InstaCalm by FoodScience of Vermont

LIKELY EFFECTIVE

• Atopic dermatitis (eczema). Consuming casein peptide as part of formula with or without breastmilk for up to 6 months reduces the risk of atopic dermatitis in infants. Details: Clinical research shows that feeding infants a casein peptide-based formula (Nutramigen or Progestimil, Mead Johnson), with or without breastmilk for 4-6 months, reduces the risk for atopic dermatitis during the first 9-24 months of life by 52% to 73% when compared to cow's milk formula (91655,91656,91658). The benefits of casein peptides appear to be most significant in infants with a family history of atopy (91655,91656). Additionally, the benefit of using a casein peptide-based formula during the first 4 months of life persists into childhood, with a 29% reduced risk of developing atopic dermatitis at 6 years of age when compared to cow's milk formula (91659,91660). Clinical research also shows that casein peptide formula is equally effective to hydrolyzed whey protein formula for reducing the risk for atopic dermatitis in infants (91657,91658,91659,91660,91661).
• Atopic disease. Consuming casein peptide as part of formula during the first 4 months of life reduces the risk of atopic disease in infants with a family history of atopy. The benefits of casein peptide in infants without a family history of atopy is unclear. Details: Clinical research in infants with a family history of atopy shows that taking a casein peptide-based formula (Nutramigen, Mead Johnson) during the first 4 months of life, or after weaning from breastmilk, reduces the risk for atopic manifestations during the first 12-18 months of life by 39% to 44% when compared with cow's milk formula (91656,91658). This benefit persists over time, with a 20% reduced risk for developing atopic disease at 6 years of age when compared to cow's milk formula (91660). However, it may not be beneficial in children without a family history of atopy. One large, ancillary clinical study in children at increased risk for development of type 1 diabetes, but not specifically at risk for atopy, shows that using an extensively hydrolyzed casein peptide formula (Nutramigen, Mead Johnson) in infancy for up to 6-8 months does not prevent persistent asthma, allergic rhinitis, or atopic dermatitis development when compared with using a conventional formula containing 80% intact cow's milk protein and 20% hydrolyzed milk protein (Enfamil, Mead Johnson). The validity of these findings is limited by the patient population and the unclear duration of follow up (106564).
• Food allergies. Consuming casein peptide formulas is a safe alternative to cow's milk in children with cow's milk allergy. Details: Clinical research shows that specific casein peptide formulas are a safe and well-tolerated alternative for children with documented allergy to cow's milk. Evaluated formulas include Alimentum (Abbot Laboratories), Damira 2000 (Nutrition & Sante S.L.), Frisolac Allergycare (Friesland Nutrition), and Nutramigen (Mead Johnson) (91663,91664,91665,111439). A cost-effective analysis in children with cow's milk allergy also suggests that using casein peptide-based formula is cost-effective dominant and reduces other allergic manifestations when compared with soy-based formula (111438).

POSSIBLY EFFECTIVE

• Colic. Clinical research shows that consuming casein peptides as part of formula reduces crying, short-term, in infants with colic. Details: Clinical research in infants with colic shows that replacing cow's milk formula with a specific casein peptide formula (Nutramigen, Mead Johnson) significantly reduces crying and colic when compared with cow's milk formula. However, this effect appears to diminish after more than four days of use (91262). Preliminary clinical research shows that consuming specific casein peptide formulas (Alimentum, Abbot Laboratories; Nutramigen, Mead Johnson) for 7 days reduces daily crying time by up to 5 hours and reduces crying intensity when compared with baseline in infants with colic (91264). The validity of this finding is limited by the lack of a comparator group.
• Diabetes. Consuming casein peptides with carbohydrates may be beneficial for reducing postprandial glucose and insulin levels in adults with type 2 diabetes. Casein peptides have also been evaluated for the prevention of type 1 diabetes in infants, with inconclusive results. Details: In adults with type 2 diabetes, casein protein may improve postprandial glucose levels. Most clinical research shows that consuming casein peptides in conjunction with a carbohydrate bolus increases postprandial insulin response by 26% to 300% and reduces postprandial glucose levels by 5% to 28% when compared with consuming carbohydrates alone (91276,91295,91297,91299). These effects seem to persist with casein peptide doses as low as 12 grams daily, but not 6 grams daily (91300). Preliminary clinical research also shows that adding leucine 5 grams or 0.1 grams/kg to casein peptides increases postprandial insulin levels by 52% to 200%, reduces postprandial glucose levels by 5% to 12%, and improves 24-hour glucose levels by 11% when compared with consuming carbohydrates alone (91296,91297). However, some preliminary clinical research shows that consuming casein peptides 0.4 grams/kg with each meal for one day does not improve glycemic control (91298). These differing outcomes might be related to the forms of carbohydrates used, which include carbohydrate boluses and carbohydrate-containing meals. Additionally, the evidence for the effects of intact casein protein, as opposed to casein peptides, on postprandial insulin and glucose levels is conflicting (91276,91299). Clinical research in infants 6-8 months of age who are genetically predisposed to type 1 diabetes shows that administering a specific casein peptide-based formula (Nutramigen, Mead Johnson) in place of breastmilk decreases the development of one or more diabetes-associated auto-antibodies when compared with cow's milk formula. However, there was no difference in type 1 diabetes incidence after 10 years. This study was not powered to detect a difference in this outcome (91675).
• Hypertension. The casein peptides isoleucine-proline-proline (IPP) and valine-proline-proline (VPP), sometimes referred to as lactotripeptides, can modestly reduce blood pressure in patients with hypertension. Lower doses given for shorter durations seem to produce greater effects, and the effects may be more pronounced in Japanese patients than in European patients. Details: The most comprehensive meta-analysis to-date in patients with hypertension shows that taking casein peptides reduces systolic blood pressure (SBP) by 3 mmHg and diastolic blood pressure (DBP) by 1.5 mmHg. The average dose of casein peptides was 10.5 mg daily, including IPP 5.2 mg and VPP 5.3 mg daily, for about 8 weeks. However, there may be an inverse dose-response relationship; daily doses of casein peptides of 10 mg or less, lasting for 8 weeks or less, reduced blood pressure to a greater degree when compared with higher doses given for longer durations. Furthermore, casein peptides produced by fermentation resulted in modestly greater blood pressure reduction when compared with casein peptides produced by enzymatic hydrolysis (103765). Patient ethnicity may also play a role in the magnitude of effect. Other meta-analyses show a 1-6 mmHg reduction in SBP and 0.6-1.5 mmHg reduction in DBP when compared with control (103762,103763,103765,111437). A small clinical study in healthy Japanese males and postmenopausal adults with prehypertension shows that supplementation with casein peptides IPP 2 mg and VPP 1.4 mg daily for 8 weeks reduces home-monitored 7-day mean DBP, but not SBP, by 0.9 mmHg, compared with an increase of 1.2 mmHg in those receiving placebo (106565). Although findings are positive overall, the validity of the above meta-analysis, as well as older or less comprehensive analyses, is limited by the poor reporting and methodology of the included studies (103763,103765,103770,103772). Some limited research in patients with metabolic syndrome shows conflicting blood pressure lowering effects. A small clinical study shows that taking IPP/VPP (Calpis Co., Ltd.) 10.2 mg in the morning before breakfast daily for 4 weeks lowers 24-hour ambulatory systolic blood pressure by 2 mmHg, but not diastolic blood pressure, when compared with placebo (103764). However, another study shows that taking casein peptides 5-25 mg daily with plant sterols 2 grams daily orally for 12 weeks does not reduce blood pressure when compared with placebo (103767). Notably, this study was not adequately powered to detect small changes in blood pressure.
• Neonatal jaundice. Clinical research suggests that consuming casein peptide reduces the risk of jaundice in neonates. Details: Preliminary clinical research shows that feeding newborns a specific casein peptide formula (Nutramigen, Mead Johnson) for 3 weeks reduces the risk of jaundice when compared with whey-predominant formula (91642) or human milk (91642,91651). Other preliminary clinical research in breastfed newborns shows that taking 5 mL of casein peptide formula, created by enzymatic hydrolysis, 6 times daily for 7 days decreases transcutaneous bilirubin levels when compared with breastfeeding alone (91643).

POSSIBLY INEFFECTIVE

• Asthma. Consuming casein peptide does not appear to reduce the risk of asthma in infants. Details: Most clinical research shows that feeding infants a casein peptide-based formula (Nutramigen or Progestimil, Mead Johnson), with or without breastmilk for 4 months, does not reduce the risk for asthma in the first 4 months to 6 years of life in children with a family history of atopy (91655,91659,91660). However, one preliminary clinical study shows that feeding infants Nutramigen beginning at about 3.8 months of age decreases wheezing by 61% compared to cow's milk formula; the incidence of asthma was not evaluated (91656).
• Infant development. Consuming casein peptide does not appear to affect growth or development in healthy infants, or in premature or low-birth weight infants. Details: Most clinical research shows that using casein peptide-predominant formula for 6 weeks to 6 months in premature, low-birth weight, or healthy infants does not affect growth when compared with breast milk, whey protein-based formula, rice hydrolysate formula, cow's milk formula, or amino acid-based formula (86085,91644,91672,91673). Additionally, feeding infants a specific casein peptide formula (Nutramigen, Mead Johnson) for 4 months does not affect growth at 6 or 10 years when compared with whey protein-based formula, cow's milk formula, or breast milk (86085,91644). However, clinical research suggests that a casein peptide-based formula might be beneficial in infants with cow's milk allergy. One study in this population shows that casein peptide-based formula significantly increases growth from 6-12 months of age when compared with soy-based formula (91672).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. It is unclear if oral casein peptides are beneficial in patients with acne. Details: Preliminary clinical research in adults with moderate to severe acne shows that taking a specific casein peptide (Lactium) 150 mg orally daily for 84 days does not reduce acne lesion count when compared with control. However, the study may have been inadequately powered to detect a difference between groups (111436).
• Aging skin. It is unclear if oral casein peptides are beneficial in patients with aging skin. Details: A small clinical study in healthy, normotensive older Japanese adults shows that taking casein peptides isoleucine-proline-proline (IPP) and valine-proline-proline (VPP) orally once daily for 48 weeks reduces facial pigmentation area by about 15%, compared with an increase of about 6% in patients taking placebo (106563).
• Anxiety. Although there has been interest in using oral casein peptides for anxiety, there is insufficient reliable information about the clinical effects of casein peptides for this purpose.
• Athletic performance. It is unclear if oral casein peptides are beneficial for athletic performance. Details: Preliminary clinical research in overweight male police officers shows that taking casein peptides 1.5 grams/kg orally daily in two divided doses for 12 weeks, in conjunction with resistance training, decreases body fat percentage by 3%, increases lean body mass by 2 kg, and improves chest, shoulder, and leg press strength by around 30% when compared with whey protein (85648).
• Cancer. Although there has been interest in using oral casein peptides for cancer, there is insufficient reliable information about the clinical effects of casein peptides for this purpose.
• Diarrhea. It is unclear if oral casein peptides are beneficial in patients with diarrhea. Details: Preliminary clinical research in male children with persistent diarrhea shows that consuming a casein peptide-based diet during hospitalization is less effective for reducing stool output than a yogurt-based diet (91648).
• Epilepsy. Although there has been interest in using oral casein peptides for epilepsy, there is insufficient reliable information about the clinical effects of casein peptides for this purpose.
• Exercise-induced muscle soreness. It is unclear if oral casein peptides are beneficial in patients with exercise-induced muscle soreness. Details: Preliminary clinical research in male cyclists shows that drinking 200 mL of a carbohydrate beverage containing 1.8% casein peptides every 5 km followed by 500 mL after cycling completion reduces exercise-induced muscle soreness and improves late-exercise time-trial performance when compared with drinking a carbohydrate beverage alone (91256).
• Fatigue. Although there has been interest in using oral casein peptides for fatigue, there is insufficient reliable information about the clinical effects of casein peptides for this purpose.
• Hyperlipidemia. Low quality research suggests that oral casein peptides are not beneficial in patients with hyperlipidemia. Details: A meta-analysis of randomized trials in subjects with and without hyperlipidemia shows that using casein peptide-based diets for 1-48 weeks does not improve low-density lipoprotein cholesterol, high-density cholesterol, or triglyceride levels when compared with control (111437).
• Insomnia. It is unclear if oral casein peptides are beneficial in patients with insomnia. Details: A small clinical study in Korean patients with poor sleep quality shows that taking a specific product (Lactium, Ingredia) containing bovine alpha-s1 casein peptides 300 mg one hour before bedtime for 4 weeks modestly improves sleep efficiency based on subjective reports and actigraphy measures when compared with placebo (103774). Casein peptides have also been studied as part of combination products. A small clinical study in adults with insomnia or disturbed sleep patterns shows that a specific product (RLX2; LiveLife Biosciences AG) containing a specific casein peptide, alpha-s1-casein tryptic hydrolysate, 150 mg, and L-theanine 50 mg, taken one hour before bedtime for 4 weeks, increases sleep duration by 45 minutes and improves habitual sleep efficiency and daytime dysfunction when compared with baseline. However, it does not affect blood pressure, heart rate, or cortisol levels (108556). It is unclear if these effects are due to L-theanine, alpha-s1-casein tryptic hydrolysate, or the combination.
• Physical performance. It is unclear if oral casein peptides are beneficial for physical performance. Details: Preliminary clinical research in healthy older males shows that taking casein peptides 10 grams before and after resistance training for 8 weeks does not improve strength or body composition when compared with placebo (91255).
• Stress. Although there has been interest in using oral casein peptides for stress, there is insufficient reliable information about the clinical effects of casein peptides for this purpose. More evidence is needed to rate casein peptides for these uses.

(Read more about CASEIN PEPTIDES)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Diabetes. It is unclear if oral stevia is beneficial in patients with diabetes; the available research is conflicting. Details: A small single-dose study shows that taking stevia leaf extract 1000 mg, standardized to contain 91% stevioside, along with a meal reduces postprandial glucose levels by 18% in adults with type 2 diabetes when compared with a starch control (11812). However, clinical research in patients with type 1 or type 2 diabetes shows that taking stevioside 250 mg three times daily for 3 months does not affect blood glucose levels or glycated hemoglobin (HbA1C) when compared with baseline (16705). Also, a small clinical study in patients with diabetes shows that drinking 200 mL of black tea, sweetened with stevia extract 2%, three times daily for 8 weeks does not affect glycemic indices when compared with drinking tea sweetened with sucralose (103695).
• Hypertension. It is unclear if oral stevia is beneficial in patients with hypertension; the available research is conflicting. Details: Some clinical research in patients with mild to moderate hypertension shows that taking stevioside, a constituent of stevia, 750-1500 mg in three divided doses daily reduces systolic blood pressure by 10-14 mmHg and diastolic blood pressure by 6-14 mmHg within one week to three months of treatment initiation and continuing for up to 2 years (11809,11810). However, other clinical research in patients with mild hypertension shows that taking stevioside in doses up to 15 mg/kg daily does not significantly reduce blood pressure (16706).
• Obesity. It is unclear if oral stevia is beneficial in patients with obesity; the available research is conflicting. Details: Although a small clinical study in healthy adults shows that drinking water with stevia (Truvia) 245 ppm as a single dose reduces appetite and energy intake when compared with drinking water alone (103697), other small, single-dose studies have shown no effect of stevia 15.3 mg or 1 gram as a single dose on satiety, energy intake, or fullness when compared with either water alone or a non-nutritive sweetener (103696,110124). A small clinical study in healthy adults shows that taking an aqueous stevia leaf extract (SweetLeaf) twice daily for 12 weeks does not affect body weight, compared with an increase in weight in the control group. This suggests that stevia extract may have attenuated weight gain in this study (106458). More evidence is needed to rate stevia for these uses.

(Read more about STEVIA)

POSSIBLY EFFECTIVE

• Cognitive function. Oral L-theanine may improve some aspects of cognitive function. It is unclear if using L-theanine in conjunction with caffeine can enhance the effects of either ingredient. Details: A single dose of L-theanine 100 mg seems to improve vigilant attention, reducing error rates in cognitive tests when compared with placebo (91747). However, taking L-theanine (Suntheanine, Taiyo Kagaku) 200 mg daily for 4 weeks does not improve verbal fluency, memory, motor speed, or executive function in an adult population, although it may moderately improve verbal fluency in a subgroup of people with lower cognitive function at baseline (101986). When L-theanine is combined with caffeine, a meta-analysis and multiple individual clinical studies show that the combination improves alertness, as well as accuracy during a test that requires switching attention between different tasks, but does not improve reaction time (38116,91750,96335,96336). Some research also shows that L-theanine plus caffeine improves cognitive performance and reduces task-induced fatigue when compared with baseline and placebo. However, it is unclear if this is due to the individual ingredients or the combination (38116,96335,96336). Some research suggests that the combination is no better than either individual ingredient alone (91747,96335,96336).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral L-theanine, taken continuously or as a single dose, improves cognition in older adults. Details: A small clinical study in healthy, Japanese adults aged 50-69 years shows that taking a specific product (Suntheanine; Taiyo International.) containing L-theanine 101 mg daily after breakfast for 12 weeks does not improve mini-mental state exam (MMSE) scores when compared with placebo. However, a single-dose analysis from this study shows that administration of L-theanine 101 mg may improve the quality of working memory and reaction times during a cognitive function test when compared with placebo (108553). Patients were permitted to consume polyphenol-rich beverages during the study period; however, consumption was not documented, limiting the validity of this finding.
• Alzheimer disease. Although there is interest in using oral theanine for Alzheimer disease, there is insufficient reliable information about the clinical effects of theanine for this condition.
• Anxiety. It is unclear if oral L-theanine is beneficial in patients with anxiety. Results of clinical research are conflicting. Details: A preliminary clinical study shows that taking a single dose of a specific L-theanine product (Suntheanine, Taiyo Kagaku) 200 mg does not reduce experimentally-induced anticipatory anxiety when compared with placebo (12188). However, another preliminary clinical study in healthy adults with stress-related anxiety shows that taking L-theanine 200 mg daily for 4 weeks reduces anxiety scale scores and sleep disturbance when compared with placebo (101986).
• Attention. It is unclear if oral theanine improves attention. Details: A small clinical study in healthy males shows that taking a single dose of L-theanine 200 mg improves selective attention similar to a single dose of caffeine 160 mg (96337). However, other small clinical studies in adults show that taking L-theanine 100-400 mg does not improve most measures of attention, especially sustained attention or attention in executive control tasks, but doses of 100-200 mg may improve performance in simple attentional tasks when compared with placebo (96338,111396). Some of these studies suggest that taking L-theanine with caffeine appears to provide more benefit than either individual ingredient alone (96337,96338).
• Attention deficit-hyperactivity disorder (ADHD). Oral L-theanine seems to improve some aspects of ADHD, including cognition and sleep. Details: Some preliminary clinical research in children with ADHD shows that taking a one-time dose of L-theanine 2.5 mg/kg increases cognition scores, but does not improve results on sustained attention or inhibitory control tests, when compared with placebo. Taking L-theanine with caffeine 2 mg/kg also increases cognition scores and improves performance on a sustained attention test, but does not improve inhibitory control, when compared with placebo (104141). Other preliminary clinical research in males aged 8-12 years with ADHD shows that taking a specific L-theanine product (Suntheanine, Taiyo Kagaku) 200 mg orally twice daily for 6 weeks increases the percent of time spent in restful sleep by about 5% and decreases the number of bouts of nocturnal activity by about 6 when compared with placebo (91744).
• Cancer. Although there is interest in using oral theanine for cancer, there is insufficient reliable information about the clinical effects of theanine for this condition.
• Chemotherapy-induced diarrhea. Oral L-theanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with colon cancer shows that taking L-cystine 700 mg and L-theanine 280 mg (Ajinomoto Co. Inc.) orally once daily, starting one week before chemotherapy with TS-1 (Taiho Pharmaceutical) and continuing for 28 days, increases the rate of therapy completion by 49%, reduces the incidence of diarrhea by 37%, reduces appetite loss by 33%, and improves the reported tolerability of chemotherapy when compared with chemotherapy alone (96334). However, this combination does not appear to be beneficial in patients with gastric cancer, or in those with colorectal cancer receiving 4 courses of capecitabine-based adjuvant chemotherapy. (96334,101985).
• Cognitive impairment. Oral L-theanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One very small clinical study in adults with mild cognitive impairment shows that taking a product containing L-theanine 120 mg and green tea extract 720 mg (LGNC-07, LG Household & Health Care, Ltd) orally twice daily after meals for 16 weeks modestly improves memory and attention when compared with baseline. However, taking this product does not appear to improve memory and attention when patients with self-reported memory problems, but without mild cognitive impairment, are also considered (96339).
• Depression. It is unclear if oral L-theanine is beneficial in patients with depression. Details: A small clinical study shows that taking a specific L-theanine product (Suntheanine, Taiyo Kagaku Co. Ltd.) 250 mg orally at bedtime for 8 weeks reduces symptoms and improves sleep quality when compared to baseline in individuals with mild major depressive disorder (MDD) (96331). The validity of these findings is limited by the lack of a comparator group.
• Erythema. Oral L-theanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in healthy females with self-perceived skin sensitivity shows that taking a specific supplement containing L-theanine, ashwagandha, and saffron (InnerCalm, Arbonne) daily for 8 weeks reduces facial pigmentation when compared to baseline (111399). The validity of this finding is limited by a lack of a placebo group. It is unclear if these effects are due to L-theanine, other ingredients, or the combination.
• Generalized anxiety disorder (GAD). It is unclear if oral L-theanine is beneficial for reducing anxiety in people with GAD. Details: One small clinical study in adults with GAD shows that taking L-theanine 225 mg twice daily for 4 weeks, then 450 mg twice daily for 4 weeks, in conjunction with prescribed antidepressants, does not reduce anxiety scores when compared with antidepressants and placebo (104976).
• Hypertension. Although there is interest in using oral theanine for hypertension, there is insufficient reliable information about the clinical effects of theanine for this condition.
• Influenza. Oral L-theanine 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 green tea catechins (THEA-FLAN 90S, Ito-en Co.) 378 mg, standardized to contain epigallocatechin gallate 270 mg and L-theanine (Suntheanine, Taiyo Kagaku) 210 mg daily for 5 months reduces the risk of developing clinically diagnosed influenza when compared with placebo. However, the combination does not seem to prevent laboratory-confirmed influenza infection (54021).
• Insomnia. Oral L-theanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults with insomnia or disturbed sleep patterns shows that a specific product (RLX2; LiveLife Biosciences AG) containing L-theanine 50 mg and a specific casein peptide, alpha-s1-casein tryptic hydrolysate, 150 mg, taken one hour before bedtime for 4 weeks, increases sleep duration by 45 minutes and improves habitual sleep efficiency and daytime dysfunction when compared with baseline. However, it does not affect blood pressure, heart rate, or cortisol levels (108556). Another very small clinical study in healthy adults shows that taking a combination product containing tryptophan, glycine, magnesium, tart cherry powder, and L-theanine 2 hours before bedtime decreases sleep onset latency and increases total sleep duration, leading to better sleep efficiency and reduced morning sleepiness, when compared with placebo (111184). Another combination product containing L-theanine, ashwagandha, and saffron (InnerCalm, Arbonne), taken daily for 8 weeks, seems to improve sleep quality when compared to baseline (111399). However, the validity of this finding is limited by a lack of a control group. It is unclear if the effects described above are due to L-theanine, other ingredients, or the combination.
• Postoperative recovery. Oral theanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study of adults with esophageal cancer undergoing esophagectomy shows that taking theanine 280 mg and cystine 700 mg daily, staring 4 days before surgery and continued for 13 days after surgery, does not improve measures of physical activity but does improve exercise tolerance and some measures of quality of life when compared with placebo (111400). It is unclear if these findings are due to theanine, cystine, or the combination.
• Schizophrenia. It is unclear if oral L-theanine is beneficial in patients with schizophrenia; the available evidence is limited and conflicting. Details: One preliminary clinical study in adults with schizophrenia or schizoaffective disorder shows that taking L-theanine (Biosynergy) 200 mg orally twice daily for 8 weeks along with antipsychotic medications improves positive symptoms, anxiety, and general psychopathology symptoms, such as poor impulse control and disorientation, when compared with placebo. However, theanine does not improve general disease severity, negative symptoms, depression, cognitive function, extrapyramidal side effects, or quality of life (96341). Another small clinical study shows that taking L-theanine 400 mg (Suntheanine, BioSynergy Health Alternatives) with pregnenolone 50 mg daily for 8 weeks, in addition to antipsychotic medications, improves negative symptoms, general psychopathology symptoms, and anxiety when compared with placebo in patients with schizophrenia or schizoaffective disorder. However, there were no improvements in positive schizophrenia symptoms or extrapyramidal side effects (97923). The inconsistency of results might be due to the small study sizes and the subjectivity of the outcomes measured.
• Stress. It is unclear if oral L-theanine is beneficial in patients with stress. Details: One very small clinical study shows that taking L-theanine 200 mg prior to a stress-inducing exam reduces tension-anxiety and may prevent blood pressure increases caused by psychological stress when compared with placebo (91746). Other preliminary clinical research in pharmacy students shows that taking theanine 200 mg twice daily for one week prior, and then for the first 10 days of a pharmacy practice period, decreases subjective stress scores when compared with placebo (91745). Another small clinical study in healthy young adults shows that drinking a beverage containing L-theanine 200 mg alone or combined with L-arginine 50 mg after a psychological stressor reduces stress, as measured by salivary alpha-amylase activity, when compared with placebo. The combination of L-arginine and L-theanine did not differ from L-theanine alone, suggesting that the combination does not act synergistically to reduce markers of stress (110393). However, not all research has been positive. A small clinical study shows that taking a specific L-theanine product (Suntheanine, Taiyo Kagaku) 200 mg induces subjective feelings of tranquility in relaxed people, but not those with experimentally-induced anticipatory anxiety, when compared with placebo (12188). Also, a small, clinical crossover study in healthy, moderately stressed adults shows that taking a single dose of a specific product (Alphawave; Ethical Naturals) containing L-theanine 200 mg prior to a stress-inducing exam does not improve anxiety at any time point when compared with placebo (108554). Due to the single-dose nature of this study, the effects of continued administration of this product are unclear. L-theanine has also been evaluated in combination with other ingredients. A small clinical study in adults with stress shows that taking a specific combination product (Mg-Teadiola, Sanofi-Aventis Group), containing green tea extract 125 mg (providing 50 mg L-theanine), magnesium 150 mg, vitamin B6 0.2 mg, vitamin B9 0.1 mg, vitamin B12 1.25 mcg, and rhodiola 222 mg, orally once daily for 28 days modestly improves stress and anxiety scores when compared with placebo. Improvements in stress scores, but not anxiety scores, appear to persist at 28 days after treatment completion (108672). It is unclear if any effects are due to L-theanine, other ingredients, or the combination.
• Tourette syndrome. It is unclear if oral L-theanine is beneficial in children with Tourette syndrome. Details: A small, nonblinded clinical study in children aged 4-17 years with untreated Tourette syndrome or with chronic tic disorder and associated symptoms of anxiety shows that taking a liquid nutritional supplement providing L-theanine 200 mg and vitamin B6 2.8 mg daily for 2 months improves scores on the Yale Global Tic Severity Scale, but does not reduce anxiety, when compared with patients receiving psychoeducation (108555). This study may have been inadequately powered to detect a difference between groups. More evidence is needed to rate theanine for these uses.

(Read more about THEANINE)

LIKELY SAFE ...when used orally and appropriately. Casein peptides have been safely used in clinical trials lasting up to 5 months (85648,103763,103764,103765,103770,103772).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Casein peptide formulas have been safely used in healthy, premature, and very low birth weight infants (91262,91264,91643,91673,91675).

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

(Read more about CASEIN PEPTIDES)

LIKELY SAFE ...when certain stevia constituents, including stevioside and rebaudiosides A, D, and M, are used orally as sweeteners in foods. These constituents have generally recognized as safe (GRAS) status in the US for this purpose (16699,16700,16702,16705,16706,108049). The stevia constituent stevioside has been safely used in doses of up to 1500 mg daily for 2 years (11809,11810,11811). There is insufficient reliable information available about the safety of whole stevia or stevia extracts when used orally. The European Food Safety Authority (EFSA) has determined that the acceptable intake of steviol glycosides is 4 mg/kg daily (106456); however, it is unclear how this relates to the use of whole stevia or stevia extract.

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

(Read more about STEVIA)

POSSIBLY SAFE ...when used orally and appropriately, short-term. L-theanine has been used safely in clinical research in doses of up to 900 mg daily for 8 weeks (12188,36439,96331,96332,96334,96341,97923,101986,104976). There is insufficient reliable information available about the safety of L-theanine when used long-term.

CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term. A specific L-theanine product (Suntheanine, Taiyo Kagaku) 200 mg twice daily has been used safely in males aged 8-12 years for up to 6 weeks (91744).

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

(Read more about THEANINE)

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, combining these casein peptides with antihypertensive drugs might increase the risk of hypotension.  Details Clinical research shows that some casein peptides, including the lactotripeptides isoleucine-proline-proline (IPP) and valine-proline-proline (VPP), can modestly reduce blood pressure in patients with hypertension (103763,103765,103770,103772).

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ANTIDIABETES DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, stevia might increase the risk for hypoglycemia when combined with antidiabetes drugs.  Details Preliminary clinical research in patients with type 2 diabetes suggests that taking a single dose of stevia extract 1000 mg reduces postprandial blood glucose levels when taken with a meal (11812). However, other clinical research in patients with type 1 or type 2 diabetes suggests that taking stevioside 250 mg three times daily does not significantly affect blood glucose levels or glycated hemoglobin (HbA1C) after three months of treatment (16705).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, combining stevia or stevia constituents with antihypertensive agents might increase the risk of hypotension.  Details Stevia extract and stevioside might lower blood pressure in patients with hypertension (3745,3747,5031,11809,11810). However, other clinical research suggests that stevioside does not significantly lower blood pressure in patients with hypertension (16706).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, stevia might decrease clearance and increase levels of lithium.  Details Animal research suggests that stevia extracts might have diuretic activity (3746,3747). Theoretically, increased reabsorption of lithium along with sodium might reduce excretion and increase levels of lithium.

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ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theanine might lower blood pressure, potentiating the effects of antihypertensive drugs.  Details Animal research shows that theanine can lower blood pressure in spontaneously hypertensive animals (7687,77354). Theoretically, concomitant use of theanine and antihypertensive drugs might potentiate the antihypertensive activity.

CNS DEPRESSANTS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, theanine might have additive sedative effects when used in conjunction with CNS depressants. However, it is unclear if this concern is clinically relevant.  Details Theoretically, theanine may compete with glutamate and/or increase plasma gamma-aminobutyric acid (GABA) levels, which could cause CNS depression (96334). In one clinical study, some subjects taking oral theanine reported drowsiness (96331).

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General ...Orally, casein peptides are well tolerated in infants and adults. Adverse effects reported in clinical trials did not occur more frequently than with placebo.

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General ...Orally, stevia and steviol glycosides appear to be well tolerated. Most minor adverse effects seem to resolve after the first week of use.
Most Common Adverse Effects:
Abdominal bloating, dizziness, headache, myalgia, nausea, and numbness.
Serious Adverse Effects (Rare):
Allergic reactions.

Gastrointestinal ...Orally, stevia and steviol glycosides such as stevioside, can cause gastrointestinal adverse effects such as abdominal fullness and nausea. However, these generally resolve after the first week of use (11809,11810).

Immunologic ...Theoretically, stevia might cause allergic reactions in individuals sensitive to plants in the Asteraceae/Compositae family (11811). Members of this family include ragweed, chrysanthemums, marigolds, daisies, and many other herbs.

Musculoskeletal ...Orally, stevia and steviol glycosides may cause myalgia, but this generally resolves after the first week of use (11809,11810).

Neurologic/CNS ...Orally, stevia and steviol glycosides may cause headache, dizziness, and numbness (11809,11810).

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General ...Orally, L-theanine seems to be well tolerated.
Most Common Adverse Effects:
Orally: Drowsiness, headaches.

Neurologic/CNS ...Orally, L-theanine may cause headaches (36439). Patients have also reported drowsiness, increased duration of sleep, and increased dream activity after oral L-theanine use (96331).
A case of subtle facial tic starting within 4 days of taking L-theanine 400 mg daily has been reported for a pediatric patient. Although the tics reportedly ceased once theanine was discontinued, the child had exhibited tics in the past. Therefore, the adverse effect was not thought to be related to L-theanine (91744).

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