Lavender (lavendula angustifolia) • Valerian (valeriana officinalis) • Chamomile flowers (chamomilla recutita) • Skullcap (scutellaria baicalensis) • Passion Flower (passiflora incarnata) • Lime blossom (citrus aurantifolia).
Brand name products often contain multiple ingredients. To read detailed information about each ingredient, click on the link for the individual ingredient shown above.
Below is general information about the effectiveness of the known ingredients contained in the product Sleep Tonic. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
Below is general information about the safety of the known ingredients contained in the product Sleep Tonic. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
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.
LIKELY SAFE ...when used orally in amounts commonly found in foods. Lavender has Generally Recognized as Safe (GRAS) status for food use in the US (4912).
POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts (9792). In clinical research, a specific product containing lavender oil (Silexan, Dr Willmar Schwabe GmbH & Co. KG) has been used safely at doses of 80-160 mg daily for up to 10 weeks (58077,58080,58098,97257,112255). Powdered dried lavender flowers 500 mg twice daily has also been used with apparent safety for up to 8 weeks (97256). ...when used topically and appropriately. Lavender oil has been used safely for up to 7 months in adults (5177,109858,109865). ...when the essential oil is inhaled as a part of aromatherapy. Clinical studies have used lavender oil aromatherapy with apparent safety for up to 12 weeks (7107,12213,16393,16394,95634,103062,103063,103065,103068).
CHILDREN: POSSIBLY SAFE
when the essential oil is inhaled as a part of aromatherapy.
Clinical studies have used lavender oil aromatherapy with apparent safety in single doses for up to 2 hours (109868,112260).
CHILDREN: POSSIBLY UNSAFE
when applied topically in males.
Anecdotal reports suggest that applying topical products containing lavender oil to prepubertal males may result in gynecomastia in some cases (15254,95643). Products with a higher concentration of lavender oil and more frequent applications might be more likely to result in gynecomastia.
PREGNANCY AND LACTATION:
Insufficient reliable evidence available.
Preliminary clinical research shows that lavender essential oil can be inhaled during labor, with no apparent adverse outcomes in the infants (95633). Although this study suggests safety, high quality assessment of safety has not been conducted.
LIKELY SAFE ...when used orally in amounts commonly found in foods. Lime has Generally Recognized As Safe status (GRAS) for use in foods in the US (4912).
POSSIBLY UNSAFE ...when used topically. Lime oil and lime juice contain photosensitizing constituents (12,11019,40894,59925,59928,100125,100126,100129). ...when used intravaginally. Lime juice has caused mild to moderate adverse effects in women using lime juice-soaked tampons or as a douche, especially in concentrations of 20% or more (100127,100128). There is insufficient reliable information available about the safety of lime when used orally in medicinal amounts.
PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using in amounts greater than those typically found in foods.
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.
LIKELY SAFE ...when used orally and appropriately, short-term. Valerian 300-600 mg daily has been safely used in clinical studies in over 12,000 patients for up to 6 weeks (2074,3484,3485,4032,15018,17577,17578,19409,96242,103221)(104010,105718). There is insufficient reliable information available about the safety of valerian when used orally for longer than 6 weeks.
CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term.
Valerian 160-320 mg has been used with apparent safety in children under 12 years of age for 4-8 weeks (14416).
PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.
Below is general information about the interactions of the known ingredients contained in the product Sleep Tonic. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
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.
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Theoretically, Baikal skullcap might increase the risk of bleeding when used concomitantly with anticoagulant and antiplatelet drugs.
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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.
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Theoretically, concomitant use of Baikal skullcap with antidiabetes drugs might enhance blood glucose lowering effects.
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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.
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Theoretically, concomitant use of Baikal skullcap with antihypertensive drugs might have additive effects and increase the risk of hypotension.
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Animal research suggests that baicalein, a constituent of Baikal skullcap, might lower blood pressure (33374).
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Theoretically, concomitant use of Baikal skullcap and antithyroid drugs may result in additive activity and increase the risk of hypothyroidism.
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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.
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Theoretically, Baikal skullcap might cause additive therapeutic and adverse effects when used concomitantly with drugs with sedative properties.
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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.
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Theoretically, Baikal skullcap may increase levels of drugs metabolized by CYP1A2 enzymes.
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Theoretically, Baikal skullcap might increase levels of drugs metabolized by CYP2C19 enzymes.
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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.
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Theoretically, concomitant use of large amounts of Baikal skullcap might interfere with hormone replacement therapy, due to competition for estrogen receptors.
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In vitro evidence suggests that Baikal skullcap has estrogenic activity (16061).
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Theoretically, Baikal skullcap might reduce lithium excretion and increase serum levels of lithium.
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Baikal skullcap is thought to have diuretic properties, which may reduce lithium excretion (5541). The dose of lithium might need to be decreased.
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Theoretically, Baikal skullcap might alter the levels and clinical effects of OATP substrates.
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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).
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Theoretically, Baikal skullcap might increase levels of drugs transported by P-glycoprotein.
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Theoretically, lavender might potentiate the therapeutic effects and adverse effects of CNS depressants.
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Laboratory research suggests that lavender has sedative effects (7). However, clinical studies in patients taking oral lavender oil (Silexan) 160 mg for 10 weeks or taking lavender flower powder 1 gram daily for 2 months have not reported side effects of drowsiness, sedation, or sleepiness (97256,103061). There is still some concern that higher doses or different preparations of lavender might have additive effects with CNS depressant medications.
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Lime juice inhibits cytochrome P450 3A4, causing increased drug levels and potentially increasing the risk of adverse effects (11976). Some drugs metabolized by CYP3A4 that might be affected are some benzodiazepines such as alprazolam (Xanax), diazepam (Valium), midazolam (Versed), triazolam (Halcion); calcium channel blockers such as amlodipine (Norvasc), diltiazem (Cardizem, Dilacor, others), felodipine (Plendil), verapamil (Calan, Verelan, others); cyclosporine (Neoral, Sandimmune); some HIV antivirals such as indinavir (Crixivan), ritonavir (Norvir), saquinavir (Fortovase, Invirase); some HMG CoA reductase inhibitors such as atorvastatin (Lipitor), lovastatin (Mevacor); some macrolide antibiotics such as erythromycin and clarithromycin (Biaxin); quinidine; and many others.
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Theoretically, concomitant use of lime oil with photosensitizing drugs may increase the risk of phototoxicity (11019).
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Concomitant use of passion flower with sedative drugs might cause additive effects and side effects.
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Theoretically, passion flower might decrease the effects of CYP3A4 substrates.
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In vitro research suggests that passion flower can induce CYP3A4 enzymes, albeit to a much lower degree than rifampin, a known CYP3A4 inducer (110704).
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Theoretically, passion flower might reduce the bioavailability of OATP2B1 and OATP1A2 substrates.
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In vitro research shows that the passion flower constituents apigenin and vitexin inhibit OATP2B1 and OATP1A2. This inhibition may be dose-dependent. One specific high-flavonoid passion flower extract (Valverde) seems to inhibit OATP2B1 and OATP1A2, while another extract with a lower flavonoid concentration (Arkocaps) shows less potent inhibition (105095). OATPs are responsible for the uptake of drugs and other compounds into the body; however, the specific activities of OATP2B1 and OATP1A2 are not well characterized.
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Valerian can have additive sedative effects when used concomitantly with alcohol.
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Valerian has sedative effects (9894). Theoretically, valerian might have an additive sedative effect when combined with alcohol. Excessive sedation has been reported in an alcohol-abusing individual who took valerian and Gingko biloba (19426). However, the potential interaction between valerian and alcohol has been disputed in other research. Limited evidence suggests that a combination of valerian 160 mg and lemon balm 80 mg (Euvegal) does not cause further deterioration in reaction ability and reaction rate when taken with alcohol as compared to the effects of alcohol alone (19427).
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Valerian can have additive sedative effects when used with alprazolam. Also, valerian in high doses might modestly increase alprazolam levels, though this is not likely to be clinically significant.
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Valerian has sedative effects (9894). Theoretically, valerian might cause additive sedation when combined with alprazolam. Also, a small pharmacokinetic study shows that taking valerian extract 1000 mg daily (providing 11 mg valerenic acid) might increase alprazolam levels by about 19%. This might be due to valerian's mild inhibition of cytochrome P450 3A4 (CYP3A4) (13014). Despite being statistically significant, this increase is not likely to be clinically significant.
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Valerian can have additive sedative effects when used concomitantly with CNS depressant drugs.
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Valerian does not seem to have a clinically relevant effect on levels of drugs metabolized by CYP2D6.
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Although some in vitro evidence suggests that valerian affects CYP2D6, clinical pharmacokinetic (PK) studies show that valerian is unlikely to affect the CYP2D6 enzyme (13014,13536,19430,19431). In one PK study, taking valerian 1000 mg (providing about 11 mg valerenic acid) nightly for 14 days did not affect the metabolism of dextromethorphan, a CYP2D6 substrate. In another PK study, taking valerian 125 mg three times daily for 28 days did not affect metabolism of debrisoquine, an accepted CYP2D6 probe-substrate (13014,13536).
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Valerian does not seem to have a clinically relevant effect on levels of drugs metabolized by CYP3A4.
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Although some in vitro evidence suggests that valerian extract might inhibit or induce CYP3A4, clinical pharmacokinetic (PK) studies show that valerian does not have a clinically significant effect on the CYP3A4 enzyme (6450,12214,13014,13536,19431). In one PK study, taking valerian 125 mg three times daily for 28 days did not affect metabolism of midazolam, an accepted CYP3A4 probe-substrate. In another PK study, taking valerian 1000 mg (providing about 11 mg valerenic acid) nightly for 14 days modestly increases levels of alprazolam, a CYP3A4 substrate, suggesting mild inhibition of CYP3A4 (13014,13536). However, this mild inhibition is unlikely to be clinically relevant.
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Valerian might weakly inhibit glucuronidation and increase concentrations of drugs metabolized by UGT1A1 and UGT2B7.
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In vitro research shows that methanolic valerian extract and valerenic acid might competitively inhibit UDP-glucuronosyltransferase (UGT) 1A1 (UGT1A1) and UGT2B7 (81685).
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Below is general information about the adverse effects of the known ingredients contained in the product Sleep Tonic. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
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).
General
...Orally, lavender is well tolerated in food amounts and seems to be well tolerated in larger amounts.
Topically, lavender oil seems to be well tolerated.
Most Common Adverse Effects:
Orally: Breath odor, constipation, diarrhea, dyspepsia, eructation, headache, and nausea.
Topically: Allergic contact dermatitis (with lavender oil).
Serious Adverse Effects (Rare):
Topically: Cases of gynecomastia have been reported in prepubertal males using lavender oil.
Cardiovascular ...Orally, a specific lavender oil ingredient (Silexan) has been associated with palpitations (103061).
Endocrine ...Topical products containing lavender oil alone, including a product referred to as agua de violetas, or in combination with tea tree oil have been linked to at least six cases of gynecomastia when used in prepubertal males. In each case, gynecomastia resolved when the lavender oil products were discontinued. It is thought that the estrogenic and antiandrogenic activity of lavender oil and tea tree oil resulted in gynecomastia in these cases (15254,95643).
Gastrointestinal ...Orally, lavender oil, including a specific lavender oil ingredient KG), may cause gastrointestinal disturbance, including dyspepsia, diarrhea, breath odor, eructation, and nausea (58077,58080,58098,93004,103061). Tincture of lavender has been linked to cases of constipation and increased appetite; however, it is unknown if this occurred at a greater rate than with placebo (9792).
Immunologic ...Topically, use of lavender oil, such as in personal care products, might cause allergic contact dermatitis in some patients (6,101728). There have been numerous case reports of allergic contact dermatitis and eczema linked to lavender oil exposure from shampoos, lotions, fragrances, or direct application of oil to pillows (10031,58043,58109,58120,101728,112253). In one case series, only 4 out of 15 cases of allergic contact dermatitis due to lavender had positive patch tests for lavender. Oxidation products of lavender essential oils such as linalool, linalyl acetate, limonene, cineol, geraniol, eugenol, and isoeugenol may be more allergenic than un-oxidized lavender essential oil, which may result in a false negative patch test (112253).
Neurologic/CNS ...Orally, lavender flower powder, tincture of lavender containing 50% alcohol, and a specific lavender oil ingredient (Silexan) have been linked to headache (9792,103061,109860). Headache has also been reported rarely following lavender oil aromatherapy (109860).
Pulmonary/Respiratory ...In one case report, a 34-year-old Japanese female presented with complaints of dyspnea, cough, and fever 2 weeks after initiating lavender essential oil therapy via humidifier. The patient had an oxygen saturation of 88% and was diagnosed with acute eosinophilic pneumonia. Symptoms improved after a course of corticosteroids and discontinuation of aromatherapy (109979).
Renal ...In one case report, a 24-year-old male presented with shortness of breath, weakness, nausea, and decreased urine output following the intake of Spanish lavender tea twice daily for 5 days. After presenting to the hospital, the patient was diagnosed with acute kidney failure secondary to acute interstitial nephritis likely due to lavender consumption (112259).
General
...Orally, lime juice may cause diarrhea or tooth sensitivity and wear, but these adverse effects are rare (59927,100123,100131).
Topically, lime oil and lime juice can cause allergic contact dermatitis (12,4058,100122,100132). Phytophotodermatitis is common when topical exposure to lime is followed by exposure to the sun (40894,59925,59928,100125,100126,100129).
Intravaginally, 20% to 100% lime juice can cause burning, dryness, pain, itching, erythema, edema, or abnormal bleeding (100127).
Dental ...Orally, tooth sensitivity and erosion of teeth have been reported for a woman who had consumed 150-300 mL of lime juice each night before bed for 3 years without brushing her teeth (100123). Tooth sensitivity has also been reported in a clinical trial (100131).
Dermatologic ...Topically, lime can cause phytophotodermatitis hours to days after exposure (40894,59925,59928,100125,100126,100129). Lime phytophotodermatites related to shaking of Mexican beer and the preparation of mojitos or sangria have been reported. Symptoms include redness, swelling, bullae, and later hyperpigmentation (100125,100126,100129).
Gastrointestinal ...Orally, diarrhea has been reported as an adverse effects in a clinical trial (59927).
Genitourinary ...Intravaginally, 20% lime juice has resulted in burning, dryness, erythema, and edema (100127). Higher doses of 25%, 50%, or 100% lime juice were dose-dependently related to vaginal, cervical, or vulval symptoms, especially pain, itching, and abnormal bleeding. The abnormal bleeding was most common in women that had applied 100% lime juice with a tampon. Peeling, erythema, discharge, and tenderness also occurred (100128).
Immunologic ...Topically, lime can rarely contribute to allergic contact dermatitis (4058,100122,100132).
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).
General
...Orally, valerian is generally well-tolerated.
Most Common Adverse Effects:
Orally: Dizziness, drowsiness, and mental slowness. Other reported side effects include headache, gastrointestinal upset, excitability, and vivid dreams. When used chronically and abruptly stopped, symptoms of withdrawal such as tachycardia, anxiety, irritability, and insomnia might occur. Advise patients to taper doses slowly after extended use.
Serious Adverse Effects (Rare):
Orally: Several case reports raise concerns about hepatotoxicity after the use of valerian and valerian-containing multi-ingredient dietary supplements. Withdrawal from chronic valerian use has been associated with cases of cardiac failure and hallucinations.
Cardiovascular ...When used orally in high doses for an extended period of time, valerian withdrawal has been associated with tachycardia and high output cardiac failure in one patient with a history of coronary artery disease (3487). Chest tightness has been reported for an 18-year-old female who took 40-50 capsules containing valerian 470 mg/capsule (659). A case of severe hypotension, suspected to be due to vasodilation, hypocalcemia, and hypokalemia, has been reported for a patient who injected an unknown quantity of a crude tap water extract of raw valerian root (81734).
Dermatologic ...Orally, valerian might rarely cause a rash. A case of valerian-related rash that resolved after valerian root discontinuation was reported in clinical research (19422).
Gastrointestinal ...Orally, valerian has been associated with increased incidence of gastrointestinal problems including diarrhea, nausea, vomiting, and stomach pain (15046,19406,19407,19422,110712). In one individual, taking 20 times the normal dose caused abdominal cramping (659).
Hepatic
...There have been several case reports of hepatotoxicity associated with the use of multi-ingredient oral preparations containing valerian (8243,96241).
In one case report, a 57-year-old man presented with acute hepatitis after consuming a cold and flu remedy containing valerian 2 grams for 3 days; the remedy also contained white willow, elderberry, and horseradish. Although the use of the cold and flu remedy was discontinued one month prior to symptom presentation, the acute hepatitis was attributed to valerian root and treated with steroids (96241). It is possible, however, that some of these preparations may have been adulterated with hepatotoxic agents (8243).
Hepatotoxicity involving long-term use of single-ingredient valerian preparations has also been reported (3484,17578). Also, a case of a 38-year-old female with liver insufficiency and cirrhosis of a vascular parenchymal nature who developed hepatotoxic symptoms following valerian and ethyl-alcohol abuse has been reported (81697). Symptoms resolved and laboratory values normalized following intense plasmapheresis treatment. Another case of acute hepatitis characterized by elevated aminotransferases, mild fibrosis, and liver inflammation has been reported for a 50-year-old female who consumed valerian root extract 5 mL three times weekly along with 10 tablets of viamine, a product containing dry valerian extract 125 mg/tablet, for 2 months (81696). Because a variety of doses were used in these cases, and many people have used higher doses safely, these hepatotoxic reactions might have been idiosyncratic. Tell patients the long-term effect of valerian on liver function is unknown.
Musculoskeletal ...In a case report, combined intake of valerian and passionflower caused throbbing and muscular fatigue when taken concomitantly with lorazepam (19429).
Neurologic/CNS ...Orally, valerian might cause dizziness, headaches, fatigue, sleepiness, and mental dullness (3484,17578,19411,19422,81723,89407). The severity of adverse effects appears to increase with higher doses (19411). However, taking valerian extracts in doses up to 1800 mg does not appear to significantly affect mood or psychomotor performance (10424,15044). Valerian does not usually have a negative impact on reaction time, alertness, and concentration the morning after intake (2074,8296). Clinical research shows that a single dose of valerian root 1600 mg is not associated with any changes in sleepiness, reaction time, or driving performance within 1-4 hours after intake (96240). More serious side effects may occur when valerian is taken at higher doses. In one individual, 20 times the normal dose caused tremor of the hand and foot and lightheadedness (659). In a case report, combined intake of valerian and passionflower caused shaking of the hands and dizziness when taken concomitantly with lorazepam (19429).
Psychiatric ...Orally, valerian has been associate with reports of restlessness, excitability, uneasiness, agitation, and vivid dreams (3484,17578,19411,19422). Chronic use and rapid cessation can lead to withdrawal syndrome with symptoms of agitation, insomnia, and hallucinations (104003). There appears to be a trend towards increased severity of adverse effects with higher doses (19411). A case of acute hypomania has been reported for a 21-year-old female patient who took a valerian decoction in water each night for one month to treat subclinical anxiety. Symptoms included euphoric mood, rapid speech, and increased sociability and sexual interest. Following cessation of valerian use and treatment with quetiapine 100 mg daily for two weeks, the patient recovered (89405). In another case report, an 85-year-old male with mild cognitive impairment, major depression, anxiety, and chronic kidney disease presented to the emergency department with hallucinations, confusion, and agitation thought to be due to abrupt cessation after taking valerian 600 mg daily for about 6 months. The symptoms resolved in about 5 days (104003).
