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EFFECTIVE

• Bowel preparation. Various magnesium salts are used for cleansing the bowel prior to procedures such as colonoscopy. Details: Various magnesium salts, including citrate, hydroxide, oxide, and sulfate, are ingredients in bowel preparation products available over-the-counter or by prescription only.
• Constipation. Magnesium salts are effective when used short-term orally to treat constipation and chronic idiopathic constipation (CIC). Details: Magnesium citrate, hydroxide, oxide, and sulfate salts are commonly used as laxatives. Magnesium citrate 11.3-17.45 grams has been used; magnesium hydroxide 2.4-4.8 grams, as 30-60 mL of milk of magnesia, has also been used (113483,113484). Magnesium sulfate, also known as Epsom salt, which seems to have the most potent effect, has been used as 10-30 grams (6430,113485). Magnesium salts should only be used for occasional treatment of constipation, and doses should be taken with a full 8-ounce glass of water. Magnesium oxide seems to be beneficial in adults with CIC when taken short-term. Clinical guidelines published by the American Gastroenterology Association and American College of Gastroenterology in 2023 give a conditional recommendation suggesting the use of magnesium oxide over managing CIC without magnesium oxide based on low-quality studies conducted over 4 weeks. The recommended starting dose is 400-500 mg daily with dose titration per symptom response and side effects (112859). A small clinical study in patients with CIC who are not taking chronic medications shows that taking magnesium oxide 1.5 grams in three divided doses daily for 28 days increases spontaneous bowel movements when compared with placebo (104397). It is unknown if magnesium is beneficial for CIC when used long-term.
• Dyspepsia. Magnesium salts are effective when used orally as antacids. Details: Magnesium carbonate, hydroxide, oxide, or trisilicate salts are used orally as antacids to reduce symptoms of gastric hyperacidity or gastroesophageal reflux. Magnesium hydroxide has the fastest onset of action. The onset for magnesium carbonate is slower due to its crystal structure. Magnesium trisilicate has the slowest onset and longest duration of action due to poor solubility (6844). Doses used include magnesium hydroxide 400-1200 mg (5-15 mL of milk of magnesia) up to four times daily, or magnesium oxide 800 mg daily (15).
• Eclampsia. Magnesium sulfate is considered the drug of choice for control of seizures. Details: Intravenous (IV) and/or intramuscular (IM) magnesium sulfate is considered the agent of choice for seizure prophylaxis during eclampsia by the American College of Obstetricians and Gynecologists (ACOG) (15,12591,12592,61012,61184). Typical doses include 4-6 grams of magnesium sulfate by IV infusion in 250 mL of dextrose 5% or normal saline solution, followed by 4-5 grams of magnesium sulfate IM every 4 hours, or 1-3 grams per hour by continuous IV infusion. Doses should be adjusted according to serum levels and urinary excretion, and should not exceed 30-40 grams of magnesium sulfate daily (15,12591). Meta-analyses of clinical research show that treatment with IV or IM magnesium reduces the risk of seizure recurrence by 33% to 69% when compared with phenytoin, and by 47% to 60% when compared with diazepam (19960,60818,60954,60964,61105). One preliminary clinical study shows that lower doses of IV magnesium sulfate (9 grams loading dose and maintenance of 2.5 grams every 4 hours for 24 hours) are as effective as higher doses (14 grams loading dose and maintenance of 5 grams every 4 hours for 24 hours) for reducing the recurrence of eclamptic seizures (89383). It is generally recommended that treatment be continued for at least 24 hours after the last seizure (15). Oral magnesium has not been evaluated for eclampsia.
• Hypomagnesemia. Hypomagnesemia can be effectively treated with oral or parenteral magnesium. Details: Taking magnesium orally or parenterally is helpful for treating and preventing hypomagnesemia associated with alcoholism, cirrhosis of the liver, congestive heart failure (CHF), severe or prolonged diarrhea or vomiting, kidney dysfunction, inflammatory bowel disease (IBD), pancreatitis, malabsorption syndromes, and other conditions (6280,6281,8088,8089). The dose and salt of magnesium for oral replacement therapy should be chosen carefully to avoid causing diarrhea. The gluconate and chloride salts cause less diarrhea, while the oxide salt is more likely to cause diarrhea and should be avoided. Magnesium chloride should also be avoided due to poor solubility which decreases absorption (6430,8099,10664). Orally, magnesium sulfate 3 grams every 6 hours for four doses has been used for hypomagnesemia (15). Parenteral magnesium doses must be individualized according to serum magnesium levels, but a typical starting dose for mild deficiency is 1 gram of magnesium sulfate intramuscularly (IM) every 6 hours for 4 doses (15). For more severe deficiency, 5 grams of magnesium sulfate may be given as an intravenous (IV) infusion in 1 liter of dextrose 5% or normal saline solution over 3 hours (15).
• Pre-eclampsia. Magnesium sulfate is considered the drug of choice for seizure prophylaxis in patients with pre-eclampsia. Details: Intravenous (IV) and/or intramuscular (IM) magnesium sulfate is considered the agent of choice for seizure prophylaxis during pre-eclampsia by the American College of Obstetricians and Gynecologists (ACOG) (12591,12592,61012,61184). Some meta-analyses show that IV administration of magnesium sulfate reduces the risk of eclampsia when compared with placebo, phenytoin, or diazepam in patients with pre-eclampsia (19960,60818,60960,60979). A typical initial dose is 4-5 grams of magnesium sulfate by IV infusion in 250 mL of dextrose 5% or normal saline solution, followed by 4-5 grams of magnesium sulfate IM every 4 hours, or 1-3 grams of magnesium sulfate per hour by continuous IV infusion. Doses should be adjusted according to serum levels and urinary excretion, and should not exceed 30-40 grams of magnesium sulfate daily (15,12591). The optimal duration of prophylaxis has not been determined. A meta-analysis suggests that using a shorter duration of 12 hours or less is not associated with an increase in risk of eclamptic seizures when compared with regimens of 24 hours or longer (108732). However, studies are likely underpowered due to the low incidence of eclampsia. Oral magnesium has been evaluated for the prevention of pre-eclampsia in healthy adults, but taking magnesium citrate 300 mg daily, starting at 12-20 weeks' gestation and continuing until delivery, does not reduce the incidence of pre-eclampsia when compared with placebo (103724).

LIKELY EFFECTIVE

• Cerebral palsy. Most evidence shows that antenatal magnesium reduces the risk of cerebral palsy in preterm infants, although there are some inconsistent results. Details: Most clinical studies and meta-analyses show that antenatal magnesium sulfate reduces the risk of cerebral palsy by about 32% and the risk of motor dysfunction by about 45% in preterm infants (60915,60927,60931,61001,97485,103734,103754,114675,114681). The lowest effective dose of magnesium sulfate seems to be 4 grams intravenously, with or without a maintenance dose of 1 gram/hour until birth or for 24 hours. In obese females, a higher dose, based on body weight, may be needed (97485,97495,103734,103754). However, some studies have inconsistent results (8093,19998,98293,98295,112784). Giving females at risk of imminent preterm birth (prior to 32 weeks), intravenous magnesium sulfate 4.5 grams over 20 minutes followed by 1 gram per hour until birth or for 24 hours, in addition to a standard treatment protocol, does not reduce the incidence of cerebral palsy (112784). Oral magnesium has not been evaluated for this purpose.
• Seizures. Intravenous magnesium sulfate is used for treating seizures of various etiologies. Details: Intravenous magnesium sulfate may be useful for controlling seizures associated with epilepsy, glomerulonephritis, hypothyroidism, and acute nephritis in children (15). Oral magnesium has not been evaluated for this purpose.
• Torsades de pointes. Intravenous magnesium sulfate is the first-line treatment for torsades de pointes after measures to correct precipitating factors have been unsuccessful. Details: Intravenous magnesium sulfate has been used successfully to treat the life-threatening ventricular tachycardia, torsades de pointes (15,6844). The Advanced Cardiac Life Support (ACLS) guidelines of the American Heart Association recommend a dose of 1 to 2 grams diluted in 50-100 mL Dextrose 5% solution given IV over 5-60 minutes, followed by a continuous IV infusion of 0.5-1 gram/hour.

POSSIBLY EFFECTIVE

• Arrhythmia. Magnesium sulfate is effective for the specific type of ventricular tachycardia known as torsades de pointes, and seems to be helpful for treating other types of arrhythmias. Evidence for the role of oral or intravenous magnesium in preventing postoperative arrhythmias is conflicting. Details: Administering magnesium intravenously or orally may be helpful for treating atrial and ventricular tachycardia and fibrillation, and supraventricular tachycardia (9497,13352,13354,13355,13356,60804,60829,60877,61113,111696). Arrhythmias associated with congestive heart failure have been treated with magnesium sulfate 8 grams infused over 12 hours (9497). For rate control in atrial fibrillation, magnesium sulfate 2.5 grams IV over 20 minutes, followed by 2.5 grams IV over 2 hours has been used (13356). For paroxysmal supraventricular tachycardia, single doses of 1-4 grams of magnesium chloride have been used (13352). For atrial tachycardia, 2 grams of magnesium sulfate in 10 mL of dextrose 5% solution has been given IV over 1-10 minutes, followed by 5-10 grams of magnesium sulfate in 250-500 mL dextrose 5% solution as an IV infusion over 5 hours (13354,13355). Research on the effects of intravenous magnesium for preventing arrhythmias after cardiac surgery is conflicting. Some meta-analyses show that intravenous magnesium reduces the risk of atrial fibrillation, ventricular arrhythmias, or supraventricular arrhythmias following cardiac surgery by 23% to 48% when compared with placebo (60814,60826,60828,60838,61008,61033,61181,97487,97490). Doses of magnesium sulfate used include 30 mg/kg in 500 mL normal saline (97490), or 80-100 mg/kg added to the cardioplegia solution (97487). Also, one small study in adults after CABG surgery suggests that taking magnesium hydroxide 1600 mg orally reduces arrhythmia as effectively as receiving magnesium sulfate 2000 mg intravenously (99315). However, other meta-analyses that only include higher-quality trials show that magnesium supplementation does not reduce the risk of ventricular or supraventricular arrhythmias following cardiac surgery (61010,61024,61031,105081). A meta-analysis of clinical trials of intravenous magnesium for prevention of new-onset atrial fibrillation after non-cardiac surgeries shows that it does not reduce the incidence significantly when compared with placebo (112778). However, there was a high risk of bias in the analysis, and variability in types of surgery, and the salt and dose of magnesium used.
• Asthma. Parenteral magnesium sulfate can help to reverse severe acute asthma attacks and reduce the need for hospital admission. It is unclear if nebulized magnesium is beneficial for acute asthma attacks. However, oral magnesium does not seem to be beneficial. Details: Overall, a single dose of intravenous magnesium seems to improve pulmonary function in acute asthma exacerbation and reduce the risk of hospitalization, particularly in patients with severe asthma, and those who have failed initial treatment with nebulized albuterol and intravenous corticosteroids (60888,90023,96483,104398,107365). The typical dose used for adults is 2 grams of magnesium sulfate infused over 20 minutes (15). For children, 25-75 mg/kg, to a maximum of 2 grams, infused over 20-30 minutes has been used (15,96483,107365). However, a post-hoc analysis of one large clinical trial (104400) designed to assess nebulized magnesium in children with acute asthma has found that adding IV magnesium to nebulized magnesium is associated with greater odds of hospitalization when compared with no IV magnesium (105919). This post-hoc analysis did not differentiate between precautionary and necessary hospitalizations. Although some clinical research and a meta-analysis in patients with acute asthma exacerbation show that nebulized magnesium in combination with standard treatment improves airway function, respiratory rate, and clinical asthma severity when compared with standard treatment alone, it is unclear whether these findings are clinically relevant (90016,113466). Most evidence, including larger clinical trials and meta-analyses, has not shown benefit of adjunct nebulized magnesium for acute asthma in adults or children (60888,90002,96484,104400,105920,113466,114674). Oral magnesium also does not seem to be beneficial. A meta-analysis of small clinical trials in children and adults with asthma shows that taking magnesium supplements orally does not improve lung function or reduce bronchodilator use when compared with control (104404).
• Colorectal cancer. Increasing dietary magnesium intake seems to lower the risk of colon cancer but not rectal cancer. Details: Epidemiological research shows that increased dietary magnesium intake is associated with a reduced risk of colon cancer, but the risk of rectal cancer is not affected (89387,90017,90027,101355).
• Diabetes. Low dietary magnesium may increase the risk of developing type 2 diabetes, but evidence on the use of supplements for treating type 2 diabetes is conflicting. Details: Higher dietary magnesium intake is associated with lower fasting insulin concentrations and a reduced risk of developing type 2 diabetes in adults and obese children (13369,15548,96473,97486,98294,103736,105918,106920). In people with existing type 2 diabetes, hypomagnesemia is found in 25% to 38% of patients, especially in those with poorly controlled diabetes (1172). Population research in adults with type 2 diabetes also shows that a dietary magnesium intake of less than 250 mg daily is associated with a 56% higher risk of mortality. Preliminary subgroup analyses suggest that the risk of mortality is higher in those with glycated hemoglobin (HbA1C) levels above 7% (110051). A meta-analysis of small, heterogeneous clinical studies in adults with type 2 diabetes suggests that magnesium may modestly reduce HbA1C in patients with hypomagnesemia, but not in patients with normal magnesium levels, when compared with control (105075). Individual clinical studies using magnesium supplements in patients with type 2 diabetes or insulin resistance have shown mixed results. Some research suggests magnesium supplements can decrease fasting blood glucose and improve insulin sensitivity, as well as reduce the risk of developing diabetes in high-risk patients (10664,12582,13376,60854,99313,106920), but other research shows no effect (1171,1172,13379,13380,112780). Discrepancies in these findings might reflect differences in magnesium salts and doses used, or differences in baseline magnesium status in study subjects.
• Hypercholesterolemia. Magnesium may help improve lipid levels by a small amount in people with this condition. Details: There is some evidence that taking magnesium oxide 1 gram orally daily for 6 weeks can produce small decreases in low-density lipoprotein (LDL) and total cholesterol levels, and small increases in high-density lipoprotein (HDL) levels in patients with hypercholesterolemia. However, magnesium does not seem to improve lipoprotein (a) levels (1193). Magnesium may also lower triglycerides in people with hypertriglyceridemia (97494).
• Metabolic syndrome. Low dietary and serum levels of magnesium seem to be associated with the development of metabolic syndrome. Details: Higher magnesium intake from diet and supplements is associated with a 27% lower risk of developing metabolic syndrome in healthy females (13371) and a 31% lower risk in healthy young adults (14304). Additional epidemiological research suggests that people with low serum magnesium levels are 6-7 times more likely to have metabolic syndrome than people with normal magnesium levels (13372). In a population analysis of over 6000 individuals without metabolic syndrome at baseline, the risk of developing this condition over a 6-year follow-up period was reduced by 16% in the highest quintile of dietary magnesium intake (median intake 371 mg daily) when compared with the lowest quintile (median intake 203 mg daily). Some, but not all, research suggests that the hazard ratio for metabolic syndrome in relation to magnesium intake may be U-shaped, with higher risk at intakes below about 150 mg daily and above 600 mg daily (108963). A combination of magnesium 20 mEq daily and potassium 40 mEq daily (magnesium potassium citrate) taken orally for 16 weeks reverses metabolic side effects of chlorthalidone, such as increased fasting plasma glucose and hypokalemia, more effectively than potassium chloride 40 mEq daily alone (112932).
• Osteoporosis. Increased dietary and supplemental magnesium intake seems to increase bone mineral density and decrease bone loss in postmenopausal patients. Details: Preliminary clinical research shows that taking magnesium hydroxide orally, 300-1800 mg daily for 6 months, then 600 mg daily for 18 months, or magnesium citrate orally 1830 mg daily for 30 days, might reduce bone loss and bone turnover in postmenopausal patients with osteoporosis (9104,60928). Some epidemiological research also suggests that magnesium intake is related to increased bone mineral density (12501,12502,12503,12504,90014), although not all studies have found an association (12505,98286).
• Postoperative pain. Injectable magnesium has been used with promising results for reducing pain and the need for other analgesics postoperatively. Details: A meta-analysis of 25 clinical trials shows that intravenous (IV) magnesium sulfate, 5-50 mg/kg bolus followed by a continuous infusion of 6 mg/kg or 500 mg hourly during surgery, seems to reduce the 24-hour postoperative use of IV morphine by 24% when compared with placebo (19968). Adding IV magnesium sulfate 3.7-5.5 grams to patient-controlled analgesia for 24 hours after surgery has also been used (19968). Additionally, meta-analyses support that adjunctive IV or intrathecal administration of magnesium reduces post-operative pain scores, improves pain relief and sensory nerve block, and decreases the need for other analgesics, when compared with control (89390,90012,90015,98287,103728,114676,114677,114678). However, some data are conflicting. In a meta-analysis of 7 trials, IV magnesium was not associated with lower pain scores over the first 48 hours postoperatively. The reasons for these discrepant findings are unclear but may be explained by differences in magnesium regimens, anesthesia protocols, and surgical populations studied. Additionally, IV magnesium appears to be less effective than dexmedetomidine (105082). Two moderate-sized clinical studies in patients undergoing total knee arthroplasty in China show that adding magnesium sulfate 2.5 mg/mL to the periarticular infiltration analgesia (PIA) cocktail or administering IV magnesium sulfate 40 mg/kg before anesthesia induction then as a 15 mg/kg infusion during surgery reduces pain scores, increases comfort levels, limits and delays the use of postoperative opioids, prolongs analgesia, and reduces markers of inflammation when compared with the usual PIA cocktail or control (111181,113677). Administering magnesium intravenously also seems to be helpful for pain control after hysterectomy. A 3-gram IV bolus of magnesium sulfate followed by an infusion of 0.5 grams per hour for 20 hours has been used. Lower doses were not effective (6848). In males undergoing laparoscopic radical resection for gastrointestinal cancer, administering IV magnesium intraoperatively, as a loading dose of 40 mg/kg followed by 15 mg/kg/hour through the end of surgery, reduces postoperative catheter-related bladder discomfort and analgesic requirements, when compared with placebo (112783). However, IV magnesium might not alleviate postoperative pain in children. Two small clinical studies show that administering a magnesium IV infusion does not reduce pain when compared with saline in children after tonsillectomy or after elective strabismus surgery (98282,105077).
• Premenstrual syndrome (PMS). Taking magnesium orally seems to relieve symptoms of PMS. Details: There is some evidence that magnesium supplementation can improve symptoms, including mood changes and fluid retention, in some patients with PMS (1187,1188,6847). Doses used include magnesium oxide 333 mg daily for 2 menstrual cycles, or magnesium pyrrolidone carboxylic acid equivalent to 360 mg elemental magnesium three times daily, from the 15th day of the menstrual cycle until onset of menstrual flow (1187,1188). Taking magnesium orally in a dose of 360 mg (elemental magnesium) three times daily for 2 months seems to prevent premenstrual migraine (1186,6847). A combination of magnesium 200 mg daily plus vitamin B6 50 mg daily seems to reduce anxiety-related premenstrual symptoms, including nervous tension, mood swings, irritability, and anxiety, when compared with placebo (8555).
• Vasospastic angina. Intravenous magnesium seems to prevent coronary spasm in patients with this condition. Details: Clinical research shows that administration of intravenous magnesium sulfate 65 mg/kg infused over 20 minutes dilates coronary arteries and suppresses acetylcholine-induced coronary spasms when compared with infusion of a dextrose solution in patients with vasospastic angina (8091).

POSSIBLY INEFFECTIVE

• Altitude sickness. Taking magnesium citrate orally does not seem to reduce acute altitude sickness risk. Details: Clinical research shows that taking magnesium citrate 1200 mg daily orally in three divided doses, beginning 3 days prior to mountain ascent and continuing until mountain descent, does not reduce the risk of acute altitude sickness when compared with placebo (60801).
• Athletic performance. Taking magnesium orally does not seem to improve energy or endurance during athletic activity. Details: Most evidence suggests that taking magnesium orally doesn't increase energy and endurance during athletic activity. Magnesium oxide, aspartate, and orotate salts do not seem to improve exercise performance when used alone or in combination with potassium, vitamin B6, or zinc (2825,2826,2828,2829,2830,60751,113655).
• Bronchiolitis. Intravenous or nebulized magnesium is not beneficial in infants with this condition. Details: Clinical research shows that administering a single IV dose of magnesium sulfate 100 mg/kg to infants with acute bronchiolitis does not improve, and may actually worsen, symptoms when compared with placebo (97482). A clinical study in infants with moderate to severe bronchiolitis shows that adding nebulized magnesium sulfate 40 mg/kg to nebulized epinephrine does not reduce hospital stay or the need for ventilator or oxygen support when compared with epinephrine alone (99317). Oral magnesium has not been evaluated for this use.
• Chemotherapy-induced peripheral neuropathy. Research on the effects of intravenous infusions of magnesium and calcium for preventing oxaliplatin neurotoxicity are inconsistent, but higher quality studies seem to show no benefit. Details: Pooled analyses of cohort studies and clinical trials show that calcium and magnesium infusions can decrease the incidence of severe oxaliplatin-induced neurotoxicity (90028,90029,90031). However, when only clinical trials are considered, the infusions do not appear to be helpful (90005,90029,90031,96474,96479).
• Complex regional pain syndrome. Intravenous magnesium is not beneficial in complex regional pain syndrome type 1. Details: Clinical research shows that receiving magnesium sulfate 70 mg/kg intravenously at the rate of 25 mL/hour for 4 hours each day for 5 days does not improve pain or level of impairment when compared with placebo in patients with chronic complex regional pain syndrome type 1 (89395).
• Emergence delirium. The majority of small clinical studies in adults and children undergoing various surgeries suggest that intravenous (IV) magnesium doesn't reduce the risk of emergence delirium. However, most clinical studies in adults suggest that IV magnesium reduces emergence agitation. Details: A small clinical study in adults undergoing surgery for endovascular aortic aneurysm repair shows that administering IV magnesium 30 mg/kg as a loading dose, followed by a 10 mg/kg/hour infusion for the duration of surgery, does not improve agitation or delirium scores when compared with administering saline (111182). Similarly, a small clinical study in children ages 2-5 years undergoing elective strabismus surgery shows that administering IV magnesium during anesthesia does not seem to prevent the occurrence of emergence delirium when compared with administering saline (105077). In a meta-analysis of 8 clinical trials in children aged 2-16 years undergoing general anesthesia for oral or ophthalmic surgery, giving IV magnesium as a 30 mg/kg loading dose followed by a 10 mg/kg/hour infusion, or as a single dose of 15-30 mg/kg, does not reduce emergence delirium scores, and may actually prolong emergence times (108729). However, there is some conflicting evidence. In patients undergoing radical mastectomy, giving intraoperative magnesium sulfate 30mg/kg over 1 hour, followed by 10 mg/kg/hour until the end of surgery, reduces emergence agitation (odds ratio 0.26) when compared with placebo (112781).
• Menopausal symptoms. Oral magnesium oxide does not seem to be beneficial for menopausal hot flashes. Details: A small, low quality study in postmenopausal patients with a history of breast cancer shows that taking magnesium oxide 400-800 mg orally daily reduces hot flashes when compared with baseline (102454). However, a larger, higher quality clinical study using magnesium oxide 800-1200 mg daily did not show any benefit when compared with placebo (98290).
• Muscle cramps. Oral magnesium does not seem to improve muscle cramp frequency or intensity. Details: Meta-analyses of small clinical trials show that magnesium supplementation for 3-6 weeks does not decrease the frequency or intensity of skeletal muscle cramps, whether the cramps are idiopathic or due to liver cirrhosis or pregnancy, when compared with placebo (90022,104395).
• Sickle cell disease. Intravenous magnesium does not add any benefit to standard therapy for sickle cell disease in children. Details: Clinical research shows that giving magnesium sulfate 40-100 mg/kg (maximum of 2 grams per dose) intravenously every hour for 6-8 doses as an adjunct to standard therapy does not decrease hospital stay, pain, or opioid use, or improve quality of life, when compared with standard therapy and placebo in children with sickle cell disease (89399,98283,101356). Oral magnesium has not been evaluated for this purpose.
• Stillbirth. Magnesium administered during pregnancy does not reduce stillbirth risk. Details: A meta-analysis of clinical research shows that magnesium supplementation does not significantly decrease the risk of stillbirths when administered during pregnancy (60925,60978).
• Tetanus. Intravenous magnesium sulfate does not seem to improve outcomes in patients with this condition. Details: A meta-analysis of clinical research shows that intravenous magnesium sulfate does not reduce mortality when compared with placebo or diazepam in patients with tetanus (61020). While some research shows that magnesium reduces the duration of hospitalization and the need for ventilation when compared with diazepam (61170), magnesium does not seem to improve these outcomes when compared with placebo (60860).
• Traumatic brain injury (TBI). Magnesium does not improve clinical outcomes in patients with moderate to severe TBI. Its effect in patients with concussions is unclear. Details: A meta-analysis of four clinical trials shows that treatment with magnesium does not significantly improve neurological outcomes or reduce the risk of mortality when compared with placebo in patients with moderate to severe TBI (60905). A small observational cohort study in adolescents with concussions has found that adding oral magnesium 400 mg twice daily for 5 days to standard treatment with acetaminophen and ondansetron is associated with a trend toward reduced symptom severity when compared with standard treatment alone (104401). The validity of this study is limited by its observational nature and small cohort size.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alcohol use disorder. Intravenous magnesium does not seem to help reduce symptoms of alcohol withdrawal but may reduce the duration of alcoholic delirium. Details: Preliminary clinical research shows that administration of four intramuscular injections of magnesium sulfate 2 grams at 6-hour intervals does not reduce symptoms of alcohol withdrawal when compared with saline (61063). A small observational study in patients with alcoholic delirium has found that administering magnesium sulfate IV 50 mg/kg every 8 hours, in addition to usual sedation, is associated with a reduction of delirium by approximately 2 days, or 4 days when given every 12 hours in addition to dexmedetomidine, when compared with usual sedation alone (111180). However, half of patients had hypomagnesemia at baseline; it is unclear if effects would be similar for patients with normal magnesium levels. Oral magnesium has not been evaluated for this purpose.
• Allergic rhinitis (hay fever). Although there has been interest in using oral magnesium for allergic rhinitis, there is insufficient reliable information about the clinical effects of magnesium for this purpose.
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral magnesium is beneficial in children with ADHD. Details: Children with ADHD seem to have lower magnesium levels in their blood and hair (9969,100262,100263). A small clinical study in children aged 7-12 years with ADHD and magnesium deficiency shows that taking magnesium aspartate and lactate 6 mg/kg daily for 6 months might improve hyperactivity and magnesium levels when compared with control (1189). Another small clinical study in children with ADHD but without magnesium deficiency shows that taking magnesium 6 mg/kg daily along with vitamin D 50,000 IU weekly for 8 weeks may modestly improve emotional problems, but not inattention or hyperactivity, as measured on the strength and difficulties questionnaire (SDQ), when compared with placebo (105914).
• Back pain. It is unclear if oral or intravenous magnesium is beneficial for acute or chronic back pain in adults. Details: One open-label clinical study in adults with acute low-back pain shows that taking magnesium 365 mg once daily in addition to taking etodolac 400 mg twice daily for 10 days does not further reduce pain when compared with taking etodolac alone (105913). Magnesium has also been tried for chronic back pain. A small clinical study in patients with chronic low-back pain shows that receiving magnesium sulfate 1 gram in 250 mL normal saline intravenously every 4 hours for 2 weeks, followed by magnesium gluconate 100 mg and magnesium oxide 400 mg by mouth daily for 4 weeks, reduces pain severity when compared with placebo (90035). It is unclear if oral magnesium used alone is beneficial.
• Bariatric surgery complications. It is unclear if oral magnesium supplementation improves metabolic parameters after bariatric surgery. Details: A retrospective study of over 3000 post-bariatric surgery patients suggests that those who take oral magnesium supplements providing 100-450 mg elemental magnesium daily may have improved metabolic parameters over 4 years of follow-up. When patients taking magnesium supplements were compared with those not taking supplements, 11% and 18% had type 2 diabetes, respectively, 30% and 42% had hypertension, respectively, and 16% and 23% had elevated low-density lipoprotein (LDL) cholesterol levels, respectively. For patients with hypomagnesemia at baseline, supplementation seemed to result in greater benefits (108968).
• Bipolar disorder. Taking magnesium orally might improve manic symptoms in some people with bipolar disorder; however, it is unclear how it compares to current standard of care. Details: One preliminary clinical study shows that magnesium 40 mEq daily (Magnesiocard) for 32 weeks has similar effects to lithium in up to 50% of patients treated for rapid cycling bipolar affective disorder (61022). Another preliminary clinical study shows that magnesium oxide 375 mg orally daily plus verapamil 80 mg taken four times daily reduces manic symptoms more effectively than verapamil alone in patients with mania (60742).
• Cancer-related neuropathic pain. It is unclear if intravenous magnesium is beneficial for this condition. Details: Single 500 mg to 1 gram doses of magnesium sulfate seem to relieve neuropathic pain for up to four hours when compared to baseline (6846). The validity of this finding is limited by the lack of a comparator group.
• Cardiac arrest. Intravenous magnesium does not seem to be helpful in cardiac arrest; however, the risk of sudden cardiac death seems to be inversely correlated to higher plasma magnesium levels or dietary intake. It is unclear if magnesium supplementation is associated with similar risk reduction. Details: Administering magnesium intravenously doesn't seem to improve successful resuscitation in people with cardiac arrest (1190). However, higher plasma magnesium levels and higher dietary magnesium intake might reduce the risk of sudden cardiac death, possibly by protecting against fatal ventricular arrhythmias. In the Nurses' Health Study, the risk of sudden cardiac death was 77% lower in females with the highest quartile of plasma magnesium levels when compared with the lowest quartile. Also, the risk was 37% lower in females with the highest quartile of dietary magnesium intake when compared with the lowest quartile (17132).
• Cardiovascular disease (CVD). Evidence regarding the effect of dietary magnesium on CVD risk is conflicting. Details: Epidemiological research in some populations shows that increased dietary magnesium intake is associated with decreased mortality due to strokes, coronary heart disease, ischemic heart disease, and heart failure, but other epidemiological research does not show any effect on these risks (89391,90003,90009,90030,90036,103735). Reasons for the discrepancies may be related to serum levels of magnesium at baseline, risk of cardiovascular disease at baseline, use of concomitant medications such as diuretics, or the presence of concomitant conditions such as kidney dysfunction. A population analysis conducted in Denmark has found that magnesium intake from drinking water may be associated with cardiovascular mortality. The overall risk of cardiovascular death and death due to stroke was reduced by 4% in the lowest 3 quintiles of intake when compared with the highest quintile. However, the risk of death due to acute myocardial infarction was increased by 22% in the lowest quintile when compared with the highest (108726). The relevance of these results is unclear, given that the main dietary source of magnesium is food rather than drinking water.
• Chronic fatigue syndrome (CFS). Limited evidence suggests that magnesium may help improve CFS symptoms, but this is controversial. Details: In people with low red blood cell magnesium, there is some evidence that intramuscular injections of 1 gram magnesium sulfate given once weekly for 6 weeks might improve CFS symptoms (7556). However, there is additional evidence that most patients with CFS have normal magnesium stores, and measurement of red cell magnesium is a poor indicator of total magnesium stores (7557,8084,8085,8086,8087).
• Chemotherapy-induced leukopenia. It is unclear if oral magnesium is beneficial in pediatric patients at risk for cisplatin-induced febrile neutropenia. Details: A small clinical study in children with solid tumors aged 9 years and older shows that taking magnesium 250 mg daily while receiving cisplatin-based chemotherapy reduces febrile neutropenia by 47% and septic shock by 57% when compared with not receiving magnesium. Results from this study suggest that four pediatric patients need to take oral magnesium to avoid one case of febrile neutropenia (104394).
• Chemotherapy-induced nephrotoxicity. It is unclear if intravenous magnesium is beneficial for chemotherapy-induced nephrotoxicity. Details: A meta-analysis of several lower quality clinical studies in adults in Japan with cancer receiving cisplatin shows that pretreatment with intravenous magnesium sulfate 5 to 20 mEq reduces the odds of chemotherapy-induced nephrotoxicity in a dose-dependent manner when compared to standard hydration therapy (115726). The validity of these findings is limited by heterogenous methods between clinical trials, including types of cancer, definitions of nephrotoxicity, and use of other nephroprotective therapies.
• Chronic obstructive pulmonary disease (COPD). Intravenous, but not nebulized, magnesium may be helpful in acute exacerbations of COPD. Details: Administering magnesium sulfate intravenously, 1.2-2.5 grams over 20 minutes, might be helpful for treating acute exacerbations of COPD (1208,6844,103733). Also, giving magnesium sulfate 2 grams intravenously seems to improve exercise capacity when compared with placebo (89384). A meta-analysis of studies using intravenous magnesium sulfate for COPD exacerbations shows that it reduces hospital admission and mean length of stay and improves dyspnea scores when compared with placebo. Based on the relative risk identified in the included studies, seven patients would need to receive intravenous magnesium to prevent one hospitalization. However, intravenous magnesium sulfate does not change the need for non-invasive ventilation and the available research did not evaluate intensive care unit (ICU) admission (108967). Nebulized magnesium has also been evaluated. In patients experiencing a COPD exacerbation, clinical research shows that administering nebulized magnesium sulfate with albuterol three times at 30-minute intervals does not improve pulmonary function as measured by the forced expiratory volume in 1 second (FEV1) when compared with placebo (89393). Also, a meta-analysis of a small number of low-quality studies shows that nebulized magnesium does not reduce hospital admission or the need for ventilatory support, although it might modestly improve dyspnea scores and reduce ICU admissions, when compared with placebo (108967).
• Cluster headache. It is unclear if a single intravenous dose of magnesium sulfate is beneficial for cluster headaches. Details: Administering magnesium sulfate intravenously, 1 gram over 5 minutes, seems to improve cluster headaches when compared with baseline(1184). The validity of this finding is limited by the lack of a comparator group.
• Cognitive impairment. It is unclear if oral magnesium is beneficial for cognitive impairment. Details: A large observational study in adults with end-stage renal disease on hemodialysis suggests that serum magnesium levels of 20.2-22.3 mg/dL are associated with the lowest odds of mild cognitive impairment, while serum magnesium levels below and above that range of values are associated with increased odds of mild cognitive impairment (111695).
• Coronary heart disease (CHD). It is unclear if magnesium supplementation is beneficial for CHD. Details: Clinical research shows that magnesium oxide 800-1200 mg daily for 3 months reduces platelet-dependent thrombosis by 35% when compared with placebo in patients with CHD (60759). It is unclear if this effect improves clinical outcomes. The effect of magnesium supplementation on coronary artery calcium has also been studied. A meta-analysis of 3 clinical studies in 196 patients with chronic kidney disease (CKD) shows that taking magnesium or increasing the concentration of magnesium in dialysate does not improve coronary artery calcification (CAC) scores when compared with standard therapy. However, magnesium reduced carotid intima-media thickness (111179). Similarly, a large clinical study in patients with CKD shows that taking slow-release magnesium hydroxide (Mablet, Denmark) 360 mg twice daily for 12 months does not slow the progression of CAC scores when compared with placebo (111178). This study may not have been adequately powered to detect a difference between groups.
• Coronavirus disease 2019 (COVID-19). It is unclear if oral magnesium is beneficial for COVID-19. Details: A small clinical study in patients hospitalized with moderate COVID-19 shows that taking magnesium 300 mg daily for the duration of hospitalization reduces the number of patients requiring oxygen therapy but not the duration of hospital stay when compared with placebo (114680).
• Depression. It is unclear if magnesium is beneficial for the treatment or prevention of depression in adults. Details: Some population research shows that dietary intake of elemental magnesium between 76-360 mg daily is associated with a reduced risk of depression, but there was no association with greater amounts of magnesium, and other population research shows no association at any intake level (96480,98289). For treatment of mild to moderate depression, one preliminary clinical study shows that taking magnesium chloride 2 grams orally daily for 6 weeks reduces depression scores by 56% and anxiety scores by about 52% when compared to baseline (96477). The validity of these findings is limited by the lack of a comparator group. However, a small clinical study in adults with recurrent depression shows that taking magnesium aspartate 120 mg daily for 8 weeks, along with fluoxetine, does not improve depression scores when compared with patients taking fluoxetine and placebo (111185). Similarly, a very small crossover clinical study in adults with mild or moderate treatment-resistant depression shows that administering a single dose of IV magnesium sulfate 4 grams does not improve depression scores when compared with an infusion of 5% dextrose (96481). However, scores were evaluated 24 hours post-infusion which may be too soon to detect improvement. Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that elemental magnesium in doses of 100-400 mg is not recommended for adjunctive or monotherapy use in patients with depression (110318).
• Diabetic foot ulcers. Oral magnesium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with grade 3 diabetic foot ulcers shows that taking magnesium oxide 250 mg plus vitamin E 400 IU daily for 12 weeks modestly reduces ulcer size when compared with placebo (101436). It is unclear if this effect is due to magnesium, vitamin E, or the combination.
• Exercise-induced muscle soreness. It is unclear if oral magnesium reduces muscle soreness in adults after resistance training. Details: A very small study in healthy adults, ages 19-23, shows that taking magnesium glycinate 350 mg daily for 10 days seems to reduce muscle soreness after bench press exercise when compared with placebo (104399).
• Fetal and premature infant mortality. It is unclear if antenatal intravenous (IV) magnesium sulfate administration reduces the risk of fetal and premature infant mortality. Details: Two meta-analyses of up to 7 clinical studies in patients at risk of preterm birth shows that antenatal IV magnesium sulfate administration does not reduce the risk of fetal or neonatal death when compared with placebo (114675,114681).
• Fibromyalgia. It is unclear if oral magnesium is beneficial for this condition. Details: A small clinical study shows that taking magnesium chloride orally 100 mg once daily for one month reduces mild to moderate, but not severe, stress associated with fibromyalgia when compared with placebo. It also reduces pain levels, but not to a clinically significant extent, and it does not affect sleep, fatigue, or quality of life (108964). Another small clinical study shows that taking magnesium citrate 300 mg daily for 8 weeks improves some symptoms of fibromyalgia, such as number of tender points and depression, when compared to baseline (89385). The validity of this finding is limited by the lack of a comparator group. A small clinical study shows that taking a combination of magnesium hydroxide and malic acid (Super Malic tablets) orally decreases fibromyalgia-related pain and tenderness in some patients when compared with placebo (3262). It is unclear if this effect is due to magnesium, malic acid, or the combination.
• Fractures. Population research suggests that higher intakes of magnesium may reduce fracture risk. Details: Observational research has found that higher dietary and supplemental magnesium intake is associated with a 34% lower odds of fracture when compared with lower magnesium intake (101395).
• Gastric cancer. Population research suggests that higher intakes of magnesium may reduce gastric cancer risk. Details: Observational research has found that higher dietary and supplemental magnesium intake is not associated with a reduced risk for gastric cancer when compared with lower intake (103730).
• Hearing loss. Oral magnesium may prevent and improve hearing loss due to environmental factors or loud noises. Details: Clinical research in healthy military recruits shows that taking magnesium aspartate 167 mg daily for 2 months prevents hearing loss from exposure to loud noises during basic military training when compared with placebo (1205). Also, in patients with acute-onset hearing loss that was not caused by environmental factors, taking magnesium aspartate 167 mg daily for 8 weeks seems to improve hearing loss when compared with placebo (60813).
• Hypertension. Oral magnesium supplementation may modestly reduce blood pressure, although these changes are not likely to be considered clinically significant. Details: Most research shows that taking oral magnesium supplements in daily doses that are at least as high as the Recommended Dietary Allowance (RDA) for adults and up to 1000 mg daily can lower diastolic blood pressure by about 2 mmHg in adults with or without hypertension (1192,1199,9465,15165,18111,96482). Significantly lower doses do not seem to have this effect (1180,1195,1197,8098). The effect of magnesium on systolic blood pressure is conflicting. Two meta-analyses shows that taking magnesium 212-970 mg daily does not lower systolic blood pressure in patients with or without hypertension (15165,115728). However, additional meta-analyses show that taking magnesium 120-970 mg daily can lower systolic blood pressure in a dose-dependent manner by about 2-4 mmHg in patients with or without hypertension (18111,96482). The reasons for these discrepant findings are unclear but may be due to heterogenous methods, including dose and duration among clinical studies. In 2022, the US Food and Drug Administration (FDA) approved a qualified health claim stating that inconsistent and inconclusive evidence suggests that diets with adequate magnesium may reduce the risk of high blood pressure. Products bearing this claim must provide at least 84 mg of magnesium daily, but no more than 350 mg daily (107451).
• Hypokalemia. It is unclear if intravenous or oral magnesium is beneficial for hypokalemia in patients with normal magnesium levels. Details: A preliminary retrospective observational study in patients with hypokalemia and unknown serum magnesium levels has found that administering oral or intravenous magnesium is not associated with improved time to normalization of serum potassium levels when compared with no magnesium treatment (110049). However, hypokalemia with concurrent hypomagnesemia can impede potassium repletion and exacerbate hypokalemia-induced rhythm disturbances. Standard of care in patients with hypokalemia and known hypomagnesemia includes prompt treatment with magnesium (110063).
• Impaired glucose tolerance (prediabetes). It is unclear if oral magnesium is beneficial for prediabetes. Details: Preliminary clinical research in patients with prediabetes shows that taking magnesium oxide 250 mg orally daily for 12 weeks does not improve fasting blood glucose levels, insulin resistance, or glycated hemoglobin (HbA1C) levels when compared with placebo. Taking magnesium also did not affect blood pressure, body weight, triglyceride levels, or low-density lipoprotein cholesterol levels; however, it did modestly improve high-density lipoprotein cholesterol levels (110053).
• Insomnia. Oral magnesium may modestly improve sleep complaints in adults, but evidence is conflicting. Details: A meta-analysis of two small clinical studies in healthy older adults with or without insomnia suggests that taking magnesium reduces the time to fall asleep by an average of 17 minutes when compared with placebo (105917). However, it does not increase the time spent asleep. Also, these findings are limited by imprecision and a high risk of bias. Studies included in the analysis used elemental magnesium 500-729 mg daily (as magnesium oxide) for up to 8 weeks (102458,105917). Another small clinical study in patients with poor sleep quality and low magnesium status shows that taking elemental magnesium 320 mg (as magnesium citrate) in divided doses daily for 7 weeks does not improve sleep quality, as measured by the Pittsburgh Sleep Quality Index (PSQI), when compared with a sodium citrate placebo (102456). Magnesium has also been evaluated in combination with other ingredients. A very small crossover clinical study in patients aged 18-40 years without a sleep disorder shows that taking a combination of magnesium 300 mg, L-tryptophan 1000 mg, glycine 3000 mg, tart cherry 220 mg, and theanine 200 mg for 3 days reduces the time to fall asleep by about 24 minutes, increases total time asleep by about 22 minutes, and improves sleep efficiency, but does not improve the total time in bed or wakefulness after falling asleep when compared with cellulose placebo (111184). Another small crossover clinical study in adults with sleep disturbances shows that taking a combination of magnesium 200 mg and melatonin nightly for 4 weeks improves sleep quality, as measured by the PSQI, reduces the length of time it takes to fall asleep by about 17 minutes, and improves some other measures of sleep, such as sleep efficiency and number of awakenings, when compared with placebo. However, despite these improvements, overall sleep quality was still categorized as poor after the intervention (113670). It is unclear if these effects are due to magnesium, other ingredients, or the combination.
• Intraventricular hemorrhage. It is unclear if antenatal intravenous (IV) magnesium sulfate can reduce the risk for intraventricular hemorrhage in neonates. Details: A meta-analysis of clinical research in premature infants shows that if the mother received antenatal intravenous magnesium sulfate, the infant had a non-significant trend toward a reduced risk of intraventricular hemorrhage when compared with infants whose mothers received placebo (103727). This analysis may have been insufficiently powered to detect a difference between groups. Another meta-analysis of up to 6 clinical studies, some of which are included in the previously referenced meta-analysis, in patients at risk of preterm birth shows that maternal antenatal (IV) magnesium sulfate administration does not reduce the risk of intraventricular hemorrhage, but does reduce the risk of severe intraventricular hemorrhage by about 24% when compared with placebo (114681).
• Kidney stones (nephrolithiasis). Taking magnesium orally may prevent the recurrence of kidney stones, although evidence is conflicting. Details: Prophylactic treatment with magnesium hydroxide, 200 mg twice daily for one year, followed by 500 mg daily for another year, might decrease the recurrence rate of calcium stone formation (2007). However, magnesium oxide does not seem to benefit patients considered to be recurrent calcium stone formers when compared with placebo, no treatment, or chlorthalidone (8097,38501,61199). Magnesium oxide 300 mg in combination with vitamin B6 10 mg daily seems to decrease urinary oxalate levels in people with hyperoxaluria who have previously had kidney stones (1201), but it is unclear if this effect translates into a reduced incidence of kidney stones.
• Liver cancer. Increased dietary magnesium intake is linked with a lower risk of liver cancer. Details: Observational research in retired older Americans has found that higher dietary magnesium intake is associated with a 35% lower risk of liver cancer when compared with lower intake. This association was especially strong in persons who were moderate or heavy alcohol users (105080).
• Lung cancer. Supplemental or dietary magnesium intake does not seem to reduce the risk of lung cancer. Details: A large epidemiological cancer screening trial with a mean follow-up of over 12 years suggests there is no association between dietary or supplemental magnesium intake and the risk of lung cancer. However, dietary magnesium seems to play an important yet unclear role in lung cancer prevention when taken as part of the diet with alpha-carotene, vitamin C, vitamin E, lycopene, selenium, lutein, and zeaxanthin (112096).
• Migraine headache. Oral magnesium may help prevent migraine in some adults and children. Also, intravenous magnesium may help treat migraine in adults, but evidence is conflicting. Details: A meta-analysis of 4 low-quality clinical studies, in adults with migraine shows that magnesium 122-600 mg daily for 4-16 weeks modestly reduces migraine frequency and severity when compared with placebo(115730). However, clinical significance is unclear, and the validity of these findings is limited by heterogeneous methods between clinical trials, including type of magnesium formulation and dose, patient population, and duration. In contrast, one small clinical study shows that taking magnesium does not reduce migraine frequency and severity by at least 50% in adults when compared with placebo (10661). Limited evidence suggests that adding oral magnesium to conventional treatment may also be beneficial. A clinical study in adults with migraine living in Iran shows that taking magnesium oxide 250 mg twice daily in addition to sodium valproate 200 mg twice daily for 12 weeks modestly reduces severity and duration of migraine, but not migraine frequency, when compared with taking sodium valproate alone (105915). It is unclear if these improvements would be considered clinically significant. For treatment of migraine, some adults with normal magnesium levels respond to intravenous (IV) magnesium sulfate 1 gram over 5 minutes, but most patients who benefit have low magnesium levels at baseline (1185,6844). Effects of IV magnesium in patients with unknown magnesium levels are conflicting. Some preliminary clinical research shows that magnesium 1-2 grams IV alleviates acute migraine for up to 2 hours, but other research has found no benefit (89388,97493,98285). In children, treatment with magnesium oxide orally 15 mg/kg daily in 3 divided doses for up to 16 weeks reduces the frequency and severity of migraine headaches when compared with placebo (10663). However, adding magnesium sulfate 400 mg orally daily to ibuprofen or acetaminophen does not further reduce migraine severity in children (89396).
• Miscarriage. Oral magnesium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in pregnant adults with threatened miscarriage between the 6th and 13th week of gestation shows that taking a specific combination product (DAV HA, Lo.Li pharma s.r.l) containing magnesium 450 mg, alpha-lipoic acid, hyaluronic acidvitamin B6, and vitamin D daily in combination with conventional treatment of vaginal progesterone over 2 weeks of observation results in a faster resorption of the subchorionic hematoma and faster decrease of patient-reported vaginal bleeding, abdominal pain, and uterine contractions when compared with vaginal progesterone alone (113893). It is unclear if these effects are due to magnesium, other ingredients, or the combination. Additionally, the validity of these findings is limited by the lack of a placebo in the control group.
• Myocardial infarction (MI). Research on the effects of intravenous or oral magnesium after myocardial infarction are conflicting. Details: Administering magnesium intravenously doesn't seem to reduce mortality after an acute MI (8999,13357,13358,13359,13360,19990,60872,61082), although there is some conflicting evidence from a meta-analysis of clinical research that shows that intravenous magnesium sulfate may reduce short-term mortality by 55% when compared with placebo (60795,60895). Clinical research with oral magnesium supplementation has found no benefit (1198,6844).
• Neonatal encephalopathy. Intravenous magnesium may improve short-term outcomes in neonates with encephalopathy. Details: A meta-analysis of clinical research shows that intravenous magnesium may improve short term outcomes of neonatal encephalopathy (hypoxic ischemic encephalopathy, HIE). However, long term outcomes are not affected (90025).
• Nocturnal leg cramps. It is unclear if oral magnesium is helpful for nocturnal leg cramps. Details: Some clinical research in adults with nocturnal leg cramps shows that taking magnesium oxide 865 mg daily at bedtime for 4 weeks does not reduce the frequency of leg cramping episodes when compared with placebo (96478). However, four weeks may be too short a time to see a benefit. In other clinical research, taking oral magnesium oxide monohydrate 226mg daily at bedtime for 60 days reduces the frequency of leg cramps when compared with placebo. This reduction was not seen after 30 days. Magnesium also reduced cramp duration and improved sleep quality, but did not affect pain scores, at 60 days when compared with placebo (106919).
• Nonalcoholic fatty liver disease (NAFLD). Oral magnesium hydroxide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults with NAFLD shows that taking magnesium hydroxide 150 mg and L-carnitine 2000 mg daily for 16 weeks does not improve liver stiffness scores when compared with baseline or controls who took placebo for 8 weeks followed by this magnesium and L- carnitine combination for 8 weeks. Taking magnesium and L-carnitine also did not improve levels of aspartate aminotransferase (AST) or alanine transaminase (ALT) when compared to baseline (111177).
• Obesity. Evidence on the use of magnesium for weight loss in obese patients is conflicting; any benefit is likely small at best. Details: A meta-analysis of 7 clinical studies in obese patients shows that taking magnesium reduces body mass index (BMI) by 0.3 when compared with control (103723). Another meta-analysis of 7 studies in obese patients shows that while magnesium supplementation does not reduce weight, it reduces waist circumference by 2 cm when compared with placebo (103729). Interestingly, subgroup analyses did not find that the dose of magnesium or baseline magnesium levels impacted effectiveness. One subgroup analysis found that magnesium supplementation lasting 12 weeks or less seemed to be more beneficial for obesity than supplementation lasting longer than 12 weeks (103723).
• Overall mortality. It is unclear if oral or IV magnesium reduces the risk of overall mortality. Details: A meta-analysis of heterogeneous observational studies has found that increased dietary magnesium intake, but not supplemental magnesium intake, is associated with a modestly reduced risk of overall mortality (105073). A meta-analysis of 3 small, low-quality clinical studies in ICU patients shows that administering IV magnesium 24-30 mmol or as a target-directed dose for 3 days reduces overall mortality when compared with patients who did not receive magnesium (111290). However, some studies included patients with hypomagnesemia; it is unclear if effects would be similar for patients with normal levels of magnesium.
• Osteoarthritis. Population research has not found a link between magnesium intake and osteoarthritis risk. Details: Observational research has found that dietary and supplemental magnesium intake is not associated with the risk of developing osteoarthritis (101395).
• Pain (acute). It is unclear if locally injected or intravenous magnesium is helpful for acute pain. Details: Preliminary clinical research in patients with renal colic shows that intravenous (IV) magnesium sulfate, 50 mg/kg infused over 20 minutes, is as effective as IV morphine sulfate 0.1 mg/kg for controlling acute renal pain at 20 minutes after the dose (107367). Magnesium has also been evaluated in a dental procedure. A single-center clinical study in India in adults with irreversible pulpitis requiring a root canal shows that a local injection of 0.2 mL of 10% magnesium sulfate with lidocaine and epinephrine reduces perioperative pain when compared to lidocaine with epinephrine alone (115729).
• Pain (chronic). Population research suggests that higher intakes of magnesium may modestly reduce the risk for chronic pain. Details: A cross-sectional observational study has found that increased magnesium intake is associated with a 7% to 8% reduced risk for chronic pain. The association was found to be stronger in females than in males (103732).
• Parturition. It is unclear if topical magnesium is beneficial for labor duration. Details: A single-center clinical study in Iranian adults shows that applying 10 mL of a 50% magnesium sulfate solution directly to the cervix during the active phase of labor reduces the time to vaginal delivery by approximately 1.5 hours and improves the childbirth experience, as reported by patients, when compared with placebo. However, clinical significance is unclear (115727).
• Perioperative anxiety. It is unclear if oral magnesium is beneficial for perioperative anxiety. Details: Preliminary clinical research in adults undergoing open heart surgery shows that taking magnesium oxide 250 mg orally twice daily during hospitalization moderately improves anxiety and depression scores when compared with no magnesium therapy. Magnesium therapy was held for the 2 days immediately following surgery (110054).
• Physical performance. Oral magnesium may modestly improve physical performance in otherwise healthy, elderly females. Details: Clinical research in otherwise healthy elderly females shows that taking a magnesium oxide supplement (Easymag, Sanofi-Aventis) 900 mg daily for 12 weeks modestly improves walking speed and chair stand speed in elderly females when compared with no treatment (90026).
• Polycystic ovary syndrome (PCOS). It is unclear if oral magnesium is beneficial for improving metabolic indices in patients with PCOS. Details: Two small clinical studies in patients with PCOS show that taking magnesium oxide orally, 250 mg daily for 8 weeks, does not affect insulin resistance, beta-cell function, lipid levels, or insulin sensitivity when compared with placebo (103725,105887). Other clinical research in patients with PCOS shows that taking magnesium oxide orally, 250 mg daily for 10 weeks, improves subjective measures of quality of life, fatigue, and emotional functioning, but not objective measures such as alopecia, abnormal uterine bleeding, or acne, when compared with placebo (108965). A clinical study using a combination of magnesium 250 mg with vitamin E 400 mg daily for 12 weeks shows a modest reduction in insulin resistance, insulin levels, and triglyceride levels, but not other lipid levels, when compared with placebo (100264). It is unclear if these beneficial effects are due to magnesium, vitamin E, or the combination.
• Postoperative nausea and vomiting (PONV). It is unclear if intravenous (IV) magnesium is beneficial for PONV due to mixed results from clinical research. Details: A meta-analysis of 5 clinical studies in adults undergoing surgery with general anesthesia shows that administering IV magnesium sulfate intraoperatively reduces PONV (114676). However, a meta-analysis of 20 clinical studies in adults undergoing surgery with general anesthesia shows that administering IV magnesium perioperatively does not reduce the incidence of PONV (114678). A moderate-sized clinical study conducted in China in older adults undergoing total knee arthroplasty shows that administering intravenous magnesium sulfate 40 mg/kg prior to anesthesia induction then 15 mg/kg during surgery reduces the incidence of postoperative vomiting but not postoperative nausea when compared with control (113677). The reasons for these discrepant findings are unclear but may be explained by differences in magnesium regimens, anesthesia protocols, and surgical populations studied.
• Postoperative recovery. It is unclear if intravenous (IV) magnesium is beneficial for postoperative recovery. Details: A moderate-sized clinical study conducted in China in older adults undergoing total knee arthroplasty shows that administering IV magnesium sulfate 40 mg/kg prior to anesthesia induction then 15 mg/kg during surgery does not reduce extubation time, time spent in the post-anesthesia care unit (PACU), or duration of hospital stay when compared with control (113677). Additionally, a meta-analysis of 3 different clinical studies in adults undergoing surgery with general anesthesia shows that administering IV magnesium intraoperatively does not reduce extubation time (114676).
• Postoperative sleep disturbance. It is unclear if oral magnesium is beneficial for postoperative sleep disturbances. Details: Preliminary clinical research in adults undergoing open heart surgery shows that taking magnesium oxide 250 mg orally twice daily during hospitalization moderately improves sleep scores when compared with no magnesium therapy. Magnesium therapy was held for the 2 days immediately following surgery (110054).
• Postoperative sore throat. It is unclear if topical magnesium sulfate is beneficial for reducing sore throat pain after endotracheal intubation. Details: Preliminary clinical research in patients undergoing endotracheal intubation for surgery shows that using a gargle containing magnesium sulfate 20% with lidocaine, 20 minutes before anesthesia induction, is less effective for reducing sore throat pain than a gargle containing dexmedetomidine and lidocaine (112779). The study did not include a comparison to lidocaine alone.
• Pregnancy-related leg cramps. It is unclear if oral magnesium reduces leg cramps during pregnancy; evidence is conflicting. Details: One small clinical study in patients with pregnancy-related leg cramps shows that taking magnesium bisglycinate chelate 300 mg daily for 4 weeks reduces the frequency and intensity of leg cramps when compared with placebo (99318). A smaller clinical study in this population shows that taking a specific mixture of magnesium lactate and citrate (Nycoplus Magnesium) providing elemental magnesium 120 mg in the morning and 240 mg in the evening for 3 weeks reduces the frequency of cramps when compared with placebo (1194). However, not all research agrees. One small clinical study using this same supplement and dose for 2 weeks found no benefit when compared with placebo (17463). It is possible that a 2-week duration of treatment is too short to be beneficial. Finally, a meta-analysis of these studies and one other more recent clinical study shows that taking magnesium does not reduce the frequency or improve the resolution of pregnancy-related leg cramps when compared with placebo (105916). This analysis may not have been adequately powered to detect a difference between treatment groups.
• Pre-procedural sedation. It is unclear if intravenous magnesium is beneficial when administered in addition to other medications used for sedation during surgery. Details: A moderate-sized study of adults aged 65-79 years old undergoing endoscopic retrograde cholangiopancreatography (ERCP) shows that administering a single intravenous bolus of magnesium sulfate 40 mg/kg prior to the procedure reduces intraoperative propofol requirements by about 21% and reduces some peri-procedural adverse events including the incidence of respiratory depression and involuntary movement when compared with control. However, there were no differences in recovery time, hemodynamic parameters, or the incidence of hypotension, bradycardia, perioperative nausea or vomiting, lethargy, or arrythmias (111694). Another moderate-sized study in older adults undergoing total knee arthroplasty shows that administering intravenous magnesium sulfate 40 mg/kg prior to anesthesia induction then 15 mg/kg during surgery does not reduce the need for medications used for anesthesia induction, intraoperative maintenance propofol requirements, or recovery time when compared with control. However, magnesium sulfate does seem to reduce the amount of remifentanil required for intraoperative anesthesia maintenance and increase norepinephrine requirements when compared with control (113677).
• Preterm labor. The use of magnesium sulfate to inhibit uterine contractions in preterm labor (tocolysis) is controversial. However, its use for the purpose of fetal neuroprotection for up to 48 hours is supported by the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine. Details: Magnesium is given intravenously (IV) during preterm labor in an effort to improve fetal neurological outcomes, such as to reduce the risk of cerebral palsy and motor dysfunction in the infant (60915,60927,60931,61001,97485,103734,103754,114681). The typical dosage of magnesium sulfate is 4 grams infused IV over 10-30 minutes, followed by a maintenance infusion of 1-4 grams/hour for 48 hours or until birth. Use beyond 5-7 days has been associated with hypocalcemia and bone abnormalities in the fetus (15,12590,12594). Some meta-analyses of clinical research suggest that magnesium sulfate is more effective at delaying delivery by 48 hours when compared with oxytocin receptor blockers, nitrates, beta-mimetics, and/or placebo (20263,61021). However, an additional meta-analysis of several clinical studies shows that magnesium sulfate 4 or 6 grams IV is not more effective at delaying preterm labor by 48 hours when compared with nifedipine (115639). The reason for these discrepant findings are unclear, but may be related to the heterogenous methods between clinical trials, including dose and duration.
• Pseudoxanthoma elasticum (PXE). It is unclear if oral magnesium is beneficial for PXE. Details: Preliminary clinical research in patients with PXE shows that taking magnesium oxide 800 mg (500 mg of elemental magnesium) twice daily for one year tends to reduce calcification of elastic skin fibers when compared with placebo, but the effect is not statistically significant (101393). This study was limited by small size and insufficient power to detect smaller effects.
• Restless legs syndrome (RLS). It is unclear if oral magnesium is beneficial for RLS. Details: Some observational research has found that hypomagnesemia is associated with RLS; however, not all research agrees (8096,9472). Preliminary clinical research in adults with RLS who are beginning treatment with pramipexole shows that also taking magnesium oxide 250 mg orally daily for 2 months moderately improves RLS scores and sleep quality scores when compared with pramipexole and placebo (110052). Other low-quality clinical research in adults with RLS or periodic limb movement during sleep shows that taking magnesium 12.4 mmol orally in the evening for 4-6 weeks decreases movement and increases sleep when compared with baseline (9466). The validity of this finding is limited by the lack of a comparator group.
• Sarcopenia. It is unclear if oral magnesium is beneficial for the prevention or treatment of sarcopenia. Details: Population research in older adults has found that lower dietary intake of magnesium is associated with sarcopenia. However, the effect of magnesium supplementation on sarcopenia prevention or treatment has not been evaluated (110055). Magnesium has been evaluated in combination with other ingredients for treatment of sarcopenia. A small clinical study in elderly individuals with sarcopenia undergoing a diet and exercise program shows that taking a combination supplement containing magnesium 300 mg, carnosine, hydroxymethylbutyrate, lactoferrin, and sodium butyrate daily for 4 months increases muscle mass, as measured by the skeletal muscle index, and improves measures of muscle function, including handgrip muscle strength, chair test, and walking speed, when compared with placebo (114682). It is unclear if these effects are due to magnesium, other ingredients, or the combination.
• Sepsis. It is unclear if intravenous magnesium is beneficial for sepsis. Details: A very large observational study in patients with sepsis and hypomagnesaemia or normomagnesemia in the intensive care unit (ICU) suggests that administering intravenous magnesium sulfate 2 or 4 grams within 24 hours of admission reduces 28-day all-cause mortality from 25% in patients who did not use magnesium sulfate to 20% in those who were administered magnesium sulfate, regardless of baseline serum magnesium level and other baseline characteristics. Administration of intravenous magnesium sulfate in this population may also reduce ICU mortality by 4%, in-hospital mortality by 3%, and the use of renal replacement therapy by 3% but also seems to increase the length of ICU and hospital stay when compared with patients who did not use magnesium sulfate (113676). The validity of these results is limited by the observational nature of the study.
• Sleep deprivation. Oral magnesium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in sleep-deprived recreational athletes shows that taking a combination of magnesium 1350 mg, zinc 90 mg, and vitamin B6 31.5 mg for 3 nights at bedtime does not change sleep quality, subjective sleepiness, mood, or fatigue the next day when compared with placebo (113655).
• Stroke. Increased dietary magnesium may decrease stroke risk, and using a magnesium-containing salt substitute may improve neurological performance post-stroke. However, intravenous magnesium has not demonstrated benefit. Details: Most population research has found that increased dietary intake of magnesium is associated with decreased stroke risk and decreased mortality from stroke (9001,9002,90013,90030,90036,92107,103736). In patients who have had a stroke, a preliminary clinical study shows that using a salt substitute providing the Dietary Reference Intake (DRI) of magnesium and potassium for 6 months improves neurological performance when compared with using regular salt (97491). However, intravenous (IV) magnesium does not seem to be beneficial in patients who have had a stroke. Large prospective clinical trials show that IV magnesium given within 12 hours of acute stroke does not reduce mortality or disability in most patients when compared with placebo. However, one subgroup analysis suggested that IV magnesium might benefit patients with lacunar (non-cortical) stroke (13361,90021). IV magnesium also doesn't seem to reduce cardiovascular complications after acute stroke. A secondary analysis of a clinical trial in patients after ischemic and hemorrhagic stroke shows that giving IV magnesium does not reduce serious cardiac adverse events when compared with placebo (104393). Another secondary analysis of this trial shows that giving IV magnesium prior to arrival at the hospital and within 2 hours of a hemorrhagic stroke does not reduce hematoma volume on hospital arrival, hematoma expansion during hospital admission, or functional outcomes at 3 months (108733).
• Subarachnoid hemorrhage. Intravenous magnesium sulfate may reduce the risk of adverse outcomes in people with subarachnoid hemorrhage, but evidence is conflicting. Details: There is mixed evidence regarding the effect of magnesium sulfate in managing aneurysmal subarachnoid hemorrhage. One meta-analysis of clinical research shows that intravenous magnesium sulfate 64-144 mmol/day for 10-18 days reduces the risk of poor outcomes following aneurysmal subarachnoid hemorrhage, including death, vegetative state, or dependency, by 46% when compared with control (60932). Also, meta-analyses of clinical research show that intravenous magnesium reduces the risk of delayed cerebral ischemia by 27% when compared with placebo (60944,89398). However, these results were not confirmed in other meta-analyses (60973,90034).
• Thrombocytopenia. It is unclear if intravenous magnesium sulfate is beneficial in patients with thrombotic thrombocytopenic purpura (TTP). Details: Addition of intravenous magnesium sulfate as a 6-gram loading dose followed by 6 grams infused over 24 hours for 3 days, to standard treatment for TTP does not reduce the time to normalization of the platelet count, the incidence of TTP-related organ dysfunction, or the recurrence rate, when compared with standard treatment alone (112777). This study may have been underpowered to detect a difference.
• Urinary incontinence. Although there has been interest in using oral magnesium for urinary incontinence, there is insufficient reliable information about the clinical effects of magnesium for this purpose. More evidence is needed to rate magnesium for these uses.

(Read more about MAGNESIUM)

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: Two meta-analyses of clinical research in adults undergoing various types of surgery with anesthesia show that taking perioperative melatonin 3-6 mg or the melatonin receptor agonist ramelteon 8 mg orally daily for 1 day to 12 weeks reduces the risk of emergence delirium by 43% to 59% when compared with placebo or no treatment (112053,114514). Subgroup analysis of one meta-analysis suggests that higher melatonin of 5 mg or greater decreases the incidence of emergence delirium, while lower melatonin doses of 3 mg and ramelteon do not impact emergence delirium incidence when compared with control. Additionally, melatonin intake is most beneficial for reducing emergence delirium in the early postoperative period within 3 days of surgery and for cardiopulmonary surgeries. No benefit was observed for hospital or intensive care unit (ICU) length of stay, mortality, late postoperative periods of 7 days up to 12 weeks, or other surgery types when compared with control (114514). However, the validity of the results of both meta-analyses is limited by high heterogeneity. Another small clinical study conducted in Egypt in older patients undergoing surgery for colorectal cancer shows that taking melatonin 5 mg the night before surgery, 5 mg twelve hours before surgery, and 5 mg two hours before surgery reduces the incidence of delirium and decreases nurse-reported delirium scores six hours postoperatively, but at no other timepoints up to three days postoperatively, when compared with placebo (114508). In children, clinical research shows that taking melatonin reduces the incidence of sevoflurane-associated emergence delirium (97440,106292,113216). Meta-analyses of 3-4 small clinical studies in children aged 2-9 years show that taking melatonin 0.05-0.5 mg/kg 40-45 minutes prior to sevoflurane reduces the incidence of agitation by 60% when compared with placebo (97440,113216). The most recent analysis also shows that taking melatonin reduces the incidence of agitation by 52% when compared with midazolam (113216). Most research shows that doses of melatonin 0.2 mg/kg or greater may be most effective (97440,106292). However, clinical research shows that taking melatonin is less effective than dexmedetomidine (109701,113216). One study shows that 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). A meta-analysis of clinical studies in healthy adults and those with sleep disorders shows that melatonin reduces sleep latency by 9 minutes and increases total sleep time by about 20 minutes when compared with placebo. Dose-response analysis indicates that melatonin doses of 3 to 5 mg daily optimally reduce sleep latency and increase total sleep time, and that higher doses provide no additional benefit. Furthermore, melatonin is most effective at reducing sleep onset latency when administered 2 to 3 hours prior to desired bedtime and in patients who are healthy rather than those with insomnia (114507). 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 with epilepsy aged 3-12 years taking 6-9 mg of melatonin before bedtime for 4 weeks and children aged 3 months to 2 years taking 3 mg of melatonin before bedtime for 2 weeks (62394,99342,113223), 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). Melatonin has also been evaluated in combination with other ingredients. A very small clinical study in middle-aged adults with poor sleep quality shows that taking melatonin 1.9 mg and magnesium citrate 200 mg at bedtime for 4 weeks improves subjective sleep quality and objective sleep measures including latency by 17 minutes, efficiency, number of awakenings, and awakening length when compared with placebo. However, the combination of melatonin and magnesium does not improve other subjective measures of mood or daytime sleepiness and reduces total sleep time by 42 minutes when compared with placebo (113670). It is unclear whether these effects are due to melatonin, magnesium, or the combination.
• 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, migraine duration, migraine frequency, migraine-related disability, and the need for analgesics 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 (12149,96316,97438,103486,110286,114512). 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. Two small clinical studies in children aged 2-10 years preparing to undergo outpatient elective surgery show that taking melatonin 0.05-0.5 mg/kg 30-45 minutes before anesthesia is less effective than midazolam 0.5 mg/kg for reducing preoperative anxiety, including 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). Another moderate-sized clinical study in critically ill adults admitted to the ICU shows that administering enteral melatonin 3 mg once daily at night for 7 days does not improve consciousness levels or reduce delirium risk, mortality risk, length of ICU stay, or length of mechanical ventilation when compared with standard care (113496).
• Dementia. It is unclear if oral melatonin improves 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, a network meta-analysis in patients with mild Alzheimer disease and mild cognitive impairment suggests that melatonin improves cognitive function more effectively than aducanumab, donanemab, lecanemab, and placebo (114515). This analysis included only two clinical trials comparing melatonin to placebo and is limited by significant heterogeneity, including differences in study durations. Other clinical 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 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). Another meta-analysis of 5 clinical trials shows that taking melatonin inhibits the occurrence of acute kidney injury in at risk patients by 44% when compared with placebo. However, changes in serum creatinine and urea nitrogen were not statistically significant. Doses of melatonin varied from single doses of up to 5 mg and 6 mg to 30 mg daily for 5 to 14 days (113225).
• 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). Another small clinical trial shows that taking melatonin 3 mg daily in combination with rehabilitative exercise training improves exercise capacity, health status, and quality of life when compared with placebo. The distance walked in 6 minutes was increased by 46 meters (113221).
• 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). Additionally, a moderate-sized clinical study in older hospitalized patients with delirium shows that taking oral melatonin immediate release 5 mg nightly for 5 nights does not reduce the severity of delirium when compared with placebo. Furthermore, subgroup analysis suggests that those with pre-existing cognitive impairment experienced less improvement in delirium but did have improved sleep quality when compared with placebo (114511). 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. Melatonin has also been investigated when administered enterally. 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). Another moderate-sized clinical study in critically ill adults admitted to the ICU shows that administering enteral melatonin 3 mg daily at 9 pm for 7 days or until discharge does not reduce the incidence of continued or new-onset delirium at 24 hours, 3 days, or 7 days after ICU admission when compared with standard care alone (113496).
• 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). However, taking melatonin might not be beneficial for seizure reduction in younger children. In infants and children aged 3 months to 2 years with infantile epileptic spasms syndrome receiving adrenocorticotrophic hormone (ACTH) and magnesium sulfate, adding on melatonin 3 mg daily for 2 weeks before bedtime does not reduce spasm frequency or improve response rate when compared with placebo (113223). 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).
• Premenstrual syndrome (PMS). Oral melatonin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study conducted in Spain in adults with normal menstrual cycles shows that taking a combination product containing melatonin 1 mg, gamma-aminobutyric acid (GABA), rhodiola, vitex agnus-castus, and vitamin B6 (Premen-Calm, Naturlider S.A., Spain) before bed starting on the day of menstruation onset for 3 months does not improve somatic or affective PMS symptoms, pain, need for analgesics, mood, quality of life, or subjective sleep quality when compared with placebo (114509).
• 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).
• Psoriasis. It is unclear if topical melatonin is beneficial for psoriasis. Details: A very small clinical study in adults with mild to moderate plaque psoriasis shows that applying melatonin 5% cream twice daily for 8 weeks does not reduce psoriasis severity when compared with placebo (114513). The validity of this result is limited by the small sample size.
• 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)

LIKELY EFFECTIVE

• Pellagra. Oral niacinamide is approved for the treatment of pellagra and niacin deficiency. Details: Niacinamide is FDA-approved for the prevention and treatment of niacin deficiency and pellagra. Niacinamide is sometimes preferred over niacin for this indication because it lacks the vasodilating and flushing effects of niacin (15,6243).

POSSIBLY EFFECTIVE

• Acne. Topical niacinamide seems to improve acne symptoms in some patients. Oral niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One clinical study shows that applying niacinamide 4% gel twice daily for 8 weeks is as effective as clindamycin 1% gel for reducing the number and severity of acne lesions. The niacinamide gel appears to be more effective in patients with oily skin than those with non-oily skin (93360). Other preliminary clinical research in adults with mild to moderate acne vulgaris shows that applying niacinamide 5% cream twice daily, 10 minutes after applying benzoyl peroxide 2.5% gel, for 12 weeks reduces the number of acne lesions, but not erythema or inflammation, when compared with benzoyl peroxide alone (107711). Niacinamide has also been studied in combination with other ingredients. In preliminary clinical research, oral niacinamide has been reported to improve acne when used in combination with zinc, copper, and folic acid (Nicomide) (25557), or in combination with azelaic acid, zinc, pyridoxine, copper, and folic acid (NicAzel, Elorac Inc.) (90800). In a small observational study, topical niacinamide 4% combined with gallic acid 1% and lauric acid 1% was associated with some improvement in acne (104931). It is unclear if the effects in these studies are due to niacinamide, other ingredients, or the combinations.
• Diabetes. Oral niacinamide does not seem to prevent the onset of type 1 diabetes, although it might slow its progression. Details: Although some older research has suggested that taking high-dose niacinamide can reduce the risk of type 1 diabetes in high-risk children (4874), results from higher quality, more rigorous clinical trials show that taking niacinamide up to 3 grams daily for 5 years does not prevent the onset of type 1 diabetes in first-degree relatives of patients with type 1 diabetes (4875,25553,25554). However, taking niacinamide 1.2 grams/m2 daily for 5 years may prevent the loss of beta-cell function in these patients (25555). Also, there is evidence showing that niacinamide can preserve residual beta-cell function in patients with newly diagnosed type 1 diabetes (4877,4878,4879,4880,25556). Clinical trials, including one placebo-controlled trial and one vitamin E-comparison study, show niacinamide can prolong the "honeymoon period" in those newly diagnosed with type 1 diabetes, when the pancreas is still capable of producing some insulin (4877,4878,4879,4880,25556). However, some scientists have raised concerns about potential induction of insulin resistance with short-term use of niacinamide 2 grams daily for 2 weeks (4881). Niacinamide has also been evaluated in adults with type 2 diabetes. A small clinical study in lean patients with type 2 diabetes who failed sulfonylurea therapy shows that taking niacinamide 500 mg three times daily for 6 months in addition to continuing insulin or a sulfonylurea increases C-peptide release and improves insulin secretion when compared with insulin alone (4882).
• Hyperphosphatemia. Adding oral niacinamide to standard treatment with phosphate binders further lowers blood levels of phosphorus in patients on hemodialysis. Details: A meta-analysis of nine small clinical trials in patients on hemodialysis with hyperphosphatemia who are using a phosphate binder shows that taking niacinamide 250-1500 mg daily for 2-6 months lowers serum phosphorus and parathyroid hormone levels when compared with placebo (98940) Another meta-analysis of two small clinical trials in the same patient population also shows that taking niacinamide, titrated from 500 mg to 1500 mg daily over 8 weeks, reduces serum phosphorus levels by about 0.9 mg/dL when compared with placebo (94188). Other clinical research in this population shows that taking modified-release niacinamide 250-1500 mg orally daily for 12-24 weeks also lowers serum phosphate and parathyroid levels when compared with placebo. However, these effects were not maintained at 40-52 weeks follow-up (107709,110499). In addition, this product was not compared with immediate-release niacinamide. Niacinamide has also been studied in place of phosphate binders. One small clinical study in patients on hemodialysis with hyperphosphatemia shows that taking niacinamide 500-1750 mg daily for 12 weeks, beginning 2 weeks after discontinuation of phosphate binders, decreases serum phosphorus levels by 1.5 mg/dL and intact parathyroid hormone levels by 50 pg/mL, without affecting calcium levels, when compared to baseline (25561).The validity of these findings is limited due to the lack of a control group.
• Osteoarthritis. Oral high-dose niacinamide might be beneficial for improving osteoarthritis symptoms. Details: Clinical research in patients with osteoarthritis shows that taking niacinamide 3 grams daily in six divided doses for 12 weeks improves joint flexibility, reduces inflammation, and modestly decreases use of nonsteroidal anti-inflammatory drugs (NSAIDs) when compared with placebo (4883).

POSSIBLY INEFFECTIVE

• Brain tumor. Adding high-dose oral niacinamide to chemotherapy does not seem to improve survival in patients with brain tumors. Details: Preliminary clinical research in patients with surgically resected brain tumors shows that treatment with radiotherapy, niacinamide, and carbogen does not improve survival when compared with radiotherapy alone or radiotherapy plus carbogen (11695,11696).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Actinic keratoses. It is unclear if oral or topical niacinamide is beneficial for reducing actinic keratoses. Research results are conflicting. Details: A large clinical trial in healthy Australian adults with actinic keratoses shows that taking a specific niacinamide product (Insolar, Blackmores) 500 mg twice daily for 12 months reduces the number of actinic keratoses by 13% when compared with placebo. The difference between the 2 groups was observed as early as 3 months after starting niacinamide (93362). Additionally, a small clinical study in healthy, older Australian adults with actinic keratoses shows that taking niacinamide (Nature's Own, Virginia) 500 mg once or twice daily for 4 months reduces the total number of actinic keratoses by 29% and 35%, respectively, when compared with placebo (93365). However, a large clinical trial in solid organ transplant recipients in Australia shows that taking a specific niacinamide product (Insolar, Blackmores) 500 mg twice daily for 6 months does not reduce the number of actinic keratoses when compared with placebo (113559). Also, a small clinical trial in kidney transplant recipients with actinic keratoses and a history of nonmelanoma skin cancer shows that taking niacinamide 500 mg twice daily for 12 months does not decrease the number of actinic keratoses when compared with placebo (113682). The study may have been inadequately powered to detect a difference between groups. Two small clinical studies conducted in Brazil in elderly adults with actinic keratoses shows that taking niacinamide 500 mg twice daily for 120 days or applying a cream containing niacinamide 5% twice daily for 56 days does not reduce the number of actinic keratoses when compared with placebo (107714,113684). Most studies were conducted in countries with high year-round ultraviolet radiation exposure, such as Australia and Brazil; results may not be readily extrapolated to populations in other geographic regions.
• Age-related cognitive decline. Although there is interest in using oral niacinamide for age-related cognitive decline, there is insufficient reliable information about the clinical effects of niacinamide for this purpose.
• Age-related macular degeneration (AMD). Oral niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in patients with early-stage age-related maculopathy shows that taking a combination of niacinamide 18 mg, vitamin E 20 mg, and lutein 15 mg daily for nearly a year improves retinal function when compared with no treatment (60134). It is unclear if this effect is due to niacinamide, other ingredients, or the combination.
• Aging skin. It is unclear if topical niacinamide improves symptoms of aging skin. Details: A small study in females with signs of facial photo-aging shows that applying niacinamide 5% cream to half of the face twice daily for 12 weeks improves blotchiness, the appearance of wrinkles, skin elasticity, and skin pigmentation when compared with applying placebo cream to the other half of the face (25551).
• Atopic dermatitis (eczema). It is unclear if topical niacinamide improves eczema symptoms. Details: A small clinical study in patients with atopic dermatitis and dry skin shows that applying niacinamide 2% cream twice daily for 8 weeks decreases skin water loss and improves skin hydration when compared with using a white petrolatum moisturizer (25560). A moderate-sized clinical study in adults with mild atopic dermatitis (AD) shows that applying a specific niacinamide containing body emollient (Bioderma Atoderm PP Baume, Bioderma Cosmetics Trading Co., Ltd.) 250 grams weekly, applied twice daily for 28 days with or without pre-cleansing with a specific niacinamide containing gel wash (Atoderm Intensive Gel Moussant, Bioderma Cosmetics Trading Co., Ltd.), improves AD severity, itching, trans-epidermal water loss, skin water content, and dermatological quality of life when compared with a control emollient and water-only skin cleansing. Additionally, using both the niacinamide containing emollient and cleansing gel improves trans-epidermal water loss and skin water content sooner when compared with niacin containing emollient only (113681). However, the study may have been inadequately powered and too short in duration to detect additional differences between the 2 niacinamide groups.
• Attention deficit-hyperactivity disorder (ADHD). Oral niacinamide has only been evaluated in combination with other vitamins; its effect when used alone is unclear. Details: A small clinical study in children with ADHD shows that taking a maximum of niacinamide 3 grams, ascorbic acid 3 grams, calcium pantothenate 1.2 grams, and pyridoxine 600 mg daily for 3 months seems to improve behavior in 29% of participants when compared with baseline (9957). The validity of this finding is limited by the lack of a comparator group.
• Bladder cancer. Oral niacinamide has only been evaluated in combination with carbogen for improving survival in advanced bladder cancer; its effect when used alone is unclear. Details: A phase II clinical study in patients with locally advanced bladder cancer shows that adding inhaled carbogen and oral niacinamide 40-60 mg/kg about 2 hours before radiotherapy shows a trend to improved survival at 3 years when compared with inhaled carbogen and radiotherapy (25558), and a larger phase III study shows that carbogen and oral niacinamide improves 3-year survival by about 13% when compared with radiotherapy alone (93366). An observational follow-up of the phase III study found a trend to increased survival at 5 years in the carbogen and niacinamide group when compared with radiotherapy alone. And in a subgroup of patients with tumor necrosis, the 5-year survival was significantly greater with carbogen and niacinamide when compared with radiotherapy alone (93356). It is unclear if these effects are due to niacinamide, carbogen, or the combination.
• Child growth. It is unclear if oral niacinamide improves child growth. Details: Preliminary clinical research in children in rural Tanzania shows that supplementing niacinamide orally from birth to 18 months of age does not improve length-for-age, weight-for-age, or head circumference when compared with control. Niacinamide was initially supplemented to breast-feeding mothers, 250 mg daily, until 6 months of age, followed by 100 mg daily taken by the child until 18 months of age (107713).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral niacinamide is beneficial for COVID-19. Details: Observational research in adults with acute kidney injury secondary to coronavirus disease-19 infection has found that taking niacinamide 1000 mg orally daily for 7 days is associated with a 55% lower risk of mortality when compared with control. However, taking niacinamide was not associated with a lower risk of renal replacement therapy (110500).
• Cutaneous lupus erythematosus (CLE). It is unclear if topical niacinamide is beneficial for CLE. Details: Preliminary clinical research in adults with discoid lupus erythematosus, a type of CLE, shows that applying topical niacinamide 2% to 4% twice daily for 12 weeks modestly improves lesion scores, but not quality of life scores, when compared with placebo. However, the study may have been inadequately powered to detect a difference between groups (110498).
• Depression. Although there is interest in using oral niacinamide for depression, there is insufficient reliable information about the clinical effects of niacinamide for this condition.
• Diabetic neuropathy. Oral niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with diabetic polyneuropathy shows that taking a specific combination product (Cytoflavin, Polysan) containing niacinamide, inosine, riboflavin, and succinate daily for 12 weeks improves symptom scores, including paresthesia and numbness scores, when compared with placebo. The therapy was first administered intravenously, providing niacinamide 200 mg, inosine 400 mg, riboflavin 40 mg, and succinate 2000 mg daily for 10 days, followed by an oral formulation providing niacinamide 100 mg, inosine 200 mg, riboflavin 20 mg, and succinate 1200 mg daily for the remainder of the study (110503).
• Erythema. Topical niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: There is interest in using niacinamide to reduce the side effects of topical tretinoin, including erythema. A small preliminary clinical study in patients using isotretinoin for acne shows that applying a specific cream (Sebiaclear Hydra, SVr Laboratoire Dermatologique) containing niacinamide 5% and omega-ceramides 8% twice daily for 6 months reduces isotretinoin-induced erythema, dryness, and itching of the skin when compared with a glycerin placebo (98938). It is not clear if this effect is due to niacinamide, omega-ceramides, or the combination.
• Head and neck cancer. Oral niacinamide has only been evaluated in combination with carbogen for improving survival in laryngeal cancer; its effect when used alone is unclear. Details: A phase III clinical trial in patients with laryngeal cancer shows that treatment with accelerated radiotherapy plus carbogen and niacinamide 60 mg/kg taken orally 1-1.5 hours prior to each fraction of radiation improves local tumor control, but does not improve overall survival or 5-year disease-free survival, when compared with accelerated radiotherapy alone. In a subgroup of patients with hypoxic tumors, anemia, or high expression of epidermal growth factor receptor, receiving niacinamide and carbogen seems to improve both survival and tumor control when compared with radiotherapy alone (93358,93359,93363).
• Melasma. It is unclear if topical niacinamide improves melasma. Details: A small clinical study in female adults with melasma shows that applying a specific niacinamide 10% serum (Bo leda, Shanghai Ruizhi Medical Technology Co., Ltd) twice daily after skin cleansing for 16 weeks improves melasma area and severity, pigmented spots, and skin texture when compared with control. Both groups were also treated with salicylic acid 30% throughout the study (113683). Topical niacinamide has also been studied in patients with hyperpigmentation. A small clinical study in Japanese females with uneven facial hyperpigmentation shows that applying niacinamide 5% moisturizer to the face twice daily reduces hyperpigmentation and increases skin lightness after 4 weeks when compared with placebo moisturizer. However, further improvements are not observed after another 4 weeks of treatment (25552). Another small clinical study in Korean females with uneven facial hyperpigmentation shows that applying a moisturizer containing niacinamide 2% plus tranexamic acid 2% (Regederm RX White Project, Aestura) twice daily for 8 weeks reduces skin pigmentation by about 9% when compared with a placebo cream (93361).
• Non-Hodgkin lymphoma. It is unclear if adding oral niacinamide to chemotherapy reduces relapses of refractory lymphoma. Details: One small clinical study in patients with relapsed or refractory lymphoma shows that 24% of patients achieve complete or partial remission and 57% achieve disease stabilization when compared with baseline, following treatment with vorinostat 400 mg daily and niacinamide titrated from 20 mg/kg to 100 mg/kg over the first 14 days of a 21-day cycle for up to 18 cycles (93355). It is unclear how these outcomes compare to using vorinostat alone, or to other control treatments.
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral niacinamide is beneficial for NAFLD. Details: Preliminary clinical research in adults with NAFLD and diabetes shows that taking a specific niacinamide product (Nature's Life) 1000 mg orally daily for 12 weeks does not improve liver function tests, liver steatosis, or liver fibrosis when compared with no intervention. However, some quality of life domain scores were moderately improved. However, the study may have been inadequately powered to detect a difference between groups (110502).
• Nonmelanoma skin cancer. It is unclear if oral or topical niacinamide reduces the risk of nonmelanoma skin cancer. Details: A meta-analysis of 4 clinical trials in adults shows that taking niacinamide 500 mg twice daily for 4-12 months does not reduce the risk of nonmelanoma skin cancer when compared with placebo. This analysis also shows no effect of niacinamide on the risk of basal cell carcinoma and squamous cell carcinoma (113560). However, there was high heterogeneity across the studies due to differences in patient populations and mixed results overall. Two studies included in the analysis show that niacinamide, including a specific niacinamide product (Nature's Own, Virginia), reduces the risk of nonmelanoma skin cancer in immunocompetent adults when compared with placebo (93362,93365). One was a large clinical trial that shows taking a specific niacinamide product (Insolar, Blackmores) 500 mg twice daily for 12 months reduces the rate of new nonmelanoma skin cancer by 23%, but it does not reduce the risk of not recurrent nonmelanoma skin cancers, when compared with placebo. However, this reduced risk appears to be transient. Follow up 6 months after niacinamide was discontinued showed no difference between groups (93362). The 2 other studies analyzed, including a large trial using a specific niacinamide product (Insolar, Blackmores), were conducted in transplant recipients showed no reduced risk of nonmelanoma skin cancer when compared with placebo (113560,113559). All studies were conducted in Australia; it is unclear if these results can be extrapolated to other geographical regions with different background ultraviolet radiation exposure and skin cancer rates. A previous meta-analysis of 5 clinical studies shows taking niacinamide 500-1000 mg daily for 6-12 months or applying niacinamide 1% twice daily for 6 months decreases the rate of basal cell and cutaneous squamous cell carcinomas by 54% and 52%, respectively when compared with control. Niacinamide was only administered topically in 1 of the 5 studies and only reduced risk of cutaneous squamous cell carcinoma (110497).
• Premenstrual syndrome (PMS). Although there is interest in using oral niacinamide for PMS, there is insufficient reliable information about the clinical effects of niacinamide for this condition.
• Pruritus. It is unclear if oral niacinamide reduces pruritus in patients with kidney failure. Details: A small clinical study in patients with pruritus due to kidney failure shows that taking niacinamide sodium 500 mg twice daily for 4 weeks does not reduce pruritus severity when compared with placebo (93364). This study is limited due to small size and short study duration.
• Psoriasis. It is unclear if oral niacinamide is beneficial for psoriasis. Details: Preliminary clinical research in adults with mild to moderate psoriasis shows that applying niacinamide 4% cream topically twice daily for 12 weeks improves psoriasis scores by 31% when compared with baseline. The validity of these results is limited by the lack of a comparator group (110501).
• Rosacea. Oral niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that 71% of adult and adolescent patients with rosacea who take a combination product (Nicomide) containing niacinamide 750 mg, zinc 25 mg, copper 1.5 mg, and folic acid 500 mcg once or twice daily report improvement in appearance after 4 weeks when compared to baseline (25557). The validity of these findings is limited by the lack of a control group.
• Schizophrenia. Although there is interest in using oral niacinamide for schizophrenia, there is insufficient reliable information about the clinical effects of niacinamide for this condition.
• Seborrheic dermatitis. It is unclear if topical niacinamide is beneficial for reducing seborrheic dermatitis symptoms. Details: One small clinical study in patients with seborrheic dermatitis shows that applying niacinamide 4% cream once daily for 12 weeks reduces the severity of symptoms such as redness and scaling by 75%, compared with a 35% reduction when using a placebo cream (93357). More evidence is needed to rate niacinamide for these uses.

(Read more about NIACINAMIDE)

EFFECTIVE

• Pyridoxine-dependent epilepsy. Intravenous vitamin B6 is effective for controlling pyridoxine-dependent seizures. Details: Pyridoxine-dependent seizures are a rare type of refractory seizures in neonates that do not respond to anticonvulsant drugs. These seizures are typically controlled within minutes of intravenous administration of pyridoxine, a form of vitamin B6. Pyridoxine-dependent seizures can be due to genetic (autosomal recessive) pyridoxine dependency, or more commonly, a result of the use of high-dose pyridoxine during pregnancy (8197,8198).
• Sideroblastic anemia. Oral vitamin B6 is effective for treating hereditary sideroblastic anemia. Details: Taking vitamin B6 (pyridoxine) orally is effective for treating hereditary sideroblastic anemia (15,9518). Taking the active form of vitamin B6 (pyridoxal-5'-phosphate) also seems to be effective in cases in which the patient does not respond to pyridoxine (93049).
• Vitamin B6 deficiency. Oral vitamin B6 is effective for preventing and treating vitamin B6 deficiency. Details: Taking oral vitamin B6 can prevent and treat vitamin B6 deficiency (15).

LIKELY EFFECTIVE

• Hyperhomocysteinemia. Taking vitamin B6 orally, alone or in combination with folic acid, is effective for reducing hyperhomocysteinemia. Details: Vitamin B6 (pyridoxine) seems to lower homocysteine concentrations when folic acid and vitamin B12 are at physiologic levels or when given with folic acid and vitamin B12 supplements (9451,83042,107136). A combination of vitamin B6 100 mg and folic acid 0.5 mg daily seems to lower homocysteine levels by about 35% and is recommended for people with postprandial hyperhomocysteinemia (1489,9406). Other research shows that taking pyridoxine 50-200 mg daily reduces postprandial homocysteine levels by 32% to 35% (9406,10350). Pyridoxine also seems to reduce homocysteine levels in patients with kidney failure, kidney transplant patients (1489,6884,9414,9415), or patients who receive general anesthesia with nitrous oxide (9481). However, some research in healthy adults suggests that adding pyridoxine to folic acid might not provide any additional benefit over folic acid alone (9400,9405,9409,50145). Hyperhomocysteinemia is considered by some to be an independent risk factor for atherosclerosis, recurrent thromboembolism, deep vein thrombosis, myocardial infarction, and ischemic stroke (1899,3323,9402,9405,9408,9409). However, elevated homocysteine levels may be a marker, as opposed to a cause, of vascular disease (11387,11388). A 5 µmol/L increase in plasma homocysteine increases the risk of cerebrovascular disease by 50% and the odds of coronary heart disease by 60% and 80% in males and females, respectively (9407,9411). However, it is not clear if reducing homocysteine levels results in reduced cardiovascular morbidity and mortality (1489,6883,6884,9308,9400,9405,9409). Folic acid, vitamin B6, and vitamin B12 supplementation can reduce total homocysteine from 13.4 to 11 µmol/L. However, this reduction does not seem to help with secondary prevention of death or myocardial infarction, and some research even suggests an increase in cardiovascular disease (CVD) risk (11387,13482,50423,83050,97619). There is also debate about whether supplementation with homocysteine-lowering B vitamins can reduce the risk of stroke. A number of large clinical studies and meta-analyses show that supplementation with folic acid, vitamin B6, and vitamin B12, alone or in combination, does not reduce the risk of stroke in patients with CVD or impaired renal function (11387,13482,50423,83050,96150). However, a more recent meta-analysis shows that B vitamin supplementation modestly reduces the relative risk of stroke by 10% when compared with placebo in patients at risk for or with a history of CVD (97619). Also, a meta-analysis in patients with a history of stroke shows that B vitamin supplementation modestly reduces the relative risk of stroke recurrence by 13% and the risk of vascular death by 11% when compared with placebo (107136).

POSSIBLY EFFECTIVE

• Antipsychotic-induced hyperprolactinemia. It is unclear if oral vitamin B6 is beneficial for patients with antipsychotic-induced hyperprolactinemia. Details: Clinical research in male patients with hyperprolactinemia who are on a consistent antipsychotic dose shows that taking vitamin B6 300 mg twice daily for 16 weeks reduces serum prolactin levels by 68%, compared with 37% in patients taking aripiprazole 5 mg twice daily. Also, 67% of patients taking vitamin B6 had prolactin levels less than 40 mcg/mL versus 2% of those taking aripiprazole (107128).
• Kidney stones (nephrolithiasis). Oral vitamin B6 seems to decrease urinary oxalate levels and decrease the risk of kidney stone formation in some patients. Details: There is some evidence that taking vitamin B6 (pyridoxine) orally, alone or in combination with magnesium, can decrease urinary oxalate levels in people with type I primary hyperoxaluria, a hereditary disorder (1201,6437,6438,6439,6440,8548,8549,8550). Additionally, a small clinical study in this population suggests that intravenous pyridoxine hydrochloride can reduce urinary oxalate by 25.5% when compared to baseline (90796). In patients with idiopathic hyperoxaluria, taking a combination of pyridoxine 25mg and magnesium oxide 400 mg for 3 months decreases urinary oxalate by approximately 16%, with 68% of patients experiencing a reduction. However, supplementation is less effective than following a low-oxalate diet, which reduces urinary oxalate in 91% of patients by an average of 31% (107127). There is also preliminary evidence that higher pyridoxine intake in females with no history of kidney stones is associated with decreased risk of kidney stone formation (6441), but this association has not been found in males (6442).
• Pregnancy-induced nausea and vomiting. Oral vitamin B6 may reduce nausea and vomiting in some pregnant patients and is sometimes used in combination with doxylamine. Details: While some conflicting evidence exists, most small clinical studies suggest that oral vitamin B6 is effective for improving nausea and vomiting associated with pregnancy when compared with baseline or placebo. However, vitamin B6 may not be as effective as ginger (110459). Two small clinical studies show that taking vitamin B6 (pyridoxine) 25 mg every 8 hours for 3-4 days decreases pregnancy-induced nausea severity and vomiting incidence when compared with placebo (6168,16306). A larger clinical trial shows that taking lower doses of vitamin B6, 10 mg every 8 hours over 5 days, improves pregnancy-induced nausea, but not vomiting, when compared with placebo (6167). A small clinical study in patients with mild to moderate nausea and vomiting shows that taking a higher dose of 40 mg twice daily for 4 days is more effective than placebo, but no better than ginger 500 mg twice daily (99404). The American College of Obstetrics and Gynecology (ACOG) considers vitamin B6 at a dose of 10-25 mg 3 to 4 times daily a first-line treatment for pregnancy-induced nausea and vomiting due to its benign safety profile (111601). However, it is not effective for all patients, such as those with hyperemesis gravidarum, a severe form of pregnancy-induced nausea and vomiting. Adding vitamin B6 20 mg three times daily for 2 weeks to intravenous rehydration, metoclopramide, and thiamine seems to be no more effective than placebo for reducing vomiting in hyperemesis gravidarum (99405). Vitamin B6 is also sometimes used in combination with doxylamine. In fact, a combination of vitamin B6 plus doxylamine (Diclegis or Bonjesta, Duchesnay Inc., and various generics) has been approved by the US Food and Drug Administration (FDA) as a prescription product111601). ACOG recommends vitamin B6 in combination with doxylamine as another first-line treatment option (111601). However, the clinical trial used to obtain FDA approval has some methodological problems, and the significance of the results has been questioned. The improvement in symptom scores seen with Diclegis was less than one point on a 13-point scale, which is unlikely to be clinically significant (97998). Also, some clinical research shows that taking pyridoxine 25 mg and doxylamine 12.5 mg is less effective than ondansetron 4 mg when taken every 8 hours for 5 days. Only 41% of the patients using pyridoxine and doxylamine had a clinically significant reduction in nausea, compared to 92% of patients using ondansetron (90797). The combination of vitamin B6 and doxylamine is also studied with acupuncture. A large clinical study in patients with moderate to severe pregnancy-induced nausea and vomiting conducted in China shows that taking vitamin B6-doxylamine (Diclegis, Duchesnay, Inc) 20 to 40 mg each at bedtime for 14 days in combination with daily acupuncture modestly improves patient-reported nausea and vomiting scores when compared with either intervention alone (111820). However, it is unclear whether this improvement is clinically significant.
• Premenstrual syndrome (PMS). Oral vitamin B6 seems to reduce PMS symptoms. Details: There is some evidence that taking vitamin B6 (pyridoxine) orally can improve symptoms of PMS such as breast pain or tenderness (mastalgia) and depression in some patients. Pyridoxine in doses of at least 50 mg daily, plus magnesium oxide 200 mg daily, seems to relieve PMS-related anxiety and other symptoms (8555,39007,82962). Although some clinicians advocate doses of pyridoxine 200-500 mg daily for PMS, doses of 50-100 mg daily seem to work just as well. There is no apparent dose-response curve for PMS, so the lowest effective dose should be used. Higher doses might increase the risk of side effects (3093).

POSSIBLY INEFFECTIVE

• Age-related cognitive decline. Oral vitamin B6 does not seem to slow age-related cognitive decline. Details: One clinical trial in elderly people with memory complaints shows that taking a combination of B vitamins, including folic acid 0.8 mg, vitamin B12 0.5 mg, and vitamin B6 (form not specified) 20 mg daily for 24 months reduces cerebral atrophy in the gray matter regions associated with Alzheimer disease by up to seven-fold when compared with placebo. However, this protection does not occur in patients with the lowest average blood levels of homocysteine (90374). Furthermore, other clinical research shows that taking vitamin B6 (pyridoxine) 3-75 mg daily in combination with folic acid and vitamin B12 does not improve cognitive function in elderly adults (14392,50225,50510).
• Alzheimer disease. Oral vitamin B6 does not seem to improve cognitive function in patients with Alzheimer disease when used in combination with other B vitamins. Also, oral vitamin B6 does not seem to reduce the risk of developing this condition. Details: Clinical research in patients with probable Alzheimer disease taking routine medications shows that taking vitamin B6 25 mg with folic acid 5 mg and vitamin B12 1 mg daily for 18 months does not have a beneficial effect on cognitive function or the severity of disease when compared with placebo. In this study, all patients were consuming a folate-fortified diet (50319). Also, population research in elderly adults has found that a high intake of vitamin B6 from dietary or supplemental sources is not associated with a decreased risk of Alzheimer disease when compared to lower vitamin B6 intake (13165,15270).
• Carpal tunnel syndrome. Oral vitamin B6 does not seem to reduce symptoms of carpal tunnel syndrome. Details: Most research shows that people with carpal tunnel syndrome are not generally deficient in vitamin B6 and do not benefit from taking vitamin B6 supplements (8203,8937,9448,9450,9478,9482). Although early studies by a single group of researchers, as well as anecdotal reports, suggest that taking vitamin B6 may relieve carpal tunnel symptoms, more reliable research has not supported these findings (8202,9445,9447,9449,9483,15955,83086). Vitamin B6 has also been evaluated in combination with other ingredients. A moderate-sized clinical study in adults with mild to moderate carpal tunnel syndrome shows that taking a combination product containing vitamin B6, alpha-lipoic acid, acetyl-L-carnitine, phosphatidylserine, turmeric, and vitamins C, E, B1, B2, and B12 twice daily for 60 days reduces symptom severity and pain but does not improve measures of hand and wrist function when compared with a control (111702). The dose of vitamin B6 was not provided. The validity of this study is limited by the lack of blinding and placebo. Additionally, it is unclear if the effects are due to vitamin B6, other ingredients, or the combination.
• Cataracts. Oral vitamin B6 does not seem to slow cataract development. Details: Clinical research in females with existing cardiovascular disease (CVD) or at increased risk of CVD shows that taking a combination of folic acid 2.5 mg, vitamin B6 (form not specified) 50 mg, and vitamin B12 1 mg daily for an average of 7.3 years does not reduce the risk of cataracts when compared with placebo. Furthermore, the risk of cataract extraction was increased by 28% (96149).
• Chemotherapy-induced acral erythema. While some conflicting evidence exists, most research suggests that oral or topical vitamin B6 does not seem to prevent or reduce the severity of acral erythema induced by chemotherapy. Details: A meta-analysis of 10 clinical trials and 4 observational studies shows that taking vitamin B6 60-500 mg daily for up to 8 chemotherapy cycles does not prevent chemotherapy-induced acral erythema or reduce the incidence of severe cases when compared with control. Most studies used capecitabine chemotherapy alone or in combination, and one study used pegylated liposomal doxorubicin; however, no subgroup analysis was conducted to differentiate chemotherapy regimens. Results did not seem to vary based on study location, study design, or vitamin B6 dose (104930). However, a more recent preliminary clinical study in patients receiving doxorubicin for multiple myeloma shows that taking vitamin B6 100 mg on the first day of chemotherapy then twice daily for 7 days with each cycle reduces the risk of developing acral erythema by 72%, but does not improve the severity of acral erythema, when compared with no vitamin B6 supplementation (110458). Also, one small, low-quality clinical study suggests that taking vitamin B6 400 mg daily reduces the risk of moderate or severe chemotherapy-induced acral erythema when compared with vitamin B6 200 mg daily; however, the higher dose also seems to be associated with worsened tumor response and increased treatment failure (97620). Topical vitamin B6 has also failed to show benefit. A small clinical study in patients with acral erythema from capecitabine or pegylated liposomal doxorubicin shows that applying vitamin B6 1% cream to affected areas three times daily for 6 weeks does not improve symptoms when compared with placebo (104929).
• Colorectal adenoma. Oral vitamin B6 does not seem to reduce the risk of developing colorectal adenomas. Details: Clinical research shows that taking a combination of B vitamins, including folic acid 2.5 mg, vitamin B6 (pyridoxine) 50 mg, and vitamin B12 1 mg, daily for up to 9.2 years does not reduce the risk of colorectal adenoma in females at high risk of cardiovascular disease when compared with placebo (90389).
• Eclampsia. Oral or intramuscular vitamin B6 does not seem to reduce the risk of eclampsia. Details: Meta-analyses of limited clinical research in pregnant patients show that taking vitamin B6 (pyridoxine), either as 25 mg daily or a single dose of 100 mg orally or intramuscularly, does not reduce the risk of eclampsia when compared with control (83046,96166).
• Osteoporosis. Oral vitamin B6 does not seem to reduce the risk of osteoporotic fractures. Details: Clinical research in patients with cerebrovascular disease shows that taking a combination of B vitamins, including folic acid 2 mg, vitamin B6 (form not specified) 25 mg, and vitamin B12 500 mcg daily for up to 10.5 years does not prevent osteoporotic fractures when compared with placebo (90377). Furthermore, a secondary analysis of two large studies in patients with cardiovascular disease has found that taking vitamin B6 (pyridoxine) 40 mg daily in addition to folic acid and vitamin B12 for 1-3 years is associated with a 42% increased risk of hip fracture over an 11-year period when compared with only folic acid and vitamin B12 (96163). This finding is limited because these studies were not designed to assess the effects of vitamin B6 on fracture risk and the analyses were not adjusted for baseline bone health or fall risk.
• Pre-eclampsia. Oral or intramuscular vitamin B6 does not seem to reduce the risk of pre-eclampsia. Details: Meta-analyses of limited clinical research in pregnant patients show that taking vitamin B6 (pyridoxine), either as 25 mg daily or a single dose of 100 mg orally or intramuscularly, does not reduce the risk of pre-eclampsia when compared with placebo (83046,96166).
• Preterm labor. Oral or intramuscular vitamin B6 does not seem to reduce the risk of preterm labor. Details: Meta-analyses of limited clinical research in pregnant patients shows that taking vitamin B6 (pyridoxine), either as 25 mg daily or a single dose of 100 mg orally or intramuscularly, does not reduce the risk of preterm labor when compared with placebo (83046,96166).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults and children with inflammatory acne shows that taking 1-4 tablets of a specific product (NicAzel, Elorac Inc.) containing vitamin B6 (pyridoxine), nicotinamide, azelaic acid, zinc, copper, and folic acid for 8 weeks reduces inflammatory lesions and improves appearance in 88% and 81% of patients, respectively, when compared to baseline (90800). The validity of these findings is limited by the lack of a comparator group.
• Age-related macular degeneration (AMD). Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large-scale clinical study shows that taking vitamin B6 (pyridoxine) 50 mg, vitamin B12 1000 mcg, and folic acid 2.5 mg daily reduces the risk for AMD in females over 40 years of age with a history of cardiovascular disease (CVD) or with risk factors for CVD. Those who took this combination for an average of 7.3 years had a 34% reduced risk of developing AMD and a 41% reduced risk of visually significant AMD when compared with placebo (14620). It is unclear if this effect is due to vitamin B6, other ingredients, or the combination.
• Angioplasty. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some evidence suggests that vitamin B6 (pyridoxine) 10 mg, folic acid 1 mg, and vitamin B12 400 mcg daily can decrease the rate of restenosis in patients treated with balloon angioplasty (8009,9412). However, this combination does not seem to be as effective for reducing restenosis in patients after coronary stenting (8009). An intravenous loading dose of folic acid, vitamin B6 (pyridoxine), and vitamin B12 followed by oral administration of folic acid 1.2 mcg, vitamin B6 (pyridoxine) 48 mg, and vitamin B12 60 mcg daily after bare metal coronary stenting also does not seem to reduce restenosis and might actually increase restenosis (12150,12151). Due to the lack of evidence of benefit and potential for harm, this combination of vitamins should not be recommended for patients receiving coronary stents (12151). It is unclear if any effects are due to vitamin B6, other ingredients, or the combination.
• Antipsychotic-induced metabolic side effects. It is unclear if oral vitamin B6, as an adjunct to progesterone, is beneficial in patients with antipsychotic-induced amenorrhea. Details: A small clinical study in females with antipsychotic-induced amenorrhea shows that taking vitamin B6 80 mg three times daily for 1 month plus intramuscular progesterone daily for 5 days increases levels of estradiol and follicle stimulating hormone, reduces prolactin levels, and increases the rate of clinical efficacy, defined as the normalization of menstruation and improvement in endocrine indicators, by 14% when compared with progesterone alone (110457).
• Anxiety. It is unclear if oral vitamin B6 is beneficial in patients with anxiety. Details: Clinical research in college students shows that taking vitamin B6 100 mg daily for one month does not reduce anxiety scores when compared with placebo (110453). However, because a diagnosis of anxiety was not a requirement for study participation, it is unclear if these findings can be generalized to patients diagnosed with anxiety.
• Asthma. It is unclear if oral vitamin B6 is beneficial in patients with asthma. Details: Preliminary clinical studies show that taking vitamin B6 (pyridoxine) 200-300 mg daily may improve symptoms of asthma in some patients, but not others, when compared with placebo (7064,7065). Studies have yielded conflicting results, with some research suggesting that it may only be beneficial in children with severe asthma (7065). Additionally, some research suggests that theophylline may lower vitamin B6 levels, although it is unclear if vitamin B6 supplementation is beneficial (4522,7066,9503).
• Atherosclerosis. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with intermediate risk for coronary heart disease shows that taking a specific supplement (Kyolic, Total Heart Health, Formula 108, Wakunga) containing vitamin B6 12.5 mg, aged garlic extract 250 mg, vitamin B12 100 mcg, folic acid 300 mcg, and L-arginine 100 mg daily for 12 months reduces coronary artery calcium progression when compared with placebo (88385). It is unclear if this effect is due to vitamin B6, other ingredients, or the combination.
• Atopic dermatitis (eczema). It is unclear if oral vitamin B6 is beneficial in patients with eczema. Details: A small clinical study in children with eczema shows that taking vitamin B6 (pyridoxine hydrochloride) 50 mg daily for 4 weeks does not reduce symptoms such as redness and itchiness when compared with placebo (83090).
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral vitamin B6 is beneficial for ADHD. Details: A small crossover study in children with ADHD shows that taking vitamin B6 600 mg, niacinamide and ascorbic acid 3 grams, and calcium pantothenate 1.2 grams daily for 6 weeks does not improve behavior scores when compared with placebo (9957).
• Autism spectrum disorder. Although there is interest in using oral vitamin B6 for autism, there is insufficient reliable information about the clinical effects of vitamin B6 for this condition.
• Bipolar disorder. It is unclear if oral vitamin B6 is beneficial in patients with bipolar disorder. Details: A small clinical trial in patients with type 1 bipolar disorder who are taking lithium and experiencing an acute episode of mania shows that taking vitamin B6 80 mg daily for 8 weeks does not improve cognitive function or the severity of mania when compared with placebo. Cognitive function was reduced in patients taking vitamin B6; any effect on sleep was unclear (107132).
• Cancer. It is unclear if oral vitamin B6 reduces overall cancer risk. Details: Population research has found that higher dietary intake of vitamin B6 is associated with a 22% reduced risk of cancer, including esophageal, pancreatic, gastric, colorectal, and breast cancer. However, when dietary and supplemental vitamin B6 intake is considered, the inverse association between vitamin B6 and cancer risk is weaker and limited to fewer tumor sites. Furthermore, a meta-analysis of 9 clinical studies shows that taking vitamin B6 3-100 mg orally daily for 2-7.3 years, in combination with vitamin B12 and folate, does not reduce the risk of cancer in patients with cardiovascular disease or kidney failure (96164).
• Cardiovascular disease (CVD). Oral vitamin B6, taken along with other B vitamins, does not seem to improve secondary prevention of death or myocardial infarction in patients with CVD. However, it might slightly lower the risk of stroke. Details: Overall evidence from clinical research and meta-analyses shows that taking vitamin B6 in combination with folic acid and/or vitamin B12 does not seem to help with secondary prevention of death or myocardial infarction in patients with or at risk for CVD (11387,13482,34540,50423,83050,90379,97619). In fact, some research suggests that long-term supplementation with vitamin B6, folic acid, and vitamin B12 for secondary prevention increases the risk of CVD by 20% despite lowering homocysteine levels by 30% (13482). However, some research shows that taking vitamin B6 in combination with other B vitamins modestly reduces the risk of stroke, although results are conflicting (11387,13482,50423,83050,96150,96165,97619,107136). Additionally, it is unclear which specific combination of B vitamins is optimal for reducing stroke risk and which patients are most likely to benefit. In 2001, prior to the publication of the highest quality research on this topic, the US Food and Drug Administration (FDA) approved a qualified health claim stating that, as part of a well-balanced diet that is low in saturated fat and cholesterol, folic acid, vitamin B6, and vitamin B12 may reduce the risk of vascular disease (102368).
• Cognitive function. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in healthy adults aged 40-65 years shows that taking a supplement containing vitamin B6, ginkgo leaf, bacopa, and other B vitamins twice daily for 12 weeks does not improve memory or attention when compared with placebo (111334).
• Colorectal cancer. It is unclear if oral vitamin B6 reduces the risk of colorectal cancer. Details: A meta-analysis of observational studies suggests that the highest dietary intake of vitamin B6 is associated with a 20% reduced risk of colorectal cancer when compared with the lowest dietary intake. However, this association was not shown in subgroup analyses of studies conducted in Australia, Europe, or North America (111600). The validity of this analysis is limited by the heterogeneity of the included studies.
• Dental caries. There is limited evidence on the oral use of vitamin B6 for dental decay during pregnancy. Details: Meta-analyses of limited clinical research show that taking vitamin B6 (pyridoxine), 25 mg daily or a single dose of 100 mg orally or intramuscularly, may reduce the risk of dental decay during pregnancy when compared with placebo (83046,96166).
• Depression. It is unclear if oral vitamin B6 reduces the risk of developing depression or improves symptoms of depression. Details: Clinical research in healthy college students shows that taking vitamin B6 100 mg daily for one month does not reduce depression scores when compared with placebo (1104453). However, because a diagnosis of depression was not a requirement for study participation, it is unclear if these findings can be generalized to patients diagnosed with depression. Whether vitamin B6 reduces the risk of developing depression is also unclear. A meta-analysis of population research has found that the highest dietary intake of vitamin B6 is associated with a 19% lower risk of depression when compared with the lowest intake. However, sub-analyses suggest that this association is only relevant in females and not males (107133). In one individual population study in community dwelling older adults included in the analysis, the consumption of at least 1.71 mg of vitamin B6 daily from food was associated with a 43% reduction in the likelihood of becoming depressed when compared with the consumption of 1.33 mg or less daily in females. However, there was no association between vitamin B6 levels and risk of depression in males, and the finding in females was no longer significant when adjusted for total energy intake, since foods rich in vitamin B6 are energy-dense (96168). Another observational longitudinal study in healthy adults starting oral contraceptives containing ethinyl estradiol and levonorgestrel has found that taking vitamin B6 25 mg daily for 6-12 months is associated with a 40% lower risk of depression when compared with no supplementation (90789). Most available studies are cross-sectional in nature, making any conclusions related to causation difficult.
• Diabetes. It is unclear if oral vitamin B6 is beneficial in patients with type 2 diabetes or gestational diabetes. Details: Observational research in Chinese adults with type 2 diabetes has found that dietary intake of vitamin B6 in the highest quartile is associated with 53% lower odds of developing cardiovascular disease, defined as a non-fatal myocardial infarction, non-fatal stroke, or hospitalization for unstable angina, when compared with vitamin B6 intake in the lowest quartile (110452). Small clinical studies in patients with gestational diabetes and vitamin B6 deficiency shows that taking vitamin B6 (pyridoxine) 100 mg daily for 2 weeks improves glucose tolerance and blood glucose levels when compared with baseline (82967,83088). However, there is concern that these findings were confounded by dietary alterations. This benefit was not observed in a subsequent small case series in patients with gestational diabetes (22380).
• Diabetic neuropathy. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research suggests that taking a combination of B vitamins, including folic acid (L-methylfolate), vitamin B12 (methylcobalamin), and vitamin B6 (pyridoxal-5'-phosphate) for 24 weeks does not improve neural dysfunction based on vibration perception when compared with placebo in patients with diabetic neuropathy. However, taking this combination appears to modestly improve neuropathy symptoms and quality of life related to mental functioning when compared with placebo (90375).
• Dysmenorrhea. It is unclear if oral vitamin B6 is beneficial in patients with dysmenorrhea. Details: Preliminary clinical research shows that taking vitamin B6 (form not specified) 200 mg daily reduces pain associated with dysmenorrhea when compared with placebo. However, taking vitamin B6 in combination with magnesium does not reduce pain when compared with placebo (77388).
• Fibromyalgia. It is unclear if oral vitamin B6 is beneficial in patients with fibromyalgia. Details: A small clinical study in patients with fibromyalgia shows that taking vitamin B6 80 mg daily for 8 weeks does not improve pain, disease severity, anxiety, depression, or quality of life when compared with placebo (110454).
• Gastroenteritis-associated nausea and vomiting. It is unclear if oral vitamin B6 is beneficial in children with gastroenteritis. Details: A small clinical study in children aged 6 months to 12 years with acute viral gastroenteritis shows that taking vitamin B6 (form not specified) does not improve symptoms of dehydration or the frequency of vomiting when compared with placebo (90793).
• Helicobacter pylori. It is unclear if oral vitamin B6 is beneficial for Helicobacter pylori. Details: A large clinical study in adults with Helicobacter pylori infection shows that taking vitamin B6 20 mg twice daily for 2 weeks alongside conventional quadruple therapy does not improve eradication rates when compared with a control group not receiving vitamin B6 (113551). Conventional therapy consisted of a proton pump inhibitor, bismuth, minocycline, and metronidazole. The validity of this study is limited by the lack of placebo and inadequate blinding.
• Hypertension. It is unclear if oral vitamin B6 reduces blood pressure. Details: One small clinical study in patients with essential hypertension shows that taking vitamin B6 (pyridoxine hydrochloride) 5 mg/kg daily for 4 weeks can reduce systolic and diastolic blood pressure when compared with baseline (83091). The validity of this finding is limited by the lack of a control group.
• Hypertriglyceridemia. It is unclear if oral vitamin B6 reduces triglyceride levels. Details: Preliminary clinical research shows that vitamin B6 (form not specified) 50 mg daily for 12 weeks does not reduce triglyceride levels in people with hypertriglyceridemia when compared with placebo. However, vitamin B6 appears to decrease total cholesterol and high-density lipoprotein (HDL) cholesterol by approximately 9% in these patients (59028).
• Infertility. Although there is interest in using oral vitamin B6 for infertility, there is insufficient reliable information about the clinical effects of vitamin B6 for this condition.
• Insomnia. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in healthy adults with self-reported sleep difficulty shows that taking a specific product (LZ Complex3, Sanofi Consumer Healthcare Pty Ltd.) containing vitamin B6, zizyphus extract, hops extract, hydrolyzed milk protein (Lactium), and magnesium oxide nightly, 30 minutes before bed, for 2 weeks does not improve sleep quality, daytime functioning, or physical fatigue when compared with placebo. However, due to the large improvement seen in both the treatment and placebo groups, the effectiveness of this product is unclear (95971).
• Isoniazid-induced neuropathy. It is unclear if oral vitamin B6 prevents the development of neuropathy in patients taking isoniazid. Details: Preliminary clinical research in patients taking isoniazid for tuberculosis shows that taking vitamin B6 (pyridoxine) 6 mg daily reduces the development of neuropathy when compared with control (83068).
• Lactation. It is unclear if oral vitamin B6 helps to suppress postpartum lactation. Details: A meta-analysis of two small clinical trials shows that taking vitamin B6 (pyridoxine) 400-600 mg daily for 6-7 days postpartum does not suppress lactation when compared with no treatment (83047).
• Levetiracetam-induced side effects. While some conflicting evidence exists, several small, low-quality studies suggest that oral vitamin B6 (pyridoxine) may reduce some neuropsychiatric adverse effects related to the use of levetiracetam. Details: In an analysis of case reports, retrospective studies, and a single low-quality prospective study, improvement in levetiracetam-associated neuropsychiatric symptoms occurred in approximately 73% of patients taking pyridoxine (107137). A more recent preliminary clinical trial in children ages 1-17 years shows that taking pyridoxine 10 or 15 mg/kg daily as needed based on symptoms improves behavioral side effects associated with levetiracetam by a small amount when compared with low-dose pyridoxine 0.5 mg/kg daily used as placebo (107124). Also, observational research in children ages 9 months to 14 years has found that taking vitamin B6 is associated with improved behavior and a 44% lower risk of levetiracetam discontinuation when compared with no vitamin B6 supplementation (110455). Some observational research in adults with levetiracetam-associated irritability has found that taking vitamin B6 is associated with an improvement in irritability in 45% of patients when compared to baseline (107129). However, a small clinical trial in adults with epilepsy shows that taking pyridoxine 40 mg daily for 3 weeks does not improve levetiracetam-related psychiatric adverse effects when compared with placebo (110456). This study may have been underpowered to detect differences between groups. Pyridoxine doses used in the studies above have ranged from 50-400 mg daily in children and 40-600 mg daily in adults (107124,107129,107137,110456).
• Lung cancer. It is unclear if dietary or oral vitamin B6 reduces lung cancer risk. Details: Epidemiological research has found that higher serum levels of vitamin B6 in male smokers is associated with a lower risk of lung cancer (9454). Also, people with blood levels of vitamin B6 in the top quartile have a modestly lower risk of lung cancer when compared with those whose levels are in the lowest quartile. The association is stronger for males and for people who have smoked (97999). However, other epidemiological research found that increased dietary intake of vitamin B6 is not associated with a reduced risk of lung cancer (96164).
• Menopausal symptoms. Although there is interest in using oral vitamin B6 for menopausal symptoms, there is insufficient reliable information about the clinical effects of vitamin B6 for this condition.
• Motion sickness. Although there is interest in using oral vitamin B6 for motion sickness, there is insufficient reliable information about the clinical effects of vitamin B6 for this condition.
• Nausea and vomiting. It is unclear if oral vitamin B6 is beneficial for nausea and vomiting in patients taking oral contraceptives or antibiotics for Helicobacter pylori. Details: A large clinical study in adults with Helicobacter pylori infection shows that taking vitamin B6 20 mg twice daily for 2 weeks alongside conventional quadruple therapy reduces the incidence and severity of gastrointestinal adverse effects when compared with a control group not receiving vitamin B6 (113551). Conventional therapy consisted of a proton pump inhibitor, bismuth, minocycline, and metronidazole. The validity of this study is limited by the lack of placebo and inadequate blinding. An observational longitudinal study in healthy females taking oral contraceptives containing ethinyl estradiol and levonorgestrel has found that taking vitamin B6 25 mg daily for 6-12 months is associated with a 43% reduced risk of nausea when compared with no supplementation (90789).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral vitamin B6 for patients with NAFLD. Details: A small clinical trial in patients with NAFLD shows that taking vitamin B6 (pyridoxine) 30 mg three times daily for 12 weeks does not reduce levels of liver transaminases or plasma lipids when compared with baseline. However, hepatic fat accumulation was modestly reduced (107130). The validity of this study is limited by the lack of a comparator group.
• Obesity. It is unclear if oral vitamin B6 in beneficial in overweight or obese individuals. Details: A small clinical trial in females with a body mass index (BMI) of at least 25 kg/m² shows that taking vitamin B6 as pyridoxine 80 mg daily for 8 weeks reduces fat mass and improves insulin resistance and triglyceride levels by a small amount when compared with placebo. Although some other anthropometric and metabolic indices were improved when compared with baseline, there was no effect of pyridoxine on body weight, visceral adiposity, or other endpoints when compared with placebo (107131).
• Overall mortality. It is unclear if oral vitamin B6 reduces the risk of overall mortality. Details: Observational research in US adults has found that dietary intake of vitamin B6 in the highest quintile is associated with a 12% to 21% lower risk of all-cause mortality and a 31% to 44% lower risk of cardiovascular mortality when compared with the lowest quintile of dietary vitamin B6 intake (110451).
• Pancreatic cancer. It is unclear if oral vitamin B6 reduces the risk of pancreatic cancer. Details: Observational research has found that higher dietary intake of vitamin B6 is associated with a 37% lower risk of developing pancreatic cancer when compared with lower intake (104927).
• Postpartum depression. It is unclear if oral vitamin B6 is beneficial in patients with postpartum depression. Details: Preliminary clinical research in individuals considered at increased risk for postpartum depression, but without clinical depression, shows that taking vitamin B6 80 mg daily from the 28th week of pregnancy until birth, and then 40 mg daily for one month, reduces symptoms of depression 1.5 months after birth when compared with baseline (measured during the third trimester) and when compared with placebo. However, it is unclear if any of the patients included in the study developed postpartum depression, as there were no changes in overall symptoms in patients taking placebo (107126).
• Proton pump inhibitor-induced gastrointestinal (GI) symptoms. It is unclear if oral vitamin B6 is beneficial for proton pump inhibitor-induced GI symptoms. Details: A large clinical study in adults with Helicobacter pylori infection shows that taking vitamin B6 20 mg twice daily for 2 weeks alongside conventional quadruple therapy reduces the incidence and severity of gastrointestinal adverse effects when compared with a control group not receiving vitamin B6 (113551). Conventional therapy consisted of a proton pump inhibitor, bismuth, minocycline, and metronidazole. The validity of this study is limited by the lack of placebo and inadequate blinding.
• Restless legs syndrome (RLS). It is unclear if oral vitamin B6 is beneficial in patients with RLS. Details: A small clinical study in adults with RLS who are beginning treatment with pramipexole shows that also taking vitamin B6 40 mg daily for 2 months moderately improves RLS scores and sleep quality scores when compared with pramipexole and placebo (110052).
• Schizophrenia. It is unclear if oral vitamin B6 is beneficial for patients with treatment-resistant schizophrenia. Details: Clinical research in male patients with treatment-resistant schizophrenia who are on a consistent antipsychotic dose shows that adding vitamin B6 300 mg twice daily for 16 weeks modestly improves psychotic symptoms and some measures of cognitive performance when compared with adding aripiprazole 5 mg twice daily (107128). More research is needed to determine if these benefits are clinically relevant.
• Seizures. It is unclear if oral vitamin B6 is beneficial for preventing seizures in patients with glycosylphosphatidylinositol (GPI) deficiency. Details: Observational case series in a small number of children and young adults with GPI deficiency has found that taking vitamin B6 20-30 mg/kg daily for 3-12 months is associated with some reduction in seizure frequency in 9 of 13 patients. However, no patient reached seizure freedom (107125,107135). In one case series, treatment for 12 months was associated with modest developmental improvements in almost all patients (107135). The study patient populations were slightly different in terms of age and underlying genetic causes for GPI deficiency.
• Sickle cell disease. Oral vitamin B6 has only been evaluated in combination with other B vitamins; its effect when used alone is unclear. Details: Preliminary clinical research in adults with sickle cell disease shows that taking vitamin B6 4.2-6 mg, vitamin B12 4.2-6 mcg, and folic acid 700 mcg daily might lower homocysteine levels. However, it is unknown if this will reduce the risk of endothelial damage in these patients (9324).
• Stroke. It is unclear if oral vitamin B6, either alone or with other B vitamins, is beneficial for stroke prevention. Details: There is some debate about whether supplementation with homocysteine-lowering B vitamins, including vitamin B6, can reduce the risk of stroke. A number of clinical studies and meta-analyses show that supplementation with folic acid, vitamin B6, and vitamin B12, alone or in combination, does not reduce the risk of stroke in patients with cardiovascular disease (CVD) or impaired kidney function (11387,13482,50423,83050,96150). However, a more recent meta-analysis of 10 clinical trials, including over 44,000 patients at risk for or with a history of CVD, shows that B vitamin supplementation reduces the relative risk of stroke by 10% when compared with placebo (97619). This meta-analysis differed from some of the earlier analyses due to the inclusion of several additional clinical trials. Also, another meta-analysis of three clinical trials including 9900 patients with a history of stroke shows that B vitamin supplementation reduces the relative risk of stroke recurrence by 13% when compared with placebo, although this finding was determined to have a low level of certainty. Based on two clinical trials, there was also a 17% reduced risk of vascular death and an 11% reduction in the combined risk of stroke, myocardial infarction, and vascular death (107136). In 2001, prior to the publication of the highest quality research on this topic, the US Food and Drug Administration (FDA) allowed a qualified health claim stating that, as part of a well-balanced diet that is low in saturated fat and cholesterol, folic acid, vitamin B6, and vitamin B12 may reduce the risk of vascular disease (102368). Unfortunately, even after the publication of higher quality research, it is still unclear which specific combination of B vitamins is optimal and which patients are most likely to benefit. One network meta-analysis shows that a combination of folic acid and vitamin B6 lowers the risk of stroke more effectively than B vitamin mixtures that include vitamin B12 (96165). However, this analysis is limited because it didn't account for dosing. Exposure to low, but not high amounts, of vitamin B12 (cyanocobalamin) seems to reduce stroke risk (96150).
• Tardive dyskinesia. It is unclear if oral vitamin B6 prevents tardive dyskinesia in patients taking neuroleptic drugs. Details: A small clinical study in patients taking neuroleptic drugs for schizophrenia shows that taking vitamin B6 (form not specified) 400 mg daily seems to improve Parkinsonian, dystonic, and dyskinetic symptoms when compared with placebo (8558).
• Tourette syndrome. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small, nonblinded clinical study in children aged 4-17 years with untreated Tourette syndrome or with chronic tic disorder and associated symptoms of anxiety shows that taking a liquid nutritional supplement providing vitamin B6 2.8 mg and L-theanine 200 mg daily for 2 months improves scores on the Yale Global Tic Severity Scale, but does not reduce anxiety, when compared with patients receiving psychoeducation (108555). This study may have been inadequately powered to detect a difference between groups.
• Vincristine-induced neuropathy. Oral vitamin B6 has only been evaluated in combination with pyridostigmine; its effect when used alone is unclear. Details: A small clinical study in children ages 11 months to 13 years with neuropathy due to vincristine treatment for acute lymphoblastic leukemia, shows that taking vitamin B6 150 mg/m2 and pyridostigmine 3 mg/kg twice daily for 3 months is associated with reduced severity of sensory and motor neuropathy when compared with baseline (104928). The validity of this finding is limited by the lack of a control group. More evidence is needed to rate vitamin B6 for these uses.

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LIKELY SAFE ...when used orally and appropriately. Oral magnesium is safe when used in doses below the tolerable upper intake level (UL) of 350 mg daily (7555). ...when used parenterally and appropriately. Parenteral magnesium sulfate is an FDA-approved prescription product (96484).

POSSIBLY UNSAFE ...when used orally in excessive doses. Doses greater than the tolerable upper intake level (UL) of 350 mg daily frequently cause loose stools and diarrhea (7555).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Magnesium is safe when used in doses below the tolerable upper intake level (UL) of 65 mg daily for children 1 to 3 years, 110 mg daily for children 4 to 8 years, and 350 mg daily for children older than 8 years (7555,89396). ...when used parenterally and appropriately (96483).

CHILDREN: LIKELY UNSAFE
when used orally in excessive doses. Tell patients not to use doses above the tolerable upper intake level (UL). Higher doses can cause diarrhea and symptomatic hypermagnesemia including hypotension, nausea, vomiting, and bradycardia (7555,8095).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately. Magnesium is safe for those pregnant and breast-feeding when used in doses below the tolerable upper intake level (UL) of 350 mg daily (7555).

PREGNANCY AND LACTATION: POSSIBLY SAFE
when prescription magnesium sulfate is given intramuscularly and intravenously prior to delivery for up to 5 days (12592,89397,99354,99355). However, due to potential adverse effects associated with intravenous and intramuscular magnesium, use during pregnancy is limited to patients with specific conditions such as severe pre-eclampsia or eclampsia. There is some evidence that intravenous magnesium can increase fetal mortality and adversely affect neurological and skeletal development (12590,12593,60818,99354,99355). However, a more recent analysis of clinical research shows that increased risk of fetal mortality seems to occur only in the studies where antenatal magnesium is used for tocolysis and not for fetal neuroprotection or pre-eclampsia/eclampsia (102457). Furthermore, antenatal magnesium does not seem to be associated with increased risk of necrotizing enterocolitis in preterm infants (104396). There is also concern that magnesium increases the risk of maternal adverse events. A meta-analysis of clinical research shows that magnesium sulfate might increase the risk of maternal adverse events, especially in Hispanic mothers compared to other racial and ethnic groups (60971,99319).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in excessive doses. Tell patients to avoid exceeding the tolerable upper intake level (UL) of 350 mg daily. Taking magnesium orally in higher doses can cause diarrhea (7555). ...when prescription magnesium sulfate is given intramuscularly and intravenously prior to delivery for longer than 5 days (12592,89397,99354,99355). Maternal exposure to magnesium for longer than 5-7 days is associated with an increase in neonatal bone abnormalities such as osteopenia and fractures. The U.S. Food and Drug Administration (FDA) recommends that magnesium injection not be given for longer than 5-7 days (12590,12593,60818,99354,99355).

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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)(97439,97446,106293,110292,113216,113223,113224). 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.

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LIKELY SAFE ...when prescription products are used orally and appropriately (12033). ...when niacinamide supplements are taken orally in doses below the tolerable upper intake level (UL) set by the Institute of Medicine (IOM). The UL of niacinamide is 30 mg daily for adults 18 years of age and 35 mg daily for adults 19 years and older (6243).

POSSIBLY SAFE ...when used orally in doses greater than 30 mg but less than 900 mg daily. The European Food Safety Authority has set the tolerable upper intake level (UL) of niacinamide at 900 mg daily (104937). However, oral niacinamide has been safely used in doses up to 1500 mg daily for 12 weeks in some clinical trials (25561,94188,98940,107709,110502) and up to 1000 mg daily for 12 months in other trials (93362,113559,113560). ...when used topically and appropriately for up to 16 weeks (5940,93360,110497,110498,110501,113681,113683,113684).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Niacinamide has been safely used in children for up to 7 years in doses below the tolerable upper intake level (UL) (4874,9957). The UL of niacinamide for children by age is: 1-3 years, 10 mg daily; 4-8 years, 15 mg daily; 9-13 years, 20 mg daily; 14-18 years, 30 mg daily (6243).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts that do not exceed the tolerable upper intake level (UL) for niacinamide. The UL of niacinamide during pregnancy and lactation is 30 mg daily for those 14-18 years of age and 35 mg daily for those 19 years and older (6243). There is insufficient reliable information available about the safety of larger oral doses of niacinamide or topical niacinamide; avoid using.

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LIKELY SAFE ...when used orally and appropriately in doses that do not exceed the tolerable upper intake level (UL) of 100 mg daily in the form of pyridoxine for adults (15,6243). ...when used parenterally and appropriately. Injectable vitamin B6 (pyridoxine) is an FDA-approved prescription product (15).

POSSIBLY SAFE ...when used orally and appropriately in doses of 101-200 mg daily (6243,8558).

POSSIBLY UNSAFE ...when used orally in doses at or above 500 mg daily. High doses, especially those exceeding 1000 mg daily or total doses of 1000 grams or more, pose the most risk. However, neuropathy can occur with lower daily or total doses (6243,8195). ...when used intramuscularly in high doses and frequency due to potential for rhabdomyolysis (90795).

CHILDREN: LIKELY SAFE
when used orally and appropriately in doses that do not exceed the tolerable upper intake level (UL) of vitamin B6 in the form of pyridoxine 30 mg daily for children aged 1-3 years, 40 mg daily for 4-8 years, 60 mg daily for 9-13 years, and 80 mg daily for 14-18 years (6243).

CHILDREN: POSSIBLY SAFE
when used orally and appropriately in amounts exceeding the recommended dietary allowance (5049,8579,107124,107125,107135).

CHILDREN: POSSIBLY UNSAFE
when used orally in excessive doses, long-term (6243).

PREGNANCY: LIKELY SAFE
when used orally and appropriately. A special sustained-release product providing vitamin B6 (pyridoxine) 75 mg daily is FDA-approved for use in pregnancy. Vitamin B6 (pyridoxine) is also considered a first-line treatment for nausea and vomiting in pregnancy by the American College of Obstetrics and Gynecology (111601). However, it should not be used long-term or without medical supervision and close monitoring. The tolerable upper intake level (UL) refers to vitamin B6 in the form of pyridoxine and is 80 mg daily for those aged 14-18 years and 100 mg daily for 19 years and older (6243).

PREGNANCY: POSSIBLY UNSAFE
when used orally in excessive doses. There is some concern that high-dose maternal vitamin B6 (pyridoxine) can cause neonatal seizures (4609,6397,8197).

LACTATION: LIKELY SAFE
when used orally in doses not exceeding the tolerable upper intake level (UL) of vitamin B6 in the form of pyridoxine 80 mg daily for those aged 14-18 years and 100 mg daily for those 19 years and older. The recommended dietary allowance (RDA) in lactating women is 2 mg daily (6243). There is insufficient reliable information available about the safety of vitamin B6 when used in higher doses in breast-feeding women.

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AMINOGLYCOSIDE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Concomitant use of aminoglycoside antibiotics and magnesium can increase the risk for neuromuscular weakness.  Details Both aminoglycosides and magnesium reduce presynaptic acetylcholine release, which can lead to neuromuscular blockade and possible paralysis. This is most likely to occur with high doses of magnesium given intravenously (13362).

ANTACIDS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Use of acid reducers may reduce the laxative effect of magnesium oxide.  Details A retrospective analysis shows that, in the presence of H2 receptor antagonists (H2RAs) or proton pump inhibitors (PPIs), a higher dose of magnesium oxide is needed for a laxative effect (90033). This may also occur with antacids. Under acidic conditions, magnesium oxide is converted to magnesium chloride and then to magnesium bicarbonate, which has an osmotic laxative effect. By reducing acidity, antacids may reduce the conversion of magnesium oxide to the active bicarbonate salt.

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, magnesium may have antiplatelet effects, but the evidence is conflicting.  Details In vitro evidence shows that magnesium sulfate inhibits platelet aggregation, even at low concentrations (20304,20305). Some preliminary clinical evidence shows that infusion of magnesium sulfate increases bleeding time by 48% and reduces platelet activity (20306). However, other clinical research shows that magnesium does not affect platelet aggregation, although inhibition of platelet-dependent thrombosis can occur (60759).

BISPHOSPHONATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Magnesium can decrease absorption of bisphosphonates.  Details Cations, including magnesium, can decrease bisphosphonate absorption. Advise patients to separate doses of magnesium and these drugs by at least 2 hours (13363).

CALCIUM CHANNEL BLOCKERS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Magnesium can have additive effects with calcium channel blockers, although evidence is conflicting.  Details Magnesium inhibits calcium entry into smooth muscle cells and may therefore have additive effects with calcium channel blockers. Severe hypotension and neuromuscular blockades may occur when nifedipine is used with intravenous magnesium (3046,20264,20265,20266), although some contradictory evidence suggests that concurrent use of magnesium with nifedipine does not increase the risk of neuromuscular weakness (60831). High doses of magnesium could theoretically have additive effects with other calcium channel blockers.

DIGOXIN Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Magnesium salts may reduce absorption of digoxin.  Details Clinical evidence suggests that treatment with oral magnesium hydroxide or magnesium trisilicate reduces absorption of digoxin from the intestines (198,20268,20270). This may reduce the blood levels of digoxin and decrease its therapeutic effects.

GABAPENTIN (Neurontin) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Unlikely •  Level of Evidence = B Gabapentin absorption can be decreased by magnesium.  Details Clinical research shows that giving magnesium oxide orally along with gabapentin decreases the maximum plasma concentration of gabapentin by 33%, time to maximum concentration by 36%, and area under the curve by 43% (90032). Advise patients to take gabapentin at least 2 hours before, or 4 to 6 hours after, magnesium supplements.

KETAMINE (Ketalar) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Magnesium might precipitate ketamine toxicity.  Details In one case report, a 62-year-old hospice patient with terminal cancer who had been stabilized on sublingual ketamine 150 mg four times daily experienced severe ketamine toxicity lasting for 2 hours after taking a maintenance dose of ketamine following an infusion of magnesium sulfate 2 grams (105078). Since both magnesium and ketamine block the NMDA receptor, magnesium is thought to have potentiated the effects of ketamine.

LEVODOPA/CARBIDOPA (Sinemet) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Magnesium can reduce the bioavailability of levodopa/carbidopa.  Details Clinical research in healthy volunteers shows that taking magnesium oxide 1000 mg with levodopa 100 mg/carbidopa 10 mg reduces the area under the curve (AUC) of levodopa by 35% and of carbidopa by 81%. In vitro and animal research shows that magnesium produces an alkaline environment in the digestive tract, which might lead to degradation and reduced bioavailability of levodopa/carbidopa (100265).

POTASSIUM-SPARING DIURETICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Potassium-sparing diuretics decrease excretion of magnesium, possibly increasing magnesium levels.  Details Potassium-sparing diuretics also have magnesium-sparing properties, which can counteract the magnesium losses associated with loop and thiazide diuretics (9613,9614,9622). Theoretically, increased magnesium levels could result from concomitant use of potassium-sparing diuretics and magnesium supplements.

QUINOLONE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Magnesium decreases absorption of quinolones.  Details Magnesium can form insoluble complexes with quinolones and decrease their absorption (3046). Advise patients to take these drugs at least 2 hours before, or 4 to 6 hours after, magnesium supplements.

SEVELAMER (Renagel, Renvela) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Sevelamer may increase serum magnesium levels.  Details In patients on hemodialysis, sevelamer use was associated with a 0.28 mg/dL increase in serum magnesium. The mechanism of this interaction remains unclear (96486).

SKELETAL MUSCLE RELAXANTS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = A Parenteral magnesium alters the pharmacokinetics of skeletal muscle relaxants, increasing their effects and accelerating the onset of effect.  Details Parenteral magnesium shortens the time to onset of skeletal muscle relaxants by about 1 minute and prolongs the duration of action by about 2 minutes. Magnesium potentiates the effects of skeletal muscle relaxants by decreasing calcium-mediated release of acetylcholine from presynaptic nerve terminals, reducing postsynaptic sensitivity to acetylcholine, and having a direct effect on the membrane potential of myocytes (3046,97492,107364). Magnesium also has vasodilatory actions and increases cardiac output, allowing a greater amount of muscle relaxant to reach the motor end plate (107364). A clinical study found that low-dose rocuronium (0.45 mg/kg), when given after administration of magnesium 30 mg/kg over 10 minutes, has an accelerated onset of effect, which matches the onset of effect seen with a full-dose rocuronium regimen (0.6 mg/kg) (96485). In another clinical study, onset times for rocuronium doses of 0.3, 0.6, and 1.2 mg/kg were 86, 76, and 50 seconds, respectively, when given alone, but were reduced to 66, 44, and 38 seconds, respectively, when the doses were given after a 15-minute infusion of magnesium sulfate 60 mg/kg (107364). Giving intraoperative intravenous magnesium sulfate, 50 mg/kg loading dose followed by 15 mg/kg/hour, reduces the onset time of rocuronium, enhances its clinical effects, reduces the dose of intraoperative opiates, and prolongs the spontaneous recovery time (112781,112782). It does not affect the activity of subsequently administered neostigmine (112782).

SULFONYLUREAS Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Magnesium increases the systemic absorption of sulfonylureas, increasing their effects and side effects.  Details Clinical research shows that administration of magnesium hydroxide with glyburide increases glyburide absorption, increases maximal insulin response by 35-fold, and increases the risk of hypoglycemia, when compared with glyburide alone (20307). A similar interaction occurs between magnesium hydroxide and glipizide (20308). The mechanism of this effect appears to be related to the elevation of gastrointestinal pH by magnesium-based antacids, increasing solubility and enhancing absorption of sulfonylureas (22364).

TETRACYCLINE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Magnesium decreases absorption of tetracyclines.  Details Magnesium can form insoluble complexes with tetracyclines in the gut and decrease their absorption and antibacterial activity (12586). Advise patients to take these drugs 1 hour before or 2 hours after magnesium supplements.

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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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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, niacinamide may have additive effects when used with anticoagulant or antiplatelet drugs, especially in patients on hemodialysis.  Details Several cases of thrombocytopenia have been reported for hemodialysis patients treated with niacinamide 1 gram daily. Hemodialysis patients receiving niacinamide had almost a three-fold higher risk of developing thrombocytopenia when compared with those receiving placebo (25563,98940).

CARBAMAZEPINE (Tegretol) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Niacinamide might increase the levels and adverse effects of carbamazepine.  Details Plasma levels of carbamazepine were increased in two children given high-dose niacinamide, 60-80 mg/kg/day. This might be due to inhibition of the cytochrome P450 enzymes involved in carbamazepine metabolism (14506). There is not enough data to determine the clinical significance of this interaction.

PRIMIDONE (Mysoline) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Niacinamide might increase the levels and adverse effects of primidone.  Details Case reports in children suggest niacinamide 60-100 mg/kg/day reduces hepatic metabolism of primidone to phenobarbital, and reduces the overall clearance rate of primidone (14506); however, there is not enough data to determine the clinical significance of this potential interaction.

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AMIODARONE (Cordarone) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, vitamin B6 might increase the photosensitivity caused by amiodarone.  Details Despite initial case reports suggesting that pyridoxine may have a protective effect against amiodarone-induced photosensitivity, preliminary clinical research suggests that pyridoxine may actually exacerbate this adverse effect (8892,8893).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, vitamin B6 may have additive effects when used with antihypertensive drugs.  Details Research in hypertensive rats shows that vitamin B6 can decrease systolic blood pressure (30859,82959,83093). Similarly, clinical research in patients with hypertension shows that taking high doses of vitamin B6 may reduce systolic and diastolic blood pressure, possibly by reducing plasma levels of epinephrine and norepinephrine (83091).

LEVODOPA Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Vitamin B6 may increase the metabolism of levodopa when taken alone, but not when taken in conjunction with carbidopa.  Details Vitamin B6 (pyridoxine) enhances the metabolism of levodopa, reducing its clinical effects. However, this interaction does not occur when carbidopa is used concurrently with levodopa (Sinemet). Therefore, it is not likely to be a problem in most people (3046).

PHENOBARBITAL (Luminal) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D High doses of vitamin B6 may reduce the levels and clinical effects of phenobarbital.  Details Preliminary clinical evidence suggests that vitamin B6 200 mg daily can reduce plasma levels of phenobarbital, possibly by increasing metabolism. It is not known whether lower doses have any effect. Advise people taking phenobarbital to avoid high doses of vitamin B6 (3046,10801).

PHENYTOIN (Dilantin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D High doses of vitamin B6 may reduce the levels and clinical effects of phenytoin.  Details Preliminary clinical evidence suggests that vitamin B6 200 mg daily can reduce plasma levels of phenytoin, possibly by increasing metabolism. It is not known whether lower doses have any effect. Advise people taking phenytoin to avoid high doses of vitamin B6 (3046,10801).

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General ...Magnesium is generally well tolerated. Some clinical research shows no differences in adverse effects between placebo and magnesium groups.
Most Common Adverse Effects:
Orally: Diarrhea, gastrointestinal irritation, nausea, and vomiting.
Intravenously: Bradycardia, dizziness, flushing sensation, hypotension, and localized pain and irritation. In pregnancy, may cause blurry vision, dizziness, lethargy, nausea, nystagmus, and perception of warmth.
Serious Adverse Effects (Rare):
All ROAs: With toxic doses, loss of reflexes and respiratory depression can occur. High doses in pregnancy can increase risk of neonatal mortality and neurological defects.

Cardiovascular ...Intravenously, magnesium can cause bradycardia, tachycardia, and hypotension (13356,60795,60838,60872,60960,60973,60982,61001,61031,114681). Inhaled magnesium administered by nebulizer may also cause hypotension (113466). Magnesium sulfate may cause rapid heartbeat when administered antenatally (60915,114681).
In one case report, a 99-year-old male who took oral magnesium oxide 3000 mg daily for chronic constipation was hospitalized with hypermagnesemia, hypotension, bradycardia, heart failure, cardiomegaly, second-degree sinoatrial block, and complete bundle branch block. The patient recovered after discontinuing the magnesium oxide (108966).

Dermatologic ...Intravenously, magnesium may cause flushing, sweating, and problems at the injection site (including burning pain) (60960,60982,111696,114681). In a case study, two patients who received intravenous magnesium sulfate for suppression of preterm labor developed a rapid and sudden onset of an urticarial eruption (a skin eruption of itching welts). The eruption cleared when magnesium sulfate was discontinued (61045). Orally, magnesium oxide may cause allergic skin rash, but this is rare. In one case report, a patient developed a rash after taking 600 mg magnesium oxide (Maglax) (98291).

Gastrointestinal ...Orally, magnesium can cause gastrointestinal irritation, nausea, vomiting, and diarrhea (1194,4891,10661,10663,18111,60951,61016,98290). In rare cases, taking magnesium orally might cause a bezoar, an indigestible mass of material which gets lodged in the gastrointestinal tract. In a case report, a 75-year-old female with advanced rectal cancer taking magnesium 1500 mg daily presented with nausea and anorexia from magnesium oxide bezoars in her stomach (99314). Magnesium can cause nausea, vomiting, or dry mouth when administered intravenously or by nebulization (60818,60960,60982,104400,113466,114681). Antenatal magnesium sulfate may also cause nausea and vomiting (60915,114681). Two case reports suggest that giving magnesium 50 grams orally for bowel preparation for colonoscopy in patients with colorectal cancer may lead to intestinal perforation and possibly death (90006).
Delayed meconium passage and obstruction have been reported rarely in neonates after intravenous magnesium sulfate was given to the mother during pregnancy (60818). In a retrospective study of 200 neonates born prematurely before 32 weeks of gestation, administration of prenatal IV magnesium sulfate, as a 4-gram loading dose and then 1-2 grams hourly, was not associated with the rate of meconium bowel obstruction when compared with neonates whose mothers had not received magnesium sulfate (108728).

Genitourinary ...Intravenously, magnesium sulfate may cause renal toxicity or acute urinary retention, although these events are rare (60818,61012). A case of slowed cervical dilation at delivery has been reported for a patient administered intravenous magnesium sulfate for eclampsia (12592). Intravenous magnesium might also cause solute diuresis. In a case report, a pregnant patient experienced polyuria and diuresis after having received intravenous magnesium sulfate in Ringer's lactate solution for preterm uterine contractions (98284).

Hematologic ...Intravenously, magnesium may cause increased blood loss at delivery when administered for eclampsia or pre-eclampsia (12592). However, research on the effect of intravenous magnesium on postpartum hemorrhage is mixed. Some research shows that it does not affect risk of postpartum hemorrhage (60982), while other research shows that intrapartum magnesium administration is associated with increased odds of postpartum hemorrhage, increased odds of uterine atony (a condition that increases the risk for postpartum hemorrhage) and increased need for red blood cell transfusions (97489).

Musculoskeletal ...Intravenously, magnesium may cause decreased skeletal muscle tone, muscle weakness, or hypocalcemic tetany (60818,60960,60973).
Although magnesium is important for normal bone structure and maintenance (272), there is concern that very high doses of magnesium may be detrimental. In a case series of 9 patients receiving long-term tocolysis for 11-97 days, resulting in cumulative magnesium sulfate doses of 168-3756 grams, a lower bone mass was noted in 4 cases receiving doses above 1000 grams. There was one case of pregnancy- and lactation-associated osteoporosis and one fracture (108731). The validity and clinical significance of this data is unclear.

Neurologic/CNS ...Intravenously, magnesium may cause slurred speech, dizziness, drowsiness, confusion, or headaches (60818,60960,114681). With toxic doses, loss of reflexes, neurological defects, drowsiness, confusion, and coma can occur (8095,12589,12590).
A case report describes cerebral cortical and subcortical edema consistent with posterior reversible encephalopathy syndrome (PRES), eclampsia, somnolence, seizures, absent deep tendon reflexes, hard to control hypertension, acute renal failure and hypermagnesemia (serum level 11.5 mg/dL), after treatment with intravenous magnesium sulfate for preeclampsia in a 24-year-old primigravida at 39 weeks gestation with a previously uncomplicated pregnancy. The symptoms resolved after 4 days of symptomatic treatment in an intensive care unit, and emergency cesarian delivery of a healthy infant (112785).

Ocular/Otic ...Intravenously, magnesium may cause blurred vision (114681). Additionally, cases of visual impairment or nystagmus have been reported following magnesium supplementation, but these events are rare (18111,60818).

Psychiatric ...A case of delirium due to hypermagnesemia has been reported for a patient receiving intravenous magnesium sulfate for pre-eclampsia (60780).

Pulmonary/Respiratory ...Intravenously, magnesium may cause respiratory depression and tachypnea when used in toxic doses (12589,61028,61180).

Other ...Hypothermia from magnesium used as a tocolytic has been reported (60818).

(Read more about MAGNESIUM)

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). Additionally, four cases of elevated left ventricular end-diastolic pressure associated with melatonin intake have been reported (114510).

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, angiokeratoma, and nasal mucosal ulcers have also been reported (62770,62914,114510). 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 ...Orally, melatonin use might be associated with higher rates of precocious puberty, growth hormone deficiency, elevated cortisol, and increased progesterone (114510). 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 (62384,62770,114510), 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), pouchitis (114510), 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). Melatonin use has also been linked to a few cases of Gilbert's syndrome (114510).

Musculoskeletal ...Orally, melatonin might increase fall risk. Analysis of a large adverse event database suggests that the rate of accidents and falls is higher with melatonin use when compared with the average rate of all other medications combined. However, the rate of accidents and falls with melatonin use seems to be lower when compared with other sleep medications (114510). Other 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). There are also reports of back pain, dropped head syndrome, fractures, growth retardation, and myalgia associated with melatonin intake (114510).

Neurologic/CNS ...Orally, melatonin may cause migraine-like headache (1070,1077,15034,62384,62450,62710,62754,62804,62792,62914,88288,88293,88294,96318)(106297,114510) 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)(106293,106297,114510). 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), tic (114510), excitement before bedtime (62811), insomnia (114510), nightmares or more intense dreams (62401,62462,62780,62784,88283,114510), 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).

Ocular/Otic ...There are six case reports of pupillary disorder associated with melatonin intake (114510).

Psychiatric ...Orally, melatonin may cause mood changes, including dysphoria (sadness) (1764), dips in mood (62345,62450,62792), nervousness (62784), suicide or self-injury (114510), or transient depression (1077). Delusions and hallucinations have also been reported in clinical research (62347). An analysis of adverse event case reports indicates that drug abuse, dependence, and withdrawal have been associated with melatonin use; however, the rate appears to be lower when compared with all other medications combined or sleep medications (114510).
This analysis also suggests that melatonin use might be associated with educational problems, social behavior disturbances, defiant behavior, oppositional defiant disorder, and school refusal at disproportionately higher rates when compared with all other drugs combined or other sleep medications (114510). 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).

Other ...There are case reports of body temperature fluctuation and post viral fatigue syndrome associated with melatonin intake (114510).

(Read more about MELATONIN)

General ...Orally, niacinamide is well tolerated in amounts typically found in food. When used topically and orally in higher doses, niacinamide seems to be generally well tolerated.
Most Common Adverse Effects:
Orally: Dizziness, drowsiness, itching, gastrointestinal disturbances, headache, and rash.
Topically: Burning sensation, itching, and mild dermatitis.

Dermatologic ...Orally, large doses of niacinamide are associated with occasional reports of rashes, itching, and acanthosis nigricans (4880,11695,11697,14504,107709), though a meta-analysis of 19 clinical studies suggests that dermatological adverse event rates are similar between niacinamide and control (110497). Topically, application of niacinamide in a cream has been reported to cause a burning sensation, itching and pruritus, crusting, and mild dermatitis (93357,93360,110501,110498).

Endocrine ...Orally, niacinamide in high doses, 50 mg/kg daily, has been associated with modestly higher insulin requirements in patients with type 1 diabetes, when compared with taking niacinamide 25 mg/kg daily. Theoretically, high-dose niacinamide might increase insulin resistance, although to a lesser extent than niacin (4881,14512).

Gastrointestinal ...Orally, large doses of niacinamide can cause gastrointestinal disturbances including nausea, vomiting, heartburn, anorexia, epigastric pain, flatulence, and diarrhea (6243,11694,11695,11696,11697,107709,110497,113682).

Hematologic ...Orally, niacinamide supplementation might increase the risk for thrombocytopenia in patients undergoing hemodialysis (98940,107709). A meta-analysis of small clinical studies shows that taking niacinamide during hemodialysis to reduce phosphate levels is associated with a 2.8-fold increased risk for thrombocytopenia when compared with placebo. In one of the included studies, platelet levels returned to normal within 20 days after niacinamide discontinuation (98940).

Hepatic ...Orally, older reports of elevated liver function tests with high doses of niacinamide (3 grams or more daily) have raised concerns about liver toxicity. However, newer studies have not reported this concern; it is possible that some of these cases were due to contamination with niacin (4880,11694,11695,14503).

Neurologic/CNS ...Orally, large doses of niacinamide can cause dizziness, drowsiness, and headaches (11694,11695,11696,11697,107709).

(Read more about NIACINAMIDE)

General ...Orally or by injection, vitamin B6 is well tolerated in doses less than 100 mg daily.
Most Common Adverse Effects:
Orally or by injection: Abdominal pain, allergic reactions, headache, heartburn, loss of appetite, nausea, somnolence, vomiting.
Serious Adverse Effects (Rare):
Orally or by injection: Sensory neuropathy (high doses).

Dermatologic ...Orally, vitamin B6 (pyridoxine) has been linked to reports of skin and other allergic reactions and photosensitivity (8195,9479,90375). High-dose vitamin B6 (80 mg daily as pyridoxine) and vitamin B12 (20 mcg daily) have been associated with cases of rosacea fulminans characterized by intense erythema with nodules, papules, and pustules. Symptoms may persist for up to 4 months after the supplement is stopped, and may require treatment with systemic corticosteroids and topical therapy (10998).

Gastrointestinal ...Orally or by injection, vitamin B6 (pyridoxine) can cause nausea, vomiting, heartburn, abdominal pain, mild diarrhea, and loss of appetite (8195,9479,16306,83064,83103,107124,107127,107135). In a clinical trial, one patient experienced infectious gastroenteritis that was deemed possibly related to taking vitamin B6 (pyridoxine) orally up to 20 mg/kg daily (90796). One small case-control study has raised concern that long-term dietary vitamin B6 intake in amounts ranging from 3.56-6.59 mg daily can increase the risk of ulcerative colitis (3350).

Hematologic ...Orally or by injection, vitamin B6 (pyridoxine) can cause decreased serum folic acid concentrations (8195,9479). One case of persistent bleeding of unknown origin has been reported in a clinical trial for a patient who used vitamin B6 (pyridoxine) 100 mg twice daily on days 16 to 35 of the menstrual cycle (83103). It is unclear if this effect was due to vitamin B6 intake.

Musculoskeletal ...Orally or by injection, vitamin B6 (pyridoxine) can cause breast soreness or enlargement (8195).

Neurologic/CNS ...Orally or by injection, vitamin B6 (pyridoxine) can cause headache, paresthesia, and somnolence (8195,9479,16306). Vitamin B6 (pyridoxine) can also cause sensory neuropathy, which is related to daily dose and duration of intake. Doses exceeding 1000 mg daily or total doses of 1000 grams or more pose the most risk, although neuropathy can occur with lower daily or total doses as well (8195). The mechanism of the neurotoxicity is unknown, but is thought to occur when the liver's capacity to phosphorylate pyridoxine via the active coenzyme pyridoxal phosphate is exceeded (8204). Some researchers recommend taking vitamin B6 as pyridoxal phosphate to avoid pyridoxine neuropathy, but its safety is unknown (8204). Vitamin B6 (pyridoxine) neuropathy is characterized by numbness and impairment of the sense of position and vibration of the distal limbs, and a gradual progressive sensory ataxia (8196,10439). The syndrome is usually reversible with discontinuation of pyridoxine at the first appearance of neurologic symptoms. Residual symptoms have been reported in patients taking more than 2 grams daily for extended periods (8195,8196). Daily doses of 100 mg or less are unlikely to cause these problems (3094).

Oncologic ...In females, population research has found that a median intake of vitamin B6 1. 63 mg daily is associated with a 3.6-fold increased risk of rectal cancer when compared with a median intake of 1.05 mg daily (83024). A post-hoc subgroup analysis of results from clinical research in adults with a history of recent stroke or ischemic attack suggests that taking folic acid, vitamin B12, and vitamin B6 does not increase cancer risk overall, although it was associated with an increased risk of cancer in patients who also had diabetes (90378). Also, in patients with nasopharyngeal carcinoma, population research has found that consuming at least 8.6 mg daily of supplemental vitamin B6 during treatment was associated with a lower overall survival rate over 5 years, as well as a reduced progression-free survival, when compared with non-users and those with intakes of up to 8.6 mg daily (107134).

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