Minor Phytocannabinoids as Candidate Multi-Target Modulators of Endoplasmic Reticulum Stress-Linked Proteostasis Failure in Alzheimer’s Disease: A Mechanistic Review

Alzheimer’s disease (AD) involves pathological processes that may limit single-target therapeutic strategies. Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) dysregulation may contribute to proteostasis failure. This review examines whether minor phytocannabinoids from Cannabis sativa L.—cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), cannabidivarin (CBDV), and tetrahydrocannabivarin (THCV)—warrant investigation as modulators of ER stress-linked proteostasis failure in AD. Evidence is organized around calcium dyshomeostasis, mitochondrial dysfunction and oxidative stress, neuroinflammation, and autophagic impairment as processes that may converge on ER stress, and limited direct evidence for UPR marker changes is evaluated separately. These compounds show overlapping but distinct target profiles involving cannabinoid receptors, transient receptor potential (TRP) channels, peroxisome proliferator-activated receptor γ, mitochondrial and redox pathways, and inflammatory signaling. Available evidence associates CBN primarily with mitochondrial stress pathways, while its involvement in ER–mitochondria signaling remains hypothetical. CBG has been associated with oxidative and inflammatory pathways, THCV with inflammatory signaling, and CBC and CBDV with TRP-related calcium signaling and autophagic pathways. CBDV and CBG have been associated with UPR marker changes in non-neuronal cells, although their functional direction and relevance to AD remain uncertain. Minor phytocannabinoids may serve as pharmacological probes for ER stress-linked proteostasis in AD, and validation in AD-relevant neuronal, organoid, in vivo, and pharmacokinetic studies is required before therapeutic potential can be established.