The gel had a mild yellowish color, cinnamon odor, and homogenous character. The pH of the gel was 4.51, the density was 0.86, and viscosity was 800 cp. The formulation was stable during the clinical study, based on the physical assessment. Cinnamaldehyde content of the gel was 0.38±0.02% (w/w).

Figure 1

Figure 2

Figure 3

For safety assessment, we used repeated open application test (ROAT) and skin biophysical measurement. Here in the study, 15 healthy volunteers applied topical 1% cinnamon gel on a 3 × 3 cm site on the flexure surface of their right forearm twice-daily for one week. The left forearm served as the control. The subjects were asked to determine the severity of the side effects as mild (did not have to stop treatment), moderate (had to stop treatment for a short while), and severe (had to stop treatment soon after beginning).

Table 1

	Right (cinnamon-treated) N=15 Mean ± SD	Left (control) N=15 Mean ± SD	P*
TEWL	0.36 ± 0.30	0.20 ± 0.33	0.268
Hydration	0.01 ± 0.20	0.02 ± 0.20	0.612
Erythema	0.17 ± 0.45	0.14 ± 0.18	0.291
Melanin	0.20 ± 0.86	0.10 ± 0.29	0.251
pH	0.09 ± 0.20	0.03 ± 0.13	0.106

p*: p-value of comparison between right and left forearm.

After one week, there was no significant difference between the mean changes in biophysical parameters values of the right and left forearm (Table 1). Adverse reaction to 1% cinnamon gel was seen in 6 subjects as follow: severe erythema, burning and itching (1 case), moderate erythema and burning (1 case), and mild erythema (3 cases). Thereafter, the test was repeated with a 0.5% (w/w) cinnamon gel. The observed side effects of this gel were mild burning and erythema (3 cases) and mild erythema (2 cases). According to lesser side effects, 0.5% (w/w) cinnamon gel was used in this trial.

Table 2

Percentage	Number of patients
More than 75%	2
50‑75%	5
25‑50%	11
Less than 25%	1
No change	0
Worse	1

In the clinical phase, 20 patients (18 females, 2 males) completed the study. The average age of the patients was 21.4 ± 3.4 years old (range: 20–40 years old).

Eight weeks after treatment, a mean decrease of 47% (from 14.1 ± 4.4 up to 7.5 ± 2.46) in total lesion count, 48% (from 10.8 ± 7.3 up to 5.6 ± 3.6) in non-inflammatory lesion count, and 42% (from 3.3 ± 2.4 up to 1.9 ± 1.7) in inflammatory lesion count were seen (Figure 1). The observed reductions in the number of total (p = 0.000), non -inflammatory (p = 0.002), and inflammatory lesions (p = 0.026), versus baseline, were statistically significant (p ≤ 0.05). Of the 20 patients, 7 showed greater than 50% relief (Table 2). The clinical effectiveness of the cinnamon gel is shown in Figure 2.

Table 3

Parameter	Baseline (N=20) Mean ± SD	4th week (N=20) Mean ± SD	8th week (N=20) Mean ± SD	p*
TEWL	17.29 ± 4.22	17.97 ± 4.38	21.14 ± 9	0.063
Hydration	64.17 ± 11.16	58.64 ± 10.71	54.11 ± 11.30	0.000
Erythema	410.05 ± 96.39	397.41 ± 75.04	348.73 ± 89.46	0.001
Melanin	180.56 ± 22.85	175.96 ± 29.65	185.04 ± 34.42	0.44
Sebum	80.40 ± 34.77	59.85 ± 25.13	49.35 ± 28.16	0.001
pH	6.17 ± 0.71	6.47 ± 0.66	6.80 ± 0.34	0.001

p*: p-value of comparison between baseline and 8^th week

At week 8, the mean decrease in sebum content (31.05 ± 36.15; P = 0.001) and erythema index (61.31 ± 68.25; P = 0.001) were significant compared with baseline. Additionally, the results showed a significant decrease in skin hydration (10.05 ± 10.16; P = 0.000) and a non-significant increase (3.84 ± 3.69; p = 0.063) in TEWA. Eventually, there was a non-significant increase (4.48 ± 25.5; p = 0.442) in melanin index and a significant increase (0.63 ± 0.75; P = 0.001) in skin pH. The mean value of six skin biophysical parameters at baseline and two follow-up visits are summarized in Table 3.

At the end of the study, the mean decrease in the percentage area covered with red fluorescence spots (size) and number of red fluorescence spots (quantity) were 0.39 ± 0.77 (P = 0.034) and 3.4 ± 7.35 (P = 0.052), respectively (Figure 3). The mean VAS score of patient satisfaction with efficiency of the cinnamon gel was 5.98 ± 1.14.

No serious adverse events were reported for the trial. Thirteen patients complained of mild burning and 11 patients reported facial redness after using the cinnamon gel for a maximum of ten minutes. The severity of these symptoms was not intolerable to stop the treatment and most of the patients stated that the intensity of these side effects was decreased after a week.

Acne vulgaris is one of the most common chronic skin diseases 3. Since the available anti-acne treatments are not completely satisfactory and safe, finding new alternative efficient treatments with fewer side effects for acne treatment is necessary. Considering the multifactorial pathogenesis of acne, use of medicinal plants with multiple mechanisms of action could be promising 9.

In the present study, we investigated the clinical efficacy and safety of a topical cinnamon gel for the treatment of mild-to-moderate facial acne. The results of this pilot study showed that topical cinnamon gel significantly decreased the count of inflammatory and non- inflammatory acne lesions. Additionally, there was also a notable decrease in the size and quantity of red fluorescent spots. The red fluorescence emission from pilosebaceous follicles correlates with the amount of porphyrin 17. Porphyrin is a metabolic product of P. acnes; inhibition of P. acnes can lead to a decrease in porphyrin production 18.

A significant decrease in skin erythema and sebum content after using the cinnamon gel was another finding of our study. Sebum hypersecretion is a major pathogenic factor for acne lesion formation. Excessive sebum (by plugging the pilosebaceous duct) provides an anaerobic lipid-rich environment for the growth of P. acne 19. An inflammatory response of innate and adaptive immune systems to P. acnes is considered as the next pathogenic factor 20. In this process, the release of reactive oxygen species (ROS) and inflammatory mediators from immune cells induce cellular damage and inflammation in acne-prone sites 21.

Considering the aforementioned mechanisms, it is rational to choose an anti-acne product which has anti-bacterial effect against P. acnes, as well as anti-inflammatory and anti-oxidant effects 22. Anti-bacterial activity of cinnamon against P. acnes has been documented in several in vitro studies 23,24,25. A recent study revealed that the inhibition zone diameters of C. verum bark extract (90%) and tetracycline (250 µg/mL) against P. acnes were 17.2 and 18.9 mm, respectively 26. In another study, the inhibition zone of Cinnamomum zeylanicum bark essential oil at 25%, 50%, and 100% concentrations were 16.7, 26.7, and 31.3 mm, respectively, compared with the inhibition zone of vancomycin which was 17 mm 25. Furthermore, cinnamon has strong antioxidant activity 27. The results of another in vitro study on antioxidant activity of C. verum bark extract showed that ROS scavenging capacity was comparable to synthetic antioxidants 14. These therapeutic effects are mainly attributed to cinnamaldehyde, which is the major (62%–90%) chemical constituent of cinnamon bark. In addition, cinnamaldehyde has anti-inflammatory effects, such as blockage of PGE2 production, suppression of synthesis, and dissemination of inflammatory mediators (e.g. IL-1β, IL-6 and TNF-α), and reduction of ROS release from immune cells 28.

In most of the patients, the cinnamon gel was well-tolerated, and there was no serious adverse events. However, some patients experienced mild transient skin irritation especially over the first week of trial. Cutaneous allergic reactions to topical cinnamon formulations are documented in several case reports 29,30,31,32. Therefore, cinnamon formulations should be used with caution, especially in patients with a history of allergic reaction to cinnamon species. Although no patient complained of dryness, there was an increase in TEWL and a significant decrease in hydration values in skin biophysical measurement. There was also a significant increase in skin pH, but it remained in the acidic range. Given that appropriate epidermal water content and acidic pH are necessary for skin barrier anti-microbial defense 33, long-term follow-up studies are needed to assess the changes in these parameters.

In conclusion, preliminary results revealed that cinnamon gel can be an effective topical treatment for mild-to-moderate acne. These therapeutic results have been most probably attributed to sebostatic, anti-bacterial, and anti-inflammatory activities of C. verum bark essential oil, as well as its major compound cinnamaldehyde. This is the first trial to investigate the clinical effectiveness of cinnamon for the treatment of acne vulgaris. To confirm these findings, further clinical trials with control groups and larger sample sizes are needed.

CA: cinnamaldehyde

GC: gas chromatography

ROS: reactive oxygen species

TEWA: transepidermal water loss

VAS: visual analogue scale

The authors declare that there is no conflict of interest regarding the publication of this paper.

Mehdi Vazirian was the principal investigator and edited the manuscript. Saman Ahmad Nasrollahi designed the drug formulation. Ziba Talebi & Maedeh Ghovvati contributed in data acquisition, pharmacognostic and pharmaceutical Part of the study. Alireza Firooz supervised the clinical part of the study. Gholamreza kordafshari & Mehrdad Karimi have done patient collection. Aniseh Samadi performed statistical analysis. Sima Kolahdooz prepared and revised the manuscript. All authors read and approved the final manuscript.

This research project was supported by Tehran University of Medical Sciences (TUMS) (grant no. 95-01-169-31056).