Impact of E-cigarettes on Smoking and Related Outcomes in Veteran Smokers With Psychiatric Comorbidity.

OBJECTIVE: Compared to the general U.S. population, smokers with comorbid psychiatric and/or substance use disorders have lower quit rates after evidence-based treatments and disproportionately high smoking-related deaths. Improved modalities for reducing tobacco-related harm in this subpopulation are needed. Because electronic cigarettes (e-cigarettes) can now deliver physiologically relevant levels of nicotine to consumers, they represent an additional nicotine delivery system that could be used in cessation interventions. While current data suggest that the use of e-cigarettes by smokers promotes a reduction in combustible cigarette use, smoking quit rates through use of e-cigarettes appears to be low. The goal of this study was to examine impact of e-cigarette use on combustible tobacco use as well as on the readiness to quit smoking and changes in nicotine dependence in a multimorbid population. METHODS: We conducted a 4-week, open-label study in 43 military veteran smokers who had no immediate intention to stop smoking and were currently receiving psychiatric services from the Department of Veterans Affairs health care system. Participants were provided with a study e-cigarette they could use ad libitum along with other tobacco products and were encouraged to attend weekly laboratory visits and a one-month follow-up visit. Main outcome measures were number of cigarettes smoked per day (CPD), the frequency of e-cigarette use, the amount of money spent on combustible cigarettes (U.S. dollars/week), alveolar carbon monoxide (CO) levels, and urine cotinine levels. RESULTS: Mean e-cigarette use was 5.7 days per week and only 9% of participants used the e-cigarette for fewer than 4 days per week. Significant reductions in breath CO (9.3 ppm to 7.3 ppm, p < .02) and CPD (from 16.6 to 5.7, p < .001) were observed across study weeks, and no serious adverse events were reported. Three participants (10% of completers) reported smoking cessation that was corroborated biochemically. At one-month follow-up, motivation to quit smoking remained significantly higher and the level of nicotine dependence was significantly lower than at baseline. CONCLUSIONS: E-cigarettes are acceptable to smokers with psychiatric comorbidities, as indicated by sustained and frequent e-cigarette use by 90% of participants, and may promote reduction and/or cessation of combustible cigarette use. E-cigarettes appear to be a viable harm reduction modality in smokers with psychiatric comorbidities.

Inhalation of Alcohol Vapor: Measurement and Implications.

Decades of alcohol research have established the health risks and pharmacodynamic profile of oral alcohol consumption. Despite isolated periods of public health concern, comparatively less research has evaluated exposure to alcohol vapor. Inhaled alcohol initially bypasses first-pass metabolism and rapidly reaches the arterial circulation and the brain, suggesting that this route of administration may be associated with pharmacological effects that increase the risk of addiction. However, detailed reviews assessing the possible effects of inhaled alcohol in humans are lacking. A comprehensive, systematic literature review was conducted using Google Scholar and PubMed to examine manuscripts studying exposure to inhaled alcohol and measurement of biomarkers (biochemical or functional) associated with alcohol consumption in human participants. Twenty-one publications reported on alcohol inhalation. Fourteen studies examined inhalation of alcohol vapor associated with occupational exposure (e.g., hand sanitizer) in a variety of settings (e.g., naturalistic, laboratory). Six publications measured inhalation of alcohol in a controlled laboratory chamber, and 1 evaluated direct inhalation of an e-cigarette with ethanol-containing "e-liquid." Some studies have reported that inhalation of alcohol vapor results in measurable biomarkers of acute alcohol exposure, most notably ethyl glucuronide. Despite the lack of significantly elevated blood alcohol concentrations, the behavioral consequences and subjective effects associated with repeated use of devices capable of delivering alcohol vapor are yet to be determined. No studies have focused on vulnerable populations, such as adolescents or individuals with alcohol use disorder, who may be most at risk of problems associated with alcohol inhalation.

The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [(1)H]-MRS.

The NMDA receptor antagonist ketamine can induce a rapid improvement in depressive symptoms that often endures for days after a single intravenous dose. The pharmacodynamic basis for this effect is poorly understood. Using a proton magnetic resonance spectroscopy ([(1)H]-MRS) method that previously detected a normalization of amino acid neurotransmitter (AANt) content after chronic treatment with conventional antidepressant treatments, we examined whether the acute action of ketamine is associated with alterations in AANt content as well. Ten subjects with major depressive disorder (MDD) received saline, then ketamine in a fixed order, one week apart, under single-blind conditions. Each infusion was associated with three [(1)H] MRS scans (baseline, 3h and 48 h post-infusion) that measured glutamate, GABA and glutamine within the occipital cortex. Rating scales were administered before, during and after each infusion. The rapid (1h) and sustained (at least 7 days) antidepressant effect we observed after ketamine infusion was not associated with either baseline measures of, or changes in, occipital AANt content. Dissociative symptoms were not correlated with changes in depression scores. While our results indicate that changes in occipital AANt content are not a correlate of ketamine's antidepressant action, this may only apply to the regional and temporal windows of our MRS measurements.

Acute effects of inhaled menthol on the rewarding effects of intravenous nicotine in smokers.

OBJECTIVE: This double-blind, placebo controlled study examined whether menthol inhaled from an electronic cigarette (e-cigarette) would change subjective and withdrawal alleviating effects of intravenous nicotine in young adult smokers. METHODS: A total of 32 menthol-preferring smokers and 25 non-menthol-preferring smokers participated in the study that consisted of a random sequence of three different inhaled menthol conditions (0.0%, 0.5%, and 3.2%) across three test sessions (a single menthol condition per session). In each test session (performed at least 24 hours apart), a random order of saline, and two different nicotine infusions of 0.25 mg and 0.5 mg/70 kg of bodyweight were administered, one hour apart, concurrent with menthol inhalation. RESULTS: While menthol did not alter the positive subjective effects of nicotine, menthol significantly enhanced aversive effects of nicotine in non-menthol-preferring smokers and reduced smoking urges in menthol-preferring smokers. In addition, menthol-preferring smokers reported blunted positive subjective responses to nicotine and less severe nicotine withdrawal after overnight nicotine deprivation. Finally, compared to non-menthol-preferring smokers, menthol-preferring smokers had a significantly lower baseline nicotine metabolite ratio indicating slower nicotine metabolism within our sample of menthol-preferring smokers. CONCLUSIONS: Our findings did not support an enhancement of nicotine's positive subjective effects from inhaled menthol. However, as compared to non-menthol-preferring smokers, menthol-preferring smokers had blunted positive subjective responses to nicotine and reduced overnight withdrawal severity that may be partly due to inhibition of nicotine metabolism from chronic exposure to inhaled menthol. Collectively, these results reveal a more complex and nuanced role of inhaled menthol in smokers than previously recognized.

Chronic unpredictable stress decreases cell proliferation in the cerebral cortex of the adult rat.

BACKGROUND: One of the most consistent morphologic findings in postmortem studies of brain tissue from depressed patients is a decrease in the number of glia in the prefrontal cortex. However, little is known about the mechanisms that contribute to this decrease in cell number. METHODS: To address this question, we subjected adult rats to chronic stress, a vulnerability factor for depression, and measured cell proliferation as a potential cellular mechanism that could underlie glial reduction in depression. RESULTS: We found that exposure to chronic unpredictable stress (CUS) for 15 days significantly decreased cell proliferation in neocortex by approximately 35%. This effect was dependent on the duration, intensity and type of stress, and was region-specific. Analysis of cell phenotype demonstrated that there was a decrease in the number of oligodendrocytes and endothelial cells. Finally, using a CUS paradigm that allows for analysis of anhedonia, we found that chronic antidepressant administration reversed the decrease in cortical cell proliferation, as well as the deficit in sucrose preference. CONCLUSION: These findings are consistent with the possibility that decreased cell proliferation could contribute to reductions in glia in prefrontal cortex of depressed subjects and further elucidate the cellular actions of stress and antidepressants.

Effect of Menthol-preferring Status on Response to Intravenous Nicotine.

OBJECTIVES: Menthol, a flavoring agent, is found in approximately 90% of cigarettes, but at much higher levels in menthol than non-menthol cigarettes. Menthol is reportedly included in cigarettes for its cooling and soothing effects, but also additional actions that affect smokers' receipt and processing of nicotine. In this study we investigated the response to short-term abstinence and acute nicotine delivery in menthol-preferring and non-menthol-preferring smokers. METHODS: Nicotine dependent participants (N = 134) participated in an intravenous nicotine delivery session following overnight smoking abstinence. Participants were intravenously administered a placebo and 2 escalating nicotine doses. We compare subjective and physiological responses to nicotine and smoking urges, withdrawal, and cognitive performance following overnight abstinence and post-nicotine between regular 'menthol' smokers and 'non-menthol' cigarette smokers. RESULTS: Relative to non-menthol-preferring smokers, menthol-preferring smokers re a smaller reduction in smoking urges from overnight abstinence baseline to post-nicotine end-of-session and rated less subjective differences between nicotine doses. CONCLUSIONS: Differences between menthol-preferring and non-menthol-preferring smokers' responses to abstinence or acute nicotine could reflect pre-existing individual differences that may have in initial development of menthol preferences, or could have arisen secondarily to pro use of menthol versus non-menthol cigarettes.

The effects of alcohol-containing e-cigarettes on young adult smokers.

BACKGROUND: The liquids (e-liquids) used in an electronic cigarette (e-cigarette) contain myriad chemicals without adequate human inhalation safety data. Furthermore, the absence of e-liquid labeling requirements poses a formidable challenge to understanding how e-liquid constituents may promote nicotine addiction and/or have independent or synergistic biological effects when combined with nicotine. Ethyl alcohol is such a constituent, but has received little scientific interest in this context. METHODS: Using a randomized, double blind, crossover design, acute changes in subjective drug effects, motor performance and biochemical measures of alcohol and nicotine intake were evaluated after directed and ad lib puffing from two commercially available e-liquids containing nicotine (8 mg/ml), vanilla flavor and either 23.5% (high) or 0.4% (trace) alcohol. RESULTS: While no differences in subjective drug effects were observed between alcohol conditions, performance on the Purdue Pegboard Dexterity Test (PPDT) improved under the trace, but not under the 23.5% alcohol condition. Although plasma alcohol levels remained undetectable during testing, urine ethyl glucuronide (EtG), an alcohol metabolite, became measurable in three participants after puffing from the 23.5% alcohol e-cigarette. CONCLUSIONS: Brief use of a widely available type of e-cigarette containing an e-liquid purchased from an internet vendor can negatively impact psychomotor performance and in some instances, produce detectable levels of a urine alcohol metabolite. Given the widespread and unregulated use of e-cigarettes, especially by youth and other vulnerable populations, further studies are needed to evaluate both the acute safety and long-term health risks of using alcohol-containing e-cigarettes.

Electroconvulsive seizure treatment increases cell proliferation in rat frontal cortex.

Recent studies have demonstrated increased neurogenesis in adult hippocampus in response to electroconvulsive seizure (ECS) or antidepressant drug treatment. Adult neurogenesis in the subgranular zone of the hippocampus and the subventricular zone is well established, whereas neuronal proliferation outside of these areas under unstimulated conditions is not observed. Since mood disorders are likely to involve brain regions in addition to hippocampus, particularly the frontal cortex, it is likely that antidepressant treatments produce cellular changes in these brain regions as well. In this study, we have investigated the effect of repeated ECS administration on the proliferation of cells in the frontal cortex, and we have examined the phenotype of these cells 4 weeks after labeling with a cell division marker. We found that ECS treatment increases the number of newly divided cells in the frontal cortex and that these new cells express markers of either endothelial cells or oligodendrocytes, but not neurons. It is possible that increased proliferation of these cell types in the frontal cortex could reverse the loss of glial cell number and the reduced volume that has been reported in the frontal cortex of depressed patients.

A CHRNA5 Smoking Risk Variant Decreases the Aversive Effects of Nicotine in Humans.

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.

Subjective, physiological, and cognitive responses to intravenous nicotine: effects of sex and menstrual cycle phase.

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.

Cortical GABA levels in primary insomnia.

STUDY OBJECTIVES: GABA is increasingly recognized as an important neurotransmitter for the initiation and maintenance of sleep. We sought to measure cortical GABA content through proton magnetic resonance spectroscopy (MRS) in persons with and without primary insomnia, and relate brain GABA levels to polysomnographic sleep measures. DESIGN: Two-group comparison study. SETTING: Outpatient study at a university research clinic. PARTICIPANTS: Non-medicated persons with primary insomnia (N = 16) and no sleep complaints (N = 17). INTERVENTIONS: Participants kept sleep diaries and a regular time-in-bed schedule for 9 days, culminating in 2 consecutive nights of ambulatory polysomnography and a single proton MRS session. The main outcome measure was occipital GABA/creatine ratios; secondary measures included sleep measurements and relationship between polysomnographically measured time awake after sleep onset and occipital GABA content. MEASUREMENTS AND RESULTS: The primary insomnia group was distinguished from persons with no sleep complaints on self-reported and polysomnographically measured sleep. The two groups did not differ in age, sex, body mass index, habitual bed- and wake-times, napping, use of caffeine, or use of cigarettes. Mean occipital GABA level was 12% higher in persons with insomnia than in persons without sleep complaints (P < 0.05). In both groups, GABA levels correlated negatively with polysomnographically measured time awake after sleep onset (P < 0.05). CONCLUSIONS: Increased GABA levels in persons with insomnia may reflect an allostatic response to chronic hyperarousal. The preserved, negative relationship between GABA and time awake after sleep onset supports this notion, indicating that the possible allostatic response is adaptive.

Targeting glial physiology and glutamate cycling in the treatment of depression.

Accumulating evidence indicates that dysfunction in amino acid neurotransmission contributes to the pathophysiology of depression. Consequently, the modulation of amino acid neurotransmission represents a new strategy for antidepressant development. While glutamate receptor ligands are known to have antidepressant effects, mechanisms regulating glutamate cycling and metabolism may be viable drug targets as well. In particular, excitatory amino acid transporters (EAATs) that are embedded in glial processes constitute the primary means of clearing extrasynaptic glutamate. Therefore, the decreased glial number observed in preclinical stress models, and in postmortem tissue from depressed patients provides intriguing, yet indirect evidence for a role of disrupted glutamate homeostasis in the pathophysiology of depression. More direct evidence for this hypothesis comes from studies using magnetic resonance spectroscopy (MRS), a technique that non-invasively measures in vivo concentrations of glutamate and other amino acids under different experimental conditions. Furthermore, when combined with the infusion of (13)C-labeled metabolic precursors, MRS can measure flux through discrete metabolic pathways. This approach has recently shown that glial amino acid metabolism is reduced by chronic stress, an effect that provides a link between environmental stress and the decreased EAAT activity observed under conditions of increased oxidative stress in the brain. Furthermore, administration of riluzole, a drug that enhances glutamate uptake through EAATs, reversed this stress-induced change in glial metabolism. Because riluzole has antidepressant effects in both animal models and human subjects, it may represent the prototype for a novel class of antidepressants with the modulation of glial physiology as a primary mechanism of action.