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Adverse Effects of Rhodiola Rosea (public)

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September 11, 2025

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

Papers identified with Elicit search

n = 999

Papers screened using: Human Participants, Safety Outcomes, Study Design, Single Ingredient Attribution, Original Data Quality

n = 999

Papers screened out

n = 962

Papers included for extraction

n = 37

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Paper search

Using your research question “What are the most common adverse effects and potential drug interactions associated with rhodiola rosea supplementation?”, we searched across over 126 million academic papers from the Semantic Scholar corpus. We retrieved the 999 papers most relevant to the query.

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.

Data extraction

We asked a large language model to extract each data column below from each paper. We gave the model the extraction instructions shown below for each column.

• Study Design:

Describe the specific type of study design used:

• Randomized controlled trial (RCT)
• Open-label study
• Observational study
• Review/meta-analysis

Specify additional design details such as:

• Single-arm or multi-arm
• Blinding status (open-label, double-blind, single-blind)
• Prospective or retrospective
• Multicentre or single-centre

If multiple design characteristics apply, list all relevant details. If design is unclear, note “design not clearly specified” and provide any available contextual information.

• Participant Characteristics:

Extract the following participant details:

• Total number of participants
• Age range or mean age
• Gender distribution
• Specific health conditions or symptoms (e.g., life-stress symptoms, depression)
• Inclusion/exclusion criteria

If any of these details are missing, note “not reported” for that specific characteristic. If ranges or means are provided, include both. Ensure to capture any specific diagnostic criteria used to define participant groups.

• Rhodiola Rosea Intervention Details:

Record the following intervention specifics:

• Extract/product name (e.g., WS® 1375)
• Dosage (mg per administration)
• Frequency of administration
• Total duration of intervention
• Method of administration (oral, etc.)

If multiple dosage regimens are reported, list all. If any details are ambiguous or partially reported, specify the available information and note what is missing.

• Adverse Effects and Drug Interactions:

Systematically document:

• Types of adverse events reported
• Severity of adverse events (mild, moderate, severe)
• Frequency of adverse events
• Specific drug interactions observed
• Any serious adverse events

Prioritize reporting of:

1. Frequency of adverse events
2. Specific nature of interactions
3. Severity of reactions

If no adverse events were reported, explicitly note “No adverse events reported”. If interactions are mentioned but not fully detailed, capture all available information.

• Safety Profile and Tolerability:

Extract overall safety assessment:

• General tolerability statement
• Proportion of participants experiencing side effects
• Whether the intervention was considered safe
• Any recommendations or cautions about use

Look for explicit statements about safety in the results or discussion sections. If multiple safety assessments are present, capture the most comprehensive evaluation. If safety is not explicitly discussed, note “safety not comprehensively reported”.

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

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Summary of Study Characteristics:

• Study design:
  • 17 randomized controlled trials
  • 9 observational studies (including open-label, case report, and retrospective designs)
  • 9 systematic reviews or meta-analyses
  • 2 studies with no clear design reported
• Population:
  • 15 studies included healthy adults
  • 16 studies included clinical populations (such as depression, anxiety, chronic fatigue, angina, or other conditions)
  • 6 studies included mixed, not applicable, or not reported populations
• Rhodiola dose and duration:
  • Dose information was reported in 25 studies, with daily doses ranging from 60 mg to 1500 mg, most commonly between 340–680 mg/day
  • 12 studies did not report dose or were not applicable
  • Duration ranged from a single dose to 12 weeks, with most studies using 2–12 week interventions
  • Formulations included SHR-5, WS® 1375, Vitano®, Vigodana®, Rosalin®, Arctic Root, Rhodiola rosea extract, Rhodiola rosea capsule, and others; in several studies, the formulation was not specified
• Primary outcome focus:
  • 6 studies focused on depression or mood
  • 9 studies focused on fatigue, stress, or burnout
  • 10 studies focused on cognition or physical/mental performance
  • 4 studies focused on drug interactions or pharmacology
  • 3 studies focused on cardiovascular outcomes (angina, ischemic heart disease, high altitude disease)
  • 5 studies focused on other outcomes such as adaptogens or herbal supplements in sport

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

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Summary of Adverse Effects Findings:

• No adverse effects reported:19 studies explicitly reported no adverse effects in the available full texts or abstracts.
• Adverse effects reported:13 studies reported adverse effects, most commonly mild and transient symptoms such as headache, gastrointestinal disturbance, dizziness, and insomnia.
• No mention of adverse effects:5 studies did not mention adverse effects.
• Frequency/incidence:
  • 19 studies reported no adverse events occurred.
  • 11 studies provided quantitative incidence data (percentages or number of cases).
  • 3 studies described frequency qualitatively (e.g., “rare,” “low,” “higher with combination”).
  • 4 studies did not mention frequency or incidence.
• Severity:
  • 19 studies reported no adverse effects (and thus no severity).
  • 7 studies reported only mild adverse effects.
  • 4 studies reported mild to moderate adverse effects.
  • 3 studies reported severe or clinically significant adverse effects; these were rare and often associated with drug interactions or were not attributed to Rhodiola rosea itself.
  • 4 studies did not mention severity.
  • 3 studies mentioned serious adverse events that were unrelated to Rhodiola rosea.

Key insights:

• Most studies either reported no adverse effects or only mild events.
• Severe or clinically significant adverse effects were rare, and when present, were often associated with drug interactions or were not attributed to Rhodiola rosea.
• We did not find mention of adverse effect data in 5 studies.

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.

Summary of Drug Interaction Findings:

• Case reports and pharmacovigilance studies suggest clinically significant interactions, especially with psychotropic drugs.
• Mechanistic studies indicate possible inhibition of cytochrome P450 enzymes, which may affect the metabolism of other drugs.
• Reviews recommend caution when combining Rhodiola rosea with medications metabolized by cytochrome P450 enzymes or with central nervous system-active drugs.
• Controlled trials rarely report drug interactions due to exclusion criteria.

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.

Summary of Dose-Response Findings:

• Rhodiola rosea appears safe and well-tolerated across a range of doses commonly used in clinical practice and research.
• No clear dose-response relationship for adverse events was observed within this range.
• Data on very high doses or long-term use remain limited.

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

S. Hung, R. Perry, E. Ernst\ (2011).The effectiveness and efficacy of Rhodiola rosea L.: a systematic review of randomized clinical trials. Phytomedicine

J. Amsterdam, A. Panossian\ (2016).Rhodiola rosea L. as a putative botanical antidepressant. Phytomedicine

Ole Kristian Forstrønen Thu, O. Spigset, O. G. Nilsen, Bent H. Hellum\ (2015).Effect of commercial Rhodiola rosea on CYP enzyme activity in humans. European Journal of Clinical Pharmacology

Sana Ishaque, Larissa Shamseer, Cecilia Bukutu, S. Vohra\ (2012).Rhodiola rosea for physical and mental fatigue: a systematic review. BMC Complementary and Alternative Medicine

V. Darbinyan, G. Aslanyan, E. Amroyan, E. Gabrielyan, C. Malmström, and 1 more\ (2007).Clinical trial of Rhodiola rosea L. extract SHR-5 in the treatment of mild to moderate depression. Nordic Journal of Psychiatry

J. Mao, S. Xie, J. Zee, Irene Soeller, Qing S Li, and 2 more\ (2015).Rhodiola rosea versus sertraline for major depressive disorder: A randomized placebo-controlled trial. Phytomedicine

M. Končić, M. Tomczyk\ (2013).New insights into dietary supplements used in sport: active substances, pharmacological and side effects. Current Drug Targets

Yao Lu, Bin Deng, Luhua Xu, Hanjiao Liu, Yinzhi Song, and 1 more\ (2022).Effects of Rhodiola Rosea Supplementation on Exercise and Sport: A Systematic Review. Frontiers in Nutrition

V. Shevtsov, B. I. Zholus, V. I. Shervarly, V. B. Vol'skij, Y. P. Korovin, and 3 more\ (2003).A randomized trial of two different doses of a SHR-5 Rhodiola rosea extract versus placebo and control of capacity for mental work. Phytomedicine

A. Spasov, G. Wikman, V. B. Mandrikov, I. A. Mironova, V. V. Neumoin\ (2000).A double-blind, placebo-controlled pilot study of the stimulating and adaptogenic effect of Rhodiola rosea SHR-5 extract on the fatigue of students caused by stress during an examination period with a repeated low-dose regimen. Phytomedicine

V. Fintelmann, J. Gruenwald\ (2007).Efficacy and tolerability of aRhodiola rosea extract in adults with physical and cognitive deficiencies. Advances in Therapy

Y. Lekomtseva, I. Zhukova, Anna Wacker\ (2017).Rhodiola rosea in Subjects with Prolonged or Chronic Fatigue Symptoms: Results of an Open-Label Clinical Trial. Complementary Medicine Research

V. Darbinyan, A. Kteyan, A. Panossian, E. Gabrielian, G. Wikman, and 1 more\ (2000).Rhodiola rosea in stress induced fatigue--a double blind cross-over study of a standardized extract SHR-5 with a repeated low-dose regimen on the mental performance of healthy physicians during night duty. Phytomedicine

R. Shanely, D. Nieman, K. Zwetsloot, A. Knab, H. Imagita, and 3 more\ (2014).Evaluation of Rhodiola rosea supplementation on skeletal muscle damage and inflammation in runners following a competitive marathon. Brain, behavior, and immunity

M. Cropley, A. Banks, J. Boyle\ (2015).The Effects of Rhodiola rosea L. Extract on Anxiety, Stress, Cognition and Other Mood Symptoms. Phytotherapy Research

S. Punja, Larissa Shamseer, K. Olson, S. Vohra\ (2014).Rhodiola Rosea for Mental and Physical Fatigue in Nursing Students: A Randomized Controlled Trial. PLoS ONE

A. Parisi, E. Tranchita, G. Duranti, E. Ciminelli, F. Quaranta, and 4 more\ (2010).Effects of chronic Rhodiola Rosea supplementation on sport performance and antioxidant capacity in trained male: preliminary results. Journal of Sports Medicine and Physical Fitness

Rubén P. Machín, Miguel Florido, Ricardo Chirino-Godoy, Laura López-Ríos\ (2023).Adaptogenic Botanicals with Emphasis on Rhodiola rosea and Withania somnifera. European Journal of Medicinal Plants

Lei Yu, Yongjie Qin, Qingqing Wang, Lu Zhang, Yaqiong Liu, and 4 more\ (2014).The efficacy and safety of Chinese herbal medicine, Rhodiola formulation in treating ischemic heart disease: a systematic review and meta-analysis of randomized controlled trials. Complementary Therapies in Medicine

M. Abidov, S. Grachev, R. Seifulla, T. Ziegenfuss\ (2004).Extract of Rhodiola rosea Radix Reduces the Level of C-Reactive Protein and Creatinine Kinase in the Blood. Bulletin of experimental biology and medicine

E. Jówko, J. Sadowski, B. Długołȩcka, D. Gierczuk, B. Opaszowski, and 1 more\ (2016).Effects of Rhodiola rosea supplementation on mental performance, physical capacity, and oxidative stress biomarkers in healthy men. Journal of Sport and Health Science

Daniel Marcos-Frutos, Žiga Leban, Zhaoqian Li, Xing Zhang, Paula M. Lara, and 8 more\ (2025).The Impact of Rhodiola Rosea Extract on Strength Performance in Alternative Bench-Press and Bench-Pull Exercises Under Resting and Mental Fatigue Conditions: A Randomized, Triple-Blinded, Placebo-Controlled, Crossover Trial. Nutrients

S. Kasper, A. Dienel\ (2017).Multicenter, open-label, exploratory clinical trial with Rhodiola rosea extract in patients suffering from burnout symptoms. Neuropsychiatric Disease and Treatment

Jianfeng Chu, Guangjiang Wu, Guo-hua Zheng, F. Zheng, Jian-feng Xu, and 2 more\ (2014).[A system review of randomized controlled trials on treating chronic stable angina by rhodiola]. Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine

M. Heldmann, G. Roth, A. Dienel, T. Münte\ (2016).EP 116. Impact of Rhodiola Rosea extract WS1375 on electrophysiological correlates of attention allocation in a dual task paradigm. Clinical Neurophysiology

Larissa Jorge Coelho, Natália de Barros Teles, Maria Laura Martins, Klismam Marques dos Santos, Tayslane Dias Castro, and 2 more\ (2025).Evaluation of the Therapeutic of the Standardized Dry Extract of Rhodiola rosea in Physical Activity Practiotioners. Journal of Advances in Medicine and Medical Research

Li-li Gao, Chenghan Wu, Yuan-sheng Liao, Jinmin Wang\ (2020).Antidepressants effects of Rhodiola capsule combined with sertraline for major depressive disorder: A randomized double-blind placebo-controlled clinical trial. Journal of Affective Disorders

B. Antkowiak, O. Antkowiak, M. Brytan, P. Cięszczyk, E. Szarska, and 5 more\ (2022).Effect of Rhodiola rosea L. roots extract on pain perception in humans. Phytomedicine Plus

Tina Koop, A. Dienel, M. Heldmann, T. Münte\ (2020).Effects of a Rhodiola rosea extract on mental resource allocation and attention: An event‐related potential dual task study. Phytotherapy Research

Zixuan Gao, Yaoyuan Liu, Weiwen Liao, Wenting Song, Xinyi Zhang, and 4 more\ (2025).Efficacy and safety of Rhodiola crenulata extract in the treatment of acute high altitude disease, based on studies involving populations in China: A systematic review and meta-analysis. Frontiers in Pharmacology

V. Darbinyan, G. Aslanyan, E. Amroyan, E. Gabrielyan, C. Malmstrom, and 1 more\ (2007).Rhodiola SHR-5 extract and the treatment of depression

No authors found (2018).Premium Rhodiola Rosea with Ginseng Reduce Your Mental & Physical Fatigue

Темирбулатова Анна Михайловна, Лежнева Лариса Петровна, Хаджиева Зара Джамалеевна, Погорелый Василий Ефимович, Глижова Тамара Николаевна, and 1 more\ (2015).Фармакологические исследования экстракта родиолы розовой

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Adaptogenic Botanicals with Emphasis on Rhodiola rosea and Withania somnifera

Rubén P. Machín, Miguel Florido, Ricardo Chirino-Godoy, Laura López-Ríos

European Journal of Medicinal Plants·

2023·

1 citation

SourceDOI

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Study Design

Review/meta-analysis

Participant Characteristics

- Total number of participants: not reported - Age range or mean age: not reported - Gender distribution: not reported - Specific health conditions or symptoms: life-stress symptoms, depression, anxiety, insomnia - Inclusion/exclusion criteria: not reported

Rhodiola Rosea Intervention Details

- Extract/product name: Root powder, dry extracts, liquid extract - Dosage: 200 to 600 mg/day - Frequency of administration: Not specified - Total duration of intervention: Not specified - Method of administration: Oral

Adverse Effects and Drug Interactions

- Types of adverse events reported: Mild headache, insomnia, hypersalivation, nausea, dizziness; potential interactions with psychotropic drugs leading to myalgia, altered consciousness, restless legs syndrome, headache, arthralgia, diarrhoea, nausea, jaundice, myoclonus, hypoglycemia, excessive sedation, priapism, dizziness, hypotension, hyperhidrosis, and hallucinations. - Severity of adverse events: Mild; potential for more severe reactions with drug interactions. - Frequency of adverse events: Rare; low frequency for severe interactions. - Specific drug interactions observed: Potential interactions with psychotropic drugs; caution advised with drugs having a narrow therapeutic window; not recommended with immunosuppressors or anxiolytics, sedatives, or antidepressants. - Serious adverse events: Not explicitly mentioned.

Safety Profile and Tolerability

- General tolerability statement: Both R. rosea and W. somnifera are generally considered safe and well-tolerated. - Proportion of participants experiencing side effects: Low incidence of side effects for R. rosea; specific side effects include mild headache, insomnia, hypersalivation, nausea, and dizziness. - Whether the intervention was considered safe: Yes, both are considered safe when used appropriately. - Any recommendations or cautions about use: R. rosea should be taken during the first half of the day, and caution is advised for individuals with bipolar spectrum disorders. W. somnifera should be used with caution in individuals prone to hypotension or those taking immunosuppressors.

This review addresses the issue of plant adaptogens, botanical products with remarkable anti-stress effects. These actions result from its ability to increase the non-specific organism's resistance process against multiple stressors (physical, chemical or biological). They are capable of exerting a normalizing effect on the human body, being both non-toxic effects and not influencing normal organic functions. Several plants with a complex phytochemical profile meet the criteria for being adaptogens. Many of them have been used in traditional medicine as tonic-vitalizing agents for centuries to treat various health conditions. This review briefly explains the organism's stress responses against stressors and the evolution of the adaptogenic concept from a historic perspective. A rational classification of adaptogens plants is formulated although it does not cover the full variability of botanical adaptogens. Nevertheless, summarizing data from two of the most important plant adaptogens, golden root (Rhodiola rosea) and Indian ginseng (Withania somnifera), are described. This includes their most deserving ethnomedicinal properties, the various families of compounds that constitute their complex phytochemical profiles, pharmacological activities along with putative mechanism of action responsible for some of their multifaceted biological actions, and the multi-therapeutic and health-promoting activities obtained from the most relevant clinical trials performed to date. Additionally, several relevant and current issues regarding the safety and toxicity of both widely used adaptogens are detailed. These include potential negative drugs interactions, putative contraindications and warnings in specific physiological statuses or health conditions. Finally, despite the overlapping activities against stress and stress-related health conditions some superior therapeutic benefits are tentatively assigned both to Withania somnifera and Rhodiola rosea taking into account the overall evidence of efficacy from pharmacological and clinical studies.

the full variability of botanical adaptogens. Nevertheless, summarizing data from two of the most important plant adaptogens, golden root (Rhodiola rosea) and Indian ginseng (Withania somnifera), are described. This includes their most deserving ethnomedicinal properties, the various families of compounds that constitute their complex phytochemical profiles, pharmacological activities along with putative mechanism of action responsible for some of their multifaceted biological actions, and the multi-therapeutic and health-promoting activities obtained from the most relevant clinical trials performed to date. Additionally, several relevant and current issues regarding the safety and toxicity of both widely used adaptogens are detailed. These include potential negative drugs interactions, putative contraindications and warnings in specific physiological statuses or health conditions. Finally, despite the overlapping activities against stress and stress-related health conditions some superior therapeutic benefits are tentatively assigned both to Withania somnifera and Rhodiola rosea taking into account the overall evidence of efficacy from pharmacological and clinical studies. Keywords: Adaptogens; Rhodiola rosea; Withania somnifera; stress; anxiety; fatigue; cognition; performance.

ABBREVIATIONS SAM :

Sympathetic system HPA :

Hypothalamic-pituitary-adrenal axis R. rosea :

Rhodiola rosea W. somnifera : Withania somnifera MAO-A : Monoamine oxidases type A enzyme MAO-B :

Monoamine oxidases type B enzyme

1.INTRODUCTION

The ability to adapt to a variable environment is a unique characteristic of living organisms. Any external or internal demand (stressor) in this environment triggers a defensive state known as "stress", aiding the organism in reacting and adapting to events [1,2]. Stressors that elicit the stress response can be physical, chemical, or psychological in nature. Selye defined the General Adaptation Syndrome as a response that develops in the body in reaction to stress, consisting of three phases:

1. Alarm reaction: an immediate response to stress, protective and designed to be short-lived. It involves the activation of the neuroendocrine system, enhancing both the sympathetic system (SAM) and the hypothalamic-pituitaryadrenal axis (HPA). This activation promotes catabolism, rapidly providing energy and drive. The organism enters a catabolic state, and the general nonspecific resistance to stressors is elevated.

(2) Resistance: Chronic or repeated low exposure of the organism to a stressor elicits the switch from a catabolic to anabolic phase, leading to the development of stressor-specific resistance. The organism may positively adapt to stress (developing resistance to stressors and improving its adaptive capacity and health) or may show poor, detrimental adaptation, leading to the next phase.

3. Exhaustion: If stress persists or increases or poor adaptation is present, the power and duration of the organism´s resistance are overloaded, leading to disruptions in normal functions and homeostasis. A combination of factors, including energy depletion contributes to hormonal depletion, eventual exhaustion, system dysfunction, and the occurrence of disease [2].

Therefore, the ability to develop and preserve resistance to stress is crucial for coping with a wide spectrum of stressors experienced in human life. The interest in modulating stress resistance processes has led to the emergence of the science of adaptation. Research has focused on understanding the mechanisms underlying the process of adaptation, elucidating what are the key variables that guide this phenomenon [3,4]. This includes screening botanicals to modulate them, aiming to avoid insufficient, disproportionate, unnecessary or erroneous stress responses. In this review, we will briefly describe the history of the concept of adaptogens and botanical adaptogenic substances. A basic classification of adaptogens will be proposed, with a focus on two of the most widely studied botanicals: Rhodiola rosea (R. rosea) and Withania somnifera (W. somnifera). This will include their most relevant bioactive compounds, pharmacological activities, evidence-based health properties, and safety concerns.

2.1Adaptogen Concept

Adaptogens encompass various medicinal plants or extracts (herbal adaptogens), specific phytochemicals and some synthetic compounds (actoprotectors) that primarily protect health by non-specifically increasing resistance to stressors. They aid individuals in coping and adapting to stress. Among them, herbal adaptogens are a category of botanical medicines historically associated with herbal tonics [5,42, 43, ] . Herbalists in various traditional medical systems have used them since ancient times to help mitigate the negative impact of chronic stress on health.

While the concept exists in various traditional medical systems at the clinical level and classifications, the scientific formalization of the term "adaptogen" dates back to the 1940s. The distinguished Russian scientist Lazarev [6] coined the term when he discovered the adaptogenic activity of Dibazol in a series of experiments designed to induce nonspecific resistance to stressors in humans. Lazarev defined the term "adaptogen" as any compound capable of promoting an increased state of nonspecific resistance in an organism, enabling it to counteract stressor signals and facilitate adaptation to exceptional overload [7,8].

In 1969, Russian scientists Brekhman and Dardymov refined the term and placed it within the field of phytomedicine. Their definition was based on an analysis of several preclinical studies conducted with relevant botanicals, commonly used as tonics in polyherbal formulations of traditional medical systems [9] . They specified that adaptogens must meet the following requirements:

1.An adaptogen should be harmless and minimally affect the normal physiological functions of the body.

2.An adaptogen must exhibit non-specific action, having the ability to enhance the organism's resistance to a wide range of harmful stress factors, whether physical, chemical, or biological nature.

3.An Adaptogen should exert a normalizing influence regardless of the direction of change from physiological norms caused by stressors.

4.Unlike classical stimulants, an adaptogen should have pro-excitatory effects that do not induce undesirable side effects such as low protein synthesis, restlessness, or increased energy expenditure.

In modern pharmacology and pharmacognosy, the definition of adaptogens is continually evolving with the expanding body of scientific evidence concerning their molecular mechanisms of action on various regulatory systems at the cellular, organic, and whole organism levels. Consequently, a cumulative body of contemporary research characterizes adaptogens as botanical compounds or plant extracts that enhance the adaptability, resilience, and survival of organisms to a variety of stressors [10,47,48]. This is achieved through multi-target and multi-channel actions on the neuroendocrine and immune systems, especially by modulating SAM and HPA (Fig. 1 ). Accordingly, herbal adaptogens support the human organism's ability to respond appropriately to stressors of different origins (acting as stress response modifiers). They also enhance the capacity of physiological systems to continually adapt to changes (resilience) through multi-level dynamic modulation of mechanisms and processes throughout the body, maintaining homeostasis (allostasis) [11].

Adaptogenic herbs have proven beneficial in the treatment of various conditions, including convalescent patients after infections or other illnesses, neuro-asthenia, depressive and burn-out syndromes, or exhaustion after intensive and/or long periods of work requiring mental or physical exertion. These conditions are characterized by multiple symptoms including fatigue, weakness, irritability, headache, malaise, insomnia, poor appetite, cognitive and memory impairment, stress, depression, and anxiety [12].

2.2Classification of Botanical Adaptogen

Adaptogens can be categorized into three groups: primary (or classical) adaptogens, secondary adaptogens, and adaptogen companions [13]. According to the principles of Brekhman and Dardymov (1969) [14] . Primary adaptogens have a wealth of scientific studies confirming their adaptogenic character, ensuring non-specific action, general resistance in the organism, support of homeostasis, and a lack of adverse or toxic effects even after prolonged intake [15].

The second group is referred to as "secondary adaptogens," sharing some characteristics or qualities of traditional adaptogen definitions but not meeting all of the criteria of primary adaptogens and lacking extensive study. These adaptogens typically modulate the nervous, endocrine, and immune systems, and may enhance anabolism, but do not directly influence the HPA. Medicinal plants in this category include Astragalus trimestris L., Bacopa monnieri (L.) Wetst., Centella asiatica (L.) Urb., Ocimum tenuiflorum L., Ptychopetalum olacoides Benth, Panax notoginseng (Burkilll) F.H. Chen, Ganoderma lucidum (Curtis) P. Karst, Asparagus racemosus Willd., Dioscorea mexicana Scheidw., Tinospora cordifolia (Willd.) Miers ex Hook.f. & Thomson, Phyllanthus emblica L. and Glycyrrhiza glabra L. [15] An additional category includes specific nonadaptogenic plants named "adaptogen companions", characterized by enhancing or synergizing the effect of primary or secondary adaptogens without directly modulating the HPA. These plants lack toxicity, exhibit increased benefits with long-term intake, supporting the ability to cope with some types of stress (notably oxidative stress & inflammation), and are typically rich in flavonoid-type nutraceutical polyphenols. Some relevant botanicals from this group include Vaccinium myrtillus L., Sambucus nigra L., Zingiber officinale Roscoe, Ginkgo biloba L., Polygonum cuspidatum Willd. ex Spreng., Rosmarinus officinalis L., Crataegus rhipidophylla Gand., Cissus quadrangularis L. [15].

2.3Rhodiola Rosea

R. rosea from the Crassulaceae family (Fig. 2 ) stands out as one of the most intensively studied medicinal plants, not only within the genus Rhodiola but also among plant-adaptogens [16]. It has been clearly recognized as a botanical adaptogen with antifatigue, antistress, and antidepressant properties. Interestingly, the current Rhodiola genus comprises 53 accepted species names [17] (wfoplantlist.org), and at least 15 of them are employed in traditional medicine in several Asian countries [16,18]. However, the majority of clinical, pharmacological and toxicological studies have been conducted on R. rosea, so whether other species confer the same medicinal properties is largely unknown [16,19]. R. rosea is considered a circumpolar Arctic-Alpine species originating in the southern Siberia highlands [20]. It extends to Asia (from Russia to Japan), the central mountains of Europe, Iceland, Greenland and even North America [21]. Commonly called roseroot, the plant is known by various names depending on its ethnobotanical origin, including arctic root (due to its distribution among arctic regions) and golden root, possibly in allusion to the perceived value of the root.

From an ethnobotanical point of view, R. rosea has been a significant traditional food source for humans and it has been used as forage for cattle. However, its roots and rhizomes are historically more prized due to its multiple beneficial health properties. R. rosea has been employed since ancient times in folk and traditional medical systems in the Nordic countries, Eastern Europe, Russia and Asia to address several conditions. These include increasing work productivity, promoting longevity, enhancing physical endurance, alleviating altitude sickness and treating fatigue from diverse origins, depression, gastrointestinal dysfunction, anaemia, impotence, infections and disorders of the nervous system [50][51] [52] . These remarkable traditional medicinal properties spurred numerous formal ethnopharmacological studies, which commenced in Russia in the 1950s, especially within the context of several research programs screening natural substances from traditional medicine with potential adaptogenic properties. As a result, R. rosea roots were characterized as one of the primary adaptogens and a standardized liquid extract was included in the official medicine from the former USSR since 1975 [14] . It was indicated for "diminished physical and mental capabilities such as weakness, exhaustion, tiredness, convalescence, and loss of concentration". Subsequent phytochemical research to identify R. rosea phytoactive compounds has led to the isolation and identification of over 120 phytochemicals from its roots and/or rhizomes [22,23]. These include phenylethanoids (p-Tyrosol and Salidroside), phenylpropanoids (cinnamyl alcohol) and their glycosides forms (rosavin, rosarin and rosin; collectively known as the "rosavins") (Fig. 3 ), terpenes (rosaridin, rosiridol & rhodiolosides A-F), essential oils (ndecanol & geraniol), simple phenolics (hydroxycinnamic acids, caffeic acid and chlorogenic acid) and Flavonoids (glycosides of kaempferol, herbacetin, and gossypetin). While extensive bioactivity-guided fractionation studies with R. rosea roots are lacking, there is a consensus among researchers that salidroside and rosavins are the major (but not the only) phytochemicals responsible for the antistress adaptogenic effects. The rosavins are specific only to R. rosea, whereas salidroside, even in higher concentrations, is found in other species of the Rhodiola genus, as well as in other plant species such as Salix trianda and Olea europaea, and in specific bacteria and yeasts [24]. Consequently, the basic chemical markers to verify the authenticity of R. rosea root preparation are represented by rosavin and by the ratio rosavin/salidroside close to 3:1 [25,26], corresponding to the natural root ratio of the compounds [16].

Pharmacopoeial standardization of products currently focuses on salidroside as well as phenylpropanoids specific to R. rosea, typically expressed as total rosavin. Nevertheless, other constituents of Rhodiola species have occasionally been suggested to potentially contribute to biological activities, including the aglycon of the phenylpropanoid cinnamyl alcohol [27], monoterpene glycosides such as rosaridin [28], gallic acid derivatives such as epigallocatechin-3-gallate [29], or lignans and some flavonoids such as rhodiosin and herbacetin [30]. From the perspective of biological activity and health effects, a summary of nearly hundreds of pharmacological studies conducted with R. rosea has been detailed in various comprehensive review articles. The most relevant pharmacological activities described in such research, performed on cells and rodent models include adaptogenic actions: anti-fatigue and anti-stress effects (cardio-, hepato-, and neuroprotective actions; normalization of altered neuro-endocrine activity), positive neuromodulation of SNC levels supporting improvement of cognitive functions (especially attention, learning and memory) with antidepressant and anxiolytic properties. In addition, R. rosea has elicited multifaceted antioxidant and anti-inflammatory activities; immunomodulatory properties aiding in viral infections and also anti-diabetic, anti-cancer, anti-hypertensive, radio-protective and antiageing activities [31][32][33][34][35] (Table 1 ).

From a mechanistic point of view it is important to note that, although the precise receptors and/or enzymes along with its downstream intracellular mediators responsible for the pleiotropic adaptogenic and stress-protective activities of R. rosea are far from being completely elucidated, the possible molecular mechanism of R. rosea actions has been unravelled (in vitro) by system biology approach linked to genome-wide effect analysis [37] and (in vivo) by behavioural phenotyping pharmacological studies in rodents [38,39]. Briefly, preclinical research has shown that the beneficial stress-protective activities of R. rosea are associated with the regulation of the HPA/SAM axis by reduction of the corticotrophinreleasing factor (CRF), the enhancement of the catecholaminergic system (increasing levels of serotonin, dopamine and norepinephrine) due the inhibition of the enzymes responsible of monoamine degradation (MAO and COM-T) and the regulation of the essential signalling systems and effectors of the adaptative stress response including heat shock protein 70,72 and 16, stress-activated c-Jun N-terminal protein kinase 1, forkhead box O (FOXO) transcription factor DAF-16, glucocorticoid receptor, β-endorphin, nitric oxide and ATP [40].

Globally, the more than 70 human clinical trials of varying quality in methodology, design and conditions analyzed have supported most of the traditional uses of R. rosea. It has demonstrated that R. rosea preparations (root powder, dry or liquid extracts and multi-ingredient formulations) may be effective with an acceptable level of evidence against stress physical-related fatigue, low mood, anxiety and depression, and in improving physical and mental working capacity in several conditions [36,41,49]. Given the clinical adaptogenic pleiotropic actions of R. rosea, its preparations may have potential benefits as an adjuvant therapy improving wellbeing and quality of life in patients with chronic diseases [44] [45] [46] by means of stress and fatigue mitigation along with improved cognitive function, among others potential beneficial effects. (Table 1 )

Based on medicinal traditional use and the background of clinical studies, the Herbal Medicinal Product Committee of the European Medicinal Agency approved its use in 2011 as an adaptogen for the "relief of symptoms of stress such as fatigue, exhaustion and sensation of weakness" in the category of Traditional Herbal Medicinal Product [53]. R. rosea preparation (commonly root powder or dry extracts) has been marketed in the EU for years as a food supplement or traditional medicinal product, it is a renowned adaptogen plant utilized in the traditional medical system and eventually included in the official pharmacopoeia of Nordic & Eastern countries. After intensive research, a liquid extract was manufactured on an industrial scale and has been marketed in Russian pharmacies since 1960 without prescription and approved as a CNS stimulant and adaptogen for oral administration [14] . Despite the abundance of studies conducted to date, further research must focus on the development of preclinical studies using high-throughput technologies to identify the complex mechanism of action at the molecular and cellular levels. Additionally, the establishment of methodologically sound and well-designed large-scale clinical trials is essential to provide unequivocal evidence of efficacy and safety. Robust and comprehensive phytochemical characterization of the R. rosea product being tested is critical for fidelity and comparability between studies. Detailed longterm studies should be conducted to identify putative interactions and adverse effects in susceptible or vulnerable populations. Collectively, these studies would help decipher the precise mechanism of action and well define the specific doses and standardizations of R. rosea to optimize the various therapeutic applications.

2.3.1Rhodiola rosea: Safety & toxicity Issues

Overall, considering the traditional use dating back to ancient times and the large number of clinical trials conducted to date, the use of R. rosea can be considered safe and generally well tolerated in individuals with various health statuses. Unlike stimulants, R. rosea does not induce addiction, habituation, or withdrawal symptoms. The incidence of side effects is extremely low, and when they do occur, they are mild in nature and demonstrate low clinical toxicity. However, some rare cases of mild headache, insomnia, hypersalivation, nausea, and dizziness have been reported in clinical trials. Clinical experience of reputable herbalists indicates that certain individuals, particularly those sensitive to stimulants like caffeine or those prone to high anxiety, may experience excessive energy, nervousness, agitation, or increased anxiety, especially at high doses. In such cases, a lower dose with very gradual increases or a combination with a more calming adaptogen is usually recommended. It is advisable to take R. rosea during the first half of the day, as it may alter sleep or cause vivid dreams if taken in the afternoon or evening, particularly during the initial weeks of use. Additionally, due to R. rosea´s stimulantantidepressant action, it is not recommended for individuals with bipolar spectrum disorders who may be prone to manic states when exposed to antidepressants or stimulants [54, 87, 113].

Preclinical toxicological studies in rodents indicate that R. rosea is generally safe and even less toxic than other adaptogens, with an LD50 of 3.36 g/kg by the intraperitoneal route. The equivalent dose for a human weighing 65-75 kg would be in the range of 218-252 g. Considering that the effective administered doses of R. rosea are between 200 and 600 mg/day, the lethal dose in humans would be 363 to 1260 times higher than the therapeutic doses, supporting a substantial margin of safety [16].

Finally, it is important to note that concurrent use of botanical preparations and drug treatments could lead to unexpected pharmacokinetic and pharmacodynamic interactions increasing the risk of side effects/toxicity [55,56]. Some side effects potentially associated with negative drugherb interaction between psychotropic drugs and R. rosea have been reported. These include, in a relatively low frequency, myalgia, altered consciousness, restless legs syndrome, headache, arthralgia, diarrhoea, nausea, jaundice, myoclonus, hypoglycemia, excessive sedation, priapism, dizziness, hypotension, hyperhidrosis, and hallucinations [57]. Consequently, concurrent administration of R. rosea with psychotropic medication should be done with caution, especially for drugs with a narrow therapeutic window.

2.4Withania somnifera

W. somnifera belonging to the Solanaceae Family, is commonly known as Ashwagandha (Fig. 4 ) or Indian ginseng [58,59]. It has been a widely used medicinal plant in Ayurveda, Unani, and both indigenous Indian and African traditional medicine since very ancient times [60]. The term "Ashwagandha" originates from Sanskrit, and means "horse smell" (ashwa=horse and gandha=smell), attributing to the strong horse-like smell of the fresh root and is believed to support horse-like powder when consumed [73,76]. In Ayurveda, W. somnifera holds a significant position within the premium medicinal group of "rasayana" herbs, denoting its tonic properties that provide physical and mental strength, promoting endurance and longevity [61,62].

Various pharmaceutical forms of W. somnifera root, such as powder, juice, paste, decoction and infusion either as single or compound formulations along with dosage, route administration and therapeutic uses, have been detailed in Ayurvedic medicinal texts since 1000 B.C. [63,79,80]. Currently, W. somnifera is recognized as an official drug with a detailed monograph in the official Ayurvedic pharmacopeia of India Part 1 (Volume 1). In the Ayurvedic formulary of India Part I, II and III, four different W. somnifera formulations are described, including their constituents, method of preparation, dosage and recommended therapeutic uses. From an ethnomedical perspective, ayurvedic text primarily elaborate on the use of root preparations for neurological conditions (dementia, loss of memory, insomnia and anxiety), as a tonic-restorative (children emaciation, pregnant women, senile debility or during convalescence period), rheumatism, vitiligo, constipation, goitre, bronchitis, asthma, ulcers, aphrodisiac-sterility in women, and liver tonic [63,81].

W. somnifera is listed in the American Herbal Pharmacopoeia and WHO monographs on Selected Medicinal Plants. Due to the documented and remarkable health properties of this plant in traditional medicine, intensive ethnopharmacological research has been carried out in the last decades. The phytochemical profile of W. somnifera has been extensively studied using classic and comprehensive metabolomic analytical techniques, resulting in the identification of nearly 140 chemical constituents belonging to several chemical classes [64] including tropane-type alkaloids [65,66], a complex group of ergostane-type steroid lactones collectively designated as Withanolides (along with their glycosylated counterparts, Withanosides & Sitoindosides) [67] (Fig. 5 ), glycoproteins, flavonoids, steroids, tannins, organic acids and other phenolics [68,69]. Among these, the best known are withanolides and glycol-withanolides. More than 70 individual withanolides derivatives have been reported in W. somnifera leaf and root [68,70], with higher levels found in the leaves than in the roots [71]. The major phytochemicals responsible for the biological activities are alkaloids (isopelletierine, anaferine, withanine), Withanolides (withaferin A) along with Glycosylated counterparts (sitoindoside VII, VIII, IX, X and withanosides), phenolics compounds, and glycoproteins. Not surprisingly, these rich and complex profiles of phytoactive compounds support the pleiotropic pharmacological action associated with various extract preparations and phytochemical constituents.

A large number of preclinical in vitro and animal studies have been conducted using various W. somnifera extracts or single phytochemicals to elucidate the wide spectrum of pharmacological effects based on several putative mechanisms of action [72,74]. Briefly, W. somnifera mixtures have demonstrated remarkable, adaptogenic and stress-relieve effects with amelioration of stressrelated conditions: anxiety, depression, and insomnia [75,77]. The mechanism related to the calming and stress-relieving effects associated with W. somnifera adaptogenic capacity is not yet fully understood, but appears to be linked to the reduction of the cortisol, adrenaline and dehydroepiandrosterone by down-regulation of the HPA/SAM axis; stimulation of GABAergic and serotoninergic neurotransmission, mitigation of the oxidative stress and inhibition of the synthesis of proinflammatory cytokines [78, 82]. In addition, neuropharmacological effects, including neuroprotective action against neurodegenerative disorders such as Alzheimer's disease, Huntington's disease, and Parkinson's disease [83] and anti-ischemic/antihypoxic activity have been described. Other significant pharmacological activities include anticancer effects, potent anti-inflammatory actions in several disease models, aphrodisiac effects, cardio-hepatoprotective activity, anti-diabetic properties and significant immunomodulatory actions [84, 85] . Owing to its broad biological mechanisms of action, there is an increasing number of human trials investigating its efficacy in treating a range of physical and mental conditions as well as promoting overall health. W. somnifera-only preparations and extracts have demonstrated clinical efficacy, supporting a potential therapeutic role as an adaptogenic antistress agent and in counteracting stress-related conditions including anxiety (anxiolytics properties), insomnia (sedative and sleepenhancing activity), fatigue (anti-tiredness action,) and depression (anti-depressant effect). In addition, trials specifically targeting depression, sleepiness and anxiety clearly indicate the anti-depressant, sedative and anxiolytic activities of W. somnifera in humans, respectively [77, 86, 88] 99]. It is important to note that many other human trials did not report any side effects associated with root intake both in adults and children [99].

As W. somnifera may lower blood pressure, it must be used with caution in individuals prone to hypotension or those being treated for hypertension, due to the risk of hypotension. Additionally, since W. somnifera may act as an immunostimulant, it is not recommended for patients taking immunosuppressors such as azathioprine, cyclosporine, daclizumab, muromonab-CD3, tacrolimus, corticosteroids, and others, especially in patients with autoimmune diseases [100].

W. somnifera root extract has been used as a pro-fertility and aphrodisiac agent in men [101] and women [102,103]. However, men with hormone-sensitive prostate cancer or prostate hyperplasia should avoid taking W. somnifera preparations. According to some studies, the plant may increase testosterone production [89], which may potentially contribute to disease progression. Additionally, W. somnifera may be contraindicated in women planning to become pregnant or who are pregnant, as higher doses of W. somnifera root extract have been used as an abortifacient in traditional Ayurvedic medicine [104]. However, although a prenatal toxicity study conducted in rodents showed no evidence of maternal or fetal toxicity [105], clinical evidence is still needed to unequivocally confirm the safety of W. somnifera intake during such a sensitive period of life. Several preclinical toxicity/safety studies performed in rodents have provided reasonable evidence of safety. Oral chronic or subchronic administration of both aqueous, hydroalcoholic and alcoholic extracts (3g/kg -1 week, 2g/kg -4 weeks 1-2 g/kg -acute) provoked neither behavioural changes, nor signs of toxicity or mortality. There are no modifications in physiological parameters, haematological or biochemical variables, nor significant pathological lesions in diverse organs. However, it is important to note that in a few studies, the oral administration of W. somnifera extract resulted in organic alterations including decrease in plasma cortisol level along with increases in liver and body weight (250 mg/kg -32 weeks; aqueous extract), CNS depressant effect associated with biogenic amine neurotransmitter alteration (1g/kg -10 days; ethanolic extract), and a significant catecholamine increase in the heart and aorta and catecholamine decrease in the adrenal gland (200 mg/kg -30 days; ethanolic extract). In addition, two nontoxicological studies in which mice were treated with root powder (1 g/kg -7 days) or aqueous W. somnifera extract (1.4 g/kg -20 days) resulted in the induction of anabolic activity and a significant increase in serum thyroxine (T4) levels in female mice, respectively. This last effects of W. somnifera extract on thyroid physiology has also been mirrored in humans, where an increase in T4 concentrations and normalization of TSH levels have been observed after administration of W. somnifera root to schizophrenic or subclinical hypothyroid patients [106,107]. Considering these antecedents, the use of W. somnifera in subjects with hyperthyroidism (even subclinical) is contraindicated, as it could promote or exacerbate the symptoms of the disease [108,109].

The risk of significant side effects due to herbdrug interactions is a possibility that should be taken into account [110,111]. The possibility of pharmacodynamic interactions between W. somnifera extracts and certain classes of psychotropic drugs cannot be completely excluded, as both treatments may act through similar CNS mechanisms (GABAergic and serotoninergic activities), as manifested by the clear additive effect observed in animal studies between W. somnifera extracts and the drugs fluoxetine [112], imipramine [112,114] and diazepam [115]. As a result, W. somnifera use is not recommended in individuals taking anxiolytic, sedative, or antidepressant medications due to the risk of exacerbating their effects through synergism or additivity [116,117]. In addition, W. somnifera may increase the somnolence in patients taking anxiolytics such as benzodiazepines [118,119].

Pharmacokinetic interactions in humans appear to be improbable because W. somnifera root extract or isolated phytocompounds did not show significant inhibition against several cytochrome P450 metabolizing isoenzymes from humans, rats or cell lines liver microsomes, with an IC50 in most cases greater than 100 ug/mL (extracts) or 100 µM (single compounds) [120][121][122][123].

In summary, while the overall safety of W. somnifera consumption appears favourable, growing data concerning interactions with specific medications with W. somnifera and potential adverse effects in susceptible individuals or those with specific health conditions or subclinical disorders highlight the importance of recognizing potential safety concerns associated with W. somnifera supplements. The clinical relevance of these findings hinges on factors such as the subject´s health status, the medications they are currently taking, and the specific type and dosage of the W. somnifera preparation. These factors collectively determine the systemic concentrations of bioactive metabolites during chronic use. To comprehensively address these pertinent issues associated with W. somnifera consumption, additional rigorous, long-term safety studies will be essential. "+++" -Good evidence from several trials; "++" -Preliminary evidence from some trials; "+" -Low level of evidence; "-" -No evidences or not conclusive

3.DISCUSSION AND CONCLUSIONS

Humans are capable of adapting to dynamic challenging or unexpected environmental, physical and psychosocial stressors. The nature of stressors in modern life is extremely diverse, and, most of the time, humans can overcome these events with the aid of internal dynamic interplay processes and mechanisms (allostasis). As a result, the human body adapts to changes and psychosomatic equilibrium is preserved (homeostasis). This normal and basic "stress response" resulting in an organism's adaptive capacity to stressors is characterized by the activation of a complex physiological network directed by the neuroendocrine and immune systems, mainly the HPA and the SAM. Both are responsible for coordinating the stress response, promoting adaptation and restoring homeostasis.

While a mild to moderate level of stress is healthy, prolonged or repeated exposure to stressors can lead to overactive stress responses, where the recovery mechanism of the stress system fails to achieve balance. Several associated conditions can emerge due to this overburden, including psychological disturbances (nervousness, irritability depression, anxiety, insomnia), cardiometabolic alterations (hypertension, obesity, food cravings), and gastrointestinal dysfunctions. However, some individuals can easily adapt to changing situations, and this superior ability to cope with stress is called resilience.

Primary herbal adaptogens enhance the efficiency of the adaptive stress response to life stressors, promoting resilience while minimizing hyperreactivity, which may play a relevant role in the pathogenesis of some of the most prevalent diseases of contemporary life. The modern utilization of these ancient botanical "tonics" from traditional medicines continues to expand, and a plethora of preclinical and human trials in the last 50 years have been performed to best characterize the biological effects of primary adaptogens. Notable among them are W. somnifera and R. rosea, both of which counteract several stress-related conditions. Due to the large heterogeneity between studies and the complex polypharmacological mechanisms of action of both adaptogenic plants that are yet to be completely elucidated, it is challenging to preferentially assign one specific biological activity or therapeutic indication to R. rosea versus W. somnifera, or vice versa. However, the overall evidence clearly indicates that both W. somnifera and R. rosea are notable adaptogens with effective anti-stress activity. They ameliorate hyperreactivity HPA and SAM, counteracting stress-related manifestations such as anxiety, nervousness, irritability, insomnia and depression against various types of acute or chronic external stressors.

Nevertheless, a detailed analysis of potential mechanisms of action derived from rodent and cell culture studies may help outline the most appropriate health indications of R. rosea versus W. somnifera. R. rosea affects the central nervous system, as evidenced by its capacity to improve symptoms of stress-induced mental and physical fatigue, depression and enhance mental and physical performance under stressful conditions. This is consistent with HPA/SAM modulation, antioxidant, anti-inflammatory activities, and central monoaminergic system upregulation through inhibition of Monoamine oxidases type A (MAO-A) or B (MAO-B) enzymes. Not surprisingly, one officially accepted traditional use for R. rosea is as an "adaptogen for the temporary relief of symptoms associated with stress, such as fatigue, exhaustion and a general sensation of weakness". Likewise, W. somnifera has demonstrated remarkable antistress activity by modulating HPA/SAM and exhibiting serotonergic-dependent antidepressant effects. However, in contrast to R. rosea, its capacity to modulate GABAergic neurotransmission may preclude superior efficacy in combating stress-associated anxiety, nervousness and insomnia. Preclinical studies and clinical evidence provide broad support for W. somnifera's ability to reduce stress, and anxiety, and improve sleep quality.

In summary, taking into account the putative neuroendocrine mechanism of action and the most robust evidence of efficacy from clinical trials, R. rosea may tentatively assigned as a regenerative "tonic vitalizing" adaptogen supporting stress-associated fatigue and weakness in several physical and psychological contexts, while W. somnifera could be considered as regenerative "tonic-nervine" counteracting stress-related anxiety and insomnia or drowsiness.

CONSENT

It is not applicable

ETHICAL APPROVAL

It is not applicable

COMPETING INTERESTS

Authors have declared that no competing interests exist.

Acknowledgements

ACKNOWLEDGEMENTSThe authors express their gratitude to Nektium Pharma, Las Palmas, Spain for providing facilities to carry out the bibliography research work.

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