Anxioton [Discontinued] by Orthoplex

Schizophrenia. Oral glycine may improve negative, but not positive, symptoms of schizophrenia when used as adjunct to therapy with typical antipsychotics in patients resistant to monotherapy. However, glycine does not seem to provide additional benefit when used with clozapine. Details: Some small clinical trials show that taking glycine 0.4-0.8 grams/kg daily in divided doses along with conventional treatment seems to reduce negative symptoms of schizophrenia in patients that are resistant to monotherapy with typical antipsychotics such as thioridazine, haloperidol, and perphenazine (10250,10251,10252,98591). However, when used with the atypical antipsychotic clozapine, glycine appears to have a negligible effect on or worsen symptoms of schizophrenia (10253,11321). Additionally, glycine does not seem to improve positive symptoms of schizophrenia (10250,10251,10252,98591).

3-phosphoglycerate dehydrogenase (3-PGDH) deficiency. It is unclear if oral glycine is beneficial in patients with 3-PGDH deficiency. Details: A case series describing two patients with 3-PGDH deficiency who did not respond to serine supplementation suggests that taking oral glycine 0.2 grams/kg daily along with serine might reduce seizure frequency. 3-PGDH deficiency is a rare condition in which serine is not synthesized properly (10254).
Aging. Oral glycine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in adults aged 61-80 years with overweight or obesity shows that taking a specific combination product (GlyNAC), providing glycine 100 mg/kg and N-acetyl cysteine 100 mg/kg, daily for 16 weeks improves some markers associated with aging, including glutathione levels, oxidative stress, mitochondrial impairment, genomic damage, inflammation, and endothelial dysfunction, when compared to baseline. Improvements in these measures were lacking in the placebo group (110624). The validity of these findings is limited by a lack of statistical comparison between groups. Also, it is unclear if these effects are due to glycine, N-acetyl cysteine, or the combination.
Attention deficit-hyperactivity disorder (ADHD). Although there has been interest in using oral glycine for ADHD, there is insufficient reliable information about the clinical effects of glycine for this purpose.
Benign prostatic hyperplasia (BPH). Although there has been interest in using oral glycine for BPH, there is insufficient reliable information about the clinical effects of glycine for this purpose.
Cognitive function. Small clinical studies suggest that oral glycine may modestly improve memory and cognitive function in some patients. Details: Two small clinical studies in healthy young adults and adults with psychosis risk syndrome show that taking glycine 0.2-0.4 grams/kg once or twice daily for up to 24 weeks may improve some measures of memory and cognitive performance when compared with baseline or placebo (11322,92321).
Cystic fibrosis. It is unclear if oral glycine is beneficial in patients with cystic fibrosis. Details: A small clinical trial in patients 6-23 years of age with cystic fibrosis shows that taking glycine 0.5 grams/kg daily for 8 weeks modestly improves some measures of lung function and reduces sputum and dyspnea by 15% and 23%, respectively, when compared with placebo. However, taking glycine does not improve appetite or energy (98583).
Gout. Oral glycine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in patients with mild hyperuricemia shows that taking a powder containing glycine 3 grams and L-tryptophan 0.2 grams nightly at bedtime for 6 weeks reduces serum uric acid levels by 0.3 mg/dL when compared with placebo. Improvements also occurred in the subgroup of patients with uric acid levels greater than 7 mg/dL, the point at which symptoms of gout can occur (99883). However, it is unclear if this combination improves gout-related pain. Also, it is not clear if these findings are due to glycine, L-tryptophan, or the combination.
Insomnia. Small clinical studies suggest that oral glycine may modestly improve sleep quality and daytime feelings of fatigue in patients with poor sleep quality or a restricted sleep duration. Details: Two very small studies in patients who have reported a subjective reduction in sleep quality show that taking glycine 3 grams one hour before bedtime for 2-4 days improves overall sleep quality and sleep efficacy when compared with placebo (92318,92320). Another very small clinical study in healthy males shows that taking glycine 3 grams 30 minutes before bedtime for 3 nights, during which time sleep duration is restricted by 25%, modestly reduces feelings of fatigue after the first night, but not after the third night, when compared with placebo (92316). The effects of glycine on sleep measures have also been evaluated in combination with other ingredients. A very small crossover study in healthy adults without documented sleep disorders shows that taking a combination product containing glycine 3000 mg, tryptophan 1000 mg, magnesium 300 mg, tart cherry powder 220 mg, and L-theanine 200 mg before bed for 3 nights reduces sleep onset latency, increases total sleep time, increases sleep efficiency, and reduces morning sleepiness when compared with placebo (111184). It is unclear if these effects are due to glycine, other ingredients, or the combination.
Isovaleric acidemia. Although there has been interest in using oral glycine for isovaleric acidemia, there is insufficient reliable information about the clinical effects of glycine for this purpose.
Metabolic syndrome. Although there has been interest in using oral glycine for metabolic syndrome, there is insufficient reliable information about the clinical effects of glycine for this purpose.
Obesity. Oral glycine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in adults aged 61-80 years with overweight or obesity shows that taking a specific combination product (GlyNAC), providing glycine 100 mg/kg and N-acetyl cysteine 100 mg/kg, daily for 16 weeks reduces waist circumference but does not improve body weight or body mass index (BMI) when compared to baseline. None of these outcomes were improved in individuals taking placebo (110624). The validity of these findings is limited by a lack of statistical comparison between groups. Also, it is unclear if these effects are due to glycine, N-acetyl cysteine, or the combination.
Overactive bladder. It is unclear if oral glycine is beneficial in patients with overactive bladder. Details: One very small, non-randomized, crossover trial in patients with overactive bladder shows that taking glycine 3 grams twice daily for 4 weeks reduces urinary urgency, urinary incontinence, and nighttime urinary frequency and improves quality of life scores when compared with placebo (106497). The validity of these findings is limited by a lack of randomization.
Physical performance. Oral glycine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in adults aged 61-80 years with overweight or obesity shows that taking a specific combination product (GlyNAC), providing glycine 100 mg/kg and N-acetyl cysteine 100 mg/kg, daily for 16 weeks improves upper and lower extremity strength and gait speed, but not walking distance, when compared to baseline. None of these outcomes were improved in individuals taking placebo (110624). The validity of these findings is limited by a lack of statistical comparison between groups. Also, it is unclear if these effects are due to glycine, N-acetyl cysteine, or the combination.
Stroke. It is unclear if sublingual glycine is beneficial in patients with acute ischemic stroke. Details: One small clinical study in patients with acute ischemic stroke in the carotid artery territory shows that taking glycine 1-2 grams sublingually daily for 5 days, starting within 6 hours after the onset of stroke, modestly improves clinical outcomes on the Orgogozo Stroke Scale, the Scandinavian Stroke Scale, and the Barthel index when compared with placebo (11320).
Venous leg ulcers. Topical glycine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study shows that applying a cream containing glycine, L-cysteine, and DL-threonine to leg ulcers reduces pain and modestly improves healing when compared with a placebo cream (10255). It is unclear if these effects are due to glycine, other ingredients, or the combination.
Wound healing. Although there has been interest in using topical glycine for wound healing, there is insufficient reliable information about the clinical effects of glycine for this purpose. More evidence is needed to rate glycine for these uses.

KAVA (Piper methysticum Root Extract, Dry, Piper methysticum, Dry, Kavalactones)

Anxiety. Oral kava seems to improve anxiety when taken for at least 5 weeks. Details: Most clinical research shows that kava extracts 150-400 mg, standardized to 70% kavalactones, daily are superior to placebo for relieving symptoms of non-psychotic anxiety (2094,2095,11372,18315,18316,18317,18320,98980), and are possibly comparable to buspirone 10 mg or low-dose benzodiazepines such as oxazepam 30 mg (18314). However, kava may not be effective for improving subthreshold anxiety. A meta-analysis of 3 small clinical studies in patients with subthreshold anxiety shows that taking kava does not improve anxiety symptoms when compared with placebo (110711). Overall, kava's effects appear to be dose-dependent and duration-dependent. One meta-analysis suggests that taking more than 200 mg kavalactones daily tends to be more beneficial for anxiety than taking less than 200 mg kavalactones daily (98980). Some clinical research also suggests that kava extract must be taken for at least 5 weeks to provide a benefit (2094,15046,18314,98980), while single-dose treatments may not be beneficial for acute anxiety (18319). Most studies have used a specific standardized extract (WS 1490, Dr. Willmar Schwabe Pharmaceuticals) 150-300 mg daily. Another specific kava extract (LI 150, Lichtwer Pharma) 400 mg daily has also been used (18314,98980). Clinical practice guidelines from a joint taskforce of the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Treatments (CANMAT) conclude that there is evidence supporting the use of kava for acute or short-term management of general anxiety symptoms but that only products standardized to a sufficient level of kavalactones should be recommended (110318).

POSSIBLY INEFFECTIVE

Generalized anxiety disorder (GAD). Oral kava doesn't seem to be effective for treating GAD. Details: A meta-analysis of 3 small, low-quality clinical studies in adults with GAD shows that kava extract standardized to 70% kavalactones, providing 140-280 mg kavalactones daily, is no more effective than placebo when used for 4-8 weeks (15130). Additionally, a more recent meta-analysis of 3 moderate-sized clinical trials in patients diagnosed with GAD shows that taking kava does not reduce anxiety when compared with placebo or conventional therapy (110711). While a small clinical trial in adults with GAD shows that taking kava rootstock extract, standardized to provide 120-240 mg of kavalactones daily, for 6 weeks reduces clinician rated anxiety scores when compared with placebo (29663), a large, multi-center clinical trial from the same research group shows that taking kava root extract standardized to 120 mg of kavalactones twice daily for 16 weeks does not reduce anxiety scores when compared with placebo in adults diagnosed with GAD (102086). Clinical practice guidelines from a joint taskforce of the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Treatments (CANMAT) recommends against the use of kava rootstock extracts (standardized to 60-250 mg kavalactones) as either monotherapy or adjunctive therapy in patients with GAD (110318). This recommendation against kava for GAD is based on high quality evidence from a meta-analysis and two additional clinical trials, along with a meta-review of two meta-analyses on the use of kava for GAD (110318,112133).

Benzodiazepine withdrawal. It is unclear if oral kava is beneficial for reducing benzodiazepine withdrawal symptoms. Details: One small clinical study in patients with non-psychotic anxiety shows that titrating a specific kava extract (WS1490, Dr. Willmar Schwabe Pharmaceuticals) up to 300 mg daily over one week while tapering the benzodiazepine over 2 weeks is no more effective than placebo for decreasing benzodiazepine withdrawal symptoms (7325).
Cancer. It is unclear if oral kava is beneficial in patients with cancer. Details: Epidemiological evidence has found that increasing kava consumption is associated with a lower incidence of cancer (8175).
Epilepsy. Although there is interest in using oral kava for epilepsy, there is insufficient reliable information about the clinical effects of kava for this condition.
Insomnia. It is unclear if oral kava is beneficial in patients with insomnia. Details: One small clinical study shows that taking a specific kava extract (WS1490, Dr. Willmar Schwabe Pharmaceuticals) 200 mg standardized to 70% kavalactones daily for 4 weeks reduces sleep disturbances associated with non-psychotic anxiety disorders (18321). However, another internet-based clinical trial in patients with self-reported insomnia associated with anxiety suggests that taking kava in a dose equivalent to 100 mg kavalactones three times daily for 4 weeks does not improve sleep when compared with placebo (15046).
Menopausal symptoms. It is unclear if oral kava is beneficial for menopausal symptoms. Details: One small clinical study shows that taking kava 100-200 mg standardized to contain 55% kavaina daily for 3 months reduces depression, anxiety, and hot flashes when compared to baseline in perimenopausal patients. However, the changes in depression and hot flashes were not better when compared with the control group that took calcium (18318).
Myalgia. Although there is interest in using oral kava for myalgia, there is insufficient reliable information about the clinical effects of kava for this condition.
Premenstrual syndrome (PMS). Although there is interest in using oral kava for PMS, there is insufficient reliable information about the clinical effects of kava for this condition.
Sexual arousal. Although there is interest in using oral kava for sexual arousal, there is insufficient reliable information about the clinical effects of kava for this condition.
Stress. It is unclear if oral kava reduces reactivity to experimental stress. Details: A small study in healthy volunteers shows that taking a single dose of kava (LI 150, Lichtwer Pharma) 120 mg orally might reduce the physiological changes associated with mentally stressful tasks when compared to baseline (9893). More evidence is needed to rate kava for these uses.

LEMON BALM (Melissa officinalis Flower and Leaf Extract, Dry, Melissa officinalis, Dry)

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

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

MAGNESIUM

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.

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.

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.

MAGNOLIA (Magnolia officinalis Stem Bark Extract, Dry, Magnolia officinalis, Dry)

Gingivitis. Magnolia bark extract might modestly reduce gum bleeding and inflammation when added to gum or toothpaste. Details: One clinical study shows that chewing gum containing magnolia bark extract plus xylitol for 5 minutes three times daily for 30 days reduces gingival bleeding by 33%, compared with 24% after chewing gum containing xylitol alone (92459). Another clinical study in adults with gingivitis shows that using a fluoride toothpaste containing magnolia extract 0.3% twice daily reduces gingivitis severity by about 0.27 points on the gingival index after 3 months, compared to 0.15 points for patients using the toothpaste without magnolia extract (92464).

Aging skin. Although there is interest in using topical magnolia for aging skin, there is insufficient reliable information about the clinical effects of magnolia for this purpose.
Allergic rhinitis (hay fever). Although there is interest in using oral magnolia for hay fever, there is insufficient reliable information about the clinical effects of magnolia for this condition.
Anxiety. Oral magnolia 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 mild anxiety shows that taking a proprietary blend of magnolia and phellodendron bark extract (Relora, Next Pharmaceuticals), standardized to 1.5% honokiol and 0.1% berberine, 250 mg three times daily for 6 weeks reduces temporary feelings of stress-induced anxiety almost 2-fold when compared with placebo. However, taking this product does not seem to improve long-standing feelings of stress-induced anxiety (34246). It is unclear if this effect is due to magnolia, other ingredients, or the combination. Additionally, this study was funded by the supplement manufacturer.
Dental plaque. It is unclear if oral magnolia is beneficial in patients with dental plaque. Details: Clinical research in adults with gingivitis shows that using a toothpaste containing 0.3% magnolia extract twice daily modestly reduces plaque severity by about 0.41 points on the mean plaque index after 3 months, compared to a 0.27 point reduction for patients using the toothpaste without magnolia extract (92464). While statistically significant, this improvement might not be clinically meaningful.
Diabetes. Although there is interest in using oral magnolia for diabetes, there is insufficient reliable information about the clinical effects of magnolia for this condition.
Headache. Although there is interest in using oral magnolia for headache, there is insufficient reliable information about the clinical effects of magnolia for this condition.
Menopausal symptoms. Oral magnolia has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in postmenopausal patients shows that taking a specific combination of magnolia, Vitex agnus-castus, soy isoflavones, vitamin D, and lactobacillus (Estromineral Serena Plus, Meda Pharma SpA) daily for one year decreases the frequency and intensity of hot flashes and improves sleep quality and the ability to fall asleep when compared with soy isoflavones alone (95031). Additionally, a small clinical study shows that taking this same product daily for one year improves vasomotor symptoms, mood disorders, somatic symptoms, sleep disorders, blood pressure, and glycemic control when compared to baseline (110708). However, the validity of these findings is limited by a lack of control group. Overall, it is unclear if the effects of this magnolia-containing product in postmenopausal patients are due to magnolia, other ingredients, or the combination.
Obesity. Oral magnolia has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in overweight females who report stress eating shows that taking a specific product containing a combination of bark extracts of magnolia plus phellodendron (Relora, Next Pharmaceuticals, Inc.) 250 mg three times daily for 6 weeks seems to prevent weight gain, compared with a 1.5 kg weight gain in those taking placebo (14349). This finding is limited because differences between groups were not statistically compared. Furthermore, it's unclear if this product induces weight loss.
Postpartum depression. It is unclear if oral magnolia tea is beneficial for preventing postpartum depression. Details: A small clinical study in healthy postpartum patients shows that drinking 1 cup of magnolia tea daily for 3 weeks may improve depressive symptoms and sleep efficiency when compared with usual care alone. Magnolia tea (plant part unspecified) was steeped in 300 mL of hot water for 12 minutes prior to consumption (105089).
Stress. Oral magnolia has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small low-quality clinical trial in moderately stressed healthy adults shows that taking a proprietary blend of magnolia and phellodendron bark extract (Relora, Next Pharmaceuticals) 250 mg twice daily for 4 weeks improves overall mood and decreases stress when compared with placebo (94904). It is unclear if this effect is due to magnolia, other ingredients, or the combination. Additionally, this study was funded by the supplement manufacturer. More evidence is needed to rate magnolia for these uses.

PASSION FLOWER (Passiflora incarnata Herb Top Flowering Extract, Dry, Passiflora incarnata, Dry)

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

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

ZIZYPHUS (Ziziphus jujuba var. spinosa Seed Extract, Dry, Ziziphus jujuba var. spinosa, Dry)

Aging skin. Although there has been interest in using topical zizyphus for aging skin, there is insufficient reliable information about the clinical effects of zizyphus for this purpose.
Anemia of chronic disease. Although there has been interest in using oral zizyphus for anemia of chronic disease, there is insufficient reliable information about the clinical effects of zizyphus for this purpose.
Anxiety. Although there has been interest in using oral zizyphus for anxiety, there is insufficient reliable information about the clinical effects of zizyphus for this purpose.
Asthma. Although there has been interest in using oral zizyphus for asthma, there is insufficient reliable information about the clinical effects of zizyphus for this purpose.
Athletic performance. Although there has been interest in using oral zizyphus to improve athletic performance, there is insufficient reliable information about the clinical effects of zizyphus for this purpose.
Cancer. Although there has been interest in using oral zizyphus for cancer, there is insufficient reliable information about the clinical effects of zizyphus for this purpose.
Constipation. It is unclear if oral zizyphus fruit extract is beneficial in patients with constipation. Details: A small clinical study in patients with idiopathic constipation shows that taking zizyphus fruit extract 20-40 drops daily for 12 weeks improves bloating, abdominal pain, difficult evacuation, and quality of life when compared to baseline. Significant improvements in constipation-related symptoms were lacking in patient taking placebo drops (93316). The validity of these findings is limited by the lack of statistical comparison between groups.
Coronavirus disease 2019 (COVID-19). Oral zizyphus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults hospitalized with confirmed COVID-19 shows that taking a combination product containing zizyphus, barley, and Assyrian plum 200 mL twice daily for 5 days in addition to standard therapy improves oxygen saturation levels and fatigue but does not improve cough severity or frequency, respiratory rate, or temperature when compared with control (112818). It is unclear if these effects are due to zizyphus, other ingredients, or the combination. It is also unclear if these changes are due to the product or the natural resolution of the condition.
Diabetes. It is unclear if oral zizyphus fruit powder is beneficial in patients with type 2 diabetes. Details: A small clinical study in patients with type 2 diabetes shows that taking zizyphus fruit powder 30 grams daily for 12 weeks reduces measures of insulin resistance and improves measures of insulin sensitivity, but does not affect fasting blood glucose levels or glycated hemoglobin, when compared with placebo (104507).
Diarrhea. Although there has been interest in using oral zizyphus for diarrhea, there is insufficient reliable information about the clinical effects of zizyphus for this purpose.
Epilepsy. Although there has been interest in using oral zizyphus for epilepsy, there is insufficient reliable information about the clinical effects of zizyphus for this purpose.
Hyperlipidemia. It is unclear if oral zizyphus fruit powder is beneficial in patients with hyperlipidemia. Details: A small clinical study in obese adolescents with hyperlipidemia shows that taking zizyphus fruit powder 5 grams three times daily for one month modestly lowers total cholesterol and low-density lipoprotein (LDL) cholesterol, but does not improve high-density lipoprotein (HDL) cholesterol, when compared with placebo (93317). However, a small clinical study in patients with type 2 diabetes shows that taking zizyphus fruit powder 30 grams daily for 12 weeks does not improve lipid levels when compared with placebo (104507).
Hypertension. Although there has been interest in using oral zizyphus for hypertension, there is insufficient reliable information about the clinical effects of zizyphus for this purpose.
Insomnia. It is unclear if oral zizyphus seed extract is beneficial in patients with insomnia. Details: A very small crossover trial in patients with chronic insomnia shows that taking zizyphus seed extract 2 grams one hour before bedtime for 4 weeks improves sleep quality as measured using the Pittsburgh Sleep Quality Index, but not when assessed on the Insomnia Severity Index, when compared with placebo. While patients self-reported significant improvements in total sleep time, sleep efficiency, and sleep onset latency with zizyphus, these findings were not consistent with data gathered from actigraphy wrist watches worn during the study (107921). Zizyphus has also been evaluated in combination with other ingredients. A clinical trial in healthy adults with mild insomnia shows that taking a specific product (LZ Complex3, Sanofi) containing zizyphus 4.5 grams, hops 500 mg, lactium 75 mg, magnesium oxide 52.5 mg, and vitamin B6 10 mg daily for 2 weeks does not improve sleep quality, daytime functioning, or physical fatigue when compared with placebo (95971). Liver disease. Although there has been interest in using oral zizyphus for liver disease, there is insufficient reliable information about the clinical effects of zizyphus for this purpose.
Melasma. Oral zizyphus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults with hyperpigmentation of facial skin shows that taking a syrup containing extracts of zizyphus and several other herbal plants 7.5 mL twice daily for 8 weeks reduces the number of pigments, total area of pigmentation, and percentage area of pigmentation when compared with baseline and placebo (112816). However, it is unclear if these changes are clinically significant. In addition, it is unclear if these effects are due to zizyphus, other ingredients, or the combination.
Neonatal jaundice. It is unclear if oral zizyphus fruit extract is beneficial for neonatal jaundice. Details: A small clinical study in hospitalized infants with jaundice who are also being treated with phototherapy shows that giving zizyphus fruit extract 1 mL/kg orally three times daily does not significantly reduce levels of bilirubin, but modestly reduces the duration of hospitalization by 0.2 days, when compared with placebo (93306).
Peptic ulcers. Although there has been interest in using oral zizyphus for peptic ulcers, there is insufficient reliable information about the clinical effects of zizyphus for this purpose.
Wound healing. Although there has been interest in using topical zizyphus for wound healing, there is insufficient reliable information about the clinical effects of zizyphus for this purpose. More evidence is needed to rate zizyphus for these uses.

Safety view details

Below is general information about the safety of the known ingredients contained in the product Anxioton. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.

GLYCINE

POSSIBLY SAFE ...when used orally and appropriately. Glycine has been used safely at doses up to 6 grams daily for 4 weeks (106497) and doses up to 9 grams daily for 3 days (10250,10251,10252,92319). There is insufficient reliable information available about the safety of glycine when used topically.

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

KAVA (Piper methysticum Root Extract, Dry, Piper methysticum, Dry, Kavalactones)

POSSIBLY SAFE ...when used orally, short-term. Kava extracts have been used safely in clinical trials under medical supervision for up to 6 months (2093,2094,2095,4032,7325,15046,15130,18314,18316,18318)(18320,29663,29671,98980,102086,112642). Historically, there has been some concern that kava preparations could induce hepatotoxicity and liver failure in patients taking relatively normal doses, short-term. At least 100 cases of liver toxicity following kava use have been reported. Although liver toxicity is more frequently associated with prolonged use of very high doses (6401,57346), in some cases the use of kava for as little as 1-3 months has been associated with the need for liver transplants, and even death (390,7024,7068,7086,7096,17086,57252)(57254,57297). However, some experts question the clinical validity of several of these cases (11369,11371).

PREGNANCY: POSSIBLY UNSAFE
when used orally. There is some concern that pyrone constituents in kava can cause loss of uterine tone (19); avoid using.

LACTATION: POSSIBLY UNSAFE
when used orally. There is concern that the toxic pyrone constituents of kava can pass into breast milk (19); avoid using.

LEMON BALM (Melissa officinalis Flower and Leaf Extract, Dry, Melissa officinalis, Dry)

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

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

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

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

MAGNESIUM

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).

MAGNOLIA (Magnolia officinalis Stem Bark Extract, Dry, Magnolia officinalis, Dry)

POSSIBLY SAFE ...when used orally and appropriately, short-term. A specific product containing magnolia extract and phellodendron extract (Relora, Next Pharmaceuticals, Inc.) has been used with apparent safety in clinical trials at a dose of 250 mg two to three times daily for up to 6 weeks (14349,34246,94904). ...when used topically in a toothpaste for up to 6 months (92464).

PREGNANCY: UNSAFE
when the magnolia flower bud is used orally due to reports of uterine stimulant activity (11953). There is insufficient reliable information available about the safety of using magnolia bark during pregnancy; avoid using.

LACTATION:
Insufficient reliable information available; avoid using.

PASSION FLOWER (Passiflora incarnata Herb Top Flowering Extract, Dry, Passiflora incarnata, Dry)

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

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

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

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

LACTATION:
Insufficient reliable information available; avoid using.

ZIZYPHUS (Ziziphus jujuba var. spinosa Seed Extract, Dry, Ziziphus jujuba var. spinosa, Dry)

LIKELY SAFE ...when zizyphus fruit is consumed in the amounts typically found in foods.

POSSIBLY SAFE ...when zizyphus fruit or seed is used orally and appropriately, short-term. Zizyphus fruit powder has been used with apparent safety at doses up to 30 grams daily for up to 12 weeks (93317,104507). Zizyphus fruit extract has been used with apparent safety at a dose of 20-40 drops daily for up to 12 weeks (93316). Zizyphus seed extract has been used with apparent safety at a dose of 2 grams daily for 4 weeks (107921). There is insufficient reliable information available about the safety of zizyphus when used topically.

PREGNANCY AND LACTATION: LIKELY SAFE
when zizyphus fruit is consumed in the amounts typically found in foods. There is insufficient reliable information available about the safety of zizyphus fruit in amounts greater than those found in foods; avoid using.

Interactions with Drugs view details

Below is general information about the interactions of the known ingredients contained in the product Anxioton. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.

GLYCINE

CLOZAPINE (Clozaril)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Mild • Occurrence = Probable • Level of Evidence = B

Theoretically, glycine might decrease the effectiveness of clozapine.

Details

One small clinical study in patients with schizophrenia shows that adding glycine to clozapine therapy worsens symptoms of schizophrenia when compared with clozapine alone (10253). The mechanism of this interaction is unclear.

KAVA (Piper methysticum Root Extract, Dry, Piper methysticum, Dry, Kavalactones)

ALCOHOL (ETHANOL)

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = A

Combining kava with alcohol may increase the risk of sedation and/or hepatotoxicity.

Details

Kava has CNS depressant effects (11373,18316). Concomitant use of kava with other CNS depressants can increase the risk of drowsiness and motor reflex depression (2093,2098). Additionally, kava has been associated with over 100 cases of hepatotoxicity. There is some concern that kava can adversely affect the liver, especially when used in combination with hepatotoxic drugs (7024,7068,7086,7096,17086,57346). Clinical practice guidelines from a joint taskforce of the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Treatments (CANMAT) recommend that alcohol not be used with kava (110318).

CNS DEPRESSANTS

Interaction Rating = Major Do not take this combination.

Severity = High • Occurrence = Probable • Level of Evidence = A

Combining kava with CNS depressants can have additive sedative effects.

Details

Kava has CNS depressant effects (11373,18316). Concomitant use of kava with other CNS depressants can increase the risk of drowsiness and motor reflex depression (2093,2098). Clinical practice guidelines from a joint taskforce of the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Treatments (CANMAT) recommend that CNS depressants, including alcohol and benzodiazepines, not be used with kava (110318).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES

Interaction Rating = Minor Be watchful with this combination.

Severity = Moderate • Occurrence = Unlikely • Level of Evidence = B

It is unclear if kava inhibits CYP1A2; research is conflicting.

Details

Although in vitro research and a case report suggest that kava inhibits CYP1A2 (8743,12479,88593), more robust clinical evidence shows that kava has no effect on CYP1A2. In a clinical study in healthy volunteers, taking kava 1000 mg twice daily (containing a daily dose of 138 mg kavalactones) for 28 days had no effect on CYP1A2 activity (13536,98979).

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, kava might increase levels of CYP2C19 substrates.

Details

In vitro research shows that kava significantly inhibits CYP2C19 enzymes (8743,12479). This effect has not yet been reported in humans.

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, kava might increase levels of CYP2C9 substrates.

Details

In vitro research shows that kava significantly inhibits CYP2C9 enzymes (8743,12479). This effect has not yet been reported in humans.

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES

Interaction Rating = Minor Be watchful with this combination.

Severity = Moderate • Occurrence = Unlikely • Level of Evidence = B

It is unclear if kava inhibits CYP1A2; research is conflicting.

Details

In vitro research shows that kava extract significantly inhibits CYP2D6 (8743,12479). However, clinical research shows that kava does not affect the metabolism of CYP2D6 substrates in humans (13536,16848,98979).

CYTOCHROME P450 2E1 (CYP2E1) SUBSTRATES

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Probable • Level of Evidence = B

Kava might increase levels of CYP2E1 substrates.

Details

In a clinical study in healthy volunteers, taking kava 1000 mg twice daily (containing a daily dose of 138 mg kavalactones) for 28 days inhibited the metabolism of CYP2E1 substrates (13536).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES

Interaction Rating = Minor Be watchful with this combination.

Severity = Moderate • Occurrence = Unlikely • Level of Evidence = B

It is unclear if kava inhibits CYP3AA; research is conflicting.

Details

Although in vitro research suggests that kava inhibits CYP3A4 (8743,12479), more robust clinical evidence shows that kava has no effect on CYP3A4. In a clinical study in healthy volunteers, taking kava 1000 mg twice daily (containing a daily dose of 138 mg kavalactones) for 28 days had no effect on CYP3A4 activity (13536,98979).

HALOPERIDOL (Haldol)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Combining kava and haloperidol might increase the risk of cardiovascular adverse effects and hypoxia.

Details

Atrial flutter and hypoxia has been reported for a patient who received intramuscular injections of haloperidol and lorazepam after using kava orally. The side effects were attributed to kava-induced inhibition of CYP2D6, but might also have been related to additive adverse effects with the concomitant use of haloperidol, lorazepam, and kava (88593).

HEPATOTOXIC DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Theoretically, using kava with hepatotoxic drugs might increase the risk of liver damage.

Details

Kava has been linked with over 100 cases of hepatotoxicity. Most cases occur with excessive and prolonged use. There is some concern that kava can adversely affect the liver, especially when used in combination with hepatotoxic drugs (7024,7068,7086,7096,17086,57346).

P-GLYCOPROTEIN SUBSTRATES

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

It is unclear if kava inhibits P-glycoprotein (P-gp); research is conflicting.

Details

In vitro research shows that kava can inhibit P-gp efflux (15131). However, a clinical study in healthy volunteers shows that taking kava standardized to provide 225 mg kavalactones daily for 14 days does not affect the pharmacokinetics of digoxin, a P-gp substrate (15132,98979). It is possible that the use of other P-gp substrates or higher doses of kava might still inhibit P-gp.

ROPINIROLE (Requip)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Taking kava with ropinirole might increase the risk for dopaminergic toxicity.

Details

A case of visual hallucinations and paranoid delusions has been reported for a patient who used kava in combination with ropinirole. The adverse effects were attributed to kava-induced inhibition of CYP1A2, which may have reduced the metabolism of ropinirole, resulting in excessive dopaminergic stimulation (88593).

LEMON BALM (Melissa officinalis Flower and Leaf Extract, Dry, Melissa officinalis, Dry)

CNS DEPRESSANTS

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = B

Theoretically, concomitant use of lemon balm might have additive effects with CNS depressant drugs.

Details

Lemon balm seems to have CNS depressant activity in animals and in humans (9994,19725).

THYROID HORMONE

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, lemon balm might interfere with thyroid hormone replacement therapy.

Details

In vitro, constituents of lemon balm extract bind to thyroid stimulating hormone (TSH), preventing TSH receptor-binding and leading to the inhibition of TSH-stimulated adenylate cyclase activity (19727,19728). In animals, lemon balm extract has been shown to decrease levels of circulating TSH and inhibit thyroid secretion (19726).

MAGNESIUM

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.

MAGNOLIA (Magnolia officinalis Stem Bark Extract, Dry, Magnolia officinalis, Dry)

ANTICOAGULANT/ANTIPLATELET DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Theoretically, magnolia might have additive effects and increase the risk of bleeding when used with anticoagulant or antiplatelet drugs.

Details

In vitro research shows that the chemicals magnolol and honokiol, isolated from magnolia bark, inhibit platelet aggregation that is experimentally induced by collagen and arachidonic acid. However, they do not inhibit platelet aggregation that is induced by adenosine diphosphate, platelet-activating factor, or thrombin (18273). This interaction has not been reported in humans.

CNS DEPRESSANTS

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Theoretically, concomitant use of large doses of magnolia bark and CNS depressants might have additive effects.

Details

In vitro and animal research shows that constituents extracted from magnolia bark, especially honokiol and magnolol, have sedative effects. These effects may be due to the inhibition of catecholamine release and modulation of gamma-aminobutyric acid-A (GABA-A) receptors (11946,11952).

PASSION FLOWER (Passiflora incarnata Herb Top Flowering Extract, Dry, Passiflora incarnata, Dry)

CNS DEPRESSANTS

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Concomitant use of passion flower with sedative drugs might cause additive effects and side effects.

Details

Research in animals and humans shows that passion flower has sedative effects which can be additive when used with sedative medications like lorazepam (8007,19235,19236,19429,68309,104206).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES

Interaction Rating = Minor Be watchful with this combination.

Severity = Insignificant • Occurrence = Possible • Level of Evidence = D

Theoretically, passion flower might decrease the effects of CYP3A4 substrates.

Details

In vitro research suggests that passion flower can induce CYP3A4 enzymes, albeit to a much lower degree than rifampin, a known CYP3A4 inducer (110704).

ORGANIC ANION-TRANSPORTING POLYPEPTIDE SUBSTRATES (OATP)

Interaction Rating = Minor Be watchful with this combination.

Severity = Mild • Occurrence = Possible • Level of Evidence = D

Theoretically, passion flower might reduce the bioavailability of OATP2B1 and OATP1A2 substrates.

Details

In vitro research shows that the passion flower constituents apigenin and vitexin inhibit OATP2B1 and OATP1A2. This inhibition may be dose-dependent. One specific high-flavonoid passion flower extract (Valverde) seems to inhibit OATP2B1 and OATP1A2, while another extract with a lower flavonoid concentration (Arkocaps) shows less potent inhibition (105095). OATPs are responsible for the uptake of drugs and other compounds into the body; however, the specific activities of OATP2B1 and OATP1A2 are not well characterized.

ZIZYPHUS (Ziziphus jujuba var. spinosa Seed Extract, Dry, Ziziphus jujuba var. spinosa, Dry)

ANTIDIABETES DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, zizyphus might increase the risk of hypoglycemia when taken with antidiabetes drugs.

Details

Animal research shows that zizyphus has hypoglycemic activity (87589,87591,87617,87637,87659,87671). However, a small clinical study shows that zizyphus fruit powder does not reduce fasting blood glucose levels in patients with type 2 diabetes (104507).

CNS DEPRESSANTS

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Theoretically, zizyphus might cause additive sedative effects when taken with CNS depressants.

Details

Some animal research has found that various parts of zizyphus have sedative effects (87572,87644,87646,87658). However, other animal research shows that zizyphus plant extract does not alter sleep parameters when used in combination with pentobarbital (93308).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, zizyphus might decrease the levels and clinical effects of drugs metabolized by CYP1A2.

Details

Animal research shows that zizyphus induces CYP1A2 enzymes (93311). However, this effect has not been reported in humans.

Report an Adverse Reaction to Anxioton

Adverse Effects view details

Below is general information about the adverse effects of the known ingredients contained in the product Anxioton. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.

GLYCINE

General ...Orally and topically, glycine seems to be well tolerated.

Gastrointestinal ...Soft stools, nausea, vomiting, and upper gastrointestinal (GI) tract discomfort have occurred rarely with oral use of glycine. These symptoms resolve rapidly with discontinuation of glycine (10252,11320,92319). Dry mouth has also been reported but any association to glycine is unclear (92321).

Neurologic/CNS ...Mild sedation has occurred rarely with oral use of glycine. Symptoms resolve rapidly with discontinuation of glycine (10252,11320,92321). Irritability, insomnia, fatigue, memory impairment, headache, and sensory impairment have been reported, but any association with glycine is unclear (92321).

KAVA (Piper methysticum Root Extract, Dry, Piper methysticum, Dry, Kavalactones)

General ...Orally, kava seems to be well tolerated.
Most Common Adverse Effects:
Orally: Drowsiness, dry mouth, dizziness, gastrointestinal upset, headache, memory problems, tremor.
Serious Adverse Effects (Rare):
Orally: There have been over 100 reported cases of hepatotoxicity and a few reported cases of rhabdomyolysis.

Cardiovascular ...Long-term use of very large amounts of kava, especially in high doses (400 mg kava pyrones daily), has been associated with overall poor health including symptoms of low body weight, reduced protein levels, puffy face, hematuria, increased red blood cell volume, decreased platelets and lymphocytes, and possibly pulmonary hypertension (4032,6402). Tachycardia and electrocardiogram (ECG) abnormalities (tall P waves) have been reported in heavy kava users (6402).

Dermatologic ...Orally, kava can cause allergic skin reactions, including sebotropic eruptions, delayed-type hypersensitivity, or urticarial eruption (4032,11370,28489,57277,57325,57343,114683). In one case of kava-associated urticarial eruption, biopsy revealed neutrophilic sebaceous glands with lymphocytic infiltrate (114683). Chronic use of high doses of kava has also been associated with kava dermopathy, which consists of reddened eyes; dry, scaly, flaky skin; and temporary yellow discoloration of the skin, hair, and nails (6240,6401,8414,8417,11370,28485,57342). This pellagra-like syndrome is unresponsive to niacinamide treatment (6240,7728,11370). The cause is unknown, but may relate to interference with cholesterol metabolism (6240). Kava's adverse effects on liver function might also contribute to kava dermopathy (6401,8417). Kava dermopathy usually occurs within three months to one year of regular kava use, and resolves when the kava dose is decreased or discontinued (6401,8414). Kava dose should be decreased or discontinued if kava dermopathy occurs (6401). In addition to kava cessation, oral or topical corticosteroids have been described as treatment options in some cases of kava associated dermatitis (114683).

Gastrointestinal ...Orally, kava may cause gastrointestinal upset, nausea, or dry mouth (2093,2094,4032,11370,18316,57228,57343).

Hematologic ...Orally, chronic use of very high doses of kava has been associated with increased red blood cell volume, reduced platelet volume, reduced lymphocyte counts, and reduced serum albumin (6402,57258). Hematuria has also been reported anecdotally (6402).

Hepatic ...Since the early 2000's, hepatotoxicity has been a particular concern with kava. Worldwide, there have been at least 100 reported cases of hepatotoxicity following use of kava products (7024,7068,7086,7096,11795,17086)(57252,57254,57297). However, some experts question the clinical validity of several of these cases (11369,11371). Some cases were reported multiple times and in some cases it was unlikely that kava was the causative agent (7068,57253).
In susceptible patients, symptoms can show up after as little as 3-4 weeks of kava use. Symptoms include yellowed skin (jaundice), fatigue, and dark urine (7024,7068). Liver function tests can be elevated after 3-8 weeks of use, possibly followed by hepatomegaly and onset of encephalopathy (7024). Kava has also been reported to exacerbate hepatitis in patients with a history of recurrent hepatitis (390). However, in many cases, symptoms seem to resolve spontaneously, and liver function tests usually normalize within eight weeks (390,7068).
Liver toxicity is more frequently associated with prolonged use of very high doses (6401,57346). But there is some concern that even short-term use of kava in typical doses might cause acute hepatitis in some patients, including severe hepatocellular necrosis. The use of kava for as little as 1-3 months has resulted in need for liver transplant and death, although these events are rare (7024,7068,7086,7096,17086).
There is some speculation that the type of extraction method could be responsible for these rare cases of hepatotoxicity (17086). The "Pacific kava paradox" holds that while the alcohol and acetone extracts of kava used for commercial products cause liver toxicity, the traditional kava rhizome preparation mixed with water might not be toxic (11794,17086). However, a more recent analysis reports cases of hepatotoxicity from the aqueous kava extract and suggests that kava's hepatotoxic effects may be due to contaminants such as mold (29676). Other suggested causes of hepatotoxicity include quality of the kava plant, concomitant medications, large doses and prolonged use, and toxic constituents and metabolites of kava (57300,88532).
Some commercial kava extracts contain parts of the stems and other aerial parts in addition to the rhizome, and it has been suggested that a constituent called pipermethysine, which is only found in these aerial parts, might be partly responsible for hepatotoxicity (17086). Other constituents of kava which might contribute to hepatotoxicity are kavalactones, which are metabolized by cytochrome P450 (CYP450) enzymes in the liver. Reactive metabolites are produced which conjugate with glutathione, and might deplete glutathione in a similar manner to acetaminophen (17086). Increased levels of gamma-glutamyl transferase, involved in the production of glutathione, have been reported in chronic kava users (17086). One of the enzymes involved in production of reactive metabolites from kavalactones is cytochrome P450 2E1 (CYP2E1), which is induced by chronic alcohol intake. Alcohol may also compete for other enzymes which clear kavalactone metabolites from the body. This might explain the observation that alcohol ingestion seems to increase the risk of hepatotoxicity with kava (7068,17086).
There is also speculation that "poor metabolizers" or those patients with deficiency in the cytochrome P450 2D6 (CYP2D6) isoenzyme, which occurs in up to 10% of people of European descent, may be at increased risk for hepatotoxic effects from kava (7068). This deficiency has not been found in Pacific Islanders. However, this theory has not been confirmed.
Due to the concerns regarding the potential hepatotoxicity of kava, kava supplements were withdrawn from European and Canadian markets in 2002 (7086). However, many of the market withdrawals of kava have been lifted after re-evaluation of kava suggested that the risk of hepatotoxicity was minimal (91593,91594,91615). Still, clinical practice guidelines from a joint taskforce of the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Treatments (CANMAT) recommend exercising caution when using kava in patients with preexisting liver issues (110318). Until more is known, tell patients to use kava cautiously and recommend liver function tests for routine users or those with underlying liver disease.

Immunologic ...Sjögren syndrome has been associated with an herbal supplement containing kava, echinacea, and St. John's wort. Echinacea may have been the primary cause, because Sjögren syndrome is an autoimmune disorder. The role of kava in this syndrome is unclear (10319).

Musculoskeletal ...Kava has been linked with reports of rhabdomyolysis. A 34-year-old man who consumed kava tea several times a week developed rhabdomyolysis with a peak creatine kinase level of 32,500 units/liter (18212). However, there is speculation that this might have been due to product impurities rather than kava itself. Another case report describes rhabdomyolysis with myoglobinuria and a creatine kinase level of 100,500 units/liter in a 29-year-old man who had taken kava in combination with guarana and ginkgo biloba (18213).
Cases of ataxia and tremors have been reported in patients taking single doses of kava powder 205 grams (11373).

Neurologic/CNS ...Orally, kava may cause headache, dizziness, and drowsiness (4032,6402,11370,11372,11373,18316,112642). It might also cause extrapyramidal side effects such as involuntary oral and lingual reflexes, twisting movements of the head and trunk, tremors, and other parkinsonian-like symptoms possibly due to dopamine antagonism (534,4055,7727,8415,102086). In one clinical trial, patients taking a kava supplement providing 120 mg of kavalactones twice daily for 16 weeks had a 3.2-fold greater risk of experiencing tremors when compared with patients taking placebo (102086). Theoretically, kava may worsen symptoms in patients with Parkinson disease or precipitate Parkinson-like symptoms in certain patients (4055,7727). Unlike benzodiazepines, kava is not thought to be associated with impaired cognitive function (2097,2098,11373,57332,57333). However, one clinical trial shows that taking a kava supplement providing 120 mg of kavalactones twice daily for 16 weeks increases the risk for memory impairment by 55% when compared with placebo (102086).
Orally, kava may reduce alertness and impair motor coordination in a dose-dependent manner. Some preliminary reports have noted a decline in accuracy of visual attention and slower reaction times after kava ingestion, particularly at higher doses and in combination with alcohol (11373,95926). Population research has also found that ingesting large amounts of kava tea (typically 50 times higher than what is used medicinally in the US) within a 12-hour period before driving increases the odds of being involved in a serious motor vehicle crash resulting in death or serious injury by almost 5-fold when compared to not drinking kava tea (95927). Use of normal doses of kava may also affect the ability to drive or operate machinery, and driving under the influence (DUI) citations have been issued to individuals observed driving erratically after drinking large amounts of kava tea (535). However, in computer-based driving simulator tests, there are no reported adverse effects of kava on performance (95926). Additionally, other research shows that consuming over 4400 mg of kavalactones over a 6-hour kava session does not seem to impair alertness or attention when compared with non-kava drinkers (103867). Similar research using a specific psychometric tool (Brain Gauge) shows that consuming approximately 3680 mg of kavalactones in a 6-hour kava session seems to impair temporal order judgment, which is associated with the brain's ability to track the order of events, when compared with non-kava drinkers. However, it does not seem to impact cognitive domains related to focus, accuracy, timing perception, plasticity, or fatigue when compared with non-kava drinkers (110435).

Ocular/Otic ...Orally, high doses of kava may cause eye irritation (7728). There is one case report of impaired accommodation and convergence, increased pupil diameter, and oculomotor disturbance following a single dose of kava (9920).

Psychiatric ...Apathy has been associated with traditional use of kava at high doses (57313).

Pulmonary/Respiratory ...Orally, kava may cause shortness of breath, possibly due to pulmonary hypertension (6402).

Renal ...Orally, kava may cause acute urinary retention (57349).

LEMON BALM (Melissa officinalis Flower and Leaf Extract, Dry, Melissa officinalis, Dry)

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

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

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

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

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

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

MAGNESIUM

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).

MAGNOLIA (Magnolia officinalis Stem Bark Extract, Dry, Magnolia officinalis, Dry)

General ...Orally, magnolia seems to be well tolerated.
Most Common Adverse Effects:
Topically: Contact dermatitis.

Dermatologic ...Topically, magnolia bark has been associated with reports of allergic contact dermatitis (92463,92468,95030,110709). In several cases, the use of anti-aging facial creams containing magnolia bark extract was associated with allergic contact dermatitis of the face (92463,92468,95030). In one case, the use of a vaginal gel containing magnolia bark extract was associated with allergic contact dermatitis of the vulva (110709). Symptoms typically resolve with the use of topical corticosteroids and discontinuation of magnolia bark extract (95030,110709). Patch testing suggests that the magnolia bark extract constituents magnolol and honokiol are responsible for this adverse effect (110709).

Endocrine ...In a clinical trial of an oral combination product containing extracts of magnolia and phellodendron, one patient reported thyroid dysfunction (14349). However, it's not known if this side effect is related to magnolia or some other factor.

Gastrointestinal ...In a clinical trial of an oral combination product containing extracts of magnolia and phellodendron, one patient reported heartburn (14349). However, it's not known if this side effect is related to magnolia or some other factor.

Neurologic/CNS ...In a clinical trial of an oral combination product containing extracts of magnolia and phellodendron, one patient reported shaking hands and perilabial numbness. Another patient reported fatigue and headache (14349). However, it's not known if these side effects are related to magnolia or some other factor.

Psychiatric ...In a clinical trial of an oral combination product containing extracts of magnolia and phellodendron, one patient reported sexual dysfunction (14349). However, it's not known if this side effect is related to magnolia or some other factor.

PASSION FLOWER (Passiflora incarnata Herb Top Flowering Extract, Dry, Passiflora incarnata, Dry)

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

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

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

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

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

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

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

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

ZIZYPHUS (Ziziphus jujuba var. spinosa Seed Extract, Dry, Ziziphus jujuba var. spinosa, Dry)

General ...Orally, zizyphus fruit extract and powder seem to be well tolerated.

Gastrointestinal ...Orally, zizyphus fruit extract was associated with three cases of mild diarrhea in newborn infants (93306). Zizyphus seed extract was associated with one case of dry mouth and one case of increased bowel movements in a small clinical study (107921).

Neurologic/CNS ...Orally, zizyphus seed extract was associated with two cases of headache in a small clinical study (107921).

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