Abstract
We conducted a systematic review to analyze the design characteristics of registered clinical trials involving natural drugs for constipation and the specific types of herbs used in these trials. This review aims to provide valuable insights that can guide future clinical interventions and pharmaceutical advancements. This study was conducted according to the PRISMA 2020 guidelines. We systematically searched the ChiDTR, ChiCTR, ICTRP, and ClinicalTrials.gov databases for randomized controlled trials (RCTs) investigating natural drugs for constipation until March 31, 2025. An analysis of 114 RCTs revealed a strong correlation between the number of registered trials and their registration duration. Applicant units are predominantly located in China, Iran, and India. The majority of trials (78.9%) lacked sex specification, 78.0% implemented blinding, and 89.5% utilized a parallel design. Herbal formulations, especially those incorporating
Introduction
Constipation, a common gastrointestinal disorder affecting 12%-19% of individuals, 1 primarily presents as a defecation disorder and can be linked to various diseases or arise as an adverse effect of medications. 2 Constipation is typically characterized by reduced bowel movements, hard or dry stools, difficulty passing stools, less than three bowel movements per week, straining, incomplete evacuation, prolonged defecation, or manual assistance. 3 Current therapeutic approaches comprise bulking agents, osmotic and stimulant laxatives, and invasive approaches such as biofeedback therapy and surgery.2,4 Although these treatments are effective for short-term symptom relief, they often yield inadequate long-term outcomes, with high recurrence rates and significant side effects. Consequently, there is a growing interest in alternative therapies, such as natural drugs.5,6 Natural interventions, such as medicinal plants, tannic acid, and fiber supplements (eg, xyloglucan and pea proteins), have demonstrated efficacy in enhancing bowel function and gut integrity.7,8
Clinical trials are crucial for evaluating the effectiveness of treatments and developing new medications.9–11 Analyzing registered clinical trial data is essential for guiding future clinical practice. 12 Since the launch of ClinicalTrials.gov by the National Institutes of Health in 2000, it has encompassed approximately two-thirds of all globally registered clinical trials. 13 Subsequently, countries worldwide have developed their own platforms for clinical trial registration. In 2006, in response to a mandate from the World Health Assembly, the World Health Organization established the International Clinical Trials Registry Platform (ICTRP), linking 18 global clinical trial registration centers to access information on more than 200,000 clinical trials.14,15 On September 6, 2013, the China Food and Drug Administration released Announcement No. 28 on the drug clinical trial information platform, stipulating that all drug clinical trials must be registered and disclose information on the “Drug Clinical Trial Registration and Information Disclosure Platform (ChiDTR)” established at the Center for Drug Evaluation. 16 Thus, these platforms, including ClinicalTrials.gov, ICTRP, and ChiDTR, constitute the global landscape of clinical trial registration in this field.
Analyzing registered trials of novel therapeutic agents is crucial for gaining insights into their design, development, and potential limitations. Ensuring adequate registration and reporting of trials is essential to mitigate publication bias and selective reporting, thereby facilitating the translation of research findings into clinical practice. Notably, there is little research on the characteristics of clinical trials investigating natural drugs for constipation. Therefore, we conducted a systematic review to analyze the design characteristics of registered clinical trials involving natural drugs for constipation and the specific types of herbs used in these trials.
Material and Methods
Data Sources and Search Methods
This systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). 17 All databases were searched from the establishment of the databases to March 31, 2025, using tailored search strategies.
The search strategy for the ChiDTR database (http://www.chinadrugtrials.org.cn/) involved setting the “drug type” as “Chinese medicine/Natural drugs” and using “constipation” as the query term for “indications,” with all other parameters left at their default settings.
The search strategy employed for the ICTRP database (https://trialsearch.who.int/) involved setting the “Recruitment status” to “all” and specifying the “Condition” as “constipation or functional defecation disorders,” with all other parameters maintained at their default values.
The search strategy for the ClinicalTrials.gov database (https://clinicaltrials.gov/) included setting the “Condition/disease” parameter to “constipation” and the “Study Type” parameter to “Intervention.”
Inclusion and Exclusion Criteria
The conceptual framework of this study was delineated as follows: chronic constipation, characterized by symptoms persisting for a minimum duration of six months, can be classified into primary and secondary categories. 18 Primary constipation includes chronic idiopathic constipation (CIC), slow-transit constipation (STC), and rectal evacuation disorders. In contrast, secondary constipation, also referred to as functional constipation, arises in the absence of identifiable structural or biochemical abnormalities in the body. This category includes constipation induced by medications (eg, opioid-induced constipation [OIC]), hormonal changes (eg, constipation during pregnancy), electrolyte imbalances, psychiatric disorders, neurological disorders (eg, constipation in individuals with Parkinson's disease), aging, generalized muscle diseases, organic gastrointestinal diseases (eg, constipation associated with colorectal cancer), and irritable bowel syndrome with predominant constipation (IBS-C). 19
This study defines natural drugs for constipation as those explicitly specified in the clinical trial protocol, including herbal medicines, herbal extracts, and bioactive compounds derived from herbal sources through extraction and isolation. Synonyms for herbal medicines include herbal remedies, herbal medications, herbal products, herbal preparations, herbal formulas, medicinal herbs, and phytopharmaceuticals. 20
The inclusion criteria were as follows: (1) study design: Randomized Controlled Trials (RCTs) without restrictions on country, race, age, or sex, with language limited to Chinese and English. (2) Participants: Patients with a precise diagnosis of constipation, including CIC, OIC, IBS-C, acute idiopathic constipation (AIC), functional defecation disorders (FDDs), constipation during pregnancy, and constipation associated with Parkinson's disease. (3) Interventions: The trial group received natural drugs with or without chemical medication, with no limitations on the dosage or treatment duration. (4) Outcomes: Number of Complete Spontaneous Bowel Movements (CSBM) or bowel movements.
The exclusion criteria were as follows: (1) study type: observational study, expanded access, or surveys; (2) interventions: non-drug interventions, including device study, behavioral, procedure, biological, diagnostic test, and dietary supplement; (3) repeated publications; (4) terminated recruitment status; and (5) no comparison group.
Quality Assessment
The modified Jadad scale was used to evaluate the quality of the included RCTs. 21 The assessment specifically encompassed blinding, randomization, allocation concealment, and withdrawals; each was rated as ‘yes’, ‘no’, or ‘not reported’. Studies attaining a score ≥4 were classified as high quality; those scoring <4 were regarded as low quality. Trials determined to possess an unacceptably low quality were excluded.
Data Entry and Processing
The search results were imported into an Excel spreadsheet, and clinical trials were selected based on predefined inclusion and exclusion criteria. Data, including registration number, study type, registration date, applicant (sponsor), Chinese/natural drug name, and trial design (such as allocation method, intervention mode, blinding, trial phase, and total sample size), were documented for each clinical trial. The Formula of Chinese or natural drug names was primarily derived from registered clinical trial data. In addition, the PubMed, CNKI, and Wanfang databases were searched for this information. Data processing and analysis were conducted using SPSS version 22. Excel was used for graphical representation.
Results
Search Process and Results
The initial search identified 2675 results, comprising 29 from ChiDTR, 1778 from ICTRP, and 868 from ClinicalTrials.gov. After deduplication, 2184 studies were screened, leading to the exclusion of 1655 trials that did not meet the inclusion criteria. Subsequently, 529 studies underwent full-text review, and 149 clinical studies were ultimately included in the analysis (Figure 1).

Process of Searching and Screening Studies. ICTRP, International Clinical Trials Registry Platform (https://www.who.int/tools/clinical-trials-registry-platform); ChiDTR, Drug Clinical Trial Registration and Information Disclosure Platform (http://www.chinadrugtrials.org.cn).
Quality Assessment
Employing the modified Jadad scale for assessment, we excluded 25 trials scoring 0 points, 3 scoring 2 points, and 7 scoring 3 points, thereby identifying 114 high-quality RCTs (score ≥4) for further analysis. Among these 114 trials, allocation concealment was reported in 111 (97.3%), adequate reporting of blinding was present in the majority (91 trials; 79.8%), and proper follow-up reporting was observed in only 29 trials (25.4%). Regarding Jadad score distribution, the majority of trials (60; 52.6%) scored 6 points. A significant proportion (25 trials; 21.9%) scored 8 points. Trials scoring 5 or 7 points were less frequent, accounting for 3.5% and 6.1% respectively. Additionally, 18 trials (15.8%) scored 4 points. These findings are detailed in Figure 2.

Jadad Quality Scores for 114 High-Quality Randomized Controlled Trials (RCTs).
General Characteristics of the Included Trials
A total of 114 clinical trials focusing on natural drugs for constipation were analyzed, with the highest number of registrations observed in 2024, 2023, and 2020, totaling 18, 11, and 16, respectively (Figure 3A). For the registrations in 2006 and 2024, a linear equation was derived as Y = 0.4809X + 1.7647, with a regression coefficient (R2) of 0.322. Linear regression analysis revealed a statistically significant positive correlation between the number of clinical trial registrations for natural drugs targeting constipation and the progression of time in recent years, suggesting a marked increase in such registrations.

General Characteristics of Clinical Trials Involving Natural Drugs for Constipation (n = 114). (A) Distribution of Declaration Time for Clinical Trials; (B) Distribution of Centers for Clinical Trial Registration; (C) Distribution of Countries of Applicants.
Analysis of clinical trial registry platform distribution demonstrated a statistically significant difference (
Regarding the registration status of clinical trials, significant differences were observed (

Distribution of Registration Status of Clinical Trials and Types for Constipation (n = 114).
The Design Characteristics Included Clinical Trials
Analysis of the 114 RCTs revealed that the majority (78.9%) imposed no sex requirement. Among these RCTs, 78.0% utilized blinding methods, with 52.6% employing double-blinding. An intervention mode using a parallel design was implemented in 89.5% of trials. Concerning participant demographics, adults were the focus in 76.3% of trials, whereas children and elderly individuals were involved in 13.2% and 4.4% of trials, respectively. A significant proportion of trials (24.6%) omitted phase specification; conversely, among trials that declared a phase, phases 2 and 3 accounted for 27.2% and 30.7%, respectively. Of the sample size, 43.9% of the trials recruited 51-100 cases, and 15.8% recruited ≤50 cases (Figure 5). Most registered clinical trials on natural remedies for constipation adhere to high-quality standards, meeting criteria such as randomization, blinding, parallel design, and appropriate sample size selection. These criteria reflect rigorous and well-controlled methods.

Design Characteristics of Clinical Trials Involving Natural Drugs for Constipation Registered on the Global Clinical Trials Registry Platform (n = 114).
Herbal Formula and Associated Herbal Origins
Analysis of the 114 RCTs revealed that 58 did not identify a Herbal Formula, while the remaining 56 yielded 42 distinct Herbal Formulas (Table 1). Notably, Herbal Formulas including Daikenchuto (TU-100), MaZiRenWan, Tong Li Changrong Capsule, and Xiao Er Bian Tong Granules recorded the highest registration frequencies. Among these 42 Herbal Formulas, the top six by application frequency comprised
Origin and Usage Frequency of Herbal Formulas (n = 56).
Note: Within the domain of 114 drug clinical trials, 58 were unsuccessful in obtaining a Herbal Formula, and the remaining 56 trials resulted in a collective sum of 42 Herbal Formulas. Of the 56 clinical trials, 34 were identified using a single registration number.
The Distribution of Sources of Herbal Medicine.
Discussion
The global incidence of non-communicable diseases (NCDs), such as diabetes, cardiovascular issues, 30 and cancer, is increasing, leading to an increased risk of constipation due to medication use and other medical conditions. 31 This study identified a direct correlation between the number of clinical trial registrations of natural drugs for constipation and registered years, highlighting a substantial increase in registrations in this domain. This trend in registrations likely reflects the expanding interest in natural drugs for treating constipation within the scientific community. Natural remedies are increasingly recognized for their potential in managing constipation worldwide, offering a safer alternative to conventional pharmaceuticals with fewer adverse effects and a more comprehensive approach to symptom relief than traditional pharmaceuticals. Recent clinical trials have been conducted to ascertain the effectiveness and optimal dosage of natural constipation remedies across various constipation subtypes.32,33
Geographically, Asia demonstrated a substantially higher proportion of applicants relative to other continents, especially East Asia. China, Iran, and India emerged as the principal contributors, constituting 32.5%, 28.1%, and 13.2% of the total applicants, respectively. This distribution reflects the prevalent use of Ayurveda and TCM within Asia. Ayurveda, an ancient medical system tracing its origins thousands of years to the Vedic era in the Indian subcontinent, encompasses classical and proprietary formulations composed of single or multiple herbs administered in various forms, such as juice, extract, powder, tablet, or decoction.34,35 TCM, another ancient medical system characterized by its personalized, holistic, and multicomponent therapeutic paradigm, has been pervasively practiced across Asia for centuries. Chinese Herbal Medicine (CHM) represents a core element of TCM, involving sliced herbs and patented Chinese remedies.36,37
This study revealed that over half of the clinical trials did not recruit participants. Despite the historical use of natural remedies for constipation in Ayurveda and TCM, clinical drug trials remain in the early stages. This study also showed that 54.4% of the projects did not specify constipation categories, whereas 36.8% targeted functional constipation. This may be linked to the predominant clinical application of TCM formulas, characterized by their holistic approach, grounded in randomized, double-blind trials, and placebo-controlled research, which stands as a focal point and challenge in present-day Ayurveda and TCM. 36 Integrating traditional and contemporary medical classifications of constipation is challenging because of the differing paradigms and methodologies. Traditional medicine categorizes diseases holistically, focusing on bodily balance and energy flow, whereas modern medicine relies on physiological and anatomical criteria. This divergence complicates alignment, particularly for constipation, which is a complex condition with diverse subtypes and causes. To address this issue, clinical trials should clearly delineate and separately document disease classifications from both perspectives.
Pregnant women and children are frequently excluded from clinical trials.38,39 This study identified eight studies on the treatment of constipation in children and five studies focusing on constipation during pregnancy. Constipation is the most prevalent issue among pediatric gastrointestinal disorders, affecting approximately 20% of children worldwide. Treatment strategies include dietary control, behavioral interventions, oral laxatives, and rectal laxatives. Polyethylene glycol (PEG) laxatives are the primary treatment for childhood constipation because of their high efficacy and minimal adverse effects. However, favored PEG laxatives have limited efficacy, necessitating supplementary therapeutic measures. Due to unsatisfactory treatment responses, numerous patients have explored natural treatment options. 40
This investigation delineated the most prevalent botanical agents employed in constipation therapy, encompassing
This study identified two food most frequently used in treating constipation, including
This study had several limitations. First, the exclusion of functional foods classified as natural drugs resulted in limitations that restricted the generalizability of the systematic review. Second, this study focused on analyzing prescription patterns and clinical trial methodologies rather than assessing the therapeutic outcomes or safety parameters of the evaluated interventions. Third, the absence of PROSPERO registration or deposition in methodological repositories reflects a limitation in protocol development, as standardized frameworks for this analytical approach were unavailable at the time of study conception. Finally, this study did not include a bias analysis or meta-analysis to assess the therapeutic efficacy and safety of individual herbal medicinal agents for treating constipation and its subcategories.
Future investigations will systematically evaluate the pharmacotherapeutic agents and botanical formulations prioritized in this work via rigorous systematic reviews and meta-analyses to validate their efficacy. Implementing a globally collaborative research framework is paramount; this necessitates integrating traditional medicinal knowledge, indigenous linguistic contexts, and foundational theoretical constructs drawn from diverse traditional medical systems, harmonizing outcome measures, and prioritizing underrepresented populations. Consequently, we propose establishing a global consortium to exhaustively appraise natural pharmacotherapies for constipation through the concerted integration of perspectives across multiple traditional medicinal disciplines.
Conclusion
This study highlights an annual increase in the number of clinical trial registrations for natural drugs targeting constipation, reflecting a growing interest in natural remedies, particularly in countries such as Iran, India, and China, where traditional medicine drives relevant research. However, some trials lack precision in categorizing constipation subtypes, affecting their practicality. Botanicals such as
Footnotes
Acknowledgements
Not applicable.
Ethical Statement
This review article does not require ethical approval or informed consent, as it is based on existing literature.
Informed Consent/Patient Consent
There are no human subjects in this study, and informed consent is not applicable.
Trial Registration Number/Date
Not applicable.
Grant Number
Not applicable.
CRediT Authorship Contribution Statement
Mei Yan: Investigation, Formal analysis, Writing-original draft, Funding acquisition. Chunhua Wu: Investigation, Writing-original draft. Wansu Xu: Formal analysis, Writing-review & editing. Ganxue Tao: Investigation, Supervision, Writing-review & editing. Zhenghua Fei: Conceptualization, Funding acquisition, Supervision, Writing-review & editing. Hao Jiang: Conceptualization, Funding acquisition, Supervision, Writing-review & editing.
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by the Program of Zhejiang Provincial TCM Sci-tech Plan (2023ZL506), Natural Science Foundation of China (82174018), Zhejiang Provincial Natural Science Foundation of China (LMS25H280007), and Chinese Medicine Science and Technology Project of Jinhua City (2023KY06).
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Data Availability Statement
All data analyzed during this study are included in this manuscript. Data will be made available on request.
