The effects of Rhodiola Rosea supplementation on depression, anxiety and mood – A Systematic Review

Rhodiola rosea is an adaptogen herb used in herbal medicines (Ross, 2014). Adaptogens are natural health products (NHPs) that produce a non-specific response aimed to promote homeostasis (Brekhman, Dardymov, 1969). For a herb to be considered an adaptogen by the European Medicines Agency, it must also be completely safe, non-toxic and to affect various organ systems of the recipient’s organism. A common characteristic of adaptogens, is their ability to reduce stress, by interfering in the HPA axis. At stressful events, adaptogens are thought to hinder the release of corticotropic-releasing hormone (CRH), cortisol, nitric oxide, pro-inflammatory cytokines, free radicals, stress-activated protein kinase (SAPK) and Jun N-terminal protein kinase (JNK), while also blocking the stress-induced decrease of BDNF, ATP production, glucocorticoid receptor sensitivity, HPS-70 and neuropeptide-Y (Panossian, Wikman, 2010; Anghelescu et al., 2018). The term adaptogen was first introduced in 1947 (European Medicines Agency 2008) and was vastly used in the Soviet Union (Brekhman, Dardymov, 1969). Most research on adaptogens was made in the Soviet Union, Korea and China. However, flaws in the studies, lack of research and data prevented the worldwide acceptance of adaptogens into clinical practice (European Medicines Agency 2008). Some of the most common adaptogen herbs are Ashwagandha, Panax Ginseng, Schisandra and Rhodiola Rosea (Panossian et al., 2007). Rhodiola rosea is a perennial flowering plant of the family Crassulaceae (Plants for a Future 2012). The plant grows naturally at Arctic regions of Europe, Asia (mostly Siberia), and in the eastern coastal regions of North America (Plants for a Future 2012). It reaches a height of up to forty centimetres and has yellow flowers (Ross, 2014). Approximately 140 different chemicals were found in the roots of Rhodiola rosea (Panossian, Wikman, Sarris, 2010). Some of these chemicals are rosavin, rosin, rosarin, phenols, organic acids, terpenoids, phenolic acids, flavonoids, alkaloids, tyrosol, anthraquinones and salidroside (Evstavieva et al., 2010), (Mao, Li, Yao, 2007). Extracts of Rhodiola rosea used in human clinical studies are standardized at > 3.0% rosavins, > 0.8% salidrosides at a ratio of 3:1 (Ross, 2014). These two substances are thought to be responsible for the anxiolytic and antidepressant actions of the herb (PerfumI, Mattioli, 2007); (Mattioli, Funari, Perfumi, 2008) and are considered the marker compounds of Rhodiola rosea (Ross, 2014).

The history of Rhodiola rosea as a medical herb traces back to 77 AD, when the Greek physician Dioscorides first recorded the plants’ medical applications in his medical book De Materia Medica (Mell 1938 as cited by Ross 2014). The herb was used by the Vikings to enhance physical strength and endurance, and in Tibetan medicine, to treat lung disorders (Ross, 2014). In the 18^th century, the Swedish Botanist Carolus Linnaeus who is recognized as the ‘Father of Taxonomy’ renamed the herb to Rhodiola rosea for the rose-like aroma of the flowers and used the herb for the treatment of leukorrhea, hysteria and headache (Ross, 2014). In the 19^th century, Rhodiola rosea was used in France as a brain tonic and in Germany for headaches, pain relief, haemorrhoids treatment, as a stimulant and as an anti-inflammatory agent (Ross, 2014). In 1969, it had already been approved and registered by the Soviet Ministry of Health for medical use. Since 1985, R. rosea has been recorded in Herbal Medicinal Product in Sweden. R. rosea has now been documented by European Medicines Agency for temporary relief of symptoms of stress.

The pharmacology involved in the antidepressant effects of the herb has been examined by numerous studies. Amsterdam, Panossian (2016) reported that the herb seems to stimulate expression and release of neuropeptide-Y in neuroglial cells, to regulate more than 50 genes involved in the regulation of behaviour, mood and depressive disorders and to be overall associated with the key mediators of stress response, regulation of homeostasis of HPA axis activity, modulation of G-protein coupled receptor (GPCR) signalling pathways and other molecular networks involved in depression. Other research has shown that Rhodiola rosea acts as a MAO-A and MAO-B inhibitor, showing evidence about the herb’s antidepressant and cognitive enhancing properties (van Diermen et al 2009). R. rosea also seems to stimulate noradrenalin, serotonin, dopamine and acetylcholine receptors in the brain (Mao et al., 2015). Finally, (Lishmanov et al., 1987) reports that studies have also shown that R. rosea promotes an increase in β-endorphins, which lowers the intensity of the stress response and the production of endorphins at stressful situations. In other words, the herb acts by decreasing or totally preventing stress-induced hormonal changes, by its adaptogenic properties (Figure 1).

Figure 1

The objective of this systematic review was to examine the effects of R. rosea on humans suffering from depression, anxiety and mood disorders. We hope that our review proves to be informative for the therapeutic effects of the herb and encourages future research.

After using the methods, a total of 39 randomized clinical trials were identified. All of the 39 trial’s abstracts were screened. After screening, 17 papers were excluded. These papers were excluded because they were not examining the effects of Rhodiola rosea on depression or anxiety or mood. The full text of the remaining 22 papers was read. After full-text reading, 17 more papers were excluded, leaving a final sample of 5 papers. Of these 17 papers, three studies were excluded because they used Rhodiola rosea interventions with other herbs; two studies were excluded because they were assessing mental work; three studies were excluded because they were assessing endurance exercise performance; and the rest of the studies were assessing the effects of Rhodiola rosea on anaerobic exercise performance, physical and mental fatigue, stress-related fatigue, skeletal muscle damage and inflammation, sport performance, skeletal muscle phosphate kinetics, and the effects on oxidants-antioxidants. Finally, two studies were duplicates. The last date of our search was 13 October 2019.

Risk of Bias

A total of five randomized controlled trials were included in our review, all of which were assessed for bias with the Cochrane tool for assessing the risk of bias. Out of the five randomized controlled studies assessed for bias, only one study had a high risk of bias in the domains of allocation concealment and blinding of participants and personnel, while also having an unclear risk of bias in random sequence generation and a low risk of bias in the remaining fields. The rest of the studies had a low risk of bias in all fields (Figure 3). All in all, 4/5 studies included in our review, had a low risk of bias.

Figure 2

Figure 3

Other systematic reviews have also been conducted on the therapeutic effects of the herb. In Pubmed, a total of eight systematic reviews were identified. One review examined the effects of the herb on ischemic heart disease and another examined the effects of the herb on altitude sickness. We believe that these reviews are irrelevant with the outcomes examined in our review. Furthermore, three systematic reviews were identified examining the effects of R. rosea on psychiatric disorders or anxiety or mood (Dwyer, Whitten, Hawrelak, 2011; Sarris et al., 2011; Sarris, 2007). Unfortunately, all three of these reviews included only one study (Darbinyan et al., 2007), which is also included in our review. Thus, no comparisons will be made. Moreover, a systematic review examining the effects of R. rosea on mental and physical fatigue was identified. The review of Ishaque et al. (2012) reports that while some evidence was found for the effects of the intervention on fatigue, this evidence is highly inconclusive due to the low quality of the existing evidence. Furthermore a systematic review examining the effectiveness and efficacy of R. rosea (Hung, Perry, Ernst, 2011) was also identified. This review concludes that beneficial effects were found for physical and mental performance and various mental conditions, some of which were stress-related. It also notes that the herb produced very little adverse effects and that it seems to be relatively safe. A systematic review on numerous herbs for depression was also identified. The review of Yeung et al. (2018) includes four of the five studies included in our review. However, it does not go into great depth, as the primary outcome is not solely the therapeutic effects of Rhodiola rosea but the antidepressant effects of various medicinal herbs. Finally, a non-systematic review was also spotted. The review of Amsterdam and Panossian (2016) provided great information on the mechanism of action of Rhodiola rosea and included both human and animal studies of the herb on depression. Despite the fact that the authors also included Russian literature, this literature was of low quality. No randomized controlled trial that was not included in our review was included in the review of Amsterdam and Panossian (2016).

The chemical composition, the pharmacology and the toxicity of the herb have been examined more rigorously. The studies of Tao et al. (2018), Panossian, Wikman and Sarris (2010) and Amsterdam and Panossian (2016) provide great information about the phytochemistry, the pharmacology, the toxicity and the animal studies performed on the herb. From these studies, it should be highlighted that Rhodiola rosea does not share the same mechanism of conventional antidepressants (Amsterdam, Panossian, 2016). Rhodiola rosea has many different possible therapeutic effects, which include antioxidant, anticancer, antidiabetic, anti-altitude sickness, anti-stress, antidepressant, anxiolytic, neuroprotective, antifatigue, anti-inflammatory, immunomodulatory, for addictive disorders and other effects (Tao et al., 2018). Finally, all three studies suggest that the herb is safe, the adverse effects are rare and mild, high doses do not cause significant adverse effects and that the therapeutic window is large. However, Tao et al. (2018) notes that drug interactions are possible and that the long-term use of the herb may pose some safety risks.

Talking all this into consideration, we conclude that the herb must be further researched. Future research should focus on providing high quality randomized controlled clinical trials with a low risk of bias. Interventions should preferably consist solely of Rhodiola rosea extract and various doses should be tested. Combined interventions of a conventional antidepressant with Rhodiola rosea are also preferable, in order to examine a potential combination therapy. Furthermore, comparisons should be made with both placebo and with conventional antidepressants. The population should preferably consist of participants diagnosed with mild to moderate depression or mild to moderate anxiety and large samples should be used. Finally, the outcomes of depression should be assessed with the HAMD questionnaire (Hamilton, 1960), the BDI-II questionnaire (Beck et al., 1996) and the MADRS questionnaire (Montgomery, Asberg, 1979). The outcomes of anxiety should be assessed with the STAI questionnaire (Spielberger et al., 1983) and the HARS questionnaire (Hamilton, 1959). Mood should be assessed with the Profile of Mood States Inventory (McNair, Lorr, Doppleman, 1971) and the MDMQ dimensions questionnaire (Steyer et al., 1997). Homogeneity of outcome measures and a low risk of bias are essential for the performance of a meta-analysis.

While a meta-analysis of the results was desirable, the authors decided it would be best not to perform one. This decision was made after observing that only two of the studies included in our review used the same outcome measures. Thus, we gave advice for future research that will enable the performance of a meta-analysis in the discussion column.

Significant results were found for the effects of the herb on mild to moderate depression, mild anxiety and overall mood. Even though these findings are not conclusive, they certainly encourage further research. Future research should aim at providing randomized controlled clinical trials with a low risk of bias and homogeneity of outcome measures. We hope that this systematic review proves to be informative of the therapeutic effects of Rhodiola rosea and encourages further research of the herb.