Effects of phenylpropanolamine on withdrawal symptoms

Psychopharmacology (1995) ll9 : 85 91 Springer-Verlag 1995 Robert C. Klesges - Lisa M. Klesges Margaret DeBon Mary L. Shelton Terry R. Isbell Mary L. Klem Effects of phenylpropanolamine on withdrawal symptoms Received: 19 August 1993 / Final version: 1 November 1994 Abstract A prior report (Klesges et al. 1990) suggested that phewlpropanolamine (PPA) was successful in reducing the smoking withdrawal symptom of weight gain in a sample of women. The current investigation evaluates whether the effects of phenylpropanolamine (PPA; up to 10/day PPA gums) on withdrawal symptoms associated with smoking cessation are specific to weight and weight-related symptoms or whether PPA alleviates withdrawal in general. One hundred and seven adult smokers (56 men, 51 women) were randomly assigned, in this double-blind trial, to chew either 8.33 mg phenylpropanolamine gum or a placebo gum. Subjects were then aided to quit smoking for 4 weeks. PPA did not enhance cessation rates. Results from the 47 subjects who successfully quit smoking indicated that postcessation weight gain and ratings of hunger were significantly reduced in both men and women for those assigned to the PPA group relative to the placebo group. Overall, no effects of PPA relative to placebo were observed for other smoking-related withdrawal symptoms. Thus, although PPA appears to reduce weight gain and alleviate weight-related symptoms, no effects on other withdrawal symptoms were observed. Future research directions are suggested. Key words Phenylpropanolamine Smoking Weight R. C. Klesges (D) The Universities Prevention Center, Department of Psychology, The University of Memphis, Memphis, TN 38152, USA L. M. Klesges Department of Preventive Medicine, Division of Biostatistics and Epidemiology, University of Tennessee, Memphis, TN 38152, USA M. DeBon. M. L. Shelton T. R. Isbell - M. L. Klem The Universities Prevention Center, Department of Psychology, The University of Memphis, Memphis, Tennessee, USA Introduction Although the health consequences and medical costs associated with cigarette smoking are well established (US DHHS 1985, 1990), very few effective strategies for smoking cessation have been developed. Up to 80% of smokers who initially stop smoking relapse within 6 months to a year (Hunt and Bespalec 1974; Schwartz 1987). Major reasons for relapse are that cigarettes are addictive (US DHHS 1988) and cessation from cigarettes produces a reliable set of withdrawal symptoms (Hughes and Hatsukami 1986; Hughes et al. 1991; US DHHS 1988). These symptoms [i.e., craving for cigarettes, anger, anxiety, decreased concentration, restlessness, hunger, and weight gain (US DHHS 1988)] generally appear within 24 h of cessation from smoking, are very intense for at least 2 weeks and then begin to abate (US DHHS, 1990; Hughes et al. 1991). The majority of smoking relapse occurs during the first 2 weeks following cessation coincident with the most severe withdrawal symptoms (US DHHS 1988, 1990). In general, withdrawal symptoms return to or near their baseline levels by 4 weeks postcessation (US DHHS 1990; Hughes et al. 1991), with the exception of craving for a cigarette, hunger, and weight gain. These three symptoms stay" significantly elevated for up to 6 months following cessation (Hughes et al. 1991). A withdrawal symptom of major concern to many smokers, particularly women (Klesges and Klesges 1988), is weight gain. It is clear that most smokers gain weight following cessation but this weight gain rarely poses an independent health risk (US DHHS 1990); however, concerns regarding postcessation weight gain may be both a barrier to cessation and a precipitant of relapse (Klesges and Klesges 1988). In addition, there is emerging evidence that adolescents initiate smoking due to weight-related concerns (Charlton 1984; Camp et al. 1993).

86 Given that many smokers are weight conscious, there has been interest in the role of pharmacologic therapy in reducing postcessation weight gain. Studies to date have examined the effect of nicotine replacement on reducing postcessation weight gain (Emont and Cummings 1987; Gross et al. 1989; Tonnesen et al. 1991; Pirie et al. 1992) as well as d-fenfluramine (Spring et al. 1991), fluoxetine (Spring et al. 1992), and phenylpropanolamine (PPA; Klesges et al. 1990). Of the drugs currently being evaluated for reducing post-cessation weight gain, PPA is the only overthe-counter product. PPA, relative to placebo, has been shown to be related to weight loss in both humans (Morgan et al. 1985) and animals (Lasagna 1988), although these effects are generally small (approximately 0.14-0.23 kg/week more than placebo; Greenway 1992). The effects of PPA on postcessation weight gain were recently evaluated by Klesges et al. (1990). Subjects were 57 adult, weight-conscious, female cigarette smokers who were randomly assigned, in a double-blind procedure, to chew gum with PPA, placebo gum, or no gum. After a baseline assessment, subjects were paid to quit smoking for 2 weeks. Fortyone (72%) of the 57 subjects were successful in quitting smoking for the 2-week period. Those receiving PPA gained significantly less weight (mean = 0.09 lb) than either those in the placebo (mean = 1.59 lb) or those in the no gum (mean = t.94 lb) conditions. Dietary intake was also significantly reduced (mean change = 630 kcal) in the PPA group relative to either the no gum (mean decrease = 103 kcal) or the placebo gum (mean increase = 41 kcal) conditions. Finally, those in the PPA group had significantly higher cessation rates (94%, 15 of 16) than those in the no gum (70%, 14 of 20) or the placebo (57%, 12 of 21) groups. Thus, the short-term efficacy of PPA on postcessation weight gain appears promising. An obvious next step is to determine the relative longer term effects of PPA in a less select sample, as the Klesges et al. (1990) study restricted the sample to females who reported being concerned about postcessation weight gain and reported gaining weight in a previous smoking cessation attempt. A second logical step would be to determine if the effects of PPA are specific to weight-related withdrawal symptoms (i.e., weight, hunger) or if PPA has an effect on other withdrawal s)~nptoms (e.g., smoking cravings, concentration). On the one hand, PPA has long been assumed to act peripherally (Lasagna 1988), primarily as an anorectic agent. If this is the case, one should observe significant effects on the hunger-related withdrawal symptoms and no effects on other symptoms related to nicotine withdrawal. On the other hand, there is uncertainty in the literature regarding the mechanism of PPA action, with many investigators arguing that the drug has important central nervous system (CNS) stimulating properties (Morgan 1986). It has been suggested, for example, that PPA is a partial agonist at atpha-adrenergic receptors (Lasagna 1988). If PPA does indeed have CNS properties, one could alternatively argue that PPA may alleviate other aspects of the nicotine withdrawal syndrome (e.g., concentration). Given the uncertainty in the literature on PPA's mechanism(s) of action, the smoking cessation differences (in favor of those receiving PPA) reported by Klesges et al. (1990) become difficult to interpret. If, on the one hand, PPA is acting centrally, it could be argued that many symptoms of withdrawal were affected and higher cessation rates would be observed in those receiving PPA. On the other hand, if PPA is acting peripherally and primarily as an anorectic agent, one would not expect PPA to have an effect on any withdrawal symptoms other than body weight or hunger. Given this, one might observe smoking cessation differences only in individuals extremely concerned about postcessation weight gain. The Klesges et al. (1990) study included only women who (a) were concerned about postcessation weight gain and (b) gained weight in previous cessation attempts. Thus, it is not known whether the cessation rate differences were due to a generalized reduction in the nicotine withdrawal syndrome or whether weight conscious individuals did not relapse to smoking merely because they were not gaining weight. Thus, the purpose of the current investigation was to evaluate the effects of PPA on both body weight and generalized withdrawal symptoms in a cohort of adult male and female smokers who quit smoking for 1 month. A 1-month cessation period was chosen because the majority of smoking-related withdrawal symptoms return to pre-cessation levels by 1 month postcessation (Hughes et al. 1991; 1992). Both men and women were selected for entry into the study and subjects were not screened for concerns related to body weight or postcessation weight gain. The longer-term nature of the study, generalization to men, to those that are not necessarily weight conscious, and most importantly, to all aspects of the nicotine withdrawal syndrome are all unique aspects of the current investigation. Materials and methods Design The current study was a placebo-controlled, double-blind prospective trial of the effect of PPA on withdrawal symptomatology associated with smoking cessation. In its simplest form, the design was a 2 (PPA gum, placebo gum) by 5 (1 week of baseline, 4 weeks of treatment) repeated measures design. The primary outcome variables were smoking withdrawal symptomatology and weight gain. Subjects Subjects were adult male and female cigarette smokers recruited from the community by advertising in the local newspapers. To

87 qualify fbr the study, subjects had to be 18-60 years of age, in good health, and reported to be motivated to stop smoking. Subjects had to report smoking at least 20 cigarettes per day and had to exceed 15 parts-per-million (ppm) of carbon monoxide in expired breath. Subjects were excluded if they had hypertension, heart disease, narcolepsy, diabetes, thyroid disease, autonomic dysfunction, or clinical depression. Subjects were also excluded if they reported taking any medication containing PPA, monoanaine oxidase inhibitors, or any cough, cold, or sinus product on a regular basis. Women were excluded if they were pregnant, nursing an infant, or not practicing a reliable birth control method. Those reporting any previous adverse reactions to stimulants, inability to chew gum, the use of other forms of tobacco, or participation in previous PPA studies were excluded from the current investigation. Finally, those with a pretest resting systolic blood pressure exceeding 145 mmhg or a resting diastolic exceeding 90 mmhg were not admitted into the study. The initial randomized sample of 107 subjects included 56 men and 51 women. Of the 107 subjects, 55 were unsuccessful at quitting smoking, as measured by weekly and random "spot" carbon monoxide checks (see below). In addition, five male subjects were dropped from the study due to elevated blood pressure, leaving a sample size of 47 subjects who stopped smoking for the entire month. Regarding the blood pressure exclusions, four of these subjects had been assigned to the PPA group and the remaining subject to the placebo group [Z a (1) = 2.070, P = 0.150). Analysis of the baseline data for these five individuals revealed systolic pressures that were marginally higher (mean = 133.4, SD = 4.9) than other male subjects (mean= 125.3, SD= 10.8) remaining in the trial [F(1, 54) = 2.71, P = 0.105]. Diastolic pressures were also higher in those exited from the study (mean = 76.4, SD = 8.2 versus mean = 72.5, SD=6.7) but were not statistically significant [F(1, 54) = 1.48, P = 0.2291. Procedure Subjects interested in study participation were contacted and administered an initial screening questionnaire over the telephone. This initial questionnaire included queries on inclusionary and exclusionary criteria. Subjects were then mailed a packet of information (i.e., description of study procedures, directions to the laboratory), along with a questionnaire on smoking behavior and on their medical history. All subjects monitored baseline withdrawal symptoms before cessation and the number of cigarettes smoked per day for a 1-week period. Upon arrival to the laboratory (approximately 10 days alter their initial phone screening), subjects were administered (via interview format) a medical screening questionnaire which again queried for all inclusionary and exclusionary criteria. Subjects reporting fulfillment of inclusionary criteria on both screenings were eligible for participation (this resulted in the exclusion of three people at orientation). Subjects' blood pressures and carbon monoxide levels were then obtained. Nine subjects whose systolic blood pressure exceeded 145 mmhg, whose diastolic blood pressure exceeded 90 mmhg, or whose carbon monoxide was less than 15 ppm were excluded from the study. Following administration of this battery, subjects were randomized into the study. Subjects then filled out demographic information, and height, body weight, smoking patterns, and smoking history information were obtained. A brief, but intensive, behavioral smoking cessation program was then delivered by trained therapists. This cessation program was a single-session, 30-rain intervention to help people quit smoking and prevent relapse. Since subjects were screened as to their willingness to quit smoking, no time was spent on preparation for quitting. The time was equally spent focusing on both quitting (e.g., removing temptations to smoke like cigarettes and ashtrays) and preventing relapse (e.g., avoiding high risk environments such as bars and dealing with temptations to smoke). Subjects were given gum containing 8.33 mg PPA per piece or an identical placebo gum in a double-blinded randomized fashion. Gums were blister-packed ten per card and boxed in cards of seven (a 1-week supply). Subjects were given instructions on gum use and told to start gum use the next morning when they quit smoking. Subjects were told to chew a piece thoroughly (30 min or more) whenever they had a cigarette craving. Subjects were told not to exceed ten pieces (or one card) per day. Assignment of product was independently randomized and group membership (e.g., gum A versus Gum B) was not revealed to the researchers until all data were coded. Identification of those using active gum was not revealed until statistical analyses were complete. Subjects were instructed to quit smoking the following day and were instructed as to dosing regimen. Subjects also continued to monitor number of cigarettes smoked (if they relapsed) and record withdrawal symptomatology. They monitored the number of pieces of gum chewed per day as well as how long each piece was chewed. Seven days later, subjects successful at abstinence returned to the laboratory with their forms. Body weight, blood pressure, and carbon monoxide levels were again obtained. Abstinent subjects were given another 7-day supply of gum and were told to continue to monitor cigarettes smoked, withdrawal symptomatology, and gum use over the next 7 days. This procedure was repeated a total of four times over a 4-week period. Subjects were exited from the study after 28 days of consecutive smoking abstinence. For adherence to treatment, subjects were paid $40, $50, $60, and $75 for abstinence at 1, 2, 3 and 4 weeks, respectively. Measures Measures of smoking status and smoking history Multiple measures of smoking status were employed in the current investigation. First, the Smoking Patterns Questionnaire (Glasgow et al. 1983) was administered at pretest. The Smoking Patterns Questionnaire produces scores on the target behaviors of nicotine content of cigarette, brand smoked, the number of cigarettes per day, and the percent of each cigarette smoked. Subjects monitored daily cigarette consumption over a 7-day baseline as well as the 4-week intervention. As the objective measure of smoking exposure, carbon monoxide (CO) in expired breath samples was collected in all smokers following the protocol outlined by Hughes et al. (1978). Subjects held their breath for 20 s and then exhaled into a small disposable balloon. The balloon was attached to a sensor that read alveolar carbon monoxide in parts per million. Subjects received CO assessments at pretest (to confirm that they were smokers) and at each weekly visit to confirm abstinence (< 8 ppm CO). Additionally, two "spot" random CO checks were collected in the field (i.e., at participants' homes or worksites) on all participants who were abstinent. Subjects had to report not smoking a single cigarette and register in the non-smoking range on all carbon monoxide assessments (four weekly visits + two spot checks) to be classified as a quitter. Resting blood pressure Pretest blood pressures were obtained at the pretest laboratory session to insure that all participants were normotensive. Nine potential participants were disqualified (six men, three women) prior to randomization, and five men were excluded after randomization. Participants were seated with a technician in a quiet room for 5 min. Using an automated blood pressure monitor (Dinamap 1846SX), two measures of blood pressure were obtained at 1-min intervals. The first reading (an acclimation reading) was discarded and the second reading was used. Anyone with a systolic blood pressure of greater than 145 mmhg or a diastolic greater than 90 mmhg was not admitted into the study.

88 Withdrawal symptoms checklist All subjects reported daily cigarette withdrawal symptoms, using the measure developed by Hughes and colleagues (Hughes and Hatsukami 1986; Hughes et al. 1991). The checklist is in diary format and lists several withdrawal symptoms commonly associated with smoking cessation. The symptoms coded and analyzed for this study were those that form the DSM-III-R criteria for nicotine withdrawal (i.e., cigarette craving, anger, anxiety, decreased concentration, restlessness, increased appetite, and weight gain; APA 1987). Participants rated their daily symptoms along a 10-point Likerttype scale, ranging from None (0) to Severe (9). Very high reliability and discriminant validity have been demonstrated with this measure (Hughes and Hatsukami 1986; Hughes et al. 1991). Assessment of height and weight Height and weight in subjects were assessed using a sensitive scale (Deteeto Electronic) accurate to -+ 2 oz and 1/4 inch. The unit was zero calibrated by project staff prior to each use. Adherence Gum use was monitored throughout the study on a daily recording tbrm. Subjects indicated how many pieces of gum were chewed per day and how long each piece was chewed. Unused packages of gum were returned by participants to verify reports of adherence. If discrepancies between self-reports and returned gum could not be reconciled, unused gum was used to determine number of pieces chewed. Approach to analysis Because the primary purpose of the current study was to evaluate the effects of PPA on those subjects who remained continuously abstinent from cigarettes, all analyses were conducted with the resultant sample of quit smokers. Our primary analysis involved two, multivariate repeated measures analyses of variance (MANOVA) with one analysis testing the effect of PPA on general withdrawal symptoms (e.g., craving for a cigarette, concentration) and the other MANOVA testing the variables related to weight (actual weight gain and self-reports of hunger). However, our first set of preliminary analyses (the only analyses conducted on the entire initial sample) evaluated the characteristics of those who were successful at quitting smoking versus those who were unable to quit smoking. The purpose of these analyses was to determine the characteristics of the initial versus the resultant cohort. Cessation As mentioned above, of the 107 subjects (55 placebo, 52 PPA) initially randomized into the trial (including those who subsequently left the study due to high blood pressure), 47 (44%; 28 placebo, 19 PPA) were successful in quitting smoking for the entirety of the study. There were no between-groups differences between the placebo and PPA conditions in terms of successful smoking cessation although power for this comparison was low (/~ = 0.32). Fiftyone percent of the placebo subjects were successful at quitting smoking, relative to 37% in the PPA condition. When analyzed at the point of relapse (e.g., not quit at all = 0 days; quit for all 4 weeks = 28 days), a continuous variable that will increase power, no differences were also observed between the placebo (mean point of relapse = 17.02 days, SD = 12.50) and the PPA (mean point of relapse =15.10 days, SD=15.11) groups [F(1, 105)= 0.673, P = 0.41). Subjects successful at quitting smoking for 4 weeks were different from those who failed to quit on several variables. Self-reported length of the most recent quit attempt revealed significant differences between successful and unsuccessful quitters IF(l, 105)= 4.990, P = 0.028). Quitters reported having stopped smoking for a longer period of time during their most recent quit attempt (mean = 12.77 days, SD = 20.80) compared to those who failed to quit smoking (mean = 5.03 days, SD = 14.98). In addition, a significantly higher proportion of successful quitters had no other smokers in their home environment compared to unsuccessful quitters [Z2(I)= 15.69, P = 0.00008]. Specifically, 70% of quitters reported no other smokers in their home environment compared to only 32% of unsuccessful quitters. Results Assessment of adverse reactions One additional preliminary set of analyses were conducted to evaluate possible increases in blood pressure and heart rate due to PPA. Apical blood pressure and heart rate following baseline (i.e., the 4 weeks following cessation) were ascertained and a change score was calculated by subtracting baseline from this apical value. Blood pressure and heart rate change were compared between treatment groups after controlling for baseline values with an analysis of covariance. Scores for those subjects who left the study because of high blood pressure were included in these analyses. Results indicated that there were no significant increases in systolic blood pressure, diastolic blood pressure, or heart rate attributable to PPA use. Adherence to treatment Although serum levels of PPA could not be collected, two proxies of adherence to treatment were collected. First, all subjects monitored daily both the number of pieces of gum chewed and the amount of time each piece was chewed. Second, to corroborate self-reports of the number of pieces chewed, subjects returned all unused gum. The average number of pieces of gum chewed among those who quit was similar between treatments [F(1,45) =0.0023, P=0.962]. The placebo group chewed an average of 8.1 (SD = 1.61) pieces of gum a day and those in the PPA condition chewed an average of 8.1 pieces (SD = 1.15). Similarly, no differences between conditions were tbund for the average length of time gum was chewed IF(l, 45) = 0.370, P = 0.5460]. The placebo condition chewed gum for an average of 5.31 (SD = 2.93) h per day and the PPA condition chewed gum for an average of 5.87 (SD = 3.25) h per day. Effects of treatment on smoking withdrawal - changes in withdrawal symptoms not related to weight To evaluate the effects of PPA on the five DSM-III-R symptoms of withdrawal not related to weight (i.e.,

89 cigarette craving, anger, tension, decreased concentration, and restlessness), a multivariate repeated measures analysis of variance (MANO?k) was conducted with the five withdrawal symptoms as the dependent variables, drug (placebo versus PPA) as the grouping factor and the respective symptoms at each time (1 week of baseline plus 4 weeks of cessation) as the repeated factor. It should be noted that the self-reported withdrawal symptom data were highly skewed. As such, Wilcoxon Rank Sum tests (also known as Mann- Whitney Utests) were conducted on change scores from baseline to subsequent weeks for each of the withdrawal components. Given that the results were highly consistent with those reported in the text, the more parsimonious MANOVA models were reported. The results of this analysis revealed a significant main effect for time IF(4, 180) = 6.55, P < 0.001], but no main effect for gum [F(1, 45) = 1.04, P = 0.41] and no significant gum by time interaction [F(4, 180) = 1.55, P = 0.15]. As can be seen by Table 1, consistent with several other investigations (US DHHS 1990; Hughes et al. 1991), marked increases were typically observed for the first 2 weeks of cessation, followed by sharp drops in symptoms of withdrawal in the final 2 weeks. By week 4, all symptoms were no longer significantly different from baseline levels. PPA had no effect on this relationship, as indicated by the non-significant interaction between gum and time. Effects of treatment on smoking withdrawal - changes in weight-related withdrawal symptoms To evaluate the effects of PPA on the two DSM-III-R symptoms of withdrawal that are weight related (actual weight gain and self-reports of hunger), a second mul- tivariate repeated measures analysis of variance (MANOVA) was conducted with the two weight-related withdrawal symptoms as the dependent variables, drug (placebo versus PPA) as the grouping factor and the respective symptoms at each time (1 week of baseline plus 4 weeks of cessation) as the repeated factor. Results of this MANOVA indicated a significant main effect for time [F(4, 180)= 8.00, P < 0.0001] and a significant gum by time interaction IF(4, 180) = 2.51, P < 0.027]. Simple main effects analysis using a Tukey follow-up revealed that for self-reported hunger ratings, these ratings significantly increased in the placebo group during week 1 of cessation before eventually returning to baseline. In contrast, there was no significant increase in hunger ratings in the PPA group. In terms of actual weight gain, by the end of 4 weeks of cessation, both groups had gained a significant amount of weight. However, the weight gain in the placebo group was significant after 1 week of cessation, while the weight gain in the PPA group was not significant (relative to baseline) until the final (fourth) week of treatment. Those in the PPA group had gained significantly less weight (relative to baseline) in both weeks 3 and 4 of treatment (see Table 1). When expressed as percent of body weight gained over time, the PPA group also had less change in percent weight (mean = 1.82%, SD = 1.84) compared to the placebo group [mean = 2.35%, SD = 1.71; F(1, 45) = 6.31, P < 0.0157]. Discussion The results of the current study indicate that PPA significantly reduced postcessation weight gain in a Table 1 Mean (SD) sympton scores and weight changes Baseline Week 2 Week 3 Week 4 Week 5 Cigarette craving a Placebo 4.25 (1.94) 5.94 (1.82) 4.65 (2.03) 3.70 (1.95) 3.00 (2.12) PPA 5.00 (1.42) 5.92 (1.29) 4.87 (1.55) 3.65 (1.83) 3.17 (1.77) Anger a Placebo 2.03 (1.49) 3.25 (2.19) 2.44 (2.03) 1.88 (1.54) 1.54 (1.44) PPA 2.83 (1.58) 4.40 (1.96) 3.44 (1.82) 2.47 (1.84) 1.88 (1.43) Tension a Placebo 2.28 (1,63) 3,46 (2.08) 2.48 (1.99) 1.96 (1.59) 1.81 (1,60) PPA 3.03 (1.62) 4.38 (2.03) 3.37 (1.75) 2.42 (1.88) 1.87 (1.25) Decreased concentration a Placebo 1.63 (1.34) 2.29 (1.73) 1.86 (1.76) 1.24 (1.22) 1.48 (1.53) PPA 2.01 (1.60) 3.50 (2.34) 2,00 (1.33) 1.63 (1.51) 1.31 (1.16) Restlessness Placebo 2.53 (1.89) 3.17 (1.98) 2.51 (1.96) 1.85 (1.51) 1.79 (1,70) PPA 2.94 (1.93) 4.17 (2.16) 3,14 (1.56) 2.25 (1.69) 1.69 (1.16) Ilunger a,b Placebo 2.69 (1.94) 3.52 (1.64) 2.97 (1.66) 2.50 (1.54) 1.89 (1,16) PPA 2.52 (I.29) 2.86 (1.82) 2.60 (1.45) 2,24 (1.56) 2.29 (1.59) Weight change (kg) a,b Placebo 0.49 (1.00) 0,79 (1.02) 1.13 (1.16) 1.73 (1.34) PPA 0.26 (1.09) 0.23 (0.97) 0.74 (0.77) 0.74 (1.19) adenotes a significant (P < 0.05) main effect for Time bdenotes a significant (P < 0.05) interaction between Drug Condition and Time

90 heterogeneous cohort of both men and women who quit smoking for 1 month. Moreover, there was evidence to indicate that PPA mollified self-reported hunger ratings. However, there was also evidence that the effects of PPA on withdrawal were hunger-and weight-specific: no significant effects of PPA on withdrawal were noted tbr any other DSM-III-R withdrawal symptom. Results indicating that PPA reduces postcessation weight gain are consistent with another double-blind, placebo-controlled study of smoking cessation in female smokers (Klesges et al. 1990). The current study indicates that these effects generalize to male smokers and to those who are not necessarily weight conscious. Moreover, there was evidence that PPA abated ratings of hunger. This finding is consistent with reported reductions in dietary intake in those receiving PPA (Klesges et al. 1990). Given that postcessation weight gain is a deterrent to smoking cessation, particularly in women (US DHHS 1988, 1990), short-term use of PPA may provide a useful adjunct to smoking cessation efforts for the weight-conscious smoker. Future research should follow smokers for a longer period of time to determine whether PPA reduces or merely delays postcessation weight gain. However, if PPA only delays postcessation weight gain (as is the case with nicotine gum; Gross et al. 1989), it is possible that PPA could be useful during the early stages of quitting, when the threat of relapse is particularly high. If, during these early stages of quitting, weight-conscious smokers are relieved of their concern about weight gain, nonsmokdng patterns could be more firmly established. Issues related to weight gain could be addressed later in the cessation process when the smoker is less likely to relapse. However, although the results showed that PPA had an effect on postcessation weight gain and ratings of hunger, it was clear that PPA did not show beneficial effects on withdrawal symptoms not related to weight. The potential implication of this finding is fairly straightforward. That is, if a smoker is concerned exclusively, or primarily, with postcessation weight gain, PPA, given its low cost, availability, and non-addictive properties, may be the drug of choice. However, if a smoker reports a large number of smoking withdrawal symptoms such as cravings for cigarettes, nicotine replacement therapy appears to be the preferential therapy. After safety issues are addressed, future researchers may want to consider combining nicotine replacement therapy with PPA. For example, the nicotine patch and nicotine gum appear to have strong, beneficial effects on most smoking withdrawal symptoms (Daughton et al. 1991; Transdermal Nicotine Study Group 1991) and are easy to use. However, reduction of postcessation weight gain is not always observed with these products, perhaps due to inadequate dosing as well as other factors (Sachs and Leischow 1991). It appears that PPA may be selective on postcessation weight gain and hunger. Perhaps combined, increased efficacy could be demonstrated, particularly in weightconscious smokers. In summar L the effects of PPA on smoking withdrawal are quite specific. PPA reduced postcessation weight gain in both men and women quitters and appeared to alleviate postcessation ratings of hunger. If future research confirms these findings, PPA may be a useful short-term pharmacologic adjunct to smoking cessation for smokers who are primarily concerned about postcessation weight gain. Acknowledgements This study was supported by two grants (HL45057, HL46352) awarded by the National Heart, Lung, and Blood Institute. We also appreciate the financial support for subject payment from Schering-Plough Corporation and fbr providing the placebo and PPA gum. Support was also received from a Centers of Excellence grant awarded to the Department of Psychology, The University of Memphis, by the state of Tennessee. The authors thank Dr. John Hughes, who was extremely helpful in providing direction for the revision of this manuscript. References APA (1987) Diagnostic and Statistical Manual of Mental Disorders (3rd edn, revised). American Psychological Association, Washington DC Camp DE, Klesges RC, Relyea G (1993) The relationship between body weight concerns and adolescent smoking. Health Psychol 12: 24-32 Charlton A (1984) Smoking and weight control in teenagers. Public Health London 98 : 277-281 Daughton DM, Heatley SA, Pendergast J J, Causey D, Knowles M, Rotf CN, Cheney RA, HatMid K, Thompson AB, Rennard SI (1991) Effect of transdermal nicotine delivery as an adjunct to low-intervention smoking cessation therapy. A randomized, placebo-controlled, double blind study. Arch Int Med 151:749-752 Emont SL, Cummings KM (1987) Weight gain following smoking cessation: a possible role for nicotine replacement in weight management. Addict Behav 12:151 155 Glasgow RE, Klesges RC, Godding PR, Gegelman R (1983) Controlled smoking, with or without carbon monoxide feedback, as an alternative for chronic smokers. Behav Ther 14:386-397 Greenway FL (1992) Clinical studies with phenylpropanolamine: a metaanalysis. Am J Clin Nutr 55: 203S-205S Gross J, Stitzer ML, Maldonado J (1989) Nicotine replacement: effects on post-cessation weight gain. J Consult Clin Psychol 57: 87-92 Hughes JR, Hatsukami D (1986) Signs and symptoms of tobacco withdrawal. Arch Gen Psychiatry 43:289 294 Hughes JE, Frederiksen LW, Frazier M (t978) A carbon monoxide analyzer for measurement of smoking behavior. Behav Ther 9:293-296 Hughes JR, Gust SW, Skoog K, Keenan RM, Fenwick JW (1991) Symptoms of tobacco withdrawal: a replication and extension. Arch Gen Psychiatry 48:52-59 Hughes JR, Gulliver SB, Solomon LJ, Flynn BS (1992) Smoking cessation and tobacco withdrawal symptoms in self-quitters. Poster presented at: Society For Behavioral Medicine Annual Meeting, New York, New York Hunt WA, Bespalec DA (1974) An evaluation of current methods of modifying smoking behavior. J Clin Psychol 30: 431~438 Klesges RC, Ktesges LM (1988) Cigarette smoking as a dieting strategy in a university population. Int J Eating Disord 7:413-419

91 Klesges RC, Klesges LM, Meyers AW, Ktem ML, Isbell T (1990) The effects of phenylpropanolamine on dietary intake, physical activity, and body weight following smoking cessation. Clin Pharmacol Ther 47: 747-754 Lasagna L (1988) Phenylpropanolamine: A review. Wiley, New York Morgan JP (1986) Phenylpropanolamine: a critical analysis of reported adverse reactions and overdosage. Jack K. Burgess, Fort Lee, New Jersey Morgan JP, Kagan DV, Brody JS (eds) (1985) Phenylpropanolamine: risks, benefits, and controversies. Praeger Publishers Division, Westport, Connecticut Pirie PL, McBride CM, Hellerstedt W, Jeffery RW, Hatsukami D, Allen S, Lando H (1992) Smoking cessation in women concerned about weight. Am J Public Health 82:1238-1243 Sachs DPL, Leischow SJ (1991) Pharmacologic approaches to smoking cessation. Clin Chest Med 12: 769-791 Schwartz JL (1987) Review and evaluation of smoking cessation methods: the United States and Canada, 1978-1985. National Cancer Institute, US Dept. of Health and Human Services. (NIH Publ. No. 87040), Division of Cancer Prevention, Bethesda, MD Spring B, Wurtman J, Gleason R, Wurtman, Kessler K (t991) Weight gain and withdrawal symptoms after smoking cessation: a preventive intervention using d-fenfluramine. Health Psychol 10:216-223 Spring B, Pingitore R, Kessler K (1992) Strategies to minimize weight gain after smoking cessation: psychological and pharmacological intervention with specific reference to dexfenfluramine. Int J Obes 16:519-523 Tonnesen P, Norregaard J, Simonsen K, Sawe U (1991) A doubleblind trial of a 16-hour transdermal nicotine patch in smoking cessation. N Engl J Med 325 : 311-315 Transdermal Nicotine Study Group (1991) Transdermal nicotine for smoking cessation. Six-month results from two multicenter controlled clinical trials. JAMA 266:3133-3138 United States Department of Health and Human Services (1990) The Health Benefits of Smoking Cessation. A Report of the Surgeon General (DHHS Publ. No. (CDC) 90-8416). US Government Printing Office United States Department of Health and Human Services (1985) The health consequences of smoking: cancer and chronic lung disease in the workplace. A report of the Surgeon General (DHHS Publ. No. PHS85-50207). US Government Printing Office United States Department of Health and Human Services (1988) The health consequences of smoking: nicotine addiction. A Report of the Surgeon General (DHHS Publ. No. (CDC) 88-8406). US Government Printing Office