Introduction to
Addiction
Sean Koon, MD
California Academy of Family Physicians
And
California Society of Addiction Medicine
April 14, 2005
Goals
• Explain the medical model of addiction
• Explain what makes some chemicals addictive
(and others not) ?
• Explain what makes some people become
addicted (and others not) ?
• What keeps them from stopping when “enough is
enough”?
• When they do stop, why do some people relapse
“after they’ve been doing so well” ?
Medical Model of Addiction
• Expression of addiction (phenotype) is based on a
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genetic predisposition (genotype) that is
influenced by environmental factors
Well-studied biological mechanism
Treatment compliance is similar to other chronic
medical conditions (diabetes, hypertension,
asthma)
Follows a relapsing and remitting course
Most effectively managed as a chronic disease
Both medical and behavioral interventions are
used
Similarities with Other Chronic Diseases
(Type II Diabetes, HTN, Asthma)
• Genetic impact is similar
• The contributions of environment and personal
choice are comparable
• Medication adherence and relapse rates are
similar.
• Long term maintenance treatments proven
most effective.
(McLellan, JAMA 2000)
Genetics: Pedigree
• Monozygotic twins have higher concordance of
addiction than dizygotic twins (the more genes
you share, the more similar your addiction
propensity)
• Men whose parents were alcoholics have an
increased likelihood of alcoholism even when
adopted and raised by non-alcoholic parents from
birth
Genetics: The Genome
• The minor (A1) allele of the TaqIA D2 dopamine
receptor gene has been linked to severe alcoholism
and polysubstance dependence
• A single nucleotide polymorphism in the gene
encoding fatty acid amide hydrolase has been
associated with increased recreational and problem
use of drugs or alcohol
Genetics: The Genome
• A Leu7Pro polymorphism of the neuropeptide Y
gene has been correlated with increased alcohol
consumption
• Single nucleotide polymorphisms of the gene
encoding the mu-opioid receptor correlates with
an increased likelihood of heroin abuse
• Genes that affect metabolism of
drugs/alcohol/nicotine affect propensity for
dependence
Pathophysiology
• Why and how do people get addicted to
drugs ?
• Why are some chemicals addictive and
others not ?
Pathophysiology
• Within our bodies we have very precise
mechanisms for maintaining homeostasis
(e.g. pituitary hormones, thyroid,
insulin/glucagon, etc.)
• These mechanisms titrate necessary
chemicals within the body to obtain this
balance
Pathophysiology
• If something is needed from outside of the
body, systems of craving and satiation are
necessary
• The urgency of the need is promoted by the
intensity of the craving
At this moment are
you more thirsty or
hungry (or neither?)
How it Works: The Reward Pathway
• Many parts of the brain work together to maintain
this homeostasis
• The “mesolimbic” pathway uses reward (often a
sense of well-being or pleasure) to promote life
sustaining and life fulfilling behaviors (eating,
drinking, sex, nurturing, etc.)
• Addiction occurs by dysregulation of this natural
function
MESOLIMBIC REWARD SYSTEM
• So, if we all have this reward
pathway, why don’t all substance
users develop addiction ?
• Why are some chemicals addictive
and others not ?
The Reward Pathway
• Drugs of addiction
are identifiable by
their ability to
stimulate dopamine
secretion in this
pathway
• Addicts are
identifiable by their
unique response to
addictive chemicals
by hypersecretion
of dopamine in this
brain pathway
Dopamine release in the Nucleus Accumbens
Cocaine Preventing Dopamine Re-Uptake in the Nucleus
Accumbens
Opiate Action on the Nucleus Accumbens
Promotes Dopamine Release
Cannabis Action on the Nucleus Accumbens
Promotes Dopamine Release
How and when does a person
“get addicted” ?
The “Switch”
“continued repetition of voluntary drug taking
begins to change into involuntary drug taking,
...at which (point) the behavior is driven by
compulsion to use the drug.” (Leshner, 2000)
• The progression from social drinking to abuse
to dependence ranges from 3-15 years in
duration in susceptible persons
• Average age of the “switch” is midthirties, but can vary
The “Switch”
• Frequent drug use in a person with
biological predisposition alters the hedonic
set-point and creates a starvation or craving
response.
• The drug loses its pleasurable effects but
becomes pathologically “wanted”
• Cravings may continue or even increase
despite satiation or drug use
Chronic Use: Hedonic
Homeostatic Dysregulation
Hedonic Set Point is Altered with Chronic Drug Use
“Feel good” Normal Affective Response
to Drugs/Alcohol
Initially use to
get high…
“Cravings”
“Feel bad”
(Koob, Science, 1997)
Now use to
“get normal”
Altered Dysregulated Set-Point
following chronic drug use
Slide from Pating,D.
So, why don’t they just
stop when they start to
suffer consequences ?
Hedonic Homeostatic Dysregulation
• The reward pathway is intimately connected, via
neural pathways, to our judgment and emotional
areas (via projections to the prefrontal cortex and
limbic system respectively)
• Judgment can be aligned or distorted to favor the
restoration of homeostasis
• The brain begins to treat the chemical as necessary
for homeostasis and thus survival
Hedonic Homeostatic Dysregulation
The patients are logically
aware they do not “need”
the drug, but survival
drives tend to take
precedence over logic and
judgment
Continued substance use
slowly takes “survival
precedence” over life
goals, self esteem,
relationships, stability,
safety, and health
So how is it that drugs with
completely opposite effects can
be equally addictive?
Each Substance of
Abuse Has Both
Primary and Secondary
Actions
Action Sites of Marijuana
Action Sites of Cocaine
Action Sites of Opiates
Substance Abuse and Moods
• Addictive substances can mimic mood
disorders directly and indirectly
– All addictive substances can cause anxiety and
depression indirectly via the secondary effect of
life chaos
– They also mimic many psychiatric disorders
directly
Substance Abuse and Moods
• Depression:
– alcohol, sedatives, MJ
– withdrawal from
stimulants, ecstacy
• Anxiety: Stimulants,
MJ (panic)
– withdrawal from alcohol
or sedatives
• Paranoia: MJ,
stimulants (intoxication
or w/d)
•Psychosis:
–stimulants,
hallucinogens
–alcohol or sedative
withdrawal
•Bipolar d/o: stimulants
•Insomnia: alcohol
(midnight awakening),
stimulants, occasionally
(short acting) sedative
withdrawal
Mood Disorders
• Chicken and the Egg: “Do I drink or use because
I’m depressed/anxious/bipolar or is it vice-versa ?”
• History will help delineate when this occurred
– Was there evidence of a mood disorder preexperimentation?
– Were there problems with mood during periods
of abstinence?
– Do they get better or worse when you detox
them?
Relapse
How can people relapse after they’ve
quit for such long periods of time?
Craving and Relapse
• During repeated drug use patients become
biologically hypersensitized to:
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The Drug of Choice
Other addictive drugs
Stimuli associated with drug use
Stress induced craving
• This hypersensitization is long-lasting due
to adaptive and structural changes in the
reward pathway
Craving and Relapse
Functional Changes
• Long lasting changes in the functional activity of
the mesocorticolimbic dopamine system, in
glutamate and dopamine transmission in the
nucleus accumbens
• Long lasting adaptive changes in gene
expression and protein activation, especially
“Fos” proteins (these occur through activation of
the cAMP cascade via D1 dopamine receptors in
the VTA)
Craving and Relapse
Structural Changes
• Changes in caliber of dopamine dendrites
and cell bodies in the VTA (opioids)
• Increase in density/number of dendritic
branches in Nucleus accumbens
(stimulants)
• Decrease in neurofilament proteins
Craving and Relapse
• By these and likely other mechanisms,
the patient remains hypersensitized to the
rewarding effects of the drug AND
exhibit the PRIMING and
CONDITIONING effects
Craving and Relapse
• Priming: An introduction of even a tiny amount of
the drug can cause intense cravings and imminent
relapse
• Conditioning: During substance use, patients also
become hypersensitized to environment cues
associated with use (associated smells, sights,
location, sounds, stressors, people, etc.)
• These cues (or “triggers”) can cause dopamine
release AS IF A SMALL AMOUNT OF THE
DRUG WERE TAKEN
• Due to the stable biological changes, both priming
and conditioning effects can persist for years
The “Formula” for Addiction
• Genetic or biological predisposition
• A specialized response to addictive
chemicals
• Risk factors (mood disorders, life trauma,
environmental factors, drug availability)
• Practice (“experimentation”)
• The “Switch”: hypersensitization and
hedonic dysregulation
The Crisis of Addiction
• When addicts initially choose to use, they are often
unaware of their genetic propensity
• Their initial experimentation is often acceptable and
typical for their subculture or society at large (or even
recommended as in the case of rx meds)
• Continued use can cause severe consequences to self,
others, and community, though these consequences
often only occur after addiction has taken hold
• Once addiction is fully developed, the use of drugs
and the behaviors that follow can become out of
control
At the same time, chemically dependent persons remain
completely responsible for their continued use of drugs
AND the resultant behaviors
Timeline of Untreated Addiction
The “Switch”
Experimentation
Predisposing factors:
•Genetics
•Co-morbid conditions
•Environment
Maintenance
LOSS
Multiple crises with brief
periods of abstinence
Chemical Dependency as a Chronic
Condition
Complex outcomes in CD treatment: relapse is
common, success is measured by retention in
recovery, decreased morbidity, life improvement
Abuse
Early Abstinence
Sobriety
Stable Maintenance
Primary Care Workshop
California Academy of Family Physicians
and
California Society of Addiction Medicine
April 14, 2005