The association of FKBP5 genotype with nicotine withdrawal severity in laboratory study participants and the large cohort of current smokers may have clinical relevance, as withdrawal severity is a strong predictor of relapse to smoking.41 Our findings regarding FKBP5 and nicotine withdrawal are consistent with a recent report of an association of FKBP5 to alcohol withdrawal in humans and mice.15 In the Huang et al. study, subjects with the FKBP5 rs3800373 minor allele reported less withdrawal. Together, these findings suggest that some effects of FKBP5 generalize to multiple addictive substances. Indeed, withdrawal symptoms that emerge during abstinence contribute to the maintenance of addiction to nicotine,41 alcohol42 and other drugs.43 These negative effects, as opposed to the positive reinforcing effects, that develop from drug use warrant attention, as they might be mechanistically distinct but independently important for the development of addiction. The pronounced effect of PTSD co-morbidity on nicotine withdrawal suggests that stress reactivity pathways are central to the negative effects that occur during nicotine withdrawal. Stress hormones modulate the activity of neurotransmitter systems in brain regions that are essential for
