Acidic cannabinoids in brain disorders: Neurobiological mechanisms, preclinical evidence, and translational challenges.

Rava A.; Di Trapano M.; Tse C.; Ji L.; Bid H.; Trezza V. · Neuroscience and biobehavioral reviews · 2026

**Background & Methods** This is a comprehensive narrative review examining acidic cannabinoids (THCA, CBDA, CBGA) as potential therapeutics for brain disorders. The authors synthesized preclinical evidence and mechanistic data from the literature to assess the neurobiological properties and therapeutic potential of acidic cannabinoids compared to their decarboxylated counterparts. **Key Findings** • Acidic cannabinoids exhibit distinct pharmacokinetic and pharmacodynamic profiles compared to neutral cannabinoids (THC, CBD), with potentially reduced psychotropic liability while maintaining bioactivity through multiple neurobiological mechanisms including serotonergic signaling, endocannabinoid modulation, neuroinflammation reduction, and oxidative stress mitigation. • Preclinical evidence supports therapeutic potential across multiple brain disorder categories: epilepsy, anxiety disorders, depression, psychosis-related conditions, and neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis), with mechanisms involving mitochondrial function optimization, calcium homeostasis restoration, and synaptic transmission modulation. • Artificial intelligence and computational approaches offer promising strategies for accelerating development through target identification, formulation optimization, pharmacokinetic modeling, and personalized intervention design, though significant methodological and translational challenges currently limit clinical application. **Dosage & Administration** Not reported. This review does not provide specific dosing or administration protocols for acidic cannabinoids in clinical settings. **Safety & Adverse Effects** Not reported. The review does not provide detailed safety data or adverse effect profiles for acidic cannabinoids, though it emphasizes reduced psychotropic liability compared to THC as a theoretical advantage. **Evidence Quality** This is a narrative review of preclinical evidence with moderate limitations. The conclusions are based primarily on animal studies and mechanistic research rather than human clinical trials. The authors acknowledge significant translational challenges and methodological constraints limiting current evidence. The review highlights that acidic cannabinoids remain underexplored compounds requiring substantial additional research before clinical applications can be established. The lack of human clinical trial data and the early-stage nature of this field represent critical gaps in the evidence base.

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