Full Spectrum Lemon Balm, Passion Flower, Scullcap Complex [Discontinued] by Swanson Premium Brand

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). Although there has been interest in using oral Baikal skullcap for allergic rhinitis, there is insufficient reliable information about the clinical effects of Baikal skullcap for this purpose.
• Anxiety. Although there has been interest in using oral Baikal skullcap for anxiety, there is insufficient reliable information about the clinical effects of Baikal skullcap for this purpose.
• Atherosclerosis. Although there has been interest in using oral Baikal skullcap for atherosclerosis, there is insufficient reliable information about the clinical effects of Baikal skullcap for this purpose.
• Attention deficit-hyperactivity disorder (ADHD). Although there has been interest in using oral Baikal skullcap for ADHD, there is insufficient reliable information about the clinical effects of Baikal skullcap for this purpose.
• Bronchiolitis. Intravenous Baikal skullcap has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that a combination of Baikal skullcap, forsythia, and honeysuckle, known as Shuang Huang Lian in traditional Chinese medicine, given intravenously, with or without antibiotics, decreases the duration of cough by about 1.5-2 days, the duration of wheezing by about 2 days, and the duration of hospitalization by about 2-3 days when compared with antibiotics alone in children with respiratory syncytial virus (RSV) infection. Baikal skullcap injection was administered as a 20 mL dose for patients under 6 months, a 40 mL dose for patients 7-36 months, or a 60 mL dose for patients older than 36 months (12613).
• Cancer. Although there has been interest in using oral Baikal skullcap for cancer, there is insufficient reliable information about the clinical effects of Baikal skullcap for this purpose.
• Diabetes. It is unclear if oral Baikal skullcap is beneficial in patients with diabetes. Details: A very small clinical trial in patients with uncontrolled diabetes taking metformin 500 mg daily shows that taking Baikal skullcap extract 3.52 grams in three divided doses daily for 8 weeks does not decrease levels of fasting glucose or insulin or improve levels of glycated hemoglobin (HbA1c) when compared with placebo. However, taking Baikal skullcap reduces blood glucose levels during an oral glucose tolerance test (OGTT) at 60 minutes, but not 120 minutes, when compared with placebo (101738). This study may have been inadequately powered to detect a difference between groups.
• Epilepsy. Although there has been interest in using oral Baikal skullcap for epilepsy, there is insufficient reliable information about the clinical effects of Baikal skullcap for this purpose.
• Hand, foot, and mouth disease. It is unclear if intravenous Baikal skullcap is beneficial in patients with hand, foot, and mouth disease. Details: Low-quality observational research in children hospitalized with severe hand, foot, and mouth disease has found that children who are given Baikal skullcap intravenously as a Tanreqing injection 0.3-0.5 mL/kg once daily have a shorter duration of fever, oral ulcers, and rash, as well as reduced viral load, when compared with those given ribavirin 10 mg/kg once daily (96281). The validity of these findings is limited by the retrospective nature of the study.
• Headache. Although there has been interest in using oral Baikal skullcap for headache, there is insufficient reliable information about the clinical effects of Baikal skullcap for this purpose.
• Hemorrhoids. Although there has been interest in using oral Baikal skullcap for hemorrhoids, there is insufficient reliable information about the clinical effects of Baikal skullcap for this purpose.
• Hepatitis. Although there has been interest in using oral Baikal skullcap for hepatitis, there is insufficient reliable information about the clinical effects of Baikal skullcap for this purpose.
• HIV/AIDS. Although there has been interest in using oral Baikal skullcap for HIV/AIDS, there is insufficient reliable information about the clinical effects of Baikal skullcap for this purpose.
• Insomnia. Although there has been interest in using oral Baikal skullcap for insomnia, there is insufficient reliable information about the clinical effects of Baikal skullcap for this purpose.
• Osteoarthritis. Oral Baikal skullcap has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a specific product (Limbrel, Primus Pharmaceuticals) that contains flavocoxid, a blend of Baikal skullcap extract and catechu flavonoid extract, 500 mg once or twice daily for up to 12 weeks reduces symptoms of osteoarthritis of the knee when compared with baseline. These studies found no significant difference between this combination product and naproxen 440 mg once daily to 500 mg twice daily for reducing symptoms (17030,18012,92776). However, in 2017, the US Food and Drug Administration (FDA) formally requested the recall of all non-expired lots of this product due to the risk for liver and lung injury (106042). See the Adverse Effects section for more information.
• Peyronie disease. It is unclear if oral Baikal skullcap is beneficial in patients with Peyronie disease. Details: Observational research has found that taking oral Baikal skullcap root extract 150 mL twice daily for 6 months is associated with reduced time to disease stabilization, with an average reduction of 5 months, when compared with no treatment. In addition, 17% of patients taking Baikal skullcap had pain resolution and only 33% required surgical correction, compared with 0% and 58%, respectively, of control patients. In patients requiring surgery, taking Baikal skullcap did not appear to affect resolution; however, the study may have been inadequately powered to detect a difference between groups (105867).
• Prostate cancer. Although there has been interest in using oral Baikal skullcap for prostate cancer, there is insufficient reliable information about the clinical effects of Baikal skullcap for this purpose.
• Psoriasis. Although there has been interest in using oral Baikal skullcap for psoriasis, there is insufficient reliable information about the clinical effects of Baikal skullcap for this purpose.
• Seizures. Although there has been interest in using oral Baikal skullcap for seizures, there is insufficient reliable information about the clinical effects of Baikal skullcap for this purpose.
• Upper respiratory tract infection (URTI). Although there has been interest in using oral and intravenous Baikal skullcap for upper respiratory tract infections, there is insufficient reliable information about the clinical effects of Baikal skullcap for this purpose. More evidence is needed to rate Baikal skullcap for these uses.

(Read more about BAIKAL SKULLCAP)

POSSIBLY EFFECTIVE

• Depression. Small clinical trials show that oral lemon balm may improve depression when used short-term; the long-term effects are unclear. It is also unclear if lemon balm aromatherapy is beneficial for depression. Details: A meta-analysis of randomized controlled trials in adults with depression and/or anxiety shows that using lemon balm, usually orally, daily for 3-56 days moderately improves depression scores when compared with control. Lemon balm was used orally as 1200-3000 mg daily or as aromatherapy for 30 minutes daily (110136). Other individual studies also show that oral lemon balm may modestly improve depression. A small clinical study in 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. Although studies have assessed oral lemon balm as monotherapy, its use in combination with other ingredients has also been explored. 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). Additionally, a single-center clinical study in Iranian adults with constipation-predominate irritable bowel syndrome (IBS-C) shows that taking a lemon balm, anise, and rose hip extract supplement twice daily for 4 weeks reduces anxiety and depression scores,on a patient-reported survey, when compared with placebo (115636). The validity of these results is limited by the lack of data regarding history or diagnosis of anxiety or depression. It is not clear if this effect is due to lemon balm, the other ingredients, or the combination.
• Herpes labialis (cold sores). Topical lemon balm 1% lotion seems to be beneficial for the healing of recurrent cold sores. Details: Clinical research in patients with recurring cold sores shows that applying a cream containing 1% lemon balm dried leaf extract (LomaHerpan, Infectopharm) at the early stages seems to shorten healing time and reduce symptoms of recurring cold sores when compared with placebo (790,9995).
• Stress. Oral lemon balm seems to be beneficial for improving experimentally-induced stress in some patients. Details: A small study in healthy adults suggests that a single dose of lemon balm extract 600 mg increases calmness and alertness during laboratory-induced psychological stress when compared with placebo (19524). Another small study in healthy adults shows that a single dose of lemon balm extract (Bluenesse, Vital Solutions) 300 mg added to food or drink reduces anxiety and improves memory and alertness during multi-task cognitive testing when compared with placebo (91733). Lemon balm has also shown benefit when used in combination with other ingredients for stress. Lemon balm 240 mg has been used in combination with valerian 360 mg (Songha Night, Pharmaton Natural Health Products) (19405). Lemon balm 50 mg has been used in combination with valerian root 90 mg, passion flower 90 mg, and butterbur 90 mg (Relaxane, Max Zeller Sӧhne AG) (97276).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral lemon balm is beneficial for improving cognitive function. Details: Preliminary clinical research in adults with age-related cognitive impairment shows that taking lemon balm leaf extract, standardized to contain 500 mg rosmarinic acid, orally daily for 96 weeks does not improve cognitive function scores when compared with placebo (110142).
• Alzheimer disease. It is unclear if oral lemon balm is beneficial for improving cognitive function. Details: A small clinical study in elderly patients with mild to moderate Alzheimer disease shows that taking a leaf extract of lemon balm (standardized to citral 500 mcg/mL) 60 drops daily for 4 months seems to reduce agitation and improve cognitive function when compared with placebo (9993). This study was limited by a large number of drop-outs in the placebo group. An even smaller clinical study in patients with mild Alzheimer disease shows that taking lemon balm extract containing 500 mg rosmarinic acid daily for 24 weeks does not seem to improve cognition, but might modestly improve neuropsychiatric symptoms, when compared with placebo (104435). The validity of these findings is limited because the study was not powered to evaluate cognition and neuropsychiatric symptoms.
• Anxiety. It is unclear if oral lemon balm or lemon balm aromatherapy is beneficial for reducing anxiety in most patients. Details: A meta-analysis of randomized controlled trials in adults with depression and/or anxiety shows that using lemon balm daily for 3-56 days moderately improves anxiety scores when compared with control. Lemon balm was used orally as 1200-3000 mg daily or as aromatherapy for 30 minutes daily (110136). The validity of this result is limited by high heterogeneity. Also, a small clinical study in patients with mild or moderate anxiety disorders shows that taking a specific standardized lemon balm extract (Cyracos, Naturex SA) 300 mg twice daily reduces anxiety-associated symptoms and improves sleep when compared with baseline (104425). The validity of this finding is limited by the lack of a comparator group. Another small clinical study in adults with type 2 diabetes and mild to moderate depression conducted in Iran shows that taking lemon balm extract capsules 350 mg twice daily for 12 weeks modestly reduces the severity of depression and anxiety based on validated patient-reported questionnaires when compared with placebo (111741). Although studies have assessed oral lemon balm as monotherapy, its use in combination with other ingredients has also been explored. A single-center clinical study in Iranian adults with constipation-predominate irritable bowel syndrome (IBS-C) shows that taking a lemon balm, anise, and rose hip extract supplement twice daily for 4 weeks reduces anxiety and depression scores, on a patient-reported survey, when compared with placebo (115636). The validity of these results is limited by the lack of data regarding history or diagnosis of anxiety or depression. It is not clear if this effect is due to lemon balm, the other ingredients, or the combination.
• 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).
• Dyslipidemia. It is unclear if oral lemon balm is beneficial in patients with dyslipidemia. Details: A meta-analysis of 5 small clinical studies in adults shows that oral lemon balm extract, leaf powder, or tea in doses ranging from 700-4000 mg daily for 8-24 weeks reduces low-density lipoprotein (LDL), total cholesterol (TC), and triglycerides (TG) when compared with placebo; however, the clinical significance of these findings is unclear (115638). The validity of these results is limited by the heterogenous methods between clinical trials, including population, dose, and study duration.
• 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. It is unclear if oral lemon balm is beneficial for insomnia. Details: A small, cross-over clinical study in Italy in adults with self-reported poor sleep quality shows that taking a specific lemon balm phytosome (Meloff, Pharmextracta SpA) 400 mg 30 minutes prior to bed for 2 weeks improves some, but not all, measures of sleep quality when compared with placebo . (115637). However, it is unclear if these improvements are clinically significant. Additionally, lemon balm has been evaluated in combination with other ingredients. Taking a specific combination product providing lemon balm leaf extract 80 mg and valerian root extract 160 mg (Euvegal forte, Dr. Willmar Schwabe Pharmaceuticals) 2-3 times daily appears to improve the quality and quantity of sleep in healthy people and those diagnosed with insomnia or sleeping disorders (10423,19528,19536). However, lower daily doses may not improve sleep (10421). Other clinical research in healthy adults with insomnia shows that using a combination product containing ground lemon balm herb 1000 mg and aqueous extract of Nepeta menthoides 400 mg at bedtime for 4 weeks improves sleep quality and sleep duration and reduces sleep disturbance, sleep latency, and daytime dysfunction when compared with placebo (97278). A clinical study in children 12 years and younger shows that a specific combination product containing lemon balm leaf extract 80 mg and valerian root extract 160 mg (Euvegal forte, Dr. Willmar Schwabe Pharmaceuticals) 1-2 tablets once or twice daily might decrease symptoms of restlessness and dyssomnia when compared to baseline (14416). It is unclear if these effects are due to lemon balm, other ingredients, or the combinations.
• Irritable bowel syndrome (IBS). Oral lemon balm has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with IBS shows that using 30 drops of a combination product providing lemon balm, spearmint, and coriander (Carmint, PurSina Pharmacy) three times daily after meals for 8 weeks reduces abdominal pain and discomfort when added to standard treatment with loperamide or psyllium, compared to standard treatment alone (19535). It is not known if the effect is due to lemon balm, the other ingredients, or the combination.
• Menopausal symptoms. Oral lemon balm has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in postmenopausal adults with sleep disturbances shows that taking lemon balm leaf 250 mg and fennel fruit 250 mg orally once daily for 8 weeks improves menopausal symptoms including vasomotor, psychomotor-social, physical, and sexual symptoms, by 24% to 38% when compared with baseline. These improvements were significant when compared with placebo (110137).
• Pain (acute). It is unclear if lemon balm aromatherapy is beneficial for reducing pain in patients with acute coronary syndrome. Details: A small clinical study in patients with acute coronary syndrome presenting to the emergency department shows that aromatherapy with lemon balm leaf and stem essential oil 1% for 10 minutes twice on the day of presentation modestly reduces chest pain scores when compared with placebo. However, pain was no longer different between groups within 15 minutes after the second aromatherapy session (110139).
• Postpartum complications. Oral lemon balm might reduce postpartum pain in some patients; however, it's not clear if it is beneficial for other postpartum complications. Details: A small clinical study shows that taking lemon balm leaf extract 395 mg every 6 hours for 24 hours following childbirth is slightly more effective for reducing postpartum pain when compared with taking mefenamic acid 250 mg using the same dosing schedule (101763).
• Psoriasis. Oral lemon balm has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with mild to moderate psoriasis shows that taking an oral combination product containing lemon balm, rose hip, and fennel as 10 mL three times daily for 12 weeks improves pruritus and psoriasis scores by 45% and 49%, respectively, when compared with baseline. In contrast, these scores worsened in the placebo group (110141). The validity of this finding is limited by the lack of statistical comparison between groups.
• Somatic symptom disorder. Oral lemon balm has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical study in individuals with somatic symptom disorder shows that taking one tablet of a combination product three times daily for 2 weeks seems to improve symptoms of depression and anxiety when compared with placebo. Each tablet of this product contains lemon balm leaf extract 60 mg, valerian root extract 90 mg, and passionflower herb extract 90 mg (19701). It is not known if the effect is due to lemon balm, other ingredients, or the combination.
• Ventricular arrhythmias. It is unclear if oral lemon balm leaf tea is beneficial for patients with premature ventricular contraction (PVC). Details: Preliminary clinical research in adults with low to moderate PVCs shows that drinking lemon balm leaf tea twice daily for 12 weeks reduces the frequency of PVCs by 32% when compared with baseline. This improvement was significant when compared with no treatment. Lemon balm tea also modestly improved heart rate, but not left ventricular ejection fraction, when compared with no treatment. The tea was prepared by steeping lemon balm leaf 2 grams in 250 mL of boiling water (110140). More evidence is needed to rate lemon balm for these uses.

(Read more about LEMON BALM)

POSSIBLY EFFECTIVE

• Anxiety. Oral passion flower has a long history of use as a sedative and may improve symptoms of anxiety in some patients. Details: Preliminary clinical research shows that taking a specific dried alcoholic extract of passion flower (Sedanxio, Tilman SA) 400 mg orally twice daily for 2-8 weeks reduces the severity of non-specific anxiety when compared to baseline (88198). The validity of this finding is limited by the lack of a placebo group. Passionflower has also been evaluated as an adjunct to conventional medication. One clinical small study in patients with generalized anxiety disorder shows that taking a specific passion flower extract (Pasipay, Iran Darouk Pharmaceutical Company) 15 drops three times daily along with sertraline 50-100 mg daily for one month reduces anxiety when compared with taking sertraline alone (95036). Passion flower has also been compared to conventional treatments. One preliminary clinical study shows that taking passion flower extract 90-180 mg daily reduces symptoms of non-specific anxiety when compared to baseline, and seems to be comparable to taking mexazolam (15391). A small clinical study in patients with generalized anxiety disorder shows that taking a specific passion flower extract (Pasipay, Iran Darouk Pharmaceutical Company) 45 drops orally once daily for 28 days reduces anxiety similarly to oxazepam 30 mg daily. However, passion flower appears to have a slower onset of action than oxazepam (8007). This finding is limited because it did not utilize a therapeutic dosing regimen for oxazepam, which is given 3-4 times daily to account for its short half-life. Passion flower has also been studied in combination with other ingredients. A small clinical study in healthy adults shows that taking a combination of herbal extracts containing passion flower 40 mg, valerian root, black horehound, and hawthorn (Euphytose, Bayer HealthCare) 6 times daily with meals for 14 days reduces anxiety and sympathetic and autonomic nervous system activation in response to a psychosocial stressor when compared with placebo (111222). It is unclear if these effects are due to valerian, other ingredients, or the combination.
• 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).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Adjustment disorders. Oral passion flower has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One clinical study in patients with adjustment disorder with anxious mood shows that taking two tablets of a specific combination product (Euphytose, Bayer Healthcare) three times daily seems to decrease anxiety symptoms when compared with placebo. One tablet contains the dry extracts of passion flower 40 mg, valerian 40 mg, hawthorn 10 mg, and black horehound 10 mg, as well as the caffeine-containing stimulant herbs kola nut 15 mg and guarana 15 mg (6250). It is unclear if this effect is due to passion flower, other ingredients, or the combination.
• Alcohol use disorder. Oral passion flower has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults experiencing alcohol withdrawal symptoms shows that taking one capsule of a combination product (Relief) three times daily for 15 days reduces the frequency of excessive sweating, reduces serum liver enzyme levels, and improves appetite and quality of life when compared to baseline. One capsule contains passion flower extract 30 mg, black seed extract 100 mg, cocoa extract 90 mg, radish extract 165 mg, and saffron extract 15 mg (97280). The validity of these findings is limited by the lack of a comparator group.
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral passion flower is beneficial in patients with ADHD. Details: A small clinical trial in children aged 6-13 years with ADHD shows that taking tablets of passion flower (Pasipay, Iran Darouk Pharmaceutical Company) 0.02 mg/kg orally twice daily for 8 weeks reduces parent and teacher ratings of ADHD symptoms no better than taking methylphenidate (0.5 mg/kg twice daily) (88197).
• Benzodiazepine withdrawal. It is unclear if oral passion flower is beneficial for benzodiazepine withdrawal. Details: A moderate-sized observational study in adults with depression or anxiety on antidepressants undergoing a benzodiazepine taper after chronic benzodiazepine use suggests that taking a specific dry extract of passion flower (Tractana, Baldacci) 200-600 mg daily for 3 months is associated with a faster benzodiazepine dose reduction and greater percentage of patients with at least 50% reduction or complete benzodiazepine discontinuation after 1 and 3 months from taper initiation when compared with control (111651). The validity of these effects is limited by a lack of placebo group and the retrospective observational study design.
• Congestive heart failure (CHF). Oral passion flower has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with mild CHF shows that taking a combination of passion flower and hawthorn extracts 2 mL three times daily for 6 weeks increases six-minute walking distance when compared with placebo. However, it does not appear to improve exercise capacity on a bicycle ergometer test (19201). It is unclear if this effect is due to passion flower, hawthorn, or the combination. Additionally, hawthorn has been evaluated alone for the management of CHF, with some research suggesting that although it may improve symptoms, it may also be associated with worsened clinical outcomes.
• Fibromyalgia. Although there is interest in using oral passion flower for fibromyalgia, there is insufficient reliable information about the clinical effects of passion flower for this condition.
• 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.

(Read more about PASSION FLOWER)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). Although there has been interest in using oral skullcap for allergic rhinitis (hay fever), there is insufficient reliable information about the clinical effects of skullcap for this purpose.
• Anxiety. It is unclear if oral skullcap is beneficial for reducing symptoms of anxiety. Details: Preliminary clinical research shows that healthy people who take a single dose of freeze-dried skullcap extract 100-350 mg feel more relaxed when compared to baseline. This effect appears to last for about 2 hours (12216). However, other preliminary clinical research in healthy patients shows that taking freeze-dried skullcap (Skullcap, Eclectic Institute) 350 mg three times daily for 2 weeks does not reduce anxiety scores when compared with placebo (91690). Because these were short-term studies in healthy patients, it's unclear if skullcap is beneficial in anxiety disorders or if extended use is beneficial.
• Atherosclerosis. Although there has been interest in using oral skullcap for atherosclerosis, there is insufficient reliable information about the clinical effects of skullcap for this purpose.
• Contact dermatitis. Although there has been interest in using oral skullcap for contact dermatitis, there is insufficient reliable information about the clinical effects of skullcap for this purpose.
• Epilepsy. Although there has been interest in using oral skullcap for epilepsy, there is insufficient reliable information about the clinical effects of skullcap for this purpose.
• Hyperlipidemia. Although there has been interest in using oral skullcap for hyperlipidemia, there is insufficient reliable information about the clinical effects of skullcap for this purpose.
• Insomnia. Although there has been interest in using oral skullcap for insomnia, there is insufficient reliable information about the clinical effects of skullcap for this purpose.
• Premenstrual dysphoric disorder (PMDD). Although there has been interest in using oral skullcap for PMDD, there is insufficient reliable information about the clinical effects of skullcap for this purpose.
• Spasticity. Although there has been interest in using oral skullcap for spasticity, there is insufficient reliable information about the clinical effects of skullcap for this purpose.
• Stress. Although there has been interest in using oral skullcap for stress, there is insufficient reliable information about the clinical effects of skullcap for this purpose.
• Stroke. Although there has been interest in using oral skullcap for stroke, there is insufficient reliable information about the clinical effects of skullcap for this purpose. More evidence is needed to rate skullcap for this use.

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POSSIBLY SAFE ...when used orally and appropriately, short-term. Oral Baikal skullcap 0.5-3.52 grams daily has been used with apparent safety for up to 8 weeks (92776,101738,101739,110023). However, a high quality assessment of safety has not been conducted. A specific product (Limbrel, Primus Pharmaceuticals) containing flavocoxid, a mixture of Baikal skullcap flavonoid extract and catechu extract, has been associated with an increased risk for liver and lung injury. In 2017, the US Food and Drug Administration (FDA) formally requested the recall of all non-expired lots of this product (106042). It is unclear if these effects were due to Baikal skullcap, catechu, or the combination. There is insufficient reliable information available about the safety of Baikal skullcap when used intravenously or topically.

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

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

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

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

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

(Read more about LEMON BALM)

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

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

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

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

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about PASSION FLOWER)

There is insufficient reliable information available about the safety of skullcap.

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

(Read more about SKULLCAP)

ALCOHOL (Ethanol) Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, Baikal skullcap might potentiate the sedative effects of alcohol.  Details In vitro and animal research suggests that Baikal skullcap binds to GABA-A receptors and causes sedation. Theoretically, Baikal skullcap might potentiate the sedative effects of alcohol (6290,6291,33477). Preliminary clinical research has not identified clinically relevant sedation after use of Baikal skullcap; however, a thorough evaluation of safety outcomes has not been conducted.

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, Baikal skullcap might increase the risk of bleeding when used concomitantly with anticoagulant and antiplatelet drugs.  Details Preliminary clinical research suggests that taking capsules containing a combination of astragalus, goldthread, and Baikal skullcap daily for 4 weeks inhibits platelet aggregation; the effect seems to be similar to that of aspirin 50 mg daily (33075). It is unclear if this effect is due to Baikal skullcap, other ingredients, or the combination.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use of Baikal skullcap with antidiabetes drugs might enhance blood glucose lowering effects.  Details Baicalein, a constituent of Baikal skullcap, has alpha-glucosidase inhibitory activity in vitro (6292). Animal research also suggests that Baikal skullcap enhances the antidiabetic effects of metformin (33408). However, in a small human study, taking Baikal skullcap extract did not enhance the antidiabetic effects of metformin, although it did modestly lower glucose levels during an oral glucose tolerance test (OGTT) (101738). Until more is known, use cautiously.

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of Baikal skullcap with antihypertensive drugs might have additive effects and increase the risk of hypotension.  Details Animal research suggests that baicalein, a constituent of Baikal skullcap, might lower blood pressure (33374).

ANTITHYROID DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of Baikal skullcap and antithyroid drugs may result in additive activity and increase the risk of hypothyroidism.  Details In an animal hyperthyroid model, Baikal skullcap improved levels of triiodothyronine (T3), thyroxine (T4), and thyroid stimulating hormone (TSH) (101736). The clinical significance of this effect is unclear.

CNS DEPRESSANTS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, Baikal skullcap might cause additive therapeutic and adverse effects when used concomitantly with drugs with sedative properties.  Details In vitro and animal research suggests that Baikal skullcap binds to GABA-A receptors and causes sedation. Theoretically, Baikal skullcap might cause additive therapeutic and adverse effects when used concomitantly with drugs with sedative properties (6290,6291,33477). Preliminary clinical research has not identified clinically relevant sedation after use of Baikal skullcap; however, a thorough evaluation of safety outcomes has not been conducted.

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, Baikal skullcap may increase levels of drugs metabolized by CYP1A2 enzymes.  Details In vitro evidence suggests that constituents of Baikal skullcap inhibit the activity of CYP1A2 (33346,33484). This effect has not been reported in humans.

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, Baikal skullcap might increase levels of drugs metabolized by CYP2C19 enzymes.  Details In vitro evidence suggest that wogonin, a constituent of Baikal skullcap, modestly inhibits the activity of CYP2C19 enzymes (33484). This effect has not been reported in humans.

ESTROGENS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of large amounts of Baikal skullcap might interfere with hormone replacement therapy, due to competition for estrogen receptors.  Details In vitro evidence suggests that Baikal skullcap has estrogenic activity (16061).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, Baikal skullcap might reduce lithium excretion and increase serum levels of lithium.  Details Baikal skullcap is thought to have diuretic properties, which may reduce lithium excretion (5541). The dose of lithium might need to be decreased.

ORGANIC ANION-TRANSPORTING POLYPEPTIDE SUBSTRATES (OATP) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, Baikal skullcap might alter the levels and clinical effects of OATP substrates.  Details Some pharmacokinetic research shows that baicalin, a constituent of Baikal skullcap, can decrease plasma levels of rosuvastatin. The mechanism is thought to involve stimulation of the activity of the organic anion-transporting polypeptide 1B1 (OATP1B1), which transports rosuvastatin into the liver. This decreases plasma levels of the drug, but increases levels at the site of action in the liver. The degree to which rosuvastatin levels are affected depends on the OATP1B1 haplotype of the individual (16395). Baikal skullcap might also affect other OATP1B1 substrates (16396,16397,16398).

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, Baikal skullcap might increase levels of drugs transported by P-glycoprotein.  Details In vitro and animal research suggests that baicalein, oroxylin A, and wogonin, constituents of Baikal skullcap, can inhibit P-glycoprotein (33372,33395,33440,33462). This effect has not been reported in humans.

(Read more about BAIKAL SKULLCAP)

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use of lemon balm might have additive effects with CNS depressant drugs.  Details Lemon balm seems to have CNS depressant activity in animals and in humans (9994,19725).

THYROID HORMONE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, lemon balm might interfere with thyroid hormone replacement therapy.  Details In vitro, constituents of lemon balm extract bind to thyroid stimulating hormone (TSH), preventing TSH receptor-binding and leading to the inhibition of TSH-stimulated adenylate cyclase activity (19727,19728). In animals, lemon balm extract has been shown to decrease levels of circulating TSH and inhibit thyroid secretion (19726).

(Read more about LEMON BALM)

CNS DEPRESSANTS Interaction Rating = 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.

(Read more about PASSION FLOWER)

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, skullcap can have additive effects when used with other CNS depressants.  Details Animal and clinical research suggests that skullcap can cause sedation and cognitive impairment (12216,74008).

(Read more about SKULLCAP)

General ...Orally, Baikal skullcap seems to be well-tolerated. There is currently a limited amount of information on the adverse effects of intravenous and topical Baikal skullcap.
Most Common Adverse Effects:
Orally: Abdominal pain, constipation, diarrhea, erythema, nausea, pruritus, and vomiting.
Intravenously: Skin reactions.
Topically: Dermatitis.
Serious Adverse Effects (Rare):
Orally: Hepatotoxicity and hypersensitivity pneumonitis have been reported with a specific combination product (Limbrel, Primus Pharmaceuticals) containing extracts of Baikal skullcap and catechu.

Cardiovascular ...Orally, in a small clinical study evaluating the safety of baicalein, a constituent of Baikal skullcap, in healthy adults, elevated triglyceride levels occurred in 1 of 10 patients who received 400 mg every 8 hours and 2 of 10 patients treated with 600 mg every 8 hours, compared with 0 of 10 patients who received 200 mg every 8 hours and 0 of 6 patients who received placebo. Triglyceride elevations were considered mild and resolved after discontinuation (110023).

Dermatologic ...Orally, taking Baikal skullcap may cause erythema and pruritus (105867). Intravenously, Baikal skullcap as part of a Tanreqing injection has been associated with reports of skin reactions in some pediatric patients (96281).
Topically, several cases of allergic contact dermatitis have been reported after applying sunscreen containing Baikal skullcap extract (105869,105870). Allergic contact dermatitis has also been reported after applying a facial cream (Resveratrol BE, Skinceuticals) containing Baikal skullcap root extract 0.5% and resveratrol 1%. Patch testing identified a positive reaction to both ingredients (110024). Baikal skullcap-induced dermatitis appears to respond to treatment with a topical corticosteroid and calcineurin inhibitor (105870).

Gastrointestinal ...Orally, use of Baikal skullcap has been associated with epigastric pain, abdominal pain, constipation, diarrhea, nausea, and vomiting (101738,105867).

Hepatic ...A specific combination product (Limbrel, Primus Pharmaceuticals) containing flavocoxid, a mixture of Baikal skullcap flavonoid extract and catechu extract, has been linked to several reports of acute liver damage. There have been at least five published reports of liver damage associated with this product. In all cases, the patients were females aged 54-68 years taking doses of 250-500 mg twice daily for 1-3 months. Signs and symptoms included jaundice, pruritus, abdominal pain, fever, rash, and elevated serum bilirubin and liver transaminase levels. All patients fully recovered and levels normalized within 3 months after discontinuation (18009,96282). In addition to these published case reports, approximately 30 liver-related adverse events have been reported to the manufacturer of this product (18009). The mechanism of hepatotoxicity is unclear (18009,18010); it is estimated that the incidence of hepatotoxicity with this product is around 1 in 10,000, although the actual incidence is unknown (18010). In 2017, the US Food and Drug Administration (FDA) formally requested the recall of all non-expired lots of this product due to the risk for liver and lung injury (106042). It is unclear if these effects were due to Baikal skullcap, catechu, or the combination.
Hepatotoxicity has also been reported in two patients taking a specific dietary supplement (Move Free Advanced, Reckitt Benckiser) containing Baikal skullcap, black catechu, glucosamine, chondroitin, and hyaluronic acid (33460) and in a patient taking Baikal skullcap, elderflower, horseradish, and white willow (101737). The investigators determined that the hepatotoxicity was likely caused by Baikal skullcap in these cases (33460,101737). Additionally, cases of liver injury are reported in 4 of 37 patients taking various Kampo formulations containing Baikal skullcap and other herbs daily. Patients presented with elevated liver function tests 7 to 38 days after consumption (112179). It is unclear if this adverse effect is from Baikal skullcap, other ingredients, or the combination.
In a small study evaluating the safety of baicalein, a constituent of Baikal skullcap, in healthy adults, liver transaminase elevations occurred in 2 of 10 patients who received 400 mg every 8 hours for 6 days, compared with 0 of 6 patients who received placebo. No patients receiving either 200 mg or 600 mg every 8 hours experienced liver transaminase elevations. The elevations were considered mild and resolved after discontinuation (110023).

Pulmonary/Respiratory ...A specific combination product (Limbrel, Primus Pharmaceuticals) containing flavocoxid, a mixture of Baikal skullcap flavonoid extract and catechu extract, has been linked to several reports of hypersensitivity pneumonitis. Symptoms include fever, chills, headache, cough, chronic bronchitis, shortness of breath, weight loss, and fatigue. In 2017, the US Food and Drug Administration (FDA) formally requested the recall of all non-expired lots of this product due to the risk for liver and lung injury (106042). It is unclear if these effects were due to Baikal skullcap, catechu, or the combination.

Renal ...Orally, in a small clinical study evaluating the safety of baicalein, a constituent of Baikal skullcap, in healthy adults, proteinuria of undefined severity occurred in 1 of 10 patients who received 200 mg every 8 hours for 6 days, 3 of 10 patients who received 400 mg every 8 hours for 6 days, and 5 of 10 patients who received 600 mg every 8 hours for 6 days, compared with 1 of 6 patients who received placebo. The proteinuria was considered mild and resolved after discontinuation (110023).

(Read more about BAIKAL SKULLCAP)

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).

(Read more about LEMON BALM)

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).

(Read more about PASSION FLOWER)

General ...There is currently a limited amount of information available on the adverse effects of skullcap.
Most Common Adverse Effects:
Orally: Cognitive impairment, digestive disturbances, sedation.

Gastrointestinal ...Orally, mild digestive disturbances were reported in around 9% of patients taking skullcap 350 mg three times daily for 2 weeks (91690).

Hepatic ...There are four reports of hepatotoxicity associated with products thought to contain skullcap. However, it is uncertain whether the products actually contained skullcap. It is thought that the products might have been contaminated with an adulterant such as germander (515), which is known to cause liver damage.

Neurologic/CNS ...A single skullcap extract dose of 100 mg does not seem to have adverse CNS effects. However, a higher dose of 200 mg might cause sedation and cognitive impairment (12216). One patient taking skullcap 350 mg three times daily for 2 weeks reported vivid dreams (91690). It is unclear if this event was associated with skullcap.

(Read more about SKULLCAP)