Convergent neuroprotective effects of omega-3 fatty acids and psilocybin in preclinical models of stress and alcohol exposure: A scoping review

Chronic stress and alcohol exposure can impair neuroplasticity through neurotrophic, inflammatory, and stress-axis dysregulation. Omega-3 fatty acids (ω-3) and psilocybin have emerged as potential neuroprotective interventions, but their convergent and divergent effects in preclinical models remain unclear. We conducted a scoping review following PRISMA-ScR and PECO guidelines to map evidence from rodent studies examining chronic stress or alcohol exposure, and the effects of ω-3 supplement and/or psilocybin on brain outcomes. Six PubMed search strategies identified 16,505 records; following the AI-assisted screening and selection process (Claude, Anthropic) 90 studies were assessed in full text and 60 met eligibility criteria. The hippocampus was most frequently studied (n=42). 16 studies assessed BDNF or TrkB, with consistent positive effects of ω-3 on BDNF, whereas responses to psilocybin varied across stress paradigms. Both interventions converged on shared intracellular signaling and structural plasticity, although their temporal profiles differed: psilocybin produced rapid effects after single administration, while ω-3 required sustained exposure. Notably, none of the 19 studies combining ω-3 or psilocybin in alcohol exposure models assessed BDNF or TrkB, revealing an evidence gap. Overall, the literature supports partially overlapping neuroprotective mechanisms but direct evidence of their combined effects is currently lacking.