ST. JOHN’S WORTBotanical name: Hypercium perforatumFamily name: ClusiacaeaSynonyms: St. Joan’s wortPart used: Flowers, upper 6 to 8 inches of the aerialportion of the herb, including leaf and flower

MAJOR CHEMICAL CONSTITUENTS

Hypericin, pseudohypericin, isohypericin, hyperforin;flavonols including kaempferol and quercetin; flavones,glycosides, bioflavonoids, catechins; phenols includingcaffeic acid, p-coumaric acid, ferulic acid, and vanillicavid; volatile oils, carotenoids, nicotinic avid, isovalerinicacid, palmitic acid, and a number of volatile oils.

PRINCIPAL USES

� Mild to moderate depression� Mild sedative and nerve tonic for excitability, anxiety,

and nervous irritability� Mild sedative/analgesic for neuralgia and sciatica� Antiviral for both internal and topical prevention and

treatment of Herpes simplex virus (HSV)� Neurovegetative menopausal complaints� Topical wound healing, for example, postpartum peri-

neal healing, hemorrhoids, sore. cracked nipples duringlactation, and vaginal abrasions in vaginitis and peri-menopausal vaginal atrophy and associate vaginaldryness� Cystitis, urinary frequency and urgency, interstitial

cystitis

TRADITIONAL AND HISTORICAL USES

St. John’s wort (SJW) has been a famed vulnerary andantidepressant herb since the Greco-Roman times. Inancient medical history, however, depression was notthe likely diagnosis—a patient was said to have beenafflicted by evil spirits or other psychic malady.

In our modern era, mounting evidence from clinicaltrials, especially those conducted in the 1980s and 1990s,established the efficacy and safety of standardized SJWextracts for treating mild to moderate depression, andpractically overnight, SJW became a ‘‘household alterna-tive’’ for the treatment of depression as well as a multi-million dollar boon for the natural products industry.Although SJW remains a top-selling herb, reports ofpotentially serious herb–drug interactions, as well aswidely publicized but poorly conducted studies question-ing its efficacy have led to some decline in its popularityas a treatment for depression.

CLINICAL INDICATIONS

SJW is indicated for mild to moderate depression.Herbalists also prescribe SJW as a mild sedative andnerve tonic for excitability, anxiety, and nervous irritabil-ity, for pain relief for neuralgia and sciatica, as an antivi-ral for both internal and topical prevention andtreatment of Herpes simplex virus (HSV), and for neuro-vegetative menopausal complaints, particularly anxietyand sleep difficulties, typically in combination withother herbs. It is commonly included as a vulnerary—or

wound healing herb—in formulae for the treatment ofcuts, scrapes, and puncture wounds, as well as to sootheand heal the perineum with or without perineal lacera-tions after childbirth, to soothe and reduce hemorrhoids,and for the treatment of vaginal abrasions in vaginitisand those that can occur with perimenopausal vaginalatrophy and vaginal dryness. Herbal practitionersmay also include SJW in formulae for the treatment ofcystitis, urinary frequency and urgency, and interstitialcystitis.

MECHANISMS OF ACTION

The precise mechanisms of action for the antidepressanteffects of SJW are not understood. In vitro studies usinghyperforin have demonstrated significant binding ofGABA A and GABA B, adenosine, MAO, and benzodiaze-pine receptors. Only GABA A and GABA B receptor activ-ity is likely to be achieved in concentrations to elicit abiological effect after oral administration in humans.Early studies focused on the inhibitory activity of hyper-icin on MAO receptors; however, most studies havedemonstrated only weak binding if at all. It appearsthat there might be some effects in inhibition of synap-tosomal uptake of serotonin (5-HT), dopamine, and nor-adrenaline, with an upregulation of 5-HT in rat cortex,with some increase in dopamine and noradrenaline.Studies have shown possible decrease in tryptophandegradation; tryptophan is a 5-HT precursor. Anotherpossible explanation for the antidepressant effect of

St. John’s wort (Hypericum perforatum). (Photo by MartinWall.)

544 PART V � Plant Profiles

SJW is via inhibition of interleukin-6 (IL-6) by hyperforinand via inhibition of substance P mediated effects ondepression.

Antiviral effects of SJW are attributed in part to theflavonoid and catechin fractions of the herb. Both hyper-icin and psuedohypericin have demonstrated in vitroinhibition of HSV Types 1 and 2, Varicella zoster virus,and HIV type 1 via a photoactivation process that is notyet elucidated.

Tannins in SJW have a mild astringent effect and mayhelp to explain some of the vulnerary effects, as well asuse in the treatment of hemorrhoids. A quercetin-likecompound in SJW has been attributed with possible anal-gesic effects of the herb. SJW extract has also beenobserved to suppress inflammation and leukocyte infil-tration in murine models. Hypericin has demonstratedin vitro ability to inhibit tumor necrosis factor inducedactivation of NF-kappa B and the release of arachadonicacid, as well as inhibition of 5-lipoxygenase and COX-1.SJW may have free-radical scavenging activity; however,this has not been a consistent finding in studies.

RATINGS

� Botanical Safety Handbook rating 2d: Not for useduring phototherapy; interaction Class C. Herbs forwhich clinically significant interactions are known tooccur� German Commission E: Internal uses include the treat-

ment of psychovegetative disturbances, depressivemoods, anxiety and/or nervous unrest. External: Oil-based preparations for the treatment of acute and con-tused injuries, myalgia, and first-degree burns.

PREPARATIONS USED CLINICALLY

� Dried herb in tea and capsules� Tincture� Standardized extract� Oil extract for topical use

DOSAGE

� Dried herb: 2 to 4 g as an infusion three times daily� Tincture: 2 to 4 mL 3x daily� Clinical trial doses: 240 to 1800 mg daily standardized

to varying concentrations of hypericin and hyperforinfor a minimum of 4 to 6 weeks. Dosing in depressionclinical trials suggests a starting dose of 300 mg of SJWstandardized to 0.3% hypericin (and possibly also to2–5% hypericin) 3x daily with a maintenance dose of300 to 600 mg per day.� Topical use as needed

SAFETY INFORMATION: HERB DRUGINTERACTIONS, TOXICITY, ANDCONTRAINDICATIONS

St. John’s wort is considered a generally well-toleratedherb, even when taken continuously for up to 8 weeks.Adverse reactions are usually mild and included skin reac-tions, GI symptoms, fatigue, sedation, restlessness, dizzi-ness, dry mouth, and headache with few side effects,most notably photosensitivity and mania, reported inclinical trials. Studies of chronic toxicity in animals

have shown only nonspecific symptoms such as weightloss. Rarely, skin reactions such as pruritus and rash havebeen reported, with a drug monitoring study of 3250patients showing 17 allergic reactions.

A European review of adverse reactions from 1991 to1999 involving nearly 8 million people documented only95 adverse reactions. Three case reports in the literaturesuggest the possibility of phototoxicity; in patients takingSJW. Two of the cases involved patients receiving laser orUVB treatments. Phase 1 trials of IV and oral hypericin inadult patients with HIV demonstrated severe cutaneousphototoxic reactions in 11 of 23 subjects, and a varietyphotosensitivity reactions in 14 of 19 hepatitis Cpatients. Several additional studies have confirmed simi-lar findings particularly at high doses of hypericin or highUVA light. One study did not find phototoxic effects.Patients receiving UV treatment are advised to avoidSJW use during treatment and those with fair skin areadvised to avoid sun exposure of skin while taking SJWinternally or topically.

Anorgasmia has been reported in 25% of patientstaking 900 to 1500 mg SJW daily for 8 weeks versus32% taking sertraline and 16% taking placebo, in addi-tional to 2 published case reports of sexual dysfunction inpatients taking the herb for mood disorders. Frequenturination was also seen in 27% of patients taking 900to 1500 mg SJW daily for 8 weeks vs. 21% taking sertra-line and 11% taking placebo.

SJW, through its actions on the hepatic metabolism ofdrugs, specifically via induction of the cytochromesystem, may lead to changes in the plasma level of anumber of drugs, preventing a patient from achievingappropriate therapeutic levels. There is evidence fromclinical trials and case reports that SJW may interactwith the following medications:� Antiarrhythmics/calcium channel blockers: May lead to

decreased plasma levels of digoxin, verapamil, andnifedipine� Anticonvulsants: May lead to decreased plasma levels

phenytoin� Anticoagulants: May lead to decreased plasma levels

warfarin� Antidepressants: May lead to decreased plasma levels

amitriptyline (a tricyclic antidepressant) and the SSRIsparoxetine, fluoxetine, and trazadone. Serotonin syn-drome can result from reduced serum levels of SSRIs.� Antihistamines: Fexofenadine (single dose may

increase while continued use may decrease plasmalevel of drug)� Antipsychotics and anxiolytics: May lead to decreased

plasma levels of buspirone, quitazepam, midazolam,and alprazolam� Antiulcer agents: May lead to decreased plasma levels of

omeprazole� Antivirals: May lead to decreased plasma levels of

indinavir� Chemotherapeutic agents: May lead to decreased

plasma levels of irinotecan and imatinib� Hormonal contraceptives: May lead to decreased

plasma levels of hormonal birth control/oralcontraceptives

545ST. JOHN’S WORT

� Immunosuppressants: May lead to decreased plasmalevels of cyclosporine and tacrolimus� Reverse transcriptase inhibitors: May lead to decreased

plasma levels of nevirapine� Skeletal muscle relaxants: May lead to decreased plasma

levels of chlorzoxazone� Statins: May lead to decreased plasma levels of

simvastatin

WARNING

Patients taking cyclosporine for the prevention of trans-plant rejection or other medical reasons should avoid theconcurrent use of SJW as it has been shown to interferewith immunosuppressant medications.

Patients taking medications metabolized by CYP450should avoid SJW or consult with the physician priorto use.

Caution is advised with SJW use for patients with fairskin, receiving photosensitizing drugs, or receiving UVtreatments. At recommended doses of whole plantextracts, the risk of photosensitization appears to bequite low.

Activation may occur in patients with a history ofmania, bipolar disorder, and other mood disorders.

SJW is suggested for the treatment of patients withmild to moderate depression, not severe depression orsuicidality.

Cases of possible serotonin syndrome has beenreported in patients taking SJW.

USE IN PREGNANCY AND LACTATION

Because of lack of clinical trials and safety data, SJW is notcommonly recommended for the treatment of mood dis-orders during pregnancy. Its use is more often reservedfor topical treatment of vaginitis, in the treatment of peri-neal tears, and for the treatment of sore, cracked nipplesduring lactation.

It is becoming increasingly well established thatuntreated depression in pregnant women and newmothers can have significant health and social conse-quences for their offspring. Comparative studies on theefficacy and safety of SJW compared to pharmaceuticalantidepressants for the treatment of prenatal and post-partum depression are needed.

Murine and rat studies on the prenatal consumptionof SJW have been generally associated with normal ges-tation and fetal development. In one study, male off-spring in a SJW exposed group had a statisticallysignificant lower birth weight than the placebo group,however, by three days after birth the difference wasnot statistically significant. The males in the SJW groupalso demonstrated a statistically significant temporarydelay in the appearance of upper incisors. In anotherrat study females were given a methanol extract of SJWstandardized to 0.3% hypericin at 100 or 1000 mg/kg

or placebo by gavage for 2 weeks prior to conception,throughout gestation, and/or for 3 weeks during lacta-tion. Histological evidence of hepatic and renal changeswas seen in the SJW exposed group, with more severelesions in the rat pups whose dams received higherdoses and the offspring of those receiving both SJWin both pregnancy and lactation. No significant impacton cognitive behaviors have been seen in the offspring ofmice given SJW throughout gestation. A slight increasein in vitro uterotonic activity has been reported withSJW use.

Overall there is a lack of toxicity studies conducted onSJW use during pregnancy. A limited number of humancase reports indicated healthy pregnancies and infantswhen SJW was used prenatally. In a small prospectivecohort safety study of breastfeeding women (n = 33)who took SJW products during pregnancy and who con-tacted a toxicology advise service, compared to 101matched controls who had also contacted the servicebut had not taken SJW, there were no maternal adverseeffects, no statistically significant differences in womenreporting decreased breast milk volume, and no medicalproblems in the offspring. Two of the infants born tomothers taking SJW experience colic, drowsiness, or leth-argy compared with the other group; a number of theseinfants were also reported to have been exposed to con-ventional antidepressant medications while breastfeed-ing. Limitations to this report include lack of productidentification or quantification in this report, andthe number of women taking SJW while pregnant wassmall.

Hyperforin was detected in low concentrations in thebreast milk who took 300 mg of SJW three times dailystarting at 5 months postpartum for the treatment ofpostpartum depression. No adverse effects were seen inher baby. The clinical significance to the infant of SJW inbreast milk is unknown; no adverse effects have beenreported. Use of topical applications of SJW oil or salveas treatment for sore, cracked nipples, particularly if well-absorbed with any excess wiped off prior to nursing doesnot appear harmful to the infant. See warnings in thepreceding regarding interactions with immunosuppres-sant and other medications.

The safety of SJW taken internally during pregnancyand breastfeeding, both in terms of effects on the motherand her child, are unknown at this time. Because of this,the herb is generally not recommended for internal con-sumption during pregnancy and lactation. Given thewidespread incidence of depression in society, and therelatively high incidence and serious consequences ofpostpartum depression on the health of mother, baby,and their relationship, as well as the family overall,research in to SJW for prophylaxis and treatmentof depression during the childbearing years should beexplored in carefully controlled studies.

546 PART V � Plant Profiles