Tart Cherry Extract + Melatonin & Herbal Relaxation Blend by Puritan's Pride

POSSIBLY EFFECTIVE

• Generalized anxiety disorder (GAD). Oral ashwagandha may modestly improve symptoms of anxiety in patients with GAD. Details: Clinical practice guidelines from the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Treatments (CANMAT) provisionally recommend ashwagandha root extract at doses of 300-600 mg, standardized to 5% withanolides, daily as monotherapy or adjunctive therapy in patients with GAD. This recommendation is based on a review of three preliminary clinical trials with consistent results (110318). Two of these studies are described below. A small clinical trial in patients with GAD who are taking selective serotonin reuptake inhibitors (SSRIs) shows that taking ashwagandha 1 gram daily for 6 weeks reduces symptoms of anxiety by 48%, compared with a 27% reduction in patients taking placebo. Furthermore, by the end of treatment, 72% of patients taking ashwagandha were determined to have mild symptoms of GAD, compared with only 32% of those taking placebo (102687). Another preliminary clinical trial in patients aged 16 years and older with GAD shows that taking ashwagandha root powder granules 4 grams three times daily for 60 days moderately improves anxious mood in 58% of patients, compared with no moderate improvement in the placebo group. Mild improvement occurred in 82% of patients in the placebo group and 40% of patients in the ashwagandha group (90654).
• Insomnia. Oral ashwagandha may modestly improve sleep in patients with insomnia or non-restorative sleep. Details: A small meta-analysis in patients with insomnia and healthy patients shows that taking a specific ashwagandha root extract (KSM-66, Ixoreal Biomed) 250-600 mg daily or a specific root and leaf extract (Shoden, Arjuna Natural) 120 mg daily for 6-12 weeks modestly improves overall sleep, as well as sleep quality, sleep latency, total sleep time, wake time after sleep onset, and sleep efficiency, when compared with placebo. Effects were more pronounced in those with insomnia, with doses of at least 600 mg daily, and with treatment durations of at least 8 weeks (106784). These findings may be limited by heterogeneity of the included studies. In patients with non-restorative sleep, clinical research shows that taking a specific ashwagandha extract (Shoden, Arjuna Natural Private Ltd) 125 mg daily for 6 weeks increases sleep quality by 72%, compared with an improvement of 29% in patients taking placebo. Small to moderate improvements also occurred in total sleep time, sleep latency, and number of times awake (103476).
• Stress. Oral ashwagandha seems to help reduce stress and may also reduce stress-related weight gain. Details: A meta-analysis of seven small clinical studies in healthy adults, patients with chronic stress, or patients with psychiatric conditions shows that taking ashwagandha 240-1000 mg daily for 8-12 weeks improves stress when compared with placebo (109587). Clinical studies included in this meta-analysis that evaluated adults with chronic stress show that taking specific ashwagandha root extracts 240 mg daily (Shoden, Arjuna Natural Ltd.) or 300 mg twice daily (KSM-66, Ixoreal Biomed) for 60 days reduces perceived stress levels by 30% to 44% and decreases cortisol levels by 22% to 28% when compared with baseline. These improvements remain significant when compared with the changes seen for patients treated with placebo (90652,95617,101816,102682). In adults reporting moderate to high stress levels, clinical research shows that treatment with specific slow-release capsules containing another ashwagandha root extract (Prolanza), 300 mg daily for 90 days, lowers perceived stress scores and cortisol levels when compared with placebo (107371). In healthy college students, clinical research also shows that taking ashwagandha root extract 350 mg twice daily for 30 days improves qualitative perceptions of stress management, but not stress scores, when compared with placebo (109589,109590). Other clinical research shows that taking ashwagandha root extract 500 mg twice daily may prevent stress-related weight gain when compared with placebo (95617).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging. A small clinical study suggests that oral ashwagandha may modestly improve well-being, sleep, and alertness in elderly patients. Details: A small clinical trial in individuals aged 65-80 years shows that taking ashwagandha root extract (KSM-66, Ixoreal Biomed) 600 mg daily for 12 weeks improves overall well-being, sleep quality, and mental alertness by small to moderate amounts when compared with placebo (102684).
• Antipsychotic-induced metabolic side effects. It is unclear if ashwagandha is beneficial for attenuating the metabolic side effects of antipsychotic agents. Details: One preliminary clinical trial shows that taking a specific ashwagandha extract (Cap Strelaxin, M/s Pharmanza Herbal Pvt. Ltd.) 400 mg three times daily for one month reduces serum triglycerides by 12% and fasting blood glucose by 15% when compared with baseline levels. Patients were taking atypical antipsychotics and had modestly elevated triglycerides and fasting blood glucose levels at baseline (90649). The validity of these findings is limited by the lack of a comparator group.
• Anxiety. It is unclear if oral ashwagandha is beneficial for reducing anxiety. Details: One small clinical study shows that taking ashwagandha root (Swiss Herbals) 300 mg twice daily for 12 weeks, in combination with standard psychotherapy interventions, including dietary counseling, deep breathing exercise instruction, and a multivitamin, reduces anxiety scores when compared with standard psychotherapy interventions and placebo (19271). However, other clinical research in young adults shows that a specific ashwagandha root and leaf extract (NooGandha, Specnova LLC) 225 mg or 400 mg daily for 30 days produces similar improvements in self-reported anxiety, stress, and depression scores when compared with placebo (107370).
• Asthma. Although there has been interest in using oral ashwagandha for asthma, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Athletic performance. It is unclear if ashwagandha is beneficial for improving athletic performance. Details: A meta-analysis of four small clinical trials shows that taking ashwagandha increases aerobic capacity in athletes and non-athletes based on the measurement of maximum oxygen consumption. Effective doses ranged from 500-1000 mg daily for up to 12 weeks (102683). Another meta-analysis shows that taking ashwagandha in doses of 120-1250 mg daily, as a single dose or divided twice daily, for up to 6 months seems to improve muscle strength, speed, time to exhaustion, recovery time, and cardiorespiratory fitness in athletes and non-athletes (105824). However, the validity of this analysis is reduced by the lack of a control group, the varied training levels of the subjects, and the wide range of outcomes assessed. More research is needed to determine whether taking ashwagandha can improve athletic performance.
• Attention deficit-hyperactivity disorder (ADHD). Oral ashwagandha has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In a preliminary clinical trial, children with ADHD were given a combination herbal extract formula (Nurture & Clarity), containing ashwagandha, white peony root, gotu kola, blue-green algae, bacopa, and sage, 3 mL three times daily for 4 months. Measures of attention, cognition, and impulse control improved significantly in children receiving ashwagandha when compared with placebo (19272). The dose of ashwagandha in the combination product was not reported, and the effect of ashwagandha alone in ADHD is unclear.
• Back pain. Although there has been interest in using oral or topical ashwagandha for back pain, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Bipolar disorder. It is unclear if oral ashwagandha is beneficial for improving cognitive function in adults with bipolar disorder. Details: Clinical research shows that taking ashwagandha extract (Sensoril, Natreon, Inc.) 250 mg daily for 1 week and then 250 mg twice daily for 7 weeks, improves some, but not all, measures of cognition by a small-to-moderate amount when compared with placebo (90653).
• Bronchitis. Although there has been interest in using oral ashwagandha for bronchitis, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Cerebellar ataxia. It is unclear if oral ashwagandha is beneficial for improving balance in patients with cerebellar ataxia. Details: A small, open-label study evaluating ashwagandha 500 mg three times daily in combination with Ayurvedic therapy for one month showed improvement in balance indices in subjects with cerebellar ataxia when compared with baseline (19273). The validity of this finding is limited by the lack of a comparator group. Additionally, it is unclear if this effect is due to ashwagandha, other ingredients, or the combination.
• Chemotherapy-related fatigue. Evidence is limited to one small clinical study in patients with breast cancer. Details: In preliminary clinical research in patients with breast cancer, taking ashwagandha powdered root extract 2 grams (Himalaya Drug Co) three times daily through six cycles of chemotherapy decreases chemotherapy-related fatigue when compared with no treatment. Fatigue scores were 16% to 52% higher in the control group when compared to the ashwagandha group (90651).
• Chronic obstructive pulmonary disease (COPD). It is unclear if oral ashwagandha is beneficial in patients with COPD. Details: A small clinical study in patients with stable COPD shows that taking ashwagandha root extract 250 mg twice daily for 12 weeks, along with conventional therapy, improves measures of lung function and exercise tolerance, but not quality of life, when compared with conventional therapy alone (109588).
• Cognitive function. Although there has been interest in using oral ashwagandha for cognitive function, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Constipation. Oral ashwagandha has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in adults with constipation shows that taking a combination product containing ashwagandha root and ambrette fruit extracts 300 mg or 500 mg daily for 14 days improves bowel movement frequency and abdominal, rectal, and stool symptoms when compared with placebo (112114). It is unclear if these effects are due to ashwagandha, ambrette, or the combination. The validity of these effects is limited by the small sample size.
• Coronavirus disease 2019 (COVID-19). Oral ashwagandha has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults hospitalized with COVID-19 shows that taking a specific combination product, (Artovid-20, Bioved Pharmaceuticals) containing ashwagandha, ginger, turmeric, and Boswellia, 1,776 mg orally twice daily for 14 days shortens the duration of symptoms by 0.9 days when compared with placebo. Taking the combination product also modestly reduced the severity ratings of some symptoms, such as sore throat and cough, however, these improvements are unlikely to be clinically relevant (109899). Another small clinical study in adults with mild to moderate COVID-19 shows that taking ashwagandha 500 mg and ginger 1000 mg twice daily for 15 days reduces time to recovery by around 6 days and increases the rate of clinical cure 14-fold and 2.6-fold at days 5 and 7, respectively, when compared with a control. However, taking this combination does not appear to improve the proportion of patients with a negative COVID-19 test, viral clearance, serum antibodies, chest findings, or disease progression when compared with control (112094). The validity of these findings is limited by a lack of blinding, and the study may have been inadequately powered to detect a difference between groups. Additionally, it is unclear if these effects are due to ashwagandha, ginger, or the combination.
• Diabetes. It is unclear if oral ashwagandha is beneficial for type 2 diabetes. Details: In patients with type 2 diabetes, preliminary clinical research shows that ashwagandha 3 grams daily for 30 days decreases blood glucose to a degree similar to oral hypoglycemic drugs (19274). However, this study did not compare ashwagandha directly to a group taking oral hypoglycemic drugs.
• Fibromyalgia. Although there has been interest in using oral ashwagandha for fibromyalgia, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Hiccups. Although there has been interest in using oral ashwagandha for hiccups, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Hypercholesterolemia. It is unclear if ashwagandha is beneficial for hypercholesterolemia. Details: A very small clinical study in subjects with hypercholesterolemia shows that ashwagandha 3 grams daily for 30 days decreases serum cholesterol, triglyceride, low-density lipoprotein (LDL) cholesterol, and very low-density lipoprotein (VLDL) cholesterol levels when compared with baseline (19274). The validity of these findings is limited by the lack of a comparator group.
• Hypothyroidism. It is unclear if ashwagandha is beneficial for hypothyroidism. Details: Preliminary clinical research in adults with subclinical hypothyroidism shows that taking a specific ashwagandha root extract (KSM-66, Ixoreal Biomed) 300 mg twice daily for 8 weeks increases triiodothyronine (T3) and thyroxine (T4) levels by 42% and 20%, respectively, and reduces serum TSH levels by 17% from baseline. These changes are significant when compared with placebo (97292). However, the effects of ashwagandha on thyroid hormone levels in patients with overt hypothyroidism, or in patients taking prescription thyroid hormones, is unknown.
• Infertility. Although there has been interest in using oral ashwagandha for infertility in females, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Male infertility. It is unclear if oral ashwagandha is beneficial for male infertility. Details: Preliminary clinical research in males with infertility shows that taking ashwagandha root powder for approximately 3 months modestly improves hormone levels, as well as sperm count and motility, when compared with baseline (19275,90650). The validity of these findings is limited by the lack of a comparator group. One study used a specific ashwagandha root extract (KSM-66 Ashwagandha, Ixoreal Biomed) 225 mg three times daily; another study provided doses of 5 grams daily (19275,90650).
• Menopausal symptoms. Oral ashwagandha may be beneficial for menopausal symptoms. Details: A small clinical study in healthy adults in perimenopause shows that taking a specific ashwagandha root extract (KSM-66, Ixoreal Biomed) 300 mg twice daily for 8 weeks improves menopausal symptom severity by 24%, compared with 11% in those receiving placebo. Quality of life and hot flashes also were improved in those taking ashwagandha (106785).
• Obsessive-compulsive disorder (OCD). It is unclear if ashwagandha is beneficial for OCD. Details: Preliminary clinical research shows that taking ashwagandha root extract 120 mg after meals for 6 weeks, in conjunction with prescribed selective-serotonin reuptake inhibitors (SSRIs), might reduce OCD symptom severity when compared with prescribed SSRIs alone. The dose was initiated at 30 mg daily and increased by 30 mg every 4 days. Although OCD scores were significantly reduced when compared with placebo, it should be noted that scores were already significantly lower in the placebo group at baseline (95618).
• Osteoarthritis. Oral ashwagandha has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In patients with osteoarthritis, taking a specific combination supplement, containing ashwagandha 450 mg, Ayurvedic zinc complex 50 mg, guggul 100 mg, and turmeric 50 mg (Articulin-F) two capsules three times daily for 3 months reduces symptoms of pain and swelling when compared with placebo. However, there were no radiological improvements (19276). It is unclear if this effect is due to ashwagandha, other ingredients, or the combination.
• Parkinson disease. Oral ashwagandha has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In patients with Parkinson disease, a small clinical study shows that taking a product containing ashwagandha 14.5 grams, cowhage 4.5 grams, Hyoscyamus reticulantus 0.75 grams, and Sida cordifolia 14.5 grams in lukewarm milk twice daily for 56 days improves symptoms like tremor, stiffness, and cramps when compared with baseline. The therapy followed 28 days of cleansing or eliminative therapy using Ayurvedic remedies (6899). The validity of these findings is limited by the lack of a comparator group. Also, it is unclear if these effects are due to ashwagandha, other ingredients, or the combination. Cowhage contains levodopa, which may contribute to any benefit seen with this combination product.
• Psychological well-being. It is unclear if oral ashwagandha is beneficial for improving psychological well-being in college students. Details: A small clinical study in healthy college students shows that taking ashwagandha root extract 350 mg twice daily for 30 days improves perceptions of well-being, including improvements in energy, mental clarity, food cravings, and sleep quality, when compared with placebo. Qualitative analysis also suggests these students had improvements in stress management, but stress scores were not reduced when compared with placebo (109589,109590).
• Rheumatoid arthritis (RA). It is unclear if ashwagandha is beneficial for improving symptoms of RA. Details: Preliminary clinical research shows that taking ashwagandha powder 5 grams twice daily for 3 weeks, followed by 4 weeks of sidh makardhwaj (a mixture of gold, mercury, and sulfur) 100 mg with honey daily, modestly improves symptoms in about 50% of males and 60% of females with RA when compared with baseline (95620). The lack of a control group limits the validity of this finding. Additionally, the effect of ashwagandha powder alone is unclear.
• Sexual dysfunction. Small clinical studies suggest that oral ashwagandha root extract may help improve sexual arousal and sexual desire in some females and males with sexual dysfunction. Details: Two, small clinical studies in adult females with sexual dysfunction show that taking ashwagandha root extract (KSM-66, Ixoreal Biomed) 300 mg twice daily with food for 8 weeks in conjunction with or without counseling increases the number of successful sexual encounters and improves orgasms, satisfaction, lubrication, and arousal when compared with placebo or counseling alone (95619,110492). Also, a small clinical study in adult males with low sexual desire shows that taking the same ashwagandha root extract 300 mg twice daily after meals for 8 weeks improves subjective sexual functioning scores, including measures of sexual arousal, sexual desire, sexual behavior, and orgasm, when compared with placebo (109586).
• Smoking cessation. Oral ashwagandha has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in adults with a history of smoking 5 or more cigarettes daily for at least 3 years shows that taking a specific combination product containing ashwagandha 100 mg, Indian gooseberry, tribulus, bacopa, Albizia lebbeck, licorice, clove, ginger, cowhage, holy basil, and turmeric (Smotect, Smotect India) daily for 3 months reduces the number of cigarettes smoked daily and levels of alveolar carbon monoxide and carboxyhemoglobin but does not improve lung capacity when compared with placebo (112115). It is unclear if these effects are due to ashwagandha, other ingredients, or the combination.
• Tuberculosis. Although there has been interest in using oral ashwagandha for tuberculosis, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Vitiligo. Although there has been interest in using oral ashwagandha for vitiligo, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Wrinkled skin. It is unclear if topical ashwagandha is beneficial in individuals with wrinkled skin. Details: A small clinical study in healthy adults with photoaged skin shows that applying ashwagandha root extract 8% lotion daily for 60 days improves physician-rated scores for skin wrinkles, hydration, brightness, tone, and pigmentation and improves other measures of skin elasticity and hydration when compared with placebo. However, changes in melanin content did not differ between treatment groups (111538).
• Wound healing. Although there has been interest in using topical ashwagandha for healing of skin ulcers and skin sores, there is insufficient reliable information about the clinical effects of ashwagandha for this condition. More evidence is needed to rate ashwagandha for these uses.

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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

• Anxiety. Oral passion flower has a long history of use as a sedative and may improve symptoms of anxiety in some patients. Details: Preliminary clinical research shows that taking a specific dried alcoholic extract of passion flower (Sedanxio, Tilman SA) 400 mg orally twice daily for 2-8 weeks reduces the severity of non-specific anxiety when compared to baseline (88198). The validity of this finding is limited by the lack of a placebo group. Passionflower has also been evaluated as an adjunct to conventional medication. One clinical small study in patients with generalized anxiety disorder shows that taking a specific passion flower extract (Pasipay, Iran Darouk Pharmaceutical Company) 15 drops three times daily along with sertraline 50-100 mg daily for one month reduces anxiety when compared with taking sertraline alone (95036). Passion flower has also been compared to conventional treatments. One preliminary clinical study shows that taking passion flower extract 90-180 mg daily reduces symptoms of non-specific anxiety when compared to baseline, and seems to be comparable to taking mexazolam (15391). A small clinical study in patients with generalized anxiety disorder shows that taking a specific passion flower extract (Pasipay, Iran Darouk Pharmaceutical Company) 45 drops orally once daily for 28 days reduces anxiety similarly to oxazepam 30 mg daily. However, passion flower appears to have a slower onset of action than oxazepam (8007). This finding is limited because it did not utilize a therapeutic dosing regimen for oxazepam, which is given 3-4 times daily to account for its short half-life. Passion flower has also been studied in combination with other ingredients. A small clinical study in healthy adults shows that taking a combination of herbal extracts containing passion flower 40 mg, valerian root, black horehound, and hawthorn (Euphytose, Bayer HealthCare) 6 times daily with meals for 14 days reduces anxiety and sympathetic and autonomic nervous system activation in response to a psychosocial stressor when compared with placebo (111222). It is unclear if these effects are due to valerian, other ingredients, or the combination.
• Pre-procedural anxiety. Oral passion flower modestly reduces preoperative anxiety. Details: Two small clinical studies in adults awaiting dental surgery or inguinal hernia repair surgery shows that taking a specific passion flower extract (Pasipay, Iran Darouk Pharmaceutical Company) reduces preoperative anxiety when compared with placebo. Passion flower extract was given as 20 drops or 500 mg 90 minutes prior to surgery, with or without another dose on the evening before surgery (88195,88196). Another small clinical study shows that drinking 5 mL of syrup containing passion flower aqueous extract (Passiflora syrup, Sandoz) 700 mg orally 30 minutes before epidural catheter insertion for inguinal hernia repair surgery seems to attenuate anxiety; the placebo group experienced a significant increase in anxiety (88194). This finding is limited because there were no statistical comparisons conducted between groups. Passion flower has also been compared with conventional medications. Three clinical studies show that taking passion flower prior to dental surgery decreases preoperative anxiety similarly to oral midazolam 15 mg. One study used passion flower 260 mg, administered 30 minutes prior to the surgery (95038), the second used 500 mg, administered 60 minutes prior (104206), and the third used 600 mg, administered 45 minutes prior (110014). Of the two studies that evaluated patient preference, patients in one study preferred midazolam, possibly due to its ability to cause perioperative amnesia (95038), whereas there was no preference in the other study (110014). Another clinical study shows that taking passion flower 1000 mg one hour prior to elective minor or moderate surgery reduces preoperative anxiety similarly to melatonin 6 mg; however, passion flower seems to cause more cognitive impairment than melatonin (95037).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Adjustment disorders. Oral passion flower has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One clinical study in patients with adjustment disorder with anxious mood shows that taking two tablets of a specific combination product (Euphytose, Bayer Healthcare) three times daily seems to decrease anxiety symptoms when compared with placebo. One tablet contains the dry extracts of passion flower 40 mg, valerian 40 mg, hawthorn 10 mg, and black horehound 10 mg, as well as the caffeine-containing stimulant herbs kola nut 15 mg and guarana 15 mg (6250). It is unclear if this effect is due to passion flower, other ingredients, or the combination.
• Alcohol use disorder. Oral passion flower has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults experiencing alcohol withdrawal symptoms shows that taking one capsule of a combination product (Relief) three times daily for 15 days reduces the frequency of excessive sweating, reduces serum liver enzyme levels, and improves appetite and quality of life when compared to baseline. One capsule contains passion flower extract 30 mg, black seed extract 100 mg, cocoa extract 90 mg, radish extract 165 mg, and saffron extract 15 mg (97280). The validity of these findings is limited by the lack of a comparator group.
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral passion flower is beneficial in patients with ADHD. Details: A small clinical trial in children aged 6-13 years with ADHD shows that taking tablets of passion flower (Pasipay, Iran Darouk Pharmaceutical Company) 0.02 mg/kg orally twice daily for 8 weeks reduces parent and teacher ratings of ADHD symptoms no better than taking methylphenidate (0.5 mg/kg twice daily) (88197).
• Benzodiazepine withdrawal. It is unclear if oral passion flower is beneficial for benzodiazepine withdrawal. Details: A moderate-sized observational study in adults with depression or anxiety on antidepressants undergoing a benzodiazepine taper after chronic benzodiazepine use suggests that taking a specific dry extract of passion flower (Tractana, Baldacci) 200-600 mg daily for 3 months is associated with a faster benzodiazepine dose reduction and greater percentage of patients with at least 50% reduction or complete benzodiazepine discontinuation after 1 and 3 months from taper initiation when compared with control (111651). The validity of these effects is limited by a lack of placebo group and the retrospective observational study design.
• Congestive heart failure (CHF). Oral passion flower has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with mild CHF shows that taking a combination of passion flower and hawthorn extracts 2 mL three times daily for 6 weeks increases six-minute walking distance when compared with placebo. However, it does not appear to improve exercise capacity on a bicycle ergometer test (19201). It is unclear if this effect is due to passion flower, hawthorn, or the combination. Additionally, hawthorn has been evaluated alone for the management of CHF, with some research suggesting that although it may improve symptoms, it may also be associated with worsened clinical outcomes.
• Fibromyalgia. Although there is interest in using oral passion flower for fibromyalgia, there is insufficient reliable information about the clinical effects of passion flower for this condition.
• Insomnia. Small clinical studies suggest that oral passion flower may modestly improve sleep quality in patients with insomnia and poor sleep quality. Details: Some preliminary clinical research in adults with insomnia shows that taking passion flower extract 60 mg every evening before bedtime for 2 weeks increases total sleep time by around 23 minutes, but doesn't seem to improve sleep efficiency, sleep latency, or awakening after sleep onset, when compared with placebo (102866). Another smaller clinical study in young adults with mild fluctuations in sleep quality shows that drinking tea prepared by steeping passion flower aerial parts 2 grams in 250 mL of boiling water for 10 minutes every evening, about an hour before bedtime for 7 nights, improves subjective ratings of sleep quality, but not other sleep parameters, when compared with placebo (parsley tea) (17374). Passion flower has also been studied in combination with other ingredients. One small clinical study in adults with primary insomnia shows that taking a specific combination product containing passion flower 80 mg, valerian 300 mg, and hops 30 mg (NSF-3, M/s Tablets India) orally at bedtime for 2 weeks yields similar effects on subjective measures of sleep as zolpidem 10 mg nightly (88193).
• Menopausal symptoms. Although there is interest in using oral passion flower for menopausal symptoms, there is insufficient reliable information about the clinical effects of passion flower for this purpose.
• Muscle cramps. Although there is interest in using oral passion flower for muscle cramps, there is insufficient reliable information about the clinical effects of passion flower for this purpose.
• Neuropathic pain. Although there is interest in using oral passion flower for neuropathic pain, there is insufficient reliable information about the clinical effects of passion flower for this condition.
• Opioid withdrawal. It is unclear if oral passion flower helps to prevent opioid withdrawal. Details: A small preliminary clinical study in adults who are completing an inpatient withdrawal program for opioid addiction shows that taking passion flower liquid extract 60 drops, in combination with clonidine 0.8 mg daily, is better than clonidine alone when used for reducing symptoms such as anxiety, irritability, insomnia, and agitation. However, the combination is no better than clonidine alone for reducing physical symptoms such as tremor and nausea (2303).
• Seizures. Although there is interest in using oral passion flower for seizures, there is insufficient reliable information about the clinical effects of passion flower for this condition.
• Stress. Oral passion flower has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in healthy adults shows that taking a specific combination product (Relaxane, Max Zeller Söhne AG) containing passion flower 90 mg, lemon balm 50 mg, valerian 90 mg, and butterbur 90 mg three times daily for 3 days modestly reduces subjective anxiety scores during social stress testing when compared with placebo or no treatment (97276). It is unclear if this effect is due to passion flower, other ingredients, or the combination. More evidence is needed to rate passion flower for these uses.

(Read more about PASSION FLOWER)

POSSIBLY EFFECTIVE

• Athletic performance. Most available research suggests that oral tart cherry modestly improves muscular strength and endurance when compared with control. However, most studies are limited by a high risk of selection bias. Details: A meta-analysis of 14 small studies involving a total of 303 trained athletes and untrained healthy adults shows that tart cherry might modestly improve recovery of muscular strength and power when compared with control. Also, some subgroup analyses show that tart cherry may improve recovery of jump height and sprint time when compared with control (105629). In another meta-analysis of 10 studies involving 147 marathon runners, cyclists, or triathletes at various levels of training, taking tart cherry juice concentrate or powder 1.5 hours before exercise, or for up to 7 days prior to exercise, seems to improve exercise endurance, as measured by the time to complete an exercise trial, when compared with control (102340). However, both analyses have a high risk of selection bias and some analyses have high heterogeneity. Specific products assessed in the meta-analyses include tart cherry juice (CherryActive, Active Edge Nutrition) 60 mL, 90 minutes prior exercise (98699); a specific tart cherry concentrate (CherryActive, Active Edge Nutrition) 30 mL twice daily for 8 days (93149); and a specific freeze-dried tart cherry supplement (CherryPURE, Shoreline Fruit LLC) 480 mg daily 7 days before, on the day of, and 2 days after exercise (93158).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aromatase inhibitor-induced arthralgia. It is unclear if oral tart cherry is beneficial in patients with aromatase inhibitor-induced arthralgia (AIIA). Details: Preliminary clinical research in a small group of females with non-metastatic, hormone-receptor positive breast cancer and AIIA after taking aromatase inhibitors for at least 4 weeks shows that taking tart cherry juice concentrate 30 mL daily for 6 weeks reduces pain scores on a visual analog scale by about 35%, compared with 1% in those taking placebo (109657).
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral tart cherry juice is beneficial in children with ADHD. Details: A small clinical study in children and adolescents aged 6 to 18 years with ADHD shows that consuming tart cherry juice concentrate 75 mL twice daily for 2 weeks with standard treatment does not improve ADHD symptoms including cognitive impairment, hyperactivity, impulsivity, or oppositional behavior when compared with placebo (112815).
• Cognitive function. It is unclear if oral tart cherry improves cognitive function. Details: Preliminary clinical research in healthy, middle-aged adults shows that taking tart cherry juice concentrate 30 mL orally twice daily for 3 months reduces mental fatigue and improves performance on tests evaluating sustained attention, psychomotor speed, and alertness when compared with placebo. However, it does not affect sleep quality or cerebral blood flow (109655).
• Exercise-induced muscle soreness. Research on the use of oral tart cherry juice or supplements for the reduction of exercise-induced muscle soreness is conflicting. Details: A meta-analysis of 12 small studies in trained athletes and untrained healthy adults shows that tart cherry might modestly attenuate delayed muscle soreness after exercise involving maximal muscle contractions or maximal effort sprints when compared with control. However, tart cherry juice seems to be no better than placebo for improving delayed muscle soreness after prolonged aerobic exercise (105629). These findings are limited by a high risk of selection bias, high heterogeneity, and imprecision. Some products assessed in the meta-analysis include a specific Montmorency tart cherry concentrate (Holland & Barrett Ltd.) 30 mL twice daily for 5 days before, on the day of, and for 2 days after intermittent sprint exercises (102341); a specific freeze-dried tart cherry supplement (CherryPURE, Shoreline Fruit LLC) 480 mg daily for 7 days before, on the day of, and 2 days after running a half-marathon or doing back squats (93157,93158); a specific Montmorency tart cherry juice concentrate (CherryActive, Active Edge Nutrition) 30 mL diluted in water and taken twice daily for 8 days (93149,93151,101880,102344); and a specific juice (Sour cherry juice, Cherrypharm Inc.) containing 90% tart cherry juice and 10% apple juice as a sweetener, twice daily (93152,93154). Some individual clinical studies have yielded mixed findings. One clinical study in professional rugby players shows that taking a Montmorency tart cherry juice concentrate gel, 30 mL (equivalent to 100 cherries) twice daily for 2 days before, on the day of, and for 2 days after a match does not improve muscle soreness when compared with placebo (102339). Similarly, in male professional soccer players, taking tart cherry juice, 60 mL before and after a 90-minute match and then 12 and 36 hours later, does not improve subjective muscle soreness when compared with placebo (102342). Also, a small study in healthy males shows that taking a specific tart cherry supplement (Tart Cherry Extract Powder NordicCherry, Specnova, LLC.) 500 mg daily for 7 days prior to performing resistance exercise does not reduce muscle soreness when compared with placebo (105631). In contrast, a small clinical study in recreational long-distance runners shows that drinking a specific tart cherry juice (Cherrish, Cherrish Corp.) 10.5 ounces twice daily for 7 days prior to a long-distance race decreases post-race muscle pain by around 65% when compared with placebo (93156). Reasons for the discrepancies may include differences in tart cherry products, the small number of subjects, and heterogeneity in study populations and evaluated endpoints. In some studies, the subjects' normal diets were continued during the study, whereas in others, a reduced polyphenol diet was consumed for the duration of the study (102342,105629).
• Exercise-induced respiratory infections. It is unclear if oral tart cherry juice reduces the risk of exercise-induced respiratory infections. Details: A small clinical study in recreational athletes shows that drinking a specific juice blend (Sour cherry juice, Cherrypharm Inc.), containing 90% tart cherry juice and 10% apple juice as a sweetener, 8 ounces twice daily for 5 days before, on the day of, and 2 days after running a marathon, decreases the risk for upper respiratory tract symptoms such as cough, sore throat, congestion, and sneezing when compared with placebo (93168).
• Fibromyalgia. It is unclear if oral tart cherry improves symptoms in patients with fibromyalgia. Details: A very small clinical study in females with fibromyalgia participating in an eccentric exercise program shows that taking a specific tart cherry concentrate (Cherrish, Cherrish Corp.) 10.5 ounces twice daily for 14 days does not improve pain or muscle strength when compared with placebo (93192).
• Gout. It is unclear if oral tart cherry juice reduces symptoms of gout; research is conflicting. Details: Preliminary clinical research shows that tart cherry juice lowers serum urate and increases urinary urate excretion in healthy people, as well as people with hyperuricemia that has not progressed to gout (93166,102338). However, in patients with gout, taking Montmorency tart cherry juice concentrate (Cherryvite) in doses of 7.5-30 mL twice daily for 28 days does not affect urate excretion or the frequency of gout flares (102343). A small, unblinded clinical study in adults with chronic gout shows that taking a combination product (GoutFighter, MaxBiocare Pty Ltd.) containing tart cherry fruit extract 100 mg, celery seed extract 300 mg, devil's claw tuber extract 150 mg, folic acid 90 mcg, potassium citrate 50 mg, and ascorbic acid 50 mg orally, as 2 tablets twice daily for 45 days, modestly reduces mean serum uric acid levels and reduces perceived pain and frequency of joint swelling when compared to baseline (106488). The validity of these findings is limited by the lack of a comparator group. Additionally, it is unclear if any effects are due to tart cherry, other ingredients, or the combination.
• Hypertension. It is unclear if oral tart cherry juice reduces blood pressure; research is conflicting. Details: A very small clinical study in males with mild hypertension shows that taking 60 mL of a specific tart cherry concentrate (CherryActive, Active Edge Nutrition) modestly decreases systolic, but not diastolic, blood pressure 1-3 hours after consumption when compared with placebo (93155). This finding is limited by the small study size and the use of a single dose. Another small study in healthy adults without hypertension shows that drinking 30 mL of Montmorency tart cherry concentrate (Cherry Marketing Institute) diluted in 240 mL of water daily for 3 months does not reduce blood pressure when compared with baseline or placebo (105633).
• Insomnia. Some small clinical studies suggest that oral tart cherry juice may modestly improve sleep and reduce insomnia. This effect might be due to the melatonin content in tart cherry juice. However, the evidence is conflicting. Details: A small clinical study in healthy adults less than 40 years of age shows that consuming a specific tart cherry juice concentrate (CherryActive, Active Edge Nutrition) 30 mL standardized to contain 1.42 mcg/mL of melatonin twice daily for 7 days modestly increases total sleep time and efficiency when compared with placebo (17199). Another small clinical study in adults aged 65 years and older with chronic insomnia shows that drinking a specific juice blend (Sour cherry juice, Cherrypharm Inc.), containing 90% tart cherry juice and 10% apple juice as a sweetener, 8 ounces twice daily for 14 days, modestly improves insomnia severity, but not sleep latency, when compared with placebo (17403). However, another very small clinical study in healthy adults shows that taking Montmorency tart cherry juice 240 mL twice daily or powdered Montmorency tart cherry capsules 1000 mg daily for 30 days does not improve sleep quality, sleep time, or serum melatonin concentration when compared with placebo (112813). The effects of tart cherry on sleep measures have also been evaluated in combination with other ingredients. A very small crossover study in healthy adults without a sleep disorder shows that taking a combination product containing tart cherry powder 220 mg, tryptophan, glycine, magnesium, and L-theanine 2 hours before bedtime for 3 nights decreases the time to fall asleep by about 24 minutes, increases total sleep duration by about 22 minutes, improves sleep efficiency, and reduces morning sleepiness, but does not improve the total time in bed or wakefulness after falling asleep when compared with placebo (111184). It is unclear if these effects are due to tart cherry, other ingredients, or the combination.
• Metabolic syndrome. Oral tart cherry juice does not seem to improve cardiovascular or metabolic biomarkers in patients at risk for or with metabolic syndrome. Details: Two meta-analyses of small, moderate-quality clinical studies in healthy adults, patients with metabolic syndrome, or those with risk factors for metabolic syndrome, that include many of the same studies, show that drinking tart cherry juice 30-480 mL daily for 1-12 weeks does not improve fasting blood glucose, insulin levels, lipid profiles, blood pressure, body weight, body mass index, fat mass, percentage body fat, or waist circumference when compared with placebo (112812,112814).
• Osteoarthritis. It is unclear if oral tart cherry juice is beneficial in patients with osteoarthritis. Details: A small clinical study in patients with osteoarthritis shows that drinking a specific juice blend (Sour cherry juice, Cherrypharm Inc.) containing 90% tart cherry juice and 10% apple juice as a sweetener, 8 ounces twice daily for 6 weeks, does not improve pain, stiffness, function, walking speed, or acetaminophen use when compared with placebo (93160). The validity of this finding is limited because the trial was not adequately powered to detect small differences between groups. More evidence is needed to rate tart cherry for these uses.

(Read more about TART CHERRY)

POSSIBLY SAFE ...when used orally and appropriately, short-term. Ashwagandha has been used with apparent safety in doses of up to 1250 mg daily for up to 6 months (3710,11301,19271,90649,90652,90653,97292,101816,102682,102683) (102684,102685,102687,103476,105824,109586,109588,109589,109590). ...when used topically. Ashwagandha lotion has been used with apparent safety in concentrations up to 8% for up to 2 months (111538).

PREGNANCY: LIKELY UNSAFE
when used orally. Ashwagandha has abortifacient effects (12).

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about ASHWAGANDHA)

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

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

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

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

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about PASSION FLOWER)

LIKELY SAFE ...when the fruit is used in amounts commonly found in foods. ...when tart cherry fruit, fruit juice, or fruit juice concentrate is used orally in supplemental amounts for up to 3 months (17403,93149,93151,93152,93153,93154,93156,93157,93158,93160)(93161,93168,93179,105633).

POSSIBLY SAFE ...when tart cherry fruit extract or powder is used orally, short term. Cherry fruit extract or freeze-dried cherry powder up to 500 mg daily for up 7 days has been used with apparent safety (93157,93158,105631). There is insufficient reliable information available about the safety of tart cherry stem when used orally.

PREGNANCY AND LACTATION: LIKELY SAFE
when the fruit is consumed in typical food amounts. There is insufficient reliable information available about the safety of tart cherry fruit or stem when used in medicinal amounts; avoid using.

(Read more about TART CHERRY)

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking ashwagandha with antidiabetes drugs might increase the risk of hypoglycemia.  Details There is preliminary clinical evidence suggesting that ashwagandha might lower blood glucose levels. Theoretically, ashwagandha might have additive effects when used with antidiabetes drugs and increase the risk of hypoglycemia (19274,90649,102685).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking ashwagandha with antihypertensive drugs might increase the risk of hypotension.  Details Animal research suggests that ashwagandha might lower systolic and diastolic blood pressure (19279). Theoretically, ashwagandha might have additive effects when used with antihypertensive drugs and increase the risk of hypotension.

BENZODIAZEPINES Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking ashwagandha might increase the sedative effects of benzodiazepines.  Details There is preliminary evidence that ashwagandha might have an additive effect with diazepam (Valium) and clonazepam (Klonopin) (3710). This may also occur with other benzodiazepines.

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking ashwagandha might increase the sedative effects of CNS depressants.  Details Ashwagandha seems to have sedative effects. Theoretically, this may potentiate the effects of barbiturates, other sedatives, and anxiolytics (3710).

IMMUNOSUPPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking ashwagandha might decrease the effects of immunosuppressants.  Details Ashwagandha has demonstrated immunostimulant effects in humans (3710,3711,4114,11301,106786). Animal research has shown that ashwagandha can attenuate the immunosuppression caused by cyclophosphamide (3711,4114).

THYROID HORMONE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Ashwagandha might increase the effects and adverse effects of thyroid hormone.  Details Concomitant use of ashwagandha with thyroid hormones may cause additive therapeutic and adverse effects. Preliminary clinical research and animal studies suggest that ashwagandha boosts thyroid hormone synthesis and secretion (19281,19282,97292). In one clinical study, ashwagandha increased triiodothyronine (T3) and thyroxine (T4) levels by 41.5% and 19.6%, respectively, and reduced serum TSH levels by 17.4% from baseline in adults with subclinical hypothyroidism (97292).

(Read more about ASHWAGANDHA)

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.

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

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

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

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General ...Orally, ashwagandha seems to be well-tolerated. Topically, no adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Orally: Diarrhea, gastrointestinal upset, nausea, and vomiting. However, these adverse effects do not commonly occur with typical doses.
Serious Adverse Effects (Rare):
Orally: Some case reports raise concerns about acute liver failure, hepatic encephalopathy, and the need for liver transplantation with ashwagandha treatment.

Dermatologic ...Orally, dermatitis has been reported in three of 42 patients in a clinical trial (19276).

Endocrine ...A case report describes a 73-year-old female who had taken an ashwagandha root extract (unspecified dose) for 2 years to treat hypothyroidism which had been previously managed with levothyroxine. The patient was diagnosed with hyperthyroidism after presenting with supraventricular tachycardia, chest pain, tremor, dizziness, fatigue, irritability, hair thinning, and low thyroid stimulating hormone (TSH) levels. Hyperthyroidism resolved after discontinuing ashwagandha (108745).

Gastrointestinal ...Orally, large doses may cause gastrointestinal upset, diarrhea, and vomiting secondary to irritation of the mucous and serous membranes (3710). When taken orally, nausea and abdominal pain (19276,110490) and gastritis and flatulence (90651) have been reported.

Genitourinary ...In one case report, a 28-year-old male with a decrease in libido who was taking ashwagandha 5 grams daily over 10 days subsequently experienced burning, itching, and skin and mucous membrane discoloration of the penis, as well as an oval, dusky, eroded plaque (3 cm) with erythema on the glans penis and prepuce (32537).

Hepatic ...Orally, ashwagandha in doses of 154-1350 mg daily has played a role in several case reports of liver injury. In most of these cases, other causes of liver injury were excluded, and liver failure did not occur. Symptoms included jaundice, pruritus, malaise, fatigue, lethargy, weight loss, nausea, diarrhea, abdominal pain, stool discoloration, and dark urine. Symptom onset was typically 5-180 days from first intake, although in some cases onset occurred after more than 12 months of use (102686,107372,110490,110491,111533,111535,112111). Laboratory findings include elevated aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase, and serum bilirubin (112111). In most cases, liver enzymes normalized within 1-5 months after discontinuation of ashwagandha (102686,107372,110491,111535,112111). However, treatment with corticosteroids, lactulose, ornithine, ursodeoxycholic acid, and plasmapheresis, among other interventions, was required in one case (111533). Rarely, use of oral ashwagandha has been reported to cause hepatic encephalopathy and liver failure requiring liver transplantation (110490).

Neurologic/CNS ...Orally, ashwagandha has been reported to cause drowsiness (110492). Headache, neck pain, and blurry vision have been reported in a 47-year-old female taking ashwagandha, cannabis, and venlafaxine. Imaging over the course of multiple years and hospital admissions indicated numerous instances of intracranial hemorrhage and multifocal stenosis of intracranial arteries, likely secondary to reversible cerebral vasoconstriction syndrome (RCVS) (112113). It is unclear whether the RCVS and subsequent intracranial hemorrhages were precipitated by ashwagandha, cannabis, or venlafaxine.

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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).

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

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

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

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

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

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

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

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

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General ...Tart cherry is generally well tolerated when consumed as whole fruit, juice concentrate, or seed extracts.
Most Common Adverse Effects:
Orally: Abdominal pain, asthenia, gastrointestinal upset, loose stools.

Endocrine ...One case of hyperglycemia after drinking a specific blend of tart cherry and apple juices ) has been reported (93160).

Gastrointestinal ...In a clinical study, 29% of children who consumed 75 mL of tart cherry juice concentrate twice daily for 2 weeks reported abdominal pain (112815). Two cases of loose stools after consumption of 90 whole tart cherries, and one case of gastrointestinal disturbance after drinking 10.5 ounces of tart cherry concentrate (Cherrish, Cherrish Corp.) twice daily for 14 days have been reported (93186,93192). One case of gastrointestinal symptoms after drinking a specific blend of tart cherry and apple juice (Sour cherry juice, Cherrypharm Inc.) has been reported (93160).

Immunologic ...One case of a skin reaction possibly due to cherry allergy after drinking a specific blend of tart cherry and apple juice ) has been reported (93160).

Musculoskeletal ...In a clinical study, 31% of children who consumed tart cherry juice concentrate 75 mLl twice daily for 2 weeks reported asthenia (112815).

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