Following a brief course of varenicline treatment (1 mg/day for 4 days), abstinent smokers displayed attenuated responses to many subjective effects of IV nicotine, including the rating of drug strength, high, head rush, and stimulated. Other subjective effects including good effects and drug liking were not attenuated by varenicline treatment. These findings are consistent with previous studies which reported attenuated subjective rewarding effects from cigarette smoking under varenicline treatment. Patterson et al. (Patterson et al. 2009
) reported reduced subjective effects from a programmed lapse to smoking in smokers, following a 3-days of abstinence. Similarly, West et al. (West et al. 2008
) reported reduced reward from smoking in smokers who were trying to quit smoking. Our work extends these findings by evaluating varenicline’s effects on subjective responses to pure nicotine administered intravenously. These findings are consistent with the partial agonistic effects of varenicline on the α4
nAChRs, which have been shown to be critical for the nicotine reward in preclinical studies (Fowler et al. 2008
; Picciotto and Corrigall 2002
Varenicline attenuated nicotine-induced heart rate increases for all three doses of nicotine. We are not aware of any previous studies evaluating varenicline’s effects on nicotine-induced cardiovascular responses. The nicotine-induced heart rate increases are thought to be mediated by α3
subtype nAChRs which are implicated in peripheral nervous system functions (Aberger et al. 2001
; Dhar et al. 2000
; Ji et al. 2002
). However, varenicline was shown to have very low affinity to α3
nAChR in equilibrium binding experiments; its affinity to the α3
subtype is 4,000 times less than to α4β2 subtype (Coe et al. 2005
). This low affinity makes it unlikely that varenicline can affect functions mediated by the α3
nAChR. Although in functional assays, varenicline showed significant potency at α3
nAChR as well as α7
subtypes, further expanding the effect of varenicline beyond the α4
nicotinic receptors (Mihalak et al. 2006
). These findings suggest that in clinically used doses, varenicline may attenuate heart rate increases induced by nicotine by its partial agonist effect in α3
nAChR. In addition to α3
, other nAChR subtypes, especially α7
may also be involved in mediating the cardiovascular effects of nicotine (Ji et al. 2002
). These possibilities need to be examined in future studies.
Smokers under varenicline treatment, compared with placebo, reported enhanced positive mood measured with PANAS. Interestingly, varenicline’s effect on positive mood was also observed under ad lib conditions (the first 3 days of each treatment period), as well as after abstinence from smoking (day 4 of each treatment period). These findings were not due to changes in smoking behavior since there were no treatment effects on plasma cotinine levels obtained on day 4 of each treatment period. Our findings are consistent with a previous study where smokers had greater positive mood with varenicline treatment during a 3-day smoking abstinence (Patterson et al. 2009
Varenicline had mixed effects on cognitive functioning. Varenicline significantly speeded RTs on the smoking block of the modified Stroop task. The absence of a treatment by word type interaction indicates that the varenicline-induced speeding was consistent on both smoking and neutral words. There are two possible explanations for the data. First, varenicline may reduce the salience of smoking cues, leading to faster responses on both smoking and neutral words in the smoking block (because the smoking words are less attention-grabbing under varenicline). This explanation leans on the evidence that carry-over effects on mixed Stroop tasks have often been documented in addiction Stroop tasks. Specifically, responses on words that follow drug-related words can be slower, possibly due to disengaging attention from the salient drug-related word (Cane et al. 2009
; Waters et al. 2003
), and varenicline may reduce a carry-over effect. Second, varenicline may simply cause a generalized speeding of cognitive functioning. However, the observation that varenicline did not significantly speed RTs on the negative affect block of the modified Stroop task or on Go trials in the SART argues against this second explanation. In a recent study, varenicline treatment improved performance in sustained attention and working memory tasks in abstinent smokers (Patterson et al. 2009
). Our study extends these findings further by demonstrating varenicline’s effect on another cognitive task. On the Go-NoGo trial, varenicline did not reduce the frequency of incorrect responses on No-Go trials. Thus, it did not exert a significant effect on impulsive responding in this task. Further research is required to determine the effects of varenicline on cognitive functioning.
Our study had several limitations. First, the study did not have a nicotine-placebo condition. We used the 0.1 mg nicotine as a placebo dose since previous studies suggested that this nicotine dose was below discrimination threshold in smokers (Djordjevic et al. 2000
; Perkins et al. 1994
). However, the 0.1 mg dose produced significant subjective and heart rate increases. Further work needs to be conducted to determine threshold doses of IV nicotine that produces subjective and physiological effects. Second, we used only one dose of varenciline, 1 mg/day, in conjunction with relatively low doses of IV nicotine. Future studies using higher doses of varenicline and nicotine may further elucidate the interaction between varenicline and nicotine. Third, the treatment duration was brief, only four days, and it is possible that longer treatment with varenicline may produce different effects.
Our findings have a number of clinical implications for the clinical efficacy of varenicline for smoking cessation. First, attenuation of nicotine’s subjective effects may contribute to varenicline’s efficacy in preventing relapse in abstinent smokers. The first few puffs of cigarette smoke in abstinent smokers (lapses) are regarded to be highly rewarding and linked to full relapse in smoking (Brandon et al. 1990
; Kenford et al. 1994
). Second, our study as well as the Patterson study (2009)
, suggests that varenicline may elevate positive mood in abstinent smokers. Negative affect is an important component of tobacco withdrawal and improvement of mood has been proposed to contribute to the efficacy of bupropion, another smoking cessation medication (Lerman et al. 2002
). Third, our preliminary findings and the Patterson (2009)
study suggest that varenicline may improve cognitive function for some tasks in smokers. Varenicline also improved the self-report item of “difficulty concentrating” in abstinent smokers. Reduced cognitive function is a component of tobacco withdrawal and nicotine’s capacity to enhance cognitive function has been suggested to contribute to its reinforcing effects especially in individuals with compromised cognitive function e.g. attention deficit hyperactivity disorder or schizophrenia (Evans and Drobes 2009
). Thus, improvement of cognitive function may contribute to varenicline’s efficacy for smoking cessation. Lastly, our findings suggest that varenicline treatment may attenuate some of the cardiovascular effects of nicotine in individuals who continue to smoke. Whether varenicline treatment can reduce the cardiovascular risks associated with ongoing smoking needs to be further examined.
To summarize, varenicline attenuates some of the subjective and physiological (i.e., heart rate) responses to IV nicotine in smokers. Varenicline also improves mood in smokers. These findings are consistent with the partial nicotinic agonist effects of nicotine. Further studies are warranted to examine which of these effects contribute to varenicline’s efficacy in smoking cessation.