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EEG effects of conventional and denicotinized cigarettes in a spaced smoking paradigm
Brain and Cognition 53 (2003) 75–81 www.elsevier.com/locate/b&c
EEG effects of conventional and denicotinized cigarettes in a spaced smoking paradigm Wallace B. Pickworth,* Elizabeth D. OÕHare, Reginald V. Fant, and Eric T. Moolchan NIDA, Intramural Research Program, 5500 Nathan Shock Drive, P.O. Box 5180, Baltimore, MD 21224, USA Accepted 21 July 2003
Abstract Although there is a documented association between plasma nicotine levels and smoking behavior, recent studies indicate that denicotinized cigarettes reduced craving and symptoms of tobacco withdrawal. Denicotinized cigarettes (that deliver tar but insignificant amounts of nicotine) and conventional cigarettes were compared in a within-subject spaced smoking study. In six sessions, subjects (n ¼ 10) smoked denicotinized cigarettes or conventional cigarettes every 30, 60 or 240 min (8, 4 or 1 cigarette(s)). EEG effects of the last cigarette of each session were deduced by comparisons with EEG recordings collected before smoking. Conventional cigarettes increased spectral edge EEG frequency, decreased h power and increased b1 power. Denicotinized cigarettes decreased spectral frequency. The EEG effects of both cigarettes depended upon the recentness of smoking. The results indicate that nicotine delivery, recentness and the process of smoking importantly influence the EEG; other, non-nicotine components of tobacco smoke may also exert EEG effects. Published by Elsevier Inc. Keywords: Placebo cigarettes; Denicotinized cigarettes; Smoking; Electrocortical; EEG; Electroencephalogram
1. Introduction Many studies with human smokers have demonstrated that cigarette smoking changes brain electrical activity (EEG) recorded from scalp electrodes in directions associated with arousal. For example, Edwards and Warburton (1983) noted electrocortical arousal after cigarette smoking. Knott and Venables (1977) also showed a decrease in EEG a activity after cigarette smoking. In a later study, Knott (1988) reported puffby-puff cortical arousal associated with cigarette smoking. The EEG arousal effects of cigarette smoking are most evident in smokers that have been deprived of cigarettes for several hours. Conversely, withholding cigarettes from heavy smokers causes changes in the EEG in the opposite direction—towards hypoarousal. For example, Ulett and Itil (1969) demonstrated EEG slowing after overnight
* Corresponding author. Fax: 1-410-550-1849. E-mail address: [email protected] (W.B. Pickworth).
0278-2626/$ - see front matter. Published by Elsevier Inc. doi:10.1016/S0278-2626(03)00205-7
smoking abstinence. Herning, Jones, and Bachman (1983) reported that EEG a frequency slowed and h power increased as soon as 4 h after the last cigarette. Decreases in EEG a frequency and increases in h power persisted for 7 days in tobacco-deprived subjects residing on a closed clinical ward (Pickworth, Herning, & Henningfield, 1989) and some EEG changes may continue for as long as 31 days in abstinent smokers (Gilbert et al., 1999). EEG changes during tobacco abstinence appear to be due to the deprivation of nicotine. Smoking a single cigarette immediately reversed abstinence-related EEG changes (Herning et al., 1983; Knott & Venables, 1977; Pickworth et al., 1989). Nicotine administration from chewing gum (Pickworth, Herning, & Henningfield, 1986) or the nicotine patch (Pickworth, Fant, Butschky, & Henningfield, 1996) caused EEG arousal. Furthermore, the EEG arousal after nicotine chewing gum was prevented by mecamylamine, a nicotine antagonist that acts in the brain (Pickworth, Herning, & Henningfield, 1988). These results suggest that nicotine administration causes significant EEG activation, whereas the behavior
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of smoking and the role of other components of tobacco smoke on the EEG response are less evident. Other studies demonstrate that the behavioral and physiologic effects of smoking are influenced by the interval since the last cigarette—as the interval increased, the effects of smoking increased. For example, smoking behavior, physiological, and subjective effects of cigarettes varied as a function of smoking pattern (Fant, Schuh, & Stitzer, 1995; Schuh & Stitzer, 1995). In those reports, subjects smoked 0, 2, 5, or 11 cigarettes that were evenly spaced throughout a 6-h period at intervals ranging from 30 to 360 min. Cigarette craving increased throughout the abstinence interval; more craving occurred during longer abstinence intervals. The response to the last cigarette of the 6-hour session was influenced by pretreatment smoking pattern. Specifically, the number of puffs drawn from the cigarette, heart rate increase, and measures of cigarette liking and satisfaction were inversely related to the recentness of smoking. The mechanism for the rapid tolerance (tachyphylaxis) that developed is unclear. It is possible that desensitization of the nicotinic receptors modulating the effects occurred. On the other hand, other components of tobacco smoke may accumulate in the rapid smoking conditions, which could diminish the incremental effects of subsequent smoking. Denicotinized cigarettes have been used in clinical studies to distinguish the effects of smoke-delivered nicotine from the behavior of smoking and the delivery of other components of tobacco smoke (Robinson, Houtsmuller, Moolchan, & Pickworth, 2000). A single denicotinized cigarette (Next, Philip Morris, Richmond, VA), failed to increase plasma nicotine levels or produce cardiovascular effects, did, however, diminish subjective effects of tobacco withdrawal (Butschky, Bailey, Henningfield, & Pickworth, 1995). Two studies reported no EEG effects of denicotinized cigarettes in overnight abstinent (Robinson, Pritchard, & Davis, 1992) and 3-h abstinent (Pickworth, Fant, Nelson, Rohrer, & Henningfield, 1999) smokers. These findings support the notion that sensory factors are important in the maintenance of smoking behavior and alleviation of tobacco withdrawal (Pritchard, Robinson, Guy, Davis, & Stiles, 1996; Robinson et al., 2000; Rose & Behm, 1991; Rose, Behm, & Levin, 1993). However, the findings of the above studies were limited because subjects only smoked a single denicotinized cigarette. The present study was designed to compare EEG effects of denicotinized cigarettes to cigarettes that contained nicotine using a paradigm in which subjects smoked at varying intervals. This paradigm made possible a determination of EEG effects of multiple exposures to conventional and denicotinized cigarettes. Furthermore, by using denicotinized cigarettes, the EEG effects of nicotine delivery could be distinguished from
the behavior of smoking and the delivery of other components of tobacco smoke.
2. Methods 2.1. Participants Ten adult (average age ¼ 37.3 year; range: 25–49) volunteers (five men, five women) were recruited from the community through newspaper advertisements and word of mouth. Six participants were African Americans, three were Caucasian, and one was Hispanic. All of the participants were current cigarette smokers. They smoked an average of 30.9 cigarettes per day (17–40); with a FTC yield (Federal Register, 1967; Pillsbury, 1996) that averaged 1.2 mg nicotine (range 1.1–1.3). All subjects ordinarily smoked menthol cigarettes. Their score on a test of nicotine dependence (Fagerstr€ om, 1978) averaged 7.2 (5–10); scores above 5 indicate a high level of tobacco dependence (Heatherton, Kozlowski, Frecker, & Fagerstr€ om, 1991). All of the subjects passed a medical examination to verify that they could safely participate in the study and they each signed a consent form that had been approved by the NIDA, Institutional Review Board that described the study, its risks and benefits. 2.2. Experimental cigarettes The Ultratech Corporation (Lafayette Hills, PA) prepared the research cigarettes of the study under a contract with the NIDA, Intramural Research Program. Two types of experimental cigarettes were used—a conventional cigarette that delivered tar (15.9 mg) and nicotine (1.1 mg) and a denicotinized cigarette that delivered similar amounts of tar (17.3 mg) but virtually no nicotine (.07 mg) (Pickworth et al., 1999). The cigarettes were filtered, non-menthol and had identical appearance. To impart a menthol flavor, experimental cigarettes were placed in a test tube with 1 g of menthol crystals overnight. Cigarettes were dispensed from the pharmacy on the day of the study labeled only with the subjectsÕ initials and date so that both experimenter and subject were blind to the cigarette type. 2.3. Dependent measure EEG recordings from three midline scalp locations, Fz, Cz, and Pz (linked ear reference), were collected while the subject relaxed with eyes closed. EEG recordings were obtained before (TIME 1) and 2 min after (TIME 2) Cigarette #1 (always own brand) and before (TIME 3) and 2 min after (TIME 4) the last cigarette of the session (always an experimental cigarette). Recordings were made from gold-platted scalp electrodes with
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impedance less than 5 kX using a computer-based automated collection/analysis system (BioLogic, Chicago, IL). EEG signals were amplified by 20,000; the high and low frequency filters were set at 1 and 30 Hz, respectively. A notch filter was in place (for the rejection of 60 Hz interference) and an automatic artifact rejection algorithm that eliminated, on-line, epochs with amplitudes above criteria was used. By using an amplitudedefined artifact rejection criterion epochs with artifacts of any sort, including eye movements, were excluded from analyses. One minute, artifact-free samples were digitized at 128 Hz and a fast Fourier transform algorithm converted analog data to the power and frequency domains. EEG frequency was computed as the spectral edge 80% indicating the frequency (Hz) at which 80% of the power of the band has accumulated. The power and frequency were derived for each of the usual clinical frequency bands: d (0.01–3.99 Hz), h (4–7.99 Hz), a (8– 12.99 Hz), b1(13–23.99 Hz), and b2 (24–31.75 Hz) and total (0.01–63 Hz).
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the power (expressed as % baseline) and the frequency (expressed as difference from baseline) were analyzed with a two way ANOVA. The main factors were cigarette type (two levels: conventional or denicotinized) and smoking interval (3 levels: 30, 60, and 240 min). Where there was a significant main effect or significant interaction, paired t tests were used to identify significant contrasts. Contrasts were verified with Tukey Honestly Significant Difference tests (Winer et al., 1991). To assess EEG signs of tobacco abstinence during the experimental session, analyses were conducted from EEG samples collected after smoking Cigarette #1 (own brand) (TIME 2) and before smoking the last research cigarette of the session (TIME 3) (4 h later). To assess differences between conventional and denicotinized cigarettes, EEG samples collected before (TIME 3) and after (TIME 4) the last experimental cigarette were compared.
3. Results 2.4. Procedure 3.1. EEG effects of tobacco abstinence The study was performed on an outpatient basis in the clinical ward of the NIDA Intramural Research Program. Subjects reported for the six experimental sessions between 8:30 and 9:30 AM. There were no restrictions on caffeine containing foods and beverages or smoking before the experimental sessions. Subjects reported smoking an average of 53.3 (6.7) min before the session (range: 42.2–64.4 min) and exhaled carbon monoxide (CO) averaged 16.5 (0.8) ppm (range: 14.8–17.8 ppm). All smoking during the experimental session was through a computer-based smoking topography system (CReSS, Plowshare Technologies, Baltimore, MD) which measured puff volume, puff velocity, puff duration, and inter-puff interval (Lee, Malson, Waters, Moolchan, & Pickworth, 2003). The first cigarette of the experimental session was one of their own brand (Cigarette #1). After smoking Cigarette #1, subjects smoked only the research cigarettes for the next 4 h of their laboratory visit. On three days, the subjects smoked denicotinized cigarettes at intervals of 30, 60 or 240 min; on the other three days they smoked conventional cigarettes at intervals of 30, 60 or 240 min. Thus, in an experimental session the subjects smoked one of their own brand of cigarettes and either 1, 4 or 8 experimental cigarettes. The type of cigarette (denicotinized or conventional) and the smoking interval were randomized among subjects according to a two-block Latin square design. 2.5. Analyses Data were analyzed using analysis of variance techniques (ANOVA) (Winer, Brown, & Michaels, 1991). For each electrode in each of the six clinical EEG bands,
Comparisons of EEG recordings at TIME 2 and TIME 3 revealed no consistently significant effects of the interval between cigarettes, the nature of the cigarettes (placebo or conventional) or the interaction between cigarette and interval. 3.2. EEG effects of cigarette smoking As described below, when EEG recordings from TIME 3 and TIME 4 were compared it was evident that EEG effects of cigarette smoking depended upon the time since the last cigarette and the nature of the cigarette (conventional or denicotinized). 3.3. EEG frequency There were no significant main effects or interactions shown within individual EEG bandwidths. However, on spectral frequency over the total frequency band there was a significant main effect of cigarette at each of the three electrode sites (Fz: F ð1; 9Þ ¼ 6:8, p ¼ :03; Cz: F ð1; 9Þ ¼ 18:9, p ¼ :002; Pz: F ð1; 9Þ ¼ 19:9, p ¼ :002). Fig. 1 illustrates those effects at the Pz electrode. Post hoc analyses showed that at each site, cigarettes with nicotine significantly increased spectral frequency compared to denicotinized cigarettes. There was also a significant interaction between cigarette type and duration interval at Fz (F ð2; 18Þ ¼ 5:0, p ¼ :02) and Cz (F ð2; 18Þ ¼ 5:4, p ¼ :02); the interaction was not significant at Pz (F ð2; 18Þ ¼ 3:0, p ¼ :08), but there was a similar pattern of effects. In general, increases in EEG frequency after smoking cigarettes that contained
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Fig. 1. Mean change (SEM) in spectral edge frequency (80%) at Pz over total frequency band (0–63 Hz) after smoking a single conventional (nicotine containing, solid bars) or denicotinized cigarettes (stippled bars). Responses are from the last cigarette of the experimental session and are expressed as differences from pre-cigarette values in a spaced smoking paradigm where subjects had smoked at 30, 60 or 240 min intervals for 4 h (8, 4 or 1 cigarettes). * indicates significant (p < :05, Tukey HSD) difference between conventional and denicotinized cigarette.
nicotine were directly related to the density of prior smoking. Specifically, in the 240 min abstinent condition smoking a conventional cigarette caused the largest increase in spectral frequency. In contrast, there were decreases in spectral frequency associated with smoking the denicotinized cigarette, with the largest decrease in the 240 min abstinent condition. 3.4. EEG power There were significant effects of measures of EEG power that depended upon the nature of the cigarette (conventional versus denicotinized) and the intensity and recentness of prior smoking. For example, there were significant main effects of the smoking interval and the type of cigarette and significant interactions between cigarette type and interval for h, a, and b1 power. Fig. 2 illustrates those changes at the Pz electrode. On the measure of h power, there was a significant interaction of interval and cigarette type at the Pz electrode (F ð2; 18Þ ¼ 3:41, p < :05). Post hoc tests indicated that there was a significant increase in h power after smoking the denicotinized cigarette but a decrease in power after the conventional cigarette was smoked. The a power increased after conventional cigarettes were smoked every 30 min but the increase diminished with the longer smoking intervals. The denicotinized cigarette caused slight decreases or no change in a power. The ANOVA indicated that there was a significant cigarette by interval interaction F ð2; 18Þ ¼ 3:48, p < :05. Post hoc tests showed that the effect was significant at the 30 min smoking interval. As shown in the middle panel of Fig. 2, power increased after cigarettes
Fig. 2. Mean change (SEM) in EEG power at Pz in h, a, and b1 frequency bands after smoking a single conventional (nicotine containing, solid bars) or denicotinized cigarettes (stippled bars). Responses are per cent of pre-smoking value in a spaced smoking paradigm where subjects had smoked at 30, 60 or 240 min intervals for 4 h (8, 4 or 1) cigarette. * indicates significant (p < :05, paired t test; p < :05, Tukey HSD h and a power) difference between conventional and denicotinized cigarette.
that delivered nicotine and decreased (or did not change) after denicotinized cigarettes. The b1 power significantly changed as a function of the interaction between cigarette type and smoking interval at the Fz (F ð2; 18Þ ¼ 4:8, p ¼ :02) and Pz (F ð2; 18Þ ¼ 3:7, p ¼ :04) electrode sites. When subjects were abstinent for 240 min before smoking, there was an approximately 30% increase in b1 power after the conventional cigarette, compared to a 10% decrease b1 power after the denicotinized cigarette. Changes in b1 power at the Pz electrode are illustrated in the lower panel of Fig. 2.
4. Discussion In this study, two new methodologies in smoking research were employed to understand the importance of recentness of smoking and the behavior of smoking
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on brain electrical activity. Denicotinized (placebo) cigarettes were used to evaluate the role of nicotine delivery (review: Robinson et al., 2000) and a spaced smoking paradigm (Fant et al., 1995; Schuh & Stitzer, 1995) was used to determine the influence of recent smoking on the acute effects of a cigarette. In general, the results indicate that both nicotine delivery and the interval since the last cigarette mediate EEG changes. Denicotinized cigarettes exerted EEG effects that were opposite to those of conventional cigarettes and these actions were influenced by the recentness of smoking. Several lines of evidence support the view that plasma nicotine concentration is an important factor in the regulation of smoking behavior (review: Russell, 1990). Smoking behavior decreased when plasma levels of nicotine were increased by: alkalization of urine pH (Benowitz & Jacob, 1985; Schachter, Kozlowski, & Silverstein, 1977) or administration of exogenous nicotine from intravenous (Lucchesi, Schuster, & Emley, 1967); gum (Kozlowski, Jarvik, & Gritz, 1975) or patch (Pickworth et al., 1996) or after administration of high yield nicotine cigarettes (Ashton & Watson, 1970; Frith, 1971). In contrast, smoking behavior increased when plasma levels of nicotine were reduced by acidification of the urine (Schachter et al., 1977) or when nicotinic receptors were blocked by mecamylamine, a centrally active antagonist (Nemeth-Coslett, Henningfield, OÕKeffe, & Griffiths, 1986). Other studies demonstrated that smoking behavior changed when the nicotine yield of the cigarette was altered (review: Russell, 1990). Nicotine has a plasma half-life of about 2 h (USDHHS, 1988), thus, a natural and frequently experienced decrease in plasma nicotine occurs after relatively short intervals of tobacco abstinence-during sleep, at work, the theater or in other places where smoking is prohibited. Although there is a vast body of literature to support the notion that plasma nicotine levels modulate smoking, there is relatively little information on the relationship between plasma nicotine levels and EEG effects of smoking. The spaced smoking paradigm provides an experimental model to explore the effects of variable periods of tobacco abstinence (Fant et al., 1995; Schuh & Stitzer, 1995). By parametrically varying the interval between cigarettes, the influence of abstinence interval on cigarette effects can be assessed. The results of studies using denicotinized cigarettes that deliver tar and carbon monoxide, but not nicotine, indicate that the behavior of smoking and/or other components of tobacco smoke may influence the subjective responses of smoking. For example, a denicotinized cigarette relieved cigarette craving and other acute signs of tobacco withdrawal in tobacco-deprived smokers (Butschky et al., 1995; Gross, Lee, & Stitzer, 1997). However, the effects of repeated administration of
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denicotinized cigarettes over extended periods of tobacco abstinence are unknown. Although denicotinized cigarettes acutely diminish subjective measures of tobacco, they do not reverse physiologic sign associated with tobacco abstinence. For example, denicotinized cigarettes did not reverse the decreased heart rate or blood pressure ordinarily seen in tobacco abstinence (Baldinger, Hasenfratz, & B€attig, 1995; Butschky et al., 1995; Gross et al., 1997). Similarly denicotinized cigarettes did not cause signs of EEG arousal (Robinson et al., 1992). Pickworth et al. (1999) reported that a denicotinized cigarette had EEG effects opposite those of cigarettes that delivered nicotine. The denicotinized cigarette increased h power whereas the conventional cigarette decreased h power. The present study is the first study to examine EEG effects of repeated administration of denicotinized cigarettes. The significant interactions between the type of cigarette and the smoking interval suggests that both the delivery of nicotine and the recentness of smoking importantly influence smoking-induced changes in brain electrical activity. Smoking (Knott & Venables, 1977) and exogenous nicotine delivery (Pickworth et al., 1986) typically increase the frequency of the EEG. In the present study conventional cigarettes increased EEG frequency and the increase was directly related to the interval since the previous cigarette. Denicotinized cigarettes had the opposite effects causing EEG slowing that increased directly with the interval since the last cigarette. Denicotinized and conventional cigarettes could be differentiated on measures of EEG power in several clinical EEG frequency classifications. As illustrated, h power (at the Pz electrode) increased after nicotine cigarettes and decreased after denicotinized cigarettes in the 30-min smoking interval but at the longer smoking intervals (60 and 240 min) conventional cigarettes decreased h power and denicotinized cigarettes increased h power. The later results were similar to those in earlier study (Pickworth et al., 1999) where denicotinized cigarettes increased h power and conventional cigarettes decreased it. At the 30 min smoking interval, but not at the other intervals, a power was increased by the conventional cigarette and decreased by the placebo cigarette. b1 power increased after smoking the conventional cigarette after 240 min of abstinence, but b1 power decreased after the denicotinized cigarette. The apparent effects of a placebo cigarette on brain electrical activity are intriguing. In a previous paper, we speculated that the EEG effects of a placebo cigarette may result from exposure of cues related to smoking (feel, sight, smell) without the subsequent delivery of nicotine (Pickworth et al., 1999). The EEG slowing and increases in h power after placebo cigarettes are in the direction of tobacco abstinence. These changes may be analogous to the
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increases in cigarette craving reported when subjects listen to audiotapes that simulate imagery of situations where cigarette smoking ordinarily occurs (Taylor, Harris, Singleton, Moolchan, & Heishman, 2000). On the other hand, we cannot rule out the possibility that a component of the denicotinized cigarette smoke exerted opposite EEG effects to that of nicotine. However, this suggestion is contrary to results of a study where a different denicotinized cigarette (Next) caused no EEG changes (Robinson et al., 1992). In the present study, there was no significant EEG evidence of tobacco abstinence during the 4-h deprivation. The onset of EEG signs associated with tobacco abstinence—EEG slowing and increased EEG power in the lower frequency bands is usually observed after overnight (12 or more hours) deprivation (Knott & Venables, 1977; Pickworth et al., 1986; Ulett & Itil, 1969). However, Herning et al. (1983) reported a significant increase in h power within 4 h of tobacco abstinence. In a study of highly dependent smokers on a residential unit undergoing observed and monitored tobacco abstinence, significant EEG signs of tobacco abstinence occurred 29 h after the last cigarette. There were non-significant EEG slowing and increases in h power as early as 5 h after the last cigarette (Pickworth et al., 1989). The inability to demonstrate EEG signs of tobacco abstinence may have been because the subjects were not required to be abstinent from caffeine. Data from our lab (Cohen, Pickworth, Bunker, & Henningfield, 1994) and elsewhere (Gilbert, Dibb, Plath, & Hiyane, 2000) indicate that caffeine ingestion diminishes EEG signs of tobacco abstinence. The failure to observe EEG signs of abstinence in the present study may be due to recentness and quantity of smoking before the experimental session. It is possible that the EEG effects of the experimental cigarettes would have been enhanced if the subjects had been in a greater state of tobacco abstinence prior to the session or if the session had been longer than 4 h. When others have used the spaced smoking paradigm a 6 h experimental observation was employed (Fant et al., 1995; Schuh & Stitzer, 1995). Although there was no significant EEG changes over the 4 h period, acute administration of conventional and denicotinized cigarettes exerted significant EEG effects. Smoking is a complex pharmacologic and behavioral process. The EEG and other effects of smoking are usually attributed to the rapid delivery of nicotine, however, other components of tobacco smoke, the behavior of smoking and the stimuli associated with smoking are also involved. The results of the present study indicate that both the delivery of nicotine and the recentness of smoking critically influence the EEG effects of smoking. The increasing availability of denicotinized cigarettes is an important development for understanding the complexities of smoking.
Acknowledgments The authors gratefully acknowledge the clinical and clerical assistance of Ms. Eun Lee and Mr. Dat Nguyen.
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EEG effects of conventional and denicotinized cigarettes in a spaced smoking paradigm Wallace B. Pickworth,* Elizabeth D. OÕHare, Reginald V. Fant, and Eric T. Moolchan NIDA, Intramural Research Program, 5500 Nathan Shock Drive, P.O. Box 5180, Baltimore, MD 21224, USA Accepted 21 July 2003
Abstract Although there is a documented association between plasma nicotine levels and smoking behavior, recent studies indicate that denicotinized cigarettes reduced craving and symptoms of tobacco withdrawal. Denicotinized cigarettes (that deliver tar but insignificant amounts of nicotine) and conventional cigarettes were compared in a within-subject spaced smoking study. In six sessions, subjects (n ¼ 10) smoked denicotinized cigarettes or conventional cigarettes every 30, 60 or 240 min (8, 4 or 1 cigarette(s)). EEG effects of the last cigarette of each session were deduced by comparisons with EEG recordings collected before smoking. Conventional cigarettes increased spectral edge EEG frequency, decreased h power and increased b1 power. Denicotinized cigarettes decreased spectral frequency. The EEG effects of both cigarettes depended upon the recentness of smoking. The results indicate that nicotine delivery, recentness and the process of smoking importantly influence the EEG; other, non-nicotine components of tobacco smoke may also exert EEG effects. Published by Elsevier Inc. Keywords: Placebo cigarettes; Denicotinized cigarettes; Smoking; Electrocortical; EEG; Electroencephalogram
1. Introduction Many studies with human smokers have demonstrated that cigarette smoking changes brain electrical activity (EEG) recorded from scalp electrodes in directions associated with arousal. For example, Edwards and Warburton (1983) noted electrocortical arousal after cigarette smoking. Knott and Venables (1977) also showed a decrease in EEG a activity after cigarette smoking. In a later study, Knott (1988) reported puffby-puff cortical arousal associated with cigarette smoking. The EEG arousal effects of cigarette smoking are most evident in smokers that have been deprived of cigarettes for several hours. Conversely, withholding cigarettes from heavy smokers causes changes in the EEG in the opposite direction—towards hypoarousal. For example, Ulett and Itil (1969) demonstrated EEG slowing after overnight
* Corresponding author. Fax: 1-410-550-1849. E-mail address: [email protected] (W.B. Pickworth).
0278-2626/$ - see front matter. Published by Elsevier Inc. doi:10.1016/S0278-2626(03)00205-7
smoking abstinence. Herning, Jones, and Bachman (1983) reported that EEG a frequency slowed and h power increased as soon as 4 h after the last cigarette. Decreases in EEG a frequency and increases in h power persisted for 7 days in tobacco-deprived subjects residing on a closed clinical ward (Pickworth, Herning, & Henningfield, 1989) and some EEG changes may continue for as long as 31 days in abstinent smokers (Gilbert et al., 1999). EEG changes during tobacco abstinence appear to be due to the deprivation of nicotine. Smoking a single cigarette immediately reversed abstinence-related EEG changes (Herning et al., 1983; Knott & Venables, 1977; Pickworth et al., 1989). Nicotine administration from chewing gum (Pickworth, Herning, & Henningfield, 1986) or the nicotine patch (Pickworth, Fant, Butschky, & Henningfield, 1996) caused EEG arousal. Furthermore, the EEG arousal after nicotine chewing gum was prevented by mecamylamine, a nicotine antagonist that acts in the brain (Pickworth, Herning, & Henningfield, 1988). These results suggest that nicotine administration causes significant EEG activation, whereas the behavior
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of smoking and the role of other components of tobacco smoke on the EEG response are less evident. Other studies demonstrate that the behavioral and physiologic effects of smoking are influenced by the interval since the last cigarette—as the interval increased, the effects of smoking increased. For example, smoking behavior, physiological, and subjective effects of cigarettes varied as a function of smoking pattern (Fant, Schuh, & Stitzer, 1995; Schuh & Stitzer, 1995). In those reports, subjects smoked 0, 2, 5, or 11 cigarettes that were evenly spaced throughout a 6-h period at intervals ranging from 30 to 360 min. Cigarette craving increased throughout the abstinence interval; more craving occurred during longer abstinence intervals. The response to the last cigarette of the 6-hour session was influenced by pretreatment smoking pattern. Specifically, the number of puffs drawn from the cigarette, heart rate increase, and measures of cigarette liking and satisfaction were inversely related to the recentness of smoking. The mechanism for the rapid tolerance (tachyphylaxis) that developed is unclear. It is possible that desensitization of the nicotinic receptors modulating the effects occurred. On the other hand, other components of tobacco smoke may accumulate in the rapid smoking conditions, which could diminish the incremental effects of subsequent smoking. Denicotinized cigarettes have been used in clinical studies to distinguish the effects of smoke-delivered nicotine from the behavior of smoking and the delivery of other components of tobacco smoke (Robinson, Houtsmuller, Moolchan, & Pickworth, 2000). A single denicotinized cigarette (Next, Philip Morris, Richmond, VA), failed to increase plasma nicotine levels or produce cardiovascular effects, did, however, diminish subjective effects of tobacco withdrawal (Butschky, Bailey, Henningfield, & Pickworth, 1995). Two studies reported no EEG effects of denicotinized cigarettes in overnight abstinent (Robinson, Pritchard, & Davis, 1992) and 3-h abstinent (Pickworth, Fant, Nelson, Rohrer, & Henningfield, 1999) smokers. These findings support the notion that sensory factors are important in the maintenance of smoking behavior and alleviation of tobacco withdrawal (Pritchard, Robinson, Guy, Davis, & Stiles, 1996; Robinson et al., 2000; Rose & Behm, 1991; Rose, Behm, & Levin, 1993). However, the findings of the above studies were limited because subjects only smoked a single denicotinized cigarette. The present study was designed to compare EEG effects of denicotinized cigarettes to cigarettes that contained nicotine using a paradigm in which subjects smoked at varying intervals. This paradigm made possible a determination of EEG effects of multiple exposures to conventional and denicotinized cigarettes. Furthermore, by using denicotinized cigarettes, the EEG effects of nicotine delivery could be distinguished from
the behavior of smoking and the delivery of other components of tobacco smoke.
2. Methods 2.1. Participants Ten adult (average age ¼ 37.3 year; range: 25–49) volunteers (five men, five women) were recruited from the community through newspaper advertisements and word of mouth. Six participants were African Americans, three were Caucasian, and one was Hispanic. All of the participants were current cigarette smokers. They smoked an average of 30.9 cigarettes per day (17–40); with a FTC yield (Federal Register, 1967; Pillsbury, 1996) that averaged 1.2 mg nicotine (range 1.1–1.3). All subjects ordinarily smoked menthol cigarettes. Their score on a test of nicotine dependence (Fagerstr€ om, 1978) averaged 7.2 (5–10); scores above 5 indicate a high level of tobacco dependence (Heatherton, Kozlowski, Frecker, & Fagerstr€ om, 1991). All of the subjects passed a medical examination to verify that they could safely participate in the study and they each signed a consent form that had been approved by the NIDA, Institutional Review Board that described the study, its risks and benefits. 2.2. Experimental cigarettes The Ultratech Corporation (Lafayette Hills, PA) prepared the research cigarettes of the study under a contract with the NIDA, Intramural Research Program. Two types of experimental cigarettes were used—a conventional cigarette that delivered tar (15.9 mg) and nicotine (1.1 mg) and a denicotinized cigarette that delivered similar amounts of tar (17.3 mg) but virtually no nicotine (.07 mg) (Pickworth et al., 1999). The cigarettes were filtered, non-menthol and had identical appearance. To impart a menthol flavor, experimental cigarettes were placed in a test tube with 1 g of menthol crystals overnight. Cigarettes were dispensed from the pharmacy on the day of the study labeled only with the subjectsÕ initials and date so that both experimenter and subject were blind to the cigarette type. 2.3. Dependent measure EEG recordings from three midline scalp locations, Fz, Cz, and Pz (linked ear reference), were collected while the subject relaxed with eyes closed. EEG recordings were obtained before (TIME 1) and 2 min after (TIME 2) Cigarette #1 (always own brand) and before (TIME 3) and 2 min after (TIME 4) the last cigarette of the session (always an experimental cigarette). Recordings were made from gold-platted scalp electrodes with
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impedance less than 5 kX using a computer-based automated collection/analysis system (BioLogic, Chicago, IL). EEG signals were amplified by 20,000; the high and low frequency filters were set at 1 and 30 Hz, respectively. A notch filter was in place (for the rejection of 60 Hz interference) and an automatic artifact rejection algorithm that eliminated, on-line, epochs with amplitudes above criteria was used. By using an amplitudedefined artifact rejection criterion epochs with artifacts of any sort, including eye movements, were excluded from analyses. One minute, artifact-free samples were digitized at 128 Hz and a fast Fourier transform algorithm converted analog data to the power and frequency domains. EEG frequency was computed as the spectral edge 80% indicating the frequency (Hz) at which 80% of the power of the band has accumulated. The power and frequency were derived for each of the usual clinical frequency bands: d (0.01–3.99 Hz), h (4–7.99 Hz), a (8– 12.99 Hz), b1(13–23.99 Hz), and b2 (24–31.75 Hz) and total (0.01–63 Hz).
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the power (expressed as % baseline) and the frequency (expressed as difference from baseline) were analyzed with a two way ANOVA. The main factors were cigarette type (two levels: conventional or denicotinized) and smoking interval (3 levels: 30, 60, and 240 min). Where there was a significant main effect or significant interaction, paired t tests were used to identify significant contrasts. Contrasts were verified with Tukey Honestly Significant Difference tests (Winer et al., 1991). To assess EEG signs of tobacco abstinence during the experimental session, analyses were conducted from EEG samples collected after smoking Cigarette #1 (own brand) (TIME 2) and before smoking the last research cigarette of the session (TIME 3) (4 h later). To assess differences between conventional and denicotinized cigarettes, EEG samples collected before (TIME 3) and after (TIME 4) the last experimental cigarette were compared.
3. Results 2.4. Procedure 3.1. EEG effects of tobacco abstinence The study was performed on an outpatient basis in the clinical ward of the NIDA Intramural Research Program. Subjects reported for the six experimental sessions between 8:30 and 9:30 AM. There were no restrictions on caffeine containing foods and beverages or smoking before the experimental sessions. Subjects reported smoking an average of 53.3 (6.7) min before the session (range: 42.2–64.4 min) and exhaled carbon monoxide (CO) averaged 16.5 (0.8) ppm (range: 14.8–17.8 ppm). All smoking during the experimental session was through a computer-based smoking topography system (CReSS, Plowshare Technologies, Baltimore, MD) which measured puff volume, puff velocity, puff duration, and inter-puff interval (Lee, Malson, Waters, Moolchan, & Pickworth, 2003). The first cigarette of the experimental session was one of their own brand (Cigarette #1). After smoking Cigarette #1, subjects smoked only the research cigarettes for the next 4 h of their laboratory visit. On three days, the subjects smoked denicotinized cigarettes at intervals of 30, 60 or 240 min; on the other three days they smoked conventional cigarettes at intervals of 30, 60 or 240 min. Thus, in an experimental session the subjects smoked one of their own brand of cigarettes and either 1, 4 or 8 experimental cigarettes. The type of cigarette (denicotinized or conventional) and the smoking interval were randomized among subjects according to a two-block Latin square design. 2.5. Analyses Data were analyzed using analysis of variance techniques (ANOVA) (Winer, Brown, & Michaels, 1991). For each electrode in each of the six clinical EEG bands,
Comparisons of EEG recordings at TIME 2 and TIME 3 revealed no consistently significant effects of the interval between cigarettes, the nature of the cigarettes (placebo or conventional) or the interaction between cigarette and interval. 3.2. EEG effects of cigarette smoking As described below, when EEG recordings from TIME 3 and TIME 4 were compared it was evident that EEG effects of cigarette smoking depended upon the time since the last cigarette and the nature of the cigarette (conventional or denicotinized). 3.3. EEG frequency There were no significant main effects or interactions shown within individual EEG bandwidths. However, on spectral frequency over the total frequency band there was a significant main effect of cigarette at each of the three electrode sites (Fz: F ð1; 9Þ ¼ 6:8, p ¼ :03; Cz: F ð1; 9Þ ¼ 18:9, p ¼ :002; Pz: F ð1; 9Þ ¼ 19:9, p ¼ :002). Fig. 1 illustrates those effects at the Pz electrode. Post hoc analyses showed that at each site, cigarettes with nicotine significantly increased spectral frequency compared to denicotinized cigarettes. There was also a significant interaction between cigarette type and duration interval at Fz (F ð2; 18Þ ¼ 5:0, p ¼ :02) and Cz (F ð2; 18Þ ¼ 5:4, p ¼ :02); the interaction was not significant at Pz (F ð2; 18Þ ¼ 3:0, p ¼ :08), but there was a similar pattern of effects. In general, increases in EEG frequency after smoking cigarettes that contained
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Fig. 1. Mean change (SEM) in spectral edge frequency (80%) at Pz over total frequency band (0–63 Hz) after smoking a single conventional (nicotine containing, solid bars) or denicotinized cigarettes (stippled bars). Responses are from the last cigarette of the experimental session and are expressed as differences from pre-cigarette values in a spaced smoking paradigm where subjects had smoked at 30, 60 or 240 min intervals for 4 h (8, 4 or 1 cigarettes). * indicates significant (p < :05, Tukey HSD) difference between conventional and denicotinized cigarette.
nicotine were directly related to the density of prior smoking. Specifically, in the 240 min abstinent condition smoking a conventional cigarette caused the largest increase in spectral frequency. In contrast, there were decreases in spectral frequency associated with smoking the denicotinized cigarette, with the largest decrease in the 240 min abstinent condition. 3.4. EEG power There were significant effects of measures of EEG power that depended upon the nature of the cigarette (conventional versus denicotinized) and the intensity and recentness of prior smoking. For example, there were significant main effects of the smoking interval and the type of cigarette and significant interactions between cigarette type and interval for h, a, and b1 power. Fig. 2 illustrates those changes at the Pz electrode. On the measure of h power, there was a significant interaction of interval and cigarette type at the Pz electrode (F ð2; 18Þ ¼ 3:41, p < :05). Post hoc tests indicated that there was a significant increase in h power after smoking the denicotinized cigarette but a decrease in power after the conventional cigarette was smoked. The a power increased after conventional cigarettes were smoked every 30 min but the increase diminished with the longer smoking intervals. The denicotinized cigarette caused slight decreases or no change in a power. The ANOVA indicated that there was a significant cigarette by interval interaction F ð2; 18Þ ¼ 3:48, p < :05. Post hoc tests showed that the effect was significant at the 30 min smoking interval. As shown in the middle panel of Fig. 2, power increased after cigarettes
Fig. 2. Mean change (SEM) in EEG power at Pz in h, a, and b1 frequency bands after smoking a single conventional (nicotine containing, solid bars) or denicotinized cigarettes (stippled bars). Responses are per cent of pre-smoking value in a spaced smoking paradigm where subjects had smoked at 30, 60 or 240 min intervals for 4 h (8, 4 or 1) cigarette. * indicates significant (p < :05, paired t test; p < :05, Tukey HSD h and a power) difference between conventional and denicotinized cigarette.
that delivered nicotine and decreased (or did not change) after denicotinized cigarettes. The b1 power significantly changed as a function of the interaction between cigarette type and smoking interval at the Fz (F ð2; 18Þ ¼ 4:8, p ¼ :02) and Pz (F ð2; 18Þ ¼ 3:7, p ¼ :04) electrode sites. When subjects were abstinent for 240 min before smoking, there was an approximately 30% increase in b1 power after the conventional cigarette, compared to a 10% decrease b1 power after the denicotinized cigarette. Changes in b1 power at the Pz electrode are illustrated in the lower panel of Fig. 2.
4. Discussion In this study, two new methodologies in smoking research were employed to understand the importance of recentness of smoking and the behavior of smoking
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on brain electrical activity. Denicotinized (placebo) cigarettes were used to evaluate the role of nicotine delivery (review: Robinson et al., 2000) and a spaced smoking paradigm (Fant et al., 1995; Schuh & Stitzer, 1995) was used to determine the influence of recent smoking on the acute effects of a cigarette. In general, the results indicate that both nicotine delivery and the interval since the last cigarette mediate EEG changes. Denicotinized cigarettes exerted EEG effects that were opposite to those of conventional cigarettes and these actions were influenced by the recentness of smoking. Several lines of evidence support the view that plasma nicotine concentration is an important factor in the regulation of smoking behavior (review: Russell, 1990). Smoking behavior decreased when plasma levels of nicotine were increased by: alkalization of urine pH (Benowitz & Jacob, 1985; Schachter, Kozlowski, & Silverstein, 1977) or administration of exogenous nicotine from intravenous (Lucchesi, Schuster, & Emley, 1967); gum (Kozlowski, Jarvik, & Gritz, 1975) or patch (Pickworth et al., 1996) or after administration of high yield nicotine cigarettes (Ashton & Watson, 1970; Frith, 1971). In contrast, smoking behavior increased when plasma levels of nicotine were reduced by acidification of the urine (Schachter et al., 1977) or when nicotinic receptors were blocked by mecamylamine, a centrally active antagonist (Nemeth-Coslett, Henningfield, OÕKeffe, & Griffiths, 1986). Other studies demonstrated that smoking behavior changed when the nicotine yield of the cigarette was altered (review: Russell, 1990). Nicotine has a plasma half-life of about 2 h (USDHHS, 1988), thus, a natural and frequently experienced decrease in plasma nicotine occurs after relatively short intervals of tobacco abstinence-during sleep, at work, the theater or in other places where smoking is prohibited. Although there is a vast body of literature to support the notion that plasma nicotine levels modulate smoking, there is relatively little information on the relationship between plasma nicotine levels and EEG effects of smoking. The spaced smoking paradigm provides an experimental model to explore the effects of variable periods of tobacco abstinence (Fant et al., 1995; Schuh & Stitzer, 1995). By parametrically varying the interval between cigarettes, the influence of abstinence interval on cigarette effects can be assessed. The results of studies using denicotinized cigarettes that deliver tar and carbon monoxide, but not nicotine, indicate that the behavior of smoking and/or other components of tobacco smoke may influence the subjective responses of smoking. For example, a denicotinized cigarette relieved cigarette craving and other acute signs of tobacco withdrawal in tobacco-deprived smokers (Butschky et al., 1995; Gross, Lee, & Stitzer, 1997). However, the effects of repeated administration of
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denicotinized cigarettes over extended periods of tobacco abstinence are unknown. Although denicotinized cigarettes acutely diminish subjective measures of tobacco, they do not reverse physiologic sign associated with tobacco abstinence. For example, denicotinized cigarettes did not reverse the decreased heart rate or blood pressure ordinarily seen in tobacco abstinence (Baldinger, Hasenfratz, & B€attig, 1995; Butschky et al., 1995; Gross et al., 1997). Similarly denicotinized cigarettes did not cause signs of EEG arousal (Robinson et al., 1992). Pickworth et al. (1999) reported that a denicotinized cigarette had EEG effects opposite those of cigarettes that delivered nicotine. The denicotinized cigarette increased h power whereas the conventional cigarette decreased h power. The present study is the first study to examine EEG effects of repeated administration of denicotinized cigarettes. The significant interactions between the type of cigarette and the smoking interval suggests that both the delivery of nicotine and the recentness of smoking importantly influence smoking-induced changes in brain electrical activity. Smoking (Knott & Venables, 1977) and exogenous nicotine delivery (Pickworth et al., 1986) typically increase the frequency of the EEG. In the present study conventional cigarettes increased EEG frequency and the increase was directly related to the interval since the previous cigarette. Denicotinized cigarettes had the opposite effects causing EEG slowing that increased directly with the interval since the last cigarette. Denicotinized and conventional cigarettes could be differentiated on measures of EEG power in several clinical EEG frequency classifications. As illustrated, h power (at the Pz electrode) increased after nicotine cigarettes and decreased after denicotinized cigarettes in the 30-min smoking interval but at the longer smoking intervals (60 and 240 min) conventional cigarettes decreased h power and denicotinized cigarettes increased h power. The later results were similar to those in earlier study (Pickworth et al., 1999) where denicotinized cigarettes increased h power and conventional cigarettes decreased it. At the 30 min smoking interval, but not at the other intervals, a power was increased by the conventional cigarette and decreased by the placebo cigarette. b1 power increased after smoking the conventional cigarette after 240 min of abstinence, but b1 power decreased after the denicotinized cigarette. The apparent effects of a placebo cigarette on brain electrical activity are intriguing. In a previous paper, we speculated that the EEG effects of a placebo cigarette may result from exposure of cues related to smoking (feel, sight, smell) without the subsequent delivery of nicotine (Pickworth et al., 1999). The EEG slowing and increases in h power after placebo cigarettes are in the direction of tobacco abstinence. These changes may be analogous to the
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increases in cigarette craving reported when subjects listen to audiotapes that simulate imagery of situations where cigarette smoking ordinarily occurs (Taylor, Harris, Singleton, Moolchan, & Heishman, 2000). On the other hand, we cannot rule out the possibility that a component of the denicotinized cigarette smoke exerted opposite EEG effects to that of nicotine. However, this suggestion is contrary to results of a study where a different denicotinized cigarette (Next) caused no EEG changes (Robinson et al., 1992). In the present study, there was no significant EEG evidence of tobacco abstinence during the 4-h deprivation. The onset of EEG signs associated with tobacco abstinence—EEG slowing and increased EEG power in the lower frequency bands is usually observed after overnight (12 or more hours) deprivation (Knott & Venables, 1977; Pickworth et al., 1986; Ulett & Itil, 1969). However, Herning et al. (1983) reported a significant increase in h power within 4 h of tobacco abstinence. In a study of highly dependent smokers on a residential unit undergoing observed and monitored tobacco abstinence, significant EEG signs of tobacco abstinence occurred 29 h after the last cigarette. There were non-significant EEG slowing and increases in h power as early as 5 h after the last cigarette (Pickworth et al., 1989). The inability to demonstrate EEG signs of tobacco abstinence may have been because the subjects were not required to be abstinent from caffeine. Data from our lab (Cohen, Pickworth, Bunker, & Henningfield, 1994) and elsewhere (Gilbert, Dibb, Plath, & Hiyane, 2000) indicate that caffeine ingestion diminishes EEG signs of tobacco abstinence. The failure to observe EEG signs of abstinence in the present study may be due to recentness and quantity of smoking before the experimental session. It is possible that the EEG effects of the experimental cigarettes would have been enhanced if the subjects had been in a greater state of tobacco abstinence prior to the session or if the session had been longer than 4 h. When others have used the spaced smoking paradigm a 6 h experimental observation was employed (Fant et al., 1995; Schuh & Stitzer, 1995). Although there was no significant EEG changes over the 4 h period, acute administration of conventional and denicotinized cigarettes exerted significant EEG effects. Smoking is a complex pharmacologic and behavioral process. The EEG and other effects of smoking are usually attributed to the rapid delivery of nicotine, however, other components of tobacco smoke, the behavior of smoking and the stimuli associated with smoking are also involved. The results of the present study indicate that both the delivery of nicotine and the recentness of smoking critically influence the EEG effects of smoking. The increasing availability of denicotinized cigarettes is an important development for understanding the complexities of smoking.
Acknowledgments The authors gratefully acknowledge the clinical and clerical assistance of Ms. Eun Lee and Mr. Dat Nguyen.
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