L-Histidine [Discontinued] by Orthoplex

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

• Cholera. Oral L-histidine seems to reduce diarrhea in adults with cholera. Details: A clinical study in adults with severe cholera receiving ciprofloxacin shows that drinking a rice-based oral rehydration solution (CeraLyte-90, CERA products) supplemented with L-histidine (Ajinomoto Chemical) 2.5 grams per liter as needed for 72 hours decreases the frequency of stool output at 32 hours, the weight of stool at 72 hours, the amount of intravenous fluid needed during the first 48 hours, and the duration of diarrhea by roughly 5 hours when compared with drinking the oral rehydration solution alone (96312).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Atopic dermatitis (eczema). It is unclear if oral L-histidine is beneficial in adults and children with atopic dermatitis. Details: A small clinical crossover study in adults with atopic dermatitis shows that taking L-histidine 4 grams daily for 8 weeks improves clinician-reported disease severity scores by 32% to 34% when compared with baseline (108621). The lack of washout period prior to crossover and its subsequent carryover effect prevents useful statistical comparison to placebo, limiting the validity of these findings. A small clinical study in children aged 1-7 years with mild to moderate atopic dermatitis shows that taking L-histidine 0.8 grams daily for 12 weeks improves disease severity by 49% when compared with baseline (108652). The lack of statistical comparison to the placebo group limits the validity of these findings.
• Kidney failure. It is unclear if oral L-histidine is beneficial for anemia in patients with kidney failure. Details: A small clinical study in patients with chronic uremia and patients undergoing maintenance hemodialysis shows that taking L-histidine 4 grams daily does not improve anemia when compared with placebo (2352).
• Metabolic syndrome. It is unclear if oral histidine is beneficial in patients with metabolic syndrome. Details: A clinical study in females with obesity and metabolic syndrome shows that taking histidine 2 grams twice daily is associated with reduced insulin resistance, body mass index, waist circumference, and fat mass at 12 weeks when compared with placebo. It is unclear if the improvement from baseline differed between groups. Other lipid parameters were not affected (96311).
• Rheumatoid arthritis (RA). It is unclear if oral L-histidine is beneficial in patients with RA. Details: A small clinical study in patients with RA shows that taking L-histidine 4.5 grams daily for 30 weeks does not improve clinical measurements when compared with placebo (2350). More evidence is needed to rate histidine for these uses.

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POSSIBLY EFFECTIVE

• Osteoporosis. Higher dietary intakes of silicon in males and premenopausal females seem to be associated with higher bone mineral density (BMD), but it is unclear whether silicon supplements reduce the risk of osteoporosis. Details: Males and premenopausal females who have dietary intakes of silicon of at least 40 mg daily seem to have higher BMD than those with lower intakes. This could reduce the risk of osteoporosis (10470,12425). However, it is unclear if silicon supplements can reduce the risk for osteoporosis. Silicon intake has also been evaluated in postmenopausal females. Clinical and population-based research suggests that higher silicon intake does not seem to benefit postmenopausal females in general, although it may benefit those on hormone replacement therapy (10470,12425,75118,92135). Bone loss in postmenopausal females is primarily due to bone resorption. Silicon seems to affect only bone formation (12425).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. It is unclear if oral silicon is beneficial in patients with aging skin. Details: A small preliminary clinical study in healthy volunteers aged 40-60 years shows that taking a specific product (Exsynutriment by Biotec) containing organic silicon 600 mg in hydrolyzed marine collagen once daily, 15 minutes before breakfast, for 90 days improves skin firmness, hydration, and texture, but not wrinkles, brightness, or softness, when compared with placebo (100837).
• Alzheimer disease. Although there has been interest in using oral silicon for Alzheimer disease, there is insufficient reliable information about the clinical effects of silicon for this condition.
• Androgenic alopecia. Although there has been interest in using oral silicon for androgenic alopecia, there is insufficient reliable information about the clinical effects of silicon for this condition.
• Cardiovascular disease (CVD). Although there has been interest in using oral silicon for CVD, there is insufficient reliable information about the clinical effects of silicon for this condition.
• Dental peri-implantitis. It is unclear if oral silicon is beneficial in patients with peri-implantitis. Details: A small, preliminary clinical study in patients aged 18-75 with peri-implantitis shows that a specific choline-stabilized orthosilicic acid product (BioSil, Bio Minerals NV) containing silicon 5 mg and choline 100 mg, taken twice daily for 12 months, does not improve markers of inflammation and periodontal disease (i.e. probing pocket depth, bleeding on probing) when compared with placebo (110028). However, this study may not have been adequately powered to detect a difference between groups. More evidence is needed to rate silicon for these uses.

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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 used orally in the amounts found in foods.

POSSIBLY SAFE ...when used orally in larger amounts, short-term. L-histidine has been used with apparent safety in doses of up to 4 grams daily for up to 12 weeks (2347,2353,96311,108621), or in doses of up to 8 grams daily for up to 4 weeks (108620).

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

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LIKELY SAFE ...when used orally and appropriately in amounts commonly found in foods (7135,10470,92135). It is estimated that the average dietary intake of silicon is 20-50 mg daily (110029); however, there is currently no established recommended dietary allowance or tolerable upper intake level for silicon (7135,92136,95009,110029).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods (7135,10470). It is estimated that the average dietary intake of silicon is 20-50 mg daily (110029). There is insufficient reliable information available about the safety of silicon when used in larger, medicinal amounts; avoid using.

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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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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, histidine has been used with apparent safety in clinical research; however, a thorough evaluation of safety outcomes has not been conducted.

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General ...Orally, silicon in the amounts found in food and water is not associated with adverse effects.
Serious Adverse Effects (Rare):
Inhaled: Crystalline silicon dioxide in the form of quartz dust found in industrial and occupational settings is associated with an increased risk of diseases such as silicosis, tuberculosis, chronic bronchitis, chronic obstructive pulmonary disease (COPD), lung cancer, glomerulonephritis, vasculitis, and rheumatoid arthritis.

Cardiovascular ...Case control studies have shown that occupational exposure to silicon dioxide-containing compounds may cause vasculitis (75114). Patients with occupational pulmonary silicosis may develop microscopic polyangiitis (inflammation of the blood vessels in the nose, sinuses, throat, lungs, and kidneys, also known as Wegener's granulomatosis).

Dermatologic ...Occupational silica exposure may be a risk factor for scleroderma, particularly in males (75099).

Genitourinary ...Limited reports in humans indicate that long-term use of large amounts of antacids containing magnesium trisilicate may be associated with urolithiasis and silicon-containing stones (11760,11861,75075,75103). However, fewer than 30 cases associated with antacids containing silicates have been reported, despite these products being commercially available since the 1930s. Although exceptionally rare, silicon dioxide kidney stones can also occur without magnesium trisilicate ingestion (11556). Their formation is caused by an acidic urinary pH. In at least one case, urine alkalinization resulted in resolution of the symptoms (75075).
Case-control studies have shown that occupational exposure to silicon dioxide is related to antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (75114). High silicon levels in patients undergoing chronic hemodialysis have been associated with nephropathy (75089).

Hepatic ...High silicon levels in patients undergoing chronic hemodialysis have been associated with liver disease (75089).

Musculoskeletal ...High silicon levels in patients undergoing chronic hemodialysis have been associated with bone disease (75089). A meta-analysis suggests that the risk of rheumatoid arthritis is elevated with occupational exposure to silicon dioxide (75078).

Neurologic/CNS ...High silicon levels in patients undergoing chronic hemodialysis have been associated with neuropathy (75089).

Pulmonary/Respiratory ...Occupational exposure to crystalline silicon dioxide dust is associated with an increased risk of pulmonary diseases such as silicosis, tuberculosis, chronic bronchitis, chronic obstructive pulmonary disease (COPD), and lung cancer (75076,75081,75084,75114). Patients with occupational pulmonary silicosis may develop microscopic polyangiitis (inflammation of the blood vessels in the nose, sinuses, throat, lungs, and kidneys, also known as Wegener's granulomatosis). Meta-analyses suggest that occupational exposure to silicon dioxide increases the risk of lung cancer (75085,75095,75115). An analysis of 19 studies shows that lung cancer risk is approximately 2 times higher for those with silicosis (75115). It is not clear whether silicon dioxide is carcinogenic in the absence of silicosis (75083).

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