St. John’s Wort Could Show Benefit in Major Depressive Disorder

Introduction

Major depressive disorder (MDD) is one of the most prevalent mental health conditions in the US.¹ The disorder is characterized by symptoms that include emotional, physical, cognitive, and psychomotor disturbances. These may present as loss of interest in usual activities, chronic fatigue, decreased concentration, and restlessness, as well as other manifestations.² The etiology of MDD is not fully understood and it may involve a combination of biological and environmental factors.² The pathophysiology of MDD revolves around the monoamine hypothesis, suggesting that depression is caused by dysregulation or decreased levels of the neurotransmitters serotonin, dopamine, and norepinephrine in the brain.² More recent research suggests that MDD may also involve gamma-aminobutyric acid and the endogenous opioid system as well as nutritional imbalances.²

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Management strategies for MDD include both non-pharmacological and pharmacological interventions. Non-pharmacological options include, but are not limited to, psychotherapy, electroconvulsive therapy, and physical activity/exercise regimens.² Pharmacologically, MDD is managed with drug classes that include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors, mixed serotonergic agents, serotonin and alpha-2 adrenergic antagonists, norepinephrine-dopamine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, and second-generation antipsychotics, as well as experimental agents.² Patients with MDD may also seek complementary or alternative therapies in the form of dietary supplements which might be perceived by patients to be natural and safer than medicinal agents. One such supplement is the herbal product St. John's Wort.²

St. John’s Wort

St. John’s Wort, or Hypericum perforatum, is a plant native to Europe that is in the Hypericaceae family.³ Historically, St. John’s Wort has been used for its suggested anti-inflammatory and healing properties, but today it is more well known for its use in MDD.³ The constituents hyperforin and adhyperforin appear to modulate the effects of various neurotransmitters but their effects on serotonin are believed to be primarily responsible for the plant’s activity as anantidepressant.⁴

According to NatMed, St. John’s Wort is “likely effective” in treating mild to moderate MDD.⁴ To examine the evidence supporting its use for this indication, we conducted a search of PubMed using the search terms “St. John's Wort,” “Hypericum perforatum,” and “depression.” We limited our search to meta-analyses published within the past 10 years. Our search yielded 12 records; of these, only 3 meta-analyses were deemed relevant for our review as they focused on the clinical use of St. John’s Wort for depression in humans.

Literature Review

Apaydin et al. performed a meta-analysis to assess the efficacy and safety of St. John’s Wort in adults with MDD compared to placebo and to an active comparator.⁵ Additionally, the investigators sought to evaluate whether the effects vary by severity of MDD. The analysis included 35 studies examining 6993 patients. Included were randomized controlled trials that examined the effect of at least a 4-week administration of the herb. The investigators reported that St. John’s Wort was associated with significantly more treatment responders than placebo(relative risk [RR] 1.53; 95% confidence interval [CI] 1.19-1.97). When compared to antidepressant medications, St. John’s Wort showed no difference in treatment efficacy in mild and moderate depression with a RR of 1.01 (95% CI 0.90-1.14). The investigators also reported that users were less likely to experience adverse events, with an odds ratio (OR) of 0.67 (95% CI 0.56-0.81). The investigators concluded that St. John’s Wort monotherapy for mild and moderate depression is superior to placebo in improving depression symptoms and not significantly different from antidepressant medications. The investigators noted that the studies’ heterogeneity and a lack of research on severe depression limit the evidence.⁵

In another meta-analysis, Ng et al. examined a total of 27 studies with 3808 patients focusing on the safety and efficacy of St. John's Wort compared to SSRIs in participants with MDD.⁶ All studies ranged from 4 to 12 weeks in duration. The investigators reported that St. John's Wort yielded a comparable response rate to SSRIs, as measured by a >50% reduction in Hamilton Depression Rating Scale (HAM-D) score with a RR of 0.983 (95% CI 0.924-1.042; p<0.001). Likewise, a comparable remission rate defined as >75% reduction in HAM-D score was also noted (RR 1.013 [95% CI 0.892-1.134]; p<0.001). Furthermore, the pooled standardized mean difference (SMD) from baseline HAM-D scores was -0.068 (95% CI -0.127-0.021; p<0.001). The investigators also reported that the discontinuation/drop-out rate of St. John’s Wort was significantly lower compared to SSRI treatment with an OR of 0.587 (95% CI 0.478-0.697; p<0.001). The investigators concluded that in patients with mild-to-moderate depression, St. John's wort has comparable efficacy and favorable safety profiles when compared to SSRIs.⁶

In a meta-analysis by Zhao et al., the investigators examined the efficacy of St. John’s Wort when compared to SSRIs and placebo in adults with mild to moderate depression.⁷ A total of 14 clinical trials involving 2270 patients with MDD were included in the analysis. The studies’ duration ranged between 6 and 26 weeks. The investigators found the effects of St. John’s Wort to be favorable when compared to both SSRIs and placebo for reducing patients' HAM-D scores. The reported RR when compared to SSRIs was 1.39 (95% CI 1.09–1.76) and 0.46 (95% CI 0.26–0.83) when compared to placebo. The investigators concluded that this analysis supports the use of St. John’s Wort for depression.⁷

Doses and Safety

St. John’s Wort is available in various formulations, including tablets, capsules, liquid extract, tincture, and tea. These preparations vary in their chemical contents and quality. Formulations of St. John’s Wort used in clinical trials were commonly standardized to contain 3% to 5% hyperforin or 0.3% hypericin.⁴ Although a precise dose has not been established, doses of St. John’s Wort for depression generally ranged from 200 mg to 1800 mg daily.³ The dose often used in clinical trials is 900 mg of the extract daily in 3 divided doses.³

St. John’s Wort is generally well tolerated with the most common adverse effects being diarrhea, dizziness, dry mouth, mild gastrointestinal discomfort, fatigue, headache, insomnia, restlessness, and sedation.⁴ Its use should be avoided in pregnant or lactating women; research involving St. John’s Wort in children is limited.⁴ Additionally, caution must be used when St. John’s Wort is used in conjunction with other pharmacologically-active substances because clinically meaningful interactions may occur.³ St. John’s Wort is a major cytochrome P-450 enzyme inducer and also induces the expression of P-glycoprotein (P-gp).³ Thus, the herb can potentially decrease the effectiveness of many commonly used drugs. Furthermore, if used with other antidepressant agents affecting the serotonin system, pharmacodynamic interactions that may result in serotonin syndrome might develop.³ 

Conclusion

The literature reviewed suggests that St. John's Wort might show efficacy when treating mild to moderate MDD. Notably, however, the evidence presented is limited in quality (e.g., heterogeneity of studies reviewed, duration of treatment). The decision to use St. John's Wort must involve consultation with a health care provider to ensure appropriate use.

References

1. Hope For Depression Research Foundation. Facts about depression. Accessed June 24, 2024. https://www.hopefordepression.org/depression-facts/?utm_source=google_cpc&utm_medium=ad_grant&utm_campaign=depression_facts&gad_source=1&gclid=CjwKCAiA3JCvBhA8EiwA4kujZiI3bZRLiSH5J4Jj-jEjsHT4Z66yvR3Jetz5nReEvqdqCn2X-0HycRoCqaQQAvD_BwE

2. VandenBerg AM. Major Depressive Disorder. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. eds. Pharmacotherapy: A Pathophysiologic Approach, 11e. McGraw-Hill Education; 2020. Accessed March 03, 2024. https://0-accesspharmacy-mhmedical-com.liucat.lib.liu.edu/content.aspx?bookid=2577&sectionid=234138584

3. UpToDate Lexidrug. Natural Products Database. St. John’s Wort. Accessed June 18, 2024. http://online.lexi.com

4. NatMed. St. John’s Wort. Accessed June 18, 2024. https://naturalmedicines.therapeuticresearch.com/

5. 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. Published 2016 Sep 2. doi:10.1186/s13643-016-0325-2

6. Ng QX, Venkatanarayanan N, Ho CY. Clinical use of Hypericum perforatum (St John's wort) in depression: A meta-analysis. J Affect Disord. 2017;210:211-221. doi:10.1016/j.jad.2016.12.048

7. Zhao X, Zhang H, Wu Y, Yu C. The efficacy and safety of St. John's wort extract in depression therapy compared to SSRIs in adults: A meta-analysis of randomized clinical trials. Adv Clin Exp Med. 2023;32(2):151-161. doi:10.17219/acem/152942