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. 2025 May 9:17:1567650.
doi: 10.3389/fnagi.2025.1567650. eCollection 2025.

Effects of cannabidiol (CBD) treatment on age-related cognitive decline in C57 mice

Behroo Mirza Agha  1 , Merrin Monteith  1 , Jarem Earl  1 , Keona Ganske  1 , Tina Kaloa  1 , Kelan J McDonald  1 , Abigail G Nixon  1 , Maleeha Panjwani  1 , Danika Robinson  1 , Valeria Rusnak  1 , Majid H Mohajerani  2 , Igor Kovalchuk  3 , Robert J Sutherland  1 , Nancy S Hong  1 , Robert J McDonald  1
Affiliations

Effects of cannabidiol (CBD) treatment on age-related cognitive decline in C57 mice

Behroo Mirza Agha et al. Front Aging Neurosci. .

Abstract

Aging is associated with cognitive decline, and currently, there are no approved medications that can prevent these impairments. Recently, cannabinoids derived from Cannabis sativa have emerged as promising therapeutic compounds with neuroprotective, anti-inflammatory, and cognitive-enhancing properties. Despite their benefits, further research is needed to fully understand their efficacy across various conditions. This study investigates the effects of cannabidiol (CBD) on memory impairment and brain inflammation in aging mice. Fourteen-month-old C57 mice were administered CBD orally for 7 months and subsequently evaluated between 19 and 21 months of age using behavioral tasks that are sensitive to dysfunction of the perirhinal cortex, hippocampus, amygdala, and various brain regions that are crucial for motor control and coordination. The findings of this study indicate that CBD reduces inflammatory response in the brain and improves cognitive decline associated with aging.

Keywords: acetylcholine; age-related cognitive decline; aging; cannabidiol (CBD); hippocampus; inflammation; learning and memory; prefrontal cortex.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

Figure 1
Figure 1
Study timeline and animal groups. (a) Time course of treatment and behavioral training/tests. Behavioral tests included novel object recognition (NOR), balance beam (BB), Morris water task (MWT), and discriminative fear conditioning to context (DFCTC). During behavioral training/testing, treatment with CBD and vehicle was continued daily. (b) The number and sex of mice per group. The CBD group received CBD in grapeseed oil and Nutella, whereas the vehicle group received only grapeseed oil and Nutella.
Figure 2
Figure 2
Effect of CBD on learning and memory function of 19-month-old C57BL/6 mice in the novel object recognition (NOR) task. (a) Investigation ratio for vehicle and CBD groups in test 1, in which a familiar and a new object are used. (b) Investigation ratio for vehicle and CBD groups in test 2, in which the new object in test 1 has become familiar and another new object is used. (c) Investigation ratio for vehicle and CBD groups 1 month later with the familiar object in test 1 and a completely novel object. *P < 0.05 and ***P < 0.001 are considered statistically significant. a—as compared to 0.5 investigation ratio (chance level). Vehicle group (n = 9; 7 male and 2 female), CBD group (n = 10; 8 male and 2 female).
Figure 3
Figure 3
Effect of CBD on motor balance and coordination of 19-month-old C57BL/6 mice in the balance beam (BB) task. (a) Average (mean ± SEM) latency to cross the beam in three trials for vehicle and CBD groups. (b) Average (mean ± SEM) number of foot slips in three trials for vehicle and CBD groups. (c) Average (mean ± SEM) number of falls in three trials for vehicle and CBD groups. Vehicle group (n = 9; 7 male and 2 female), CBD group (n = 10; 8 male and 2 female).
Figure 4
Figure 4
Effect of CBD on spatial learning and memory function of 19-month-old C57BL/6 mice in the Morris water task (MWT). (a) Mean latency (mean ± SEM) to find the hidden platform during the acquisition phase for vehicle and CBD groups. (b) Mean swimming speed (mean ± SEM) of mice during the acquisition phase for vehicle and CBD groups. (c) Percent thigmotaxis during the acquisition phase for vehicle and CBD groups. (d) Percent time spent in the target quadrant and average of other three quadrants during the probe trial for vehicle and CBD groups. (e) Mean (mean ± SEM) number of annulus crossing during the probe trial for vehicle and CBD groups. (f) Mean (mean ± SEM) proximity during the probe trial for vehicle and CBD groups. *P < 0.05 and **P < 0.01, are considered statistically significant. a—as compared to day 1 in CBD group. b—as compared to day 1 in vehicle group. Vehicle group (n = 9; 7 male and 2 female), CBD group (n = 10; 8 male and 2 female).
Figure 5
Figure 5
Effect of CBD on fear learning and memory function of 19-month-old C57BL/6 mice in discriminative fear conditioning to context task (DFCTC). (a) Mean dwell time (mean ± SEM) of mice during pre-exposure to contexts that were later assigned paired or unpaired in vehicle and CBD groups. (b) Mean freezing time (mean ± SEM) of mice in paired and unpaired contexts in vehicle and CBD groups. (c) Mean dwell time (mean ± SEM) of mice during the preference test in paired and unpaired contexts in vehicle and CBD groups. **P < 0.01 and ***P < 0.001 are considered statistically significant. Vehicle group (n = 9; 7 male and 2 female), CBD group (n = 10; 8 male and 2 female).
Figure 6
Figure 6
Effect of CBD on hippocampus volume in 21-month-old C57BL/6 mice. Hippocampal volume (mean ± SEM) in aged vehicle and CBD groups. Scale bars represent 1 mm. Vehicle group (n = 9; 7 male and 2 female), CBD group (n = 9; 7 male and 2 female).
Figure 7
Figure 7
Effect of CBD on astrocytes in the mPFC, HPC, and PRh of 21-month-old C57BL/6 mice. (a) Percent coverage of GFAP in the mPFC (mean ± SEM) in vehicle and CBD groups. (b) Percent coverage of GFAP in the HPC (mean ± SEM) in vehicle and CBD groups. (c) Percent coverage of GFAP in the PRh (mean ± SEM) in vehicle and CBD groups. (d) Photomicrograph of GFAP in representative half slices for the mPFC, HPC, and PRh in aged vehicle and CBD-treated mice. Scale bars represent 1 mm. *P < 0.05 is considered statistically significant. Vehicle group (n = 9; 7 male and 2 female), CBD group (n = 9; 7 male and 2 female).
Figure 8
Figure 8
Effect of CBD on microglia in the mPFC and HPC of 21-month-old C57BL/6 mice. (a) Percent coverage of Iba1 in the mPFC (mean ± SEM) in vehicle and CBD groups. (b) Percent coverage of Iba1 in the HPC (mean ± SEM) in vehicle and CBD groups. (c) Photomicrograph of Iba1 in representative half slices for the mPFC and HPC in aged vehicle and CBD-treated mice. Scale bars represent 1 mm. Vehicle group (n = 9; 7 male and 2 female), CBD group (n = 9; 7 male and 2 female).
Figure 9
Figure 9
Effect of CBD on ChAT-positive neurons in the MS and DB basal forebrain of 21-month-old C57BL/6 mice. (a) Number of ChAT-positive neurons per slices in the MS (mean ± SEM) in vehicle and CBD groups. (b) Number of ChAT-positive neurons per slices in the DB (mean ± SEM) in vehicle and CBD groups. (c) Representative photomicrographs of ChAT-positive neurons in the MS and DB in aged vehicle and CBD-treated mice. Scale bar represents 500 μm. Vehicle group (n = 9; 7 male and 2 female), CBD group (n = 9; 7 male and 2 female).
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