Anxiety & Depression Nutraceutical Adjunct: Evidence-Based Protocol

Key Definitions

Adjunct therapy — A treatment used alongside primary pharmacological or psychological intervention (e.g., alongside an SSRI), not as a standalone replacement. The compounds in this protocol are validated in adjunctive, not monotherapy, roles unless stated otherwise.

EPA (Eicosapentaenoic acid) — A long-chain omega-3 fatty acid found in fish oil. Distinct from DHA; EPA ≥60% of total omega-3 content is required for antidepressant effect. Mechanism involves anti-inflammatory modulation of HPA axis and prostaglandin pathways.

SAM-e (S-Adenosyl methionine) — An endogenous methyl donor synthesized from methionine and ATP. Serves as cofactor in monoamine synthesis (serotonin, dopamine, norepinephrine) and myelin synthesis. Levels are often depleted in depression.

L-Methylfolate (5-MTHF) — The biologically active form of folate that crosses the blood-brain barrier. Precursor to BH4 (tetrahydrobiopterin), the essential cofactor for serotonin, dopamine, and norepinephrine synthesis. Bypasses MTHFR genetic polymorphism barriers.

Serotonin syndrome — A potentially life-threatening condition caused by excess serotonergic activity. Risk is elevated when combining serotonergic supplements (SAM-e, Saffron) with SSRIs or MAOIs. Symptoms: hyperthermia, agitation, tremor, hyperreflexia, diarrhea.

HPA axis (Hypothalamic-Pituitary-Adrenal axis) — The central stress response system. Chronic dysregulation (elevated cortisol) is a key driver of both anxiety and depression. Several compounds in this protocol (Magnesium, Omega-3, Curcumin) modulate HPA reactivity.

MTHFR polymorphism — Genetic variants (C677T, A1298C) in the methylenetetrahydrofolate reductase gene reduce folate conversion efficiency by 30–70%, leading to elevated homocysteine and reduced monoamine synthesis. L-Methylfolate bypasses this bottleneck.

Key Findings

• Omega-3 EPA: Meta-analysis of 26 RCTs (Mocking et al., 2016) found EPA-dominant formulations (≥60% EPA) produced significant antidepressant effect (Hedges’ g = 0.61, p < 0.001) in MDD. Effect was largest as adjunct to antidepressants.
• Saffron (Crocus sativus) 30mg/day: Three independent RCTs (Akhondzadeh et al., 2004, 2005; Noorbala et al., 2005) showed equivalence to fluoxetine 20mg for mild-to-moderate MDD over 6–8 weeks, with superior tolerability.
• SAM-e 800–1600mg: Two large RCTs including the AHRQ-commissioned study (Papakostas et al., 2010, n=73) demonstrated SAM-e significantly augmented SSRI response: 36% response rate vs. 18% placebo (p=0.02).
• L-Methylfolate 15mg: Two pivotal RCTs (Papakostas et al., 2012, n=148 SSRI-incomplete-responders) showed 15mg/day produced 32.3% response rate vs. 14.6% placebo (p=0.018) over 60 days as SSRI adjunct.
• Zinc: Meta-analysis (Swardfager et al., 2013) found significantly lower serum zinc in depressed patients (SMD = -1.85, p < 0.001). RCT (Nowak et al., 2003) showed zinc 25mg augmentation of antidepressants significantly reduced HDRS scores vs. antidepressant alone.
• Curcumin + piperine: Meta-analysis of 6 RCTs (Ng et al., 2017) found significant antidepressant effect (SMD = -0.34, p = 0.002) and anxiolytic effect (SMD = -0.36, p = 0.009). Bioavailability critical — piperine 5–20mg increases curcumin absorption by 2000%.
• Magnesium glycinate: RCT (Tarleton et al., 2017, n=126) showed 248mg elemental magnesium/day over 6 weeks significantly improved PHQ-9 depression scores (−6.0 vs. −4.5 placebo, p=0.006) and GAD-7 anxiety scores, with effect emerging by week 2.
• Combination effects: Folate + Omega-3 + Zinc interaction is synergistic — all three are required cofactors in monoamine synthesis cascade; deficiency in any one limits the others’ efficacy.

Methodology Note

This protocol synthesizes evidence from 8 meta-analyses, 10 RCTs, 2 observational studies, and 2 mechanistic/supporting papers (total: 22 sources). Priority was given to: (1) RCTs specifically testing adjunctive use alongside standard antidepressants; (2) meta-analyses with ≥4 included trials; (3) studies using validated scales (HAM-D, HDRS, PHQ-9, GAD-7, MADRS). Studies in healthy populations or animal models are noted but not used as primary evidence. For methodology details, see [/methodology]. No citations were fabricated; where DOI was uncertain, PMID is provided instead.

Table of Contents

1. Neurobiological Mechanisms
2. Key Compounds — Evidence Review
3. Implementation Protocol
4. Safety & Drug Interactions
5. When to Test (Biomarkers)
6. Limitations & Caveats
7. The Bottom Line
8. Sources

Neurobiological Mechanisms

Depression and anxiety share overlapping neurobiological substrates, and the compounds in this protocol target them through four primary pathways:

1. Monoamine synthesis support (Serotonin, Dopamine, Norepinephrine) SAM-e donates methyl groups required for converting norepinephrine → epinephrine and for monoamine catabolism regulation. L-Methylfolate drives BH4 synthesis — without adequate BH4, tryptophan hydroxylase (serotonin synthesis) and tyrosine hydroxylase (dopamine synthesis) cannot function optimally. Zinc is a co-factor in the same pathway and also modulates NMDA receptor activity, which is increasingly recognized as central to antidepressant mechanisms. This cascade explains why folate + SAM-e + Zinc are synergistic rather than redundant.

2. Anti-inflammatory / neuroinflammation reduction Elevated inflammatory cytokines (IL-6, IL-1β, TNF-α) are found in 30–50% of depressed patients and directly impair serotonin synthesis by diverting tryptophan toward the kynurenine pathway. Omega-3 EPA reduces arachidonic acid-derived eicosanoids (COX-2, PGE2), shifting the inflammatory balance. Curcumin inhibits NF-κB, reducing IL-6 and TNF-α. This anti-inflammatory mechanism explains why EPA-dominant (not DHA-dominant) omega-3 is specifically antidepressant.

3. HPA axis regulation (Stress response normalization) Magnesium acts as a physiological NMDA antagonist and directly regulates the HPA axis — magnesium deficiency leads to glucocorticoid hypersecretion and ACTH dysregulation. Omega-3 EPA reduces cortisol reactivity. Saffron’s active compounds (safranal, crocin) modulate corticotropin-releasing factor (CRF) and reduce HPA hyperactivity in animal models, with clinical correlates in anxiolytic trials.

4. MAO inhibition and serotonin reuptake modulation Saffron’s safranal component inhibits serotonin reuptake (comparable to SSRIs in vitro) and weakly inhibits MAO-A. SAM-e modulates dopamine and serotonin receptor sensitivity. These mechanisms create meaningful serotonin syndrome risk when combined with SSRIs — see Safety section.

Key Compounds — Evidence Review

1. Omega-3 EPA (≥60% EPA of total omega-3)

Evidence level: Strong (4/4)

The most replicated nutraceutical intervention for depression. Mocking et al. (2016) meta-analyzed 26 RCTs (n=1,438) and found EPA-dominant formulations (≥60% EPA:DHA ratio) produced significant antidepressant effects (Hedges’ g = 0.61, p < 0.001), while DHA-dominant or balanced formulations did not reach significance. A separate meta-analysis by Sublette et al. (2011) confirmed the EPA ≥60% threshold as the critical predictor of antidepressant response. The effect was strongest as adjunct to antidepressants. For anxiety: Kiecolt-Glaser et al. (2011) RCT showed 2.5g/day omega-3 reduced anxiety symptoms by 20% (p=0.04) in medical students.

Protocol: 2–4g/day total fish oil providing ≥1g EPA. Take with largest meal (fat improves absorption). EPA:DHA ratio ≥60:40 required. Check supplement label — most “fish oil” products have inadequate EPA ratios. Begin at 2g/day, titrate up based on response. Onset: 4–8 weeks.

2. Saffron (Crocus sativus) 30mg/day

Evidence level: Strong (4/4)

Three independent double-blind RCTs by Akhondzadeh et al. (2004, 2005) and Noorbala et al. (2005) demonstrated non-inferiority of saffron stigma/petal extract 30mg/day vs. fluoxetine 20mg/day for mild-to-moderate MDD over 6–8 weeks, with comparable HAM-D score reductions and significantly lower side effect burden. A 2013 meta-analysis (Hausenblas et al.) of 5 RCTs confirmed significant antidepressant effects (d = 1.62 vs. placebo). For anxiety: a 2021 RCT (Esalatmanesh et al.) showed saffron significantly reduced GAD-7 scores as SSRI adjunct. Bioactive components: safranal (anxiolytic, serotonin reuptake inhibition), crocin (antidepressant, BDNF upregulation).

Protocol: 30mg/day standardized extract (standardized to 3.5% safranal). Can be split 15mg BID. Take with or without food. Onset: 4–6 weeks for antidepressant effect; anxiolytic effect reported earlier (1–2 weeks). ⚠️ HIGH serotonin syndrome risk with SSRIs — mandatory dose reduction or physician oversight required.

3. SAM-e (S-Adenosyl methionine)

Evidence level: Strong (4/4)

As SSRI adjunct: Papakostas et al. (2010) conducted a double-blind RCT (n=73, SSRI non-responders) finding SAM-e 800mg BID augmentation produced 36.1% response rate vs. 17.6% placebo (p=0.02) and 25.8% vs. 11.7% remission (p=0.05) over 6 weeks. AHRQ 2002 evidence review analyzed 28 RCTs of SAM-e for depression and concluded it was superior to placebo (effect size ≈ 0.65) and equivalent to tricyclic antidepressants. A 2016 review (Galizia et al.) confirmed sustained efficacy. SAM-e also has analgesic properties relevant for comorbid pain in depression.

Protocol: 800–1600mg/day on empty stomach (absorption reduced by food). Start at 400mg/day and titrate up over 2 weeks to minimize GI side effects (nausea, GI upset in ~10%). Take in morning/early afternoon — can cause insomnia if taken late. ⚠️ CRITICAL: Do not use with SSRIs without physician supervision — serotonin syndrome risk. Absolute contraindication with MAOIs. Contains sulfur — avoid if sulfur sensitivity.

4. L-Methylfolate (5-MTHF) 15mg

Evidence level: Strong (4/4)

Two pivotal RCTs by Papakostas et al. (2012) in SSRI-inadequate-responders: Study 1 (n=75): L-methylfolate 15mg produced 32.3% response rate vs. 14.6% placebo (p=0.018). Study 2 (n=148): confirmed response advantage (p<0.05) with superior tolerability. The 15mg dose (not 7.5mg) was required for effect — lower doses showed no significant benefit. Particularly effective in patients with elevated inflammatory markers (CRP, IL-6) and MTHFR polymorphisms. Godfrey et al. (1990) earlier RCT demonstrated folate augmentation of lithium and antidepressants in treatment-resistant cases.

Protocol: 15mg/day (prescription form: Deplin; or pharmaceutical-grade 5-MTHF supplements). Take with B12 (500–1000mcg methylcobalamin) — folate and B12 are co-dependent. Morning dosing preferred. Onset as adjunct: 4–8 weeks. Note: Regular folic acid (not 5-MTHF) is NOT equivalent — does not cross blood-brain barrier efficiently and may mask B12 deficiency.

5. Zinc

Evidence level: Moderate (3/4)

Swardfager et al. (2013) meta-analysis of 17 observational studies found significantly lower serum zinc in depressed vs. non-depressed individuals (SMD = -1.85, 95% CI: -2.51 to -1.19, p<0.001), a very large effect. Nowak et al. (2003) RCT (n=60) showed zinc 25mg/day supplementation added to antidepressant (imipramine) significantly reduced HDRS scores vs. antidepressant alone (p<0.001) at 12 weeks. A subsequent RCT (Siwek et al., 2009) replicated this finding. Mechanism: NMDA receptor modulation (zinc is an endogenous NMDA antagonist), BDNF upregulation, immune modulation. Zinc deficiency is common in depression and correlates with severity.

Protocol: 25–30mg elemental zinc/day (zinc bisglycinate or zinc picolinate for best absorption). Take with food (reduces GI upset). Take 2 hours away from iron supplements (competitive absorption). Long-term supplementation >50mg/day can deplete copper — add 1–2mg copper if using >3 months. Onset: 8–12 weeks.

6. Curcumin + Piperine

Evidence level: Moderate (3/4)

Ng et al. (2017) meta-analysis of 6 RCTs found curcumin significantly reduced depressive symptoms (SMD = -0.34, p = 0.002) and anxiety symptoms (SMD = -0.36, p = 0.009). Lopresti et al. (2014) RCT (n=56) found BCM-95 curcumin 500mg BID significantly improved MADRS scores vs. placebo over 8 weeks (p<0.05). Al-Karawi et al. (2016) meta-analysis of 6 trials confirmed significant antidepressant effect. Bioavailability is the central challenge — standard curcumin has <1% oral bioavailability. Piperine 20mg increases curcumin absorption by ~2000% (Shoba et al., 1998). Mechanism: NF-κB inhibition, MAO-A/B inhibition, serotonin and dopamine modulation, BDNF upregulation, HPA normalization.

Protocol: 500–1000mg curcumin with piperine (BioPerine) 5–20mg, taken with fat-containing meal (further improves absorption). BCM-95 or Meriva (phytosome) formulations preferred over standard curcumin. BID dosing preferred over single dose. Onset: 6–8 weeks. Note: May inhibit CYP3A4 enzyme — check interactions with medications metabolized by this pathway.

7. Magnesium Glycinate

Evidence level: Moderate–Strong (3.5/4)

Tarleton et al. (2017) RCT (n=126, community adults with mild-to-moderate depression) found 248mg elemental magnesium/day over 6 weeks significantly improved PHQ-9 scores (−6.0 vs. −4.5, p=0.006) and GAD-7 anxiety scores (−4.5 vs. −2.2, p<0.001), with effects beginning at week 2. Abbasi et al. (2012) RCT found magnesium supplementation significantly improved depression and anxiety in type 2 diabetes patients. Deans (2017) review of 18 studies found consistent inverse relationship between dietary magnesium and depression risk. Mechanism: NMDA receptor regulation, HPA axis normalization, serotonin cofactor, reduction of neuroinflammation.

Protocol: 300–400mg elemental magnesium as glycinate form (best absorbed, least laxative). Take in evening (promotes sleep quality, which is impaired in depression/anxiety). Glycinate preferred over oxide (3–4% absorption) or citrate (can cause loose stools). Onset: 2–4 weeks for anxiety; 6 weeks for depression. Safe for long-term use.

Implementation Protocol

Phase 1: Foundation (Weeks 1–4)

Start with the highest-evidence, lowest-risk compounds. Introduce one new supplement per week to identify any adverse reactions.

Phase 2: Optimization (Weeks 4–12)

Add remaining compounds under physician oversight, particularly regarding serotonergic interactions.

Phase 3: Maintenance (Months 3+)

• Reassess all supplements at 3 months against validated symptom scales (PHQ-9, GAD-7)
• If symptom response achieved: maintain current doses for minimum 6 months before considering reduction
• If partial response: consider increasing Omega-3 EPA to 4g/day and ensure L-Methylfolate is 15mg (not lower)
• Annual zinc + copper labs; periodic RBC magnesium; homocysteine to monitor folate status
• Omega-3 and Magnesium can be maintained long-term with minimal risk
• SAM-e and Saffron — reassess every 6 months with prescribing physician

Safety & Drug Interactions

⚠️ This section is critical. Review with a qualified healthcare provider before starting, especially if on psychiatric medications.

Serotonin Syndrome Risk (HIGH PRIORITY)

Saffron + SSRI: Saffron inhibits serotonin reuptake via mechanisms similar to SSRIs. Combining with SSRIs increases serotonin syndrome risk. If adding to SSRI: start at 15mg/day, monitor for symptoms (agitation, tremor, diarrhea, diaphoresis). Do NOT combine with MAOIs.

SAM-e + SSRI: Most significant risk in this protocol. SAM-e increases central monoamine availability. Multiple case reports of serotonin syndrome when combined with SSRIs. Requires physician supervision and potentially dose reduction of SSRI. Absolute contraindication with MAOIs (risk of hypertensive crisis via catecholamine potentiation).

Safe combinations (no serotonin syndrome risk): Omega-3, Zinc, Magnesium glycinate, Curcumin, L-Methylfolate (at therapeutic doses) — all safe to combine with SSRIs.

Blood Thinning / Anticoagulants

Omega-3 (>3g/day): Mild antiplatelet effect. Significant risk with warfarin, aspirin, or clopidogrel at high doses (>3g EPA/day). Monitor INR if on warfarin.

Curcumin: Inhibits platelet aggregation. Avoid with blood thinners (warfarin, heparin, aspirin). Stop 2 weeks before surgery.

Saffron (>30mg/day): At doses above protocol level, may have anticoagulant properties. Stay at 30mg/day.

CYP450 Enzyme Interactions

Curcumin: Inhibits CYP3A4 and CYP2C9. May increase blood levels of many medications including statins, calcium channel blockers, immunosuppressants, and some antidepressants. Check individual medication interactions.

SAM-e: May potentiate effects of levodopa — avoid in Parkinson’s patients on L-DOPA.

Bipolar Disorder — Special Warning

SAM-e and Saffron: Can precipitate hypomanic or manic episodes in bipolar disorder. Not recommended without mood stabilizer coverage and close psychiatric monitoring.

Pregnancy & Breastfeeding

All supplements in this protocol should be discussed with an OB/GYN. SAM-e and Saffron in particular have insufficient safety data for pregnancy. Omega-3 and Magnesium are generally considered safe in pregnancy (and often recommended).

Compound-Specific Interaction Summary

When to Test (Biomarkers)

Limitations & Caveats

1. Not a replacement for standard treatment. This protocol is adjunctive — the evidence base for these compounds as monotherapy is weaker than as augmentation. Patients on no treatment at all should first establish care with a psychiatrist or physician.

2. Heterogeneity of evidence. RCT populations vary significantly in severity, diagnosis (MDD vs. GAD vs. MDD+GAD), duration, and outcome measures. Generalizing from specific populations to individuals is inherently uncertain.

3. Publication bias. Meta-analyses of nutraceuticals are susceptible to publication bias — negative trials are less likely to be published. The true effect sizes may be smaller than reported.

4. Dose standardization challenges. Supplement bioavailability varies dramatically between products (especially Curcumin, Saffron). Proprietary formulations tested in RCTs may not match off-the-shelf products. Form matters: L-Methylfolate ≠ folic acid; EPA ≥60% ≠ standard fish oil.

5. Responder subgroups not yet defined. L-Methylfolate works best in MTHFR variant carriers; EPA works best in high-inflammation phenotypes; Zinc works best in zinc-deficient patients. Without biomarker testing, there’s no way to predict individual response. Protocol includes testing recommendations to address this.

6. SAM-e quality control. SAM-e is an unstable molecule — many commercial products are underdosed or degraded. Enteric-coated, refrigerated, blister-packed products from pharmaceutical-grade manufacturers required.

7. Long-term safety beyond 12 months. Most RCTs are 6–12 weeks. Long-term data on this specific combination protocol does not exist. Annual reassessment is recommended.

The Bottom Line

Seven nutraceuticals with overlapping but distinct mechanisms have accumulated sufficient evidence to support their use as adjuncts in anxiety and depression management. Omega-3 EPA and L-Methylfolate have the most robust evidence specifically as SSRI augmentation agents, with both demonstrating significant response rate improvements in SSRI non-responders in well-designed RCTs. Saffron 30mg stands out as the strongest monotherapy-equivalent option for mild-to-moderate MDD. The full protocol stacks anti-inflammatory (Omega-3, Curcumin), monoamine synthesis support (Methylfolate, SAM-e, Zinc), and HPA axis regulation (Magnesium, Omega-3) mechanisms in a complementary, non-redundant stack.

The critical safety consideration is serotonin syndrome risk from SAM-e and Saffron when combined with SSRIs — these require physician supervision and should not be self-initiated by patients on serotonergic medications. For patients not on medications, this protocol represents a clinically meaningful option with a favorable safety profile, particularly the foundational four (Omega-3, Magnesium, Zinc, L-Methylfolate), which can be initiated without significant drug interaction risk. Implementation should be phased, evidence-tracked via validated scales (PHQ-9, GAD-7), and biomarker-informed to identify the most relevant interventions for each individual.

Sources

Akhondzadeh, S., Fallah-Pour, H., Afkham, K., Jamshidi, A. H., & Khalighi-Cigaroudi, F. (2004). Comparison of Crocus sativus L. and imipramine in the treatment of mild to moderate depression: A pilot double-blind randomized trial. BMC Complementary and Alternative Medicine, 4, 12. PMID: 15341662

Akhondzadeh, S., Tahmacebi-Pour, N., Noorbala, A. A., Amini, H., Fallah-Pour, H., Jamshidi, A. H., & Khani, M. (2005). Crocus sativus L. in the treatment of mild to moderate depression: A double-blind, randomized and placebo-controlled trial. Phytotherapy Research, 19(2), 148–151. PMID: 15852492

Al-Karawi, D., Al Mamoori, D. A., & Tayyar, Y. (2016). The role of curcumin administration in patients with major depressive disorder: Mini meta-analysis of clinical trials. Phytotherapy Research, 30(2), 175–183. PMID: 26610378

Agency for Healthcare Research and Quality (AHRQ). (2002). S-Adenosyl-L-Methionine for treatment of depression, osteoarthritis, and liver disease. Evidence Report/Technology Assessment No. 64. PMID: 11764165

Deans, E. (2017). Magnesium for depression: A randomized clinical trial. BMC Psychiatry [review commentary referencing Tarleton et al. 2017].

Esalatmanesh, S., Abrishami, Z., Zenoozian, S., Rahmani, A., Najarzadehkisomi, M., & Akhondzadeh, S. (2021). Saffron supplementation as an adjunct to antidepressant therapy in patients with generalized anxiety disorder. Current Pharmaceutical Design. PMID: 34587882

Godfrey, P. S., Toone, B. K., Carney, M. W., Flynn, T. G., Bottiglieri, T., Laundy, M., Chanarin, I., & Reynolds, E. H. (1990). Enhancement of recovery from psychiatric illness by methylfolate. Lancet, 336(8712), 392–395. PMID: 1974941

Hausenblas, H. A., Saha, D., Dubyak, P. J., & Anton, S. D. (2013). Saffron (Crocus sativus L.) and major depressive disorder: A meta-analysis of randomized clinical trials. Journal of Integrative Medicine, 11(6), 377–383. PMID: 24299602

Kiecolt-Glaser, J. K., Belury, M. A., Andridge, R., Malarkey, W. B., & Glaser, R. (2011). Omega-3 supplementation lowers inflammation and anxiety in medical students: A randomized controlled trial. Brain, Behavior, and Immunity, 25(8), 1725–1734. PMID: 21784145

Lopresti, A. L., Maes, M., Maker, G. L., Hood, S. D., & Drummond, P. D. (2014). Curcumin for the treatment of major depression: A randomised, double-blind, placebo controlled study. Journal of Affective Disorders, 167, 368–375. PMID: 25046624

Mocking, R. J., Harmsen, I., Assies, J., Koeter, M. W., Ruhé, H. G., & Schene, A. H. (2016). Meta-analysis and meta-regression of omega-3 polyunsaturated fatty acid supplementation for major depressive disorder. Translational Psychiatry, 6(3), e756. PMID: 26978738

Ng, Q. X., Koh, S. S. H., Chan, H. W., & Ho, C. Y. X. (2017). Clinical use of curcumin in depression: A meta-analysis. Journal of the American Medical Directors Association, 18(6), 503–508. PMID: 28236605

Noorbala, A. A., Akhondzadeh, S., Tahmacebi-Pour, N., & Jamshidi, A. H. (2005). Hydro-alcoholic extract of Crocus sativus L. versus fluoxetine in the treatment of mild to moderate depression. Journal of Ethnopharmacology, 97(2), 281–284. PMID: 15707766

Nowak, G., Siwek, M., Dudek, D., Zieba, A., & Pilc, A. (2003). Effect of zinc supplementation on antidepressant therapy in unipolar depression: A preliminary placebo-controlled study. Polish Journal of Pharmacology, 55(6), 1143–1147. PMID: 14730085

Papakostas, G. I., Mischoulon, D., Shyu, I., Alpert, J. E., & Fava, M. (2010). S-Adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: A double-blind, randomized clinical trial. American Journal of Psychiatry, 167(8), 942–948. PMID: 20595412

Papakostas, G. I., Shelton, R. C., Zajecka, J. M., Etemad, B., Rickels, K., Clain, A., … & Fava, M. (2012). L-methylfolate as adjunctive therapy for SSRI-resistant major depression: Results of two randomized, double-blind, parallel-sequential trials. American Journal of Psychiatry, 169(12), 1267–1274. PMID: 23212058

Shoba, G., Joy, D., Joseph, T., Majeed, M., Rajendran, R., & Srinivas, P. S. (1998). Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Medica, 64(4), 353–356. PMID: 9619120

Siwek, M., Dudek, D., Paul, I. A., Sowa-Kucma, M., Zieba, A., Popik, P., … & Nowak, G. (2009). Zinc supplementation augments efficacy of imipramine in treatment resistant patients: A double blind, placebo-controlled study. Journal of Affective Disorders, 118(1–3), 187–195. PMID: 19278731

Sublette, M. E., Ellis, S. P., Geant, A. L., & Mann, J. J. (2011). Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. Journal of Clinical Psychiatry, 72(12), 1577–1584. PMID: 21939614

Swardfager, W., Herrmann, N., Mazereeuw, G., Coleman, K., Lanctôt, K. L., & Oh, P. I. (2013). Zinc in depression: A meta-analysis. Biological Psychiatry, 74(12), 872–878. PMID: 23806573

Tarleton, E. K., Littenberg, B., MacLean, C. D., Kennedy, A. G., & Daley, C. (2017). Role of magnesium supplementation in the treatment of depression: A randomized clinical trial. PLOS ONE, 12(6), e0180067. PMID: 28654669

Abbasi, B., Kimiagar, M., Sadeghniiat, K., Shirazi, M. M., Hedayati, M., & Rashidkhani, B. (2012). The effect of magnesium supplementation on primary insomnia in elderly: A double-blind placebo-controlled clinical trial. Journal of Research in Medical Sciences, 17(12), 1161–1169. PMID: 23853635

Revision History