Persistent brain alterations after adolescent exposure to the synthetic cannabinOid 5F-MDMB-PICA in male mice: a metabolomic fingerprint.

Locci E.; Pintori N.; Chighine A.; Kesharwani R.; Serra M.; Aloja E.; De Luca M. · Toxicology · 2026

**Background & Methods** This preclinical study investigated persistent brain metabolomic changes following adolescent exposure to 5F-MDMB-PICA, a synthetic cannabinoid receptor agonist (SCRA). Male C57BL/6 mice received intraperitoneal injections of 5F-MDMB-PICA (0.01 mg/kg) daily for 14 consecutive days during adolescence (Post Natal Days 38-51), with brain tissue analysis performed 15 days post-discontinuation using 1H Nuclear Magnetic Resonance (NMR) spectroscopy. **Key Findings** • Regional metabolomic remodeling was dose- and region-dependent, with the caudate-putamen (CPu) showing the most extensive changes, followed by medial prefrontal cortex (mPFC) and cerebellum (Cb), while nucleus accumbens (NAc) demonstrated robust homeostatic buffering. • CPu exhibited significant metabolite alterations including increased GABA, O-phosphocholine, choline, and lysine alongside decreased creatine, glutamate, glutamine, and lactate; mPFC showed decreased glutamine with increased aspartate; Cb demonstrated increased succinate and inosine. • Detected metabolic patterns suggest disrupted mitochondrial respiration, impaired neuron-astrocyte metabolic coupling, energetic deficits, neurotransmitter imbalances, and potential neuroinflammatory processes persisting into adulthood despite drug discontinuation. **Dosage & Administration** 5F-MDMB-PICA at 0.01 mg/kg administered via intraperitoneal injection daily for 14 consecutive days during adolescence (Post Natal Days 38-51). **Safety & Adverse Effects** Not reported. The study focused on metabolomic alterations rather than acute behavioral or physiological toxicity markers. **Evidence Quality** This review-type preclinical study has notable limitations: single-dose investigation limits dose-response characterization; male-only cohort restricts sex-comparative conclusions; short 15-day post-exposure observation window may not capture longer-term trajectories; lack of behavioral or functional correlates to metabolomic changes; and absence of mechanistic validation (e.g., mitochondrial function assays, neuroinflammatory markers). The study demonstrates strong NMR metabolomic methodology but represents early-stage evidence requiring functional validation and replication. The findings provide important foundational data regarding SCRA neurotoxicity during critical developmental windows, supporting regulatory concerns about adolescent synthetic cannabinoid exposure, though clinical applicability requires human translational studies.

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