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Major Depressive Disorder (MDD)

Major depression involves shifting brain chemistry, inflammation, oxidative stress and weaker connections between neurons, not simply low serotonin. Among supplements, the evidence is strongest for curcumin, where anxiety symptoms improved in people with depression, followed by vitamin D, where depression symptoms improved, and omega-3s, which also eased anxiety. Most of these studies were small, and only curcumin's evidence reaches moderate.

Sources: PMID 23832433; PMID 39450108; PMID 30317101

Supplements studied
9
Graded outcomes
8
Trials
9
People studied
1,084

Evidence by supplement

  • Strong
  • Moderate
  • Limited
  • Very limited

9 supplements

Saffron

Saffron: outcomes studied for Major Depressive Disorder (MDD)
GradeOutcomeEffectSizeStudiesPeopleStudies list
Blood glucose

Small Improvement

Improves (the measure goes down)Small effect6 studies20 people

Studies that measured blood glucose

and 3 more on the Saffron page

TriglyceridesImproves (the measure goes down)2 studies20 people

Studies that measured triglycerides

HemoglobinImproves (the measure goes up)1 study20 people

Studies that measured hemoglobin

HematocritImproves (the measure goes up)20 people
UreaImproves (the measure goes up)20 people
White Blood Cell CountImproves (the measure goes up)20 people

Vitamin D

Vitamin D: outcomes studied for Major Depressive Disorder (MDD)
GradeOutcomeEffectSizeStudiesPeopleStudies list
Depression Symptoms

Small Improvement

Improves (the measure goes down)Small effect5 studies40 people

Studies that measured depression symptoms

and 2 more on the Vitamin D page

Glycemic ControlImproves (the measure goes up)4 studies40 people

Studies that measured glycemic control

and 1 more on the Vitamin D page

InsulinChanges; see studies3 studies40 people

Studies that measured insulin

Omega-3 Fatty Acids

  • Anxiety Symptoms: improves
  • Depression Symptoms: improves
  • Sleep Quality: improves
Omega-3 Fatty Acids: outcomes studied for Major Depressive Disorder (MDD)
GradeOutcomeEffectSizeStudiesPeopleStudies list
Anxiety Symptoms

Small Improvement

Improves (the measure goes down)Small effect2 studies50 people

Studies that measured anxiety symptoms

Depression SymptomsImproves (the measure goes down)5 studies50 people

Studies that measured depression symptoms

and 2 more on the Omega-3 Fatty Acids page

Sleep QualityImproves (the measure goes up)50 people

Bacopa Monnieri

  • Anhedonia: improves
  • Depression Symptoms: changes; see studies
Bacopa Monnieri: outcomes studied for Major Depressive Disorder (MDD)
GradeOutcomeEffectSizeStudiesPeopleStudies list
Anhedonia

Small Improvement

Improves (the measure goes down)Small effect1 study42 people

Studies that measured anhedonia

Depression SymptomsChanges; see studies42 people

L-Carnitine

  • Cortisol: improves
  • Depression Symptoms: improves
L-Carnitine: outcomes studied for Major Depressive Disorder (MDD)
GradeOutcomeEffectSizeStudiesPeopleStudies list
Cortisol

Small Decrease

Improves (the measure goes down)Small effect30 people
Depression SymptomsImproves (the measure goes down)2 studies30 people

Studies that measured depression symptoms

Curcumin

  • Anxiety Symptoms: improves
  • Depression Symptoms: improves
Curcumin: outcomes studied for Major Depressive Disorder (MDD)
GradeOutcomeEffectSizeStudiesPeopleStudies list
Anxiety Symptoms

Large Improvement

Improves (the measure goes down)Large effect111 people
Depression SymptomsImproves (the measure goes down)9 studies156 people

Studies that measured depression symptoms

and 6 more on the Curcumin page

Agmatine

  • Depression Symptoms: improves
Agmatine: outcomes studied for Major Depressive Disorder (MDD)
GradeOutcomeEffectSizeStudiesPeopleStudies list
Depression Symptoms

Case series only (n=3) - very preliminary

Improves (the measure goes down)Moderate effect3 people

N-Acetylcysteine

  • Anxiety Symptoms
  • Depression Symptoms: improves
N-Acetylcysteine: outcomes studied for Major Depressive Disorder (MDD)
GradeOutcomeEffectSizeStudiesPeopleStudies list
Anxiety Symptoms

No effect

NoneNo effect315 people
Depression SymptomsImproves (the measure goes down)4 studies579 people

Studies that measured depression symptoms

and 1 more on the N-Acetylcysteine page

Chromium

  • Depression Symptoms: improves
Chromium: outcomes studied for Major Depressive Disorder (MDD)
GradeOutcomeEffectSizeStudiesPeopleStudies list
Depression SymptomsImproves (the measure goes down)4 studies15 people

Studies that measured depression symptoms

and 1 more on the Chromium page

Key findings

  • Blood glucoseSaffronImproves (the measure goes down)
  • Depression SymptomsVitamin DImproves (the measure goes down)
  • Anxiety SymptomsOmega-3 Fatty AcidsImproves (the measure goes down)

The Major Depressive Disorder protocol

2 primary supplements · 4 supporting supplements

See the full protocol

Shop the evidence-backed picks

Support alongside medical care. These supplements are not a treatment for Major Depressive Disorder (MDD). If you are being treated for it, talk to your clinician before adding one: supplements can interact with medicines.

Fullscript collectionStress and mood: evidence-graded picksOpen on Fullscript

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Studies cited

48 studies from PubMed

  1. Vitamin D protects against depression: Evidence from an umbrella meta-analysis on interventional and observational meta-analyses.Pharmacol Res · PMID 36509315
  2. The effect of vitamin D supplementation on depression: a systematic review and dose-response meta-analysis of randomized controlled trials.Psychol Med · PMID 39552387
  3. Vitamin D Supplementation Affects the Beck Depression Inventory, Insulin Resistance, and Biomarkers of Oxidative Stress in Patients with Major Depressive Disorder: A Randomized, Controlled Clinical TrialJ Nutr · PMID 26609167
  4. Vitamin D3 supplementation improves insulin sensitivity in subjects with impaired fasting glucoseTransl Res · PMID 22005267
  5. Effects of cholecalciferol supplementation on depressive symptoms, C-peptide, serotonin, and neurotrophin-3 in type 2 diabetes mellitus: A double-blind, randomized, placebo-controlled trial.Narra J · PMID 39816051
  6. Efficacy of vitamin D supplementation on glycaemic control in type 2 diabetes: An updated systematic review and meta-analysis of randomized controlled trials.Diabetes Obes Metab · PMID 39355942
  7. The effect of vitamin D3 on insulin secretion and peripheral insulin sensitivity in type 2 diabetic patientsInt J Clin Pract · PMID 12800453
  8. Evaluating the effects of vitamin D and vitamin E supplement on premenstrual syndrome: A randomized, double-blind, controlled trialIran J Nurs Midwifery Res · PMID 27095989
  9. Efficacy of vitamin D supplementation on depressive symptoms in older patients: a meta-analysis of randomized controlled trials.Front Med · PMID 39450108
  10. Effects of vitamin D and calcium supplementation on pancreatic β cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the Calcium and Vitamin D for Diabetes Mellitus (CaDDM) randomized controlled trialAm J Clin Nutr · PMID 21715514
  11. A randomized, placebo-controlled trial of vitamin D supplementation to improve glycaemia in overweight and obese African AmericansDiabetes Obes Metab · PMID 22486948
  12. Impact of vitamin D supplementation during a resistance training intervention on body composition, muscle function, and glucose tolerance in overweight and obese adultsClin Nutr · PMID 23034474
  13. Safety evaluation of saffron (Crocus sativus) tablets in healthy volunteersPhytomedicine · PMID 18693099
  14. The effect of saffron supplementation on liver and kidney function, blood glucose and pressure in patients with diabetes and prediabetes: A grade assessed systematic review and meta-analysis of randomized controlled trials.Prostaglandins Other Lipid Mediat · PMID 39818282
  15. Effect of Crocus sativus L. (saffron) and crocin in the treatment of patients with type-2 diabetes mellitus: A systematic review and meta-analysis.J Ethnopharmacol · PMID 37778521
  16. Effects Of Saffron Supplementation On Inflammation And Metabolic Responses In Type 2 Diabetic Patients: A Randomized, Double-Blind, Placebo-Controlled TrialDiabetes Metab Syndr Obes · PMID 31686882
  17. Effects of Cinnamon, Cardamom, Saffron, and Ginger Consumption on Markers of Glycemic Control, Lipid Profile, Oxidative Stress, and Inflammation in Type 2 Diabetes PatientsRev Diabet Stud · PMID 26177486
  18. The effect of hydroalcoholic Saffron (Crocus sativus L.) extract on fasting plasma glucose, HbA1c, lipid profile, liver, and renal function tests in patients with type 2 diabetes mellitus: A randomized double-blind clinical trialPhytother Res · PMID 30942510
  19. Effects of Crocus sativus on glycemic control and cardiometabolic parameters among patients with metabolic syndrome and related disorders: a systematic review and meta-analysis of randomized controlled trials.Nutr Metab · PMID 38796446
  20. The effect of saffron (Crocus sativus L.) hydroalcoholic extract on metabolic control in type 2 diabetes mellitus: A triple-blinded randomized clinical trialJ Res Med Sci · PMID 29531568
  21. Saffron and crocin improved appetite, dietary intakes and body composition in patients with coronary artery diseaseJ Cardiovasc Thorac Res · PMID 29391933
  22. Influence of adjuvant omega-3-polyunsaturated fatty acids on depression, sleep, and emotion regulation among outpatients with major depressive disorders - Results from a double-blind, randomized and placebo-controlled clinical trialJ Psychiatr Res · PMID 30317101
  23. Omega-3 fatty acids for depression in adultsCochrane Database Syst Rev · PMID 34817851
  24. Omega-3 for bipolar disorder: meta-analyses of use in mania and bipolar depressionJ Clin Psychiatry · PMID 21903025
  25. Exploration of the optimized portrait of omega-3 polyunsaturated fatty acids in treating depression: A meta-analysis of randomized-controlled trials.J Affect Disord · PMID 40049535
  26. Effects of long-chain omega-3 polyunsaturated fatty acids on reducing anxiety and/or depression in adults; A systematic review and meta-analysis of randomised controlled trialsProstaglandins Leukot Essent Fatty Acids · PMID 37028202
  27. Omega-3 fatty acids for depression in adultsCochrane Database Syst Rev · PMID 26537796
  28. Efficacy and safety of omega-3 fatty acids supplementation for anxiety symptoms: a systematic review and dose-response meta-analysis of randomized controlled trials.BMC Psychiatry · PMID 38890670
  29. N-acetylcysteine as an adjunctive treatment for bipolar depression and major depressive disorder: a systematic review and meta-analysis of double-blind, randomized placebo-controlled trials.Psychopharmacology · PMID 32767039
  30. N-acetylcysteine as an adjunctive treatment for bipolar depression: A systematic review and meta-analysis of randomized controlled trials.Bipolar Disord · PMID 33354859
  31. The effect of N-acetylcysteine on bipolar depression: a systematic review and meta-analysis of randomized controlled trials.Psychopharmacology · PMID 33641060
  32. N-Acetylcysteine in depressive symptoms and functionality: a systematic review and meta-analysis.J Clin Psychiatry · PMID 27137430
  33. Efficacy and safety of curcumin in major depressive disorder: a randomized controlled trialPhytother Res · PMID 23832433
  34. Investigation of the efficacy of adjunctive therapy with bioavailability-boosted curcuminoids in major depressive disorderPhytother Res · PMID 25091591
  35. An investigation of the effects of curcumin on anxiety and depression in obese individuals: A randomized controlled trialChin J Integr Med · PMID 25776839
  36. Add-on Treatment with Curcumin Has Antidepressive Effects in Thai Patients with Major Depression: Results of a Randomized Double-Blind Placebo-Controlled StudyNeurotox Res · PMID 29327213
  37. Curcumin as an add-on to antidepressive treatment: a randomized, double-blind, placebo-controlled, pilot clinical studyClin Neuropharmacol · PMID 23673908
  38. Chronic Supplementation of Curcumin Enhances the Efficacy of Antidepressants in Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled Pilot StudyJ Clin Psychopharmacol · PMID 26066335
  39. Curcumin for the treatment of major depression: a randomised, double-blind, placebo controlled studyJ Affect Disord · PMID 25046624
  40. Efficacy of curcumin, and a saffron/curcumin combination for the treatment of major depression: A randomised, double-blind, placebo-controlled studyJ Affect Disord · PMID 27723543
  41. Curcumin for depression: a meta-analysisCrit Rev Food Sci Nutr · PMID 31423805
  42. Chromium potentiation of antidepressant pharmacotherapy for dysthymic disorder in 5 patientsJ Clin Psychiatry · PMID 10221284
  43. Effectiveness of chromium in atypical depression: a placebo-controlled trialBiol Psychiatry · PMID 12559660
  44. A double-blind, placebo-controlled, exploratory trial of chromium picolinate in atypical depression: effect on carbohydrate cravingJ Psychiatr Pract · PMID 16184071
  45. A 2-year, open-label pilot study of adjunctive chromium in patients with treatment-resistant rapid-cycling bipolar disorderJ Clin Psychopharmacol · PMID 17224731
  46. L-Acetylcarnitine in dysthymic disorder in elderly patients: a double-blind, multicenter, controlled randomized study vs. fluoxetineEur Neuropsychopharmacol · PMID 23428336
  47. Acetyl-L-Carnitine Supplementation and the Treatment of Depressive Symptoms: A Systematic Review and Meta-AnalysisPsychosom Med · PMID 29076953
  48. Bacopa monnieri as augmentation therapy in the treatment of anhedonia, preclinical and clinical evaluationPhytother Res · PMID 32236999