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RationaleGiven that tetrahydrocannabinol (THC) and nicotine have similar effects on negative affect (NA), we hypothesized that a 7-mg nicotine patch (NP) would reduce NA-related cannabis (CAN) withdrawal symptoms in cannabis-dependent (CD) individuals who were not nicotine dependent.ObjectiveWe sought to determine whether NP reduces NA across 15 days of CAN abstinence in two groups: non-tobacco smokers (NTS) and light tobacco smokers (LTS).MethodsCD participants (N = 127; aged 18–35) who used CAN at least 5 times/week for the past 12 + months were randomized to (1) NP or (2) a placebo patch (PP) and received $300 for sustained biochemically verified CAN abstinence. Of those randomly assigned, 52 of 63 NP, and 56 of 64 PP maintained biochemically verified CAN abstinence and 51 NP and 50 PP participants complied with all aspects of the study. Affect and other withdrawal symptoms were measured every 48 h across 15 days of CAN abstinence.ResultsAfter controlling for age, tobacco use, baseline THC concentration, and baseline measurements of the dependent variable, NP reduced NA symptoms across the 15-day treatment relative to PP. Differences in NA and CAN withdrawal symptoms were not moderated by tobacco user status.ConclusionsThe findings provide the first evidence that NP may be able to attenuate NA-related withdrawal symptoms in individuals with cannabis use disorder who are not heavy users of tobacco or nicotine.Clinical trials registryNCT01400243 http://www.clinicaltrials.gov

Rationale Each year, over 300,000 individuals in the USA enter treatment for cannabis use disorder (CUD). The development of effective pharmacotherapy for CUD is a priority. Objective This placebo-controlled study examined the effects of zolpidem alone and in combination with nabilone on cannabis withdrawal and a laboratory measure of relapse. Methods Eleven daily, non-treatment-seeking cannabis users completed three, 8-day inpatient phases; each phase tested a different medication condition in counter-balanced order. On the first day of each phase, participants were administered placebo capsules t.i.d. and smoked experimenter-administered active cannabis (5.6 % Δ 9 -tetrahydrocannabinol (THC)). On days 2–8, the participants were administered capsules containing either placebo (0 mg at 0900, 1800, and 2300 hours), zolpidem (0 mg at 0900 and 1800, and 12.5 mg at 2300), or zolpidem (12.5 mg at 2300) and nabilone (3 mg at 0900 and 1800). Cannabis withdrawal, subjective capsule effects, and cognitive performance were examined on days 3–4, when only inactive cannabis (0.0 % THC) was available for self-administration. “Relapse” was measured on days 5–8, when participants could self-administer active cannabis. Results Both medication conditions decreased withdrawal-related disruptions in sleep, but only zolpidem in combination with nabilone decreased withdrawal-related disruptions in mood and food intake relative to placebo. Zolpidem in combination with nabilone, but not zolpidem alone, decreased self-administration of active cannabis. Zolpidem in combination with nabilone also produced small increases in certain abuse-related subjective capsule ratings, while zolpidem alone did not. Neither medication condition altered cognitive performance. Conclusions Clinical testing of nabilone, either alone, or in combination with zolpidem is warranted.

Given that cannabis use is increasing in the United States, pharmacological treatment options to treat cannabis use disorder are needed. Opioid antagonists modulate cannabinoid effects and may offer a potential approach to reducing cannabis use. In this double-blind, placebo-controlled human laboratory study, we assessed the effects of naltrexone maintenance on the reinforcing, subjective, psychomotor, and cardiovascular effects of active and inactive cannabis. Nontreatment-seeking, daily cannabis smokers were randomized to receive naltrexone (50 mg: n=18 M and 5 F) or placebo (0 mg; n=26 M and 2 F) capsules for 16 days. Before, during, and after medication maintenance, participants completed 10 laboratory sessions over 4-6 weeks, assessing cannabis' behavioral and cardiovascular effects. Medication compliance was verified by observed capsule administration, plasma naltrexone, and urinary riboflavin. Relative to placebo, maintenance on naltrexone significantly reduced both active cannabis self-administration and its positive subjective effects ('good effect'). Participants in the placebo group had 7.6 times (95% CI: 1.1-51.8) the odds of self-administering active cannabis compared with the naltrexone group. This attenuation of reinforcing and positive subjective effects also influenced cannabis use in the natural ecology. Naltrexone had intrinsic effects: decreasing ratings of friendliness, food intake, and systolic blood pressure, and increasing spontaneous reports of stomach upset and headache, yet dropout rates were comparable between groups. In summary, we show for the first time that maintenance on naltrexone decreased cannabis self-administration and ratings of 'good effect' in nontreatment-seeking daily cannabis smokers. Clinical studies in patients motivated to reduce their cannabis use are warranted to evaluate naltrexone's efficacy as a treatment for cannabis use disorder.

Rationale One of the most often reported cognitive deficits of acute cannabis administration is an impaired recall of previously learned information. Objective The aim of the present study was to determine whether cannabis-induced memory impairment in humans is mediated via glutamatergic or cholinergic pathways. Methods Fifteen occasional cannabis users participated in a double-blind, placebo-controlled, six-way cross-over study. On separate test days, subjects received combinations of pretreatment (placebo, vardenafil 20 mg or rivastigmine 3 mg) and treatment (placebo or 1,376 mg cannabis/kg body weight). Cognitive tests were administered immediately after inhalation of treatment was finished and included measures of memory (visual verbal learning task, prospective memory test, Sternberg memory test), perceptual-motor control (critical tracking task), attention (divided attention task) and motor impulsivity (stop signal task). Results The results of this study demonstrate that subjects under the influence of cannabis were impaired in all memory tasks, in critical tracking, divided attention and the stop signal task. Pretreatment with rivastigmine attenuated the effect of cannabis on delayed recall and showed a trend towards significance on immediate recall. When cannabis was given in combination with vardenafil, there were no significant interaction effects in any of the tasks. Conclusions The present data therefore suggest that acetylcholine plays an important role in cannabis-induced memory impairment, whereas similar results for glutamate have not been demonstrated in this study.

Objective This study aims to compare treatment response in bipolar I or II depression and generalized anxiety disorder (GAD) with and without recent alcohol and/or cannabis use disorder (ALC/CAN) to quetiapine-XR (extended release) or placebo. Methods A randomized, double-blind, 8-week study of quetiapine-XR versus placebo in patients with bipolar I or II depression and GAD with or without a recent ALC/CAN was used to compare changes in Hamilton Depression Rating Scale-17, Hamilton Anxiety Rating Scale, the 16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR-16), Clinical Global Impression for Bipolar Disorder-Severity (CGI-BP-S), and Timeline Follow Back within and between groups. Results In the quetiapine-XR group, patients with a recent ALC/CAN ( n  = 22) had significant decreases in QIDS-SR-16 (−9.6 ± 1.6 vs. −3.7 ± 1.7) and CGI-BP-S (−1.6 ± 0.4 vs. −0.8 ± 0.03) than those without a recent ALC/CAN ( n  = 24). In the placebo group, both patients with a recent ALC/CAN ( n  = 23) and those without ( n  = 21) had similar reductions in these measures. The reduction of QIDS-SR-16 scores in patients with a recent ALC/CAN was also significantly different from that of their counterparts in the placebo group. Patients who received quetiapine-XR had larger decreases in the number of drinking days/week ( p  = 0.17) and number of cannabis joints/week ( p  = 0.09) compared to those who received placebo. Conclusion Quetiapine-XR was superior to placebo in reducing QIDS-SR-16 total score in patients with a recent ALC/CAN. Patients taking quetiapine-XR used less alcohol and cannabis than patients on placebo, suggesting that quetiapine-XR may be of use in patients with bipolar disorder accompanied by GAD and other comorbidities.

Abstract Introduction The co-use of cannabis and alcohol among tobacco-using youth is common. Alcohol co-use is associated with worse tobacco cessation outcomes, but results are mixed regarding the impact of cannabis on tobacco outcomes and if co-use leads to increased use of non-treated substances. This secondary analysis from a youth smoking cessation trial aimed to (1) evaluate the impact of cannabis or alcohol co-use on smoking cessation, (2) examine changes in co-use during the trial, and (3) explore secondary effects of varenicline on co-use. Methods The parent study was a 12-week, randomized clinical trial of varenicline for smoking cessation among youth (ages 14–21, N = 157; Mage = 19, 40% female; 76% White). Daily cigarette, cannabis, and alcohol use data were collected via daily diaries during treatment and Timeline Follow-back for 14 weeks post-treatment. Results Baseline cannabis co-users (68%) had double the odds of continued cigarette smoking throughout the trial compared with noncannabis users, which was pronounced in males and frequent cannabis users. Continued smoking during treatment was associated with higher probability of concurrent cannabis use. Baseline alcohol co-users (80%) did not have worse smoking outcomes compared with nonalcohol users, but continued smoking was associated with higher probability of concurrent drinking. Varenicline did not affect co-use. Conclusions Inconsistent with prior literature, results showed that alcohol co-users did not differ in smoking cessation, whereas cannabis co-users had poorer cessation outcomes. Youth tobacco treatment would benefit from added focus on substance co-use, particularly cannabis, but may need to be tailored appropriately to promote cessation. Implications Among youth cigarette smokers enrolled in a pharmacotherapy evaluation clinical trial, alcohol and/or cannabis co-use was prevalent. The co-use of cannabis affected smoking cessation outcomes, but more so for males and frequent cannabis users, whereas alcohol co-use did not affect smoking cessation. Reductions in smoking were accompanied by concurrent reductions in alcohol or cannabis use. Substance co-use does not appear to affect all youth smokers in the same manner and treatment strategies may need to be tailored appropriately for those with lower odds of smoking cessation.

Few individuals seeking treatment for marijuana use achieve sustained abstinence. The cannabinoid receptor agonist, Δ(9)-tetrahydrocannabinol (THC; dronabinol), decreases marijuana withdrawal symptoms, yet does not decrease marijuana use in the laboratory or clinic. Dronabinol has poor bioavailability, which may contribute to its poor efficacy. The FDA-approved synthetic analog of THC, nabilone, has higher bioavailability and clearer dose-linearity than dronabinol. This study tested whether nabilone administration would decrease marijuana withdrawal symptoms and a laboratory measure of marijuana relapse relative to placebo. Daily, nontreatment-seeking marijuana smokers (8 men and 3 women), who reported smoking 8.3±3.1 marijuana cigarettes/day completed this within-subject study comprising three, 8-day inpatient phases; each phase tested a different nabilone dose (0, 6, 8 mg/day, administered in counter-balanced order on days 2-8). On the first inpatient day, participants took placebo capsules and smoked active marijuana (5.6% THC) at six timepoints. For the next 3 days, they had the opportunity to self-administer placebo marijuana (0.0% THC; withdrawal), followed by 4 days in which active marijuana was available for self-administration (5.6% THC; relapse). Both nabilone dose conditions decreased marijuana relapse and reversed withdrawal-related irritability and disruptions in sleep and food intake (p<0.05). Nabilone (8 mg/day) modestly worsened psychomotor task performance. Neither dose condition increased ratings of capsule 'liking' or desire to take the capsules relative to placebo. Thus, nabilone maintenance produced a robust attenuation of marijuana withdrawal symptoms and a laboratory measure of relapse even with once per day dosing. These data support testing of nabilone for patients seeking marijuana treatment.

Worldwide cannabis dependence is increasing, as is the concentration of Delta(9)-tetrahydrocannabinol (THC) in street cannabis. At the same time, the concentration of the second most abundant cannabinoid in street cannabis, cannabidiol (CBD), is decreasing. These two cannabinoids have opposing effects both pharmacologically and behaviorally when administered in the laboratory. No research has yet examined how the ratio of these constituents impacts on the appetitive/reinforcing effects of cannabis in humans. A total of 94 cannabis users were tested 7 days apart, once while non-intoxicated and once while acutely under the influence of their own chosen smoked cannabis on dependence-related measures. Using an unprecedented methodology, a sample of cannabis (as well as saliva) was collected from each user and analyzed for levels of cannabinoids. On the basis of CBD : THC ratios in the cannabis, individuals from the top and bottom tertiles were directly compared on indices of the reinforcing effects of drugs, explicit liking, and implicit attentional bias to drug stimuli. When intoxicated, smokers of high CBD : THC strains showed reduced attentional bias to drug and food stimuli compared with smokers of low CBD : THC. Those smoking higher CBD : THC strains also showed lower self-rated liking of cannabis stimuli on both test days. Our findings suggest that CBD has potential as a treatment for cannabis dependence. The acute modulation of the incentive salience of drug cues by CBD may possibly generalize to a treatment for other addictive disorders.

Research is scant regarding differential effects of specific types of recreational drugs use on antiretroviral therapy adherence among women, particularly to single-tablet regimens (STR). This is increasingly important in the context of marijuana legalization. We examined the effects of self-reported substance use on suboptimal (<95%) adherence in the Women’s Interagency HIV Study, 2003–2014. Among 1799 HIV-infected women, the most prevalent substance used was marijuana. In multivariable Poisson GEE regression, substance use overall was significantly associated with suboptimal adherence (adjusted prevalence ratio, aPR = 1.20, 95% CI 1.10–1.32), adjusting for STR use, socio-demographic, behavioral, and clinical factors. Among STR users, compared to no drug use, substance use overall remained detrimental to ART adherence (aPR = 1.61, 95% CI 1.24–2.09); specifically, both marijuana (aPR = 1.48, 95% CI: 1.11–1.97) and other drug use (aPR = 1.87, 95% CI 1.29–2.70) predicted suboptimal adherence. These findings highlight the need to intervene with drug-using women taking antiretroviral therapy to maintain effective adherence.

Rationale Advancing marijuana prevention and intervention efforts are important given the decreasing perception of harm among adolescents and increasing marijuana legalization. Objectives This study evaluates how a monitored abstinence protocol may contribute to emotional functioning and changes in marijuana problems that can enhance successful outcomes for non-treatment-seeking adolescent marijuana users. Methods Adolescent marijuana users ( n  = 26) and demographically matched controls ( n  = 30) completed 28 days of monitored abstinence confirmed by biweekly urine toxicology. Participants were given measures of emotional functioning, marijuana use symptoms, and reward sensitivity during monitored abstinence. Results All participants ( n  = 56) completed the protocol, and 69% of marijuana users ( n  = 18 of 26) were confirmed abstinent for 28 days, with all users showing decreasing marijuana use. Reductions in subsyndromal depression, positive marijuana use expectancies, and poor sleep quality were observed by the end of the monitored abstinence period ( n  = 26, p values < .05). Marijuana users also reported more attentional impulsivity and less responsiveness to reward stimuli during the second week of abstinence compared to controls. Later age of onset of regular marijuana use and more cumulative lifetime use were associated with a greater degree of emotional change and increased recognition of the negative effects of marijuana use. Conclusions Monitored abstinence programs may be beneficial in reducing marijuana use, subsyndromal emotional distress symptoms, and changing beliefs about marijuana use. Future prevention and intervention efforts may consider targeting reward sensitivity and impulsivity, in addition to marijuana use, expectancies, and emotional functioning.