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Background: The purpose of this study was to evaluate the efficacy of buspirone, a partial 5-HT1A agonist, for treatment of cannabis dependence.Methods: One hundred seventy-five cannabis-dependent adults were randomized to receive either up to 60mg/day of buspirone (n=88) or placebo (n=87) for 12 weeks combined with a brief motivational enhancement therapy intervention and contingency management to encourage study retention. Cannabis use outcomes were assessed via weekly urine cannabinoid tests.Results: Participants in both groups reported reduced cannabis craving over the course of the study; however, buspirone provided no advantage over placebo in reducing cannabis use. Significant gender by treatment interactions were observed, with women randomized to buspirone having fewer negative urine cannabinoid tests than women randomized to placebo (p=0.007), and men randomized to buspirone having significantly lower creatinine adjusted cannabinoid levels as compared to those randomized to placebo (p=0.023). An evaluation of serotonin allelic variations did not find an association with buspirone treatment response.Conclusions: Buspirone was not more efficacious than placebo in reducing cannabis use. Important gender differences were noted, with women having worse cannabis use outcomes with buspirone treatment. Considerations for future medication trials in this challenging population are discussed. [ABSTRACT FROM AUTHOR]

Abstract: Background: Personality characteristics have been associated with cocaine use. However, little is known about the mechanisms through which personality could impact drug use. The present study investigated the cross-sectional and prospective relationships between personality dimensions (i.e., impulsivity, neuroticism) and problematic cocaine use. Reactivity to a pharmacological stressor as a potential mediator of the relationship between neuroticism and future cocaine use was also examined. Methods: Participants were 53 cocaine-dependent individuals and 47 non-dependent controls. Subjects completed the Eysenck Personality Questionnaire (EPQ) at baseline and were administered i.v. corticotrophin releasing hormone (CRH; 1μg/kg). Cocaine use in the 30 days following CRH administration was measured. Results: Cocaine-dependent individuals had higher scores on the psychoticism (i.e., impulsivity, aggression; p =0.02) and neuroticism (p <0.01) scales of the EPQ than non-dependent controls. Cocaine-dependent individuals also had a greater subjective stress response to CRH than controls (p <0.01). Cocaine-dependent individuals with elevated psychoticism used significantly more cocaine over the follow-up period (p <0.05), whereas individuals with elevated neuroticism trended towards using cocaine more frequently over the follow-up (p =0.07). Finally, there was a trend for an indirect effect of neuroticism on frequency of cocaine use through subjective reactivity to CRH. Conclusions: The findings extend past research on the association between personality and cocaine use, and suggest that motives for cocaine use may systematically vary across personality characteristics. Moreover, tailoring therapeutic interventions to individuals’ personalities may be an area that warrants further investigation. [Copyright &y& Elsevier]

Abstract: The present study investigated the potential efficacy of buspirone for treating marijuana dependence. Participants received either buspirone (maximum 60mg/day) (n =23) or matching placebo (n =27) for 12 weeks, each in conjunction with motivational interviewing. In the modified intention-to-treat analysis, the percentage of negative UDS results in the buspirone-treatment group was 18 percentage points higher than the placebo-treatment group (95% CI: −2% to 37%, p =0.071). On self-report, participants receiving buspirone reported not using marijuana 45.2% of days and participants receiving placebo reported not using 51.4% of days (p =0.55). An analysis of participants that completed the 12-week trial showed a significant difference in the percentage negative UDS (95% CI: 7–63%, p =0.014) and a trend for participants randomized to the buspirone-treatment group who completed treatment to achieve the first negative UDS result sooner than those participants treated with placebo (p =0.054). Further study with buspirone in this population may be warranted; however, strategies to enhance study retention and improve outcome measurement should be considered in future trials. [Copyright &y& Elsevier]

Background: An efficacious pharmacotherapy for cannabis use disorder (CUD) has yet to be established. This study preliminarily evaluated the safety and efficacy of varenicline for CUD in a proof-of-concept clinical trial.Methods: Participants in this 6-week randomized, placebo-controlled pilot trial received either varenicline (n = 35) or placebo (n = 37), added to a brief motivational enhancement therapy intervention. Outcomes included cannabis withdrawal, cannabis abstinence, urine cannabinoid levels, percent cannabis use days, and cannabis sessions per day.Results: Both treatment groups noted significant decreases in self-reported cannabis withdrawal, percentage of days used, and use sessions per day during treatment compared to baseline. While this pilot trial was not powered to detect statistically significant between-group differences, participants randomized to varenicline evidenced numerically greater rates of self-reported abstinence at the final study visit [Week 6 intent-to-treat (ITT): Varenicline: 17.1% vs. Placebo: 5.4%; RR = 3.2 (95% CI: 0.7,14.7)]. End-of-treatment urine creatinine corrected cannabinoid levels were numerically lower in the varenicline group and higher in the placebo group compared to baseline [Change from baseline: Varenicline -1.7 ng/mg (95% CI: -4.1,0.8) vs. Placebo: 1.9 ng/mg (95% CI: -0.4,4.3); Δ = 3.5 (95% CI: 0.1,6.9)]. Adverse events related to study treatment did not reveal new safety signals.Conclusions: Findings support the feasibility of conducting clinical trials of varenicline as a candidate pharmacotherapy for CUD, and indicate that a full-scale efficacy trial, powered based on effect sizes and variability yielded in this study, is warranted. [ABSTRACT FROM AUTHOR]

Background: Distress tolerance (DT) has been implicated as an important factor in the experience of negative affect (NA) and cannabis craving. However, previous research is limited by its use of laboratory paradigms that may not replicate in naturalistic settings. The current study examined how DT influenced reactivity to NA cues in daily life in a sample of frequent (≥3 times per week) cannabis-using emerging adults (age 18-21).Methods: Using cue-reactivity ecological momentary assessment (CREMA), 63 (54 % female; 85.7 % white; Mage = 19.62) participants reported on their cannabis craving and affect (sadness, relaxation) four semi-random times per day for two weeks (56 possible CREMA sessions/participant). We assessed affect and cannabis craving before and after exposure to neutral and NA cues. Multilevel modeling was used to examine within- and between-participant effects of cues, DT, and sex, as well as within- and between-participant average pre-cue affect and craving, on post-cue affect and craving.Results: NA cues consistently predicted higher-than-normal post-cue sadness and lower relaxation, but not greater-than-normal post-cue craving. Cue type interacted with sex and DT to predict post-cue sadness, but not craving. Female participants and those reporting low DT reported higher sadness following NA cues compared to males and those with high DT, respectively.Conclusions: Frequent cannabis-using emerging adults differed in affect, but not cannabis craving, reactivity to NA cues as a function of sex and DT. Our results were partially consistent with prior human laboratory and CREMA research finding greater reactivity to NA cues among females and individuals with low DT. [ABSTRACT FROM AUTHOR]

Cannabis use disorder (CUD) is a common and consequential disorder. When applied to the dorsolateral prefrontal cortex (DLPFC), repetitive transcranial magnetic stimulation (rTMS) reduces craving across substance use disorders and may have therapeutic clinical effects when applied in serial-sessions. The present study sought to preliminarily determine whether serial-sessions of rTMS applied to the DLPFC had a therapeutic effect in CUD. This study was a two-site, phase-2, double-blind, randomized-controlled-trial. Seventy-two treatment-seeking participants (37.5% Women, mean age 30.2±9.9 SD) with ≥moderate-CUD were randomized to active or sham rTMS (Beam-F3, 10 Hz, 20-total-sessions, two-sessions-per-visit, two-visits-per-week, with cannabis cues) while undergoing a three-session motivational enhancement therapy intervention. The primary outcome was the change in craving between pre- and post- treatment (Marijuana Craving Questionnaire Short-Form—MCQ-SF). Secondary outcomes included the number of weeks of abstinence and the number of days-per-week of cannabis use during 4-weeks of follow-up. There were no significant differences in craving between conditions. Participants who received active-rTMS reported numerically, but not significantly, more weeks of abstinence in the follow-up period than those who received sham-rTMS (15.5%-Active; 9.3%-Sham; rate ratio = 1.66 [95% CI: 0.84, 3.28]; p =0.14). Participants who received active-rTMS reported fewer days-per-week of cannabis use over the final two-weeks of the follow-up period than those receiving sham-rTMS (Active vs. Sham: −0.72; Z=−2.33, p =0.02). This trial suggests rTMS is safe and feasible in individuals with CUD and may have a therapeutic effect on frequency of cannabis use, though further study is needed with additional rTMS-sessions and a longer follow-up period. • This phase-2 RCT tested the efficacy of prefrontal rTMS for cannabis use disorder. • The study paradigm was safe and feasible, and participants tolerated rTMS well. • The active-group had numerically more weeks of abstinence during follow-up. • The active-group had fewer days-per-week of cannabis use during follow-up. • More rTMS and a longer follow-up may result in a larger effect in future studies.. [ABSTRACT FROM AUTHOR]

Hedonic dysregulation is a core mechanism of addiction. There is a dearth of research on hedonic dysregulation in cannabis use disorder (CUD). The current study tested whether personalized scripted imagery may be an efficacious approach to remediate reward functioning in adults with CUD. Adults with CUD (n=10) and non-CUD controls (n=12) completed a single session personalized scripted imagery procedure. Non-drug (i.e. natural) reward and neutral scripts were transcribed and participants listened to the scripts in counterbalanced order. Primary outcomes included positive affect (PA), galvanic skin response (GSR), and cortisol and were assessed at four timepoints. Mixed effects models were used to compare between and within subject effects. Mixed effects models revealed a Condition (reward vs. neutral) X Group (CUD vs. control) interaction (p=0.01) on PA response, indicating blunted PA response to the neutral script relative to the reward script in CUD participants. Likewise, GSR response in CUD participants was decreased in response to the neutral script relative to the reward script (p=0.034; interaction n.s.). An interaction effect of Group X PA on cortisol response was found (p=.036) indicating that cortisol was positively correlated with PA in healthy control participants, but not CUD participants. Adults with CUD may demonstrate acute deficits in hedonic tone under neutral conditions relative to healthy controls. Personalized scripted imagery may be an efficacious tool to remediate hedonic dysregulation in CUD. Cortisol may play a role in healthy positive affect regulation warranting further investigation. • Natural reward processing in adults with cannabis use disorder (CUD) was investigated. • Adults with CUD showed blunted positive affect (PA) under neutral conditions. • Adults with CUD showed blunted galvanic skin response (GSR) under neutral conditions. • Cortisol and PA were positively correlated in healthy controls but not adults with CUD. [ABSTRACT FROM AUTHOR]

Background: The agreement between self-reported cannabis abstinence with urine cannabinoid concentrations in a clinical trials setting is not well characterized. We assessed the agreement between various cannabinoid cutoffs and self-reported abstinence across three clinical trials, one including contingency management for abstinence.Methods: Three cannabis cessation clinical trials where participants reported use and provided weekly urine samples for cannabis and creatinine concentration measurements were included. Bootstrapped data were assessed for agreement between self-reported 7+ day abstinence and urine cannabinoid tests using generalized linear mixed effects models for clustered binary outcomes. One study implemented contingency management for cannabis abstinence. Four hundred and seventy-three participants with 3787 valid urine specimens were included. Urine was analyzed for 11-nor-9-carboxy-Δ9-tetrahydrocannabinol and creatinine using immunoassay methods Biological cutoffs of 50, 100, and 200 ng/ml, as well as changes in CN normalized THCCOOH (25%/50% decrease), were assessed for agreement with self-reported abstinence during the three clinical trials.Results: Agreement between measured THCCOOH and self-reported abstinence increases with increasing cutoff concentrations, while the agreement with self-reported non-abstinence decreases with increasing cutoff concentrations. Combining THCCOOH cutoffs with recent changes in CN-THCCOOH provides a better agreement in those self-reporting abstinence. Participants in the studies that received CM for abstinence had a lower agreement between self-reported abstinence and returned to use than those in studies that did not have a contingency management component.Conclusion: Using combinations of biological measurements and self-reported abstinence, confirmation of study related abstinence may be verifiable earlier and with greater accuracy than relying on a single measurement. [ABSTRACT FROM AUTHOR]

Background: Quantifying cannabis use is complex due to a lack of a standardized packaging system that contains specified amounts of constituents. A laboratory procedure has been developed for estimating physical quantity of cannabis use by utilizing a surrogate substance to represent cannabis, and weighing the amount of the surrogate to determine typical use in grams.Method: This secondary analysis utilized data from a multi-site, randomized, controlled pharmacological trial for adult cannabis use disorder (N=300), sponsored by the National Drug Abuse Treatment Clinical Trials Network, to test the incremental validity of this procedure. In conjunction with the Timeline Followback, this physical scale-based procedure was used to determine whether average grams per cannabis administration predicted urine cannabinoid levels (11-nor-9-carboxy-Δ9-tetrahydrocannabinol) and problems due to use, after accounting for self-reported number of days used (in the past 30 days) and number of administrations per day in a 12-week clinical trial for cannabis use disorder.Results: Likelihood ratio tests suggest that model fit was significantly improved when grams per administration and relevant interactions were included in the model predicting urine cannabinoid level (X2=98.3; p<0.05) and in the model predicting problems due to cannabis use (X2=6.4; p<0.05), relative to a model that contained only simpler measures of quantity and frequency.Conclusions: This study provides support for the use of a scale-based method for quantifying cannabis use in grams. This methodology may be useful when precise quantification is necessary (e.g., measuring reduction in use in a clinical trial). [ABSTRACT FROM AUTHOR]

Previous studies have identified common trajectories of single type substance use over the course of adolescence; however, no study to date has examined joint trajectories of cannabis and alcohol concurrent use. Given that expansion of legal cannabis has increased availability, it is important to understand patterns of concurrent use in adolescents and factors that place male and female youth at risk for harmful trajectories of concurrent use. The current study sought to identify joint trajectories of cannabis and alcohol use – and predictors of harmful use trajectories – among male and female adolescents. We used 4 waves of data from 6997 early adolescent participants (age 12–14 years at Wave 1) in the Population Assessment of Tobacco and Health, a nationally representative longitudinal study in the United States. Participants reported their cannabis and alcohol use reassessed yearly for 5 years (2013–2018). We used joint trajectory growth mixture modeling to identify trajectory groups as defined by changes in alcohol and cannabis use over time. Five classes of alcohol and cannabis concurrent use trajectories were identified. Both internalizing and externalizing symptoms at Wave 1 increased the odds of membership in trajectory groups characterized by more harmful use trajectories. Internalizing symptomatology was a stronger predictor of membership in escalating use trajectories among girls, whereas externalizing symptomatology stronger predictor among boys. These findings underscore the utility of jointly considering alcohol and cannabis use when describing common developmental trajectories of use and identifying risk factors for trajectories characterized by harmful use. • We identified common trajectories of alcohol and cannabis concurrent use in adolescents. • Five trajectory groups were identified with distinct patterns of use. • Internalizing and externalizing psychopathology predicted trajectory group membership. • Sex differences in psychopathology risk factors were identified.. [ABSTRACT FROM AUTHOR]

Background: Cannabis use disorder (CUD) is a prevalent and impairing condition, and established psychosocial treatments convey limited efficacy. In light of recent findings supporting the efficacy of N-acetylcysteine (NAC) for CUD in adolescents, the objective of this trial was to evaluate its efficacy in adults.Methods: In a 12-week double-blind randomized placebo-controlled trial, treatment-seeking adults ages 18-50 with CUD (N=302), enrolled across six National Drug Abuse Treatment Clinical Trials Network-affiliated clinical sites, were randomized in a 1:1 ratio to a 12-week course of NAC 1200mg (n=153) or placebo (n=149) twice daily. All participants received contingency management (CM) and medical management. The primary efficacy measure was the odds of negative urine cannabinoid tests during treatment, compared between NAC and placebo participants.Results: There was not statistically significant evidence that the NAC and placebo groups differed in cannabis abstinence (odds ratio=1.00, 95% confidence interval 0.63-1.59, p=0.984). Overall, 22.3% of urine cannabinoid tests in the NAC group were negative, compared with 22.4% in the placebo group. Many participants were medication non-adherent; exploratory analysis within medication-adherent subgroups revealed no significant differential abstinence outcomes by treatment group.Conclusions: In contrast with prior findings in adolescents, there is no evidence that NAC 1200mg twice daily plus CM is differentially efficacious for CUD in adults when compared to placebo plus CM. This discrepant finding between adolescents and adults with CUD may have been influenced by differences in development, cannabis use profiles, responses to embedded behavioral treatment, medication adherence, and other factors. [ABSTRACT FROM AUTHOR]

Background: Cannabis use rates are increasing among adults in the United States (US) while the perception of harm is declining. This may result in an increased prevalence of cannabis use disorder and the need for more clinical trials to evaluate efficacious treatment strategies. Clinical trials are the gold standard for evaluating treatment, yet study samples are rarely representative of the target population. This finding has not yet been established for cannabis treatment trials. This study compared demographic and cannabis use characteristics of a cannabis cessation clinical trial sample (run through National Drug Abuse Treatment Clinical Trials Network) with three nationally representative datasets from the US; 1) National Survey on Drug Use and Health, 2) National Epidemiologic Survey on Alcohol and Related Conditions-III, and 3) Treatment: Episodes Data Set - Admissions.Methods: Comparisons were made between the clinical trial sample and appropriate cannabis using sub-samples from the national datasets, and propensity scores were calculated to determine the degree of similarity between samples.Results: showed that the clinical trial sample was significantly different from all three national datasets, with the clinical trial sample having greater representation among older adults, African Americans, Hispanic/Latinos, adults with more education, non-tobacco users, and daily and almost daily cannabis users.Conclusions: These results are consistent with previous studies of other substance use disorder populations and extend sample representation issues to a cannabis use disorder population. This illustrates the need to ensure representative samples within cannabis treatment clinical trials to improve the generalizability of promising findings. [ABSTRACT FROM AUTHOR]

Abstract: Background: The development of addiction is marked by a pathological associative learning process that imbues incentive salience to stimuli associated with drug use. Recent efforts to treat addiction have targeted this learning process using cue exposure therapy augmented with d-cycloserine (DCS), a glutamatergic agent hypothesized to enhance extinction learning. To better understand the impact of DCS-facilitated extinction on neural reactivity to drug cues, the present study reports fMRI findings from a randomized, double-blind, placebo-controlled trial of DCS-facilitated cue exposure for cocaine dependence. Methods: Twenty-five participants completed two MRI sessions (before and after intervention), with a cocaine-cue reactivity fMRI task. The intervention consisted of 50mg of DCS or placebo, combined with two sessions of cocaine cue exposure and skills training. Results: Participants demonstrated cocaine cue activation in a variety of brain regions at baseline. From the pre- to post-study scan, participants experienced decreased activation to cues in a number of regions (e.g., accumbens, caudate, frontal poles). Unexpectedly, placebo participants experienced decreases in activation to cues in the left angular and middle temporal gyri and the lateral occipital cortex, while DCS participants did not. Conclusions: Three trials of DCS-facilitated cue exposure therapy for cocaine dependence have found that DCS either increases or does not significantly impact response to cocaine cues. The present study adds to this literature by demonstrating that DCS may prevent extinction to cocaine cues in temporal and occipital brain regions. Although consistent with past research, results from the present study should be considered preliminary until replicated in larger samples. [Copyright &y& Elsevier]

Background: The ability to predict potential for relapse to substance use following treatment could be very useful in targeting aftercare strategies. Recently, a number of investigators have focused on using neural activity measured by fMRI to predict relapse propensity. The purpose of the present study was to use fMRI to investigate prospective associations between brain reactivity to cocaine and response inhibition cues and relapse to cocaine use. Methods: Thirty cocaine-dependent participants with clean cocaine urine drug screens (UDS) completed a baseline fMRI scan, including a cocaine-cue reactivity task and a go no-go response inhibition task. After participating in a brief clinical trial of c-cycloserine for the facilitation of cocaine-cue extinction, they returned for a one-week follow-up UDS. Associations between baseline activation to cocaine and inhibition cues and relapse to cocaine use were explored. Results: Positive cocaine UDS was significantly associated with cocaine-cue activation in the right putamen and insula, as well as bilateral occipital regions. Associations between positive cocaine UDS and activation to no-go cues were concentrated in the postcentral gyri, a region involved in response execution. Conclusions: Although preliminary, these results suggest that brain imaging may be a useful tool for predicting risk for relapse in cocaine-dependent individuals. Further, larger-scale naturalistic studies are needed to corroborate and extend these findings. [ABSTRACT FROM AUTHOR]

Abstract: Background: Cocaine dependence is a chronic relapsing disorder characterized by periods of abstinence and high rates of return to drug using behavior. Elevated levels of stress have been associated with relapse to cocaine; however, the nature of this association is not well understood. Methods: The relationship between reactivity to three human laboratory provocations and relapse to cocaine was investigated. Participants were 53 cocaine-dependent individuals who were admitted for a 2-day inpatient stay during which a psychosocial provocation (i.e., the Trier Social Stress Task), a pharmacological provocation (i.e., administration of 1μg/kg corticotrophin releasing hormone; CRH), and a drug cue exposure paradigm were completed. Adrenocortico-trophic hormone (ACTH), cortisol, heart rate, and subjective cocaine craving and stress were assessed at baseline and at multiple time points post-task. Participants’ cocaine use was monitored for approximately 1 month following testing. Results: The majority (72.3%) of participants relapsed to cocaine during the follow-up period. In response to the CRH and drug cue exposure, elevated subjective craving and stress were significant predictors of cocaine use during follow-up. In response to the Trier, attenuated neuroendocrine responses were significant predictors of cocaine use. Conclusions: The findings provide further evidence of the ability of laboratory paradigms to predict relapse. The observed associations between stress reactivity and subsequent cocaine use highlight the clinical importance of the findings. Predictors of relapse may vary based on the type of provocation utilized. Interventions aimed at normalizing stress response, as measured using laboratory paradigms, may prove useful in relapse prevention. [Copyright &y& Elsevier]

Background: Time from first cannabis use to cannabis dependence (latency) may be an important prognostic indicator of cannabis-related problems and treatment outcomes. Gender differences in latency have been found; however, research in this general area is limited. As cannabis use increases and perceived risk declines, a better understanding of how these factors interact in predicting treatment outcomes is critical.Methods: A secondary data analysis of a randomized, double-blind, placebo-controlled pharmacotherapy trial for cannabis dependence (N = 302) examined the associations between age of cannabis use onset, time to cannabis dependence (latency), and gender on cannabis use during the trial. Mediation analysis tested whether the association between age of onset and cannabis use during the trial was mediated by latency to cannabis dependence differentially for men and women.Results: Age of use initiation was inversely correlated with latency to dependence prior to treatment [HR(95% CI) = 1.18 (1.06, 1.30); p = .002] and cannabis use during treatment (β=-1.27; SE = 0.37; p < .001). There was a significant mediation effect between age of onset, latency, and cannabis use that varied by gender. Earlier age of onset predicted longer latency, and subsequently, greater cannabis use during the trial in men (21.4% mediated; p < .05), but not women. Other substance use, race, and past psychiatric diagnosis did not predict latency either independently or in interaction models.Conclusion: Findings support existing evidence that early cannabis use onset is associated with worse outcomes and add new knowledge on the differential associations between age of onset, latency to cannabis dependence, and treatment outcomes for men and women. [ABSTRACT FROM AUTHOR]

There is considerable variability in the use of outcome measures in clinical trials for cannabis use disorder (CUD), and a lack of consensus regarding optimal outcomes may have hindered development and approval of new pharmacotherapies. The goal of this paper is to summarize an evaluation of assessment measures and clinical endpoints for CUD clinical trials, and propose a research agenda and priorities to improve CUD clinical outcome assessments. The primary recommendation is that sustained abstinence from cannabis should not be considered the primary outcome for all CUD clinical trials as it has multiple limitations. However, there are multiple challenges to the development of a reliable and valid indicator of cannabis reduction, including the lack of a standard unit of measure for the various forms of cannabis and products and the limitations of currently available biological and self-report assessments. Development of a core toolkit of assessments is needed to both allow flexibility for study design, while facilitating interpretation of outcomes across trials. Four primary agenda items for future research are identified to expedite development of improved clinical outcome assessments for this toolkit: (1) determine whether minimally invasive biologic assays could identify an acute level of cannabis use associated with psychomotor impairment or other cannabis-related harms; (2) create an indicator of quantity of cannabis use that is consistent across product types; (3) examine the presence of cannabis-specific functional outcomes; and (4) identify an optimal duration to assess changes in CUD diagnostic criteria. [ABSTRACT FROM AUTHOR]