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
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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.
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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
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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
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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
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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
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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 Numberof 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 lever Number 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
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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
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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
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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
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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
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CBD Reduced Cue-induced Physiological Measures of Stress Response – Cortisol Levels (b) Neutral cue Drug cue 40 110 110
30 Neutral cue Drug cue 105 105
20
100 100 10 * * 95 95 0
-10 90 90
% change from baseline from change % Percent change from baseline from change Percent Placebo -20 400 mg CBD 85 Placebo 85 800 mg CBD 400 mg CBD -30 800 mg CBD 15 mins 35 mins 15 mins 35 mins 80 80 1 2 3 4 5 6 1 2 3 4 5 6 -40 Time Post-cues Samples post first cues
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Yasmin Hurd, PhD 8 2019 Cannabinoids in Clinical Practice conference March 21-22, 2019
Medical Cannabidiol?
• Cannabidiol holds promise for opioid use disorder treatment — craving and anxiety OH • Effective dose, treatment regimen….needs to be fully determined OH • Treatment for specific features of OUD (and other substances)? • Formulations/delivery systems need to be developed • Urgency for clinical trials
Medicine?
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•GW Pharmaceuticals The “Wonder Drug”
Cranial Neuropathy Interstitial Cystitis Rheumatoid Arthritis Crohn's Disease Intractable Pain Rheumatoid Arthritis CRPS (Complex Regional Pain Intractable Vomitting Rheumatoid Arthritis Jacqueline Ferland Anissa Bara Gregory Rompala Syndrome Type II) Irritable Bowel Syndrome Rosacea Henrietta Szutorisz Noel Warren Cystic Fibrosis Irritable Bowl Syndrome RSD (Complex Regional Pain Damage to Spinal Cord Nervous Lipomatosis Syndrome Type 1) Tissue Lou Gehrig's Disease Schizoaffective Disorder Darier's Disease Lupus Schizophrenia Degenerative Arthritis Lyme Disease Scoliosis Degenerative Arthropathy Lymphoma Sedative Dependence Delirium Tremens Major Depression Seizures Dermatomyositis Malignant Melanoma Senile Dementia Diabetes, Adult Onset Mania Severe Nausea Diabetes, Insulin Dependent Melorheostosis Severe Pain Diabetic Neuropathy Meniere's Disease Severe Vomiting Diabetic Peripheral Vascular Disease Mitochondrial disease Shingles (Herpes Zoster) Diarrhea Motion Sickness Sickle cell disease Diverticulitis Mucopolysaccharidosis (MPS) Sinusitis Edwin Salsitz Dysthymic Disorder Multiple Sclerosis (MS) Sjoren's Syndrome Dystonia Muscle Spasms Skeletal Muscular Spasticity Tanni Rahman Diana Akpoyibo Randy Ellis Claire Mann Natasha Berryman Eczema Muscular Dystrophy Sleep Apnea Elevated Intraocular Pressure Myasthenia Gravis Sleep Disorders Emphysema Myeloid Leukemia Small Fiber Neuropathy Emphysema Myoclonus Spasticity Endometriosis Nail-Patella Syndrome Spinal Cord Disease Epidermolysis Bullosa Neurofibromatosis Spinal Cord Injury Spinal Cord Injury with spasticity Back Sprain Epididymitis Neuropathy Acquired Hypothyroidism Spinal Stenosis Bell's Palsy Epilepsy Nightmares Acute Gastritis Spinocerebellar Ataxia Bipolar Disorder Felty's Syndrome Obesity Agoraphobia Sturge-Weber Syndrome (SWS) Brain Tumor, Malignant Fibromyalgia Obsessive Compulsive Disorder AIDS Related Illness Stuttering Bruxism Fibrous Dysplasia Opiate Dependence Alcohol Abuse Syringomyelia Bulimia Focal Neuropathy Optic Neuropathy Alcoholism Tardive Dyskinesia (TD) Cachexia Friedreich's Ataxia Osteoarthritis Alopecia Areata Tarlov Cysts Cancer Gastritis Panic Disorder Alzheimer's Disease Temporomandibular joint disorder (TMJ) Cancer, Adrenal Cortical Genital Herpes Parkinson's Disease Amphetamine Dependency Tenosynovitis Anna Oprescu Annie Ly Cancer, Endometrial Glaucoma Peripheral Neuropathy Joseph Landry Nayana Patel James Callens Teddy Uzamere Amyloidosis Terminal Illness Cancer, Prostate Glioblastoma Multiforme Peritoneal Pain Amyotrophic Lateral Sclerosis (ALS) Thyroiditis Cancer, Testicular Graves Disease Persistent Insomnia Angina Pectoris Tic Douloureux Cancer, Uterine Headaches, Cluster Porphyria Ankylosis Tietze's Syndrome Carpal Tunnel Syndrome Headaches, Tension Post Concussion Syndrome Anorexia Tinnitus Causalgia Hemophilia A Post Polio Syndrome (PPS) Anorexia Nervosa Tobacco Dependence Cerebral Palsy Henoch-Schonlein Purpura Post-traumatic arthritis Anxiety Disorders Tourette's Syndrome Cervical Disk Disease Hepatitis C Post-Traumatic Stress Disorder (PTSD) Any chronic medical symptom that Traumatic Brain Injury Cervicobrachial Syndrome Hereditary Spinal Ataxia Premenstrual Syndrome (PMS) limits major life activities Trichotillomania Chemotherapy HIV/AIDS Prostatitis Arachnoiditis Viral Hepatitis Chemotherapy Induced Anorexia Hospice Patients Psoriasis Arnold-Chiari Malformation Wasting Syndrome Chronic Fatigue Syndrome Huntington's Disease Pulmonary Fibrosis Arteriosclerotic Heart Disease Whiplash Chronic Inflammatory Demyelinating Polyneuropathy Hydrocephalus Quadriplegia Arthritis Wittmaack-Ekbom's Syndrome Chronic Migraine Hydromyelia Radiation Therapy Arthritis (Rheumatoid) Writers' Cramp Chronic Pain Hypertension Raynaud's Disease Arthropathy, gout Reflex Sympathetic Dystrophy NIH/ NIDA Hyperventilation Asthma Chronic Pancreatitis Hypoglycemia (Learn more Reiter's Syndrome Attention Deficit Hyperactivity Disorder (ADD/ADHD) Chronic renal failure Michael Miller Anahita Bassir Nia Impotence Residual Limb Pain Gabor Egervari Sharron Spriggs Auditory Neuropathy Cocaine Dependence Colitis Inflammatory autoimmune-mediated Restless Legs Syndrome (RLS) DA030359 Autism/Aspergers arthritis Autoimmune Disease Complex Regional Pain Syndrome Inflammatory Bowel Disease (IBD) Autonomic Neuropathy Conjunctivitis Constipation Insomnia 34 35
Yasmin Hurd, PhD 9