Phytocannabinoid cannabidiol (CBD) in neurodegenerative diseases: From polypharmacology to drug development.

Zhang B.; Nan J.; Zhang Y.; Zhang B.; Ke C.; Wang W.; Wu T.; Xia J.; Yang F.; He M. et al. · European journal of medicinal chemistry · 2026

**Background & Methods** This is a comprehensive review article examining cannabidiol (CBD), a non-intoxicating phytocannabinoid, as a multi-target neurotherapeutic candidate for neurodegenerative diseases. The review synthesizes preclinical evidence and clinical findings across multiple neurodegenerative conditions including Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis. **Key Findings** • CBD engages a broad pharmacological target network relevant to neurodegeneration, including cannabinoid receptors, transient receptor potential channels, peroxisome proliferator-activated receptor-γ, adenosine and serotonin signaling systems, voltage-gated calcium channels, and redox-regulatory pathways that converge on key pathogenic mechanisms including neuroinflammation, excitotoxicity, mitochondrial dysfunction, impaired proteostasis, and synaptic injury. • Preclinical studies consistently demonstrate CBD's anti-inflammatory, antioxidant, mitochondria-protective, and neuroprotective pharmacology across multiple disease models, with effects varying by dose, treatment timing, model system, and route of administration. • Clinical evidence remains preliminary and primarily symptomatic rather than disease-modifying, with observed signals in agitation, sleep disturbance, spasticity, quality of life, and neuropsychiatric symptoms but no proven modification of underlying disease progression. **Dosage & Administration** Not reported. The review notes that dose, treatment timing, and route of administration significantly influence CBD's biological activity, but does not specify standardized clinical dosing regimens. **Safety & Adverse Effects** Not reported. The review does not provide specific adverse event data but identifies formulation-dependent exposure and cytochrome P450-mediated metabolism as factors influencing both tolerability and efficacy. **Evidence Quality** This is a narrative review article representing Level IV evidence. Major limitations include reliance on primarily preclinical data, preliminary nature of clinical evidence, and identified knowledge gaps including: low and variable oral bioavailability, incomplete brain exposure characterization, uncertain contributions of active metabolites, limited target-engagement biomarkers, and insufficient exposure-response definition. The review emphasizes that future development requires medicinal chemistry optimization for improved potency, selectivity, metabolic stability, and CNS penetration, alongside biomarker-driven clinical trials to establish pharmacokinetic-pharmacodynamic relationships and evaluate disease-modifying potential.

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