Cytisinicline for Smoking Cessation: A Randomized Clinical Trial.

Importance: Cytisinicline (cytisine) is a plant-based alkaloid that, like varenicline, binds selectively to α4ß2 nicotinic acetylcholine receptors, which mediate nicotine dependence. Although not licensed in the US, cytisinicline is used in some European countries to aid smoking cessation, but its traditional dosing regimen and treatment duration may not be optimal. Objective: To evaluate the efficacy and tolerability of cytisinicline for smoking cessation when administered in a novel pharmacokinetically based dosing regimen for 6 or 12 weeks vs placebo. Design, Setting, and Participants: A 3-group, double-blind, placebo-controlled, randomized trial (ORCA-2) compared 2 durations of cytisinicline treatment (6 or 12 weeks) vs placebo, with follow-up to 24 weeks, among 810 adults who smoked cigarettes daily and wanted to quit. It was conducted at 17 US sites from October 2020 to December 2021. Interventions: Participants were randomized (1:1:1) to cytisinicline, 3 mg, 3 times daily for 12 weeks (n = 270); cytisinicline, 3 mg, 3 times daily for 6 weeks then placebo 3 times daily for 6 weeks (n = 269); or placebo 3 times daily for 12 weeks (n = 271). All participants received behavioral support. Main Outcomes and Measures: Biochemically verified continuous smoking abstinence for the last 4 weeks of cytisinicline treatment vs placebo (primary) and from end of treatment to 24 weeks (secondary). Results: Of 810 randomized participants (mean age, 52.5 years; 54.6% female; mean of 19.4 cigarettes smoked daily), 618 (76.3%) completed the trial. For the 6-week course of cytisinicline vs placebo, continuous abstinence rates were 25.3% vs 4.4% during weeks 3 to 6 (odds ratio [OR], 8.0 [95% CI, 3.9-16.3]; P < .001) and 8.9% vs 2.6% during weeks 3 to 24 (OR, 3.7 [95% CI, 1.5-10.2]; P = .002). For the 12-week course of cytisinicline vs placebo, continuous abstinence rates were 32.6% vs 7.0% for weeks 9 to 12 (OR, 6.3 [95% CI, 3.7-11.6]; P < .001) and 21.1% vs 4.8% during weeks 9 to 24 (OR, 5.3 [95% CI, 2.8-11.1]; P < .001). Nausea, abnormal dreams, and insomnia occurred in less than 10% of each group. Sixteen participants (2.9%) discontinued cytisinicline due to an adverse event. No drug-related serious adverse events occurred. Conclusions and Relevance: Both 6- and 12-week cytisinicline schedules, with behavioral support, demonstrated smoking cessation efficacy and excellent tolerability, offering new nicotine dependence treatment options. Trial Registration: ClinicalTrials.gov Identifier: NCT04576949.

The effect of long-term doxycycline treatment in a mouse model of cigarette smoke-induced emphysema and pulmonary hypertension.

Chronic obstructive pulmonary disease (COPD) is a major cause of death and a still incurable disease, comprising emphysema and chronic bronchitis. In addition to airflow limitation, patients with COPD can suffer from pulmonary hypertension (PH). Doxycycline, an antibiotic from the tetracycline family, in addition to its pronounced antimicrobial activity, acts as a matrix metalloproteinase (MMP) inhibitor and has anti-inflammatory properties. Furthermore, doxycycline treatment exhibited a beneficial effect in several preclinical cardiovascular disease models. In preclinical research, doxycycline is frequently employed for gene expression modulation in Tet-On/Tet-Off transgenic animal models. Therefore, it is crucial to know whether doxycycline treatment in Tet-On/Tet-Off systems has effects independent of gene expression modulation by such systems. Against this background, we assessed the possible curative effects of long-term doxycycline administration in a mouse model of chronic CS exposure. Animals were exposed to cigarette smoke (CS) for 8 mo and then subsequently treated with doxycycline for additional 3 mo in room air conditions. Doxycycline decreased the expression of MMPs and general pro-inflammatory markers in the lungs from CS-exposed mice. This downregulation was, however, insufficient to ameliorate CS-induced emphysema or PH. Tet-On/Tet-Off induction by doxycycline in such models is a feasible genetic approach to study curative effects at least in established CS-induced emphysema and PH. However, we report several parameters that are influenced by doxycycline and use of a Tet-On/Tet-Off system when evaluating those parameters should be interpreted with caution.

Optimal dosing for psilocybin pharmacotherapy: Considering weight-adjusted and fixed dosing approaches.

BACKGROUND: Growing evidence suggests psilocybin, a naturally occurring psychedelic, is a safe and promising pharmacotherapy for treatment of mood and substance use disorders when administered as part of a structured intervention. In most trials to date, psilocybin dose has been administered on a weight-adjusted basis rather than the more convenient procedure of administering a fixed dose. AIMS: The present post hoc analyses sought to determine whether the subjective effects of psilocybin are affected by body weight when psilocybin is administered on a weight-adjusted basis and when psilocybin is administered as a fixed dose. METHODS: We analyzed acute subjective drug effects (mystical, challenging, and intensity) associated with therapeutic outcomes from ten previous studies (total N = 288) in which psilocybin was administered in the range 20 to 30 mg/70 kg (inclusive). Separate multivariate regression analyses examined the relationships between demographic variables including body weight and subjective effects in participants receiving 20 mg/70 kg (n = 120), participants receiving 30 mg/70 kg (n = 182), and participants whose weight-adjusted dose was about 25 mg (to approximate the fixed dose that is currently being evaluated in registration trials for major depressive disorder) (n = 103). RESULTS: In the 20 mg/70 kg and 30 mg/70 kg weight-adjusted groups, and in the fixed dose group, no significant associations were found between subjective effects and demographic variables including body weight or sex. Across a wide range of body weights (49 to 113 kg) the present results showed no evidence that body weight affected subjective effects of psilocybin. CONCLUSIONS: These results suggest that the convenience and lower cost of administering psilocybin as a fixed dose outweigh any potential advantage of weight-adjusted dosing.

PDE4 inhibition as a therapeutic strategy for improvement of pulmonary dysfunctions in Covid-19 and cigarette smoking.

Angiotensin-converting enzyme 2 (ACE2) is the binding-site and entry-point for SARS-CoV-2 in human and highly expressed in the lung. Cigarette smoking (CS) is the leading cause of pulmonary and cardiovascular diseases. Chronic CS leads to upregulation of bronchial ACE2 inducing a high vulnerability in COVID-19 smoker patients. Interestingly, CS-induced dysregulation of pulmonary renin-angiotensin system (RAS) in part contributing into the potential pathogenesis COVID-19 pneumonia and acute respiratory distress syndrome (ARDS). Since, CS-mediated ACE2 activations is not the main pathway for increasing the risk of COVID-19, it appeared that AngII/AT1R might induce an inflammatory-burst in COVID-19 response by up-regulating cyclic nucleotide phosphodiesterase type 4 (PDE4), which hydrolyses specifically the second intracellular messenger 3', 5'-cyclic AMP (cAMP). It must be pointed out that CS might induce PDE4 up-regulation similarly to the COVID-19 inflammation, and therefore could potentiate COVID-19 inflammation opening the potential therapeutic effects of PDE4 inhibitor in both COVID-19-inflammation and CS.

Epigallocatechin gallate diminishes cigarette smoke-induced oxidative stress, lipid peroxidation, and inflammation in human bronchial epithelial cells.

Cigarette smoke (CS), the major risk factor of chronic obstructive pulmonary disease (COPD), contains numerous free radicals that can cause oxidative stress and exaggerated inflammatory responses in the respiratory system. Lipid peroxidation which is oxidative degradation of polyunsaturated fatty acids and results in cell damage has also been associated with COPD pathogenesis. Increased levels of lipid peroxidation as well as its end product 4-hydroxynonenal have indeed been detected in COPD patients. Additionally, reactive oxygen species such as those contained in CS can activate nuclear factor-κB signaling pathway, initiating cascades of proinflammatory mediator expression. As emerging evidence attests to the antioxidative and anti-inflammatory properties of tea catechins, we sought to determine whether epigallocatechin gallate, the most abundant tea catechin, can provide protection against oxidative stress, lipid peroxidation, and inflammatory responses caused by CS. We found that EGCG treatment blocked cigarette smoke extract (CSE)-induced oxidative stress as indicated by decreased production and accumulation of reactive oxygen species in airway epithelial cells (AECs). Likewise, lipid peroxidation in CSE-stimulated AECs was suppressed by EGCG. Our findings further suggest that EGCG sequestered 4-hydroxynonenal and interfered with its protein adduct formation. Lastly, we show that EGCG inhibited nuclear factor-κB activation and the downstream expression of proinflammatory mediators. In summary, our study describing the antioxidative and anti-inflammatory effects of EGCG in CSE-exposed AECs provide valuable information about the therapeutic potential of this tea catechin for COPD.

Effectiveness of transdermal nicotine patch in premenopausal female smokers is moderated by within-subject severity of negative affect and physical symptoms.

RATIONALE: Nicotine patches may be less effective in female compared with male smokers. However, it is unknown if negative affect and physical symptoms influence transdermal nicotine patch-related effects on smoking behaviors. METHODS: Eighty-one acutely tobacco-abstinent premenopausal female smokers attended three counter-balanced experimental sessions across the menstrual cycle (early follicular, late follicular, and mid-luteal) and were randomized to patch condition (nicotine [21 mg] vs. placebo [0 mg] transdermal patch). Negative affect and physical symptoms were assessed prior to patch administration. The patch was removed 5 h post-administration, and participants completed a smoking reinstatement task. Multilevel linear models tested associations of patch condition, negative affect and physical symptoms, and their interaction on smoking behavior. RESULTS: There was a significant patch condition × Negative Affect and Pain symptoms interaction on the number of cigarettes smoked (p < 0.05). When Negative Affect and Pain were lower-than-usual, females administered a nicotine patch smoked significantly fewer cigarettes than females administered a placebo patch (p < .05), but there were no significant patch differences when Negative Affect and Pain were higher-than-usual. There was also a significant patch condition × Negative Affect interaction on time delay. The effects of patch condition on time delay to smoking were greater during sessions in which Negative Affect was higher-than-usual. CONCLUSIONS: Results suggest that among female smokers transdermal nicotine patch effectiveness may interact with negative affect and pain. Understanding and considering female-specific factors that may impact the efficacy of one of the most commonly used cessation medications is important for improving smoking cessation in female smokers.

The effect of varenicline on mood and cognition in smokers with HIV.

RATIONALE: Barriers to smoking cessation, including negative affect and cognitive dysfunction, may contribute to high smoking rates among people living with HIV/AIDS (PLWH). Varenicline may help PLWH quit smoking by improving mood and cognition, yet this has not been explored. OBJECTIVES: The goal of this study was to evaluate the effect of varenicline on mood and cognition among PLWH enrolled in a smoking cessation clinical trial. METHODS: In this secondary analysis of a varenicline trial (NCT01710137), we assessed mood (depression, anxiety) and cognition (attention, working memory) at weeks 0 (baseline), 1, 3, and 12 (end-of-treatment, EOT). Primary outcomes were changes in mood and cognition from baseline to EOT. Secondarily, mood and cognition were evaluated as predictors of biochemically confirmed 7-day point-prevalence abstinence at EOT. RESULTS: Overall, 173 subjects (87 varenicline, 86 placebo) were included. At EOT, varenicline reduced anxiety (P < 0.001), vs. placebo (P = 0.31; interaction P = 0.05). Across both treatment arms, reductions in anxiety from baseline to EOT were associated with a higher likelihood of abstinence (OR = 1.3, 95% CI 1.1 to 1.6, P = 0.01). There were no significant treatment by time interactions for cognition or depression. CONCLUSIONS: These data suggest that varenicline operates, at least in part, by reducing anxiety. Anxiety should be an intervention target for smokers with HIV interested in quitting.

Disparities in hospital smoking cessation treatment by immigrant status.

Despite the efficacy of nicotine replacement therapy (NRT) in promoting smoking cessation, no studies have been done to evaluate NRT prescribing rates among immigrants, a vulnerable minority population in the United States. The aim of this study is to explore for differences in NRT prescribing behavior by immigrant status. Participants were enrolled in a smoking cessation trial for hospitalized patients between July 2011 and April 2014 at two NYC hospitals. For this analysis, we used baseline data from patient surveys and electronic medical-record reviews to examine associations between immigrant status and prescription of NRT in-hospital and on discharge, as well as acceptance of NRT in-hospital. We included age, gender, education, health literacy, race, ethnicity, English language ability, inpatient service, and site insurance in the models as potential confounders. Our study population included 1,608 participants, of whom 21% were not born in the United States. Bivariate analysis found that nonimmigrants were more likely than immigrants to be prescribed NRT in the hospital (46.1% vs. 35.7%, p = .0006) and similarly on discharge (19.4% vs. 15.3%, p = .09). Both groups were equally likely to accept NRT in-hospital when prescribed. On multivariable analysis, being an immigrant (OR 0.65), Black race (OR 0.52), and Hispanic ethnicity (OR 0.63) were associated with lower likelihood of being prescribed NRT in-hospital. Multivariable analysis for provision of NRT prescription at discharge showed no significant difference between immigrants and nonimmigrants. These findings show differences in in-hospital smoking cessation treatment between immigrants and nonimmigrants.

The influence of gender and oxytocin on stress reactivity, cigarette craving, and smoking in a randomized, placebo-controlled laboratory relapse paradigm.

RATIONALE: Female cigarette smokers tend to show greater cessation failure compared with males. Variables that contribute to the maintenance of smoking, including stress and craving, may differentially impact male and female smokers. Novel pharmacotherapies, such as oxytocin, may attenuate stress reactivity and craving in smokers, but work in this area is limited. OBJECTIVES: This study assessed the influence of gender and oxytocin on stress reactivity, craving, and smoking in a randomized, placebo-controlled laboratory relapse paradigm. METHODS: Male and female adult cigarette smokers (ages 18-45) were enrolled (women oversampled 2:1) and completed a laboratory session, in which intranasal oxytocin or placebo was administered followed by a laboratory social stress task. The role of gender and oxytocin were assessed on measures of stress reactivity, cigarette craving, latency to smoke in a resistance task, subjective responses to smoking, and ad-libitum smoking. RESULTS: Participants (N = 144) had a mean age of 31 were 63% female and 56% White. Following stress induction, female smokers evidenced greater subjective stress than males, though males demonstrated greater neuroendocrine reactivity and smoking intensity than females. No gender differences were demonstrated for craving. Oxytocin did not attenuate any aspect of stress reactivity, craving, smoking, or subjective responses to smoking compared with placebo. CONCLUSIONS: Gender differences in stress reactivity were shown in the hypothesized direction, but oxytocin appeared to exert little impact on subjective or behavioral metrics. Results highlight the complex relationship between gender, stress, and smoking, as well as the implications for oxytocin as a potential pharmacotherapy for smoking cessation.

The plant flavonoid, fisetin alleviates cigarette smoke-induced oxidative stress, and inflammation in Wistar rat lungs.

In the present study, we tested the antioxidant and anti-inflammatory potential of the plant flavonoid, fisetin against cigarette smoke-induced oxidative stress, and inflammation in rat lungs. Male Wistar rats were chronically exposed to cigarette smoke (CS) with or without administration of fisetin. Fisetin administration to CS-exposed rats resulted in a significant reduction in neutrophils and macrophages in bronchoalveolar lavage fluid as well as malondialdehyde, 3-nitrotyrosine, 8-isoprostane, tumor necrosis factor-alpha, interleukin-1beta, granulocyte macrophage-colony stimulating factor, interleukin-4, and interleukin-10 levels in lung tissues compared to those in CS-exposed rats not treated with fisetin. Fisetin also significantly augmented lung hemoxinase-1, glutathione peroxidase-2, reduced glutathione, superoxide dismutase, nitric oxide, and nuclear factor erythroid 2-related factor (Nrf2) levels in CS-exposed rats. In addition, a marked reversal in CS-induced histopathological changes was noted in fisetin-treated rats. Collectively, these data demonstrate the potential of fisetin to blunt CS-induced oxidative stress and inflammation in the lung and to prevent tissue damage via the Nrf2-mediated upregulation of antioxidant gene expression. PRACTICAL APPLICATIONS: In the present study, we found that the plant flavonoid, fisetin significantly abrogated the oxidative stress, inflammation, and tissue damage induced by cigarette smoke, a powerful pro-oxidant in rat lungs. Additionally, fisetin markedly reversed cigarette smoke-induced increases in neutrophil and macrophage cell populations in bronchoalveolar lavage fluid. These findings are particularly significant considering the association of cigarette smoking with increased oxidative stress and inflammation, which are central to the pathologies of a wide variety of chronic diseases including chronic obstructive pulmonary disease, cancer, and cardiovascular diseases. Therefore, the present work underscores the beneficial effects of the regular consumption of plant-based foods with medicinal properties for the effective prevention of these chronic diseases.

The risk of varenicline-induced seizure among those who have attempted to quit smoking using pharmacotherapy.

OBJECTIVE: Varenicline is an effective smoking cessation agent; however, its use is limited because of black box warnings issued by regulatory agencies in the U.S. and Australia. The U.S. Food and Drug Administration updated the label for varenicline in 2015 to warn about the risk of varenicline-induced seizures. The objective of this study was to examine the risk of seizure associated with varenicline use. METHODS: A nested case-control study was performed using IMS LifeLink PharMetrics Plus administrative claims data (2009-2015). The outcome was presumptive seizures. All smokers making an attempt to quit smoking and having no recent seizure events were included in the nest. Cases and controls were matched (1:4) on age (±5 years), sex, index date (±30 days), event date, and duration of enrollment. An exposure period of 90 days preceding the event date was used. Chi-square tests were used to compare the characteristics of cases and controls. Conditional logistic regression was conducted to determine if an association between presumptive seizures and varenicline use exists. RESULTS: Our final sample was comprised of 1342 cases and 5368 controls. The adjusted analysis showed that odds of a seizure for patients with a varenicline prescription were 1.09 (confidence interval [CI] = 0.88-1.36) times those of patients with no varenicline exposure. CONCLUSIONS: This study did not find a significant association between varenicline and increased risk of presumptive seizures. These findings raise questions regarding the necessity for a warning label for increased risk of seizures associated with varenicline.

Exogenous progesterone for smoking cessation in men and women: a pilot double-blind, placebo-controlled randomized clinical trial.

BACKGROUND AND AIMS: In some clinical studies men and women have been found to differ in their ability to quit smoking, perhaps as a result of progesterone. The primary aim of this study was to provide a preliminary test of whether progesterone (PRO), compared with placebo (PBO), was more effective for smoking cessation in men and women. DESIGN: Pilot double-blind, placebo-controlled randomized clinical trial. SETTING: Minneapolis/St Paul metro area, Minnesota, USA. PARTICIPANTS: A total of 216 participants were randomized, including 113 men (18-60 years; PRO = 56, PBO = 57) and 103 women (18-50 years, pre-menopausal with self-reported regular menstrual cycles; PRO = 51, PBO = 52). INTERVENTION: Participants were randomized (1 : 1 within sex group) to either PRO (200 mg twice daily) or PBO. Participants were assigned a quit date approximately 7 days after starting medication (luteal phase for women) and were followed for 12 weeks to assess relapse. MEASUREMENTS: The primary outcome was self-reported 7-day point prevalence abstinence (PPA) at week 4. Secondary outcomes included 7-day PPA at weeks 8 and 12, prolonged abstinence, continuous abstinence, urine cotinine < 50 ng/ml, expired carbon monoxide ≤ 5 parts per million (p.p.m.) and days to relapse. FINDINGS: There was a significant difference in 7-day PPA at week 4 among women [PRO: 18 (35.3%) versus PBO: 9 (17.3%), odds ratio (OR) = 2.61, 95% confidence interval (CI) = 1.04, 6.54, P = 0.041], but not among men [PRO: 13 (23.2%) versus PBO: 12 (21.1%), 1.13 (0.47, 2.76), P = 0.782]. There was some evidence that PRO delayed relapse in women (days to relapse; PRO: 20.5 ± 29.6 versus PBO: 14.3 ± 26.8, P = 0.03) but not in men (PRO: 13.4 ± 25.9 versus PBO: 13.3 ± 23.8, P = 0.69). CONCLUSIONS: Oral micronized progesterone may aid smoking cessation in women.

Longitudinal associations between smoking and affect among cancer patients using varenicline to quit smoking.

During a quit attempt, high negative affect predicts relapse to smoking. In this study, we evaluated bidirectional longitudinal associations between smoking and negative affect among cancer patients treated with varenicline. Participants (N = 119, 50% female, Mage = 59 years) were smokers (≥5 cigarettes/week) who were diagnosed with cancer and were recruited for a 24-week trial of extended duration varenicline plus behavioral counseling; data for this secondary analyses were drawn from the 12-week open-label phase of the trial. Smoking was assessed via self-reported number of cigarettes in the past 24 h. Negative affect was assessed using the Positive and Negative Affect Scale (PANAS). Data were collected at pre-quit (week 0), target quit day (week 1), week 4, and week 12. We evaluated cross-lagged panel models for negative affect and smoking using PROC CALIS in SAS. Models were run separately for participants who were adherent (≥80% of medication taken) or nonadherent to varenicline. Among adherent participants (n = 96), smoking accounted for up to 22% of variance in subsequent negative affect throughout treatment. Cross-lagged associations were not observed between smoking and negative affect among non-adherent participants (n = 23). Negative affect did not predict subsequent smoking among either adherent or nonadherent participants. These results suggest that varenicline may attenuate abstinence-induced negative affect among cancer patients treated for nicotine dependence.

Longitudinal Findings from a Randomized Clinical Trial of Varenicline for Alcohol Use Disorder with Comorbid Cigarette Smoking.

BACKGROUND: This study is the first to examine longitudinal posttreatment outcomes of a placebo-controlled trial of varenicline for alcohol use disorder (AUD) with comorbid cigarette smoking. METHODS: Participants were 131 adults (n = 39 female) seeking alcohol treatment in a randomized, double-blind, parallel group, placebo-controlled, 16-week multisite trial of varenicline combined with medical management (MM). Timeline follow-back assessments of alcohol and smoking behavior were conducted at the end of treatment (4 months), with follow-ups at 6, 9, and 12 months. Outcomes were percentage of heavy drinking days (PHDD), percent of participants with no heavy drinking days (NHDD), cotinine-confirmed prolonged smoking abstinence (PA), and good clinical outcome on either NHDD or PA. RESULTS: Treatment improvements were maintained posttreatment. For the sample overall, PHDD or NHDD did not differ significantly by treatment condition (ps > 0.13), but varenicline produced higher rates of PA versus placebo at 4, 9, and 12 months (p < 0.05). Significant differences were observed by sex: Males had higher rates of NHDD with varenicline (28.9%) versus placebo (6.4%) at the end of treatment (p = 0.004), and these effects were maintained at 12 months (varenicline: 40.0% vs. placebo: 19.2%, p = 0.03). Higher rates of PA were seen for varenicline in both males (8.9%) and females (21.1%) versus placebo (males/females: 0%) at the end of treatment (p = 0.05), and this effect was maintained at 12 months for females (varenicline: 21.1% vs. placebo, 0.0%, p = 0.05). CONCLUSIONS: Varenicline treatment combined with MM appears to have enduring benefits for patients with co-occurring AUD and cigarette smoking, and these effects may differ by sex.

Oxytocin Reduces Cigarette Consumption in Daily Smokers.

INTRODUCTION: Despite widespread knowledge of the dangers of cigarette consumption, smoking continues to be a public health concern. One compound that has shown potential for treatment in preclinical models is the neuropeptide oxytocin (OT). The purpose of the present study was to examine the effects of intranasal oxytocin on cigarette craving, behavioral economic demand for cigarettes, and cigarette consumption, in regular smokers after 18 hours of abstinence. METHOD: Otherwise healthy daily smokers (n = 35) completed two sessions where they received OT (40 IU intranasal) or placebo (PBO) and completed measures of craving and cigarette demand, and they were given six opportunities to smoke partial cigarettes in exchange for money. RESULTS: On average participants smoked few cigarettes after receiving OT than after receiving PBO, and they reported less desire for additional cigarettes during the smoking period. OT did not affect cigarette demand or standardized measures of cigarette craving. CONCLUSIONS: This study suggests that OT decreases some indices of smoking desire and consumption, providing modest support for the idea that OT might be effective for reducing cigarette smoking. IMPLICATIONS: This study provides new evidence that oxytocin might have clinical value in the treatment of addictive disorders, in this case tobacco addiction. The study adds to a growing literature suggesting that this neuropeptide, which is mainly known for its role in social bonding and attachment, may also affect mood and motivational states relevant to addiction.

Varenicline and nabilone in tobacco and cannabis co-users: effects on tobacco abstinence, withdrawal and a laboratory model of cannabis relapse.

Tobacco and cannabis co-users (T+CUs) have poor cannabis cessation outcomes, but the mechanisms underlying this are not well understood. This laboratory study examined the effects of (1) the partial nicotinic agonist, varenicline, on tobacco cessation among T+CUs, and (2) varenicline, alone, and when combined with the cannabinoid agonist nabilone, on cannabis withdrawal and a laboratory model of cannabis relapse. Non-treatment-seeking T+CUs were randomized to active-varenicline or placebo-varenicline, and completed a 15-day outpatient phase; varenicline was titrated to 1 mg BID during days 1-8, and participants were instructed to abstain from tobacco during days 9-15. Participants then moved inpatient for 16 days, where they continued their outpatient medication and tobacco abstinence. Inpatient testing included two, 8-day medication periods, where active-nabilone and placebo-nabilone were administered in counterbalanced order, and measures of acute cannabis effects (days 1-2), withdrawal (days 4-5) and 'relapse' (days 6-8) were collected. Participants in the active-varenicline group were more likely to achieve cotinine-verified tobacco abstinence during the outpatient period versus placebo-varenicline group (46 percent versus 24 percent, respectively), and also reported less mood disturbance and cigarette craving while inpatient. Active-nabilone attenuated cannabis withdrawal in both groups but did not affect cannabis relapse. Regression analyses revealed that two tobacco-related variables, i.e. age of first cigarette use, and cigarette craving while inpatient, were independent predictors of cannabis relapse outcomes. Thus, varenicline holds promise in this population, as a tool to examine the effects of tobacco abstinence on cannabis use outcomes, and as a component of smoking cessation treatments targeting T+CUs.

A pilot investigation of the effect of electronic cigarettes on smoking behavior among opioid-dependent smokers.

INTRODUCTION: Compared to the general population, smoking rates are 2-4 times higher among individuals with opioid use disorders (OUDs). These smokers also have poor long-term cessation rates, even with pharmacotherapy or other interventions. Low success rates with traditional approaches may prompt smokers with OUDs to try more novel products like electronic cigarettes (ECIGs). This pilot study was designed to examine the feasibility, acceptability, and effect of ECIGs on smoking behavior among smokers with OUD. METHODS: Participants (N = 25) were daily smokers receiving buprenorphine/naloxone for OUD at an outpatient clinic. They were randomized to use a second-generation ECIG (0 or 18 ng/ml nicotine) ad libitum for two weeks while completing assessments via text messaging daily, and also via in-person visits at baseline, end of the two-week intervention, and a 4-week follow-up. RESULTS: Feasibility was evidenced by high enrollment (93.9%) and retention (70.9%) rates. ECIG adherence was relatively high as measured by self-report (80.6% active, 91.7% placebo), while the average volume of liquid used per week was low (~3 ml). Both ECIG doses produced reductions in self-reported cigarettes per day that were not supported by average carbon monoxide levels. Biologically-confirmed smoking abstinence was observed in 8% of participants. CONCLUSIONS: Preliminary results suggest that smokers with OUD are interested in using ECIGs, but their adherence may be less than ideal. Poor medication adherence rates are often observed in this disparate population, and future work should consider the use of other ECIG device types and a combination of methods to verify and quantify ECIG use.