We propose a multi-site, double-blind, randomized clinical trial of the 5-HT2A receptor agonist psilocybin for smoking cessation. We previously conducted an open-label pilot trial (N = 15) of psilocybin paired with cognitive behavior therapy (CBT). Data showed a biologically-verified 7-day point-prevalence abstinence rate of 67% at 12 months and 60% at 2.5 years (continuous abstinence rates: 53% and 47%, respectively) (Johnson et al., 2014; Johnson et al., 2017). We are now conducting an open-label randomized comparative efficacy trial of psilocybin vs. nicotine patch, both in combination with CBT. Interim results (N = 44; 22 per group) show greater biologically-verified abstinence rates at 12 months for psilocybin: 7-day point-prevalence: 59% vs. 27%; continuous abstinence: 36% vs. 9%. Despite these promising findings, we have yet to conduct a double-blind study of psilocybin for smoking cessation. Furthermore, previous psilocybin study samples have been largely White with higher socioeconomic status (SES), partly due to lack of participant compensation and modest funding from non-profit organizations. The current trial will address these issues across three sites with experience in conducting psilocybin research: Johns Hopkins, the University of Alabama at Birmingham (UAB), and New York University (NYU). A diverse sample with regard to ethnoracial identity and SES will be recruited at each site with compensation for study visits. The proposed double-blind study will treat 66 participants (22 at each site), randomized to receive either: 1) psilocybin; 20 mg/70 in session 1 and 30 mg/70 kg in session 2, with sessions 1 week apart; or 2) niacin; 250 mg in session 1 and 375 mg in session 2, with sessions 1 week apart. Niacin was selected because it has been used as an active placebo in two previous randomized therapeutic trials of psilocybin (Grob et al., 2011; Ross et al., 2016), and the FDA has informed us that niacin is their preferred active placebo for psilocybin. CBT will be administered to both groups and will allow us to test psilocybin?s efficacy above and beyond an established treatment approach. Biochemically-confirmed 7-day point-prevalence abstinence will be assessed throughout for up to 12 months. We hypothesize that psilocybin (compared to niacin) will cause increased biologically-confirmed 7-day point-prevalence abstinence at 12-month follow-up. Based on pilot data, we will test cognitive/psychological mediators of treatment response. We hypothesize that psilocybin will be associated with improved cognitive control and decreased anticipation of withdrawal relief (from smoking) 1 day after the target quit date, which will be associated with greater 7-day point-prevalence abstinence at 12- month follow-up. Although psychedelic therapy is a novel approach, the Johns Hopkins site has conducted psilocybin trials with >700 sessions for >16 years, and has set the standard for the safe conduct of human psychedelic research with appropriate risk mitigation strategies (Johnson et al., 2008). This trial will provide a rigorous test of efficacy in a diverse study sample, and test relevant mechanisms, for an innovative smoking cessation treatment showing potential for substantial efficacy.