St John’s wort may be effective for mild-to-moderate depression but only when used as an approved, standardized medicinal product rather than an over-the-counter supplement. Clinicians should also be aware of potential adverse effects and drug interactions and carefully review a patient’s concomitant medications before recommending treatment.

When It May Help

St John’s wort may be considered for adults with mild-to-moderate depressive episodes, particularly those who prefer an herbal treatment. The German National Care Guideline for Unipolar Depression recommends approved St John’s wort preparations as a first-line pharmacologic option when medication is appropriate for mild depression.

A meta-analysis of randomized controlled trials found that standardized St John’s wort extracts produced antidepressant effects comparable to those of selective serotonin reuptake inhibitors (SSRI) while showing better overall tolerability. Earlier randomized trials also reported significant benefits compared with placebo in patients with mild-to-moderate depression.

Use Approved Products

The available evidence applies only to standardized medicinal extracts and not to herbal teas, oils, over-the-counter products, or dietary supplements purchased in supermarkets or drugstores.

From an evidence-based perspective, only approved medicinal products with standardized daily doses and well-defined compositions can be recommended. The concentrations of hyperforin, hypericin, and other active constituents in nonstandardized products are often unknown. Similarly, the German guideline recommends using only approved medicinal products because the dosing and composition of commercially available supplements remain uncertain.

Mechanism of Action

Researchers believe that hyperforin, together with other constituents, is primarily responsible for the antidepressant effects of St John’s wort.

Unlike SSRI, which primarily inhibit serotonin reuptake, St John’s wort appears to affect multiple neurotransmitter systems simultaneously, including those that involve serotonin, norepinephrine, and dopamine.

Preclinical studies also suggested that transient receptor potential canonical channel 6 (TRPC6) channels may represent an important molecular target of hyperforin. TRPC6 channels are expressed in the hippocampus and prefrontal cortex, brain regions involved in depression.

When to Avoid It

St John’s wort is not suitable for patients with severe depression, psychotic symptoms, acute suicidal ideation, bipolar disorder, or an uncertain psychiatric diagnosis. In these situations, guidelines-recommended psychiatric assessment and treatment are required.

Case reports and review articles also suggest that St John’s wort may trigger manic or psychotic episodes in susceptible individuals.

Clinicians should also exercise caution when treating patients receiving multiple medications because St John’s wort is associated with numerous clinically important drug interactions. By inducing cytochrome P450 (CYP) 3A4 and P-glycoprotein, it can substantially reduce the effectiveness of many medications. Important interactions include the following:

• St John’s wort can markedly reduce blood concentration levels of cyclosporine and tacrolimus, and cases of organ transplant rejection have been reported. 
• St John’s wort may lower concentrations of contraceptive steroids, increasing the risk for breakthrough bleeding and contraceptive failure. 
• St John’s wort should not be combined with SSRI, serotonin-norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, triptans, linezolid, or other serotonergic agents because of the risk for serotonin syndrome. 

While products with low hyperforin levels might be safe and have shown little evidence of clinically relevant interactions with CYP enzymes or P-glycoprotein in clinical pharmacology studies, these findings cannot be generalized to all St John’s wort preparations.

Adverse Effects

Standardized St John’s wort extracts are generally well tolerated.

The most commonly reported adverse effects include gastrointestinal symptoms, fatigue or restlessness, headache, dizziness, and allergic skin reactions. Photosensitivity may occur but appears to be uncommon at standard antidepressant doses.

Psychiatric adverse effects are of particular concern in susceptible individuals.

In individuals with bipolar disorder or underlying bipolar susceptibility, St John’s wort may trigger hypomania or mania. Worsening of psychotic symptoms has also been reported.

Although St John’s wort is widely believed to increase photosensitivity, available evidence suggests the risk at standard antidepressant doses is low. In a controlled study involving healthy volunteers, researchers found no significant increase in photosensitivity at therapeutic doses, with only a slight increase in ultraviolet A sensitivity observed at extremely high doses. Another clinical study found that a standardized St John’s wort extract did not produce detectable phototoxic effects when used at recommended antidepressant doses.

Clinical Considerations

Overall, standardized St John’s wort preparations may be a reasonable treatment option for selected adults with mild-to-moderate depression but only when approved medicinal products are used rather than over-the-counter supplements sold in supermarkets, drugstores, or online.

Clinicians should perform a comprehensive medication review before prescribing St John’s wort or before patients begin self-medication because of its extensive potential for drug interactions. St John’s wort is not a good choice in cases of severe depression, suicidal ideation, bipolar disorder, psychosis, or a history of organ transplantation, as well as in those receiving anticoagulants, hormonal contraceptives, HIV therapy, antiepileptic medications, or multiple concomitant drugs.

This story was translated from Medscape’s German edition.