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Purpose: Nicotine is the primary constituent of cigarette smoke responsible for dependence but other components may play a role. Carbon monoxide (CO) is one candidate since it is synthesized endogenously with multiple physiological effects. This investigation was conducted to determine whether CO alters cravings associated with cigarette smoke withdrawal. Methods: With ethics approval and consent, 131 smokers were assigned to receive: (1) inhaled CO ++ Nicotine nasal spray (2) Air ++ Nicotine nasal spray (3) CO ++ Placebo nasal spray or (4) Air ++ Placebo nasal spray. Two craving scales (adapted from Hughes and Hatsukami [Hughes, J.R., & Hatsukami, D. (1986). Signs and symptoms of tobacco withdrawal. Archives of General Psychiatry, 43, 289-294] and Shiffman-Jarvik [Shiffman, S.M., & Jarvik, M.E. (1976). Smoking withdrawal symptoms in two weeks of abstinence. Psychopharmacology, 50, 35-39] referred to as HH and SJ, respectively) and a mood state questionnaire were used to assess withdrawal relief. Results: Craving scores were reduced pre- to post-treatment to some extent in all groups. On the last test day, HH revealed time by treatment differences between CO ++ Nicotine and either CO Only ( p == 0.03) or Nicotine Only ( p == 0.02). SJ revealed overall differences in pre- to post-treatment cravings ( p == 0.03) with marginal time by treatment differences between craving scores in the Placebo group versus the Nicotine Only and the Nicotine ++ CO groups ( p == 0.06 and 0.07, respectively). Treatment subjects were almost twice as likely to inhale the maximal gas (odds ratios == 1.6-2.0) compared to Placebo, suggesting that all treatments (including CO Only) were discriminated from Placebo. Conclusions: Our investigation suggests that CO exerts pharmacological effects, which may modulate craving processes associated with cigarette withdrawal, and exploration for the role of CO and other cigarette smoke constituents is warranted. [ABSTRACT FROM AUTHOR]