Progress in Natural Drugs for Constipation Registered on Global Clinical Trials Registry Platform: A Systematic Review

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 Citrus × aurantium, Cortex Magnoliae officinalis, Atractylodes macrocephala Koidz., Cannabis sativa L., Rheum palmatum L., and Semen armeniacae amarum, were most frequently applied. Botanicals exhibit substantial pharmacotherapeutic potential against constipation. Nations with highly developed traditional medicine practices, including China, Iran, and India, should initiate cross-cultural discourse rooted in their respective traditional medical frameworks. Collaborative research endeavors targeting distinct subcategories of constipation are imperative for continued development in this field.

Keywords

ayurvedic defecation irritable bowel syndrome traditional Chinese medicine natural drug

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).

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.

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.

Figure 3.

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. P-Value Based on Chi-Square Test.

Analysis of clinical trial registry platform distribution demonstrated a statistically significant difference (P < .001), with IRCT representing the largest proportion (32; 28.1%), followed by ClinicalTrials.gov (20; 17.5%) and ChiDTR (18; 15.8%) (Figure 3B). Analysis of the geographic distribution of applicants for herbal constipation medications enrolled in the global clinical trial registry platform demonstrated that Asia comprised a significantly higher proportion than the Americas, Oceania, and Europe (P < .001). Further analysis revealed that East Asia surpassed South Asia and West Asia (P < .001). Applicants from China, Iran, and India collectively constituted the majority, accounting for 32.5%, 28.1%, and 13.2% of the total applicants, respectively (Figure 3C).

Regarding the registration status of clinical trials, significant differences were observed (P < .001). A majority (55.0%) were categorized as “not recruiting,” while 30.2% were actively recruiting and 14.8% had been completed. Of the 114 clinical trials, marked differences emerged (P < .001): 54.4% were uncategorized (35.6% addressing constipation and 6.0% focusing on chronic constipation), whereas 36.8% explicitly focused on functional constipation. Notably, 15 clinical trials addressed constipation in the pediatric population, and four clinical trials targeted constipation during pregnancy (Figure 4).

Figure 4.

Distribution of Registration Status of Clinical Trials and Types for Constipation (n = 114). P-Value Based on Chi-Square Test.

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.

Figure 5.

Design Characteristics of Clinical Trials Involving Natural Drugs for Constipation Registered on the Global Clinical Trials Registry Platform (n = 114). P-Value Based on Chi-Square Test.

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 Citrus × aurantium L., Magnoliae officinalis Cortex, Atractylodes macrocephala Koidz., Cannabis sativa L., Rheum palmatum L., and Semen armeniacae amarum (Table 2).

Table 1.

Origin and Usage Frequency of Herbal Formulas (n = 56).

Name of Drugs	Number of registrations n(%)	Formula Origin
Daikenchuto (TU-100)	4 (7.1%)	Iturrino et al ²²
MaZiRenWan	3 (5.4%)	Huang et al²³
Tong Li Changrong Capsule	3 (5.4%)	Yuexiang Feng ²⁴
Xiao Er Bian Tong Granules	3 (5.4%)	Yan Wang²⁵
Aster tataricus and Raphani Semen	2 (3.6%)	Information on Clinical Trial Registration
Actinidia Deliciosa	2 (3.6%)	Information on Clinical Trial Registration
Chinese Herbal Formula (CCH1)	2 (3.6%)	Huang et al²⁶
Cong Rong Run Tong Oral Liquid	2 (3.6%)	Information on Clinical Trial Registration
Shou Hui Tong Bian capsule	3 (2.5%)	Hongbao Liang et al²⁷
Daikenchuto (TJ-100)	1 (1.8%)	Horiuchi et al²⁸
Xing Qi Tannikaer Capsule	1 (1.8%)	Yuan Luo et al²⁹

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.

Table 2.

The Distribution of Sources of Herbal Medicine.

Botanical name	Frequency, n (%)
Citrus × aurantium L.	21 (9.0%)
Magnoliae officinalis Cortex	11 (4.7%)
Atractylodes macrocephala Koidz.	10 (4.3%)
Cannabis sativa L.	9 (3.8%)
Rheum palmatum L.	9 (3.8%)
Semen armeniacae amarum	9 (3.8%)
Aloe vera (L.) Burm. F.	7 (3.0%)
Paeonia lactiflora PALL.	7 (3.0%)
Zingiber officinale Rose.	7 (3.0%)
Panax ginseng C. A. Mey.	6 (2.6%)
Rheum tanguticum Maxim ex Balf.	6 (2.6%)
Cassia obtusifolia L. or Cassia tora L.	5 (2.1%)
Cistanche deserticola Y.C.Ma	5 (2.1%)
Raphanus sativus L.	5 (2.1%)

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 Citrus × aurantium L., Magnoliae officinalis Cortex, Atractylodes macrocephala Koidz. Citrus × aurantium L. is a preeminent Qi-activating herb in traditional Chinese medicine, with millennia of documented use for its potent regulation of Qi dynamics and tonification of the spleen and stomach (Pharmacopoeia Committee of PR China, 2020).⁴¹ Flavonoids derived from Citrus × aurantium, particularly naringin, nobiletin, and hesperidin, exhibit pronounced anti-inflammatory properties. These compounds exert their anti-inflammatory effects through the suppression of NF-κB and COX-2 expression, thereby attenuating the synthesis of pro-inflammatory cytokines. This protective mechanism preserves colonic mucosal integrity in trinitrobenzene sulfonic acid (TNBS)-induced ulcerative colitis models.^42,43 Additionally, these flavonoids enhance intestinal motility by modulating small intestinal contractile activity.⁴² Citrus × aurantium extract also demonstrates a significant capacity for modulating gut microbiota. Empirical studies have confirmed its role in enhancing microbial diversity, correcting high-fat diet-induced dysbiosis, promoting beneficial bacterial taxa, and reducing the prevalence of pathobionts.⁴⁴

Magnoliae officinalis cortex have been used in folklore medicine for thousands of years in Asia.⁴⁵ Moreover, Magnoliae officinalis cortex is listed in the newest European Pharmacopoeia 9.0 as an official pharmaceutical raw plant material in Europe.⁴⁶ The primary components of Magnolia officinalis, magnolol and honokiol, demonstrate significant efficacy in modulating intestinal smooth muscle contraction. This activity occurs predominantly via activation of 5-hydroxytryptamine (5-HT) receptors within the enteric plexus. Investigations confirm that 5-HT fulfills a critical neuromodulatory role there, influencing multiple physiological functions including intestinal motility, secretion, and inflammatory responses.⁴⁷ Intestinally, 5-HT exerts its effects chiefly through 5-HT3 and 5-HT4 receptors, which are essential for mediating smooth muscle contraction and peristalsis.^48,49 Regarding clinical applications, the functions of magnolol and honokiol encompass not only intestinal smooth muscle modulation but also inhibition of intestinal inflammation. Research establishes that these compounds safeguard intestinal mucosal integrity through modulating gut microbiota and suppressing inflammatory factor expression.⁵⁰ Moreover, magnolol and honokiol modify overall intestinal function by altering signal transduction in the enteric nervous system, thereby establishing a theoretical basis for their therapeutic use in intestinal dysfunctions.^51,52

This study identified two food most frequently used in treating constipation, including Actinidia Deliciosa and Cassia obtusifolia, Plantago Asiatica. Actinidia Deliciosa, commonly known as Kiwifruit (Actinidia deliciosa var. Hayward), is a highly nutritious fruit abundant in vitamin C, water, and dietary fiber. The fiber in Actinidia Deliciosa exhibits unique properties, including significant water retention capacity and swelling capacity, which may aid in reducing bowel mixing and diffusion, thereby promoting fecal bulking within a well-rounded diet. Furthermore, Actinidia Deliciosa is noteworthy for its protein content, which is rich in essential amino acids, such as glutathione, arginine, and γ-amino butyric acid, and contains moderate levels of serotonin, tryptophan, and tryptamine. These findings highlight the multifaceted potential of Actinidia Deliciosa in the management of constipation. Actinidia Deliciosa may impact constipation through various mechanisms, such as promoting motility via protease-activated signaling, modulating the gut microbiota, affecting colonic methane levels and bile flow, or regulating inflammatory pathways.⁵³ Cassia obtusifolia L., a member of the Leguminosae family, has significant therapeutic value in traditional medicine. The seeds of this renowned medicinal plant in East Asia are ingested to alleviate liver heat, enhance eyesight, moisten the intestines, and stimulate bowel movements. These seeds are rich in anthraquinones, naphthopyrones, and lipid derivatives, which exhibit diverse biological activities that may affect human health.⁵⁴ Cassia obtusifolia L. is commonly used in traditional medicine as a gentle laxative for children and pregnant women. A study comparing Cassia Fistula Syrups with mineral oil in the treatment of functional constipation in children found the former to be more effective. Furthermore, the efficacy of Cassia Fistula Syrups in treating functional constipation in children was comparable to that of PEG.⁵⁵

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 Citrus × aurantium L., Magnoliae officinalis cortex demonstrate potential in addressing constipation. Despite these limitations, this study highlights the potential of natural drugs for treating constipation and calls for more high-quality research to improve patient outcomes in this area.

Footnotes

Acknowledgements

Not applicable.

ORCID iD

Hao Jiang

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.

References

Gras-Miralles

Cremonini

. A critical appraisal of lubiprostone in the treatment of chronic constipation in the elderly. Clin Interv Aging. 2013;8:191–200. doi:10.2147/cia.S30729. 20130215.

Wald

. Constipation. JAMA. 2016;315:185–185. doi:10.1001/jama.2015.16994

Drossman

. The functional gastrointestinal disorders and the Rome III process. Gastroenterology. 2006;130:1377–1390. doi:10.1053/j.gastro.2006.03.008

Chang

Lembo

Sultan

. American Gastroenterological association institute technical review on the pharmacological management of irritable bowel syndrome. Gastroenterology. 2014;147:1149–1172.e1142. doi:10.1053/j.gastro.2014.09.002

Yan

Liu

Yan

, et al. Effect of traditional Chinese medicine external therapy for functional constipation: a meta-analysis. Am J Transl Res. 2023;15(1):13–26.

Wang

Hong

, et al. Research progress in the treatment of slow transit constipation by traditional Chinese medicine. J Ethnopharmacol. 2022;290:115075. doi:10.1016/j.jep.2022.115075

Dae Youn

. Therapeutic role of natural products containing tannin for treatment of constipation. In: Gyula

, ed. Constipation. IntechOpen; 2018:Ch. 5.

Filippone

Ardizzone

Bova

, et al. A combination of xyloglucan, pea protein and chia seed ameliorates intestinal barrier integrity and mucosa functionality in a rat model of constipation-predominant irritable bowel syndrome. J Clin Med. 2022;11(23):7073. doi:10.3390/jcm11237073

Feizabadi

Fahimnia

Mosavi Jarrahi

, et al. Iranian Clinical trials: an analysis of registered trials in international clinical trial registry platform (ICTRP). J Evid Based Med. 2017;10:91–96. doi:10.1111/jebm.12248

10.

Chen

Quan

, et al. Clinical trials focusing on drug control and prevention of ventilator-associated pneumonia: a comprehensive analysis of trials registered on ClinicalTrials.gov. Front Pharmacol. 2019;9. doi:10.3389/fphar.2018.01574

11.

Jacobsen

Wells

Meade

, et al. Effects of a brief multimedia psychoeducational intervention on the attitudes and interest of patients with cancer regarding clinical trial participation: a multicenter randomized controlled trial. J Clin Oncol. 2012;30:2516–2521. doi:10.1200/JCO.2011.39.5186

12.

Šaler

Viđak

Puljak

. Methodology of clinical trials on sodium-glucose cotransporter 2 inhibitors registered on ClinicalTrials.gov: a cross-sectional study. BMC Med Res Methodol. 2024;24:164. doi:10.1186/s12874-024-02292-5

13.

Zarin

Tse

Williams

, et al. Update on trial registration 11 years after the ICMJE policy was established. N Engl J Med. 2017;376:383–391. doi:10.1056/NEJMsr1601330

14.

Sun

Lee

Collins

, et al. Assessment of consistency between peer-reviewed publications and clinical trial registries. JAMA Ophthalmol. 2019;137:552–556. doi:10.1001/jamaophthalmol.2019.0312

15.

Merson

Ndwandwe

Malinga

, et al. Promotion of data sharing needs more than an emergency: an analysis of trends across clinical trials registered on the international clinical trials registry platform. Wellcome Open Res. 2022;7:101. doi:10.12688/wellcomeopenres.17700.1

16.

Huang

Wang

Fan

, et al. Introducing the platform for registry and publicity of drug clinical trials and analyzing the common questions in trial registry. Chinese Journal of New Drugs. 2014;23(23):4.

17.

Page

McKenzie

Bossuyt

, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Br Med J. 2021;372:n71. doi:10.1136/bmj.n71

18.

Association tGGoTDDBoCM . Chinese Guidelines for diagnosis and treatment of chronic constipation (2013, Wuhan). Chin J Gastroenterol. 2013;18:605–612. doi:10.3969/j.issn.1008-7125.2013.10.007

19.

Camilleri

Ford

Mawe

, et al. Chronic constipation. Nat Rev Dis Primers. 2017;3:17095. doi:10.1038/nrdp.2017.95

20.

Cui

Trinh

Wang

. Chinese Herbal medicine for chronic neck pain due to cervical degenerative disc disease. Cochrane Database Syst Rev. 2010;2010:Cd006556. doi:10.1002/14651858.CD006556.pub2

21.

Jadad

Moore

Carroll

, et al.

Assessing the quality of reports of randomized clinical trials: is blinding necessary?

Control Clin Trials. 1996;17:1–12. doi:10.1016/0197-2456(95)00134-4

22.

Iturrino

Camilleri

Wong

, et al. Randomised clinical trial: the effects of daikenchuto, TU-100, on gastrointestinal and colonic transit, anorectal and bowel function in female patients with functional constipation. Aliment Pharmacol Ther. 2013;37:776–785. doi:10.1111/apt.12264

23.

Huang

Ning

, et al. Uncovering the mechanisms of Chinese herbal medicine (MaZiRenWan) for functional constipation by focused network pharmacology approach. Front Pharmacol. 2018;9:270. doi:10.3389/fphar.2018.00270

24.

Yuexiang

. Evaluation of clinical efficacy of Tong Li Changrong Capsule in the treatment of chronic functional constipation. Chinese Academy of Traditional Chinese Medicine; 2011.

25.

Wang

. Clinical research on Xiao’er Biantong granule for functional constipation of dyspepsia type. Chengdu University of Traditional Chinese Medicine; 2014.

26.

Huang

C-H

Y-C

T-C

, et al. Treatment of constipation in long-term care with Chinese herbal formula: a randomized, double-blind placebo-controlled trial. The Journal of Alternative and Complementary Medicine. 2011;17:639–646. doi:10.1089/acm.2010.0150

27.

Liang

Sun

Jiang

, et al. Study on quality markers of Shouhui Tongbian capsule based on GC-MS and UPLC-Q-exactive MS technology. Chinese Traditional and Herbal Drugs. 2022;53:6674–6685. doi:10.7501/j.issn.0253-2670.2022.21.004

28.

Horiuchi

Nakayama

Tanaka

. Effect of traditional Japanese medicine, daikenchuto (TJ-100) in patients with chronic constipation. Gastroenterology Res. 2010;3:151–155. doi:10.4021/gr219w

29.

Luo

Fang

Wang

, et al. Identification of Xingqi Tannikaer capsule and determination of Borax. West China Journal of Pharmaceutical Sciences. 2008;23(02):237–238. doi:10.3969/j.issn.1006-0103.2008.02.050

30.

Rabail

Sultan

Khalid

, et al. Clinical, nutritional, and functional evaluation of chia seed-fortified muffins. Molecules. 2022;27. doi:10.3390/molecules27185907

31.

Bellini

Tonarelli

Barracca

, et al. Chronic constipation: is a nutritional approach reasonable?. Nutrients. 2021;13. doi:10.3390/nu13103386

32.

Zhou

Wang

Sun

, et al. Effects of natural products on functional constipation: analysis of active ingredient and mechanism. Naunyn-Schmiedeberg’s Arch Pharmacol. 2024;397:2083–2103. doi:10.1007/s00210-023-02786-x

33.

Wang

Sawadogo

, et al. Herbal medicines for constipation and phytochemical comparison of active components. Am J Chin Med. 2022;50:723–732. doi:10.1142/s0192415x2250029x

34.

, et al. Comparison of medicinal preparations of ayurveda in India and five traditional medicines in China. J Ethnopharmacol. 2022;284:114775. doi:10.1016/j.jep.2021.114775

35.

Jaiswal

Liang

Zhao

. Botanical drugs in ayurveda and traditional Chinese medicine. J Ethnopharmacol. 2016;194:245–259. doi:10.1016/j.jep.2016.06.052

36.

Zhang

Wang

, et al. A comprehensive review of integrative pharmacology-based investigation: a paradigm shift in traditional Chinese medicine. Acta Pharm Sin B. 2021;11:1379–1399. doi:10.1016/j.apsb.2021.03.024

37.

Xiang

Guo

Zhu

, et al. Traditional Chinese medicine as a cancer treatment: modern perspectives of ancient but advanced science. Cancer Med. 2019;8:1958–1975. doi:10.1002/cam4.2108

38.

Sewell

Sheehan

Gill

, et al. Scientific, ethical, and legal considerations for the inclusion of pregnant people in clinical trials. Am J Obstet Gynecol. 2022;227:805–811. doi:10.1016/j.ajog.2022.07.037

39.

Swain

. Clinical trials for children: some concerns. Indian J Pharmacol. 2014;46:145–146. doi:10.4103/0253-7613.129300

40.

Qiao

Wang

, et al. A randomized, double-blind, and placebo-controlled trial of Chinese herbal medicine in the treatment of childhood constipation. Clin Transl Gastroenterol. 2021;12:e00345. doi:10.14309/ctg.0000000000000345

41.

Yuan

Wei

Luo

, et al. Multi-component comparative pharmacokinetics in rats after oral administration of Fructus aurantii extract, naringin, neohesperidin, and naringin-neohesperidin. Front Pharmacol. 2020;11:933. doi:10.3389/fphar.2020.00933

42.

Liu

, et al. Citrus aurantium L. and its flavonoids regulate TNBS-induced inflammatory bowel disease through anti-inflammation and suppressing isolated jejunum contraction. Int J Mol Sci. 2018;19. doi:10.3390/ijms19103057

43.

Liu

, et al. Flavonoids from Citrus aurantium ameliorate TNBS-induced ulcerative colitis through protecting colonic mucus layer integrity. Eur J Pharmacol. 2019;857:172456. doi:10.1016/j.ejphar.2019.172456

44.

Shen

Wan

Wang

, et al. Citrus aurantium L. var. amara Engl. inhibited lipid accumulation in 3T3-L1 cells and caenorhabditis elegans and prevented obesity in high-fat diet-fed mice. Pharmacol Res. 2019;147:104347. doi:10.1016/j.phrs.2019.104347

45.

Lee

, et al. Therapeutic applications of compounds in the Magnolia family. Pharmacol Ther. 2011;130:157–176. doi:10.1016/j.pharmthera.2011.01.010

46.

Elansary

Szopa

Kubica

, et al. Phenolic compounds of catalpa speciosa, Taxus cuspidate, and magnolia Acuminata have antioxidant and anticancer activity. Molecules. 2019;24. doi:10.3390/molecules24030412

47.

Liu

Sun

Wang

, et al. The mechanism of secretion and metabolism of gut-derived 5-hydroxytryptamine. Int J Mol Sci. 2021;22. doi:10.3390/ijms22157931

48.

Liu

Ohya

Nishizawa

, et al. Serotonin augments gut pacemaker activity via 5-HT3 receptors. PLoS One. 2011;6:e24928. doi:10.1371/journal.pone.0024928

49.

Kato

. Role of serotonin 5-HT₃ receptors in intestinal inflammation. Biol Pharm Bull. 2013;36:1406–1409. doi:10.1248/bpb.b13-00363

50.

Miao

Zhang

Wang

, et al. Magnolol pretreatment prevents sepsis-induced intestinal dysmotility by maintaining functional interstitial cells of Cajal. Inflammation. 2013;36:897–906. doi:10.1007/s10753-013-9617-z

51.

Zhu

, et al. Gut microbiota drives macrophage-dependent self-renewal of intestinal stem cells via niche enteric serotonergic neurons. Cell Res. 2022;32:555–569. doi:10.1038/s41422-022-00645-7

52.

Mandić

Woting

Jaenicke

, et al. Clostridium ramosum regulates enterochromaffin cell development and serotonin release. Sci Rep. 2019;9:1177. doi:10.1038/s41598-018-38018-z

53.

Bayer

Gearry

Drummond

. Putative mechanisms of kiwifruit on maintenance of normal gastrointestinal function. Crit Rev Food Sci Nutr. 2018;58:2432–2452. doi:10.1080/10408398.2017.1327841

54.

Ali

Park

Chang

. Phytochemistry, ethnopharmacological uses, biological activities, and therapeutic applications of Cassia obtusifolia L.: a comprehensive review. Molecules. 2021;26(20):6252. doi:10.3390/molecules26206252

55.

Esmaeilzadeh

Tahmasebi

Shirafkan

, et al. Efficacy of Cassia fistula syrup on constipation in pregnant women: an open-label controlled randomised clinical trial. J Herb Med. 2023;42:100794. doi:10.1016/j.hermed.2023.100794