Open Source Apothecary At Home / Mind and sleep

Low mood and depression

St John's wort works for moderate depression and is one of the most interacting substances in this handbook. Both facts are load-bearing.

remedy

Depression is common, treatable, and the treatment with the best evidence is not a herb. Psychological therapy and, where indicated, medication, have the outcome data — and this page exists because the opposite is often implied by the herbal industry.

St John's wort has the best trial evidence of any herb for depression. Pooled analyses in mild to moderate depression show effects comparable to standard antidepressants in some trials, with fewer side effects than SSRIs in several comparisons, though the trials are heterogeneous and the preparations vary enormously in hyperforin content. The interaction profile is the critical part: St John's wort induces CYP3A4, CYP2C19 and P-glycoprotein, and it measurably reduces blood levels of a long list of drugs. In a systematic review and meta-analysis it significantly decreased the exposure to midazolam, a probe for CYP3A4. The practical consequences include failure of hormonal contraception, reduced immunosuppressant levels with the risk of organ rejection, reduced antiretroviral levels, and reduced anticoagulant effect. It also causes serotonin syndrome in combination with SSRIs, triptans, tramadol and other serotonergic drugs. And it causes photosensitivity.

Saffron has small trials in depression showing effects over placebo, sometimes comparable to an SSRI at low dose. The trials are small and the product is expensive.

Omega-3 — pooled analyses show a small effect in depression, strongest for EPA-dominant preparations. The evidence is inconsistent.

Exercise has randomised evidence for depression, with effect sizes comparable to medication for mild to moderate depression in some trials. This is the strongest non-pharmacological recommendation on the page.

The safety framing is the most important part of this page. Depression can be severe, it can be fatal, and a person who is having suicidal thoughts needs help today, not a supplement trial. Anything that delays effective treatment — including a well-meaning suggestion to try an herb first — costs time that matters.

What the studies found

Preparation

St John's wort

• Standardised extract with a stated hyperforin content; trials have commonly used 300 mg three times daily of a 0.3% hyperforin extract
• Read the interaction list before taking it. It affects many drugs.
• Do not combine with an SSRI, SNRI, triptan, tramadol, or other serotonergic drug. Serotonin syndrome is a medical emergency.
• Causes photosensitivity: use sun protection
• Do not start or stop abruptly; it affects drug levels going in both directions
• Never with ciclosporin, tacrolimus, antiretrovirals, or hormonal contraception.

Saffron

• 30 mg daily in the trials, as a standardised extract
• Expensive; small trials

Omega-3

• 1-2 g daily of EPA-dominant fish oil; the evidence is inconsistent and best for EPA-dominant preparations
• Choose a product with a stated oxidation value

Exercise

• 30-45 minutes of moderate aerobic exercise, 3-5 times weekly, has randomised evidence in depression
• Resistance training also has evidence
• The effect is comparable to medication for mild to moderate depression in some trials

The interventions that are the actual treatment

• Psychological therapy — CBT, behavioural activation, interpersonal therapy, all with strong evidence
• Antidepressant medication where indicated, which is a clinician's decision
• Sleep, alcohol reduction, and social contact, all of which have measurable effects
• Sunlight and vitamin D where deficient, particularly at high latitude in winter

If there is any suicidal thought

• Get help today. In the US, call or text 988. The emergency department if there is immediate risk.
• Do not start a supplement trial instead.

Cautions and interactions

• St John's wort interacts with a very long list of drugs. Hormonal contraception, immunosuppressants, antiretrovirals, anticoagulants, and many others.
• St John's wort + serotonergic drugs = serotonin syndrome risk. Do not combine.
• St John's wort causes photosensitivity.
• Do not use St John's wort in pregnancy or breastfeeding.
• Do not substitute a herb for treatment of severe or psychotic depression. Where there is psychosis or severe functional impairment, this is a medical emergency.

When this is not a self-care problem — get help

• Any suicidal thought, plan or intent — immediate help. Call or text 988 in the US, or emergency services.
• Psychosis, severe agitation, or inability to care for yourself — emergency assessment.
• Depression with a sudden switch to elevated, agitated or unusually energetic mood — this is a change needing urgent assessment, and it occurs with some antidepressants in bipolar disorder.

Known interactions

• St John's wort: CYP3A4, CYP2C19 and P-gp induction. Reduces levels of many drugs including oral contraceptives, ciclosporin, tacrolimus, antiretrovirals, and warfarin.
• St John's wort + SSRIs, triptans, tramadol: serotonin syndrome.
• St John's wort + photosensitising drugs: additive photosensitivity.

Related

• Anxiety: kava, lavender and the herbs with trials
• Insomnia: what works before the herbs
• Herb-drug interactions: the ones with numbers behind them
• Winter low mood: light, and the things that are not a supplement
• Herbal liver injury, and the plant that ends the matter

Sources

1. Nutraceuticals and phytoceuticals in the treatment of schizophrenia: a systematic review and network meta-analysis "Nutra NMA SCZ". Molecular psychiatry 2025; doi:10.1136/bmj.n71 PubMed 39026098
2. Effect of Saffron Versus Selective Serotonin Reuptake Inhibitors (SSRIs) in Treatment of Depression and Anxiety: A Meta-analysis of Randomized Controlled Trials. Nutrition reviews 2025; doi:10.1093/nutrit/nuae076 PubMed 38913392
3. Comparative efficacy and tolerability of nutraceuticals for depressive disorder: A systematic review and network meta-analysis. Psychological medicine 2025; doi:10.1016/j.cell.2015.02.047 PubMed 40314175
4. The Effects of Aerobic and Resistance Exercise on Depression and Anxiety: Systematic Review With Meta-Analysis. International journal of mental health nursing 2025; doi:10.1016/j.psychres.2019.112601 PubMed 40432290
5. Exercise Interventions for Depression, Anxiety, and Quality of Life in Older Adults With Cancer: A Systematic Review and Meta-Analysis. JAMA network open 2025; doi:10.1200/JCO.23.02780 PubMed 39903465
6. Impact of postpartum physical activity on maternal depression and anxiety: a systematic review and meta-analysis. British journal of sports medicine 2025; doi:10.1136/bjsports-2024-108478 PubMed 39500542