The clinical efficacy of Olibanum gum chewing in patients with Mild‐to‐Moderate Alzheimer disease: A randomized Parallel‐Design controlled trial

Abstract

Background

Alzheimer's disease is a common neurodegenerative disorder in elderly with progressive decline in cognitive functions. This study aimed to investigate the possible memory‐improving effects of Olibanum on patients with Alzheimer's disease.

Research Design and Method

This double‐blind, randomized clinical trial was carried out on 72 participants aged 50–75 years. The intervention group (n = 36) received 1.6 g/day of olibanum chewing gum for 18 weeks. The placebo group (n = 36) received chewing gum without olibanum. Neuropsychological assessments were performed at baseline, every 4 weeks, and after 18 weeks of the intervention.

Results

There was no significant difference between (MD: 0.84, 95%CI: −1.10 to 2.78, p = 0.392) at baseline. Both groups had linear improvements over time. There was no significant difference between two groups regarding the improvements after the intervention (F = 0.157, p = 0.693). There were no significant differences between the groups for MMSE score (Mini‐Mental State Examination) after the intervention (F = 0.141, p = 0.708).

Conclusions

This study revealed that 18 weeks of gum chewing with Olibanum did not change the neuropsychological status. More clinical studies are needed to confirm these findings.

The mean score of Wechsler memory scale (WMS) in the intervention and placebo groups during 18 weeks of the sudy.

1. INTRODUCTION

Neurodegenerative diseases such as cognitive disorders are among the diseases that increase with age. It is predicted that by 2050, the number of elderly people will increase to 152 million and the rate of aging will reach 37.5%. Cognitive disorder is a type of disease that can impair attention, memory, and performance. ¹ Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss and personality changes, eventually leading to dementia. ¹ Alzheimer's disease (AD) is a leading cause of morbidity and mortality and the most common cause of dementia worldwide. ² About 121 499 deaths were recorded from AD in 2019, the latest year for which data are available. Alzheimer's disease was officially listed as the sixth‐leading cause of death in the United States in 2019 and the seventh‐leading cause of death in 2020 and 2021, when COVID‐19 entered the ranks of the top 10 causes of death. ³ Regardless of the increasing prevalence of AD due to the world's aging population and related health problems, there are no effective strategies for the prevention and treatment of this disease. ³ Many studies have reported that higher levels of inflammatory cytokines such as interleukin‐1, interleukin −6 and tumor necrosis factor alpha (TNF‐α) in AD patients impair memory and learning performance. ⁴

Recent studies reported that herbal compounds may have a beneficial effect on improvement of inflammatory diseases such as osteoarthritis, ⁵ psychological disorders, ⁶ and inflammatory bowel disease. ⁷ Several studies have also demonstrated the effectiveness of herbal medicines in memory‐related disorders. ³ , ⁸ Effectiveness of saffron extract and crocin have been reported on recognition and spatial memory after chronic cerebral hypoperfusion in rats. ⁹ In addition, Foroumandi et al. reported that fenugreek seed extract supplementation improved memory function in patients with Alzheimer's disease. ¹⁰

Olibanum gum resin, known as Frankincense, is one from the family Burseraceae and the genus Boswellia. ¹¹ Olibanum gum resin was recognized as an herbal component with positive effects on neuroinflammation diseases. ¹² The extract of Boswellia species contains a broad variety of different components such as acid resin, gum, alpha‐boswellic acid, 3‐acetyl‐beta‐boswellic acid, 4‐O‐methyl‐glucuronic acid, incensole acetate and phellandrene. ¹³ Olibanum and its active components might be useful in improving cognitive dysfunction and memory impairment. ¹² , ¹³ , ¹⁴

Olibanum in Iranian traditional medicine is called Kundur and is known as a remedy for various memory and learning disorders. ¹⁵ Recent in vivo and in vitro studies have demonstrated that boswellic acid may improve memory function in rats. ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ The administration of boswellic acid was reported to improve memory impairment induced by lipopolysaccharide in rats. ²⁰ However, to the best of our knowledge, there is no clinical trial that evaluated the effect of Olibanum on memory function. Based on this evidence, the present clinical trial was aimed to investigate the possible memory‐improving effects of Olibanum on patients with AD.

2. MATERIALS AND METHODS

The present study was a randomized, double‐blind, placebo‐controlled trial to assess the memory‐improving efficacy of Olibanum chewing gum in patients with mild to moderate AD.

2.1. Participants

This study included 72 participants aged 50–75 years. All surveys conducted in the rural Health Centers of Sabzevar, Iran. Inclusion criteria was having mild to moderate AD, not receiving a supplement or diet containing olibanum and consent to participate. Exclusion criteria was significant neurologic or psychiatric disease, serious gastrointestinal, renal, hepatic, endocrine or cardiovascular disease, gastrointestinal, hepatic, renal or significant obstructive pulmonary disorders, other diseases which could lead to dementia other than AD, pregnancy, inability to using chewing gum, using any treatments which probably improve cognitive function within the past 1 month or during study. The Patients who were unable to continue the study were also excluded from study.

The screening process consisted of several phases to identify patients with probable mild to moderate AD. In the first phase, demographic information of the participants was collected and those who had 20–27 points of Mini‐Mental State Examination Persian Version (F‐ MMSE) scores were included. In addition, all patients were required to meet the criteria for mild to moderate AD based on the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM‐V). In the second phase, the selected participants were assessed using Geriatric Depression Scale (GDS) in order to exclude depressive pseudodementia. In the third phase, patients were confirmed by a neurologist based on medical history and nervous system medical examination.

2.2. Interventions

Participants were allocated 1:1 to either the Olibanum chewing gum or placebo group, using a blocked randomization method by a computer‐generated sequence. All participants and researchers were blinded to the group assignment. Participants allocated to the intervention group received 1.6 g/day of Olibanum chewing gum for 18 weeks. Participants were instructed to chew one Olibanum chewing gum for 20 min three times a day. Each Olibanum chewing gum contained 100 mg of Olibanum (Biodent chewing gum; Masterfoodeh Co., Iran). The placebo group received chewing gum without Olibanum that were identical in appearance to the Olibanum chewing gum. A relatively low dose of Olibanum was assessed in this study due to lack of data on the safety of Olibanum for older adults. Participants were recommended to follow their usual dietary and activity patterns. Olibanum chewing gum and placebo were assessed and confirmed regarding the composition and absence of contaminants (Consumer Lab, Tehran, IR). The cognitive abilities of patients were evaluated in baseline, every 4 weeks, and after 18 weeks using neuropsychological tests.

2.3. Outcome measures

The primary outcome measure was Wechsler memory scale (WMS‐III), which is a test to assess basic and instrumental activities of daily living composed of 6 primary and 5 optional subtests. ²¹ The second outcome measure was MMSE, which consists of 20 tasks to assess multiple cognitive domains including memory, language, praxis, and orientation. ²² In this study, the standardized Persian version of MMSE and WMS‐III were used. ²³ The safety parameters were assessed using serious adverse events (SAEs) and spontaneously reported adverse events (AEs).

2.4. Statistical analysis

Data were presented as mean ± SD or frequencies and percentages. The Chi‐squared test and independent samples t‐test were used for the comparison of the qualitative and quantitative variables between the intervention and control groups, respectively. Efficacy outcome parameters were analyzed on an intent‐to‐treat basis. Repeated measures analysis of variance was used to determine the effects of the intervention. All statistical analysis was performed using SPSS software version 21 and the p value of less than 0.05 was considered statistically significant.

3. RESULTS

Recruitment of the patients commenced in June 2018 and ended in June 2019. A total number of 106 patients were assessed from which 26 were not eligible according to the inclusion and exclusion criteria. Eight eligible patients were not willing to participate. Finally, 72 patients were randomized into the study groups (36 in each group). During the 6 months of the study, one patient was lost to follow‐up (Figure 1). Demographic and baseline characteristics of the patients are summarized in Table 1. No statistically significant differences were observed among two groups regarding the baseline characteristics.

FIGURE 1.

Flow diagram.

TABLE 1.

Characteristics of the study population.

	Frankincense (n = 36)	Placebo (n = 35)	p‐value
Age (year) a	56.61 ± (5.64)	54.71 ± (4.25)	0.115
Sex b
Male	6 (16.7)	11 (31.4)	0.145
Female	30 (83.3)	24 (68.6)
Marital status b
Married	31 (86.1)	32 (91.4)	0.564
Wife's death	5 (13.9)	3 (8.6)
Education level b
Illiterate	20 (55.55)	22 (62.9)	0.853
Primary school	5 (13.88)	5 (14.3)
High school	11 (30.55)	8 (22.9)
Employment status b
Employed	9 (25)	11 (31.4)	0.547
Non‐employment	27 (75)	24 (68.6)
Other underlying illnesses b
Yes	16 (44.4)	10(28.6)	0.165
No	20 (55.6)	25 (71.4)

^a Values given as mean ± SD (standard deviation).

^b Values given as number (percentage).

The mean score of WMS and MMSE for the groups from baseline to week 18 are presented in Figures 2 and 3. The mean pretreatment scores of WMS in the intervention and placebo groups were 44.92 ± (3.7) and 45.76 ± (4.48), respectively (MD: 0.84, 95%CI: −1.10 to 2.78, p = 0.392). The two groups had similar scores at the baseline, and then both made linear improvements over time. However, there was no significant difference between two groups from pretreatment toward end of treatment (F (1, 67) = 0.157, p = 0.693). No group‐by‐time interaction was found for the score of WMS (F (1, 67) = 1.56, p = 0.216). For the secondary end point (MMSE), the results showed that both groups improved slightly from pretreatment toward end of treatment, but there were no significant differences between the groups (F (1, 67) = 0.141, p = 0.708). No group‐by‐time interaction was found for the score of MMSE (F (1, 67) = 1.84, p = 0.179).

FIGURE 2.

Mean of wechsler memory scale III from baseline over time.

FIGURE 3.

Mean of mini‐mental status examination from baseline over time.

4. DISCUSSION

In this study, we assess the effect of olibanum gum chewing in AD patients compared to placebo (gum chewing without olibanum). We found that the patients in both groups who had used gum chewing with or without Olibanum had better results after an 18 weeks treatment period; however, this difference in the intervention group was not significant compared to the control group. Previously, physiological studies confirmed the effect of Olibanum on improvement of learning and memory. ⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ²⁴ Although clinical study on the effect of olibanum on AD is scarce, Beheshti et al. reported the effect of olibanum in a rat model of AD. ¹⁷ In addition, an inclusive review focused on the significance of olibanum metabolites indicated that the anti‐inflammatory and anti‐AD effects of Olibanum may be associated with the intriguing biological and pharmacological potentials of Olibanum. ²⁵

The exact mechanisms of the possible effects of Olibanum on AD is not yet clear. During inflammatory responses, the release of inflammatory cytokines including interleukin‐1 beta (IL‐1β), IL‐6 and tumor necrosis factor alpha (TNF‐α) is increased in the brain. ⁴ These inflammatory cytokines directly affect neuronal functions including long‐term potentiation (LTP), glutamate release, AMPA receptor density, and cellular signaling pathways involved in memory. ⁴ There is also evidence that oxidative stress and reactive oxygen species (ROS) impair memory and learning. ⁵ Olibanum was reported to have anti‐inflammatory, antioxidant, and neuroprotective effects. ²⁶

The chemical analysis of oleo‐gum resin water extract of Boswellia dalzielii (Burseraceae) demonstrated the presence of total phenols, flavonoids, anthocyanins and tannins. Tannin‐rich plants have been proven to have anti‐inflammatory properties. ¹² , ¹⁹ Afsar et al. showed that the methanol fraction of B. serrata leaves contains high amounts of total phenolics, flavonoids, and tannins and exhibited strong in vitro anti‐inflammatory activity. ²⁷ Methanol extract of the resin of B. carterii exhibited marked anti‐inflammatory activity for their inhibitory effect against 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA)‐induced inflammation in mice. In addition, anti‐inflammatory effects of B. elongate have been frequently reported. ²⁸ , ²⁹ , ³⁰ , ³¹

The resin of Boswellia serrata has shown a beneficial effect on treatment of inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, bronchial asthma osteoarthritis, and chronic colitis. ²⁶ More than 200 constituents of Olibanum may be responsible for therapeutic properties against inflammatory diseases ³² . For example, the triterpenoids such as pentacyclic triterpenoid are known to have anti‐inflammatory effects ³³ . Olibanum inhibits inflammation in many inflammatory diseases by specifically inhibiting 5‐lipooxygenase enzyme, preventing leukotriene synthesis and stopping glycosaminoglycan production. ⁶ According to some evidence obtained by animal studies, Olibanum and its constituent, boswellic acid have obvious positive effects on neuroinflammation diseases and they could be useful in improving a variety of models of cognitive dysfunction and memory impairment caused by hypothyroidism, diabetes, seizure, and stroke. ⁷ Olibanum is traditionally used in Iran for pregnant women during the first trimester to enhance the learning ability of the child. ³⁴

To the best of our knowledge, this is the first clinical trial that investigated the effect of Olibanum on memory function. We failed to find any association between Olibanum and AD. However, this study had some limitations. Since this study was the first clinical trial to assess the effect of olibanum on human participants with AD, we use minimal dose in chewing gum in order to avoid the possible side effects. Another limitation was selecting chewing gum for the placebo group. Several studies demonstrated the effects of chewing on cognitive improvement. ³⁵ , ³⁶ The positive effect of chewing gum on cognition in both groups may influence the results.

5. CONCLUSION

The result of this study indicates that the use of olibanum (1.6 g/day) as chewing gum compared to chewing gum without olibanum had no significant effect on AD. Future studies with higher doses of olibanum and on larger samples are warranted to investigate the effect of olibanum on AD.

AUTHOR CONTRIBUTIONS

SD, FGH, MS, FS, MR, and SHSH designed the study, and were involved in the data collection, analysis, and drafting of the manuscript. MGH and SD were involved in the design of the study, analysis of the data, and critically reviewed the manuscript. All authors read and approved the final manuscript.

FUNDING INFORMATION

Funding for this study was provided by Sabzevar University of Medical Sciences, Sabzevar, Iran. (6655).

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

ETHICS STATEMENT

The study protocol had been approved by the Research Ethical Committee of Sabzevar University of medical sciences, Sabzevar, Iran (Medsab.Rec.96.1). The trial protocol had been registered in the Iranian registry of clinical trials (IRCT) (ID: IRCT2017060918951N3).

INFORMED CONSENT

The present study followed the Declaration of Helsinki, and written informed consent was obtained from all the participants.

REGISTRY AND REGISTRATION NUMBER OF STUDY/TRIAL

Clinical trial registration number: ID: IRCT2017060918951N3.

ANIMAL STUDIES

Not applicable.

Supporting information

Data S1.

Data S2.

Ghorat F, Sepidarkish M, Saadattalab F, Rezghi M, Shahrestani S, Gholamalizadeh M, et al. The clinical efficacy of Olibanum gum chewing in patients with Mild‐to‐Moderate Alzheimer disease: A randomized Parallel‐Design controlled trial. Neuropsychopharmacol Rep. 2024;44:109–114. 10.1002/npr2.12398

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are made available in the Supplementary Material of this article (Data S1 and Data S2) following approval by Iranian Registry of Clinical Trials (IRCT) (ID: IRCT2017060918951N3).