Medicinal Plants in the Treatment of Depression. II: Evidence from Clinical Trials

Inés Moragrega; José Luis Ríos

doi:10.1055/a-1517-6882

Planta Medica, Table of Contents

Planta Med 2022; 88(12): 1092-1110
DOI: 10.1055/a-1517-6882

Pharmacokinetics

Reviews

Medicinal Plants in the Treatment of Depression. II: Evidence from Clinical Trials

Authors

Inés Moragrega

¹Departament de Psicobiologia, Facultat de Psicologia, Universitat de València, Valencia, Spain
José Luis Ríos

²Departament de Farmacologia, Facultat de Farmàcia, Universitat de València, Valencia, Spain

Abstract

Depression is a syndrome characterized by deep sadness and the inhibition of psychic functions, sometimes accompanied by neurovegetative disorders, with symptoms of anxiety almost always present. The disease produces alterations in a variety of neural networks and neurotransmission systems, along with a dysfunction of the hypothalamic-pituitary-adrenal axis, which leads to concomitant alterations in the immunological response. Generally, there is a parallel increase in proinflammatory mediators as well as oxidative and nitrosative damage caused by a reduction of antioxidant defenses. In a previous review, we compiled and examined studies of medicinal plants that had been evaluated in preclinical assays, including existing data on 155 species studied and reported as antidepressants or as sources of active principles for treating this condition. This review will thus limit its focus to the 95 clinical trials found in PubMed among the 670 articles on antidepressant-like medicinal plants. To this end, we have reviewed the publications cited in the Cochrane Database of Systematic Reviews, PubMed, and the Science Citation Index from 2000 to 2020. Our review emphasizes those species that have demonstrated the greatest pharmacological potential when studied for their antidepressant properties in humans through clinical trials. Saffron, turmeric, St. Johnʼs wort, ginkgo, kava, and golden root are the most relevant plants that have provided important evidence for the treatment of depression in clinical trials.

Key words

antidepressant - medicinal plants - clinical trials - natural products - curcumin - saffron

Full Text

References

References
1 American Psychiatric Association. Diagnostic and statistical Manual for mental Disorders, 5^a ed (DSM-5). Arlington: American Psychiatric Publishing; 2013
2 Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature 2008; 455: 894-902
3 World Health Organization. Depression and other common mental Disorders. Global Health Estimates. Geneve: WHO; 2017
4 Lim GY, Tam WW, Lu Y, Ho CS, Zhang MW, Ho RC. Prevalence of depression in the community from 30 countries between 1994 and 2014. Sci Rep 2018; 8: 2861
5 Saveanu RV, Nemeroff CB. Etiology of depression: genetic and environmental factors. Psychiatr Clin North Am 2012; 35: 51-71
6 Kaymaz N, van Os J, Loonen AJM, Nolen WA. Evidence that patients with single versus recurrent depressive episodes are differentially sensitive to treatment discontinuation: a meta-analysis of placebo-controlled randomized trials. J Clin Psychiatry 2008; 69: 1423-1436
7 Carvalho LA, Pariante CM. In vitro modulation of the glucocorticoid receptor by antidepressants. Stress 2008; 11: 411-424
8 Cepeda MS, Stang P, Makadia R. Depression is associated with high levels of C-reactive protein and low levels of fractional exhaled nitric oxide: results from the 2007–2012 National Health and Nutrition Examination Surveys. J Clin Psychiatry 2016; 77: 1666-1671
9 Moragrega I, Ríos JL. Medicinal plants in the treatment of depression: evidence from preclinical studies. Planta Med 2021;
10 Dantzer R, OʼConnor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008; 9: 46-56
11 Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol 2016; 16: 22-34
12 Jha MK, Trivedi MH. Personalized antidepressant selection and pathway to novel treatments: clinical utility of targeting inflammation. Int J Mol Sci 2018; 19: 233
13 Setiawan E, Attwells S, Wilson AA, Mizrahi R, Rusjan PM, Miler L, Xu C, Sharma S, Kish S, Houle S, Meyer JH. Association of translocator protein total distribution volume with duration of untreated major depressive disorder: a cross-sectional study. Lancet Psychiatry 2018; 5: 339-347
14 Zunszain PA, Hepgul N, Pariante CM. Inflammation and depression. Curr Topics Behav Neurosci 2013; 14: 135-151
15 Christmas DM, Potokar J, Davies SJ. A biological pathway linking inflammation and depression: activation of indoleamine 2,3-dioxygenase. Neuropsychiatr Dis Treat 2011; 7: 431-439
16 Pariante CM. Why are depressed patients inflamed? A reflection on 20 years of research on depression, glucocorticoid resistance and inflammation. Eur Neuropsychopharmacol 2017; 27: 554-559
17 Frodl TS, Koutsouleris N, Bottlender R, Born C, Jäger M, Scupin I, Reiser M, Möller HJ, Meisenzahl EM. Depression-related variation in brain morphology over 3 years: effects of stress?. Arch Gen Psychiatry 2008; 65: 1156-1165
18 Yu JJ, Pei LB, Zhang Y, Wen ZY, Yang JL. Chronic supplementation of curcumin enhances the efficacy of antidepressants in major depressive disorder: a randomized, double-blind, placebo-controlled pilot study. J Clin Psychopharmacol 2015; 35: 406-410
19 Sahebkar A, Cicero AFG, Simental-Mendía LE, Aggarwal BB, Gupta SC. Curcumin downregulates human tumor necrosis factor-α levels: A systematic review and meta-analysis of randomized controlled trials. Pharmacol Res 2016; 107: 234-242
20 Sarris J. Herbal medicines in the treatment of psychiatric disorders: 10-year updated review. Phytother Res 2018; 32: 1147-1162
21 Manji HK, Drevets WC, Charney DS. The cellular neurobiology of depression. Nat Med 2001; 7: 541-547
22 Maes M, Yirmyia R, Noraberg J, Brene S, Hibbeln J, Perini G, Kubera M, Bob P, Lerer B, Maj M. The inflammatory and neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression. Metab Brain Dis 2009; 24: 27-53
23 Raison CL, Miller AH. Is depression an inflammatory disorder?. Curr Psychiatry Rep 2011; 13: 467-475
24 Leonard B, Maes M. Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. Neurosci Biobehav Rev 2012; 36: 764-785
25 Lopresti AL, Hood SD, Drummond PD. Multiple antidepressant potential modes of action of curcumin: a review of its anti-inflammatory, monoaminergic, antioxidant, immune-modulating and neuroprotective effects. J Psychopharmacol 2012; 26: 1512-1524
26 Vadnie CA, McClung CA. Circadian rhythm disturbances in mood disorders: insights into the role of the suprachiasmatic nucleus. Neural Plast 2017; 2017: 1504507
27 Miller AH, Raison CL. Immune system contributions to the pathophysiology of depression. Focus 2008; 6: 36-45
28 Coleman JA, Green EM, Gouaux E. X-ray structures and mechanism of the human serotonin transporter. Nature 2016; 532: 334-339
29 Zhang FH, Wang ZM, Liu YT, Huang JS, Liang S, Wu HH, Xu YT. Bioactivities of serotonin transporter mediate antidepressant effects of Acorus tatarinowii Schott. J Ethnopharmacol 2019; 241: 111967
30 Matveychuk D, Thomas RK, Swainson J, Khullar A, MacKay MA, Baker GB, Dursun SM. Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers. Ther Adv Psychopharmacol 2020; 10: 2045125320916657
31 Dhingra D, Sharma A. A review on antidepressant plants. Nat Prod Rad 2006; 5: 144-152
32 Sarris J, Panossian A, Schweitzer I, Stough C, Scholey A. Herbal medicine for depression, anxiety and insomnia: a review of psychopharmacology and clinical evidence. Eur Neuropsychopharmacol 2011; 21: 841-860
33 Farahani MS, Bahramsoltani R, Farzaei MH, Abdollahi M, Rahimi R. Plant-derived natural medicines for the management of depression: an overview of mechanisms of action. Rev Neurosci 2015; 26: 305-321
34 Lee G, Bae H. Therapeutic effects of phytochemicals and medicinal herbs on depression. Biomed Res Int 2017; 2017: 6596241
35 Bakhshaeil S. Effect of nine medicinal plants as a traditional treatment on depression. J Appl Pharm 2017; 9: 244
36 Rahman MR, Ali M, Sharif M, Tajmin A. A review study on the traditional plants has potential antidepressant property. MOJ Cell Sci Rep 2017; 4: 00100
37 Muszyńska B, Łojewski M, Rojowski J, Opoka W, Sułkowska-Ziaja K. Natural products of relevance in the prevention and supportive treatment of depression. Psychiatr Pol 2015; 49: 435-453
38 Dong X, Yang C, Cao S, Gan Y, Sun H, Gong Y, Yang H, Yin X, Lu Z. Tea consumption and the risk of depression: a meta-analysis of observational studies. Aust N Z J Psychiatry 2015; 49: 334-345
39 Sarris J, McIntyre E, Camfield DA. Plant-based medicines for anxiety disorders, part 2: a review of clinical studies with supporting preclinical evidence. CNS Drugs 2013; 27: 301-319
40 Puttarak P, Dilokthornsakul P, Saokaew S, Dhippayom T, Kongkaew C, Sruamsiri R, Chuthaputti A, Chaiyakunapruk N. Effects of Centella asiatica (L.) Urb. on cognitive function and mood related outcomes: A systematic review and meta-analysis. Sci Rep 2017; 7: 10646
41 Chusak C, Thilavech T, Henry CJ, Adisakwattana S. Acute effect of Clitoria ternatea flower beverage on glycemic response and antioxidant capacity in healthy subjects: a randomized crossover trial. BMC Complement Altern Med 2018; 18: 6
42 Shafiee M, Arekhi S, Omranzadeh A, Sahebkar A. Saffron in the treatment of depression, anxiety and other mental disorders: Current evidence and potential mechanisms of action. J Affect Disord 2018; 227: 330-337
43 Ulbricht C, Conquer J, Costa D, Hollands W, Iannuzzi C, Isaac R, Jordan JK, Ledesma N, Ostroff C, Serrano JM, Shaffer MD, Varghese M. An evidence-based systematic review of saffron (Crocus sativus) by the Natural Standard Research Collaboration. J Diet Suppl 2011; 8: 58-114
44 Lopresti AL, Drummond PD. Saffron (Crocus sativus) for depression: a systematic review of clinical studies and examination of underlying antidepressant mechanisms of action. Hum Psychopharmacol 2014; 29: 517-527
45 Tabeshpour J, Sobhani F, Sadjadi SA, Hosseinzadeh H, Mohajeri SA, Rajabi O, Taherzadeh Z, Eslami S. A double-blind, randomized, placebo-controlled trial of saffron stigma (Crocus sativus L.) in mothers suffering from mild-to-moderate postpartum depression. Phytomedicine 2017; 36: 145-152
46 Tóth B, Hegyi P, Lantos T, Szakács Z, Kerémi B, Varga G, Tenk J, Pétervári E, Balaskó M, Rumbus Z, Rakonczay Z, Bálint ER, Kiss T, Csupor D. The efficacy of saffron in the treatment of mild to moderate depression: a meta-analysis. Planta Med 2019; 85: 24-31
47 Khaksarian M, Behzadifar M, Behzadifar M, Alipour M, Jahanpanah F, Re TS, Firenzuoli F, Zerbetto R, Bragazzi NL. The efficacy of Crocus sativus (Saffron) versus placebo and fluoxetine in treating depression: a systematic review and meta-analysis. Psychol Res Behav Manag 2019; 12: 297-305
48 Kashani L, Eslatmanesh S, Saedi N, Niroomand N, Ebrahimi M, Hosseinian M, Foroughifar T, Salimi S, Akhondzadeh S. Comparison of saffron versus fluoxetine in treatment of mild to moderate postpartum depression: a double-blind, randomized clinical trial. Pharmacopsychiatry 2017; 50: 64-68
49 Kashani L, Esalatmanesh S, Eftekhari F, Salimi S, Foroughifar T, Etesam F, Safiaghdam H, Moazen-Zadeh E, Akhondzadeh S. Efficacy of Crocus sativus (saffron) in treatment of major depressive disorder associated with post-menopausal hot flashes: a double-blind, randomized, placebo-controlled trial. Arch Gynecol Obstet 2018; 297: 717-724
50 Milajerdi A, Jazayeri S, Shirzadi E, Hashemzadeh N, Azizgol A, Djazayery A, Esmaillzadeh A, Akhondzadeh S. The effects of alcoholic extract of saffron (Crocus sativus L.) on mild to moderate comorbid depression-anxiety, sleep quality, and life satisfaction in type 2 diabetes mellitus: A double-blind, randomized and placebo-controlled clinical trial. Complement Ther Med 2018; 41: 196-202
51 Marx W, Lane M, Rocks T, Ruusunen A, Loughman A, Lopresti A, Marshall S, Berk M, Jacka F, Dean OM. Effect of saffron supplementation on symptoms of depression and anxiety: a systematic review and meta-analysis. Nutr Rev 2019; 77: 557-571
52 Mazidi M, Shemshian M, Mousavi SH, Norouzy A, Kermani T, Moghiman T, Sadeghi A, Mokhber N, Ghayour-Mobarhan M, Ferns GA. A double-blind, randomized and placebo-controlled trial of Saffron (Crocus sativus L.) in the treatment of anxiety and depression. J Complement Integr Med 2016; 13: 195-199
53 Leone S, Recinella L, Chiavaroli A, Orlando G, Ferrante C, Leporini L, Brunetti L, Menghini L. Phytotherapic use of the Crocus sativus L. (saffron) and its potential applications: A brief overview. Phytother Res 2018; 32: 2364-2375
54 Yang X, Chen X, Fu Y, Luo Q, Du L, Qiu H, Qiu T, Zhang L, Meng H. Comparative efficacy and safety of Crocus sativus L. for treating mild to moderate major depressive disorder in adults: a meta-analysis of randomized controlled trials. Neuropsychiatr Dis Treat 2018; 14: 1297-1305
55 Jelodar G, Javid Z, Sahraian A, Jelodar S. Saffron improved depression and reduced homocysteine level in patients with major depression: A randomized, double-blind study. Avicenna J Phytomed 2018; 8: 43-50
56 Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctôt KL. A meta-analysis of cytokines in major depression. Biol Psychiatry 2010; 67: 446-457
57 Lopresti AL. Cognitive behaviour therapy and inflammation: A systematic review of its relationship and the potential implications for the treatment of depression. Aust N Z J Psychiatry 2017; 51: 565-582
58 Esmaily H, Sahebkar A, Iranshahi M, Ganjali S, Mohammadi A, Ferns G, Ghayour-Mobarhan M. An investigation of the effects of curcumin on anxiety and depression in obese individuals: a randomized controlled trial. Chin J Integr Med 2015; 21: 332-338
59 Bergman J, Miodownik C, Bersudsky Y, Sokolik S, Lerner PP, Kreinin A, Polakiewicz J, Lerner V. Curcumin as an add-on to antidepressive treatment: a randomized, double-blind, placebo-controlled, pilot clinical study. Clin Neuropharmacol 2013; 36: 73-77
60 Lopresti AL, Maes M, Maker GL, Hood SD, Drummond PD. Curcumin for the treatment of major depression: a randomised, double-blind, placebo controlled study. J Affect Disord 2014; 167: 368-375
61 Sanmukhani J, Satodia V, Trivedi J, Patel T, Tiwari D, Panchal B, Goel A, Tripathi CB. Efficacy and safety of curcumin in major depressive disorder: a randomized controlled trial. Phytother Res 2014; 28: 579-585
62 Lopresti AL, Maes M, Meddens MJ, Maker GL, Arnoldussen E, Drummond PD. Curcumin and major depression: a randomised, double-blind, placebo-controlled trial investigating the potential of peripheral biomarkers to predict treatment response and antidepressant mechanisms of change. Eur Neuropsychopharmacol 2015; 25: 38-50
63 Ng QX, Koh SSH, Chan HW, Ho CYX. Clinical use of curcumin in depression: a meta-analysis. J Am Med Dir Assoc 2017; 18: 503-508
64 Kanchanatawan B, Tangwongchai S, Sughondhabhirom A, Suppapitiporn S, Hemrunrojn S, Carvalho AF, Maes M. Add-on treatment with curcumin has antidepressive effects in Thai patients with major depression: results of a randomized double-blind placebo-controlled study. Neurotox Res 2018; 33: 621-633
65 Panahi Y, Badeli R, Karami GR, Sahebkar A. Investigation of the efficacy of adjunctive therapy with bioavailability-boosted curcuminoids in major depressive disorder. Phytother Res 2015; 29: 17-21
66 Al-Karawi D, Al Mammori DA, Tayyar Y. The role of curcumin administration in patients with major depressive disorder: mini meta-analysis of clinical trials. Phytother Res 2016; 30: 175-183
67 Lopresti AL, Drummond PD. Efficacy of curcumin, and a saffron/curcumin combination for the treatment of major depression: A randomised, double-blind, placebo-controlled study. J Affect Disord 2017; 207: 188-196
68 Lopresti AL. The problem of curcumin and its bioavailability: could its gastrointestinal influence contribute to its overall health-enhancing effects?. Adv Nutr 2018; 9: 41-50
69 Kaufmann FN, Gazal M, Bastos CR, Kaster MP, Ghisleni G. Curcumin in depressive disorders: An overview of potential mechanisms, preclinical and clinical findings. Eur J Pharmacol 2016; 784: 192-198
70 Antony B, Merina B, Iyer S, Judy N, Lennertz K, Joyal S. A pilot cross-over study to evaluate human oral bioavailability of BCM-95 CG (Biocurcumax), a novel bioenhanced preparation of curcumin. Indian J Pharm Sci 2008; 70: 445-4590
71 Cuomo J, Appendino G, Dern AS, Schneider E, McKinnon TP, Brown MJ, Togni S, Dixon BM. Comparative absorption of a standardized curcuminoid mixture and its lecithin formulation. J Nat Prod 2011; 74: 664-669
72 Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol 2006; 27: 24-31
73 Dantzer R, OʼConnor JC, Lawson MA, Kelley KW. Inflammation-associated depression: from serotonin to kynurenine. Psychoneuroendocrinology 2011; 36: 426-436
74 Maes M, Berk M, Goehler L, Song C, Anderson G, Gałecki P, Leonard B. Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways. BMC Med 2012; 10: 66
75 Lotrich FE. Inflammatory cytokine-associated depression. Brain Res 2015; 1617: 113-125
76 Ghandadi M, Sahebkar A. Curcumin: an effective inhibitor of interleukin-6. Curr Pharm Des 2017; 23: 921-931
77 Hannestad J, DellaGioia N, Bloch M. The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis. Neuropsychopharmacology 2011; 36: 2452-2459
78 Eyre HA, Air T, Pradhan A, Johnston J, Lavretsky H, Stuart MJ, Baune BT. A meta-analysis of chemokines in major depression. Prog Neuropsychopharmacol Biol Psychiatry 2016; 68: 1-8
79 Hewlings SJ, Kalman DS. Curcumin: a review of itsʼ effects on human health. Foods 2017; 6: E92
80 Derosa G, Maffioli P, Simental-Mendía LE, Bo S, Sahebkar A. Effect of curcumin on circulating interleukin-6 concentrations: A systematic review and meta-analysis of randomized controlled trials. Pharmacol Res 2016; 111: 394-404
81 Mantzorou M, Pavlidou E, Vasios G, Tsagalioti E, Giaginis C. Effects of curcumin consumption on human chronic diseases: A narrative review of the most recent clinical data. Phytother Res 2018; 32: 957-975
82 Lopresti AL. Curcumin for neuropsychiatric disorders: a review of in vitro, animal and human studies. J Psychopharmacol 2017; 31: 287-302
83 De Feudis FV. Ginkgo biloba Extract (EGb 761). From Chemistry to the Clinic. Wiesbaden: Ullstein Medical; 1998: 1-6
84 Meston CM, Rellini AH, Telch MJ. Short- and long-term effects of Ginkgo biloba extract on sexual dysfunction in women. Arch Sex Behav 2008; 37: 530-547
85 Beaubrun G, Gray GE. A review of herbal medicines for psychiatric disorders. Psychiatr Serv 2000; 51: 1130-1134
86 Ashton AK, Ahrens K, Gupta S, Masand PS. Antidepressant-induced sexual dysfunction and Ginkgo biloba . Am J Psychiatry 2000; 157: 836-837
87 Waddell DL, Hummel ME, Sumners AD. Three herbs you should get to know. Am J Nurs 2001; 101: 48-53
88 Kang BJ, Lee SJ, Kim MD, Cho MJ. A placebo-controlled, double-blind trial of Ginkgo biloba for antidepressant-induced sexual dysfunction. Hum Psychopharmacol 2002; 17: 279-284
89 Wheatley D. Triple-blind, placebo-controlled trial of Ginkgo biloba in sexual dysfunction due to antidepressant drugs. Hum Psychopharmacol 2004; 19: 545-548
90 Hemmeter U, Annen B, Bischof R, Brüderlin U, Hatzinger M, Rose U, Holsboer-Trachsler E. Polysomnographic effects of adjuvant Ginkgo biloba therapy in patients with major depression medicated with trimipramine. Pharmacopsychiatry 2001; 34: 50-59
91 Linde K, Mulrow CD. St Johnʼs wort for depression. Cochrane Database Syst Rev 2000; (02) CD000448
92 Linde K, Mulrow CD, Berner M, Egger M. St Johnʼs wort for depression. Cochrane Database Syst Rev 2005; (02) CD000448
93 Linde K, Berner MM, Kriston L. St Johnʼs wort for major depression. Cochrane Database Syst Rev 2008; (04) CD000448
94 Rahimi R, Nikfar S, Abdollahi M. Efficacy and tolerability of Hypericum perforatum in major depressive disorder in comparison with selective serotonin reuptake inhibitors: a meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33: 118-127
95 Szegedi A, Kohnen R, Dienel A, Kieser M. Acute treatment of moderate to severe depression with hypericum extract WS 5570 (St Johnʼs wort): randomised controlled double blind non-inferiority trial versus paroxetine. BMJ 2005; 330: 503
96 Fava M, Alpert J, Nierenberg AA, Mischoulon D, Otto MW, Zajecka J, Murck H, Rosenbaum JF. A double-blind, randomized trial of St Johnʼs wort, fluoxetine, and placebo in major depressive disorder. J Clin Psychopharmacol 2005; 25: 441-447
97 Ng QX, Venkatanarayanan N, Ho CY. Clinical use of Hypericum perforatum (St Johnʼs wort) in depression: A meta-analysis. J Affect Disord 2017; 210: 211-221
98 Russo E, Scicchitano F, Whalley BJ, Mazzitello C, Ciriaco M, Esposito S, Patanè M, Upton R, Pugliese M, Chimirri S, Mammì M, Palleria C, De Sarro G. Hypericum perforatum: pharmacokinetic, mechanism of action, tolerability, and clinical drug-drug interactions. Phytother Res 2014; 28: 643-655
99 Kuo CH, Chou YC, Liao KC, Shieh CJ, Deng TS. Optimization of light intensity, temperature, and nutrients to enhance the bioactive content of hyperforin and rutin in St. Johnʼs wort. Molecules 2020; 25: 4256
100 Zirak N, Shafiee M, Soltani G, Mirzaei M, Sahebkar A. Hypericum perforatum in the treatment of psychiatric and neurodegenerative disorders: Current evidence and potential mechanisms of action. J Cell Physiol 2019; 234: 8496-8508
101 Sarris J, Kavanagh DJ, Byrne G, Bone KM, Adams J, Deed G. The Kava Anxiety Depression Spectrum Study (KADSS): a randomized, placebo-controlled crossover trial using an aqueous extract of Piper methysticum . Psychopharmacology (Berl) 2009; 205: 399-407
102 Witte S, Loew D, Gaus W. Meta-analysis of the efficacy of the acetonic kava-kava extract WS1490 in patients with nonpsychotic anxiety disorders. Phytother Res 2005; 19: 183-188
103 Darbinyan V, Aslanyan G, Amroyan E, Gabrielyan E, Malmström C, Panossian A. Clinical trial of Rhodiola rosea L. extract SHR-5 in the treatment of mild to moderate depression. Nord J Psychiatry 2007; 61: 343-348
104 Dwyer AV, Whitten DL, Hawrelak JA. Herbal medicines, other than St. Johnʼs Wort, in the treatment of depression: a systematic review. Altern Med Rev 2011; 16: 40-49
105 Mao JJ, Xie SX, Zee J, Soeller I, Li QS, Rockwell K, Amsterdam JD. Rhodiola rosea versus sertraline for major depressive disorder: A randomized placebo-controlled trial. Phytomedicine 2015; 22: 394-399
106 Mao JJ, Li QS, Soeller I, Xie SX, Amsterdam JD. Rhodiola rosea therapy for major depressive disorder: a study protocol for a randomized, double-blind, placebo-controlled trial. J Clin Trials 2014; 4: 170
107 Amsterdam JD, Panossian AG. Rhodiola rosea L. as a putative botanical antidepressant. Phytomedicine 2016; 23: 770-783
108 Akhondzadeh S, Kashani L, Fotouhi A, Jarvandi S, Mobaseri M, Moin M, Khani M, Jamshidi AH, Baghalian K, Taghizadeh M. Comparison of Lavandula angustifolia Mill. tincture and imipramine in the treatment of mild to moderate depression: a double-blind, randomized trial. Prog Neuropsychopharmacol Biol Psychiatry 2003; 27: 123-127
109 Nikfarjam M, Rakhshan R, Ghaderi H. Comparison of effect of Lavandula officinalis and venlafaxine in treating depression: a double blind clinical trial. J Clin Diagn Res 2017; 11: KC01-KC04
110 Haybar H, Javid AZ, Haghighizadeh MH, Valizadeh E, Mohaghegh SM, Mohammadzadeh A. The effects of Melissa officinalis supplementation on depression, anxiety, stress, and sleep disorder in patients with chronic stable angina. Clin Nutr ESPEN 2018; 26: 47-52
111 Jeong HG, Ko YH, Oh SY, Han C, Kim T, Joe SH. Effect of Korean red ginseng as an adjuvant treatment for women with residual symptoms of major depression. Asia Pac Psychiatry 2015; 7: 330-336
112 Diaper A, Hindmarch I. A double-blind, placebo-controlled investigation of the effects of two doses of a valerian preparation on the sleep, cognitive and psychomotor function of sleep-disturbed older adults. Phytother Res 2004; 18: 831-836
113 Stough C, Lloyd J, Clarke J, Downey LA, Hutchison CW, Rodgers T, Nathan PJ. The chronic effects of an extract of Bacopa monniera (Brahmi) on cognitive function in healthy human subjects. Psychopharmacology (Berl) 2001; 156: 481-484
114 Stough C, Lloyd J, Clarke J, Downey LA, Hutchison CW, Rodgers T, Nathan PJ. The chronic effects of an extract of Bacopa monniera (Brahmi) on cognitive function in healthy human subjects. Psychopharmacology (Berl) 2015; 232: 2427
115 Stough C, Downey LA, Lloyd J, Silber B, Redman S, Hutchison C, Wesnes K, Nathan PJ. Examining the nootropic effects of a special extract of Bacopa monniera on human cognitive functioning: 90 day double-blind placebo controlled randomized trial. Phytother Res 2008; 22: 1629-1634
116 Niu K, Hozawa A, Kuriyama S, Ebihara S, Guo H, Nakaya N, Ohmori-Matsuda K, Takahashi H, Masamune Y, Asada M, Sasaki S, Arai H, Awata S, Nagatomi R, Tsuji I. Green tea consumption is associated with depressive symptoms in the elderly. Am J Clin Nutr 2009; 90: 1615-1622
117 Rothenberg DO, Zhang L. Mechanisms underlying the anti-depressive effects of regular tea consumption. Nutrients 2019; 11: E1361
118 Sayyah M, Sayyah M, Kamalinejad M. A preliminary randomized double blind clinical trial on the efficacy of aqueous extract of Echium amoenum in the treatment of mild to moderate major depression. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 166-169
119 Yamatsu A, Yamashita Y, Maru I, Yang J, Tatsuzaki J, Kim M. The improvement of sleep by oral intake of GABA and Apocynum venetum leaf extract. J Nutr Sci Vitaminol (Tokyo) 2015; 61: 182-187
120 Firoozabadi A, Zarshenas MM, Salehi A, Jahanbin S, Mohagheghzadeh A. Effectiveness of Cuscuta planiflora Ten. and Nepeta menthoides Boiss. & Buhse in major depression: a triple-blind randomized controlled trial study. J Evid Based Complement Altern Med 2015; 20: 94-97
121 Black N, Stockings E, Campbell G, Tran LT, Zagic D, Hall WD, Farrell M, Degenhardt L. Cannabinoids for the treatment of mental disorders and symptoms of mental disorders: a systematic review and meta-analysis. Lancet Psychiatry 2019; 6: 995-1010 Erratum in: Lancet Psychiatry 2020; 7: e3 Erratum in: Lancet Psychiatry 2020; 7: e3
122 Ferber SG, Namdar D, Hen-Shoval D, Eger G, Koltai H, Shoval G, Shbiro L, Weller A. The “entourage effect”: terpenes coupled with cannabinoids for the treatment of mood disorders and anxiety disorders. Curr Neuropharmacol 2020; 18: 87-96
123 Bangratz M, Ait Abdellah S, Berlin A, Blondeau C, Guilbot A, Dubourdeaux M, Lemoine P. A preliminary assessment of a combination of rhodiola and saffron in the management of mild-moderate depression. Neuropsychiatr Dis Treat 2018; 14: 1821-1829
124 Müller D, Pfeil T, von den Driesch V. Treating depression comorbid with anxiety – results of an open, practice-oriented study with St Johnʼs wort WS 5572 and valerian extract in high doses. Phytomedicine 2003; 10 (Suppl. 04) 25-30
125 Sarris J, Kavanagh DJ, Deed G, Bone KM. St. Johnʼs wort and Kava in treating major depressive disorder with comorbid anxiety: a randomised double-blind placebo-controlled pilot trial. Hum Psychopharmacol 2009; 24: 41-48
126 Zhang JJ, Gao TT, Wang Y, Wang JL, Guan W, Wang YJ, Wang CN, Liu JF, Jiang B. Andrographolide exerts significant antidepressant-like effects involving the hippocampal BDNF system in mice. Int J Neuropsychopharmacol 2019; 22: 585-600
127 Bartels C, Belz M, Vogelgsang J, Hessmann P, Bohlken J, Wiltfang J, Kosteve K. To be continued? long-term treatment effects of antidepressant drug classes and individual antidepressants on the risk of developing dementia: a German case-control study. J Clin Psychiatry 2020; 81: 19m13205
128 National Center for Complementary and Integrative Health (NCCIH). St. Johnʼs wort and depression: in depth. Accessed February 3, 2021 at: https://www.nccih.nih.gov/health/st-johns-wort-and-depression-in-depth
129 Guy A, Brown M, Lewis S, Horowitz M. The ‘patient voice’: patients who experience antidepressant withdrawal symptoms are often dismissed or misdiagnosed with relapse or a new medical condition. Ther Adv Psychopharmacol 2020; 10: 1-15
130 Davies J, Read J. A systematic review into the incidence, severity and duration of antidepressant withdrawal effects: Are guidelines evidence-based?. Addict Behav 2019; 97: 111-121
131 Jordan SA, Cunningham DG, Marles RJ. Assessment of herbal medicinal products: challenges, and opportunities to increase the knowledge base for safety assessment. Toxicol Appl Pharmacol 2010; 243: 198-216
132 Pennington K, Focking M, McManus CA, Pariante CM, Dunn MJ, Cotter DR. A proteomic investigation of similarities between conventional and herbal antidepressant treatments. J Psychopharmacol 2009; 23: 520-530