Nervinat by Les Laboratoires du Saint-Laurent E.H. Ltee

There is insufficient reliable information available about the effectiveness of linden.

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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.
• 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.
• Insomnia. Small clinical studies suggest that oral passion flower may modestly improve sleep quality in patients with insomnia and poor sleep quality. Details: Some preliminary clinical research 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). Another 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).
• 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. Oral passion flower has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: 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.

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POSSIBLY EFFECTIVE

• Insomnia. Most research shows that taking valerian whole root extract 300-600 mg daily modestly improves subjective sleep quality, although it might take up to 4 weeks to provide benefit. Valerian does not seem to improve sleep latency, sleep duration, or insomnia severity. Details: Although there is a great deal of conflicting research, overall, taking valerian 300-600 mg before bedtime seems to improve sleep quality when compared with placebo. In contrast, no consistent benefit has been seen for sleep latency, sleep duration, or insomnia severity (15046,17577,19406,19409,104010). Older meta-analyses show that valerian root improves sleep quality regardless of its formulation. However, the most recent meta-analysis shows that valerian whole root extract improves sleep quality, while it's unclear whether an unspecified valerian extract is effective (17577,19406,104010). These analyses are limited by significant heterogeneity in valerian dosage and formulation, treatment duration, and included patient populations. Some experts claim that valerian does not work acutely for sleep, and it can take up to 4 weeks for a benefit to be seen (10209,104010). Indeed, most short-term studies assessing valerian as a single dose, or used daily for up to one week, show no benefit for sleep quality when compared with placebo (19407,19408,19411,19414). However, a meta-analysis of studies lasting 4 weeks or longer also did not find a consistent benefit (104010). The benefits of valerian for sleep might vary in different patient populations. A large post-marketing surveillance study in children with restlessness or dyssomnia under the age of 12 has found that taking a specific combination product (Euvegal Forte, Dr. Willmar Schwabe Pharmaceuticals) containing valerian root extract 160 mg and lemon balm extract 80 mg 1-2 tablets once or twice daily is associated with moderate sleep improvement (14416). Also, one clinical study in postmenopausal adults shows that taking valerian root extract 530 mg (Sadamine) twice daily for 28 days moderately improves sleep quality when compared with placebo (19425). Another clinical study in patients undergoing treatment for cancer shows that taking valerian 450 mg 1 hour before bedtime for 8 weeks does not improve objective sleep measures, but might improve subjective sleep ratings and mood, when compared with placebo (19424). Small clinical studies in adults on hemodialysis show that taking valerian 530 mg before bedtime for 1 month improves sleep quality when compared with baseline or placebo. (105718,110712). In one of these studies, improvements in sleep quality were similar when compared with gabapentin (110712). Research also shows that taking specific combination products containing valerian and other ingredients can improve sleep quality. These combination products have combined valerian with hops; lemon balm (Euvegal Forte); lemon balm and hops (Valerina Natt); or passionflower and hops (NSF-3, M/s Tablets India) (10423,15018,19413,19417,19418,19419,88193,89408). Finally, limited research has compared valerian to benzodiazepines. A small clinical study in patients with non-organic insomnia shows that taking valerian extract (LI 156, Sedonium) 600 mg daily for 6 weeks seems to be no different for improving sleep quality when compared with taking low-dose oxazepam 10 mg (19416). Valerian might also improve sleep quality in patients who are resistant to chronic benzodiazepine therapy. In one small study, after tapering the benzodiazepine over two weeks, valerian extract 100 mg three times daily for 15 days improves sleep quality when compared with placebo (8006).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Anxiety. It is unclear if valerian is beneficial for anxiety. Details: Meta-analyses of heterogeneous clinical research show that there is insufficient and contradictory evidence on the use of valerian root for anxiety (104010,110711). However, one analysis suggests that using whole root preparations seems to have greater efficacy than valerian extracts (104010). These meta-analyses are limited by significant heterogeneity in valerian dosage and formulation, treatment duration, and patient populations and concerns related to publication bias (104010,110711). One small clinical study in patients with generalized anxiety disorder (GAD) shows that taking valerian extract containing 81.3 mg valepotriates daily for 4 weeks is no different for reducing anxiety scores when compared with diazepam 6.5 mg or placebo (9896). This study was not adequately powered to detect a difference between groups. Also, a small, quasi-randomized trial in adults with poor sleep quality who are undergoing hemodialysis shows that taking a specific valerian root product (Sedamin, Goldaru Company) 530 mg daily for 1 month improves anxiety scores by 2-3.9 times when compared with placebo. However, not all patients reported anxiety at baseline (105718). In contrast, a small clinical study in healthy adults shows that taking a combination of herbal extracts containing valerian root, passionflower, ballota, and hawthorn (Euphytose) daily for 14 days reduces subjective anxiety and objective 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.
• Delirium. Oral valerian has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adult intensive care unit (ICU) patients with agitation and delirium receiving quetiapine 50-200 mg every 12 hours shows that taking 5 mL of syrup containing valerian root 625 mg and an extract of lemon balm leaf 50 mg every 12 hours improves agitation from baseline similarly to placebo. It is unclear if the improvement from baseline differed between groups (106627).
• Depression. It is unclear if valerian is beneficial in patients with depression. Details: A retrospective case series in patients with mild to moderate depression and reports of anxiety has found that taking high-dose valerian 1000 mg with St. John's wort is associated with more rapidly improved depressive symptoms than low-dose valerian 500 mg with St. John's wort (19402). The validity of this study is limited by its retrospective nature and small size. Also, it is unclear if this effect is due to valerian, St. John's wort, or the combination. One small, quasi-randomized trial in adults with poor sleep quality who are undergoing hemodialysis shows that taking a specific valerian root product (Sedamin, Goldaru Company) 530 mg daily for 1 month improves depression scores by 2-3.9 times when compared with placebo. However, not all patients reported depression at baseline (105718).
• Dysmenorrhea. One small study suggests that oral valerian may reduce symptoms of dysmenorrhea. Details: A small clinical study shows that taking powdered valerian root 255 mg three times daily for two menstrual cycles reduces pain severity associated with menstruation when compared with placebo (19342).
• Menopausal symptoms. Two small studies suggest that oral valerian may reduce hot flashes. Details: Two small clinical studies in postmenopausal adults show that taking valerian root (Zardband or Goldaroo Co.) 225 mg three times daily or 530 mg twice daily for 2 months moderately reduces hot flash frequency and severity when compared with placebo (89407,96243). Both studies were conducted in Iran, so it is unclear if these results are generalizable to other geographic locations.
• Premenstrual syndrome (PMS). One small study suggests that oral valerian may reduce PMS symptoms. Details: A small clinical study in young adults with PMS shows that taking valerian root extract (Goldaroo Co.) 530 mg twice daily on the last 7 days of the menstrual cycle for 3 cycles moderately reduces the severity of self-reported PMS symptoms when compared with placebo (96239).
• Pre-procedural anxiety. One small study suggests that oral valerian may reduce anxiety during wisdom tooth extraction. Details: A small crossover clinical study in patients undergoing impacted mandibular molar extraction shows that taking valerian extract (Dermatologica Ltda.) 100 mg one hour prior to the extraction reduces physiological responses to anxiety to a satisfactory but lesser degree than midazolam 15 mg. Patients expressed no clear preference for either valerian or midazolam for reducing perioperative anxiety (102242). The validity of these findings is limited by the use of subjective outcome measures.
• Restless legs syndrome (RLS). It is unclear if oral valerian is beneficial in patients with RLS. Details: A small clinical study in patients with RLS shows that taking valerian (Pharmavite, LLC) 800 mg daily for 8 weeks does not improve RLS symptoms or sleep latency when compared with placebo (19422). However, this study was not adequately powered to detect a difference in RLS symptoms between groups. Conversely, another small clinical study in adults with RLS on hemodialysis shows that taking valerian 530 mg nightly before bed for 1 month reduces symptoms of RLS when compared to baseline; however, valerian's effects were weaker when compared with gabapentin 100 mg nightly (110712). The validity of this study is limited by a lack of a placebo group and a small sample size.
• Stress. Two small studies suggest that oral valerian may reduce the stress response in healthy adults who are performing a stressful mental task or a verbal presentation. Details: Two small clinical studies in healthy volunteers shows that taking valerian 100 mg once or 600 mg daily for 7 days prior to participating in a mental stress task or public verbal test reduces physiologic responses to stress and feelings of anxiety when compared to baseline (9893,9895). The validity of these findings is limited by the lack of statistical comparison to the control group. Another small study in healthy volunteers shows that taking a specific combination product containing valerian 360 mg and lemon balm 240 mg (Songha Night, Pharmaton Natural Health Products) reduces anxiety associated with laboratory-induced stress. However increasing the dose to valerian 1080 mg and lemon balm 720 mg seems to increase anxiety (19405).
• Tension headache. One small study suggests that oral valerian may reduce tension headache. Details: A small clinical study in patients with frequent tension headaches shows that taking valerian root extract (Sedamin, Goldaru Pharmaceutical Company) 1060 mg daily after dinner for one month modestly reduces headache severity and disability when compared with placebo (103221). More evidence is needed to rate valerian for these uses.

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LIKELY SAFE ...when linden leaf is used orally and appropriately in amounts normally found in foods (12). Linden leaf has Generally Recognized as Safe (GRAS) status in the US (4912). There is insufficient reliable information available about the safety of linden when used orally or topically in medicinal amounts.

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

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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.

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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.

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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.

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ALCOHOL (Ethanol) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B 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).

ALPRAZOLAM (Xanax) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B 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.

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Valerian can have additive sedative effects when used concomitantly with CNS depressant drugs.  Details Theoretically, concomitant use of valerian and drugs with sedative and anesthetic properties may cause additive therapeutic and adverse effects (3486,12720,19429).

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Unlikely •  Level of Evidence = B 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).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B 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.

GLUCURONIDATED DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D 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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General ...There is limited information about the adverse effects of linden. Orally, there is one case report of allergic reaction to linden pollen in a linden flower tea (12). Frequent consumption of linden tea is thought to be associated with cardiac damage, but this seems to be rare (6).
Topically, linden extract can cause contact urticaria (12).

Cardiovascular ...Frequent consumption of linden tea is thought to be associated with cardiac damage, but this seems to be rare (6).

Immunologic ...Orally, there is one case report of allergic reaction to linden pollen in a linden flower tea (12). Topically, there is one case report of contact urticaria following the use of a linden extract-containing shampoo (12).

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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).

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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).

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