Acute Ultra Low Dose THC Attenuates Anxiety-Like Behavior in a Mouse Model for Major-Depressive Disorder.

Grad M.; Volkov H.; Shomron N. · Journal of molecular neuroscience : MN · 2026

**Background & Methods** This review examines the potential therapeutic effects of ultra-low dose THC (0.002 mg/kg) in a chronic mild stress mouse model of major depressive disorder. The study employed next-generation sequencing techniques to characterize molecular mechanisms underlying anxiolytic effects and identified changes in neuronal differentiation and synaptic plasticity-related gene expression. **Key Findings** - Acute, ultra-low dose THC (0.002 mg/kg) significantly attenuated anxiety-like behavior in mice exposed to chronic mild stress, a validated MDD model - Molecular analysis identified Elmo domain containing 1 (Elmod1) as a key molecular mediator of the observed anxiolytic effects, suggesting a specific mechanistic pathway independent of traditional cannabinoid psychoactivity - Glucocorticoid-related mRNA expression changes were implicated in mediating the anxiolytic response, indicating involvement of the hypothalamic-pituitary-adrenal (HPA) axis and stress-response regulation **Dosage & Administration** Ultra-low dose THC: 0.002 mg/kg administered acutely to mouse models. Route of administration not specified. **Safety & Adverse Effects** Not reported. The study does not provide information on adverse effects, tolerability, or toxicity profiles. The ultra-low dose employed may have been specifically selected to minimize psychoactive effects typical of standard THC dosing. **Evidence Quality** This is a review-type study with significant limitations regarding clinical translational potential. Findings are derived exclusively from preclinical mouse models and cannot be directly extrapolated to human populations. The extreme ultra-low dosing (0.002 mg/kg) requires careful interpretation regarding practical human application and dose scaling. The study's strength lies in its mechanistic investigation using next-generation sequencing, identifying specific molecular pathways rather than merely documenting behavioral outcomes. However, lack of reported controls, blinding methodology, and sample sizes limits internal validity assessment. The involvement of glucocorticoid pathways suggests potential interactions with endocrine systems requiring further investigation in clinical settings. Before clinical translation, findings require validation in additional animal models, dose-response studies, and eventual human trials examining safety, efficacy, and optimal dosing parameters.

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