Medicinal properties of ‘true’ cinnamon (Cinnamomum zeylanicum): a systematic review

Literature search

The literature search using the above search criteria identified the following number of articles in the respective databases; PubMed® (n = 54), Web of Science® (n = 76) and SciVerse Scopus® (n = 591). Thirteen additional articles were identified by manually searching the reference lists and forward citations of included papers. After removing duplicates the total number of articles included in the present review is 70. The search strategy is summarized in Figure 1.

In-vitro and in-vivo anti-microbial properties

There were 30 different studies evaluating the in-vitro anti-microbial properties of CZ. Table 1 summarizes the findings of these studies. Accordingly CZ has shown potential anti-microbial action against a wide variety of bacteria (Acinetobacter baumannii, Acinetobacter lwoffii, Bacillus cereus, Bacillus coaguiaris, Bacillus subtilis, Brucella melitensis, Clostridium difficile, Clostridium perfringens, Enterobacter aerogenes, Enterobacter cloacae, Enterococcus faecalis, Enterococcus faecium, Escherichia coli, Haemophilus Influenza, Helicobacter pylori, Klebsiella pneumonia, Listeria ivanovii, Listeria monocytogenes, Mycobacterium smegmatis, Mycobacterium tuberculosis, Proteus mirabilis, Pseudomonas aeruginosa, Saccharomyces cerevisiae, Salmonella typhi, Salmonella typhimurium, Staphylococcus albus, Staphylococcus aureus, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes and Yersinia enterocolitica). In addition there seems to be activity against numerous fungi (Aspergillus fiavus, Aspergillus fumigatus.

Aspergillus nididans, Aspergillus niger, Aspergillus ochraceus, Aspergillus parasiticus, Aspergillus terreus, Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis, Candida tropicalis, Crytococcus neoformans, Epidermophyton floccosum, Hisioplasma capsulatum, Malassezia furfur, Microsporum audouini, Microsporum canis Microsporum gypseum, Trichophyton mentagraphytes, Trichophyton rubrum and Trichophyton tonsurans). CZ has also demonstrated activity against the human rota-virus (Table 1).

There were 5 studies evaluating in-vivo anti-microbial properties in animals. Abu, et al. [44] investigated the effect of administration CZ oil on the development and progression of the experimental cryptosporidiosis in mice, and they showed that administration of CZ oil was beneficial in protecting susceptible hosts against opportunistic zoonotic parasites such as Cryptosporidium parvum. Rosti, et al. [45,46] reported two cases of infants who were chronic carriers of Salmonella enteritidis who received short term (10 days) administration of grounded CZ bark which led to consistently negative stool cultures and no clinical or microbiological relapses. Activity of CZ against fluconazole resistant and susceptible candida were studied in HIV infected patients having pseudo-membranous Candida, where 3 patients out of 5 showed improvements in their oral candidiasis [47]. The effects of sugared chewing gum containing cinnamic aldehyde and natural flavours from CZ on the short-term germ-killing effect on total and H₂S-producing salivary anaerobes was investigated by Zhu, et al. [48]. Significant reductions in total salivary anaerobes and H₂S-producing salivary anaerobes were observed 20 minutes after subjects chewed the gum.

In-vitro and in-vivo anti-parasitic effects

Samarasekera, et al. [49] investigated the mosquito control properties of essential oils of leaf and bark of CZ against Culex quinquefasciatus, Anopheles tessellatus and Aedes aegypti. CZ bark oil showed good knock-down and mortality against A. tessellatus (LD₅₀ 0.33 μg/mL) and C. quinquefasciatus (LD₅₀ 0.66 μg/mL) than leaf oil (LD₅₀ 1.03 and 2.1 μg/mL). Yang, et al. [50] showed that CZ bark essential oil was slightly less effective than either d-phenothrin or pyrethrum against eggs and adult females of human head louse, Pediculus humanus capitis, using direct contact and vapour phase toxicity bioassays.

In-vitro and in-vivo effects on blood pressure, glycaemic control and lipids

A recent meta-analysis by Ranasinghe, et al. and a systematic review by Bandara et al., on the effects of CZ extracts on diabetes demonstrates numerous beneficial effects both in-vitro and in-vivo[51,52]. In-vitro CZ has demonstrated a potential for; a) reducing post-prandial intestinal glucose absorption by inhibiting the activity of enzymes involved in carbohydrate metabolism (pancreatic α–amylase and α–glucosidase), b) stimulating cellular glucose uptake by membrane translocation of GLUT-4, c) stimulating glucose metabolism and glycogen synthesis, d) inhibiting gluconeogenesis by effects on key regulatory enzymes and f) stimulating insulin release and potentiating insulin receptor activity [51]. Cinnamtannin B1 was identified as the potential active compound responsible for these effects [51]. The beneficial effects of CZ In-vivo includes; a) attenuation of weight loss associated with diabetes, b) reduction of Fasting Blood Glucose, c) reducing LDL and increasing HDL cholesterol, d) reducing HbA1c and e) increasing circulating insulin levels [51]. In addition CZ also showed beneficial effects against diabetic neuropathy and nephropathy [51].

Hasan et al. [53], also confirmed these effects and demonstrated that CZ reduced total cholesterol, LDL cholesterol and triglycerides while increasing HDL-cholesterol in diabetic rats. Similar results have also been observed in hyper-lipidaemic albino rabbits [54]. However, feeding CZ to animals at levels corresponding to the average human dietary intake has not shown to reduce lipid levels significantly [55]. Nyadjeu et al. [56] examined the effects of CZ extracts (CZA) on mean arterial blood pressure (BP) of normotensive (NR) rats, salt-loaded hypertensive rats (SLHR), L-NAME hypertensive rats (LNHR) and spontaneously hypertensive rats (SHR). Immediately after intravenous administration a significant drop of BP was shown in NTR, SLHR and LNHR in a dose dependent manner, the drop in BP was not dose dependent in SHR [56]. Wansi, et al. demonstrated similar effects in NTR and SLHR, they also showed that CZ has a vaso-relaxant effect on the rat thoracic aortic ring segments, suggesting that, CZ might be inhibiting extracellular Ca²⁺ through L-type voltage-sensitive channels [57]. Markey, et al. [58] tested the hypothesis that supplementing a single high fructose breakfast with 3g of cinnamon would delay gastric emptying of a high-fat solid meal utilizing the ¹³C octanoic acid breath test, and consequently reduce postprandial blood glucose and lipid concentrations. There concluded that cinnamon did not change gastric emptying parameters, postprandial triacylglycerol or glucose concentrations after a single administration [58]. It is important to note that all in-vivo studies except the above study were conducted in animals.

In-vitro and in-vivo anti-oxidant properties

The essential oils obtained from the bark of CZ and eugenol has shown very powerful activities, decreasing 3-nitrotyrosine formation and inhibiting the peroxynitrite-induced lipid peroxidation in in-vitro assays [59]. The volatile oils of CZ has shown 55.9% and 66.9% antioxidant activity at 100 and 200 ppm concentration, respectively [60]. The dried fruit extracts of CZ with ethyl acetate, acetone, methanol and water exhibited antioxidant activity in the order of water > methanol > acetone > ethyl acetate [61]. The etheric (0.69 mg), methanolic (0.88 mg) and aqueous (0.44 mg) cinnamon extracts, inhibited the oxidative process in 68%, 95.5% and 87.5% respectively [62]. A. Kitazuru, et al. [63] studied the effects of ionizing radiation on natural CZ antioxidants and showed that irradiation in the dose range applied did not have any effect on the antioxidant potential of the cinnamon compounds.

CZ bark extracts were found to be potent in free radical scavenging activity especially against DPPH radicals and ABTS radical cations, while the hydroxyl and superoxide radicals were also scavenged by the tested compounds [64]. Similar findings were noted by Prakash, et al. who showed that CZ has 65.3% of anti-oxidant activity and strong free radical scavenging activity [65]. Ranjbar, et al. [66] treated 18 operating room personnel with CZ (100 mg/300 mL tea) daily for 10 days and blood samples were analyzed for biomarkers of oxidative stress biomarkers including Lipid Peroxidation Level (LPO), Total Antioxidant Power (TAP) and Total Thiol Molecules (TTM). Treatment of subjects with cinnamon induced a significant reduction in plasma LPO, however no statistically significant alteration was found for plasma TAP and TTM after 10 days treatment with CZ [66]. Treatment of 54 healthy volunteers with CZ 100 mg/30ml of tea daily were significantly effective in the reduction of lipid peroxidation and increasing TAP and TTM in comparison with controls [67]. The extent of increase in plasma TBARS and TAP for the CZ group was significantly higher than in those give regular tea only [67].

Other in-vitro effects

An aqueous extract of CZ is known to inhibit tau aggregation and filament formation, which are hallmarks of Alzheimer’s disease [68]. The extract also promotes complete disassembly of recombinant tau filaments and cause substantial alteration of the morphology of paired-helical filaments isolated from brains of those with Alzheimer’s disease, however it was not deleterious to the normal cellular function of tau. An A-linked proanthocyanidin trimer molecule isolated from the CZ extract has shown to contain a significant proportion of this inhibitory activity [68]. Takasao, et al. [69] demonstrated that CZ extracts facilitates collagen biosynthesis in human dermal fibroblasts. CZ extract up-regulated both mRNA and protein expression levels of type I collagen without cytotoxicity, cinnamaldehyde was the major active component promoting the expression of collagen by HPLC and NMR analysis. This suggests that CZ extracts might be useful in anti-aging treatment of skin [69]. CZ extracts have also exhibited the strong inhibitory effects on osteoclastogenesis [70]. CZ dose-dependently inhibited osteoclast-like cell formation at concentrations of 12.5-50 μg/ml without affecting cell viability. This finding raises prospects for the development of a novel approach in the treatment of osteopenic diseases [70].

Other in-vivo effects in animals

CZ is known to have anti-secretagogue and anti-gastric ulcer effects as shown by a study conducted by Alqasoumi [71]. CZ suspension pre-treatment decreased the basal gastric acid secretion volume in pylorus ligated rats and it effectively inhibited gastric hemorrhagic lesions induced by 80% ethanol, 0.2M NaOH, and 25% NaCl. It also showed antiulcer activity against indomethacin. CZ treatment replenished the ethanol-induced decreased levels of gastric wall mucus [71]. Rao and Lakshmi induced diarrhoea in mice using the magnesium sulphate-induced diarrhoea test and showed that CZ extracts at 100 and 200 mg/kg doses significantly reduced the extent of the diarrhoea (71.7% and 80.4%) in test animals [72].

In a study using two animal models for the investigation of the anti-nociceptive and anti-inflammatory effects of CZ and selected plants, CZ induced a dose-dependent analgesic protective effect against both thermal stimuli and the writhing syndrome, furthermore, CZ showed an anti-inflammatory effect against chronic inflammation induced by cotton pellet granuloma indicating anti-proliferative effect [73]. These effects have been verified by other authors [74]. CZ is also known to have wound healing properties in rats, in a study using thirty-two rats where experimental excision wounds were induced and treated with topical CZ containing ointments. The CZ extracts served to accelerate the wound healing process and specifically increased epithelialisation [75]. In Wister rats CZ given orally increased the wound breaking strength significantly in incision wounds model and in dead space wounds the granulation tissue breaking strength and hydroxyproline content were significantly increased [76].

CZ has also been shown to have hepato-protective effects in a study where liver injury was induced in rats by CCl₄[77]. Administration of CZ extracts (0.01, 0.05 and 0.1 g/kg) for 28 days significantly reduced the impact of CCl₄ toxicity on the serum markers of liver damage (AST, ALT and ALP). In addition, treatment with CZ markedly increased the levels of superoxide dismutase and catalase enzymes in rats [77]. Water-based extract from CZ was a potent inhibitor of VEGFR2 kinase (Vascular Endothelial Growth Factor Receptor) activity which is involved in angiogenesis [78]. As a result, CZ inhibited VEGF-induced endothelial cell proliferation, migration and tube formation in-vitro, sprout formation from aortic ring ex-vivo and tumor-induced blood vessel formation in-vivo[78].

Toxic effects

In-vivo studies in animals have also highlighted lack of significant toxic effects on liver and kidney, with a significantly high therapeutic window [51]. Domaracký et al., [79] administered CZ for two weeks to female mice and evaluated the effects on the viability of embryos of mice, number of nuclei and the distribution of embryos according to nucleus number. Cinnamon significantly decreased the number of nuclei and the distribution of embryos according to nucleus number was significantly altered and these changes were attributed to the anti-proliferative effects of cinnamaldehyde [79]. However these findings have been contradicted by others who have demonstrated that CZ does not have significant abortive or embryo toxic effects in animals [80]. Furthermore, Shah et al, showed that CZ induced a significant increase in reproductive organ weights, sperm motility, sperm count and demonstrated no spermatotoxic effects in mice [81].

Chulasiri et al., demonstrated that petroleum ether and chloroform extracts from CZ showed cytotoxic effects on KB (human mouth carcinoma cell line) and L1210 cells (mouse lymphoid leukaemia cell line) [82]. The average ED₅₀ from the first and second tests of the petroleum ether extract on these tumour cells were 60 and 24 pg/ml respectively and of the chloroform extract were 58 and 20 pg/ml respectively. Singh, et al. [83] investigated the cytotoxic effects of aqueous cinnamon extract from the bark of CZ on human and mouse cell lines. The aqueous cinnamon extract proved to be more cytotoxic to cancerous cells at concentrations just above 0.16 mg/mL. At a critical concentration of 1.28 mg/mL, CZ treatment resulted in 35-85% growth inhibition of the majority of the cancerous cells.