Little is known about how electronic cigarette (EC) users manipulate device parameters, what factors drive their use, and how non-nicotine ingredients influence the stimulus effects of EC aerosols. The ingredients propylene glycol (PG) or vegetable glycerin (VG) serve as the base for virtually all electronic cigarette liquids, and information on how they affect the using experience would provide important groundwork for the study of other ingredients. In this dissertation, results from a survey and laboratory study focused on the stimulus effects of ECs, and the influence of PG and VG, will be discussed. A total of 522 regular EC users completed a survey comprised of an electronic cigarette dependence questionnaire, questions on tobacco and electronic cigarette use, and device and liquid preferences. This was followed by a laboratory study with sixteen electronic cigarette users completing five test days (one practice and four assessment days). In the laboratory study, following one hour of nicotine deprivation, two sampling puffs from liquid formulations containing 100/0, 75/25, 50/50, 25/75, and 0/100% PG/VG concentrations were administered in random order during five assessments, each separated by 20 min. Primary outcome measures were self-reported stimulus characteristics and breakpoint on a multiple-choice procedure. Survey results indicated that ability to change device voltage, and level of resistance, was significantly associated with level of nicotine dependence, as was amount of liquid consumed, nicotine concentration, and milligrams of nicotine used per week. Participants also rated 'good taste' as the most important consideration when purchasing and using liquids, and PG was associated with undesirable effects and VG with desirable effects. Laboratory results indicated that greater VG content was associated with greater reports of visibility of the exhalant (i.e. “cloud”). Liquids with mixtures of PG or VG were associated with conventional cigarette smoking sensations and greater reductions of systolic blood pressure compared to formulations with only PG or VG. There was no significant effect of liquid formulation on the multiple-choice procedure, but puffs were rarely chosen over even the smallest monetary option ($0.05), suggesting minimal reinforcing efficacy. In conclusion, survey data indicate that a wide range device parameter settings and liquid ingredients are preferred by daily e-cigarette users, and that individuals with greater nicotine dependence favor voltage control devices, and lower resistance heating elements. Survey data also indicated that taste is a key factor for EC liquid selection, and relative concentrations of propylene glycol and vegetable glycerin may have a significant impact on the reinforcing effects of liquids. In contrast, laboratory data suggests that PG or VG do not significantly impact the abuse liability of EC liquids, though reinforcing effects of these ingredients was unclear in the laboratory study.

Little is currently known about the ability of electronic cigarettes to manage tobacco withdrawal symptoms and their abuse liability. In the current study eight conventional cigarette smokers completed nine within-subject study sessions. In the first session participants practiced using an electronic cigarette containing 16 mg/ml of nicotine over six 10-puff bouts. Remaining study sessions were comprised of four two-day blocks (one for each condition), which assessed measures of tobacco withdrawal symptoms and abuse liability following unrestricted cigarette smoking and 24-hour tobacco deprivation. Study conditions included an electronic cigarette with 0, 8, or 16 mg/ml nicotine concentrations, or preferred brand of conventional cigarette. Following 24-hours of tobacco deprivation, smoking conventional cigarettes ameliorated many of the self-report and physiological symptoms (decreased heart rate) associated with tobacco deprivation, while no attenuation of withdrawal symptoms was indicated following using electronic cigarettes, independent of nicotine dose. On abuse liability measures there were no significant changes following using an electronic cigarette (regardless of nicotine concentration), while conventional cigarettes engendered significant changes on abuse liability measures. Within the conditions of this study, first-generation electronic cigarettes had no measurable efficacy in ameliorating tobacco withdrawal symptoms and a reduced abuse liability compared to conventional tobacco cigarettes.

The noncompetitive NMDA receptor antagonist ketamine produces rapid and sustained antidepressant effects in patients suffering from major depressive disorder. However, abuse liability is a concern. To further evaluate the relationship between antidepressant-like and abuse-related effects of NMDA receptor antagonists, this study evaluated the effects of ketamine, MK-801, and phencyclidine in male Sprague-Dawley rats responding under two procedures that have been used to assess antidepressant-like effects [differential-reinforcement-of-low-rate (DRL) 72 s schedule of food reinforcement] and abuse-related drug effects [intracranial self-stimulation (ICSS)]. Under DRL 72 s, ketamine produced an antidepressant-like effect by increasing reinforcers, decreasing responses, and producing a rightward shift in the peak location of the interresponse time (IRT) distributions. Phencyclidine produced a modest antidepressant-like effect by increasing reinforcers and decreasing responses, but did not shift the IRT distributions. In contrast, MK-801 produced a psychostimulant-like effect by decreasing reinforcers, increasing responses, and producing a leftward shift in the peak location of the IRT distributions. The antidepressant-like effects of ketamine on the DRL 72 s procedure do not appear to be mediated by inhibiting the reuptake of serotonin via serotonin transporters or antagonism of 5-HT2 receptors. Additionally, the dissociable effects of ketamine and MK-801 in the DRL 72 s procedure may be mediated by 5-HT2 receptors. Following acute administration, ketamine produced only dose- and time-dependent depression of ICSS and failed to produce an abuse-related facilitation of ICSS at any dose or pretreatment time. Repeated dosing with ketamine produced dose-dependent tolerance to the rate-decreasing effects of ketamine but failed to unmask expression of ICSS facilitation. Termination of ketamine treatment failed to produce withdrawal-associated decreases in ICSS. In contrast, MK-801 and phencyclidine effects produced dose- and time-dependent facilitation of ICSS by MK-801. Taken together, our findings provide further evidence that expression of these antidepressant-like and abuse-related effects of ketamine, phencyclidine, and MK-801 may be related to NMDA receptor affinity.

Electronic cigarettes have grown in popularity across the U.S. and concerns have been raised about their abuse liability. The purpose of the current study was to evaluate and compare the abuse liability of an electronic cigarette with and without nicotine to a nicotine inhaler (the Nicotrol inhaler) and participants’ own brand of cigarettes. A total of 24 smokers attended four sessions in which the abuse liability of each product was examined using the Multiple-Choice Procedure (MCP), nicotine delivery, nicotine abstinence symptom suppression, and subjective reinforcing effects. Results revealed that the nicotine containing and non-nicotine containing electronic cigarette had a higher reinforcing efficacy on the MCP than the nicotine inhaler, but on average had a lower reinforcing efficacy than participants own brand of cigarettes. The nicotine containing electronic cigarette delivered nicotine to participants in amounts that did not differ significantly from participants’ own brand of cigarettes. The electronic cigarette with nicotine reduced nicotine abstinence symptoms to a greater degree than the electronic cigarette without nicotine, and both electronic cigarettes were rated as subjectively more reinforcing than the inhaler but less reinforcing than participants’ own brand of cigarettes. In sum, the results from this study suggest that the electronic cigarette examined had a moderate level of abuse liability that was higher than an FDA-approved nicotine inhaler but lower than traditional cigarettes. Furthermore, findings also suggest that electronic cigarette abuse liability may extend beyond factors related to nicotine delivery.

Rationale: Nicotine is the addictive component in cigarettes which maintains cigarette smoking that subsequently leads to morbidity and mortality. There are growing regulatory efforts to lower the nicotine content in cigarettes so that they are minimally addictive. Valid methods for assessing the abuse liability of cigarettes are essential to these efforts. While subjective effect measures and hypothetical purchase tasks are appealing because they are far easier to administer, it is unclear whether these methods can be used to evaluate acute relative reinforcing, a critical component of abuse liability. This secondary analysis sought to evaluate the utility of one subjective effects measure, the modified Cigarette Evaluation Questionnaire (mCEQ), and one hypothetical purchase task, the Cigarette Purchase Task (CPT), for predicting acute relative reinforcing efficacy as measured by concurrent choice Self-Administration (SA) Method: Current smokers (N=169) belonging to one of three vulnerable populations (socioeconomically disadvantaged women of childbearing age, opioid-maintained individuals, or individuals with affective disorders) participated in a multi-site, double blind study evaluating research cigarettes with varying levels of nicotine content (0.4, 2.4, 5.2, 15.8 mg/g). In Phase 1 (4 sessions, 1 research cigarette per session) participants completed the mCEQ and CPT following ad-lib smoking of the research cigarette. In Phase II (6 sessions) cigarette preference was assessed using two-dose concurrent choice tests. Difference scores were calculated for each of the five mCEQ subscales and five CPT indices for all six possible dose comparisons evaluated in Phase II. We evaluated the utility of the mCEQ subscale and CPT index difference scores for predicting preference for the higher dose in a given dose comparison using a mixed-model of repeated measures analysis of variance. Finally, we used stepwise regressions to determine which subscales and indices served as independent predictors of concurrent choice SA. Results: Among mCEQ subscales, higher Satisfaction and Enjoyment of Respiratory Tract Sensation were independently predictive of higher dose preference in the choice testing regardless of dose comparison. There was a significant Satisfaction X Vulnerable Population interaction where increases in Satisfaction difference scores corresponded to greater changes in higher dose preference among socioeconomically disadvantaged women of childbearing age compared to other Vulnerable Populations. Among CPT indices, Elasticity was the only independent predictor of choice. However, there was a significant Elasticity X Dose Comparison X Vulnerable Population interaction associated with its predictive utility where the relationship between elasticity and choice differed by dose among opioid-maintained individuals. In a final model, including all subscales and indices, Satisfaction and Enjoyment of Respiratory Tract Sensations remained the only significant predictors of choice. Discussion: Concurrent choice testing, subjective effects and hypothetical purchase tasks capture some common features of abuse liability. Concurrent choice testing and the Satisfaction subscale were the most concordant measures. The observation that CPT indices are not robust predictors of choice in a concurrent arrangement suggests this measure may have greater utility for capturing individual differences as opposed to isolating the acute relative reinforcing effects of nicotine. Nevertheless, all three measures can contribute to efforts to assess the abuse liability of cigarettes varying in nicotine dose and important work aimed at regulating these products to improve human health.

Drugs of abuse have a long history in humanity. Currently however, a subject of great interest is the phenylalkylamine family of drugs. Not only is the abuse liability of interest but also the potential therapeutic expansion of the capabilities of this family of drugs by utilizing the unique stereospecific effects of the newly discovered hybrid compounds. Based upon prior data of N-Alkyl 4-MA the enantiomers of N-Methyl, N-Ethyl, and N-Propyl were analyzed in hDAT, hNET, and hSERT. It was found that there was a negative correlation between chain length and potency and dopaminergic component. In agreement with the currently established paradigm it was also found that in almost all cases the S(+) enantiomer was the more potent.