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Many cigarette smokers express a desire to quit smoking, but ˜ 85% of cessation attempts fail. In our attempt to delineate genetic modulators of smoking persistence, we have earlier shown that a locus within an ˜ 250 kb haplotype block spanning the 5' untranslated region region of insulin-degrading enzyme is associated with serum cotinine levels; the study's measure of smoking quantity. Based on our findings, and coupled with recent preclinical studies showing the importance of multiple neuropeptides in reinstatement of drug use, we formulated intranasal insulin to evaluate its efficacy during acute abstinence from smoking. Our original study was a crossover trial including 19 otherwise healthy smokers who abstained from smoking for 36 h. The morning following their second night of abstinence, in random order, study participants received intranasal insulin (60 IU) or placebo (8.7% sodium chloride). The goal of our second study was to replicate the craving findings from the original trial and expand this research by including additional stress-related measures. Thirty-seven study participants abstained from smoking overnight. The next day, they were administered either intranasal insulin (60 IU) or placebo, following which they participated in the Trier Social Stress Test Task. This was a parallel design study focusing on the standard stress subjective, hormonal and cardiovascular measures. We also evaluated any changes in circulating glucose, insulin and c-peptide (a marker of endogenous insulin). In the original study, intranasal insulin significantly reduced morning nicotine craving (b = 3.65, P ≤ 0.05). Similarly, in the second study, intranasal insulin reduced nicotine cravings over time (b = 0.065, P ≤ 0.05) and the effect lasted through the psychosocial stress period. Intranasal insulin also increased circulating cortisol levels (F = 12.78, P ≤ 0.001). No changes in insulin or c-peptide were detected. A significant treatment × time interaction (P ≤ 0.05) was detected for glucose, but subjects remained well within the euglycemic range. Previous studies have shown that heightened nicotine cravings and blunted response to stress are independent and significant predictors of relapse to smoking. In our study, intranasal insulin normalized the subjective and hormonal response to stress. As such, intranasal insulin should further be studied in a larger clinical trial of smoking cessation. In support of this, we provide evidence that the treatment is safe and effective and, based on absence of peripheral insulin changes, conclude that the pharmacodynamic effect is centrally driven.