Preclinical evidence for statin modulation of analgesic tolerance and substance use disorders: a narrative review

<i>Background:</i> Statins, widely prescribed for their lipid-lowering effects, have emerged as potential neuroactive agents with anti-inflammatory and neuromodulatory properties relevant to neurobiology of substance use disorders (SUDs). However, preclinical evidence supporting their role in modulating drug use-related behaviors remains scattered and requires critical synthesis.<i>Methods:</i> A comprehensive narrative search was conducted in Google Scholar, Scopus, and PubMed up to May 2025 using combinations of terms related to drug dependence, SUD, relapse, withdrawal, and statins. Eligible studies included original animal or in vitro investigations assessing statins in contexts of drug exposure, tolerance, or relapse. Non-preclinical and non-brain-focused studies were excluded. The screening process followed PRISMA principles, and data were categorized by experimental model and outcome domain.<i>Results:</i> Of 61 initial records, 13 preclinical studies met all inclusion criteria. These studies encompassed both pain-related opioid tolerance/withdrawal models and SUDs paradigms involving morphine, nicotine, or cocaine. Across models, lipophilic statins such as simvastatin and atorvastatin consistently attenuated withdrawal symptoms, relapse behaviors, oxidative stress, and neuroinflammatory markers, while enhancing neurotrophic signaling and cognitive outcomes.<i>Conclusion:</i> Preclinical evidence suggests that statins, particularly lipophilic agents, may influence neural and behavioral mechanisms underlying addiction through anti-inflammatory and neuromodulatory actions. These findings highlight a promising translational avenue for adjunctive use of statins in SUDs, warranting further mechanistic and clinical studies.