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Table of Contents
REVIEW ARTICLE
Year : 2021  |  Volume : 4  |  Issue : 4  |  Page : 243-250

Clinical research on cinnamomi cortex: A scoping review


1 Mi Healing Healthcare Centre, Petaling Jaya 47301, Malaysia
2 School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Pharmaceutical Services Program, Ministry of Health, Selangor 46200, Malaysia
3 School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203; Engineering Research Centre of Shanghai Colleges for TCM New Drug Discovery, Shanghai 201203, China

Date of Submission18-Sep-2021
Date of Acceptance05-Nov-2021
Date of Web Publication28-Dec-2021

Correspondence Address:
Prof. Hong-Xi Xu
Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203; Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai 201203
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CMAC.CMAC_42_21

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  Abstract 


There are over 250 species of cinnamon. Each has its distinct morphology and phytochemical composition, which may result in varied therapeutic effects. However, clinical studies have rarely put emphasis on the species of cinnamon being investigated. This scoping review summarized the clinical evidence of Cinnamomum cassia (also known as Cinnamomum aromaticum), which is the species of cinnamon used in traditional Chinese medicine. Electronic searches were conducted on PubMed from its inception till August 2021. Clinical studies that were published in English, stating monotherapy with Cinnamomum cassia, Cinnamomum aromaticum, or “Rou Gui” were included. The 15 included clinical studies investigated the effects of Cinnamomum cassia on type-2 diabetes patients (n=7), and healthy adults (n=8). In the type 2 diabetes population, Cinnamomum cassia supplementation of as low as 1 g/d seemed to improve HbA1c in only poorly controlled diabetes. In the healthy population, Cinnamomum cassia supplementation appeared to influence blood glucose response in a dose-dependent manner, with current studies indicating a minimum of 5 g/d to achieve significant improvement. Studies also showed potential improvement in insulin sensitivity with prolonged Cinnamomum cassia supplementation. However, there were apparent heterogeneity among studies and uncertainties regarding the accuracy of reported cinnamon species. Therefore, the therapeutic effects of Cinnamomum cassia remain inconclusive. Future larger scale and more rigorous clinical studies, with clear identification of Cinnamomum species used, are needed for more conclusive evidence of the clinical effects of Cinnamomum cassia.

Keywords: Cinnamomum cassia, Cinnamo, Rou Gui, review, clinical trial


How to cite this article:
Tan HY, Nabil WN, Xu HX. Clinical research on cinnamomi cortex: A scoping review. Chin Med Cult 2021;4:243-50

How to cite this URL:
Tan HY, Nabil WN, Xu HX. Clinical research on cinnamomi cortex: A scoping review. Chin Med Cult [serial online] 2021 [cited 2022 May 25];4:243-50. Available from: https://www.cmaconweb.org/text.asp?2021/4/4/243/334091




  Introduction Top


Cinnamomi Cortex is part of the Lauracae family, and its genus Cinnamomum contains more than 250 species.[1] Each of the species has specific morphological characteristics and phytochemical compositions.[1],[2] However, there is often a lack of clear indications of the Cinnamomum species being investigated within studies,[3],[4],[5],[6],[7] and systematic reviews often evaluate “cinnamon supplementation” without differentiating the species.[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19]

The Chinese herb known as “Rou Gui” has been recorded in the Chinese Pharmacopoeia as the bark of Cinnamomum cassia (syn. Cinnamomum aromaticum).[2],[20],[21] This scoping review aims to summarize the currently available clinical evidence on this specific species of cinnamon used in traditional Chinese medicine.


  Methods Top


Data sources and search strategies

Electronic searches were conducted on PubMed from its inception to August 2021. The search strategy used here was as follows:

  1. “rou gui”
  2. “rougui”
  3. “cinnamon”
  4. “cassia”
  5. “cinnamomi cortex” [Supplementary Concept]
  6. “cinnamomum” [Mesh]
  7. “cinnamomum aromaticum” [Mesh]
  8. “cinnamomum cassia”
  9. “Chinese cinnamon”
  10. “Chinese cassia”
  11. “cinnamon bark”
  12. #a or #b or #c or d or #e or #f or #g or #h or #i or #j or #k
  13. “Randomized Controlled Trials as Topic” [Mesh]
  14. “Randomized Controlled Trial” [Publication Type]
  15. “Clinical Trial” [Publication Type]
  16. “Clinical Trials as Topic” [Mesh]
  17. “Controlled Clinical Trial” [Publication Type]
  18. “Clinical Study” [Publication Type]
  19. “Clinical Studies as Topic” [Mesh]
  20. “Observational Study” [Publication Type]
  21. #m or #n or #o or #p or #q or #r or #s or #t
  22. #l AND #u.


Study selection criteria

Studies were included if they were published in English; if they were clinical studies (i.e., randomized controlled trials, controlled trials, observational studies) that evaluated therapeutic effects in humans; if they specifically mentioned monotherapy with Cinnamomum cassia, Cinnamomum aromaticum, “Rou Gui,” or Chinese Cassia, and if the full article were retrievable. Studies were excluded if they did not specify the Cinnamomum species used or mentioned the use of species other than Cinnamomum cassia, Cinnamomum aromaticum, “Rou Gui,” or Chinese Cassia. Studies that mentioned the use of “Gui Zhi” or cinnamon twigs were also excluded because that refers to a different herb used in traditional Chinese medicine. Studies were also excluded if the intervention involved a formula or a mixture of herbs or if the intervention involved specific phytochemical compounds of cinnamon.

Study screening and data extraction

A data extraction sheet was created by using Microsoft Excel based on the data items listed on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension for Scoping Reviews.[22]

All hits from the electronic database searches were exported to EndNote X9,[23] and duplicates were removed by using the “Find Duplicates” function. The initial screening of titles and abstracts, subsequent full article screening, and data extraction were conducted by one author and checked by another author. Any discrepancies were resolved through discussion. The final extracted data were tabulated into summary tables for ease of reference.


  Results Top


Description of studies

In total, 206 hits were obtained from the electronic searches [Figure 1]. After initial screening, 165 were excluded for not meeting the inclusion criteria. Forty-one full articles were sought, but one full article could not be obtained. Among the 40 full articles for evaluation, 19 articles did not specify the Cinnamomum species used, four used species other than Cinnamomum cassia, while one did not use monotherapy because it used Cinnamomum cassia mixed with zinc gluconate and tricalcium phosphate, and one was an editorial. A total of 15 studies were included in this review.
Figure 1: Study flow diagram

Click here to view


The examined studies included five from the United States, three from the United Kingdom, two from Sweden, and one each from China, Germany, the Netherlands, Pakistan, and Switzerland. Eleven studies used capsules containing freshly ground or extracts of Cinnamomum cassia or Cinnamomum aromaticum, three studies added cinnamon to a meal, and one study used cinnamon tablets. The dosages of cinnamon ranged from 0.5 g to 14.4 g/d with varying administration protocols. Eleven studies compared the intervention to placebo, one study compared the intervention to usual care, and three studies that added cinnamon to meals compared the intervention to the same meal without cinnamon.

Seven studies involved patients with type-2 diabetes,[24],[25],[26],[27],[28],[29],[30] with one study specifically focusing on type-2 diabetes in postmenopausal patients.[30] Another eight studies enrolled healthy subjects,[31],[32],[33],[34],[35],[36],[37],[38] including one study involving both healthy and obese adults,[35] one study involving overweight or obese adults with impaired fasting glucose,[36] one study involving obese women,[37] and one study involving healthy adults with impaired glucose tolerance.[38] It is interesting to note that all the included studies investigated physiological parameters relating to blood glucose.

Type-2 diabetes population

Among the seven studies involving patients with type 2 diabetes, six of them were placebo-controlled studies, and one study compared cinnamon to usual care [Table 1].[26] The latter study only evaluated hemoglobin A1c (HbA1c) and found that supplementation with 1 g/d Cinnamomum cassia for 90 days significantly lowered HbA1c and that the treatment was effective as an adjunct to usual care. The author attributed the positive outcome to the study population of patients with “poorly controlled” type 2 diabetes.
Table 1: Summary of studies of type 2 diabetes populations

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Among the six placebo-controlled studies, the outcomes were conflicting without an obvious correlation with the cinnamon dosage or treatment duration. The study by Khan et al.[27] was one of the first clinical studies using Cinnamomum cassia, and it has been a common reference and comparator for newer studies. Their study found that daily supplementation with 1 g, 3 g, or 6 g of Cinnamomum cassia for 40 days significantly improved fasting blood glucose, low-density lipoprotein (LDL), triglyceride (TG), and total cholesterol levels. However, later studies indicated that Khan et al.'s study may have obtained positive outcomes because the study population had poorly controlled diabetes, citing the high fasting glucose level at baseline.[25],[29],[30] Although Khan et al. did not evaluate HbA1c, Mang et al. stated that the mean fasting blood glucose in the former study corresponded to HbA1c levels of 8.0%–10.5%.[29] Lu et al.[28] highlighted that Cinnamomum cassia supplementation significantly improved HbA1c levels in studies of patients with higher baseline HbA1c levels, as observed in three clinical studies of patients with a baseline level of HbA1c >8%,[24],[26],[28] in addition to Khan et al.'s study.

While, most studies employed cinnamon powder in capsules, it is noteworthy that two studies applied Cinnamomum cassia extracts, which may be a confounding factor when comparing interventions. One study indicated that each capsule contained 60 mg of aqueous extract isolated from 2.4 g of cinnamon, and the daily dose of cinnamon was two or six capsules.[28] This may be interpreted as 4.8 g of cinnamon every two capsules and 14.4 g of cinnamon every six capsules, and the latter dose was significantly higher than other studies, which may have impacted study outcomes. Another study used an aqueous extract in which each capsule contained 112 mg of extract, equivalent to 1 g of cinnamon.[29] Although the daily dose of cinnamon in this study was comparable to those in other studies, the different forms of the extract could be a potential explanation for the significant improvement in fasting blood glucose even though the baseline HbA1c levels were <8%. This extract form was selected as a safer option because it contained <0.1% coumarin and <0.1% essential oil to avoid a potential influence on blood coagulation and reduce allergic potential.[29] Moreover, the aqueous fraction of the extracts contains the vital constituents of Cinnamomum cassia that enhance the effects of insulin.

Healthy population

The remaining eight included studies involved healthy populations, including a subgroup of healthy adults with impaired glucose tolerance and a subgroup of healthy but overweight or obese people with impaired fasting glucose or impaired glucose tolerance [Table 2]. One study involved two study populations: normal healthy young adults (aged 18–30) and obese (body mass index [BMI]≥30) young adults (aged 18–30).[35] However, the authors found no difference in the glycemic response between the two populations, attributing the lack of abnormalities in glucose metabolism in this obese population to the subjects being otherwise young and healthy. The authors subsequently incorporated the two populations into one group to compare the effects of the two interventions. Accordingly, this review evaluated the results of the paper under the “healthy population.” Meanwhile, another study that included obese but otherwise healthy but otherwise healthy women, stated that, of their 10 participants, four may have had impaired fasting glucose, and another two met the criteria for impaired glucose tolerance.[37] Therefore, this study was evaluated under the subgroup of healthy but overweight or obese with impaired fasting glucose or impaired glucose tolerance.
Table 2: Summary of studies of healthy populations

Click here to view


Four studies evaluated the acute effects of cinnamon on glycemic response when it was taken 12 h before or together with a meal,[31],[32],[33],[35] whereas one study evaluated the effects of cinnamon when taken daily for 14 days as well as the persistence of the effects after stopping cinnamon.[34] Hlebowicz et al.[31] found that 3 g of cinnamon taken with a meal significantly reduced postprandial insulin levels and increased glucagon-like peptide 1 levels. Although 1 g of cinnamon also showed a decrease in postprandial insulin levels, the difference was insignificant, plausibly because of the small sample size. Hlebowicz et al. also postulated that a higher dose of cinnamon might be required to influence the gastric emptying rate and postprandial blood glucose concentrations. This notion is apparently supported by the significant reduction of postprandial blood glucose levels in other studies that applied 5 g-6 g of cinnamon.[33],[35] Interestingly, one study that employed 4 g of cinnamon found no significant changes in postprandial blood glucose levels.[32] Aside from the dose of cinnamon, the authors also considered the difference in the carbohydrate/cinnamon ratio and suggested that a carbohydrate/cinnamon ratio of approximately 15 or lower, as recorded in other studies,[33],[35] may be required to achieve a dose-response effect on postprandial blood glucose.

In the study on prolonged cinnamon supplementation, daily supplementation with 3 g of cinnamon for 14 days significantly reduced plasma glucose levels and insulin response starting from Day 1, as well as improved insulin sensitivity on Day 14, indicating that prolonged cinnamon supplementation may be a factor in improving insulin sensitivity.[34] In relation to the aforementioned dose-response requirement, this study, which employed 3 g of cinnamon, detected significantly reduced plasma glucose levels on Day 1, but the change did not achieve significance on Day 14. The authors speculated that the study was underpowered to detect significance, which would have been achievable with a larger sample size.

Healthy adults with impaired glucose tolerance

There was only one study in this subgroup; however, the baseline BMI of the study population was notably above 25, indicating that participants were likely overweight.[38] This study found no significant changes in fasting blood glucose, fasting insulin, HbA1c, insulin sensitivity, lipid profiles, and liver enzymes in the experiment group. It should be noted that the dosage of cinnamon used in the study was unclear because the dosage reported in the abstract, discussion, and conclusion was 12 g/d, but the methods section reported the use of two capsules a day, with each capsule containing 0.5 g of cinnamon and 0.2 g of cellulose. Cinnamon extracts may have been used so that each capsule contained extracts equivalent to 6 g of cinnamon, but this was not clarified. As such, it is difficult to compare the outcomes of this study with those of other studies. Furthermore, this study reported a significant decrease of fasting insulin levels and a significant increase of insulin sensitivity in the placebo group. Cellulose might have been a sufficient additional source of fiber that affected the insulin response. Another study that used microcrystalline cellulose observed the same effects.[29]

Healthy but overweight/obese population with impaired fasting glucose or impaired glucose tolerance

In this population, one study evaluated the acute effects of cinnamon, which was taken by participants 3 h before an oral glucose tolerance test,[37] whereas another study evaluated supplementation with cinnamon over 12 weeks.[36] The former reported significant improvements in plasma glucose response and serum insulin levels with 5 g of cinnamon,[37] which supported the aforementioned dose-response theory. In the latter study, the authors wanted to investigate the effects of cinnamon in improving oxidative stress in overweight or obese people, subsequently reducing the risk of further health complications.[36] They found that the cinnamon extract (Cinnulin PF) at 0.5 g/d for 12 weeks resulted in significant improvements in fasting blood glucose levels and oxidative stress markers such as plasma malondialdehyde, plasma thiol group oxidation, and ferric reducing activity of plasma. This study, however, did not report the amount of crude cinnamon that is equivalent to the dose of cinnamon extract that was used. The extract was reported to be sourced from Cinnamomum cassia, but further investigations revealed that Cinnulin PF is a registered trademark product that has been reported to be sourced from Cinnamomum burmannii.[40] An extract dose of 0.5 g was said to be equivalent to approximately 10 g of whole cinnamon powder (extract ratio of 20:1).[39]

While previous reviews discussed the clinical effects of cinnamon at length, this is the first review that focused on one specific species, namely Cinnamomum cassia. One of the main challenges in conducting this review was to identify studies that accurately reported the use of Cinnamomum cassia. Although all authors of the 15 studies included in this review mentioned the use of Cinnamomum cassia, we discovered potential inaccuracies in species identification, such as the use of Cinnulin PF, as discussed previously. Another example is a study that cited the use of Cinnamomum cassia from the commercially available brand Puritan's Pride;[26] however, on the brand's official website, the source of cinnamon quoted was Cinnamomum burmannii.[41]

The main bioactive component of Cinnamomum cassia is cinnamaldehyde (75%–90%),[42] where its content, as is outlined in the Pharmacopeia of the People's Republic of China, determines the quality of the plant.[43] Preclinical findings of cinnamaldehyde include antitumor activity by inducing cancer cells to apoptosis or by inhibiting tyrosinase activity in cancer cells. Cinnamaldehyde also demonstrates anti-inflammatory action through the suppression of lipopolysaccharide-stimulated inflammatory cytokines, nitric oxide production, and elevation of antioxidants such as catalase, superoxide dismutase, and glutathione peroxidase.[43] Coumarin, another bioactive compound found in the barks and twigs of Cinnamomum cassia, possesses analgesic effects. In the case of rats injected with chemotherapy oxaliplatin, coumarin blocked oxaliplatin-induced neuropathic cold allodynia by suppressing the activation of glial cells in the sacral spinal cord.[43] Other compounds of Cinnamomum cassia include polyphenols, benzaldehyde, cinnamic acid, eugenol, and cinnamyl alcohol, which contribute to its pharmacological effects such as hypoglycemic activity, antibacterial, antifungal, and cardioprotective actions.[43],[44]

The names “cinnamon” and “cassia” have been used commonly and synonymously in the US.[45] Furthermore, many people are unaware of or confused about the difference in species among the commercially available cinnamon, possibly because of labeling errors.[46] The importance of identifying the specific species used in clinical trials has been reported by many researchers,[30],[45] especially in consideration of the difference in phytochemical compounds among different Cinnamomum species, which may result in different clinical effects. For example, Wickenberg reported a study that investigated the effects of Cinnamomum cassia on postprandial blood glucose and obtained positive outcomes, but another study using Cinnamomum zeylanicum did not replicate these results.[38] Furthermore, correctly identifying the species will allow the identification and management of potential health risks. For example, high coumarin levels, which were detected in Cinnamomum cassia but not in Cinnamomum verum,[20] may lead to adverse effects such as hepatoxicity[20] or blood coagulation problems,[32] especially in clinical trials where higher than usual doses may be used. With this information, researchers would be able to take appropriate precautions, monitor relevant parameters, and/or employ safer methodologies. For example, one study included the monitoring of liver enzymes,[38] whereas another study used an aqueous extract of Cinnamomum cassia that is nearly free of lipophilic compounds, including coumarin.[29] Chen et al.[45] further emphasized the importance of identifying the species of cinnamon and the importance of characterizing the composition of cinnamon samples before administration to facilitate comparisons between studies and elucidate potential differences in outcomes.


  Conclusions Top


This scoping review included 15 clinical studies that used Cinnamomum cassia as an intervention, with all studies investigating outcomes related to the glycemic response. A summary of the findings is as follows: (1) As little as 1 g/d Cinnamomum cassia may improve HbA1c in patients with poorly controlled diabetes (HbA1c >8%); (2) There may be a dose-response relationship between Cinnamomum cassia and postprandial blood glucose levels, as a dose of at least 5 g of crude cinnamon appeared necessary in healthy or pre-diabetic people. This dose-response relationship was not observed in the type 2 diabetes population; (3) Prolonged cinnamon supplementation might improve insulin sensitivity; (4) Future studies on cinnamon should clearly identify the species of cinnamon used, as well as the form of cinnamon (i.e., powdered, extract, etc.), and enroll larger sample sizes for stronger evidence.

Acknowledgments

We would like to thank Joe Barber Jr., Ph.D. from Liwen Bianji (Edanz) for the basic language editing of this manuscript.

Funding

This work was supported by the 3-year Development Plan Project for Traditional Chinese Medicine of China (No. ZY (2018–2020)-CCCX-2001–02), and the Key-Area Research and Development Program of Guangdong Province of China (No. 2020B1111110003).

Ethical approval

This study does not contain any studies with human or animal subjects performed by any of the authors.

Author contributions

Hsiewe Ying Tan and Wan Najbah Nik Nabil participated in conceptualization, research design and literature search; Hsiewe Ying Tan participated in data acquisition and data analysis; Hsiewe Ying Tan and Wan Najbah Nik Nabil prepared and edited the manuscript; Hong-Xi Xu edited and reviewed the manuscript.

Conflict of interest

None.



 
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