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Identifying Distinct Striatonigral and Striatopallidal Disturbances After 2019 Cannabinoids in Clinical Practice conference March 21-22, 2019 DISCLOSURES Anahita Bassir Nia Henrietta Szutorisz Noel Warren Jacqueline Ferland Anissa Bara Gregory Rompala Tanni Rahman Diana Akpoyibo Randy Ellis Claire Mann Natasha Berryman Gabor Egervari Michael Miller Yasmin Hurd Director, Addiction Institute, Mount Sinai Behavioral Health System Departments of Psychiatry and Neuroscience Icahn School of Medicine at Mount Sinai Joseph Landry Nayana Patel James Callens Teddy Uzamere Anna Oprescu Annie Ly Sharron Spriggs New York City • No financial disclosure • GW Pharmaceuticals – medication for clinical trial 0 1 Relationship between opioid prescribing rate (per 1,000 Wonder drug OPDP-eligible population) and opioid-related mortality rate (per 100,000 population) among Ontario counties 3400 B.C., when the Sumerians in lower Mesopotamia were cultivating the opium poppy, known as “Hul Gil”—the “Joy Plant.” Opium was~220 used-264 by A.D., many the ancient noted Chinese cultures—surgeonthe Assyrians, Hua To Egyptians,of the Three Arabs, Greeks,Kingdoms Romans, used opiumand Chinese.preparationsBy and1527 Cannabis, the Swiss indica-German for his patientsalchemist to swallow Paracelus beforehad undergoingintroduced major surgery. the use of opium pills 1806, German chemist Friedrich Wilhelm in medicine Adam Sertürner isolated morphine from opium, namedMorphine after the became Ancient a Greekmainstay in U.S. “god of dreams,”medical Morpheus. treatment throughout the 19th century for pain, anxiety, respiratory problems, “consumption,” “women’s ailments.”Heroin was then synthesized in 1898 by Bayer as a cough suppressant and “non-addictive” morphine substitute for medical1914 use., the Harrison Narcotics Tax Act essentially prohibited prescription opioids; In 1924, The Heroin Act made the drug 1916 German scientists synthesized illegal even for medical use. a new wonder drug—oxycodone. 1997 Purdue Pharma, the makers of OxyContin, promoted it as a miracle drug for all chronic pain. 2 3 Yasmin Hurd, PhD 1 2019 Cannabinoids in Clinical Practice conference March 21-22, 2019 OPIOID CRISIS ▶ USA, Nationally, ~120 people a day die from Fatalities overdosing on heroin and 700,000 painkillers 600,000 ▶ Four in five new heroin 500,000 users started out misusing opioid 400,000 prescription painkillers 300,000 ▶ Over 200 million opioid painkiller prescriptions 200,000 annually, approximating the entire adult population 100,000 in the USA 0 Wars/conflicts (1941-present) Drug O/D (1999-2016) Opioid abuse cost 3 times more to treat than other medical disorders 4 4 5 Medications Used To Treat Opioid Use Disorder ▶ Opioid Addiction – Methadone [Dolophine, Methadose.…; mu-opioid receptor (MOR) agonist] ~6500 opioid use disorders – BuprenorphineOnly(Buprenex ~20, percentSubutex; partial of MOR agonist) + – Suboxone = Buprenorphinepeople who andneed Naloxone OUD (MOR antagonist) >10K chronic pain patients/yr – Naltrexone (Vivitroltreatment, Revia; MOR/ receivekappa itantagonist) Behavioral Therapies Cognitive Behavioral Therapy Barriers: Contingency Management Motivational Enhancement Therapy Stigma Group/ Family Therapy Governmental regulation Science-based novel treatments 6 7 6 7 Yasmin Hurd, PhD 2 2019 Cannabinoids in Clinical Practice conference March 21-22, 2019 Opioid Use Disorder – New Thoughts for Treatment Ratio THC/CBD Cannabis contains over 500 chemicals including >140 cannabinoids which have a Chandra et al., Eur Arch Psych Clin Neurosci, 2019 greater or lesser degree of psycho- pharmarmaco-activity Alternative Treatments? ElSohly et al., Biological Psychiatry, 2016 8 8 9 Psychosis is Potentiated by Cannabinoid Use in Psychiatric Inpatient Population Long term effects on addiction vulnerability 90 SC+MJ+Synthetic Cb + MJ 80 * SC+MJ-Synthetic±MJ Cb 70 * SC-MJ+Marijuana 60 * * 50 40 30 20 10 0 based on data adapted from Fergusson et al. (2006) based on data adapted from Lynskey et al. (2003) Psychosis Mood SuicidalSI SuicidalSA Agitation Aggression symptoms ideation Action Daily adolescent users were 18 times more likely to become dependent on marijuana, eight times more likely to use Bassir Nia, et al. (2016). Psychiatric comorbidity associated with synthetic cannabinoid use compared to cannabis. Journal of other illegal drugs in the future and seven times more likely to attempt suicide. Psychopharmacology, 30(12), 1321-1330. 10 11 Yasmin Hurd, PhD 3 2019 Cannabinoids in Clinical Practice conference March 21-22, 2019 Adolescent Cannabis Exposure D9-THC 70 Vehicle active lever 60 Vehicle inactive lever 50 THC active lever THC inactive lever pressing - 40 30 Number of lever of Number 20 10 Psychosis 0 Anxiety 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Molecular studies Session Addiction-related behaviors THC exposure THC CBD CB1R ? Heroin PND 28 49 62 dependence 12 13 Effect of CBD on Maintenance of Heroin Self- CBD Reduces Cue-induced Reinstatement Administration Cannabidiol of Heroin-Seeking Behavior Cannabidiol CBD does not alter maintenance of heroin SA 24hr prior to heroin reinstatement session 30 Vehicle CBD5 25 CBD20 VehicleVehicle 20 *** 30 CBD5 * CBD 5 mg/kg 15 CBDCBD20 20 mg/kg 10 Number of Lever pressesLever Numberof 5 Maintenance of heroin SA 20 0 Active Lever Inactive Lever 10 Her-AL CBD does not alter Locomotor activity Her-IL 4000 Number of lever press lever Numberof Sal-AL 3000 Sal-IL 0 2000 Active Lever Inactive Lever 1000 Number of beam-breaking Number of CBD 0 Ren et al, Journal CBD Vehicle CBD5 CBD20 Neuroscience, 2009 Initial training Maintenance Abstinence Drug seeking Acquisition Maintenance 14 15 Yasmin Hurd, PhD 4 2019 Cannabinoids in Clinical Practice conference March 21-22, 2019 Cannabidiol has a Long-Lasting Effect on Cue-Induced Relapse Cannabidiol >2 Weeks after CBD administration 9 CBD 25 D -THC 20 VehicleVehicle Decrease heroin seeking Environmental cues CBD 5 mg/kg Enhance heroin self-adminstration 25 (3 days) 15 3xCBD 70 Vehicle Vehicle active lever 20 ** 60 3xCBD THC active lever 10 50 15 Number of pressesof leverNumber 40 5 pressing - 10 30 20 0 Number of leverpresses Active Lever Inactive Lever 5 Number of lever of Number 10 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Active Lever Inactive Lever CBD 5 mg/kg Session Ren et al, Journal Initial Extinction/Ab Neuroscience, 2009 Drug self- Drug seeking acquisition administration stinence 16 17 Heroin Abuse is Characterized by Impairments of Cannabidiol has Multiple Pharmacological Glutamatergic Transmission Properties Dopamine – reward Glutamate – excitatory neurotransmission; modulate reward system; drug seeking Nucleus accumbens Synaptic plasticity PFC: Gene transcription Glutamate VTA: Control Heroin Dopamine Nucleus accumbens - related genes related Glutamatergic Lee et al., British J. Pharmacology, 2017 18 19 Yasmin Hurd, PhD 5 2019 Cannabinoids in Clinical Practice conference March 21-22, 2019 CBD Normalizes Heroin-Induced Alteration of CBD Normalizes Heroin-Induced Alteration of AMPA Glutamate Receptor the Cannabinoid CB1 Receptor 1200 CB1R - Protein 800 Glutamat e 400 Average Intensity Integrated Average 0 Accumbens Medial Lateral Nucleus accumbens Average Integrated Intensity Integrated Average core Accumbens shell Accumbens Medial Lateral core Saline Heroin Heroin Accumbens shell SA/Vehicle SA/Vehicle SA/CBD Saline Heroin Heroin SA/Vehicle SA/Vehicle SA/CBD 20 21 Cannabidiol as Potential Treatment Intervention for Opioid Relapse CBD: PK and Opioid Interaction Co-administration Fentanyl: 0.5 mg/Kg 1.0 mg/Kg 250 400 mg (5 mg/kg) 800 mg (10 mg/kg) 200 Placebo L m 150 / g n 100 ▶FDA Approval ▶IRB Approval 50 Clinical Lab Study ▶NIH Grant 0 ▶Pharmaceutical company 0 1 2 3 4 5 6 7 8 Time (hours) Plasma CBD Cmax and tmax were not significantly altered by fentanyl co-administration 22 23 Yasmin Hurd, PhD 6 2019 Cannabinoids in Clinical Practice conference March 21-22, 2019 Craving is a Key factor in relapse Pilot: Determine Whether CBD Reduces Cue- Induced Craving in Heroin-Abstinent Subjects Double blind, Placebo-Controlled: Environmental cues Stress least 7 days) Drug Percentages Percentages of heroin abusers who remain abstinent remain abstinent after treatment (%) (Number of days after a period of treatment) Gossop, 2002 24 25 Cannabidiol as Potential Treatment for Opioid Relapse Replication Clinical Study Cue-induced Anxiety Cue-induced craving Neutral cue Double blind, Placebo-Controlled: Neutral cue Heroin cue Heroin cue least 7 days) Placebo CBD Placebo CBD General Craving 15.00 Placebo 10.00 5.00 CBD 0.00 No Tweets; no photos -5.00 -10.00 -15.00 -20.00 24h post 1st 7days post final CBD/placebo CBD/placebo Hurd et al., Neurotherapeutics. 2015 26 27 Yasmin Hurd, PhD 7 2019 Cannabinoids in Clinical Practice conference March 21-22, 2019 Cue-Induced Effects: Craving Cue-Induced Effects: Anxiety VAS-C VAS-A Session 1 (1-2hr post CBD/Placebo) (1-2hr postSession CBD/Placebo) 1 4 4 3 Neutral cue Neutral cue 3 heroin cue heroin cue 2 (7 days postSession CBD/Placebo) 4 (7 days Sessionpost CBD/Placebo) 4 2 2 2 1 1.5 1 1.5 0 1 0 1 -1 0.5 Placebo 400mg CBD 800mg CBD CHANGE FROM BASELINE CHANGE FROM BASELINE -1 0.5 -2 0 -0.5 Placebo 400mg CBD 800mg CBD (~24hrs Sessionpost CBD/Placebo) 2 -2 0 3 CHANGE FROM BASELINE -1 (~24hrs post CBD/Placebo) CHANGE FROM BASELINE Placebo 400mg CBD 800mg CBD Session 2 -0.5 2.5 -1.5 2 Placebo 400mg CBD 800mg CBD 2 -1 1.5 1.5 1 1 0.5 0.5 0 0 -0.5 Placebo 400mg CBD 800mg CBD CHANGE FROM BASELINE -1 CHANGE FROM BASELINE-0.5 Placebo 400mg CBD 800mg CBD -1 VAS, Visual analog scale 28 29 CBD Reduced Cue-induced Physiological
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