Sleep Optimizer [Discontinued] by Jarrow Formulas

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Anxiety. Although there has been interest in using oral GABA for anxiety, there is insufficient reliable information about the clinical effects of GABA for this condition.
• Athletic performance. Although there has been interest in using sublingual GABA for athletic performance, there is insufficient reliable information about the clinical effects of GABA for this purpose.
• Attention deficit-hyperactivity disorder (ADHD). Although there has been interest in using oral GABA for ADHD, there is insufficient reliable information about the clinical effects of GABA for this condition.
• Cerebral palsy. It is unclear if oral GABA is beneficial for cerebral palsy in children. Details: Preliminary clinical research in children with cerebral palsy shows that taking a specific product containing GABA (Gammalon) one to four tablets daily (depending on age) for 2 months, in addition to standard therapy for cerebral palsy, improves mental development, learning, vocabulary, physical function, motor strength and activity, and motor hyperactivity in a greater percentage of children when compared with standard therapy alone (19362). These findings are limited by poor study design.
• Chronic bronchitis. It is unclear if oral GABA is beneficial for chronic bronchitis. Details: Preliminary clinical research in adults with chronic bronchitis shows that taking a specific GABA product (Aminalon) 1.5-3 grams daily for 18-20 days, along with conventional treatment for acute exacerbations of bronchitis, increases the duration of subsequent remission by about 3 months when compared with conventional treatment alone (19361).
• Cushing syndrome. It is unclear if oral GABA is beneficial for Cushing syndrome. Details: Preliminary clinical research shows that taking a specific GABA product (Aminalon) 1-3 grams daily for one month decreases plasma levels of adrenocorticotropic hormone (ACTH) 60 minutes after administration, as well as cortisol and ACTH levels up to 2 days after GABA discontinuation, when compared with baseline (19363). The validity of these findings is limited by the lack of a comparator group.
• Depression. Although there has been interest in using oral GABA for depression, there is insufficient reliable information about the clinical effects of GABA for this condition.
• Epilepsy. It is unclear if oral GABA is beneficial for epilepsy. Details: Preliminary clinical research shows that taking a combination of GABA 2.5-3 grams and phosphatidylserine 500 mg daily for 3-8 months reduces seizure frequency when compared with placebo in patients with absence seizures, but not in those with focal aware or focal impaired awareness seizures (19364). Other preliminary clinical research suggests that taking GABA 3 grams with phosphatidylserine 600-1200 mg daily for 2 days does not affect the seizure photosensitivity range in people with photoconvulsive responses (5113).
• Hypertension. Preliminary clinical research suggests that oral GABA may modestly reduce blood pressure in patients with mild or borderline hypertension. Details: Preliminary clinical research in adults with hypertension shows that drinking 100 mL of fermented milk containing GABA 10-12 mg daily at breakfast for 12 weeks reduces systolic and diastolic blood pressure by about 17 mmHg and 7 mmHg, respectively, when compared with baseline. Compared with patients treated with a placebo milk, these reductions were significant. However, it is unclear if the placebo milk also differed from the fermented milk in other ways (19367). Other preliminary clinical research in patients with borderline hypertension shows that taking a chlorella supplement containing GABA 20 mg twice daily for 12 weeks reduces systolic blood pressure when compared with placebo (19368). However, these findings are limited by poor study design.
• Insomnia. It is unclear if oral GABA is beneficial for insomnia. Details: Two small clinical studies in adults with insomnia show that taking fermented rice germ extract, standardized to provide GABA 75 mg or 300 mg, one hour before bedtime for 4 weeks modestly decreases sleep latency when compared with placebo, but does not improve sleep efficacy or reduce episodes of waking after sleep onset (110134,110135). As these doses were evaluated in separate studies, no direct comparison between GABA 75 mg and 300 mg has been conducted.
• Meningitis. It is unclear if oral GABA is beneficial for meningitis. Details: Preliminary clinical research in children aged 7 months to 16 years with meningitis shows that taking a specific GABA product (Aminalon) 0.5-1.5 grams daily, starting within 2-4 weeks of illness and continuing for one month thereafter, decreases the incidence of residual disease manifestations and prevents the development of cerebrospinal syndrome when compared with control (19369). However, this study was conducted prior to the development of current treatment guidelines for meningitis; it is unclear if GABA is beneficial when used in conjunction with current standard care.
• Menopausal symptoms. Although there has been interest in using oral GABA for menopausal symptoms, there is insufficient reliable information about the clinical effects of GABA for this purpose.
• Motion sickness. It is unclear if oral GABA is beneficial for motion sickness. Details: Preliminary clinical research shows that taking a specific GABA product (Aminalon) 0.5 grams as a single dose 40-50 minutes before induced motion sickness or three times daily for 4 days significantly delays onset of motion sickness when compared with placebo. GABA also decreases the occurrence of motion sickness symptoms including chills, cold sweats, and pallor when compared with placebo (19370).
• Obesity. Although there has been interest in using oral and sublingual GABA for weight loss, there is insufficient reliable information about the clinical effects of GABA for this purpose.
• Pain (acute). Although there has been interest in using oral and sublingual GABA for acute pain, there is insufficient reliable information about the clinical effects of GABA for this purpose.
• Post-traumatic stress disorder (PTSD). Although there has been interest in using oral GABA for PTSD, there is insufficient reliable information about the clinical effects of GABA for this condition.
• Premenstrual syndrome (PMS). Although there has been interest in using oral GABA for PMS, there is insufficient reliable information about the clinical effects of GABA for this condition.
• Psychological well-being. Although there has been interest in using oral and sublingual GABA to improve well-being, there is insufficient reliable information about the clinical effects of GABA for this purpose.
• Stress. It is unclear if oral GABA is beneficial for stress. Details: Preliminary clinical research shows that taking a single dose of GABA 100-200 mg by mouth 10-70 minutes prior to completing a mentally stressful task does not appear to reduce subjective measure of stress when compared with placebo (90568). However, it does attenuate alpha wave reduction and reduces beta wave upsurge on the EEG during testing when compared with placebo (19373,90568). More evidence is needed to rate GABA for these uses.

(Read more about GAMMA-AMINOBUTYRIC ACID (GABA))

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 menopausal patients 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).
• 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 has found 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.
• 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 diminishes sleep latency by about 8 minutes, decreases total activity during the night, and decreases anxiety when compared with baseline. However, it does not appear to increase 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

• 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.

(Read more about LEMON BALM)

POSSIBLY INEFFECTIVE

• Depression. Although it is unclear if oral L-tryptophan is beneficial in patients with depression, there is a lack of supporting evidence and a rare risk of adverse effects such as serotonin syndrome. Details: Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that L-tryptophan is not currently recommended for adjunctive or monotherapy use for major depressive disorder. The available small and low-quality studies have not supported L-tryptophan for this use (110318). Some older research suggests that taking L-tryptophan with clomipramine might improve the effectiveness of clomipramine (10856). However, it is not clear whether L-tryptophan is beneficial when taken along with newer classes of antidepressants. Also, the CANMAT Taskforce cautions the co-use of L-tryptophan with serotonergic antidepressants due to the rare risk of serotonin syndrome (110318).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Anxiety. Although there is interest in using oral L-tryptophan for anxiety, there is insufficient reliable information available about the clinical effects of L-tryptophan for this condition.
• Athletic performance. It is unclear if oral L-tryptophan is beneficial for improving athletic performance. Details: Some clinical research shows that taking L-tryptophan 300 mg orally along with a sugar and electrolyte drink twice daily for 3 days prior to exercise and on the day of exercise improves power output during the last 20 minutes of exercise when compared with taking a sugar and electrolyte drink without L-tryptophan. The improvement in power output increases distance covered by about 5% without increasing perceived exhaustion (91462). However, other clinical research shows that taking L-tryptophan 12 mg/kg after 5 minutes of warm-up and then 6 mg/kg orally every 15 minutes during exercise does not improve time to exhaustion in endurance-trained male athletes (1135). Reasons for the discrepancy are not clear. It is possible that L-tryptophan benefits some measures of athletic performance, but not others.
• Bruxism. It is unclear if oral L-tryptophan is beneficial for bruxism. Details: A very small clinical trial in adults with nocturnal bruxism shows that taking L-tryptophan 50 mg/kg daily orally for 8 days does not improve levels of teeth grinding when compared with placebo (1139).
• Cognitive impairment. It is unclear if oral L-tryptophan is beneficial in patients with cognitive impairment. Details: Clinical research in elderly individuals with mild cognitive impairment shows that taking L-tryptophan 95 mg orally with docosahexaenoic acid (DHA) 720 mg, eicosapentaenoic acid (EPA) 286 mg, vitamin E 16 mg, soy phospholipids 160 mg, and melatonin 5 mg (IBSA Farmaceutici Italia) nightly for 12 weeks improves cognitive function and sensitivity to smells by a small amount when compared with placebo. Patients treated with the combination showed a 1-point improvement in cognitive function based on the mini-mental state examination (MMSE) scale, while patients in the placebo group showed a 2-point decline (62847). However, these results might not be clinically significant. Also, it is not known if any potential benefit is due to L-tryptophan, other ingredients, or the combination.
• Fibromyalgia. It is unclear if oral L-tryptophan is beneficial in patients with fibromyalgia. Details: Preliminary clinical research in females with fibromyalgia shows that eating a standardized Mediterranean diet supplemented with walnuts, to supply L-tryptophan 60 mg daily and magnesium 60 mg daily for 16 weeks, modestly reduces anxiety, mood disturbance, eating disorders, and dissatisfaction with body image, but does not affect sleep, when compared with the Mediterranean diet alone. It is unclear if these effects are due to L-tryptophan, magnesium, other components of the added foods, or the combination (103172).
• Gout. Oral L-tryptophan has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with mild hyperuricemia shows that taking a powder containing L-tryptophan 0.2 grams and glycine 3 grams nightly for 6 weeks decreases serum uric acid levels by 0.3 mg/dL when compared with placebo. Improvements also occurred in the subgroup of patients with uric acid levels greater than 7 mg/dL, the point at which symptoms of gout can occur (99883). However, the effect of this combination for gout-related pain is unknown. Also, it is not clear if this effect is due to L-tryptophan, glycine, or the combination.
• Helicobacter pylori. A small clinical study suggests that adding L-tryptophan to treatment with omeprazole increases ulcer healing. Details: Clinical research shows that taking L-tryptophan (Ardeydorm, Ardeypharm GmbH) 250 mg twice daily in combination with omeprazole 20 mg twice daily for 21 days improves ulcer healing rates when compared with omeprazole alone in individuals with H. pylori-associated gastroduodenal ulcers (62803).
• Insomnia. Small clinical studies suggest that oral or intravenous L-tryptophan may modestly improve symptoms, particularly sleep latency, in patients with insomnia. Details: Clinical research shows that taking L-tryptophan 500 mg twice daily for 2 weeks improves insomnia in patients undergoing detoxification from methamphetamine or ketamine when compared with placebo. However, it does not seem to improve psychological symptoms in these patients (97242). One small clinical study shows that taking L-tryptophan orally, 1 gram 20 minutes before bed, might decrease sleep latency and improve mood when compared with placebo in healthy people with insomnia. Smaller doses of 250 mg and 500 mg did not demonstrate benefit (1146). Other clinical research shows that a single 5 gram intravenous infusion of L-tryptophan decreases sleep latency and increases total sleep time when compared with baseline in patients with insomnia (14896).
• Migraine headache. The incidence of migraine headaches may decrease with increased dietary L-tryptophan intake. Details: Preliminary clinical research shows that a dietary L-tryptophan intake of 0.84-1.06 grams per day reduces the odds of experiencing a migraine of any type by 54% to 60% when compared with an intake of 0.56 grams per day or less (103171).
• Myofascial pain syndrome. It is unclear if oral L-tryptophan is beneficial in patients with myofascial pain syndrome. Details: Some clinical research in adults with chronic maxillofacial pain shows that taking L-tryptophan orally 3 grams daily for 4 weeks is associated with a greater reduction in pain score and an increase in pain tolerance when compared with placebo (1145). However, other clinical research shows that L-tryptophan does not reduce pain when compared with placebo (1140).
• Obesity. Although there is interest in using oral L-tryptophan for obesity, there is insufficient reliable information available about the clinical effects of L-tryptophan for this condition.
• Premenstrual dysphoric disorder (PMDD). Limited clinical research suggests that L-tryptophan may reduce symptoms of PMDD. Details: A small clinical study in adults with PMDD shows that taking L-tryptophan orally 6 grams daily for approximately 17 days, from the time of ovulation to the third day of menstruation, for three consecutive cycles reduces mood swings, tension, and irritability when compared with placebo (6246).
• Premenstrual syndrome (PMS). Although there is interest in using oral L-tryptophan for premenstrual syndrome, there is insufficient reliable information available about the clinical effects of L-tryptophan for this condition.
• Seasonal affective disorder (SAD). It is unclear if oral L-tryptophan is beneficial in patients with SAD. Details: One very small clinical crossover study shows that taking L-tryptophan 4-6 grams orally daily in divided doses for 4 weeks improves seasonal affective disorder to a similar degree as receiving light therapy for 2 weeks (6247). However, this study was not powered to detect a difference between groups.
• Sleep apnea. Although there is interest in using oral L-tryptophan for sleep apnea, there is insufficient reliable information available about the clinical effects of L-tryptophan for this condition.
• Smoking cessation. It is unclear if oral L-tryptophan is beneficial for smoking cessation. Details: A small clinical study in adults attempting to quit smoking shows that taking L-tryptophan 50 mg/kg daily orally for 2 weeks in conjunction with standard smoking cessation treatments results in fewer daily cigarettes smoked when compared with placebo. Reported anxiety and other withdrawal symptoms were also lower in the L-tryptophan group (1138). However, the study was not powered to detect a statistically significant difference in these outcomes between groups.
• Tourette syndrome. Although there is interest in using oral L-tryptophan for Tourette syndrome, there is insufficient reliable information available about the clinical effects of L-tryptophan for this condition. More evidence is needed to rate L-tryptophan for these uses.

(Read more about L-TRYPTOPHAN)

LIKELY EFFECTIVE

• Delayed sleep phase syndrome (DSPS). Oral melatonin shortens the time needed to fall asleep in children and adults with DSPS. Details: Most clinical research shows that taking melatonin orally reduces the length of time needed to fall asleep and advances sleep onset time in young adults and children with DSPS (8244,12226,15005,62714,62792,63055,88288,88290,89509). In adults, 0.3-5 mg daily for up to 9 months has been used (8244,62714,62792,63055,88290,89509). In children, 1-6 mg before bedtime for up to one month has been used (62714,62792,89509). In addition to improving sleep, melatonin also improves measures of quality of life such as mental health, vitality, and bodily pain in young adults with DSPS (8244,12226,15005). However, relapse to pre-treatment sleeping patterns seems to occur within one year after stopping supplementation (63048).
• Non-24-hour sleep wake disorder. Oral melatonin improves non-24-hour sleep wake disorder in blind children and adults. Details: Taking oral melatonin 0.5-4 mg daily in children and 0.5-10 mg daily in adults for up to 6 years helps improve circadian rhythm sleep disorders in blind children and adults (1082,1744,1749,6585,62346,62350).

POSSIBLY EFFECTIVE

• Beta blocker-induced insomnia. Oral melatonin seems to improve sleep in patients with insomnia related to the use of beta-blockers. Details: Beta-blockers such as atenolol and propranolol seem to decrease endogenous melatonin levels (1780). This might result in insomnia as a side effect. Clinical and preclinical research shows that taking a melatonin supplement might decrease the insomnia caused by beta-blockers (1062,89502). Taking melatonin 5 mg at night after taking atenolol 100 mg appears to attenuate the changes in sleep onset latency, total wake time, and wakefulness after sleep onset when compared with taking atenolol 100 mg alone (1062). Also, in patients taking atenolol or metoprolol, taking melatonin 2.5 mg one hour before bedtime for 20-28 days increases total sleep time by 13-37 minutes and decreases sleep latency by 8-14 minutes when compared with placebo (89502).
• Cancer. In patients with various types of cancer, most research shows that oral or combined intramuscular/oral melatonin in combination with chemotherapy or other treatments seems to improve tumor regression and survival rates. Details: There is some evidence that taking combined high-dose melatonin with conventional chemotherapy or with interleukin-2 (IL-2) might improve tumor regression rate in patients with breast, lung, kidney, liver, pancreatic, stomach, or colon cancer (1692,5854,5855,5857,7040,7043,8268,62407,62844). Melatonin plus chemotherapy in patients with metastatic solid tumors seems to increase the regression rate and one-year survival rate by about 40% to 50% when compared with chemotherapy alone (7040,62407,62844,89504). The addition of melatonin also seems to help reduce chemotherapy toxicities, including hematologic complications, cachexia, asthenia, and neuropathy (8268,62844,89504). There is also some preliminary evidence that melatonin alone, orally or intramuscularly, might improve stabilization rate and possibly one-year survival rate in patients with resistant or untreatable neoplasms of the lung, liver, pancreas, colon, breast, or brain (1080,1688,1693,2566). Also, when used in combination with radiotherapy, high-dose melatonin seems to increase the survival time and percent survival in patients with brain glioblastomas when compared with radiotherapy alone (62991). However, high-dose melatonin treatment does not seem to improve the survival of patients with brain metastases who receive radiation therapy (62455). Melatonin 10-40 mg daily has been used in most clinical trials (1080,1692,1693,2566,5854,5855,5857,7040,7043,8268)(62455,62844,62991,89504). In one study, melatonin 20 mg intramuscularly daily for 2 months, followed by oral melatonin 10 mg daily as maintenance, was used (1688). The effect of melatonin on quality of life and sleep quality in patients with cancer has also been investigated. A meta-analysis of six clinical trials shows that taking melatonin 20 mg daily does not improve sleep quality or quality of life when compared with a control, usually placebo. The duration of studies varied widely; from a period of 7 days or until death. However, there was a modest effect of melatonin on symptoms of depression in patients taking it for at least 14 days or those who underwent surgery (109697).
• Emergence delirium. Oral melatonin seems to be beneficial for reducing sevoflurane-induced agitation in children. It is unclear if oral melatonin is beneficial for adults undergoing surgery. Details: A meta-analysis of clinical research in perioperative adults shows that taking melatonin 3-5 mg or ramelteon 8 mg orally daily for 1-7 days reduces the risk of emergence delirium by 59% when compared with placebo or no treatment. However, the validity of these results is limited by high heterogeneity (112053). Clinical research in children aged 3-9 years shows that taking melatonin 0.3 mg/kg as part of a multimodal anxiolytic strategy reduces the incidence of sevoflurane-associated emergence delirium when compared with placebo or midazolam 0.3 mg/kg. Emergence delirium occurred in 27% of those children given melatonin, compared with 50% of those given placebo and 56% of those given midazolam (106292). In addition, a meta-analysis of three small clinical studies in children aged 2-9 years shows that taking melatonin 0.05-0.5 mg/kg 40-45 minutes prior to sevoflurane reduces the incidence of agitation when compared with placebo, with inconclusive outcomes when compared with midazolam and dexmedetomidine. A sub-group analysis indicates that doses of melatonin 0.2 mg/kg or greater may be most effective (97440). However, taking melatonin 0.5 mg/kg before surgery is 55% less effective than intranasal dexmedetomidine 2 mg/kg for reducing the incidence of sevoflurane-associated emergence delirium (109701).
• Hypertension. Oral controlled-release melatonin seems to reduce blood pressure by a small amount in patients with hypertension. Immediate-release melatonin may not have the same effect. Details: Controlled-release melatonin 2-24 mg, taken before bedtime for up to 4 weeks, seems to lower systolic blood pressure (SBP) by 4-6 mmHg and diastolic blood pressure (DBP) by about 4 mmHg in individuals with essential hypertension or high blood pressure at nighttime (62359,62416,62441,62826,108947). Some evidence shows that immediate-release melatonin does not have this effect (62826). Some evidence also suggests that melatonin seems to slightly reduce blood pressure in patients without hypertension, but to a lesser degree (103689). However, a very small clinical study in healthy young adults consuming a high sodium diet (6900 mg daily) shows that taking melatonin 10 mg before bedtime for 10 days decreases nighttime SBP but does not improve nighttime DBP, daytime SBP or DBP, 24-hour SBP or DBP, or nocturnal dipping of SBP or DBP when compared with placebo (112442).
• Insomnia. In patents with insomnia, oral melatonin seems to shorten the time it takes to fall asleep by about 7-12 minutes, although the effect on the amount of time asleep is inconclusive. Melatonin is more likely to be beneficial in older adults or people with certain comorbidities. Details: Short-term melatonin treatment appears to modestly reduce the time it takes to fall asleep (sleep latency) in otherwise healthy adults with insomnia. This reduction in sleep latency appears to amount to only about 7-12 minutes and might not be considered clinically relevant. Melatonin does not appear to improve sleep efficiency and may only increase total sleep time by about 8 minutes (15005,88290). Despite lack of substantial improvements in objective measures, some patients report minor improvement in subjective feelings of sleep quality (1070,1083,12226,88290). In children aged 6-12 years with insomnia due to delayed onset of sleep, melatonin 5 mg or 0.05-0.15 mg/kg at bedtime for up to 4 weeks seems to shorten the time that it takes to fall asleep and increases the duration of sleep (9708,62345,62770). More evidence is needed on the long-term effects of melatonin for insomnia. Some evidence shows that taking oral melatonin might be most beneficial for insomnia in elderly patients who could be melatonin deficient (1072,1729,1738,1754,7081,15005,62357,62465,62472,62613)(62776,62789). Taking sustained-release melatonin preparations 2 mg daily seems to improve sleep maintenance and sleep quality in elderly individuals (1738,1754,62465,62472,62613,62776), while immediate-release preparations seem to decrease sleep latency (1738,63041). In these clinical trials, controlled-release, fast-release, or slow-release melatonin 2-3 mg before bedtime for up to 29 weeks has been used (1072,1738,1754,7081,62357,62465,62472,62613,62776,62789). However, using a melatonin patch placed on the gums does not improve sleep parameters in elderly patients with insomnia (63062). Some research shows that taking melatonin when taken either alone or in combination with other sleep aids such as bright-light treatment seems to be beneficial for insomnia in patients with certain comorbid conditions. Taking melatonin 2-12 mg for up to 4 weeks has been used to improve insomnia in patients with depression (1053,1729), schizophrenia (8245,62452), bipolar disorder (62140), asthma (62375), cystic fibrosis (62708), hospitalization (9709,106295), and insomnia termed "ICU syndrome", which refers to sleep disturbances while in the intensive care unit (8240). Insomnia is also improved in children aged 3-12 years with epilepsy taking 6-9 mg of melatonin before bedtime for 4 weeks (62394,99342) and quality of sleep is modestly improved in adults with epilepsy taking 3 mg before bedtime for 8 weeks (110299). There is also evidence that melatonin can improve total sleep time and sleep-onset latency in children with tuberous sclerosis (1747), autism spectrum disorders (1056,62811,88286,96318,106293,110290), developmental disabilities (9707), and neurodevelopmental disorders (21819,62143,88283). It also appears to decrease sleep latency and increase sleep time in adults and children with intellectual disabilities, with or without epilepsy (62373,62561). While some evidence shows that fast-release melatonin is more effective for improving the time to fall asleep in children with sleep-wake cycle disturbances and neurodevelopmental disabilities, it is unclear if controlled-release melatonin provides any additional benefits in this population (62143,95746). However, there is conflicting evidence regarding the effects of melatonin in patients with insomnia and comorbid conditions such as Alzheimer disease or dementia. Some clinical research shows that taking melatonin 3-5 mg before bedtime for up to 10 weeks, either alone or in combination with bright-light treatment, improves impaired sleep related to Alzheimer disease or dementia (1729,62474,63059). But not all research agrees. Meta-analyses of several clinical studies show that taking melatonin 3-10 mg daily improves subjective sleep quality, but not objective outcomes such as number of awakenings at night and sleep efficiency in these patients. Also, immediate-release melatonin 2.5-10 mg or prolonged-release melatonin 1.5-2.5 mg for 10 days to 24 weeks shows inconsistent effects on total sleep time at night in patients with Alzheimer disease (96319,96320). There is also mixed evidence regarding the effects of melatonin in patients with Parkinson disease. Some subjective outcomes such as sleep quality seem to improve. However, the improvement might not be clinically significant, and objective outcomes such as sleep efficiency and total sleep time at night do not seem to improve (62403,62454,62829,96320). Melatonin has also been evaluated in postoperative patients and patients with traumatic brain injury (TBI). Taking melatonin before bed does not improve sleep quality soon after tracheostomy, laparoscopic cholecystectomy, or total knee arthroplasty (62439,62552,99343,100255) or 2-6 weeks after total joint arthroplasty (106305). In adults with TBI, one clinical study shows that taking prolonged-release melatonin (Circadin, Sigma Pharmaceuticals) 2 mg two hours prior to bedtime for 4 weeks improves sleep quality, efficiency, and fatigue when compared with placebo. However, melatonin did not improve sleep onset latency or daytime sleepiness. There appears to be no association between TBI severity and the effect of treatment (96317). There is mixed evidence regarding the effect of melatonin in patients undergoing hemodialysis. Some evidence shows that taking melatonin (Pharma Nord) 3 mg before bed for 6 weeks reduces time needed to fall asleep, improves sleep efficiency, and increases actual sleep time when compared with placebo (62521). Other clinical research in patients undergoing hemodialysis shows that taking immediate-release melatonin 3 mg (Puritans Pride, USA) for 3 months modestly improves various sleep measures when compared with placebo. After treatment, 63.0% of those taking melatonin had no insomnia compared with 7.7% of those taking placebo (110291). However, other evidence shows that taking immediate-release melatonin (Pharma Nord) 3 mg nightly for 12 months does not improve quality of life or sleep efficiency in these patients, indicating that melatonin may not improve sleep long-term (89501). Finally, limited evidence shows that melatonin does not improve insomnia in patients with substance use disorders (97441).
• Jet lag. Taking oral melatonin 2-3 mg daily while travelling seems to improve alertness and reduce daytime sleepiness in people with jet lag. It is unclear if it improves sleep efficiency in this population. Higher doses might have a hypnotic effect. Details: Most research shows that melatonin can modestly improve certain symptoms of jet lag such as alertness and psychomotor performance. Melatonin also seems to improve, to a lesser extent, other jet lag symptoms such as daytime sleepiness and fatigue (12226). Melatonin might not be effective for decreasing the time to fall asleep (sleep latency) or sleep efficiency in patients with jet lag (6496,14283), although some research shows a beneficial effect of melatonin on these outcomes (62364). Doses between 0.5-5 mg appear to be equally effective. Although doses of up to 8 mg have been used, doses greater than 5 mg do not seem to be more effective and seem to produce a greater hypnotic effect. Travelers traveling eastward through five or more time zones may find 2-3 mg of melatonin, either slow-release or fast-release, to be useful when taken at local bedtime on the day of arrival and for 2-5 nights thereafter. Taking melatonin in advance of travel does not help prevent jet lag. The usefulness of melatonin for westward travel or over fewer time zones is less clear, although some evidence suggests that slow-release formulations are less effective than fast-release preparations (1049,1077,1079,1085,1722,8273,9181,9750,62706).
• Migraine headache. Oral melatonin 3-4 mg seems to prevent migraines when used prophylactically. It is unclear if oral melatonin is beneficial for treating migraine. Details: Melatonin production might be altered in people with migraine headache (6712,96316). Meta-analyses and individual clinical studies in adults have shown that taking melatonin modestly reduces migraine severity, duration, and frequency, and increases the likelihood of a 50% reduction in the baseline frequency of migraine, when compared with placebo or baseline. Immediate- or prolonged-release melatonin (occasionally as Circadin, Sigma Pharmaceuticals) in doses of 3-4 mg each evening for up to 6 months have been used in these studies (12149,96316,97438,103486,110286). Meta-analyses have included two or three individual clinical trials (103486,110286). One meta-analysis shows that taking melatonin reduces the frequency of migraine days by about 1.7 (103486). An additional meta-analysis in adults with migraines shows that taking melatonin modestly reduces the use of analgesic medications from baseline, when compared with placebo (110286). In contrast, other clinical research shows that taking extended-release melatonin (Circadin, Neurim Pharmaceuticals Ltd.) 2 mg nightly for 8 weeks does not reduce migraine attack frequency when compared with placebo (62784). Some clinical research also shows that melatonin is as effective as standard treatment for migraine prevention. Some research shows that taking melatonin 3 mg daily for 12 weeks is as effective as amitriptyline 25 mg in reducing migraine frequency, intensity, and duration, as well as reducing analgesic use (96316). A meta-analysis of two clinical trials shows that taking melatonin 3 mg each evening for 8-12 weeks is as effective as standard treatment; however, only one study each compared melatonin with amitriptyline (96316) and valproate (110286). More research comparing melatonin with standard treatments is needed. Melatonin has also been investigated in children. Preliminary clinical research in children 5-15 years of age with migraine headache shows that taking melatonin 0.3 mg/kg daily for 90 days reduces migraine frequency, severity, and duration, and decreases analgesic use when compared to baseline (97446). Some research also suggests that melatonin might help to TREAT migraine headache in children and adolescents aged 9-17 years. Preliminary clinical research shows that taking melatonin 1-8 mg reduces pain by a small amount 2-4 hours later. The higher doses of 2 mg for children weighing less than 40 kg and 8 mg for children weighing at least 40 kg seemed to have the greatest benefit (103487). This study is limited by the lack of a comparator group and a very high drop-out rate.
• Pre-procedural anxiety. Most research shows that oral or sublingual melatonin reduces preoperative anxiety in adults. The benefit in children is unclear. Details: A meta-analysis of 18 clinical studies in adults shows that taking oral or sublingual melatonin 3-10 mg or 0.05-0.4 mg/kg 20-120 minutes prior to surgery reduces preoperative anxiety by an average of 12 points on a 100-point visual analogue scale when compared with placebo. It also reduces postoperative anxiety by about 5 points when compared with placebo. Furthermore, a meta-analysis of 7 small clinical trials suggests that melatonin is comparable to benzodiazepines such as midazolam, oxazepam, or alprazolam for reducing preoperative anxiety (105005). In some cases, melatonin might also be preferable to benzodiazepines because it does not cause anterograde amnesia, respiratory depression, or impairment of cognitive and psychomotor skills (88299,99337). However, research in children is conflicting. One small clinical study in children aged 2-8 years preparing to undergo outpatient elective surgery shows that taking melatonin 0.05-0.4 mg/kg 45 minutes before anesthesia is less effective than midazolam 0.5 mg/kg for reducing anxiety during separation from parents and when putting on the anesthesia mask (62601). In contrast, another small clinical study in children aged 2-5 years undergoing minor elective surgery shows that taking oral melatonin 0.25-0.5 mg/kg 1 hour before anesthesia is similar to midazolam 0.25-0.5 mg/kg for reducing anxiety when separating from parents and when putting on the anesthesia mask (62399). A third study in children aged 3-8 years found no differences between melatonin 0.3 mg/kg, midazolam 0.3 mg/kg, and placebo for reducing preoperative anxiety (106292).
• Pre-procedural sedation. Oral melatonin might reduce the sedative dose required to achieve adequate sedation in children. It is unclear if oral melatonin is beneficial for this purpose in adults. Details: A clinical study in children aged 5-14 years undergoing surgery shows that oral melatonin 0.5 mg/kg reduces the propofol dose required for adequate sedation by 0.77 mg/kg when compared with midazolam 0.5 mg/kg (97444). However, taking melatonin 0.5 mg/kg 45 minutes before surgery is less effective than intranasal dexmedetomidine 2 mg/kg for successful mask acceptance and parental separation (109701). A meta-analysis of clinical and observational studies in children undergoing non-operative procedures, such as electroencephalogram (EEG) and magnetic resonance imaging (MRI), suggests that enteral or parenteral melatonin is no better for adequate sedation than sleep deprivation or chloral hydrate (105884). This finding is limited by imprecision, inconsistency, and a high risk of bias. A small clinical study in adults undergoing total abdominal hysterectomy shows that taking extended-release melatonin 5 mg, 90 minutes before surgery, decreases the use of midazolam for sedation during surgery when compared with placebo (108945). However, the validity of this finding is unclear, as 0% of patients in the melatonin group required midazolam, compared with 100% of patients in the placebo group. In adults undergoing lower extremity orthopedic surgery with spinal anesthesia, a small study shows that giving melatonin 10 mg orally the night before surgery, followed by 10 mg 2 hours prior to surgery, increases the sedation score when compared with placebo (108951).
• Sunburn. Most research shows that topical melatonin seems to protect against erythema from ultraviolet (UV) light exposure. Details: When applied prior to UV light exposure, a gel containing melatonin 0.05% to 2.5% seems to significantly decrease erythema (1066,1768,1769). In one study, topically applied melatonin in combination with vitamin E 2% and/or vitamin C 5%, was modestly photoprotective when used prior to UV exposure, but had no effect when used during or after UV exposure (4713,4714). Other preliminary clinical research shows that applying a cream containing melatonin 12.5% prior to sun exposure reduces erythema in adults with high sun reactivity, but not in those with mild to moderate sun reactivity. Creams containing melatonin 0.5% or 2.5% did not reduce erythema in any skin types when compared with placebo (97443). The differences in these findings may be related to the different topical formulations used.
• Temporomandibular disorders (TMD). Oral melatonin seems to moderately reduce pain in females with TMD. Details: Clinical research shows that taking melatonin 5 mg at bedtime for 4 weeks reduces pain by 44% and increases the ability to withstand pain by 39% when compared with placebo in females with TMD. This results in reduced analgesic use and improved sleep quality (89508).
• Thrombocytopenia. Oral melatonin seems to improve and prevent thrombocytopenia associated with cancer, cancer treatment, and other disorders. Details: Clinical research shows that taking melatonin can improve thrombocytopenia associated with cancer, cancer treatment, and other disorders. Melatonin 20-40 mg daily beginning up to 7 days before chemotherapy and continuing for up to four chemotherapy cycles or until disease progression has been used (1694,1695,1696,1697,2564,8268).

POSSIBLY INEFFECTIVE

• Athletic performance. Most research suggests that oral melatonin does not improve athletic performance or physical strength. Details: Taking melatonin 6 mg one hour prior to heavy resistance exercise does not seem to improve maximal strength or maximal jumping ability (62424). Also, taking melatonin 5 mg at night does not appear to improve exercise performance the following morning in healthy athletes (62179). Furthermore, taking melatonin 5 mg 15 minutes prior to exercise does not appear to impact endurance during a cycling trial when compared with placebo (99338). However, some research disagrees. One small clinical trial in professional soccer players shows that taking melatonin 5 mg daily during a six-day training schedule modestly attenuates deterioration in physical performance, such as jumping, agility, and sprints, when compared with placebo (109700).
• Cachexia. Oral melatonin does not seem to improve appetite or body composition in patients with cachexia and cancer. Details: Clinical research in cachectic patients with advanced lung or gastrointestinal cancers shows that taking melatonin 20 mg each evening for 28 days does not improve appetite, body weight, or body composition when compared with placebo (88287).
• Cancer-related fatigue. Oral melatonin does not seem to improve fatigue in patients with cancer. Details: A meta-analysis of five clinical trials shows that taking melatonin does not reduce fatigue in patients with cancer (109697). Most studies used melatonin 20 mg daily, with a duration of 7 days to one year (99344,109697). Although most studies included in the analysis were small, one contained over 700 patients and lasted one year. However, some research disagrees. Preliminary clinical research in adults with breast cancer shows that taking melatonin 18 mg orally daily for 2 years moderately improves fatigue scores when compared with placebo (112054).
• Cancer-related pain. Oral melatonin does not seem to improve pain in patients with cancer. Details: A meta-analysis of five clinical trials shows that taking melatonin does not reduce pain in patients with cancer (109697). Most studies used melatonin 20 mg daily, with a duration of 10 days to one year (109697). Although most studies included in the analysis were small, one contained over 700 patients and lasted one year.
• Critical illness (trauma). Oral melatonin does not seem to be beneficial for reducing hospital stay in critically ill patients. Details: A meta-analysis of clinical research in critically ill patients shows that taking melatonin does not reduce the length of stay in the ICU or the hospital, or affect mortality or sleep quality, when compared with placebo (109696). One additional small clinical study shows that receiving melatonin 3 mg through a nasogastric tube once at 9 pm, followed by a 0.5 mg hourly maintenance dose for 6 hours during the overnight period, does not improve sleep when compared with placebo in patients in the ICU that are being weaned off sedatives and mechanical ventilation (104997).
• Dementia. Oral melatonin does not seem to improve behavior or cognition in patients with dementia. However, it might reduce evening confusion (sundowning). Details: Most clinical research shows that taking melatonin does not improve cognition or behavioral or affective symptoms in patients with probable Alzheimer disease or other forms of dementia (62421,62530,96319). However, some research shows that taking melatonin 2.5-3 mg before bedtime for up to 10 weeks reduces sundowning, which is the confusion and restlessness experienced by some dementia patients in the evening (62788).
• Infertility. Oral melatonin does not seem to increase fertility in females undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). Details: Some clinical research shows that taking melatonin does not improve fertility rate or clinical pregnancy rate in adults undergoing IVF, although oocyte and embryo quality might be improved (62775,62818,62819,88297,89512). Also, results from meta-analyses of clinical research show that melatonin does not improve clinical pregnancy rate, total number of oocytes retrieved, or the rate of miscarriage, although it seems to increase the number of mature oocytes (89505,106304). Most studies have used single doses of 3 mg daily which may not be adequate (106304). Melatonin has also been evaluated in adults undergoing ICSI. Although one study shows that taking melatonin improves the fertilization rate, the clinical pregnancy rate was not evaluated (88297). Other research in females taking melatonin and undergoing ICSI does not show an increase in clinical pregnancy rate (97445).
• Shift work disorder. Oral melatonin does not seem to improve sleep in individuals doing shift work. Details: Taking melatonin orally doesn't seem to significantly improve the time it takes to fall asleep (sleep latency), sleep efficiency, or adjustment to rotating shift work. However, slight increases in total sleep time during the day or overall sleep quality may occur (1052,1054,1721,14283,62200,62401,62462,62942).

LIKELY INEFFECTIVE

• Benzodiazepine withdrawal. Oral melatonin does not facilitate benzodiazepine discontinuation in patients with insomnia. Details: Although some small studies show benefit (349,1751), results from larger clinical studies and a meta-analysis of clinical research show that taking melatonin 2-5 mg before bedtime for up to 6 weeks does not help facilitate benzodiazepine discontinuation in patients with insomnia (62464,62467,63075,88295,96321,96323).
• Depression. Most research shows that oral melatonin does not reduce symptoms of depression or prevent depression. In some patients, taking melatonin might make symptoms worse. Details: Most research shows that taking melatonin 5-10 mg daily before bedtime for 4-12 weeks, alone or with fluoxetine, does not improve depression symptoms in patients with rapid cycling bipolar disorder (1766) or major depressive disorder (MDD) (1053,62746,96326). However, some research shows that taking slow-release melatonin 3 mg in combination with immediate-release buspirone 15 mg daily for 6 weeks is more effective at improving depression severity and depression symptoms than placebo or buspirone alone in patients with MDD (88289). However, buspirone is not commonly used for the management of depression. Also, there is some concern that oral melatonin may worsen symptoms in some patients with unipolar or bipolar depression (1764). Evidence regarding the effects of melatonin for preventing depression is unclear. One clinical study shows that taking melatonin 6 mg daily for 12 weeks reduces the percentage of breast cancer patients who develop depression following a lumpectomy or mastectomy by about 75% when compared with placebo when an intention to treat analysis is used. However, when only patients who took all of the doses are considered, melatonin does not appear to have an effect (89511). Also, a meta-analysis of clinical research including two studies in patients with irritable bowel syndrome (IBS) who were at risk for depression shows that melatonin does not prevent depression when compared with placebo (96326).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acute kidney injury (AKI). It is unclear if oral melatonin is beneficial for acute kidney injury. Details: A meta-analysis of randomized clinical trials in adults with drug-induced acute kidney injury shows that taking melatonin 3-30 mg orally daily for up to 6 days modestly improves glomerular filtration rate, but not serum creatinine or incidence of acute kidney injury, when compared with placebo (111463).
• Age-related macular degeneration (AMD). It is unclear if oral melatonin prevents vision loss in patients with AMD. Details: Preliminary clinical research shows that taking melatonin 3 mg daily for 3-6 months may delay the loss of clear vision in individuals with AMD when compared with baseline (62419). The validity of this finding is limited by the lack of a comparator group.
• Atopic dermatitis (eczema). Oral melatonin might improve some symptoms of atopic dermatitis. However, it is unclear if it improves sleep in this population. Details: Preliminary clinical research in children ages 1-18 years with atopic dermatitis and sleep disturbance shows that taking melatonin 3 mg daily for 4 weeks modestly reduces the overall atopic dermatitis symptom score by 19% when compared with placebo (97439). In another clinical study in children with atopic dermatitis, taking melatonin 6 mg daily 1 hour before bedtime for 6 weeks seems to improve disease severity and sleep quality when compared with placebo (99347). It is unclear whether melatonin improves sleep latency in this population, as conflicting results exist (97439,99347).
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral melatonin is beneficial for ADHD. Details: Some small clinical studies in children with ADHD who are taking stimulants show that melatonin 3-5 mg daily for up to 3 months might reduce insomnia when compared with placebo (9980,15034). However, improved sleep related to melatonin treatment does not seem to result in fewer symptoms of ADHD (15034).
• Autism spectrum disorder. It is unclear if oral melatonin is beneficial for this condition. Details: One clinical trial in children aged 6-15 years with autism spectrum disorder shows that taking melatonin (Nobelpharma Co., Ltd) 1 mg or 4 mg before bedtime does not affect behavior when compared with placebo. However, this study was designed to evaluate sleep outcomes, not behavior, as a primary endpoint (106293). Also, a secondary analysis of results from a clinical trial in children with autism spectrum disorder shows that taking prolonged-release melatonin mini-tablets (PedPRM) 2-5 mg nightly for 13 weeks improves externalizing behavior in 26% more patients when compared with those taking placebo. There was no difference between groups in behaviors such as hyperactivity, inattention, emotional behavior, and relationships with peers (101256). The validity of these findings is limited by the secondary nature of the analysis, which was not designed to evaluate these outcomes.
• Benign prostatic hyperplasia (BPH). It is unclear if oral melatonin is beneficial for BPH. Details: One very small clinical study shows that taking controlled-release melatonin 2 mg nightly for 4 weeks reduces excessive urination at night in some men with BPH when compared with placebo. However, it is unclear if this improvement is clinically significant (62360).
• Bipolar disorder. It is unclear if oral melatonin is beneficial for this condition. Details: Preliminary clinical research shows that taking melatonin 3 mg at bedtime for 30 days increases sleep duration and reduces mania severity when compared to baseline in patients with bipolar disorder and treatment-resistant insomnia (62140). However, other research shows that melatonin is not beneficial in patients with bipolar disorder when compared with placebo. Taking melatonin 3-10 mg daily before bedtime for 3-12 weeks does not seem to improve mania or other symptoms when compared with placebo (1766,103694). Also, taking a specific brand of slow-release melatonin (Cronocaps, Productos Medix) 5 mg each evening for 8 weeks may attenuate the increase in blood pressure and fat mass that is associated with use of second-generation antipsychotics, but it does not appear to improve mania or depression in patients with bipolar disorder (88300). There is also some concern that oral melatonin may worsen symptoms in some patients with bipolar depression (1764).
• Bronchopulmonary dysplasia. It is unclear if oral melatonin reduces the risk of bronchopulmonary dysplasia (BPD) in premature infants. Details: A small clinical study in premature infants with respiratory distress syndrome who received surfactant shows that giving melatonin 3 mg daily for 7 days reduces the incidence of BPD to 45%, compared with 60% in those not receiving melatonin. Melatonin also reduced the duration of hospital stay, need for mechanical ventilation, and mortality (108948).
• Chronic fatigue syndrome (CFS). It is unclear if oral melatonin is beneficial for patients with CFS. Details: Many patients with CFS have circadian rhythm disturbances. Some very small clinical studies have evaluated the use of melatonin for addressing these disturbances. One study shows that taking melatonin 5 mg in the evening for 12 weeks might improve some measures of fatigue, concentration, motivation, and activity when compared with baseline (14437). However, other preliminary clinical research shows that taking the same dose of melatonin does not improve CFS symptoms when compared with placebo (9705). Melatonin has also been studied in combination with zinc. In patients with CFS, taking melatonin 1 mg plus zinc 10 mg before bedtime for 16 weeks modestly reduces self-reported levels of physical fatigue, but not self-reported cognitive or psychological symptoms, mood, sleep quality, or quality of life (QOL) measures, when compared with placebo. However, some measures of sleep quality and QOL worsened within 4 weeks of melatonin discontinuation, suggesting that there may have been a modest benefit (106241). It is unclear whether any benefit is related to melatonin, zinc, or the combination. Also, all patients in this study were White females, limiting the generalizability of the results.
• Chronic obstructive pulmonary disease (COPD). It is unclear if oral melatonin is beneficial for COPD. Details: Some clinical research shows that taking melatonin 3 mg daily for 3 months improves shortness of breath in patients with COPD when compared with placebo, although melatonin does not seem to improve lung function or exercise capacity (62854).
• Cluster headache. It is unclear if oral melatonin prevents cluster headaches. Details: A very small clinical study in adults with cluster headaches shows that taking melatonin orally 10 mg every evening for 14 days might reduce the frequency of episodic cluster headaches when compared with placebo (1127). However, 2 mg at bedtime does not seem to be effective (9702).
• Cognitive impairment. Oral melatonin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in adults 70 years and older with mild cognitive impairment shows that taking two capsules containing melatonin 5 mg, docosahexaenoic acid (DHA) 720 mg, eicosapentaenoic acid (EPA) 286 mg, vitamin E 16 mg, soy phospholipids 160 mg, and L-tryptophan 95 mg (IBSA Farmaceutici) before bedtime for 12 weeks modestly improves cognitive function and sensitivity to smells when compared with placebo. The observed improvement on the mini-mental state examination (MMSE) scale falls below the score generally considered to be indicative of true changes in cognitive function, and may not be clinically significant. Also, it is not known if any potential benefit is due to melatonin, other ingredients, or the combination (62847).
• Colorectal cancer. It is unclear if oral melatonin is beneficial for colorectal cancer prevention. Details: Population research suggests that any history of melatonin use is associated with an approximate 20% reduction in the incidence of colorectal cancer, especially rectal cancer, in individuals aged 60 years and older (106291).
• Contraception. Although there has been interest in using oral melatonin for contraception, there is insufficient reliable information about the clinical effects of melatonin for this use.
• Coronary artery bypass graft (CABG) surgery. It is unclear if oral melatonin is beneficial for recovery from CABG surgery. Details: Clinical research shows that taking melatonin perioperatively during CABG surgery reduces the length of stay in the ICU by about 0.5 days and modestly reduces levels of creatine kinase-MB when compared with placebo. However, there was no effect on the length of hospital stay or levels of cardiac troponin-I, C-reactive protein, or erythrocyte sedimentation rate. Oral melatonin 3 mg was provided the night before and morning of surgery, as well as at bedtime for 3 days after surgery (109699).
• Coronavirus disease 2019 (COVID-19). Preliminary clinical studies suggest that oral melatonin may reduce disease severity in patients with COVID-19, although some conflicting findings exist. Details: A meta-analysis of mainly small and preliminary randomized clinical trials in patients with COVID-19 shows that taking melatonin improves clinical outcomes when compared with placebo. However, the clinical outcomes differed between individual trials, and included specific symptoms, hospital discharge, removal from quarantine, and survival. Dosing also varied, with doses of 2-24 mg daily in 1-4 divided doses for 6-14 days. There was no effect of melatonin on C-reactive protein levels or oxygen saturation (109695). Individual clinical trials have been conducted in hospitalized and/or non-hospitalized patients with mild to severe COVID-19. One clinical trial in outpatients with mild to moderate COVID-19 shows that taking melatonin 10 mg daily modestly reduces time to symptom resolution and quality of life improvement when compared with placebo (109462). However, it is unclear if any beneficial effects are clinically meaningful. In patients hospitalized and receiving standard care for mild to moderate COVID-19, a small clinical trial shows that taking melatonin 3 mg three times daily for 14 days reduces the mean time to hospital discharge by approximately 3.5 days when compared with placebo. Also, persistent symptoms of cough, dyspnea, and fatigue after 14 days occurred in only 0% to 8% of patients taking melatonin, compared with 15% to 30% of those taking placebo. However, there was no difference in the number of patients with other symptoms, including fever, myalgia, chill, and headache (106300). The validity of this study is limited by its high attrition rate. Another small clinical trial in patients hospitalized with COVID-19 shows that taking melatonin (Norm Life Vanatonin Melatonin) 3 mg nightly for 7 days does not reduce symptoms or prevent ICU admission or death when compared with standard care alone (106295). The low dose and short duration of use in this study might have played a role in the lack of benefit. Melatonin has also been evaluated in patients hospitalized for severe COVID-19. One large single-center preliminary clinical trial shows that taking melatonin 10 mg daily reduces the incidence of thrombosis at day 17 and the incidence of sepsis at day 11 when compared with standard care alone. Death occurred in approximately 17% of patients taking placebo, compared with 1% of those taking melatonin (106289). Another preliminary clinical trial in patients in the ICU for severe COVID-19 shows that taking melatonin (Danna Pharmaceutical Company, Iran) 5 mg twice daily for 7 days results in mortality and invasive mechanical ventilation rates of 67% and 51.4%, respectively, compared with 94% and 70.9% in patients given standard care only. There were also modest improvements in the time to improvement of clinical status and lengths of stay in the hospital and ICU (110297). The validity of these studies is limited by a lack of blinding.
• Delirium. It is unclear if oral melatonin is beneficial for preventing delirium in hospitalized patients; the available research is conflicting. Details: Research is conflicting on whether melatonin reduces the incidence of delirium. One meta-analysis of 10 clinical trials shows that melatonin reduces the incidence of delirium in critically ill patients in the intensive care unit (ICU) by 21% when compared with a control, usually placebo (109696). However, other meta-analyses of 14 small clinical and observational studies of hospitalized patients show that taking melatonin does not reduce the incidence of delirium when compared with control (105003,112440). Melatonin might be less beneficial in non-acute medical patients when compared with postoperative patients or those in the ICU (105003). There is also a lack of consensus within the available research on whether melatonin reduces the duration of delirium in hospitalized patients. One meta-analysis of 10 clinical trials shows that melatonin does not reduce the duration of delirium (109696). However, a meta-analysis of 2 small, randomized controlled trials shows that taking melatonin 3-5 mg daily for 5 or more days reduces the duration of delirium by approximately 2 days when compared with placebo (112051). This analysis is limited by substantial heterogeneity and a lack of dose-response evaluation. Most studies in these analyses have used doses of 0.5-10 mg daily for up to 14 days, although one study used a very high single dose of 50 mg/kg (105003,105891,107809,108949,109696,112051). Some research suggests that melatonin may be beneficial for patients undergoing cardiac procedures. A subgroup analysis of one meta-analysis including 3 small studies suggests that melatonin reduces the incidence of delirium in patients in cardiovascular care units, but not in the general ICU population (112440). Two large clinical studies in the meta-analysis suggest that, in older patients admitted to the ICU after acute heart failure or percutaneous coronary intervention (PCI), taking melatonin 3 mg once daily for up to 7 days is associated with a 27% incidence of delirium, compared with a 37% to 40% incidence with placebo (107809,108949). Additionally, a small clinical study in patients undergoing coronary artery bypass graft (CABG) surgery suggests that taking prolonged-release melatonin (Webber Naturals) 3 mg twice before surgery and twice after surgery reduces the occurrence of delirium over the next 48 hours when compared with placebo (105891). The validity of this study is limited by a high risk of bias due to insufficient blinding and incomplete outcome data. Additionally, a small clinical study shows that receiving melatonin 3 mg through a nasogastric tube once at 9 pm, followed by a 0.5 mg hourly maintenance dose for 6 hours during the overnight period, does not reduce delirium or improve sleep when compared with placebo in patients in the ICU that are being weaned off sedatives and mechanical ventilation (104997).
• Diabetes. Most research shows that oral melatonin is beneficial for improving glycemic control. However, it is unclear if oral melatonin is beneficial in patients with type 2 diabetes. Details: Most research on the use of melatonin for glycemic control has been conducted in mixed populations, such as those with schizophrenia, metabolic syndrome, nonalcoholic steatohepatitis (NASH), or perimenopause (103490,106294,106298). Two recent meta-analyses of clinical research in these populations show that taking melatonin modestly reduces fasting glucose and insulin, insulin resistance, and glycated hemoglobin (HbA1c), and improves insulin sensitivity (106294,106298). The most common doses of melatonin used were 3 -10 mg for 8-24 weeks; however, 10 mg may be more effective (106294,106298). This contrasts with an earlier meta-analysis showing only modest beneficial effects of melatonin on fasting glucose levels and insulin sensitivity (103490). Research on the use of melatonin in patients with type 2 diabetes is limited. One small clinical trial in patients with type 2 diabetes show that taking melatonin (NatureMade) 6 mg daily for 8 weeks does not improve glycemic control (104368). However, this trial may have been underpowered to detect a difference. Another very small study in adults with type 2 diabetes shows that taking melatonin 3 mg daily before bed for 7 days increases absolute glucose level at breakfast on day 7 and the glycemic difference between post-dinner on day 6 and pre-breakfast on day 7 but does not change most measures of glycemic variability including mean glucose levels, pre-prandial glucose levels, and post-prandial glucose levels compared with placebo (112441).
• Diabetic neuropathy. It is unclear if oral melatonin is beneficial for improving pain in patients with diabetic neuropathy. Details: A clinical study in patients with painful diabetic neuropathy living in Iran shows that taking melatonin 3 mg nightly for 1 week and then 6 mg nightly for 7 weeks, in conjunction with pregabalin 150 mg daily seems to reduce pain and sleep interference to a greater degree than placebo and pregabalin (105895).
• Dry mouth. It is unclear if oral melatonin is beneficial for dry mouth caused by radiation treatment. Details: A small clinical study in patients with head and neck cancer undergoing chemoradiation shows that taking melatonin 20 mg orally at bedtime and using 10 mL of melatonin 0.2% oral gargle 15 minutes before each radiation session does not delay the onset or reduce the incidence of grade 2 dry mouth when compared with placebo. However, the incidence of grade 3 dry mouth is delayed by approximately 16 days (96314).
• Dysmenorrhea. It is unclear if oral melatonin is beneficial for dysmenorrhea. Details: A small clinical trial shows that taking melatonin 10 mg nightly before bed during the week of menstruation has a statistically significant effect on pain severity when compared with placebo. However, the pain reduction was not considered clinically significant (106301).
• Dyspepsia. It is unclear if oral melatonin is beneficial for dyspepsia in adults. Details: Preliminary clinical research shows that taking melatonin 5 mg nightly for 12 weeks improves dyspeptic symptoms in individuals with functional dyspepsia. However, the benefit seems to be decreased in patients with prior Helicobacter pylori infection (62456).
• Endotracheal intubation-associated adverse effects. It is unclear if oral melatonin is beneficial for endotracheal intubation-related hemodynamic effects. Details: Clinical research shows that taking immediate-release melatonin (Healthy Hey Nutrition) 6 mg, 2 hours prior to the induction of anesthesia, is as effective as clonidine 0.2 mg for attenuating the hemodynamic response to laryngoscopy and tracheal intubation (103483). It is not known if melatonin prevents other adverse effects associated with endotracheal intubation.
• Endometriosis. It is unclear if oral melatonin reduces endometriosis-related pain. Details: Preliminary clinical research shows that taking melatonin 10 mg daily for 8 weeks reduces pain by about 39% and analgesic use by about 46%, as well as pain during menstruation, intercourse, and evacuation, when compared with placebo in adults with endometriosis (89503). Other clinical research in adults with endometriosis shows that taking melatonin 20 mg orally daily does not improve pain scores or reduce pain during intercourse, urination, or defecation when compared with placebo (111464). However, the study may have been inadequately powered to detect a difference between groups.
• Epilepsy. It is unclear if oral melatonin is beneficial for epilepsy in children or adults. Details: There is some low-quality evidence that taking melatonin 3 mg at bedtime for 3 months might reduce the frequency and duration of both nocturnal and daytime seizures in children aged 2-15 years with epilepsy (9699,9745,9746,62785). Also, taking melatonin 1.5 mg before bed for 3 months might reduce the seizure severity in children with epilepsy that is not successfully controlled with other treatment (62754). Furthermore, taking fast-release melatonin 10 mg daily for 3 weeks seems to reduce diurnal seizure frequency in both adults and children aged 9 years and up with intractable epilepsy (88291). Limited research has also assessed melatonin as an adjunct therapy in adults with seizure disorders. A small clinical study in adults with epilepsy involving generalized onset motor seizures that recurred within the last three days shows that adding melatonin 3 mg before bed to therapy with valproate 20 mg/kg in two divided doses daily for 8 weeks results in 82% of patients having at least a 50% reduction in seizure frequency, compared with only 53% of patients in the group taking valproate and placebo. Adding melatonin may also improve seizure severity (105006). However, other clinical research in adults under valproic acid treatment for idiopathic generalized tonic-clonic seizures alone shows that taking melatonin 3 mg before bed for 8 weeks modestly reduces seizure severity, but not frequency (110299).
• Fibromyalgia. It is unclear if oral melatonin is beneficial for this condition. Details: Preliminary clinical research shows that taking melatonin 3-5 mg daily for up to 60 days may decrease the severity of pain and stiffness, as well as the number of painful joints, in people with fibromyalgia when compared with placebo (9701,62797).
• Gastroesophageal reflux disease (GERD). It is unclear if oral melatonin is beneficial for GERD. Details: Clinical research shows that taking melatonin 3 mg daily at bedtime for 8 weeks may improve symptoms of GERD, including heartburn and epigastric pain. However, taking omeprazole 20 mg twice daily seems to be more effective (62723).
• Helicobacter pylori. It is unclear if oral melatonin is beneficial for Helicobacter pylori eradication. Details: One very small clinical study shows that taking melatonin 5 mg twice daily in combination with omeprazole 20 mg twice daily for 21 days improves ulcer healing rates when compared with omeprazole alone in individuals with H. pylori-associated gastroduodenal ulcers (62803).
• Heart failure. It is unclear if oral melatonin is beneficial for heart failure. Details: A small clinical study in adults with stable NYHA class II or III heart failure with reduced ejection fraction (HFrEF) and a left ventricular ejection fraction (LVEF) below 40%, shows that taking melatonin 10 mg orally every evening for 24 weeks improves a composite score reflecting all-cause mortality, hospitalization for exacerbation, and quality of life when compared with placebo. Melatonin also attenuates an increase in serum B-type natriuretic peptide levels, but does not affect LVEF or left ventricular end-diastolic or end-systolic diameter (108950).
• Irritable bowel syndrome (IBS). It is unclear if oral melatonin is beneficial for IBS. Details: In patients with IBS who also have poor sleep, taking melatonin 3 mg at bedtime for 2 weeks seems to decrease symptoms of IBS-related abdominal pain and increase the rectal pain threshold when compared with placebo. However, taking melatonin does not seem to influence stool frequency or consistency, bloating, mood, sleep, or overall quality of life (13112). In other small clinical studies, taking melatonin 3 mg at bedtime for 8 weeks decreased severity and frequency of pain, reduced bloating, improved bowel habits, decreased extracolonic symptoms such as headache, heartburn and nausea, and improved overall quality of life when compared with placebo (15216,62410). However, other clinical research shows that melatonin does not significantly affect the amount of time needed for food to travel through the colon in patients with IBS (62500). Also, one small clinical study shows that taking melatonin 3 mg in the morning and 5 mg in the evening for 6 months improves abdominal pain, bloating, and bowel habits in 50% to 70% of postmenopausal patients with constipation-predominant IBS when compared with placebo. However, beneficial effects were reduced in patients with diarrhea-predominant IBS (89510). Other clinical research in patients with IBS shows that taking melatonin 6 mg orally daily for 8 weeks improves IBS symptom severity scores, abdominal pain scores, and bloating scores, when compared with placebo. These results were not different between those with or without sleep disorders at baseline (112055). The large number of endpoints, many with inconsistent results, in these studies makes it difficult to draw conclusions.
• Ischemia-reperfusion injury. It is unclear if intravenous or intracoronary melatonin is beneficial for ischemia-reperfusion injury. Details: A meta-analysis of 9 low-quality clinical trials in patients with myocardial ischemia-reperfusion injury shows that giving melatonin in doses of 2-50 mg by intravenous or intracoronary injection within 2.5-3.5 hours of ischemia onset improves left ventricular ejection fraction and reduces the infarct size, but does not improve left ventricular end-diastolic or end-systolic volumes, when compared with control. Also, giving melatonin orally for up to 12 weeks does not improve cardiac function. The patients in this study experienced injury as a result of an ST-elevation myocardial infarction, ischemic heart disease, acute coronary syndrome, or coronary heart disease (108946).
• Kidney failure. It is unclear if oral melatonin is beneficial for improving mood and quality of life in patients on hemodialysis. Details: A small clinical trial in patients undergoing hemodialysis shows that taking immediate-release melatonin 3 mg (Puritans Pride, USA) for 3 months modestly improves depression, anxiety, and quality of life when compared with placebo. After treatment, 73.1% and 57.7% of those taking placebo had severe depression and anxiety, respectively, when compared with 22.2% and 14.8% of those taking melatonin (110291).
• Kidney transplant. It is unclear if oral melatonin is beneficial for improving post-transplant kidney function. Details: A small clinical study in patients that have received kidney transplants shows that taking melatonin 3 mg daily for an average of 25 days does not affect urine volume or kidney function, as measured by the blood urea nitrogen over creatinine (BUN/Cr) ratio, when compared with placebo (103693).
• Lung cancer. It is unclear if melatonin is beneficial in patients with early stage non-small cell lung cancer (NSCLC). Details: A clinical study in patients who have undergone complete surgical resection of early stage NSCLC shows that taking melatonin 20 mg daily for 1 year does not improve 2-5 year disease-free survival, pain, anxiety, fatigue, or quality of life when compared with placebo (105894). The validity of these findings is limited by a high study withdrawal rate.
• Melasma. Although there has been interest in using oral melatonin for melasma and other causes of hyperpigmentation, there is insufficient reliable information about the clinical effects of melatonin for these conditions.
• Menopausal symptoms. It is unclear if oral melatonin is beneficial for improving symptoms of menopause; evidence is conflicting. Details: A meta-analysis of 3-5 clinical studies in patients with menopausal symptoms shows that taking melatonin does not seem to improve vasomotor or psychological symptoms, but may modestly improve physical symptoms, when compared with placebo (105897). This analysis is limited due to inconsistent evidence and some risk of bias within the included studies. Studies included in the meta-analysis used melatonin 3 mg daily for 3-12 months alone or in combination with soy isoflavones 80 mg or fluoxetine 20 mg (11806,62840,105897). In contrast, a small study in adults with menopausal symptoms shows that taking melatonin 3 mg daily for 12 weeks improves climacteric symptoms, anxiety, depressive symptoms, sleep quality, and menopausal quality of life and decreases luteinizing hormone and follicle stimulating hormone levels but does not change uterine volume, endometrial thickness, or estradiol levels when compared with placebo (112443).
• Metabolic syndrome. It is unclear if oral melatonin is beneficial for this condition. Details: Preliminary clinical research in adults with metabolic syndrome shows that taking melatonin 5 mg nightly for 2 months reduces systolic and diastolic blood pressure, as well as low-density lipoprotein (LDL) cholesterol levels, when compared to baseline (62795). The validity of these findings is limited by the lack of a comparator group.
• Multiple sclerosis (MS). It is unclear if oral melatonin is beneficial for MS. Details: A small clinical study in patients with relapsing-remitting MS (RRMS) receiving interferon-beta once weekly shows that taking melatonin 3 mg daily for 12 months does not affect relapse rate, disability, brain lesions, fatigue, or depression when compared with placebo (99345). This small study may not have been adequately powered to detect a difference between groups.
• Myocardial infarction (MI). The benefits of administering oral or intravenous melatonin immediately after an MI are unclear. Details: A meta-analysis of 5 small clinical studies in patients after MI shows that oral or intravenous melatonin, used in conjunction with medical reperfusion, is associated with modestly lower troponin levels and modestly higher left ventricular ejection fraction when compared with control (105889). One clinical study included in this analysis that evaluated patients with ST-segment elevation myocardial infarction (STEMI) shows that intravenous administration of melatonin 51.7 mcmol over 60 minutes immediately prior to percutaneous coronary intervention, combined with a bolus intracoronary dose of melatonin 8.6 mcmol administered within 60 seconds after restoration of blood flow to the infarcted artery, does not reduce myocardial infarct size when compared with placebo. However, subgroup analyses suggest that the timing of melatonin administration after symptom onset may alter its effects (96324).
• Neonatal encephalopathy. It is unclear if oral or intravenous melatonin is beneficial for neonates with encephalopathy. Details: A meta-analysis of two small clinical studies in term or late preterm infants with neonatal encephalopathy who are receiving therapeutic hypothermia shows that receiving melatonin 5 mg/kg intravenously daily for 3 days, or 10 mg/kg orally daily for 5 days, does not reduce mortality when compared with hypothermia alone, although a nonsignificant trend towards a reduction was noted (104994). One of those small studies in term infants with neonatal encephalopathy also shows that receiving adjunct oral melatonin treatment results in fewer seizures and less white matter abnormalities when compared with hypothermia alone (99333).
• Nocturnal enuresis. It is unclear if oral melatonin is beneficial for reducing nighttime wettings. Details: Preliminary clinical research shows that taking melatonin 5 mg nightly before bedtime for 3 months does not reduce the number of wet beds when compared with placebo in children with nighttime wettings (nocturnal enuresis) (62824).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral melatonin is beneficial for NAFLD. Details: A meta-analysis of clinical research, as well as individual clinical trials, show that taking melatonin 6-18 mg daily for 4-56 weeks improves some liver indices, but not others (62853,88285,103484,103485). Overall, taking melatonin seems to modestly reduce levels of alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT). However, there is no effect on alanine aminotransferase (ALT) and levels of aspartate aminotransferase (AST) slightly increased (103485). One small clinical study shows that taking melatonin (Nature Made, USA) 6 mg daily for 12 weeks has a small benefit on systolic and diastolic blood pressure, body mass index (BMI), abdominal circumference, and liver enzymes, but not plasma lipid levels, when compared with placebo (103484). Larger studies are needed to determine the effect of melatonin in this population.
• Obesity. It is unclear if melatonin is beneficial for improving weight loss. Details: A meta-analysis of clinical research shows that taking melatonin up to 10 mg daily, usually for 4-24 weeks, modestly reduces body weight when compared with placebo. However, there was no effect on body mass index (BMI) or waist circumference. Also, the studies included in the analysis were not limited to overweight or obese individuals. Populations included those with metabolic syndrome, nonalcoholic steatohepatitis (NASH), schizophrenia, polycystic ovary syndrome (PCOS), and others, as well as postmenopausal adults (106288). A small clinical trial in overweight or obese individuals shows that although taking melatonin 3 mg daily for 12 weeks modestly reduces waist circumference and body fat mass when compared with placebo, there is no effect on body weight or BMI (106290).
• Oral mucositis. Most research shows that melatonin does not prevent or reduce the severity of oral mucositis in patients with head and neck cancer receiving radiation and chemotherapy. It is unclear if oral or topical melatonin is beneficial in patients with other types of cancer. Details: A meta-analysis of seven clinical trials including patients undergoing chemotherapy or radiotherapy shows that melatonin does not reduce the rate of oral mucositis when compared with a control, usually placebo (109697). Although a small clinical study in patients with head and neck cancer undergoing radiation and chemotherapy with cisplatin shows that melatonin delays the onset of severe mucositis by 16 days when compared with placebo (96314), a meta-analysis shows that melatonin does not reduce the rate of oral mucositis in patients with head and neck cancer (109697). A sub-analysis in one meta-analysis suggests that taking melatonin, usually 20 mg daily, reduces the rate of oral mucositis by 53% in patients with cancer types other than head and neck (109697). Most studies investigating the effect of melatonin have used oral melatonin 20 mg at bedtime. However, in one study, 10 mL of melatonin 0.2% oral gargle was also used 15 minutes before radiation (96314). In another, swishing with 10 mL of a melatonin 3% gel mouthwash for 2 minutes and then swallowing, starting 2-3 days before radiotherapy and continuing until 1-4 weeks after the end of radiotherapy, was used (105893). Melatonin has also been investigated for oral mucositis severity. Although some individual research disagrees (96314), a meta-analysis of three clinical trials shows that melatonin does not reduce the severity of oral mucositis when compared with placebo. However, the form of melatonin provided in these studies was heterogeneous, including oral, gargle, and gel formulations (96314,105893,109697).
• Osteopenia. It is unclear if oral melatonin is beneficial for improving bone mineral density. Details: A small clinical study in postmenopausal adults with osteopenia shows that taking melatonin 3 mg nightly for 1 year increases tibia thickness by 2.2% and volumetric bone mineral density (BMD) in the spine by 3.6% when compared with placebo. However, the BMD of other skeletal sites was not impacted. Additionally, a 1 mg melatonin dose was not beneficial (99334).
• Osteoporosis. Although there has been interest in using oral melatonin for osteoporosis, there is insufficient reliable information about the clinical effects of melatonin for this condition.
• Pain (acute). It is unclear if oral melatonin is beneficial for acute pain. Details: Clinical research in patients undergoing laparoscopic cholecystectomy shows that taking melatonin 6 mg two hours before induction with propofol reduces the number of patients requiring intraoperative fentanyl to 10%, compared with 35% of those taking placebo (106299). Also, preliminary clinical research in preterm infants also given standard treatments shows that oral melatonin (Syrup Trunap, Brio Bliss Life Science Pvt. Ltd) 20 minutes prior to retinopathy of prematurity screening, is not inferior to 24% sucrose for reducing pain (110295). However, the effect of sucrose itself is inconclusive and this study is limited by a lack of blinding. Also, it is unclear if melatonin is beneficial for other causes of acute pain.
• Pain (chronic). It is unclear if melatonin is beneficial for most causes of chronic pain. Details: A meta-analysis of 5 clinical studies shows that taking melatonin 3-12 mg daily for up to 12 weeks modestly reduces chronic pain when compared with placebo (103692). However, it is difficult to draw clinical conclusions from this analysis, as it pools the effects observed in various types of chronic pain, including migraine, burning mouth syndrome, endometriosis, and irritable bowel syndrome (IBS).
• Periodontitis. Small clinical studies suggest that oral melatonin may improve some measures of periodontitis severity. Details: A meta-analysis of 7 small clinical trials in patients with periodontitis treated with subgingival instrumentation to remove calculus and bacterial biofilms shows that adding oral melatonin in doses of 3-10 mg daily improves probing depth, clinical attachment loss, and gingival index when compared with instrumentation alone (108953).
• Polycystic ovary syndrome (PCOS). It is unclear if melatonin is beneficial for PCOS. Details: A prospective cohort study in patients with PCOS has found that taking melatonin (Armonia Fast, Nathura) 2 mg before bedtime for 6 months increases follicle-stimulating hormone and the total number of menstrual cycles from approximately 2.5 to 4 when compared to baseline (96313). The validity of this study is limited by its observational nature and the lack of a comparator group. Additionally, a small clinical study in patients with PCOS shows that taking melatonin 6 mg daily for 8 weeks does not affect insulin levels, fasting blood glucose, lipid levels, or weight, but might modestly reduce testosterone levels, when compared with placebo (105887). This study may have not been adequately powered to detect differences between groups.
• Postoperative nausea and vomiting (PONV). It is unclear if melatonin is beneficial for reducing PONV. Details: A small clinical trial shows that taking melatonin (Nature Made, USA) 3 mg, 5 mg, or 10 mg, one hour prior to lumbar discectomy surgery does not reduce postoperative nausea when compared with placebo (110294).
• Postoperative pain. It is unclear if melatonin is beneficial for reducing pain postoperatively. Details: Three meta-analyses, as well as most individual clinical studies, show that taking melatonin in addition to standard therapy modestly alleviates pain and reduces analgesic use after surgery when compared with placebo (62471,62512,62551,62743,88293,88294,103488,103691,103692,105892)(110294,111462). However, any benefit is likely to be small and may not be clinically relevant (103488,109701,111462). Melatonin has been used in doses of 1-10 mg daily for a duration of 1-21 days, usually starting the night before surgery (62471,62512,62743,103488,103691,105892,110294,111462). This research is limited by poor methodology, as well as the heterogeneity of the included studies. The studies evaluated melatonin across a wide variety of surgeries, including abdominal hysterectomy, cataract surgery, cesarean section, prostatectomy, lumbar laminectomy, lumbar discectomy, laparoscopic cholecystectomy, wisdom teeth extraction, and corrective jaw surgery.
• Postoperative recovery. It is unclear if oral melatonin improves the rate of recovery after surgery. Details: In females undergoing total abdominal hysterectomy, taking extended-release melatonin 5 mg, 90 minutes before surgery, shortens hospital stay to a mean of 2.7 days, compared with 3.4 days for placebo (108945).
• Postoperative sleep disturbance. It is unclear if melatonin is beneficial for improving postoperative sleep disturbance. Details: A meta-analysis of randomized trials in adults undergoing anesthesia for surgery shows that taking melatonin 5-12 mg orally or sublingually or ramelteon 8 mg orally daily for 1-6 days does not improve sleep scores or sleep time when compared with placebo or no intervention (112052). In addition, a small clinical trial shows that taking melatonin (Nature Made) 5 mg each night before bed for 4 weeks, starting 2 weeks after surgery for orthopedic trauma, does not reduce postoperative sleep disturbance when compared with placebo. All patients were also given education related to sleep hygiene (110293).
• Postural tachycardia syndrome (POTS). It is unclear if melatonin is beneficial for POTS. Details: Preliminary clinical research in patients with POTS shows that taking a single dose of melatonin 3 mg reduces sitting and standing heart rate, after 2 and 4 hours, when compared with placebo. However, melatonin does not appear to affect blood pressure or orthostatic symptoms (88292). It is unclear if melatonin is beneficial when taken as more than a single dose.
• Pre-eclampsia. It is unclear if oral melatonin reduces the severity of pre-eclampsia. Details: A small clinical trial in patients with pre-eclampsia shows that taking sustained-release melatonin 10 mg with vitamin B6 10 mg three times daily, starting during recruitment and continuing until delivery, attenuates the need to increase the dose of antihypertensive medication on certain days, but does not affect overall pre-eclampsia severity, when compared with control (99341).
• Prostate cancer. Oral melatonin has only been evaluated in combination with medication; its effect when used alone is unclear. Details: One small clinical study in patients with metastatic prostate cancer that is refractory or resistant to treatment with the luteinizing hormone-releasing hormone (LHRH) analogue triptorelin shows that taking melatonin 20 mg daily in combination with intramuscular triptorelin injected every 28 days can decrease levels of prostate-specific antigen (PSA) and growth factors for prostate cancer when compared to baseline (7255). The validity of these findings is limited by the small study size and lack of a comparator group.
• Pruritus. Small clinical trials suggest that oral melatonin might be beneficial for some types of pruritus. Details: One small clinical trial in patients with pruritus due to various types of chronic liver disease shows that taking melatonin 10 mg nightly for 2 weeks modestly reduces the severity, frequency, and extent of pruritus when compared with placebo (106297). Another small clinical study in patients undergoing hemodialysis shows that taking melatonin 10 mg daily for 2 weeks reduces the severity of pruritus and reduces the affected body area when compared with placebo (104996).
• Radiation dermatitis. It is unclear if topical melatonin is beneficial for radiation-related dermatitis. Details: In females with breast cancer, a small clinical study shows that applying a specific melatonin emulsion cream (Praevoskin, PraevoMed GmbH) twice daily during radiation treatment and continuing for another 2 weeks results in fewer cases of grade 1 or 2 acute radiation dermatitis when compared with placebo (99336). In contrast, another clinical trial in patients with breast cancer shows that applying a cream providing melatonin 25 mg and dimethylsulfoxide 150 mg twice daily during and for 3 weeks after radiation treatment does not improve quality of life or breast symptoms at the end of treatment when compared with placebo. However, there was a modest reduction in breast symptoms over time (110298). Other preliminary clinical research in adults receiving radiation for breast cancer shows that applying melatonin cream 25 mg/gram twice daily throughout radiation therapy does not improve radiation dermatitis scores or reduce the need for adjunctive treatment when compared with placebo (112056).
• Rapid eye movement sleep behavior disorder (RBD). It is unclear if oral melatonin is beneficial for RBD. Details: One very small clinical study shows that taking melatonin 3 mg before bed for 4 weeks increases the likelihood of muscle atonia during rapid eye movement (REM) sleep in patients with RBD when compared with placebo (62762). The validity of this finding is limited by the small study size.
• Restless legs syndrome (RLS). It is unclear if oral melatonin is beneficial for RLS. Details: One very small clinical study shows that taking melatonin 3 mg before bedtime does not improve symptoms of RLS and may actually worsen motor symptoms in individuals with RLS when compared with baseline (62753). The validity of this finding is limited by the small study size and lack of a comparator group.
• Rheumatoid arthritis (RA). It is unclear if oral melatonin is beneficial for RA. Details: A small clinical study in patients with RA shows that taking melatonin 6 mg daily for 12 weeks does not affect disease activity or erythrocyte sedimentation rate (ESR) when compared with placebo (105890).
• Sarcoidosis. It is unclear if oral melatonin is beneficial for this condition. Details: One very small clinical study shows that taking melatonin 20 mg daily for one year, followed by 10 mg daily for another year, improves lung function and skin lesions in patients with chronic sarcoidosis when compared with baseline (62435). The validity of this finding is limited by the small study size and lack of a comparator group.
• Schizophrenia. It is unclear if oral melatonin is beneficial for schizophrenia or for attenuating the adverse effects associated with antipsychotic medications. Details: Some clinical research shows that taking melatonin orally 3 mg each evening for 8 weeks reduces the weight gain and increased waist circumference associated with olanzapine when compared with placebo. It also seems to improve some symptoms of schizophrenia (88296). Other clinical research shows that taking a specific brand of slow-release melatonin (Cronocaps, Productos Medix) 5 mg each evening for 8 weeks reduces adverse effects from second generation antipsychotics, such as increased diastolic blood pressure and waist circumference, when compared with placebo. However, it does not seem to improve symptoms of schizophrenia (88300).
• Seasonal affective disorder (SAD). It is unclear if oral melatonin is beneficial for SAD. Details: Some preliminary clinical research shows that oral melatonin, 0.25-2 mg taken daily for 3 weeks, may decrease winter depression symptoms in patients with SAD (10670,62308). However, sublingual melatonin 0.5 mg daily for 6 days does not appear to improve this condition (62388). Reasons for these discrepancies may include the duration of treatment, route of administration, or the severity of SAD at baseline.
• Smoking cessation. It is unclear if oral melatonin is beneficial in patients trying to quit smoking. Details: One very small clinical study shows that taking melatonin 0.35 mg as a single oral dose 3.5 hours after initiation of nicotine withdrawal in smokers seems to reduce subjective symptoms of anxiety, restlessness, irritability, depression, and cigarette craving over the next 10 hours when compared with baseline (2424). The validity of these findings is limited by the small study size and lack of a comparator group.
• Sepsis. It is unclear if oral melatonin is beneficial for sepsis in neonates or adults. Details: There is conflicting research about the effect of melatonin on neonatal sepsis. While some preliminary research in Egypt shows that giving a single dose of melatonin 20 mg in addition to antibiotics reduces sepsis severity, another more recent study did not find a difference in outcomes between groups receiving antibiotics only or antibiotics with melatonin (99339,99340). In adults with early septic shock given standard care, a small clinical trial shows that taking melatonin 50 mg daily for 5 days increases the number of ventilator-free days by 6.9 and the number of vasopressor-free days by 2.6. ICU and hospital lengths of stay were reduced by 5.25 and 6.9 days, respectively. However, after 28 days there was no significant difference in the mortality rate, the number of patients requiring ventilation or renal replacement therapy, or the number of patients recovered from organ dysfunction (106296). Intravenous melatonin has also been investigated. A small clinical trial in patients with severe sepsis shows that a continuous infusion of melatonin, 60 mg over 24 hours, for 5 days following post-surgical sepsis diagnosis modestly reduces sepsis severity when compared with placebo. Hospital stay was reduced by approximately 5.2 days in patients given melatonin; however, it is unclear if this difference is statistically significant (110300).
• Stabbing headache. Although there has been interest in using oral melatonin for stabbing headaches, there is insufficient reliable information about the clinical effects of melatonin for this condition.
• Stress. It is unclear if oral melatonin is beneficial for stress reduction. Details: Preliminary clinical research shows that taking melatonin 3 mg one hour prior to stress modestly improves memory accuracy during a laboratory-induced stressful situation when compared with placebo (62509).
• Tardive dyskinesia. It is unclear if oral melatonin is beneficial for this condition. Details: One small clinical study shows that taking melatonin orally 10 mg daily for 6 weeks decreases symptoms by 24% to 30% in patients with tardive dyskinesia when compared with placebo (7082). However, other small clinical studies show that taking melatonin 2-20 mg daily for 4-12 weeks does not reduce abnormal, involuntary movement in patients with tardive dyskinesia when compared with placebo (62146,62825).
• Tension headache. It is unclear if oral melatonin is beneficial for reducing the frequency of tension headaches. Details: A small clinical study in patients with chronic tension headache shows that taking a specific melatonin supplement (Melaxen) 3 mg nightly for 30 days seems to reduce headache severity and reduce the median number of days with a headache by 6 when compared with baseline (104998). The validity of this finding is limited by the lack of a control group.
• Tinnitus. It is unclear if oral melatonin is beneficial for improving tinnitus intensity or severity. Details: Some clinical research shows that taking melatonin 3 mg nightly for one month reduces tinnitus intensity and improves the quality of sleep in individuals with chronic tinnitus when compared with placebo. The effect seems to be greatest in men, those who have not received prior treatment for tinnitus, and those with a history of noise exposure (62820). Other clinical research shows that taking melatonin 3 mg daily for 3 months is more effective for reducing tinnitus severity than sertraline 50 mg daily (97447). However, other clinical research shows that taking melatonin 3 mg nightly for 30-40 days does not significantly reduce tinnitus intensity when compared with placebo, although the effects might be significant when melatonin is combined with sulpiride or sulodexide (62469,62614).
• Traumatic brain injury (TBI). It is unclear if oral melatonin is beneficial for children who have experienced a concussion. Details: A small clinical study in children ages 8-18 years who have experienced a concussion shows that taking melatonin 3 mg or 10 mg one hour before bedtime for 28 days does not improve persistent post-concussive symptoms when compared with placebo (103690). One small observational study in children in the same age group who have experienced a concussion within 14 days has found that receiving a prescription for melatonin is not associated with improved symptoms and recovery at 15-35 days after concussion (105001). The validity of these findings is limited by small study size and short duration of follow-up.
• Ulcerative colitis. Oral melatonin may be modestly beneficial for reducing symptoms or sustaining remission in patients using the medication mesalazine. Details: A small clinical study shows that taking melatonin 5 mg daily in combination with mesalazine 1 gram twice daily for 12 months may help to sustain remission in patients with ulcerative colitis when compared with mesalazine alone (62821). Another small clinical trial in patients with mild to moderate ulcerative colitis shows that taking melatonin 3 mg daily for 3 months modestly improves overall symptoms, some measures of quality of life, and levels of fecal calprotectin when compared with placebo. However, there was no effect on other markers of inflammation, such as C-reactive protein and erythrocyte sedimentation rate (106303). More evidence is needed to rate melatonin for these uses.

(Read more about MELATONIN)

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. Two small studies suggest that oral valerian may reduce hot flashes. 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). Both 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)

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

POSSIBLY SAFE ...when used orally in medicinal amounts, short-term. GABA has been used with apparent safety in doses of 75 mg to 1.5 grams daily for up to one month in small clinical studies (19361,19363,19369,110134,110135). There is insufficient reliable information available about the safety of GABA when used orally for longer than one month or when used sublingually or intravenously.

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

(Read more about GAMMA-AMINOBUTYRIC ACID (GABA))

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)

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 in the amounts commonly found in foods. L-tryptophan is an essential amino acid that must be obtained from the diet. A typical diet in the United States supplies 0.5-2 grams of L-tryptophan daily (1146).

POSSIBLY SAFE ...when used orally in medicinal amounts, short-term. L-tryptophan 5 grams daily for 21 days has been used with apparent safety (91460,97243). In 1989, L-tryptophan was linked to over 1500 reports of eosinophilia-myalgia syndrome (EMS) and several deaths (7067,8053,10085,11474,11478), leading to its removal from the U.S. market in 1990 (7067). The exact cause of EMS in patients taking L-tryptophan is unknown, but some evidence suggests that nearly all cases were due to contaminated L-tryptophan products from a single manufacturer (8050,8051,11477,11478). Under the Dietary Supplement Health and Education Act (DSHEA) of 1994, L-tryptophan is currently available and marketed as a dietary supplement. There is insufficient reliable information available about the safety of L-tryptophan when used orally, long-term.

PREGNANCY: LIKELY SAFE
when used orally in amounts commonly found in foods.

PREGNANCY: POSSIBLY UNSAFE
when used orally in medicinal amounts because it may cause respiratory depression in utero (1142). Avoid using in amounts greater than those found in foods.

LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods. There is insufficient reliable information available about the safety of larger medicinal amounts; avoid using.

(Read more about L-TRYPTOPHAN)

LIKELY SAFE ...when used orally and appropriately, short-term or as a single dose. Melatonin seems to be safe when used up to 8 mg daily for up to 6 months. Melatonin 10 mg daily has been used safely for up to 2 months (1049,1068,1077,1085,1738,1754,5854,5855,5857,12226), (14283,15005,62850,89502,89503,88285,88289,88293,88294,88295)(88296,88299,89508,89510,89511,96313,96314,96316,96317,96319)(96321,97438,99345,103484,106301,106303,107811,110286,110299). ...when used topically and appropriately (1066,1768,1769,4713,4714,96314).

POSSIBLY SAFE ...when doses of up to 8 mg daily are used orally and appropriately for longer than 6 months, doses of 10 mg daily are used for longer than 2 months, or doses of 50 mg daily are used for up to 5 days (7040,7043,62435,106296,107811). There is some evidence melatonin can be used safely in doses of up to 10 mg daily for up to 2 years in some patients (7040,7043,62435). ...when used intravenously under the supervision of a healthcare professional. A one-time dose of intravenous melatonin combined with a single bolus of intracoronary melatonin has been used with apparent safety in one clinical trial (96324).

CHILDREN: POSSIBLY SAFE
when used orally in low doses, short-term (9980,15034,62792,88282,88283,88286,88288,95748,96318,97434)(97439,97446,106293,110292). Although melatonin has been safely used in clinical research in doses up to 12 mg daily (88283), it is often advised that daily doses of melatonin be limited to 3 mg daily for children and infants 6 months or older and 5 mg daily for adolescents (95746). There is some concern that taking melatonin might adversely affect gonadal development in children (1739,1740,1742,1743). While some evidence suggests that long-term use of melatonin in children may delay puberty, the available research includes only three small, observational studies with incomplete follow-up and poor measures of pubertal timing (95747). Although rare, pediatric overdose with melatonin has resulted in hospitalization, mechanical ventilation, and death (108145). Due to potential risks, melatonin should be used only in children with a medical reason for use; it should not be used to promote sleep in otherwise healthy children. There is insufficient reliable information available about the safety of melatonin when used long-term.

PREGNANCY: POSSIBLY UNSAFE
when used orally or parenterally in high doses or with frequent use. High doses of melatonin 75-300 mg daily seem to inhibit ovulation, causing a contraceptive effect (769,1740,6002,8271,95728). Advise pregnant patients and patients wishing to become pregnant to avoid using melatonin frequently or in high doses. There is insufficient reliable information available about the safety of melatonin in lower doses during pregnancy. Some research shows that taking melatonin 2 mg daily does not affect anterior pituitary hormone levels in females who are not pregnant; this suggests that low doses may not have a contraceptive effect (62898). Other research shows that taking melatonin 3 mg daily during the follicle stimulating stage of in vitro fertilization does not negatively impact pregnancy rates (62818,62819,88297,89512,88297). However, it is not known if melatonin is safe for use throughout pregnancy (95729). Until more is known about the safety of melatonin, avoid using during pregnancy.

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about MELATONIN)

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)

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking GABA with antihypertensive drugs might increase the risk of hypotension.  Details Some clinical research shows that GABA can decrease blood pressure in patients with hypertension (19367).

CNS DEPRESSANTS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, GABA might have additive sedative effects when used in conjunction with CNS depressants. However, it is unclear if this concern is clinically relevant.  Details Endogenous GABA has well-established relaxant effects (51152) and GABA(A) receptors have an established physiological role in sleep (51143). However, the effects of GABA supplements are unclear, as it is unknown whether exogenous GABA crosses the blood-brain barrier (51120,51153,90570). Although there have been limited reports of drowsiness or tiredness with GABA supplements (5115,19364), these effects have not been widely reported in clinical studies. Additionally, intravenous GABA 0.1-1 mg/kg has been shown to induce anxiety in a dose-dependent manner (5116).

(Read more about GAMMA-AMINOBUTYRIC ACID (GABA))

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)

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 = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Theoretically, concomitant use of L-tryptophan with CNS depressants might cause additive sedative effects.  Details Clinical research shows that L-tryptophan can cause fatigue and drowsiness (1143).

SEROTONERGIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, combining L-tryptophan with serotonergic drugs might cause additive serotonergic effects.  Details L-tryptophan is a precursor to serotonin (1141). Theoretically, combining serotonergic drugs with L-tryptophan might increase the risk of serotonergic side effects, including serotonin syndrome and cerebral vasoconstrictive disorders (8056).

(Read more about L-TRYPTOPHAN)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, melatonin may have anticoagulant effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details There are isolated case reports of minor bleeding and decreased prothrombin activity in people taking melatonin with warfarin (Coumadin) (63067). The mechanism, if any, of this interaction is unknown (9181). Taking melatonin orally seems to decrease coagulation activity within one hour of dosing in healthy men (62481).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking melatonin with antidiabetes drugs might increase the risk of hypoglycemia.  Details Some clinical research shows that melatonin reduces levels of fasting blood glucose and improves glycemic control (19034,19035,103490). However, other research suggests that melatonin might impair glucose utilization and increase insulin resistance (9713), while other research has found no effect on glucose levels (19036,104368). Until more is known, use melatonin cautiously in combination with antidiabetes drugs.

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = A Theoretically, taking melatonin with antihypertensive drugs might increase the risk of hypotension or hypertension.  Details Some clinical research suggests that taking melatonin decreases blood pressure in healthy adults (1724,62165,62187,63042). Also, melatonin seems to lower systolic and diastolic blood pressure in individuals with high blood pressure at nighttime or untreated essential hypertension (62359,62416,62441,62826). However, melatonin seems to worsen blood pressure in patients who are taking antihypertensive medications. Immediate-release melatonin 5 mg at night in combination with nifedipine GITS (Procardia XL) increases systolic blood pressure an average of 6.5 mmHg, diastolic blood pressure by an average of 4.9 mmHg, and heart rate by 3.9 bpm (6436). Also, results from animal research suggest that melatonin reduces the effectiveness of certain antihypertensive drugs, including methoxamine and clonidine (62432).

CAFFEINE Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, taking caffeine with melatonin might increase levels of melatonin.  Details Some evidence suggests that caffeine consumption can decrease endogenous melatonin levels (8265,22303,37585), while other evidence suggests that caffeine increases endogenous melatonin levels (62328). When administered in combination with melatonin supplements, caffeine seems to increase melatonin effects and levels (62352,96315). The reason for this discrepancy is not completely clear. Part of the discrepancy may result from the fact that caffeine can inhibit melatonin synthesis as well as inhibit melatonin metabolism. By functioning as an adenosine receptor antagonist, caffeine may indirectly inhibit the synthesis of melatonin. Conversely, because melatonin and caffeine are both metabolized by cytochrome P450 1A2 (CYP1A2) enzyme, concomitant use of melatonin and caffeine may reduce the metabolism of melatonin, resulting in higher serum levels (22306,96315).

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking melatonin might increase the sedative effects of CNS depressants.  Details Melatonin has sedative effects. Theoretically, concomitant use of melatonin with alcohol, benzodiazepines, or other sedative drugs might cause additive sedation (96315).

CONTRACEPTIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, taking contraceptive drugs with melatonin might increase the effects and adverse effects of melatonin.  Details Contraceptive drugs can increase the levels of endogenous melatonin (8265). Theoretically, these drugs may increase the effects and adverse effects of oral melatonin.

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = D Theoretically, melatonin might increase levels of drugs metabolized by CYP1A2. Also, other CYP1A2 substrates might decrease the metabolism of melatonin, increasing melatonin levels.  Details Melatonin is metabolized in the liver primarily by the CYP2C19 and CYP1A2 enzymes (62118,62405,96315). Theoretically, combined administration of melatonin with drugs metabolized by the CYP1A2 enzyme might reduce the metabolism of these drugs, resulting in increased serum levels. Conversely, some drugs metabolized by CYP1A2 may inhibit the metabolism of melatonin, resulting in increased serum levels of melatonin. Until more is known, use melatonin cautiously in patients taking drugs metabolized by these enzymes.

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = D Theoretically, melatonin might increase levels of drugs metabolized by CYP2C19. Also, other CYP2C19 substrates might decrease the metabolism of melatonin, increasing melatonin levels.  Details Melatonin is metabolized in the liver primarily by the CYP2C19 and CYP1A2 enzymes (62118,62405). Theoretically, combined administration of melatonin with certain drugs metabolized by the CYP2C19 enzyme may reduce the metabolism of these drugs, resulting in increased serum levels. Conversely, some drugs metabolized by CYP2C19 may inhibit the metabolism of melatonin, resulting in increased serum levels of melatonin. Until more is known, use melatonin cautiously in patients taking drugs metabolized by these enzymes.

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, melatonin might increase levels of drugs metabolized by CYP2D6.  Details Laboratory research suggests that certain lots of melatonin inhibit CYP2D6 (96315). Theoretically, combined administration of melatonin with certain drugs metabolized by the CYP2D6 enzyme may reduce the metabolism of these drugs, resulting in increased serum levels. Until more is known, use melatonin cautiously in patients taking drugs metabolized by these enzymes.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, melatonin might increase levels of drugs metabolized by CYP3A4.  Details Laboratory research shows that certain lots of melatonin inhibit CYP3A4 (96315). Theoretically, combined administration of melatonin with certain drugs metabolized by CYP3A4 may reduce the metabolism of these drugs, resulting in increased serum levels. Until more is known, use melatonin cautiously in patients taking drugs metabolized by these enzymes.

FLUMAZENIL (Romazicon) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking flumazenil with melatonin might reduce the effects of melatonin.  Details Animal research shows that flumazenil may inhibit the effect of melatonin (9703).

FLUVOXAMINE (Luvox) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, taking fluvoxamine with melatonin might increase levels of melatonin.  Details Fluvoxamine can significantly increase melatonin levels. In some cases, fluvoxamine might increase bioavailability of exogenously administered melatonin by up to 20 times (5038,6499,8251). Some researchers think this might be a beneficial interaction and be potentially useful for cases of refractory insomnia (6499). However, this interaction might also cause unwanted excessive drowsiness and possibly other adverse effects. Fluvoxamine is known to increase endogenous melatonin secretion (6498,22313). It seems to increase serum levels of exogenously administered melatonin possibly by decreasing melatonin metabolism by inhibiting cytochrome P450 (CYP450) 1A2 and 2C19 or by inhibiting melatonin elimination. This effect has been found in healthy people taking fluvoxamine 50-75 mg and melatonin 5 mg (5038,6498,6499,8251).

IMMUNOSUPPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, melatonin might interfere with immunosuppressive therapy.  Details Melatonin can stimulate immune function. Theoretically, melatonin might interfere with immunosuppressive therapy (7040).

METHAMPHETAMINE (Desoxyn) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking melatonin with methamphetamine may increase the adverse effects of methamphetamine.  Details Animal research suggests that melatonin exacerbates the adverse effects of methamphetamine, resulting in greater depression of tryptophan hydroxylase (TPH) and tyrosine hydroxylase (TH) activity, as well as a significant reduction in dopamine levels (22307). This has not been shown in humans.

NIFEDIPINE GITS (Procardia XL) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, taking melatonin with extended release nifedipine reduces the effects of nifedipine.  Details Melatonin can decrease the effectiveness of extended release nifedipine (GITS). Immediate-release melatonin 5 mg at night in combination with nifedipine GITS 30-60 mg daily increases systolic and blood pressure by an average of 6.5 mmHg and 4.9 mmHg, respectively. Concomitant use with melatonin also increases heart rate by 3.9 bpm (6436). The mechanism of this interaction is not known.

SEIZURE THRESHOLD LOWERING DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking melatonin with drugs that lower the seizure threshold might increase the risk of seizure activity.  Details Some clinical evidence suggests that melatonin may increase the frequency of seizures in certain patients, particularly children with neurological disabilities (8248,9744).

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, melatonin may have antiplatelet effects and may increase the risk of bleeding with warfarin.  Details Three cases of increased prothrombin time have been reported for patients aged 48-72 years who took melatonin orally in combination with warfarin (9181). However, three cases of decreased prothrombin time have also been reported for patients aged 51-84 years who took melatonin orally in combination with warfarin (9181). Until more is known, use melatonin cautiously in patients taking warfarin.

(Read more about MELATONIN)

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, GABA seems to be generally well tolerated. Sublingually, no adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Orally: Drowsiness, gastric upset, minor throat burning, muscle weakness, and nausea.

Cardiovascular ...Intravenously, GABA can cause dose-related increases in blood pressure and pulse (5116).

Gastrointestinal ...Orally, minor throat burning has been associated with GABA in one study (5115). In another study in which GABA was administered with phosphatidylserine, one patient experienced severe gastric distress, two patients reported moderate nausea, and one reported constipation (19364). Children with cerebral palsy taking GABA experienced nausea and decreased appetite (19362).

Genitourinary ...In one study, one patient treated with oral GABA and phosphatidylserine reported transient amenorrhea (19364).

Musculoskeletal ...Orally, minor adverse effects associated with GABA included muscle weakness (5115).

Neurologic/CNS ...Orally, GABA may cause drowsiness or tiredness (5115,19364). Four children with cerebral palsy taking GABA had convulsions, and an unspecified number experienced motor restlessness. However, causality of these adverse effects was not clear, and the dose of GABA was not specified (19362). Intravenously, GABA 50 mg has been associated with a "lack of alertness" in healthy female volunteers (51159).

Psychiatric ...Intravenously, GABA 0. 1-1.0 mg/kg has been shown to induce anxiety, dysphoria, and mood disturbances in a dose-dependent manner (5116).

Other ...In one study, patients taking GABA experienced a slight warming of the body (19370).

(Read more about GAMMA-AMINOBUTYRIC ACID (GABA))

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, 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.

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, L-tryptophan is generally well tolerated.
Most Common Adverse Effects:
Orally: Belching, diarrhea, drowsiness, dry mouth, flatulence, headache, heartburn, lightheadedness, nausea, stomach pain, visual blurring, and vomiting.
Serious Adverse Effects (Rare):
Orally: L-tryptophan has been associated with the neurological disorder eosinophilia-myalgia syndrome (EMS). However, almost all cases were traced to L-tryptophan produced by a single manufacturer in Japan and are likely related to contamination.

Cardiovascular ...Orally, L-tryptophan has been associated with eosinophilia-myalgia syndrome (EMS), which can include cardiovascular symptoms such as myocarditis, arrhythmias, and palpitations (8053,11477).

Dermatologic ...Orally, L-tryptophan has been associated with eosinophilia-myalgia syndrome (EMS), which can include dermatological symptoms such as sclerodermiform skin changes, alopecia, and rash (8053,11477).

Gastrointestinal ...Orally, L-tryptophan can cause gastrointestinal side effects such as heartburn, stomach pain, belching and flatulence, nausea, vomiting, diarrhea, dry mouth, and anorexia (10853,99884).

Hematologic ...Orally, L-tryptophan has been associated with eosinophilia-myalgia syndrome (EMS), which can include hematologic symptoms such as eosinophilia (8053,11477).

Hepatic ...Orally, L-tryptophan has been associated with eosinophilia-myalgia syndrome (EMS), which can include hepatic symptoms such as hepatomegaly (8053,11477).

Musculoskeletal ...Orally, L-tryptophan has been associated with eosinophilia-myalgia syndrome (EMS), which can include musculoskeletal symptoms such as myalgia and inflammation of the joints and connective tissue (8053,11477).

Neurologic/CNS ...Orally, L-tryptophan can cause headache, lightheadedness, and ataxia (10853,99884).
In 1989, more than 1500 cases of the neurological disorder EMS were associated with oral L-tryptophan use in the US. About 95% of all EMS cases were traced to contaminated L-tryptophan produced by a single manufacturer in Japan (8054,10288,10289,11475,11476). In 1990, L-tryptophan was recalled in the U.S. and an FDA alert was put into force limiting the importation of all over-the-counter L-tryptophan products (7067,11477,11478). After the limitation of L-tryptophan products, the incidence of EMS dropped abruptly (11474). Symptoms of EMS associated with L-tryptophan use include intense eosinophilia; fatigue; myalgia; neuropathy; sclerodermiform skin changes; alopecia; rash; and inflammatory disorders affecting the joints, connective tissue, lungs, heart, and liver (8053,11477). Symptoms tend to improve over time, however some individuals may still experience symptoms up to 2 years after the onset of EMS and complete resolution of symptoms may not occur (8053,10287).
There is some evidence of an association between L-tryptophan-related EMS and the occurrence of chronic B-cell lymphocytic leukemia (8055).

Ocular/Otic ...Orally, L-tryptophan can cause side effects such as visual blurring (10853).

Pulmonary/Respiratory ...Orally, L-tryptophan has been associated with eosinophilia-myalgia syndrome (EMS), which can include respiratory symptoms such as dyspnea and cough (8053,11477).

(Read more about L-TRYPTOPHAN)

General ...Orally, melatonin is generally well tolerated.
Most Common Adverse Effects:
Orally: Dizziness, drowsiness, headache, and nausea.
Serious Adverse Effects (Rare):
Orally: There is concern that melatonin may increase the risk for seizure.

Cardiovascular ...Melatonin might increase levels of very low-density lipoprotein (VLDL) cholesterol and triglycerides (62176). Several rare or poorly described cases of abnormal heart rhythms, palpitations, fast heart rate, or chest pain have been reported. However, in these cases, the patients were taking other drugs that could account for the symptoms, and melatonin was not thought to be the cause (1079,9181,62776,62789,63067).

Dermatologic ...Papular skin rash and pruritus has been reported with melatonin use. However, the effect was generally mild and did not require cessation of melatonin treatment (62450,62754,109696), and had similar rates as placebo (96316). Cutaneous flushing has also been reported (62770,62914). Two cases of fixed drug eruption on the genitalia have been reported for patients who used oral melatonin (Nature's Bounty Natural melatonin) for preventing jet lag (88284).

Endocrine ...A case of gynecomastia (increased breast size) has been reported for a 56 year-old patient with amyotrophic lateral sclerosis (ALS) who used oral melatonin, long-term (89430). Also, reduced sperm concentration and sperm motility has been reported for two men who used oral melatonin 3 mg daily for 6 months. Improvement in sperm quality was observed for only one of the two men following melatonin cessation (62231).

Gastrointestinal ...Orally, melatonin may cause nausea (62384,62770), abdominal cramps, or mild abdominal pain (62450,62754,62914,96316), diarrhea (62804,62811,62914), constipation (96316), or decreased appetite (62345,62792). Often these symptoms occur during the first few days of treatment and subside after a few days (62804). In some cases, rates of symptoms are similar between melatonin and placebo (96316). Less often, melatonin has been reported to cause abnormal feces (62450), odd taste in the mouth (1070), or reflux esophagitis (1745) when used orally. A case of exacerbated symptoms of Crohn disease, including increased diarrhea and abdominal cramps, has been reported for a patient who took oral melatonin 3 mg at bedtime for 4 days. Symptoms resolved within 24 hours of melatonin treatment cessation (62218).

Genitourinary ...Orally, melatonin may increase enuresis in adults and children (58685,62450,62710,62770,62804,62804,62811). In perimenopausal adults, melatonin has caused a resumption of spotting or menstrual flow (11806). Decreased libido has been noted for one patient treated with melatonin 3 mg daily for 8 weeks (15216).

Hematologic ...A case of nose bleed has been reported with oral melatonin (62450). Some melatonin preparations contain contaminants that are associated with eosinophilia-myalgia syndrome (9715,9716).

Hepatic ...A case of autoimmune hepatitis has been reported for a patient who took melatonin orally to treat insomnia (63037).

Musculoskeletal ...Preliminary clinical evidence shows that a single dose of melatonin 3 mg may increase fall risk due to increased postural swaying while standing on one or both feet in healthy adults ages 60-71 years (97442). A single case of ataxia has been reported for an 81-year-old female who used melatonin for 4 days (9181). Weakened muscle power has been reported for two patients treated with melatonin 5 mg in the evening (62456). Some melatonin preparations contain contaminants that are associated with eosinophilia-myalgia syndrome (9715,9716).

Neurologic/CNS ...Orally, melatonin may cause migraine-like headache (1070,1077,15034,62384,62450,62710,62754,62804,62792,62914,88288,88293,88294,96318)(106297) or dizziness (62345,62384,62450,62456,62770,62784,62792,62804,62811,89510)(110297). Often these symptoms occur during the first few days of treatment and subside after a few days (62804). Melatonin may also cause drowsiness or fatigue when taken orally (1077,8273,15216,62384,62456,62784,62804,62811,88288,89510,96314,96316,96318,97446)(106293,106297). These symptoms appear to be more common if melatonin is taken in the morning or at very high doses (greater than 50 mg) (8269,62874). A case of excessive drowsiness has been reported when melatonin was combined with citalopram, nortriptyline, and oxycodone. Sedation improved with discontinuation of melatonin (96315). Indiscriminate use of melatonin may cause irregular sleep-wake cycles to occur (62998). Less commonly, melatonin may also cause behavior worsening (62811), confusion or disorientation (63014,63067), nighttime awakening (62710,62811), mood swings or agitation (96318), stereotypy (96318), excitement before bedtime (62811), nightmares or more intense dreams (62401,62462,62780,62784,88283), feelings of a "rocking" sensation (62155), or reduced alertness when taken orally.
A case of generalized epilepsy has reportedly occurred after treatment with melatonin for 4 months (9708). Also, some case reports raise concerns about increased risk of seizure with melatonin treatment, but conflicting evidence suggests that melatonin may decrease the risk of seizures (1699,8248,9695,9697,9744,9746,62123,62256,62384,62754)(63070,63071,89431). One patient experienced hyponatremia with confusion and seizures after taking prolonged-release melatonin 2 mg. However, malnutrition and cannabis abuse were also thought to contribute to this reaction (96321).
Although there is concern that melatonin might affect cognitive function in healthy adults, research in humans suggests that oral or topical melatonin do not impact most measures of cognitive function (97442,97448).

Psychiatric ...Orally, melatonin may cause mood changes, including dysphoria (sadness) (1764), dips in mood (62345,62450,62792), nervousness (62784), or transient depression (1077). Delusions and hallucinations have also been reported in clinical research (62347). An isolated incident of aggressiveness was also noted in a child diagnosed with attention deficit-hyperactivity disorder (ADHD) who took melatonin in combination with methylphenidate (9980). Severe irritability has been reported in two children with autism spectrum disorder who had abruptly discontinued melatonin due to the completion of a clinical trial (106293).

(Read more about MELATONIN)

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).

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