WEEK 4

Epidemiology and Neurobiology of Addiction

Pharmacology of Drugs of Abuse

Therapeutic Potential for Drugs of Abuse

• New or novel psychoactive substances (NPS)
• Explosive growth in illegal drug varieties
• Not controlled by United Nations’ 1961 and 1971
Psychotropic Substances Conventions, but may
pose public health threat
• NPS prevalence
• Reported in almost 100 countries and territories
• 500 NPS identified worldwide
• 5 percent of adult population
Pharmacology of Drugs of Abuse

Therapeutic Potential for Drugs of Abuse

• National Institute on Drug Abuse (NIDA)
• Launched National Drug Early Warning System in
2014 for information and local drug research
assistance
• NPS: significant problems
• More likely to be used by children, adolescents, and
young adults
• Side effects unpredictable, severe, and more
dangerous than classic drugs of abuse
Epidemiology and Neurobiology of Addiction

• Drugs and other substances considered controlled

substances
• Under the Controlled Substances Act (CSA) and divided
into five schedules that are updated annually in Title 21
Code of Federal Regulations (C.F.R.) §§ 1308.11 through
1308.15
• Criteria for substance schedule placement
• Currently accepted medical use in treatment in the United
States.
• Relative abuse potential
• Likelihood of causing dependence when abused
Pharmacology of Drugs of Abuse

Extent of the Problem

• National Drug Control Strategies initiative (2010)
• Drug addiction is treatable and preventable brain
disease
• Key areas
• Substance abuse prevention
• Treatment
• Recovery
• Five schedules
Controlled Substance Schedules
Schedule I

Substances in this schedule have:

• No currently accepted medical use in the United States
• A lack of accepted safety for use under medical supervision, and
• A high potential for abuse.
Examples include: heroin, lysergic acid diethylamide (LSD), marijuana (cannabis),
peyote, and 3,4-methylenedioxymethamphetamine (“ecstasy”), “spice”, and “bath salts.”

Schedule II

Substances have a high potential for abuse, which may lead to severe psychological or
physical dependence.
Examples of opiates include: methadone (Dolophine®), oxycodone (OxyContin®,
Percocet®), fentanyl (Sublimaze®, Duragesic®), morphine, opium, and codeine.
Examples of stimulants include: amphetamine (Dexedrine®, Adderall®),
methamphetamine (Desoxyn®), and methylphenidate (Ritalin®).
Controlled Substance Schedules
Schedule III
Substances have less potential for abuse than substances in Schedules I or II and abuse
may lead to moderate or low physical dependence or high psychological dependence.
Examples include: products containing not more than 90 milligrams of codeine per
dosage unit (Tylenol with Codeine®), buprenorphine (Suboxone®), ketamine, and
anabolic steroids such as Depo®-Testosterone.

Schedule IV
Substances have a low potential for abuse relative to substances in Schedule III.
Examples include: alprazolam (Xanax®), clonazepam (Klonopin®), diazepam (Valium®),
lorazepam (Ativan®), midazolam (Versed®), and triazolam (Halcion®).

Schedule V
Substances have a low potential for abuse relative to substances listed in Schedule IV
and consist primarily of preparations containing limited quantities of certain opiates.
Examples include: cough preparations containing not more than 200 milligrams of
codeine per 100 milliliters or per 100 grams (Robitussin AC®, Phenergan with Codeine®).
Pharmacology of Drugs Of Abuse

Extent of the Problem

• 2010 National Drug Control Strategies
• Establish and promote a balance of evidence-based
public health and safety initiatives focusing on key areas
such as substance abuse prevention, treatment, and
recovery
• Reduce drug use and its consequences in the United
States.
• 2015 National Drug Control Strategy
• Focus on seven core areas and emphasize commitment
to confront prescription opiate medications and heroin
misuse
 Extent of the Drug Problem

National Survey on Drug Use and Health (NSDUH)

• Annual SAMHSA survey of substance use, misuse,
or addiction in U.S. individual age 12 years and older
• 27 million current illicit drug users
• 6.5 million nonmedical users of psychotherapeutic drugs,
including 4.3 million nonmedical users of pain relievers
• One in five young adults (18 to 25 years) current users of
illicit drugs
 Extent of the Drug Problem

Monitoring the Future study (2015)

• Surveys drug use, behaviors, attitudes, and values
of U.S. secondary school and college students and
young adults
• Modest increase from 30 to 38 percent in cannabis
use; daily use decline from 5.0 to 4.6 percent
Extent of the Drug Problem

2015 Overview of Key Findings on Adolescent

Drug Use
• No significant increase across broad spectrum of drugs
• Continued decline in cigarette and alcohol use
• Annual prevalence decline for synthetic marijuana,
heroin, MDMA, sedatives, and nonmedical prescription
drug use
• Use of any illicit drug remained unchanged in all three
grades
• Annual prevalence was 14.8 percent, 27.9 percent, and
38.6 percent in 8th, 10th, and 12th grades, respectively”
(Johnston et al., 2016)
Extent of the Drug Problem

Facing Addiction in America: The Surgeon

General’s Report on Alcohol, Drugs, and
Health (2016)
• Addiction viewed as chronic neurological
disorder, not a “moral failing”
• Evidence-based treatment focus; reduce drug
harm and imprisonment of addicts
• Screening and early intervention in primary care

• Little guidance on implementation

Nosology and Psychopathology of
Substance Abuse
DSM-5: Substance Use Disorder (SUD) (2013)
• New category allows diagnose of people with
alcohol and/or drug problem more easily by looking
at a continuum of severity (mild, moderate, severe)
• Diagnosis bases
• Impaired control
• Social impairment
• Risky use
• Pharmacological criteria
• Dual diagnosis; comorbidity among 1/3 with SUD
• 47% with schizophrenia have had SUD
• 24% with an anxiety disorder have had SUD
Neurobiology of Addiction

• Common Effects of Abused Drugs on Brain

Reward Circuits
• Mesolimbic dopamine pathway
• Dopamine neurons in activated VTA release dopamine in
other brain structures
• Dopamine pathway from VTA to NAc crucial to addiction
• Lesions in this pathway protect against addiction
• Most drugs of abuse directly or indirectly increase dopamine
availability released from the VTA to the Nac, amygdala,
hippocampus, and frontal lobe.
Neurobiology of Addiction

Neurobiology of Pleasure
• Electrical stimulation of brain
• Existence of reward circuit in rat brain (Olds and
Milner in 1950s)
• Brain Disease Model of Addiction (BDMA)
• Drugs of abuse act through same reward system and
promotes repeated use
• Neurobiological changes are responsible for cravings
and relapses
Neurobiology of Addiction

Neurobiology of Pleasure
• Most abused drugs share common action with
mesolimbic dopamine pathway
• This pathway is integrated to other structures
• Hippocampus – Pleasure memories
• Amygdala – Pleasure memories
• Prefrontal cortex – Executive functioning, planning
 The Reward Circuit

Pathway starts with dopamine-releasing neurons in the ventral tegmental area (VTA).
Axons from the VTA neurons release dopamine to the amygdala, nucleus accumbens
(ventral striatum), and prefrontal cortex.
Neurobiology of Addiction

Effect of Drugs on Dopaminergic Activity

• Related to pleasurable subjective effects in
animals and humans
• Methylphenidate-blocked dopamine transporter
increased amount of dopamine in synapse
• Greater reported highs related to proportion of
blocked transporters
• Chronic drug exposure may reduce responsiveness
• Risk for addiction may be related to biological deficit
(dopamine receptor deficiency)
Neurobiology of Addiction

What is the difference between someone who can

drink or dabble in illicit drugs without developing
dependence (or many negative consequences)
versus someone who becomes an addict?
Only a small percentage of users develop
dependence (e.g., heroin)
Variability in stress and coping ability
 From Abuse to Addiction

• Repeated drug use may develop into chronic drug

use that can become compulsive (addiction)
• Frontal lobe is profoundly altered by chronic drug
abuse
• Cortical hypofrontality occurs after long-term drug
use
• Fewer dopamine receptors in the NAc than normal
and a lower metabolic rate in the frontal lobe
Did You Know?

Brain images showing decreased dopamine (D2) receptors

in the brain of a person addicted to cocaine versus a nondrug user.
From Abuse to Addiction

• As a result of chronic drug use, natural rewards become

less pleasurable, and release less dopamine despite
greater response in dopaminergic transmission than
normal.
• The frontal cortex becomes inherently less active and
less responsive to normal rewards, but it is overactive in
response to drugs or the stimuli that predict drug.
• The memory of positive effects of a drug provides the
motivation for compulsive use, and is believed to be
responsible for relapse. This memory is mediated by the
amygdala and hippocampus.
From Abuse to Addiction

• Over time, stimuli that “predict” drugs produce a

greater response in the reward pathway than
the rewarding stimuli themselves.
• Such conditioned, or learned, responses could
elicit powerful craving sensations in the frontal
cortex.
• Frontal lobes become sensitized to drug-related
stimuli.
 Major Brain Structures Involved in Addiction

The ventral tegmental area (VTA) and nucleus accumbens are key components of the
reward system.
These, together with the amygdala, hippocampus, and prefrontal cortex (PFC),
coordinate drives, emotions, and memories.
From Abuse to Addiction

Relapse
• Can be triggered by three major conditions:
• Reexperience with the drug
• Conditioned drug cues
• Stress (including withdrawal-induced reactions)
Glutamatergic Substrates of Addiction

• Heightened craving sensations

• Transmitter glutamate released
• Glial cells help maintain glutamate
• xCT pushes glutamate from glial cell
• Hypersensitivity of the frontal cortex supports
craving following drug cues
• Chronic use produces common biochemical
changes across drugs
• Several drugs of abuse also reduce neurogenesis
 Schematic of the Brain Circuitry of Addiction

Dopamine fibers that originate from the VTA and release dopamine in the NAc with other
structures in the limbic system (Left)
Excitatory glutamatergic structures that interact with the VTA and mediate the
development of drug addiction (Right)
Glutamatergic Substrates of Addiction

• Hypersensitivity of the frontal cortex to drugs or

drug cues (learning), which develops in
addiction, is the basis of the phenomenon of
craving
• Craving is biologically mediated as increased
glutamatergic reactivity within the reward circuit
The Brain Disease Model of Addiction

Summary
• Changes in reward circuit and emotional system
of brain produced by chronic use
• Drug-induced high
• Withdrawal-induced low
• Changes in prefrontal cortex (glutamatergic
function) and executive control functions
• Vulnerability due to genetic, social, and
environmental factors
• Treatment approaches derived from model
The Brain Disease Model of Addiction

Criticism
• Evidence strongest for stimulants; not consistently reported
in other drug addiction (Nutt and colleagues)
• Dopamine receptor blockade not very effective in reduction
of rewarding effect of stimulants or treatment of addiction
• Lower striatal dopamine density of cocaine user may be due
to chronic drug use rather than preaddictive condition;
differential blunted dopamine release not seen in cannabis-
dependent subjects
• Only minority of addicts fit criteria for BDMA (Hall and
colleagues)
• Few treatment drugs developed from BDMA
Pharmacotherapy of Substance Use Disorders

Current Approaches
• Still consist mostly of traditional, relatively
specific therapies, focusing on medications that
directly affect the biological actions of primary
drug of abuse
• Agonist substitution treatment
• Partial agonist substitution treatment
• Antagonists as treatments for addiction
• Treatment approaches derived from the
glutamatergic model of addiction
Pharmacotherapy of Substance Use Disorders

Agonist Substitution Treatment

• Reduces rewarding effect of abused drugs and discomfort of
withdrawal
• Improves compliance and provide safer routes
• Opioid addiction
• Methadone
• Nicotine addiction
• Nicotine lozenges, gum, and patches
• Clinical trials for drug PF-04457845
• Alcohol addiction
• Disulfiram (Antabuse); also cocaine addiction
• Clinical trials for Nepicastat (selective DbH inhibitor)
Pharmacotherapy of Substance Use Disorders

Partial Agonist Substitution Treatment

• Buprenorphine: partial agonist for opiate addiction
• Varenicline: α4 β2 partial nicotinic agonist for nicotine
addiction and reduction of alcohol consumption
• Sazetidine-A: novel nAChR desensitizing agent and α4
β2 partial nicotinic agonist to reduce nicotine self-
administration
• Dopamine Partial Agonists
• Should provide enough dopamine activation to reduce the
effects of withdrawal yet block the consequences of illicit
stimulant use
Pharmacotherapy of Substance Use Disorders

Antagonists as Treatments for Addiction

• Antagonists directly block the reinforcing effect and eventually
reduce the compulsive behavior
• Opiate antagonists
• Naloxone
• Naltrexone
• Nalmefene
• No positive reinforcement makes adherence difficult and relapse likely
• Not clear if effective against alcohol or stimulants
• Benzodiazepine antagonist/partial agonist flumazenil (Anexate,
Romazicon)
• Doxazosin adrenergic antagoinst for cocaine addiction treatment
• Rimonabant (Acomplia) selective antagonist for cannabis CB1 receptor;
suicide side effects
Pharmacotherapy of Substance Use Disorders

Additional Neurotransmitter Targets

• GABAergic system
• GABA-B agonists, such as baclofen, can reduce the
reinforcing effects of several different classes of abused
drugs
• Other GABAergic medications being tested as possible
agents for preventing cocaine relapse are anticonvulsants
(gamma-vinyl-GABA/GVG; Vigabatrin); CPP-115 currently
in clinical trials
• Gabapentin (Neurontin) increases GABA
synthesis/treating cannabis dependence
Pharmacotherapy of Substance Use Disorders

Treatment Approaches Derived from the

Glutamatergic Model of Addiction
• Incorporating glutamate into the BDMA as a
possible mediator of learned associations between
drugs and environmental stimuli
• N-acetylcysteine: Increase brain production of xCT;
ACCENT clinical trial with cannabis cessation
• Ceftriaxone: increase levels of GLT-1/cocaine relapse (rat
study)
• Modafinil (Provigil): increase glutamate levels/cocaine
withdrawal inconsistent clinical results
Pharmacotherapy of Substance Use Disorders

Treatment Approaches Derived from the Glutamatergic

Model of Addiction
• Acamprosate (Campral): reduces glutamate overactivity-
NMDA modulator/maintains alcohol abstinence; inconsistent
clinical trial effectiveness
• Topiramate: reduces glutamatergic actions and blocks AMPA
receptors/reduces subjective effects, craving/alcohol
addiction and behavioral addictions; cocaine and cannabis
abuse
• Gabapentin and lamotrigine: inhibit release of
glutamate/reduces some alcohol withdrawal somatic
symptoms; inconsistent clinical results for addiction treatment
Pharmacotherapy of Substance Use Disorders

Other Approaches Involving Glutamate

• Agonists that act directly on the presynaptic
glutamate autoreceptor, the mGluR2/3
subtype/animal and preclinical human trials
• Agonists that affect ionotropic glutamate
receptors, the AMPA subtype (tezampanel;
talampanel; perampanel; ampakines)
• Agonists that affect NMDA receptors/DCS-
NMDA coagonist drug D-cycloserine; NR2B
Pharmacotherapy of Substance Use Disorders

Opioid System
• 𝜇 type of MORs located on GABA neurons in VTA
are key in modulation of ventral tegmental area
dopaminergic activity
• 𝜇-opiate receptor critically involved in the rewarding
properties of several abused drugs and in the
development of physical dependence to nicotine
and cannabinoids
• Naltrexone (clinical trials) blocks 𝜇-opioid
receptor/reduction of alcohol self-administration and
relapse; may promote amphetamine abstinence
Pharmacotherapy of Substance Use Disorders

Cannabinoid System
• Cannabinoid-opiate interactions are gaining more
attention in research involving addiction and reward
mechanisms, including nicotine and alcohol addiction,
relapse similarities, abuse overlap, and cross-tolerance.
• Parolaro and colleagues’ model
• Cannabinoids can release opioid peptides and opioids can
release endogenous cannabinoids (endocannabinoids).
• When receptors for these two systems are both located on the
same cells, there is evidence for direct receptor–receptor
interaction.
• There is an interaction between their intracellular pathways.
Epidemiology and Neurobiology of Addiction

New Directions
• Drugs
• Drug targeting GPCRs may influence drug-seeking behavior
and be useful as addiction medications.
• Vaccines provide promising therapy for relapse prevention via
stimulation of drug-specific antibodies production.
• Drug and natural reward system stimuli overlap may reduce
rewarding effect of cocaine (as also seen in highly palatable
food).
• Deep brain stimulation (DBS) may be used for refractory
addiction.
• Neuroscience
• Interventions like religious rituals may make prefrontal cortical
systems more resilient and less vulnerable to enhance their executive
functions.