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Review
. 2024 Aug 7;25(16):8630.
doi: 10.3390/ijms25168630.

A Comprehensive Exploration of the Multifaceted Neuroprotective Role of Cannabinoids in Alzheimer's Disease across a Decade of Research

Petros Tyrakis  1 , Christina Agridi  1 , Malamati Kourti  1
Affiliations
Review

A Comprehensive Exploration of the Multifaceted Neuroprotective Role of Cannabinoids in Alzheimer's Disease across a Decade of Research

Petros Tyrakis et al. Int J Mol Sci. .

Abstract

Alzheimer's disease (AD), a progressive neurodegenerative disorder, manifests through dysregulation of brain function and subsequent loss of bodily control, attributed to β-amyloid plaque deposition and TAU protein hyperphosphorylation and aggregation, leading to neuronal death. Concurrently, similar cannabinoids to the ones derived from Cannabis sativa are present in the endocannabinoid system, acting through receptors CB1R and CB2R and other related receptors such as Trpv-1 and GPR-55, and are being extensively investigated for AD therapy. Given the limited efficacy and adverse effects of current available treatments, alternative approaches are crucial. Therefore, this review aims to identify effective natural and synthetic cannabinoids and elucidate their beneficial actions for AD treatment. PubMed and Scopus databases were queried (2014-2024) using keywords such as "Alzheimer's disease" and "cannabinoids". The majority of natural (Δ9-THC, CBD, AEA, etc.) and synthetic (JWH-133, WIN55,212-2, CP55-940, etc.) cannabinoids included showed promise in improving memory, cognition, and behavioral symptoms, potentially via pathways involving antioxidant effects of selective CB1R agonists (such as the BDNF/TrkB/Akt pathway) and immunomodulatory effects of selective CB2R agonists (TLR4/NF-κB p65 pathway). Combining anticholinesterase properties with a cannabinoid moiety may enhance therapeutic responses, addressing cholinergic deficits of AD brains. Thus, the positive outcomes of the vast majority of studies discussed support further advancing cannabinoids in clinical trials for AD treatment.

Keywords: Alzheimer’s disease; CB1R; CB2R; Cannabis sativa; GPR-55; Trpv-1; cannabinoids.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Summary of the effects of CB1R and CB2R agonists in in vitro and in vivo models.
Figure 2
Figure 2
Summary of the effects of non-selective CB1R and CB2R agonists in in vitro and in vivo models and in patients with Alzheimer’s disease.
Figure 3
Figure 3
Summary of the effects of TRPV-1 and GPR-55 agonists in in vitro and in vivo models.
See this image and copyright information in PMC

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