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RationaleReducing nicotine content of inhaled tobacco products may prevent nicotine addiction, but the threshold for nicotine reinforcement has not been systematically evaluated in controlled human laboratory studies.ObjectivesThe current study uses a novel double-blind placebo-controlled intravenous (IV) nicotine self-administration (NSA) model to determine threshold for subjective effects of nicotine and nicotine reinforcement using a forced choice self-administration procedure.MethodsYoung adults (n = 34) had 5 laboratory sessions after overnight nicotine abstinence. In each session, participants sampled and rated the subjective effects of an IV dose of nicotine (0.0125, 0.025, 0.05, 0.1, or 0.2 mg nicotine/70 kg bodyweight) versus saline (placebo), then were given a total of 10 opportunities to self-administer either the IV dose of nicotine or placebo.ResultsMixed effect models revealed a significant effect of nicotine dose for positive (i.e., “stimulatory” and “pleasurable”; p < .0001) effects, but not “aversive” effects during sampling period. Post hoc comparisons showed that higher doses (i.e., 0.1 and 0.2 mg) were associated with greater stimulatory, pleasurable, and physiological effects than placebo and lower doses. Mixed effect models revealed that only the highest dose (i.e., 0.2 mg) was consistently preferred over placebo. Sex differences were generally weak (p = .03–.05).ConclusionsUsing our IV nicotine NSA model, the threshold for detecting positive effects of nicotine in young adult smokers is about 0.1 mg, but a higher dose of nicotine, 0.2 mg, is required to produce a consistent nicotine reinforcement. Regarding the regulatory impact, our findings further support the value of nicotine reinforcement threshold as a tobacco regulatory target.

Although expanding the availability of buprenorphine—a first-line pharmacotherapy for opioid-use disorder (OUD)—has increased the capacity of healthcare systems to offer treatment, starting this medication is fraught with significant barriers. Standard induction regimens require persons with OUD to taper and discontinue full opioid agonists and experience opioid withdrawal prior to the first dose of buprenorphine. Further, emerging evidence indicates that precipitated withdrawal during induction may impact long-term treatment outcomes. Microinduction is a novel approach that, by harnessing buprenorphine’s unique pharmacological profile, may allow circumventing the needed for prolonged opioid tapers, and reduce the risk of precipitated withdrawal—holding promise to enhance treatment access. In this review, we examine the pharmacological basis for microinduction and appraise the evidence of this approach to improve clinical outcomes among persons with OUD. First, we highlight the potential dose-dependent effects of buprenorphine on two key neuroadaptations at the mu-opioid receptor (MOR)—resensitization and upregulation. We then focus on how microinduction may reverse these chronic MOR neuroadaptations, allowing the maintenance of an adequate opioid tone, and thereby potentially circumventing opioid withdrawal. Second, we describe the clinical evidence available, derived from observational reports and open-label studies, examining the potential efficacy of microinduction. Despite significant heterogeneity—exemplified by variable buprenorphine formulations, daily doses, and schedules of administration—these data provide preliminary support for the feasibility of microinduction. Finally, we provide new mechanistic, methodological, and clinical insights to guide future translational research, as well as randomized, placebo-controlled clinical trials in this compelling agenda of pharmacotherapy development.

RationaleNo previous studies examined the discriminative stimulus effects of intravenous (IV) nicotine in humans.ObjectivesTo evaluate a pulsed IV nicotine infusion procedure designed to mimic inhaled nicotine delivery and to identify a range of nicotine doses that may capture the threshold doses for the subjective and discriminative stimulus effects of nicotine. By determining these thresholds, we can gain valuable insights into the addictive threshold of nicotine.MethodsEleven participants had 2 Test Sessions following overnight abstinence from smoking. Test Session 1 examined participants’ ability to discriminate 0.1 mg nicotine/pulse nicotine from saline. Test Session 2 examined if participants can discriminate 0.05, 0.025, and 0.0125 mg nicotine/pulse of nicotine from saline. These nicotine doses were delivered as a cluster of 4 pulsed-nicotine infusions of 2-second duration with a 28-second interval between each pulse.ResultsThe lowest doses of nicotine that produced greater responses than saline for discrimination, subjective effects, and heart rate ranged from 0.05 to 0.1 mg nicotine/pulse.ConclusionsThese findings support the validity of our pulsed-infusion procedure as a model for nicotine delivery by smoking and its utility in examining factors that may impact the addictive threshold of nicotine.

Abstract RationaleAlthough nicotine from cigarettes is delivered in puff-sized amounts, most preclinical and human intravenous (IV) nicotine studies have used bolus or continuous infusions.ObjectivesTo determine the feasibility of a pulsed-nicotine infusion model in smokers.MethodsFollowing overnight abstinence, 12 adult smokers underwent 5 laboratory sessions. Using a crossover design, in each session, participants were assigned to 1 of 5 conditions: (1) high/fast: 1.0 mg nicotine delivered over 5 pulsed-infusions, then 15 saline infusions; (2) high/slow: 1.0 mg nicotine delivered over 20 pulsed-infusions; (3) low/fast: 0.2 mg nicotine delivered over 5 pulsed-infusions, then 15 saline infusions; (4) low/slow: 0.2 mg nicotine delivered over 20 pulsed-infusions; and (5) placebo: Saline delivered over 20 pulsed-infusions. Subjective drug effects, urges to smoke, nicotine withdrawal, and cognitive performance were measured in each session.ResultsBoth the high/fast and high/slow conditions were associated with greater “head rush” and “high” (p < 0.05). The high/fast condition also provided greater suppression of urges to smoke and nicotine withdrawal (p < 0.05), indexed by the Questionnaire of Urges to Smoke-Brief, and the Minnesota Nicotine Withdrawal Scale, respectively. The high/fast and high/slow conditions produced greater increases in heart rate (p < 0.01) than saline. Finally, there were no main effects of dosing conditions on cognitive performance, indexed by the continuous performance test.ConclusionsThese findings demonstrate the feasibility of pulsed-nicotine infusions to model nicotine delivery by smoking. This model could inform future studies testing novel smoking cessation therapies and tobacco regulatory studies testing the impact of nicotine reduction approaches.

The 2011 Accreditation Council for Graduate Medical Education (ACGME) regulations include many of the recommendations of the IOM report, such as naps during extended shifts, a 16-hour limit for shifts without naps, and reduced workloads (5). The study findings that long calls were associated with greater fatigue and with adverse impact on attention levels and clinical performance, as compared with short calls, seem in line with studies in the literature that have linked fatigue and sleep-deprivation among resident physicians to increased medical errors (1, 2).