Authors' objectives

To review the adverse drug reactions associated with the use of extracts of the herb St. John's wort (Hypericum perforatum L.) for the treatment of mild to moderate depression.

Searching

The following databases were searched; MEDLINE, from inception to September 1997; AMED, from inception to July 1997; the Cochrane Library (Issue 2, 1997); and EMBASE from inception to July 1997. Articles published in any language were considered. Further publications obtained by checking all the reference lists, through discussion with colleagues, and by searching the authors' own extensive files. The World Health Organization (WHO) Collaborating Centre for International Drug Monitoring, the drug safety bodies for the United Kingdom (Committee on Safety of Medicines) and Germany (Bundesinstitut fur Arzneimittel and Medizinprodukte), and twelve German manufacturers of hypericum products, were contacted for information on adverse drug reactions associated with hypericum.

Study selection

Assessment of study quality

The authors do not state that they assessed validity.

Data extraction

The data were extracted in a predefined fashion, and any discrepancies were resolved through discussion.

Methods of synthesis

Results of the review

Placebo-controlled trials of hypericum in depression: 14 randomised controlled trials (RCTs; N=932).

Trials comparing hypericum with conventional antidepressants: 7 RCTs (N=797).

Drug-monitoring and post-marketing surveillance: 4 studies (N=4,587).

Photosensitivity: 1 randomised placebo-controlled multiple crossover study; the relationship between dermal photosensitivity and plasma concentration of hypericum and pseudohypericin involved 13 patients, and the effects of excessive doses of hypericum on solar and UVA sensitivity involved 50 patients.

Placebo-controlled trials: 7 of the 14 studies explicitly stated no adverse reactions were observed; 2 trials gave no information; and 5 trials reported a total of 7 patients with mild adverse reactions (the incidence ranged from 1.7 to 9.4%). The nature of the adverse reactions included unspecified stomach complaints, sleep disturbances, nausea, skin rash, pruritus, drowsiness, skin reddening, itching and tiredness.

Hypericum versus conventional antidepressants: the incidence of adverse reactions ranged from 7 to 75% for the reference drug, and from 12 to 38% for hypericum. The adverse reactions included the following:

gastrointestinal symptoms (hypericum 8.5% versus conventional drug 9.4%);

dizziness or confusion (hypericum 4.5% versus conventional drug 6.5%);

tiredness or sedation (hypericum 4.3% versus conventional drug 20.4%);

dry mouth (hypericum 4% versus conventional drug 19.8%);

restlessness (hypericum 2.6% versus conventional drug 1.8%);

headache (hypericum 1.7% versus conventional drug 2.4%);

insomnia (hypericum 0.9% versus conventional drug 0.6%);

tremor (hypericum 0.6% versus conventional drug 1.2%);

pruritus (hypericum 0.6% versus conventional drug 0.3%);

photophobia (hypericum 0.6% versus conventional drug 0.3%);

apathy (hypericum 0.3% versus conventional drug 1.2%);

allergic skin reaction (hypericum 0.3% versus conventional drug 1.2%);

others (hypericum 4.8% versus conventional drug 14.2%).

No difference in effect was calculated.

Data from drug safety bodies: until May 1998, National Centres had provided 57 reports relating to monopreparations and 49 reports relating to multi-ingredient preparations to the WHO. The adverse reactions relating to monotherapy included: allergies and skin disorders (16 reports); psychiatric disorders (15 reports); cerebral and peripheral nervous system disorders (5 reports); respiratory system disorders (4 reports); platelet, bleeding and clotting disorders (4 reports); liver and biliary system disorders (4 reports); gastrointestinal system disorders (2 reports) and others (7 reports). The manufacturers of hypericum products did not provide any new data.

Drug-monitoring and post-marketing surveillance: the reported incidence of adverse reactions ranged from 2 to 6.1%. The adverse reactions included gastrointestinal symptoms (0.6, 1.1 or 2.6%), allergic reactions (0.5%), fatigue (0.4%), confusion or restlessness or anxiety (0.4%), and sweating (0.2%). The withdrawal rates ranged from 0.8 to 1.5%.

Dermal photosensitivity and plasma concentration of hypericum (after total doses of 2.8, 5.6, and 11.3 mg) and pseudohypericin: there was no increase in solar light sensitivity, and UVA sensitivity only increased after the highest dose.

Excessive doses of hypericum (600 mg, three times daily): after 15 days, there was a slight but significant increase in solar and UVA light sensitivity.

There has been little investigation of any interactions between hypericum and other drugs.

Authors' conclusions

Hypericum has an encouraging safety profile. However, as most of the current data originate from short-term investigations, more long-term studies are desirable.

CRD commentary

The aim of the review was defined. An extensive search was undertaken to locate relevant published studies. Unpublished material was not sought. The participants were merely defined as having depression, with no criteria given for determining this diagnosis. No details were given of the methods used to select the primary studies or to extract the data. Validity was not assessed. More comprehensive details of the comparative primary studies, such as the methods used to detect adverse reactions and the patients' characteristics, would have been helpful. No difference in the effect was calculated, and the results were not reported in terms of the statistical significance.

Implications of the review for practice and research

Practice: The authors consider that due to the absence of evidence regarding the safety of hypericum in interaction with other drugs, concurrent use of hypericum with other medications, in particular other antidepressants, is not recommended. There is no evidence on the safety of hypericum during pregnancy or lactation; hence, its use should be avoided in these situations.

Research: The authors consider there is a need for systematic data from long-term monitoring.

Bibliographic details

Ernst E, Rand J I, Barnes J, Stevinson C. Adverse effects profile of the herbal antidepressant St. John's wort (Hypericum perforatum L.) European Journal of Clinical Pharmacology 1998; 54(8): 589-594. [PubMed: 9860144]

Indexing Status

Subject indexing assigned by NLM

MeSH

Antidepressive Agents /adverse effects; Drug Monitoring; Humans; Photosensitizing Agents /adverse effects; Plant Extracts /adverse effects; Randomized Controlled Trials as Topic; Theales /adverse effects

AccessionNumber

11998002129

Database entry date

31/12/1999

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.