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BackgroundDespite the high prevalence of polysubstance use, outcomes and potential risks associated with common drug combinations are not well characterized. Many individuals who use cocaine also use cannabis, yet little is known about how interactions between the two drugs might contribute to continued co-use.MethodsThe aim of this double-blind, placebo-controlled study was to determine the physiological and subjective effects of smoked cannabis with smoked cocaine, to identify variables that may contribute to the continued use of this drug combination. Healthy, non-treatment seeking volunteers who reported smoking both cocaine and cannabis (N=9, all males) completed a 13-day inpatient protocol. On session days, cannabis [0.0 or 5.6 % tetrahydrocannabinol (THC)] was administered 28min prior to cocaine (0, 12, or 25mg). Dependent measures included pharmacokinetic assessment of THC and cocaine and their respective metabolites, in addition to subjective and cardiovascular effects.ResultsActive cannabis (5.6 % THC) increased plasma levels of THC and the metabolite 11-nor-9-carboxy-Δ9-THC (THCCOOH), as well as subjective ratings of cannabis effects and heart rate relative to inactive cannabis. Cocaine dose-dependently increased plasma cocaine and metabolites and subjective ratings of cocaine effects. Active cannabis pre-treatment decreased plasma levels of cocaine and metabolites. Furthermore, active cannabis attenuated cocaine-related reductions in 'Hunger' and 'Calm.'ConclusionsCannabis pre-treatment altered the subjective experience of smoked cocaine and reduced peak plasma levels of cocaine. Future studies should explore additional doses of each drug and whether these changes also impact cocaine's reinforcing effects.

Background: Impulsive choice – the tendency to choose immediate over larger delayed rewards – is associated with both cocaine use and relapse. Little is known about the influence of transient states on impulsive choice in people who use cocaine (PWUC). This study investigated the direct effects of induced boredom on impulsive choice (i.e., temporal discounting) in PWUC relative to well-matched community controls. Methods: In a mixed within-between subject design, 41 PWUC (≥1x cocaine use in past 3 months; 7 females) and 38 demographically-matched controls (5 females) underwent two experimental conditions in counterbalanced order. Temporal discounting was assessed immediately after a standardized boredom induction task (peg-turning) and a self-selected video watched for the same duration (non-boredom). Subjective mood state and perceived task characteristics were assessed at baseline, during experimental manipulations, and after the choice task. Results: PWUC and controls were demographically well-matched and similar in reported drugs use other than cocaine, except for recent cigarette and alcohol use (PWUC>controls). As expected, peg-turning increased boredom in the sample overall, with higher boredom reported during peg-turning than the video (p.05, BF01=2.9). Conclusion: Experimentally-induced boredom increased state impulsivity irrespective of cocaine use status, suggesting a broad link between boredom and impulsive choice. This is the first study to show that transient boredom directly increases impulsive choice. Data support a viable laboratory method to further parse the effects of boredom on impulsive choice.

Due to the poor oral bioavailability of buprenorphine, an oral formulation has not been thought possible. Lyndra Therapeutics is developing a once-weekly long-acting oral product containing buprenorphine. We evaluated the efficacy of this formulation in reducing intravenous (i.v.) fentanyl self-administration by three male and three female rhesus monkeys.Buprenorphine HCl and naloxone HCl were co-formulated using an 11:1 ratio of buprenorphine:naloxone in a controlled-release gastric residence formulation administered in an oral capsule (LYN-013). Naloxone was included to determine the feasibility of combining naloxone with buprenorphine in the formulation as an abuse deterrent. Complete fentanyl dose-response functions were determined during each session. The efficacy of single doses of 56/5, 112/10 and 168/15 mg buprenorphine/naloxone in reducing fentanyl self-administration was examined over 13 days.LYN-013 significantly decreased the rate of responding for fentanyl for 3 days and significantly reduced total intake of fentanyl for 8 days. Time to maximal buprenorphine levels (Tmax) ranged between 56 and 68 h for all 3 doses. The maximal buprenorphine level (Cmax) following 168 mg was 2.3 ng/ml which was significantly greater that those observed for 56 mg (1.22 ng/ml) and 112 mg (1.35 ng/ml). Finally, the area-under-curves (AUCtau) were buprenorphine dose-dependently increased from 88 to 127-265 h*ng/ml. There were no signs of non-specific changes in behavior.A once-weekly oral buprenorphine/naloxone formulation produced sustained suppression of fentanyl self-administration in monkeys suggesting that oral delivery of buprenorphine with this formulation could provide a new opportunity to treat opioid use disorders (OUD).

Attenuating enzymatic degradation of endocannabinoids (eCBs) by fatty acid amide hydrolase (FAAH) reduces cannabis withdrawal symptoms in preclinical and clinical studies. In mice, blocking cyclooxygenase-2 (COX-2) activity increases central eCB levels by inhibiting fatty acid degradation. This placebo-controlled study examined the effects of the FDA-approved COX-2 selective inhibitor, celecoxib, on cannabis withdrawal, ‘relapse,’ and circulating eCBs in a human laboratory model of cannabis use disorder. Daily, nontreatment-seeking cannabis smokers (12M,3F) completed a crossover study comprising two 11-day study phases (separated by >14 days for medication clearance). In each phase, the effects of daily BID placebo (0 mg) or celecoxib (200 mg) on cannabis (5.3% THC) intoxication, withdrawal symptoms (4 days of inactive cannabis self-administration) and ‘relapse’ (3 days of active cannabis self-administration following abstinence) were assessed. Outcome measures included mood, cannabis self-administration, sleep, food intake, cognitive performance, tobacco cigarette use, and circulating eCBs and related lipids. Under placebo maintenance, cannabis abstinence produced characteristic withdrawal symptoms (negative mood, anorexia, dreaming) relative to cannabis administration, and was associated with increased OEA (a substrate of FAAH) and oleic acid (metabolite of OEA), with no change in eCB levels. Compared to placebo, celecoxib improved subjective (but not objective) measures of sleep and did not affect mood or plasma levels of eCBs or associated lipids, and increased cannabis craving. The overall absence of effects on cannabis withdrawal symptoms, self-administration, or circulating eCBs relative to placebo, combined with an increase in cannabis craving, suggests celecoxib does not show promise as a potential pharmacotherapy for CUD.