Abstract Methamphetamine (MP) is a widely abused psychostimulant. There are currently no FDA approved pharmacotherapies for the MP addict. The antidepressant, mirtazapine (Mirt) is a high affinity antagonist at several monoaminergic receptors that are affected by MP. This study evaluated the potential of Mirt as a therapeutic agent for MP addiction and described associated changes in neuronal signaling. A single pairing conditioned place preference (CPP) paradigm was utilized as a behavioral measure of MP -induced effects. Rats learned to associate unique environmental cues with the effects of 1.0 mg/kg (i.p.) MP (day 1) or saline (day 2). Mirt (5.0 mg/kg i.p.) was given in the home cage on day 3 and CPP was assessed on day 4. To evaluate signaling events that correlate with this behavior, brain tissue of these rats were dissected for immunoblot assays of extracellular signal-regulated kinase (ERK) and a transcriptional regulator, cAMP response element-binding protein (CREB) after the CPP test. During the CPP test, rats conditioned with MP spent more time in the environment associated with MP. Importantly, rats given Mirt did not express CPP. MP-induced CPP was associated with a decrease in phosphorylated CREB (pCREB) in the ventral tegmental area, and decreased phosphorylated ERK and pCREB in the nucleus accumbens and treatment with Mirt did not reverse these changes. No changes in signaling proteins were obtained from rats similarly treated with MP and Mirt, without exposure to cues of the conditioning paradigm. Overall, a post-conditioning treatment with Mirt can nullify MP-induced associative learning. However, additional studies are needed to ascertain the molecular events underlying this effect of Mirt.