Uterine Balance by Eclectic Institute

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Asthma. Although there has been interest in using oral black haw for asthma, there is insufficient reliable information about the clinical effects of black haw for this purpose.
• Diarrhea. Although there has been interest in using oral black haw for diarrhea, there is insufficient reliable information about the clinical effects of black haw for this purpose.
• Dysmenorrhea. Although there has been interest in using oral black haw for dysmenorrhea, there is insufficient reliable information about the clinical effects of black haw for this purpose.
• Miscarriage. Although there has been interest in using oral black haw for miscarriage, there is insufficient reliable information about the clinical effects of black haw for this purpose. More evidence is needed to rate black haw for these uses

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POSSIBLY EFFECTIVE

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

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Diabetes. Although there has been interest in using oral Viburnum opulus for diabetes, there is insufficient reliable information about the clinical effects of Viburnum opulus for this purpose.
• Dysmenorrhea. Although there has been interest in using oral Viburnum opulus for dysmenorrhea, there is insufficient reliable information about the clinical effects of Viburnum opulus for this purpose.
• Kidney stones (nephrolithiasis). It is unclear if oral Viburnum opulus extract is beneficial in patients with kidney stones. Details: One small observational study in patients with distal ureteral stones has found that taking Viburnum opulus extract 3000 mg twice daily for 4 weeks increases the relative rate of stone expulsion by 24%, reduces the time to stone expulsion by 5 days, and decreases the need for analgesics when compared with no treatment (103879). Clinical research has compared Viburnum opulus with tamsulosin. In patients with distal ureteral stones taking diclofenac as needed, taking Viburnum opulus 3000 mg twice daily for 4 weeks is at least as effective as taking tamsulosin 0.4 mg daily for the rate of stone expulsion and time to complete expulsion. Taking Viburnum opulus reduced the number of patients requiring diclofenac by 43% and emergency admission by 67% (110883).
• Muscle cramps. Although there has been interest in using oral Viburnum opulus for muscle cramps, there is insufficient reliable information about the clinical effects of Viburnum opulus for this purpose.
• Pregnancy-related leg cramps. Although there has been interest in using oral Viburnum opulus for pregnancy-related leg cramps, there is insufficient reliable information about the clinical effects of Viburnum opulus for this purpose. More evidence is needed to rate Viburnum opulus for these uses.

(Read more about VIBURNUM OPULUS)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Atopic dermatitis (eczema). Although there is interest in using topical yarrow for atopic dermatitis, there is insufficient reliable information about the clinical effects of yarrow for this condition.
• Dysmenorrhea. It is unclear of oral yarrow tea is beneficial for improving symptoms of dysmenorrhea. Details: Preliminary clinical research in patients with moderate to severe dysmenorrhea shows that drinking a tea made with yarrow 4 grams three times daily for the first three days of two menstrual cycles modestly reduces dysmenorrhea pain when compared with a placebo tea (105361).
• Gingivitis. A mouthwash containing yarrow has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that using a mouthwash containing a combination of yarrow, juniper, and stinging nettle for 3 months does not improve dental plaque or gingivitis in patients with gingival inflammation when compared with a control group (76443).
• Irritable bowel syndrome (IBS). Oral yarrow has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with mild to moderate IBS shows that taking a capsule containing yarrow, ginger, and Boswellia serrata three times daily for 30 days improves pain by 46% and gastrointestinal symptoms by 60% when compared with placebo. Patients also experienced an improvement in overall mood when compared with placebo (96673). It is not clear if these effects are due to yarrow, the other ingredients, or the combination.
• Multiple sclerosis (MS). It is unclear if oral yarrow is beneficial for patients with MS. Details: A small clinical study in adults with relapsing-remitting MS shows that taking yarrow whole plant extract 250 mg or 500 mg daily in conjunction with conventional treatments for 12 months reduces the annual relapse rate and increases time to first relapse when compared with placebo. Taking yarrow 500 mg daily also reduced disability scores and improved functional scores when compared with either yarrow 250 mg daily or placebo (100346). However, most of the patients enrolled in the study were under 40 years of age, with undefined disease severity.
• Nipple fissures. It is unclear if topical yarrow is beneficial for patients with nipple fissures. Details: Preliminary clinical research in patients with inflamed nipples and/or nipple fissures shows that topical application with yarrow twice daily after breastfeeding for 7 days reduces redness and pain when compared with baseline. Yarrow 30 grams was boiled in 1 liter of water for 10 minutes. The benefits seen with yarrow were not significantly different from topical mountain honey or breast milk, both of which were also beneficial when compared with baseline (105359).
• Oral mucositis. It is unclear if gargling with yarrow is beneficial for oral mucositis. Details: Preliminary clinical research in patients with chemotherapy-induced oral mucositis shows that gargling with 15 mL of a routine solution containing yarrow distillate 50%, 4 times daily for 14 days, reduces symptom severity by 87%, compared with a worsening in severity in those using the routine solution alone. Of those using yarrow, all patients were able to eat solid foods at 14 days compared with about 40% of those using routine treatment alone. About 3.75 grams of yarrow flower was needed for each 7.5 mL of distillate and the solution was held for 3 minutes in the mouth before gargling (106664). It is unclear if the patients were adequately blinded, as the taste of the two solutions may have differed.
• Tonsillitis. Oral yarrow has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in children 6-18 years of age with acute non-bacterial tonsillitis shows that taking a specific combination product (Imupret, Bionorica AG) containing yarrow and six other herbal ingredients along with standard care reduces the severity of tonsillitis symptoms when compared with standard care alone. Additionally, taking this combination product improved physician- and patient-rated assessments of general condition when compared with standard care alone (100347). It is not clear if these effects are due to yarrow, other ingredients, or the combination.
• Vaginal candidiasis. It is unclear if intravaginal yarrow is beneficial for vaginal candidiasis. Details: Clinical research in patients with vulvovaginal candidiasis shows that intravaginal application of 5 grams of a cream containing yarrow extract 2% for 7 days modestly reduces Candida growth and improves vulvar erythema and other general symptoms when compared with baseline. However, the cream was less effective overall than vaginal clotrimazole 1% cream (105360).
• Wound healing. It is unclear if topical yarrow is beneficial for wound healing. Details: Clinical research in postpartum adults who have had an episiotomy shows that applying approximately 1 cm of an ointment containing yarrow 5% over the clean and dried suture area twice daily for ten days reduces perineal pain, redness, and edema 1-2 weeks after the procedure when compared with placebo ointment or no treatment. However, using the yarrow ointment did not affect discharge time or reduce the occurrence of dehiscence (96910). More evidence is needed to rate yarrow for these uses.

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LIKELY SAFE ...when the stem bark is used orally in amounts commonly found in foods. Black haw has Generally Recognized As Safe status (GRAS) for use in foods in the US (4912).

POSSIBLY SAFE ...when the root bark is used orally and appropriately in medicinal amounts (12).

PREGNANCY: POSSIBLY UNSAFE
when used orally. Some evidence suggests black haw has uterine relaxant effects (11); avoid using.

LACTATION:
Insufficient reliable information available.

(Read more about BLACK HAW)

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

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

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

(Read more about KAVA)

There is insufficient reliable information available about the safety of Viburnum opulus.

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

(Read more about VIBURNUM OPULUS)

LIKELY SAFE ...when used orally in amounts commonly found in foods. Yarrow products that are thujone-free have Generally Recognized As Safe (GRAS) status for use in foods in the US (4912); however, products containing thujone might not be safe. Thujone is a chemical that stimulates the central nervous system and is poisonous in large doses.

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts (2,12,100346). Yarrow whole plant extract has been used with apparent safety at a dose of 250-500 mg daily for 12 months (100346). ...when used intravaginally as a cream containing yarrow extract 2% daily for 7 days (105360). There is insufficient reliable information available about the safety of yarrow when applied topically.

PREGNANCY: LIKELY UNSAFE
when used orally; yarrow is believed to be an abortifacient and affect the menstrual cycle (12).

LACTATION:
Insufficient reliable information available; avoid use.

(Read more about YARROW)

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ALCOHOL (ETHANOL) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = A Combining kava with alcohol may increase the risk of sedation and/or hepatotoxicity.  Details Kava has CNS depressant effects (11373,18316). Concomitant use of kava with other CNS depressants can increase the risk of drowsiness and motor reflex depression (2093,2098). Additionally, kava has been associated with over 100 cases of hepatotoxicity. There is some concern that kava can adversely affect the liver, especially when used in combination with hepatotoxic drugs (7024,7068,7086,7096,17086,57346). Clinical practice guidelines from a joint taskforce of the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Treatments (CANMAT) recommend that alcohol not be used with kava (110318).

CNS DEPRESSANTS Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = A Combining kava with CNS depressants can have additive sedative effects.  Details Kava has CNS depressant effects (11373,18316). Concomitant use of kava with other CNS depressants can increase the risk of drowsiness and motor reflex depression (2093,2098). Clinical practice guidelines from a joint taskforce of the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Treatments (CANMAT) recommend that CNS depressants, including alcohol and benzodiazepines, not be used with kava (110318).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B It is unclear if kava inhibits CYP1A2; research is conflicting.  Details Although in vitro research and a case report suggest that kava inhibits CYP1A2 (8743,12479,88593), more robust clinical evidence shows that kava has no effect on CYP1A2. In a clinical study in healthy volunteers, taking kava 1000 mg twice daily (containing a daily dose of 138 mg kavalactones) for 28 days had no effect on CYP1A2 activity (13536,98979).

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, kava might increase levels of CYP2C19 substrates.  Details In vitro research shows that kava significantly inhibits CYP2C19 enzymes (8743,12479). This effect has not yet been reported in humans.

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, kava might increase levels of CYP2C9 substrates.  Details In vitro research shows that kava significantly inhibits CYP2C9 enzymes (8743,12479). This effect has not yet been reported in humans.

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B It is unclear if kava inhibits CYP1A2; research is conflicting.  Details In vitro research shows that kava extract significantly inhibits CYP2D6 (8743,12479). However, clinical research shows that kava does not affect the metabolism of CYP2D6 substrates in humans (13536,16848,98979).

CYTOCHROME P450 2E1 (CYP2E1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Kava might increase levels of CYP2E1 substrates.  Details In a clinical study in healthy volunteers, taking kava 1000 mg twice daily (containing a daily dose of 138 mg kavalactones) for 28 days inhibited the metabolism of CYP2E1 substrates (13536).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B It is unclear if kava inhibits CYP3AA; research is conflicting.  Details Although in vitro research suggests that kava inhibits CYP3A4 (8743,12479), more robust clinical evidence shows that kava has no effect on CYP3A4. In a clinical study in healthy volunteers, taking kava 1000 mg twice daily (containing a daily dose of 138 mg kavalactones) for 28 days had no effect on CYP3A4 activity (13536,98979).

HALOPERIDOL (Haldol) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Combining kava and haloperidol might increase the risk of cardiovascular adverse effects and hypoxia.  Details Atrial flutter and hypoxia has been reported for a patient who received intramuscular injections of haloperidol and lorazepam after using kava orally. The side effects were attributed to kava-induced inhibition of CYP2D6, but might also have been related to additive adverse effects with the concomitant use of haloperidol, lorazepam, and kava (88593).

HEPATOTOXIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, using kava with hepatotoxic drugs might increase the risk of liver damage.  Details Kava has been linked with over 100 cases of hepatotoxicity. Most cases occur with excessive and prolonged use. There is some concern that kava can adversely affect the liver, especially when used in combination with hepatotoxic drugs (7024,7068,7086,7096,17086,57346).

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D It is unclear if kava inhibits P-glycoprotein (P-gp); research is conflicting.  Details In vitro research shows that kava can inhibit P-gp efflux (15131). However, a clinical study in healthy volunteers shows that taking kava standardized to provide 225 mg kavalactones daily for 14 days does not affect the pharmacokinetics of digoxin, a P-gp substrate (15132,98979). It is possible that the use of other P-gp substrates or higher doses of kava might still inhibit P-gp.

ROPINIROLE (Requip) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Taking kava with ropinirole might increase the risk for dopaminergic toxicity.  Details A case of visual hallucinations and paranoid delusions has been reported for a patient who used kava in combination with ropinirole. The adverse effects were attributed to kava-induced inhibition of CYP1A2, which may have reduced the metabolism of ropinirole, resulting in excessive dopaminergic stimulation (88593).

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LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, taking yarrow with lithium might increase the levels and adverse effects of lithium.  Details Animal research shows that yarrow has diuretic activity (106018). Theoretically, due to these potential diuretic effects, yarrow might reduce excretion and increase levels of lithium. The dose of lithium might need to be decreased.

(Read more about YARROW)

General ...No adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.

(Read more about BLACK HAW)

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

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

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

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

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

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

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

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

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

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

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

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

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

(Read more about KAVA)

General ...No adverse effects have been reported; however, a thorough evaluation of safety outcomes has not been conducted.

(Read more about VIBURNUM OPULUS)

General ...Orally and intravaginally, yarrow seems to be well tolerated.
Most Common Adverse Effects:
Topically: Dermatitis.

Dermatologic ...Topically, yarrow can cause atopic or allergic dermatitis or urticaria due to its sesquiterpene lactone content (52558,68385,77007). Yarrow has also been reported to cause phototoxic and photo-allergic dermatitis and airborne contact dermatitis (68385).
Intravaginally, aggravated facial acne was reported by 1 of 40 patients in a clinical trial (105360).

Endocrine ...Intravaginally, an early menses was reported by 1 of 40 patients in a clinical trial (105360).

Genitourinary ...Intravaginally, aggravated vaginal pruritus and dryness were reported by 1 of 40 patients in a clinical trial (105360).

Immunologic ...Topically, yarrow can cause atopic or allergic dermatitis or urticaria due to its sesquiterpene lactone content (52558,68385,77007,96911). It has also been reported to cause phototoxic and photo-allergic dermatitis and airborne contact dermatitis (68385). In one 44-year-old female, handling yarrow flowers resulted in rhinitis and asthma (96911).

(Read more about YARROW)