| Ingredients | Amount Per Serving |
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| 2 mg | |
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Proprietary Botanical Blend
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0.098 mL |
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(flower)
(Matricaria recutita Flower Extract)
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Hops Flower Extract
(Humulus lupulus )
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(Passiflora incarnata Aerial Parts Extract)
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(Valeriana officinalis )
(root)
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Water, Glycerin, Agave Nectar, Invert Sugar, Natural Flavors, Potassium Sorbate (Alt. Name: K Sorbate), Citric Acid, Propylene Glycol, Sorbitan Monolaurate, Lauric Arginate
Below is general information about the effectiveness of the known ingredients contained in the product SleepWell Spray Lemon Flavor. 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
Below is general information about the safety of the known ingredients contained in the product SleepWell Spray Lemon Flavor. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
LIKELY SAFE ...when used orally in amounts commonly found in foods. German chamomile has Generally Recognized as Safe (GRAS) status in the US (4912,110318).
POSSIBLY SAFE ...when used orally, for medicinal purposes, short-term. German chamomile has been used with apparent safety at doses of up to 1500 mg daily for up to 26 weeks (6655,12724,12729,13089,19377,19716,104806,111380). ...when applied topically. A lotion containing 0.2% microencapsulated German chamomile extract has been applied to the skin with apparent safety for up to 35 days (108993). ...when used topically as an oral rinse (99853).
CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term.
Preliminary clinical research suggests that several multi-ingredient products containing German chamomile are safe in infants when used for up to 4 weeks (16735,19705,19715,96278). ...when used topically and appropriately, short-term. Six drops of oil infused with German chamomile flower has been applied nightly with apparent safety for up to 6 weeks in children 6-18 years old (98621).
PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.
LIKELY SAFE ...when used orally and appropriately, short-term or as a single dose. Melatonin seems to be safe when used up to 8 mg daily for up to 6 months. Melatonin 10 mg daily has been used safely for up to 2 months (1049,1068,1077,1085,1738,1754,5854,5855,5857,12226), (14283,15005,62850,89502,89503,88285,88289,88293,88294,88295)(88296,88299,89508,89510,89511,96313,96314,96316,96317,96319)(96321,97438,99345,103484,106301,106303,107811,110286,110299). ...when used topically and appropriately (1066,1768,1769,4713,4714,96314).
POSSIBLY SAFE ...when doses of up to 8 mg daily are used orally and appropriately for longer than 6 months, doses of 10 mg daily are used for longer than 2 months, or doses of 50 mg daily are used for up to 5 days (7040,7043,62435,106296,107811). There is some evidence melatonin can be used safely in doses of up to 10 mg daily for up to 2 years in some patients (7040,7043,62435). ...when used intravenously under the supervision of a healthcare professional. A one-time dose of intravenous melatonin combined with a single bolus of intracoronary melatonin has been used with apparent safety in one clinical trial (96324).
CHILDREN: POSSIBLY SAFE
when used orally in low doses, short-term (9980,15034,62792,88282,88283,88286,88288,95748,96318,97434)(97439,97446,106293,110292,113216,113223,113224).
Although melatonin has been safely used in clinical research in doses up to 12 mg daily (88283), it is often advised that daily doses of melatonin be limited to 3 mg daily for children and infants 6 months or older and 5 mg daily for adolescents (95746). There is some concern that taking melatonin might adversely affect gonadal development in children (1739,1740,1742,1743). While some evidence suggests that long-term use of melatonin in children may delay puberty, the available research includes only three small, observational studies with incomplete follow-up and poor measures of pubertal timing (95747). Although rare, pediatric overdose with melatonin has resulted in hospitalization, mechanical ventilation, and death (108145). Due to potential risks, melatonin should be used only in children with a medical reason for use; it should not be used to promote sleep in otherwise healthy children. There is insufficient reliable information available about the safety of melatonin when used long-term.
PREGNANCY: POSSIBLY UNSAFE
when used orally or parenterally in high doses or with frequent use.
High doses of melatonin 75-300 mg daily seem to inhibit ovulation, causing a contraceptive effect (769,1740,6002,8271,95728). Advise pregnant patients and patients wishing to become pregnant to avoid using melatonin frequently or in high doses.
There is insufficient reliable information available about the safety of melatonin in lower doses during pregnancy. Some research shows that taking melatonin 2 mg daily does not affect anterior pituitary hormone levels in females who are not pregnant; this suggests that low doses may not have a contraceptive effect (62898). Other research shows that taking melatonin 3 mg daily during the follicle stimulating stage of in vitro fertilization does not negatively impact pregnancy rates (62818,62819,88297,89512,88297). However, it is not known if melatonin is safe for use throughout pregnancy (95729). Until more is known about the safety of melatonin, avoid using during pregnancy.
LACTATION:
Insufficient reliable information available; avoid using.
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 SleepWell Spray Lemon Flavor. 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, German chamomile might have additive effects when used with CNS depressants.
 Details
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Theoretically, large amounts of German chamomile might reduce the effectiveness of oral contraceptives.
Details
In vitro, German chamomile has demonstrated antiestrogenic activity (12728). Theoretically, concomitant use of large amounts of German chamomile might interfere with contraceptive drugs through competition for estrogen receptors.
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Theoretically, German chamomile might inhibit CYP1A2 and increase levels of drugs metabolized by these enzymes.
Details
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Theoretically, German chamomile might inhibit CYP2C9 and increase levels of drugs metabolized by these enzymes.
Details
In vitro evidence shows that German chamomile might inhibit CYP2C9 (19720). So far, this interaction has not been reported in humans. However, there might be an increase in the levels of drugs metabolized by CYP2C9 in patients taking German chamomile.
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Theoretically, German chamomile might inhibit CYP2D6 and increase levels of drugs metabolized by these enzymes.
Details
In vitro evidence shows that German chamomile might inhibit CYP2D6 (19720). So far, this interaction has not been reported in humans. However, there might be an increase in the levels of drugs metabolized by CYP2D6 in patients taking German chamomile.
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Theoretically, German chamomile might inhibit CYP3A4 and increase levels of drugs metabolized by these enzymes.
Details
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Theoretically, large amounts of German chamomile might reduce the effectiveness of estrogens.
Details
In vitro, German chamomile has demonstrated antiestrogenic activity (12728). Theoretically, large amounts of German chamomile might interfere with hormone replacement therapy through competition for estrogen receptors.
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Theoretically, large amounts of German chamomile might interfere with the activity of tamoxifen.
Details
In vitro, German chamomile has demonstrated antiestrogenic activity (12728).
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German chamomile might increase the effects of warfarin and increase the risk of bleeding.
Details
In one case, a 70-year-old female taking warfarin developed retroperitoneal hematoma and bilateral recti muscle bleeding along with an INR of 7.9 following ingestion of German chamomile tea 4-5 cups daily and use of a topical chamomile-based lotion applied 4-5 times daily (14309).
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Theoretically, melatonin may have anticoagulant effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.
Details
There are isolated case reports of minor bleeding and decreased prothrombin activity in people taking melatonin with warfarin (Coumadin) (63067). The mechanism, if any, of this interaction is unknown (9181). Taking melatonin orally seems to decrease coagulation activity within one hour of dosing in healthy men (62481).
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Theoretically, melatonin may reduce the effects of anticonvulsants.
Some clinical research suggests that melatonin may increase the frequency of seizures in certain patients, particularly children with neurological impairment (8248,9744).
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Theoretically, taking melatonin with antidiabetes drugs might increase the risk of hypoglycemia.
Details
Some clinical research shows that melatonin reduces levels of fasting blood glucose and improves glycemic control (19034,19035,103490). However, other research suggests that melatonin might impair glucose utilization and increase insulin resistance (9713), while other research has found no effect on glucose levels (19036,104368). Until more is known, use melatonin cautiously in combination with antidiabetes drugs.
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Theoretically, taking melatonin with antihypertensive drugs might increase the risk of hypotension or hypertension.
Details
Some clinical research suggests that taking melatonin decreases blood pressure in healthy adults (1724,62165,62187,63042). Also, melatonin seems to lower systolic and diastolic blood pressure in individuals with high blood pressure at nighttime or untreated essential hypertension (62359,62416,62441,62826). However, melatonin seems to worsen blood pressure in patients who are taking antihypertensive medications. Immediate-release melatonin 5 mg at night in combination with nifedipine GITS (Procardia XL) increases systolic blood pressure an average of 6.5 mmHg, diastolic blood pressure by an average of 4.9 mmHg, and heart rate by 3.9 bpm (6436). Also, results from animal research suggest that melatonin reduces the effectiveness of certain antihypertensive drugs, including methoxamine and clonidine (62432).
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Theoretically, taking caffeine with melatonin might increase levels of melatonin.
Details
Some evidence suggests that caffeine consumption can decrease endogenous melatonin levels (8265,22303,37585), while other evidence suggests that caffeine increases endogenous melatonin levels (62328). When administered in combination with melatonin supplements, caffeine seems to increase melatonin effects and levels (62352,96315). The reason for this discrepancy is not completely clear. Part of the discrepancy may result from the fact that caffeine can inhibit melatonin synthesis as well as inhibit melatonin metabolism. By functioning as an adenosine receptor antagonist, caffeine may indirectly inhibit the synthesis of melatonin. Conversely, because melatonin and caffeine are both metabolized by cytochrome P450 1A2 (CYP1A2) enzyme, concomitant use of melatonin and caffeine may reduce the metabolism of melatonin, resulting in higher serum levels (22306,96315).
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Theoretically, taking melatonin might increase the sedative effects of CNS depressants.
Details
Melatonin has sedative effects. Theoretically, concomitant use of melatonin with alcohol, benzodiazepines, or other sedative drugs might cause additive sedation (96315).
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Theoretically, taking contraceptive drugs with melatonin might increase the effects and adverse effects of melatonin.
Details
Contraceptive drugs can increase the levels of endogenous melatonin (8265). Theoretically, these drugs may increase the effects and adverse effects of oral melatonin.
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Theoretically, melatonin might increase levels of drugs metabolized by CYP1A2. Also, other CYP1A2 substrates might decrease the metabolism of melatonin, increasing melatonin levels.
Details
Melatonin is metabolized in the liver primarily by the CYP2C19 and CYP1A2 enzymes (62118,62405,96315). Theoretically, combined administration of melatonin with drugs metabolized by the CYP1A2 enzyme might reduce the metabolism of these drugs, resulting in increased serum levels. Conversely, some drugs metabolized by CYP1A2 may inhibit the metabolism of melatonin, resulting in increased serum levels of melatonin. Until more is known, use melatonin cautiously in patients taking drugs metabolized by these enzymes.
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Theoretically, melatonin might increase levels of drugs metabolized by CYP2C19. Also, other CYP2C19 substrates might decrease the metabolism of melatonin, increasing melatonin levels.
Details
Melatonin is metabolized in the liver primarily by the CYP2C19 and CYP1A2 enzymes (62118,62405). Theoretically, combined administration of melatonin with certain drugs metabolized by the CYP2C19 enzyme may reduce the metabolism of these drugs, resulting in increased serum levels. Conversely, some drugs metabolized by CYP2C19 may inhibit the metabolism of melatonin, resulting in increased serum levels of melatonin. Until more is known, use melatonin cautiously in patients taking drugs metabolized by these enzymes.
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Theoretically, melatonin might increase levels of drugs metabolized by CYP2D6.
Details
Laboratory research suggests that certain lots of melatonin inhibit CYP2D6 (96315). Theoretically, combined administration of melatonin with certain drugs metabolized by the CYP2D6 enzyme may reduce the metabolism of these drugs, resulting in increased serum levels. Until more is known, use melatonin cautiously in patients taking drugs metabolized by these enzymes.
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Theoretically, melatonin might increase levels of drugs metabolized by CYP3A4.
Details
Laboratory research shows that certain lots of melatonin inhibit CYP3A4 (96315). Theoretically, combined administration of melatonin with certain drugs metabolized by CYP3A4 may reduce the metabolism of these drugs, resulting in increased serum levels. Until more is known, use melatonin cautiously in patients taking drugs metabolized by these enzymes.
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Theoretically, taking flumazenil with melatonin might reduce the effects of melatonin.
Details
Animal research shows that flumazenil may inhibit the effect of melatonin (9703).
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Theoretically, taking fluvoxamine with melatonin might increase levels of melatonin.
Details
Fluvoxamine can significantly increase melatonin levels. In some cases, fluvoxamine might increase bioavailability of exogenously administered melatonin by up to 20 times (5038,6499,8251). Some researchers think this might be a beneficial interaction and be potentially useful for cases of refractory insomnia (6499). However, this interaction might also cause unwanted excessive drowsiness and possibly other adverse effects. Fluvoxamine is known to increase endogenous melatonin secretion (6498,22313). It seems to increase serum levels of exogenously administered melatonin possibly by decreasing melatonin metabolism by inhibiting cytochrome P450 (CYP450) 1A2 and 2C19 or by inhibiting melatonin elimination. This effect has been found in healthy people taking fluvoxamine 50-75 mg and melatonin 5 mg (5038,6498,6499,8251).
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Theoretically, melatonin might interfere with immunosuppressive therapy.
Details
Melatonin can stimulate immune function. Theoretically, melatonin might interfere with immunosuppressive therapy (7040).
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Theoretically, taking melatonin with methamphetamine may increase the adverse effects of methamphetamine.
Details
Animal research suggests that melatonin exacerbates the adverse effects of methamphetamine, resulting in greater depression of tryptophan hydroxylase (TPH) and tyrosine hydroxylase (TH) activity, as well as a significant reduction in dopamine levels (22307). This has not been shown in humans.
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Theoretically, taking melatonin with extended release nifedipine reduces the effects of nifedipine.
Details
Melatonin can decrease the effectiveness of extended release nifedipine (GITS). Immediate-release melatonin 5 mg at night in combination with nifedipine GITS 30-60 mg daily increases systolic and blood pressure by an average of 6.5 mmHg and 4.9 mmHg, respectively. Concomitant use with melatonin also increases heart rate by 3.9 bpm (6436). The mechanism of this interaction is not known.
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Theoretically, taking melatonin with drugs that lower the seizure threshold might increase the risk of seizure activity.
Details
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Theoretically, melatonin may have antiplatelet effects and may increase the risk of bleeding with warfarin.
Details
Three cases of increased prothrombin time have been reported for patients aged 48-72 years who took melatonin orally in combination with warfarin (9181). However, three cases of decreased prothrombin time have also been reported for patients aged 51-84 years who took melatonin orally in combination with warfarin (9181). Until more is known, use melatonin cautiously in patients taking warfarin.
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Concomitant use of passion flower with sedative drugs might cause additive effects and side effects.
Details
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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).
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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.
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Valerian can have additive sedative effects when used concomitantly with alcohol.
Details
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.
Details
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.
Details
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Valerian does not seem to have a clinically relevant effect on levels of drugs metabolized by CYP2D6.
Details
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.
Details
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.
Details
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 SleepWell Spray Lemon Flavor. 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 and topically, German chamomile is well tolerated.
Most Common Adverse Effects:
Orally and topically: Allergic reactions and irritation.
Dermatologic ...Topically, German chamomile may cause allergic dermatitis and eczema (9766,9768,10377,110318).
Gastrointestinal ...When used topically as an oral rinse, German chamomile has been reported to cause nausea and burning in the mouth in some patients (99853).
Immunologic ...Orally, German chamomile tea can cause allergic reactions including severe hypersensitivity reactions and anaphylaxis in some patients (567). In one case report, a 47-year-old female who tolerated drinking chamomile tea, reported sneezing, nasal and ocular itching, red and watery eyes, and severe rhinorrhea after 10 years of occupational exposure to German chamomile dust (90542).
Ocular/Otic ...If used near the eyes, German chamomile can cause irritation (10377).
General
...Orally, melatonin is generally well tolerated.
Most Common Adverse Effects:
Orally: Dizziness, drowsiness, headache, and nausea.
Serious Adverse Effects (Rare):
Orally: There is concern that melatonin may increase the risk for seizure.
Cardiovascular ...Melatonin might increase levels of very low-density lipoprotein (VLDL) cholesterol and triglycerides (62176). Several rare or poorly described cases of abnormal heart rhythms, palpitations, fast heart rate, or chest pain have been reported. However, in these cases, the patients were taking other drugs that could account for the symptoms, and melatonin was not thought to be the cause (1079,9181,62776,62789,63067). Additionally, four casesof elevated left ventricular end-diastolic pressure associated with melatonin intake have been reported (114510).
Dermatologic ...Papular skin rash and pruritus has been reported with melatonin use. However, the effect was generally mild and did not require cessation of melatonin treatment (62450,62754,109696), and had similar rates as placebo (96316). Cutaneous flushing, angiokeratoma, and nasal mucosal ulcers have also been reported (62770,62914,114510). Two cases of fixed drug eruption on the genitalia have been reported for patients who used oral melatonin (Nature's Bounty Natural melatonin) for preventing jet lag (88284).
Endocrine ...Orally, melatonin use might be associated with higher rates of precocious puberty, growth hormone deficiency, elevated cortisol, and increased progesterone (114510). A case of gynecomastia (increased breast size) has been reported for a 56 year-old patient with amyotrophic lateral sclerosis (ALS) who used oral melatonin, long-term (89430). Also, reduced sperm concentration and sperm motility has been reported for two men who used oral melatonin 3 mg daily for 6 months. Improvement in sperm quality was observed for only one of the two men following melatonin cessation (62231).
Gastrointestinal ...Orally, melatonin may cause nausea (62384,62770,114510), abdominal cramps, or mild abdominal pain (62450,62754,62914,96316), diarrhea (62804,62811,62914), constipation (96316), or decreased appetite (62345,62792). Often these symptoms occur during the first few days of treatment and subside after a few days (62804). In some cases, rates of symptoms are similar between melatonin and placebo (96316). Less often, melatonin has been reported to cause abnormal feces (62450), odd taste in the mouth (1070), pouchitis (114510), or reflux esophagitis (1745) when used orally. A case of exacerbated symptoms of Crohn disease, including increased diarrhea and abdominal cramps, has been reported for a patient who took oral melatonin 3 mg at bedtime for 4 days. Symptoms resolved within 24 hours of melatonin treatment cessation (62218).
Genitourinary ...Orally, melatonin may increase enuresis in adults and children (58685,62450,62710,62770,62804,62804,62811). In perimenopausal adults, melatonin has caused a resumption of spotting or menstrual flow (11806). Decreased libido has been noted for one patient treated with melatonin 3 mg daily for 8 weeks (15216).
Hematologic ...A case of nose bleed has been reported with oral melatonin (62450). Some melatonin preparations contain contaminants that are associated with eosinophilia-myalgia syndrome (9715,9716).
Hepatic ...A case of autoimmune hepatitis has been reported for a patient who took melatonin orally to treat insomnia (63037). Melatonin use has also been linked to a few cases of Gilbert's syndrome (114510).
Musculoskeletal
...Orally, melatonin might increase fall risk.
Analysis of a large adverse event database suggests that the rate of accidents and falls is higher with melatonin use when compared with the average rate of all other medications combined. However, the rate of accidents and falls with melatonin use seems to be lower when compared with other sleep medications (114510). Other clinical evidence shows that a single dose of melatonin 3 mg may increase fall risk due to increased postural swaying while standing on one or both feet in healthy adults ages 60-71 years (97442).
A single case of ataxia has been reported for an 81-year-old female who used melatonin for 4 days (9181). Weakened muscle power has been reported for two patients treated with melatonin 5 mg in the evening (62456). Some melatonin preparations contain contaminants that are associated with eosinophilia-myalgia syndrome (9715,9716). There are also reports of back pain, dropped head syndrome, fractures, growth retardation, and myalgia associated with melatonin intake (114510).
Neurologic/CNS
...Orally, melatonin may cause migraine-like headache (1070,1077,15034,62384,62450,62710,62754,62804,62792,62914,88288,88293,88294,96318)(106297,114510) or dizziness (62345,62384,62450,62456,62770,62784,62792,62804,62811,89510)(110297).
Often these symptoms occur during the first few days of treatment and subside after a few days (62804). Melatonin may also cause drowsiness or fatigue when taken orally (1077,8273,15216,62384,62456,62784,62804,62811,88288,89510,96314,96316,96318,97446)(106293,106297,114510). These symptoms appear to be more common if melatonin is taken in the morning or at very high doses (greater than 50 mg) (8269,62874). A case of excessive drowsiness has been reported when melatonin was combined with citalopram, nortriptyline, and oxycodone. Sedation improved with discontinuation of melatonin (96315). Indiscriminate use of melatonin may cause irregular sleep-wake cycles to occur (62998). Less commonly, melatonin may also cause behavior worsening (62811), confusion or disorientation (63014,63067), nighttime awakening (62710,62811), mood swings or agitation (96318), stereotypy (96318), tic (114510), excitement before bedtime (62811), insomnia (114510), nightmares or more intense dreams (62401,62462,62780,62784,88283,114510), feelings of a "rocking" sensation (62155), or reduced alertness when taken orally.
A case of generalized epilepsy has reportedly occurred after treatment with melatonin for 4 months (9708). Also, some case reports raise concerns about increased risk of seizure with melatonin treatment, but conflicting evidence suggests that melatonin may decrease the risk of seizures (1699,8248,9695,9697,9744,9746,62123,62256,62384,62754)(63070,63071,89431). One patient experienced hyponatremia with confusion and seizures after taking prolonged-release melatonin 2 mg. However, malnutrition and cannabis abuse were also thought to contribute to this reaction (96321).
Although there is concern that melatonin might affect cognitive function in healthy adults, research in humans suggests that oral or topical melatonin do not impact most measures of cognitive function (97442,97448).
Ocular/Otic ...There are six case reports of pupillary disorder associated with melatonin intake (114510).
Psychiatric
...Orally, melatonin may cause mood changes, including dysphoria (sadness) (1764), dips in mood (62345,62450,62792), nervousness (62784), suicide or self-injury (114510), or transient depression (1077).
Delusions and hallucinations have also been reported in clinical research (62347). An analysis of adverse event case reports indicates that drug abuse, dependence, and withdrawal have been associated with melatonin use; however, the rate appears to be lower when compared with all other medications combined or sleep medications (114510).
This analysis also suggests that melatonin use might be associated with educational problems, social behavior disturbances, defiant behavior, oppositional defiant disorder, and school refusal at disproportionately higher rates when compared with all other drugs combined or other sleep medications (114510). An isolated incident of aggressiveness was also noted in a child diagnosed with attention deficit-hyperactivity disorder (ADHD) who took melatonin in combination with methylphenidate (9980). Severe irritability has been reported in two children with autism spectrum disorder who had abruptly discontinued melatonin due to the completion of a clinical trial (106293).
Other ...There are case reports of body temperature fluctuation and post viral fatigue syndrome associated with melatonin intake (114510).
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).
