Addiction: Science Drives New & Novel Treatments
Yasmin Hurd Director, Addiction Institute of Mount Sinai Icahn School of Medicine at Mount Sinai Depts Psychiatry, Neuroscience and Pharmacological Sciences ADDICTION AND AMERICA >> 30 40 million million OVERDOSE STIGMA DEATHS
HEALTHCARE STIMULANTS Economic + Intangible OPIOIDS SYSTEM Costs (USD in Billions) UNDER SEIGE CANNABIS synthetics ECONOMIC $>1000 BURDEN tobacco $749 Alcohol
Total (Drug & Alcohol) + Intangible Costs (Quality of Life Lost) Lifespan
2 COVID: stress, social isolation and drug use
National increase in urine drug test positivity rates during COVID-19
fentanyl 67%
heroin 33%
methamphetamine 23%
~85,000 drug overdose cocaine 19%
0% 20% 40% 60% 80%
Wainwright et al., JAMA. 2020;324(16):1674-1677. Morphine maintenance clinics Treatments for Substance Use Disorders created (1919-1924) Alcoholics Anonymous formed (1935) Model of rehab created (1948-1950)
Disulfiram (1948-1950)
Methadone introduced for addiction (1964) Drug toxicology (1971)
Narcan (1971)
Naltrexone (1994)
FDA approves buprenorphine for clinical use (2002)
Acamprosate (2004)
Varenicline (Chantix) (2006)
1919 2006 2020 Medications Used To Treat Substance Use Disorder
Only ~17 percent of people who need SUD treatment receive it Barriers: Stigma Governmental regulation Science-based novel treatments
Behavioral Therapies Cognitive Behavioral Therapy Contingency Management Motivational Enhancement Therapy Group/ Family Therapy
Neurodevelopment
Environmental Genetics factors (e.g., stress, impoverished conditions, early drug exposure) Drug use
Inhibitory control
Behavioral traits/ Impulsivity Reward Psychiatric sensitivity comorbidity Anxiety/ Depression Neurobiology of Addiction
DS
PFC NAc (ventral striatum; Nucleus accumbens): reward VTA expectation; goal-directed behavior OFC DS (Dorsal striatum): habit formation NAc AMG PFC (Prefrontal cortex): cognitive control OFC (orbitofronal cortex): goal-directed behavior, motivational drive; cognitive flexibility AMG (amygdala): emotional regulation; drug- seeking behavior HIPP (hippocampus): memory VTA (ventral tegmental area): reward, cognition, emotional regulation Impaired Cortical Function in Drug-Addicted Subjects and Individuals With Orbitofrontal Cortical Lesions
• Poor decision • Poor impulse control • Emotional lability • Rapid temporal discounting of rewards Ventral Striatum (nucleus accumbens and reward)
COCAINE Dorsolateral Striatum = CaudateNAc and SLEA responsible for the stimulus– signal changes response (S–R) associations; correlate strongly habitual responding with rush measures. Associative striatum (caudate nucleus) = Crucial for the learning and expression of goal- By contrastPutamen, directed actions; involved in the amygdala signal selection of actions that lead to NAc changes correlate more strongly with reward craving measures,
Ventral striatum (NAc) = Reinforcement Breiter and Rosen, 1999
Reut Avinun et al. J. Neurosci. 2017;37:9724-9729 Amygdala
Craving Cue reactivity Emotional regulation
Wiers et al., Am J Psychiatry, 2015 Neurobiology of Addiction
Drug USE EUPHORIA
SYNAPTIC (DA)
Drug URGES DYSPHORIA Dopamine Glutamate GABA Nucleus accumbens Opioid Endocannabinoid Treatment Development
Human molecular studies Neurobiological Clinical Studies targets Preclinical Animal Models
ResearchS Molecular Insights: Human Brain
Transcriptional Profile of Heroin Abusers
Control Heroin Dysregulation of Glutamatergic Genes and Epigenetic Remodelers in the Striatum of Human Heroin Abusers
Glutamatergic system Glutamatergic-related genes Epigenetic
Ac
Synaptic plasticity PFC: Glutamate Whole genome co-expression network analysis Striatum EpiGenetics Addiction — Complex Disorder
Environment -control gene activity
Describes the study of mechanisms by which genes are turned on or off without altering their genetic code or DNA sequences. Epigenetics
Cellular and physiological trait Decondensed chromatin Condensed chromatin variations that are not caused by changes in Histone deacetylases the DNA sequence; the (HDACs) study of changes in Histone acetyltransferases organisms caused by (HATs) modification of gene expression rather than methyltransferases alteration of the genetic code itself demethylation
Histone methyltransferases
Histone demethylation
Transcriptional Transcriptional activation repression Sawan et al, 2008 Dysregulation of Epigenetic Remodelers in the Striatum of Human Heroin Abusers Predict Increased Acetylation and Transcription
More accessible state of DNA = enhanced transcription
DNA
HAT Increased histone H3 acetylation HDAC - elevated histone acetyl transferase (HAT) levels (e.g., Ncoa1, Ncoa3) decreased histone deaceylase (HDAC) (e.g., HDAC5)
Egervari et al., Biological Psychiatry, 2016 Epigenetic Marks Related to Transcriptional Activation Correlate to Glutamatergic Impairments
Control Heroin Abusers Epigenetic marks Epigenetic Glutamate receptor gene expression
Ac
Years of heroin use
Egervari et al., Biological Psychiatry, 2016 Translational: Consistent Hyperacetylation in the Rat Heroin Self-administration Model
HumanHuman RatRat Model GRIA1 Gria1
AcH3
Control Heroin
Control H3K27ac GRIA1 - Neurons Heroin
ATAC-seq: Assay for Transposase-Accessible Chromatin with high throughput sequencing
TSS, transcription start site Egervari et al., Biological Psychiatry, 2016 Bromodomain and Extraterminal (BET) Inhibitors - Potential Drug Abuse Treatment?
Reader
Bromodomain Ac ‘readers’: Bind Bromodomain complex binds acetylated histones Acetylated Lysine BET domain proteins reads acetylated lysine residues Residues
Modified from Taverna and Cole, 2010 Bromodomain and Extraterminal (BET) Inhibitors - Potential Drug Abuse Treatment
Ac
Heroin self-administration behavior can be reduced Specific Epigeneticby specific Inhibitors epigenetic reduce rewarding inhibitors effects of heroin
Heroin self-administration Vehicle Intra-dorsal striatal infusion BET inhibitor vehicle BET inhib
Systemic administration Egervari et al., Biological Psychiatry, 2016 Treatment Development - Part II
Human molecular studies Neurobiological Clinical Studies targets Preclinical Animal Models
ResearchS Epigenetics
Epigenome sequencing
Neuron Glia Molecular Neurobiology of Opioid Abuse
Epigenome Most significant epigenomic change in neurons relate to the FYN gene
Nygaard et al., Alzheimer's Research & Therapy, 2014 FYN – (tyrosine kinase) is a component of the Increased phosphorylated-Tau in synaptic machinery that regulates the the brains of heroin users phosphorylation of Tau; hyperphosphorylated Tau is a pathological feature of neurodegenerative disorders (tauopathies)
Kovacs et al.,. Neurobiol Aging, 2015
Phosphorylated Tau-Y18 Vehicle Opioid
Activated Fyn
hyperphosphorylated Tau
pTau Synaptic dysfunction Neurodegeneration
Stable Microtubule microtubule destabilization Egervari et al., Nature Communications, 2020 Inhibiting FYN (that reduces pTau) reduces heroin self-administration in animal models **
Epigenetic and synaptic regulation Clinical Trials target drugs Fyn Expression Regulates Heroin Seeking Behavior
Knockdown of Fyn Reduces Cue-Induced Reinstatement Behavior
Active Lever presses Inactive Lever presses
Egervari et al., Nat Communication, 2020 Fyn Medication Development
Saracatinib (AZD0530)
**
AZD0530Compound X Specific epigenetic and synaptic dysregulation associated with Epigenetic and Food selfheroin-administration abuse linked to glutamatergic pathology may provide synaptic regulation Clinical Trials targetstarget drugs for treatment development
Egervari et al., Nature Commun. 2020 AZD0530 Reduces Alcohol Self‐ Administration and Seeking Behavior
Morisot et al., Addict Biol, 1227-1234, 2019 Treatment Development - Part III
Human molecular studies Neurobiological Clinical Studies targets Preclinical Animal Models
ResearchS Developmental THC Exposure Increases Heroin Self-Administration in Adulthood 120 Latency to 1st drug 140 lever press 100 ** vehicle 120 THC presses 80 **
- 100
60 80
60 40 Time (sec) Time * 40 20
20 Number Number lever of 0 0 0 7.5 15 30 60 100 Vehicle THC heroin dose (ug/kg/inf) 70
60 Vehicle active 50 lever
presses Vehicle - 40 inactive lever 30
20
10 Number Number lever of 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Session Epigenetic Mechanisms me
m Prenatal and Adolescent THC exposures induce e protracted alteration of epigenetic modifications K4 Environment -control gene activity
Synaptic Plasticity D9-THC CBD
9- D tetrahydrocannabinol Cannabidiol
Cannabis contains over 500 chemicals including >140 cannabinoids which have a greater or lesser degree of psycho-pharmaco-activity THC and CBD: Cannabinoids with Different Actions
CBD Reward THC
CBD THC Intoxication
CBD Anxiety THC Low dose High dose
Diarrhea, dry mouth, CBD drowsiness (high dose) Side effects
short-term memory deficit, impaired judgement, impaired motor coordination, THC tachycardia, sedation, withdrawal symptoms CBD Reduces Cue-induced Reinstatement of Heroin-Seeking Behavior Cannabidiol
24hr prior to heroin reinstatement session
Vehicle *** Vehicle 30 CBD5 * CBD 5 mg/kg CBDCBD20 20 mg/kg
20
10 Number of lever press lever Numberof
0 Active Lever Inactive Lever
CBD
Ren et al, Journal Neuroscience, 2009 Initial training Maintenance Abstinence Drug seeking D9-THC CBD
Decrease heroin seeking Enhance heroin self-adminstration 25 Vehicle 70 Vehicle active lever 20 3xCBD 60 THC active lever 50 15
40
pressing 10
30-
20 5
10 presses lever of Number
0 0
Number Number of lever 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Active Lever Inactive Lever Session Heroin Abuse is Characterized by Impairments of Glutamatergic Transmission
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 CBD Normalizes Heroin-Induced Alteration of AMPA Glutamate Receptor
1200
800
Glutamat
e 400 AverageIntegrated Intensity
0 NAc core Medial Lateral NAc shell
Saline Heroin Heroin SA/Vehicle SA/Vehicle SA/CBD
Ren et al, Journal Neuroscience, 2009 CBD Normalizes Heroin-Induced Alteration of the Cannabinoid CB1 Receptor
CB1R - Protein
Nucleus AverageIntegrated Intensity accumbens Accumbens Medial Lateral core Accumbens shell
Saline Heroin Heroin Ren et al, Journal Neuroscience, 2009 SA/Vehicle SA/Vehicle SA/CBD
CBD promotes dendritic remodeling indirectly through CB1 and/or CB2 receptors and increases synaptic protein expression: Fogaça et al., Neuropharmacology, 135:22-33, 2018. Cannabidiol as Potential Treatment Intervention for Opioid Relapse: Double- Blinded Placebo Control Study
Double-blind, Randomized, Placebo-Controlled: Participants with Opioid Use Disorder
Day 1 Day 2 Day 3 Day 10
Prescreen Session 1 Session 2 Session 3 Session 4 tests •CBD/Pl •Cue tests •CBD/Pl •Cue tests •Cue tests •CBD/Pl •Cognitive tests Cue-Induced Effects: Craving VAS-C (1-2hr post SessionCBD/Placebo) 1
4
3 Neutral cue heroin cue 2
1
0 CHANGE BASELINE CHANGE FROM
-1 Placebo 400mg CBD 800mg CBD (7 days post CBD/Placebo) -2 Session 4 2
1.5
1
0.5
0
-0.5 CHANGE BASELINE CHANGE FROM -1 Placebo 400mg CBD 800mg CBD -1.5
VAS, Visual analog scale Hurd et al., Am J Psychiatry, 2019 Cue-Induced Effects: Anxiety VAS-A (1-2hr post CBD/Placebo)Session 1
4 Neutral cue 3 heroin cue
2
1
0 CHANGE BASELINE CHANGE FROM -1 (7 days Sessionpost CBD/Placebo) 4 2 -2 Placebo 400mg CBD 800mg CBD
1.5
1
0.5
0 CHANGE BASELINE CHANGE FROM
-0.5 Placebo 400mg CBD 800mg CBD -1 VAS, Visual analog scale Hurd et al., Am J Psychiatry, 2019 Cannabidiol Reduces Cue-induced Physiological Measures of Stress – Cortisol Levels
40
30 Neutral cue Drug cue
20
10
0
-10 % change from baselinefrom change %
-20 Placebo 400 mg CBD 800 mg CBD -30 15 mins 35 mins 15 mins 35 mins -40 Time Post-cues
Hurd et al., Am J Psychiatry, 2019 Cannabidiol Reduces Cue-induced Physiological Measures of Stress – Heart rate
Neutral cue Drug cue 110 110
105 105
100 100
95 95 Percent change from baselinefrom change Percent
90 90
85 85 Placebo 400 mg CBD 800 mg CBD 80 80 1 2 3 4 5 6 1 2 3 4 5 6 Samples post first cues
Hurd et al., Am J Psychiatry, 2019 Medical Cannabidiol?
• Cannabidiol holds promise for opioid use disorder treatment — OH craving and anxiety • Effective dose, treatment OH regimen….needs to be fully determined • Treatment for specific features of OUD (and other substances)? • Formulations/delivery systems need to be developed Medical Cannabidiol?
• Cannabidiol holds promise for opioid use disorder treatment — OH craving and anxiety • Effective dose, treatment OH regimen….needs to be fully determined • Treatment for specific features of OUD (and other substances)? • Formulations/delivery systems need to be developed
Gonzalez-Cuevas et al., Neuropsychopharmacology. 43:2036-2045, 2018 Treatment Development - Part IV
Human molecular studies Neurobiological Clinical Studies targets Preclinical Animal Models
ResearchS Psychiatric Comorbidity with Substance Use Disorders
Anxiety and Major depression are the most common disorders comorbid with drug abuse (Conway 2006, NIDA 2010) Amygdala Dysfunction in Psychiatric Disorders
Dynorphin: opioid neuropeptide; dysphoria Co PAC Prefrontal cortex AB AHA Striatum
AHA = amygdalohippocampal area AB = accessory basal nucleus Co = cortical nuclei Amygdala PAC = periamygdaloid cortex PAC = Periamygdaloid cortex Anderson et al., J. Clinical Investigation, 2013
Control Control Control Heroin Heroin Major depression disorder Prodynorphin mRNA in the Rat PAC is Reduced Following Heroin Self-Administration during the Acute Stress Withdrawal Period
Pdyn mRNA in PAC Crf mRNA in CeA *
*
Saline Heroin Saline Heroin
24 hours after self-administration session DREADD-Assisted Metabolic Mapping (DREAMM) Map behavior to neurochemistry Manipulate neurochemistry & behavior
Remote Behavioral neuronal Imaging manipulation Pdyn (FDG-µPET) DREAMM 18F-fluorodeoxyglucose (DREADD)
hM4Di – Gi coupled CNO – clozapine-N-oxide
DREAMM: Whole-brain functional anatomy of PAC Pdyn-expressing cells
In vivo imaging Viral vector
Inert agonist targeting the designer receptor
Michaelides et al., J Clinical Investigations, 2013 Chemogenetic inhibition of Prodynorphin Neurons in the PAC Activates the Extended Amygdala
Central amygdala, bed nucleus stria terminalis and nucleus accumbens shell (L. Heimer & G. Alheid 1991) ▶ Roles: – Adaptive motivational behaviors – Maladaptive response to fear, anxiety and stress ▶ Dysregulation of the extended amygdala has been implicated in psychiatric disorders Anderson, Michaelides et al., J Clinical Investigations, 2013 Inhibition of Prodynorphin PAC Neurons Enhance Physiological and Behavioral Measures of Stress and Negative Affect
Increased stress hormone: Anhedonia: Attenuated Depression-like behavior: Forced Corticosterone levels sucrose preference Swim Enhanced Immobility
Anderson et al., J Clinical Investigations, 2013
•GW Pharmaceuticals
Jacqueline Ferland Anissa Bara Henrietta Szutorisz Gregory Rompala Alex Chisholm Michel Miller Ben Chadwick Edwin Salsitz Claudia Morris Julia Alishayev Yoko Nomura Gabor Egervari Gary Winkel, Kristina Queens College and Gurgov, Chris Kudrich Graduate Center, Tanni Rahman CUNY Diana Akpoyibo Randy Ellis Jeremy Sherman Sharon Spriggs Lexi Pritchett Annie Ly Patricia Pehme Nayana Patel Melissa Huang
Anna Oprescu Joseph Landry James Callens Teddy Uzamere Micah Frier
Kristen Brennand Chris Kudrich Prashanth Rajarajan Philip Kamilar-Britt Ehsan Moazen-Zadeh Lauren Noble NIH Vyoma Sahani DA030359 Yuanqi Sun Keren Bachi MH102729