Effects of Beta Lactams on Behavioral Outcomes of Substance Use Disorders: A Meta-Analysis of Preclinical Studies

Introduction: Preclinical studies demonstrated that beta-lactams have neuroprotective effects in conditions involving glutamate neuroexcitotoxicity, including substance use disorders (SUDs). This meta-analysis aims to analyze the existing evidences on the effects of beta-lactams as glutamate transporter 1 (GLT-1) upregulators in animal models of SUDs, identification of gaps in the literature, and setting the stage for potential translation into clinical phases.

Methods: Meta-analysis was conducted on preclinical studies retrieved systematically from MEDLINE and ScienceDirect databases. Abused substances were identified by refereeing to the National Institute on Drug Abuse (NIDA). The results were quantitatively described with a focus on the behavioral outcomes. Treatment effect sizes were described using standardized mean difference, and they were pooled using random effect model. I²-statistic was used to assess heterogeneity, and Funnel plot and Egger's test were used for assessment of publication bias.

Results: Literature search yielded a total of 71 studies that were eligible to be included in the analysis. Through these studies, the effects of beta-lactams were evaluated in animal models of nicotine, cannabis, amphetamines, synthetic cathinone, opioids, ethanol, and cocaine use disorders as well as steroids-related aggressive behaviors. Meta-analysis showed that treatments with beta-lactams consistently reduced the pooled undesired effects of the abused substances in several paradigms, including drug-self administration, conditioned place preference, drug seeking behaviors, hyperlocomotion, withdrawal syndromes, tolerance to analgesic effects, hyperalgesia, and hyperthermia.

Conclusion: This meta-analysis revealed that enhancing GLT-1 expression in the brain through beta-lactams seemed to be a promising treatment approach in the context of substance use disorders, as indicated by results in animal models.