Drug Utilization and Real-World Therapeutic Outcomes of Ginkgo biloba L. Leaf Extract in Prevention and Treatment of Cognitive Impairment

Drug Utilization and Real-World Therapeutic Outcomes of Ginkgo biloba L. 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Leaf Extract in Prevention and Treatment of Cognitive Impairment Annika Johanna Scholl, Alexandra Drebka, Ralph Mösges, Svenja Beatrice Frenzel, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8146289/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract Background Although therapeutic efficacy and tolerability of Ginkgo biloba L. leaf extract (GBE) in cognitive impairment have been demonstrated in clinical trials, its use remains limited in everyday medical practice. Nevertheless, rather than being part of standard treatment strategies, GBE is often used in self-medication. As the therapeutic benefit of any medication depends on its appropriate use, real-world evidence on drug utilization is essential to ensure effective and safe therapy. However, real-world data on usage patterns, perceived effectiveness, and tolerability of GBE are still lacking. Methods This study evaluated data from 191 users of GBE collected via the PhytoVIS study. Information included demographics, reason for application (prevention, acute or chronic symptoms), usage patterns (dosage, frequency and duration of intake) as well as therapeutic outcomes like perceived therapeutic benefits and tolerability. Descriptive statistics and inferential tests (Chi-square test, Mann-Whitney-U test, Spearman correlation) were applied to analyze statistical relationships between variables. Results Most participants (over 60%) used GBE for chronic symptoms of cognitive impairment; about 40% for prevention. Nearly all (97.9%) reported daily intake, with over 85% using GBE for longer than 30 days. Older adults tended to take GBE longer. Over half of GBE-users took less than the recommended 240 mg daily dose, especially women and participants over 75. More than 90% perceived a therapeutic benefit, and effectiveness was positively correlated with longer use. Tolerability was rated favorably with mild adverse events reported by only around 10% - serious events were rare and not clearly linked to GBE. Conclusion The study demonstrates high adherence and perceived effectiveness and tolerability of GBE. Variations in daily doses among certain groups warrant further investigation, especially regarding potential polypharmacy interactions. Despite this, the generally positive findings support broader consideration of GBE in managing and preventing cognitive impairment. Cognitive impairment Herbal medicinal products Ginkgo biloba Usage patterns Medication adherence Pharmacoepidemiology Patient-reported-outcomes Patient Care Management Public Health Real-world-data Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Background Cognitive impairment and dementia are associated with a decline in cognitive abilities such as memory, attention, and the ability to perform everyday activities ( 1 ). While dementia and neurodegenerative diseases are predominantly linked to aging ( 2 ), cognitive impairment can occur across all age groups ( 3 ). The severity of cognitive impairment ranges from mild or moderate respectively short-term conditions to severe, permanent or progressive forms ( 4 ). According to the Global Burden of Disease Study 2019, around 57 million people worldwide are living with dementia. This number is expected to rise to approximately 153 million by 2050, which is almost three times as many ( 5 ). Worldwide, the prevalence of dementia is higher in women than in men ( 6 ). It is estimated, that about 1.8 million individuals in Germany aged 40 or older are living with dementia ( 7 ). Standard therapy in Germany for dementia includes cholinesterase inhibitors (ChEIs) like Donepezil, Galantamine or Rivastigmine and the NMDA antagonist Memantine ( 8 ), which can lead to statistically significant, yet clinically limited improvements in cognitive performance ( 9 ). Their overall effectiveness remains modest for the majority of patients and especially ChEIs are associated with neuropsychiatric and serious cardiovascular adverse events ( 10 ). Lecanemab, a new monoclonal antibody approved very recently in Europe for the treatment of early Alzheimer’s disease ( 11 ) decreases cognitive decline in patients with very mild to mild dementia. However, the difference between treatment and placebo groups was only 0.45 points on the 18-level CDR-SB Score (Clinical Dementia Rating – Sum of Boxes) ( 12 ). Due to the recent approval, there is hardly any pharmacovigilance data yet. As well tolerated yet efficacious option for patients with mild to moderate forms of dementia and non-psychotic neuropsychiatric symptoms the German S3 guideline recommends (grade B) a clearly specified Ginkgo biloba L., folium (Ginkgo leaf) extract (GBE) in a daily dosage of 240 mg for a minimum treatment duration of 8 weeks ( 8 , 13 ). It is noteworthy that medical care is primarily focused on manifest dementia, rather than on forms of mild or moderate cognitive impairment, which are in fact precursors to dementia. Yet it is precisely in this area that prevalence is particularly high: In 2023, 15.9% of German adults reported to have experienced subjective memory decline, with women being more frequently affected than men ( 3 ). Unfortunately, there are no pharmaceutical treatment recommendations for mild to moderate cognitive impairment, and as a result, those affected often manage their symptoms through self-medication. However, the HMPC of the EMA (European Medicines Agency/ Herbal Medicinal Products Committee) has recognized monographed GBE under “well-established use” for the improvement of (age-associated) cognitive impairment, because its efficacy and safety have been proven clinically ( 13 ). On the other hand significant preventive effects have not yet been proven ( 14 ). The reason might be the complexity of designing prevention trials ( 15 ). Complementary to clinical data, several real-world data analyses indicate potential benefits of GBE on cognitive impairment. The prospective, population-based PAQUID study found that long-term use of GBE over 20 years was associated with decelerated cognitive decline ( 16 ). Recent retrospective studies of routinely collected data from office-based physicians showed that GBE slows down progression of dementia ( 17 ) and reduces the incidence of dementia in patients with mild cognitive impairment ( 18 ). Both studies used secondary data from the IQVIA Disease Analyzer, with strengths including large sample sizes and follow-up periods of up to ten years. Limitations included physician-assessed dementia severity degrees, which may not be standardized across physicians, and potential bias from unrecorded use of over the counter (OTC) GBE preparations ( 17 ). Outcome reports of therapeutic benefits on the level of individual patients and drug utilization or treatment habits of GBE have not been investigated so far. The pharmaco-epidemiological database PhytoVIS contains experience reports of patients who utilized herbal medicinal products (HMPs) to treat their non-life-threatening medical conditions. The information collected indication-related information, therapeutic outcomes and usage patterns ( 19 ). Thereby this database exerts a valuable source to provide the missing piece of information in comparison to previous clinical and real-world studies. In particular, usage patterns play a crucial role when medicines are available for self-medication as OTC-preparation. In everyday clinical practice, it is not uncommon for such products to be obtained without a formal consultation of a healthcare professional or detailed counseling. However, the therapeutic benefit of any medication depends on its appropriate use - including the correct dosage, proper frequency, and sufficient duration of intake ( 20 ). If these factors are not adhered to, the effectiveness may be reduced and the benefit-risk ratio potentially attenuated. In order to improve pharmaceutical care, the aim of our study was to analyze in depth self-reports from patients who utilized GBE in self-medication to treat or prevent symptoms associated with cognitive impairment. By analyzing real-world effectiveness, tolerability and usage patterns our study goes beyond already existing clinical and real-world studies and provides valuable complementary information. Methods Data Source The data sample was taken from the pharmaco-epidemiological database PhytoVIS established in 2013 by the German scientific society “Kooperation Phytopharmaka” and the Institute for Medical Statistics and Computational Biology (IMSB) with the aim of assessing the therapeutic benefits of HMPs ( 19 ) as described previously ( 21 ). The database consists of real-world data (RWD) in the form of anonymized patient-reported outcomes (PRO), providing cross-product information on the indication-related use of HMPs in everyday medical practice. Data collection took place between April 2014 and December 2016 in pharmacies by interviewing customers and patients on their personal experiences with HMPs ( 19 ). To be included in the PhytoVIS study, patients had to have taken HMPs during the eight weeks before the survey and consented to the interview. A 20-item questionnaire was used to collect information on medical conditions/diseases, product information, drug utilization, concomitant factors/diseases, and demographic data. Ethics The Ethics Commission of the University Hospital of Cologne approved the project (reference: 14–101). The ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards involving human participants were met. The study protocol of PhytoVIS is registered in the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP), according to the guidelines of the ENCePP Guide on Methodological Standards in Pharmacoepidemiology (EMA/95098/2010, Rev.2, 18 June 2013). The study is identified by the ID number 28113 and has the corresponding EU PAS number EUPAS7082 ( 22 ). Variables The 20 items in the questionnaire resulted in a total of 103 variables. For our study, we chose the variables listed below and created new variables where indicated. type of indication (free-text field) ◊ generated new variable: indication group gender (woman/man) age in predefined age groups (18–30 years, 31–50 years, 51–65 years, 66–75 years, > 75 years) information on the applied HMP (free-text field: product name) ◊ generated 3 new variables: medicinal plant species, herbal substance (standardized extract), and amount of standardized extract per single dose (mg) reason for application (acute/chronic symptoms, preventive use) severity of symptoms (on a Likert-scale ranging from 0 to 5: 0 „no symptoms“, 1, 2, 3, 4, 5 „most severe imaginable symptoms“) frequency of application (daily, if required) duration of application (number of days or longer undefined duration) ◊ generated new variable: duration of application (≤ 7 days, 8–30 days, > 30 days or longer undefined duration) dosage ◊ generated new variables: daily dose (mg) and daily dose categories ( 240 mg of GBE) therapeutic effectiveness of the HMP (on a Likert-scale ranging from 0 to 3: 0 “very good”, 1 “moderate-distinct”, 2“minimal-mild”, 3“unchanged or worsened”) 2 variables regarding the perceived tolerability of the HMP (on a Likert scale ranging from 0 to 3: 0 “no undesired events”, 1 “no significant undesired events”, 2 “significant undesired events”, 3“undesired events outweigh the therapeutic effectiveness”) and comment (free-text field) Answers and comments in the free-text field “concluding remarks” at the end of the questionnaire were assigned to the respective variable(s), where appropriate. Study Cohort From the PhytoVIS dataset, containing information on 20,870 patients ( 19 ), we selected our study population according to defined inclusion and exclusion criteria (Fig. 1 ): Inclusion criterium: Patients with mental health issues, including cognitive impairment, reported to treat their symptoms with HMPs (n = 2.781) Exclusion criteria (n = 1.156): Treatment with non-HMPs: Herbal supplements, homeopathic preparations, topical products, non-HMPs, herbal preparations without bibliographic approval according to EMA/HMPC or approval as a proprietary medicinal product, herbal teas (n = 1.028) Indication was unclear or not mental health associated, or multiple indications were reported (n = 81) HMP was not indicated for the treatment of mental health issues (n = 39) Information provided by the patients was not plausible (e.g. applied for 0 days) (n = 8) Exclusion criteria for study cohort (n = 1.434) Patients younger than 18 years (n = 19) Patients with indications other than cognitive impairment (n = 1.405) All HMPs not containing GBE (n = 10) Grouping of the Study Cohort The study cohort containing 191 patients was grouped based on the following criteria: gender (woman, man) age group (18–30 years, 31–50 years, 51–65 years, 66–75 years, > 75 years) condition for application (acute/chronic symptoms, preventive use) severity of symptoms (0 „no symptoms“, 1, 2, 3, 4, 5 „most severe imaginable symptoms“) duration of application (≤ 7 days, 8–30 days, > 30 days or longer undefined duration) dosage of GBE ( 240 mg) Statistical Analysis Descriptive statistics were applied to analyze the data. Non-parametric bivariate statistical tests (Pearson's chi-square test, Mann-Whitney-U test or Spearman correlation) were applied where appropriate. Results were defined as statistically significant when p < 0.05. P-values for multiple comparisons were adjusted using the Bonferroni correction. All statistical analyses were performed using IBM SPSS Statistics (version 29.0.2.0 ( 20 )) for Windows and MacOS, developed by IBM Corp., Armonk, NY, USA. GraphPad Prism (version 10.4.1 (627)), provided by GraphPad Software LLC, Boston, USA was used for illustrating the results. All numerical values (n and %) on which the results, statistical analyses and graphical representations are based are available in the supplementary material. Results Description of the Sample The sample comprised a total of 191 patients who were taking GBE for the treatment of cognitive impairment. The proportion of women in the sample was two-thirds (61.3%, n = 117), and thereby significantly higher than that of men (38.7%, n = 74). It was also striking that more than three quarters of patients were over 50 years old (78.0%, n = 149). Patients aged between 66 and 75 years (29.8%, n = 57) and over 75 (27.7%, n = 53) formed the largest age groups, each accounting for around one third. Less than a quarter of patients were between 18 and 30 years old (15.7%, n = 30), and 31 to 50-year-olds were the smallest age group with only 6.3% (n = 12). Interestingly, there were differences in the age distribution within the genders, especially among older patients: Most of the women in the sample belonged to the 66- to 75-year-old age group (30.8%, n = 36). This means that women tended to be slightly younger than men, the majority of whom were over 75 years old (31.1%, n = 23). Around two thirds of the patients in the sample (64.9%, n = 124) were taking at least one other medication in addition to GBE. All figures on the demographic characteristics of the study population can be found in Table 1 . Table 1 Characteristics of the study cohort Variable Patients n (%) Total 191 Gender Women 117 (61.3) Men 74 (38.7) Age-Group Total n (%) Women n (%) Men n (%) 18–30 years 30 (15.7) 18 (15.4) 12 (16.2) 31–50 years 12 (6.3) 8 (6.8) 4 (5.4) 51–65 years 39 (20.4) 25 (21.4) 14 (18.9) 66–75 years 57 (29.8) 36 (30.8) 21 (28.4) > 75 years 53 (27.7) 30 (25.6) 23 (31.1) GBE drug utilization Reason for application The majority of patients used GBE to treat chronic symptoms (41.3%; n = 76). The second most common reason for use was the prevention of cognitive impairment (38.6%, n = 71), while only a fifth used GBE in the context of acute symptoms (20.1%; n = 37) (Fig. 2 ). Our sample showed a significant association between the gender of the patients and the reason for utilizing GBE therapeutically as evidenced by Pearson's chi-square test (χ²(2,n = 184) = 6.93, p = 0.031*, Cramer’s V = 0.19): Women used GBE significantly more often for the treatment of chronic complaints (43.9%, n = 50) or for prevention (42.1%, n = 48), whereas men used GBE significantly more often for the treatment of acute complaints (30%, n = 21). All numerical data used to generate the figure are available in supplementary table 1 . Prevention Regarding the preventive use of GBE (n = 69), we distinguished between participants with (72.5%; n = 50) and without (27.5%; n = 19) pre-existing symptom burden (Fig. 3 ). Among those using GBE without having symptoms - women even outnumbered men by a factor of three (73.7%; n = 14 vs. 26.3%; n = 5). In contrast, within the group using GBE for pre-existing symptoms - women were twice as numerous as men (66.0%; n = 33 vs. 34.0%; n = 17). All numerical data underlying the figure are available in supplementary table 2. Severity of Symptoms More than half of the patients rated the severity of their symptoms as moderate (level 2–3; 57.6%; n = 106). Slightly less than a quarter of patients evaluated their symptoms as mild (level 1; 22.3%; n = 41) and around a tenth each had severe (level 4 & 5; 9.7%; n = 18) or no symptoms at all (level 0; 10.3%; n = 19) (Fig. 4 ). Participants who described having no symptoms reported that they used GBE exclusively preventatively, while patients who mentioned already suffering from symptoms (severity level 1–5) applied GBE both preventatively and curatively (to treat chronic or acute symptoms). All numerical data used to generate the figure are available in supplementary table 3. Intake Regimen of GBE Frequency of Application Almost all patients (97.9%, n = 187) took GBE on a daily basis (supplementary table 4). Duration of Application The vast majority of patients 85.9% (n = 159) took GBE over a longer period of time namely more than 30 days or for a longer undefined duration. A further 13.0% (n = 24) reported to use it between 8 and 30 days. Only very few (1.1%; n = 2) used GBE for one week or less (0–7 days) (Fig. 5 ). Interestingly, the duration of intake correlated with the age of the patients, regardless of gender with a small to medium effect size (Spearman correlation: p = 0.002**, r = 0.23). With increasing age, the patients took GBE for longer periods of time. All numerical data underlying the figure are available in supplementary table 5. GBE was utilized the longest for the treatment of chronic symptoms. Here, over 97% of patients took GBE for longer than 30 days. Shorter periods of 8–30 days were observed when GBE was taken for acute symptoms (about one third of users) or for preventive reasons (about one in seven users) (Fig. 6 ). The differences in the periods of utilization (> 30 days or 8–30 days) between “chronic symptoms” and “acute symptoms” or “preventive use” were statistically highly significant with small to medium effect size (chronic versus preventive: p adj =0.006**, r = 0.25; chronic versus acute p adj <0.001***, r = 0.39) as evidenced by Mann-Whitney-U test (Bonferroni-corrected). This means that the duration of GBE utilization for chronic symptoms was statistically significantly longer than for acute symptoms or the prevention. All numerical data used to generate the figure are available in supplementary table 5. Dosage The total daily dose of GBE, calculated on the basis of the patients' statements, varied between 30 mg and 480 mg per day, whereby 120 mg (37.4%; n = 70) and 240 mg (35.3%; n = 66) daily were used most frequently (Table 2 ). Table 2 Daily dose of GBE Daily Dose 30 mg 40 mg 60 mg 80 mg 120 mg 160 mg 240 mg 360 mg 480 mg All Patients n (%) 2 (1.1) 13 (7.0) 3 (1.6) 11 (5.9) 70 (37.4) 8 (4.3) 66 (35.3) 2 (1.1) 12 (6.4) Based on the daily dose of 240 mg recommended in the dementia guidelines ( 8 ), we categorized the patients into three groups: 240 mg (Fig. 7 ). Interestingly, more than half of the patients (57.2%, n = 107) took a total daily dose below the recommendation, slightly more than a third (35.3%, n = 66) adhered to the recommended daily dose, and only a few patients (7.5%, n = 14) exceeded the recommended daily dose of 240 mg. More than half of the men (52.8%, n = 38) took a higher daily dose (240 mg or more) than most of the women (63.5%, n = 73), who took a daily dose of less than 240 mg. This difference was statistically significant (Mann-Whitney-U test: p = 0.021* r = 0.17). All numerical data underlying the figure are available in supplementary table 6. With increasing age lower dosages were taken (Fig. 8 ). This was particularly noticeable among those over 75 years of age: Here, over 70% took less than 240 mg of GBE daily. The correlation was statistically significant as evidenced by Spearman test (p = 0.046*; r = 0.15). All numerical data used to generate the figure are available in supplementary table 6. Perceived Therapeutic Effectiveness The vast majority of patients (over 90%) described the application of GBE as beneficial for the treatment or prevention of cognitive impairment regardless of age and gender or the circumstances for its use. Slightly less than half of these patients rated the level of effectiveness as “moderate - significant” (43.5%, n = 83), around one in three patients (28.3%, n = 54) as “minimal - mild” and just under a fifth (18.8%; n = 36) as “very good - distinct”. Less than one out of 10 patients (9.4%, n = 18) reported that they felt their condition was “unchanged or had worsened” after treatment. Those who took GBE for longer than 30 days or longer rated the effectiveness as significantly better (Mann-Whitney-U test: p = 0.005**, r = 0.21) than those who used the preparations for a shorter period. The vast majority of study participants (93.7%; n = 149) reported that they perceived a therapeutic benefit when taking the medication for longer durations, almost half (45.9%) described the effectiveness as “moderate - significant” and one in five (21.4%) even as “very good - significant”. On the other hand, 25.0% (n = 6) of the patients who took GBE for 8–30 days perceived no therapeutic benefit (Fig. 9 ). Two persons in our sample took GBE for a very short period (0–7 days) and were not included in the statistical analysis due to the small size of this group and the short duration of treatment (one patient perceived no therapeutic benefit, the other rated the efficacy as “minimal-mild”). All numerical data underlying the figure are available in supplementary table 7. Perception of Tolerability Issues The predominant portion (89.0%; n = 170) of patients did not experience any adverse drug reactions when using GBE. Only about one in ten (9.4%; n = 18) reported non-impairing tolerability issues. Tolerability issues associated with significant undesired effects were rare (1.0%, n = 2) and only one person reported that undesired drug events outweighed therapeutic effectiveness (0.5%, n = 1) (Fig. 10 ). All numerical data used to generate the figure are available in supplementary table 8. Two of the patients specified the tolerability issues in more detail: one of the patients complained of ear noise, which occurred a few minutes after taking the drug, and another patient reported itching, gastrointestinal complaints, headaches, and dizziness, which occurred after 14 days of taking GBE. A causal relationship with the use of GBE could not be established. However, the intake was discontinued after the occurrence of the tolerability issues. Discussion The therapeutic efficacy and tolerability of HMPs based on a GBE for the treatment of cognitive impairment has been proven by numerous clinical studies ( 23 ). However, the transferability of these results to everyday medical practice can be challenging because multimorbid patients, people with complex health conditions or concomitant medication are usually underrepresented in clinical studies. Yet these groups are particularly frequently affected by cognitive impairment ( 24 ). There are only isolated records on how often multimorbid patients use GBE and how successful the therapy is. This lack of evidence on the actual effectiveness and tolerability in these vulnerable patients can lead to reservations among doctors regarding the prescription or recommendation. In consequence HMPs based on GBE are still underrepresented in therapy strategies although they are listed as a treatment option in the German S3 dementia guidelines ( 8 ). At the same time GBE preparations can be purchased over the counter or online by any patient without a doctor's diagnosis and prescription. As a result, many aspects of drug utilization and effectiveness or tolerability remain unrecorded. It is also difficult to monitor whether a thorough consultation with health professionals took place prior to self-medication. In our study we analyzed information from patients and users of GBE who treated or intended to prevent cognitive impairment thus providing insight into real-world self-medication practices. Our results provide information on drug utilization and perceived therapeutic benefits representing an important add-on to clinical studies. We observed that GBE was used both preventively and curatively (for acute and chronic symptoms). We showed that patients, regardless of age and gender, took GBE for the treatment or prevention of cognitive impairment - particularly frequently patients over the age of 50 and women. These results confirm previously observed trends captured by a health survey which found that already from the age of 45, every seventh person stated that they were concerned about their mental capacity. Women were affected more often than men, regardless of age ( 3 ). In our study population about 10% of the participants stated to use GBE preventively without indicating any symptom load. We interpret this approach as primary prevention. In this context we observed that 3 times more women than man took GBE already before having symptoms of cognitive impairment and that women started taking GBE at a younger age. One possible explanation for this could be that women have a higher level of health literacy ( 25 ) and therefore possibly start prevention earlier. Nevertheless, the question arises as to whether it makes sense to take GBE before symptoms of cognitive impairment are present, as a primary preventive effect has not yet been clinically proven ( 14 ). On the other hand the methodological complexity of prevention studies such as the demanding study design, recruiting a sufficient sample size, long observation periods and suitable endpoints ( 15 ) suggest that it may never be possible to conclusively determine whether GBE exerts a primary preventive effect. Even in the context of secondary data analyses, it remains difficult to clarify whether individuals can be recorded who never suffered from cognitive impairment because they had taken GBE preventively as self-medication. As in such cases neither a medical diagnosis nor a prescription has been made, these people are not registered in healthcare data (e.g. claims data). Although the argument of prevention is methodologically challenging, we conclude that the utilization of GBE for primary prevention among our study participants indicates a high level of trust. In our study cohort slightly less than one third reported to have used GBE preventively and at the same time indicated to have considerable symptoms of cognitive impairment. We assume that these participants took GBE to prevent pre-existing symptoms from worsening, which fits the definition of secondary prevention. This is well in line with previous studies reporting that GBE can slow down the progression of existing symptoms or that in the course of the disease, more severe forms occur less often ( 17 , 18 ). With more than 60% of our study population, patients who used GBE curatively made up the largest proportion, including cases with a considerable symptom load (levels 4 and 5). The use of HMPs in such cases indicates that patients have a high level of confidence in its effectiveness - despite advanced symptoms. This underlines the relevance of GBE in everyday practice as a treatment option alongside non-herbal medications such as memantine, which the guideline recommends for moderate to severe forms of dementia ( 8 ). Using an appropriate dose of a medicine, at the right frequency, for the correct duration, is required for all medicines to optimize therapeutic effects ( 20 ). This also and especially applies to medicines used for self-medication. Here, a certain level of health literacy is a prerequisite for the patient to use the medicine correctly. In our study, we analyzed the treatment habits and adherence of GBE users for the first time using systematically and structured patient reports. Adherence to GBE was very good regardless of whether the reason was treatment or prevention of cognitive impairment: GBE was used daily by almost all patients (> 97%). The majority of patients (over 85%) utilized GBE for longer than 30 days or for a longer undefined duration, however the latter could not be determined from the available data. It was therefore not possible to fully verify whether the patients adhered to the minimum intake duration of 8 weeks recommended in relevant literature ( 13 ). However, similar previous evaluations of a data set on self-medication for gynecological complaints showed that users largely followed the recommendations regarding the duration of use for HMPs ( 21 ). In contrast, the dosage recommendation from the EMA/HMPC and dementia guidelines of 240 mg/day ( 8 , 13 ) were not always strictly adhered to: More than half of the participants in our sample reported a daily intake below that. This may be due to the fact that, for some of the preparations, the package inserts recommend lower doses in the range of 120–240 mg per day. However, it is well in line with previous reports on adherence to non-prescription medicines in self-medication, where over 60% of users stated that they were taking too low a dose ( 26 ). In our sample, we observed this effect particularly frequently in women (> 60%). In this context, a study from Slovenia found that women seem to be more cautious about self-medication than men, also with regard to dosage ( 27 ). A further reason for the underdosing of GBE may also be the relatively high price, as GBE is only reimbursed by statutory health insurance if a diagnosis of dementia is present ( 28 ). Underdosing may partly be explained by concerns about side effects and potential drug interactions - factors that are particularly relevant in older adults ( 29 ). This tendency was also observed among our participants aged over 75 years. Given the high prevalence of polypharmacy in this age group (estimated at 40–50%) ( 30 , 31 ), dose reductions may also reflect a cautious self-regulatory approach to avoid adverse drug interactions. Effectiveness and Tolerability The vast majority of patients (over 90%) were convinced of the benefits of taking GBE for treating or preventing cognitive impairment. Notably, the subjectively perceived effectiveness increased significantly with longer duration of use. This is in line with existing recommendations to take GBE for at least eight weeks ( 8 ) in order to achieve therapeutically relevant effects. In addition to the high perceived effectiveness, tolerability was also rated positively by the majority of the respondents: Only about 11% reported adverse drug reactions, most of which were mild and did not impact daily life. More severe symptoms were reported by just 1.5% of participants (3 out of 191); however, in none of these cases could a clear causal link be established with GBE. In one case, the symptoms occurred 14 days after starting GBE and were therefore not even temporally associated with its use. In light of these findings, the risk-benefit ratio of GBE can be considered favorable. This assessment aligns with the results of randomized controlled trials, which have demonstrated both the therapeutic efficacy and good tolerability of HMPs including GBE compared to placebo or synthetic alternatives ( 32 ). Strengths and Limitation With over 20.000 participants, the PhytoVIS database currently constitutes the largest real-world data source on HMPs. It enables comprehensive cross-product and cross-indication analyses of the usage patterns, effectiveness and tolerability. By including patients with polymedication – who represent approximately 65% of our sample, PhytoVIS offers opportunities for data evaluations that go beyond the scope of clinical studies, which typically involve highly selected patient populations. Additionally free text fields allow participants to report information that was not explicitly requested but is considered relevant from their perspective. This feature enables further qualitative analyses, which we utilized in the assessment of tolerability. Participants were not required to have a formal medical diagnosis of cognitive impairment; instead, data were based on self-reported symptoms and perceived therapeutic benefits. While this approach may introduce recall bias or other forms of subjective bias, studies have shown that individuals with subjectively perceived memory decline often exhibit objectively measurable cognitive deficits ( 33 , 34 ). Since the surveys were conducted primarily in pharmacies and medical practices located in western Germany, the results cannot be fully generalized to the entire country or to populations beyond its borders ( 19 ). It is also worth noting that women account for 67% of the total PhytoVIS database ( 35 ). The observed gender distribution suggests a potential sampling bias, representing a limitation to the generalizability of the findings. Due to the recruitment strategy, the study sample includes predominantly individuals with a positive attitude towards HMPs introducing a potential selection bias. Furthermore, a tendency known as 'effort justification' - where people rate a product more favorably after spending money on it - may have influenced the results, particularly the self-reported outcomes ( 36 ). Although the overall number of participants in the PhytoVIS study is large, the subgroup of GBE users with cognitive impairment is relatively small comprising only 191 individuals. As a results, statistical analysis of subgroup comparisons and potential influencing factors on effectiveness and tolerability revealed only small effect sizes. Larger sample sizes would be necessary to draw more robust conclusions. Furthermore, the data collection period (2014–2016) limits the applicability of the findings to preparations approved after that time. Conclusion The study offers valuable insights into the usage patterns, as well as patients’ self-assessed effectiveness and tolerability of GBE when used in self-medication for cognitive impairment. Our key observations include the following: GBE is commonly used not only for primary and secondary prevention, but also in the treatment of more pronounced symptoms. The frequent and sustained use of GBE among participants suggests a high level of adherence. Doses lower than the recommended 240 mg/day were observed primarily among women and individuals over the age of 75. Overall, both the perceived effectiveness and tolerability of GBE were rated as good to very good, with serious adverse events were reported only rarely. These findings support a stronger integration of GBE into pharmacological strategies for the prevention and treatment of cognitive impairment. The results also highlight the need for further research into the factors influencing dosage - such as in the context of polymedication or gender / age - and into potential interactions that may affect the effectiveness and tolerability of GBE when taken alongside other (non-herbal) medications. Abbreviations GBE - Ginkgo biloba L., folium (ginkgo leaf) extract ChEIs - Cholinesterase inhibitors CDR-SB - Clinical dementia rating – sum of boxes HMPC - Herbal Medicinal Products Committee EMA - European Medicines Agency PAQUID - Personnes Agées QUId HMP - Herbal medicinal product OTC - Over the counter IMSB - Institute for Medical Statistics and Computational Biology RWD - Real-world data PRO - Patient-reported outcomes ENCePP - European Network of Centres for Pharmacoepidemiology and Pharmcovigilance Declarations Ethics Approval and Consent to Participate The Ethics Commission of the University Hospital of Cologne approved the project (reference: 14-101). The ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards involving human participants were met. Inclusion criterion was the informed consent of the patient or caregiver before the individual interview. The study protocol of PhytoVIS is registered in the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP). Clinical trial number: not applicable Consent for Publication Not applicable Availability of Data and Materials Data was extracted from the pharmaco-epidemiological database PhytoVIS which is owned by the Kooperation Phytopharmaka. Requests concerning the raw data has been addressed to the Kooperation Phytopharmaka. Analyzed Data supporting the results can be obtained from the corresponding author on reasonable request. Competing Interest The authors declare that they have no competing interests. Funding The authors affiliated at Goethe University, Institute of Pharmaceutical Biology, are funded by Dr.-Willmar-Schwabe. The funder had no role in the conceptualization, design, data collection, analysis, decision to publish, or preparation of the manuscript. Authors Contributions BEB (corresponding author): Conceptualization and design of the study, supervision and project administration, investigation, methodology, writing – original draft, presentation and visualization of results, substantial contribution to the conception, design and interpretation of the data, revising critically for important intellectual content, approval of the final version for submission, funding acquisition and resources AJS (first author): Conceptualization and design of the study, data curation, formal analysis, investigation, methodology, presentation and visualization of results, software, validation, writing – original draft, substantial contribution to the conception, design and interpretation of the data, approval of the final version for submission AD, SBF (co-authors): Substantial contribution to the conception, design and interpretation of the data, writing – revising critically for important intellectual content, approval of the final version for submission RM (co-author): Planning and design of PhytoVIS database and the questionnaire, management of the data base and the data generation, data cleaning and statistics, writing -review and editing, approval of the final version for submission All authors read and approved the final version of the manuscript for submission. Acknowledgements We sincerely thank the Kooperation Phytopharmaka, Bonn, Germany, for providing access to the PhytoVIS data. We thank Dr. Olaf Kelber and Prof. Dr. Karin Kraft for the critical review of the manuscript and valuable intellectual contribution to the discussion. We are also grateful to the student assistants, Emilia Rappold and Lisa Küpper, from Dr. Svenja B. Frenzel’s team, for their support in assigning indications and categorizing the cases and Linrui Qian for his support in the classification and coding of the dosages. References Bradfield NI. Mild Cognitive Impairment: Diagnosis and Subtypes. Clin EEG Neurosci. 2023;54(1):4–11. Azam S, Haque ME, Balakrishnan R, Kim IS, Choi DK. The Ageing Brain: Molecular and Cellular Basis of Neurodegeneration. Front Cell Dev Biol. 2021;9:683459. Robert-Koch-Institut. Kognitive Einschränkungen (ab 18 Jahre) Gesundheitsberichterstattung des Bundes. 2024. Dhakal A, Bobrin BD. Cognitive Deficits. StatPearls. Treasure Island (FL)2025. GBD. 2019; Dementia Forecasting Collaborators. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. Lancet Public Health. 2022;7(2):e105-e25. World Health Organization. Global status report on the public health response to dementia. 2021. Blotenberg I, Hoffmann W, Thyrian JR. Dementia in Germany: Epidemiology and Prevention Potential. Dtsch Arztebl Int. 2023;120(27–28):470–6. DGN & DGPPN e. V. S3-Leitlinie Demenzen, Version 4.0. 2025 03.11.2025. Raina P, Santaguida P, Ismaila A, Patterson C, Cowan D, Levine M, et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med. 2008;148(5):379–97. Kroger E, Mouls M, Wilchesky M, Berkers M, Carmichael PH, van Marum R, et al. Adverse Drug Reactions Reported With Cholinesterase Inhibitors: An Analysis of 16 Years of Individual Case Safety Reports From VigiBase. Ann Pharmacother. 2015;49(11):1197–206. EMA. Approval of the marketing authorisation for Leqembi (lecanemab), Reference: EMA/63941/2025 EMEA/H/C/005966. 2025. van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, et al. Lecanemab in Early Alzheimer's Disease. N Engl J Med. 2023;388(1):9–21. HMPC. Assessment report on Ginkgo biloba L., folium, EMA/HMPC/321095/2012 2014. Charemboon T, Jaisin K. Ginkgo biloba for prevention of dementia: a systematic review and meta-analysis. J Med Assoc Thai. 2015;98(5):508–13. Enserro DM, Gunn HJ, Elsaid MI, Duan F, Pugh SL. Challenges to and considerations of designing cancer prevention trials. JNCI Monogr. 2025;2025(68):49–55. Amieva H, Meillon C, Helmer C, Barberger-Gateau P, Dartigues JF. Ginkgo biloba extract and long-term cognitive decline: a 20-year follow-up population-based study. PLoS ONE. 2013;8(1):e52755. Bohlken J, Hajek A, Burkart M, Kostev K. Ginkgo biloba Extract Prescriptions Are Associated with Slower Progression of Dementia Severity-Analysis of Longitudinal Real-World Data. Brain Sci. 2024;15(1). Bohlken J, Peters O, Kostev K. Association Between Ginkgo Biloba Extract Prescriptions and Dementia Incidence in Outpatients with Mild Cognitive Impairment in Germany: A Retrospective Cohort Study. J Alzheimers Dis. 2022;86(2):703–9. Wegener TNK, Kraft K, Siegmund S, Kelber O, Jobst D, et al. Versorgungsforschung mit pflanzlichen Arzneimitteln – Die pharmako-epidemiologische Datenbank PhytoVIS. Z für Phytotherapie. 2021;42(03):127–35. Brown MT, Bussell JK. Medication adherence: WHO cares? Mayo Clin Proc. 2011;86(4):304 – 14. Drebka A, Scholl AJ, Ochs T, Kelber O, Mosges R, Raskopf E, et al. Patient-reported therapeutic benefits of herbal medicinal products in the treatment of gynecological ailments. BMC Complement Med Ther. 2025;25(1):99. PhytoVIS Project. Observational Plan - Investigation of Experience with the Use of Herbal Medicinal Products (Phytopharmaceuticals) based on an online questionnaire. 2013. Tomino C, Ilari S, Solfrizzi V, Malafoglia V, Zilio G, Russo P et al. Mild Cognitive Impairment and Mild Dementia: The Role of Ginkgo biloba (EGb 761((R))). Pharmaceuticals (Basel). 2021;14(4). Xin B, Zhang D, Fu H, Jiang W. Association between multimorbidity and the risk of dementia: A systematic review and meta-analysis. Arch Gerontol Geriatr. 2025;131:105760. Doris Schaeffer E-MB, Svea Gille LG, Julia Klinger, Steffen de Sombre DV, Klaus Hurrelmann. Gesundheitskompetenz der Bevölkerung in Deutschland vor und während der Corona Pandemie Ergebnisse des HLS-GER 2. Bielefeld: Universität Bielefeld, Interdisziplinäres Zentrum für Gesundheitskompetenzforschung; 2021. Vong SK, Kang L, Carter SR. Consumers' self-reported adherence to directions for non-prescription medicines and the role of risk perception. Res Social Adm Pharm. 2022;18(11):3929–38. Klemenc-Ketis Z, Hladnik Z, Kersnik J. A cross sectional study of sex differences in self-medication practices among university students in Slovenia. Coll Antropol. 2011;35(2):329–34. Gemeinsamer Bundesausschuss. Richtlinie des Gemeinsamen Bundesausschusses über die Verordnung von Arzneimitteln in der vertragsärztlichen Versorgung (Arzneimittel-Richtlinie/AM-RL). Bundesanzeiger Nr. 49a (Beilage) 31. März 20092024. Dijkstra NE, Sino CGM, Schuurmans MJ, Schoonhoven L, Heerdink ER. Medication self-management: Considerations and decisions by older people living at home. Res Social Administrative Pharm. 2022;18(3):2410–23. Knopf H, Grams D. Arzneimittelanwendung von Erwachsenen in Deutschland. Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz. 2013;56(5–6):868–77. Wang X, Liu K, Shirai K, Tang C, Hu Y, Wang Y, et al. Prevalence and trends of polypharmacy in U.S. adults, 1999–2018. Glob Health Res Policy. 2023;8(1):25. Salm S, Rutz J, van den Akker M, Blaheta RA, Bachmeier BE. Current state of research on the clinical benefits of herbal medicines for non-life-threatening ailments. Front Pharmacol. 2023;14. Pike KE, Cavuoto MG, Li L, Wright BJ, Kinsella GJ. Subjective Cognitive Decline: Level of Risk for Future Dementia and Mild Cognitive Impairment, a Meta-Analysis of Longitudinal Studies. Neuropsychol Rev. 2021;32(4):703–35. Tangen GG, Langballe EM, Strand BH. Subjective memory impairment, instrumental activities of daily living and longitudinal effect on mortality among older adults in a population-based cohort study: The HUNT Study. Scand J Public Health. 2019;48(8):825–31. Esther Raskopf SS. Survey on experiences with phytopharmaceuticals via an online based questionnaire - Retrospective online survey. Institute of Medical Statistics, Informatics and Epidemiology (IMSIE) University Hospital Cologne; 2018. Harmon-Jones E, Mills J. An introduction to cognitive dissonance theory and an overview of current perspectives on the theory. Cognitive dissonance: Reexamining a pivotal theory in psychology (2nd ed)2019. pp. 3–24. Additional Declarations No competing interests reported. Supplementary Files SupplementaryDataTablesGBEpaper1.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 11 Feb, 2026 Reviewers invited by journal 06 Feb, 2026 Editor invited by journal 19 Jan, 2026 Editor assigned by journal 21 Nov, 2025 Submission checks completed at journal 21 Nov, 2025 First submitted to journal 18 Nov, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8146289","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":588074327,"identity":"5de08804-8006-411f-9b1b-c6fcca75b967","order_by":0,"name":"Annika Johanna Scholl","email":"","orcid":"","institution":"Goethe-University","correspondingAuthor":false,"prefix":"","firstName":"Annika","middleName":"Johanna","lastName":"Scholl","suffix":""},{"id":588074328,"identity":"1481fc49-ffed-4420-81c3-fe3e9e652e8a","order_by":1,"name":"Alexandra Drebka","email":"","orcid":"","institution":"Goethe-University","correspondingAuthor":false,"prefix":"","firstName":"Alexandra","middleName":"","lastName":"Drebka","suffix":""},{"id":588074329,"identity":"b8ed6c61-037f-4f6f-9c2c-4cc0b49ae39b","order_by":2,"name":"Ralph Mösges","email":"","orcid":"","institution":"University of Cologne","correspondingAuthor":false,"prefix":"","firstName":"Ralph","middleName":"","lastName":"Mösges","suffix":""},{"id":588074330,"identity":"408e1998-31b1-476b-be5d-8bff70377f64","order_by":3,"name":"Svenja Beatrice Frenzel","email":"","orcid":"","institution":"Leibniz Institute for Psychology (ZPID)","correspondingAuthor":false,"prefix":"","firstName":"Svenja","middleName":"Beatrice","lastName":"Frenzel","suffix":""},{"id":588074331,"identity":"d1a8f21b-f927-41a7-8e34-7afa3cb0eab3","order_by":4,"name":"Beatrice Elisabeth Bachmeier","email":"data:image/png;base64,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","orcid":"","institution":"Goethe-University","correspondingAuthor":true,"prefix":"","firstName":"Beatrice","middleName":"Elisabeth","lastName":"Bachmeier","suffix":""}],"badges":[],"createdAt":"2025-11-18 13:53:35","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8146289/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8146289/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102439540,"identity":"5f931ee8-d0a4-4a6a-8678-a5cf852fefdb","added_by":"auto","created_at":"2026-02-11 16:40:50","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":280984,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStudy cohort according to defined inclusion and exclusion criteria\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Fig.1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8146289/v1/8d5b525e012c692eba75cbc8.jpg"},{"id":102439563,"identity":"6eef478d-1088-4375-94b5-e3cbfdfdaa54","added_by":"auto","created_at":"2026-02-11 16:40:55","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":2013558,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDifferences between men and women in the reason for application of GBE\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWomen were more likely to report using GBE for chronic symptoms and preventive purposes, while men more frequently treated acute symptoms.\u003c/p\u003e","description":"","filename":"Fig.2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8146289/v1/94fe35c885f87a6f89c046d1.jpg"},{"id":102439557,"identity":"2eb49275-2a22-4122-89d9-60cafd1048c4","added_by":"auto","created_at":"2026-02-11 16:40:54","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1763065,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGender distribution in preventive use of GBE with or without symptoms\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePreventive use was more pronounced among women than among men – independent of symptom status (no/pre-existing symptoms).\u003c/p\u003e","description":"","filename":"Fig.3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8146289/v1/fee4ed643cd78054c6b7804d.jpg"},{"id":102439549,"identity":"b254d228-9056-4191-8397-b69924f9a6ba","added_by":"auto","created_at":"2026-02-11 16:40:53","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":2108219,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSeverity of symptoms among all patients and by reason for application of GBE\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGBE is used not only for prevention and treatment of cognitive impairment, but also in cases of high symptom severity.\u003c/p\u003e","description":"","filename":"Fig.4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8146289/v1/2a42473c55ead261557b2577.jpg"},{"id":102439518,"identity":"316355d3-e202-424a-9514-386a22be5c3e","added_by":"auto","created_at":"2026-02-11 16:40:46","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":2749021,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDuration of intake of GBE among all patients and by age group\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIntake duration increased with age, as indicated by the directional arrow representing the observed correlation.\u003c/p\u003e","description":"","filename":"Fig.5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8146289/v1/7f8b3c41e2fe10e7e0316fcb.jpg"},{"id":102745810,"identity":"27c6c122-96da-4508-955a-e796e8986673","added_by":"auto","created_at":"2026-02-16 08:54:08","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":1964159,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDuration of intake of GBE by reason for application\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe longest intake duration was reported by participants using GBE for chronic symptoms.\u003c/p\u003e","description":"","filename":"Fig.6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8146289/v1/f33f90428533f87e2cd11bfa.jpg"},{"id":102439553,"identity":"073afab0-3a2f-42b7-a912-07c2c97f7a47","added_by":"auto","created_at":"2026-02-11 16:40:54","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":1983015,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDaily GBE dose among all patients and by gender\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWomen reported to take lower doses compared to men.\u003c/p\u003e","description":"","filename":"Fig.7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8146289/v1/e2d497bc01227d6b306ba3a0.jpg"},{"id":102745735,"identity":"e7b25c34-c076-43d5-9f03-0a746f78e285","added_by":"auto","created_at":"2026-02-16 08:53:39","extension":"jpg","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":376075,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDaily dose of GBE by age group\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOlder people tend to decrease the dosage as indicated by the directional arrow representing the observed correlation.\u003c/p\u003e","description":"","filename":"Fig.8.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8146289/v1/f55241213b6f5dae3b3ea726.jpg"},{"id":102439546,"identity":"c559b1bd-fd48-412f-82fe-2cd7c94c4e34","added_by":"auto","created_at":"2026-02-11 16:40:53","extension":"jpg","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":2734089,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePerceived therapeutic effectiveness of GBE among all patients and by duration of application\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLonger intake was associated with higher perceived effectiveness.\u003c/p\u003e","description":"","filename":"Fig.9.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8146289/v1/45bd5698fbb99c96dcbf79ec.jpg"},{"id":102439559,"identity":"d069eca1-f84d-4c88-8c22-e7db64c725b9","added_by":"auto","created_at":"2026-02-11 16:40:54","extension":"jpg","order_by":10,"title":"Figure 10","display":"","copyAsset":false,"role":"figure","size":1015156,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePerceived Tolerability of GBE among all patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe vast majority of patients reported good tolerability.\u003c/p\u003e","description":"","filename":"Fig.10.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8146289/v1/b3e0f21d0156fd4638911114.jpg"},{"id":103049587,"identity":"d8a45190-4d38-4d1d-b767-2a666854c12b","added_by":"auto","created_at":"2026-02-20 07:43:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":18065291,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8146289/v1/b4c3021c-09b2-438d-b1fd-23b652ae01a2.pdf"},{"id":102439517,"identity":"e827eb32-70ec-40a9-bfdd-ccb6ba272072","added_by":"auto","created_at":"2026-02-11 16:40:44","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":34001,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryDataTablesGBEpaper1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8146289/v1/f3e240b41c3f95a72417181e.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eDrug Utilization and Real-World Therapeutic Outcomes of \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eGinkgo biloba\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e L. Leaf Extract in Prevention and Treatment of Cognitive Impairment\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eCognitive impairment and dementia are associated with a decline in cognitive abilities such as memory, attention, and the ability to perform everyday activities (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). While dementia and neurodegenerative diseases are predominantly linked to aging (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e), cognitive impairment can occur across all age groups (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). The severity of cognitive impairment ranges from mild or moderate respectively short-term conditions to severe, permanent or progressive forms (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAccording to the Global Burden of Disease Study 2019, around 57\u0026nbsp;million people worldwide are living with dementia. This number is expected to rise to approximately 153\u0026nbsp;million by 2050, which is almost three times as many (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Worldwide, the prevalence of dementia is higher in women than in men (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). It is estimated, that about 1.8\u0026nbsp;million individuals in Germany aged 40 or older are living with dementia (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eStandard therapy in Germany for dementia includes cholinesterase inhibitors (ChEIs) like Donepezil, Galantamine or Rivastigmine and the NMDA antagonist Memantine (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), which can lead to statistically significant, yet clinically limited improvements in cognitive performance (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Their overall effectiveness remains modest for the majority of patients and especially ChEIs are associated with neuropsychiatric and serious cardiovascular adverse events (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Lecanemab, a new monoclonal antibody approved very recently in Europe for the treatment of early Alzheimer\u0026rsquo;s disease (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) decreases cognitive decline in patients with very mild to mild dementia. However, the difference between treatment and placebo groups was only 0.45 points on the 18-level CDR-SB Score (Clinical Dementia Rating \u0026ndash; Sum of Boxes) (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Due to the recent approval, there is hardly any pharmacovigilance data yet.\u003c/p\u003e \u003cp\u003eAs well tolerated yet efficacious option for patients with mild to moderate forms of dementia and non-psychotic neuropsychiatric symptoms the German S3 guideline recommends (grade B) a clearly specified \u003cem\u003eGinkgo biloba\u003c/em\u003e L., folium (Ginkgo leaf) extract (GBE) in a daily dosage of 240 mg for a minimum treatment duration of 8 weeks (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIt is noteworthy that medical care is primarily focused on manifest dementia, rather than on forms of mild or moderate cognitive impairment, which are in fact precursors to dementia. Yet it is precisely in this area that prevalence is particularly high: In 2023, 15.9% of German adults reported to have experienced subjective memory decline, with women being more frequently affected than men (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eUnfortunately, there are no pharmaceutical treatment recommendations for mild to moderate cognitive impairment, and as a result, those affected often manage their symptoms through self-medication.\u003c/p\u003e \u003cp\u003eHowever, the HMPC of the EMA (European Medicines Agency/ Herbal Medicinal Products Committee) has recognized monographed GBE under \u0026ldquo;well-established use\u0026rdquo; for the improvement of (age-associated) cognitive impairment, because its efficacy and safety have been proven clinically (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). On the other hand significant preventive effects have not yet been proven (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). The reason might be the complexity of designing prevention trials (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eComplementary to clinical data, several real-world data analyses indicate potential benefits of GBE on cognitive impairment. The prospective, population-based PAQUID study found that long-term use of GBE over 20 years was associated with decelerated cognitive decline (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Recent retrospective studies of routinely collected data from office-based physicians showed that GBE slows down progression of dementia (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) and reduces the incidence of dementia in patients with mild cognitive impairment (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Both studies used secondary data from the IQVIA Disease Analyzer, with strengths including large sample sizes and follow-up periods of up to ten years. Limitations included physician-assessed dementia severity degrees, which may not be standardized across physicians, and potential bias from unrecorded use of over the counter (OTC) GBE preparations (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOutcome reports of therapeutic benefits on the level of individual patients and drug utilization or treatment habits of GBE have not been investigated so far. The pharmaco-epidemiological database PhytoVIS contains experience reports of patients who utilized herbal medicinal products (HMPs) to treat their non-life-threatening medical conditions. The information collected indication-related information, therapeutic outcomes and usage patterns (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Thereby this database exerts a valuable source to provide the missing piece of information in comparison to previous clinical and real-world studies.\u003c/p\u003e \u003cp\u003eIn particular, usage patterns play a crucial role when medicines are available for self-medication as OTC-preparation. In everyday clinical practice, it is not uncommon for such products to be obtained without a formal consultation of a healthcare professional or detailed counseling. However, the therapeutic benefit of any medication depends on its appropriate use - including the correct dosage, proper frequency, and sufficient duration of intake (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). If these factors are not adhered to, the effectiveness may be reduced and the benefit-risk ratio potentially attenuated.\u003c/p\u003e \u003cp\u003eIn order to improve pharmaceutical care, the aim of our study was to analyze in depth self-reports from patients who utilized GBE in self-medication to treat or prevent symptoms associated with cognitive impairment. By analyzing real-world effectiveness, tolerability and usage patterns our study goes beyond already existing clinical and real-world studies and provides valuable complementary information.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData Source\u003c/h2\u003e \u003cp\u003eThe data sample was taken from the pharmaco-epidemiological database PhytoVIS established in 2013 by the German scientific society \u0026ldquo;Kooperation Phytopharmaka\u0026rdquo; and the Institute for Medical Statistics and Computational Biology (IMSB) with the aim of assessing the therapeutic benefits of HMPs (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) as described previously (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). The database consists of real-world data (RWD) in the form of anonymized patient-reported outcomes (PRO), providing cross-product information on the indication-related use of HMPs in everyday medical practice. Data collection took place between April 2014 and December 2016 in pharmacies by interviewing customers and patients on their personal experiences with HMPs (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). To be included in the PhytoVIS study, patients had to have taken HMPs during the eight weeks before the survey and consented to the interview.\u003c/p\u003e \u003cp\u003eA 20-item questionnaire was used to collect information on medical conditions/diseases, product information, drug utilization, concomitant factors/diseases, and demographic data.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEthics\u003c/h3\u003e\n\u003cp\u003e The Ethics Commission of the University Hospital of Cologne approved the project (reference: 14\u0026ndash;101). The ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards involving human participants were met. The study protocol of PhytoVIS is registered in the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP), according to the guidelines of the ENCePP Guide on Methodological Standards in Pharmacoepidemiology (EMA/95098/2010, Rev.2, 18 June 2013). The study is identified by the ID number 28113 and has the corresponding EU PAS number EUPAS7082 (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e\n\u003ch3\u003eVariables\u003c/h3\u003e\n\u003cp\u003eThe 20 items in the questionnaire resulted in a total of 103 variables. For our study, we chose the variables listed below and created new variables where indicated.\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003etype of indication (free-text field) \u0026loz; generated new variable: indication group\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003egender (woman/man)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eage in predefined age groups (18\u0026ndash;30 years, 31\u0026ndash;50 years, 51\u0026ndash;65 years, 66\u0026ndash;75 years, \u0026gt;\u0026thinsp;75 years)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003einformation on the applied HMP (free-text field: product name) \u0026loz; generated 3 new variables: medicinal plant species, herbal substance (standardized extract), and amount of standardized extract per single dose (mg)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ereason for application (acute/chronic symptoms, preventive use)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eseverity of symptoms (on a Likert-scale ranging from 0 to 5: 0 \u0026bdquo;no symptoms\u0026ldquo;, 1, 2, 3, 4, 5 \u0026bdquo;most severe imaginable symptoms\u0026ldquo;)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003efrequency of application (daily, if required)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eduration of application (number of days or longer undefined duration) \u0026loz; generated new variable: duration of application (\u0026le;\u0026thinsp;7 days, 8\u0026ndash;30 days, \u0026gt;\u0026thinsp;30 days or longer undefined duration)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003edosage \u0026loz; generated new variables: daily dose (mg) and daily dose categories (\u0026lt;\u0026thinsp;240 mg, exactly 240 mg, \u0026gt;\u0026thinsp;240 mg of GBE)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003etherapeutic effectiveness of the HMP (on a Likert-scale ranging from 0 to 3: 0 \u0026ldquo;very good\u0026rdquo;, 1 \u0026ldquo;moderate-distinct\u0026rdquo;, 2\u0026ldquo;minimal-mild\u0026rdquo;, 3\u0026ldquo;unchanged or worsened\u0026rdquo;)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e2 variables regarding the perceived tolerability of the HMP (on a Likert scale ranging from 0 to 3: 0 \u0026ldquo;no undesired events\u0026rdquo;, 1 \u0026ldquo;no significant undesired events\u0026rdquo;, 2 \u0026ldquo;significant undesired events\u0026rdquo;, 3\u0026ldquo;undesired events outweigh the therapeutic effectiveness\u0026rdquo;) and comment (free-text field)\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eAnswers and comments in the free-text field \u0026ldquo;concluding remarks\u0026rdquo; at the end of the questionnaire were assigned to the respective variable(s), where appropriate.\u003c/p\u003e\n\u003ch3\u003eStudy Cohort\u003c/h3\u003e\n\u003cp\u003eFrom the PhytoVIS dataset, containing information on 20,870 patients (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e), we selected our study population according to defined inclusion and exclusion criteria (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e):\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eInclusion criterium:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003ePatients with mental health issues, including cognitive impairment, reported to treat their symptoms with HMPs (n\u0026thinsp;=\u0026thinsp;2.781)\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eExclusion criteria (n\u0026thinsp;=\u0026thinsp;1.156):\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eTreatment with non-HMPs: Herbal supplements, homeopathic preparations, topical products, non-HMPs, herbal preparations without bibliographic approval according to EMA/HMPC or approval as a proprietary medicinal product, herbal teas (n\u0026thinsp;=\u0026thinsp;1.028)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eIndication was unclear or not mental health associated, or multiple indications were reported (n\u0026thinsp;=\u0026thinsp;81)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eHMP was not indicated for the treatment of mental health issues (n\u0026thinsp;=\u0026thinsp;39)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eInformation provided by the patients was not plausible (e.g. applied for 0 days) (n\u0026thinsp;=\u0026thinsp;8)\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eExclusion criteria for study cohort (n\u0026thinsp;=\u0026thinsp;1.434)\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003ePatients younger than 18 years (n\u0026thinsp;=\u0026thinsp;19)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ePatients with indications other than cognitive impairment (n\u0026thinsp;=\u0026thinsp;1.405)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eAll HMPs not containing GBE (n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e\n\u003ch3\u003eGrouping of the Study Cohort\u003c/h3\u003e\n\u003cp\u003eThe study cohort containing 191 patients was grouped based on the following criteria:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003egender (woman, man)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eage group (18\u0026ndash;30 years, 31\u0026ndash;50 years, 51\u0026ndash;65 years, 66\u0026ndash;75 years, \u0026gt;\u0026thinsp;75 years)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003econdition for application (acute/chronic symptoms, preventive use)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eseverity of symptoms (0 \u0026bdquo;no symptoms\u0026ldquo;, 1, 2, 3, 4, 5 \u0026bdquo;most severe imaginable symptoms\u0026ldquo;)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eduration of application (\u0026le;\u0026thinsp;7 days, 8\u0026ndash;30 days, \u0026gt;\u0026thinsp;30 days or longer undefined duration)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003edosage of GBE (\u0026lt;\u0026thinsp;240 mg, 240 mg, \u0026gt;\u0026thinsp;240 mg)\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eDescriptive statistics were applied to analyze the data. Non-parametric bivariate statistical tests (Pearson's chi-square test, Mann-Whitney-U test or Spearman correlation) were applied where appropriate. Results were defined as statistically significant when p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. P-values for multiple comparisons were adjusted using the Bonferroni correction. All statistical analyses were performed using IBM SPSS Statistics (version 29.0.2.0 (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e)) for Windows and MacOS, developed by IBM Corp., Armonk, NY, USA. GraphPad Prism (version 10.4.1 (627)), provided by GraphPad Software LLC, Boston, USA was used for illustrating the results. All numerical values (n and %) on which the results, statistical analyses and graphical representations are based are available in the supplementary material.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eDescription of the Sample\u003c/h2\u003e \u003cp\u003eThe sample comprised a total of 191 patients who were taking GBE for the treatment of cognitive impairment. The proportion of women in the sample was two-thirds (61.3%, n\u0026thinsp;=\u0026thinsp;117), and thereby significantly higher than that of men (38.7%, n\u0026thinsp;=\u0026thinsp;74). It was also striking that more than three quarters of patients were over 50 years old (78.0%, n\u0026thinsp;=\u0026thinsp;149). Patients aged between 66 and 75 years (29.8%, n\u0026thinsp;=\u0026thinsp;57) and over 75 (27.7%, n\u0026thinsp;=\u0026thinsp;53) formed the largest age groups, each accounting for around one third. Less than a quarter of patients were between 18 and 30 years old (15.7%, n\u0026thinsp;=\u0026thinsp;30), and 31 to 50-year-olds were the smallest age group with only 6.3% (n\u0026thinsp;=\u0026thinsp;12). Interestingly, there were differences in the age distribution within the genders, especially among older patients: Most of the women in the sample belonged to the 66- to 75-year-old age group (30.8%, n\u0026thinsp;=\u0026thinsp;36). This means that women tended to be slightly younger than men, the majority of whom were over 75 years old (31.1%, n\u0026thinsp;=\u0026thinsp;23). Around two thirds of the patients in the sample (64.9%, n\u0026thinsp;=\u0026thinsp;124) were taking at least one other medication in addition to GBE. All figures on the demographic characteristics of the study population can be found in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of the study cohort\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003ePatients n (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e191\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWomen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e117 (61.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e74 (38.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"5\" rowspan=\"6\"\u003e \u003cp\u003eAge-Group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTotal n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWomen n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMen n (%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18\u0026ndash;30 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (15.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18 (15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12 (16.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31\u0026ndash;50 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (6.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (6.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 (5.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e51\u0026ndash;65 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39 (20.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25 (21.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14 (18.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e66\u0026ndash;75 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57 (29.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e36 (30.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e21 (28.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;75 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53 (27.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30 (25.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e23 (31.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eGBE drug utilization\u003c/em\u003e \u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eReason for application\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eThe majority of patients used GBE to treat chronic symptoms (41.3%; n\u0026thinsp;=\u0026thinsp;76). The second most common reason for use was the prevention of cognitive impairment (38.6%, n\u0026thinsp;=\u0026thinsp;71), while only a fifth used GBE in the context of acute symptoms (20.1%; n\u0026thinsp;=\u0026thinsp;37) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Our sample showed a significant association between the gender of the patients and the reason for utilizing GBE therapeutically as evidenced by Pearson's chi-square test (χ\u0026sup2;(2,n\u0026thinsp;=\u0026thinsp;184)\u0026thinsp;=\u0026thinsp;6.93, p\u0026thinsp;=\u0026thinsp;0.031*, Cramer\u0026rsquo;s V\u0026thinsp;=\u0026thinsp;0.19): Women used GBE significantly more often for the treatment of chronic complaints (43.9%, n\u0026thinsp;=\u0026thinsp;50) or for prevention (42.1%, n\u0026thinsp;=\u0026thinsp;48), whereas men used GBE significantly more often for the treatment of acute complaints (30%, n\u0026thinsp;=\u0026thinsp;21). All numerical data used to generate the figure are available in supplementary table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003ePrevention\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eRegarding the preventive use of GBE (n\u0026thinsp;=\u0026thinsp;69), we distinguished between participants with (72.5%; n\u0026thinsp;=\u0026thinsp;50) and without (27.5%; n\u0026thinsp;=\u0026thinsp;19) pre-existing symptom burden (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Among those using GBE without having symptoms - women even outnumbered men by a factor of three (73.7%; n\u0026thinsp;=\u0026thinsp;14 vs. 26.3%; n\u0026thinsp;=\u0026thinsp;5). In contrast, within the group using GBE for pre-existing symptoms - women were twice as numerous as men (66.0%; n\u0026thinsp;=\u0026thinsp;33 vs. 34.0%; n\u0026thinsp;=\u0026thinsp;17). All numerical data underlying the figure are available in supplementary table 2.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eSeverity of Symptoms\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eMore than half of the patients rated the severity of their symptoms as moderate (level 2\u0026ndash;3; 57.6%; n\u0026thinsp;=\u0026thinsp;106). Slightly less than a quarter of patients evaluated their symptoms as mild (level 1; 22.3%; n\u0026thinsp;=\u0026thinsp;41) and around a tenth each had severe (level 4 \u0026amp; 5; 9.7%; n\u0026thinsp;=\u0026thinsp;18) or no symptoms at all (level 0; 10.3%; n\u0026thinsp;=\u0026thinsp;19) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Participants who described having no symptoms reported that they used GBE exclusively preventatively, while patients who mentioned already suffering from symptoms (severity level 1\u0026ndash;5) applied GBE both preventatively and curatively (to treat chronic or acute symptoms). All numerical data used to generate the figure are available in supplementary table 3.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eIntake Regimen of GBE\u003c/em\u003e \u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eFrequency of Application\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eAlmost all patients (97.9%, n\u0026thinsp;=\u0026thinsp;187) took GBE on a daily basis (supplementary table 4).\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eDuration of Application\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eThe vast majority of patients 85.9% (n\u0026thinsp;=\u0026thinsp;159) took GBE over a longer period of time namely more than 30 days or for a longer undefined duration. A further 13.0% (n\u0026thinsp;=\u0026thinsp;24) reported to use it between 8 and 30 days. Only very few (1.1%; n\u0026thinsp;=\u0026thinsp;2) used GBE for one week or less (0\u0026ndash;7 days) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eInterestingly, the duration of intake correlated with the age of the patients, regardless of gender with a small to medium effect size (Spearman correlation: p\u0026thinsp;=\u0026thinsp;0.002**, r\u0026thinsp;=\u0026thinsp;0.23). With increasing age, the patients took GBE for longer periods of time. All numerical data underlying the figure are available in supplementary table 5.\u003c/p\u003e \u003cp\u003eGBE was utilized the longest for the treatment of chronic symptoms. Here, over 97% of patients took GBE for longer than 30 days. Shorter periods of 8\u0026ndash;30 days were observed when GBE was taken for acute symptoms (about one third of users) or for preventive reasons (about one in seven users) (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe differences in the periods of utilization (\u0026gt;\u0026thinsp;30 days or 8\u0026ndash;30 days) between \u0026ldquo;chronic symptoms\u0026rdquo; and \u0026ldquo;acute symptoms\u0026rdquo; or \u0026ldquo;preventive use\u0026rdquo; were statistically highly significant with small to medium effect size (chronic versus preventive: p\u003csub\u003e\u003cem\u003eadj\u003c/em\u003e\u003c/sub\u003e=0.006**, r\u0026thinsp;=\u0026thinsp;0.25; chronic versus acute p\u003csub\u003e\u003cem\u003eadj\u003c/em\u003e\u003c/sub\u003e\u0026lt;0.001***, r\u0026thinsp;=\u0026thinsp;0.39) as evidenced by Mann-Whitney-U test (Bonferroni-corrected). This means that the duration of GBE utilization for chronic symptoms was statistically significantly longer than for acute symptoms or the prevention. All numerical data used to generate the figure are available in supplementary table 5.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eDosage\u003c/h2\u003e \u003cp\u003eThe total daily dose of GBE, calculated on the basis of the patients' statements, varied between 30 mg and 480 mg per day, whereby 120 mg (37.4%; n\u0026thinsp;=\u0026thinsp;70) and 240 mg (35.3%; n\u0026thinsp;=\u0026thinsp;66) daily were used most frequently (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDaily dose of GBE\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDaily Dose\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 mg\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40 mg\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60 mg\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e80 mg\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e120 mg\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e160 mg\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e240 mg\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e360 mg\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003e480 mg\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAll Patients \u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 \u003c/p\u003e \u003cp\u003e(1.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 \u003c/p\u003e \u003cp\u003e(7.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 \u003c/p\u003e \u003cp\u003e(1.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11 \u003c/p\u003e \u003cp\u003e(5.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e70 \u003c/p\u003e \u003cp\u003e(37.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e8 \u003c/p\u003e \u003cp\u003e(4.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e66 \u003c/p\u003e \u003cp\u003e(35.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2 \u003c/p\u003e \u003cp\u003e(1.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e12 \u003c/p\u003e \u003cp\u003e(6.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eBased on the daily dose of 240 mg recommended in the dementia guidelines (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), we categorized the patients into three groups: \u0026lt;240 mg, exactly 240 mg and \u0026gt;\u0026thinsp;240 mg (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e). Interestingly, more than half of the patients (57.2%, n\u0026thinsp;=\u0026thinsp;107) took a total daily dose below the recommendation, slightly more than a third (35.3%, n\u0026thinsp;=\u0026thinsp;66) adhered to the recommended daily dose, and only a few patients (7.5%, n\u0026thinsp;=\u0026thinsp;14) exceeded the recommended daily dose of 240 mg. More than half of the men (52.8%, n\u0026thinsp;=\u0026thinsp;38) took a higher daily dose (240 mg or more) than most of the women (63.5%, n\u0026thinsp;=\u0026thinsp;73), who took a daily dose of less than 240 mg. This difference was statistically significant (Mann-Whitney-U test: p\u0026thinsp;=\u0026thinsp;0.021* r\u0026thinsp;=\u0026thinsp;0.17). All numerical data underlying the figure are available in supplementary table 6.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eWith increasing age lower dosages were taken (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003e). This was particularly noticeable among those over 75 years of age: Here, over 70% took less than 240 mg of GBE daily. The correlation was statistically significant as evidenced by Spearman test (p\u0026thinsp;=\u0026thinsp;0.046*; r\u0026thinsp;=\u0026thinsp;0.15). All numerical data used to generate the figure are available in supplementary table 6.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003ePerceived Therapeutic Effectiveness\u003c/h2\u003e \u003cp\u003eThe vast majority of patients (over 90%) described the application of GBE as beneficial for the treatment or prevention of cognitive impairment regardless of age and gender or the circumstances for its use. Slightly less than half of these patients rated the level of effectiveness as \u0026ldquo;moderate - significant\u0026rdquo; (43.5%, n\u0026thinsp;=\u0026thinsp;83), around one in three patients (28.3%, n\u0026thinsp;=\u0026thinsp;54) as \u0026ldquo;minimal - mild\u0026rdquo; and just under a fifth (18.8%; n\u0026thinsp;=\u0026thinsp;36) as \u0026ldquo;very good - distinct\u0026rdquo;. Less than one out of 10 patients (9.4%, n\u0026thinsp;=\u0026thinsp;18) reported that they felt their condition was \u0026ldquo;unchanged or had worsened\u0026rdquo; after treatment. Those who took GBE for longer than 30 days or longer rated the effectiveness as significantly better (Mann-Whitney-U test: p\u0026thinsp;=\u0026thinsp;0.005**, r\u0026thinsp;=\u0026thinsp;0.21) than those who used the preparations for a shorter period. The vast majority of study participants (93.7%; n\u0026thinsp;=\u0026thinsp;149) reported that they perceived a therapeutic benefit when taking the medication for longer durations, almost half (45.9%) described the effectiveness as \u0026ldquo;moderate - significant\u0026rdquo; and one in five (21.4%) even as \u0026ldquo;very good - significant\u0026rdquo;. On the other hand, 25.0% (n\u0026thinsp;=\u0026thinsp;6) of the patients who took GBE for 8\u0026ndash;30 days perceived no therapeutic benefit (Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e9\u003c/span\u003e). Two persons in our sample took GBE for a very short period (0\u0026ndash;7 days) and were not included in the statistical analysis due to the small size of this group and the short duration of treatment (one patient perceived no therapeutic benefit, the other rated the efficacy as \u0026ldquo;minimal-mild\u0026rdquo;). All numerical data underlying the figure are available in supplementary table 7.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003ePerception of Tolerability Issues\u003c/h2\u003e \u003cp\u003eThe predominant portion (89.0%; n\u0026thinsp;=\u0026thinsp;170) of patients did not experience any adverse drug reactions when using GBE. Only about one in ten (9.4%; n\u0026thinsp;=\u0026thinsp;18) reported non-impairing tolerability issues. Tolerability issues associated with significant undesired effects were rare (1.0%, n\u0026thinsp;=\u0026thinsp;2) and only one person reported that undesired drug events outweighed therapeutic effectiveness (0.5%, n\u0026thinsp;=\u0026thinsp;1) (Fig.\u0026nbsp;\u003cspan refid=\"Fig10\" class=\"InternalRef\"\u003e10\u003c/span\u003e). All numerical data used to generate the figure are available in supplementary table 8.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTwo of the patients specified the tolerability issues in more detail: one of the patients complained of ear noise, which occurred a few minutes after taking the drug, and another patient reported itching, gastrointestinal complaints, headaches, and dizziness, which occurred after 14 days of taking GBE. A causal relationship with the use of GBE could not be established. However, the intake was discontinued after the occurrence of the tolerability issues.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe therapeutic efficacy and tolerability of HMPs based on a GBE for the treatment of cognitive impairment has been proven by numerous clinical studies (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). However, the transferability of these results to everyday medical practice can be challenging because multimorbid patients, people with complex health conditions or concomitant medication are usually underrepresented in clinical studies. Yet these groups are particularly frequently affected by cognitive impairment (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). There are only isolated records on how often multimorbid patients use GBE and how successful the therapy is. This lack of evidence on the actual effectiveness and tolerability in these vulnerable patients can lead to reservations among doctors regarding the prescription or recommendation. In consequence HMPs based on GBE are still underrepresented in therapy strategies although they are listed as a treatment option in the German S3 dementia guidelines (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAt the same time GBE preparations can be purchased over the counter or online by any patient without a doctor's diagnosis and prescription. As a result, many aspects of drug utilization and effectiveness or tolerability remain unrecorded. It is also difficult to monitor whether a thorough consultation with health professionals took place prior to self-medication.\u003c/p\u003e \u003cp\u003eIn our study we analyzed information from patients and users of GBE who treated or intended to prevent cognitive impairment thus providing insight into real-world self-medication practices. Our results provide information on drug utilization and perceived therapeutic benefits representing an important add-on to clinical studies.\u003c/p\u003e \u003cp\u003eWe observed that GBE was used both preventively and curatively (for acute and chronic symptoms). We showed that patients, regardless of age and gender, took GBE for the treatment or prevention of cognitive impairment - particularly frequently patients over the age of 50 and women. These results confirm previously observed trends captured by a health survey which found that already from the age of 45, every seventh person stated that they were concerned about their mental capacity. Women were affected more often than men, regardless of age (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn our study population about 10% of the participants stated to use GBE preventively without indicating any symptom load. We interpret this approach as primary prevention. In this context we observed that 3 times more women than man took GBE already before having symptoms of cognitive impairment and that women started taking GBE at a younger age. One possible explanation for this could be that women have a higher level of health literacy (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) and therefore possibly start prevention earlier.\u003c/p\u003e \u003cp\u003eNevertheless, the question arises as to whether it makes sense to take GBE before symptoms of cognitive impairment are present, as a primary preventive effect has not yet been clinically proven (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). On the other hand the methodological complexity of prevention studies such as the demanding study design, recruiting a sufficient sample size, long observation periods and suitable endpoints (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) suggest that it may never be possible to conclusively determine whether GBE exerts a primary preventive effect.\u003c/p\u003e \u003cp\u003eEven in the context of secondary data analyses, it remains difficult to clarify whether individuals can be recorded who never suffered from cognitive impairment because they had taken GBE preventively as self-medication. As in such cases neither a medical diagnosis nor a prescription has been made, these people are not registered in healthcare data (e.g. claims data). Although the argument of prevention is methodologically challenging, we conclude that the utilization of GBE for primary prevention among our study participants indicates a high level of trust.\u003c/p\u003e \u003cp\u003eIn our study cohort slightly less than one third reported to have used GBE preventively and at the same time indicated to have considerable symptoms of cognitive impairment. We assume that these participants took GBE to prevent pre-existing symptoms from worsening, which fits the definition of secondary prevention. This is well in line with previous studies reporting that GBE can slow down the progression of existing symptoms or that in the course of the disease, more severe forms occur less often (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWith more than 60% of our study population, patients who used GBE curatively made up the largest proportion, including cases with a considerable symptom load (levels 4 and 5).\u003c/p\u003e \u003cp\u003eThe use of HMPs in such cases indicates that patients have a high level of confidence in its effectiveness - despite advanced symptoms. This underlines the relevance of GBE in everyday practice as a treatment option alongside non-herbal medications such as memantine, which the guideline recommends for moderate to severe forms of dementia (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eUsing an appropriate dose of a medicine, at the right frequency, for the correct duration, is required for all medicines to optimize therapeutic effects (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). This also and especially applies to medicines used for self-medication. Here, a certain level of health literacy is a prerequisite for the patient to use the medicine correctly. In our study, we analyzed the treatment habits and adherence of GBE users for the first time using systematically and structured patient reports.\u003c/p\u003e \u003cp\u003eAdherence to GBE was very good regardless of whether the reason was treatment or prevention of cognitive impairment: GBE was used daily by almost all patients (\u0026gt;\u0026thinsp;97%). The majority of patients (over 85%) utilized GBE for longer than 30 days or for a longer undefined duration, however the latter could not be determined from the available data. It was therefore not possible to fully verify whether the patients adhered to the minimum intake duration of 8 weeks recommended in relevant literature (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). However, similar previous evaluations of a data set on self-medication for gynecological complaints showed that users largely followed the recommendations regarding the duration of use for HMPs (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn contrast, the dosage recommendation from the EMA/HMPC and dementia guidelines of 240 mg/day (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) were not always strictly adhered to: More than half of the participants in our sample reported a daily intake below that. This may be due to the fact that, for some of the preparations, the package inserts recommend lower doses in the range of 120\u0026ndash;240 mg per day.\u003c/p\u003e \u003cp\u003eHowever, it is well in line with previous reports on adherence to non-prescription medicines in self-medication, where over 60% of users stated that they were taking too low a dose (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). In our sample, we observed this effect particularly frequently in women (\u0026gt;\u0026thinsp;60%). In this context, a study from Slovenia found that women seem to be more cautious about self-medication than men, also with regard to dosage (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eA further reason for the underdosing of GBE may also be the relatively high price, as GBE is only reimbursed by statutory health insurance if a diagnosis of dementia is present (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eUnderdosing may partly be explained by concerns about side effects and potential drug interactions - factors that are particularly relevant in older adults (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). This tendency was also observed among our participants aged over 75 years. Given the high prevalence of polypharmacy in this age group (estimated at 40\u0026ndash;50%) (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e), dose reductions may also reflect a cautious self-regulatory approach to avoid adverse drug interactions.\u003c/p\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eEffectiveness and Tolerability\u003c/h2\u003e \u003cp\u003eThe vast majority of patients (over 90%) were convinced of the benefits of taking GBE for treating or preventing cognitive impairment. Notably, the subjectively perceived effectiveness increased significantly with longer duration of use. This is in line with existing recommendations to take GBE for at least eight weeks (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) in order to achieve therapeutically relevant effects. In addition to the high perceived effectiveness, tolerability was also rated positively by the majority of the respondents: Only about 11% reported adverse drug reactions, most of which were mild and did not impact daily life. More severe symptoms were reported by just 1.5% of participants (3 out of 191); however, in none of these cases could a clear causal link be established with GBE. In one case, the symptoms occurred 14 days after starting GBE and were therefore not even temporally associated with its use.\u003c/p\u003e \u003cp\u003eIn light of these findings, the risk-benefit ratio of GBE can be considered favorable. This assessment aligns with the results of randomized controlled trials, which have demonstrated both the therapeutic efficacy and good tolerability of HMPs including GBE compared to placebo or synthetic alternatives (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cem\u003eStrengths and Limitation\u003c/em\u003e \u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eWith over 20.000 participants, the PhytoVIS database currently constitutes the largest real-world data source on HMPs. It enables comprehensive cross-product and cross-indication analyses of the usage patterns, effectiveness and tolerability.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eBy including patients with polymedication \u0026ndash; who represent approximately 65% of our sample, PhytoVIS offers opportunities for data evaluations that go beyond the scope of clinical studies, which typically involve highly selected patient populations.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eAdditionally free text fields allow participants to report information that was not explicitly requested but is considered relevant from their perspective. This feature enables further qualitative analyses, which we utilized in the assessment of tolerability.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eParticipants were not required to have a formal medical diagnosis of cognitive impairment; instead, data were based on self-reported symptoms and perceived therapeutic benefits. While this approach may introduce recall bias or other forms of subjective bias, studies have shown that individuals with subjectively perceived memory decline often exhibit objectively measurable cognitive deficits (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eSince the surveys were conducted primarily in pharmacies and medical practices located in western Germany, the results cannot be fully generalized to the entire country or to populations beyond its borders (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eIt is also worth noting that women account for 67% of the total PhytoVIS database (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). The observed gender distribution suggests a potential sampling bias, representing a limitation to the generalizability of the findings.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eDue to the recruitment strategy, the study sample includes predominantly individuals with a positive attitude towards HMPs introducing a potential selection bias. Furthermore, a tendency known as 'effort justification' - where people rate a product more favorably after spending money on it - may have influenced the results, particularly the self-reported outcomes (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eAlthough the overall number of participants in the PhytoVIS study is large, the subgroup of GBE users with cognitive impairment is relatively small comprising only 191 individuals. As a results, statistical analysis of subgroup comparisons and potential influencing factors on effectiveness and tolerability revealed only small effect sizes. Larger sample sizes would be necessary to draw more robust conclusions.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eFurthermore, the data collection period (2014\u0026ndash;2016) limits the applicability of the findings to preparations approved after that time.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe study offers valuable insights into the usage patterns, as well as patients\u0026rsquo; self-assessed effectiveness and tolerability of GBE when used in self-medication for cognitive impairment. Our key observations include the following: GBE is commonly used not only for primary and secondary prevention, but also in the treatment of more pronounced symptoms.\u003c/p\u003e \u003cp\u003e The frequent and sustained use of GBE among participants suggests a high level of adherence. Doses lower than the recommended 240 mg/day were observed primarily among women and individuals over the age of 75. Overall, both the perceived effectiveness and tolerability of GBE were rated as good to very good, with serious adverse events were reported only rarely. These findings support a stronger integration of GBE into pharmacological strategies for the prevention and treatment of cognitive impairment.\u003c/p\u003e \u003cp\u003eThe results also highlight the need for further research into the factors influencing dosage - such as in the context of polymedication or gender / age - and into potential interactions that may affect the effectiveness and tolerability of GBE when taken alongside other (non-herbal) medications.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eGBE - \u003cem\u003eGinkgo biloba\u003c/em\u003e L., folium (ginkgo leaf) extract\u003c/p\u003e\n\u003cp\u003eChEIs \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;- \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Cholinesterase inhibitors\u003c/p\u003e\n\u003cp\u003eCDR-SB \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;-\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Clinical dementia rating – sum of boxes\u003c/p\u003e\n\u003cp\u003eHMPC \u0026nbsp;-\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Herbal Medicinal Products Committee\u003c/p\u003e\n\u003cp\u003eEMA \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;-\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;European Medicines Agency\u003c/p\u003e\n\u003cp\u003ePAQUID \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;-\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Personnes Agées QUId\u003c/p\u003e\n\u003cp\u003eHMP \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;-\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Herbal medicinal product\u003c/p\u003e\n\u003cp\u003eOTC \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;-\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Over the counter\u003c/p\u003e\n\u003cp\u003eIMSB\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;-\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Institute for Medical Statistics and Computational Biology\u003c/p\u003e\n\u003cp\u003eRWD \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;-\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Real-world data\u003c/p\u003e\n\u003cp\u003ePRO\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;-\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Patient-reported outcomes\u003c/p\u003e\n\u003cp\u003eENCePP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;-\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;European Network of Centres for Pharmacoepidemiology and\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Pharmcovigilance\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cem\u003eEthics Approval and Consent to Participate\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe Ethics Commission of the University Hospital of Cologne approved the project (reference: 14-101). \u003cstrong\u003e\u003cu\u003eThe ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards involving human participants were met. Inclusion criterion was the informed consent of the patient or caregiver before the individual interview.\u003c/u\u003e\u003c/strong\u003e The study protocol of PhytoVIS is registered in the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP).\u003c/p\u003e\n\u003cp\u003eClinical trial number: not applicable\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConsent for Publication\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAvailability of Data and Materials\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eData was extracted from the pharmaco-epidemiological database PhytoVIS which is owned by the Kooperation Phytopharmaka. Requests concerning the raw data has been addressed to the Kooperation Phytopharmaka. Analyzed Data supporting the results can be obtained from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCompeting Interest\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe authors affiliated at Goethe University, Institute of Pharmaceutical Biology, are funded by Dr.-Willmar-Schwabe. The funder had no role in the conceptualization, design, data collection, analysis, decision to publish, or preparation of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAuthors Contributions\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eBEB (corresponding author):\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConceptualization and design of the study, supervision and project administration, investigation, methodology, writing – original draft, presentation and visualization of results, substantial contribution to the conception, design and interpretation of the data, revising critically for important intellectual content, approval of the final version for submission, funding acquisition and resources\u003c/p\u003e\n\u003cp\u003eAJS (first author): Conceptualization and design of the study, data curation, formal analysis, investigation, methodology, presentation and visualization of results, software, validation, writing – original draft, substantial contribution to the conception, design and interpretation of the data, approval of the final version for submission\u003c/p\u003e\n\u003cp\u003eAD, SBF (co-authors): Substantial contribution to the conception, design and interpretation of the data, writing – revising critically for important intellectual content, approval of the final version for submission\u003c/p\u003e\n\u003cp\u003eRM (co-author): Planning and design of PhytoVIS database and the questionnaire, management of the data base and the data generation, data cleaning and statistics, writing -review and editing, approval of the final version for submission\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final version of the manuscript for submission.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe sincerely thank the Kooperation Phytopharmaka, Bonn, Germany, for providing access to the PhytoVIS data. We thank Dr. Olaf Kelber and Prof. Dr. Karin Kraft for the critical review of the manuscript and valuable intellectual contribution to the discussion. We are also grateful to the student assistants, Emilia Rappold and Lisa Küpper, from Dr. Svenja B. Frenzel’s team, for their support in assigning indications and categorizing the cases and Linrui Qian for his support in the classification and coding of the dosages.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBradfield NI. Mild Cognitive Impairment: Diagnosis and Subtypes. Clin EEG Neurosci. 2023;54(1):4\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAzam S, Haque ME, Balakrishnan R, Kim IS, Choi DK. The Ageing Brain: Molecular and Cellular Basis of Neurodegeneration. Front Cell Dev Biol. 2021;9:683459.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRobert-Koch-Institut. 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Bielefeld: Universit\u0026auml;t Bielefeld, Interdisziplin\u0026auml;res Zentrum f\u0026uuml;r Gesundheitskompetenzforschung; 2021.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVong SK, Kang L, Carter SR. Consumers' self-reported adherence to directions for non-prescription medicines and the role of risk perception. Res Social Adm Pharm. 2022;18(11):3929\u0026ndash;38.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKlemenc-Ketis Z, Hladnik Z, Kersnik J. A cross sectional study of sex differences in self-medication practices among university students in Slovenia. Coll Antropol. 2011;35(2):329\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGemeinsamer Bundesausschuss. Richtlinie des Gemeinsamen Bundesausschusses \u0026uuml;ber die Verordnung von Arzneimitteln in der vertrags\u0026auml;rztlichen Versorgung (Arzneimittel-Richtlinie/AM-RL). Bundesanzeiger Nr. 49a (Beilage) 31. 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Current state of research on the clinical benefits of herbal medicines for non-life-threatening ailments. Front Pharmacol. 2023;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePike KE, Cavuoto MG, Li L, Wright BJ, Kinsella GJ. Subjective Cognitive Decline: Level of Risk for Future Dementia and Mild Cognitive Impairment, a Meta-Analysis of Longitudinal Studies. Neuropsychol Rev. 2021;32(4):703\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTangen GG, Langballe EM, Strand BH. Subjective memory impairment, instrumental activities of daily living and longitudinal effect on mortality among older adults in a population-based cohort study: The HUNT Study. Scand J Public Health. 2019;48(8):825\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEsther Raskopf SS. Survey on experiences with phytopharmaceuticals via an online based questionnaire - Retrospective online survey. Institute of Medical Statistics, Informatics and Epidemiology (IMSIE) University Hospital Cologne; 2018.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHarmon-Jones E, Mills J. An introduction to cognitive dissonance theory and an overview of current perspectives on the theory. Cognitive dissonance: Reexamining a pivotal theory in psychology (2nd ed)2019. pp. 3\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-complementary-medicine-and-therapies","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcam","sideBox":"Learn more about [BMC Complementary Medicine and Therapies](https://bmccomplementmedtherapies.biomedcentral.com/)","snPcode":"","submissionUrl":"","title":"BMC Complementary Medicine and Therapies","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Cognitive impairment, Herbal medicinal products, Ginkgo biloba, Usage patterns, Medication adherence, Pharmacoepidemiology, Patient-reported-outcomes, Patient Care Management, Public Health, Real-world-data","lastPublishedDoi":"10.21203/rs.3.rs-8146289/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8146289/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eAlthough therapeutic efficacy and tolerability of \u003cem\u003eGinkgo biloba\u003c/em\u003e L. leaf extract (GBE) in cognitive impairment have been demonstrated in clinical trials, its use remains limited in everyday medical practice. Nevertheless, rather than being part of standard treatment strategies, GBE is often used in self-medication. As the therapeutic benefit of any medication depends on its appropriate use, real-world evidence on drug utilization is essential to ensure effective and safe therapy. However, real-world data on usage patterns, perceived effectiveness, and tolerability of GBE are still lacking.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis study evaluated data from 191 users of GBE collected via the PhytoVIS study. Information included demographics, reason for application (prevention, acute or chronic symptoms), usage patterns (dosage, frequency and duration of intake) as well as therapeutic outcomes like perceived therapeutic benefits and tolerability. Descriptive statistics and inferential tests (Chi-square test, Mann-Whitney-U test, Spearman correlation) were applied to analyze statistical relationships between variables.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eMost participants (over 60%) used GBE for chronic symptoms of cognitive impairment; about 40% for prevention. Nearly all (97.9%) reported daily intake, with over 85% using GBE for longer than 30 days. Older adults tended to take GBE longer. Over half of GBE-users took less than the recommended 240 mg daily dose, especially women and participants over 75. More than 90% perceived a therapeutic benefit, and effectiveness was positively correlated with longer use. Tolerability was rated favorably with mild adverse events reported by only around 10% - serious events were rare and not clearly linked to GBE.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe study demonstrates high adherence and perceived effectiveness and tolerability of GBE. Variations in daily doses among certain groups warrant further investigation, especially regarding potential polypharmacy interactions. Despite this, the generally positive findings support broader consideration of GBE in managing and preventing cognitive impairment.\u003c/p\u003e","manuscriptTitle":"Drug Utilization and Real-World Therapeutic Outcomes of Ginkgo biloba L. Leaf Extract in Prevention and Treatment of Cognitive Impairment","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-11 16:40:05","doi":"10.21203/rs.3.rs-8146289/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"89182835341648876135182649930382844038","date":"2026-02-11T11:45:20+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-06T11:09:05+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-01-19T11:52:55+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-21T08:46:06+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-21T08:45:54+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Complementary Medicine and Therapies","date":"2025-11-18T13:45:01+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-complementary-medicine-and-therapies","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcam","sideBox":"Learn more about [BMC Complementary Medicine and Therapies](https://bmccomplementmedtherapies.biomedcentral.com/)","snPcode":"","submissionUrl":"","title":"BMC Complementary Medicine and Therapies","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"47c22d67-51fe-4364-8471-9609dc1ea861","owner":[],"postedDate":"February 11th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-02-11T16:40:05+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-11 16:40:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8146289","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8146289","identity":"rs-8146289","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}