St. John's wort is natural, therefore safe

herbal origin does not guarantee safety. St. John's wort has dozens of clinically significant drug interactions, some of which can be life-threatening (graft rejection, serotonin syndrome, loss of HIV control).

St. John's wort works for any depression

only for mild-to-moderate; not used in severe forms.

St. John's wort can be combined with antidepressants for synergy

combination with SSRIs, SNRIs, TCAs and MAOIs raises serotonin syndrome risk and is not used.

Hypericum perforatum

Antidepressants. Other antidepressants of herbal origin

ATC code: N06AX25 (Hypericum perforatum (St. John's wort))

Brand names

St. John's Wort, Kira, Perika

Mechanism of action

Active components of the extract – hypericin, hyperforin and flavonoids. Hyperforin inhibits synaptic reuptake of serotonin, norepinephrine, dopamine and GABA and activates TRPC6 calcium channels. The effect is weaker than that of SSRIs. In addition, St. John's wort is a potent inducer of CYP3A4 and P-glycoprotein, which underlies clinically significant interactions with dozens of drugs.

Indications

Mild-to-moderate depression

Second line

For mild-to-moderate depression in adults, standardized St. John's wort extract (hypericin and hyperforin content per the manufacturer's label) shows efficacy non-inferior to SSRIs and superior to placebo. The 2008 Cochrane review confirms this result; in severe depression, efficacy is insufficient. NG222 (2022) considers St. John's wort as a first-line alternative in selected clinical situations of mild depression but explicitly warns about drug interactions.

Not used in patients on other serotonergic drugs, anticoagulants, immunosuppressants, antiretrovirals, COCs or hypoglycemic agents – risk of serotonin syndrome or loss of efficacy of the primary drug.

Sources

Combined oral contraception

Not recommended

St. John's wort is not combined with combined oral contraceptives. CYP3A4 induction accelerates estrogen and progestin metabolism, reducing contraceptive efficacy and risking unplanned pregnancy. Cases of unintended pregnancy in women taking COCs with St. John's wort are documented.

Sources

CDC: U.S. Medical Eligibility Criteria for Contraceptive Use, 2016 (2016)

Severe depression

Not recommended

St. John's wort is not used in severe depression. Evidence is limited to mild and moderate episodes; severe forms require SSRI, SNRI or TCA therapy combined with psychotherapy, in inpatient settings when needed. Use in severe cases delays adequate treatment and increases suicide risk.

Sources

Cochrane: St John's wort for major depression (2008)

Practical notes

Timing and administration

Taken 2–3 times daily, preferably with meals. Effect develops over 2–4 weeks of regular use. Standardized extracts specify hypericin and hyperforin content – products of different manufacturers are not interchangeable at the same tablet weight.

Monitoring

Before initiation and every 4 weeks, depression severity is assessed by scales (, HAM-D). If there is no improvement at 4–6 weeks, the strategy is reviewed. ALT/AST monitoring at least every 3 months; rare cases of transaminase elevation have been reported.

Special situations

St. John's wort is a potent CYP3A4 and P-glycoprotein inducer. It reduces concentrations of warfarin (bleeding risk on withdrawal of St. John's wort), cyclosporine and tacrolimus (graft rejection risk), digoxin, theophylline, antiretrovirals (loss of viral control in HIV), COCs (unplanned pregnancy risk), statins (loss of efficacy), glibenclamide ( rise). Before initiation, all medications and supplements the patient takes must be reviewed.

Photoprotection

Photosensitization is possible in fair-skinned patients. During use, intense sun exposure and tanning beds are avoided, and SPF 50 sunscreens are used.

Common myths

Drug–nutrient interactions

Iron

Tannins in St. John's wort herb bind iron in the gut lumen and reduce its absorption. With concurrent iron supplements and St. John's wort, a 2-hour interval is maintained between them.

Drug–drug interactions

1 pair found. Sorted from critical to minor.

Major

sertraline

Selective serotonin reuptake inhibitors (SSRIs)

Mechanism

Аддитивное серотонинергическое действие + индукция CYP3A4 зверобоем, снижающая концентрации множества препаратов.

Management

Избегать сочетания. Если пациент уже принимает зверобой – отменить за 2 недели до начала .

Sources

PubMed: Serotonin syndrome with St. John's wort and SSRIs: a systematic review (2018)

Pair details →

Safety

Contraindications

Severe depression with suicidal ideation
Bipolar affective disorder (risk of manic switch)
Concomitant SSRIs, SNRIs, TCAs, MAOIs, triptans – risk of serotonin syndrome
Concomitant warfarin, cyclosporine, tacrolimus, digoxin, antiretrovirals, COCs
Pregnancy, breastfeeding
Age under 18 (insufficient data)
Fair-skinned patients with photodermatoses
Hypersensitivity to plant components

Serious adverse effects

Serotonin syndrome when combined with serotonergic drugs
Manic or hypomanic switch in patients with bipolar disorder
Severe photosensitization (phototoxic dermatitis)
Loss of HIV control when combined with antiretrovirals
Graft rejection when combined with immunosuppressants

Common adverse effects

Dyspepsia, nausea
Dry mouth
Fatigue, less often anxiety
Headache
Photosensitization

Uncommon adverse effects

Rash, allergic dermatitis
Emotional lability
ALT/AST elevation

Pregnancy

Frequently asked

What is Hypericum perforatum used for?

Hypericum perforatum is evaluated for the following indications with varying evidence strength: Mild-to-moderate depression (evidence tier B), Severe depression (evidence tier F), Combined oral contraception (evidence tier F). See the full indication matrix with dosing and citations above on this page.

What are the side effects of Hypericum perforatum?

Common side effects of Hypericum perforatum (≥ 1 in 100): Dyspepsia, nausea, Dry mouth, Fatigue, less often anxiety, Headache, Photosensitization. See the Safety section for uncommon and serious reactions.

Is Hypericum perforatum safe during pregnancy?

No FDA category assigned. Not used during pregnancy – safety data are insufficient and isolated reports of adverse outcomes exist. Alternatives for depression in pregnancy: psychotherapy (CBT) and, if needed, SSRIs with a known safety profile (sertraline).

Is Hypericum perforatum compatible with breastfeeding?

Extract components transfer into breast milk. Cases of infant colic and drowsiness have been reported. Not used during breastfeeding. Alternatives – psychotherapy and, if needed, sertraline (low milk transfer).

Who should not take Hypericum perforatum?

Hypericum perforatum is contraindicated in: Severe depression with suicidal ideation; Bipolar affective disorder (risk of manic switch); Concomitant SSRIs, SNRIs, TCAs, MAOIs, triptans – risk of serotonin syndrome; Concomitant warfarin, cyclosporine, tacrolimus, digoxin, antiretrovirals, COCs; Pregnancy, breastfeeding. Full list in the Safety section.

Mechanism of action

Indications

Practical notes

Timing and administration

Monitoring

Special situations

Photoprotection

Common myths

Drug–nutrient interactions

Iron

Drug–drug interactions

sertraline

Safety

Contraindications

Serious adverse effects

Common adverse effects

Uncommon adverse effects

Pregnancy

Frequently asked

Breastfeeding