The effect of concurrent application of the deep brain stimulation of the nucleus accumbens and cannabidiol injection during extinction period on reinstatement of METH-induced conditioned place preference in extinguished rats.

Mohammadi M.; Zendehdel M.; Haghparast A. · Physiology & behavior · 2026

**Background & Methods** This experimental study evaluated the combined effects of low-frequency deep brain stimulation (DBS) of the nucleus accumbens and cannabidiol (CBD) injection on methamphetamine (METH)-induced addiction in rats. CBD was administered intracerebroventricularly at doses of 2.5, 5, and 10 μg/5 μL during the extinction phase, while low-frequency DBS (10 Hz for 30 minutes) was simultaneously applied to the nucleus accumbens; outcomes were assessed using conditioned place preference (CPP) methodology during extinction and reinstatement phases. **Key Findings** • CBD at the highest dose (10 μg/5 μL) and DBS alone both facilitated extinction of METH-induced CPP, with DBS showing numerically faster extinction latency, though this difference was not statistically significant compared to CBD alone. • The combination of DBS with CBD at all tested doses significantly reduced mean extinction latency compared to control groups, with the highest CBD dose (10 μg/5 μL) combination showing statistically significant improvement over DBS monotherapy. • Neither CBD (10 μg/5 μL) nor DBS alone prevented CPP reinstatement; however, the combination treatment at all CBD doses significantly decreased CPP scores during reinstatement testing, suggesting synergistic effects requiring concurrent application. **Dosage & Administration** CBD: Injected intracerebroventricularly at doses of 2.5, 5, and 10 μg/5 μL during the extinction phase. DBS: Low-frequency stimulation at 10 Hz administered to the nucleus accumbens for 30 minutes during extinction phase. Both interventions were applied concurrently. **Safety & Adverse Effects** Not reported. **Evidence Quality** This preclinical animal study (rat model) provides mechanistic insights into addiction neurobiology but cannot be directly extrapolated to human clinical applications. Significant limitations include the use of an animal model rather than human subjects, lack of long-term follow-up data, absence of reported adverse effects or safety monitoring, and limited mechanistic explanation of how CBD and DBS produce synergistic effects. The findings suggest potential therapeutic benefit of combination treatment but require further validation in clinical trials before clinical implementation.

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