In the first randomized controlled trial comparing the efficacy of Rhodiola rosea and a pharmaceutical antidepressant, the result was technically a draw. But the study also raises important questions about whether trials on biologics—pharmaceutical or herbal—alone truly address the multiple layers of depression treatment.
Mao JJ, Xie SX, Zee J, et al. Rhodiola rosea versus sertraline for major depressive disorder: A randomized placebo-controlled trial. Phytomedicine. 2015;22(3):394-399.
This study was a phase-2 randomized, placebo-controlled trial.
A total of 57 subjects with mild to moderate major depression (MDD) were recruited for this study. Exclusions included severe major depression, bipolar disorder, substance abuse, dependence disorder, or primary anxiety at time of assessment. Participants were also excluded if they were already undergoing antidepressant or herbal therapies or had other major illness that may affect mood or cognition.
Participants were randomized to receive either capsules of 340 mg of a powdered extract of Rhodiola rosea standardized to a content of 3.7% rosavin, 50 mg of sertraline HCl (Zoloft), or placebo (lactose monohydrate) for 12 weeks. Twenty patients were randomized to the Rhodiola rosea group, 19 to the sertraline group, and 18 to the placebo group.
The medicine was administered in a dose-escalation manner. One capsule was given for the first 2 weeks. If patients were assessed to be at less than 50% reduction of the Hamilton Depression Rating (HAM-D) scale, the dosage was moved up to 2 capsules daily for weeks 3 and 4. For patients who still had less than a 50% HAM-D scale reduction were moved up to 3 capsules daily during weeks 5 and 6. After 6 weeks, if reduction still did not improve to a 50% HAM-D reduction vs baseline, dosage was increased to 4 capsules for the remainder of the study.
Patients were assessed at baseline using the HAM-D as the primary outcome assessment with the Beck Depression Inventory (BDI) and Clinical Global Impression Change (CGI/C) scores for secondary outcome measurements. Patients were assessed at baseline and at 2, 4, 6, 8, and 12 weeks.
All treatment groups enjoyed statistically nonsignificant reductions in HAM-D, BDI, and CGI/C assessments with no significant difference among the groups. The decline in HAM-D was greater for sertraline vs Rhodiola rosea (‒8.2 vs ‒5.1) or placebo (‒4.6), with more patients suffering adverse reactions with sertraline (63.2%) over Rhodiola rosea (30.0%) or placebo (16.7%) (P=0.012). Overall efficacy of either medication did not differ from that of placebo.
This study is the first time Rhodiola rosea was compared to selective serotonin reuptake inhibitor like sertraline in a double-blind placebo-controlled randomized trial. These results suggest sertraline had a slightly greater effect vs Rhodiola rosea, while the botanical medicine had significantly fewer side effects. It should be noted that benefits of neither the drug nor the herb differed much over placebo. Meta-analysis has shown that in cases of mild to moderate depression, pharmaceuticals generally do not work any better than placebo,1 which boasts a 25%-to-30% effectiveness rate. This study pitting Rhodiola rosea against sertraline is consistent with a greater body of research that shows minimal but measurable effects for monotherapeutic approaches to mild and moderate depression.
This research underscores the need for 2 research-based modifications in order to treat depressive disorder more effectively in the future. One modification is for medical research to focus more on multidimensional treatment paradigms. In this particular study, like most double-blind studies, the only change in patient care was the pharmaceutical or herbal intervention. It is likely that expanding treatment by working on patient lifestyle choices and using dietary and psychological therapy concomitantly with the intervention would lead to greater benefits. While this may confound the exact mechanism that provides benefit, I believe efficacy rates for treatment would improve considerably.
It is likely that expanding treatment by working on patient lifestyle choices and using dietary and psychological therapy concomitantly with the intervention would lead to greater benefits.
The second necessity is to strive to create a better understanding of patient individuality in order to choose more effective therapies. For example, I often recommend Rhodiola rosea to patients who have a long-term history of chronic stress and have been tested to show high cortisol levels in the early morning that increase the patient’s awakening response. Previous work has shown Rhodiola rosea to decrease the cortisol response to awakening stress.2 This current study, like most studies, does not consider the individuality of each participant. For future studies, it may be advantageous to measure cortisol levels in participants to learn whether rhodiola may have been of particular benefit in a subset of people with early-morning high levels of cortisol.
One limitation to this study is the dropout of 13 patients by week 8. Two of these patients were taking sertraline (which was working effectively) but withdrew due to side effects, and 4 patients left due to lack of efficacy. A second limitation was that the study started with lower dosages and moved up in dosage if effect was not observed. It is possible that starting at the higher dosages at week 1 may have had a greater effect that is measurable over the 12-week period. Antidepressants typically require a full 12 weeks at a given dosage before an effect is discerned. This may be true for herbal remedies like Rhodiola rosea as well.
Rhodiola rosea was originally observed in the Russian literature as a plant medicine useful to combat physical, biological, and chemical stressors. As an adaptogenic herb, rhodiola acts as a neuroprotective, cardioprotective, antifatigue, antidepressive, anxiolytic, and nootropic (cognitive enhancing) agent that also yields life-span increasing effects as well as central nervous system-stimulation activity. It has been my experience that when this herb is used in the full scope of naturopathic care, it can be a support to rejuvenate patients, especially those who feel like they have “been through a war.”
This particular study may not suggest any greater efficacy for Rhodiola rosea over medication, but it seems to have at least the same overall efficacy as sertraline with fewer side effects. Conventional pharmaceutical therapy may suppress rather than eliminate depression symptoms, which increases overall risk of suicide or relapse.4 Given this fact and the results of this study, it is reasonable to consider Rhodiola rosea as having a superior risk-to-benefit ratio. In conclusion, if a therapeutic intervention is desired, Rhodiola rosea may be a better overall choice for mild to moderate depression over medication.