Physiologic effects of nicotine polacrilex.

Nicotine is the pharmacologically active agent in tobacco responsible for the maintenance of cigarette smoking behavior. Paradoxically, nicotine also offers the most promise in the successful treatment of cigarette smoking when it is delivered to the central nervous system in a safer and more manageable form. By transferring the physiologic dependence from nicotine contained in tobacco to nicotine bound in a polacrilex, the behavioral aspects associated with cigarette smoking can be removed with a minimal amount of discomfort or risk of relapse. Nicotine bound to a polacrilex and administered as a chewing gum is currently the replacement of choice since many of the systemic effects of nicotine delivered via this route are similar to the effects of nicotine delivered in cigarette smoke without the accompanying exposure to carbon monoxide and tar. Factors such as administered dose, schedule of dosing, and rate and vigor of chew, however, can significantly alter the desired effects. This paper provides a summary of the physiologic changes which may affect the effectiveness of nicotine gum as a pharmacologic adjunct in the treatment of tobacco dependence.

Relative abuse liability of lorazepam and diazepam: an evaluation in 'recreational' drug users.

The subjective, psychomotor and cognitive effects of oral doses of lorazepam (0, 1.5, 3 and 6 mg) and diazepam (0, 10, 20 and 40 mg) were studied under double-blind conditions in 14 volunteers with histories of 'recreational' benzodiazepine use/abuse. For each subject, drug was administered over 4 test days in a 2 (drug) by 4 (dose level) mixed design. Drug was the between-groups factor while dose was the within-subjects factor. Test days were separated by at least 1 week. The results showed that subjective ratings of drug 'liking' and the psychomotor and cognitive effects of lorazepam were generally similar to those of diazepam over the range of doses studied. Lorazepam, however, tended to produce effects of longer duration than diazepam. Since previous studies have shown that diazepam has a relatively high abuse liability among the benzodiazepines, the present findings suggest that lorazepam shares this property with diazepam is subjects with a history of 'recreational' drug use/abuse.

Nicotine gum: chew rate, subjective effects and plasma nicotine.

Two studies were conducted to assess the effects of varying the rate at which single pieces of nicotine gum (4 mg) were chewed. In each study, six cigarette-deprived volunteers were tested during four sessions. In each session, they were required to chew the gum for 10 min at varying rates; a variety of self-report and physiologic responses were recorded before and after chewing. All chewed gum was analyzed for amount of nicotine extracted, and blood samples were collected for nicotine analysis. Additionally, in Experiment 2, a measure of masticatory pressure was employed to assess the intensity of chewing and to empirically verify the number of chews. In both studies, we found a weak, but direct, relation between chew rate and the amount of extracted nicotine. Experiment 2 revealed a probable cause of the weaker than expected "dose-effect" function: subjects showed compensatory changes in behavior by chewing slower than instructed in the high rate conditions, and by chewing faster than instructed in the low rate conditions. Thus, despite instructions to vary chew rates across an 8-fold range, actual chew rate varied by only 2.2-fold. Intensity of chewing remained constant across conditions. Taken together, the findings suggest that rate of chewing nicotine gum can make a difference in the amount of nicotine extracted from the gum; however, compensatory changes in chew rate may attenuate attempts to systematically vary nicotine dose in this manner.

Nicotine gum: dose-related effects on cigarette smoking and subjective ratings.

The effects of nicotine-containing chewing gum on cigarette smoking and subjective and physiological response were evaluated in eight normal volunteers. Isolated subjects smoked their regular brand of cigarettes freely in a naturalistic laboratory environment while watching television or reading. Before 90-min smoking sessions subjects chewed two pieces of placebo or nicotine-containing gum (0, 2, 4, or 8 mg) under double-blind conditions. Each subject received each treatment four times in a mixed order across days. Analysis of the chewed gum for remaining nicotine revealed that the mean delivered nicotine doses were 0, 1.02, 2.39, and 5.20 mg nicotine. Nicotine preloading produced dose-related increases in plasma nicotine, while producing dose-related decreases in various measures of cigarette smoking including number of cigarettes smoked, number of puffs taken, expired air carbon monoxide level, and ratings of smoking satisfaction. Nicotine preloading produced dose-related increases in ratings of gum dose-strength, while producing decreases in ratings of gum dose acceptability and liking. Heart rate and blood pressure were not significantly affected by nicotine gum. Taken together, the present results confirm that responses to nicotine in the gum preparation are orderly and related to dose, and the results suggest that the efficacy of treating tobacco dependence with nicotine gum may be enhanced by increasing the administered dose.

Effects of marijuana smoking on subjective ratings and tobacco smoking.

Multiple measures of tobacco cigarette smoking and subjective and physiological effect were collected during 90 minute test sessions in volunteer cigarette smokers who also had histories of recreational marijuana use. Before sessions, subjects smoked one marijuana cigarette (placebo or 1.29%, 2.84%, 4.00%) using a standardized puffing procedure. Each dose and placebo was given four times to each subject in a randomized block sequence. Marijuana smoking produced dose-related increases in heart rate, ratings of dose strength and drug liking. However, marijuana produced no significant alterations in tobacco cigarette smoking. Puff duration within each marijuana cigarette varied in a fashion similar to that observed in previous studies of tobacco cigarette smoking: puff duration progressively decreased as the cigarette was smoked. This effect is probably due to progressive decreases in resistance to draw as the cigarette is smoked. Expired air carbon monoxide (CO) levels following marijuana smoking were inversely related to marijuana dose, suggesting the occurrence of some compensatory changes in marijuana smoking in response to dose manipulations. It is concluded that, although marijuana produces dose-related effects on physiological and subjective effects and on marijuana smoking behavior, marijuana differs from a variety of other psychoactive drugs previously studied in this paradigm in that no reliable changes in tobacco smoking were produced.

Effects of nicotine chewing gum on cigarette smoking and subjective and physiologic effects.

Our study was conducted to assess the effects of multiple doses of nicotine chewing gum on a variety of measures of cigarette smoking, affect, and physiologic response. Cigarette smokers resided on a research unit for the duration of the study, during which time their smoking behavior was measured during nine 12-hour test sessions. At the start of each session and every 2 hours thereafter, subjects received oral doses of nicotine (2 or 4 mg) or placebo in the form of a chewing gum (nicotine polacrilex). Each dose of active drug and placebo was given for three sessions in a randomized block sequence. Total number of puffs per day was significantly decreased at both the 2 and 4 mg doses when compared with placebo, and the total number of cigarettes smoked per day was significantly decreased at the 4 mg dose. There were dose-related changes in certain subjective effects: Self-reported ratings of dose strength were directly related to dose, desire to smoke tended to be inversely related to dose, and prominent measures of abuse liability did not change. The only cardiovascular measure that was significantly changed by nicotine dose was systolic blood pressure, which showed an attenuation of the diurnal pattern as the dose increased.

Effects of mecamylamine on human cigarette smoking and subjective ratings.

Multiple measures of cigarette smoking, subjective effect and physiological effect were collected during 90-min test sessions in normal volunteers. Before sessions subjects received oral doses of mecamylamine (2.5, 5.0, 10, 20 mg) or placebo. Each dose and placebo was given three times in a randomized block sequence. Mecamylamine increased several measures of cigarette smoking, including number of cigarettes, number of puffs per cigarette, and expired air carbon monoxide level. Mecamylamine also produced modest, dose-related decreases in standing blood pressure and increases in standing heart rate. The subjective effects produced by mecamylamine were not characteristic of those of psychoactive drugs. Mecamylamine appears to have increased cigarette smoking by decreasing the effective dose level of nicotine available from cigarette smoking.

Naloxone does not affect cigarette smoking.

In order to provide information about the hypothesis that endogenous opioids mediate the reinforcing properties of cigarette smoking, the present study examined the effects of naloxone, an opioid antagonist, on cigarette smoking in seven normal volunteers. The study used experimental procedures that had previously been shown sensitive for detecting the effects of other drugs, (including a nicotine antagonist) on smoking. Isolated subjects smoked their regular brand of cigarettes freely in a naturalistic laboratory environment while watching television or reading. Sixty minutes before each 2 h smoking session subjects received an IM injection of naloxone HCl (0.0625, 0.25, 1.0, or 4.0 mg/kg) or placebo. Each subject received each treatment three times in a mixed order across days. Naloxone did not significantly affect any measure of cigarette smoking including number of cigarettes, number of puffs, or expired air carbon monoxide level. Naloxone did, however, produce significant dose-related increases in subject ratings of yawning, stretching, and relaxation. The results of the present study provide no support for the endogenous opioid theory of smoking reinforcement.

Effects of cigarette rod length on puff volume and carbon monoxide delivery in cigarette smokers.

As part of a continuing series of studies to investigate the variables controlling various topographical aspects of cigarette smoking, the present study examined the extent to which cigarette rod length influenced smoking. Cigarette smoking was examined under conditions in which subjects smoked cigarettes they could not see. Both puff volume and puff duration varied as a direct function of rod length, although they were not highly correlated. Peak flow rate was not affected by rod length. Other results suggest that visual stimulus control and satiation did not affect puff volume. Comparison of puffing whole cigarettes versus short cigarette rods suggests that puff volume, but not puff duration, may be decreased in response to increased pharmacological delivery as a result of particulate build-up during smoking of a whole cigarette. Carbon monoxide (CO) exposure was substantially greater after puffing full length cigarette rods than after short cigarette rods. Comparison of these human CO data with CO delivery from syringe-simulated puffing of full length and short cigarette rods indicates that knowledge of puff volume and duration during human smoking is insufficient for accurately predicting biological (CO) exposure.

Determinants of puff duration in cigarette smokers: II.

Studies were conducted to provide information about variables that might account for decreases in puff duration that consistently occur as a whole cigarette is smoked. In two experiments, cigarette smoking was investigated under conditions in which subjects smoked cigarettes which they could not see. Puff duration was shown to covary with manipulations of resistance to draw--increasing tobacco rod length or adding filters proximal or distal to the smoke stream increased puff duration. Filtration of the smoke stream did not influence puff duration when resistance to draw was controlled. Comparison of changes in smoke temperature with changes in puff duration across a whole cigarette, and manipulation of smoke temperature by use of different length cigarette holders suggested that temperature did not appreciably control puff duration. A final experiment with nonhuman stimulated puffing of constant puff volume showed that both tobacco rod length and cigarette brand affected puff duration and suggests the possibility that the physics of smoke passing through the cigarette may be fundamental determinant of changes in puff duration during human smoking.

Determinants of puff duration in cigarette smokers: I.

This research was undertaken to provide information about variables offt might account for the decreases in puff duration that consistently occur as a whole cigarette is smoked. Cigarette smoking was investigated under conditions in which subjects smoked cigarettes which they could not see. In a series of three experiments, the length of the tobacco rod, the length of the cigarette holder, and the cigarette nicotine delivery were systematically manipulated. The results showed that puff duration correlates with the length of the tobacco rod, and that visual stimulus control, satiation, distance from the burning ember to the smoker's mouth, nicotine delivery, particulate build-up during smoking, and subjective acceptability of cigarette smoke do not contribute significantly to the control of puff duration.