Psychopharmacology (1992) 108:432-436
Psychopharmacology © Springer-Verlag 1992
Psychomotor performance in smokers following single and repeated doses of nicotine gum N. Sherwood, J.S. Kerr, and I. Hindmarch Human Psychopharmacology Research Unit, Robens Institute, University of Surrey, Milford Hospital, Godalming GU7 1UF, UK Received November 3, 1991 / Final version January 27, 1992
Abstract. The psychomotor effects of single and repeated doses of 2 rag nicotine gum were investigated in 13 regular smokers who had abstained from tobacco overnight. In comparison to baseline, a first dose of nicotine led to significantly raised critical flicker fusion thresholds, faster motor reaction times, improved compensatory tracking performance, and faster short-term memory reaction times. Performance after a second and third dose of nicotine remained significantly improved on all measures in comparison to baseline, and absolutely improved when comparing first and third nicotine doses on measures of sensorimotor performance. Throughout, comparisons with a placebo gum condition confirmed that these effects were genuine and not subject to the development of acute nicotine tolerance, suggesting that the enhancement of psychomotor performance experienced by smokers after a first cigarette may be maintained by repeated smoking. Key words: Nicotine gum - Psychomotor performanceSmoking
The last decade has seen a rapid growth in the number of studies which suggest that smoking or nicotine can improve psychomotor function. Two effects that have often been found are the enhancement of central information processing (Wesnes and Warburton 1978; Revell 1988), and improvements in sensorimotor performance (Petrie and Deary 1989; Hindmarch et al. 1990a). Such results have formed the basis for extended speculation on the "positive" role of nicotine in the smoking habit (Warburton 1987), the characterisation of nicotine as a cognitive enhancer (Hindmarch et al. 1990b) and the use of nicotine as a potential anti-dementia agent (Sahakian et al. 1989). Most of these studies chose to investigate the effects of a single dose of nicotine. This is in contrast to the Correspondence to: J.S. Kerr
behaviour of individuals who choose to use tobacco socially, and who usually dose themselves repeatedly with nicotine by smoking a series of cigarettes during the day. As yet, it remains unclear if improvements in performance occur on each occasion a cigarette is smoked. A particular difficulty exists (Hughes 1991) in attempting to distinguish between those effects of nicotine that can be attributed to an absolute improvement in performance (primary effects) and those which suggest relief of withdrawal after a period of abstinence (secondary effects). The results of many studies can be interpreted as supporting either hypothesis: subjects abstain for several hours prior to baseline assessments, are then administered nicotine or allowed to smoke and subsequently show improved performance. However, evidence from those studies where abstinence has been controlled by the use of non-smokers (Warwick and Eysenck 1963; Provost and Woodward 1991) or minimally abstinent smokers (West and Hack 1990; Sherwood et al. 1990) suggest that primary effects do exist and may explain many results. Even if primary effects of nicotine can be established, the possible existence of acute tolerance to such effects could limit the scope for regarding smoking as reinforcing to the smoker. Acute tolerance (tachyphylaxis), which can develop within minutes and may last for several hours, appears to relate to occupancy of nervous system receptor sites by a compound, such that the initial neuronal response is masked on repeated presentations. In behavioural terms, acute tolerance appears as increasingly diminished responses to repeated administrations of a fixed dose of a compound over a few hours (Kalant et al. 1971). Acute tolerance has been found to develop to the heart rate increase produced by an initial exposure to nicotine (Benowitz et al. 1982), and to the subjective effects of dizziness, nausea and tremor (West and Russell 1986). However, West and Jarvis (1986) found that the enhancement of a simple motor function (finger tapping rate) after the first dose of 2 mg nasal nicotine solution, administered to non-smokers on an hourly schedule, still
433 o c c u r r e d after e a c h s u b s e q u e n t d o s e over the six h o u r s d u r a t i o n o f the study. S i m i l a r l y W e s n e s et al. (1983) f o u n d t h a t the p r e v e n t i o n o f f a t i g u e - r e l a t e d p e r f o r m a n c e d e c r e m e n t s in b o t h s m o k e r s a n d n o n - s m o k e r s o n a visual vigilance t a s k after a 1 m g o r 2 m g n i c o t i n e t a b l e t c o n t i n u e d a f t e r a s e c o n d a n d t h i r d t a b l e t given o n a 20 rain schedule. A d d i t i o n a l l y , s m o k e r s ' subjective r a t i n g s o f C N S a r o u s a l a p p e a r to r e m a i n e l e v a t e d o n r e p e a t e d challenges o f 2 m g n i c o t i n e g u m ( S h e r w o o d et al. 1991). T h e p r e s e n t s t u d y s o u g h t to e x p a n d t h e t r a d i t i o n a l single d o s e m e t h o d o l o g y t o i n c l u d e r e p e a t e d d o s e s to e x p l o r e f u r t h e r the p e r f o r m a n c e p h a r m a c o d y n a m i c s o f nicotine. N i c o t i n e g u m was c h o s e n as t h e r o u t e o f a d m i n i s t r a t i o n in p r e f e r e n c e to s m o k i n g t o p r o v i d e a m o r e r e g u l a t e d d o s i n g vehicle a n d to p r o v i d e a r e a s o n a b l e p l a c e b o c o n d i t i o n . P h a r m a c o d y n a m i c profiles o f s m o k ing suggest t h a t , o n a r e g i m e n o f o n e c i g a r e t t e p e r h o u r after a p e r i o d o f a b s t i n e n c e , m e a n b l o o d n i c o t i n e levels rise r a p i d l y after the first c i g a r e t t e o f the d a y , then r a t h e r m o r e slowly o n s u b s e q u e n t cigarettes t o w a r d a p r e f e r r e d level (Russell et al. 1976). A s e p a r a t e s t u d y (Russell et al. 1983) s h o w e d t h a t 30 m i n after a d m i n i s t r a t i o n , p l a s m a n i c o t i n e levels f r o m 2 m g n i c o t i n e g u m c a n be e q u i v a l e n t to t h o s e f o u n d f r o m one s t a n d a r d cigarette. By a d m i n i s tering 2 m g n i c o t i n e g u m every 60 m i n a n d assessing subjects 30 m i n after each a d m i n i s t r a t i o n , the p r e s e n t s t u d y s o u g h t to s i m u l a t e this process.
Materials and methods
Subjects. Seventeen smokers volunteered to participate in the experiment. All had smoked at least ten cigarettes a day for a minimum of 5 years. All subjects underwent a full medical examination. One volunteer was excluded due to a urine sample which tested positively for drugs of abuse, two volunteers were excluded for biochemistry anomalies and one further volunteer was not admitted due to personal time constraints. The remaining 13 volunteers, 7 female and 6 male aged between 20 and 42 years (mean 32.5 years), were all entered as subjects for the study. A further medical examination was given to subjects at the end of the study. No further abnormalities were found. Medication. The study medication was administered as 2 mg or 0 mg (placebo) nicotine polacrilex gum (Nicorette). One drop of red pepper sauce (Tabasco) was added to all gum to disguise the presence of nicotine. Critical Flicker Fusion (CFF). CFF is used as an index of overall central nervous system activity (Hindmarch 1982) and correlates highly with measures of alertness (Parrott 1982). Subjects are required to discriminate flicker from fusion in a set of four red light emitting diodes held in foveal fixation at 1 m. Individual thresholds (the frequency at which the change from flicker to fusion and vice versa is seen to occur) are determined by the psychophysical method of limits on three ascending and three descending scales. Choice reaction time. A choice reaction time task was used as an indicator of sensorimotor performance, and to assess the efficiency of output mechanisms in the response chain. The latency of a motor response to a critical stimulus is recorded, but since this stimulus is one of a number of alternatives attentional monitoring capacities are also investigated. From a central starting position, subjects are required on each trial to extinguish one of six equidistant red lights, illuminated at random, by touching the appropriate contingent response button. Both recognition (time taken to spot the light and
to remove the finger from its starting position) and motor (time taken to reach the appropriate response button) components of the total reaction time are recorded by subtraction from the mean latency for 20 presentations.
Compensatory tracking. One criticism of simple tests is that they allow the subject to re-allocate cognitive resources and focus on the task in hand, masking effects that may be clear if the subject were required to undertake additional tasks. This trade-off of resources can be controlled by using laboratory analogues of skilled performance, which also possess letter face validity. A compensatory tracking task is used as a low-level representation of car driving. The subject is required to attend to two tasks: keeping a joystick controlled cursor in line with a moving target, while simultaneously responding with a button push to visual stimuli presented at random in the peripheral field of vision. Psychomotor co-ordination (RMS - the root mean square of the tracking error) over 5 rain of tracking and the mean reaction time to 20 random peripheral stimuli (RT) are both recorded at each presentation. Memory scanning. High speed scanning and retrieval from short term memory (STM) may be assessed using a technique based on the reaction time method developed by Sternberg (1966). Subjects are required to judge whether a test digit is contained within a short memorised sequence of 4 digits which were presented sequentially for 1.2 s each. The test digit appeared 1 s later and the time taken for the subject to react recorded. Twenty-four such presentations were made at each assessment, and the mean reaction time used in subsequent analyses. Procedure. Each subject attended the laboratory on 3 days, each separated by 1 week. The first day served as a practice session to familiarise subjects with the tasks and surroundings; no medication was given on this day. The remaining 2 days were experimental days, and subjects were administered gum on the hour every hour for 3 h. On one day each piece of gum contained nicotine. On the other day placebo gum was administered. The order of presentation was counterbalanced between subjects to control for order effects. Subjects were asked to abstain from alcohol, tobacco and caffeine containing drinks from retiring to bed the night before experimental days. After a standard breakfast at 8 a.m. baseline assessments were taken, the first piece of gum was administered at 9 a.m. and subjects instructed to chew steadily for 20 rain after which the gum was removed. After a further 10 min assessments were again taken. Subjects then sat quietly, reading or watching television until the next piece of gum was administered at 10 a.m. This was chewed for 20 min, removed, and assessments again taken 10 min later. A final piece of gum was then given at 11 a.m., exactly 2 h after the first piece, chewed and removed following the above procedure and final assessments made. Subjects were then served a standard lunch at midday and allowed to leave the laboratory at 1 p.m..
Results
T w o c o m p a r i s o n s were r e g a r d e d as c e n t r a l to the s t u d y : a general c o m p a r i s o n b e t w e e n the n i c o t i n e a n d the p l a c e b o c o n d i t i o n to e s t a b l i s h w h e t h e r a d r u g effect w a s present, a n d a c o m p a r i s o n b e t w e e n the r e s p o n s e to each d o s e o f n i c o t i n e a n d the n i c o t i n e b a s e l i n e score so as to e s t a b l i s h a n y influence o f a c u t e tolerance. R e p e a t e d m e a s u r e s a n a l y s e s o f v a r i a n c e were u s e d t o a n a l y s e all d a t a . Baseline ( p r e - d r u g ) scores were i n c l u d e d so i n t e r a c t i o n r a t h e r t h a n m a i n effects were t h e focus o f the analyses. P o s t - h o c c o m p a r i s o n s b e t w e e n d o s e s were m a d e u s i n g N e w m a n - K e u l s tests. T a b l e 1 gives t h e m e a n response data.
434 Table 1. Means (SEM) on each of the six
response measures at baseline and after each dose of gum
Baseline CFF (Hz) Placebo Nicotine
Dose 1
27.7 (0.8) 27.0 (0.8)
Dose 2
27.1 (0.8) 27.8 (0.8)~
Dose 3
27.3 (0.9) 27.7 (0.8)~
27.2 (0.8) 27.8 (0.9)~
RRT (ms) Placebo Nicotine
643 646
(25) (25)
655 652
(21) (24)
692 651
(27) (21)
656 646
(30) (26)
MRT (ms) Placebo Nicotine
i97 226
(15) (13)
202 216
(17) (13)
209 205
(12) (13)"b
209 192
(15) (14)"b
RMS Placebo Nicotine
10.5 (1.4) 10.5 (1.5)
10.2 (1.3) 9.3 (1.2)a
10.1 (1.3) 8.8 (1.2)~
10.3 (1.4) 8.4 (1.0)"b
RT (ms) Placebo Nicotine
378 390
(15) (14)
423 406
(18)" (14)
424 400
(14)~ (14)
438 410
(17)" (12)
STM (ms) Placebo Nicotine
614 683
(41) (73)
628 578
(78) (46)a
606 566
(60) (44)"
603 550
(48) (32)"
Significantly different from condition baseline (P< 0.05) b Significantly different from condition first dose (P < 0.05)
Critical Flicker Fusion
Threshold (Hz) 29~
The interaction between treatment and repeated dosing (i.e. dose n u m b e r ) p r o v e d significant in the C F F analysis [F(3,36)=5.22, P < 0 . 0 0 5 ] , with C F F thresholds higher after each active dose o f gum. In c o m p a r i s o n to the nicotine baseline, C F F thresholds were significantly elevated after each dose. W h e r e placebo g u m was administered, no significant differences f r o m the placebo baseline score were f o u n d (Fig. 1).
!
a
28
a
...........~
27
26
Choice reaction time
Nicotine
a
b
p
B
1
__
i
2
__
Placebo
i
3
Dose
D a t a were analysed by their recognition ( R R T ) and m o t o r ( M R T ) c o m p o n e n t s . N o factor p r o v e d significant in the R R T analysis. In the M R T analysis, the interaction between treatment a n d repeated dosing p r o v e d significant [F(3,36)= 9.866, P < 0 . 0 0 1 ] , with reaction times slower after placebo a n d faster after nicotine gum. Posthoc tests s h o w e d that all scores after nicotine g u m were significantly i m p r o v e d over the nicotine baseline score, and that reaction times were significantly faster after the second a n d third doses o f active g u m c o m p a r e d to the score after the first dose (Fig. 2).
Fig. 1. Mean CFF thresholds after each dose of gum. " P < 0.05 vs condition baseline
Reaction Time (ms) 25O
'''"•.•
225
Placebo
200
Nicotine ab 175
Compensatory tracking task Analysis o f the R M S scores p r o d u c e d a m a i n effect o f repeated dosing on tracking [F(3,36)=3.34, P < 0 . 0 5 ] , showing p e r f o r m a n c e to be i m p r o v e d after nicotine. A significant interaction term [F(3,36) = 5.17, P < 0.005]
150
i B
= 1
f 2
i 3
Dose
Fig. 2. Mean motor reaction times after each dose of gum. " P < 0.05 vs condition baseline; b p < 0.05 vs condition first dose
435 t2
Error (rms)
11 Placebo 10 9
a
a
8
ab Nicotine
Memory reaction time
7
B
1
2
3
Dose
Fig. 3. Mean tracking error after each dose of gum. a p< 0.05 vs condition baseline; b p < 0.05 vs condition first dose
475
showed a general trend of increasing length after each dose [F(3,36)= 4.88, P < 0.01] (Fig. 4). However, the significant interaction of treatment with the repeated dosing term [F(3,36)=3.70, P 0.06]. Whereas memory reaction times remained stable after placebo gum, they were significantly shorter, compared to baseline, after each dose of nicotine gum (Fig. 5).
Reaction Time (ms)
Discussion 450
a
a 425
I
a ~
Placebo
~"
/ Nicotine
400I 375f 350
i
i
I
i
B
1
2
3
Dose
Fig. 4. Mean peripheral reaction times after each dose of gum. " P < 0.05 vs conditionbaseline
750
Reaction Time (ms)
700 650 600
•- - ~ - - ~ ' - ~ ' - ~ ' " ~ ~
550
~ " aa
~
~
~
Placebo
Nicotine
500 450 !
~ B
~ 1
~ 2
r.............. 3
Dose
Fig. 5. Mean memory reaction times after each dose of gum. a P
Psychopharmacology © Springer-Verlag 1992
Psychomotor performance in smokers following single and repeated doses of nicotine gum N. Sherwood, J.S. Kerr, and I. Hindmarch Human Psychopharmacology Research Unit, Robens Institute, University of Surrey, Milford Hospital, Godalming GU7 1UF, UK Received November 3, 1991 / Final version January 27, 1992
Abstract. The psychomotor effects of single and repeated doses of 2 rag nicotine gum were investigated in 13 regular smokers who had abstained from tobacco overnight. In comparison to baseline, a first dose of nicotine led to significantly raised critical flicker fusion thresholds, faster motor reaction times, improved compensatory tracking performance, and faster short-term memory reaction times. Performance after a second and third dose of nicotine remained significantly improved on all measures in comparison to baseline, and absolutely improved when comparing first and third nicotine doses on measures of sensorimotor performance. Throughout, comparisons with a placebo gum condition confirmed that these effects were genuine and not subject to the development of acute nicotine tolerance, suggesting that the enhancement of psychomotor performance experienced by smokers after a first cigarette may be maintained by repeated smoking. Key words: Nicotine gum - Psychomotor performanceSmoking
The last decade has seen a rapid growth in the number of studies which suggest that smoking or nicotine can improve psychomotor function. Two effects that have often been found are the enhancement of central information processing (Wesnes and Warburton 1978; Revell 1988), and improvements in sensorimotor performance (Petrie and Deary 1989; Hindmarch et al. 1990a). Such results have formed the basis for extended speculation on the "positive" role of nicotine in the smoking habit (Warburton 1987), the characterisation of nicotine as a cognitive enhancer (Hindmarch et al. 1990b) and the use of nicotine as a potential anti-dementia agent (Sahakian et al. 1989). Most of these studies chose to investigate the effects of a single dose of nicotine. This is in contrast to the Correspondence to: J.S. Kerr
behaviour of individuals who choose to use tobacco socially, and who usually dose themselves repeatedly with nicotine by smoking a series of cigarettes during the day. As yet, it remains unclear if improvements in performance occur on each occasion a cigarette is smoked. A particular difficulty exists (Hughes 1991) in attempting to distinguish between those effects of nicotine that can be attributed to an absolute improvement in performance (primary effects) and those which suggest relief of withdrawal after a period of abstinence (secondary effects). The results of many studies can be interpreted as supporting either hypothesis: subjects abstain for several hours prior to baseline assessments, are then administered nicotine or allowed to smoke and subsequently show improved performance. However, evidence from those studies where abstinence has been controlled by the use of non-smokers (Warwick and Eysenck 1963; Provost and Woodward 1991) or minimally abstinent smokers (West and Hack 1990; Sherwood et al. 1990) suggest that primary effects do exist and may explain many results. Even if primary effects of nicotine can be established, the possible existence of acute tolerance to such effects could limit the scope for regarding smoking as reinforcing to the smoker. Acute tolerance (tachyphylaxis), which can develop within minutes and may last for several hours, appears to relate to occupancy of nervous system receptor sites by a compound, such that the initial neuronal response is masked on repeated presentations. In behavioural terms, acute tolerance appears as increasingly diminished responses to repeated administrations of a fixed dose of a compound over a few hours (Kalant et al. 1971). Acute tolerance has been found to develop to the heart rate increase produced by an initial exposure to nicotine (Benowitz et al. 1982), and to the subjective effects of dizziness, nausea and tremor (West and Russell 1986). However, West and Jarvis (1986) found that the enhancement of a simple motor function (finger tapping rate) after the first dose of 2 mg nasal nicotine solution, administered to non-smokers on an hourly schedule, still
433 o c c u r r e d after e a c h s u b s e q u e n t d o s e over the six h o u r s d u r a t i o n o f the study. S i m i l a r l y W e s n e s et al. (1983) f o u n d t h a t the p r e v e n t i o n o f f a t i g u e - r e l a t e d p e r f o r m a n c e d e c r e m e n t s in b o t h s m o k e r s a n d n o n - s m o k e r s o n a visual vigilance t a s k after a 1 m g o r 2 m g n i c o t i n e t a b l e t c o n t i n u e d a f t e r a s e c o n d a n d t h i r d t a b l e t given o n a 20 rain schedule. A d d i t i o n a l l y , s m o k e r s ' subjective r a t i n g s o f C N S a r o u s a l a p p e a r to r e m a i n e l e v a t e d o n r e p e a t e d challenges o f 2 m g n i c o t i n e g u m ( S h e r w o o d et al. 1991). T h e p r e s e n t s t u d y s o u g h t to e x p a n d t h e t r a d i t i o n a l single d o s e m e t h o d o l o g y t o i n c l u d e r e p e a t e d d o s e s to e x p l o r e f u r t h e r the p e r f o r m a n c e p h a r m a c o d y n a m i c s o f nicotine. N i c o t i n e g u m was c h o s e n as t h e r o u t e o f a d m i n i s t r a t i o n in p r e f e r e n c e to s m o k i n g t o p r o v i d e a m o r e r e g u l a t e d d o s i n g vehicle a n d to p r o v i d e a r e a s o n a b l e p l a c e b o c o n d i t i o n . P h a r m a c o d y n a m i c profiles o f s m o k ing suggest t h a t , o n a r e g i m e n o f o n e c i g a r e t t e p e r h o u r after a p e r i o d o f a b s t i n e n c e , m e a n b l o o d n i c o t i n e levels rise r a p i d l y after the first c i g a r e t t e o f the d a y , then r a t h e r m o r e slowly o n s u b s e q u e n t cigarettes t o w a r d a p r e f e r r e d level (Russell et al. 1976). A s e p a r a t e s t u d y (Russell et al. 1983) s h o w e d t h a t 30 m i n after a d m i n i s t r a t i o n , p l a s m a n i c o t i n e levels f r o m 2 m g n i c o t i n e g u m c a n be e q u i v a l e n t to t h o s e f o u n d f r o m one s t a n d a r d cigarette. By a d m i n i s tering 2 m g n i c o t i n e g u m every 60 m i n a n d assessing subjects 30 m i n after each a d m i n i s t r a t i o n , the p r e s e n t s t u d y s o u g h t to s i m u l a t e this process.
Materials and methods
Subjects. Seventeen smokers volunteered to participate in the experiment. All had smoked at least ten cigarettes a day for a minimum of 5 years. All subjects underwent a full medical examination. One volunteer was excluded due to a urine sample which tested positively for drugs of abuse, two volunteers were excluded for biochemistry anomalies and one further volunteer was not admitted due to personal time constraints. The remaining 13 volunteers, 7 female and 6 male aged between 20 and 42 years (mean 32.5 years), were all entered as subjects for the study. A further medical examination was given to subjects at the end of the study. No further abnormalities were found. Medication. The study medication was administered as 2 mg or 0 mg (placebo) nicotine polacrilex gum (Nicorette). One drop of red pepper sauce (Tabasco) was added to all gum to disguise the presence of nicotine. Critical Flicker Fusion (CFF). CFF is used as an index of overall central nervous system activity (Hindmarch 1982) and correlates highly with measures of alertness (Parrott 1982). Subjects are required to discriminate flicker from fusion in a set of four red light emitting diodes held in foveal fixation at 1 m. Individual thresholds (the frequency at which the change from flicker to fusion and vice versa is seen to occur) are determined by the psychophysical method of limits on three ascending and three descending scales. Choice reaction time. A choice reaction time task was used as an indicator of sensorimotor performance, and to assess the efficiency of output mechanisms in the response chain. The latency of a motor response to a critical stimulus is recorded, but since this stimulus is one of a number of alternatives attentional monitoring capacities are also investigated. From a central starting position, subjects are required on each trial to extinguish one of six equidistant red lights, illuminated at random, by touching the appropriate contingent response button. Both recognition (time taken to spot the light and
to remove the finger from its starting position) and motor (time taken to reach the appropriate response button) components of the total reaction time are recorded by subtraction from the mean latency for 20 presentations.
Compensatory tracking. One criticism of simple tests is that they allow the subject to re-allocate cognitive resources and focus on the task in hand, masking effects that may be clear if the subject were required to undertake additional tasks. This trade-off of resources can be controlled by using laboratory analogues of skilled performance, which also possess letter face validity. A compensatory tracking task is used as a low-level representation of car driving. The subject is required to attend to two tasks: keeping a joystick controlled cursor in line with a moving target, while simultaneously responding with a button push to visual stimuli presented at random in the peripheral field of vision. Psychomotor co-ordination (RMS - the root mean square of the tracking error) over 5 rain of tracking and the mean reaction time to 20 random peripheral stimuli (RT) are both recorded at each presentation. Memory scanning. High speed scanning and retrieval from short term memory (STM) may be assessed using a technique based on the reaction time method developed by Sternberg (1966). Subjects are required to judge whether a test digit is contained within a short memorised sequence of 4 digits which were presented sequentially for 1.2 s each. The test digit appeared 1 s later and the time taken for the subject to react recorded. Twenty-four such presentations were made at each assessment, and the mean reaction time used in subsequent analyses. Procedure. Each subject attended the laboratory on 3 days, each separated by 1 week. The first day served as a practice session to familiarise subjects with the tasks and surroundings; no medication was given on this day. The remaining 2 days were experimental days, and subjects were administered gum on the hour every hour for 3 h. On one day each piece of gum contained nicotine. On the other day placebo gum was administered. The order of presentation was counterbalanced between subjects to control for order effects. Subjects were asked to abstain from alcohol, tobacco and caffeine containing drinks from retiring to bed the night before experimental days. After a standard breakfast at 8 a.m. baseline assessments were taken, the first piece of gum was administered at 9 a.m. and subjects instructed to chew steadily for 20 rain after which the gum was removed. After a further 10 min assessments were again taken. Subjects then sat quietly, reading or watching television until the next piece of gum was administered at 10 a.m. This was chewed for 20 min, removed, and assessments again taken 10 min later. A final piece of gum was then given at 11 a.m., exactly 2 h after the first piece, chewed and removed following the above procedure and final assessments made. Subjects were then served a standard lunch at midday and allowed to leave the laboratory at 1 p.m..
Results
T w o c o m p a r i s o n s were r e g a r d e d as c e n t r a l to the s t u d y : a general c o m p a r i s o n b e t w e e n the n i c o t i n e a n d the p l a c e b o c o n d i t i o n to e s t a b l i s h w h e t h e r a d r u g effect w a s present, a n d a c o m p a r i s o n b e t w e e n the r e s p o n s e to each d o s e o f n i c o t i n e a n d the n i c o t i n e b a s e l i n e score so as to e s t a b l i s h a n y influence o f a c u t e tolerance. R e p e a t e d m e a s u r e s a n a l y s e s o f v a r i a n c e were u s e d t o a n a l y s e all d a t a . Baseline ( p r e - d r u g ) scores were i n c l u d e d so i n t e r a c t i o n r a t h e r t h a n m a i n effects were t h e focus o f the analyses. P o s t - h o c c o m p a r i s o n s b e t w e e n d o s e s were m a d e u s i n g N e w m a n - K e u l s tests. T a b l e 1 gives t h e m e a n response data.
434 Table 1. Means (SEM) on each of the six
response measures at baseline and after each dose of gum
Baseline CFF (Hz) Placebo Nicotine
Dose 1
27.7 (0.8) 27.0 (0.8)
Dose 2
27.1 (0.8) 27.8 (0.8)~
Dose 3
27.3 (0.9) 27.7 (0.8)~
27.2 (0.8) 27.8 (0.9)~
RRT (ms) Placebo Nicotine
643 646
(25) (25)
655 652
(21) (24)
692 651
(27) (21)
656 646
(30) (26)
MRT (ms) Placebo Nicotine
i97 226
(15) (13)
202 216
(17) (13)
209 205
(12) (13)"b
209 192
(15) (14)"b
RMS Placebo Nicotine
10.5 (1.4) 10.5 (1.5)
10.2 (1.3) 9.3 (1.2)a
10.1 (1.3) 8.8 (1.2)~
10.3 (1.4) 8.4 (1.0)"b
RT (ms) Placebo Nicotine
378 390
(15) (14)
423 406
(18)" (14)
424 400
(14)~ (14)
438 410
(17)" (12)
STM (ms) Placebo Nicotine
614 683
(41) (73)
628 578
(78) (46)a
606 566
(60) (44)"
603 550
(48) (32)"
Significantly different from condition baseline (P< 0.05) b Significantly different from condition first dose (P < 0.05)
Critical Flicker Fusion
Threshold (Hz) 29~
The interaction between treatment and repeated dosing (i.e. dose n u m b e r ) p r o v e d significant in the C F F analysis [F(3,36)=5.22, P < 0 . 0 0 5 ] , with C F F thresholds higher after each active dose o f gum. In c o m p a r i s o n to the nicotine baseline, C F F thresholds were significantly elevated after each dose. W h e r e placebo g u m was administered, no significant differences f r o m the placebo baseline score were f o u n d (Fig. 1).
!
a
28
a
...........~
27
26
Choice reaction time
Nicotine
a
b
p
B
1
__
i
2
__
Placebo
i
3
Dose
D a t a were analysed by their recognition ( R R T ) and m o t o r ( M R T ) c o m p o n e n t s . N o factor p r o v e d significant in the R R T analysis. In the M R T analysis, the interaction between treatment a n d repeated dosing p r o v e d significant [F(3,36)= 9.866, P < 0 . 0 0 1 ] , with reaction times slower after placebo a n d faster after nicotine gum. Posthoc tests s h o w e d that all scores after nicotine g u m were significantly i m p r o v e d over the nicotine baseline score, and that reaction times were significantly faster after the second a n d third doses o f active g u m c o m p a r e d to the score after the first dose (Fig. 2).
Fig. 1. Mean CFF thresholds after each dose of gum. " P < 0.05 vs condition baseline
Reaction Time (ms) 25O
'''"•.•
225
Placebo
200
Nicotine ab 175
Compensatory tracking task Analysis o f the R M S scores p r o d u c e d a m a i n effect o f repeated dosing on tracking [F(3,36)=3.34, P < 0 . 0 5 ] , showing p e r f o r m a n c e to be i m p r o v e d after nicotine. A significant interaction term [F(3,36) = 5.17, P < 0.005]
150
i B
= 1
f 2
i 3
Dose
Fig. 2. Mean motor reaction times after each dose of gum. " P < 0.05 vs condition baseline; b p < 0.05 vs condition first dose
435 t2
Error (rms)
11 Placebo 10 9
a
a
8
ab Nicotine
Memory reaction time
7
B
1
2
3
Dose
Fig. 3. Mean tracking error after each dose of gum. a p< 0.05 vs condition baseline; b p < 0.05 vs condition first dose
475
showed a general trend of increasing length after each dose [F(3,36)= 4.88, P < 0.01] (Fig. 4). However, the significant interaction of treatment with the repeated dosing term [F(3,36)=3.70, P 0.06]. Whereas memory reaction times remained stable after placebo gum, they were significantly shorter, compared to baseline, after each dose of nicotine gum (Fig. 5).
Reaction Time (ms)
Discussion 450
a
a 425
I
a ~
Placebo
~"
/ Nicotine
400I 375f 350
i
i
I
i
B
1
2
3
Dose
Fig. 4. Mean peripheral reaction times after each dose of gum. " P < 0.05 vs conditionbaseline
750
Reaction Time (ms)
700 650 600
•- - ~ - - ~ ' - ~ ' - ~ ' " ~ ~
550
~ " aa
~
~
~
Placebo
Nicotine
500 450 !
~ B
~ 1
~ 2
r.............. 3
Dose
Fig. 5. Mean memory reaction times after each dose of gum. a P
