MAJOR CHEMICAL CONSTITUENTS

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

PRINCIPAL USES

TRADITIONAL AND HISTORICAL USES

St. John’s wort (SJW) has been a famed vulnerary and antidepressant herb since the Greco-Roman times. In ancient medical history, however, depression was not the likely diagnosis—a patient was said to have been afflicted by evil spirits or other psychic malady.

In our modern era, mounting evidence from clinical trials, especially those conducted in the 1980s and 1990s, established the efficacy and safety of standardized SJW extracts for treating mild to moderate depression, and practically overnight, SJW became a “household alternative” 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 of potentially serious herb–drug interactions, as well as widely publicized but poorly conducted studies questioning its efficacy have led to some decline in its popularity as a treatment for depression.

CLINICAL INDICATIONS

SJW is indicated for mild to moderate depression. Herbalists also prescribe SJW as a mild sedative and nerve tonic for excitability, anxiety, and nervous irritability, for pain relief for neuralgia and sciatica, as an antiviral for both internal and topical prevention and treatment of Herpes simplex virus (HSV), and for neurovegetative menopausal complaints, particularly anxiety and sleep difficulties, typically in combination with other herbs. It is commonly included as a vulnerary—or

St. John’s wort (Hypericum perforatum).

Photo by Martin Wall.

wound healing herb—in formulae for the treatment of cuts, scrapes, and puncture wounds, as well as to soothe and heal the perineum with or without perineal lacerations after childbirth, to soothe and reduce hemorrhoids, and for the treatment of vaginal abrasions in vaginitis and those that can occur with perimenopausal vaginal atrophy and vaginal dryness. Herbal practitioners may also include SJW in formulae for the treatment of cystitis, urinary frequency and urgency, and interstitial cystitis.

MECHANISMS OF ACTION

The precise mechanisms of action for the antidepressant effects of SJW are not understood. In vitro studies using hyperforin have demonstrated significant binding of GABA A and GABA B, adenosine, MAO, and benzodiazepine receptors. Only GABA A and GABA B receptor activity is likely to be achieved in concentrations to elicit a biological effect after oral administration in humans. Early studies focused on the inhibitory activity of hypericin on MAO receptors; however, most studies have demonstrated only weak binding if at all. It appears that there might be some effects in inhibition of synaptosomal uptake of serotonin (5-HT), dopamine, and noradrenaline, with an upregulation of 5-HT in rat cortex, with some increase in dopamine and noradrenaline. Studies have shown possible decrease in tryptophan degradation; tryptophan is a 5-HT precursor. Another possible explanation for the antidepressant effect of SJW is via inhibition of interleukin-6 (IL-6) by hyperforin and via inhibition of substance P mediated effects on depression.

Antiviral effects of SJW are attributed in part to the flavonoid and catechin fractions of the herb. Both hypericin and psuedohypericin have demonstrated in vitro inhibition of HSV Types 1 and 2, Varicella zoster virus, and HIV type 1 via a photoactivation process that is not yet elucidated.

Tannins in SJW have a mild astringent effect and may help to explain some of the vulnerary effects, as well as use in the treatment of hemorrhoids. A quercetin-like compound in SJW has been attributed with possible analgesic effects of the herb. SJW extract has also been observed to suppress inflammation and leukocyte infiltration in murine models. Hypericin has demonstrated in vitro ability to inhibit tumor necrosis factor induced activation of NF-kappa B and the release of arachadonic acid, 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

PREPARATIONS USED CLINICALLY

DOSAGE

SAFETY INFORMATION: HERB DRUG INTERACTIONS, TOXICITY, AND CONTRAINDICATIONS

St. John’s wort is considered a generally well-tolerated herb, even when taken continuously for up to 8 weeks. Adverse reactions are usually mild and included skin reactions, GI symptoms, fatigue, sedation, restlessness, dizziness, dry mouth, and headache with few side effects, most notably photosensitivity and mania, reported in clinical trials. Studies of chronic toxicity in animals have shown only nonspecific symptoms such as weight loss. Rarely, skin reactions such as pruritus and rash have been reported, with a drug monitoring study of 3250 patients showing 17 allergic reactions.

A European review of adverse reactions from 1991 to 1999 involving nearly 8 million people documented only 95 adverse reactions. Three case reports in the literature suggest the possibility of phototoxicity; in patients taking SJW. Two of the cases involved patients receiving laser or UVB treatments. Phase 1 trials of IV and oral hypericin in adult patients with HIV demonstrated severe cutaneous phototoxic reactions in 11 of 23 subjects, and a variety photosensitivity reactions in 14 of 19 hepatitis C patients. Several additional studies have confirmed similar findings particularly at high doses of hypericin or high UVA light. One study did not find phototoxic effects. Patients receiving UV treatment are advised to avoid SJW use during treatment and those with fair skin are advised to avoid sun exposure of skin while taking SJW internally or topically.

Anorgasmia has been reported in 25% of patients taking 900 to 1500 mg SJW daily for 8 weeks versus 32% taking sertraline and 16% taking placebo, in additional to 2 published case reports of sexual dysfunction in patients taking the herb for mood disorders. Frequent urination was also seen in 27% of patients taking 900 to 1500 mg SJW daily for 8 weeks vs. 21% taking sertraline and 11% taking placebo.

SJW, through its actions on the hepatic metabolism of drugs, specifically via induction of the cytochrome system, may lead to changes in the plasma level of a number of drugs, preventing a patient from achieving appropriate therapeutic levels. There is evidence from clinical trials and case reports that SJW may interact with the following medications:

WARNING

Patients taking cyclosporine for the prevention of transplant rejection or other medical reasons should avoid the concurrent use of SJW as it has been shown to interfere with immunosuppressant medications.

Patients taking medications metabolized by CYP450 should avoid SJW or consult with the physician prior to use.

Caution is advised with SJW use for patients with fair skin, receiving photosensitizing drugs, or receiving UV treatments. At recommended doses of whole plant extracts, the risk of photosensitization appears to be quite low.

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

SJW is suggested for the treatment of patients with mild to moderate depression, not severe depression or suicidality.

Cases of possible serotonin syndrome has been reported in patients taking SJW.

USE IN PREGNANCY AND LACTATION

Because of lack of clinical trials and safety data, SJW is not commonly recommended for the treatment of mood disorders during pregnancy. Its use is more often reserved for topical treatment of vaginitis, in the treatment of perineal tears, and for the treatment of sore, cracked nipples during lactation.

It is becoming increasingly well established that untreated depression in pregnant women and new mothers can have significant health and social consequences for their offspring. Comparative studies on the efficacy and safety of SJW compared to pharmaceutical antidepressants for the treatment of prenatal and postpartum depression are needed.

Murine and rat studies on the prenatal consumption of SJW have been generally associated with normal gestation and fetal development. In one study, male offspring in a SJW exposed group had a statistically significant lower birth weight than the placebo group, however, by three days after birth the difference was not statistically significant. The males in the SJW group also demonstrated a statistically significant temporary delay in the appearance of upper incisors. In another rat study females were given a methanol extract of SJW standardized 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 lactation. Histological evidence of hepatic and renal changes was seen in the SJW exposed group, with more severe lesions in the rat pups whose dams received higher doses and the offspring of those receiving both SJW in both pregnancy and lactation. No significant impact on cognitive behaviors have been seen in the offspring of mice given SJW throughout gestation. A slight increase in in vitro uterotonic activity has been reported with SJW use.

Overall there is a lack of toxicity studies conducted on SJW use during pregnancy. A limited number of human case reports indicated healthy pregnancies and infants when SJW was used prenatally. In a small prospective cohort safety study of breastfeeding women (n = 33) who took SJW products during pregnancy and who contacted a toxicology advise service, compared to 101 matched controls who had also contacted the service but had not taken SJW, there were no maternal adverse effects, no statistically significant differences in women reporting decreased breast milk volume, and no medical problems in the offspring. Two of the infants born to mothers taking SJW experience colic, drowsiness, or lethargy compared with the other group; a number of these infants were also reported to have been exposed to conventional antidepressant medications while breastfeeding. Limitations to this report include lack of product identification or quantification in this report, and the number of women taking SJW while pregnant was small.

Hyperforin was detected in low concentrations in the breast milk who took 300 mg of SJW three times daily starting at 5 months postpartum for the treatment of postpartum depression. No adverse effects were seen in her baby. The clinical significance to the infant of SJW in breast milk is unknown; no adverse effects have been reported. Use of topical applications of SJW oil or salve as treatment for sore, cracked nipples, particularly if well-absorbed with any excess wiped off prior to nursing does not appear harmful to the infant. See warnings in the preceding regarding interactions with immunosuppressant and other medications.

The safety of SJW taken internally during pregnancy and breastfeeding, both in terms of effects on the mother and her child, are unknown at this time. Because of this, the herb is generally not recommended for internal consumption during pregnancy and lactation. Given the widespread incidence of depression in society, and the relatively high incidence and serious consequences of postpartum depression on the health of mother, baby, and their relationship, as well as the family overall, research in to SJW for prophylaxis and treatment of depression during the childbearing years should be explored in carefully controlled studies.