Psychopharmacology (2004) 175: 259–261 DOI 10.1007/s00213-004-1931-6 LETTER TO THE EDITORS Reuven Dar . Hanan Frenk Smokers do not self-administer nicotine other than in tobacco: a reply to Perkins (2004) Received: 2 May 2004 / Accepted: 4 May 2004 / Published online: 10 August 2004 # Springer-Verlag 2004 The assertion that nicotine is the reinforcing agent that sustains smoking is widely accepted, to the point that most current authors are content to quote the Surgeon General’ s Report (US Department of Health and Human Services 1988) as the sole reference for this thesis (for examples, see Frenk and Dar 2000). Whenever specific experiments on humans are mentioned in this context, they typically include those where smokers purportedly self-administer nicotine, mainly in the form of intravenous injections, gum or nasal spray. In our recent review (Dar and Frenk 2004a), we explored whether this body of research indeed supports the claim that nicotine is reinforcing to smokers. We did not find a single study in which nicotine in any other form than tobacco was preferred to placebo in normal smokers, even following significant periods of abstinence. Our review was criticized by Perkins (2004) on three counts. First, he claims that “robust self-administration of novel forms of nicotine” was demonstrated in studies that we did not include in our review. Second, that we “confuse procedures aimed at assessing changes in relative reinfor- cing value of drugs with those intended to show absolute reinforcement.” Finally, Perkins maintains that our review disregards the fact that “robust self-administration of novel forms of any drug usually requires extended drug access.” Before responding to Perkins’ criticism, it is important to note that Perkins does not dispute our conclusion, namely that the studies we reviewed do not provide evidence for the presumed reinforcing properties of nicotine. Perkins’ first contention is that such evidence is found in other studies, whereas the other two are that studies such as those produced in his laboratory are not suitable for providing evidence on this question in the first place. Studies that we did not include in our review Perkins (2004) cites several studies that were not included in our review, in which smokers did self-administer nicotine more than placebo over the course of days or weeks. The studies he cites, however, including his own (Perkins et al. 1996b), are clinical studies in which nicotine was presented to smokers wishing to quit as an aid to cessation. We expressly excluded such studies from our review (Dar and Frenk 2004a), as nicotine self- administration in these studies cannot be taken as evidence of reinforcement. As we elaborated in our review, several studies, including a series by Perkins and his colleagues (Perkins et al. 1994, 1996a, 1997, 2001), have shown that most smokers can discriminate between nicotine and placebo. As most smokers also believe that their difficulty in quitting reflects addiction to nicotine (for evidence and discussion, see Frenk and Dar 2000), any preference for nicotine over placebo in clinical studies may reflect participants’ belief that nicotine would help them quit. As discussed in our review, studies by Hughes et al. (1985, 1989) demonstrate that if smokers who receive placebo are made to believe that they are given nicotine, or vice versa, preference for nicotine over placebo is eliminated. Similarly, Dar et al. (unpublished data) conducted a secondary analysis of a large NRT study (Etter et al. 2002) in which participants were asked to guess whether they had received nicotine or placebo. They found that those who believed they had received nicotine, regardless of which treatment they had actually received, had a much better outcome than those who guessed they had received placebo. Moreover, when these guesses were included in the analysis, the effect of the actual drug condition on all outcome measures was no longer statistically significant. In summary, smokers may self-administer more placebo than nicotine in clinical studies because they are able to R. Dar (*) . H. Frenk Department of Psychology, Tel Aviv University, Tel Aviv, 69978, Israel e-mail: ruvidar@freud.tau.ac.il Tel.: +972-3-6408624 Fax: +972-3-6409547 H. Frenk The Academic College of Tel Aviv-Yafo, Tel Aviv, Israel