Abstract

Introduction. This study aimed to evaluate the impact of Revital Ginseng Plus on fatigue, stress and overall Quality-of-Life in Moroccan patients. Materials and Methods. A prospective study was conducted on eligible patients in Morocco who were visiting their physicians for a variety of reasons ranging from general symptoms such as weakness and pain to specific symptoms such as hypotension and asthma. Revital Ginseng Plus was subscribed as a dietary supplement to be consumed once daily for 3 months. Data was captured onsite at monthly follow-up. Descriptive analytics were used to present data pertaining to change in clinical parameters at each follow-up. Mean visit scores were analyzed using Welsch’s test to allow for varying numbers of returning patients at each visit and validated by Repeated Measures ANOVA. Results. A total of 313 patients was included in this study. At the end of 3 months, patients experienced significantly reduced levels of fatigue, pain and stress, and enhanced Quality of Life through improved physical and mental function. Fatigue reduced notably by 79.4% and freedom from pain increased by 35.2%, while physical function and cognition scores increased by 29.7% and 44.4% respectively. All outcome measures showed statistically significant improvement from Month 1 onwards. No patients reported any adverse events through the study. Conclusion. Revital Ginseng Plus, used as a daily dietary supplement, has shown improving energy and cognition, thereby significantly improving Quality of Life.

1. Introduction

Owing to rapidly transforming lifestyles and higher worldly aspirations, increased stress levels and anxiety are now a common worldwide phenomenon. Under stress, the hypothalamic-pituitary-adrenal (HPA) axis triggers the release of cortisol and adrenaline, suppressing endocrine and immune systems in flight-or-fight situations. Consequently, heart rate and blood pressure are elevated ¹.

Stress induces increased production of free oxygen radicals, known collectively as Reactive Oxygen Species (ROS), which cause damage resulting in inflammation, necrosis and apoptosis when unchecked ².

In conditions resulting in chronic stress, overproduction of ROS overwhelms antioxidant capacity to neutralize free radicals, resulting in oxidative stress (OS).

A study reporting the etiology of palpitations observed that 31.0% of palpitations under consideration had psychiatric etiology ^{3, 4}. A systematic review noted a link between hypertension and psychosocial stress ⁵. There is evidence that exposure to chronic stress can produce maladaptive neurobiological changes in pathways associated with pain processing, resulting in stress-induced hyperalgesia (SIH) ^{6, 7}.

Consistently high levels of stress create physical and mental fatigue. Recurrent fatigue may lead to Chronic Fatigue Syndrome (CFS), a condition of overwhelming fatigue that is not relieved through rest. Symptoms of CFS include weakness, physical pain and sleep disorders ^{8, 9}.

CFS may affect individuals on a day-to-day basis in complex ways, including inability to keep a job, take part in family life or even perform simple tasks like taking a shower. A study exploring cognitive performance in CFS showed that that almost 90% of patients presented impaired cognitive function ¹⁰. Physical activity, social interaction and emotional stability may be severely compromised, substantially lowering Quality-of-Life (QoL).

Chronic stress has also been associated with lowered immunity, increasing the body’s susceptibility to infection.

International surveys indicate that suboptimal intake from foods and supplements makes micronutrient deficiencies a global phenomenon. Studies on the use of multi-vitamins and minerals (MVMs) have demonstrated that adequate doses of vitamins and minerals are critical in maintaining normal physical and cognitive function ^{11, 12, 13}. Research shows that red ginseng extract improves sleep quality in sleep-deprived subjects ^{14, 15}. Studies have demonstrated the synergistic effect of the combination of ginseng and an MVM formulation in improving QoL and energy levels in stressed patients, without any major side effects ^{16, 17, 18}.

Revital Ginseng Plus contains Panax ginseng, vitamins and minerals. Its nutritional components are described in Supplementary Table 1.

Ginseng has been used in traditional Chinese medicine over centuries. Various studies have been conducted to assess its effect on stress and have demonstrated its ability to regulate the HPA axis ¹⁹.

A 2007 article on an epidemiological study in Moroccan population revealed that 25.5% suffered at least one sort of anxiety disorder and 29.4% resorted to alcoholism, smoking or cannabis to cope with stress ²⁰. A study on fatigue and work-related stress in Morocco showed that 32.8% of respondents were in a high state of exhaustion, and 22.9% were in a state of perpetual threat ²¹.

The present observational study was aimed to evaluate the effectiveness and safety of a ginseng-MVM formulation when given in a fixed dose combination to Moroccan population.

The study’s primary objective was to evaluate impact of Revital Ginseng Plus on fatigue and resultant QoL and its safety in Moroccan patients. Secondary objectives were to evaluate the effect of daily supplementation with Revital Ginseng Plus on improvement in physical performance, palpitations, blood pressure, stress levels and sleep disorders.

2. Materials and Methods

This was a multi-center, prospective, observational study, conducted in adult patients paying routine visits to their general physicians (GPs) across eight Moroccan cities, between December 2018 and October 2019.

313 male and non-pregnant, non-lactating female patients aged between 35 and 55 years were enrolled in the study.

Of the 313 subjects to whom Revital Ginseng Plus was administered to study its effect on energy levels and its tolerability, 193 general complaints were initially reported, including weakness (103 patients), fatigue (23 patients), and stress (15 patients).

Of the 39 patients (12.4%) reporting pain at their initial visit to the GP; 18 reported arthralgia (46.15%), 9 reported headache (23.1%), 7 reported backache (17.9%) and related symptoms and 4 reported myalgia (10.3%).

Other significant complaints included gastrointestinal (37 patients, 11.8%), urogenital (34 patients, 10.8%), respiratory (31 patients, 9.9%) and neuro-psychiatric complaints (28 patients, 8.9%) including anxiety and insomnia.

Details of the nature and classification of complaints are presented in Supplementary Table 2 and Supplementary Table 3.

Patients were screened to ensure they had no prior history of renal, hepatic, psychiatric or central nervous system diseases, no severe diastolic hypertension (<115 mmHg), no recent history of myocardial infarction, no congestive heart failure or uncontrolled blood sugar. Apart from these criteria, the study did not interfere with the GP’s decision to enroll any patient that they believed could benefit from an MVM in an endeavor to reflect a real-world population as much as possible.

Patients were asked to consume one tablet of Revital Ginseng Plus once a day, often along with other prescribed medication.

As an observational study, patients paid routine visits to their GPs as per the clinical practice of the treating physician. However, data for this study were collected systematically at four time points for all patients: first consultation or Baseline and three subsequent monthly follow-ups.

The SF-12 scale was used to measure physical and mental components of QoL. The 11-item Chalder Fatigue Scale (CFQ) was used to measure physical and mental fatigue. These scales and their validity are discussed in Supplementary Boxes 1 and 2.

Data related to stress levels and sleep patterns for each patient were captured on the Visual Analogue Scale (VAS) ranging from 0 to 10.

Participation in physical activity, presence of palpitations and presence of high blood pressure were measured as proportions, based on Yes-No responses.

Data entry was carried out in accordance with the recommendations of the Scientific Committee for the study. Approximately 10% of the collected data was validated against source documents, adhering to the good pharmacoepidemiologic practice of Epstein (GPP) and ADELF ^{22, 23}. Only data corresponding to the norms of Quality Control were included for analysis.

Procedures for computation and statistical analysis for primary and secondary endpoints are described below.

1. QoL (SF-12) scoring: Raw scores were generated on the basis of responses to 12 questions ²⁴.

These scores were then used to derive eight composite scores of physical and mental components.

Higher scores indicate a more positive outcome. These composite scores were z-standardized and used to compute total Physical and Mental Components (PCS and MCS) using Linear Regression.

2. Fatigue (CFQ) scoring: Scores were measured using the Likert scale ^{25, 26}.

Study parameters were summarized using descriptive statistics. Mean scores and SD were used to ascertain individual progress over the three-month treatment period to a statistical significance of 5%.

SF-12, CFQ, Sleep disorders and Stress level parameters were analyzed using Welch’s T-test. In light of unequal populations at different visits, this test was used to compare results between baseline and each follow-up. To verify the results achieved by this method, Repeated Measures ANOVA, a test which takes into consideration observations for only those subjects with measurements at all visits, was applied.

Chi-square test was used to analyze dichotomous variables against parameters for physical performance, palpitations and blood pressure.

Imputation of missing data was not carried out for any primary or secondary outcome parameters other than SF-12 data, where the value estimated was the average of the patient’s responses to the other SF-12 questions.

Each parameter was analyzed based on the actual number of observations recorded.

Analysis was carried out using SPSS (Version 13.0, SPSS Inc., Chicago-US) and Epi Info (Version 7.2.0.1, CDC, Atlanta, US).

3. Results

A total of 313 patients were enrolled in the study. Their socio-demographic characteristics are presented in Supplementary Table 4. All tables and figures indicate the actual number of observations (n) at individual visits on which the analysis was performed.

QoL was assessed on the SF-12 scale by measuring individual components of physical and mental wellbeing. Overall physical and mental wellbeing scores are presented in Table 1. Both components showed evidence of a statistically significant improvement in mean scores at the end of the first month, second month and third month.

Individual parameters for Physical and Mental components of QoL are presented in Table 2 and Table 3 respectively, along with measurements from Baseline to Month 3.

The mean Physical Wellbeing score, which includes parameters such as ‘Freedom from Body Pain’ and ‘Overall Health’, improved from 40.9 at Baseline to 45.7 at Month 1 (11.8%, p<0.001), 49.0 at Month 2 (19.9%, p<0.001) and 53.0 at Month 3 (29.7%, p<0.001). Scores reflecting freedom from body pain increased from 35.9 at Baseline to 48.5 at Month 3, a statistically significant improvement of 35.2% (p<0.001). Overall Health scores increased notably from 38.8 to 56.3 at Month 3, improving by 45.0%. All parameters within the domain of Physical Wellbeing demonstrated statistical significant improvement (p<0.001) between Baseline and each month’s reading.

The Mental Wellbeing score improved from 34.6 at Baseline to 41.6 at Month 1 (20.3%, p<0.001), 45.6 at Month 2 (31.8%, p<0.001) and 49.9 at Month 3 (44.4%, p<0.001). Individual parameters include Energy and Vitality (improvement of 28.0% at Month 3), Limitations in Roles due to Emotional Problems (improvement of 51.5% from Baseline to Month 3) and Mental Health, Psychological Stress and Psychological Wellbeing (improvement of 40.5% from Baseline to Month 3). All parameters within the domain of Mental Wellbeing demonstrated statistically significant improvement (p<0.001) at each follow up month, as compared with baseline.

Each SF-12 parameter presented in Table 1, Table 2 and Table 3 was re-tested using Repeated Measures ANOVA from Baseline to 3 months to validate that the results were statistically significant. It was confirmed that improvement observed for each parameter was similar to that computed according to Welch’s T-test (p<0.001 for all visits from baseline). Results can be viewed in Supplementary Table 5.

Mean fatigue scores measured by CFQ and presented in Table 1 showed substantial reduction from 17.3 at Baseline to 9.0 at Month 1 (47.9%, p<0.001), 5.9 at Month 2 (65.4%, p<0.001) and 3.5 by the third month (79.4%, p<001).

No adverse events were reported at any visit during the study.

Physical Activity, Palpitations and High Blood Pressure

The proportion of patients engaging in physical activity improved steadily from 38.1% at Baseline to 45.9% at Month 1, 49.7% at Month 2 and 54.6% at the end of Month 3 (p<0.001 for all visits from baseline).

A noteworthy reduction was observed in palpitations at the end of 3 months. The proportion of patients experiencing palpitations, a well reported symptom of stress, reduced from 64.2% at Baseline to 13.5% at Month 1, 6.2% at Month 2 and 5.3% at the end of Month 3 (p<0.001 for all visits from baseline).

A reduction was also observed in proportion of patients reporting high blood pressure at the end of 3 months (7.3% at Baseline to 4.2% at Month 1, 2.3% at Month 2 and 1.3% at the end of Month 3; p<0.001 for all visits from baseline). Results are presented in Table 4.

A reduction in stress was observed as measured using stress scores, which demonstrated a decrease from 5.5 at Baseline to 3.7 (32.8% reduction) at Month 1 (p<0.001), 2.7 (50.1% reduction) at Month 2 (p<0.001) and 2.1 (62.6% reduction) at Month 3 (p<0.001).

Improvement in sleep was measured by sleep disorder scores, which demonstrated a decrease from 3.9 at Baseline to 2.8 (28.0% reduction) at Month 1 (p<0.001), 2.3 (40.1% reduction) at Month 2 (p<0.001) and 1.6 (58.4% reduction) at Month 3 (p<0.001). Results are presented in Table 5.

4. Discussion

Data from other studies conducted in Moroccan populations clearly indicate the need for healthy coping mechanisms with respect to everyday stress and anxiety ^{20, 21}. Given the large proportion of patients reporting QoL-related complaints such as weakness, fatigue and stress at the initial visit (141 patients, 45.04%), the results of this study are likely to bear significance to a substantial population of patients in Morocco as a positive indication that daily supplementation of diet with Revital Ginseng Plus will significantly improve energy levels, as well as other aspects of physical and mental wellbeing that directly impact QoL. Results notably indicate freedom from body pain as well as statistically significant improvement in Mental Health, Psychological Stress and Psychological Well-being, which are critical to high QoL and long-term health and therefore especially relevant within Moroccan population with high stress levels.

All eligibility criteria were met in the study to ensure data homogeneity required to achieve reliable results. Importantly, since Revital Ginseng Plus was prescribed to outpatients consulting their physicians for regular complaints, patients enrolled in this study were not required to satisfy extensive criteria for inclusion in this study, thereby allowing data to be collected in a heterogeneous population, in a manner akin to a real-world setting. While the eligibility criteria allowed a wide range of patients to be included, the study design parameters, structured data collection and stable retention of patients through the study duration offer credence to study outcomes, allowing meaningful conclusions to be drawn.

There are a few limitations of this study. By its very nature, an observational study raises questions about confounders and bias. Further, the absence of a control group means that the effectiveness of Revital Ginseng Plus was not validated against a placebo or a comparator.

No adverse events were reported in this study. Under-reporting of adverse events is a frequent phenomenon in clinical practice that undermines pharmacovigilance efforts, which are critical to a thorough risk-benefit analysis at national and international levels. There is certainly a need to create more awareness about the benefits of timely safety reporting by healthcare professionals responsible for generation of study data the world over.

There have been numerous studies to test the effects of vitamins, minerals and ginseng, both individually and in combination, on general well-being and on QoL, which is a composite of mental and physical health.

A Mexican study comparing an MVM and ginseng formulation against only the MVM formulation used an 11-item questionnaire to evaluate QoL in 338 patients and showed an average increase of 11.9 points in QoL scores in the study arm as compared to 6.4 in the control arm over 12 weeks (p<0.0001) ¹⁶. The study found minimal adverse events in both groups.

Demonstrating similar results, a Brazilian double blind, placebo-controlled study of an MVM-ginseng formulation used a 10-item questionnaire to assess QoL in 114 patients and showed a mean change in QoL of 12.7 in the study group compared with 2.4 in the placebo group over a 2-month period (p<0.01) ¹⁷. However, it observed no difference in blood pressure between the treatment and placebo arms. The Brazilian study recorded similar mild adverse events in both treatment and placebo arms.

Our observational study validates the effectiveness outcomes of both these studies as well as supports the strong safety profile of an MVM-ginseng formulation. The high proportion of patients reporting weakness, fatigue or stress at the initial visit (45.0%) provides a strong indicator that an MVM+ginseng formulation is a simple and effective treatment option in the management of stress.

Our study, conducted on 313 patients over a period of three months, showed a difference of 12.1 in the physical component of QoL and 15.4 in the mental component. A reduction of 35.2% in body pain was observed along with an increase of 16.5% in the number of patients engaging in physical activity. No adverse events were reported in our study.

Given the ubiquitous nature of chronic stress, especially in urban settings all over the world, the need for safe, effective and accessible solutions to manage stress is paramount. Achievement of optimal energy levels and mental function coupled with reduced risk of adverse events means that dietary supplements such as Revital Ginseng Plus could have a beneficial impact on health, both as a prophylactic and a therapeutic. Managing stress and fatigue through the use of a daily MVM with ginseng containing dietary supplement may have a positive impact, by helping boost immunity, managing stress more effectively and improving overall QoL.

Using the encouraging findings of this observational study as a foundation, double-blind placebo-controlled trials are required to confirm these study outcomes, thereby providing a scientific basis for greater adoption of supplements such as Revital Ginseng Plus as an effective and well tolerated option in clinical practice.

5. Conclusion

The results of this study indicate that Revital Ginseng Plus, when taken as a dietary supplement, reduces stress and pain, increases energy levels and most importantly, allows a better QoL for people coping with the daily stressors of urban living. Its significance in clinical practice deserves serious consideration as a low-cost, low-risk product that manages short -term stress and mitigates the serious health risks of everyday stress and anxiety.

Funding Statement

This study was funded by Sun Pharmaceuticals Laboratories Ltd. India.

Disclosure of Interest

Malki Fatima is an employee of Sun Pharmaceuticals Morocco LLC, Suyog Mehta is an employee of Sun Pharmaceuticals Laboratories Ltd. India and Sadhna Joglekar is an employee of Sun Pharmaceuticals Industries Ltd. India.

Authors Contributions

MO, conception of the study protocol, data analysis and wrote the article. AEH, data management and data analysis. RR, participated to conception of the study and reviewed the article. MF, participated to the conception of the study and reviewed the article. SM, revision of the data analysis and reviewed the article. SJ, supervision of the whole study and reviewed the article. RA, supervision of the whole study, data analysis and reviewed the article. CY, supervision of the whole study, data analysis and reviewed the article.

Publication Consent

All the authors gave their consent to publish this study.

Acknowledgments

Authors would like to thank all the investigators and patients who took part in the study. The authors also thank PPCE World Pvt. Ltd. for providing support with writing and publication services.

References

Supplementary