Sound A Sleep [Discontinued] by Bronson

POSSIBLY EFFECTIVE

• Depression. Oral 5-HTP seems to improve symptoms of depression. Details: A meta-analysis of preliminary clinical research shows that taking 5-HTP for up to 8 weeks might improve symptoms of depression in some patients. The pooled remission rate across 13 studies was 65%, and the pooled effect size across 7 studies assessing the change in depressive symptom scores from baseline was large (102854). In most studies, the dose of 5-HTP administered ranged from 150-800 mg daily, although doses as high as 3 grams daily have been used (903,30000,30125,30138,102854). Some research has compared 5-HTP to conventional antidepressants. In one clinical trial of adults experiencing a first episode of depression, taking 5-HTP orally, titrated up to a daily dose of 400 mg, decreased depression symptoms similarly to fluoxetine titrated up to 40 mg daily (30112). Limited research also suggests that taking 5-HTP 300-800 mg daily seems to work similarly to fluvoxamine 50 mg (2203) or imipramine 150 mg daily (30125). Adding 5-HTP 300 mg orally daily to clomipramine 50 mg daily for 28 days has also been shown to reduce depressive symptoms when compared with clomipramine alone (6245).

POSSIBLY INEFFECTIVE

• Down syndrome. Oral 5-HTP does not seem to improve muscle tone or cognitive skills in patients with this condition. Details: Although early reports suggested that 5-HTP might improve muscle tone and activity levels in infants with Down syndrome (88172), other research has shown no benefit. One small clinical study suggests that taking 5-HTP 0.5-5 mg/kg daily orally from early infancy until 3-4 years of age does not improve muscle tone or developmental ability scores in children with Down syndrome when compared with a control group (88173). Also, a prospective, double-blind study shows that taking 5-HTP 1-2 mg/kg daily orally, alone or with pyridoxine 5-10 mg/kg daily orally, beginning at birth and continuing until 3 years of age, does not improve muscle tone or development of cognitive, social, or language skills when compared with placebo (30153).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alcohol use disorder. Oral 5-HTP has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a food supplement containing 5-HTP 5 mg, phenylalanine 300 mg, and glutamine 150 mg daily for 40 days during alcohol detoxification therapy reduces withdrawal symptoms when compared with alcohol detoxification therapy alone (30100). However, taking a combination of 5-HTP 25-100 mg with carbidopa 25 mg four times daily for one year does not seem to improve alcohol abstinence rates when compared with placebo (30007). The effect of 5-HTP alone is unclear.
• Alzheimer disease. Although there has been interest in using oral 5-HTP for Alzheimer disease, there is insufficient reliable information about the clinical effects of 5-HTP for this condition.
• Anxiety. It is unclear if oral 5-HTP is beneficial in patients with anxiety disorders. Details: A small clinical study in people with anxiety disorders shows that taking 5-HTP 25-150 mg daily with carbidopa 150 mg daily for 8 weeks reduces anxiety when compared with baseline, but not when compared with clomipramine 25-150 mg daily (30124).
• Attention deficit-hyperactivity disorder (ADHD). Although there is interest in using oral 5-HTP for ADHD, there is insufficient reliable information about the clinical effects of 5-HTP for this condition.
• Cerebellar ataxia. It is unclear if oral 5-HTP reduces cerebellar ataxia symptoms. Details: One small clinical trial in people with cerebellar ataxia of various etiologies shows taking 5-HTP orally 10 mg/kg daily for 4 months improve quantitative ataxia scores when compared with placebo. Further improvement was noted in subjects continuing treatment for another 8 months (916). However, in a subsequent trial in this population, taking 5-HTP orally 1 gram daily for 10 months did not improve symptom scores when compared with placebo (30164). Also, a small clinical study in people with Friedreich's ataxia shows that taking 5-HTP 200-300 mg daily for 1 month, then 600-900 mg daily for 5 months (depending on body weight), does not improve symptoms when compared with placebo (30165).
• Fibromyalgia. Small clinical studies suggest that oral 5-HTP may improve symptoms of primary fibromyalgia syndrome. Details: Small clinical studies in people with primary fibromyalgia syndrome suggest that taking 5-HTP 100 mg orally three times daily for 30-90 days might improve pain, tenderness, sleep, anxiety, fatigue, and morning stiffness when compared with baseline or placebo (913,10286).
• Inflammatory bowel disease (IBD). It is unclear if oral 5-HTP is beneficial for IBD. Details: Preliminary clinical research in adults with stable IBD and fatigue shows that taking a specific 5-HTP (Levotonine, Panpharma) 100 mg orally twice daily for 8 weeks does not improve fatigue scores when compared with placebo. However, the validity of this study is limited by high patient drop-out (111311).
• Menopausal symptoms. It is unclear if oral 5-HTP is beneficial for symptoms of menopause. Details: A small clinical study in postmenopausal patients shows that taking 5-HTP orally 50 mg three times daily for 4 weeks does not reduce hot flash frequency when compared with placebo (30061).
• Migraine headache. It is unclear if oral 5-HTP reduces frequency of migraines. Details: Preliminary clinical research shows that taking 5-HTP 600 mg daily decreases migraine attack frequency similarly to methysergide 3 mg daily (30129). However, other small clinical studies show that taking 5-HTP 400 mg daily does not reduce the frequency or severity of migraine attacks when compared with placebo (30130,30184). Also, in children 6-12 years of age, one very small clinical study shows that taking 5-HTP 5 mg/kg daily in 3 divided doses for 12 weeks does not reduce the frequency or severity of migraine attacks when compared with placebo (30128).
• Obesity. It is unclear if oral 5-HTP is beneficial in for weight loss. Details: Some very small clinical studies show that taking 5-HTP orally, 300 mg three times daily 30 minutes before meals for 2-12 weeks, improves early satiety and decreases daily caloric intake in females with obesity when compared with placebo (914,30018). 5-HTP was also associated with a mean weight loss of 1.7 kg over 6 weeks when caloric intake was not restricted, and a mean weight loss of 3.3 kg over 6 weeks when caloric intake was restricted to about 1200 calories daily (914,30114). In moderately overweight adults with type 2 diabetes, taking 5-HTP 250 mg three times daily 30 minutes before meals for 2 weeks reduces caloric intake by about 22% and decreases body weight by about 2 kg when compared to baseline (30175).
• Obsessive-compulsive disorder (OCD). It is unclear if oral 5-HTP is beneficial in patients with OCD. Details: A small clinical study in patients with moderate to severe OCD shows that adding 5-HTP 200 mg orally daily to fluoxetine, titrated up to 60 mg daily, for 12 weeks reduces symptom severity when compared with placebo and fluoxetine. A complete response, defined as greater than or equal to 35% improvement in overall Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score, was seen in 54% of those taking 5-HTP at week 12, compared with only 12% of those taking placebo (104250). These results were not observed until week 12, which indicates that a longer treatment period may be needed to see the full effects of the intervention.
• Opioid withdrawal. Oral 5-HTP has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in Chinese males undergoing detoxification for heroin addiction shows that taking 5-HTP 200 mg orally daily for 6 days, in combination with tyrosine, phosphatidylcholine, and L-glutamine, might reduce insomnia and withdrawal symptoms and improve mood when compared with a control group (88178).
• Panic disorder. It is unclear if intravenous 5-HTP is beneficial for reducing anxiety in panic disorder. Details: A small clinical trial in females with panic disorders shows that receiving an intravenous (IV) infusion of 5-HTP, 60 mg over 30 minutes after premedication with carbidopa 100 mg orally, does not appear to reduce anxiety when compared with control (30093).
• Parkinson disease. It is unclear if oral 5-HTP is beneficial for improving Parkinson disease symptoms. Details: Two preliminary clinical trials show that taking 5-HTP 50 mg daily for 1 month seems to improve levodopa-induced dyskinesia and symptoms of depression, but not motor functioning or apathy, when compared with placebo in patients with Parkinson disease (102853,104251). Both studies used a crossover design to correct for the small sample size, but may still have been inadequately powered to detect small changes in these outcomes. However, in another study, taking larger doses of 5-HTP, 275-1500 mg orally daily along with carbidopa 150-1000 mg daily for up to 38 days, worsened rigidity, bradykinesia, and functional disability (30140). Other research has evaluated 5-HTP in patients with Parkinson disease and REM sleep behavior disorder (RBD). A small crossover study in these patients shows taking oral 5-HTP 50 mg daily for 4 weeks does not improve the percentage of REM sleep without atonia or the frequency of RBD events when compared with baseline or placebo. Patients taking 5-HTP report modest improvements in part II (motor function; e.g. swallowing, walking, and dressing) of the Unified Parkinson Disease Rating Scale (UPDRS), but not other parts of the UPDRS, when compared with placebo (107793). This study may have been inadequately powered to detect a difference between groups.
• Premenstrual syndrome (PMS). Although there is interest in using oral 5-HTP for PMS, there is insufficient reliable information about the clinical effects of 5-HTP for this condition.
• Seizures. Although there is interest in using oral 5-HTP for seizures, there is insufficient reliable information about the clinical effects of 5-HTP for this condition.
• Tension headache. It is unclear if oral 5-HTP reduces tension headache severity. Details: A small clinical study in adults with a history of chronic tension headaches suggests that taking 5-HTP 100 mg three times daily for 8 weeks does not reduce pain intensity or the number of days with headache when compared with placebo (2204).
• Tinnitus. Oral 5-HTP has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Research has evaluated a specific capsule formulation (Tinnitan Duo; Laboratorios Salvat) containing 5-HTP, ginkgo extract, magnesium, melatonin, pantothenic acid, vitamin B6, and zinc at undeclared doses. A small clinical trial in patients with subjective tinnitus shows taking this product as one capsule twice daily for 3 months improves Tinnitus Handicap Inventory (THI) total score and THI emotional subscale score at 3 months when compared with baseline. Patients also report improvement in tinnitus-related distress (107792). The validity of this study is limited by the lack of randomization and placebo-control; additionally, it is unclear if any effects are due to 5-HTP, other ingredients, or the combination. More evidence is needed to rate 5-HTP for these uses.

(Read more about 5-HTP)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral hops-derived bitter acids are beneficial for memory and attention in patients with age-related cognitive decline. Details: A small exploratory clinical study in older adults aged 45-64 years, with self-awareness of cognitive decline, shows that taking matured hops bitter acids (Kirin Holdings Co. Ltd) 35 mg daily for 12 weeks does not improve memory, attention, or performance on most cognitive tests when compared with placebo (102899). A follow-up clinical study in patients aged 45-69 years with subjective cognitive decline shows that taking the same dose of the same product for 12 weeks also does not improve memory, learning, or selective attention, but might improve divided attention as measured on the Symbol Digit Modalities Test (SDMT), when compared with placebo (105953). Both studies were funded by the supplement manufacturer and conducted in Japan; it is unclear if these findings are generalizable to other geographic locations.
• Anxiety. Although there is interest in using oral hops for anxiety, there is insufficient reliable information about the clinical effects of hops for this condition.
• Attention deficit-hyperactivity disorder (ADHD). Although there is interest in using oral hops for ADHD, there is insufficient reliable information about the clinical effects of hops for this condition.
• Body odor. Although there is interest in using topical hops to reduce body odor, there is insufficient reliable information about the clinical effects of hops for this purpose.
• Insomnia. Taking oral hops extract in combination with valerian root extract seems to be modestly beneficial in patients with insomnia. However, the effect of hops extract when used alone is unclear. Details: In patients with diagnosed sleep disorders, taking hops extract in combination with valerian root for at least 28 days seems to be beneficial. One clinical study in adults with mild insomnia shows that taking two tablets of a combination product containing a total of 83.8 mg hops extract and 374 mg valerian root extract nightly seems to modestly improve subjective sleep measures, including sleep latency, when compared with placebo, after 28 days. However, there was no difference in efficacy between treatment groups after only 14 days (15018). Additionally, a small clinical study in patients with non-organic sleep disorders shows that taking a specific fixed combination product (Ze91019) containing hops extract 120 mg and valerian root extract 500 mg daily for 28 days improves sleep latency when compared with placebo (19413). It is unclear if taking hops and valerian root as a single dose is beneficial in healthy patients. One small clinical study in healthy volunteers with poor sleep shows that taking a specific preparation (Dormeasan, Bioforce AG) containing hops extract 460 mg and valerian root extract 460 mg dissolved in 50 mL of honey water once at night increases total sleep time and time spent in deep sleep when compared with placebo (19418). However, another preliminary clinical study in healthy adults shows that taking a single dose of a specific product (Hova, Zyma S.A.) containing hops extract 200 mg and valerian root extract 400 mg does not improve sleep latency when compared with placebo (6248). Research also shows that taking certain combination products containing hops and at least two other ingredients can improve sleep quality. These combination products have combined hops with lemon balm and valerian (Valerina Natt) (19417); or passionflower and valerian (NSF-3, M/s Tablets India) (88193,89406). However, other combination products have not been beneficial. These have combined hops with soya oil, soya lecithin, and cannabis (Cyclamax, Persee Medica) (55382); or with vitamin B6, zizyphus extract, hydrolyzed milk protein (Lactium), and magnesium oxide (LZ Complex3, Sanofi) (95971).
• Dyspepsia. Although there is interest in using oral hops-derived bitter acids for dyspepsia, there is insufficient reliable information about the clinical effects of hops for this condition.
• Lactation. Although there is interest in using oral hops for increasing lactation, there is insufficient reliable information about the clinical effects of hops for this purpose.
• Menopausal symptoms. It is unclear if oral hops extract is beneficial in patients with menopausal symptoms. Details: Small clinical studies in patients with menopausal symptoms show that taking a specific hops extract (MenoHop, Biodynamics) 75.1-300 mg standardized to contain 100-200 mcg of 8-prenylnaringenin daily does not improve menopausal symptoms, including hot flashes, after 8-12 weeks of treatment when compared with placebo (55338,55370).
• Obesity. It is unclear if administering bitter hops extract intraduodenally or intragastrically is beneficial in patients with obesity. Details: A very small clinical study in healthy young adult males shows that intraduodenal or intragastric administration of bitter hops extract 100-250 mg once does not affect appetite perception, gastrointestinal symptoms, or subsequent energy intake when compared with control (112233). It is unclear if these results are generalizable to individuals with overweight or obesity.
• Overactive bladder. Oral hops extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: An observational study in females with overactive bladder suggests that taking a specific combination product (Granu Fink femina, Omega Pharma) containing hops extract 18 mg, sweet sumac bark extract 56 mg, and pumpkin seed oil 227 mg three times daily for 12 weeks decreases the frequency of urination from an average of 0.9 to 0.4 episodes daily and the frequency of leakage when compared with baseline. The study also shows this specific combination product (Granu Fink femina, Omega Pharma) improves quality of life when compared with baseline (103253). The validity of these findings is limited by the lack of a control group. Also, it is unclear if these findings are due to hops extract, other ingredients, or the combination.
• Psychological well-being. It is unclear if drinking non-alcoholic beer containing matured hops bitter acids is beneficial in healthy adults. Details: A clinical study in healthy adults shows that consuming 350 mL of non-alcoholic beer containing matured hops bitter acids 35 mg (Kirin Holdings Co. Ltd) daily for 3 weeks improves mood scores on the Profile of Mood States 2 (POMS2) and Two-dimensional Mood Scale (TDMS) when compared with baseline (107813). The validity of these findings is limited by the lack of a control group.
• Sexual dysfunction. It is unclear if topical hops gel is beneficial in patients with postmenopausal vaginal atrophy. Details: A small clinical study in adults with postmenopausal vaginal atrophy shows that applying intravaginal topical gel containing hops extract (Barij Essence) daily for 7 days and then twice weekly thereafter for 2 months does not improve sexual desire, sexual arousal, vaginal lubrication, satisfaction, orgasm, sexual pain, or overall measures of sexual dysfunction when compared with intravaginal estradiol (112125). The validity of these effects is limited by baseline differences between groups.
• Shift work disorder. It is unclear if drinking non-alcoholic beer containing hops is beneficial in patients with shift work disorder. Details: A small open-label clinical study in healthy female nurses working rotating or night shifts shows that drinking 333 mL of non-alcoholic beer containing hops (San Miguel 0% alcohol) at dinner for 2 weeks reduces sleep latency by about 8 minutes, total activity during the night, andanxiety when compared with baseline. However, it does not appear to increase the duration of sleep (55403). The validity of these findings is limited by the lack of a control group and unconfirmed hops content in the beer.
• Vaginal atrophy. Topical hops extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: An open-label, multicenter clinical study in postmenopausal patients with vaginal atrophy shows that inserting 2.5 grams of a vaginal gel containing hops extract 1%, hyaluronic acid, liposomes, and vitamin E (Gynomunal Vaginal gel or Esvegyne, Polichem SA) into the vagina daily for one week followed by twice weekly for 11 weeks reduces vaginal dryness, burning, itching, and rash when compared with baseline (55339). The validity of these findings is limited by the lack of a control group. Also, it is unclear if these effects are due to hops, other ingredients, or the combination.
• Venous leg ulcers. Although there is interest in using topical hops for venous leg ulcers, there is insufficient reliable information about the clinical effects of hops for this condition. More evidence is needed to rate hops for these uses.

(Read more about HOPS)

POSSIBLY EFFECTIVE

• Metabolic syndrome. Oral inositol seems to modestly improve lipid parameters, blood pressure, and insulin resistance in patients with metabolic syndrome. Details: Some clinical research in postmenopausal adults with metabolic syndrome following a low-calorie diet shows that taking myo-inositol 2 grams twice daily for one year reduces total cholesterol by 29 mg/dL, triglycerides by 64 mg/dL, systolic and diastolic blood pressure by 9 mmHg and 6 mmHg, respectively, increases high-density lipoprotein (HDL) cholesterol by 6 mg/dL, and improves insulin resistance when compared with placebo. It did not reduce body mass index or waist circumference in these patients (91554). A meta-analysis of clinical studies in a mixed population shows similar effects on blood pressure, especially among postmenopausal adults with metabolic syndrome, at durations exceeding 8 weeks, and at doses of at least 4 grams (108820). Another clinical study in postmenopausal adults with metabolic syndrome and at risk for breast cancer shows that taking a combination of inositol and alpha-lipoic acid daily for 6 months, in combination with a low-calorie diet, reduces insulin resistance (HOMA-IR) by at least 20% when compared with a low-calorie diet alone. Also, taking inositol and alpha-lipoic acid seems to increase HDL cholesterol by about 6% and reduce triglycerides by 5% when compared to baseline (91543). It is unclear if these effects are due to inositol, alpha-lipoic acid, or the combination.
• Polycystic ovary syndrome (PCOS). Oral inositol, often in combination with folic acid, seems to improve some glycemic, lipid, metabolic, hormonal, and reproductive parameters in patients with PCOS. However, research is conflicting. Details: Oral inositol, most frequently in the forms of myo-inositol or D-chiro-inositol, has been evaluated for efficacy in a wide range of outcomes associated with PCOS including reproductive and pregnancy outcomes, metabolic parameters, and anthropomorphic measures. Often, inositol is taken in combination with folic acid or metformin. Inositol has been investigated for its effect on metabolic parameters that are often altered in PCOS. A meta-analysis of 9 studies in patients with PCOS shows that taking myo-inositol or D-chiro-inositol with or without folic acid marginally decreases body mass index (BMI) by about 0.5 kg/m2 when compared with placebo (111670). Inositol has also been evaluated for its effect on glucose metabolism in adults with PCOS. Meta-analyses of about 10 studies show that taking myo-inositol or D-chiro-inositol with or without folic acid reduces fasting plasma glucose by 1-4 mg/dL (98944,111670). However, evidence is conflicting on the effect of inositol on insulin levels and measures of insulin resistance (98944,111670). Additionally, most studies show that inositol does not improve measures of glucose metabolism more than metformin. The effect of inositol on lipid profiles has also been studied. A meta-analysis of 2 clinical studies and other small clinical studies show that taking inositol as D-chiro-inositol with or without folic acid modestly reduces total cholesterol and triglycerides when compared with control (2028,98944,91552). Some studies have also investigated the effect of inositol on hormone levels. Meta-analyses show that inositol modulates androgen levels as shown by reduced total and free testosterone, androstenedione, and increased sex-hormone binding globulin when compared with placebo. (2028,91552,98944,111670). The validity of these effects is limited by high heterogeneity in terms of inclusion and exclusion criteria, dose, and treatment duration within the included studies. Myo-inositol has also been compared with metformin in some clinical research, with some evidence of benefit (95085,95086). Meta-analyses of small clinical studies show that taking myo-inositol 2-4 grams daily, with or without folic acid, for 12-24 weeks does not improve fasting blood glucose, fasting insulin, insulin resistance (HOMA-IR), BMI, waist-hip circumference, or androgen levels when compared with metformin 1.5-2.5 grams daily (100705,108823,111670,111670). However, inositol seems to have a lower risk of adverse effects than metformin. These analyses are limited due to the small size, methodological issues, and high heterogeneity of the included studies. In combination with metformin, small clinical studies show that taking metformin, myo-inositol 550 mg, and D-chiro-inositol 150 mg twice daily is associated with improved lipid parameters and postprandial insulin levels when compared with metformin alone (108822). Meta-analyses and clinical studies have investigated the effect of inositol on ovulation, reproduction, and pregnancy outcomes. Some research suggests that inositol increases ovulation rate, promotes cycle normalization, and improves ovarian function in patients with PCOS (2028,91552,98944,111670). A small clinical study shows that taking myo-inositol 4 grams and folic acid 400 mcg (Inofolic, Lo.Li.Pharma) daily for three spontaneous cycles induces ovulation in about 62% of individuals with anovulatory PCOS and insulin resistance. Adding clomiphene citrate with myo-inositol induces ovulation in about 72% of the patients who remain anovulatory after treatment with myo-inositol alone (91547). Another clinical study shows that taking a combination of inositol 2 grams, folic acid 200 mcg, and N-acetyl cysteine 600 mg (Ovaric HP, Just Pharma) twice daily for 12 months improves ovulation rates in PCOS patients with oligomenorrhea, regardless of insulin sensitivity at baseline (91553). Despite evidence that inositol improves ovulation rates, it does not appear to impact pregnancy rates (111670). Some research has also investigated the effects of taking both isomers of inositol concomitantly. Taking myo-inositol 550 mg plus D-chiro-inositol 13.8 mg (Inofolic Combi, Lo.Li.Pharma) twice daily, beginning 12 weeks before ovarian hyperstimulation and continuing throughout pregnancy, improves oocyte quality when compared to treatment with D-chiro-inositol alone. The combination appears to increase fertilization rate in patients aged 35 years or younger, but not those older than 35 years (91544). Other clinical research shows that taking myo-inositol 550 mg and D-chiro-inositol 150 mg twice daily for 12 weeks improves pregnancy rates and live birth rates by an additional 10% and 11%, respectively, when compared with myo-inositol 550 mg plus D-chiro-inositol 13.8 mg. The higher-dose combination also resulted in a 15% lower rate of ovarian hyperstimulation syndrome when compared with those taking the lower dose of D-chiro-inositol (102317). Lastly, other research shows that taking myo-inositol and D-chiro-inositol together may improve metabolic parameters faster than taking myo-inositol alone (91550). Research has also evaluated the effects of inositol on other pertinent clinical outcomes in PCOS. Several small clinical studies show that taking the combination of myo-inositol and D-chiro-inositol, alone or in combination with metformin, improves menstrual cycle irregularity when compared with metformin alone, but not as much as a taking a combined hormonal contraceptive (108822,108824). The validity of these findings is limited by the unblinded nature of the studies. Also, a small clinical study shows that taking metformin with myo-inositol 550 mg and D-chiro-inositol 150 mg twice daily is associated with improved acne, but not hirsutism, at 6 months, when compared with metformin alone (108822). The validity of these findings is limited by the unblinded nature of the study. More research is needed to clarify the effect of inositol on anthropometric, metabolic, and endocrine outcomes in patients with PCOS.
• Preterm labor. Oral inositol in combination with folic acid seems to prevent preterm labor in individuals at risk for gestational diabetes. Details: A meta-analysis of five clinical trials in individuals at risk for gestational diabetes shows that taking myo-inositol plus folic acid daily, beginning during the first trimester and continuing throughout pregnancy, decreases the risk of preterm delivery by 64% when compared with folic acid alone. Patients in all but one study included in this analysis took myo-inositol 2 grams plus folic acid 200 mcg twice daily, while patients in the other study took myo-inositol 1100 mg plus D-chiro-inositol 27.6 mg and folic acid 400 mcg daily (100706). It's unclear if these results are generalizable to individuals with a low risk for gestational diabetes.

POSSIBLY INEFFECTIVE

• Acute respiratory distress syndrome (ARDS). Oral or intravenous inositol does not seem to prevent ARDS in preterm infants and may be associated with worsened outcomes. Details: Historically, small clinical trials in infants with or at risk for ARDS have suggested that myo-inositol, given parenterally and enterally for 5-10 days, might improve survival and reduce the risk of death and serious complications (2191,2192,91546). However, a large, high-quality clinical study in infants born at less than 28 weeks' gestation at risk for ARDS shows that myo-inositol 40 mg/kg given intravenously and then enterally every 12 hours for up to 70 days does not reduce the risk of death or retinopathy of prematurity (ROP). In fact, the rate of death or type 1 ROP increased by 7% in the myo-inositol group when compared to the control group, and a higher incidence of adverse events in the myo-inositol group, including poor perfusion, hypotension, and infections, led to early trial discontinuation (98946). Long-term follow-up until 24 months corrected age confirms that the initial increase in mortality rate in the myo-inositol group remained stable; however, there was no difference in a composite outcome of death or survival with moderate or severe neurodevelopmental impairment, as well as no difference in the risk of ROP, between the treatment and control groups (108819). The most recent meta-analysis, which incorporates this large clinical study, concludes that inositol supplementation does not reduce the risk of death in infants at risk for ARDS (102319).
• Anxiety. Oral inositol does not seem to be beneficial for patients with anxiety. Details: A meta-analysis of four clinical trials shows that taking inositol orally does not improve anxiety severity in patients with anxiety disorders, including obsessive-compulsive disorder, panic disorder, or post-traumatic stress disorder, when compared with placebo (91549).
• Depression. Oral inositol does not seem to be beneficial for patients with depression. Details: Guidelines from the World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that inositol in doses up to 12 grams daily is not currently recommended as monotherapy or adjunctive use for major depressive disorder due to a lack of evidence for efficacy (110318). Additionally, a meta-analysis of seven clinical trials shows that inositol does not significantly improve symptoms of depression in patients with bipolar depression, major depressive disorder, or premenstrual dysphoric disorder (PMDD) (91549). While limited research shows that patients receiving inositol for 4 weeks may improve, patients initially responding to inositol seem to relapse rapidly upon discontinuation of treatment (2026,2185). Additionally, taking inositol with a selective serotonin reuptake inhibitor (SSRI) doesn't appear to improve the effectiveness of SSRI therapy or improve depression in SSRI treatment failures (2025,10851).
• Diabetic neuropathy. Oral inositol does not seem to be beneficial for patients with diabetic neuropathy. Details: Most preliminary clinical research shows that taking inositol orally doesn't improve the symptoms of diabetic neuropathy (2193,2194,2195).
• Retinopathy of prematurity. Oral or intravenous inositol does not seem to prevent retinopathy of prematurity (ROP) in preterm infants. Details: A meta-analysis of six clinical trials shows that myo-inositol, given parenterally and/or enterally, does not seem to reduce the risk of ROP when compared with placebo in preterm infants (100704). A large, high-quality clinical study included in this meta-analysis shows that myo-inositol 40 mg/kg given intravenously and then enterally every 12 hours for up to 70 days does not reduce the risk of death or ROP in infants born at less than 28 weeks' gestation. In fact, the rate of death or type 1 ROP increased by 7% in the myo-inositol group when compared with placebo and a higher incidence of adverse events in the myo-inositol group, including poor perfusion, hypotension, and infections, led to early trial discontinuation (98946). Long-term follow-up until 24 months corrected age confirms that the initial increase in mortality rate in the myo-inositol group remained stable; however, there was no difference in a composite outcome of death or survival with moderate or severe neurodevelopmental impairment, as well as no difference in the risk of ROP, between the treatment and control groups (108819).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related testosterone deficiency. It is unclear if oral D-chiro-inositol is beneficial in patients with age-related testosterone deficiency. Details: A very small clinical study in males aged 65-75 years with low-normal morning testosterone levels and signs and symptoms of androgen deficiency shows that taking D-chiro-inositol 600 mg twice daily for 30 days improves sexual function and physical strength when compared with baseline (108821). The validity of these findings is limited by the lack of a comparator group.
• Bipolar disorder. It is unclear if oral inositol is beneficial in patients with bipolar disorder. Details: Evidence is conflicting on whether inositol helps treat bipolar disorder in children. One very small preliminary study in children aged 5-12 years with bipolar disorder not on concomitant mood-stabilizing medications shows that taking inositol 80 mg/kg (maximum 2 grams) daily for 12 weeks reduces manic symptoms when compared to baseline. Additionally, taking a combination of inositol 80 mg/kg and high eicosapentaenoic acid omega-3 fatty acid capsules (EPA; Nordic Naturals) 1650-3000 mg daily for 12 weeks reduces manic and depressive symptoms when compared to baseline (95092). However, another more recent study with the same intervention and protocol shows that the combination of inositol and high eicosapentaenoic acid omega-3 fatty acid reduces symptoms of depression, but does not improve manic symptoms, when compared with either ingredient taken alone (111676).
• Chemotherapy-induced leukopenia. Oral inositol has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults undergoing breast cancer surgery and adjuvant chemotherapy shows that taking inositol orally 390 mg twice daily and applying IP-6 gel 4% twice daily to the surgical site, starting 2 weeks before adjuvant chemotherapy and stopping 2 weeks after the last cycle, attenuates reductions in white and red blood cell counts when compared with no intervention. Using inositol and IP-6 also improves breast and arm symptom scores and some quality of life scores; however, these improvements were not consistent over time.
• Diabetes. It is unclear if oral inositol is beneficial for the treatment of type 1 diabetes or the prevention of gestational diabetes. Details: Preliminary clinical research in patients with type 1 diabetes and a body mass index of at least 25 kg/m2 shows that taking a specific combination product containing D-chiro-inositol and folic acid (Chirofol 500, LJ Pharma) daily for 6 months, along with insulin therapy, decreases glycated hemoglobin (HbA1c) by approximately 0.5% when compared to taking folic acid alone with insulin therapy. However, there was no difference between groups with respect to insulin resistance or body mass index (95088). Most research shows that taking inositol during pregnancy prevents gestational diabetes. However, most studies conducted to date are of low quality and it is unclear if the results are generalizable. Meta-analyses of 4-7 clinical studies in pregnant adults, some with overweight and obesity, shows that taking myo-inositol 200-4000 mg daily may reduce the risk of gestational diabetes and gestational hypertension, improve 1- and 2-hour glucose tolerance test results, and reduce insulin requirements. Inositol may also be associated with improved infant outcomes such as increased gestational age at birth and reduced preterm delivery but does not seem to influence birth weight, NICU admission rate, neonatal hypoglycemia, the incidence of shoulder dystocia, macrosomia or cesarian delivery when compared with control (111664,111667,111671,111677). The validity of these effects is limited by significant heterogeneity within the included studies, concerns about blinding, and overall low-quality evidence. Most clinical research shows that taking myo-inositol 2 grams plus folic acid 200 mcg twice daily (usually as Inofolic, Lo.Li. Pharma International), beginning during the first trimester and continuing throughout pregnancy, decreases the incidence of gestational diabetes by 57% to 92% when compared with folic acid alone in patients at risk for gestational diabetes. Myo-inositol seems to be more effective than D-chiro-inositol (91545,91548,95083,95084,100706,103750,104688). However, supplementation with lower doses of inositol, mimicking natural inositol occurring in the body, may not be effective. Other evidence is conflicting about whether inositol prevents gestational diabetes. One clinical study shows that taking a combination of myo-inositol 1.1 grams, D-chiro-inositol 27.6 mg, and folic acid 400 mcg (Inofolic Combi, Lo.Li. Pharma International) daily during pregnancy does not decrease the incidence of gestational diabetes when compared with folic acid alone in patients with a family history of diabetes (95082,103750). In patients eventually diagnosed with gestational diabetes, one small clinical study shows that taking myo-inositol 2 grams reduces the number of patients requiring insulin by at least 50% (104688), although another small clinical study shows that adding D-chiro-inositol, myo-inositol, or both to folic acid does not affect insulin resistance when compared with placebo (98945).
• Dyslipidemia. Although there has been interest in using oral inositol for hypercholesterolemia and hypertriglyceridemia, there is insufficient reliable information about the clinical effects of inositol for these conditions.
• Hypertension. Although there has been interest in using oral inositol for hypertension, there is insufficient reliable information about the clinical effects of inositol for this condition.
• Hypothyroidism. It is unclear if oral inositol is beneficial for subclinical hypothyroidism. Details: Clinical research in females aged 18 to 50 years with or at risk for subclinical hypothyroidism in Slovakia shows that taking myo-inositol 600 mg and selenium 83 mcg daily for 6 months modestly reduces thyroid stimulating hormone (TSH) and thyroid auto-antibody titers when compared to baseline. Myo-inositol and selenium supplementation also reduces patient-reported hypothyroid symptoms including fatigue, menstrual cycle irregularity, and intolerance to heat or cold (110591). The interpretation of these results is limited by the lack of a control group. In addition, it is unclear if these effects are due to myo-inositol, selenium, or the combination.
• Infertility. It is unclear if oral inositol is beneficial in patients undergoing intracytoplasmic sperm injection (ICSI) or in vitro fertilization (IVF). Details: Several small studies in patients undergoing ICSI show that taking a specific combination product containing myo-inositol 4 grams and folic acid 400 mcg (Inofolic, Lo.Li. Pharma International S.r.l) daily, starting 1-3 months before ICSI and continuing until ovulation, improves fertilization rate, but does not improve implantation or pregnancy rates, when compared with taking folic acid alone (103752,108825). However, another moderate-sized clinical study in adults with infertility undergoing ICSI and IVF shows that taking the same combination of myo-inositol 4000 mg and folic acid 400 mcg daily for 2 months starting on the third day of the cycle improves mean number of oocytes, meiosis II oocytes, 2 pronuclear embryos, and clinical pregnancy and live birth rates when compared with taking folic acid alone (111672). The effects of inositol on fertility have been studied in patients with specific comorbidities. A case-control study in long-term survivors of lymphoma suggests that taking myo-inositol 400 mg and D-chiro-inositol 45 mg (Ovofert Fast, CRL Pharma) three times daily for 12 months is associated with reductions in follicle stimulating hormone (FSH), luteinizing hormone (LH), dyspareunia, and dysmenorrhea and a modest increase in antral follicle count of the right ovary when compared with control (111673). The validity of these effects is limited by a lack of blinding. Inositol has also been evaluated in females with polycystic ovary syndrome (PCOS). A meta-analysis of clinical studies in adults with PCOS undergoing IVF or ICSI shows that inositol does not improve pregnancy rates when compared to no treatment. However, inositol may increase clinical pregnancy rates when compared with metformin (111675). Inositol has also been evaluated in combination with other ingredients. A large clinical study in females planning to conceive shows that taking a combination product containing myo-inositol 4 grams, vitamin D, riboflavin, vitamin B6, vitamin B12, zinc, and probiotics does not improve time-to-conception, clinical pregnancy rates, or live birth rates when compared with a standard micronutrient supplement. However, the supplement shortens time-to-conception in adults with overweight to durations equivalent to patients who are not overweight, but lengthens time to conception in adults with obesity when compared with placebo (111665). It is unclear whether these effects are due to inositol, other ingredients, or the combination.
• Insomnia. It is unclear if oral inositol is beneficial for improving sleep during pregnancy. Details: Clinical research shows that taking myo-inositol 2 grams plus folic acid 200 mcg (Inofolic, Lo.Li. Pharma International) before bed for 10 weeks, starting at 14 weeks gestation, improves overall measures of sleep quality by a small amount when compared with folic acid alone. However, this improvement was not maintained until 37-38 weeks' gestation. Also, the study was not limited to patients with poor sleep quality during pregnancy, but to any healthy pregnant individual (104687).
• Lithium-induced side effects. It is unclear if oral inositol is beneficial for reducing lithium-induced side effects. Details: A small clinical study suggests that taking inositol 6 grams daily for 10 weeks may improve psoriasis associated with lithium therapy when compared with baseline (11972). However, taking inositol orally does not seem to improve other lithium-induced adverse effects, such as tremor, thirst, and changes in thyroid and adrenal function (2027).
• Lung cancer. It is unclear if oral inositol is beneficial for slowing the rate of bronchial dysplasia. Details: Preliminary clinical research in smokers with bronchial dysplasia considered at high risk for lung cancer shows that taking myo-inositol (Tsuno Food Industries Co., Ltd.) 9 grams orally once daily for 2 weeks then twice daily for 6 months, does not increase the rate of complete or partial response when compared with placebo (95090).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral inositol is beneficial for NAFLD. Details: A small clinical study in adults with NAFLD and obesity shows that taking myo-inositol powder 4 grams daily for 8 weeks does not improve liver health markers, such as liver function test levels or liver steatosis, but does improve some components of lipid profiles, glycemic indices, and anthropometric measures when compared to baseline (111304) However, this study may have been inadequately powered to detect differences in some of the outcomes.
• Obesity. It is unclear if oral inositol is beneficial in patients with overweight or obesity. Details: A meta-analysis of 15 clinical studies in adults shows that taking inositol 600-4450 mg daily for 6-48 weeks decreases body mass index (BMI) by about 0.4 kg/m2. Subgroup analysis suggests that myo-inositol may be beneficial at a dosage less than 1000 mg for less than 12 weeks, especially in patients with polycystic ovary syndrome (PCOS) and overweight or obesity, with higher baseline BMI, and above 40 years of age (111666). However, the validity of this finding is limited by significant heterogeneity in the included studies.
• Obsessive-compulsive disorder (OCD). It is unclear if oral inositol is beneficial in patients with OCD. Details: One preliminary clinical study in adults with OCD shows that taking inositol 18 grams daily for 6 weeks improves Yale-Brown Obsessive Compulsive Scale scores when compared with placebo (2186). However, taking inositol does not seem to improve the severity or type of OCD symptoms in patients already taking a selective serotonin reuptake inhibitor (91556). Both of these studies were small, and treatment was administered for only 6 weeks.
• Panic disorder. Oral inositol seems to improve symptoms of panic disorder. Details: A very small clinical study shows that taking inositol 12 grams daily reduces the severity and rate of panic attacks and the severity of agoraphobia over 4 weeks of treatment when compared with placebo (2184). Another very small clinical study shows that taking inositol 18 grams daily for one month may be as effective as fluvoxamine 150 mg daily for treatment of panic disorder (10387). However, the one-month duration may not have provided adequate time to see the full effects of fluvoxamine.
• Post-traumatic stress disorder (PTSD). It is unclear if oral inositol is beneficial in patients with PTSD. Details: Preliminary clinical research shows that taking inositol 12 grams daily for 4 weeks does not improve distress when compared with placebo in patients with PTSD (91557).
• Pregnancy-induced hypertension. It is unclear if oral inositol is beneficial for preventing hypertension during pregnancy. Details: In patients with a body mass index (BMI) between 25-29.9 kg/m2, preliminary clinical research shows that taking myo-inositol 2 grams plus folic acid 200 mcg (Inofolic, Lo.Li. Pharma International) twice daily, beginning during the first trimester and continuing throughout pregnancy, decreases the incidence of pregnancy-induced hypertension by 66% when compared with folic acid alone (104688).
• Psoriasis. It is unclear if oral or topical inositol is beneficial for improving symptoms of psoriasis. Details: One small clinical study shows that taking inositol 6 grams daily for 10 weeks does not improve symptoms of psoriasis in a small group of patients when compared to baseline. However, taking this dose of inositol has a moderate effect on overall symptoms in patients with psoriasis related to lithium use (11972). Preliminary clinical research also shows that topical use of D-chiro-inositol is unlikely to be beneficial for reducing overall symptoms of psoriasis. Topical application of inositol 0.25% or 1% for 6 weeks improves overall symptoms when compared with baseline. However, the inositol-containing creams were no more effective than the control cream (104686). Inositol has also been evaluated in combination with other ingredients. A small prospective observational study in adults with mild plaque psoriasis suggests that applying amino-inositol and urea 40% cream (Inosit U40, Biogena) 1-2 times daily for 4 weeks is associated with reductions in the severity and extent of psoriasis symptoms and improvements in quality of life measures when compared to baseline (111668). The validity of these effects is limited by a small sample size, a lack of a comparator group, insufficient blinding, and the observational study design.
• Trichotillomania. It is unclear if oral inositol is beneficial for reducing hair pulling. Details: Preliminary clinical research shows that taking inositol in doses ranging from 6-18 grams daily over a period of 10 weeks is no more effective than placebo in reducing subjective or clinician-documented symptoms of hair pulling in patients with trichotillomania (95089). More evidence is needed to rate inositol for these uses.

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POSSIBLY EFFECTIVE

• Depression. Small clinical trials show that oral lemon balm may improve depression when used short-term; the long-term effects are unclear. It is also unclear if lemon balm aromatherapy is beneficial for depression. Details: A meta-analysis of randomized controlled trials in adults with depression and/or anxiety shows that using lemon balm, usually orally, daily for 3-56 days moderately improves depression scores when compared with control. Lemon balm was used orally as 1200-3000 mg daily or as aromatherapy for 30 minutes daily (110136). Other individual studies also show that oral lemon balm may modestly improve depression. A small clinical study in patients with mild or moderate depression shows that taking lemon balm 600 mg with fertilized egg powder (Young Tissue Extract) 1,680 mg daily for 12 weeks improves symptoms when compared with placebo, but not when compared with taking fertilized egg powder alone (19534). Another small clinical study in adults with mostly mild depression shows that taking lemon balm 2 grams daily for 8 weeks moderately improves depressive symptoms when compared with baseline. The improvement appears to be similar to taking lavender powder 2 grams daily or fluoxetine 20 mg daily (104433). However, this study was inadequately powered to detect differences between groups. A small clinical study in adults with type 2 diabetes and mild to moderate depression conducted in Iran shows that taking lemon balm extract capsules 350 mg twice daily for 12 weeks modestly reduces the severity of depression and anxiety based on validated patient-reported questionnaires when compared with placebo (111741). However, the interpretation of these findings is limited by methodological flaws in outcome analysis.
• Herpes labialis (cold sores). Topical lemon balm 1% lotion seems to be beneficial for the healing of recurrent cold sores. Details: Clinical research in patients with recurring cold sores shows that applying a cream containing 1% lemon balm dried leaf extract (LomaHerpan, Infectopharm) at the early stages seems to shorten healing time and reduce symptoms of recurring cold sores when compared with placebo (790,9995).
• Stress. Oral lemon balm seems to be beneficial for improving experimentally-induced stress in some patients. Details: A small study in healthy adults suggests that a single dose of lemon balm extract 600 mg increases calmness and alertness during laboratory-induced psychological stress when compared with placebo (19524). Another small study in healthy adults shows that a single dose of lemon balm extract (Bluenesse, Vital Solutions) 300 mg added to food or drink reduces anxiety and improves memory and alertness during multi-task cognitive testing when compared with placebo (91733). Lemon balm has also shown benefit when used in combination with other ingredients for stress. Lemon balm 240 mg has been used in combination with valerian 360 mg (Songha Night, Pharmaton Natural Health Products) (19405). Lemon balm 50 mg has been used in combination with valerian root 90 mg, passion flower 90 mg, and butterbur 90 mg (Relaxane, Max Zeller Sӧhne AG) (97276).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral lemon balm is beneficial for improving cognitive function. Details: Preliminary clinical research in adults with age-related cognitive impairment shows that taking lemon balm leaf extract, standardized to contain 500 mg rosmarinic acid, orally daily for 96 weeks does not improve cognitive function scores when compared with placebo (110142).
• Alzheimer disease. It is unclear if oral lemon balm is beneficial for improving cognitive function. Details: A small clinical study in elderly patients with mild to moderate Alzheimer disease shows that taking a leaf extract of lemon balm (standardized to citral 500 mcg/mL) 60 drops daily for 4 months seems to reduce agitation and improve cognitive function when compared with placebo (9993). This study was limited by a large number of drop-outs in the placebo group. An even smaller clinical study in patients with mild Alzheimer disease shows that taking lemon balm extract containing 500 mg rosmarinic acid daily for 24 weeks does not seem to improve cognition, but might modestly improve neuropsychiatric symptoms, when compared with placebo (104435). The validity of these findings is limited because the study was not powered to evaluate cognition and neuropsychiatric symptoms.
• Anxiety. It is unclear if oral lemon balm or lemon balm aromatherapy is beneficial for reducing anxiety in most patients. Details: A meta-analysis of randomized controlled trials in adults with depression and/or anxiety shows that using lemon balm daily for 3-56 days moderately improves anxiety scores when compared with control. Lemon balm was used orally as 1200-3000 mg daily or as aromatherapy for 30 minutes daily (110136). The validity of this result is limited by high heterogeneity. Also, a small clinical study in patients with mild or moderate anxiety disorders shows that taking a specific standardized lemon balm extract (Cyracos, Naturex SA) 300 mg twice daily reduces anxiety-associated symptoms and improves sleep when compared with baseline (104425). The validity of this finding is limited by the lack of a comparator group. Another small clinical study in adults with type 2 diabetes and mild to moderate depression conducted in Iran shows that taking lemon balm extract capsules 350 mg twice daily for 12 weeks modestly reduces the severity of depression and anxiety based on validated patient-reported questionnaires when compared with placebo (111741).
• Attention deficit-hyperactivity disorder (ADHD). Although there is interest in using oral lemon balm for ADHD, there is insufficient reliable information about the clinical effects of lemon balm for this condition.
• Chronic bronchitis. Although there is interest in using oral lemon balm for bronchitis, there is insufficient reliable information about the clinical effects of lemon balm for this condition.
• Cognitive function. It is unclear if oral lemon balm is beneficial for improving memory and response time in healthy patients. Details: A small study in healthy young adults shows that taking a single dose of lemon balm 1600 mg increases memory accuracy, but may slow performance on timed memory tasks, when compared with placebo (19530). Another small study shows that taking a combination product containing equal parts lemon balm, sage, and rosemary, 5 grams of plant material per 10 mL solution, twice daily for 2 weeks might modestly improve delayed, but not immediate, word recall when compared with placebo in healthy adults 62 years of age or younger. No benefits were seen in adults 63 years of age and older (97277). It is not clear if this effect is due to lemon balm, the other ingredients, or the combination.
• Colic. Oral lemon balm has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical studies in breast-fed or formula-fed infants with colic show that giving specific multi-ingredient products containing lemon balm 65-97 mg and German chamomile 9-178 mg, with or without fennel 164 mg and inactivated Lactobacillus acidophilus (ColiMil; ColiMil Plus, Milte Italia SPA), orally twice daily for 1-4 weeks reduces crying times when compared with either placebo or simethicone (16735,96278). Another small clinical study in infants shows that giving 150 mL of a specific herbal tea preparation (Calma-Bebi, Bonomelli), containing German chamomile, vervain, licorice, fennel, and lemon balm, up to three times daily after an episode of colic for one week, modestly reduces colic when compared with placebo water without herbs (19715). It is not known if the benefits of these multi-ingredient preparations are due to lemon balm, other ingredients, or the combination.
• Delirium. Oral lemon balm has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults in the intensive care unit with agitation and delirium who are receiving quetiapine 50-200 mg every 12 hours shows that taking 5 mL of a syrup containing lemon balm leaf extract 50 mg and valerian root 625 mg orally every 12 hours improves agitation when compared to baseline. Although the improvement appeared to similar to that seen in those taking placebo, no statistical comparison was conducted between groups (106627).
• Dementia. It is unclear if oral lemon balm is beneficial for reducing neuropsychiatric symptoms of dementia, such as agitation. Details: A small clinical study in patients with severe dementia and agitation shows that applying a lotion containing essential oil of lemon balm to the faces and hands of patients for 4 weeks reduces agitation based on the Cohen-Mansfield Agitation Inventory (CMAI) scale when compared with applying a placebo lotion (19523). However, another small clinical study in patients with Alzheimer disease and prolonged agitation shows that applying lemon balm oil by gentle massage for 1-2 minutes twice daily for 12 weeks does not reduce agitation when compared with applying placebo oil (19522). The validity of these results is limited by the notable improvement observed in the placebo group, which may have been due to the regular physical touch and increased social interaction that occurred in this group. A small clinical study in patients with dementia shows that inhaling lemon balm oil from a small pad attached to the collar of clothing for 2 hours once daily for 2 weeks does not reduce agitation based on the Neuropsychiatric Inventory (NPI) and CMAI scales when compared with placebo (99710).
• Dysmenorrhea. Although there is interest in using oral lemon balm for dysmenorrhea, there is insufficient reliable information about the clinical effects of lemon balm for this condition.
• Dyspepsia. Oral lemon balm has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A meta-analysis of four small clinical studies in patients with IBS shows that using a specific combination product containing lemon balm (Iberogast, Steigerwald Arzneimittelwerk GmbH) 1 mL orally three times daily over a period of 4 weeks reduces severity of acid reflux, epigastric pain, cramping, nausea, and vomiting when compared with placebo. The combination includes lemon balm, peppermint leaf, German chamomile, caraway, licorice, clown's mustard plant, celandine, angelica, and milk thistle (13089). In another clinical study, taking a similar combination product containing extracts from peppermint leaf, clown's mustard plant, German chamomile flower, caraway, licorice root, and lemon balm (STW 5-II, Steigerwald Arzneimittelwerk GmbH), 1 mL orally three times daily for up to 8 weeks eliminates gastrointestinal symptoms in 40% more dyspepsia patients when compared with placebo (12724).
• Headache. Although there is interest in using oral lemon balm for headache, there is insufficient reliable information about the clinical effects of lemon balm for this condition.
• Hypertension. It is unclear if oral lemon balm is beneficial for hypertension. Details: Preliminary clinical research in adults with uncontrolled hypertension while on 1-3 active treatments shows that taking lemon balm extract 400 mg, standardized to contain 8 mg rosmarinic acid, orally daily for 4 weeks reduces systolic and diastolic blood pressure by 8% to 14% and 11% to 16%, respectively, when compared with baseline. These improvements were significant when compared with placebo (110138).
• Hyperthyroidism. Although there is interest in using oral lemon balm for hyperthyroidism, there is insufficient reliable information about the clinical effects of lemon balm for this condition.
• Insect repellent. Although there is interest in using topical lemon balm as insect repellant, there is insufficient reliable information about the clinical effects of lemon balm for this condition.
• Insomnia. Oral lemon balm has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Taking a specific combination product providing lemon balm leaf extract 80 mg and valerian root extract 160 mg (Euvegal forte, Dr. Willmar Schwabe Pharmaceuticals) 2-3 times daily appears to improve the quality and quantity of sleep in healthy people and those diagnosed with insomnia or sleeping disorders (10423,19528,19536). However, lower daily doses may not improve sleep (10421). Other clinical research in healthy adults with insomnia shows that using a combination product containing ground lemon balm herb 1000 mg and aqueous extract of Nepeta menthoides 400 mg at bedtime for 4 weeks improves sleep quality and sleep duration and reduces sleep disturbance, sleep latency, and daytime dysfunction when compared with placebo (97278). A clinical study in children 12 years and younger shows that a specific combination product containing lemon balm leaf extract 80 mg and valerian root extract 160 mg (Euvegal forte, Dr. Willmar Schwabe Pharmaceuticals) 1-2 tablets once or twice daily might decrease symptoms of restlessness and dyssomnia when compared to baseline (14416). It is unclear if these effects are due to lemon balm, other ingredients, or the combinations.
• Irritable bowel syndrome (IBS). Oral lemon balm has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with IBS shows that using 30 drops of a combination product providing lemon balm, spearmint, and coriander (Carmint, PurSina Pharmacy) three times daily after meals for 8 weeks reduces abdominal pain and discomfort when added to standard treatment with loperamide or psyllium, compared to standard treatment alone (19535). It is not known if the effect is due to lemon balm, the other ingredients, or the combination.
• Menopausal symptoms. Oral lemon balm has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in postmenopausal adults with sleep disturbances shows that taking lemon balm leaf 250 mg and fennel fruit 250 mg orally once daily for 8 weeks improves menopausal symptoms including vasomotor, psychomotor-social, physical, and sexual symptoms, by 24% to 38% when compared with baseline. These improvements were significant when compared with placebo (110137).
• Pain (acute). It is unclear if lemon balm aromatherapy is beneficial for reducing pain in patients with acute coronary syndrome. Details: A small clinical study in patients with acute coronary syndrome presenting to the emergency department shows that aromatherapy with lemon balm leaf and stem essential oil 1% for 10 minutes twice on the day of presentation modestly reduces chest pain scores when compared with placebo. However, pain was no longer different between groups within 15 minutes after the second aromatherapy session (110139).
• Postpartum complications. Oral lemon balm might reduce postpartum pain in some patients; however, it's not clear if it is beneficial for other postpartum complications. Details: A small clinical study shows that taking lemon balm leaf extract 395 mg every 6 hours for 24 hours following childbirth is slightly more effective for reducing postpartum pain when compared with taking mefenamic acid 250 mg using the same dosing schedule (101763).
• Psoriasis. Oral lemon balm has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with mild to moderate psoriasis shows that taking an oral combination product containing lemon balm, rose hip, and fennel as 10 mL three times daily for 12 weeks improves pruritus and psoriasis scores by 45% and 49%, respectively, when compared with baseline. In contrast, these scores worsened in the placebo group (110141). The validity of this finding is limited by the lack of statistical comparison between groups.
• Somatic symptom disorder. Oral lemon balm has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical study in individuals with somatic symptom disorder shows that taking one tablet of a combination product three times daily for 2 weeks seems to improve symptoms of depression and anxiety when compared with placebo. Each tablet of this product contains lemon balm leaf extract 60 mg, valerian root extract 90 mg, and passionflower herb extract 90 mg (19701). It is not known if the effect is due to lemon balm, other ingredients, or the combination.
• Ventricular arrhythmias. It is unclear if oral lemon balm leaf tea is beneficial for patients with premature ventricular contraction (PVC). Details: Preliminary clinical research in adults with low to moderate PVCs shows that drinking lemon balm leaf tea twice daily for 12 weeks reduces the frequency of PVCs by 32% when compared with baseline. This improvement was significant when compared with no treatment. Lemon balm tea also modestly improved heart rate, but not left ventricular ejection fraction, when compared with no treatment. The tea was prepared by steeping lemon balm leaf 2 grams in 250 mL of boiling water (110140). More evidence is needed to rate lemon balm for these uses.

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POSSIBLY EFFECTIVE

• Anxiety. Oral passion flower has a long history of use as a sedative and may improve symptoms of anxiety in some patients. Details: Preliminary clinical research shows that taking a specific dried alcoholic extract of passion flower (Sedanxio, Tilman SA) 400 mg orally twice daily for 2-8 weeks reduces the severity of non-specific anxiety when compared to baseline (88198). The validity of this finding is limited by the lack of a placebo group. Passionflower has also been evaluated as an adjunct to conventional medication. One clinical small study in patients with generalized anxiety disorder shows that taking a specific passion flower extract (Pasipay, Iran Darouk Pharmaceutical Company) 15 drops three times daily along with sertraline 50-100 mg daily for one month reduces anxiety when compared with taking sertraline alone (95036). Passion flower has also been compared to conventional treatments. One preliminary clinical study shows that taking passion flower extract 90-180 mg daily reduces symptoms of non-specific anxiety when compared to baseline, and seems to be comparable to taking mexazolam (15391). A small clinical study in patients with generalized anxiety disorder shows that taking a specific passion flower extract (Pasipay, Iran Darouk Pharmaceutical Company) 45 drops orally once daily for 28 days reduces anxiety similarly to oxazepam 30 mg daily. However, passion flower appears to have a slower onset of action than oxazepam (8007). This finding is limited because it did not utilize a therapeutic dosing regimen for oxazepam, which is given 3-4 times daily to account for its short half-life. Passion flower has also been studied in combination with other ingredients. A small clinical study in healthy adults shows that taking a combination of herbal extracts containing passion flower 40 mg, valerian root, black horehound, and hawthorn (Euphytose, Bayer HealthCare) 6 times daily with meals for 14 days reduces anxiety and sympathetic and autonomic nervous system activation in response to a psychosocial stressor when compared with placebo (111222). It is unclear if these effects are due to valerian, other ingredients, or the combination.
• Insomnia. Moderate-sized clinical studies suggest that oral passion flower may modestly improve total sleep time in patients with insomnia; however, its effects on sleep latency and maintenance are mixed. Details: A moderate-sized clinical study in adults in India with insomnia and stress shows that taking passion flower extract 600 mg daily at bedtime for 30 days increases total sleep time by about 30 minutes and reduces both the time to fall asleep and wake time after sleep onset by about 10 minutes when compared with placebo (114529). The validity of these findings is limited by lack of reporting on baseline use of medications or other substances which may impact sleep and exclusion of patients with severe insomnia. Another moderate-sized clinical study in adults with insomnia shows that taking passion flower extract 60 mg every evening before bedtime for 2 weeks increases total sleep time by around 23 minutes, but doesn't seem to improve sleep efficiency, sleep latency, or awakening after sleep onset, when compared with placebo (102866). Additionally, a smaller clinical study in young adults with mild fluctuations in sleep quality shows that drinking tea prepared by steeping passion flower aerial parts 2 grams in 250 mL of boiling water for 10 minutes every evening, about an hour before bedtime for 7 nights, improves subjective ratings of sleep quality, but not other sleep parameters, when compared with placebo (parsley tea) (17374). Passion flower has also been studied in combination with other ingredients. One small clinical study in adults with primary insomnia shows that taking a specific combination product containing passion flower 80 mg, valerian 300 mg, and hops 30 mg (NSF-3, M/s Tablets India) orally at bedtime for 2 weeks yields similar effects on subjective measures of sleep as zolpidem 10 mg nightly (88193).
• Pre-procedural anxiety. Oral passion flower modestly reduces preoperative anxiety. Details: Two small clinical studies in adults awaiting dental surgery or inguinal hernia repair surgery shows that taking a specific passion flower extract (Pasipay, Iran Darouk Pharmaceutical Company) reduces preoperative anxiety when compared with placebo. Passion flower extract was given as 20 drops or 500 mg 90 minutes prior to surgery, with or without another dose on the evening before surgery (88195,88196). Another small clinical study shows that drinking 5 mL of syrup containing passion flower aqueous extract (Passiflora syrup, Sandoz) 700 mg orally 30 minutes before epidural catheter insertion for inguinal hernia repair surgery seems to attenuate anxiety; the placebo group experienced a significant increase in anxiety (88194). This finding is limited because there were no statistical comparisons conducted between groups. Passion flower has also been compared with conventional medications. Three clinical studies show that taking passion flower prior to dental surgery decreases preoperative anxiety similarly to oral midazolam 15 mg. One study used passion flower 260 mg, administered 30 minutes prior to the surgery (95038), the second used 500 mg, administered 60 minutes prior (104206), and the third used 600 mg, administered 45 minutes prior (110014). Of the two studies that evaluated patient preference, patients in one study preferred midazolam, possibly due to its ability to cause perioperative amnesia (95038), whereas there was no preference in the other study (110014). Another clinical study shows that taking passion flower 1000 mg one hour prior to elective minor or moderate surgery reduces preoperative anxiety similarly to melatonin 6 mg; however, passion flower seems to cause more cognitive impairment than melatonin (95037).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Adjustment disorders. Oral passion flower has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One clinical study in patients with adjustment disorder with anxious mood shows that taking two tablets of a specific combination product (Euphytose, Bayer Healthcare) three times daily seems to decrease anxiety symptoms when compared with placebo. One tablet contains the dry extracts of passion flower 40 mg, valerian 40 mg, hawthorn 10 mg, and black horehound 10 mg, as well as the caffeine-containing stimulant herbs kola nut 15 mg and guarana 15 mg (6250). It is unclear if this effect is due to passion flower, other ingredients, or the combination.
• Alcohol use disorder. Oral passion flower has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults experiencing alcohol withdrawal symptoms shows that taking one capsule of a combination product (Relief) three times daily for 15 days reduces the frequency of excessive sweating, reduces serum liver enzyme levels, and improves appetite and quality of life when compared to baseline. One capsule contains passion flower extract 30 mg, black seed extract 100 mg, cocoa extract 90 mg, radish extract 165 mg, and saffron extract 15 mg (97280). The validity of these findings is limited by the lack of a comparator group.
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral passion flower is beneficial in patients with ADHD. Details: A small clinical trial in children aged 6-13 years with ADHD shows that taking tablets of passion flower (Pasipay, Iran Darouk Pharmaceutical Company) 0.02 mg/kg orally twice daily for 8 weeks reduces parent and teacher ratings of ADHD symptoms no better than taking methylphenidate (0.5 mg/kg twice daily) (88197).
• Benzodiazepine withdrawal. It is unclear if oral passion flower is beneficial for benzodiazepine withdrawal. Details: A moderate-sized observational study in adults with depression or anxiety on antidepressants undergoing a benzodiazepine taper after chronic benzodiazepine use suggests that taking a specific dry extract of passion flower (Tractana, Baldacci) 200-600 mg daily for 3 months is associated with a faster benzodiazepine dose reduction and greater percentage of patients with at least 50% reduction or complete benzodiazepine discontinuation after 1 and 3 months from taper initiation when compared with control (111651). The validity of these effects is limited by a lack of placebo group and the retrospective observational study design.
• Congestive heart failure (CHF). Oral passion flower has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with mild CHF shows that taking a combination of passion flower and hawthorn extracts 2 mL three times daily for 6 weeks increases six-minute walking distance when compared with placebo. However, it does not appear to improve exercise capacity on a bicycle ergometer test (19201). It is unclear if this effect is due to passion flower, hawthorn, or the combination. Additionally, hawthorn has been evaluated alone for the management of CHF, with some research suggesting that although it may improve symptoms, it may also be associated with worsened clinical outcomes.
• Fibromyalgia. Although there is interest in using oral passion flower for fibromyalgia, there is insufficient reliable information about the clinical effects of passion flower for this condition.
• Menopausal symptoms. Although there is interest in using oral passion flower for menopausal symptoms, there is insufficient reliable information about the clinical effects of passion flower for this purpose.
• Muscle cramps. Although there is interest in using oral passion flower for muscle cramps, there is insufficient reliable information about the clinical effects of passion flower for this purpose.
• Neuropathic pain. Although there is interest in using oral passion flower for neuropathic pain, there is insufficient reliable information about the clinical effects of passion flower for this condition.
• Opioid withdrawal. It is unclear if oral passion flower helps to prevent opioid withdrawal. Details: A small preliminary clinical study in adults who are completing an inpatient withdrawal program for opioid addiction shows that taking passion flower liquid extract 60 drops, in combination with clonidine 0.8 mg daily, is better than clonidine alone when used for reducing symptoms such as anxiety, irritability, insomnia, and agitation. However, the combination is no better than clonidine alone for reducing physical symptoms such as tremor and nausea (2303).
• Seizures. Although there is interest in using oral passion flower for seizures, there is insufficient reliable information about the clinical effects of passion flower for this condition.
• Stress. It is unclear if oral passion flower reduces stress. Details: A moderate-sized clinical study in adults in India with stress and insomnia shows that taking passion flower 600 mg daily at bedtime for 30 days modestly reduces stress when compared with placebo (114529). It is unclear how changes in stressors over the course of the study may have affected results. Additionally, a small clinical study in healthy adults shows that taking a specific combination product (Relaxane, Max Zeller Söhne AG) containing passion flower 90 mg, lemon balm 50 mg, valerian 90 mg, and butterbur 90 mg three times daily for 3 days modestly reduces subjective anxiety scores during social stress testing when compared with placebo or no treatment (97276). It is unclear if this effect is due to passion flower, other ingredients, or the combination. More evidence is needed to rate passion flower for these uses.

(Read more about PASSION FLOWER)

POSSIBLY EFFECTIVE

• Congestive heart failure (CHF). Oral taurine may improve left ventricular function, heart failure-related symptoms, and exercise capacity in patients with CHF. Details: Taking taurine 2-6 grams in two or three divided doses daily for 6-8 weeks seems to improve left ventricular function (5248,5271,8221) and symptoms of heart failure (5271,5306,8221) when compared with placebo or coenzyme Q10 in patients with New York Heart Association (NYHA) functional class II to IV. Also, taking taurine 500 mg three times daily for 2 weeks seems to improve exercise capacity when compared with placebo in patients with heart failure (77176). Some patients with severe heart failure rapidly improve from NYHA class IV to II after 4-8 weeks of treatment. Improvement seems to continue for as long as taurine treatment is continued, up to one year (5306,8217,8218,8221).
• Hepatitis. Oral taurine may improve liver function in patients with acute or chronic hepatitis. Details: Several small clinical trials show that taking taurine 1.5-4 grams daily for up to 3 months improves liver function in patients with acute and chronic hepatitis when compared with placebo (10454,77114,77147).

POSSIBLY INEFFECTIVE

• Obesity. Oral taurine does not appear to improve body weight in adults who are obese or overweight. Details: A meta-analysis of 12 small clinical trials shows that taurine supplementation does not reduce body weight or body mass index (BMI) when compared with placebo. The studies included in this analysis evaluated taurine doses of 0.5-6 grams daily for 15 days to 6 months. Most of the patient populations evaluated in the included studies had liver or metabolic disorders; three studies specifically evaluated overweight or obese adults (104166). Additionally, a more recent clinical trial in a small group of females with obesity shows that taking taurine 1 gram three times daily along with a calorie-restricted diet for 8 weeks does not reduce body weight, BMI, or waist circumference when compared with calorie restriction alone (104167). In contrast, a very small study in adults with type 2 diabetes on antidiabetes medication shows that taking taurine 500 mg twice daily for 8 weeks reduces body mass, BMI, and body fat percentage when compared with control (112271). The validity of these effects is limited by the small sample size.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Academic performance. It is unclear if oral taurine is beneficial to improve academic performance. Details: A very small clinical study in college entrance examinees over age 19 shows that taking a jelly containing taurine 3 grams daily for 14 days does not improve academic achievement when compared with baseline or placebo (110579). Due to its small size, this study may have been inadequately powered to detect a difference between groups.
• Age-related macular degeneration (AMD). Although there has been interest in using oral taurine for AMD, there is insufficient reliable information about the clinical effects of taurine for this purpose.
• Androgenic alopecia. Oral taurine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in adults with androgenic alopecia or telogen effluvium shows that taking a combination product containing taurine, cysteine, methionine, iron, selenium, and hydrolyzed collagen (GFM Oral, Cantabria Labs) along with conventional therapy, consisting primarily of finasteride or minoxidil, daily for 12 weeks improves hair loss when compared with conventional therapy alone (111636). It is unclear if this effect is due to taurine, other ingredients, or the combination.
• Athletic performance. Research on the use of taurine for improving endurance or power output is limited and conflicting; however, it may improve performance by a small amount in some athletes. Details: Research is conflicting on the effects of taurine on athletic performance. Several clinical studies in trained and untrained athletes show that taking taurine 1-6 grams as a single dose before endurance exercise, or 3 grams daily for 8 weeks after endurance exercise, does not improve endurance or aerobic capacity when compared with placebo (77159,77203,95613,98334). However, a meta-analysis of 7 small clinical trials shows that taking taurine 1-6 grams daily for up to 2 weeks slightly improves endurance when compared with control. Also, preliminary studies in male cyclists, recreationally active males, Olympic-level athletes, and female athletes habituated to caffeine show that taking taurine 50 mg/kg or 1-6 grams one time 1.5-2 hours prior to a cycling test increases the time to exhaustion and peak, mean, and minimum power output but does not improve perceived exertion, fatigue index, heart rate, or anaerobic capacity when compared with placebo (101475,103211,112265,112269). The reasons for these discrepancies are unclear; the meta-analysis did not identify a dose or duration-related benefit. One small clinical trial shows that taking taurine 40 mg/kg improves muscle power in caffeine-deprived athletes who regularly use caffeine, but actually seems to worsen muscle power in athletes who do not regularly use caffeine (98335). Overall, it is not clear which population is most likely to benefit from taurine use (98337,98338). Study results are mixed when taurine has been evaluated in combination with other ingredients. One small study shows that taking a specific product containing taurine and caffeine (AdvoCare Spark) does not improve sprint performance in college athletes when compared with placebo (77195). However, other small studies of cyclists and boxers suggest that taking taurine in combination with a variety of other ingredients including B vitamins, caffeine, and glucuronolactone (Red Bull Energy Drink) or ginseng, kudzu, and soybean, may improve measures such as endurance, power, balance, or agility (37815,57945,110577,112269). It is unclear if the benefits seen in these studies are due to taurine, other ingredients, or the combinations.
• Attention deficit-hyperactivity disorder (ADHD). Although there has been interest in using oral taurine for ADHD, there is insufficient reliable information about the clinical effects of taurine for this purpose.
• Autism spectrum disorder. Although there has been interest in using oral taurine for autism spectrum disorder, there is insufficient reliable information about the clinical effects of taurine for this purpose.
• Chemotherapy-induced nausea and vomiting (CINV). It is unclear if oral taurine is beneficial in patients with CINV. Details: One small clinical trial in patients with acute lymphoblastic leukemia receiving 6 months of chemotherapy shows that taking taurine (pure powder, Aviforme) 1000 mg twice daily, starting 6 hours after receiving chemotherapeutic agents, significantly improves CINV in 87.5% of patients. Other symptoms, such as reduced appetite and smell and taste impairment, are also improved in some patients (91512).
• Chemotherapy-induced nephrotoxicity. It is unclear if oral taurine is beneficial for preventing or treating chemotherapy-induced nephrotoxicity. Details: One small clinical trial in patients with acute lymphoblastic leukemia receiving 6 months of chemotherapy shows that taking taurine (pure powder, Aviforme) 1000 mg twice daily reduces plasma creatinine, urea, bilirubin, and liver enzymes after 4 months when compared with placebo. This suggests a protective effect against chemotherapy-induced nephrotoxicity and hepatotoxicity. A reduction in overall fatigue is also observed (95616).
• Cirrhosis. It is unclear if oral taurine is beneficial in patients with cirrhosis. Details: One small, uncontrolled clinical study in patients with cirrhosis shows that taking taurine 1 gram three times daily for 4 weeks reduces the severity and frequency of muscle cramps when compared to baseline (104165). Another small clinical trial in patients with cirrhosis shows that taking taurine 6 grams daily for 4 weeks reduces portal hypertension by 12%, compared with a 2% increase in the placebo group (98336). However, it is unclear if this is associated with a reduced risk for complications such as variceal bleeding and ascites.
• Cognitive function. It is unclear if oral taurine is beneficial for improving cognitive function; however, taking an energy drink (Red Bull Energy Drink) containing taurine and other ingredients may modestly improve some measures of cognitive function. Details: Levels of taurine decrease with age, but supplementation does not seem to have neuroprotective effects or cognitive benefits in the elderly (101471,110574,110578). In one small crossover study, taurine alone did not reduce errors in sleep-deprived individuals when compared with placebo (38154). However, taurine taken as part of an energy drink formulation containing taurine, caffeine, glucuronolactone, and B vitamins (Red Bull Energy Drink) improves focused and sustained attention, wakefulness, verbal reasoning, driving ability and quality, and reaction speed when compared with placebo (9899,38117,77088,77202). Preliminary clinical research in young adults also shows that consuming the Red Bull Energy Drink might improve attention and verbal reasoning, but does not seem to improve memory, when compared with placebo (9899,77088).
• Cystic fibrosis. Oral taurine may reduce steatorrhea in children with cystic fibrosis, but it does not seem to improve other measures of nutritional status. Details: Some small clinical studies in children with cystic fibrosis show that taking taurine 30-40 mg/kg daily for 7 days to 6 months might be useful as adjunctive therapy to reduce steatorrhea when compared with baseline or placebo (10455,77227,77231). However, it does not seem to improve growth, lung function, muscle protein breakdown, or other symptoms of cystic fibrosis (77224,77228). Also, adding taurine 500-1500 mg daily to treatment with ursodeoxycholic acid for up to one year does not improve liver function tests, fat absorption, or nutritional status in patients with cystic fibrosis and associated liver disease when compared with ursodeoxycholic acid alone (77246,77256).
• Delirium. It is unclear if oral taurine prevents delirium in patients in the intensive care unit. Details: A large clinical study of hospitalized adults in Iran who underwent liver transplantation shows that taking a specific taurine powder product (100% Taurine Amino Acid, MyProtein) 2 grams daily for 30 days post-transplant reduces the risk of delirium by 73% when compared with placebo. These results also suggest that for every four patients treated with taurine over placebo, one additional case of delirium is prevented. Patients who took taurine also had less time on the ventilator and shorter intensive care and hospital stays (110575). However, it is unclear if these effects are due to taurine or other factors since ventilator time and intensive care length of stay are risk factors for delirium.
• Diabetes. It is unclear if oral taurine is beneficial in patients with diabetes. Details: Plasma levels of taurine are reported to be lower in patients with diabetes than in healthy controls (101473). However, clinical research evaluating taurine for glycemic control is mixed (77074,103212). One small clinical trial in patients with type 2 diabetes shows that taking taurine 1 gram three times daily for 8 weeks reduces blood glucose, insulin resistance, total cholesterol, and low-density lipoprotein (LDL) cholesterol when compared with placebo (103212). Although there was no improvement in glycated hemoglobin (HbA1c), the study was not long enough to detect a meaningful reduction in HbA1c. Other preliminary clinical research shows that taking taurine 1-1.5 grams twice daily for 2-4 months does not affect fasting blood glucose, HbA1c, or insulin but may improve measures of insulin resistance in patients with type 2 diabetes when compared with placebo (77074,112271). However, taking taurine while following an exercise program 3 times weekly does appear to reduce fasting blood sugar and HbA1c when compared with exercise plus placebo (112271). The reasons for these discrepant findings are unclear; however, all the included studies were small and potentially inadequately powered to detect a difference in outcomes.
• Epilepsy. Although there has been interest in using oral taurine for epilepsy, there is insufficient reliable information about the clinical effects of taurine for this condition.
• Exercise-induced muscle soreness. Small clinical studies suggest that oral taurine may modestly improve exercise-induced muscle soreness. Details: One small clinical trial in healthy, untrained adults shows that taking taurine 2 grams in combination with branched chain amino acids (BCAAs) three times daily for 2 weeks reduces subjective muscle soreness by 37% when compared with placebo (77212). Another small clinical trial in young, untrained males shows that taking taurine (Taisho Pharmaceutical Co., LTD.) 2 grams three times daily after meals before exercise, and continuing for three days after exercise, reduces delayed onset muscle soreness (DOMS), but not creatine kinase levels, when compared with placebo (91513).
• Fatigue. It is unclear if oral taurine is beneficial for improving fatigue. Details: One small clinical trial shows that taurine seems to reduce fatigue when taken alone, but increases fatigue when taken in combination with caffeine (77202). However, an observational study in young adults has found that subjective scores for physical and mental fatigue do not seem to correlate with dietary taurine intake (101472). One small clinical trial shows that drinking 500 mL of an energy drink providing taurine 1 gram plus other ingredients including caffeine and B vitamins decreases measures of driving-related fatigue in a driving simulation when compared with placebo (91075).
• Helicobacter pylori. It is unclear if oral taurine can aid in the eradication of helicobacter pylori (H. pylori). Details: One clinical trial shows that taking taurine 500 mg twice daily in combination with conventional treatment for 6 weeks increases H. pylori eradication and shortens duodenal ulcer scarring time in patients with confirmed H. pylori infection when compared with conventional treatment alone (77145).
• Hyperlipidemia. It is unclear if oral taurine is beneficial for lowering lipid levels. Details: A meta-analysis of 12 small clinical trials in adults with various liver or metabolic disorders, but without a specific diagnosis of hyperlipidemia, shows that taurine supplementation reduces total cholesterol by 11 mg/dL and triglycerides by 13 mg/dL, but does not seem to improve low-density lipoprotein (LDL) cholesterol or high-density lipoprotein (HDL) cholesterol levels, when compared with placebo. The studies included in this analysis evaluated doses of 0.5-6 grams daily for 15 days to 6 months (104166). The benefits of taurine in adults with hyperlipidemia are unclear. The effect of taurine has also been investigated in combination with exercise. A very small study in adults with type 2 diabetes on antidiabetes medication shows that taking taurine 500 mg twice daily while participating in an exercise program 3 times weekly for 8 weeks reduces triglycerides, total cholesterol, and LDL cholesterol and increases HDL cholesterol when compared with exercise plus placebo (112271).
• Hypertension. Oral taurine may modestly reduce blood pressure in patients with hypertension; however, the long-term antihypertensive effects of taurine are unclear. Details: One clinical study in patients with elevated blood pressure or stage 1 hypertension shows that taking taurine 1.6 grams daily for 12 weeks reduces systolic blood pressure (SBP) by 5 mmHg and diastolic blood pressure (DBP) by 3 mmHg when compared with placebo. The benefit is seen after 8 weeks of continued supplementation (95614). A small clinical trial in patients with stage 2 hypertension (previously classified as borderline hypertension) shows that taking taurine 6 grams daily for 7 days reduces both SBP and DBP when compared to baseline (77229). The long-term effects of taurine on blood pressure are unclear. A meta-analysis of 12 small clinical trials in adults with various liver or metabolic disorders, but without a specific hypertension diagnosis, shows that taurine supplementation reduces SBP by 5 mmHg and DBP by 3 mmHg when compared with placebo. The studies included in this analysis evaluated doses of 0.5-6 grams daily for 15 days to 6 months (104166). Taurine is commonly found in energy drinks, and its effect on blood pressure when used in combination with other ingredients in the form of an energy drink has been evaluated. A small observational study in young adults suggests that drinking a specific combination product containing taurine 100 mg, caffeine, and group B vitamins (Redbull Energy Drink) reduces heart rate but does not change SBP or DBP when compared to baseline (112266). However, another small observational study in young healthy adults suggests that drinking a specific combination product containing taurine 2000 mg, caffeine, ginseng, glucuronolactone, inositol, guarana, L-carnitine, and B vitamins (Monster Energy Drink) increases both SBP and DBP by about 16 mmHg and raises heart rate by 17 beats per minute 15 minutes after consumption when compared to baseline. However, 90 minutes after consumption only DBP and heart rate remain elevated (112268). In both studies, the validity of the effects is limited by a lack of a comparator group. Additionally, it is unclear if the effects are due to taurine, other ingredients, or the combination.
• Infant development. Higher maternal intake of taurine from the diet may be linked to increased newborn length and weight; however, feeding taurine-containing formula to newborns does not appear to improve infant development. Details: One observational study has found a positive correlation between maternal dietary taurine intake and newborn length. In pregnant patients with high taurine intake (>120 mg/day), neonatal birth weight and length were significantly higher when compared with groups with lower taurine intake (101474). However, clinical research shows that administering infant formula containing taurine 45 mg/L for up to 12 weeks does not affect weight, length, head circumference, or behavior in preterm and full-term infants when compared with formula without taurine (77119,77216,77218,77239,77260).
• Iron deficiency anemia. It is unclear if oral taurine is beneficial in patients with iron deficiency anemia. Details: One small clinical trial in females with iron deficiency anemia shows that taking taurine 1000 mg plus ferrous sulfate 325 mg daily for 20 weeks improves hemoglobin concentrations, red blood cell counts, and serum ferritin levels when compared with ferrous sulfate plus placebo (77070).
• Muscular dystrophy. It is unclear if oral taurine is beneficial in patients with muscular dystrophy. Details: One very small crossover trial in patients with muscular dystrophy shows that taking taurine 100-150 mg/kg for 6 months improves the ability to relax muscles after voluntary use when compared with placebo (77235).
• Physical performance. It is unclear if oral taurine improves physical performance in older adults. Details: A small study in elderly females living in a care facility shows that taking taurine powder 1.5 grams daily for 14 weeks in addition to standardized exercise training may modestly improve some measures of physical fitness (i.e. agility, endurance) when compared to baseline. These measures were not improved in patients who took taurine but did not participate in exercise training or who participated in exercise training but did not take taurine (110574). The validity of these findings is limited by lack of randomization, blinding, and statistical comparison between groups.
• Postoperative recovery. It is unclear if oral taurine is beneficial for improving postoperative recovery. Details: One small clinical trial in patients recovering from surgery after a hip fracture shows that taking taurine 6 grams daily for 7 days after surgery does not improve morbidity and mortality outcomes after 1 year when compared with placebo (95615).
• Psychosis. It is unclear if oral taurine is beneficial in patients with psychosis. Details: One small clinical trial in adults up to 25 years of age with first-episode psychosis shows that taking taurine 4 grams daily for 12 weeks in combination with prescribed antipsychotics reduces positive psychotic symptoms, but not negative or cognitive symptoms, when compared with placebo (95612).
• Sleep deprivation. Oral taurine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a combination product containing taurine, caffeine, glucuronolactone, and B vitamins (Red Bull Energy Drink) reduces lane drifting and sleepiness and improves driving quality and reaction time during a car-driving simulator exercise in sleep-deprived individuals when compared with placebo (38117,77066). Other preliminary clinical research in sleep-deprived surgical trainees shows that taking taurine 2 grams in addition to caffeine 150 mg improves reaction time during performance of simulated laparoscopic surgery when compared with placebo, although error-making is not reduced (38154).
• Tourette syndrome. Oral taurine may improve tic severity in children with Tourette syndrome who are taking tiapride at a dose of 300 mg or less. Taurine may not be effective in children taking higher doses of tiapride. Details: One clinical trial in children 6-16 years of age with Tourette syndrome or other tic disorders shows that taking taurine along with tiapride reduces the severity of tics when compared with tiapride alone. For every 6 children taking taurine, one additional child saw a 60% or greater reduction in tic severity as measured on the Yale Global Tic Severity Scale when compared with placebo. However, taurine did not improve tic severity in children taking tiapride at a dose greater than 300 mg daily (103210). Taurine was taken in age-dependent doses of 2.4 grams daily in those 6-8 years, 3.6 grams daily in those 9-13 years, and 4.8 grams daily in those 14-16 years.
• Traumatic brain injury (TBI). It is unclear if oral taurine is beneficial in patients with a TBI. Details: A small clinical study of adults in Iran receiving treatment in the intensive care unit (ICU) following TBI shows that adding a specific taurine powder product (Nutricost) 30 mg/kg/day up to 3 grams daily to enteral nutrition for 14 days may modestly improve disease severity scores, but does not reduce days on the ventilator, ICU length of stay, or mortality at 30 days when compared with usual enteral nutrition (110573). Due to its small size, this study may have been underpowered to detect differences between groups. More evidence is needed to rate taurine for these uses.

(Read more about TAURINE)

POSSIBLY EFFECTIVE

• Insomnia. Most research shows that taking valerian whole root extract 300-600 mg daily modestly improves subjective sleep quality, although it might take up to 4 weeks to provide benefit. Valerian does not seem to improve sleep latency, sleep duration, or insomnia severity. Details: Although there is a great deal of conflicting research, overall, taking valerian 300-600 mg before bedtime seems to improve sleep quality when compared with placebo. In contrast, no consistent benefit has been seen for sleep latency, sleep duration, or insomnia severity (15046,17577,19406,19409,104010). Older meta-analyses show that valerian root improves sleep quality regardless of its formulation. However, the most recent meta-analysis shows that valerian whole root extract improves sleep quality, while it's unclear whether an unspecified valerian extract is effective (17577,19406,104010). These analyses are limited by significant heterogeneity in valerian dosage and formulation, treatment duration, and included patient populations. Some experts claim that valerian does not work acutely for sleep, and it can take up to 4 weeks for a benefit to be seen (10209,104010). Indeed, most short-term studies assessing valerian as a single dose, or used daily for up to one week, show no benefit for sleep quality when compared with placebo (19407,19408,19411,19414). However, a meta-analysis of studies lasting 4 weeks or longer also did not find a consistent benefit (104010). The benefits of valerian for sleep might vary in different patient populations. A large post-marketing surveillance study in children with restlessness or dyssomnia under the age of 12 has found that taking a specific combination product (Euvegal Forte, Dr. Willmar Schwabe Pharmaceuticals) containing valerian root extract 160 mg and lemon balm extract 80 mg 1-2 tablets once or twice daily is associated with moderate sleep improvement (14416). Also, one clinical study in postmenopausal adults shows that taking valerian root extract 530 mg (Sadamine) twice daily for 28 days moderately improves sleep quality when compared with placebo (19425). Another clinical study in patients undergoing treatment for cancer shows that taking valerian 450 mg 1 hour before bedtime for 8 weeks does not improve objective sleep measures, but might improve subjective sleep ratings and mood, when compared with placebo (19424). Small clinical studies in adults on hemodialysis show that taking valerian 530 mg before bedtime for 1 month improves sleep quality when compared with baseline or placebo. (105718,110712). In one of these studies, improvements in sleep quality were similar when compared with gabapentin (110712). Research also shows that taking specific combination products containing valerian and other ingredients can improve sleep quality. These combination products have combined valerian with hops; lemon balm (Euvegal Forte); lemon balm and hops (Valerina Natt); or passionflower and hops (NSF-3, M/s Tablets India) (10423,15018,19413,19417,19418,19419,88193,89408). Finally, limited research has compared valerian to benzodiazepines. A small clinical study in patients with non-organic insomnia shows that taking valerian extract (LI 156, Sedonium) 600 mg daily for 6 weeks seems to be no different for improving sleep quality when compared with taking low-dose oxazepam 10 mg (19416). Valerian might also improve sleep quality in patients who are resistant to chronic benzodiazepine therapy. In one small study, after tapering the benzodiazepine over two weeks, valerian extract 100 mg three times daily for 15 days improves sleep quality when compared with placebo (8006).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Anxiety. It is unclear if valerian is beneficial for anxiety. Details: Meta-analyses of heterogeneous clinical research show that there is insufficient and contradictory evidence on the use of valerian root for anxiety (104010,110711). However, one analysis suggests that using whole root preparations seems to have greater efficacy than valerian extracts (104010). These meta-analyses are limited by significant heterogeneity in valerian dosage and formulation, treatment duration, and patient populations and concerns related to publication bias (104010,110711). One small clinical study in patients with generalized anxiety disorder (GAD) shows that taking valerian extract containing 81.3 mg valepotriates daily for 4 weeks is no different for reducing anxiety scores when compared with diazepam 6.5 mg or placebo (9896). This study was not adequately powered to detect a difference between groups. Also, a small, quasi-randomized trial in adults with poor sleep quality who are undergoing hemodialysis shows that taking a specific valerian root product (Sedamin, Goldaru Company) 530 mg daily for 1 month improves anxiety scores by 2-3.9 times when compared with placebo. However, not all patients reported anxiety at baseline (105718). In contrast, a small clinical study in healthy adults shows that taking a combination of herbal extracts containing valerian root, passionflower, ballota, and hawthorn (Euphytose) daily for 14 days reduces subjective anxiety and objective sympathetic and autonomic nervous system activation in response to a psychosocial stressor when compared with placebo (111222). It is unclear if these effects are due to valerian, other ingredients, or the combination.
• Delirium. Oral valerian has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adult intensive care unit (ICU) patients with agitation and delirium receiving quetiapine 50-200 mg every 12 hours shows that taking 5 mL of syrup containing valerian root 625 mg and an extract of lemon balm leaf 50 mg every 12 hours improves agitation from baseline similarly to placebo. It is unclear if the improvement from baseline differed between groups (106627).
• Depression. It is unclear if valerian is beneficial in patients with depression. Details: A retrospective case series in patients with mild to moderate depression and reports of anxiety has found that taking high-dose valerian 1000 mg with St. John's wort is associated with more rapidly improved depressive symptoms than low-dose valerian 500 mg with St. John's wort (19402). The validity of this study is limited by its retrospective nature and small size. Also, it is unclear if this effect is due to valerian, St. John's wort, or the combination. One small, quasi-randomized trial in adults with poor sleep quality who are undergoing hemodialysis shows that taking a specific valerian root product (Sedamin, Goldaru Company) 530 mg daily for 1 month improves depression scores by 2-3.9 times when compared with placebo. However, not all patients reported depression at baseline (105718).
• Dysmenorrhea. One small study suggests that oral valerian may reduce symptoms of dysmenorrhea. Details: A small clinical study shows that taking powdered valerian root 255 mg three times daily for two menstrual cycles reduces pain severity associated with menstruation when compared with placebo (19342).
• Menopausal symptoms. Small studies suggest that oral valerian may reduce menopausal symptoms. Details: Two small clinical studies in postmenopausal adults show that taking valerian root (Zardband or Goldaroo Co.) 225 mg three times daily or 530 mg twice daily for 2 months moderately reduces hot flash frequency and severity when compared with placebo (89407,96243). Another small study in adults with menopausal symptoms shows that taking a combination of valerian and fennel extracts 500 mg twice daily for 8 weeks reduces the severity of hot flashes and improves sleep quality but does not reduce the duration or frequency of hot flashes when compared with control (112369). It is unclear if these effects are due to valerian, fennel, or the combination. All 3 studies were conducted in Iran, so it is unclear if these results are generalizable to other geographic locations.
• Premenstrual syndrome (PMS). One small study suggests that oral valerian may reduce PMS symptoms. Details: A small clinical study in young adults with PMS shows that taking valerian root extract (Goldaroo Co.) 530 mg twice daily on the last 7 days of the menstrual cycle for 3 cycles moderately reduces the severity of self-reported PMS symptoms when compared with placebo (96239).
• Pre-procedural anxiety. One small study suggests that oral valerian may reduce anxiety during wisdom tooth extraction. Details: A small crossover clinical study in patients undergoing impacted mandibular molar extraction shows that taking valerian extract (Dermatologica Ltda.) 100 mg one hour prior to the extraction reduces physiological responses to anxiety to a satisfactory but lesser degree than midazolam 15 mg. Patients expressed no clear preference for either valerian or midazolam for reducing perioperative anxiety (102242). The validity of these findings is limited by the use of subjective outcome measures.
• Restless legs syndrome (RLS). It is unclear if oral valerian is beneficial in patients with RLS. Details: A small clinical study in patients with RLS shows that taking valerian (Pharmavite, LLC) 800 mg daily for 8 weeks does not improve RLS symptoms or sleep latency when compared with placebo (19422). However, this study was not adequately powered to detect a difference in RLS symptoms between groups. Conversely, another small clinical study in adults with RLS on hemodialysis shows that taking valerian 530 mg nightly before bed for 1 month reduces symptoms of RLS when compared to baseline; however, valerian's effects were weaker when compared with gabapentin 100 mg nightly (110712). The validity of this study is limited by a lack of a placebo group and a small sample size.
• Stress. Two small studies suggest that oral valerian may reduce the stress response in healthy adults who are performing a stressful mental task or a verbal presentation. Details: Two small clinical studies in healthy volunteers shows that taking valerian 100 mg once or 600 mg daily for 7 days prior to participating in a mental stress task or public verbal test reduces physiologic responses to stress and feelings of anxiety when compared to baseline (9893,9895). The validity of these findings is limited by the lack of statistical comparison to the control group. Another small study in healthy volunteers shows that taking a specific combination product containing valerian 360 mg and lemon balm 240 mg (Songha Night, Pharmaton Natural Health Products) reduces anxiety associated with laboratory-induced stress. However increasing the dose to valerian 1080 mg and lemon balm 720 mg seems to increase anxiety (19405).
• Tension headache. One small study suggests that oral valerian may reduce tension headache. Details: A small clinical study in patients with frequent tension headaches shows that taking valerian root extract (Sedamin, Goldaru Pharmaceutical Company) 1060 mg daily after dinner for one month modestly reduces headache severity and disability when compared with placebo (103221). More evidence is needed to rate valerian for these uses.

(Read more about VALERIAN)

POSSIBLY SAFE ...when used orally and appropriately. 5-HTP has been used safely in doses up to 400 mg daily for up to one year (913,30007,30130). Doses up to 1.2 grams daily have been used with apparent safety for up to 10 months (914,30018,30125,30164,30165). Doses of 3 grams daily have been used safely for 3 weeks (30138). There is some controversy about the safety of 5-HTP due to concerns for eosinophilia myalgia syndrome (EMS) (902,919,7067,10084,30178). There is speculation that only certain, contaminated 5-HTP products may cause this serious adverse effect (88174). So far, there is not enough evidence to know if EMS is caused by 5-HTP, contaminants, or other unknown factors (919,7067,10084).

POSSIBLY UNSAFE ...when used orally in large doses. Doses of 6-10 grams daily have been associated with severe gastrointestinal effects and hyperkinesis (30139,30183). The risk may be reduced if the dose is increased gradually.

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

CHILDREN: POSSIBLY SAFE
when used orally and appropriately. Doses of 5-HTP up to 5 mg/kg daily have been used safely for up to 3 years in infants and children up to 12 years old (30128,30153,88173). There is some controversy about the safety of 5-HTP due to concerns for eosinophilia myalgia syndrome (EMS) (902,919,7067,10084,30178). There is speculation that only certain, contaminated 5-HTP products may cause this serious adverse effect (88174). So far, there is not enough evidence to know if EMS is caused by 5-HTP, contaminants, or other unknown factors (919,7067,10084).

(Read more about 5-HTP)

LIKELY SAFE ...when consumed in amounts commonly found in foods. Hops extract and hops oil have Generally Recognized as Safe (GRAS) status in the US (4912).

POSSIBLY SAFE ...when hops extract and hops-derived bitter acids are used orally and appropriately for medicinal purposes, short-term. Hops extract has been used with apparent safety in doses of up to 300 mg daily for 2-3 months. Hops-derived bitter acids have been used with apparent safety at a dose of 35 mg daily for 3 months (12,55338,55370,102899,105953,107813).

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

(Read more about HOPS)

POSSIBLY SAFE ...when used orally and appropriately, short-term. Inositol has been used with apparent safety in doses up to 18 grams daily for up to 6 weeks or 6 grams daily for 10 weeks (2184,2185,2187,95089). Myo-inositol 4 grams daily has also been used with apparent safety for 6 months (95085). There is insufficient reliable information available about the safety of inositol when used topically.

CHILDREN: POSSIBLY SAFE
when used orally and appropriately. Inositol 80 mg/kg (maximum 2 grams) has been taken daily for up to 12 weeks in children aged 5-12 years (95092). ...when used enterally or intravenously and appropriately in premature infants for treating acute respiratory distress syndrome for up to 10 days (2191,2192,91546,91551).

CHILDREN: POSSIBLY UNSAFE
when used enterally or intravenously for extended durations in premature infants. A large clinical study in infants born at less than 28 weeks' gestation found that myo-inositol 40 mg/kg, given intravenously and then enterally every 12 hours for up to 10 weeks, was associated with a small increased risk of death (98946). Long-term follow-up until 24 months corrected age confirms that the initial increase in mortality rate in the myo-inositol group remained stable; however, there was no difference in a composite outcome of death or survival with moderate or severe neurodevelopmental impairment, as well as no difference in the risk of retinopathy of prematurity, between those who received myo-inositol or control (108819).

PREGNANCY: POSSIBLY SAFE
when used orally and appropriately, short-term. Myo-inositol has been used with apparent safety in amounts up to 4000 mg daily during pregnancy (91548,95082,104688).

LACTATION:
Insufficient reliable information available; avoid using. Breast milk is rich in endogenous inositol (2138); however, the effects of exogenously administered inositol are not known.

(Read more about INOSITOL)

LIKELY SAFE ...when used orally in amounts commonly found in foods. Lemon balm has Generally Recognized as Safe (GRAS) status in the US (4912).

POSSIBLY SAFE ...when used orally and appropriately, short-term. Lemon balm extract has been used with apparent safety at a dose of 500 mg daily for 6 months or at a dose of 3000 mg daily for 2 months (9993,9994,104435,104435,110136). ...when used topically and appropriately, short-term. Lemon balm 1% dried leaf extract has been used up to 4 times daily with apparent safety for a few days (790,9995).

CHILDREN: POSSIBLY SAFE
when used orally and appropriate, short-term. A single dose of lemon balm extract 3-6 mg/kg has been safely used in children aged 6-7 years (19525). A specific combination product providing lemon balm leaf extract 80 mg and valerian root extract 160 mg (Euvegal forte, Dr. Willmar Schwabe Pharmaceuticals) 1-2 tablets once or twice daily has been safely used in children under 12 years of age for 30 days (14416). In infants up to 4 weeks old, multi-ingredient products (ColiMil, ColiMil Plus) containing lemon balm 64-97 mg daily have been used with apparent safety for up to 7 days (16735,96278).

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

(Read more about LEMON BALM)

LIKELY SAFE ...when used orally as a flavoring in foods. The US Food and Drug Administration (FDA) lists passion flower as a permitted food flavoring additive, to be used in the minimum quantity necessary (91203).

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts, short-term. Passion flower extract has been used with apparent safety at doses up to 800 mg daily for up to 8 weeks (88198,102866). A specific passion flower extract (Pasipay, Iran Darouk Pharmaceutical Company) has been safely used at a dose of 45 drops daily for up to one month (8007,95036). Also, a tea prepared by steeping 2 grams of the dried aerial parts of passion flower in 250 mL of boiling water for 10 minutes has been used nightly for 7 nights (17374). There is insufficient reliable information available about the safety of passion flower when used topically.

CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term. A specific passion flower product (Pasipay, Iran Darouk Pharmaceutical Company) has been used safely in children aged 6-13 years at a dose of 0.04 mg/ kg daily for 8 weeks (88197).

PREGNANCY: POSSIBLY UNSAFE
when used orally. Some case reports suggest that passion flower use during the first and second trimesters of pregnancy may be associated with an increased risk for premature rupture of membranes and meconium aspiration syndrome; however, causality has not been confirmed (97279). The alkaloids harman and harmaline, which are sometimes found in passion flower, have been reported to have uterine stimulant activity (4,11020,95037). It is not known whether these constituents are present in sufficient quantities to have an effect.

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about PASSION FLOWER)

LIKELY SAFE ...when used in amounts found in foods. Typical daily intakes for adults range from 40-400 mg (101471).

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts. Taurine 2-4 grams daily in two or three divided doses has been used safely in studies lasting up to 3 months (5248,5271,8217,8221,10454,77147,95612,98337,104165,104167). Higher doses of taurine 6 grams daily have been used safely in studies lasting up to 4 weeks (98336,98337). A risk assessment of orally administered taurine has identified an Observed Safe Level (OSL) of up to 3 grams daily for healthy adults (31996).

CHILDREN: LIKELY SAFE
when used in amounts found in foods.

CHILDREN: POSSIBLY SAFE
when used orally and appropriately in medicinal amounts. Taurine 2.4-4.8 grams daily in three divided doses has been safely used in children 6-16 years of age for up to 12 weeks (103210).

PREGNANCY AND LACTATION: LIKELY SAFE
when used in amounts found in foods. There is insufficient reliable information available about the safety of taurine when used in medicinal amounts during pregnancy and lactation; avoid using.

(Read more about TAURINE)

LIKELY SAFE ...when used orally and appropriately, short-term. Valerian 300-600 mg daily has been safely used in clinical studies in over 12,000 patients for up to 6 weeks (2074,3484,3485,4032,15018,17577,17578,19409,96242,103221)(104010,105718). There is insufficient reliable information available about the safety of valerian when used orally for longer than 6 weeks.

CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term. Valerian 160-320 mg has been used with apparent safety in children under 12 years of age for 4-8 weeks (14416).

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

(Read more about VALERIAN)

CARBIDOPA (Lodosyn) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Combining 5-HTP and carbidopa can increase the risk of serotonergic side effects.  Details Carbidopa is sometimes used with 5-HTP to minimize peripheral 5-HTP metabolism and boost the amount that reaches the brain. However, this combination might also increase the risk of some side effects including hypomania, restlessness, rapid speech, anxiety, insomnia, and aggressiveness (30076,30132,30158). Combining carbidopa and 5-HTP might also increase the risk of scleroderma-like skin changes due to elevated serotonin levels (1403).

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of 5-HTP with medications that cause sedation might have additive effects.  Details In clinical trials, 5-HTP has been associated with drowsiness and somnolence (914,30093,30129,30130).

SEROTONERGIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Combining serotonergic drugs with 5-HTP might cause additive serotonergic effects.  Details 5-HTP can increase serotonin levels and cause serotonergic effects (901). Theoretically, combining serotonergic drugs with 5-HTP might increase the risk of serotonergic side effects, including serotonin syndrome and cerebral vasoconstrictive disorders (8056). However, serotonin syndrome with 5-HTP has not yet been reported in humans (104941). Monitor patients for signs of serotonin syndrome and other serotonergic side effects if using 5-HTP with serotonergic drugs.

(Read more about 5-HTP)

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of hops with sedative drugs might cause additive sedation.  Details Some animal research shows that hops has sedative effects (55415,55340,105930).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Hops extract does not seem to affect the metabolism of CYP1A2 substrates.  Details In vitro research suggests that flavonoid constituents of hops inhibit CYP1A2 enzyme activity (10686). However, a pharmacokinetic study in healthy postmenopausal patients shows that taking a standardized extract of spent hops containing prenylated phenols, as 59.5 mg twice daily for 2 weeks, does not affect levels of caffeine, a CYP1A2 probe substrate (105954).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, hops extract might alter metabolism of CYP3A4 substrates; however, this effect may not be clinically significant.  Details Animal research suggests that specific constituents of hops, called lupulones, can induce hepatic CYP3A4 enzyme activity (55325). However, a pharmacokinetic study in healthy postmenopausal patients with normal metabolism shows that taking a standardized extract of spent hops containing prenylated phenols, as 59.5 mg twice daily for 2 weeks, decreases the concentration of alprazolam, a CYP3A4 probe substrate, by 7.6%. This reduction is unlikely to be clinically relevant (105954).

ESTROGENS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of large amounts of hops might interfere with hormone replacement therapy due to competition for estrogen receptors.  Details In vitro research suggests that certain hops constituents can competitively bind to estrogen receptors (3701,10684,10685). However, most hops extracts contain very small amounts of these constituents (105930).

(Read more about HOPS)

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = A Theoretically, taking inositol with antidiabetes drugs might increase the risk of hypoglycemia.  Details Clinical research shows that inositol lowers blood glucose levels and glycated hemoglobin (HbA1c) levels in patients with diabetes (95083,95084,95088).

(Read more about INOSITOL)

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use of lemon balm might have additive effects with CNS depressant drugs.  Details Lemon balm seems to have CNS depressant activity in animals and in humans (9994,19725).

THYROID HORMONE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, lemon balm might interfere with thyroid hormone replacement therapy.  Details In vitro, constituents of lemon balm extract bind to thyroid stimulating hormone (TSH), preventing TSH receptor-binding and leading to the inhibition of TSH-stimulated adenylate cyclase activity (19727,19728). In animals, lemon balm extract has been shown to decrease levels of circulating TSH and inhibit thyroid secretion (19726).

(Read more about LEMON BALM)

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Concomitant use of passion flower with sedative drugs might cause additive effects and side effects.  Details Research in animals and humans shows that passion flower has sedative effects which can be additive when used with sedative medications like lorazepam (8007,19235,19236,19429,68309,104206).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Possible •  Level of Evidence = D Theoretically, passion flower might decrease the effects of CYP3A4 substrates.  Details In vitro research suggests that passion flower can induce CYP3A4 enzymes, albeit to a much lower degree than rifampin, a known CYP3A4 inducer (110704).

ORGANIC ANION-TRANSPORTING POLYPEPTIDE SUBSTRATES (OATP) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, passion flower might reduce the bioavailability of OATP2B1 and OATP1A2 substrates.  Details In vitro research shows that the passion flower constituents apigenin and vitexin inhibit OATP2B1 and OATP1A2. This inhibition may be dose-dependent. One specific high-flavonoid passion flower extract (Valverde) seems to inhibit OATP2B1 and OATP1A2, while another extract with a lower flavonoid concentration (Arkocaps) shows less potent inhibition (105095). OATPs are responsible for the uptake of drugs and other compounds into the body; however, the specific activities of OATP2B1 and OATP1A2 are not well characterized.

(Read more about PASSION FLOWER)

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, taurine might increase the risk of hypotension when taken with antihypertensive drugs.  Details Some clinical evidence suggests that taurine can reduce both systolic and diastolic blood pressure (77229,95614,104166).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, taurine might reduce excretion and increase plasma levels of lithium.  Details Taurine is thought to have diuretic properties (3647), which might reduce the excretion of lithium.

(Read more about TAURINE)

ALCOHOL (Ethanol) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Valerian can have additive sedative effects when used concomitantly with alcohol.  Details Valerian has sedative effects (9894). Theoretically, valerian might have an additive sedative effect when combined with alcohol. Excessive sedation has been reported in an alcohol-abusing individual who took valerian and Gingko biloba (19426). However, the potential interaction between valerian and alcohol has been disputed in other research. Limited evidence suggests that a combination of valerian 160 mg and lemon balm 80 mg (Euvegal) does not cause further deterioration in reaction ability and reaction rate when taken with alcohol as compared to the effects of alcohol alone (19427).

ALPRAZOLAM (Xanax) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Valerian can have additive sedative effects when used with alprazolam. Also, valerian in high doses might modestly increase alprazolam levels, though this is not likely to be clinically significant.  Details Valerian has sedative effects (9894). Theoretically, valerian might cause additive sedation when combined with alprazolam. Also, a small pharmacokinetic study shows that taking valerian extract 1000 mg daily (providing 11 mg valerenic acid) might increase alprazolam levels by about 19%. This might be due to valerian's mild inhibition of cytochrome P450 3A4 (CYP3A4) (13014). Despite being statistically significant, this increase is not likely to be clinically significant.

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Valerian can have additive sedative effects when used concomitantly with CNS depressant drugs.  Details Theoretically, concomitant use of valerian and drugs with sedative and anesthetic properties may cause additive therapeutic and adverse effects (3486,12720,19429).

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Unlikely •  Level of Evidence = B Valerian does not seem to have a clinically relevant effect on levels of drugs metabolized by CYP2D6.  Details Although some in vitro evidence suggests that valerian affects CYP2D6, clinical pharmacokinetic (PK) studies show that valerian is unlikely to affect the CYP2D6 enzyme (13014,13536,19430,19431). In one PK study, taking valerian 1000 mg (providing about 11 mg valerenic acid) nightly for 14 days did not affect the metabolism of dextromethorphan, a CYP2D6 substrate. In another PK study, taking valerian 125 mg three times daily for 28 days did not affect metabolism of debrisoquine, an accepted CYP2D6 probe-substrate (13014,13536).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Valerian does not seem to have a clinically relevant effect on levels of drugs metabolized by CYP3A4.  Details Although some in vitro evidence suggests that valerian extract might inhibit or induce CYP3A4, clinical pharmacokinetic (PK) studies show that valerian does not have a clinically significant effect on the CYP3A4 enzyme (6450,12214,13014,13536,19431). In one PK study, taking valerian 125 mg three times daily for 28 days did not affect metabolism of midazolam, an accepted CYP3A4 probe-substrate. In another PK study, taking valerian 1000 mg (providing about 11 mg valerenic acid) nightly for 14 days modestly increases levels of alprazolam, a CYP3A4 substrate, suggesting mild inhibition of CYP3A4 (13014,13536). However, this mild inhibition is unlikely to be clinically relevant.

GLUCURONIDATED DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Valerian might weakly inhibit glucuronidation and increase concentrations of drugs metabolized by UGT1A1 and UGT2B7.  Details In vitro research shows that methanolic valerian extract and valerenic acid might competitively inhibit UDP-glucuronosyltransferase (UGT) 1A1 (UGT1A1) and UGT2B7 (81685).

(Read more about VALERIAN)

General ...Orally, 5-HTP is generally well tolerated, short-term.
Most Common Adverse Effects:
Orally: Abdominal pain, anorexia, dizziness, diarrhea, drowsiness, fatigue, headache, insomnia, nausea, and vomiting. Severity appears to be dose-dependent.
Serious Adverse Effects (Rare):
Orally: Aggression, hallucinations, mania, severe gastrointestinal complaints.

Cardiovascular ...Orally, palpitations have been reported with 5-HTP (30076,30130,30167). Conversely, bradycardia has been reported in patients taking 5-HTP 0.4-2 grams daily in combination with carbidopa 100-300 mg daily (30132). In patients with schizophrenia, a combination of 5-HTP in doses up to 6 grams daily and carbidopa 150 mg daily was associated with diaphoresis and mild diastolic hypotension, especially when doses were increased at a rate faster than 200 mg per day (30183).

Dermatologic ...Orally, 5-HTP has been reported to cause urticaria, other allergic-type skin reactions, and flushing (2204,30000,30140). A scleroderma-like illness was reported in a 70-year-old man who had been taking 5-HTP 1400 mg daily and carbidopa 150 mg daily for 20 months. Elevated serotonin levels may be linked to this condition (1403).

Gastrointestinal ...Orally, 5-HTP has been reported to cause gastrointestinal side effects such as nausea, vomiting, abdominal or epigastric pain, heartburn, constipation, diarrhea, flatulence, anorexia, and taste alteration at any dose (2203,2204,30000,30112,30114,30125,30132,30139,30140)(30165,30183,104250). Severity may be dose-dependent and also related to how quickly doses are increased (30183). Some data suggests that these effects may diminish or disappear with continued use of 5-HTP (30132).

Hematologic ...Symptoms suggestive of eosinophilia myalgia syndrome (EMS) have been reported in some patients using 5-HTP (902,10084,30178,88174,90927). In one case, a woman was exposed to 5-HTP, tetrahydrobiopterin, carbidopa, and levodopa while administering them to her children for 2 years (90927). Her diagnosis was not confirmed, and the validity of the tests performed on the 5-HTP product has been questioned (88174). Other cases of eosinophilia or EMS in patients taking 5-HTP have been attributed to impurities that resemble previously identified contaminants found in L-tryptophan products (902,919,7067,10084). The L-tryptophan contaminants associated with EMS were linked to a specific manufacturer's production method that is not used in the preparation of 5-HTP (88174). Although 5-HTP supplements have been associated with EMS, it seems that this adverse effect is likely due to the presence of contaminants in the 5-HTP products, not 5-HTP itself.

Musculoskeletal ...Orally, rhabdomyolysis was noted in one patient with progressive myoclonus epilepsy who was treated with 5-HTP 300 mg daily for 21 days (30162).

Neurologic/CNS ...Orally, 5-HTP has been reported to cause drowsiness, dizziness, insomnia, fatigue, and headache (30076,30112,30132).

Psychiatric ...Orally, 5-HTP has been associated with euphoria, hypomania and mania, anxiety, insomnia, and aggressiveness (30076,30132,30158,88179). In patients with schizophrenia, a combination of high-dose 5-HTP, up to 6 grams daily, and carbidopa 150 mg daily was associated with transient increases in hallucinations, delusions, marked confusion, looseness of associations, flight of ideas, and a hyperkinetic syndrome consisting of restlessness, hand wringing, pacing, and an inability to sit quietly in a chair (30183).

(Read more about 5-HTP)

General ...Orally, hops extract and oil are generally well tolerated when used in food amounts. Hops extract also seems to be well tolerated when used in supplemental amounts.
Most Common Adverse Effects:
Orally: Drowsiness, sedation.

Dermatologic ...Topically, allergic reactions have been reported after contact with the fresh hops plant and plant dust. Contact dermatitis is attributed to the pollen (4,12,105930).

Genitourinary ...Orally, supplements containing hops and soy have been associated with 4 cases of postmenopausal bleeding (55404). It is unclear if this effect is due to hops, soy, or the combination. Also, menstrual disturbances have been reported in female workers harvesting hops (10684,55405).

Neurologic/CNS ...Orally, hops might cause drowsiness and sedation. Historically, hops are thought to have sedative effects, since workers harvesting hops were observed to tire easily after oral contact with hop resin. The European Medicines Agency states that hops may have sedative effects; however, there is a lack of clinical research confirming that hops extract causes drowsiness and sedation (105930).

Pulmonary/Respiratory ...Occupational exposure to dust from hops, usually in combination with dust from other products, is associated with chronic respiratory symptoms such as dry cough, dyspnea, chronic bronchitis, and other occupational respiratory diseases (55333,55414).

(Read more about HOPS)

General ...Orally and intravenously, inositol seems to be well tolerated. Topically, no adverse effects have been reported, although a thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Orally: Diarrhea, gas, and nausea.

Gastrointestinal ...Orally, inositol may cause nausea, diarrhea, gas, and gastrointestinal discomfort (10387,11972,91547,91549,95089,95090,95092).

Immunologic ...Orally, inositol in combination with omega-3 fatty acids has been associated with reports of cold and allergy symptoms in children in clinical research (95092).

Musculoskeletal ...Orally, inositol in combination with omega-3 fatty acids has been associated with reports of tics and other musculoskeletal side effects in children in clinical research (95092).

Neurologic/CNS ...Orally, inositol may cause dizziness, tiredness, insomnia, agitation, and headache (10387,11972,95089,95092). In combination with omega-3 fatty acids, inositol has been associated with reports of feelings of thirst in children in clinical research (95092).

Psychiatric ...In one case report, a 36-year-old male with adequately controlled bipolar disorder was hospitalized with symptoms of mania after consuming several cans of an energy drink containing inositol, caffeine, taurine, and other ingredients (Red Bull Energy Drink) over a period of 4 days (14302). It is not known if this is related to inositol, caffeine, taurine, a different ingredient, or a combination of the ingredients.

(Read more about INOSITOL)

General ...Orally, lemon balm seems to be well tolerated in food amounts and larger, medicinal amounts. Topically, lemon balm seems to be well tolerated.
Serious Adverse Effects (Rare):
Orally: Wheezing has been rarely reported.

Cardiovascular ...Orally, a case of transient complete atrioventricular block and QT prolongation is reported in a 25-year-old female following the post-workout use of a specific product (Muscle Eze Advanced) containing lemon balm and several other ingredients. Symptoms of fatigue and lightheadedness started 1 week into use of the product. Product discontinuation led to restoration of normal sinus rhythm within 24 hours and normalization of the electrocardiogram within 2 weeks (112556). It is unclear whether this occurrence is due to lemon balm, other ingredients, or the combination.

Dermatologic ...Topically, lemon balm 1% cream applied 5 times daily to cold sores has been associated with two cases of irritation and one case of cold sore exacerbation. However, these effects do not appear to occur more often with lemon balm than with placebo (790).

Gastrointestinal ...Orally, lemon balm might increase appetite in some patients (91732,104433). Nausea, vomiting, and abdominal pain have been reported rarely and do not seem to occur more often than in patients taking placebo (9993).

Neurologic/CNS ...Orally, lemon balm has been reported to cause dizziness and sedation; however, it does not seem to occur more often with lemon balm than placebo (9993,104433). Additionally, other clinical research shows that using lemon balm in conjunction with alcohol does not affect reaction time or influence cognitive performance (19427,19723).

Pulmonary/Respiratory ...Orally, lemon balm has been associated with rare cases of wheezing (9993).

(Read more about LEMON BALM)

General ...Orally, passion flower is well tolerated.
Most Common Adverse Effects:
Orally: Confusion, dizziness, hypersensitivity, and sedation.

Cardiovascular ...There is a case report involving a 34-year-old female who was hospitalized with severe nausea, vomiting, drowsiness, prolonged QT interval, and episodes of nonsustained ventricular tachycardia following use of passion flower extract tablets (Sedacalm, Bioplus Healthcare), 1500 mg on day 1 and 2000 mg on day 2 to relieve stress. All symptoms resolved within one week after passion flower was discontinued (6251).

Genitourinary ...The alkaloids harman and harmaline, which are sometimes found in small amounts in passion flower, have been reported to have uterine stimulant activity (4,11020,95037).

Hematologic ...Orally, passion flower has been reported to cause epistaxis in one clinical trial (95038). Vasculitis has also been reported with use of a specific herbal product (Relaxir) produced mainly from the fruits of passion flower (6).

Hepatic ...There is debate about whether passion flower contains cyanogenic glycosides. Several related Passiflora species do contain these constituents (3), including Passiflora edulis, which is associated with liver and pancreatic toxicity (7).

Immunologic ...An idiosyncratic hypersensitivity reaction characterized by urticaria and cutaneous vasculitis has been reported in a 77-year-old male with rheumatoid arthritis after taking a specific combination product that included passion flower extract (Naturest) (68308). It is unclear if these effects were caused by passion flower or other ingredients.
In clinical trials, passion flower has been reported to cause allergy symptoms including sinus irritation; however, the frequency of these events was statistically nonsignificant when compared to treatment with midazolam 15 mg (95038).

Musculoskeletal ...Orally, passion flower has been reported to cause muscle relaxation in a clinical trial (95038).

Neurologic/CNS ...Orally, sedation, dizziness, ataxia, and confusion have been reported in clinical trials. However, these events generally do not necessitate discontinuation (8007,15391,15392,95036,95038). Altered consciousness has been reported with use of a specific herbal product (Relaxir) produced mainly from the fruits of passion flower (6).

(Read more about PASSION FLOWER)

General ...Orally, taurine is generally well-tolerated when used in typical doses for up to one year.
Most Common Adverse Effects:
Orally: Constipation, diarrhea, and dyspepsia.
Serious Adverse Effects (Rare):
Orally: Hypersensitivity reactions in sensitive individuals. Case reports raise concerns for serious cardiovascular adverse effects, but these reports have involved energy drinks containing taurine and other ingredients. It is unclear if these adverse effects are due to taurine, other ingredients, or the combination.

Cardiovascular ...Changes in heart rate and increased blood pressure have been reported following the co-administration of taurine and caffeine, although the effects of taurine alone are unclear (77088). In healthy individuals, consumption of energy drinks containing taurine increased platelet aggregation and decreased endothelial function (77151,112268,112741). A case of cardiac arrest following strenuous exercise and an excessive intake of energy drinks containing caffeine and taurine has been reported (77136). In another case report, a 28-year-old male without cardiovascular risk factors presented to the hospital with radiating chest pain, shortness of breath, and diaphoresis after excessive intake of an energy drink containing taurine, caffeine, sugar, and glucuronolactone. Electrocardiogram findings confirmed myocardial infarction, and subsequent catheterization confirmed thrombotic occlusion (112741).

Endocrine ...Orally, taurine has been reported to cause hypoglycemia (77153).

Gastrointestinal ...Orally, constipation has been reported following the administration of taurine (77231). Dyspepsia has also been reported after oral taurine use (104165).

Hematologic ...In clinical research, taurine reduced platelet aggregation (77245). A case of massive intravascular hemolysis, presenting with confusion, dark urine, dyspnea, emesis, and fever, has been reported following the administration of a naturopathic vitamin infusion containing taurine, free amino acids, magnesium, and a vitamin B and D complex (77177). However, the effects of taurine alone are unclear.

Immunologic ...A case report describes a hypersensitivity reaction in a female patient with a history of allergies to sulfonamides, sulfites, and various foods, after ingestion of taurine and other sulfur-containing supplements. The amount of taurine in the products ranged from 50-500 mg per dose. The allergic reaction recurred upon rechallenge with taurine 250-300 mg (91514).

Neurologic/CNS ...In a case study, encephalopathy occurred in a body-builder who took approximately 14 grams of taurine in combination with insulin and anabolic steroids. It is not known if this was due to the taurine or the other drugs taken (15536).
Cases of seizures following the consumption of energy drinks containing taurine have been reported (77105,77196). In clinical research, taurine has been reported to cause drowsiness and ataxia in epileptic children (77241).

Psychiatric ...In a case report, a 36-year-old male with adequately controlled bipolar disorder was hospitalized with symptoms of mania after consuming several cans of an energy drink containing taurine, caffeine, glucuronolactone, B vitamins, and other ingredients (Red Bull Energy Drink) over a period of four days (14302). It is unknown if this effect was related to taurine.

Pulmonary/Respiratory ...In human research, an exacerbation of pulmonary symptoms of cystic fibrosis has been associated with taurine supplementation, although this could also be caused by progression of the disease (77231).

Renal ...A case of acute kidney failure has been reported following the concomitant intake of 1 liter of vodka and 3 liters of an energy drink providing taurine 4. 6 grams, caffeine 780 mg, and alcohol 380 grams (77185).

(Read more about TAURINE)

General ...Orally, valerian is generally well-tolerated.
Most Common Adverse Effects:
Orally: Dizziness, drowsiness, and mental slowness. Other reported side effects include headache, gastrointestinal upset, excitability, and vivid dreams. When used chronically and abruptly stopped, symptoms of withdrawal such as tachycardia, anxiety, irritability, and insomnia might occur. Advise patients to taper doses slowly after extended use.
Serious Adverse Effects (Rare):
Orally: Several case reports raise concerns about hepatotoxicity after the use of valerian and valerian-containing multi-ingredient dietary supplements. Withdrawal from chronic valerian use has been associated with cases of cardiac failure and hallucinations.

Cardiovascular ...When used orally in high doses for an extended period of time, valerian withdrawal has been associated with tachycardia and high output cardiac failure in one patient with a history of coronary artery disease (3487). Chest tightness has been reported for an 18-year-old female who took 40-50 capsules containing valerian 470 mg/capsule (659). A case of severe hypotension, suspected to be due to vasodilation, hypocalcemia, and hypokalemia, has been reported for a patient who injected an unknown quantity of a crude tap water extract of raw valerian root (81734).

Dermatologic ...Orally, valerian might rarely cause a rash. A case of valerian-related rash that resolved after valerian root discontinuation was reported in clinical research (19422).

Gastrointestinal ...Orally, valerian has been associated with increased incidence of gastrointestinal problems including diarrhea, nausea, vomiting, and stomach pain (15046,19406,19407,19422,110712). In one individual, taking 20 times the normal dose caused abdominal cramping (659).

Hepatic ...There have been several case reports of hepatotoxicity associated with the use of multi-ingredient oral preparations containing valerian (8243,96241). In one case report, a 57-year-old man presented with acute hepatitis after consuming a cold and flu remedy containing valerian 2 grams for 3 days; the remedy also contained white willow, elderberry, and horseradish. Although the use of the cold and flu remedy was discontinued one month prior to symptom presentation, the acute hepatitis was attributed to valerian root and treated with steroids (96241). It is possible, however, that some of these preparations may have been adulterated with hepatotoxic agents (8243).
Hepatotoxicity involving long-term use of single-ingredient valerian preparations has also been reported (3484,17578). Also, a case of a 38-year-old female with liver insufficiency and cirrhosis of a vascular parenchymal nature who developed hepatotoxic symptoms following valerian and ethyl-alcohol abuse has been reported (81697). Symptoms resolved and laboratory values normalized following intense plasmapheresis treatment. Another case of acute hepatitis characterized by elevated aminotransferases, mild fibrosis, and liver inflammation has been reported for a 50-year-old female who consumed valerian root extract 5 mL three times weekly along with 10 tablets of viamine, a product containing dry valerian extract 125 mg/tablet, for 2 months (81696). Because a variety of doses were used in these cases, and many people have used higher doses safely, these hepatotoxic reactions might have been idiosyncratic. Tell patients the long-term effect of valerian on liver function is unknown.

Musculoskeletal ...In a case report, combined intake of valerian and passionflower caused throbbing and muscular fatigue when taken concomitantly with lorazepam (19429).

Neurologic/CNS ...Orally, valerian might cause dizziness, headaches, fatigue, sleepiness, and mental dullness (3484,17578,19411,19422,81723,89407). The severity of adverse effects appears to increase with higher doses (19411). However, taking valerian extracts in doses up to 1800 mg does not appear to significantly affect mood or psychomotor performance (10424,15044). Valerian does not usually have a negative impact on reaction time, alertness, and concentration the morning after intake (2074,8296). Clinical research shows that a single dose of valerian root 1600 mg is not associated with any changes in sleepiness, reaction time, or driving performance within 1-4 hours after intake (96240). More serious side effects may occur when valerian is taken at higher doses. In one individual, 20 times the normal dose caused tremor of the hand and foot and lightheadedness (659). In a case report, combined intake of valerian and passionflower caused shaking of the hands and dizziness when taken concomitantly with lorazepam (19429).

Psychiatric ...Orally, valerian has been associate with reports of restlessness, excitability, uneasiness, agitation, and vivid dreams (3484,17578,19411,19422). Chronic use and rapid cessation can lead to withdrawal syndrome with symptoms of agitation, insomnia, and hallucinations (104003). There appears to be a trend towards increased severity of adverse effects with higher doses (19411). A case of acute hypomania has been reported for a 21-year-old female patient who took a valerian decoction in water each night for one month to treat subclinical anxiety. Symptoms included euphoric mood, rapid speech, and increased sociability and sexual interest. Following cessation of valerian use and treatment with quetiapine 100 mg daily for two weeks, the patient recovered (89405). In another case report, an 85-year-old male with mild cognitive impairment, major depression, anxiety, and chronic kidney disease presented to the emergency department with hallucinations, confusion, and agitation thought to be due to abrupt cessation after taking valerian 600 mg daily for about 6 months. The symptoms resolved in about 5 days (104003).

(Read more about VALERIAN)