St. John’s Wort and Photosensitivity

March 2001; Volume 3; 20-23

By Jerry M. Cott, PhD

Photosensitization after exposure to st. john’s wort (Hypericum perforatum) may develop in fair-skinned people. First noted in animals that grazed in fields dotted with St. John’s wort, an early report was about a case of St. John’s wort poisoning in German Blackface sheep. After St. John’s wort ingestion, all lightly pigmented hairless parts of skin were photosensitized. In summer, many sheep suffered from inflammatory skin conditions around the ears, the eyes, and the bridge of the nose.1


Two case reports of photoactivated toxicity with St. John’s wort have been reported. A 61-year-old woman who had been using St. John’s wort for three years developed elevated itchy erythematous lesions in light-exposed areas; these resolved after discontinuation of the herb.2 The second report is an unusual case report of neuropathy associated with St. John’s wort and sun exposure. A 35-year-old woman who took St. John’s wort (ground whole herb, 500 mg/d) for mild depression developed subacute polyneuropathy after sun exposure.3 One month after starting St. John’s wort, the patient developed stinging pain in sun-exposed areas, including the face and hands; she noted mild pain that appeared to be worsened by sun exposure. A few hours after sunbathing she developed symptoms on her arms and legs (again confined to sun-exposed skin). Examination was consistent with allodynia; St. John’s wort was withdrawn and symptoms began to improve in two weeks and disappeared over two months.

For most fair-skinned people receiving high doses of St. John’s wort, the extent of photosensitivity is a slight reduction in the minimum tanning dose. This has been demonstrated in a randomized, placebo-controlled trial in which fair-skinned subjects who burned easily were given metered doses of hypericum extract (LI 160) and were exposed to UVA and UVB irradiation.4 Hypericin and pseudohypericin plasma concentrations also were monitored. The study was conducted in winter.

In a single-dose segment, 13 volunteers received placebo or a standardized hypericum extract (900, 1,800 or 3,600 mg, containing 0, 2.8, 5.6, and 11.3 mg of total hypericins [sum of hypericin and pseudohypericin]) in a double-blind, crossover design. Maximum total hypericin plasma concentrations were observed about four hours after drug administration, and were 0, 28, 61, and 159 mcg/mL, respectively. At baseline and then four hours after drug intake, subjects were exposed on small areas of their back to increasing doses of solar simulated irradiation (SSI, containing both UVA and UVB); another part was exposed to selective UVA irradiation. Minimal erythema dose was determined five, 20, and 68 hours after irradiation. SSI sensitivity was the same in both groups after hypericum treatment. Sensitivity to selective UVA light was increased slightly (approximately 20%) after the highest dose of hypericum. There was no correlation between total hypericin plasma concentrations and photosensitivity.

In the multiple dose segment, 50 volunteers received 600 mg hypericum extract tid (twice the normal recommended dose) with a daily dose of 5.6 mg of total hypericin. Maximum plasma concentration of hypericins was approximately 44 mcg/mL. In the St. John’s wort group, there was a slight increase in SSI sensitivity (approximately 9%) and a larger increase to UVA light (approximately 21%).

Phototoxic Compounds

Phototoxic photosensitivity from hypericum preparations appears to be due to the naphthodianthrones, hypericin, and pseudohypericin. These hypericins are photoactive quinones that produce singlet oxygen and free radicals when exposed to light. There is a wide range of susceptibility to phototoxic effects of drugs, and there is clearly a dose-related effect.

An in vitro study utilizing fetal calf serum indicates that pseudohypericin is more photoactive than hypericin. Therefore, the authors speculate that pseudohypericin, which is present in higher concentrations than hypericin in hypericum, may be of greater concern regarding phototoxicity.5 However, at steady state, plasma levels of pseudohypericin are only half that of hypericin.6

Hypericin itself, however, is clearly phototoxic. Because hypericin has demonstrated significant antiviral activity in vitro, a Phase I safety study using intravenous synthetic hypericin was performed in 30 HIV-infected adults.7 All patients receiving multiple intravenous. doses of 0.5 mg/kg and more than 73% of those receiving 0.25 mg/kg experienced moderate-to-severe phototoxicity. Severe cutaneous phototoxicity (an erythematous rash associated with painful dysesthesias involving the areas exposed to light) was observed in 11 of 23 subjects. All reactions resolved after discontinuation of therapy.

Photosensitivity rarely is reported in St. John’s wort clinical trials; however, pale patients who burn easily may not realize they burn more easily. Hypericum is well tolerated with an incidence of adverse reactions similar to placebo. The most common adverse effects are gastrointestinal symptoms, dizziness/confusion, and tiredness/sedation. Kasper and Schulz reviewed efficacy and safety from 20 controlled clinical trials (a total of 1,787 patients) of the standardized hypericum extract approved for the treatment of depression in Austria and Germany.8 The authors concluded that the effective dosage of the currently used extract is 600-900 mg/d, and that the risk of photosensitization was without clinical relevance at the recommended dosages.

Based on animal and human experimental studies, Schulz et al estimates that it would take approximately 30-50 times the recommended dose of 900 mg/d of the standardized extract to produce severe phototoxic effects in humans.9 However, the Schulz book misstates the hypericin plasma level to be 50 mcg/mL rather than 50 ng/mL. The Brockmoller et al study in fair-skinned individuals showed that plasma levels of total hypericins (44 ng/mL)4 not far above therapeutic levels (14 ng/mL)6 can increase sensitivity to artificial UV irradiation by approximately 21% (intensities approximately three times higher than average daily exposure in Miami, FL).10

Schempp et al reported the high-performance liquid chromatographic detection of hypericin and pseudohypericin in human serum after oral administration of the hypericum extract LI 160 in 12 healthy volunteers.11 After single-dose administration of 1,800 mg hypericum, the mean serum level of total hypericins was 43 mcg/mL. After steady-state administration (300 mg/d tid for seven days) the mean serum level of hypericins was 12.5 mcg/mL. These levels are far below hypericin levels that are estimated to be phototoxic by these investigators (> 100 mcg/mL).

Bernd et al attempted to estimate the potential risk of phototoxic skin damage with St. John’s wort by comparing the phototoxic agent psoralens to hypericin in cultivated human keratinocyte cultures.12 A concentration- and light-dependent decrease in DNA synthesis (determined by the incorporation rate of bromodeoxyuridine) was noted with very high hypericin concentrations (> 50 mcg/mL) combined with UVA or visible light (but not UVB) radiation. Phototoxic effects were seen with 10 mcg/mL psoralens. The authors conclude that the results confirm a phototoxic effect of hypericin on human keratinocytes, but note that blood levels achieved with normal therapeutic use would be too low to induce phototoxic skin reactions.

Cataract Risk

In 1999, alarm spread regarding the association of St. John’s wort with the development of cataracts. Misinformed press reports warned that people taking St. John’s wort on a regular basis could put themselves at risk if they were exposed to bright light.13 These reports arose as a result of work carried out by Schey et al.14 This was an vitro study in which alpha-crystallins isolated from calf lenses were incubated in 50 micromolar hypericin (approximately 1,000 times therapeutic plasma concentrations) in the presence and absence of light. Hypericin induced photo-polymerization of crystallins in the presence of light. The clinical implications of this are unclear. It should be kept in mind that UV light is a risk factor for cataracts on its own.15 Additionally, antioxidant intake appears to have a protective effect. An in vitro test in which a large concentration of hypericin (inconsistent with achievable serum levels), in the absence of any antioxidants normally present in sera, is applied directly on an avascular lens preparation is of questionable clinical significance. No eye problems have been reported in any of the many trials involving St. John’s wort.

Topical Hypericum

Although the most common use of St. John’s wort in North America is for the treatment of depression, the traditional use of this herb includes its topical use for superficial wounds, burns (including sunburn), and dermatitis. Schempp et al tested the immunomodulatory properties of topical preparations of hypericum and a synthesized constituent, hyperforin.16 They investigated the alloantigen function of human epidermal cells (EC) in vivo in a mixed EC lymphocyte reaction (MECLR). The results demonstrated an inhibitory effect of both hypericum extract and hyperforin on the MECLR and on the proliferation of T lymphocytes. The authors suggest that this may provide a rationale for the traditional treatment of inflammatory skin disorders with hypericum extracts.

The photosensitizing effects of topical hypericum also have been studied and appear to be much more mild than the effects of oral or intravenous administration. Schempp et al also studied the effects of topical application of hypericum oil (hypericin 110 mcg/mL) and hypericum ointment (hypericin 30 mcg/mL) on skin sensitivity to solar simulated radiation.17 Sixteen volunteers received either oil (n = 8) or ointment (n = 8). The minimal erythema dose was determined by visual assessment, and skin erythema was evaluated photometrically. No change was apparent in visual erythema score after application of either hypericum oil or ointment. However, with the more sensitive photometric measurement, an increase of the erythema index after treatment with hypericum oil could be detected. The results suggested a trend toward increased photosensitivity that might become relevant in fair-skinned individuals, in diseased skin, or after extended sun exposure.


Oral ingestion of high doses of St. John’s wort is associated with a significant increase in UV-induced erythema in fair-skinned individuals and rarely is associated with phototoxic photosensitivity reactions. Intravenous administration of high-dose hypericin results in severe phototoxicity that precludes its clinical use. Topical St. John’s wort preparations appear to have low potential for photosensitization. Although hypericin clearly is linked to photosensitivity reactions, pseudohypericin also may be involved. The association of St. John’s wort with cataracts is based on overinterpretation of an in vitro study; there is no human evidence of increased risk of cataracts.

Dr. Cott is Scientific Director and Chief Science Officer at Scientific Herbal Products, Inc. in College Park, MD.


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