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Protocol development in integrative medicine is not typically a simple process. Individuals require individualized care, and what works for one patient may not work for another.

To establish these protocols, we first developed a Rating Scale that could be used to discern the rigor of evidence supporting a specific nutrient’s therapeutic effect.

The following protocols were developed using only A through C-quality evidence.

Qualifying studies
Minimum requirements
Systematic review or meta-analysis of human trials
RDBPC human trials
2+ studies and/or 1 study with 50 + subjects
RDBPC human trials
1 study

Fluctuations in mood are common and normal; however, prolonged disruptive patterns in mood can present themselves at various times in life. One of the most common mood conditions is that of depression or depressive symptoms, with an overall pooled prevalence cited at 27%. (28)

Specific populations may be more susceptible to these symptoms. Factors such as gender and age play a role in risk factors associated with depressed moods. (23)  Depressed moods may be present in conjunction with other cognitive dysfunction such as anxiety, memory problems, and sleep disorders.
Depending on the individual patient’s needs, there are a variety of options to address their symptoms. Pharmaceutical interventions such as antidepressants are typically used to address prolonged periods of low mood or diagnosed depression. Supplements such as the herb St. John’s Wort (Hypericum perforatum) and 5-HTP have shown potential promising effects on mood symptoms. (11)(19) Omega-3 fatty acids are another option that might also have benefits on memory and sleep symptoms. (10)  Moderating stress with an adaptogen such as Rhodiola can also play a role in assisting with mood function. (1)

The ingredients presented in the protocol below reflect research findings demonstrating the efficacy of herbs and supplements that might be used to support mood and associated symptoms.

St. John’s Wort (Hypericum perforatum)

600 mg, total per day of 0.3 % hypericin and 1-4 % hyperforin standardized formula, minimum 6 weeks (2)(4)(5)(6)(7)

  • Hypericum perforatum demonstrated similar efficacy to SSRIs for remission rate and HAM-D symptom scores after 4-12 weeks in patients with mild to moderate depression (3)(19)
  • Improvement in relapse rates, Hamilton-Anxiety Scale, Beck Depression Inventory time courses, and greater overall improvement (Clinical Global Impressions (CGI) scale) was observed; additional potential for a prophylactic effect on symptoms in patients with chronic depression or depression alone (13)(15)(25)
  • May have a similar magnitude of effect as antidepressant medications, including an increased memory for positive words, and a decreased ability to recognize disgusted faces or fearful faces (29)
St. John’s Wort in the Fullscript catalog

930-1400 mg EPA and 200-750 mg DHA, total per day, minimum of 12 weeks (4)(6)(11)(12)

  • Dietary omega-3 polyunsaturated fatty acids may be related to a lower the risk of depressive symptoms (9)(17)(26)
  • Increased plasma levels of EPA and DHA, as well as a higher EPA/DHA:AA ratio, may be correlated with improved remission rate (6)
  • Omega-3 polyunsaturated fatty acids containing more than or equal to 60% EPA and a total of at least 1 gram per day improved mood symptoms and inflammatory markers (14)
  • When provided as adjuvant therapy to sertraline, patients experienced improved mood symptoms, improved sleep, and reduced sensitivity to anxiety symptoms (10)
Omega-3 fatty acids in the Fullscript catalog

Rhodiola (Rhodiola rosea)

340 mg, total per day, minimum of 6 weeks (7)(16)

  • May improve mood symptoms through improved cell response to stress and neuroendocrine-immune and neurotransmitter effects (1)
  • Improved symptoms of insomnia, somatization, and emotional instability (7)
  • A decrease in HAM-D score was observed with fewer adverse effects than sertraline (16)
  • Improved self-rated symptoms for mood and anxiety, as well as decreased serum superoxide dismutase and malondialdehyde levels, suggesting improvements in oxidative stress (30)
Rhodiola rosea in the Fullscript catalog


250-500 mg equivalent of elemental magnesium, per day, for a minimum of 6 weeks (5)(21)(27)

  • Magnesium chloride for two weeks reduced PHQ-9 scores by six points in adults with mild to moderate symptoms of depression (27)
  • When given to elderly patients with type 2 diabetes and hypomagnesemia, magnesium chloride had similar outcomes to imipramine (5)
  • After eight weeks, patients who received magnesium oxide at 500 mg total per day reported improved Beck Depression Inventory-II scores and normalized magnesium levels by 88.5% (21)
  • A systematic review found dietary magnesium levels to be associated with lower depressive symptoms, and indicated possible use as adjuvant therapy (8)
Magnesium in the Fullscript catalog

5-Hydroxytryptophan (5-HTP)

100-400 mg per day, up to 8 weeks, either alone or with an antidepressant (1)(2)(22)

  • A systematic review of 13 studies supported the use of 5-HTP for improving remission rate (0.65), as determined by questionnaire results (12)
  • Patients receiving L-5-hydroxytryptophan (73%) experienced similar improvements in HAM-D mood scores compared to those receiving fluoxetine medication (80%) for two to eight weeks following their first depressive episode (11)
  • Patients receiving chlorimipramine with concomitant L-5-HTP (vs. placebo) experienced greater improvements in HAM-D mood scores after 28 days (18)
5-HTP in the Fullscript catalog


The Fullscript Integrative Medical Advisory team has developed or collected these protocols from practitioners and supplier partners to help health care practitioners make decisions when building treatment plans. By adding this protocol to your Fullscript template library, you understand and accept that the recommendations in the protocol are for initial guidance and may not be appropriate for every patient.

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  1. Amsterdam, J. D., & Panossian, A. G. (2016). Rhodiola rosea L. as a putative botanical antidepressant. Phytomedicine: International Journal of Phytotherapy and Phytopharmacology, 23 (7), 770–783. (A)
  2. Angst, J., Woggon, B., & Schoepf, J. (1977). The treatment of depression with L-5-hydroxytryptophan versus imipramine. Results of two open and one double-blind study. Archiv Fur Psychiatrie Und Nervenkrankheiten, 224 (2), 175–186. (C)
  3. Apaydin, E. A., Maher, A. R., Shanman, R., Booth, M. S., Miles, J. N. V., Sorbero, M. E., & Hempel, S. (2016). A systematic review of St. John’s wort for major depressive disorder. Systematic Reviews, 5 (1), 148. (A)
  4. Arnold, L. E., Young, A. S., Belury, M. A., Cole, R. M., Gracious, B., Seidenfeld, A. M., Wolfson, H., & Fristad, M. A. (2017). Omega-3 Fatty Acid Plasma Levels Before and After Supplementation: Correlations with Mood and Clinical Outcomes in the Omega-3 and Therapy Studies. Journal of Child and Adolescent Psychopharmacology, 27 (3), 223–233. (C)
  5. Barragán-Rodríguez, L., Rodríguez-Morán, M., & Guerrero-Romero, F. (2008). Efficacy and safety of oral magnesium supplementation in the treatment of depression in the elderly with type 2 diabetes: a randomized, equivalent trial. Magnesium Research: Official Organ of the International Society for the Development of Research on Magnesium, 21 (4), 218–223. (C) 
  6. Carney, R. M., Steinmeyer, B. C., Freedland, K. E., Rubin, E. H., Rich, M. W., & Harris, W. S. (2016). Baseline blood levels of omega-3 and depression remission: a secondary analysis of data from a placebo-controlled trial of omega-3 supplements. The Journal of Clinical Psychiatry, 77 (2), e138–e143. (C)
  7. Darbinyan, V., Aslanyan, G., Amroyan, E., Gabrielyan, E., Malmström, C., & Panossian, A. (2007). Clinical trial of Rhodiola rosea L. extract SHR-5 in the treatment of mild to moderate depression. Nordic Journal of Psychiatry, 61 (5), 343–348. (B)
  8. Derom, M.-L., Sayón-Orea, C., Martínez-Ortega, J. M., & Martínez-González, M. A. (2013). Magnesium and depression: a systematic review. Nutritional Neuroscience, 16 (5), 191–206. (A)
  9. Grosso, G., Micek, A., Marventano, S., Castellano, S., Mistretta, A., Pajak, A., & Galvano, F. (2016). Dietary n-3 PUFA, fish consumption and depression: A systematic review and meta-analysis of observational studies. Journal of Affective Disorders, 205, 269–281. (A) 
  10. Jahangard, L., Sadeghi, A., Ahmadpanah, M., Holsboer-Trachsler, E., Sadeghi Bahmani, D., Haghighi, M., & Brand, S. (2018). 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 trial. Journal of Psychiatric Research, 107, 48–56. (B) 
  11. Jangid, P., Malik, P., Singh, P., Sharma, M., & Gulia, A. K. D. (2013). Comparative study of efficacy of l-5-hydroxytryptophan and fluoxetine in patients presenting with first depressive episode. Asian Journal of Psychiatry, 6 (1), 29–34. (C) 
  12. Javelle, F., Lampit, A., Bloch, W., Häussermann, P., Johnson, S. L., & Zimmer, P. (2020). Effects of 5-hydroxytryptophan on distinct types of depression: a systematic review and meta-analysis. Nutrition Reviews, 78 (1), 77–88. (A)
  13. Kasper, S., Volz, H. P., Möller, H. J., Dienel, A., & Kieser, M. (2008). Continuation and long-term maintenance treatment with Hypericum extract WS 5570 after recovery from an acute episode of moderate depression–a double-blind, randomized, placebo controlled long-term trial. European Neuropsychopharmacology: The Journal of the European College of Neuropsychopharmacology, 18 (11), 803–813. (B)
  14. Liao, Y., Xie, B., Zhang, H., He, Q., Guo, L., Subramaniapillai, M., Fan, B., Lu, C., & Mclntyer, R. S. (2019). Efficacy of omega-3 PUFAs in depression: A meta-analysis. Translational Psychiatry, 9 (1), 190. (A)
  15. Mannel, M., Kuhn, U., Schmidt, U., Ploch, M., & Murck, H. (2010). St. John’s wort extract LI160 for the treatment of depression with atypical features – a double-blind, randomized, and placebo-controlled trial. Journal of Psychiatric Research, 44 (12), 760–767. (B)
  16. Mao, J. J., Xie, S. X., Zee, J., Soeller, I., Li, Q. S., Rockwell, K., & Amsterdam, J. D. (2015). Rhodiola rosea versus sertraline for major depressive disorder: A randomized placebo-controlled trial. Phytomedicine: International Journal of Phytotherapy and Phytopharmacology, 22 (3), 394–399. (C)
  17. Mocking, R. J. T., Harmsen, I., Assies, J., Koeter, M. W. J., 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, e756. (A)
  18. Nardini, M., De Stefano, R., Iannuccelli, M., Borghesi, R., & Battistini, N. (1983). Treatment of depression with L-5-hydroxytryptophan combined with chlorimipramine, a double-blind study. International Journal of Clinical Pharmacology Research, 3(4), 239–250. (C)
  19. Ng, Q. X., Venkatanarayanan, N., & Ho, C. Y. X. (2017). Clinical use of Hypericum perforatum (St John’s wort) in depression: A meta-analysis. Journal of Affective Disorders, 210, 211–221. (A)
  20. Rahimi, R., Nikfar, S., & Abdollahi, M. (2009). Efficacy and tolerability of Hypericum perforatum in major depressive disorder in comparison with selective serotonin reuptake inhibitors: a meta-analysis. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 33 (1), 118–127. (A)
  21. Rajizadeh, A., Mozaffari-Khosravi, H., Yassini-Ardakani, M., & Dehghani, A. (2017). Effect of magnesium supplementation on depression status in depressed patients with magnesium deficiency: A randomized, double-blind, placebo-controlled trial. Nutrition , 35, 56–60. (B)
  22. Rousseau, J. J. (1987). Effects of a levo-5-hydroxytryptophan-dihydroergocristine combination on depression and neuropsychic performance: a double-blind placebo-controlled clinical trial in elderly patients. Clinical Therapeutics, 9 (3), 267–272. (B)
  23. Salk, R. H., Hyde, J. S., & Abramson, L. Y. (2017). Gender differences in depression in representative national samples: Meta-analyses of diagnoses and symptoms. Psychological Bulletin, 143 (8), 783–822. (A)
  24. Sarris, J., Fava, M., Schweitzer, I., & Mischoulon, D. (2012). St John’s wort (Hypericum perforatum) versus sertraline and placebo in major depressive disorder: continuation data from a 26-week RCT. Pharmacopsychiatry, 45 (7), 275–278. (B)
  25. Singer, A., Schmidt, M., Hauke, W., & Stade, K. (2011). Duration of response after treatment of mild to moderate depression with Hypericum extract STW 3-VI, citalopram and placebo: a reanalysis of data from a controlled clinical trial. Phytomedicine: International Journal of Phytotherapy and Phytopharmacology, 18 (8-9), 739–742. (C)
  26. 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. The Journal of Clinical Psychiatry, 72 (12), 1577–1584. (C)
  27. 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. (C) 
  28. Wang, J., Wu, X., Lai, W., Long, E., Zhang, X., Li, W., Zhu, Y., Chen, C., Zhong, X., Liu, Z., Wang, D., & Lin, H. (2017). Prevalence of depression and depressive symptoms among outpatients: a systematic review and meta-analysis. BMJ Open, 7 (8), e017173. (A)
  29. Warren, M. B., Cowen, P. J., & Harmer, C. J. (2019). Subchronic treatment with St John’s wort produces a positive shift in emotional processing in healthy volunteers. Journal of Psychopharmacology, 33(2), 194–201. (C)
  30. Yu H. L., Zhang P. P., Zhang C., Zhang X., Li Z. Z., Li W. Q., & Fu A. S. (2019). [Effects of rhodiola rosea on oxidative stress and negative emotional states in patients with obstructive sleep apnea]. Lin chuang er bi yan hou tou jing wai ke za zhi = Journal of clinical otorhinolaryngology, head, and neck surgery, 33 (10), 954–957. (C) 

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