Elicit: Adverse Effects of Rhodiola Rosea (public)
What are the most common adverse effects and potential drug interactions associated with rhodiola rosea supplementation?
The most common adverse effects of rhodiola rosea are headache, nausea (up to 30%), gastrointestinal disturbances, dizziness, and insomnia, while potential drug interactions include serotonin syndrome with SSRIs and effects on drugs metabolized by cytochrome P450 2C9.
Abstract
Rhodiola rosea supplementation has most often been linked to mild, transient adverse effects. In several controlled trials using daily doses between 340 and 680 milligrams, subjects reported symptoms such as headache, nausea (up to 30% in one trial), gastrointestinal disturbances, dizziness, and insomnia. Many trials noted no adverse events at all.
Studies documenting drug interactions indicate that Rhodiola rosea can, in some instances, precipitate clinically significant events. Case reports have linked its combined use with selective serotonin reuptake inhibitors to serotonin syndrome. Pharmacokinetic investigations point to inhibition of cytochrome P450 2C9, suggesting that drugs with a narrow therapeutic index, as well as other central nervous system–active agents, might be affected when taken with Rhodiola rosea.
Methods
We analyzed 37 sources from an initial pool of 999, using 5 screening criteria. Each paper was reviewed for 5 key aspects that mattered most to the research question.
More on methods
Screening
We screened in sources based on their abstracts that met these criteria:
- Human Participants: Does this study involve human participants taking rhodiola rosea supplements?
- Safety Outcomes: Does this study report adverse effects, side effects, safety outcomes, or drug interactions related to rhodiola rosea?
- Study Design: Is this study a randomized controlled trial, cohort study, case-control study, case series, case report, systematic review, or meta-analysis?
- Single Ingredient Attribution: Can the effects reported in this study be attributed specifically to rhodiola rosea (i.e., is rhodiola rosea studied as a single ingredient or can its individual effects be distinguished from other components)?
- Original Data Quality: Does this study contain original data with sufficient methodological detail (i.e., is it NOT a conference abstract, editorial, letter to the editor, or opinion piece without original data)?
We considered all screening questions together and made a holistic judgement about whether to screen in each paper.
Results
Characteristics of Included Studies
| Study | Study Design | Population | Rhodiola Dose/Duration | Primary Outcome Focus | Full text retrieved |
|---|---|---|---|---|---|
| Mao et al., 2015 | Randomized controlled trial, multi-arm, double-blind, prospective, single-centre | 57 adults with mild-moderate major depressive disorder | SHR-5 extract, 340 mg escalating to 4 capsules/day, 12 weeks, oral | Efficacy and safety vs sertraline/placebo | Yes |
| Punja et al., 2014 | Randomized controlled trial, parallel-group, double-blind, placebo-controlled, single-centre | 48 healthy nursing students (81% female), 18–55 years | 364 mg daily, 42 days, oral | Fatigue reduction, safety | Yes |
| Bystritsky et al., 2008 | Single-arm, open-label, prospective, single-centre | 10 adults with generalized anxiety disorder, 34–55 years | 340 mg/day, 10 weeks, oral | Generalized anxiety disorder symptom reduction, safety | No |
| Maniscalco et al., 2014 | Observational (case report), retrospective | 1 female, 68 years, recurrent depression | No mention found | Drug interaction (Rhodiola + paroxetine) | No |
| Edwards et al., 2012 | Open-label, single-arm, prospective, multicentre | 101 adults, 30–60 years, life-stress symptoms | WS® 1375, 200 mg twice daily, 4 weeks, oral | Stress symptom improvement, safety | Yes |
| Hung et al., 2011 | Systematic review/meta-analysis | 503 participants, various randomized controlled trials | 60–680 mg, 1–42 days, oral | Efficacy/safety for various indications | Yes |
| Amsterdam and Panossian, 2016 | Review/meta-analysis | 860 (146 major depressive disorder, 714 stress-induced depression) | 340–680 mg/day, up to 12 weeks, oral | Antidepressant effects, safety | Yes |
| Thu et al., 2015 | Randomized controlled trial, cross-over, single-centre | 13 healthy males, 20–26 years | Arctic Root, 290 mg/day, 14 days, oral | Cytochrome P450 enzyme activity, safety | Yes |
| Darbinyan et al., 2007 | Randomized controlled trial, multi-arm, double-blind, prospective, single-centre | 89 adults, 18–70 years, mild-moderate depression | SHR-5, 340/680 mg/day, 6 weeks, oral | Depression symptom reduction, safety | Yes |
| Lekomtseva et al., 2017 | Open-label, single-arm, multicentre, prospective | 100 adults, 18–60 years, chronic fatigue | WS® 1375, 400 mg/day, 8 weeks, oral | Fatigue improvement, safety | Yes |
Effects
Adverse Effects Profile
| Study | Adverse Effects Reported | Frequency/Incidence | Severity Assessment |
|---|---|---|---|
| Mao et al., 2015 | Nausea, sexual dysfunction, appetite change, insomnia, palpitations, gastrointestinal disturbance, yawning, dry mouth, fatigue, headache, nervousness | Rhodiola rosea: 30.0%; Sertraline: 63.2%; Placebo: 16.7% | No explicit detail; no serious adverse events |
| Punja et al., 2014 | Headache, light-headedness, diarrhea/nausea, dark stool, nosebleed, blurred vision, excess energy, heartburn, palpitations, sore throat | 10 events in each group | Mild to moderate; no severe adverse events |
| Bystritsky et al., 2008 | Dizziness, dry mouth | No mention found | Mild or moderate |
| Maniscalco et al., 2014 | Vegetative syndrome, restlessness, trembling (serotonin syndrome with paroxetine) | Single case | No explicit description; clinically significant |
| Edwards et al., 2012 | Dizziness, abdominal distension, nervous system, gastrointestinal, psychiatric, infections, injury, respiratory, musculoskeletal, renal, general, metabolic, reproductive, skin | 36/101 (35.6%) | Mostly mild; no serious adverse events |
| Hung et al., 2011 | Headache, hypersalivation, unknown illness | 3/503 | Mild |
| Amsterdam and Panossian, 2016 | No explicit detail | 30.0% | Likely mild; no discontinuations |
| Thu et al., 2015 | Increased energy/concentration, nightmares, flatulence | 2/13 | Mild |
| Darbinyan et al., 2007 | None | None | None |
| Lekomtseva et al., 2017 | Cardiac, gastrointestinal, general, hepatobiliary, infections, metabolic, musculoskeletal, nervous, psychiatric, renal, reproductive, respiratory | 41/101 (40.6%) | Mild (81.8%), moderate (18.2%); 1 unrelated serious adverse event |
Drug Interactions
Several studies and reviews highlighted the potential for drug interactions with Rhodiola rosea, particularly with psychotropic medications:
- Case reports and pharmacovigilance studies: Maniscalco et al., 2014 and Woroń and Siwek, 2018 documented serotonin syndrome and other serious reactions when Rhodiola rosea was combined with selective serotonin reuptake inhibitors or other psychotropic drugs.
- Pharmacokinetic studies: Thu et al., 2015 suggested that Rhodiola rosea may inhibit cytochrome P450 2C9 activity, potentially affecting drugs with a narrow therapeutic index such as warfarin or phenytoin.
- Reviews: Machín et al., 2023 cautioned about possible interactions with drugs metabolized by cytochrome P450 enzymes, and recommended avoiding Rhodiola rosea in combination with immunosuppressants, anxiolytics, sedatives, or antidepressants without medical supervision.
- Randomized controlled trials: Most excluded participants on concomitant medications, limiting detection of drug interactions in controlled settings.
Dose-Response Relationships for Safety
- Across the studies reviewed, there is no clear evidence of a dose-dependent increase in adverse events within the commonly used dose range (100–680 milligrams per day).
- Higher doses (for example, 680 milligrams per day in Darbinyan et al., 2007) did not appear to increase the frequency or severity of adverse events compared to lower doses.
- Single high-dose studies (such as Antkowiak et al., 2022, 50 milligrams per kilogram) reported no significant adverse effects.
- Reviews (Machín et al., 2023) noted that effective and safe doses are typically 200–600 milligrams per day, with rare and mild side effects at these doses.
References
J. Woroń, M. Siwek (2018). Unwanted effects of psychotropic drug interactions with medicinal products and diet supplements containing plant extracts. Psychiatria Polska
A. Bystritsky, Lauren E Kerwin, Jamie D. Feusner (2008). A pilot study of Rhodiola rosea (Rhodax) for generalized anxiety disorder (GAD). Journal of Alternative and Complementary Medicine
I. Maniscalco, Elda Toffol, G. Giupponi, A. Conca (2014). Das Zusammenwirken von Rhodiola rosea (Eisenwurz) und Antidepressiva. Neuropsychiatrie (Deisenhofen)
D. Edwards, A. Heufelder, A. Zimmermann (2012). Therapeutic Effects and Safety of Rhodiola rosea Extract WS® 1375 in Subjects with Life‐stress Symptoms – Results of an Open‐label Study. Phytotherapy Research