Depression and complementary medicines

Around one in 16 Australians will suffer from depression at some time during their life.1,2 What evidence is there that complementary medicines such as S-Adenosyl-L-methionine and St John’s wort offer any relief? 

The World Health Organization has predicted that depression will be the number one health problem in the world (both in developed and developing nations) by 2030.3

Mental health should be treated holistically and medicines only form part of this treatment. Encourage patients to discuss any complementary therapy they take for mental health with their doctor and pharmacist to see if it can form part of a mental health care plan.


What is it?

S-Adenosyl-L-methionine (SAMe) is an endogenous enzyme cofactor, acting as a methyl group donor for biochemical reactions and cellular functions. SAMe synthesis is linked to folic acid and vitamin B12 metabolism and levels.4,5

Evidence for depression

The 2015 Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines advise that SAMe may help alleviate depressive symptoms when used as an adjunct to prescription medication.6

A 2016 Cochrane review of eight RCTs (n = 934) couldn’t draw any firm conclusions about the effects of SAMe (as monotherapy or add-on therapy to SSRIs) on depression in adults. Separating data on oral and parenteral administration of SAMe did not affect the outcome. SAMe target oral dose was 1,600 mg daily, and target parenteral dose was 200–400 mg daily. Treatment duration was 2–12 weeks.4

A 2017 systematic review of 115 clinical trials found promising but limited evidence of efficacy and safety to support the use of SAMe as monotherapy or add-on therapy in major depressive disorder.

In addition, preliminary evidence suggested that SAMe may ameliorate symptoms in certain neurocognitive, substance abuse and psychotic disorders, and comorbid medical conditions.7

Suggested counselling advice

SAMe may take 8 weeks or more of daily use to improve symptoms of depression.4

SAMe can cause gastrointestinal upset (e.g. nausea, heartburn, diarrhoea). It can also interact with certain medicines.5,7

Ask your pharmacist or doctor before taking SAMe in combination with any other medicines.

St John’s wort

What is it?

Native to Europe, St John’s wort (Hypericum perforatum) is a perennial plant now found in many parts of the world. The flowers and aerial parts have been used medicinally for millennia.

Evidence for depression

A 2008 updated Cochrane review of 29 RCTs lasting 4–12 weeks (n = 5,489) in patients with major depression included 18 comparisons with placebo and 17 comparisons with conventional antidepressants.

The authors concluded that the hypericum extracts tested in the included trials were superior to placebo in patients with major depression, had similar effectiveness to standard antidepressants and had fewer side e­ffects than standard antidepressants. However, the size of the e­ffect was dependent on the country of origin of the St John’s wort and the precision of the trials.8

A 2016 systematic review of 35 RCTs (n = 6,993) concluded that St John’s wort monotherapy for ≥4 weeks is superior to placebo and not significantly di­fferent from antidepressants for improving symptoms of mild to moderate depression. Heterogeneity between studies and lack of research on severe depression reduced the quality of the evidence.9

A 2017 meta-analysis of 27 RCTs (n = 3,808) concluded that the efficacy and safety of St John’s wort are comparable to those of SSRIs in mild to moderate depression. Duration of studies was 4–12 weeks.10

Suggested counselling advice

St John’s wort may take 4 weeks or more of daily use to improve symptoms of depression.8,9,10 Take St John’s wort in the morning, because evening doses can cause insomnia.5

St John’s wort can make your skin more sensitive to the sun (and other ultraviolet light). Protect your skin from the sun while using St John’s wort.5

St John’s wort interacts with many medicines. Ask your pharmacist or doctor before taking St John’s wort in combination with any other medicines.11

Do not stop taking St John’s wort abruptly unless advised by your doctor. If you stop treatment abruptly (e.g. miss one or two doses), you may get withdrawal effects, such as headache, nausea, dizziness, fatigue and sleep problems.5,12

Learn more

For more evidence-based information about these and other complementary medicines – including clinical notes on adverse e­ffects, contraindications and interactions, as well as full references, refer to the Australian Pharmaceutical Formulary and Handbook 24th edition (APF24). APF is available in print or digital format. Digital APF is available at (subscription required).


  1. Australian Bureau of Statistics. National survey of mental health and wellbeing: summary of results. 2007. At:
  2. Tiller J. Depression and anxiety. MJA Open. 2012;Suppl4:28−32.
  3. World Health Organization. Global burden of mental disorders and the need for a comprehensive, coordinated response from health and social sectors at the country level. 2011. At:
  4. Galizia I, Oldani L, Macritchie K, et al. S-adenosyl methionine (SAMe) for depression in adults. Cochrane Database of Systematic Reviews 2016, Issue 10.
  5. Gregory PJ. Natural medicines. 2017. At:
  6. Mahli G, Bassett D, Boyce P, et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Aust N Z J Psychiatry 2015;49(12):1–185.
  7. Sharma A, Gerbarg P, Bottiglieri T, et al. S-adenosylmethionine (SAMe) for neuropsychiatric disorders: a clinician-oriented review of research. J Clin Psychiatry 2017;78(6):e656–67.
  8. Linde K, Berner MM, Kriston L. St John’s wort for major depression. Cochrane Database of Systematic Reviews 2008, Issue 4.
  9. Apaydin EA, Maher AR, Shanman R, et al. A systematic review of St. John’s wort for major depressive disorder. Syst Rev 2016;5(1):148.
  10. Ng QX, Venkatanarayanan N, Ho CY. Clinical use of Hypericum perforatum (St John’s wort) in depression: a meta-analysis. J Affect Disord 2017;210:211–21.
  11. Williamson E, Driver S, Baxter K, eds. Stockley’s herbal medicines interactions. 2nd edn. London: Pharmaceutical Press; 2013.
  12. Brayfield A, ed. Martindale: the complete drug reference. London: Pharmaceutical Press. At: