Cannabinoid and Terpene Modulation of Microglial Neuroinflammatory Pathways in Neurodegenerative Disease: Implications for Cognitive and Emotional Dysfunction

Precious Melchizedek, MS
University of Maryland - Baltimore

Background: Neurodegenerative diseases such as Alzheimer’s, Parkinson’s disease, and multiple sclerosis, have distinct pathological characteristics but converge on chronic neuroinflammation, microglial dysfunction, oxidative stress, and progressive neuronal injury. These hallmarks contribute to cognitive decline and disturbances in emotional processing and regulation. Research has emerged supporting phytocannabinoids and cannabis-derived terpenes as potential multi-target novel therapeutic agents capable of influencing neuroimmune and neuronal signaling pathways.

Objective(s): This review examined evidence regarding the effects of phytocannabinoids and cannabis-derived terpenes on microglial activation and associated neuroinflammatory pathways in neurodegenerative disease, with particular emphasis on mechanisms potentially relevant to cognitive and emotional function.

Methods: A structured literature review was conducted of peer-reviewed studies examining cannabinoids, terpenes, microglial activation, neuroinflammation, oxidative stress, neuroprotection, cognition, and emotional function in neurodegenerative disorders. Literature was evaluated according to compound, molecular target, disease context, experimental model, and reported neurological or behavioral outcomes.

Results: The literature demonstrates that cannabinoid signaling, particularly through CB2-associated pathways, can influence microglial inflammatory responses, cytokine signaling, and oxidative stress. Additional evidence implicates cannabinoid-responsive pathways including PPARγ, NF-κB, NLRP3, and TRP channels in neuroinflammatory regulation. Emerging preclinical evidence suggests that minor phytocannabinoids and selected terpenes, including β-caryophyllene, linalool, and α-pinene, may exert complementary anti-inflammatory, antioxidant, and neuroprotective effects. Across neurodegenerative models, these mechanisms may converge on preservation of neuronal and synaptic function within circuits supporting cognition and emotional processing.

Conclusions: Current evidence supports further investigation of cannabinoids and cannabis-derived terpenes as multi-target modulators of neuroimmune dysfunction in neurodegenerative disease. Although clinical evidence remains limited and substantial mechanistic and translational gaps persist, targeting microglial dysregulation, oxidative stress, and neural circuit dysfunction represents a promising framework for developing novel cannabinoid-based therapeutic strategies.