Biomedical subjects
W B Pickworth
Publications and source records attributed to W B Pickworth.
Smoking without nicotine delivery decreases withdrawal in 12-hour abstinent smokers.
The contribution of sensory factors to smoking satisfaction and nicotine withdrawal symptoms was assessed by evaluating responses to three types of cigarettes: a regular cigarette, a de-nicotinized cigarette (de-nic), and a lettuce leaf cigarette. Doses were varied by requiring subjects to smoke cigarettes using a five-port cigarette manifold. The ratio of the regular or de-nic cigarettes to the lettuce cigarettes was varied across the following values: zero, one, two, and four of five. Seven male smokers were tobacco-deprived for 12 h before testing. On one test day they smoked the de-nic cigarettes, and on another day they smoked the regular cigarettes. Ratings of satisfaction and cigarette linking were directly related to the number of regular or de-nic cigarettes, but were generally higher after the regular cigarette. The regular and de-nic cigarettes were equivalent in reducing acute withdrawal symptoms. Expired CO was similar on both experimental days. The regular cigarette dose-dependently increased plasma nicotine, but the de-nic cigarette did not increase plasma nicotine. These results indicate that sensory characteristics of cigarettes contribute to the abuse liability of smoke-delivered nicotine. The results suggest that smoking cigarettes that do not provide nicotine may temporarily suppress cigarette withdrawal symptoms.
Transdermal nicotine: reduction of smoking with minimal abuse liability.
Cigarette consumption as well as the physiologic, performance and subjective effects of the nicotine patch were evaluated in ten subjects who smoked ad libitum while residing on a residential research ward for 30 days. Nicotine transdermal systems ("patches") delivering a total of 0, 22 or 44 mg per 24 h were applied daily at a constant dose during each 7-day condition; the order of dosing conditions was varied according to a randomized, double-blind, crossover design. Nicotine patches significantly but modestly reduced spontaneous smoking and significantly increased venous plasma nicotine levels. Self ratings of patch liking, satisfaction with cigarettes and the ability to identify the patch condition did not change as a function of the nicotine dose, indicating minimal abuse liability. There were no consistent changes in the puffing pattern measures; however, in all patch conditions, subjects with extensive histories of illicit drug use smoked cigarettes faster than subjects with histories of occasional drug use. Small changes in resting heart rate, pulse and blood pressure occurred when the nicotine patch was worn. Thus large changes in venous plasma nicotine levels engender only modest changes in ad libitum cigarette consumption, measures of abuse liability and cardiovascular effects. These findings are consistent with the notion that the addictive and toxic effects of nicotine are partially determined by the rate of drug administration.
Lack of evidence for context-dependent cocaine-induced sensitization in humans: preliminary studies.
Cocaine-induced behavioral sensitization is the well-documented phenomenon where repeated doses of cocaine elicit increasingly greater effects on motoric activity in rats. Some observations suggest that behavioral sensitization may provide a model for understanding the mechanisms of drug-craving elicited by environmental triggers or cues. The process of fully validating such an animal model for its ability to detect effective anticraving medicines is a difficult and long-term undertaking. As a first step in that direction, we decided to determine if cocaine can produce conditioned behavioral sensitization in humans using a paradigm fairly similar to that used for rodents. Because humans do not react to cocaine with the pronounced motor activation observed in rodents, we measured a variety of end points, including blood pressure (BP), heart rate (HR), respiratory rate, pupil diameter, hormones (prolactin and cortisol), and subjective responses using the questionnaire for drug-related feelings (QDRF) and the EEG. To mimic the home and test cages used in rodent studies, two rooms were used: a small test chamber and a regular room with a window and furnishings. On day 1 each subject received a drug infusion (either saline or 40 mg cocaine IV) in both locations. On day 2, all subjects received an infusion (saline or 25 mg cocaine IV) in the test chamber. All drug infusions were conducted double blind. The paired group received cocaine on both days in the test chamber. The unpaired group received cocaine in regular room on day 1, and cocaine in the test chamber on day 2.(ABSTRACT TRUNCATED AT 250 WORDS)
Caffeine antagonizes EEG effects of tobacco withdrawal.
Six current cigarette smokers and coffee drinkers were given combinations of 0, 150, or 300 mg caffeine and 0, 2, or 4 mg nicotine polacrilex following 12-h nicotine and caffeine abstinence. On one study day, subjects were allowed to smoke cigarettes and to drink caffeinated beverages and no drugs were given. Tobacco and caffeine abstinence impaired performance on the serial addition/subtraction and digit recall tasks; decreased scores on the MBG scale and ratings of "clear-headed" and "quick-witted"; and increased ratings of "irritability," "muscular tension," "headache," "drowsy," "clumsy," "feeble," and "dreamy." The deprivation caused characteristic EEG signs of nicotine withdrawal including increased theta power and decreased alpha frequency. These EEG effects were reversed by cigarette smoking and caffeine administration, but nicotine polacrilex was less effective. Deprivation-induced performance and subjective measures were not changed by administration of nicotine and caffeine combinations.
Acetaminophen fails to inhibit ethanol-induced subjective effects in human volunteers.
In animals, ethanol causes some of its CNS effects by releasing prostaglandins (PG); this is demonstrated by reports that prostaglandin synthetase inhibitors (PGSIs) diminish ethanol-induced effects. However, use of animals in these studies has precluded testing for subjective effects. We studied the interaction of ethanol and acetaminophen, a PGSI, in a double-blind crossover experiment. Six adult males were given no drug or acetaminophen (0, 325, 650, 1300 or 1950 mg) 75 min before ethanol (total dose = 0.625 g/kg; five divided doses). Physiologic, subjective and performance measures were collected. Compared to the no drug condition, ethanol significantly increased ratings of drug "liking," "drunk," "sluggish" and "drug strength" and decreased ratings of "sober." Ethanol increased heart rate and acetaminophen did not diminish or enhance this effect. The failure to antagonize ethanol-induced subjective and physiologic effects by acetaminophen in humans may be due to species differences or inadequate dosage of the PGSI. It is also possible that subjective and certain physiologic effects of ethanol in humans are not mediated by prostaglandin-dependent neural processes. Nevertheless, the finding that at greater than typical analgesic doses, acetaminophen failed to prevent subjective effects of ethanol is of clinical significance.
Daily variation and effects of ambient light and circadian factors on the human light reflex.
Measures of pupillary size and the dynamic light reflex are safe and noninvasive methods to quantify and characterize the mechanism and site of drug action. The effects of variations in ambient light and time of day on pupillary measures were determined. In dark adapted volunteers (n = 13), ambient light was incrementally increased at < 0.1, 4, 40, 100 and 200 foot-candle (ftcd). Subjects adjusted to each light level for 1 min before the light reflex was elicited. Replicate measures were collected with the contralateral eye open and covered with an opaque patch. Data were collected every 3 h between 6 a.m. and 9 p.m. The prestimulus diameter of the dark adapted pupil averaged 6.4 mm at < 0.1 ftcd and 2.3 mm at 200 ftcd. Constriction amplitude decreased with increases in ambient light from 2.1 mm (< 0.1 ftcd) to 0.2 mm (200 ftcd) while constriction and dilatation velocities decreased from 7.7 to 2.8 mm/sec and 4.3 to 2.8 mm/sec, respectively. Time of day effects were small but statistically significant and the interaction of ambient light and time of recording suggests the pupil is differentially sensitive to ambient and phasic light stimuli over the course of the day. A patch over the contralateral eye increased pupil size and velocities of the light reflex. In a second study, 10 volunteers were tested twice a day at 4 and 80 ftcd for four days. While there was wide between subject variability, the within subject differences were small. Such baseline data may be useful in describing the normal variations in these increasingly popular indices of drug action.
Intravenous buprenorphine reduces pupil size and the light reflex in humans.
The pupillary effects of intravenous buprenorphine were studied in eight nondependent male subjects who reported previous opiate use. Buprenorphine (0.3, 0.6, and 1.2 mg) decreased pupil size, the amplitude of the light reflex, and the velocities of constriction and dilation. Significant pupillary effects occurred within 15 min of the injection and persisted for 24 hr. At 48 hr most measures returned to baseline levels. Generally the magnitude of the effect was not dose related although recovery occurred sooner after the lower dose. The time course of the pupillary effects of buprenorphine exceeds duration of its analgesic and subjective effects. Previous studies have reported that pupillary measures are especially sensitive to the acute effects of full opiate agonists. The results of the present study indicate that buprenorphine, a partial opiate agonist, causes profound and persistent effects on pupillary size and dynamic measures.
Cigarette smoking and addiction.
Tobacco use is a form of drug addiction, as shown by studies assessing the abuse liability of tobacco and nicotine in humans and animals. Tobacco experimentation frequently leads to daily use, which is characterized by a highly consistent pattern of drug intake. Such a pattern is controlled by the biologic concentrations of nicotine, a psychoactive constituent of tobacco smoke. Nicotine is a euphoriant, self-administered by humans as well as by animals in laboratory settings. Nicotine controls smokers' behavior in such a way that reducing or suppressing tobacco consumption produces a withdrawal syndrome characterized by irritability, difficulty concentrating, cognitive impairments, and weight gain. Nonpharmacologic factors are also important determinants of tobacco addiction that interfere with successful cessation. Strategies to treat tobacco addiction are comparable to those developed for other drug addictions. For example, therapy may include the use of alternate forms of nicotine and possibly also nicotine antagonists and medications targeted to alleviate specific withdrawal symptoms, if such therapies become available. As in all drug addiction treatment strategies, behavioral intervention is important whether or not a medication is used.
Buprenorphine-induced pupillary effects in human volunteers.
The pupillary effects of the partial opiate agonist buprenorphine were studied in 16 male subjects who were heroin dependent at the time of admission to the study. Sublingual buprenorphine (8 mg) was administered daily for 18 days and continued either daily or on alternate days from study days 19 through 36. On days 37 through 56, all subjects received buprenorphine placebo. Compared to placebo, buprenorphine decreased pupil size and diminished the constriction and dilation velocities of the light reflex. These effects occurred within 5 hours of buprenorphine administration. Following placebo administration during alternate-day dosing of buprenorphine, pupil size increased and constriction and dilation velocities of the light reflex were significantly greater than after buprenorphine administration in the same subjects. This pattern of effects was observed after buprenorphine was discontinued (day 37). The results indicated that buprenorphine has pupillary effects like those of full opiate agonists. The time course of these effects was similar to previously-reported effects of buprenorphine on the electroencephalogram but not to the time course of subjective effects.
Effects of self-reported drug use and antisocial behavior on evoked potentials in adolescents.
From a sample of 35 adolescents, 17 were chosen who represented extremes of self-reported drug use and delinquent behavior. Three comparison groups were derived: Group 1, n = 7, high drug use/high delinquency; Group 2, n = 4 no drug use/high delinquency; Group 3, n = 6, no drug use/no delinquency. The three groups were similar for age, IQ, race and neighborhood characteristics. Group 1 showed significantly more drug use than Groups 2 and 3; Groups 1 and 2 had comparable levels of delinquency which were significantly greater than Group 3. The subjects performed the auditory oddball task under conditions of low and high background noise. In the high background noise condition, Group 1 had longer latency P300 responses than Groups 2 and 3, while Group 2 had smaller N100 amplitude than Groups 1 and 3. Performance was similar for each group and no group differences occurred in the low background noise condition. The results support and extend previous research on the relationship between attentional and cognitive processes, and delinquent and drug using behaviors.
Assessment of mazindol for abuse liability.
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Dose-dependent atropine-induced changes in spontaneous electroencephalogram in human volunteers.
Atropine is an anticholinergic drug used in military medicine as an antidote following exposure to cholinesterase-inhibiting nerve agents. However, atropine causes neuropsychologic effects that impair performance. In the present study, we examined electrophysiologic indices that may accompany performance deficits. Quantitative electroencephalographic (EEG) analyses of changes induced by atropine (1.5, 3.0, and 6.0 mg/70 kg, intramuscularly) were assessed in seven male volunteers in a placebo-controlled, double-blind, cross-over experiment. Spontaneous EEG recordings were obtained from relaxed subjects before, 2 hours after, and 8 hours after atropine. Atropine significantly increased delta power, decreased alpha power, and tended to increase theta power and reduce beta and theta frequency. EEG indices of vigilance were reduced by the drug. Dose-related increases in sedation and dysphoria were obtained; some subjects liked these effects. Together, these findings confirmed that atropine causes dose- and time-related electrophysiologic and subjective effects that predict impaired performance.
Auditory event-related potentials in adolescents at risk for drug abuse.
We evaluated sensory and cognitive information processing in noninstitutionalized delinquent male adolescents and in age-matched low delinquency controls. Detailed psychometric testing documented the nature of the aggressive behavior of these young men. Deficits in information processing, as assessed by event-related potential (ERP) techniques, were observed at several levels of the auditory system in the delinquent group. The delinquent group showed delays in wave V of the brainstem auditory evoked potential, shorter N100 latency, and decreased slow wave amplitude of cognitive event-related potentials when subjects were asked to perform a mental task in a noisy environment. It remains to be determined whether or not such information-processing deficiencies are common among delinquent populations and how they might influence the development of delinquent behavior and drug abuse.
EEG and brainstem auditory evoked response potentials in adult male drug abusers with self-reported histories of aggressive behavior.
Auditory brainstem evoked response (BAER) and spontaneous electroencephalogram (EEG) were measured in 124 adult male drug abusers. We examined the relationships among psychiatric diagnoses, paper and pencil measures of aggression and hostility, and electrophysiological features. Subjects meeting criteria for antisocial personality disorder (ASP), as defined by DSM-III, were not significantly different from non-ASP subjects for either BAER or spontaneous EEG measures. The more overtly aggressive subjects had significant delays in BAER latency. Aggressive subjects also had more delta activity and less alpha activity in the spontaneous EEG, as have been observed in "psychopaths" and "criminals." Although ASP and aggression are related, these data indicate that aggressiveness may be a separate, albeit overlapping, trait. As both early aggression and a diagnosis of ASP are predictors of later drug use, the findings that only aggression was associated with EEG slowing and brainstem delays may indicate that ASP and aggression make independent contributions to vulnerability to the development of drug abuse.
Spontaneous EEG changes during tobacco abstinence and nicotine substitution in human volunteers.
Electroencephalographic correlates of tobacco abstinence and nicotine substitution were measured in adult male cigarette smokers in residence on a research ward in two experiments. After ad libitum smoking, seven subjects were deprived of nicotine for 10 days and then resumed smoking. During tobacco abstinence, there were significant decreases in alpha frequency and beta frequency and increases in theta power. These effects were observed as early as 29 hr and in some instances persisted for 7 days. In the second experiment, a group of eight heavy smokers chewed 12 pieces of either placebo or nicotine-containing polacrilex gum (2 or 4 mg) per day while deprived of cigarettes. In the placebo condition, electroencephalographic signs were similar to those accompanying tobacco deprivation in the first experiment. Administration of nicotine polacrilex prevented the appearance of these tobacco withdrawal signs. This study provides new information on the time course of certain electrophysiologic components of the tobacco withdrawal syndrome and confirms that the effects are specific to the deprivation of nicotine. The data also suggest that the 4-mg polacrilex was more effective than the 2-mg dose when the results across all measures were considered.
Opiate-induced pupillary effects in humans.
The pupillary effects of several opiates were assessed in human volunteers (N = 6) by means of a newly developed hand-held pupilometer, Pupilscan. Static (diameter) and dynamic (light reflex) responses after morphine, heroin, codeine, oxycodone, oxymorphone and hydrocodone were recorded. The opiates caused dose-related decreases in pupillary size and in the velocity of constriction to a light stimulus. The velocity of redilation after a light stimulus was also decreased. These data indicate that opiates cause systematic changes in dynamic pupillary responses in humans and that measures of these changes may be useful in the quantitative estimation of drug-induced impairment.
Mecamylamine reduces some EEG effects of nicotine chewing gum in humans.
Spontaneous EEG was recorded in nine cigarette smokers who had been abstinent from tobacco for 12 hr. Subjects were treated with a capsule containing either centrally acting nicotine blocker, mecamylamine (10 mg), or placebo. At each of three 60-min intervals after the capsule was ingested, the subjects chewed two pieces of gum containing a total of 0, 4 or 8 mg of nicotine. Nicotine and mecamylamine dose combinations were randomized across subjects. Two three-minute periods of spontaneous EEG were recorded before the capsule and before and after gum chewing from bipolar electrode montages at the following positions: Cz-T5, Cz-T6, Cz-F7 and Cz-F8. During one period the subjects relaxed with eyes closed, in the other period they performed a math task with eyes open. When the drugs were given individually, mecamylamine decreased beta power and nicotine gum (4 and 8 mg) increased alpha frequency. Mecamylamine pretreatment prevented the increase in alpha frequency caused by the 4 mg gum dose but not the 8 mg dose. Alpha power was increased by the 8 mg gum dose and that increase was prevented by mecamylamine. Self-reported ratings of the "strength" of the gum were significantly diminished by mecamylamine pretreatment. The data are consistent with the results of earlier studies which indicate that the effects of tobacco administration and withdrawal are mediated by central actions of nicotine.