Hypericum (St. John’s Wort) for Treatment of Depression
January 1998; Volume 1: 4-7
By Mady Hornig, MD
Primary care physicians regularly encounter patients with mild-to-moderate depression, for which physicians might ordinarily prescribe an antidepressant. However, many patients are reluctant to take prescription medications for such conditions, and seek alternatives including stress reduction techniques and natural remedies. One such remedy that has recently achieved wide popularity is St. John’s wort. This herbal agent may have fewer side effects and may be especially helpful for depressed patients who present with somatic symptoms. In fact, some of your patients, encouraged by reports on the popular television program "20/20," among others, may already be taking St. John’s wort products.History
The extract of the St. John’s wort flower, Hypericum perforatum, as been used for centuries in the treatment of depression. Hypericin, a photoactive pigment derived from Hypericum, is thought to be the active ingredient in St. John’s wort extract. Since 1988, in addition to its use in depressive syndromes, there has been increased interest in hypericin’s light-activated antiviral activity.1 Over the past decade, Hypericum has become the most widely prescribed antidepressant in Germany, surpassing fluoxetine (Prozac).
Culture
Hypericum has achieved a wide consumer following for use in self-diagnosed depression, most likely due to its availability without a prescription in health food stores as well as drug and food stores. Individuals who suffer from fatigue, concentration difficulties, and chronic low-grade depressive symptoms may turn to an herbal preparation such as Hypericum for several reasons: The belief that taking a "natural" agent is safer and less toxic than a synthetic medication, avoidance of the stigma associated with a formal diagnosis of depression or being prescribed an antidepressant by a physician, and media reports about the efficacy and low toxicity of Hypericum compared with other modern antidepressants. HIV-positive patients are also using this herbal extract for its putative antiretroviral properties.
Pharmacokinetics
There is little available information concerning the pharmacokinetics of Hypericum extract. One study in healthy volunteers found a plasma half-life of 24.8-26.5 hours and a peak concentration time (Tmax) of 5.2 hours. Steady state appears to be achieved after four days.2
Mechanism of Action
The mode of Hypericum’s antidepressant action is as yet unknown.3 Although it has been speculated that Hypericum’s weak MAO inhibitory effects may be responsible, the putative active ingredient, hypericin, is devoid of MAO inhibitory capacity.4 Decreases in serotonin receptor density are another putative mode of action.5 Changes in sleep EEG have also been noted in healthy volunteers: Stage 3/4 (slow-wave) sleep was enhanced by high doses (300 mg tid) of the extract (Schulz, Jobert. 1994). However, as hypericin is unable to cross the blood-brain barrier, it is possible that effects of the herbal compound on cytokine production by peripheral blood mononuclear cells may be responsible. Hypericum has been shown to dramatically suppress the in vitro production of interleukin-6 (IL-6) in human mitogen-stimulated human peripheral blood monocytes, and it produced mild reductions in IL-1beta and tumor necrosis factor.6 Lastly, second-messenger system effects, including robust inhibition of protein kinases, could potentially be responsible for both the antidepressant and the antiviral effects.7
Clinical Studies
Controlled studies of Hypericum have been performed in physicians’ offices in Europe. Fifteen double-blind, placebo-controlled trials (14 using single preparations of Hypericum, 1 using a combination of plant extracts) and eight studies comparing Hypericum to another active drug treatment for depression (6 using single preparations, 2 using combined herbal preparations) were reviewed in a meta-analysis by Linde et al.8 Outpatients (n = 1757) with mild-to-moderate depression were included in these trials. Sixty-one percent improved on a low dose of Hypericum (< 1.2 mg daily); higher doses (up to 2.7 mg daily) yielded a 75% improvement rate.
Although a few studies have included small numbers of patients with more severe depression (who also appeared to receive benefit from the agent), most patients studied thus far have had chronic depressions of milder severity. Patients with somatic symptoms associated with their depression may be particularly responsive to the extract; one study (n = 39 patients with somatic symptoms of depression) noted dramatic improvement of symptoms such as decreased activity, fatigue, and sleep disturbances after only four weeks.9 Similarly, patients with seasonal affective disorder, who also typically exhibit prominent atypical neurovegetative symptoms such as fatigue, increased carbohydrate craving, and hypersomnia, also were as responsive to Hypericum extract as to light therapy (Martinez, et al. 1994). Thus, there is some suggestion that patients with particular types of depression may benefit the most from this type of treatment.
Adverse Effects
Side effects are infrequent and typically mild. The overall incidence of side effects in the 23 studies included in the meta-analysis by Linde et al was 19.8% for Hypericum compared with 52.8% for standard antidepressant therapy;8 only 0.8% of patients on Hypericum vs. 3% of patients on typical antidepressant medications dropped out of the clinical trials due to adverse events. The most common side effects of the herbal extract include dry mouth, dizziness, gastrointestinal complaints (most commonly constipation), and confusion. Rarely, allergic reactions have been reported. As yet, there is no information available regarding the safety of Hypericum in overdose. Safety in pregnant or lactating women is not known. Although there have been reports of photosensitivity, this side effect did not emerge as a significant problem relative to placebo in controlled trials.
Drug Interactions
No information is as yet available on drug interactions. The potential for MAO inhibitor-type interactions with tyramine-containing food substances is considered to be quite low given hypericin’s lack of MAO inhibitory capacity, as noted above.4 The safety in combination with prescribed antidepressants such as selective serotonin reuptake inhibitors (e.g., fluoxetine, paroxetine, sertraline, fluvoxamine) or monoamine oxidase inhibitors (e.g., tranylcypromine, phenelzine) is unknown and should be avoided until further information is available.
Formulation
Currently, there is wide variation in the quality and content of Hypericum extract and hypericin preparations available through health food stores. It is not known whether such variability could be responsible for differences in therapeutic responsiveness or side effects.
Dosage
The higher doses of Hypericum, 300 mg tid, appear to yield a greater therapeutic response without an appreciable increase in side effects. Thus, most European practitioners recommend the upper range dosing for their depressed outpatients.
Conclusion
Hypericum extract appears to be a promising and well-tolerated herbal antidepressant with low toxicity. However, it is unclear whether only certain types of depression may respond to the agent, as patients with more anergic types of depression seem to be more responsive, yet the comparative response of different depressive subtypes has not yet been directly studied. Given the growing body of evidence that certain types of depression, particularly those with the atypical symptoms of depression such as lethargy, fatigue, and hypersomnia, may be associated with increases in interleukins and other acute phase proteins,10 and noting Hypericum’s capacity to reduce certain interleukins and to act as an antiviral agent,6 it is conceivable that the extract may be most effectively used in these depressed subpopulations. Additionally, the quality of different commercially available preparations is unknown, and the overall toxicity and its safety in overdose are unclear. Until such information is available, practitioners who are approached regarding the use of Hypericum for depression should advise patients about the significant lack of information and the potential for previously unrecognized adverse events. v
References
1. Meruelo D, et al. Therapeutic agents with dramatic antiretroviral activity and little toxicity at effective doses: Aromatic polycyclic diones hypericin and pseudohypericin. Proc Natl Acad Sci 988;85:5230-5234.
2. Staffeldt B, et al. Pharmacokinetics of hypericin and pseudohypericin after oral intake of the hypericum perforatum extract LI 160 in healthy volunteers. J Geriatric Psychiatry Neurol 994;7:S47-S53.
3. Thiede HM, Walper A. Inhibition of MAO and COMT by hypericum extracts and hypericin. J Geriatric Psychiatry Neurol 994;7:S54-S56.
4. Bladt S, Wagner H. Inhibition of MAO by fractions and constituents of hypericum extract. J Geriatric Psychiatry Neurol 994;7:S57-S59.
5. Muller WE, Rossol R. Effects of hypericum extract on the expression of serotonin receptors. J Geriatric Psychiatry Neurol 994;7:S63-S64.
6. Thiele B, et al. Modulation of cytokine expression by hypericum extract. J Geriatric Psychiatry Neurol 994;7:S60-S62.
7. Agostinis P, et al. A comparative analysis of the photosensitized inhibition of growth factor regulated protein kinases by hypericin derivatives. Biochem Biophys Res Commun 996;220:613-617.
8. Linde K, et al. St. John’s wort for depression—An overview and meta-analysis
of randomised clinical
trials. BMJ 996;313:253-258.
9. Hubner WD, et al. Hypericum treatment of mild depressions with somatic
symptoms. J Geriatric
Psychiatry Neurol 994;7:S12-S14.
10. Hornig-Rohan M, et al. Immune dysfunction in affective subtypes. Biol Psychiatry 996;39:524.
Dr. Hornig is Visiting Assistant Researcher, Laboratory for Neurovirology, Department of Neurology, University of California Irvine.
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