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It is well established that nicotine meets all criteria of a highly addictive drug. However, as recognized by the U.S. surgeon general, the nicotine delivery system itself is an important determinant of the toxic and addictive effects engendered by nicotine use. Therefore, altering the form of nicotine dosing may allow for selective therapeutic action in efforts to develop safer and less addictive nicotine replacement therapies. While it is the case that initial tobacco use often escalates to compulsive use accompanied by tolerance and physical dependence, this is not usually observed with nicotine replacement therapies. These observations are consistent with laboratory data indicating that (a) nicotine polacrilex and transdermal systems deliver nicotine more slowly and at lower dose levels than tobacco-based forms, and (b) human data suggesting that the abuse liability of these systems is substantially lower than that of the tobacco-based nicotine delivery systems. Because the drug dosage form can be systematically manipulated and evaluated, further research in developing alternative nicotine delivery forms may hold substantial promise in the treatment of tobacco dependence. Psychological research methods can play an important part in their evaluation.

Smokers (n = 315) who wished to quit were randomly assigned in a double-blind manner to groups using either nicotine or placebo gum. Self-reported and observed symptoms of tobacco withdrawal were collected before cessation and at follow-ups of 1 to 2 weeks, 1 month, and 6 months. Self-reported and/or observed anger, anxiety, craving, difficulty concentrating, hunger, impatience, and restlessness were the most prominent symptoms of tobacco withdrawal. These symptoms had returned to precessation levels by 1 month except increased weight, hunger, and craving continued for 6 months in many smokers. Nicotine gum decreased most symptoms, including craving and hunger but not weight. Abstinent smokers with more intense withdrawal were not more likely to relapse. Abstinent smokers who gained more weight were less likely to relapse.

Seventy-eight smokers trying to quit were randomly assigned to 0-, 0.5-, 2- and 4-mg doses of nicotine gum and tracked for 9 months. In the 1st week of abstinence, self-administration of gum did not differ by dose (4 mg = 2 mg = 0.5 mg = 0 mg). Higher doses did not more effectively suppress withdrawal than lower doses nor induce more accurate nicotine identification (4 mg = 2 mg = 0.5 mg greater than 0 mg). Higher doses slightly increased ratings of adverse effects in the 1st week (4 mg greater than 2 mg greater than 0.5 mg greater than 0 mg). Over the next 6 months, the two higher doses appeared to support more gum self-administration than the two lower doses (4 mg = 2 mg greater than 0.5 mg = 0 mg) in the subsample of long-term quitters (n = 20). Our results suggest the dose-response curves differ for nicotine gum's reinforcing, withdrawal-suppression and self-reported effects.

Three studies examined self-administration of nicotine among exsmokers given concurrent access to nicotine (2 mg) and placebo gums during the first 2 weeks of abstinence from smoking. In Study 1 subjects were told they would receive either nicotine or placebo gum. With this instructional set, nicotine served as a reinforcer; i.e., subjects consistently self-administered nicotine but not placebo gum. However, subjects could discriminate gums on the basis of side-effects; thus, the ability of nicotine to serve as a reinforcer may have been due, not to its psychoactive effects, but rather because subjects believed the gum with more side-effects to be the active gum. In Study 2 we attempted to change this belief by telling subjects they would receive either the marketed nicotine gum or a new nicotine gum that is as effective as the marketed gum but has less side-effects (i.e., placebo). In Study 3 we attempted to change the belief by telling subjects that placebo gum had more side-effects than nicotine gum. With these two instructional sets, the stimulus properties of nicotine did not serve as reinforcer; i.e., subjects self-administered equal amounts of nicotine and placebo gums. To our knowledge, this is the first demonstration that instructions can control whether a drug will serve as a reinforcer.

Three hundred fifteen smokers who attended a family practice clinic and wished to quit smoking were assigned in a random, double-blind manner to receive either nicotine (2 mg) or placebo gum. Smokers initially received brief advice from a physician and nurse, a slide presentation and written materials (29 to 35 minutes), and a single follow-up visit (12 to 20 minutes) one week after cessation. After corrections for marital status and income, 10% of those who received nicotine gum and 7% of those who received placebo gum reported continuous abstinence for 11 months and passed observer and biochemical verification (this difference was not statistically significant). We conclude that, when used in a nonselected group of smokers along with a brief intervention in a general medical practice, the pharmacologic effects of nicotine gum to increase cessation are either small or nonexistent.

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.

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.