Immediate Switching to Reduced Nicotine Cigarettes in a U.S.-Based Sample: The Impact on Cannabis Use and Related Variables at 20 Weeks.

INTRODUCTION: The FDA proposed rule-making to reduce nicotine in cigarettes to minimally addictive levels. Research suggests decreasing nicotine levels (i.e. very low nicotine content cigarettes [VLNCs]) produced greater quit attempts, reduced smoking, and reduced exposure to harmful constituents among smokers. The impact of long-term VLNC use among people who co-use cigarettes and cannabis on non-tobacco-specific toxicant and carcinogen exposure has not been investigated. AIMS AND METHODS: This study presents secondary analyses of a controlled clinical trial examining switching to VLNC (versus a normal nicotine cigarettes control group [NNCs]) between people who co-use cigarettes and cannabis (n = 174) versus smoked cigarettes (n = 555). Linear mixed-effects models compared changes in smoking behavior, and tobacco-specific (i.e. total nicotine equivalents [TNE], 4-[methylnitrosamino]-1-[3-pyridyl]-1-butanone [NNK; total NNAL]) and non-tobacco-specific (i.e. carbon monoxide (CO), 2-cyanoethylmercapturic acid [CEMA], phenanthrene tetraol [PheT]) toxicant and carcinogen exposure at week 20 (with random intercept for participants). Cannabis use was measured among co-use groups. RESULTS: CO was significantly lower only among the cigarette-only group assigned VLNCs (interaction: p = .015). Although both VLNC groups demonstrated decreased CEMA, greater decreases emerged among the cigarette-only group (interaction: p = .016). No significant interactions emerged for TNE, cigarettes per day (CPD), NNAL, and PheT (ps > .05); both VLNC groups decreased in TNE, CPD, and NNAL. Only the cigarette-only group assigned VLNCs demonstrated decreased PheT (p < .001). The VLNC co-use group showed increased cannabis use over time (p = .012; 0.5 more days per week by week 20). CONCLUSIONS: Those who co-use cannabis and cigarettes may still be at risk for greater exposure to non-tobacco-specific toxicants and carcinogens compared to those who only smoke cigarettes. IMPLICATIONS: The present study is the longest longitudinal, prospective comparison study of smoking behavior and exposure to harmful constituents among those who co-use cigarettes and cannabis versus cigarette-only after immediately switching to very low nicotine content cigarettes (VLNC). Those who co-use experienced similar reductions in CPD and tobacco-specific exposure, compared to those who only use cigarettes. However, co-use groups experienced smaller reductions in non-tobacco-specific toxicants and carcinogens compared to the cigarette-only group, potentially because of combustible cannabis use. Additionally, those who co-use and switched to VLNC may be susceptible to slight increases in cannabis use (approximately two more days per year).

Smoking abstinence and cessation-related outcomes one month after an immediate versus gradual reduction in nicotine content of cigarettes.

The United States Food and Drug Administration has the authority to reduce the nicotine content in cigarettes to minimal or non-addictive levels and could do so immediately or gradually over time. A large clinical trial compared the two approaches. This secondary analysis assesses abstinence and cessation-related outcomes one month after the trial concluded, when participants no longer had access to very low nicotine content (VLNC) research cigarettes. Smokers not interested in quitting (N = 1250) were recruited for the parent trial from 2014 to 2016 across 10 sites throughout the US and randomized to a 20-week study period during which they immediately switched to VLNC cigarettes, gradually transitioned to VLNC cigarettes with five monthly dose reductions, or smoked normal nicotine research cigarettes (control). At the one-month follow-up, both immediate and gradual reduction resulted in greater mean cigarette-free days (4.7 and 4.6 respectively) than the control group (3.2, both p < .05). Immediate reduction resulted in fewer mean cigarettes per day (CPD = 10.3) and lower Fagerström Test for Cigarette Dependence (FTCD = 3.7) than the gradual (CPD = 11.7, p = .001; FTCD = 3.8, p = .039) and control (CPD = 13.5, p < .001; FTCD = 4.0, p < .001) groups. Compared to controls, gradual reduction resulted in reduced CPD (p = .012) but not FTCD (p = .13). Differences in CO-verified 7-day point-prevalence abstinence were not significant. Findings demonstrate that switching to VLNC cigarettes resulted in reduced smoking and nicotine dependence severity that was sustained for at least a month after the VLNC trial period in smokers who were not interested in cessation. The greatest harm reduction endpoints were observed in those who immediately transitioned to VLNC cigarettes.

Cannabinoids for Agitation in Alzheimer's Disease.

Agitation is a common neuropsychiatric symptom of Alzheimer's disease (AD) that greatly impacts quality of life and amplifies caregiver burden. Agitation in AD may be associated with volume loss in the anterior cingulate cortex, posterior cingulate cortex, insula, amygdala, and frontal cortex, as well as with degeneration of monoaminergic neurotransmission, disrupted circadian rhythms, and frailty. Current pharmacologic options have troubling safety concerns and only modest efficacy. There is increasing interest in cannabinoids as promising agents due to preclinical and early clinical research that suggest cannabinoids can elicit anxiolytic, antidepressant, and/or anti-inflammatory effects. Cannabinoids may relieve agitation by regulating neurotransmitters, improving comorbidities and circadian rhythms, and increasing cerebral circulation. Here we discuss the possible contributory mechanisms for agitation in AD and the therapeutic relevance of cannabinoids, including CBD and THC.

An Evaluation of Potential Unintended Consequences of a Nicotine Product Standard: A Focus on Drinking History and Outcomes.

INTRODUCTION: A nicotine product standard reducing the nicotine content in cigarettes could improve public health by reducing smoking. This study evaluated the potential unintended consequences of a reduced nicotine product standard by examining its effects on (1) smoking behaviors based on drinking history; (2) drinking behavior; and (3) daily associations between smoking and drinking. METHODS: Adults who smoke daily (n = 752) in the United States were randomly assigned to smoke very low nicotine content (VLNC) cigarettes versus normal nicotine content (NNC; control) cigarettes for 20 weeks. Linear mixed models determined if baseline drinking moderated the effects of VLNC versus NNC cigarettes on Week 20 smoking outcomes. Time-varying effect models estimated the daily association between smoking VLNC cigarettes and drinking outcomes. RESULTS: Higher baseline alcohol use (vs no use or lower use) was associated with a smaller effect of VLNC on Week 20 urinary total nicotine equivalents (ps < .05). No additional moderation was supported (ps > .05). In the subsample who drank (n = 415), in the VLNC versus NNC condition, daily alcohol use was significantly reduced from Weeks 17 to 20 and odds of binge drinking were significantly reduced from Weeks 9 to 17. By Week 7, in the VLNC cigarette condition (n = 272), smoking no longer predicted alcohol use but remained associated with binge drinking. CONCLUSIONS: We did not support negative unintended consequences of a nicotine product standard. Nicotine reduction in cigarettes generally affected smoking behavior for individuals who do not drink or drink light-to-moderate amounts in similar ways. Extended VLNC cigarette use may improve public health by reducing drinking behavior. IMPLICATIONS: There was no evidence that a VLNC product standard would result in unintended consequences based on drinking history or when considering alcohol outcomes. Specifically, we found that a very low nicotine standard in cigarettes generally reduces smoking outcomes for those who do not drink and those who drink light-to-moderate amounts. Furthermore, an added public health benefit of a very low nicotine standard for cigarettes could be a reduction in alcohol use and binge drinking over time. Finally, smoking VLNC cigarettes may result in a decoupling of the daily associations between smoking and drinking.

Cross-sectional and longitudinal evaluation of cannabidiol (CBD) product use and health among people with epilepsy.

Recent approval of Epidiolex® (pharmaceutical cannabidiol/CBD) for the treatment of Lennox Gastaut syndrome (LGS) and Dravet syndrome highlights a therapeutic efficacy of CBD in the treatment of epilepsy. However, a large number of patients with epilepsy elect to use alternative artisanal CBD products due to cost or access constraints. Despite widespread availability and variety of these artisanal CBD products, studies evaluating their safety or efficacy are rare, making conclusions about clinical utility uncertain. The purpose of the present study was to evaluate cross-sectional and longitudinal associations of artisanal CBD product use with quality of life, mental health, healthcare utilization, and epilepsy-specific outcomes within a large, observational cohort of people with epilepsy. Participants who reported using artisanal CBD products at baseline (Artisanal CBD Users; n = 280) and participants who used no cannabis-based products (Controls; n = 138) completed web-based assessments evaluating psychiatric symptoms, healthcare utilization, and epilepsy-specific factors. Follow-up surveys were collected in a subset of participants (n = 190) following baseline assessment for longitudinal comparison. Cross-sectionally, higher quality of life, lower psychiatric symptom severity, and improved sleep were observed among Artisanal CBD Users at baseline compared with Controls. Initiation of artisanal CBD product use was also related to improved health outcomes longitudinally. No group differences were observed for seizure control, but both groups included a high number of individuals with no past month seizures. Artisanal CBD Users reported significantly better epilepsy medication tolerability, use of fewer prescription medications overall, and reduced healthcare utilization compared with Controls. These findings are consistent with research indicating that practitioners recommending CBD in clinical care for epilepsy report integrating the use of CBD both as a means to improve patient quality of life as well as for seizure control.

Sex differences in the acute effects of oral and vaporized cannabis among healthy adults.

Policy changes have increased access to cannabis for individuals with little or no prior exposure. Few studies have examined sex differences in cannabis effects among individuals with sporadic cannabis use or for nonsmoked routes of cannabis administration. Data from four double-blind, placebo-controlled studies were pooled to compare the acute pharmacodynamic effects of vaporized and oral cannabis in male (n = 27) and female (n = 23) participants who used cannabis infrequently (no use ≥30 days prior to randomization). Analyses compared peak change-from-baseline scores between male and female participants for subjective drug effects, cognitive/psychomotor performance, cardiovascular effects, and blood concentrations of Δ9-tetrahydrocannabinol (THC) and its primary metabolites (11-OH-THC, THC-COOH) after exposure to placebo cannabis or cannabis containing low-dose (5 or 10 mg) or high-dose THC (20 or 25 mg). Overall, cannabis elicited dose-orderly increases in subjective effects, impairment of cognitive/psychomotor performance, heart rate, and blood cannabinoid concentrations. Females exhibited greater peak blood 11-OH-THC concentrations and reported greater peak subjective ratings of "drug effect" that remained when controlling for body weight. When controlling for both body weight and peak blood cannabinoid concentrations, ratings of "anxious/nervous," "heart racing," and "restless" were significantly higher for females than males. Although additional research is needed to elucidate sex differences in responses to cannabis at a wider range of THC doses, other routes of administration, and products with diverse chemical composition, the current data indicate that public health messaging and clinical decision making around the use of cannabinoids should recommend lower starting doses for females and warnings about acute anxiogenic reactions.

Brain imaging of cannabinoid type I (CB1 ) receptors in women with cannabis use disorder and male and female healthy controls.

Cannabis effects are predominantly mediated by pharmacological actions on cannabinoid type 1 (CB1 ) receptors. Prior positron emission tomography (PET) studies in individuals who use cannabis included almost exclusively males. PET studies in females are needed because there are sex differences in cannabis effects, progression to cannabis use disorder (CUD), and withdrawal symptom severity. Females with CUD (N = 10) completed two double-blind cannabis smoking sessions (Session 1: placebo; Session 2: active), and acute cannabis effects were assessed. After Session 2, participants underwent 3 days of monitored cannabis abstinence; mood, craving, and withdrawal symptoms were assessed and a PET scan (radiotracer: [11 C]OMAR) followed. [11 C]OMAR Distribution volume (VT ) from these participants was compared with VT of age/BMI-similar female non-users of cannabis ("healthy controls"; N = 10). VT was also compared between female and male healthy controls (N = 7). Females with CUD displayed significantly lower VT than female healthy controls in specific brain regions (hippocampus, amygdala, cingulate, and insula). Amygdala VT was negatively correlated with mood changes (anger/hostility) during abstinence, but VT was not correlated with other withdrawal symptoms or cannabis effects. Among healthy controls, females had significantly higher VT than males in all brain regions examined. Chronic cannabis use appears to foster downregulation of CB1 receptors in women, as observed previously in men, and there are inherent sex differences in CB1 availability. Future studies should elucidate the time course of CB1 downregulation among females who use cannabis and examine the relation between CB1 availability and cannabis effects among other populations (e.g., infrequent users; medicinal users).

Study rationale and baseline data for pilot trial of dronabinol adjunctive treatment of agitation in Alzheimer's dementia (THC-AD).

Agitation is a common complication of Alzheimer's dementia (Agit-AD) associated with substantial morbidity, high healthcare service utilization, and adverse emotional and physical impact on care partners. There are currently no FDA-approved pharmacological treatments for Agit-AD. We present the study design and baseline data for an ongoing multisite, three-week, double-blind, placebo-controlled, randomized clinical trial of dronabinol (synthetic tetrahydrocannabinol [THC]), titrated to a dose of 10 mg daily, in 80 participants to examine the safety and efficacy of dronabinol as an adjunctive treatment for Agit-AD. Preliminary findings for 44 participants enrolled thus far show a predominately female, white sample with advanced cognitive impairment (Mini Mental Status Examination mean 7.8) and agitation (Neuropsychiatric Inventory-Clinician Agitation subscale mean 14.1). Adjustments to study design in light of the COVID-19 pandemic are described. Findings from this study will provide guidance for the clinical utility of dronabinol for Agit-AD. ClinicalTrials.gov Identifier: NCT02792257.

Cigarette Smokers Versus Cousers of Cannabis and Cigarettes: Exposure to Toxicants.

INTRODUCTION: Cannabis and tobacco couse is common and could expose users to higher levels of toxicants. No studies have examined biomarkers of toxicant exposure in cousers of cannabis and cigarettes, compared with cigarette smokers (CS). AIMS AND METHODS: Adult daily CS were recruited from 10 US sites for a study of reduced nicotine cigarettes. In this analysis of baseline data, participants were categorized as either cousers of cannabis and tobacco (cousers; N = 167; urine positive for 11-nor-9-carboxy-Δ 9-tetrahydrocannnabinol and self-reported cannabis use ≥1×/week), or CS (N = 911; negative urine and no self-reported cannabis use). Participants who did not meet either definition (N = 172) were excluded. Self-reported tobacco and cannabis use and tobacco and/or combustion-related biomarkers of exposure were compared between groups. RESULTS: Compared to CS, cousers were younger (couser Mage = 38.96, SD = 13.01; CS Mage = 47.22, SD = 12.72; p < .001) and more likely to be male (cousers = 67.7%, CS = 51.9%, p < .001). There were no group differences in self-reported cigarettes/day, total nicotine equivalents, or breath carbon monoxide, but cousers had greater use of non-cigarette tobacco products. Compared to CS, cousers had higher concentrations of 3-hydroxypropylmercapturic acid, 2-cyanoethylmercapturic acid, S-phenylmercapturic acid, 3-hydroxy-1-methylpropylmercapturic acid (ps < .05), and phenanthrene tetraol (p < .001). No biomarkers were affected by number of cannabis use days/week or days since last cannabis use during baseline (ps > .05). CONCLUSIONS: Cousers had higher concentrations of biomarkers of exposure than CS, but similar number of cigarettes per day and nicotine exposure. Additional studies are needed to determine whether cannabis and/or alternative tobacco products are driving the increased toxicant exposure. IMPLICATIONS: Cousers of cannabis and tobacco appear to be exposed to greater levels of harmful chemicals (ie, volatile organic compounds and polycyclic aromatic hydrocarbons), but similar levels of nicotine as CS. It is unclear if the higher levels of toxicant exposure in cousers are due to cannabis use or the increased use of alternative tobacco products compared with CS. It is important for studies examining biomarkers of exposure among CS to account for cannabis use as it may have a significant impact on outcomes. Additionally, further research is needed examining exposure to harmful chemicals among cannabis users.

Effects of Very Low Nicotine Content Cigarettes on Smoking Behavior and Biomarkers of Exposure in Menthol and Non-menthol Smokers.

INTRODUCTION: Because 30% of cigarettes sold in the United States are characterized as menthol cigarettes, it is important to understand how menthol preference may affect the impact of a nicotine reduction policy. METHODS: In a recent trial, non-treatment-seeking smokers were randomly assigned to receive very low nicotine cigarettes (VLNC; 0.4 mg nicotine/g tobacco) or normal nicotine cigarettes (NNC; 15.5 mg/g) for 20 weeks. On the basis of preference, participants received menthol or non-menthol cigarettes. We conducted multivariable regression analyses to examine whether menthol preference moderated the effects of nicotine content on cigarettes per day (CPD), breath carbon monoxide (CO), urinary total nicotine equivalents (TNE), urinary 2-cyanoethylmercapturic acid (CEMA), and abstinence. RESULTS: At baseline, menthol smokers (n = 346) reported smoking fewer CPD (14.9 vs. 19.2) and had lower TNE (52.8 vs. 71.6 nmol/mg) and CO (17.7 vs. 20.5 ppm) levels than non-menthol smokers (n = 406; ps < .05). At week 20, significant interactions indicated that menthol smokers had smaller treatment effects than non-menthol smokers for CPD (-6.4 vs. -9.3), TNE (ratio of geometric means, 0.22 vs. 0.10) and CEMA (ratio, 0.56 vs. 0.37; ps < .05), and trended toward a smaller treatment effect for CO (-4.5 vs. -7.3 ppm; p = .06). Odds ratios for abstinence at week 20 were 1.88 (95% confidence interval [CI] = 0.8 to 4.4) for menthol and 9.11 (95% CI = 3.3 to 25.2) for non-menthol VLNC smokers (p = .02) relative to the NNC condition. CONCLUSIONS: Although menthol smokers experienced reductions in smoking, toxicant exposure, and increases in quitting when using VLNC cigarettes, the magnitude of change was smaller than that observed for non-menthol smokers. IMPLICATIONS: Results of this analysis suggest that smokers of menthol cigarettes may respond to a nicotine reduction policy with smaller reductions in smoking rates and toxicant exposure than would smokers of non-menthol cigarettes.

The Impact of Gradual and Immediate Nicotine Reduction on Subjective Cigarette Ratings.

BACKGROUND: A recent clinical trial showed that an immediate transition to very low nicotine content (VLNC) cigarettes, compared with a gradual transition, produced greater reductions in smoking behavior, smoke exposure, and dependence. However, there was less compliance with the instruction to smoke only VLNC cigarettes in the immediate versus gradual reduction condition. The goal of this study was to test whether nicotine reduction method alters subjective ratings of VLNC cigarettes, and whether subjective ratings mediate effects of nicotine reduction method on smoking behavior, smoke exposure, dependence, and compliance. METHODS: This is a secondary analysis of a randomized trial conducted across 10 sites in the United States. Smokers (n = 1250) were randomized to either a control condition, or to have the nicotine content of their cigarettes reduced immediately or gradually to 0.04 mg nicotine/g of tobacco during a 20-week study period. Participants completed the modified Cigarette Evaluation Questionnaire (mCEQ). RESULTS: After Week 20, the immediate reduction group scored significantly lower than the gradual reduction group on multiple subscales of the mCEQ (ps < .001). The Satisfaction subscale of the mCEQ mediated the impact of nicotine reduction method on smoke exposure, smoking behavior, dependence, compliance, and abstinence. Other subscales also mediated a subset of these outcomes. CONCLUSIONS: An immediate reduction in nicotine content resulted in lower product satisfaction than a gradual reduction, suggesting that immediate reduction further reduces cigarette reward value. This study will provide the Food and Drug Administration with information about the impact of nicotine reduction method on cigarette reward value. IMPLICATIONS: These data suggest that an immediate reduction in nicotine content will result in greater reductions in cigarette satisfaction than a gradual reduction, and this reduction in satisfaction is related to changes in smoking behavior and dependence.

Randomized Trial of Reduced-Nicotine Standards for Cigarettes.

BACKGROUND: The Food and Drug Administration can set standards that reduce the nicotine content of cigarettes. METHODS: We conducted a double-blind, parallel, randomized clinical trial between June 2013 and July 2014 at 10 sites. Eligibility criteria included an age of 18 years or older, smoking of five or more cigarettes per day, and no current interest in quitting smoking. Participants were randomly assigned to smoke for 6 weeks either their usual brand of cigarettes or one of six types of investigational cigarettes, provided free. The investigational cigarettes had nicotine content ranging from 15.8 mg per gram of tobacco (typical of commercial brands) to 0.4 mg per gram. The primary outcome was the number of cigarettes smoked per day during week 6. RESULTS: A total of 840 participants underwent randomization, and 780 completed the 6-week study. During week 6, the average number of cigarettes smoked per day was lower for participants randomly assigned to cigarettes containing 2.4, 1.3, or 0.4 mg of nicotine per gram of tobacco (16.5, 16.3, and 14.9 cigarettes, respectively) than for participants randomly assigned to their usual brand or to cigarettes containing 15.8 mg per gram (22.2 and 21.3 cigarettes, respectively; P<0.001). Participants assigned to cigarettes with 5.2 mg per gram smoked an average of 20.8 cigarettes per day, which did not differ significantly from the average number among those who smoked control cigarettes. Cigarettes with lower nicotine content, as compared with control cigarettes, reduced exposure to and dependence on nicotine, as well as craving during abstinence from smoking, without significantly increasing the expired carbon monoxide level or total puff volume, suggesting minimal compensation. Adverse events were generally mild and similar among groups. CONCLUSIONS: In this 6-week study, reduced-nicotine cigarettes versus standard-nicotine cigarettes reduced nicotine exposure and dependence and the number of cigarettes smoked. (Funded by the National Institute on Drug Abuse and the Food and Drug Administration Center for Tobacco Products; ClinicalTrials.gov number, NCT01681875.).

Perceived nicotine content of reduced nicotine content cigarettes is a correlate of perceived health risks.

BACKGROUND: Reducing cigarette nicotine content may reduce smoking. Studies suggest that smokers believe that nicotine plays a role in smoking-related morbidity. This may lead smokers to assume that reduced nicotine means reduced risk, and attenuate potential positive effects on smoking behaviour. METHODS: Data came from a multisite randomised trial in which smokers were assigned to use cigarettes varying in nicotine content for 6 weeks. We evaluated associations between perceived and actual nicotine content with perceived health risks using linear regression, and associations between perceived nicotine content and perceived health risks with smoking outcomes using linear and logistic regression. FINDINGS: Perceived-not actual-nicotine content was associated with perceived health risks; compared with those perceiving very low nicotine, individuals who perceived low (ß=0.72, 95% CI 0.26 to 1.17), moderate (ß=1.02, 95% CI 0.51 to 1.53) or high/very high nicotine (ß=1.66, 95% CI 0.87 to 2.44) perceived greater health risks. Nevertheless, individuals perceiving low (OR=0.48, 95% CI 0.32 to 0.71) or moderate nicotine (OR=0.42, 95% CI 0.27 to 0.66) were less likely than those perceiving very low nicotine to report that they would quit within 1 year if only investigational cigarettes were available. Lower perceived risk of developing other cancers and heart disease was also associated with fewer cigarettes/day at week 6. CONCLUSIONS: Although the perception of reduced nicotine is associated with a reduction in perceived harm, it may not attenuate the anticipated beneficial effects on smoking behaviour. These findings have implications for potential product standards targeting nicotine and highlight the need to clarify the persistent harms of reduced nicotine combusted tobacco products.

Cannabis and cannabinoid drug development: evaluating botanical versus single molecule approaches.

Accumulating evidence suggests that the endocannabinoid system is a promising target for the treatment of a variety of health conditions. Two paths of cannabinoid drug development have emerged. One approach is focused on developing medications that are directly derived from the cannabis plant. The other utilizes a single molecule approach whereby individual phytocannabinoids or novel cannabinoids with therapeutic potential are identified and synthesized for pharmaceutical development. This commentary discusses the unique challenges and merits of botanical vs single molecule cannabinoid drug development strategies, highlights how both can be impacted by legalization of cannabis via legislative processes, and also addresses regulatory and public health considerations that are important to consider as cannabinoid medicine advances as a discipline.

Effect of Immediate vs Gradual Reduction in Nicotine Content of Cigarettes on Biomarkers of Smoke Exposure: A Randomized Clinical Trial.

Importance: The optimal temporal approach for reducing nicotine to minimally or nonaddictive levels in all cigarettes sold in the United States has not been determined. Objectives: To determine the effects of immediate vs gradual reduction in nicotine content to very low levels and as compared with usual nicotine level cigarettes on biomarkers of toxicant exposure. Design, Setting, and Participants: A double-blind, randomized, parallel-design study with 2 weeks of baseline smoking and 20 weeks of intervention was conducted at 10 US sites. A volunteer sample of daily smokers with no intention to quit within 30 days was recruited between July 2014 and September 2016, with the last follow-up completed in March 2017. Interventions: (1) Immediate reduction to 0.4 mg of nicotine per gram of tobacco cigarettes; (2) gradual reduction from 15.5 mg to 0.4 mg of nicotine per gram of tobacco cigarettes with 5 monthly dose changes; or (3) maintenance on 15.5 mg of nicotine per gram of tobacco cigarettes. Main Outcomes and Measures: Between-group differences in 3 co-primary biomarkers of smoke toxicant exposure: breath carbon monoxide (CO), urine 3-hydroxypropylmercapturic acid (3-HPMA, metabolite of acrolein), and urine phenanthrene tetraol (PheT, indicator of polycyclic aromatic hydrocarbons) calculated as area under the concentration-time curve over the 20 weeks of intervention. Results: Among 1250 randomized participants (mean age, 45 years; 549 women [44%]; 958 [77%] completed the trial), significantly lower levels of exposure were observed in the immediate vs gradual reduction group for CO (mean difference, -4.06 parts per million [ppm] [95% CI, -4.89 to -3.23]; P < .0055), 3-HPMA (ratio of geometric means, 0.83 [95% CI, 0.77 to 0.88]; P < .0055), and PheT (ratio of geometric means, 0.88 [95% CI, 0.83 to 0.93]; P < .0055). Significantly lower levels of exposure were observed in the immediate reduction vs control group for CO (mean difference, -3.38 [95% CI, -4.40 to -2.36]; P < .0055), 3-HPMA (ratio of geometric means, 0.81 [95% CI, 0.75 to 0.88]; P < .0055), and PheT (ratio of geometric means, 0.86 [95% CI, 0.81 to 0.92]; P < .0055). No significant differences were observed between the gradual reduction vs control groups for CO (mean difference, 0.68 [95% CI, -0.31 to 1.67]; P = .18), 3-HPMA (ratio of geometric means, 0.98 [95% CI, 0.91 to 1.06]; P = .64), and PheT (ratio of geometric means, 0.98 [95% CI, 0.92 to 1.04]; P = .52). Conclusions and Relevance: Among smokers, immediate reduction of nicotine in cigarettes led to significantly greater decreases in biomarkers of smoke exposure across time compared with gradual reduction or a control group, with no significant differences between gradual reduction and control. Trial Registration: clinicaltrials.gov Identifier: NCT02139930.

Effects of 6-Week Use of Reduced-Nicotine Content Cigarettes in Smokers With and Without Elevated Depressive Symptoms.

BACKGROUND: The FDA recently acquired regulatory authority over tobacco products, leading to renewed interest in whether reducing the nicotine content of cigarettes would reduce tobacco dependence in the United States. Given the association between depressive symptoms and cigarette smoking, it is important to consider whether smokers with elevated depressive symptoms experience unique benefits or negative consequences of nicotine reduction. METHODS: In this secondary analysis of a randomized clinical trial that examined the effects of cigarettes varying in nicotine content over a 6-week period in non-treatment-seeking smokers, we used linear regression to examine whether baseline depressive symptom severity (scores on the Center for Epidemiologic Studies Depression Scale [CES-D]) moderated the effects of reduced-nicotine content (RNC) cigarettes, relative to normal-nicotine content (NNC) cigarettes, on smoking rates, depressive symptom severity, and related subjective and physiological measures. RESULTS: Of the 717 participants included in this analysis, 109 (15.2%) had CES-D scores ≥ 16, indicative of possible clinical depression. Relative to NNC cigarettes, RNC cigarettes reduced smoking rates, nicotine dependence, and cigarette craving, and these effects were not significantly moderated by baseline CES-D score. A significant interaction between baseline CES-D score and cigarette condition on week 6 CES-D score was observed (p < .05); among those with CES-D scores ≥ 16 at baseline, those assigned to RNC cigarettes had lower week 6 CES-D scores than those assigned to NNC cigarettes. Among those in the lowest nicotine content conditions, biochemically confirmed compliance with the RNC cigarettes was associated with an increase in CES-D score for those with baseline CES-D scores < 16 and no change in CES-D score for those with baseline CES-D scores ≥ 16. CONCLUSIONS: These findings provide initial evidence that a reduced-nicotine standard for cigarettes may reduce smoking, without worsening depressive symptoms, among smokers with elevated depressive symptoms. IMPLICATIONS: This secondary analysis of a recent clinical trial examined whether depressive symptom severity moderated the effects of reduced-nicotine cigarettes on smoking and depressive symptoms. Results indicate that, regardless of baseline depressive symptoms, participants randomized to reduced-nicotine cigarettes had lower smoking rates, nicotine intake, nicotine dependence, and craving at week 6 post-randomization than those assigned to normal-nicotine cigarettes. In participants with higher baseline depressive symptoms, those assigned to reduced-nicotine cigarettes had lower week 6 depressive symptoms than those assigned to normal-nicotine cigarettes. These results suggest that a nicotine reduction policy could have beneficial effects for smokers, regardless of depressive symptom severity.

Reducing nicotine exposure results in weight gain in smokers randomised to very low nicotine content cigarettes.

BACKGROUND: The Food and Drug Administration can reduce the nicotine content in cigarettes to very low levels. This potential regulatory action is hypothesised to improve public health by reducing smoking, but may have unintended consequences related to weight gain. METHODS: Weight gain was evaluated from a double-blind, parallel, randomised clinical trial of 839 participants assigned to smoke 1 of 6 investigational cigarettes with nicotine content ranging from 0.4 to 15.8 mg/g or their own usual brand for 6 weeks. Additional analyses evaluated weight gain in the lowest nicotine content cigarette groups (0.4 and 0.4 mg/g, high tar) to examine the effect of study product in compliant participants as assessed by urinary biomarkers. Differences in outcomes due to gender were also explored. FINDINGS: There were no significant differences in weight gain when comparing the reduced nicotine conditions with the 15.8 mg/g control group across all treatment groups and weeks. However, weight gain at week 6 was negatively correlated with nicotine exposure in the 2 lowest nicotine content cigarette conditions. Within the 2 lowest nicotine content cigarette conditions, male and female smokers biochemically verified to be compliant on study product gained significantly more weight than non-compliant smokers and control groups. CONCLUSIONS: The effect of random assignment to investigational cigarettes with reduced nicotine on weight gain was likely obscured by non-compliance with study product. Men and women who were compliant in the lowest nicotine content cigarette conditions gained 1.2 kg over 6 weeks, indicating weight gain is a likely consequence of reduced exposure to nicotine. TRIAL REGISTRATION NUMBER: NCT01681875, Post-results.

The Impact of Smoking Very Low Nicotine Content Cigarettes on Alcohol Use.

BACKGROUND: Reducing the nicotine content in cigarettes could improve public health by reducing smoking and toxicant exposure, but may also have unintended consequences on alcohol use. The primary objective of this study was to examine the effect of reducing the nicotine content in cigarettes on alcohol outcomes. The secondary aim was to examine whether the effects of these cigarettes on alcohol outcomes were mediated by changes in nicotine exposure, smoking behavior, or withdrawal. METHODS: Between June 2013 and July 2014, we conducted a 7-arm, double-blind, randomized clinical trial at 10 U.S.-based sites. Daily smokers not currently interested in quitting (n = 839) were assigned to equally sized groups to smoke for 6 weeks cigarettes containing either normal nicotine content (NNC; 15.8 mg/g, 9 mg tar), moderate nicotine content (5.2 mg/g nicotine, 9 mg tar), or very low nicotine content (VLNC; 0.4 to 2.4 mg/g, 9 to 13 mg tar). This investigation focused on a subsample of current drinkers (n = 403). Each reduced nicotine content cigarette condition was compared to the NNC control condition with respect to trajectories over the 6-week period of average daily alcohol use and occurrence of binge drinking. Moderating variables were considered. Mediation analyses tested potential explanatory processes including changes in nicotine exposure, cigarettes per day, and withdrawal. RESULTS: Over time, reduced nicotine exposure and smoking rate mediated effects of VLNC cigarette use on reduced alcohol use. There was no evidence of compensatory drinking in response to nicotine reduction or nicotine withdrawal, even among subgroups expected to be at greater risk (e.g., relatively heavier drinkers, highly nicotine-dependent individuals). CONCLUSIONS: The findings suggest that compensatory drinking is unlikely to occur in response to switching to VLNC cigarettes. In contrast, reducing the nicotine content of cigarettes may reduce alcohol use (clinicalTrials.gov number, NCT01681875).

Zonisamide Reduces Withdrawal Symptoms But Does Not Enhance Varenicline-Induced Smoking Cessation.

INTRODUCTION: Varenicline (Chantix) is a first-line treatment for smoking cessation but does not produce cessation in many individuals. It may be possible to improve abstinence by co-administering varenicline with other medications. Zonisamide (Zonegran) has a similar pharmacologic profile to topiramate, which has been shown to reduce smoking, but is better tolerated. This study evaluated whether combined zonisamide and varenicline reduced tobacco withdrawal and increased abstinence among smokers trying to quit, relative to varenicline and placebo. METHODS: This was a double-blind, randomized, placebo-controlled pilot trial of zonisamide + varenicline versus placebo + varenicline for smoking cessation. Smokers received brief counseling and study medications, and completed weekly assessments for 10 consecutive weeks. The primary outcome was continuous abstinence rates (biochemically verified) during the final 4 weeks of treatment. RESULTS: Results are presented as intent-to-treat and completer analyses. Seventy-four individuals were enrolled; 45 completed the study. Overall, 14.9% (intent-to-treat) and 25.0% (completer) of participants maintained sustained abstinence during the final 4 weeks of treatment. There were no differences between groups for biochemically-verified smoking, but zonisamide + varenicline reduced self-reported smoking, nicotine withdrawal, and craving compared to placebo + varenicline. CONCLUSIONS: Zonisamide decreased nicotine withdrawal and craving, though not of sufficient magnitude to modify smoking behavior. The sample size was small and low rates of abstinence across groups suggest the study population was difficult to treat. Additional evaluation of zonisamide or other medications that increase GABA or decrease glutamate in larger or more diverse populations may yield positive clinical benefit for nicotine/tobacco cessation. IMPLICATIONS: This study provides support for layering novel medications with varenicline for smoking cessation, for investigating medications that target the GABA and glutamate system, and for assessing the contribution that reductions in nicotine withdrawal have on ultimate cessation outcomes.