Document Type : Original Article


1 Department of Clinical Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

2 Department of Psychiatry, Roozbeh Hospital, Tehran University of Medical Sciences, Tehran, Iran

3 Department of Pharmacognosy, Tehran University of Medical Sciences, Tehran, Iran

4 Research Center for Rational Use of Drugs, Tehran University of Medical Sciences, Tehran, Iran

5 Bahar Sepinood Company, Tehran University Science and Technology Park, College of Agriculture, Alborz, Iran


Objective: This study aimed to assess the efficacy of an herbal formulation 
based on Boswellia sacra in improving cognitive and behavioral symptoms 
in patients with mild cognitive impairment (MCI) and mild-to-moderate 
stages of Alzheimer’s disease (AD). Methods: A 3-month, parallel-group, 
placebo-controlled trial was implemented from October 2021 to April 
2022. Patients with MCI and mild-to-moderate stages of AD aged above 
50 years (n = 60; 40 women, 20 men) enrolled in the study using clinical 
diagnosis and a score of 10–30 on the mini-mental state examination (MMSE) 
test. They were assigned into two groups; one receiving a herbal formulation) 
include B. sacra, Melissa officinalis, Piper longum, Cinnamomum verum, and 
Physalis alkekengi) three times a day and the other receiving a placebo for 
3 months. The main efficacy measures were the changes in cognitive domains 
based on the MMSE and changes in behavioral and psychiatric symptoms 
based on neuropsychiatric inventory (NPI) scores compared with baseline. Side 
effects were also recorded. Findings: Results of this study showed significant 
differences between the two groups after 3 months in terms of all the assessed 
variables, including the overall result of the mean score of MMSE and NPI 
tests (P ≤ 0.001). The herbal formulation had the most considerable effects 
on the domains of orientation, attention, working memory, delay recall, and 
language of the MMSE test. Conclusion: Herbal formulation based on B. sacra
was significantly effective compared to a placebo in improving cognitive and 
behavioral symptoms in patients with MCI and mild-to-moderate AD.


1. Blennow K, de Leon MJ, Zetterberg H. Alzheimer’s disease. 
Lancet 2006;368:387-403.
2. Breijyeh Z, Karaman R. Comprehensive review on Alzheimer’s 
disease: Causes and treatment. Molecules 2020;25:5789.
3. Hardy J, Allsop D. Amyloid deposition as the central event 
in the aetiology of Alzheimer’s disease. Trends Pharm Sci 
4. Liu PP, Xie Y, Meng XY, Kang JS. Erratum: Author Correction: 
History and progress of hypotheses and clinical trials for 
Alzheimer’s disease. Signal Transduct Target Ther 2019;4:37.
5. Xu SS, Cai ZY, Qu ZW, Yang RM, Cai YL, Wang GQ, et al.
Huperzine-A in capsules and tablets for treating patients with 
Alzheimer disease. Zhongguo Yao Li Xue Bao 1999;20:486‑90.
6. Shukla S, Mehta A. Anticancer potential of medicinal plants and 
their phytochemicals: A review. Braz J Bot 2015;38:199-210.
7. Gupta VK, Sharma B. Role of phytochemicals in neurotrophins 
mediated regulation of Alzheimer’s disease. Int J Complement 
Alt Med 2017;7:00231.
8. Roy A. Role of medicinal plants against Alzheimer’s disease. Int 
J Complement Alt Med 2018;11:205-8.
9. Pandey SN, Rangra NK, Singh S, Arora S, Gupta V. Evolving 
role of natural products from traditional medicinal herbs in 
the treatment of Alzheimer’s disease. ACS Chem Neurosci 
10. Zeng GF, Zhang ZY, Lu L, Xiao DQ, Zong SH, He JM. 
Protective effects of ginger root extract on Alzheimer 
disease-induced behavioral dysfunction in rats. Rejuvenation Res 
11. Ozarowski M, Mikolajczak PL, Piasecka A, Kachlicki P, 
Kujawski R, Bogacz A, et al. Influence of the Melissa officinalis
leaf extract on long-term memory in scopolamine animal 
model with assessment of mechanism of action. Evid Based 
Complement Alternat Med 2016;2016:9729818.
12. Baptista FI, Henriques AG, Silva AM, Wiltfang J, 
da Cruz e Silva OA. Flavonoids as therapeutic compounds 
targeting key proteins involved in Alzheimer’s disease. ACS 
Chem Neurosci 2014;5:83-92.
13. Kamal Z, Ullah F, Ayaz M, Sadiq A, Ahmad S, Zeb A, et al. 
Anticholinesterse and antioxidant investigations of crude 
extracts, subsequent fractions, saponins and flavonoids of 
Atriplex laciniata L.: Potential effectiveness in Alzheimer’s and 
other neurological disorders. Biol Res 2015;48:21.
14. Kumar A, Singh A, Aggarwal A. Therapeutic potentials of herbal 
drugs for Alzheimer’s disease – An overview. Indian J Exp Biol 
15. Mahboubi M, Taghizadeh M, Talaei SA, Takht Firozeh SM, 
Rashidi AA, Tamtaji OR. Combined administration of Melissa 
officinalis and Boswellia serrata extracts in an animal model of 
memory. Iran J Psychiatry Behav Sci 2016;10:e681.
16. Hosseini M, Hadjzadeh MA, Derakhshan M, Havakhah S, 
Rassouli FB, Rakhshandeh H, et al. The beneficial effects 
of olibanum on memory deficit induced by hypothyroidism 
in adult rats tested in Morris water maze. Arch Pharm Res 
17. Eivani M, Khosronezhad N. Melissa officinalis: A memory 
enhancer remedy. Physiol Pharmacol 2020;24:159-64.
18. Ulbricht C, Brendler T, Gruenwald J, Kligler B, Keifer D, 
Abrams TR, et al. Lemon balm (Melissa officinalis L.): An 
evidence-based systematic review by the Natural Standard 
Research Collaboration. J Herb Pharmacother 2005;5:71-114.
19. Mahboubi M. Melissa officinalis and rosmarinic acid in 
management of memory functions and Alzheimer disease. Asian 
Pac J Trop Biomed 2019;9:47-52.
20. Naseri M, Mianroodi RA, Pakzad Z, Falahati P, Borbor M, 
Azizi H, et al. The effect of Melissa officinalis L. extract on 
learning and memory: Involvement of hippocampal expression 
of nitric oxide synthase and brain-derived neurotrophic factor in 
diabetic rats. J Ethnopharmacol 2021;276:114210.
21. Malik J, Munjal K, Deshmukh R. Attenuating effect of 
standardized lyophilized Cinnamomum zeylanicum bark 
extract against streptozotocin-induced experimental dementia 
of Alzheimer’s type. J Basic Clin Physiol Pharmacol 
22. Ramazani E, YazdFazeli M, Emami SA, Mohtashami L, 
Javadi B, Asili J, et al. Protective effects of Cinnamomum 
verum, Cinnamomum cassia and cinnamaldehyde against 
6-OHDA-induced apoptosis in PC12 cells. Mol Biol Rep 
23. Momtaz S, Hassani S, Khan F, Ziaee M, Abdollahi M. 
Cinnamon, a promising prospect towards Alzheimer’s disease. 
Pharmacol Res 2018;130:241-58.
24. Yadav V, Krishnan A, Vohora D. A systematic review on Piper 
longum L.: Bridging traditional knowledge and pharmacological 
evidence for future translational research. J Ethnopharmacol 
25. Hritcu L, Noumedem JA, Cioanca O, Hancianu M, Postu P, 
Mihasan M. Anxiolytic and antidepressant profile of the 
methanolic extract of Piper nigrum fruits in beta-amyloid (1–42) 
rat model of Alzheimer’s disease. Behav Brain Funct 2015;11:13.
26. Ahmadian-Attari MM, Ahmadiani A, Kamalinejad M, 
Dargahi L, Shirzad M, Mosaddegh M. Treatment of Alzheimer’s 
disease in Iranian traditional medicine. Iran Red Crescent Med J 
27. Moniruzzaman M, Chin YW, Cho J. HO‑1 dependent antioxidant 
effects of ethyl acetate fraction from Physalis alkekengi fruit 
ameliorates scopolamine-induced cognitive impairments. Cell 
Stress Chaperones 2018;23:763-72.
28. Liu X, Bian J, Li D, Liu C, Xu S, Zhang G, et al. Structural 
features, antioxidant and acetylcholinesterase inhibitory activities 
of polysaccharides from stem of Physalis alkekengi L. Ind Crops 
Prod 2019;129:654-61.
29. Vicas LG, Jurca T, Baldea I, Filip GA, Olteanu D, Clichici SV, 
et al. Physalis alkekengi L. extract reduces the oxidative stress, 
inflammation and apoptosis in endothelial vascular cells exposed 
to hyperglycemia. Molecules 2020;25:3747.
30. Gruenwald J, Brendler T, Jaenicke C, editors. PDR for Herbal 
Medicines. 2nd ed. Montvale (NJ): Thomson Healthcare Inc; 
31. Velioglu YS, Mazza G, Gao L, Oomah BD. Antioxidant activity 
and total phenolics in selected fruits, vegetables and grain 
products. J Agric Food Chem 1998;46:4113-7.
32. Seyedian M, Mahtab F, Maryam N, Saharnaz N, 
Delavar A, Ghasemzadeh HA. Validity of the Farsi version of 
mini mental state examination. J Med Counc Islam Repub Iran 
33. Noroozian M, Reisberg B, Farhadi A, Sharifi F, 
Sadeghi Zangeneh A, Mohammadi M. Translation and 
psychometric evaluation of a Persian version of the functional 
assessment staging scale (I-FAST) in older patients with mild 
cognitive impairment and Alzheimer’s disease in Iran. Acta 
Neurol Belg 2022;122:987-96.
34. Cummings JL. The Neuropsychiatric Inventory: Assessing 
psychopathology in dementia patients. Neurology 
1997;48 5 Suppl 6:S10-6.
35. Nemat AZ, Siham MA, Karam AM, Nadia AM, 
Abdel Fattah HM, Abdel Razik HF, et al. Effect of Boswellia 
serrata on Alzheimer’s disease induced in rats. J Arab Soc Med 
Res 2013;8:1-11.
36. Hosseini-Sharifabad M, Esfandiari E. Effect of Boswellia serrata
gum resin on the morphology of hippocampal CA1 pyramidal 
cells in aged rat. Anatom Sci Int 2015;90:47-53.
37. Ebrahimpour S, Fazeli M, Mehri S, Taherianfard M, 
Hosseinzadeh H. Boswellic acid improves cognitive function in 
a rat model through its antioxidant activity: – Neuroprotective 
effect of boswellic acid. J Pharmacopuncture 2017;20:10-7.
38. Ameen AM, Elkazaz AY, Mohammad HM, Barakat BM. 
Anti‑inflammatory and neuro‑protective activity of boswellic 
acids in rotenone parkinsonian rats. Can J Physiol Pharmacol 
39. Sayed AS, Gomaa IE, Bader M, Sayed ND. Role of 
3-Acetyl-11-Keto-Beta-Boswellic acid in counteracting 
LPS‑induced neuro inflammation via modulation of miRNA‑155. 
Mol Neurobiol 2018;55:5798-80.
40. Noguchi-Shinohara M, Ono K, Hamaguchi T, Nagai T, 
Kobayashi S, Komatsu J, et al. Safety and efficacy of Melissa 
officinalis extract containing rosmarinic acid in the prevention of 
Alzheimer’s disease progression. Sci Rep 2020;10:1862.
41. Kamli MR, Sharaf AA, Sabir JS, Rather IA. Phytochemical 
screening of Rosmarinus officinalis L. as a potential 
anticholinesterase and antioxidant-medicinal plant for cognitive 
decline disorders. Plants (Basel) 2022;11:514.
42. Akhondzadeh S, Noroozian M, Mohammadi M. Melissa 
officinalis extract inthe treatment of patients with mild to 
moderate Alzheimer’s disease: A double-blind, randomised, 
placebo controlled trial. J Neurol Neurosurg Psychiatry 
43. Peterson DW, George RC, Scaramozzino F, LaPointe NE, 
Anderson RA, Graves DJ, et al. Cinnamon extract inhibits 
tau aggregation associated with Alzheimer’s disease in vitro. 
J Alzheimers Dis 2009;17:585-97.
44. Kang YJ, Seo DG, Park SY. Phenylpropanoids from cinnamon 
bark reduced β-amyloid production by the inhibition of 
β-secretase in Chinese hamster ovarian cells stably expressing 
amyloid precursor protein. Nutr Res 2016;36:1277-84.
45. Hussain G, Rasul A, Anwar H, Aziz N, Razzaq A, Wei W,
et al. Role of plant derived alkaloids and their mechanism in 
neurodegenerative disorders. Int J Biol Sci 2018;14:341-57.
46. Hritcu L, Noumedem JA, Cioanca O, Hancianu M, Kuete V, 
Mihasan M. Methanolic extract of Piper nigrum fruits improves 
memory impairment by decreasing brain oxidative stress in 
amyloid beta (1-42) rat model of Alzheimer’s disease. Cell Mol 
Neurobiol 2014;34:437-49.