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.)

Discovery of the behavioral, pharmacological, and anatomic specificity of nicotinic effects on learning, memory, and attention not only aids the understanding of nicotinic involvement in the basis of cognitive function, but also helps in the development of novel nicotinic treatments for cognitive dysfunction. Nicotinic treatments directed at specific receptor subtypes and nicotinic cotreatments with drugs affecting interacting transmitter systems may provide cognitive benefits most relevant to different syndromes of cognitive impairment such as Alzheimer's disease, schizophrenia, and attention deficit hyperactivity disorder. Further research is necessary in order to determine the efficacy and safety of nicotinic treatments of these cognitive disorders.

clinicaltrials.gov Identifier: NCT02139930.

Little is known about the reproductive effects of paternal cannabis exposure. We evaluated associations between cannabis or tetrahydrocannabinol (THC) exposure and altered DNA methylation in sperm from humans and rats, respectively. DNA methylation, measured by reduced representation bisulfite sequencing, differed in the sperm of human users from non-users by at least 10% at 3,979 CpG sites. Pathway analyses indicated Hippo Signaling and Pathways in Cancer as enriched with altered genes (Bonferroni p < 0.02). These same two pathways were also enriched with genes having altered methylation in sperm from THC-exposed versus vehicleexposed rats (p < 0.01). Data validity is supported by significant correlations between THC exposure levels in humans and methylation for 177 genes, and substantial overlap in THC target genes in rat sperm (this study) and genes previously reported as having altered methylation in the brain of rat offspring born to parents both exposed to THC during adolescence. In humans, cannabis use was also associated with significantly lower sperm concentration. Findings point to possible pre-conception paternal reproductive risks associated with cannabis use.

Smokers are highly reactive to smoking-related cues that are directly linked, or most proximal, to actual smoking behavior (e.g., lit cigarettes). However, over the course of smoking, proximal cues may not be the only stimuli to become strongly associated with smoking. Distal cues, such as the environments in which smoking occurs (e.g., bar) might also gain associative properties and come to evoke robust reactivity from smokers. To test this, a pilot study was first conducted to develop standard pictorial stimuli of smoking and nonsmoking environments, all of which were completely devoid of proximal smoking cues. A comparison set of smoking and nonsmoking proximal cues was then created. Using the 12 total pictorial cues developed, 62 adult smokers participated in a cuereactivity study during which they viewed and rated pictorial smoking and nonsmoking environment and proximal cues. Results demonstrate that, similar to proximal cues, environments associated with smoking can alone function as stimuli capable of evoking strong subjective reactivity from smokers. This work supports a broader conceptualization of drug-related cues in cue-based research and treatment development that includes proximal and distal cues as distinct categories. Keywordscraving; cue reactivity; proximal and distal stimuli; environments; smoking Cue-based research offers a wealth of information regarding how smokers respond to smokingrelated stimuli, or cues, associated with past cigarette use. Studies aimed at eliciting responses to such cues in smokers typically employ a paradigm in which smokers are exposed to smokingand nonsmoking-related stimuli through in vivo (e.g., watching someone smoke), imaginal (e.g., imagining smoking scenes), audio (e.g., hearing a description of smoking), and less commonly video (e.g., seeing a film of someone smoking), and/or pictorial (e.g., viewing pictures of smoking-related paraphernalia) stimulus modes. On balance this research has revealed that, regardless of presentation mode, smokers consistently show robust subjective

No abstract

Background Although functional brain imaging has established that individuals with unipolar major depressive disorder (MDD) are characterized by frontostriatal dysfunction during reward processing, no research to date has examined the chronometry of neural responses to rewards in euthymic individuals with a history of MDD. Method A monetary incentive delay task was used during fMRI scanning to assess neural responses in frontostriatal reward regions during reward anticipation and outcomes in 19 participants with remitted major depressive disorder (rMDD) and in 19 matched control participants. Results During the anticipation phase of the task, the rMDD group was characterized by relatively greater activation in bilateral anterior cingulate gyrus, in right midfrontal gyrus, and in the right cerebellum. During the outcome phase of the task, the rMDD group was characterized by relatively decreased activation in bilateral orbital frontal cortex, right frontal pole, left insular cortex, and left thalamus. Exploratory analyses indicated that activation within a right frontal pole cluster that differentiated groups during reward anticipation predicted the number of lifetime depressive episodes within the rMDD group. Limitations Replication with larger samples is needed. Conclusions Results suggest a double dissociation between reward network reactivity and temporal phase of the reward response in rMDD, such that rMDD is generally characterized by reward network hyperactivation during reward anticipation and reward network hypoactivation during reward outcomes. More broadly, these data suggest that aberrant frontostriatal response to rewards may potentially represent a trait marker for MDD, though future research is needed to evaluate the prospective utility of this functional neural endophenype as a marker of MDD risk.

Smoking abstinence responses were characterized in 96 female smokers. Participants completed subjective state measures twice per week for 5 weeks and were then randomly assigned to a group required to abstain for 31 days or a control group that continued to smoke. Financial incentives for biochemically verified abstinence resulted in an 81% completion rate. Abstinence-related increases in depression, tension, anger, irritability, and appetite showed little tendency to return to prequit levels and remained significantly elevated above smoke-group levels. In contrast to psychological components of anxiety, physical components decreased to smoke group levels by the 2nd week of abstinence. Trait depression and neuroticism predicted larger increased abstinence-associated negative affect. The Big Five personality dimensions predicted variance not associated with depressive traits.