Therapeutic properties of multi-cannabinoid treatment strategies for Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a debilitating neurodegenerative disease characterized by declining cognition and behavioral impairment, and hallmarked by extracellular amyloid-β plaques, intracellular neurofibrillary tangles (NFT), oxidative stress, neuroinflammation, and neurodegeneration. There is currently no cure for AD and approved treatments do not halt or slow disease progression, highlighting the need for novel therapeutic strategies. Importantly, the endocannabinoid system (ECS) is affected in AD. Phytocannabinoids, including cannabidiol (CBD) and Δ⁹-tetrahydrocannabinol (THC), interact with the ECS, have anti-inflammatory, antioxidant, and neuroprotective properties, can ameliorate amyloid-β and NFT-related pathologies, and promote neurogenesis. Thus, in recent years, purified CBD and THC have been evaluated for their therapeutic potential. CBD reversed and prevented the development of cognitive deficits in AD rodent models, and low-dose THC improved cognition in aging mice. Importantly, CBD, THC, and other phytochemicals present in Cannabis sativa interact with each other in a synergistic fashion (the "entourage effect") and have greater therapeutic potential when administered together, rather than individually. Thus, treatment of AD using a multi-cannabinoid strategy (such as whole plant cannabis extracts or particular CBD:THC combinations) may be more efficacious compared to cannabinoid isolate treatment strategies. Here, we review the current evidence for the validity of using multi-cannabinoid formulations for AD therapy. We discuss that such treatment strategies appear valid for AD therapy but further investigations, particularly clinical studies, are required to determine optimal dose and ratio of cannabinoids for superior effectiveness and limiting potential side effects. Furthermore, it is pertinent that future in vivo and clinical investigations consider sex effects.

Keywords: Alzheimer’s disease; cannabidiol (CBD); cannabis extract; cannabis therapeutics; delta-9-tetrahydrocannabinol (THC); dementia; endocannabinod system.

FIGURE 1

The cellular effects of CBD, THC, and CBD+THC in AD. Top: Extracellular; Bottom: Intracellular. (1) CBD and THC each block Aβ deposition and ↑ aggregated Aβ removal. CBD and THC also (weakly) inhibit β-secretase. (2) CBD+THC ↓ Aβ plaques and soluble Aβ₄₂. (3) CBD ↓ transcription of PS1, PS2, BACE1, and GSK-3β, resulting in ↓ enzymes involved Aβ and tau production. (4) Acting via PPARγ, CBD (a) induces APP ubiquitination, resulting in ↓Aβ, (b) ↑ neurogenesis, and (c) ↓ neuroinflammation by suppressing GFAP, IL-1β and iNOS expression. (5) CBD also ↓ iNOS via p38 MAPK and NF- κB. (6) CBD+THC also ↓ neuroinflammation. (7) CBD, THC, and/or CBD+THC ↓astrogliosis and microgliosis. CBD+THC also ↑ Trx2. (8) CBD and THC ↓ROS (with some potential synergism). CBD also ↓ mitochondrial ferritin. (9) CBD ↓ tau hyperphosphorylation via a TRPV1/PI3K/AKT/GSK-3β axis. CBD+THC also ↓ NFT. Aβ, Amyloid-β; APP, amyloid precursor protein; AD, Alzheimer’s disease; BACE1, β-secretase 1; CBD, cannabidiol; Fe, ferritin; GFAP, glial fibrillary acidic protein; GSK-3β, glycogen synthase kinase 3β; iNOS, inducible nitric oxide synthase; IL-1β, interleukin 1 beta; NFT, neurofibrillary tangle; NO, nitric oxide; NF-κB, nuclear factor-κB; p38 MAPK, p38 mitogen-activated protein kinase; P, phosphate group; PI3K/Akt, phosphatidylinositol 3-kinase/Akt kinase; PPARγ, peroxisome proliferator-activated receptor gamma; PS1, presenilin 1; PS2, presenilin 2; ROS, reactive oxygen species; THC, delta-9-tetrahydrocannabinol; TRPVI, transient receptor potential vallinoid 1; Trx2, thioredoxin 2; Ub, ubiquitin. Created with BioRender.com.