Opioid Addiction: Novel Potential Non-

Opioid Treatments Based on Neuroscience

Yasmin Hurd
Director, Addiction Institute of Mount Sinai
Icahn School of Medicine at Mount Sinai
Depts Psychiatry, Neuroscience and
Pharmacological Sciences
 HEALTHCARE
OVERDOSE SYSTEM UNDER
DEATHS: ~130 SEIGE: 3x cost of
deaths daily other medical dx

ECONOMIC TREATMENTS -
BURDEN: NOT USED OR
~$1.2 Trillion NOT SUITABLE

1
COVID: stress, social isolation and drug use

National increase in urine drug test

positivity rates during COVID-19

fentanyl 67%

heroin 33%

methamphetamine 23%
32% increase in substance abuse
since the start of the pandemic cocaine 19%

0% 20% 40% 60% 80%

Wainwright et al., JAMA. 2020;324(16):1674-1677.

Drug Overdose Deaths
~84,000

2020
 Opioid Receptors in the Body
(Heroin)
Morphine Opioid receptors dispersed throughout the body, but a few
regions are involved in many of the major effects (and side
effects) of opioid drugs

BRAIN: Opioid binds to receptors expressed in many parts of

the brain, including the cerebral cortex, nucleus accumbens and
hypothalamus. Many of these regions are involved in pain
perception, emotion, reward and addiction

BRAINSTEM: Opioid activity in the brainstem can affect

breathing by quieting neurons that control respiration.
Respiratory depression is a dangerous side effect of opioid
4
drugs and is commonly the cause of opioid overdose deaths.

SPINAL CORD: The transmission of pain signals in the spinal

cord, especially in a region called the dorsal horn, is dampened
by opioids binding to receptors on these cells. This is one target
of opioid treatments and a mechanism of the drugs’ unrivaled
analgesic properties.

PERIPHERAL NEURONS: Pain-sensing neurons send

nociceptive messages from the periphery to the spinal cord.
Opioid receptor binding in these neurons is another way that
opioid drugs curb pain sensations.

INTESTINE: Opioid receptors are expressed in neurons

regulating peristalsis. Inhibition of these cells upon opioid
binding leads to constipation, another side effect of opioid
medications,
 Medications Used To Treat
(Heroin)
Morphine
Opioid Use Disorder
– Methadone [Dolophine, Methadose.…; mu-opioid receptor
(MOR) agonist; 1964]
– Buprenorphine (Buprenex, Subutex; partial MOR agonist)
– Suboxone = Buprenorphine and Naloxone (MOR antagonist)
Only ~20 percent
– Naltrexone ofRevia; MOR/kappa antagonist)
(Vivitrol,
5
people who need OUD
treatment receive it

Barriers:
Stigma
Governmental regulation
Science-based novel treatments
Opioid Addiction Cycle and Associated Treatment
Strategies

• Detoxification • Opioid agonist

• Naloxone • α-agonist
• Medical • Medical
supportive supportive
treatment treatment

Intoxication Withdrawal

Craving and
Relapse drug-seeking
behaviors
• Naltrexone
• Medical supportive • Opioid agonist
treatment
• Psychosocial
• Psychosocial
intervention
treatment

Opioid system – primary target for treatment

 Medication Development: Alternative Approach

Human molecular
studies
Neurobiological Clinical Studies
targets
Preclinical Animal Models

S
Research
 Alternative Approach- Epigenetics I

Human molecular
studies
Neurobiological Clinical Studies
targets
Preclinical Animal Models

S
Research
Molecular Insights: Human Brain
 Neurobiology of Addiction

DS

PFC NAc (ventral striatum; Nucleus accumbens): reward

VTA expectation; goal-directed behavior
OFC DS (Dorsal striatum): habit formation
NAc PFC (Prefrontal cortex): cognitive control
AMG
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
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
 Epi Genetics
Addiction — Complex Disorder
Environment
-control gene activity

Describes mechanisms by which genes are turned on or off without

altering the genetic code or DNA sequences
Dysregulation of Epigenetic Remodelers in the Striatum of Human
Heroin Abusers Predict Increased Acetylation and Transcription

More accessible state

of DNA = enhanced
transcription

Increased histone H3 acetylation

- 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

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

Human
Human Rat
RatModel
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
 Bromodomain and Extraterminal (BET)
Inhibitors - Potential Drug Abuse Treatment

Ac

Heroin self-administration behavior can be reduced

by specific
Specific Epigenetic epigenetic
Inhibitors inhibitors
reduce rewarding effects of heroin

Heroin self-administration Vehicle

Intra-dorsal striatal infusion
BET inhibitor
vehicle
BET inhib

Systemic administration
Egervari et al., Biological Psychiatry, 2016
 Alternative Approach- Epigenetics II

Human molecular
studies
Neurobiological Clinical Studies
targets
Preclinical Animal Models

S
Research
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 – component of the synaptic machinery
Increased phosphorylated-Tau in that regulates the accumulation of
hyperphosphorylated Tau, a pathological
the brains of human heroin users feature of neurodegeneration

Kovacs et al.,. Neurobiol Aging, 2015

Phosphorylated Tau-Y18

Vehicle Opioid

FYN
Tau Tau

Src family of nonreceptor tyrosine kinases (SFKs)

Egervari et al., Nature Communications, 2020

 Fyn Expression Regulates Heroin
Seeking Behavior

Knockdown (gene silencing) of Fyn Reduces

Cue-Induced Heroing Seeking Behavior
Drug-specific
Active lever
Lever presses Non-drug
Inactive lever
Lever presses

Egervari et al., Nat Communication, 2020

 Fyn Medication Development

Saracatinib (AZD0530)

**
AZD0530
Compound X

Specific epigenetic and synaptic dysregulation associated with

Epigenetic and
heroin abuse
Food self-administration linked to glutamatergic pathology may provide
synaptic regulation Clinical Trials
targets
target drugsfor treatment development

Egervari et al., Nature Commun. 2020

 Alternative Approach- Cannabinoid

Human molecular
studies
Neurobiological Clinical Studies
targets
Preclinical Animal Models

S
Research
 ∆9-THC CBD

∆9-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
 ∆9-THC CBD

Decrease heroin seeking

Enhance heroin self-adminstration 25

70 Vehicle

Number of lever presses

Vehicle active lever 20
60
3xCBD
THC active lever
50 15
Number of lever-pressing

40
10
30

20
5
10

0 0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Active Lever Inactive Lever
Session

Ren et al, Journal Neuroscience, 2009

 Opioid Abuse is Characterized by Impairments
of Glutamatergic Transmission Nucleus accumbens

Dopamine – reward
Glutamate – excitatory neurotransmission; modulate
Synaptic plasticity
reward system; drug seeking

1200

Average Integrated Intensity

800 Gene transcription
Control Heroin

Prefrontal Cortex:
Glutamate VTA: 400

Glutamatergic-
related genes
Dopamine
Nucleus
accumbens NAc core Medial Lateral
0 NAc shell

Saline Heroin Heroin

SA/Vehicle SA/Vehicle SA/CBD
 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 Session 1
CBD/Placebo)
4

CHANGE FROM BASELINE 3 Neutral cue

heroin cue
2

-1

Placebo 400mg CBD 800mg CBD (7 days postSession

CBD/Placebo)
4
-2
2

1.5

CHANGE FROM BASELINE

1

0.5

-0.5

-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
Session 1
(1-2hr post CBD/Placebo)
4

3
Neutral cue
heroin cue
CHANGE FROM BASELINE

-1 (7 days Session
post CBD/Placebo)
4
2
-2 Placebo 400mg CBD 800mg CBD
1.5

CHANGE FROM BASELINE

1

0.5

-0.5
Placebo 400mg CBD 800mg CBD
-1
VAS, Visual analog scale Hurd et al., Am J Psychiatry, 2019
CBD Reduces Cue-induced Physiological
Measures of Stress
40
Heart rate
Cortisol Level
30 Neutral cue Drug cue
110 Neutral cue 110 Drug cue
20
Percent change from baseline
% change from baseline

105 105
10

100 0 100

95-10 95

-20
Placebo
90 400 mg CBD 90
800 mg CBD
-30

85 15 mins
Placebo 35 mins 85 15 mins 35 mins
-40 400 mg CBD
Time Post-cues
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
 Medicinal Cannabidiol?

• Cannabidiol holds promise for

OH opioid use disorder treatment —
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
Cannabis is not medicine
 Specific Cannabinoids

Risks Benefits?

• SUD (THC) • SUD (opioid; tobacco, cannabis, alcohol) (CBD)

• Psychosis (THC) • Psychosis (CBD)
• Anxiety/negative affect (THC) • Anxiety/negative affect (CBD)
• Negative impact on the developing • Developmental disorders (CBD?; THC?)
brain (THC) • Pain/ inflammation (CBD?; THC)
• Epilepsy (CBD)**

Many outcomes are still uncertain about both THC and CBD

? **, only FDA-approved cannabinoid

Path to Medicine

The stats does not favor translation of basic science research

~3.9% of publications produced by basic
research awards are translational

Moving new drug candidates from preclinical research into human

studies and the approved drug is only approximately 0.1%.

Basic science Translational Clinical trials New treatment

research research
 Path to Medicine: guided by neuroscience

▶Substance use disorders share neurobiological features similar to

other disorders for which medications
▶Repurpose medications

– Shown to be generally safe for human consumption

– Already completed phase 1 and 2 trials

▶Dose relevance for particular syndromes