Agent Detail - ST JOHN'S WORT

Agent Summary

Quick take: St. John’s wort does not increase congenital anomalies in rats and mice. There are few reports of use in human pregnancy. Concomitant use of St. John’s Wort may reduce the efficacy of oral contraceptives.

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St. John's wort (Hypericum perforatum; Klamath weed) is used as an antidepressant and to treat neuralgia; topically, it is used to treat wounds, sprains, and bruises. Active components include hypericin and hyperforin. St. John's wort interferes with the metabolism and efficacy of some drugs, apparently by inducing the cytochrome P450 enzyme system (primarily CYP3A4) and p-glycoprotein (15). Hypericin may cause photosensitization (9).

The administration of St. John's wort to mice was associated with small decreases in pup weights, which may have been an effect of maternal toxicity (1,2). When doses ten times the routine equivalent human dose were administered to pregnant rats, histologic evidence was seen of both maternal and fetal organ toxicity (16). When 15 pregnant rats were exposed to an oral dose of St. John’s wort equivalent to a human dose of 1800 mg/d (twice the usual dose of 900 mg/d) during organogenesis, there were no significant maternal or fetal effects (17). Rats exposed to St. John's wort at up to 450 ppm in the diet from gestational day 3 to weaning on postnatal day 21 were tested for developmental effects. St. John's wort did not affect maternal weight gain or duration of gestation, nor did it affect behavioral assessments or brain weights in offspring (3). In the offspring of mice exposed orally to St John's wort (182 mg/kg/d in feed for 2 weeks before mating and throughout gestation), there were no major effects on cognitive testing (4).

Feeding St John's wort at 750 ppm in the diet of pregnant mice resulted in a decrease in birth weight of male but not female pups. Subsequent behavioral testing, including reproductive behavior, was not adversely affected in either males or females (5). Administration of St. John's wort 180 mg/kg/d in food bars to female mice from 2 weeks before mating through gestation produced similar results (6). Reproductive capabilities, perinatal outcomes, and growth and development of second-generation offspring were not affected. The dose in these 2 mouse studies was chosen to achieve oral doses similar on a surface area basis to the human dose (based on hypericin content). A secondary source noted that oral doses of 900 and 2700 mg/kg St. John's wort in rats and dogs were not associated with adverse effects on reproductive organs (7). Rat embryos cultured in hypericin at 71 ng/mL showed a small but significant decrease in somite number (8).

Two human pregnancies were reported that included the use of 900 mg/d St. John's wort without adverse outcomes (10).  A 2009 report compared the of outcomes from 58 pregnancies (49 including first trimester exposure) with 2 control groups, one including pregnant women reporting other pharmacologic therapy for depression and a second group of healthy women without known teratogenic exposures (23).  The rates of major malformations, live births and prematurity were not significantly different among the three groups. The utility of this study is decreased by the possibility that groups were not recruited contemporaneously and by the questionable reliability of the outcome information.

An in vitro test for possible effects on sperm penetration of hamster ova found that an extract of St. John's wort blocked penetration at high concentrations (0.6 mg/mL), but had no effect at 1/10th of that dose (11). High concentrations of St. John's wort decreased sperm viability at 7 d and denatured DNA; these results would not be expected to be relevant clinically. In one case report (10), a nursing mother who had taken St. John's wort throughout gestation resumed ingesting this herb at a dose of 300 mg/d on her 20th day of lactation. There was no discernible effect on the suckling infant. A teratogen information service retrospective cohort study compared 3 groups of breastfeeding women: 33 who took St. John’s wort primarily for depression, 101 self-reported disease-matched controls who were not taking St. John’s wort, and 33 healthy controls (12). The average dose was 704.9 mg/d (range, 225-2150 mg/d) with a median onset of treatment at 4.0 months postpartum (range 0-11 months). Three of the exposed women had started treatment during pregnancy. The mean duration of infant exposure was 2.1±3.5; 42.4% of the treated group and 17.8% of the disease-matched control group were also taking other antidepressants. There were 5 reports of colic or lethargy in the exposed group (2/5 were also exposed to antidepressants), compared to only 1 report in each of the other groups. None of the infants or mothers required medical attention. Weight gain data for the first year of life were collected from the pediatricians for 24, 21, and 41 of the infants in Groups 1, 2, and 3 respectively, and were reported to be within normal limits (18).

Hypericin and hyperforin steady-state levels (after 8 weeks treatment) were analyzed in the milk and plasma of a breastfeeding woman treated for postpartum depression with a standardized St. John's wort extract (Jarsin; 300 mg three times daily) beginning five months after giving birth (13). Hypericin was not excreted into milk; hyperforin was excreted into milk in low concentrations (ranging from 0.58 ng/mL to 18.2 ng/mL, the latter a morning hindmilk determination after a 10 hour nursing break). Hyperforin and hypericin levels in maternal plasma were 151 ng/mL and 10.71 ng/mL; hyperforin was excluded from milk, as indicated by a milk/plasma ratio far below 1. Neither hypericin nor hyperforin were found in the infant's plasma. The infant manifested no side effects or developmental delays. Another study found hyperforin in milk in small amounts with estimated weight-adjusted infant doses 1-2.5% of maternal doses (14).

Because St. John’s wort is a potent inducer of the cytochrome P-450 enzyme system, it may interfere with the efficacy of oral contraceptives (18). There have been individual case reports of midcyclic bleeding and unwanted pregnancies in women taking both St John's wort and oral contraceptives (18 citing other case reports, 19). A randomized controlled trial evaluated eighteen women who were administered low-dose oral contraceptives randomized to receive either 400 mg/d or 600 mg/d of St. John’s wort (20). Women treated concomitantly with St John's wort showed a higher risk of midcyclic bleeding, although there was no evidence of ovulation (as measured by follicle maturation, serum estradiol or progesterone concentrations), and there were no unwanted pregnancies. In a non-randomized, single-blind, sequential treatment trial, 16 women were given low-dose oral contraceptives plus placebo for two 28 day cycles, followed by two cycles of oral contraceptives plus St. John’s wort (900 mg/d) (21). During the treatment cycles, northethindrone and ethinyl estradiol exposures decreased by 13-15%, breakthrough bleeding increased, and follicle growth and ovulation increased. There were no unintended pregnancies. Another study confirmed increased clearance of oral contraceptive steroids on St. John’s wort (22).

Selected References

1. Gonzalez CL Stewart JD, Rayburn WF, Christensen HD: Establishment of a relevant dose of antenatal hypericum (St. John's wort) for neurobehavioral development study. Neurotoxicol Teratol 1998;20:369.

2. Christensen HD, Rayburn WF, Coleman FH, Gonzalez CL: Effect of antenatal hypericum (St. John's wort) on growth and physical development of mice offspring. Teratology 1999;59:411.

3. Cada AM, Hansen DK, LaBorde JB, Ferguson SA. Minimal effects from developmental exposure to St. John's wort (Hypericum perforatum) in Sprague-Dawley rats Nutr Neurosci. 2001;4(2):135-41.

4. Rayburn WF, Gonzalez CL, Christensen HD, Harkins TL, Kupiec TC. Impact of hypericum (St.-John's-wort) given prenatally on cognition of mice offspring. Neurotoxicol Teratol. 2001 Nov-Dec;23(6):629-37.

5. Rayburn WF, Christensen HD, Gonzalez CL. Effect of antenatal exposure to Saint John's wort (Hypericum) on neurobehavior of developing mice. Am J Obstet Gynecol 2000;183:1225-31.

6. Rayburn WF, Gonzalez CL, Christensen HD, Stewart JD. Effect of prenatally administered hypericum (St John's wort) on growth and physical maturation of mouse offspring. Am J Obstet Gynecol 2001;184:191-5.

7. Upton R (ed.): St. John's wort monograph. American Herbal Pharmacopoeia, Santa Cruz CA, 1997.

8. Chan LY, Chiu PY, Lau TK. A study of hypericin-induced teratogenicity during organogenesis using a whole rat embryo culture model. Teratology 2001;63:264.

9. Ernst E. Adverse effects of herbal drugs in dermatology. Br J Dermatol 2000;143:923-929.

10. Grush LR, Nierenberg A, Keefe B, Cohen LS: St. John's wort during pregnancy. JAMA 280: 1566, 1998.

11. Ondrizek RR, Chan PJ, Patton WC, King A: An alternative medicine study of herbal effects on the penetration of zona-free hamster oocytes and the integrity of sperm deoxyribonucleic acid. Fertil Steril 1999; 71:517-22.

12. Lee A, Minhas R, Matsuda N, Lam M, Ito S. The safety of St. John's wort (Hypericum perforatum) during breastfeeding. J Clin Psychiatr 2003;64:966-968.

13. Klier CM, Schafer MR, Schmid-Siegel B, Lenz G, Mannel M. St. John's wort (Hypericum perforatum)--is it safe during breastfeeding? Pharmacopsychiatry. 2002 Jan;35(1):29-30.

14. Klier CM, Schmid-Siegel B, Schafer MR, Lenz G, Saria A, Lee A, Zernig G. St John’s wort (Hypericum perforatum) and breastfeeding: plasma and breast milk concentrations of hyperforin for 5 mothers and 2 infants. J Clin Psychiatry 2006;67:305-309.

15. Garrovo C, Rosati A, Barotoli F, Decorti G. St. John’s wort modulation and developmental expression of multidrug transporters in the rat. Phytother Res 2006;20(6):468-473.

16. Gregoretti B, Stebel M, Candussio L, Crivellato E, Bartoli F. Decorti G Toxicity of Hypericum perforatum (St. John's wort)administered during pregnancy and lactation in rats. Toxicology and Applied Pharmacology. 2004; 200(3):201-5.

17.Borges LV, do Carmo Cancino JC, Peters VM, Las Casas L, de Oliveira Guerra M. Development of pregnancy in rats treated with Hypericum perforatum. Phytotherapy Research. 2005, Oct; 19(10):885-7.

18. Ernst E. Second thoughts about safety of St John's wort. Lancet 1999; 354: 2014– 2016.

19. Schwarz UI, Buschel B, Kirch W. Unwanted pregnancy on self-medication with St John's wort despite hormonal contraception. Br J Clin Pharmacol. 2003; 55: 112– 113.

20. Pfrunder A, Schiesser M, Gerber S, Haschke M, Bitzer J, Drewe J. Interaction of St John's wort with low-dose oral contraceptive therapy: a randomized controlled trial. Br J Clin Pharmacol. 2003; 56:683-90.

21. Murphy PA, Kern SE, Stanczyk FZ, et al.: Interaction of St. John's Wort with oral contraceptives: effects on the pharmacokinetics of norethindrone and ethinyl estradiol, ovarian activity and breakthrough bleeding. Contraception 71:402-408, 2005.

22. Hall SD, Wanf Z, Shiew-Mei H et al., The interaction between St. John's Wort and an oral contraceptive. Clin Pharmacol Ther 2003;74: 525–535.

23. Moretti ME, Maxson A, Hanna F, Koren G: Evaluating the safety of St. John's Wort in human pregnancy. Reprod Toxicol 28:96-99, 2009.