2021 Meeting Abstractsts
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College on Problems of Drug Dependence (CPDD) Virtual Scientific Meeting, June 21-24, 2021 *All times are listed in the Eastern U.S. Time Zone Monday, June 21, 2021 Late-Breaking Oral Presentations I Initial Results From STAMPOUT: Study of IXT-M200 in Non-Treatment Seeking Persons Who Use Methamphetamine W. Brooks Gentry*1, Lynn Webster2, Keith Ward1, Misty Stevens1 1InterveXion Therapeutics, LLC; University of Arkansas for Medical Sciences, 2PRA Health Sciences Drug Category Stimulants Topic Substance Use Disorder Abstract Detail Human Abstract Category Original Research Aim: IXT-m200 is a high-affinity, anti-methamphetamine (METH) antibody. The aim of this study was to determine the safety, tolerability and pharmacokinetics (PK) of single IV doses of IXT-m200 followed by weekly IV METH challenges in subjects with METH use disorders. The impacts of IXT-m200 on METH PK and on METH effects as measured by drug effects questionnaires (DEQ) were determined. Methods: This was a parallel-group, placebo-controlled, double-blind study in otherwise healthy, non-treatment seeking participants. Subjects were required to discriminate METH (30 mg, IV) from placebo with DEQ to qualify. Those who qualified received single doses of IXT-m200 (6 or 20 mg/kg) or placebo followed by weekly METH challenges for up to 4 weeks. The challenges consisted of METH (30 mg, IV) and placebo, separated by 4 hr. Safety, METH and IXT-m200 PK, and DEQ data were collected for up to 126 days. Results: 56 subjects were included in the pharmacokinetic and safety sets, with 20 receiving the IXT-m200 placebo, 18 receiving 6 mg/kg and 18 receiving 20 mg/kg IXT-m200. IXT-m200 was well-tolerated. There were no SAEs and all AEs were grades 1 and 2; all resolved as expected. Importantly, IXT-m200 did not result in substantial hemodynamic changes when compared with METH alone. IXT-m200 met the primary study endpoint, and significantly (p<0.001) altered METH AUC and Cmax with all METH challenges, up to 30-fold and 8-fold respectively without altering METH renal elimination. IXT-m200 decreased METH Vd over 9-fold after the first METH challenge. Conclusions: IXT-m200 was well-tolerated in non-treatment seeking METH users who were given METH challenges following single doses of IXT-m200. The primary endpoint of alteration in METH PK by IXT-m200 was easily met, with significant (p<0.001) changes in METH PK observed. Safety and effect analyses are ongoing, but there were favorable trends in DEQ data. Extended-Release Lorcaserin for Cocaine Use Disorder Among Men Who Have Sex With Men Glenn-Milo Santos*1, Janet Ikeda2, Phillip Coffin2, John Walker2, Tim Matheson2, Matthew McLaughlin2, Jennifer Jain1, Eric Vittinghoff1, Steven Batki3 1University of California San Francisco, 2San Francisco Department of Public Health, 3UCSF and San Francisco VA Medical Center Select Drug Category Stimulants Topic Substance Use Disorder Abstract Detail Human Abstract Category Original Research Aim: To 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. Methods: This 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. College on Problems of Drug Dependence (CPDD) Virtual Scientific Meeting, June 21-24, 2021 *All times are listed in the Eastern U.S. Time Zone Results: Eighty-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 (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). Conclusions: We 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. Dose-Specific Effects of Pregnenolone on Stress-Induced Craving and Anxiety in Cocaine Use Disorder Verica Milivojevic*1, Zachary Magin1, Philip Himmelstein1, Gretchen Hermes1, Gustavo Angarita1, Rajita Sinha1 1Yale University School of Medicine Select Drug Category Stimulants Topic Substance Use Disorder Abstract Detail Human Abstract Category Original Research Aim: Chronic substance use related adaptations have been shown to down-regulate GABAergic transmission (Biggio et al., 2007) and levels of neuroactive steroids (Purdy et al., 1991), which are potent modulators of the GABAA receptor. Moreover, chronic drug use results in significant changes to stress biology which contributes to high stress-induced craving and anxiety and risk of relapse (Milivojevic and Sinha, 2018). Therefore, interventions that could potentiate the neurosteroid system and thereby normalize drug use-related adaptations in the stress system may prove clinically relevant in the larger treatment of substance use disorders (SUDs). Here we tested the effects of two doses of the neuroactive steroid precursor pregnenolone (PREG) vs. placebo (PLA) on stress- induced craving and anxiety in treatment seeking individuals with substance use disorder (SUD). Methods: Eleven inpatient treatment-seeking individuals with SUD were randomly assigned to receive either placebo (PLA; n=4), 300mg PREG/day (n=3) or 500mg PREG/day (n=4). In week 2, they were exposed to three 5-minute personalized guided imagery conditions (stress, drug cue, neutral/relaxing), one per day, on three consecutive days in a random, counterbalanced order. Craving and anxiety were assessed at baseline, immediately following imagery exposure and at regular recovery time points. Results: Individuals receiving 500mg PREG had lower craving compared to individuals receiving 300mg PREG or PLA. Moreover, individuals in the 300mg PREG and the 500mg PREG group had significantly lower anxiety ratings compared to the PLA group. Conclusions: Findings highlight dose-specific reductions in stress-induced craving and anxiety in individuals with SUD receiving PREG treatment. Defining GM-CSF as a Mediator of Behavioral and Molecular Responses to Cocaine Kelsey Lucerne*1, Drew Kiraly1 1Icahn School of Medicine at Mount Sinai Select Drug Category Stimulants Topic Neurobiology/Neuroscience Abstract Detail Animal Study Abstract Category Original Research Aim: The gut microbiome markedly effects behavioral and neurobiological responses to cocaine, but the precise mechanisms underlying gut-brain communication are not fully understood. Here we investigate the hypothesis that the immune system acts as a gut-brain mediator of response to cocaine. Methods: Quantitative serum multiplex analysis measured circulating cytokines in mice with intact or depleted gut microbiomes after chronic cocaine or saline (n=10/group). Mice with intact or depleted microbiomes, receiving daily injections of GM-CSF (10μg/kg) or vehicle, underwent a cocaine conditioned place preference (CPP) assay to measure preference for 2 doses of cocaine (7.5mg/kg or 3.75mg/kg) (n=8/group). Quantitative polymerase chain reaction (qPCR) and RNAscope in-situ hybridization were used to quantify GM-CSF receptor College on Problems of Drug Dependence (CPDD) Virtual Scientific Meeting, June 21-24, 2021 *All times are listed in the Eastern U.S. Time Zone expression in the nucleus accumbens (NAc) following cocaine treatment (n=5/group). NAc tissue from GM- CSF+cocaine treated animals was used for RNA-sequencing (n=8/group). Pairwise comparisons used two-tailed Student’s t-test, 2×2 comparisons used two-way ANOVA with repeated measures and Holm-Sidak’s post-hoc tests, and limma analysis was used for RNA-seq. Results: Multiplex analysis identified granulocyte-macrophage colony-stimulating factor (GM-CSF) to be significantly increased by repeated cocaine only in animals with an intact gut microbiome. On the CPP test, microbiome-depleted animals injected with vehicle developed a robust place preference for low doses of cocaine, as seen in our previously published data. However, injection of microbiome-depleted animals with GM-CSF returned place preference to control levels. Further, GM-CSF attenuated cocaine preference in microbiome-intact animals. qPCR and RNAscope showed cell-type specific cocaine-induced increases in GM-CSF receptor expression in the