Search

Background: Despite the critical role of choice processes in substance use disorders, the neurobehavioral mechanisms guiding human decisions about drugs remain poorly understood. We adapted a neuroeconomic framework to characterize the neural encoding of subjective value (SV) for cannabis versus non-drug rewards (snacks) in near-daily cannabis users. We also assessed the impact of cannabis and snack stimuli (‘cues’) on SV encoding.Methods: Twenty-one non-treatment-seeking cannabis users (≥4 days/week; 1 female) participated in an inpatient, crossover experiment with four counterbalanced conditions: 1. neutral cues/cannabis choices; 2. cannabis cues/cannabis choices; 3. neutral cues/snack choices; and 4. snack cues/snack choices. In each condition, participants were exposed to cues before an fMRI scan during which they repeatedly chose between 0-6 cannabis puffs/snacks and a set monetary amount, with randomly-selected choices implemented. The SV signal was operationalized as the neural correlates of the strength of preference for cannabis/snack choices. fMRI data were analyzed for twenty participants. Results: Despite equivalent choice behavior, SV signals for cannabis, but not snacks, were observed in regions known to encode SV for various rewards (ventromedial prefrontal cortex, vmPFC; ventral striatum; dorsal posterior cingulate cortex, dPCC). SV encoding in vmPFC was stronger for cannabis than snacks. In the dPCC, the impact of cues on SV signals was moderated by the reward type.Conclusions: Near-daily cannabis users had expected neural value encoding for cannabis but disrupted non-drug SV encoding, despite equivalent choice behavior. Results provide support for models identifying dysregulated neural valuation of non-drug rewards as a hallmark of problematic substance use.

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.

AIMS: Preclinical studies demonstrate that cannabidiol (CBD) elicits an antinociceptive response in animal models of neuropathic pain; in humans, limited data are available to support such analgesic effects. Few studies have examined CBD's analgesic effects when administered without other compounds, and little is known regarding dose-dependent effects in noncannabis users. METHODS: This double-blind, placebo-controlled, within-subject outpatient clinical laboratory study sought to determine the analgesic effects, abuse liability, safety and tolerability of acute CBD (0, 200, 400 and 800 mg orally) in healthy noncannabis-using volunteers (n = 17; 8 men, 9 women). Outcomes included experimental pain threshold and pain tolerance using the cold pressor test (CPT), subjective ratings of CPT painfulness and bothersomeness, subjective ratings of abuse liability and mood, and cardiovascular measures, which were assessed at baseline and several time points after drug administration. Data analyses included repeated measures analysis of variance (ANOVA) with planned comparisons. RESULTS: CBD failed to consistently affect pain threshold and tolerance in the CPT relative to placebo. All doses of CBD increased ratings of painfulness compared to placebo (P

Background Preclinical data implicate the endocannabinoid system in the pathology underlying obsessive-compulsive disorder (OCD), while survey data have linked OCD symptoms to increased cannabis use. Cannabis products are increasingly marketed as treatments for anxiety and other OCD-related symptoms. Yet, few studies have tested the acute effects of cannabis on psychiatric symptoms in humans. Methods We recruited 14 adults with OCD and prior experience using cannabis to enter a randomized, placebo-controlled, human laboratory study to compare the effects on OCD symptoms of cannabis containing varying concentrations of Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on OCD symptoms to placebo. We used a within-subjects design to increase statistical power. Across three laboratory sessions, participants smoked three cannabis varietals in random order: placebo (0% THC/0% CBD); THC (7.0% THC/0.18% CBD); and CBD (0.4% THC/10.4% CBD). We analyzed acute changes in OCD symptoms, state anxiety, cardiovascular measures, and drug-related effects (e.g., euphoria) as a function of varietal. Results Twelve participants completed the study. THC increased heart rate, blood pressure, and intoxication compared with CBD and placebo. Self-reported OCD symptoms and anxiety decreased over time in all three conditions. Although OCD symptoms did not vary as a function of cannabis varietal, state anxiety was significantly lower immediately after placebo administration relative to both THC and CBD. Conclusions This is the first placebo-controlled investigation of cannabis in adults with OCD. The data suggest that smoked cannabis, whether containing primarily THC or CBD, has little acute impact on OCD symptoms and yields smaller reductions in anxiety compared to placebo.

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.

Risky decision-making is characteristic of drug users, but little is known about the effects of circumstances, such as abstinence, on risky choice behavior in human drug users. We hypothesized that cocaine users would make more risky choices for cocaine (defined as taking a chance to receive a large number of cocaine doses as opposed to choosing to receive a fixed amount of cocaine) after 3 or 7 days of cocaine abstinence, compared to 1 day of cocaine abstinence. Six male nontreatment-seeking current cocaine smokers were enrolled in a 21-day inpatient within-subject study. Participants repeatedly smoked six 25 mg doses of cocaine during a training session and were instructed that they would be making decisions about smoking this dose throughout the study. After 1, 3 and 7 days of cocaine abstinence, participants completed a computerized task in which they repeatedly decided between receiving a guaranteed number of cocaine doses (between 1 and 5; fixed option) or receiving a chance (0.13 to 0.75) to smoke a larger number of cocaine doses (probabilistic option). After completing the computerized task, one of the participants' choices was randomly implemented and they smoked either the fixed number of cocaine doses or had the specified chance to smoke the greater number of doses. Contrary to our hypothesis, 5 of the 6 participants made fewer risky choices after 3 and 7 days of cocaine abstinence compared to one day of abstinence suggesting greater risk-aversion. Thus, even during cocaine abstinence cocaine users make rational decisions related to their drug use.

The expanding legalization of cannabis across the United States is associated with increases in cannabis use, and accordingly, an increase in the number and severity of individuals with cannabis use disorder (CUD). The lack of FDA-approved pharmacotherapies and modest efficacy of psychotherapeutic interventions means that many of those who seek treatment for CUD relapse within the first few months. Consequently, there is a pressing need for innovative, evidence-based treatment development for CUD. Preliminary evidence suggests that repetitive transcranial magnetic stimulation (rTMS) may be a novel, non-invasive therapeutic neuromodulation tool for the treatment of a variety of substance use disorders (SUDs), including recently receiving FDA clearance (August 2020) for use as a smoking cessation aid in tobacco cigarette smokers. However, the potential of rTMS for CUD has not yet been reviewed. This paper provides a primer on therapeutic neuromodulation techniques for SUDs, with a particular focus on reviewing the current status of rTMS research in people who use cannabis. Lastly, future directions are proposed for rTMS treatment development in CUD, with suggestions for study design parameters and clinical endpoints based on current gold-standard practices for therapeutic neuromodulation research.

There are no FDA-approved treatments for cannabis use disorder (CUD). Preclinical research has shown that the 5HT-2c agonist, lorcaserin, attenuates cue-induced reinstatement of THC-seeking and self-administration. The goal of this placebo-controlled, counterbalanced, within-subject human laboratory study was to examine lorcaserin’s effects on cannabis intoxication and self-administration. Lorcaserin (10 mg BID) was administered during one of two 13-day inpatient phases, and placebo during the other; each phase was separated by ≥ 7-days of washout. Inpatient phases comprised: 1) standardized cannabis administration (7.0% THC) at no financial cost (intoxication), counterbalanced with 2) the option to self-administer cannabis following either 0 or 3 days of abstinence. Cognitive task performance, food intake, subjective ratings of drug effects, objective/subjective sleep measures, and tobacco cigarette use were also assessed. Fifteen normal-weight, daily cannabis users (4F, 11M) not seeking treatment for CUD completed the study. Lorcaserin significantly reduced cannabis self-administration following 0 and 3 days of cannabis abstinence, and also reduced craving for cannabis during abstinence. Lorcaserin produced small but significant increases in positive cannabis ratings and body weight relative to placebo. Lorcaserin also reduced tobacco cigarette smoking on days of cannabis administration relative to placebo. During abstinence, subjective but not objective measures of sleep quality worsened during lorcaserin maintenance. Overall, lorcaserin’s ability to decrease drug-taking and cannabis craving in non-treatment seeking cannabis users supports further investigation of 5HT-2C agonists as potential pharmacotherapies for CUD.

Background The absence of an FDA-approved medication for the treatment of cocaine use disorder (CUD) may, in part, reflect the varying conditions present when the decision to use cocaine is made, with one medication unlikely to work under all conditions. The objective of this double-blind, placebo-controlled, human laboratory study was to test the effects of modafinil, a medication with mixed efficacy for the treatment of CUD, using a novel self-administration procedure designed to model distinct clinical scenarios. Methods During modafinil maintenance (0, 300 mg/day), participants chose to self-administer up to 7 doses of smoked cocaine (25 mg) under 9 conditions: immediately after exposure to: (a) cues associated with cocaine and a non-contingent cocaine administration, i.e. 'prime' (25 mg), (b) only cocaine cues, and (c) neither cues nor cocaine. Each condition was tested when self-administered cocaine cost $5, $10 and $15/dose. Results Nontreatment-seeking cocaine smokers (3 F,13 M), spending $388 ± 218/week on cocaine and with no history of alcohol use disorder, completed the study. Relative to placebo, modafinil robustly attenuated self-administration when cocaine was expensive ($10,$15/dose) and when there was no 'prime.' Modafinil had no effect on self-administration when cocaine was inexpensive ($5/dose) or when participants received a 'prime.' Conclusions Modafinil's effects on cocaine-taking varied substantially as a function of recent cocaine exposure and cost, which may help explain the mixed clinical findings. Modafinil may be most effective for preventing relapse in abstinent patients, particularly under conditions in which cocaine is costly, rather than initiating abstinence for those continuing to use cocaine.

Illicit drug use among aging cohorts is increasing, yet little is known about functional impairments in older drug users. Given the importance of social integration for aging and documented social decrements in cocaine users, we examined social function and its neurocognitive substrates in aging cocaine users relative to carefully matched non-cocaine users. Regular (≥twice/week), long-term (≥15 years) cocaine smokers 50-60 years old (COCs; n = 22; four women) and controls (CTRLs; n = 19; four women) underwent standardized probes of social reward and threat processing during functional magnetic resonance imaging and a behavioral facial affect recognition task. Self-report and peer-report of daily interpersonal function were also collected. COCs, and CTRLs reporting current marijuana or alcohol use, were tested after four drug-free inpatient days. COCs had pronounced problems in daily social function relative to CTRLs indicated by both their own and their peers' reports. Compared with CTRLs, COCs had stronger amygdala responses to social threat versus control stimuli, with no other differences in social processing or cognition. Aging cocaine users appear to have marked, generalized difficulties in 'real-world' interpersonal function but largely intact social processing on laboratory-based measures when compared with appropriately matched controls and tested under well-controlled conditions. Daily social difficulties may be related to transient factors such as acute/residual drug effects or cocaine-related changes in health behaviors (e.g. disrupted sleep and poor diet). These data suggest that interpersonal function may be a valid intervention target for aging cocaine users and warrants further study in older drug users.

Background Stress responding is linked to drug use, but little is known about stress responses in cannabis smokers. We investigated acute stress responding in cannabis smokers as a function of trauma exposure and sex, and relationships between stress responses and cannabis relapse. Methods 125 healthy, non-treatment-seeking daily cannabis smokers (23F, 102 M) completed the Trier Social Stress Task (TSST), a standardized laboratory stressor; subsets also completed a trauma questionnaire ( n = 106) and a laboratory cannabis relapse measure ( n = 54). Stress responding was assessed with heart rate (HR), salivary cortisol (CORT), and self-rated mood. Results Cannabis smokers reporting at least one trauma exposure had higher CORT and anxiety overall compared to those reporting no trauma. Stress responding did not differ as a function of binary trauma exposure, although total number of exposures correlated positively with CORT and anxiety during stress. Females reported increased nervousness after stress relative to males matched to the females for cannabis and cigarette use. An interactive effect of sex and trauma on HR suggested that females with trauma exposure have increased cardiovascular stress responding relative to those without such exposure, with no differential effect in males. Stress responding did not predict laboratory cannabis relapse. Conclusion We report differences in acute stress responding as a function of trauma, sex, and their interaction in a large sample of relatively homogenous cannabis smokers. Further investigation of how trauma impacts stress responding in male and female cannabis smokers, and how this relates to different aspects of cannabis use, is warranted.

Individuals who work nonstandard schedules, such as rotating or night shifts, are more susceptible to workplace injuries, performance decrements, and reduced productivity. This population is also almost twice as likely to use illicit drugs as individuals working a standard day shift. The purpose of this study was to examine the effects of smoked marijuana on performance, mood, and sleep during simulated shift work. Ten experienced marijuana smokers completed this 23-day, within-participant residential study. They smoked a single marijuana cigarette (0, 1.9, 3.56% Δ9-THC) one hour after waking for three consecutive days under two shift conditions: day shift and night shift. Shifts alternated three times during the study, and shift conditions were separated by an ‘off’ day. When participants smoked placebo cigarettes, psychomotor performance and subjective-effect ratings were altered during the night shift compared to the day shift: performance (e.g., vigilance) and a few subjective ratings were decreased (e.g., “Self-Confident”), whereas other ratings were increased (e.g., “Tired”). Objective and subjective measures of sleep were also disrupted, but to a lesser extent. Marijuana attenuated some performance, mood, and sleep disruptions: participants performed better on vigilance tasks, reported being less miserable and tired and sleep a greater number of minutes. Limited negative effects of marijuana were noted. These data demonstrate that abrupt shift changes produce performance, mood, and sleep decrements during night shift work and that smoked marijuana containing low to moderate Δ9-THC concentrations can offset some of these effects in frequent marijuana smokers.

Introduction: Obsessive-compulsive disorder (OCD) is a disabling illness that is associated with significant functional impairment. Although evidence-based pharmacotherapies exist, currently available medications are ineffective in some patients and may cause intolerable side effects in others. There is an urgent need for new treatments. Discussion: A growing body of basic and clinical research has showed that the endocannabinoid system (ECS) plays a role in anxiety, fear, and repetitive behaviors. At the same time, some patients with OCD who smoke cannabis anecdotally report that it relieves their symptoms and mitigates anxiety, and several case reports describe patients whose OCD symptoms improved after they were treated with cannabinoids. Taken together, these findings suggest that the ECS could be a potential target for novel medications for OCD. In this study, we review evidence from both animal and human studies that suggests that the ECS may play a role in OCD and related disorders. We also describe findings from studies in which cannabinoid drugs were shown to impact symptoms of these conditions. Conclusions: An emerging body of evidence suggests that the ECS plays a role in OCD symptoms and may be a target for the development of novel medications. Further exploration of this topic through well-designed human trials is warranted.

Little is known about the functional status of older drug users, who may pose challenges to public health systems in coming years. Here, we assessed cognitive function in aging cocaine smokers compared to demographically matched controls.A total of 22 non-treatment-seeking aging (50-60 years old) cocaine smokers (⩾twice/week; ⩾15 years of weekly use) and 19 controls completed a comprehensive cognitive battery. Controls with cannabis, tobacco, and alcohol use were included to better match the cocaine users. All cocaine users, and current cannabis- or alcohol-using controls, completed testing after 4 drug-free inpatient days to better control for acute and residual drug effects.Cocaine users (52.9 ± 2.5 years old, four female; cocaine use 3.9 ± 1.4 days/week) and controls (52.7 ± 2.6 years old, four female) were well matched demographically, but cocaine users reported a more extensive substance use profile. Cocaine users showed marginally worse verbal learning than controls, recalling on average one word fewer across immediate and delayed word recall trials. Their performance was intact relative to controls across all other measures of cognitive function. Bayesian analysis indicated the absence of group differences was not due to power limitations.These data suggest that aging, long-term cocaine users have similar cognitive functioning to appropriately matched controls when tested under drug-free conditions, with only marginal decreases in verbal learning. Findings, although reassuring with regard to broad cognitive capacities in aging cocaine smokers, suggest that future investigations of cognitive function in aging drug users are warranted.

Preclinical studies demonstrate that cannabinoid-mediated antinociceptive effects vary according to sex; it is unknown if these findings extend to humans.This retrospective analysis compared the analgesic, subjective and physiological effects of active cannabis (3.56-5.60% THC) and inactive cannabis (0.00% THC) in male (N=21) and female (N=21) cannabis smokers under double-blind, placebo-controlled conditions. Pain response was measured using the Cold-Pressor Test (CPT). Participants immersed their hand in cold water (4°C); times to report pain (pain sensitivity) and withdraw the hand (pain tolerance) were recorded. Subjective drug ratings were also measured.Among men, active cannabis significantly decreased pain sensitivity relative to inactive cannabis (p0.01). In women, active cannabis failed to decrease pain sensitivity relative to inactive. Active cannabis increased pain tolerance in both men women immediately after smoking (p0.001); a trend was observed for differences between men and women (p0.10). Active cannabis also increased subjective ratings of cannabis associated with abuse liability ('Take again,' 'Liking,' 'Good drug effect'), drug strength, and 'High' relative to inactive in both men and women (p0.01).These results indicate that in cannabis smokers, men exhibit greater cannabis-induced analgesia relative to women. These sex-dependent differences are independent of cannabis-elicited subjective effects associated with abuse-liability, which were consistent between men and women. As such, sex-dependent differences in cannabis's analgesic effects are an important consideration that warrants further investigation when considering the potential therapeutic effects of cannabinoids for pain relief.

Marijuana use is associated with psychosis, but its effects are understudied in individuals with preexisting risk for psychotic disorders. This preliminary study examined the acute psychological and physiological effects of smoked marijuana (0.0% or 5.5% Δ9-THC) in marijuana users at clinical high-risk (CHR; n = 6) to develop a psychotic disorder, and those not at risk (n = 6), under controlled laboratory conditions. CHR marijuana users exhibited temporary increases in psychotic-like states and decreases in neurocognitive performance during marijuana intoxication but control marijuana smokers did not. These findings, if replicated, may support a psychotogenic role for marijuana in CHR individuals.

This chapter describes the use of human laboratory procedures to characterize key behavioral features of cannabis use disorder (CUD). First, we provide a brief overview of recent shifts in cannabis policy in the United States and how these policy changes may affect CUD prevalence. This overview is followed by sections describing the scientific rationale, and methodologies used, for studying discrete behavioral features of CUD (intoxication, positive reinforcing effects, tolerance, withdrawal, abstinence initiation, and relapse) under carefully controlled human laboratory conditions. The methodological primer is followed by sections that summarize studies that have used human laboratory models to examine various classes of medications as potential treatments for CUD. We then conclude with a discussion that synthesizes the results of these studies into the broader CUD treatment development literature, examining potential ways in which human laboratory and clinical trial research methodologies could be further refined.

Cannabis is the most widely used illicit drugs and the changing legal, political and cultural climate will likely increase cannabis use further. One factor that may underlie the transition from recreational use to problematic use is stress. The hormone oxytocin (OXT) modulates stress and may have therapeutic efficacy for substance use disorders, but few studies have examined OXT in cannabis users. Another factor is sex; although more men smoke cannabis, the transition from recreational to problematic use is faster in women. Using a within-subjects design, the effects of intranasal (i.n.) oxytocin (OXT; 40 IU) administration on stress reactivity (using the Trier Social Stress Test; TSST) and cannabis (5.6% THC) self-administration was assessed in recreational cannabis using men (n = 31) and women (n = 32) relative to i.n. placebo (PBO) and no-stress (NST) conditions. The TSST produced expected subjective and cardiovascular effects compared to the NST. However, in the i.n. OXT-TSST condition, positive subjective effects were lower and negative subjective effects were higher in women compared to PBO administration and compared to men. Further, latency to self-administer cannabis was longer in women than men and women self-administered less cannabis than men regardless of stress condition. There were no differences in cannabis craving as a function of sex, stress, or medication. These results suggest that OXT administration may lead to greater stress reactivity in recreational cannabis users, particularly women, and support growing evidence that sex differences should be carefully considered when examining the therapeutic potential of OXT.

Illicit drug use among aging cohorts is increasing, yet little is known about functional impairments in older drug users. Given the importance of social integration for aging and documented social decrements in cocaine users, we examined social function and its neurocognitive substrates in aging cocaine users relative to carefully matched non-cocaine users. Regular (≥twice/week), long-term (≥15 years) cocaine smokers 50-60 years old (COCs; n = 22; four women) and controls (CTRLs; n = 19; four women) underwent standardized probes of social reward and threat processing during functional magnetic resonance imaging and a behavioral facial affect recognition task. Self-report and peer-report of daily interpersonal function were also collected. COCs, and CTRLs reporting current marijuana or alcohol use, were tested after four drug-free inpatient days. COCs had pronounced problems in daily social function relative to CTRLs indicated by both their own and their peers' reports. Compared with CTRLs, COCs had stronger amygdala responses to social threat versus control stimuli, with no other differences in social processing or cognition. Aging cocaine users appear to have marked, generalized difficulties in 'real-world' interpersonal function but largely intact social processing on laboratory-based measures when compared with appropriately matched controls and tested under well-controlled conditions. Daily social difficulties may be related to transient factors such as acute/residual drug effects or cocaine-related changes in health behaviors (e.g. disrupted sleep and poor diet). These data suggest that interpersonal function may be a valid intervention target for aging cocaine users and warrants further study in older drug users.

Human drug use involves repeated choices to take drugs or to engage in alternative behaviors. The purpose of this study was to examine how response cost for cocaine and the value of an alternative reinforcer (opportunity to play a game of chance) and how ‘free’ doses (with minimal response cost) affected cocaine choice. Two laboratory studies of cocaine self-administration were conducted in a group of humans who were habitual cocaine smokers and in a group of rhesus monkeys that intravenously self-administered cocaine. Nine human cocaine smokers who were not seeking treatment for their cocaine were repeatedly presented with the choice to smoke 25 mg cocaine base or play a game of chance for a monetary bonus paid at study completion. The response cost for choosing cocaine varied (up to 4000 responses/dose) and the number of game plays varied (up to 8). In this sample of humans, increasing either the response cost for cocaine or increasing the value of the alternative reinforcer did not significantly affect cocaine choice, while increasing both simultaneously slightly decreased cocaine choice and increased choice of the alternative. In monkeys, the dose–response function for cocaine self-administration (10 choices of 0.0125–0.1 mg/kg/infusion vs. candy coated chocolate) was steep and we failed to achieve a 50/50 cocaine/candy choice even after substantially manipulating cost and number of candies available. Providing a large ‘free’ self-administered cocaine dose to humans did not significantly affect cocaine choice, whereas in monkeys, a large free dose of cocaine decreased cocaine choice when higher doses of cocaine were available for self-administration. The present results demonstrate that in the laboratory, it is difficult to modify on-going cocaine self-administration behavior in both humans and non-human primates.

The α2a-adrenergic agonist, lofexidine, reduced cannabis withdrawal-related sleep disruption in the laboratory, but side effects (e.g. fatigue, hypotension) limit its utility as a treatment for cannabis use disorder. This study tested the potential efficacy and tolerability of a daily bedtime administration of the FDA-approved α2a-adrenergic agonist, guanfacine, in a human laboratory model of cannabis use disorder. Daily, nontreatment-seeking cannabis smokers (13M, 2F) completed a within-subject study comprising two 9-day inpatient study phases. Each phase tested the effects of daily placebo or immediate-release guanfacine (2 mg) on cannabis intoxication (5.6 percent THC; 2 days), withdrawal (4 days of abstinence) and subsequent 'relapse' (3 days of cannabis self-administration). Ratings of mood, sleep, cardiovascular effects, food intake, psychomotor performance and cannabis self-administration were assessed. An outpatient phase preceded each inpatient phase for medication clearance or dose induction. Under placebo medication conditions, cannabis abstinence produced significant withdrawal, including irritability, sleep disruption and anorexia. Guanfacine reduced ratings of irritability and improved objective measures of sleep during cannabis withdrawal relative to placebo but did not reduce cannabis self-administration. Guanfacine was well tolerated with little evidence of fatigue and only small decreases in blood pressure: no dose was held due to hypotension. Thus, a single daily administration of guanfacine at bedtime improved sleep and mood during cannabis withdrawal relative to placebo. This positive signal supports further studies varying the guanfacine dose, formulation or frequency of administration, or combining it with other medications to increase the likelihood of having an impact on cannabis use.

Women exhibit an accelerated progression from first cannabis use to cannabis use disorder (CUD) and show pronounced negative clinical issues related to CUD relative to men. Whether sex-dependent differences in cannabis' direct effects contribute to the heightened risk in women is unknown. This analysis directly compared cannabis' abuse-related subjective effects in men and women matched for current cannabis use.Data from four double-blind, within-subject studies measuring the effects of active cannabis (3.27-5.50% THC, depending on study) relative to inactive cannabis (0.00% THC) were combined for this analysis. Data from equal numbers of men and women from each study matched for current cannabis use were pooled (total n=35 men; 35 women); cannabis' effects were analyzed according to cannabis condition (active versus inactive) and sex.Active cannabis produced more robust subjective effects associated with abuse liability ('Good,' 'Liking,' 'Take Again') and intoxication ('High,' 'Stimulated') relative to inactive cannabis (p≤0.0001). Women reported higher ratings of abuse-related effects ['Take Again' and 'Good' (p≤0.05)] relative to men under active cannabis conditions but did not differ in ratings of intoxication. Active cannabis increased heart rate (p≤0.0001) equally for both sexes.The results from this study suggest that when matched for cannabis use, women are more sensitive to the subjective effects related to cannabis' abuse liability relative to men, which may contribute to the enhanced vulnerability to developing CUD. Thus, sex is an important variable to consider when assessing the development of CUD.

Despite the prevalent worldwide abuse of stimulants, such as amphetamines and cocaine, no medications are currently approved for treating this serious public health problem. Both preclinical and clinical studies suggest that the opioid antagonist naltrexone (NTX) is effective in reducing the abuse liability of amphetamine, raising the question of whether similar positive findings would be obtained for cocaine. The purpose of this study was to evaluate the ability of oral NTX to alter the cardiovascular and subjective effects of D-amphetamine (D-AMPH) and cocaine (COC). Non-treatment-seeking COC users (N=12) completed this 3-week inpatient, randomized, crossover study. Participants received 0, 12.5, or 50 mg oral NTX 60 min before active or placebo stimulant administration during 10 separate laboratory sessions. Oral AMPH (0, 10, and 20 mg; or all placebo) was administered in ascending order within a laboratory session using a 60-min interdose interval. Smoked COC (0, 12.5, 25, and 50 mg; or all placebo) was administered in ascending order within a laboratory session using a 14-min interdose interval. Active COC and AMPH produced dose-related increases in cardiovascular function that were of comparable magnitude. In contrast, COC, but not AMPH, produced dose-related increases in several subjective measures of positive drug effect (eg, high, liking, and willingness to pay for the drug). NTX did not alter the cardiovascular effects of AMPH or COC. NTX also did not alter positive subjective ratings after COC administration, but it did significantly reduce ratings of craving for COC and tobacco during COC sessions. These results show that (1) oral AMPH produces minimal abuse-related subjective responses in COC smokers, and (2) NTX reduces craving for COC and tobacco during COC sessions. Future studies should continue to evaluate NTX as a potential anti-craving medication for COC dependence.

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

Background Few marijuana smokers in treatment achieve sustained abstinence, yet factors contributing to high relapse rates are unknown. Methods Study 1: data from five inpatient laboratory studies assessing marijuana intoxication, withdrawal, and relapse were combined to assess factors predicting the likelihood and severity of relapse. Daily, nontreatment-seeking marijuana smokers ( n = 51; 10 ± 5 marijuana cigarettes/day) were enrolled. Study 2: to isolate the effects of cigarette smoking, marijuana intoxication, withdrawal, and relapse were assessed in daily marijuana and cigarette smokers ( n = 15) under two within-subject, counter-balanced conditions: while smoking tobacco cigarettes as usual (SAU), and after at least 5 days without cigarettes (Quit). Results Study 1: 49% of participants relapsed the first day active marijuana became available. Tobacco cigarette smokers (75%), who were not abstaining from cigarettes, were far more likely to relapse than non-cigarette smokers (odds ratio: 19, p .01). Individuals experiencing more positive subjective effects (i.e., feeling "high") after marijuana administration and those with more negative affect and sleep disruption during marijuana withdrawal were more likely to have severe relapse episodes ( p 87%) relapsed to marijuana whether in the SAU or Quit phase. Tobacco cigarette smoking did not significantly influence relapse, nor did it affect marijuana intoxication or most symptoms of withdrawal relative to tobacco cessation. Conclusions Daily marijuana smokers who also smoke cigarettes have high rates of marijuana relapse, and cigarette smoking versus recent abstinence does not directly influence this association. These data indicate that current cigarette smoking is a clinically important marker for increased risk of marijuana relapse.

Opioid use disorder (OUD) is a major public health problem. High relapse rates and poor treatment retention continue to pose major challenges in OUD treatment. Of the abused opioids, oxycodone is well described to maintain self-administration and evoke the durable conditioned responses (“cue reactivity”) that result from pairing of opioid-related stimuli (e.g., paraphernalia) with repeated abuse. Serotonin (5-HT) neurotransmission, particularly through the 5-HT2C receptor (5-HT2CR), regulates psychostimulant reward and cue reactivity, and in the present experiments, we investigated the hypothesis that the selective 5-HT2CR agonist lorcaserin, which is FDA-approved for the treatment of obesity, will suppress oxycodone self-administration and oxycodone-associated cue reactivity in rats. We found that lorcaserin inhibited oxycodone intake, an effect blocked by the selective 5-HT2CR antagonist SB242084. Lorcaserin also decreased responding for the discrete cue complex (“cue reactivity”) previously associated with delivery of oxycodone (i.e., stimulus lights, infusion pump sounds) in both abstinence and extinction-reinstatement models. The selected dose range of lorcaserin (0.25–1 mg/kg) does not overtly alter spontaneous behaviors nor operant responding on inactive levers in the present study. Taken together, the ability of lorcaserin to reduce the oxycodone self-administration and decrease cue reactivity associated with relapse highlights the therapeutic potential for lorcaserin in the treatment of OUD.

Most drugs of abuse lead to a general blunting of dopamine release in the chronic phase of dependence, which contributes to poor outcome. To test whether cannabis dependence is associated with a similar dopaminergic deficit, we examined striatal and extrastriatal dopamine release in severely cannabis-dependent participants (CD), free of any comorbid conditions, including nicotine use. Eleven CD and 12 healthy controls (HC) completed two positron emission tomography scans with [(11)C]-(+)-PHNO, before and after oral administration of d-amphetamine. CD stayed inpatient for 5-7 days prior to the scans to standardize abstinence. Magnetic resonance spectroscopy (MRS) measures of glutamate in the striatum and hippocampus were obtained in the same subjects. Percent change in [(11)C]-(+)-PHNO-binding potential (ΔBPND) was compared between groups and correlations with MRS glutamate, subclinical psychopathological and neurocognitive parameters were examined. CD had significantly lower ΔBPND in the striatum (P=0.002, effect size (ES)=1.48), including the associative striatum (P=0.003, ES=1.39), sensorimotor striatum (P=0.003, ES=1.41) and the pallidus (P=0.012, ES=1.16). Lower dopamine release in the associative striatum correlated with inattention and negative symptoms in CD, and with poorer working memory and probabilistic category learning performance in both CD and HC. No relationships to MRS glutamate and amphetamine-induced subclinical positive symptoms were detected. In conclusion, this study provides evidence that severe cannabis dependence-without the confounds of any comorbidity-is associated with a deficit in striatal dopamine release. This deficit extends to other extrastriatal areas and predicts subclinical psychopathology

Background Cannabidiol (CBD) is a naturally occurring constituent of the marijuana plant. In the past few years, there has been great interest in the therapeutic effects of isolated CBD and it is currently being explored for numerous disease conditions (e.g., pain, epilepsy, cancer, various drug dependencies). However, CBD remains a Schedule I drug on the U.S. Controlled Substances Act (CSA). Despite its status, there are no well-controlled data available regarding its abuse liability. Methods Healthy, frequent marijuana users (n = 31) were enrolled in this within subject, randomized, placebo-controlled, double-blind, multisite study that administered oral cannabidiol (0, 200, 400, 800 mg) alone and in combination with smoked marijuana (0.01%, 5.3–5.8% THC). Participants received one dose combination across 8 once-weekly outpatient sessions (7.5 h). The primary findings on the drug interaction effects were previously reported ( Haney et al., 2016 ). The present study is a secondary analysis of the data to examine the abuse liability profile of oral cannabidiol (200, 400, 800 mg) in comparison to oral placebo and active smoked marijuana (5.3–5.8% THC). Results Active marijuana reliably produced abuse-related subjective effects (e.g., high) (p 0.05). Conclusions Overall, CBD did not display any signals of abuse liability at the doses tested and these data may help inform U.S. regulatory decisions regarding CBD schedule on the CSA.

Marijuana withdrawal contributes to the high relapse rates in individuals seeking treatment for marijuana-use disorders. Quetiapine, an atypical antipsychotic, reduces characteristic symptoms of marijuana withdrawal in a variety of psychiatric conditions, including mood lability, sleep disruption and anorexia. This human laboratory study investigated the effectiveness of quetiapine to decrease marijuana withdrawal and relapse to marijuana use in non-treatment-seeking marijuana smokers. Volunteers were maintained on placebo or quetiapine (200 mg/day) in this double-blind, counter-balanced, within-subject study consisting of two 15-day medication phases, the last 8 days of which were in-patient. On the first in-patient day, active marijuana [6.2% delta (9)-tetrahydrocannabinol (THC)] was repeatedly smoked under controlled conditions. For the next 3 days, inactive marijuana (0.0% THC) was available for self-administration (withdrawal). On the subsequent 4 days, active marijuana (6.2% THC) was available for self-administration (relapse). Volunteers (n = 14) who smoked an average of 10 marijuana cigarettes/day, 7 days/week, completed the study. Under placebo, withdrawal was marked by increased subjective ratings of negative mood, decreased sleep quality, and decreased caloric intake and weight loss. Compared with placebo, quetiapine improved sleep quality, increased caloric intake and decreased weight loss. However, quetiapine increased marijuana craving and marijuana self-administration during the relapse phase. These data do not suggest that quetiapine shows promise as a potential treatment for marijuana dependence.

Marijuana dependence is a substantial public health problem, with existing treatments showing limited efficacy. In laboratory and clinical studies, the cannabinoid receptor 1 agonist oral Δ9tetrahydrocannabinol (THC; dronabinol) has been shown to decrease marijuana withdrawal but not relapse. Dronabinol has poor bioavailability, potentially contributing to its failure to decrease relapse. The synthetic THC analogue, nabilone, has better bioavailability than dronabinol. We therefore aimed to characterize nabilone's behavioral and physiological effects across a range of acute doses in current marijuana smokers and compare these with dronabinol's effects. Participants (4 female; 10 male) smoking marijuana 6.6 (standard deviation = 0.7) days/week completed this outpatient, within-subjects, double-blind, randomized protocol. Over seven sessions, the time-dependent subjective, cognitive and cardiovascular effects of nabilone (2, 4, 6, 8 mg), dronabinol (10, 20 mg) and placebo were assessed. Nabilone (4, 6, 8 mg) and dronabinol (10, 20 mg) increased ratings of feeling a good effect, a strong effect and/or 'high' relative to placebo; nabilone had a slower onset of peak subjective effects than dronabinol. Nabilone (6, 8 mg) modestly lowered psychomotor speed relative to placebo and dronabinol. There were dose-dependent increases in heart rate after nabilone, and nabilone (2 mg) and dronabinol (10 mg) decreased systolic blood pressure. Thus, nabilone produced sustained, dose-related increases in positive mood, few cognitive decrements and lawful cardiovascular alterations. It had a longer time to peak effects than dronabinol, and effects were more dose-related, suggesting improved bioavailability. Nabilone was well tolerated by marijuana smokers, supporting further testing as a potential medication for marijuana dependence.

Despite their chemical similarities, methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) produce differing neurochemical and behavioral responses in animals. In humans, individual studies of methamphetamine and MDMA indicate that the drugs engender overlapping and divergent effects; there are only limited data comparing the two drugs in the same individuals.This study examined the effects of methamphetamine and MDMA using a within-subject design.Eleven adult volunteers completed this 13-day residential laboratory study, which consisted of four 3-day blocks of sessions. On the first day of each block, participants received oral methamphetamine (20, 40 mg), MDMA (100 mg), or placebo. Drug plasma concentrations, cardiovascular, subjective, and cognitive/psychomotor performance effects were assessed before drug administration and after. Food intake and sleep were also assessed. On subsequent days of each block, placebo was administered and residual effects were assessed.Acutely, both drugs increased cardiovascular measures and "positive" subjective effects and decreased food intake. In addition, when asked to identify each drug, participants had difficulty distinguishing between the amphetamines. The drugs also produced divergent effects: methamphetamine improved performance and disrupted sleep, while MDMA increased "negative" subjective-effect ratings. Few residual drug effects were noted for either drug.It is possible that the differences observed could explain the differential public perception and abuse potential associated with these amphetamines. Alternatively, the route of administration by which the drugs are used recreationally might account for the many of the effects attributed to these drugs (i.e., MDMA is primarily used orally, whereas methamphetamine is used by routes associated with higher abuse potential).

Partial dopamine receptor agonists have been proposed as candidate pharmacotherapies for cocaine dependence.This 42-day, within-subject, human laboratory study assessed how maintenance on aripiprazole, a partial D(2) receptor agonist, influenced smoked cocaine self-administration, cardiovascular measures, subjective effects, and cocaine craving in nontreatment-seeking, cocaine-dependent volunteers.In order to achieve steady-state concentrations, participants (n = 8 men) were administered placebo and aripiprazole (15 mg/day) capsules in counter-balanced order for 21 days. A smoked cocaine dose-response curve (0, 12, 25, 50 mg) was determined twice under placebo and aripiprazole maintenance. Sessions comprised a "sample" trial, when participants smoked the cocaine dose available that session, and five choice trials, when they responded on a progressive-ratio schedule of reinforcement to receive the cocaine dose or receive $5.00.Cocaine's reinforcing, subjective, and cardiovascular effects were dose-dependent. Aripiprazole significantly increased cocaine (12, 25 mg) self-administration. Following a single administration of cocaine (25 mg), aripiprazole decreased ratings of how much participants would pay for that dose. Following repeated cocaine (50 mg) self-administration, aripiprazole decreased ratings of cocaine quality, craving, and good drug effect as compared to placebo.These data suggest that aripiprazole may have increased self-administration to compensate for a blunted subjective cocaine effect. Overall, the findings do not suggest aripiprazole would be useful for treating cocaine dependence.

Zolpidem attenuates shift-change-related sleep and performance disruptions. It is unknown whether these benefits alter the reinforcing effects of the drug during shift work. This study examined zolpidem-related reinforcing effects during simulated shift work. Eleven volunteers (3F, 8M) completed this 16-day within-participant, residential laboratory study. Each day participants were given an opportunity to self-administer oral zolpidem (10 mg) or receive a $1 voucher immediately following a 9-h work period and immediately before going to bed. Participants worked under two shift conditions: (1) during the night shift, participants completed computerized task batteries from 00:30 to 09:30 h and went to bed at 16:00 h and (2) during the day shift, participants completed task batteries from 08:30 to 17:30 h and went to bed at 24:00 h. Shift conditions alternated three times during the study. Despite the fact that sleep, psychomotor performance, and some ratings of mood were disrupted during night-shift work, there was no significant effect of shift on choice to take zolpidem. Overall, participants selected markedly fewer zolpidem doses than monetary vouchers (17% versus 83%). Thus, zolpidem did not serve as a reinforcer even when sleep was disrupted. These data are consistent with previous reports indicating that sedatives produce limited reinforcing effects in individuals without a history of drug abuse.

Studies in laboratory animals strongly suggest reciprocal modulation of the opioidergic and endocannabinoid systems, a relationship that has not been demonstrated in humans. This study sought to clarify this interaction by assessing how a range of naltrexone doses altered the subjective, cognitive, and cardiovascular effects of marijuana.Daily marijuana smokers (n = 29) participated in this within-subject, randomized, double-blind, placebo-controlled study. Naltrexone (0, 12, 25, 50, or 100 mg) was administered before active or inactive marijuana (3.27 or 0% THC) was smoked.Active marijuana increased subjective ratings of marijuana 'Strength,' 'High,' and positive subjective ratings of marijuana quality and drug effect including 'Liking,' 'Good,' and 'Take Again' compared to inactive marijuana. Naltrexone alone decreased ratings of 'Liking,' 'Take Again,' and 'Stimulated' compared with placebo, but increased ratings of drug 'Strength,' 'High,' 'Good,' 'Liking,' 'Stimulated,' and 'Take Again' when administered under active marijuana conditions. Active marijuana did not affect performance on cognitive tasks relative to inactive marijuana, whereas naltrexone decreased performance when administered alone or in combination with active marijuana. Active marijuana increased heart rate compared to inactive marijuana under placebo naltrexone conditions. Although naltrexone alone decreased heart rate, it further increased marijuana's cardiovascular effect.In heavy marijuana smokers opioid-receptor blockade enhanced the subjective and cardiovascular effects of marijuana, suggesting that endogenous opioids dampen cannabinoid effects in this population. These findings demonstrate that a broad range of clinically used doses of naltrexone potentially increases the abuse liability and cardiovascular risks of cannabinoids.

The purpose of this double-blind, randomized, outpatient study was to evaluate the reinforcing and subjective effects of modafinil (200, 400, or 600 mg) in cocaine abusers. Twelve participants (2 female, 10 male) completed this study, consisting of 3 blocks of 7 sessions; each block tested a difference dose of modafinil. During the first 2 sessions of each block, participants "sampled" 1 of the doses of modafinil, and placebo. These doses of modafinil and placebo were available for the subsequent five choice sessions of the block. In each choice session, participants had an opportunity to administer active or placebo capsules. Modafinil administration did not differ from placebo administration, and subjective-effects ratings were not systematically altered as a function of modafinil dose. Results suggest that modafinil does not have abuse liability in cocaine abusers.

A post hoc analysis examined depressive symptoms in regular marijuana smokers interested in nontreatment, laboratory studies, and marijuana-dependent treatment-seekers considering clinical trial participation. Among marijuana-dependent treatment-seeking patients screened for a clinical trial, the mean Beck Depression Inventory Score (BDI) was significantly higher than for marijuana-using volunteers screened for nontreatment laboratory studies. Mean self-reported baseline marijuana use was not significantly different between groups, and BDI score was not correlated with use. Although the methods by which the two groups were selected influenced their characteristics (i.e., treatment-seekers are more likely to be experiencing some degree of clinical distress), it is notable that treatment-seeking, and not marijuana use per se, is associated with significantly higher rates of depression.