Effects of Smoking and Smoking Abstinence on Cognition in Adolescent Tobacco Smokers Leslie K. Jacobsen, John H. Krystal, W. Einar Mencl, Michael Westerveld, Stephen J. Frost, and Kenneth R. Pugh Background: In adult animals and humans, nicotine can produce short-term cognitive enhancement and, in some cases, neuroprotection. Recent work in animals, however, suggests that exposure to nicotine during adolescence might be neurotoxic. We tested for evidence of acute and chronic effects of tobacco smoking on cognition in adolescents who smoked tobacco daily and were compared with adolescent nonsmokers. Methods: Verbal working memory, verbal learning and memory, selective, divided, sustained attention, mood, symptoms of nicotine withdrawal, and tobacco craving were examined in 41 adolescent daily smokers and 32 nonsmokers who were similar in age, gender, and education. Analyses were controlled for general intelligence, reading achievement, parental educational attainment, baseline affective symptoms, and lifetime exposure to alcohol and cannabis. Results: In adolescent smokers, cessation of tobacco use increased tobacco craving, symptoms of nicotine withdrawal, and depressed mood. Adolescent smokers were found to have impairments in accuracy of working memory performance irrespective of recency of smoking. Performance decrements were more severe with earlier age of onset of smoking. Adolescent smokers experienced further disruption of working memory and verbal memory during smoking cessation. As a group, male smokers initiated smoking at an earlier age than female smokers and were significantly more impaired during tests of selective and divided attention than female smokers and nonsmokers. Conclusions: Adolescent daily tobacco smokers experience acute impairments of verbal memory and working memory after smoking cessation, along with chronic decrements in cognitive performance that are consistent with preclinical evidence that neurotoxic effects of nicotine are more severe when exposure to nicotine occurs at earlier periods in development. Key Words: Adolescent, tobacco, selective attention, divided at- tention, memory, working memory R ates of tobacco use among adolescents are increasing worldwide (Global Youth Tobacco Survey Collaborative Group 2002). Within the United States, more than 5.5 million high school students use tobacco, with more than 4.5 million of these teenagers smoking cigarettes (Centers for Dis- ease Control 2001b; US Census Bureau 2002). In adult humans, cessation of regular tobacco smoking pro- duces a withdrawal syndrome, one characteristic of which is disruption of attention and memory (Pineda et al 1998; Shiffman et al 1995; Snyder et al 1989; West and Hack 1991). Tobacco smoking or administration of nicotine can reverse withdrawal- related deficits in focused and selective attention, recognition memory, prose recall, and working memory (Baldinger et al 1995; Bates et al 1995; Foulds et al 1996; Gilbert et al 1997; Houlihan et al 1996; Krebs et al 1994; Lawrence et al 2002; Perkins et al 1994; Pineda et al 1998). In nonsmokers and in nondeprived smokers, some studies have found that nicotine improves finger tapping, focused, sustained, and selective atten- tion, recognition memory, and working memory, suggesting true enhancement of performance by nicotine (Ernst et al 2001; Foulds et al 1996; Kumari et al 2003; Le Houezec et al 1994; Perkins et al 1994; Phillips and Fox 1998; Pritchard et al 1992). Other studies have found that smoking or nicotine administration had no effect on, or impaired the performance of, nonabstinent smokers or nonsmokers during tests of focused attention (Land- ers et al 1992; Petrie and Dreary 1989), selective attention (Heishman et al 1993; Spilich et al 1992), sustained attention (Hasenfratz et al 1989; Keenan et al 1989), and memory (Heish- man et al 1993; Hindmarch et al 1990; Spilich et al 1992). Studies of adult animals have shown that nicotine administration can produce short-term enhancement of attention and memory (Hahn and Stolerman 2002; Hahn et al 2002; Levin et al 1996; Puma et al 1999; Sansone et al 1991). Furthermore, stimulation of nicotinic acetylcholine receptors (nAChRs) on mature cells by nicotine or endogenous acetylcholine has been shown to exert a neuroprotective effect, reducing cell death resulting from cyto- toxic treatments (Kaneko et al 1997; Maggio et al 1998; Yamashita and Nakamura 1996; Zoli et al 1999). Consistent with this, epidemiologic studies have provided evidence suggesting that chronic exposure to tobacco smoke might protect against the development of Parkinson’s disease, the second most common neurodegenerative disease in adult humans (Gorell et al 1999; Ross and Petrovitch 2001). In contrast, gestational tobacco exposure has well-established neurotoxicity and neurodevelopmental sequelae (Fried 1995; Fried et al 2003). Recent work with a rat model of adolescent nicotine exposure has provided evidence that vulnerability to the neurotoxic effects of nicotine might extend postnatally into adolescence (Slotkin 2002). In doses designed to model typical human exposures, nicotine treatment of rats during adolescence (postnatal days 30 – 47) reduces cell numbers in cortex, midbrain, and hippocampus and increases markers of apoptosis in hip- pocampus in females (Trauth et al 2000b). After cessation of nicotine exposure, elevations in high-affinity nAChR binding persist across brain regions in adolescent males longer than in adult and in female adolescent rodents submitted to the same treatment regimen (Trauth et al 1999). Behavioral studies indicate that adolescent nicotine exposure produces decrements in open From the Departments of Psychiatry (LKJ, JHK), Pediatrics (LKJ, KRP), Neuro- surgery (MW), and Child Study (MW), Yale University School of Medicine; and Haskins Laboratory (WEM, SJF), Yale University, New Haven, Con- necticut. Address reprint requests to Leslie K. Jacobsen, M.D., Yale University School of Medicine, Psychiatry and Pediatrics, 100 York Street 2B, New Haven, CT 06511; E-mail: leslie.jacobsen@yale.edu. Received February 27, 2004; revised June 15, 2004; revised September 28, 2004; accepted October 20, 2004. BIOL PSYCHIATRY 2005;57:56 – 66 0006-3223/05/$30.00 doi:10.1016/j.biopsych.2004.10.022 © 2005 Society of Biological Psychiatry