine 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 knee pain and chronic low back pain that is primarily neuropathic in nature shows that taking L-serine 594 mg with eicosapentaenoic acid (EPA) 149 mg daily for 8 weeks decreases knee pain scores by 36% and 43% at weeks 4 and 8, respectively, compared with changes of 24% and 29%, respectively, in those taking placebo. At 4 weeks after treatment discontinuation, pain reductions were maintained in both groups (105831). It is unclear if these effects are due to serine, EPA, or the combination.
• Muscle fatigue. Oral serine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in healthy male volunteers shows that taking serine 200 mg, arginine 3600 mg, and valine 2200 mg daily for 14 days reduces fatigue and perceived exertion after 120 minutes on a cycle ergometer when compared with placebo (102234). It is unclear if these findings are due to serine, other ingredients, or the combination.
• Parkinson disease. It is unclear if oral D-serine is beneficial in patients with Parkinson disease. Details: A small clinical study in patients with Parkinson disease shows that taking D-serine 30 mg/kg daily for 6 weeks modestly improves involuntary movements and behavioral symptoms when compared with placebo (102206).
• Post-traumatic stress disorder (PTSD). It is unclear if oral D-serine is beneficial in patients with PTSD. Details: A small clinical study in patients with PTSD shows that taking D-serine 30 mg/kg daily for 6 weeks improves symptoms of anxiety and depression when compared with placebo (102209).
• Tourette syndrome. It is unclear if oral D-serine is beneficial in children with Tourette syndrome. Details: A very small clinical study in children 8-17 years of age with Tourette syndrome shows that taking D-serine up to 30 mg/kg daily for 8 weeks does not improve symptoms when compared with placebo (102218). This study is limited by a small sample size and insufficient power to detect differences between groups. More evidence is needed to rate serine for these uses.

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POSSIBLY INEFFECTIVE

• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). Several small clinical studies suggest that oral threonine does not improve symptoms or slow the progression of ALS. Details: Small clinical trials show that taking threonine 2 grams daily for 7 days or 4 grams daily, divided into two or four doses, for up to 12 months does not seem to slow the progression of early-stage ALS or reduce symptoms when compared with placebo (681,12057,60069). There is also concern that threonine might actually worsen pulmonary function in these patients. The decline in forced vital capacity (FVC) associated with threonine therapy was about 2.5 times greater than that with placebo (681).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Familial spastic paraparesis (FSP). It is unclear if oral threonine is beneficial in patients with FSP. Details: A small clinical study in patients with FSP shows that taking threonine 1.5 grams to 2 grams three times daily for 2 weeks slightly improves some measures of motor impairment and spasticity when compared with placebo. However, these improvements do not seem to be clinically significant (12059).
• Multiple sclerosis (MS). It is unclear if oral threonine is beneficial in patients with MS. Details: A small clinical study in individuals with inactive or slowly progressive MS shows that taking threonine 2.5 grams three times daily for 8 weeks does not significantly reduce spasticity when compared with placebo (60073).
• Spasticity. It is unclear if oral threonine is beneficial in patients with spasticity. Details: A small clinical study in patients with spasticity arising from spinal cord injuries, multiple sclerosis, or syringomyelia shows that taking threonine 2 grams three times daily for 2 weeks slightly improves leg muscle tone when compared with placebo (12056). However, methodological concerns limit the validity of this finding. More evidence is needed to rate threonine for these uses.

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

POSSIBLY SAFE ...when used orally and appropriately. Alpha-alanine 100-140 mg/kg daily has been used with apparent safety for up to 3 months (16026,16027,16444). A single dose of alanine 40 grams has also been used with apparent safety (14612,16019,16020).

CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term. Alanine 90 mmol/L, as a component of an oral rehydration solution, has been used with apparent safety for approximately 48 hours in children age 3-48 months (16021).

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

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LIKELY SAFE ...when used orally and appropriately. BCAAs 12 grams daily have not been associated with significant adverse effects in studies lasting for up to 2 years (68,72,73,74,10117,10146,10147,37120,92643,97531,103351,103352). ...when used intravenously and appropriately. BCAAs are an FDA-approved injectable product (13309).

CHILDREN: LIKELY SAFE
when used orally in dietary amounts of 71-134 mg/kg daily (11120,13308).

CHILDREN: POSSIBLY SAFE
when larger, supplemental doses are used orally and appropriately for up to 6 months (13307,13308,37127).

PREGNANCY:
Insufficient reliable information available; avoid using amounts greater than those found in food. Although adverse effects have not been reported in humans, some animal research suggests that consumption of supplemental isoleucine, a BCAA, during the first half of pregnancy may have variable effects on birth weight, possibly due to abnormal placental development (103350).

LACTATION:
Insufficient reliable information available; avoid using amounts greater than those found in food. Although the safety of increased BCAA consumption during lactation is unclear, some clinical research suggests that a higher concentration of isoleucine and leucine in breastmilk during the first 6 months postpartum is not associated with infant growth or body composition at 2 weeks, 2 months, or 6 months (108466).

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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.

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LIKELY SAFE ...when L-serine is used orally in food amounts. Average dietary consumption of L-serine from combined food and supplemental sources ranges from 3.5-8 grams daily (91405).

POSSIBLY SAFE ...when used orally in medicinal amounts. D-serine 30 mg/kg (about 2 grams) orally daily for 6-16 weeks or 60 mg/kg (about 4 grams) daily for 4 weeks has been used with apparent safety (102202,102206,102214,102215,102237). L-serine up to 400 mg/kg (about 25 grams) daily for up to 1 year has been used with apparent safety (102204,102220,108550).

POSSIBLY UNSAFE ...when used orally in large doses. L-serine in doses greater than 400 mg/kg (about 25 grams) daily has caused reversible side effects including nausea, vomiting, nystagmus, and seizures (102204). D-serine 120 mg/kg (about 8 grams) or more daily might increase the risk of nephrotoxicity (102215).

PREGNANCY AND LACTATION:
Insufficient reliable information available. Animal research in lactating mice shows that dietary L-serine transfers to milk and increases free L-serine while decreasing glutamic acid, L-alanine, D-alanine, and taurine levels in milk. However, this does not affect serine levels in the offspring (102228). It is unknown what effect supplemental serine may have in humans. Avoid using in amounts greater than those found in food.

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LIKELY SAFE ...when used orally in food amounts. Threonine as L-threonine in doses of 7-14 mg/kg daily (about 0.5-1 gram daily) has been suggested to be the minimum amount required to maintain a positive nitrogen balance in humans and is generally considered to be safe (60072,94096).

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts. Taking threonine in doses up to 4 grams daily for up to 12 months seems to be safe (681,12056,12057,12059,60069).

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

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ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, BCAAs might alter the effects of antidiabetes medications.  Details Some evidence suggests that BCAAs might stimulate insulin release (10105,10110,10113,10114,10118). However, a small clinical study in adults with liver cirrhosis and high nocturnal levels of blood glucose suggests that BCAAs might increase blood glucose levels (103348).

LEVODOPA Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B BCAAs in large doses can reduce the effects of levodopa.  Details BCAAs may compete with levodopa for transport systems in the intestine and brain and decrease the effectiveness of levodopa (66,2719). Small clinical studies how that concomitant ingestion of protein or high doses of leucine or isoleucine (100 mg/kg) and levodopa can exacerbate tremor, rigidity, and the "on-off" syndrome in patients with Parkinson disease (3291,3292,3293,3294).

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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.

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NMDA ANTAGONISTS Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Theoretically, threonine might decrease the effects of NMDA antagonists.  Details Threonine increases central nervous system (CNS) glycine levels (12058). Glycine seems to bind a site on NMDA receptors and enhance the activity of the receptors (681,12057).

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General ...There is currently a limited amount of information on the adverse effects of alanine.

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General ...Orally or intravenously, BCAAs are generally well tolerated.
Most Common Adverse Effects:
Orally: Abdominal distension, diarrhea, nausea, vomiting.
All routes of administration: High doses can lead to fatigue and loss of motor coordination.

Cardiovascular ...Orally, a single case of hypertension following the use of BCAAs has been reported (37143).

Dermatologic ...Orally, a single case of skin blanching following the use of BCAAs has been reported (681). It is not known if this effect was due to use of BCAAs or other factors.

Gastrointestinal ...Orally, BCAAs can cause nausea, vomiting, diarrhea, and abdominal distension. Nausea and diarrhea has been reported to occur in about 10% of people taking BCAAs (10117,37143,92643,97531).

Neurologic/CNS ...Orally and intravenously, BCAAs can cause fatigue and loss of motor coordination due to increased plasma ammonia levels (693,694,10117). Short-term use of 60 grams of BCAAs containing leucine, isoleucine, and valine for 7 days in patients with normal metabolic function seems to increase levels of ammonia, but not to toxic plasma levels (10117). However, liver function should be monitored with high doses or long-term use (10117). Due to the potential of increased plasma levels of ammonia and subsequent fatigue and loss of motor coordination, BCAAs should be used cautiously before or during activities where performance depends on motor coordination (75). Orally, BCAAs may also cause headache, but this has only been reported in one clinical trial (681).

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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).

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General ...Orally, L-serine and D-serine seem to be well tolerated in medicinal doses. Side effects appear to be dose-dependent.
Most Common Adverse Effects:
Orally: Gastrointestinal distress, including abdominal pain, bloating, dyspepsia, loss of appetite, and nausea.
Serious Adverse Effects (Rare):
Orally: Seizures with high doses of L-serine.

Gastrointestinal ...Orally, D-serine 120 mg/kg (about 8 grams) daily has been reported to cause gastrointestinal distress (102215). L-serine 5-30 grams daily has been reported to cause abdominal pain, dyspepsia, bloating, nausea, and loss of appetite (102204,102220).

Genitourinary ...Orally, D-serine 120 mg/kg (about 8 grams) daily for 4 weeks has been reported to cause proteinuria without glycosuria or creatine elevation. Proteinuria resolved completely after discontinuation of serine (102215).

Hepatic ...Orally, D-serine 120 mg/kg (about 8 grams) daily has been reported to cause asymptomatic transaminitis which resolved after discontinuation of serine (102215).

Immunologic ...Orally, in one very small, exploratory study, patients taking L-serine 400 mg/kg (about 25 grams) daily for one year had a higher rate of localized infections than those taking placebo (102204). Whether ingestion of L-serine caused or increased the risk of these infections is unknown.

Neurologic/CNS ...Orally, D-serine 120 mg/kg (about 8 grams) daily has been reported to cause insomnia after a single dose (102215). Taking L-serine in doses greater than 400 mg/kg (about 25 grams) can cause reversible nystagmus and seizures (102204).

(Read more about SERINE)

General ...Orally, threonine seems to be well tolerated.

Dermatologic ...Orally, skin rash has been reported in people who have taken threonine (681).

Gastrointestinal ...Orally, some patients can experience minor gastrointestinal upset including diarrhea (12056). Other side effects reported in people who have taken threonine include flatus and constipation (681).

Neurologic/CNS ...Orally, headache has been reported in people who have taken threonine (681).

Pulmonary/Respiratory ...Orally, rhinorrhea has been reported in people who have taken threonine (681).

Other ...Orally, a two-fold increase in serum ammonia levels occurred in one patient following administration of threonine 4 grams daily (681).

(Read more about THREONINE)