The Effects of Sedatives on Tobacco Use Disorder Version 2

This double-blind, placebo-controlled, randomized mechanistic clinical trial will test non-treatment seeking smokers with an intravenous infusion of ketamine (0.71 mg/kg), midazolam (0.025 mg/kg), dexmedetomidine (0.025 mg/kg), or placebo, at least 2 weeks apart. Participants will complete 7-day ecological momentary assessment (EMA) of daily craving, withdrawal, and smoking behavior before and after each infusion. They will be asked to abstain from tobacco/nicotine for twenty-four hours post-infusion to induce withdrawal symptoms and return to the lab the following day to complete measures of craving, withdrawal, an MRI scan, and smoking latency. After this study visit, participants will be allowed to smoke as usual for the rest of the EMA diary period. Physical and subjective effects and adverse effects will be closely monitored throughout.