Calm Capsules by Natural Vitality

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 (60882,60915,60927,60931,61001,97485,103734,103754). 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 a meta-analysis, has not shown benefit of adjunct nebulized magnesium for acute asthma in adults or children (60888,90002,96484,104400,105920,113466). 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: Intravenous 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 intravenous morphine by 24% when compared with placebo (19968). Adding intravenous magnesium sulfate 3.7-5.5 grams to patient-controlled analgesia for 24 hours after surgery has also been used (19968). Meta-analyses also support that adjunctive intravenous and intrathecal administration of magnesium improves pain relief and sensory nerve block, and decreases the need for other analgesics, when compared with control (89390,90012,90015,98287,103728); however, it 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 intravenous 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 intravenous 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, intravenous magnesium might not alleviate postoperative pain in children. Two small clinical studies show that administering a magnesium intravenous 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. 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.
• 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).
• 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).
• 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.
• 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).
• 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. One meta-analysis shows that taking magnesium 240-970 mg daily does not lower systolic blood pressure (15165). However, more recent 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). 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). 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). It is unclear if these effects are due to magnesium, other ingredients, or the combination.
• Intraventricular hemorrhage. It is unclear if antenatal intravenous 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.
• 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: Small clinical studies in adults with migraine suggest that taking oral high-dose magnesium citrate 600-1830 mg daily in divided doses for up to 3 months seems to modestly reduce the frequency and severity of headaches when compared with baseline or placebo (4891,9498,60902). 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. 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). 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).
• 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 intravenous magnesium is helpful for acute pain associated with kidney dysfunction. 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).
• 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).
• 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).
• 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.
• 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 magnesium is beneficial for PONV. Details: 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).
• Postoperative recovery. It is unclear if intravenous 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 intravenous 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, or duration of hospital stay when compared with control (113677).
• 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).
• 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 during preterm labor in an effort to improve fetal neurological outcomes. 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). Administration of magnesium during preterm labor has been shown to reduce the risk of cerebral palsy and motor dysfunction in the infant (60882,60915,60927,60931,61001,97485,103734,103754).
• 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).
• 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)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Altitude sickness. It is unclear if oral rhodiola is beneficial for altitude sickness. Details: Preliminary clinical research shows that taking rhodiola 447 mg four times daily for 7 days does not improve blood oxygenation or markers of oxidative stress when compared with placebo in subjects exposed to simulated high-altitude conditions (25402).
• Anthracycline cardiotoxicity. It is unclear if oral rhodiola is beneficial for epirubicin-induced cardiotoxicity. Details: Preliminary clinical research in breast cancer patients shows that taking salidroside, a constituent of rhodiola, 600 mg daily, beginning one week prior to chemotherapy and continuing throughout chemotherapy administration, reduces epirubicin-induced early left ventricular regional systolic dysfunction when compared with placebo (90434).
• Anxiety. It is unclear if oral rhodiola is beneficial for anxiety. Details: Preliminary clinical research in college students with anxiety shows that taking a specific dried rhodiola extract (Vitango, Schwabe Pharma) 200 mg twice daily for 14 days modestly reduces reported levels of anxiety, anger, confusion, negative mood, and stress when compared with a control group. However, rhodiola extract does not seem to improve cognition (96462).
• Arrhythmia. Although there has been interest in using oral rhodiola for arrhythmia, there is insufficient reliable information about the clinical effects of rhodiola for this condition.
• Athletic performance. The evidence related to the use of rhodiola for athletic performance is mixed, although specific standardized extracts might be beneficial for certain performance endpoints. Details: The available evidence for rhodiola in athletic performance includes small clinical trials in recreationally active or trained athletes. Trials using rhodiola extracts standardized to 3% rosavins and 1% salidroside (eg. Finzelberg, GmbH) show that taking 3 mg/kg, 200 mg, or 500 mg prior to exercise testing, either as a single dose or with a 3-day lead-in dose, modestly improves performance endpoints on a cycle ergometer. Improved endpoints included time to exhaustion, peak oxygen use, time to completion, perceived exhaustion, anaerobic capacity, and power (13109,90432,100168). However, in trials in which rhodiola was not taken the morning of testing, or when performance endpoints included forearm endurance or marathon time and recovery, rhodiola 170 mg to 1500 mg daily did not affect perceived exertion, time to exhaustion, or peak oxygen use (15574,19284,90433). A small crossover trial shows that taking 500 mg of rhodiola extract, standardized to 3% rosavins and 1% salidroside, three times daily for 3 days followed by 500 mg 30-minutes before exercise testing increases bench press velocity but decreases bench press repetition volume when compared with placebo (110543). Furthermore, limited evidence suggests that rhodiola extract does not affect muscle strength, speed of limb movement, reaction times, or attention span (13109) but might reduce plasma creatine kinase levels (19284). Also, while some evidence suggests that rhodiola extract can reduce blood lactate levels (19284), other research shows that it increases blood lactate levels after resistance training to a greater degree than placebo (110543). In general, it appears that acute doses of rhodiola may improve specific physical performance parameters, but neither acute nor chronic doses appear to notably improve muscle function. Some research has also assessed rhodiola when used in combination with other ingredients. A small clinical study in trained male cyclists shows that taking a specific combination product (Optygen, First Endurance) containing rhodiola 600 mg (standardized to 3% rosavin and 2.5% salidroside) plus cordyceps 2000 mg (standardized to 7% cordycepic acid), daily for 6 days followed by a half-dose daily for 7 days does not improve time to exhaustion or muscle tissue oxygen saturation when compared with placebo (15573). Additionally, a small crossover study in healthy, recreationally active adult males shows that taking a 30:70 blend of rhodiola and maral root extracts at a dose of 350 mg or 175 mg, ninety minutes prior to isokinetic leg strength exercises, does not influence fatigability, performance variables, or affective responses when compared with placebo (105855).
• Bladder cancer. Although there has been interest in using oral rhodiola for bladder cancer, there is insufficient reliable information about the clinical effects of rhodiola for this condition.
• Chronic fatigue syndrome (CFS). Although there has been interest in using oral rhodiola for CFS, there is insufficient reliable information about the clinical effects of rhodiola for this condition.
• Coronavirus disease 2019 (COVID-19). Oral rhodiola extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults a with confirmed history of COVID-19 infection and at least 3 of 9 long COVID-19 symptoms for at least 30 days, but no longer than 3 months, after discharge shows that taking a specific combination product (ADAPT-232/Chisan, Swedish Herbal Institute), containing rhodiola extract 90 mg, schisandra extract 300 mg, and eleuthero extract 78 mg, twice daily for 14 days increases walking duration by around 13 minutes but does not reduce the duration of cough, fatigue, headache, pain, or other respiratory problems when compared with placebo (109635). It is unclear if these findings are due to rhodiola, other ingredients, or the combination.
• Depression. It is unclear if oral rhodiola is beneficial for depression. Details: Clinical practice guidelines from the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Treatments (CANMAT) state that rhodiola is not currently recommended for monotherapy or adjunctive use in major depressive disorder based on mixed evidence (110318). Clinical research shows that taking a specific rhodiola extract (SHR-5, Swedish Herbal Institute) 340 mg once or twice daily reduces symptoms of mild-to-moderate depression after 6 weeks of treatment when compared with placebo. Rhodiola decreased overall depressive symptoms, emotional instability, insomnia, and somatization; however, it did not improve feelings of self-esteem (17616). Another small clinical study in patients with major depressive disorder of moderate severity shows that adding a higher dose of rhodiola 600 mg to sertraline daily for 12 weeks improves depressive symptoms when compared with either sertraline alone or sertraline with a lower dose of rhodiola (300 mg) (102283).
• Diabetes. Although there has been interest in using oral rhodiola for diabetes, there is insufficient reliable information about the clinical effects of rhodiola for this condition.
• Fatigue. Preliminary clinical research suggests that oral rhodiola extract decreases fatigue in stressful situations. Details: Most preliminary clinical trials have evaluated a specific rhodiola root extract (SHR-5, Swedish Herbal Institute) in various doses and populations. Taking 50 mg of this product twice daily reduces mental fatigue and improves subjective well-being in students during an examination period (1927). Taking 144 mg twice daily for 7 days reduces fatigue, but not stress, in university students (19287). In night shift workers, 170 mg daily for 2 weeks reduces feelings of fatigue and improves mental performance (6877). In military cadets, a single dose of 370-555 mg after 24 hours without sleep improves tests of mental processing and short-term memory (16411). Finally, taking 576 mg daily for 28 days decreases symptoms of fatigue and increases attention, but does not improve quality of life or symptoms of depression, in patients with stress-related fatigue (19286). Other clinical research shows that taking a different rhodiola root extract (Rhodaxon, Teknofarm), 660 mg daily for 20 days, reduces mental fatigue by 30% in first-year university students (19288). Clinical research using another specific dried rhodiola extract (Vitango, Schwabe Pharma) also shows that taking 200 mg twice daily for 12 weeks modestly reduces perceived levels of stress, burnout, and fatigue when compared to baseline in adults experiencing symptoms of burnout. The validity of these findings is limited by the lack of a control group (96459). Rhodiola extract has also been studied in combination schisandra berry extract and Siberian ginseng root extract (ADAPT-232, Swedish Herbal Institute). However, evidence is mixed, with one study showing that 270 mg daily improves attention, accuracy, and speed in tired individuals performing stressful cognitive tasks (19289), and another study showing that 280 mg daily for 7 days does not reduce mental fatigue or stress in university students (19287).
• Generalized anxiety disorder (GAD). It is unclear if oral rhodiola is beneficial for GAD. Details: A small clinical study shows that taking a specific rhodiola extract (Rhodax, Bodyonics Ltd.) 170 mg twice daily for 10 weeks decreases anxiety and depression and improves symptom scores when compared to baseline in patients with GAD (16410). The validity of these findings is limited by the lack of a comparator group.
• Hearing loss. Although there has been interest in using oral rhodiola for hearing loss, there is insufficient reliable information about the clinical effects of rhodiola for this purpose.
• Hyperlipidemia. Although there has been interest in using oral rhodiola for hyperlipidemia, there is insufficient reliable information about the clinical effects of rhodiola for this condition.
• Menopausal symptoms. Oral rhodiola has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients experiencing menopausal symptoms shows that taking a combination product (Menopause Relief EP, EuroPharma USA) containing rhodiola extract 400 mg and black cohosh extract 13 mg daily for 12 weeks improves psychological symptoms of menopause when compared with placebo or black cohosh alone (103269). It is unclear if these findings are due to rhodiola, black cohosh, or the combination.
• Premature ejaculation. Oral rhodiola has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with lifelong premature ejaculation shows that taking a specific combination product (EndEP) containing rhodiola 200 mg, folic acid 200 mcg, zinc 10 mg, and biotin 50 mcg once daily for 90 days increases time to ejaculation by about 29 seconds and improves control of ejaculation in about 60% of participants when compared to baseline. These improvements disappear within 90 days of discontinuing treatment. The validity of these findings is limited by the lack of a control group (96460).
• Sexual arousal. Although there has been interest in using oral rhodiola for improving sexual arousal, there is insufficient reliable information about the clinical effects of rhodiola for this condition.
• Stress. Preliminary clinical research suggests that oral rhodiola extract reduces feelings of stress. Details: Preliminary clinical research in adults with general stress shows that taking a specific dried rhodiola extract (Vitango, Schwabe Pharma) modestly reduces levels of stress in certain situations. Taking 200 mg twice daily before breakfast and lunch for 4 weeks improves stress, disability, and functional impairment when compared to baseline (90431). A small study in college students with anxiety shows that taking 200 mg twice daily for 14 days modestly reduces reported levels of stress, anxiety, anger, confusion, and negative mood when compared to a control group (96462). In adults experiencing symptoms of burnout, taking this specific extract 200 mg twice daily for 12 weeks modestly reduces perceived levels of stress, burnout, and fatigue and improves sexual satisfaction when compared to baseline. The validity of these findings is limited by the lack of a control group (96459). Rhodiola has also been evaluated in combination with other ingredients in individuals with stress. A small clinical study in healthy adults with chronic stress shows that taking a specific combination product (Mg-Teadiola, Sanofi-Aventis), containing rhodiola extract 222 mg, magnesium 150 mg, green tea extract 125 mg (providing theanine 50 mg), vitamin B6 0.7 mg, vitamin B9 0.1 mg, and vitamin B12 1.25 mcg, daily for 4 weeks reduces stress scores when compared with placebo (108672). It is unclear if these findings are due to rhodiola, other ingredients, or the combination.
• Tuberculosis. Although there has been interest in using oral rhodiola for tuberculosis, there is insufficient reliable information about the clinical effects of rhodiola for this condition.
• Upper respiratory tract infection (URTI). Although there has been interest in using oral rhodiola for URTI prevention, there is insufficient reliable information about the clinical effects of rhodiola for this purpose. More evidence is needed to rate rhodiola for these uses.

(Read more about RHODIOLA)

POSSIBLY EFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral L-theanine, taken continuously or as a single dose, improves cognition in older adults. Details: A small clinical study in healthy, Japanese adults aged 50-69 years shows that taking a specific product (Suntheanine; Taiyo International.) containing L-theanine 101 mg daily after breakfast for 12 weeks does not improve mini-mental state exam (MMSE) scores when compared with placebo. However, a single-dose analysis from this study shows that administration of L-theanine 101 mg may improve the quality of working memory and reaction times during a cognitive function test when compared with placebo (108553). Patients were permitted to consume polyphenol-rich beverages during the study period; however, consumption was not documented, limiting the validity of this finding.
• Alzheimer disease. Although there is interest in using oral theanine for Alzheimer disease, there is insufficient reliable information about the clinical effects of theanine for this condition.
• Anxiety. It is unclear if oral L-theanine is beneficial in patients with anxiety. Results of clinical research are conflicting. Details: A preliminary clinical study shows that taking a single dose of a specific L-theanine product (Suntheanine, Taiyo Kagaku) 200 mg does not reduce experimentally-induced anticipatory anxiety when compared with placebo (12188). However, another preliminary clinical study in healthy adults with stress-related anxiety shows that taking L-theanine 200 mg daily for 4 weeks reduces anxiety scale scores and sleep disturbance when compared with placebo (101986).
• Attention. It is unclear if oral theanine improves attention. Details: A small clinical study in healthy males shows that taking a single dose of L-theanine 200 mg improves selective attention similar to a single dose of caffeine 160 mg (96337). However, other small clinical studies in adults show that taking L-theanine 100-400 mg does not improve most measures of attention, especially sustained attention or attention in executive control tasks, but doses of 100-200 mg may improve performance in simple attentional tasks when compared with placebo (96338,111396). Some of these studies suggest that taking L-theanine with caffeine appears to provide more benefit than either individual ingredient alone (96337,96338).
• Attention deficit-hyperactivity disorder (ADHD). Oral L-theanine seems to improve some aspects of ADHD, including cognition and sleep. Details: Some preliminary clinical research in children with ADHD shows that taking a one-time dose of L-theanine 2.5 mg/kg increases cognition scores, but does not improve results on sustained attention or inhibitory control tests, when compared with placebo. Taking L-theanine with caffeine 2 mg/kg also increases cognition scores and improves performance on a sustained attention test, but does not improve inhibitory control, when compared with placebo (104141). Other preliminary clinical research in males aged 8-12 years with ADHD shows that taking a specific L-theanine product (Suntheanine, Taiyo Kagaku) 200 mg orally twice daily for 6 weeks increases the percent of time spent in restful sleep by about 5% and decreases the number of bouts of nocturnal activity by about 6 when compared with placebo (91744).
• Cancer. Although there is interest in using oral theanine for cancer, there is insufficient reliable information about the clinical effects of theanine for this condition.
• Chemotherapy-induced diarrhea. Oral L-theanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with colon cancer shows that taking L-cystine 700 mg and L-theanine 280 mg (Ajinomoto Co. Inc.) orally once daily, starting one week before chemotherapy with TS-1 (Taiho Pharmaceutical) and continuing for 28 days, increases the rate of therapy completion by 49%, reduces the incidence of diarrhea by 37%, reduces appetite loss by 33%, and improves the reported tolerability of chemotherapy when compared with chemotherapy alone (96334). However, this combination does not appear to be beneficial in patients with gastric cancer, or in those with colorectal cancer receiving 4 courses of capecitabine-based adjuvant chemotherapy. (96334,101985).
• Cognitive impairment. Oral L-theanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One very small clinical study in adults with mild cognitive impairment shows that taking a product containing L-theanine 120 mg and green tea extract 720 mg (LGNC-07, LG Household & Health Care, Ltd) orally twice daily after meals for 16 weeks modestly improves memory and attention when compared with baseline. However, taking this product does not appear to improve memory and attention when patients with self-reported memory problems, but without mild cognitive impairment, are also considered (96339).
• Depression. It is unclear if oral L-theanine is beneficial in patients with depression. Details: A small clinical study shows that taking a specific L-theanine product (Suntheanine, Taiyo Kagaku Co. Ltd.) 250 mg at bedtime for 8 weeks reduces symptoms and improves sleep quality when compared to baseline in individuals with mild major depressive disorder (MDD) (96331). The validity of these findings is limited by the lack of a comparator group. Another small clinical study in adults with MDD shows that taking L-theanine 200 mg daily with sertraline for 6 weeks reduces depression symptoms and increases remission rates but does not improve treatment response rates when compared with sertraline and placebo (112278). The validity of these effects is limited by the small sample size and short study duration. Additionally, it is unclear if the reduction in depressive symptoms is clinically significant.
• Erythema. Oral L-theanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in healthy females with self-perceived skin sensitivity shows that taking a specific supplement containing L-theanine, ashwagandha, and saffron (InnerCalm, Arbonne) daily for 8 weeks reduces facial pigmentation when compared to baseline (111399). The validity of this finding is limited by a lack of a placebo group. It is unclear if these effects are due to L-theanine, other ingredients, or the combination.
• Generalized anxiety disorder (GAD). It is unclear if oral L-theanine is beneficial for reducing anxiety in people with GAD. Details: One small clinical study in adults with GAD shows that taking L-theanine 225 mg twice daily for 4 weeks, then 450 mg twice daily for 4 weeks, in conjunction with prescribed antidepressants, does not reduce anxiety scores when compared with antidepressants and placebo (104976).
• Hypertension. Although there is interest in using oral theanine for hypertension, there is insufficient reliable information about the clinical effects of theanine for this condition.
• Influenza. Oral L-theanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a combination of green tea catechins (THEA-FLAN 90S, Ito-en Co.) 378 mg, standardized to contain epigallocatechin gallate 270 mg and L-theanine (Suntheanine, Taiyo Kagaku) 210 mg daily for 5 months reduces the risk of developing clinically diagnosed influenza when compared with placebo. However, the combination does not seem to prevent laboratory-confirmed influenza infection (54021).
• Insomnia. It is unclear if oral L-theanine is beneficial for insomnia. Details: A very small clinical study in young healthy adults with sleep quality worsened by caffeine intake shows that taking L-theanine 50 mg (Suntheanine, Taiyo Kagaku Co. Ltd) once 10 minutes before bedtime suppresses caffeine-induced elevations in wake after sleep onset time but does not improve parameters of sleep quality including sleep onset latency, sleep time, or number of times waking after sleep onset when compared with placebo (112275). L-theanine has also been studied in combination with other ingredients. A small clinical study in adults with insomnia or disturbed sleep patterns shows that a specific product (RLX2; LiveLife Biosciences AG) containing L-theanine 50 mg and a specific casein peptide, alpha-s1-casein tryptic hydrolysate, 150 mg, taken one hour before bedtime for 4 weeks, increases sleep duration by 45 minutes and improves habitual sleep efficiency and daytime dysfunction when compared with baseline (108556). Another very small clinical study in healthy adults shows that taking a combination product containing tryptophan, glycine, magnesium, tart cherry powder, and L-theanine 2 hours before bedtime decreases sleep onset latency and increases total sleep duration, leading to better sleep efficiency and reduced morning sleepiness, when compared with placebo (111184). Another combination product containing L-theanine, ashwagandha, and saffron (InnerCalm, Arbonne), taken daily for 8 weeks, seems to improve sleep quality when compared to baseline (111399). However, the validity of this finding is limited by a lack of a control group. It is unclear if the effects described above are due to L-theanine, other ingredients, or the combination.
• Obsessive-compulsive disorder (OCD). It is unclear if oral L-theanine is beneficial for OCD. Details: A small clinical study in adults with OCD shows that taking L-theanine 100 mg twice daily for 10 weeks with fluvoxamine reduces OCD symptoms, particularly obsessive symptoms, and increases the proportion of patients with a complete response to treatment but does not improve compulsive symptoms, partial response rates, or remission rates when compared with placebo and fluvoxamine (112276).
• Postoperative recovery. Oral theanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study of adults with esophageal cancer undergoing esophagectomy shows that taking theanine 280 mg and cystine 700 mg daily, staring 4 days before surgery and continued for 13 days after surgery, does not improve measures of physical activity but does improve exercise tolerance and some measures of quality of life when compared with placebo (111400). It is unclear if these findings are due to theanine, cystine, or the combination.
• Schizophrenia. It is unclear if oral L-theanine is beneficial in patients with schizophrenia; the available evidence is limited and conflicting. Details: One small preliminary clinical study in adults with schizophrenia or schizoaffective disorder shows that taking L-theanine (Biosynergy) 200 mg orally twice daily for 8 weeks along with antipsychotic medications improves positive symptoms, anxiety, and general psychopathology symptoms, such as poor impulse control and disorientation, when compared with placebo. However, theanine does not improve general disease severity, negative symptoms, depression, cognitive function, extrapyramidal side effects, or quality of life (96341). In contrast, two small clinical studies show that taking L-theanine 400 mg (Suntheanine, BioSynergy Health Alternatives) with antipsychotics and with or without pregnenolone 50 mg daily for 8 weeks reduces negative symptoms, general psychopathology symptoms, and anxiety when compared with placebo in patients with schizophrenia or schizoaffective disorder. However, there were no improvements in positive schizophrenia symptoms, extrapyramidal side effects, or symptoms of depression (97923,112277). The inconsistency of results might be due to the small study sizes and the subjectivity of the outcomes measured.
• Stress. It is unclear if oral L-theanine is beneficial in patients with stress. Details: One very small clinical study shows that taking L-theanine 200 mg prior to a stress-inducing exam reduces tension-anxiety and may prevent blood pressure increases caused by psychological stress when compared with placebo (91746). Other preliminary clinical research in pharmacy students shows that taking theanine 200 mg twice daily for one week prior, and then for the first 10 days of a pharmacy practice period, decreases subjective stress scores when compared with placebo (91745). Another small clinical study in healthy young adults shows that drinking a beverage containing L-theanine 200 mg alone or combined with L-arginine 50 mg after a psychological stressor reduces stress, as measured by salivary alpha-amylase activity, when compared with placebo. The combination of L-arginine and L-theanine did not differ from L-theanine alone, suggesting that the combination does not act synergistically to reduce markers of stress (110393). However, not all research has been positive. A small clinical study shows that taking a specific L-theanine product (Suntheanine, Taiyo Kagaku) 200 mg induces subjective feelings of tranquility in relaxed people, but not those with experimentally-induced anticipatory anxiety, when compared with placebo (12188). Also, a small, clinical crossover study in healthy, moderately stressed adults shows that taking a single dose of a specific product (Alphawave; Ethical Naturals) containing L-theanine 200 mg prior to a stress-inducing exam does not improve anxiety at any time point when compared with placebo (108554). Due to the single-dose nature of this study, the effects of continued administration of this product are unclear. L-theanine has also been evaluated in combination with other ingredients. A small clinical study in adults with stress shows that taking a specific combination product (Mg-Teadiola, Sanofi-Aventis Group), containing green tea extract 125 mg (providing 50 mg L-theanine), magnesium 150 mg, vitamin B6 0.2 mg, vitamin B9 0.1 mg, vitamin B12 1.25 mcg, and rhodiola 222 mg, orally once daily for 28 days modestly improves stress and anxiety scores when compared with placebo. Improvements in stress scores, but not anxiety scores, appear to persist at 28 days after treatment completion (108672). It is unclear if any effects are due to L-theanine, other ingredients, or the combination.
• Tourette syndrome. It is unclear if oral L-theanine is beneficial in children with Tourette syndrome. Details: A small, nonblinded clinical study in children aged 4-17 years with untreated Tourette syndrome or with chronic tic disorder and associated symptoms of anxiety shows that taking a liquid nutritional supplement providing L-theanine 200 mg and vitamin B6 2.8 mg daily for 2 months improves scores on the Yale Global Tic Severity Scale, but does not reduce anxiety, when compared with patients receiving psychoeducation (108555). This study may have been inadequately powered to detect a difference between groups. More evidence is needed to rate theanine for these uses.

(Read more about THEANINE)

LIKELY SAFE ...when used orally and appropriately. 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).

(Read more about MAGNESIUM)

POSSIBLY SAFE ...when used orally and appropriately, short-term. There is some clinical research showing that taking rhodiola extract up to 300 mg twice daily has been used without adverse effects for up to 12 weeks (13109,16410,17616,71172,96459,102283,103269).

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

(Read more about RHODIOLA)

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

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

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

(Read more about THEANINE)

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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ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking rhodiola with antidiabetes drugs might increase the risk of hypoglycemia.  Details In vitro and animal research shows that rhodiola extract can decrease blood glucose due to alpha-glucosidase activity (15717,15719).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking rhodiola with antihypertensive drugs might increase the risk of hypotension.  Details In vitro and animal research shows that rhodiola extract inhibits angiotensin-converting enzyme (ACE) and might lower blood pressure (15719,19495).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, rhodiola might increase levels of drugs metabolized by CYP1A2.  Details In vitro research shows that rhodiola inhibits CYP1A2. This effect is highly variable and appears to be dependent on the rhodiola product studied (96461). However, a clinical study in healthy young males found that taking rhodiola extract 290 mg daily for 14 days does not inhibit the metabolism of caffeine, a CYP1A2 substrate (96463).

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, rhodiola might increase levels of drugs metabolized by CYP2C9.  Details In vitro research shows that rhodiola inhibits CYP2C9. This effect is highly variable and appears to be dependent on the rhodiola product studied (96461). Also, a clinical study in healthy young males found that taking rhodiola extract 290 mg daily for 14 days reduces the metabolism of losartan, a CYP2C9 substrate, by 21% after 4 hours (96463).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, rhodiola might increase levels of drugs metabolized by CYP3A4.  Details In vitro research shows that rhodiola inhibits CYP3A4 (19497,96461). This effect is highly variable and appears to be dependent on the rhodiola product studied (96461). However, a clinical study in healthy young males found that taking rhodiola extract 290 mg daily for 14 days does not inhibit the metabolism of midazolam, a CYP3A4 substrate (96463).

IMMUNOSUPPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, rhodiola use might interfere with immunosuppressive therapy.  Details In vitro and animal research show that rhodiola has immunostimulatory effects (19498,19499,19500,19501).

LOSARTAN (Cozaar) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Rhodiola might increase the levels and adverse effects of losartan.  Details A clinical study in healthy young males found that taking rhodiola extract 290 mg daily for 14 days reduces the metabolism of losartan, a CYP2C9 substrate, by 21% after 4 hours (96463).

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, rhodiola might increase levels of P-glycoprotein substrates.  Details In vitro research shows that rhodiola inhibits P-glycoprotein (19497). Theoretically, using rhodiola with P-glycoprotein substrates might increase drug levels and potentially increase the risk of adverse effects.

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

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

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General ...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). Inhaled magnesium administered by nebulizer may also cause hypotension (113466). Magnesium sulfate may cause rapid heartbeat when administered antenatally (60915).
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). 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). Antenatal magnesium sulfate may also cause nausea and vomiting (60915). 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). 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 ...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).

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General ...Orally, rhodiola seems to be well tolerated.
Most Common Adverse Effects:
Orally: Dizziness, increased or decreased production of saliva.

Gastrointestinal ...Orally, rhodiola extract may cause dry mouth or excessive saliva production (16410,16411).

Neurologic/CNS ...Orally, rhodiola extract can cause dizziness (16410).

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

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

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