St. John's Wort
Scientific Name(s): Hypericum perforatum L. Family: Hypericaceae
Common Name(s): St. John's wort , klamath weed , John's wort , amber touch-and-heal , goatweed , rosin rose , and millepertuis
Clinical Overview
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Uses of St. John's Wort
St. John's wort has been studied primarily for its potential antidepressant and antiviral effects. Information supports St. John's wort's effectiveness in treating mild to moderate depression compared with placebo, but evidence is still lacking regarding its efficacy compared with standard antidepressants, partially because of poor clinical trial design and inadequate standardization.
St. John's Wort Dosing
Traditional use of the St. John's wort herb indicated 2 to 4 g/day doses. However, most clinical studies have been conducted with extracts, with the hypericin content of 0.3% as the earliest form of standardization. With the discovery of hyperforin's bioactivity, a content of 3% to 5% hyperforin has been used as a new standard. Some of the many products include LI 160 (Lichtwer, 0.3% hypericin), Kira (Lichtwer, 300 mcg hypericin in 125 to 225 mg extract tablets), Hyperiforce (Bioforce, 0.33 mg hypericin in 60 mg extract/tablet), Ze 117 , WS 5573 (300 mg extract, 0.5% hyperforin), WS 5572 (300 mg, 5% hyperforin), STEI 300 (Steiner, 0.2% to 0.3% hypericin and 2% to 3% hyperforin), Psychotonin , Esbericum , Neuroplant , Sedariston , and Hyperforat . Doses of the extracts have ranged from 500 to 1,800 mg/day.
Contraindications
Concomitant use with HIV protease inhibitors, HIV nonnucleoside reverse transcriptase inhibitors, cyclosporine, tacrolimus, irinotecan, and imatinib mesylate.
Pregnancy/Lactation
Avoid use. No systematic information is available about the effects of hypericum.
St. John's Wort Interactions
St. John's wort increases the hepatic metabolism of alprazolam, erlotinib, indinavir, midazolam, nevirapine, nifedipine, omeprazole, oral contraceptives, simvastatin, tacrolimus, theophylline, verapamil, and warfarin, decreasing plasma concentrations of these drugs. Because St. John's wort induces intestinal P-glycoprotein, as well as intestinal (CYP3A4) and hepatic (CYP 1A2, 2C9, and 3A4) metabolism, plasma concentrations of amitriptyline, cyclosporine, digoxin, fexofenadine, methadone, nortriptyline, and sirolimus may be decreased. St. John's wort also has been implicated in additive serotonin reuptake inhibition of nefazodone and sertraline, altering the metabolism of irinotecan and increasing the sedative-hypnotic effects of paroxetine. Emergence from anesthesia may be delayed in patients who receive propofol or sevoflurane while taking St. John's wort. Carbamazepine and cimetidine may increase plasma concentrations of components of St. John's wort extracts (eg, hypericin). Patients should be cautioned that St. John's wort may interact with numerous medications and to consult their health care provider before taking St. John's wort with prescription or nonprescription drugs.
St. John's Wort Adverse Reactions
Side effects are usually mild. Potential adverse reactions include dry mouth, dizziness, constipation, other GI symptoms, and confusion. Photosensitization also may occur. In clinical trials, side effects and medication discontinuation with St. John's wort were usually less than those observed with standard antidepressants. Other possible rare side effects include induction of mania and effects on male and female reproductive capabilities.
Toxicology
St. John's wort should be avoided during pregnancy and lactation.
Botany
St. John's wort is a perennial plant native to Europe but now also found throughout the US and parts of Canada. It is an aggressive weed that grows in the dry ground of roadsides, meadows, woods, and hedges. It generally grows to a height of 0.3 to 0.61 m, except on the Pacific coast where it has been known to reach heights of 1.5 m. 1 The plant has oval-shaped leaves and yields golden-yellow flowers that bloom from June to September, with petals containing black or yellow glandular dots and lines. There are approximately 370 species in the genus Hypericum , which is derived from the Greek words hyper and eikon meaning “over an apparition,” alluding to the plant's ancient use to ward off evil spirits. Perforatum refers to the leaf's appearance; when held up to light, the translucent leaf glands resemble perforations. 2 , 3 Harvest of the plant for medicinal purposes must occur in July and August, and it must be dried immediately to avoid loss of potency. 4 The dried herb consists of the plant's flowering tops. 2
History
St. John's wort has been used as an herbal remedy for its anti-inflammatory and healing properties since the Middle Ages. 4 Many noteworthy ancient herbalists, including Hippocrates and Pliny, recorded the medicinal properties of St. John's wort. It was noted for its wound healing and diuretic properties as well as for the treatment of neuralgic conditions, such as back pain. In 1633, Gerard's Herbal recorded the plant's use as a balm for burns and its oil was also popularly used during this time. 2 An olive oil extract of the fresh flowers, which acquires a reddish color after standing in the sunlight for several weeks, has been taken internally for the treatment of anxiety but also has been applied externally to relieve inflammation and promote healing. Topical application was believed to be particularly useful in the management of hemorrhoids.
Although it fell into disuse, a renewed interest in St. John's wort occurred during the past decade, and it is now a component of numerous herbal preparations for the treatment of anxiety and depression. The plant has been used in traditional medicine as an antidepressant and diuretic and for the treatment of gastritis and insomnia. Since 1995, St. John's wort has become the most prescribed antidepressant in Germany.
Chemistry
Several reports regarding the chemical components in St. John's wort are available. 5 , 6 , 7 The most commonly described constituents are naphthodianthrones, flavonoids, phloroglucinols, and essential oils. Naphthodianthrones occur in St. John's wort in concentrations of less than 0.1% to 0.15%. The anthraquinone derivatives hypericin and pseudohypericin (also emodin-anthranol and cyclo-pseudohypericin) are the best known components of the plant. Isohypericin and protohypericin are also present. The reddish dianthrone pigment hypericin (hypericum red) is found in a concentration ranging from 0.02% to 2.5%, depending on harvesting period, drying process, and storage. 4 , 8 Hypericin content also varies widely among growing regions and concentration varies among plant parts: Flowers, buds, top leaves, and secondary stems yield the highest amount. 2 Microscopic evaluation finds hypericin to accumulate in secretory cell globules within these plant structures. 9 Numerous reports concerning high-performance liquid chromatography analysis of hypericin in St. John's wort exist. 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 Liposoluble pigments from the plant, including hypericin, carotenoids, and chlorophylls, also have been reported. 18 Flavonoid concentrations in St. John's wort occur at less than 12% in flowers and approximately 7% in leaves/stalks 2 and include kaempferol, quercetin, quercitrin, isoquercitrin, amentoflavone, luteolin, myricetin, hyperin, hyperoside, and rutin. 2 , 4 , 8 Other flavonoids found are miquelianin and astilbin. 19 The proanthocyanidins (approximately 12% of aerial parts) are certain forms of catechin and epicatechin. 2 Hyperforin and adhyperforin are in the phloroglucinol class of compounds. 2 , 3 , 20 Hyperforin appears in St. John's wort in concentrations of 2% to 4%, and its isolation, purity, and stability have been reported. 21 The recovery of hyperforin in plasma has been measured. 22 The related structure furohyperforin, an oxygenated analog of hyperforin, has been isolated from the plant, 23 as have other hyperforin analogs. 24
The essential oil component of St. John's wort is reported to be between 0.05% and 0.9%. 2 , 3 It consists of mono- and sesquiterpenes, mainly 2-methyl-octane (16% to more than 30%), n-nonane, alpha- and beta-pinene, alpha-terpineol, geraniol, and traces of myrecene, limonene, caryophyllene, and others. 2 , 4 , 8
Other compounds present in St. John's wort include xanthones (1.28 mg/100 g) and tannins (3% to 16%). One study reports that tannin content in extracts is influenced by parameters such as temperature of maceration. 25 Phenol constituents include caffeic, chlorogenic, p-coumaric acids, and hyperfolin. Other plant constituents include acids (eg, nicotinic, myristic, palmitic, stearic), carotenoids, choline, pectin, hydrocarbons, and long-chain alcohols. Amino acids include cysteine, gamma-aminobutyric acid (GABA), glutamine, leucine, lysine, and others. 2 , 3 , 4 , 8
Because St. John's wort products are classified as dietary supplements, they are not regulated by the FDA. 26 Several reports evaluating commercial preparations of St. John's wort have found inconsistencies in active ingredients, such as variations from 47% to 165% of labeled hypericin concentrations, 27 different concentrations of major components among brands, 28 and marked deviations in hyperforin (and adhyperforin) amounts in certain St. John's wort preparations. 29 Several reports are available addressing these issues, with various proposed standardization methods. 30 , 31 , 32 , 33
St. John's Wort Uses and Pharmacology
DepressionEarly research focused on the hypericin constituents in St. John's wort. Originally, hypericin was thought to exert its tranquilizing effect by increasing capillary blood flow. Later studies in rats found hypericin to be a strong inhibitor of the enzyme monoamine oxidase (MAO). 34 However, in the mid-1990s, 2 studies examined H. perforatum fractions in vitro and ex vivo and reported no evidence of any relevant MAO inhibition, concluding that St. John's wort's antidepressant effects cannot be explained by this mechanism alone. 35 , 36
Many reports have postulated certain mechanisms and behavioral characteristics of H. perforatum , concentrating mostly on hypericin as the active ingredient. Some major findings include the following: inhibition of serotonin uptake by postsynaptic receptors has been confirmed in a number of reports; in rat synaptosomes, H. perforatum caused a 50% inhibition of serotonin uptake; 37 neuroblastoma cells treated with the extract demonstrated reduced expression of serotonin receptors; 38 H. perforatum extract inhibited both serotonin and norepinephrine uptake in astrocytes, the cells surrounding synaptic terminals that regulate neurotransmission by their uptake systems; 39 and H. perforatum also has increased brain dopamine function in humans. 40 St. John's wort extract has been found to modulate interleukin-6 (IL-6) activity, linking the immune system with mood. IL-6 is involved in cell communication within the immune system and in modulating the hypothalamic-pituitary-adrenal (HPA) axis. St. John's wort has the ability to reduce IL-6 levels, thus reducing HPA axis elevations and certain hormones, which if increased, are associated with depression. 36 Sigma receptor binding of hypericin has been demonstrated. 41 H. perforatum does not act as a classical serotonin inhibitor but resembles reserpine's properties. Its antidepressant effects are unlikely to be associated with serotonin, benzodiazepine, or GABA receptors. 42 In addition, H. perforatum differs from selective serotonin reuptake inhibitors (SSRIs) by failing to enhance natural killer cell activity (NKCA). 43 Other hypericin effects on neurotransmitters include inhibition of dopamine-beta-hydroxylase 44 and inhibition of metekephaline and tyrosine dimerization.
Hyperforin is the major lipophilic constituent in the plant and also is a potent inhibitor of serotonin, norepinephrine, and dopamine uptake, increasing concentrations in the synaptic cleft. Some researchers identify it as the major active principle for St. John's wort's efficacy as an antidepressant. 45 , 46 , 47 , 48 Antidepressant activity was found in rodent models given extracts containing hyperforin (less than 39%) but devoid of hypericins. However, hyperforin's spectrum of central activity is affected by other constituents, as proven by alteration of serotonergic effects using different extracts of the plant. 49 , 50 Hyperforin is confirmed to be a major neuroactive component of H. perforatum extracts; modulating neuronal ionic conductances is only one of many mechanisms of action it possesses. 51 Hyperforin inhibits serotonin uptake by elevating free intracellular sodium, an action not seen with conventional SSRIs. 52 In a clinical trial involving 147 patients with mild to moderate depression, subjects given H. perforatum extract containing greater concentrations of hyperforin exhibited the largest Hamilton Depression (HAMD) scale reduction compared with those given lower concentrations or placebo, confirming that the therapeutic effects of St. John's wort depend on its hyperforin content. 53
Animal dataSt. John's wort continues to be of interest because of its antidepressant effects. 54 , 55
Clinical dataReports from 1994 to 1996, including a study using the HAMD scale, concluded that St. John's wort is clinically effective in the treatment of depression, 56 , 57 , 58 rating close to 70% in treatment response. 59 A meta-analysis evaluating 23 randomized trials, including 1,757 mild to moderately depressed patients, was conducted to investigate St. John's wort vs placebo and other conventional antidepressants. St. John's wort was found to be superior to placebo. Side effects occurred in approximately 20% of patients on H. perforatum and 53% of patients on standard antidepressants. 60 Other reviews described similar outcomes; lower doses of standard antidepressants were used. 4 , 56 , 61
More recently, review articles and meta-analyses evaluating H. perforatum 's antidepressant effects have become available, 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 of which the most notable are the following: question and answer format in common language containing tables summarizing clinical trials; 71 a review of clinical studies, most commonly using 300 mg 3 times daily of 0.3% hypericin (600 mg in severe depression); a review of H. perforatum 's equivalence in efficacy to numerous antidepressants with fewer incidences of side effects; 72 meta-analyses of H. perforatum finding a response rate of 60% to 70% (estimate of pooled data) in patients with mild to moderate depression, 73 and its use resulting in 1.5 times the likelihood to observe antidepressant response than placebo, along with equivalence in efficacy to tricyclic antidepressants (TCAs); 74 a clinical trial review confirming greater efficacy vs placebo and equal efficacy to TCAs, MAO inhibitors, and SSRIs, with superior side-effect profile; 68 a review of 20 clinical trials including 1,787 patients, describing similar outcomes; 75 and a broad-based literature search from 1980 to 1998, yielding approximately 1,300 records confirming St. John's wort's increased efficacy over placebo in treating mild to moderate depressive disorders. 76 Evidence also was found that extracts of hypericum are more effective than placebo for the short-term treatment of mild to moderately severe depressive disorders. 77
Some opposing views mention a lack of information regarding long-term effects, use in other depressive states, use of different preparations, 78 and unknown mechanism of action as proof that more definitive data is needed. 79 Mechanisms of action similar to SSRIs or MAO inhibitors are seen in H. perforatum , but its clinical efficacy is probably attributable to the combination of several mechanisms. 80
Literature describing the antidepressant effects of St. John's wort also includes the following: Ongoing confirmation of H. perforatum 's benefits for depression; dose-dependent response rates were seen using 3 different standardized extracts; 81 different population-type trials, including adolescents with psychiatric problems, 82 elderly patients experiencing dementia such as Alzheimer disease, 83 and mild to moderate depression; 84 H. perforatum compared with conventional antidepressant medications was found to have effects similar to the antidepressant properties of TCAs and fluoxetine; 85 St. John's wort extract 800 mg compared with fluoxetine 20 mg was equally effective in approximately 150 depressed elderly patients (however, both groups experiencing adverse reactions); 86 certain dosages of St. John's wort significantly increased latency to rapid-eye movement sleep without affecting other sleep patterns, consistent with other antidepressant mechanisms of action; 87 and seasonal affective disorder (SAD), a type of depression in which symptoms occur in fall/winter and resolve in spring/summer, benefited from St. John's wort, in combination with light therapy. 88 Conclusions about St. John's wort's efficacy in treating depression are difficult to reach due to a few trial limitations. In most of the studies, the antidepressant doses were low, the diagnosis of depression was not uniformly documented, and the trials were of short duration (average, 4 to 6 weeks). In addition, the investigations standardized St. John's wort to hypericin that varied widely among studies, and there is evidence that hyperforin might be the active ingredient, which was not quantified in the trials. 53
Pharmacokinetic studies of hypericin and pseudohypericin performed in humans found that, while similar in structure, they possess substantial pharmacokinetic differences. 89 Single-dose and steady-state pharmacokinetics also have been evaluated. 90 A daily dose of H. perforatum , is 200 to 900 mg of alcohol extract, 5 or 300 mg 3 times daily of a 0.3% hypericin-containing, standardized extract. 71
One meta-analysis, which found that St. John's wort was effective in the treatment of depression, also established a trend toward a decrease in effect size as the number of studies over time increased. 91 Problems of previous studies indicate variability in clinical trial characteristics and small-study effects. Other issues include variability with the active ingredient.
Further investigations of hypericum vs standard antidepressants in well-defined groups of patients over longer observational periods, looking at long-term effects, and making comparisons among different extracts and doses are needed. 77 , 92 Current data is insufficient to recommend hypericum for more severe forms of depression. 77
HIVAlthough hypericin has been shown to have anti-retroviral activity in vitro this has not extended to clinical trials and is limited by the prevalence of interactions with standard HIV therapy.
Animal dataResearch reveals no animal data for the use of St. John's wort for HIV.
Clinical dataOne study found 16 of 18 patients had improved CD4 cell counts over a 40-month period. CD4/CD8 ratios also improved in the majority of patients. Hypericin and pseudohypericin inhibit a variety of encapsulated viruses, including HIV. 2
In late 1996, results from a study of hypericin as an investigational new drug indicated that viral load measured in 12 patients ranged from no change to 97% reduction. 93 However, research was discontinued after studies found that it was cytotoxic and not synergistic with licensed anti-HIV drugs. A phase 1 study in 1999 evaluating hypericin's effects in 30 patients concluded that hypericin had no antiretroviral activity, with phototoxicity being observed. 94
Other usesAntiviral
Hypericin and pseudohypericin exert effects against a wide spectrum of other viruses, including influenza, herpes simplex types 1 and 2, Sindbis, poliovirus, retrovirus infection in vitro and in vivo, murine cytomegalovirus, and hepatitis C. 2 , 4 , 8 , 95 Hypericin and pseudohypericin have been found to exert unique and uncommonly effective antiviral actions, possibly because of nonspecific association with cellular and viral membranes. It has been reported that the antiviral activity involves a photoactivation process. 2 Exposure of hypericin to fluorescent light markedly increases its antiviral activity. 4 The in vitro activity of hypericin against certain viruses has not extended into patient groups studied in trials. 96
AntibacterialExtracts of the plant have been active against gram-negative and gram-positive bacteria in vitro. 97 Reports have documented antimicrobial effects against Strongylus equinus , Klebsiella pneumoniae , Escherichia coli , B. licheniformis , and Shigella flexneri . 98 Antibacterial activity of constituent hyperforin against Staphylococcus aureus and other gram-positive bacteria has also been reported. 99 In another study, H. perforatum extract showed bacteriostatic activity at a dilution of 1:200,000 and bactericidal action at 1:20,000. 4 St. John's wort also has been used in a 20% tincture form to treat otitis. The tannin component of the plant probably exerts an astringent action that contributes to it's traditional use as a wound-healing agent. 3
Miscellaneous usesOther uses of St. John's wort include the following: wound-healing, including burn treatment; 2 , 4 , 100 oral and topical administration for treatment of vitiligo (failure of skin to form melanin) 101 and other skin diseases; 102 anti-inflammatory and anti-ulcerogenic properties from the component amentoflavone (a biapigenin derivative); 3 , 103 treatment of hemorrhoids, 4 alcoholism, 85 bedwetting, 3 glioblastoma, 104 and menopausal symptoms of psychological origin. 105 St. John's wort is capable of increasing and suppressing immunity. 106 Hypericin has been shown to inhibit T-type calcium channel activity. 107 H. perforatum enhances coronary flow and also may be useful in treating certain headaches. 2 The cytocidal activity of hyperforin and its effect on tumor growth inhibition warrant further study in cancer treatment. 108 Fibromyalgia, causing chronic musculoskeletal pain and fatigue, may also benefit from St. John's wort extracts by maintaining serotonin levels and decreasing pain sensations. Other neuralgias may also improve. 3 , 71
Dosage
Traditional use of the St. John's wort herb indicated 2 to 4 g/day doses or 0.2 to 1 mg hypericin. However, most clinical studies have been conducted on extracts, with hypericin content of 0.3% as the earliest form of standardization. With the discovery of hyperforin's bioactivity, a content of 3% to 5% hyperforin has been used as a new standard. Some of the many available products include LI 160 (Lichtwer, 0.3% hypericin), Kira (Lichtwer, hypericin 300 mcg in 125 to 225 mg extract tablets), Hyperiforce (Bioforce, hypericin 0.33 mg in 60 mg extract/tablet), Ze 117 , WS 5573 (300 mg extract, 0.5% hyperforin), WS 5572 (300 mg, 5% hyperforin), STEI 300 (Steiner, 0.2% to 0.3% hypericin and 2% to 3% hyperforin), Psychotonin , Esbericum , Neuroplant , Sedariston , and Hyperforat . Doses of the extracts have ranged from 500 to 1800 mg/day. 53 , 59 , 81 , 89 , 105 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124
Pregnancy/Lactation
One study in rats demonstrated that chronic treatment with St. John's wort during pregnancy or lactation was responsible for histological changes in the liver and kidneys, evident at doses used to treat depression. 125 The effect appears to be dose-dependent. 125 An observational study in breast-feeding women taking St. John's wort also demonstrated an increased incidence of side effects in their children. 126 However, this study did not detect decreased milk production due to St. John's Wort use, which had been suggested in previous reports.
Emmenagogue and abortifacient effects due to uterine stimulant action have been documented. 127 , 128 , 129 St. John's wort should be avoided during pregnancy and lactation until further long-term studies demonstrate a lack of toxicity toward the developing fetus and breast-feeding newborn.
Interactions
St. John's wort has an excellent tolerability profile in monotherapy but has been reported to interact with numerous drugs. 130 , 131 The mechanisms of many of the drug interactions with St. John's wort involve an increase in intestinal metabolism (cytochrome P450 [CYP] 3A4) and hepatic metabolism (CYP 1A2, 2C9, and 3A4) and/or an increase in activation of intestinal P-glycoprotein efflux in a clinically relevant manner. 130 , 132 , 133 The mechanisms for other drug interactions with St. John's wort remain to be established. Physicians should be aware of the potential for interactions as they emerge and for either a decrease or increase in efficacy of concurrent medications. Drugs with a narrow therapeutic window should be monitored closely when St. John's wort is added, discontinued, or the dosage is changed. 130
Drugs that are most prominently affected, and therefore for which concomitant use with St. John's wort should be avoided, include HIV protease inhibitors (eg, saquinavir), HIV non-nucleoside reverse transcriptase inhibitors (eg, nevirapine), cyclosporine, tacrolimus, irinotecan, and imatinib mesylate. 130 The interaction with cyclosporine is well-documented and several cases have reported organ rejection. 134
Oral contraceptives may be affected as reflected by reports of irregular bleeding and unwanted pregnancies. 130 , 134 , 135 Patients should be advised of this risk when these drugs are taken concurrently and additional nonhormonal methods of contraception are advised.
Drug plasma concentrations decreased by St. John's wort because of increased hepatic metabolism include the following: Alprazolam (CYP3A4), 136 erlotinib (CYP3A4), 137 indinavir (CYP3A4), 134 , 138 irinotecan (CYP3A4), 134 , 139 midazolam (CYP3A4), 140 , 141 nevirapine (CYP3A4), 142 nifedipine (CYP3A4), 143 omeprazole (CYP2C19 and CYP3A4), 144 oral contraceptives (CYP3A4), 145 , 146 , 147 quazepam (CYP3A4), 148 simvastatin (CYP3A4), 149 tacrolimus (CYP3A4), 134 , 150 theophylline (CYP1A2), 134 , 151 verapamil (CYP3A4), 152 warfarin (CYP2C9 or inhibition of absorption). 134 , 143
Drug plasma concentrations decreased by St. John's wort because of increased hepatic metabolism and/or activation of intestinal P-glycoprotein efflux include the following: amitriptyline, 134 , 152 cyclosporine, 134 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 digoxin, 163 , 164 fexofenadine, 134 , 140 , 165 , 166 imatinib, 167 methadone, 134 , 168 nortriptyline, 151 sirolimus. 169
Drugs for which an additive serotonin reuptake inhibition with St. John's wort is suspected include the following: nefazodone 146 and sertraline. 170 The risk of developing serotonin syndrome and other CNS adverse reactions cannot be ruled out, so extreme caution is needed with combinations of psychotropic medications, particularly serotonergic drugs. 130
Paroxetine may cause an increased sedative-hypnotic effect with St. John's wort administration (mechanism unknown). 171
Drugs for which delayed emergence from anesthesia may occur with St. John's wort (mechanism unknown) include the following: propofol and sevoflurane. 172
Carbamazepine may decrease plasma concentrations of components of St. John's wort extract (eg, pseudohypericin). 173
Cimetidine may increase plasma concentrations of components of St. John's wort (eg, hypericin). 173
Drugs that do not appear to interact with St. John's wort based on available documentation include the following: carbamazepine, dextromethorphan, and pravastatin. 134 , 173
St. John's wort preparations should be discontinued at least 5 days prior to elective surgery. 130
A number of factors including dose, dosage regimen, pharmacokinetics, and individual drug toxicities, as well as patient factors, such as age, gender, and concurrent conditions, affect the clinical importance of interactions with St. John's wort. Physicians should take these factors into account when assessing an individual patient's risk when taking St. John's wort; although, safety data published collectively indicates that it is well-tolerated. 77 , 92
Patients should be cautioned that St. John's wort may interact with numerous medications and to consult their health care provider before taking it with prescription and nonprescription drugs. See also Appendix: Potential Drug Interactions with St. John's Wort.
Adverse Reactions
A systematic review concluded that current evidence suggests hypericum extracts to be well tolerated and safe if taken under the direction of a physician who is aware of individual circumstances and potential risk factors. The most relevant risk associated with hypericum appears to be its interaction with other drugs. Many of these interactions remain theoretical; although, some can be clinically severe and are of great importance. The most frequently described adverse effects in clinical trials were GI complaints (such as nausea), itching, fatigue, sleep disorders, and headache. 135
When ingested, hypericin can induce photosensitization characterized by inflammation of the skin and mucous membranes following exposure to light, which was recognized in animals grazing on the plant. 174 , 175 Mice given 0.2 to 0.5 mg of herb also developed severe photodynamic effects. 8 Phototoxicity by H. perforatum has been observed when tested on human keratinocytes. 176 A review of the chemistry of phenanthroperylene quinones from hypericin reveals photosensory pigments. 177 After oral administration, concentrations of hypericin in human serum and blister fluid have been detected. 178 However, most reports of photosensitivity have been limited to those taking excessive doses of H. perforatum , primarily to treat HIV. 71 For example, both IV (eg, 0.5 mg/kg twice weekly) and oral dosing (eg, 0.5 mg/kg/day) of H. perforatum caused significant phototoxicity in 30 HIV patients tested, with 16 of 30 discontinuing treatment for this reason. 96
A number of studies report no serious adverse effects. In a trial of 22 patients, 50% reported no side effects. Those reported included jitteriness, insomnia, change in bowel habits, or headache. 179 In a study of 3,250 patients taking St. John's wort for 1 month, fewer than 3% suffered from dry mouth, GI distress, or dizziness. 180 In another review of clinical trials, St. John's wort was associated with fewer and milder adverse reactions as compared with any other conventional antidepressant. Adverse effects from H. perforatum were rare and mild. One case report describes acute neuropathy after sun exposure in a patient using St. John's wort. 181 A review on photodermatitis is available that discusses mechanisms, clinical features, and treatment options. 182 A 7-patient evaluation reports St. John's wort to be unlikely to inhibit cytochrome P450 enzymes 2D6 and 3A4 activity. 183 Induction of mania has been associated with St. John's wort. 184 , 185 Uterotonic actions also have been reported 186 and a letter discussing St. John's wort's use during pregnancy has been published. 187 Potent inhibition of sperm motility was observed in vitro. 188 The volatile oil of St. John's wort is an irritant. 8
Toxicology
No information on overdose was found. 189 St. John's wort should be avoided during pregnancy and lactation.
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185. Moses EL Mallinger AG. St. John's wort: Three cases of possible mania induction. J Clin Psychopharmacol . 2000;20:115-117.
186. Shipochliev T. Uterotonic action of extracts from a group of medicinal plants. Vet Med Nauki . 1981;18:94-98.
187. Grush LR, Nierenberg A, Keefe B, Cohen LS. St. John's wort during pregnancy. JAMA . 1998;28:1566.
188. Ondrizek RR, Chan PJ, Patton WC, King A. Inhibition of human sperm motility by specific herbs used in alternative medicine. J Assist Reprod Genet . 1999;16:87-91.
189. Stevinson C, Ernst E. Safety of Hypericum in patients with depression: a comparison with conventional antidepressants. CNS Drugs . 1999;11:125-132.
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