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RationaleThe nicotine delivery rate is a key feature of tobacco product design, yet there have been limited human studies examining the effects of nicotine as a function of delivery rate.ObjectiveWe developed an intravenous nicotine infusion protocol to evaluate differential effects of nicotine delivery rate on subjective drug effects, smoking urges, abstinence symptoms, heart rate, and blood pressure.MethodsEighteen non-treatment seeking, overnight abstinent male and female smokers (18 to 30 years old), who smoked ≥ 5 cigarettes per day for the past year completed four sessions, in which they were randomly assigned to a saline infusion, or a 1 mg per 70-kg body weight dose of nicotine delivered over 1, 5, or 10 min at rates of 0.24, 0.048, or 0.024 μg/kg/s, respectively.ResultsSmoking urges, as assessed by the Brief Questionnaire of Smoking Urges, were reduced relative to placebo for the 1- and 5-min infusion, but not the 10-min infusion. Although the 1- and 5-min infusions reduced smoking urges to a similar extent, the 1-min infusion induced a greater heart rate and blood pressure increase. Changes to subjective drug effects, heart rate, and blood pressure delineate the differential effects of nicotine delivery rate for these outcomes.ConclusionsWe have characterized the delivery rate-response curve for a nicotine dose that is roughly the amount of nicotine (~ 1 mg) delivered by smoking a standard tobacco cigarette. Our findings reinforce the importance of nicotine delivery rate when evaluating the potential effects of nicotine from tobacco products.

Cocaine use disorder (CUD) is a devastating disorder, impacting both individuals and society. Individuals with CUD face many barriers in accessing treatment for CUD, and most individuals with CUD never receive treatment. In this review, we provide an overview of CUD, including risk factors for CUD, common co-occurring disorders, acute and chronic effects of cocaine use, and currently available pharmacological and behavioral treatments. There are no FDA-approved pharmacological treatments for CUD. Future studies with larger sample sizes and testing treatment combinations are warranted. However, individuals with CUD and co- occurring disorders (eg, a mood or anxiety disorder) may benefit from medication treatments. There are behavioral interventions that have demonstrated efficacy in treating CUD--contingency management (CM) and cognitive-behavioral therapy for substance use disorders (CBT-SUD) in particular--however many barriers remain in delivering these treatments to patients. Following the discussion of current treatments, we highlight some promising emerging treatments, as well as offer a framework that can be used in building a treatment plan for individuals with CUD. Keywords: cocaine, cocaine use disorder, treatment, pharmacotherapy, behavioral interventions

Nicotine dependence is a serious public health concern. Optimal treatment of nicotine dependence will require greater understanding of the mechanisms that contribute to the maintenance of smoking behaviors. A growing literature indicates sex and menstrual phase differences in responses to nicotine. The aim of this study was to assess sex and menstrual phase influences on a broad range of measures of nicotine response including subjective drug effects, cognition, physiological responses, and symptoms of withdrawal, craving, and affect. Using a well-established intravenous nicotine paradigm and biochemical confirmation of overnight abstinence and menstrual cycle phase, analyses were performed to compare sex (age 18-50 years; 115 male and 45 female) and menstrual cycle phase (29 follicular and 16 luteal) effects. Females had diminished subjective drug effects of, but greater physiological responses to, nicotine administration. Luteal-phase females showed diminished subjective drug effects and better cognition relative to follicular-phase women. These findings offer candidate mechanisms through which the luteal phase, wherein progesterone is dominant relative to estradiol, may be protective against vulnerability to smoking.

Genome-wide association studies have implicated the CHRNA5-CHRNA3-CHRNB4 gene cluster in risk for heavy smoking and several smoking-related disorders. The heavy smoking risk allele might reduce the aversive effects of nicotine, but this hypothesis has not been tested in humans. We evaluated the effects of a candidate causal variant in CHRNA5, rs16969968, on the acute response to nicotine in European American (EA) and African American (AA) smokers (n=192; 50% AA; 73% male). Following overnight abstinence from nicotine, participants completed a protocol that included an intravenous (IV) dose of saline and two escalating IV doses of nicotine. The outcomes evaluated were the aversive, pleasurable, and stimulatory ratings of nicotine's effects, cardiovascular reactivity to nicotine, withdrawal severity, and cognitive performance before and after the nicotine administration session. The heavy smoking risk allele (rs16969968*A; frequency=28% (EA) and 6% (AA)) was associated with lower ratings of aversive effects (P<5 × 10(-8)) with marked specificity. This effect was evident in EA and AA subjects analyzed as separate groups and was most robust at the highest nicotine dose. Rs16969968*A was also associated with greater improvement on a measure of cognitive control (Stroop Task) following nicotine administration. These findings support differential aversive response to nicotine as one likely mechanism for the association of CHRNA5-CHRNA3-CHRNB4 with heavy smoking.

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.

Cigarette smoking is a major public health problem that causes more than 5 million deaths annually worldwide. Cigarette smoking is especially common among individuals with psychiatric comorbidity, including individuals with primary psychiatric disorders and other addictions. Effective behavioral and pharmacologic treatments for smoking cessation are available. Behavioral treatments including brief (< 3 min) counseling by physicians are effective. Seven first-line pharmacologic treatments are currently available: five nicotine replacement therapies, bupropion, and varenicline. In addition, clonidine and nortriptyline are second-line treatments for smoking cessation. These treatments increase the chances of quitting smoking by two- to threefold, supporting their use in smokers who are motivated to quit. However, effective treatments for many subpopulations, including smokers with psychiatric comorbidities as well as adolescent, pregnant, or postpartum smokers, remain to be developed and represent an important challenge.

Rationale Minocycline, a tetracycline antibiotic, interacts with brain glutamate and dopamine neurotransmission. In preclinical studies, minocycline attenuated amphetamine-induced acute dopamine release and subsequent behavioral sensitization. The goal of this study was to determine minocycline’s effects on the acute physiological, behavioral, and subjective responses to dextroamphetamine (DAMP) in healthy volunteers. Methods Ten healthy volunteers participated in an outpatient double-blind, placebo-controlled, crossover study. Subjects had a 5-day treatment period with either minocycline (200 mg/day) or placebo and then were crossed over for 5 days of the other treatment. After 2 days of taking the study medication, on days 3 and 4, subjects were randomly assigned to double-blind acute challenge with either 20 mg/70 kg DAMP or placebo DAMP (randomly labeled as drug A or B) and then crossed over to the other challenge. On day 5 (experimental session 3), subjects had the opportunity to self-administer either placebo or DAMP capsules by working on a progressive ratio computer task. Results Minocycline attenuated DAMP-induced subjective rewarding effects but did not change DAMP choice behavior. Minocycline treatment speeded reaction times on a Go No-Go task and reduced plasma cortisol levels. Conclusions These findings warrant further studies examining the potential use of minocycline for stimulant addiction.

This secondary analysis sought to determine if plasma menthol glucuronide (MG) concentrations predict changes in three outcomes, subjective drug effects, urges to smoke, and heart rate, following concurrent inhaled menthol and intravenous nicotine. A total of 45 menthol and non-menthol cigarettes smokers (36 male, nine female, 20 Black, and 23 White) were included in this double-blind, placebo-controlled study. Across three test sessions, participants were assigned to a different flavor condition for each session: 0% (no menthol), 0.5%, or 3.2% menthol. In each test session, participants received in a random order one intravenous delivery of saline and two intravenous deliveries of nicotine (0.25 mg/70 kg and 0.5 mg/70 kg), each 1 h apart, concurrent with menthol delivery by e-cigarettes. The main outcomes were subjective drug effects, urges to smoke, and heart rate. The results showed that following e-cigarette inhalation, changes in plasma MG concentrations or “menthol boost” increased proportionally to the menthol concentration in the e-liquids. While changes in plasma MG concentrations were not predictive of increases in heart rate or subjective drug effects that are reflective of acute effects from nicotine (i.e., feel good effects, stimulated, aversive effects ), they were predictive of cooling effect , a typical effect of menthol, but only in menthol smokers in the absence of concurrent active nicotine infusion. These findings demonstrate the utility of plasma MG as a biomarker both for acute menthol exposure by e-cigarette inhalation and for the examination of the concentration-dependent behavioral and physiological effects of menthol in humans.

High-strength steel alloys, titanium, ceramics, composites are in the group of materials that are hard to machine. Conventional manufacturing techniques are not sufficient to machine these materials. For this reason, these materials are generally machined with non-conventional manufacturing methods. In this study, a fuzzy application of Best–Worst method and a novel hybrid decision-making model (Best–Worst decision-making approach with fuzzy TOPSIS) are proposed to solve different non-traditional machining method selection problems which were taken from the literature. Using these models, the Best–Worst method shortens the steps of solutions in the fuzzy environment compared to the AHP/ANP-based fuzzy solutions in the literature. The proposed models produce successful results.

Background Progesterone administration has therapeutic effects in tobacco use disorder (TUD), with females benefiting more than males. Conversion of progesterone to the neurosteroid allopregnanolone is hypothesized to partly underlie the therapeutic effects of progesterone; however, this has not been investigated clinically. Methods Smokers ( n  = 18 males, n  = 21 females) participated in a randomized, double-blind, placebo-controlled crossover study of 200 mg progesterone daily across 4 days of abstinence. The ratio of allopregnanolone:progesterone was analyzed in relationship to nicotine withdrawal, smoking urges, mood states, subjective nicotine effects, and neural response to smoking cues. Results Allopregnanolone:progesterone ratio interacted with sex to predict withdrawal symptoms ( p  = 0.047), such that females with higher allopregnanolone:progesterone ratios reported lower withdrawal severity ( b  = − 0.98 [− 1.95, − 0.01]; p  = 0.048). In addition, allopregnanolone:progesterone ratio interacted with sex to predict confusion ( p  = 0.014) and fatigue ( p  = 0.034), such that females with higher allopregnanolone:progesterone ratios reported less confusion ( b  = − 0.45 [− 0.78, − 0.12]; p  = 0.008) and marginally lower fatigue ( b  = − 0.50 [− 1.03, 0.02]; p  = 0.062. Irrespective of sex, higher ratios of allopregnanolone:progesterone were associated with stronger “good effects” of nicotine ( b  = 8.39 [2.58, 14.20]); p  = 0.005) and weaker “bad effects” of nicotine ( b  = − 7.13 [− 13.53, − 0.73]; p  = 0.029). Conclusions Conversion of progesterone to allopregnanolone correlated with smoking-related outcomes in both sex-dependent and sex-independent ways. Sex-dependent effects suggest that conversion of progesterone to allopregnanolone may contribute to greater therapeutic benefits in females but not males with TUD. Trial registration Clinicaltrials.gov registration, retrospectively registered: NCT01954966; https://clinicaltrials.gov/ct2/show/NCT01954966 \\ Highlights Progesterone has sex-dependent effects on smoking measures in individuals with Tobacco Use Disorder. Higher conversion of progesterone to allopregnanolone (as indicated by the allopregnanolone:progesterone ratio) was associated with lower nicotine withdrawal in female but not male smokers during a brief abstinence. Higher conversion of progesterone to allopregnanolone was associated with lower ratings of confusion and marginally lower ratings of fatigue in female but not male smokers. Irrespective of sex, higher conversion of progesterone to allopregnanolone was associated with stronger “good effects” and weaker “bad effects” of nicotine during active smoking.