Robert M. Keenan

A method for delivery of precise doses of smoked cocaine-base to humans

Despite increasing smoked cocaine-base use, there have been relatively few parametric studies in this area. The major reason for the limited number of studies is the lack of a simple procedure for the administration of precise doses of smoked cocaine-base to human volunteers. This paper describes a new method that allows for the delivery of precise doses of smoked cocaine-base. A complete description of the method and the precision of the administration procedure are presented. Furthermore, a study is described which was undertaken to determine: 1) the reproducibility of peak blood cocaine levels when the same dose of cocaine was given on two separate occasions; and 2) the dose-related effects on smoking topography, biochemical, physiological and subjective measures. Subjects (N = 5) were administered three doses of cocaine-base (10, 20 and 40 mg). Four subjects were given repeated doses of cocaine-base. Subjects were blind to the dose and in most cases randomly assigned to different doses. The results showed: 1) a significant correlation of peak whole blood cocaine concentrations among similar doses within subjects (r = .99); 2) no significant effects of dose on smoking topography; and 3) significant dose effects for whole blood cocaine concentrations, heart rate and systolic blood pressure.

Physiologic and subjective changes from smokeless tobacco withdrawal

This study prospectively examined withdrawal symptoms in persons using Copenhagen smokeless tobacco and in persons smoking cigarettes. Smokeless tobacco chewers (N = 16) and cigarette smokers (N = 11) were examined during a 6‐day period, during which time a number of measures were administered. Subjects used smokeless tobacco or smoked cigarettes on an ad libitum basis for a 3‐day baseline period and then underwent tobacco deprivation. The significant changes that occurred relative to baseline after smokeless tobacco deprivation included decreased heart rate and orthostatic pulse change and increased craving for tobacco, confusion, eating, number of awakenings, and total scores on a withdrawal symptoms checklist for both self‐rated and observer‐rated measures. There were more changes and changes of greater severity among cigarette smokers.

The relationship between chronic ethanol exposure and cigarette smoking in the laboratory and the natural environment

Few studies have examined the association between ethanol use and cigarette smoking topography. In particular, no study has objectively investigated the relationship between chronic ethanol exposure and cigarette smoking. The aim of this study was to quantify the relationship between cigarette smoking and past and current ethanol use. Male and female cigarette smokers (n=77) between the ages of 30 and 65 years were recruited and grouped as a function of their past and current ethanol use. Group 1 (n=18) included subjects who were ethanol abstinent for the 3 months prior to the study and had no history of alcohol abuse (as defined by DSM-III criteria). Group 2 (n=19) included subjects who were current regular ethanol users and had no history of alcohol abuse. Group 3 (n=20) included subjects who were ethanol abstinent and had a history of alcohol abuse. Group 4 (n=20) included current regular ethanol users with a history of alcohol abuse. A history of alcohol abuse was associated with an intensified pattern of cigarette smoking. Significant differences were observed for total daily smoke exposure, cigarette number, puff number, total puff and inhalation volume, and the nicotine, tar and carbon monoxide yields of the cigarettes smoked. Increased expired-air carbon monoxide and serum cotinine levels were also observed. Current ethanol use was not associated with an increased cigarette smoking pattern. These data suggest that alcohol abusers are at greater risk of contracting cigarette-related pathology.

Pharmacodynamic effects of cotinine in abstinent cigarette smokers

The nicotine metabolite cotinine was administered to abstinent cigarette smokers to determine whether it has pharmacologic activity as assessed by various physiologic and subjective measurements. By means of a randomized, double‐blind, placebo‐controlled counterbalanced‐order design, subjects received cotinine base (30 mg) intravenously after 48 hours of abstinence from cigarette smoking. Serum cotinine concentrations increased to levels commonly achieved during daily cigarette smoking, whereas no change in serum nicotine concentration was observed. Cotinine compared with placebo produced subjective differences in self‐reported ratings of restlessness, anxiety and tension, insomnia, sedation, and pleasantness. Cotinine had minimal effects on cardiovascular measurements. These findings indicate that cotinine is behaviorally active in the setting of cigarette abstinence at blood concentrations similar to those commonly achieved through daily cigarette smoking.

The effects of short-term smokeless tobacco deprivation on performance

Several past studies have reported reliable changes in reaction time performance and self-rated withdrawal scores as a consequence of cigarette deprivation. The purpose of the present study was to determine, prospectively, the effect 24 h of smokeless tobacco deprivation in regular users has on performance and the associated withdrawal symptomology. Forty smokeless tobacco users (Copenhagen brand) were randomly divided evenly into two groups gen brand) were randomly divided evenly into two groups (N=20)∶24 h of deprivation and no deprivation. A third group of ten nonchewers was added as another control group. The results indicated that behavioral, subjective and physiological changes are associated with smokeless tobacco deprivation in regular users. These include increased craving scores, reaction time, self-rated withdrawal symptoms and decreased heart rate.

Nicotine dependence in rats

Health hazards associated with nicotine and tobacco use are well known. A contributing factor, the dependence producing potential of this drug, has become widely accepted. However, there are only a few human and animal studies that provide objective measures of the behavioral consequences of nicotine abstinence. The purpose of the present experiment was to use sensitive measures to examine behavioral disruptions that resulted when nicotine administration was terminated. Six rats were administered 96 daily intravenous infusions of nicotine (0.125 mg/kg/infusion) for at least 10 days. They were trained to respond on a tongue-operated solenoid-driven drinking device that delivered 0.005 ml of a glucose and saccharin solution (G + S) per lick. When nicotine access was terminated for six days, there was a marked suppression in behavior reinforced by the sweetened solution, and this disruption was immediately reversed when nicotine was reinstated. In contrast, nicotine removal also resulted in a decrease in food intake on the first day, but on subsequent days food intake was significantly higher than when nicotine was administered. When cotinine (0.25 mg/kg/infusion), a metabolite of nicotine was substituted for nicotine for six days, similar disruptions resulted in responding maintained by G + S, but food intake was not significantly decreased on the first day of nicotine abstinence. These findings illustrate the utility of sensitive behavioral tests to reveal effects of nicotine abstinence.

Effect of tobacco withdrawal on sustained attention

Sixteen smokers completed a sustained attention task, were randomly assigned to either continue smoking or abstain for 24 h, and were retested. Eight nonsmokers served as a control group. Abstinence increased the variability in responding. Abstinence also appeared to impair the ability to inhibit responding. Abstinence did not potentiate fatigue during the task. These results are consistent with reports that tobacco withdrawal increases difficulty concentrating and impatience but does not increase fatigue.

EFFECTS OF CARBAMAZEPINE ON ACUTE RESPONSES TO SMOKED COCAINE-BASE IN HUMAN COCAINE USERS

A double-blind, placebo-controlled cross-over study was conducted to determine the effects of carbamazepine on the acute physiological and subjective responses to a single dose of smoked cocaine-base. Male cocaine users (N=6) were given 400 mg carbamazepine or placebo, each for a period of 5 days. At the end of the 5-day period, a 40 mg dose of smoked cocaine was administered. The results showed a significantly higher heart rate, diastolic blood pressure elevation, and blood pressure-heart rate product under the carbamazepine compared to the placebo condition. There were no effects of carbamazepine on the subjective responses from cocaine. The increase in cardiovascular functions indicates a need to be cautious in the use of carbamazepine in the treatment of cocaine abusers.

Smokeless tobacco abstinence effects and nicotine gum dose

There were two experiments on abstinence from smokeless tobacco. The purpose of the first experiment was to determine abstinence effects from smokeless tobacco. The purpose of the second experiment was to examine the effects of different doses of nicotine gum on smokeless tobacco abstinence effects. The subjects were male Copenhagen smokeless tobacco users who underwent 3 days of baseline measurement while continuing to use smokeless tobacco ad libitum, and 5 days of the experimental condition. In the first experiment, the subjects were assigned randomly to one of two groups and compared: continuous smokeless tobacco users (n=10), and deprivation plus no nicotine gum (n=10). In the second experiment, subjects were assigned randomly and in a double-blind fashion to one of three groups and compared: (1) deprivation plus 0 mg nicotine gum (n=20); (2) deprivation plus 2 mg nicotine gum (n=20); and (3) deprivation plus 4 mg nicotine gum (n=20). The first experiment showed significant increases upon abstinence for the following variables: (1) craving; (2) difficulty concentrating; (3) restlessness; (4) excessive hunger; (5) eating; (6) reaction time; (7) variability of reaction time and (8) total withdrawal scores for both the self-rated and the observer-rated forms. The second experiment showed that nicotine gum failed to significantly reduce smokeless tobacco abstinence effects, although those with high cotinine levels may receive some benefit from nicotine gum.

Topographical features of smokeless tobacco use

There is an increasing prevalence of smokeless tobacco use. However, very little descriptive information is available on the pattern of use. This study examines topographical features of smokeless tobacco use in a male college-age population (N=56). Subjects were required to use smokeless tobacco ad lib. for a period of 3 days. During this time, they were asked to record the time of onset and completion of each dip of smokeless tobacco. Smokeless tobacco use was significantly associated with time of day. The mean dips/day was 6.3 (SD±2.2), mean inter-dip interval was 102.6 (SD±42.1) min, mean duration/dip was 39.9 (SD±16.5) min, and mean total dip duration/day was 254.6 (SD±129.3) min. The mean grams of tobacco/dip was 1.97 (SD±0.96) and the total grams of tobacco used/day was 12.0 (SD±6.8) g. There were significant correlations between saliva cotinine and number of dips/day, mean duration/dip, total dip duration/day and mean inter-dip interval, suggesting that smokeless tobacco has the potential for producing dependence.