Pipeline of Medications to Treat Substance Use Disorders Iván D. Montoya, M.D., M.P.H. Clinical Director and Deputy Director Division of Therapeutics and Medical Consequences NIDA • Cocaine Outline • Methamphetamine • Cannabis Past-Year Prevalence Per 1,000 1,000 People Per NSDUH, 2018 Past-Year Prevalence Per 1,000 1,000 People Per NSDUH, 2018 Number of Overdose Deaths CDC, 2018 Molecular Neurobiology of Stimulant Use Disorders Glutamate Enkephalin or Excitatory Input Dynorphin Inhibitory Neuron k Opioid Dopamine Receptors Enkephalin Receptors Inhibitory Dopamine Neuron GABA Neuron Neuron m Opioid REWARD Receptors GABA-A Receptors GABA Inhibitory Feedback GABA Presynaptic Inhibitory Opioid Neuron Receptors (m, d?) Ventral Tegmental Area Nucleus Accumbens (VTA) (NAc) Adapted from Koop, 2016 • 5HT2c Agonist - Lorcaserin (Belviq XR®) • Orexin 1 antagonists Cocaine • EMB-101 (Oxazepam + Metyrapone) • Buprenorphine + Opioid Antagonist – Clinical Studies • Ketamine • Oxytocin • L-Tetrahydropalmatine (L-THP) 5-HT2C Agonist - Lorcaserin • Clinically available • Selective agonist • Modulate mesolimbic dopamine, decreasing dopamine release • FDA-approved for weight loss • Lorcaserin (Belviq®)10 mg bid • Lorcaserin XR (Belviq XR®) 20 mg qd • Schedule IV • Arena Pharmaceuticals - Eisai Inc. Lorcaserin Pre-clinical Studies - Stimulants • Decrease cocaine self-administration and the reinstatement of responding for cocaine (Grottick et al., 2000; Burmeister et al., 2004; Burbassi and Cervo 2008; Cunningham et al., 2011; Manvich et al., 2012; RüediBettschen et al., 2015, Howell and Cunningham 2015). • Attenuates self-administration of cocaine (Collins et al., 2016; Harvey-Lewis et al., 2016) and nicotine (Levin et al., 2011; Higgins et al., 2012, 2013) • Tolerance does not develop to the effects of lorcaserin on cocaine self-administration (Collins et al., 2016) • Attenuates the ability of stress or conditioned cues to stimulate cocaine-seeking behavior in rats with a prior history of cocaine self-administration (Fletcher et al., 2008) • Efficacy against methamphetamine cue reinstatement and nicotine Selective serotonin 2C receptor agonist Modulates the dopaminergic reward system. Approved by the FDA for chronic weight management Lorcaserin – Clinical Trials NCT03007394 • Phase 2 multicenter RCT - NIDA • N=272 • 10 mg bid * 13 weeks • Recruitment complete • Data analysis in progress • Primary endpoint:proportion of subjects that successfully achieve abstinence from cocaine during the last three weeks of treatment in the "pre-qualified for primary efficacy endpoint" (PPEE) population [ Time Frame: Treatment weeks 11 - 13 ] NCT03192995 • Pilot RCT (n=45) UCSF Orexin (Hypocretin) Neurons - 10,000–20,000 orexin-producing neurons in the human brain - Located predominantly in the perifornical area and lateral hypothalamus - Project widely throughout the central nervous system - There are two types of orexin peptide and two types of orexin receptor - Regulates arousal, wakefulness, reproduction, and appetite. Peyron et al. J. Neurosci. 1998;18:9996-10015 OX1 Antagonists and Cocaine • Reduce dopamine transporter sensitivity to cocaine in the VTA and NAc • Disrupt the expression of Pavlovian associations formed by cocaine • Reduce compulsive-like cocaine taking under long access self- administration conditions • Suppress motivation to obtain cocaine under high effort conditions • Reduce the strength of stress-,cue- and context-induced cocaine reinstatement. Orexin 1 Antagonists – Why clinically? • Sleep problems frequently precede SUD • Sleep is directly impaired by SUD • Drug (opioids) modify the sleep-wake cycle (Orexin system) • Drug withdrawal associated with sleep disruptions • Sleep problems have been independently associated with increased comorbidity • Benzodiazepines are frequently abused in conjunction with opioids • Benzodiazepines co-administration with opioid agonists is associated with increased lethality Suvorexant • Dual OX1R/OX2R antagonist and schedule IV compound, FDA approved for treatment of insomnia • Suvorexant (10 mg vs placebo) in reducing anxiety, improving sleep, and reducing cocaine cravings or cocaine use(n=20) • Urine samples positive for cocaine: 90% vs 82% • Preliminary evidence favoring Suvorexant for inhibitory control, sleep, stress reactivity, and craving. (Lane, 2018) • NCT03937986: Human lab Study. PI: Bill Stoops. • Mirtazapine • Monoclonal Antibody • Vaccine Methamphetamine • Naltrexone • Ibudilast – Clinical Studies • Bupropion • Buspirone • Oxytocin Mirtazapine • Potent antagonist or inverse agonist of the α2A-, α2B- , and α2C-adrenergic receptors, the serotonin 5- HT2A, 5-HT2C, and the histamine H1 receptor • Does not inhibit the reuptake of serotonin, norepinephrine, or dopamine, nor does it inhibit monoamine oxidase. • Safe and no abuse potential • SE: somnolence, weight gain, dry mouth • May reduce meth craving (Kingsakon, 2005) Mirtazapine N=56 Mirtazapine 30 mg qd D-B RCT Weekly urine Colfax, 2011 • Phase 1, double-blind, randomized, placebo-controlled, ascending single-dose safety and tolerability study • ch-mAb7F9 administered as an intravenous infusion to healthy volunteers • Forty-two subjects were treated in 5 dose groups ranging from 0.2 to 20 mg/kg ch-mAb7F9, with 10 of the 42 subjects receiving normal saline as a placebo control. • Subjects were followed for 147 d after dosing with regular safety assessments and for pharmacokinetic and immunogenicity analyses. • It is predicted that 20 mg/kg will be effective in humans • The concentration of ch-mAb7F9 required to bind this much METH is »50 mg/mL • Ch-mAb7F9 concentrations remain above 50 mg/ml for 1 to 2 weeks after 6 mg/kg, and for about 5 weeks after 20 mg/kg Past-Year Prevalence Per 1,000 1,000 People Per NSDUH, 2018 • Fatty acid amide hydrolase (FAAH): enzyme that degrades the endocannabinoid anandamide • FAAH inhibition Increase anandamide • double-blind, placebo-controlled, parallel group phase 2a trial at one site in men aged 18–55 years with cannabis dependence • Participants were admitted to hospital for 5 days (maximum 8 days) to achieve abstinence and precipitate cannabis withdrawal, after which they were discharged to continue the remaining 3 weeks of treatment as outpatients FAAH Inhibitor F-04457845 Neuropsychopharmacology, Dec 2018 Summary • Cocaine • Lorcaserin • Methamphetamine • Mirtazepine • Monoclonal antibody • Cannabis • FAAH Inhibitor Preclinical Pharmacological Targets • Vesicle Monoaminte Transporter 2 (VMAT2) • Neurotensing Receptor 1 (NTR1) • Trace Amine-Associated Receptor 1 (TAAR1) • Organic Cation Transporter 3 • Chemokine receptor type 4 (CXCR-4) • Ghrelin Receptor Antagonist • Muscarinic M5 • Nociceptive Orphanin Receptor (NOP/ORL) • Metabotropic Glutamate 2/3 Receptor (mGLUR2/3) Past-Year Prevalence – Thousands of People Bolliger, 2019 .