Natural Compound

St. John's Wort

Hypericum perforatum

Evidence TierAWADA NOT PROHIBITED

tuneTypical Dose

300–900 mg per day (standardized to 0.3% hypericin)

watchEffect Window

4-6 weeks for full antidepressant effect

check_circleCompliance

WADA NOT PROHIBITED

Overview

Clinical Summary

St. John’s wort (Hypericum perforatum) contains hyperforin and related compounds that affect neurotransmitter systems. It is used for mild-to-moderate depressive symptoms and related anxiety and sleep complaints.

Meta-analyses support efficacy for mild-to-moderate depression, often comparable to standard antidepressants with fewer sexual side effects in some studies. Anxiety and sleep can improve when depressive symptoms remit. Minority evidence includes benefits for menopausal symptoms and somatic symptom burden. Extensive drug interactions through enzyme induction can reduce effectiveness of many medications, which can negate benefit.

Non-selective reuptake inhibitor of serotonin, dopamine, and norepinephrine via hypericin and hyperforin. Also induces CYP3A4, CYP2C9, CYP1A2, and P-glycoprotein.

Outcomes

What This Is Expected To Influence

Primary Outcomes

  • Alleviation of mild-to-moderate depression
  • Mood improvement comparable to SSRIs

Secondary Outcomes

  • Fewer side effects than prescription SSRIs (less sexual dysfunction, less emotional blunting)

Safety

Contraindications and Interactions

Contraindications

  • Concurrent SSRIs/SNRIs/MAOIs or other serotonergic drugs
  • Oral contraceptives or other hormonal therapies (reduced efficacy and unintended pregnancy risk)
  • Immunosuppressants (cyclosporine, tacrolimus)
  • HIV protease inhibitors and related antiretrovirals
  • Warfarin and anticoagulants
  • Bipolar disorder
  • Pregnancy or lactation without clinician oversight

Side effects

  • Photosensitivity
  • GI upset (abdominal pain, indigestion, stomach cramps, nausea)
  • Headache
  • Fatigue
  • Insomnia
  • Dizziness
  • Dry mouth

Interactions

  • CYP3A4 induction (oral contraceptives/hormonal agents, statins, cyclosporine, tacrolimus, digoxin)
  • CYP2C9 induction (warfarin)
  • CYP1A2/CYP2C19 substrate interactions (reduced medication exposure possible)
  • P-glycoprotein induction (HIV antiretrovirals, some chemotherapy agents)
  • Digoxin (probable/moderate reduction in exposure)
  • Zolpidem (possible/moderate reduction in exposure)
  • Clozapine (possible/moderate reduction in exposure or efficacy)
  • Serotonergic drugs (SSRIs, SNRIs, MAOIs, triptans, with serotonin syndrome risk)

Avoid if

  • Taking prescription medications without interaction screening
  • Bipolar disorder
  • Relying on oral contraceptives or hormonal contraception
  • Pregnancy or lactation
  • Severe major depression

Evidence

Study-level References

st-johns-wort-SRC-001Meta-analysis of 29 RCTs (5489 patients)
Sourceopen_in_new

Linde K, et al. "St John's wort for major depression." Cochrane Database Syst Rev. 2008.

Population: Patients with major depression (mild-to-moderate)

Key findings: St. John's wort extracts are superior to placebo in patients with major depression, are similarly effective as standard antidepressants, and have fewer side effects than standard antidepressants.

Paper content

St. John's wort extracts are superior to placebo in patients with major depression, are similarly effective as standard antidepressants, and have fewer side effects than standard antidepressants.

st-johns-wort-SRC-002Prospective observational study.
Sourceopen_in_new

Kalbermatten N, Saller R. St John's Wort (Hypericum perforatum) fresh plant tincture for patients with mild to moderate depression: a prospective observational study. Complement Med Res. 2025. doi:10.1159/000547920. PMID:40906611.

Population: 52 adults with mild to moderate depressive episodes (ICD-10/DSM-IV), 75% female, mean age 51 years.

Dose protocol: Fresh plant tincture daily for 6 weeks in mild to moderate depression

Key findings: HAM-D decline of 49-52% with responder rates of 50-57%, comparable to reference high-dose dry extract trials. Adverse event rate only 4%.

Notes: Observational, no placebo arm. Adds real-world tolerability data for a lower-dose tincture formulation.

Paper content

This 2025 prospective observational study tested a St. John's Wort fresh plant tincture (lower dose than standard dry extract preparations) in 52 adults with mild to moderate depression over 6 weeks. The HAM-D 17 decline of 49-52% and responder rates of 50-57% were comparable to reference high-dose dry extract trial results (45-59% decline, 42-70% responder rates). The standout finding was the very low adverse event rate of 4%, notably lower than the 20-39% range seen in reference trials. The study lacks a placebo arm and randomization, so it cannot establish efficacy on its own. However, it adds real-world tolerability data and suggests that lower-dose fresh tincture preparations may achieve comparable symptom improvement with even better tolerability than standard extracts.

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