Learning from lorcaserin: lessons from the negative clinical trial of lorcaserin to treat cocaine use disorder.
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SUBMITTER: Negus SS
PROVIDER: S-EPMC7547654 | biostudies-literature | 2020 Nov
REPOSITORIES: biostudies-literature
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Learning from lorcaserin: lessons from the negative clinical trial of lorcaserin to treat cocaine use disorder.
Negus S Stevens SS Banks Matthew L ML
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20200824 12
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Project description:Background and Objectives: Preclinical studies show serotonin (5-HT) 5-HT2C receptor (5-HT2CR) agonists reduce cocaine-seeking and cocaine intake. This study examined safety of the 5-HT2CR agonist lorcaserin administered with cocaine in participants with cocaine use disorder (CocUD). Secondarily, subjective response to cocaine and choice of cocaine vs. money were examined. Methods: A double-blind, randomized, placebo-controlled trial of 25 inpatient non-treatment seeking participants with CocUD. Participants were randomized to either lorcaserin (n = 17) or placebo (n = 8). Primary outcome measures included cardiovascular measures and plasma cocaine levels. Secondary measures of subjective response to cocaine were assessed using a visual analog scale (VAS) and cocaine vs. money progressive ratio choice sessions. Results: Thirteen randomized participants were included in the final analysis. No serious or unexpected adverse events were related to lorcaserin. There were no significant interactions between cocaine and lorcaserin on cardiovascular measures, plasma cocaine, or subjective ratings. After multiple comparisons correction, cocaine significantly increased blood pressure, heart rate, and QTc. Lorcaserin significantly decreased VAS ratings of "feel irritable," "feel hungry," and "I am craving." For the cocaine vs. money choice procedure, there was a significant interaction between choice (cocaine vs. money) and lorcaserin. Participants treated with lorcaserin were more likely to choose cocaine. Discussion and Conclusions: This study showed safety of lorcaserin administered with cocaine but lack of efficacy to reduce the reinforcing effects of cocaine. Scientific Significance: This study is the first to show a disconnect between effects of 5-HT2CR agonists on craving and cocaine choice in human cocaine users.
| S-EPMC8283411 | biostudies-literature
Project description:ObjectiveTo determine if men who have sex with men (MSM) with cocaine use disorder (CUD) and actively-using cocaine could be enrolled and retained in a pharmacologic intervention trial of lorcaserin-a novel 5-HT2cR agonist-and determine the degree to which participants would adhere to study procedures.MethodsThis was a phase II randomized, double-blind, placebo-controlled pilot study with 2:1 random parallel group assignment to daily extended-release oral lorcaserin 20 mg versus placebo (clinicaltrials.gov identifier-NCT03192995). Twenty-two of a planned 45 cisgender MSM with CUD were enrolled and had weekly follow-up visits during a 12-week treatment period, with substance use counseling, urine specimen collection, and completion of audio-computer assisted self-interview (ACASI) behavioral risk assessments. Adherence was measured by medication event monitoring systems (MEMS) caps and self-report. This study was terminated early because of an FDA safety alert for lorcaserin's long-term use.ResultsEighty-six percent completed the trial, with 82% of weekly study follow-up visits completed. Adherence was 55.3% (lorcaserin 51.6% vs. placebo 66.2%) by MEMS cap and 56.9% (56.5% vs. placebo 57.9%) by self-report and did not differ significantly by treatment assignment. Intention-to-treat analyses (ITT) did not show differences in cocaine positivity by urine screen between the lorcaserin and placebo groups by 12 week follow-up (incidence risk ratio [IRR]: 0.96; 95%CI = 0.24-3.82, P = 0.95). However, self-reported cocaine use in timeline follow-back declined more significantly in the lorcaserin group compared to placebo (IRR: 0.66; 95%CI = 0.49-0.88; P = 0.004).ConclusionWe found that it is feasible, acceptable, and tolerable to conduct a placebo-controlled pharmacologic trial for MSM with CUD who are actively using cocaine. Lorcaserin was not associated with significant reductions in cocaine use by urine testing, but was associated with significant reductions in self-reported cocaine use. Future research may be needed to continue to explore the potential utility of 5-HT2cR agonists.
| S-EPMC8282062 | biostudies-literature
Project description:BackgroundMedication development research for cocaine use disorder (CUD) has been a longstanding goal in addiction research, but has not resulted in an FDA-approved treatment. Rising cocaine use rates underscore the need for efficient adaptive designs. This study compared differences between two doses of the selective serotonin reuptake inhibitor (SSRI) citalopram (versus placebo) on duration of cocaine abstinence and applied adaptive decision rules to select the 'best efficacy' dose.MethodsA double-blind, placebo-controlled, randomized Bayesian drop-the-loser (DTL) trial with three arms compared placebo to citalopram 20 mg and 40 mg. Adults (N = 107) with CUD attended thrice-weekly clinic visits for 9 weeks. The primary outcome was longest duration of abstinence (LDA), based on continuous cocaine-negative urine drug screens (UDS). The secondary outcome was probability of cocaine-negative UDS during treatment. A planned interim analysis performed at approximately 50% of recruitment dropped the least-effective active medication. Bayesian inference was used for all analyses with a pre-specified posterior probability (PP) threshold PP ≥ 95% considered statistically reliable evidence RESULTS: Citalopram 40 mg satisfied interim efficacy criteria and was retained for the second half of the trial. For LDA, analyses indicated PP = 82% and PP = 65% of benefit for 40 mg and 20 mg, respectively (each relative to placebo). The odds of having cocaine-negative UDS decreased in all groups over 9 weeks but remained higher for 40 mg (PP = 97.4%) CONCLUSIONS: Neither dose met the 95% PP threshold for the primary outcome; however, 40 mg provided moderate-to-strong evidence for positive effects on LDA and cocaine-negative UDS. The 40 mg dose was declared the "winner" in this DTL trial.
| S-EPMC8595787 | biostudies-literature
Project description:Background and aimsCocaine use disorder (CUD) is a significant public health issue for which there is no Food and Drug Administration (FDA) approved medication. Drug repurposing looks for new cost-effective uses of approved drugs. This study presents an integrated strategy to identify repurposed FDA-approved drugs for CUD treatment.DesignOur drug repurposing strategy combines artificial intelligence (AI)-based drug prediction, expert panel review, clinical corroboration and mechanisms of action analysis being implemented in the National Drug Abuse Treatment Clinical Trials Network (CTN). Based on AI-based prediction and expert knowledge, ketamine was ranked as the top candidate for clinical corroboration via electronic health record (EHR) evaluation of CUD patient cohorts prescribed ketamine for anesthesia or depression compared with matched controls who received non-ketamine anesthesia or antidepressants/midazolam. Genetic and pathway enrichment analyses were performed to understand ketamine's potential mechanisms of action in the context of CUD.SettingThe study utilized TriNetX to access EHRs from more than 90 million patients world-wide. Genetic- and functional-level analyses used DisGeNet, Search Tool for Interactions of Chemicals and Kyoto Encyclopedia of Genes and Genomes databases.ParticipantsA total of 7742 CUD patients who received anesthesia (3871 ketamine-exposed and 3871 anesthetic-controlled) and 7910 CUD patients with depression (3955 ketamine-exposed and 3955 antidepressant-controlled) were identified after propensity score-matching.MeasurementsEHR analysis outcome was a CUD remission diagnosis within 1 year of drug prescription.FindingsPatients with CUD prescribed ketamine for anesthesia displayed a significantly higher rate of CUD remission compared with matched individuals prescribed other anesthetics [hazard ratio (HR) = 1.98, 95% confidence interval (CI) = 1.42-2.78]. Similarly, CUD patients prescribed ketamine for depression evidenced a significantly higher CUD remission ratio compared with matched patients prescribed antidepressants or midazolam (HR = 4.39, 95% CI = 2.89-6.68). The mechanism of action analysis revealed that ketamine directly targets multiple CUD-associated genes (BDNF, CNR1, DRD2, GABRA2, GABRB3, GAD1, OPRK1, OPRM1, SLC6A3, SLC6A4) and pathways implicated in neuroactive ligand-receptor interaction, cAMP signaling and cocaine abuse/dependence.ConclusionsKetamine appears to be a potential repurposed drug for treatment of cocaine use disorder.
| S-EPMC10631254 | biostudies-literature
Project description:ImportanceOpioid-stimulant co-use is a common problem with few evidence-based treatments.ObjectiveTo examine bupropion slow release (SR) enhancement of a tailored abstinence incentive program for stimulant use in persons with opioid use disorder.Design, setting, and participantsThis 26-week, double-blind, placebo-controlled randomized clinical trial with a 4-week follow-up period was conducted at 4 methadone treatment programs in Baltimore, Maryland. Included participants were persons receiving methadone for the treatment of opioid use disorder with past 3-month cocaine use and current cocaine use disorder between March 2015 and September 2019. Data were analyzed from November 2020 through August 2022.InterventionsA 6-week incentive induction period with monetary incentives for evidence of cocaine abstinence during thrice-weekly urine testing was conducted. Persons achieving 2 weeks of consecutive abstinence during induction were assigned to the relapse prevention group (20 individuals); otherwise, individuals were assigned to the abstinence initiation group (60 individuals). Participants were randomized within incentive groups to bupropion SR (150 mg oral twice daily; 40 participants) or placebo (40 participants). Incentives were available until week 26, and study medication ended week 30.Main outcomes and measuresThe mean percentage of participants with cocaine abstinence (by negative urinalysis or self-report) during weeks 7 to 26 (ie, the incentive intervention period) and 27 to 30 (ie, the follow-up period) and the percentage of participants testing negative for cocaine at weeks 26 and 30 were assessed. Main effects of medication collapsed across incentive conditions and sensitivity analyses of medications within incentive conditions were assessed. Analyses were conducted in the modified intention-to-treat sample (ie, 80 individuals who received ≥1 dose of study medication) and completers (ie, 52 individuals who completed ≥1 visit during week 30).ResultsAmong 80 participants (42 Black [52.5% ] and 35 White [43.8%]; mean [SD] age, 45.7 (9.4) years; 52 males [65.0%]) receiving methadone for opioid use disorder, 40 participants were randomized to receive bupropion SR and 40 participants to receive placebo. No significant difference on urinalysis or self-reported cocaine use was observed between medication groups. Sensitivity analyses revealed differential patterns for incentive subgroups. Participants in the relapse prevention group had high abstinence (>80%; eg, during weeks 7-26 in the modified intention-to-treat analysis, 410 of 456 samples [89.9%] from participants in the bupropion SR group tested negative for cocaine) throughout the trial regardless of whether they were randomized to bupropion SR or placebo. Participants in the abstinence initiation group had better outcomes with bupropion SR than placebo throughout the trial (mean [SD] total number of samples testing negative for cocaine, 30.3 [21.6] samples for bupropion SR vs 17.1 [14.9] samples for placebo; P = .05) and more participants receiving bupropion SR than placebo were abstinent at the end of the study (20 of 30 participants [66.7%] vs 9 of 30 participants [30.0%]; P = .04).Conclusions and relevanceIn this randomized clinical trial, an overall benefit for bupropion SR vs placebo when combined with a financial abstinence incentive program was not observed. Results among incentive subgroups suggest that continued evaluation of medications, including bupropion SR, for stimulant treatment using a tailored approach that factors early abstinence into study design and interpretation may be needed.Trial registrationClinicalTrials.gov Identifier: NCT02111798.
| S-EPMC10018324 | biostudies-literature
Project description:ObjectivesCocaine use is on the rise and it is comorbid with marijuana use. We examined the association between lifetime cocaine + marijuana polysubstance use (CM PSU) versus cocaine only and lifetime cocaine use disorder (CocUD) and examined the potential mediation by cocaine use patterns. Methods: A total of 2,968 lifetime cocaine users were identified from the National Epidemiologic Survey on Alcohol and Related Conditions-III. Mediation analysis was utilized to examine cocaine use quantity, frequency, and duration as potential mediators in the association between CM PSU and CocUD. A parallel multiple mediator model and a structural equation model were used, respectively, to examine: (1) the individual contribution of cocaine use quantity, frequency, and duration, and (2) combined contribution as a set specified by a latent variable. Results: Cocaine users were divided into 2,782 (93.7%) CM polysubstance users and 186 (6.3%) cocaine only users. CM PSU was associated with decreased risk of CocUD, but after including the mediators, the association was no longer significant. Examined separately, only quantity was found to be a significant mediator over and above frequency and duration, while the latent variable with three cocaine use pattern indicators explained 56.6% of the total association between CM PSU and CocUD. Conclusions: Compared to cocaine only users, CM polysubstance users were less likely to use cocaine heavily; this lower intensity of cocaine use was in turn associated with decreased risk of CocUD. Future research is warranted to determine the nature of the association between CM PSU and reduced CocUD.
| S-EPMC7902454 | biostudies-literature
Project description:No pharmacotherapies are approved for the treatment of cocaine use disorder (CUD). Galantamine, a cholinesterase inhibitor, has shown initial promise for cocaine use reduction in methadone-maintained individuals with CUD and cognitive improvement in abstinent individuals with past CUD. However, galantamine has not previously tested in individuals with current CUD and no comorbid opioid use disorder or methadone maintenance. The goal of this 13-week, double-blind, placebo-controlled, randomized controlled trial was to test the efficacy of galantamine (8 mg or 16 mg/day; extended release (ER)) for reducing cocaine use and improving cognitive function in individuals with cocaine use disorder (CUD). Ninety-three treatment-seeking cocaine users were randomized to placebo (n = 32), 8 mg/day galantamine (n = 31) or 16 mg/day galantamine (n = 30). The medication was well-tolerated with minimal reports of side-effects. However, there were no significant treatment group differences in cocaine use outcomes (as measured by self-report or urines). The 16 mg galantamine group had a greater improvement in working memory capacity (Backwards Digit Span), but there were no other significant treatment group differences on key cognitive outcomes. These findings did not provide support for the efficacy of galantamine as a treatment for cocaine use in this sample of individuals with CUD.
| S-EPMC6918721 | biostudies-literature
Project description:ImportanceAdult attention-deficit/hyperactivity disorder (ADHD) is prevalent but often unrecognized, in part because it tends to co-occur with other disorders such as substance use disorders. Cocaine use disorder is one such disorder with high co-occurrence of ADHD.ObjectiveTo examine whether treatment of co-occurring ADHD and cocaine use disorder with extended-release mixed amphetamine salts is effective at both improving ADHD symptoms and reducing cocaine use.Design, setting, and participantsThirteen-week, randomized, double-blind, 3-arm, placebo-controlled trial of participants meeting DSM-IV-TR criteria for both ADHD and cocaine use disorder conducted between December 1, 2007, and April 15, 2013, at 2 academic health center substance abuse treatment research sites. One hundred twenty-six adults diagnosed as having comorbid ADHD and cocaine use disorder were randomized to extended-release mixed amphetamine salts or placebo. Analysis was by intent-to-treat population.InterventionsParticipants received extended-release mixed amphetamine salts (60 or 80 mg) or placebo daily for 13 weeks and participated in weekly individual cognitive behavioral therapy.Main outcomes and measuresFor ADHD, percentage of participants achieving at least a 30% reduction in ADHD symptom severity, measured by the Adult ADHD Investigator Symptom Rating Scale; for cocaine use, cocaine-negative weeks (by self-report of no cocaine use and weekly benzoylecgonine urine screens) during maintenance medication (weeks 2-13) and percentage of participants achieving abstinence for the last 3 weeks.ResultsMore patients achieved at least a 30% reduction in ADHD symptom severity in the medication groups (60 mg: 30 of 40 participants [75.0%]; odds ratio [OR] = 5.23; 95% CI, 1.98-13.85; P < .001; and 80 mg: 25 of 43 participants [58.1%]; OR = 2.27; 95% CI, 0.94-5.49; P = .07) compared with placebo (17 of 43 participants [39.5%]). The odds of a cocaine-negative week were higher in the 80-mg group (OR = 5.46; 95% CI, 2.25-13.27; P < .001) and 60-mg group (OR = 2.92; 95% CI, 1.15-7.42; P = .02) compared with placebo. Rates of continuous abstinence in the last 3 weeks were greater for the medication groups than the placebo group: 30.2% for the 80-mg group (OR = 11.87; 95% CI, 2.25-62.62; P = .004) and 17.5% for the 60-mg group (OR = 5.85; 95% CI, 1.04-33.04; P = .04) vs 7.0% for placebo.Conclusions and relevanceExtended-release mixed amphetamine salts in robust doses along with cognitive behavioral therapy are effective for treatment of co-occurring ADHD and cocaine use disorder, both improving ADHD symptoms and reducing cocaine use. The data suggest the importance of screening and treatment of ADHD in adults presenting with cocaine use disorder.Trial registrationclinicaltrials.gov Identifier:NCT00553319.
| S-EPMC4456227 | biostudies-literature
Project description:Background/aimsCocaine use disorder (CUD) persists as a major public health problem in the United States. Response to evidence-based behavioral treatment has been shown to be predicted by dopaminergic dysfunction. Amphetamine formulations modulate dopaminergic systems and are one of the few agents with positive clinical findings but are associated with unique risks. We aimed to find a model for determining the most appropriate patients for treatment with mixed amphetamine salts-extended-release (MAS-ER) for CUD using an adaptive trial design.MethodsWe are enrolling treatment-seeking adults ages 18-60 years. All eligible participants receive bi-weekly individual counseling augmented with a computer-based intervention based on the community reinforcement approach with contingency management (CRA + CM) for 4 weeks. Participants who fail to achieve abstinence are additionally randomly assigned to 10 weeks of either MAS-ER, titrated up to 80 mg daily, or placebo. All participants complete a follow-up assessment after 12 weeks.ResultsFrequency and amount of cocaine use, cravings, retention, and quality of life will be compared between groups. The primary outcome will be having at least 3 weeks of urine toxicology-confirmed self-reported abstinence. Analyses will also be conducted to identify variables that may help identify who is more or less likely respond to the behavioral intervention during the first 4-weeks of treatment.ConclusionsThis trial more closely mimics a personalized medicine approach that is often used in clinical practice. It will help us understand who may be appropriate for psychostimulant therapy as an enhancement to evidence-based behavioral interventions, while limiting exposure to those who would respond to a psychosocial intervention alone. ClinicalTrials.gov Identifier: NCT01986075.
| S-EPMC7683357 | biostudies-literature
Project description:RationaleDrug addiction has been suggested to develop through drug-induced changes in learning and memory processes. Whilst the initiation of drug use is typically goal-directed and hedonically motivated, over time, drug-taking may develop into a stimulus-driven habit, characterised by persistent use of the drug irrespective of the consequences. Converging lines of evidence suggest that stimulant drugs facilitate the transition of goal-directed into habitual drug-taking, but their contribution to goal-directed learning is less clear. Computational modelling may provide an elegant means for elucidating changes during instrumental learning that may explain enhanced habit formation.ObjectivesWe used formal reinforcement learning algorithms to deconstruct the process of appetitive instrumental learning and to explore potential associations between goal-directed and habitual actions in patients with cocaine use disorder (CUD).MethodsWe re-analysed appetitive instrumental learning data in 55 healthy control volunteers and 70 CUD patients by applying a reinforcement learning model within a hierarchical Bayesian framework. We used a regression model to determine the influence of learning parameters and variations in brain structure on subsequent habit formation.ResultsPoor instrumental learning performance in CUD patients was largely determined by difficulties with learning from feedback, as reflected by a significantly reduced learning rate. Subsequent formation of habitual response patterns was partly explained by group status and individual variation in reinforcement sensitivity. White matter integrity within goal-directed networks was only associated with performance parameters in controls but not in CUD patients.ConclusionsOur data indicate that impairments in reinforcement learning are insufficient to account for enhanced habitual responding in CUD.
| S-EPMC6695345 | biostudies-literature