Lecture 2: Drug Addiction Flashcards
Defining Addiction Is there a single definition? (A) (B) (C)
*There is no single, universally accepted definition of addiction
“The compulsive seeking (drug craving) and
administration of a drug despite grave
adverse consequences or as a loss of
control over drug intake” (Nestler, 2004)
• i.e., when I drink coffee, it doesn’t have
grave consequences so is not an addiction
under this definition. This definition is
missing the physiological aspect, get a
headache as a withdrawal symptom which is
a sign your body is saying they need the
chemical (caffeine) and to drink a cup of
coffee.
“a term used to indicate the most severe,
chronic stage of substance-use disorder, in
which there is a substantial loss of self-
control, as indicated by compulsive drug-
taking despite the desire to stop taking the
drug” Volkow, Koob, and McLellan (2016)
• A second definition. coffee is not extreme
and not an addiction under this definition.
Chronic – repeated and uncontrollable
behaviour. To take drug to stop withdrawal
symptoms and feed cravings despite
negative consequences and desire to stop.
Classifies it as a part of substance use
disorder (qualifies it)
“a chronic, relapsing brain disease that is
characterized by compulsive drug seeking
and use, despite harmful consequences”
National Institute for Drug Abuse (NIDA)
• Third definition: brain disease (chemical
reactions in the brain, every sense of you
are, belief, memory, needs, or behaviour
starts in the brain)
“addiction is, at its core, a consequence of
fundamental changes in brain function
means that a major goal of treatment must
be to either reverse or compensate for
those brain changes”
(Alan Leshner in 1997)
• Criticists argue that the disease model
disregards human decision making and
choice
• Fourth: changes in brain function.
• Problem with calling ‘alcoholism’ a brain
disease? Argues the addictive behaviour is
the physiological consequence of a brain
disease. It implies that the person was born
with a brain with genetic make-up that made
them predisposed to addiction and removes
the nurture/choice behaviour which results
in addiction.
• We need to separate the brain from being a
physiological organ and a mechanism that
makes decisions. The brain is you; it makes
your decisions, and you are your
decisions/thoughts. If we say someone has
stage four cancer, we do not say hey man
you could’ve pulled through if you just
thought positive thoughts. When we say
alcoholism, we say there was a choice, you
had a choice to drink.
• Like cancer and addiction (depending on
circumstance but in general) there is an
initial choice, the initial behaviour to smoke
which lead to the unintended and
uncontrollable consequence of either
addiction or cancer. If there was no cocaine
in the world, then they could not be
addicted to cocaine. However, it could
manifest in another way with another
substance if it is a disease. Addiction is not
just about the drug. It’s about the self-
destruction. They know it is wrong and they
should stop but they can’t get rid of the drug
taking lifestyle, they are not looking for the
chemical, but the ability to
forget/escape/numb themselves to pain.
Drug overdose deaths in the USA
• More common for males to overdose than
women
• Overall, 91,000 people overdosed in 2020
• Alarming that this is such a prevalent issue
and trend is increasing. Clearly,
punishment/arrests are not working at
preventing drug use. It seems anything else
could be better. Would legalizing drugs be
better?
Opioids in New Zealand
• Different drugs are more prevalent in
different geographical locations in New
Zealand.
• Guessing the reason, would be that
Northland have a social problem (low ses is
linked to drug use; gangs & violence; MDMA
in cities with clubs/universities).
• Opioids = despair & low socioeconomic
status
Classifying addiction (DSM-V)
• Substance-related and addictive disorders
o Substance induced disorders
o Substance use disorders
*There are many things you can be addicted
to that are not substances (i.e., pornography,
gambling etc. which do NOT include
chemicals). Substance – chemicals
ingested/injected/snorted into the body
*DSM-5 uses addiction and substance use
disorder synonymously
Substance-induced disorders
• Substance intoxication (drink too much and
get sick)
• Substance withdrawal (headaches, pain, get
sick)
• Substance/medication-induced mental
disorders (i.e., psychosis)
*physiological & psychological symptoms
Substance use disorders
• Cluster of cognitive, behavioral, and physiological symptoms • Continued use of a substance despite significant substance-related problems (continue using despite consequences)
*Behavioural changes
(9) Drugs included in Substance Abuse Disorder
- Alcohol
- Cannabis
- Hallucinogens
- PCP
- Opioids
- Inhalants
- Sedatives
- Stimulants
- Tobacco
*A variety of drugs people can be addicted
to. People are usually addicted to one not
all of them. Indicating that they have their
own pathways, mechanisms, chemical
reactions, and physiological changes.
*Makes it harder to fix when there are so
many and not a single substance
(prevention wise)
General criteria of substance use disorders
*How to determine when someone has a substance use disorder
- Increasing larger amounts of use of the
substance (i.e., tolerance builds and more is
needed too feel good, do it in the morning,
most of the day) - Unsuccessful efforts to decrease use
(relapse/withdrawal/cravings so continue to
use) - Drug craving (always wanting to do it that is
hard to resist, harder when near it or in
same place you usually ingest it in) - Impairment in occupational, home, or social
functioning (whole life becomes about using
the drug) - Substantial time spent procuring or
recovering from use - Risky use of the substance
- Use of the substance despite negative
consequences (more you do it, the drug
becomes the number one priority and are
less concerned about the consequences,
continue to use it despite them).
*Tolerance and withdrawal are additional
criteria for substance use disorders but are
not required for the diagnosis!
Tolerance
Increased amounts of the substance are needed to achieve the desired effect (or a substantially reduced effect when the usual amount is taken)
*Tolerance: body uses a compensatory
response to counteract the drug and
maintain homeostasis, so you need to take a
higher dosage to get the same effect of the
drug. They are chasing the high of the first
use that they will never get.
*Physiology changes: receptors, dopamine
change with continued use.
*Pentanol: is a synthetic opioid people use
when they have built a tolerance, leads to
overdose, due to our body not being able to
handle the repeated physiological changes
results in heart attacks etc.
*Tolerance varies among individuals
Withdrawal
Aversive physiological effects that ensue when the addictive substance is removed or reduced and may include insomnia, anxiety, agitation, and digestive problems
• Symptoms vary substantially across drugs!
And not all substances are associated with
withdrawal symptoms.
• Withdrawal: when the body has undergone
physiological changes to maintain
homeostasis after repetitive drug use,
when the cues for drug using are present
but a drug is not ingested, you go through
withdrawal and crave the drug to make it
go away.
• When drugs are removed the body tries to
reach a new equilibrium which results in
withdrawal physiological symptoms. Pretty
bad in opioids, they will vary across
substances. E.g., caffeine withdrawal is
headaches till the new equilibrium is
reached.
Prevalence
• ~10% of individuals 12 years of age or older
(22 million people in the U.S.) are addicted
to alcohol or other drugs
• Cannabinoids, depressants, hallucinogens,
opioids, stimulants, alcohol, PCP, nicotine
are commonly abused (worldwide)
*High prevalence. Terrifying that some 12- year-olds use substances. *It is a worldwide issue *A solution/prevention strategy can be implemented worldwide
Prevalence (alcohol)
• Alcohol use disorder affects 7.8% of men
and 1.5% of women worldwide
• 8.5% of adults and 4.6% of adolescents in
the United States
*men > women (alcohol)
*Early onset of drug use is associated with
heavy drug use in adulthood
Prevalence (opioids)
• Opioid addiction rates continue to increase
o prescription opioid use has increased by
500% in the last 7 years
o ~Two million (0.8%) of the U.S. population
is addicted to prescription opioids
o In 2015 one in three Americans were
prescribed opioids
Class Discussion:
• Drug use is increasing (upward trend)
• Pentanol is included here
• Wisdom tooth taken out and given pain
reliever (oxycodone) is that a problem.
Adderall and Ritalin are methamphetamines.
People assume if it is given to you at the
doctors the drug is different than getting it
on the street corner. The brain chemistry
changes, and the chemical is the same.
• Still get hooked if it is given to you at the
doctors, they won’t prescribe anymore, so
you go to the streets to compensate. Street
drugs are laced with rat poison, or other
drugs (fentanyl) which can cause you to OD
and get hooked on their strain or bulk up
product to make a profit.
• Ritalin = methamphetamine salts (cleaner
but not better)
*People can get addicted to their prescription
without realizing because people deny that
you can be addicted to prescriptions (i.e.,
pain meds, wine)
Withdrawal Symptoms
• Not associated with some types of hallucinogens o LSD o Mescaline o Psilocybin (mushrooms)
*Withdrawal symptoms are not associated
with these drugs!
*Some students do micro dosing of
psychedelics to improve academic
performance, every day, without being
addicted. No convincing evidence of it
reliably improving performance.
*All drugs have the same effect prescribed or
not.
*Hallucinogens are not considered addictive
Addictive Substances
*highly addictive substances include, alcohol,
benzodiazepines, nicotine, and opioids.
*cigarette smoking is the most prevalent
addiction (22.5% adults), alcohol (7.8% men;
1.5% women)
Five substances with the highest potential for addiction worldwide
Criteria:
• the extent to which the drug activates the
brains dopamine system
• degree of pleasure experienced from the
drug
• the degree to which the drug causes
withdrawal symptoms
• the degree of physical and cognitive harm
caused by the drug
• how quickly the drug results in addiction
Substances • heroin • alcohol • nicotine • cocaine • sedatives
Comorbidity
• Commonly co-occurs with psychiatric
disorders
• Increases the complexity of providing
effective treatment interventions
• Study: 400 patients - 54% exhibited
comorbid psychiatric and substance use
disorders (a larger % of public health
patients meet the criteria for comorbidity
than those from the substance abuse
settings)
• The presence of co-occurring psychiatric
disorders (bipolar disorder, major
depressive disorder) increases the risk of a
poor prognosis
Epidemiological studies
• Males are more likely than females to
suffer from substance-related disorders
o However, the prevalence gap appears to
be narrowing as substance use disorders
are increasing among females (study in
2017)
• Initiation of substance use is occurring at
younger ages
Males vs. Females
• Females appear to have: o Accelerated progression to dependence o More severe adverse medical, psychiatric, and functional consequences o More vulnerable to medical, physical, mental, and social consequences of substance use and dependance o potential risk of drug-induced complications during pregnancy • However, no differences in treatment outcomes detected between males and females • Boys and girls aged 12–17 years have comparable rate of use and initiation for alcohol, cocaine, heroin, and tobacco • ~5% of pregnant women abuse illicit drugs during their pregnancy (other studies found higher rates of opioid use in low socioeconomic status women)
Do most people who take addictive substances become addicted?
• The majority of individuals who use drugs
do not become addicted suggesting that
some people are more susceptible to
addiction than others
§ Genetic?
§ Environmental?
§ Social?
- What is the cause? Genetic (allele),
environment (ACEs), social? (gang/drug
presence). No, it is the combination of all of
them
Percentage of people who become addicted?
• ~10% of individuals are highly susceptible to
addiction
• This varies across drug types
• 23% of individuals who try heroin become
addicted (80% of heroin users started with
prescription opioids first)
• less than 1% of prescription benzodiazepine
(Valium, Xanax, Ambien) users become
addicted
• The interaction between genetics,
environment, and social factors influences
susceptibility to addiction
• First Experiment (humans)
• Vietnam soldiers took heroin during the war
and the military were concerned when they
came back the the US would be addicts
with guns. However, only 5% of them
continued to take heroin but 35-38%, who
had physiology changes and liked it,
stopped because the environmental factors
which induced the need to take drugs was
gone. 8-12% of those who misuse
prescription opiates become addicted.
• It is never entirely genetics, it’s the gene-
environment interaction!
• Second Experiment Bruce Alexander
• Mice put into a cage and was trained to
push the lever for cocaine to be released
into the brain. The article stated that the
behaviours related to cocaine addiction and
found that mice will press the lever until
they die (overdose). He re-did the
experiment with the rat in the park with
more stimuli in the cage, press the lever for
cocaine, he found a significantly smaller
percentage rats pressed the lever.
Introducing social, mating, sensory
stimulation changed their behaviour (80 vs
20%). Drugs is only a small percentage of
addiction. Unless you change the social
environment, you are not going to be able
to change addictive behaviour (it is not the
chemical in the drug, it is the combination of
the chemical and the environment).
• Gin Craze (London 18th Century)
• People moved from rural to urban areas.
Struggled to adjust and started to consume
gin (opioids). People blamed gin for the high
rates of death.
• The problem is the environment, the
stress/trauma of the environment, leads you
to addictive behaviours
• Experiment 3 (NZ is liberal; Switzerland is
conservative)
• Switzerland late 1990’s had huge heroin
problem. The government responded by
punishing people who take heroin (shame,
prison, you can say no in USA) they
legalized it rather than criminalized it.
Anyone who wants to do it goes to the
clinic and for free (clean needles, in a safe
place) people were fearful of the
chaos/violence would rise BUT the number
of overdoses was 0, there was less crime
(no need to steal, sell body, be violent), and
they engaged with the addicts and helped
them by social working, find job,
counselling, which was way more effective
than US’s response.
*Conditions to how drugs should be legal,
clinical safe spaces with treatment without
punishment or shame. We don’t want
unknown people selling unknown drugs to
unknown people.
*Is addiction an illness? Is it their fault/choice
or a mental illness that needs treatment? If
it’s a gene-environment then there is no
choice. Like depression, social anxiety,
cancer, bipolar, addiction is NOT a choice!
Impact of trauma
• Exposure to child maltreatment increases
the risk of lifetime substance use disorders
o 50% - 75% of college students with
substance use problems have a history of
adverse childhood experiences
• Physical abuse, sexual abuse, and parental
violence are correlated with substance use
disorder are similar across race and
ethnicities
Addiction in childhood associated with…
• Intention to use substances in childhood is
related to subsequent use
• Adolescents are vulnerable to addiction
due to
o Environmental factors
o Psychosocial factors
o Brain development factors
• Elementary school students intentions and
prevalence of substance use increased with
grade level. Intentions to use cigarettes and
alcohol early on were associated with
substance use in subsequent grades (i.e.,
intention is a warning sign)
• College students are at high-risk population
for use of alcohol and illicit drugs
o ~98% of drug users ingest more than one
substance
o At risk of using prescription stimulants
without a valid prescription (especially
lower point grade averages and
psychological difficulties)
Multicultural Findings
• Alcohol is the most frequently used substance (3.6% of the world population between the ages of 15-64 being alcoholics) o Eastern Europe 10.9% (highest) o Americas 5.2% o Africa 1.1%
Multicultural Findings (alcohol)
• Within the USA the prevalence rates of
alcohol use disorder vary across race and
ethnicity
o Native Americans and Alaska Natives:
12.1% (highest)
o Whites: 8.9%
o Hispanics: 7.9%
o African Americans: 6.9%
o Asian Americans and Pacific Islanders:
4.5% (lowest)
Multicultural Findings (cannabis)
• Within the USA the prevalence rates of
cannabis use disorder vary across race and
ethnicity
o Native Americans and Alaska Natives:
3.4% (highest)
o African Americans: 1.8%
o Whites: 1.4%
o Hispanics: 1.2%
o Asian Americans and Pacific Islanders:
1.2% (lowest)
Multicultural findings (longitudinal study)
• Steady and steep reduction of heavy
drinking in white men and women in 20s
• Black men and women heavy drinking
increased in frequency during their mid
20s
• Blacks and Hispanics (compared to whites)
showed a slower decline in heavy drinking
over time
*However, stimulants and opioids misuse
are higher among whites!
*mixed findings on whether individuals with
disabilities are at risk of substance misuse
Onset of Substance Use Disorders
• Development and course of substance use
disorders varies among individuals and the
substance used
• Onset for alcohol use disorder typically
occurs in late teens to mid-20s (can occur
in late teens) and majority of alcohol use
disorders are developed by their late 30s
• Onset (abuse and dependence) for most
drugs occurs in 20s to 40s
• Substance use disorder is chronic with
periods of exacerbation and remission
Psychosocial factors
Two predictors of drug use/relapse
• Psychological factors influence the course
and outcomes of substance use disorders
• Depression (and drug cravings) are major
triggers for relapse in both men and
women
• Age is another predictor factor: the earlier
the onset the higher the relapse rate (and
physical and psychological comorbidity)
Inebriated Mice Chow Down (Reading)
• Inject mice with the equivalence of two
bottles of wine per day over three
consecutive days to mimic a weekend of
heavy drinking (experimental). Control mice
were injected with saline.
• Results indicate that both male and female
intoxicated mice consumed far more chow
food than control mice.
• Autopsies of their brain revealed alcohol
(ethanol) induced activation of specialised
neurons called agouti-related protein
(AgRP). These neurons typically become
activated following fasting or release of
hunger hormones in the brain. The
researchers concluded that increased AgRP
following alcohol consumption plays a
critical role in alcohol-induced binge eating
Initiation and Maintenance of Addiction Theories: How does the addiction cycle begin?
(A) Reinforcement Theories
*There is no single cause of substance use
disorders or additive behaviours (i.e.,
combination of physiology and environment
interactions). Our knowledge is based on
animal models but some argue that
addiction is a uniquely human condition
which animal models cannot fully capture.
- Pleasurable effects reinforce initial drug
use
- Positive reinforcement of initial drug use
(reading)
- Negative reinforcement in those who use
drugs to escape emotional distress,
negative affect, or stress (lecture) - Rewarding effects are reduced and
compulsive drug-taking behavior begins
- Overtime the rewarding effects of drug use
are reduced and compulsive drug-taking
behaviour results from a need to achieve a
state of homeostasis (i.e., to feel normal,
alleviate pain, discomfort, and withdrawal
symptoms)
- The rewarding properties of the drugs do
not justify the negative consequences
which accompany their repeated use.
However, Classical Conditioning theories
argue that environmental stimuli can be
paired with drug use, becoming
conditioned stimuli which triggers drug-
taking behaviours. - Impaired cognitive processes
- Salience attribution (i.e., attention towards
stimuli heightened towards drug-
associated cues)
- response inhibition (i.e., inhibiting
behaviour which interferes with goal-
directed behaviour)
Reinforcement Theories (anatomy)
• Salience attribution, response inhibition,
drug reward, drug cravings are mediated by
the mesocorticolimbic pathway
o Striatum
o Midbrain
o Limbic system
o Prefrontal regions
Mesocorticolimbic Pathway: Rodents
• Connections between striatal, midbrain,
limbic, and prefrontal regions
o Addictive drugs activate “reward
pathways”
o Release of dopamine
• After 60 years of investigation, details
concerning the specific functioning of these
pathways remains poorly understood.
However, what is in common among all
addictive drugs is that they activate ‘reward
pathways’ in the brain by triggering the
release of neurotransmitter dopamine
(linked to experiencing pleasure or reward)
• mesocorticolimbic system involves several
interconnected brain regions including the
ventral tegmental area (VTA), substantia
nigra, caudate nucleus, and putamen
(striatum), nucleus accumbens, amygdala,
and frontal cortical regions that correspond
to a rats prefrontal cortex or a humans
anterior cingulate (READING)
Addiction Study (Rats)
• Rats learn to press self-administer cocaine
o Will do so despite adverse consequences
o Will do so in lieu of drink or food
o Mothers will abandon their newborn pups
in order to self-administer drugs
Addiction Study (Rats)
• Self-administer bursts of electrical
stimulation to brain sites that mediate
pleasurable effects of natural rewards like
food, water, and sex (i.e., intracranial self-
stimulation)
• Dopamine levels in the nucleus accumbens
increases during intravenous cocaine
administration
• Administering dopamine antagonists
decreased lever-pressing behaviour and
lesioning of the nucleus accumbens
drastically reduced the rate of drug self-
administration which strongly supports the
role of dopamine and the mesolibiccortico
pathways in drug addiction
PET and fMRI: Humans
• Increases in dopamine levels in the nucleus
accumbens, caudate, and putamen during
amphetamine administration
• Dopamine release is increased in the
nucleus accumbens and striatum in
anticipation of drug administration and drug
cues
• Differences in brain activation patterns in
the mesolimbiccortico pathway in
participants with cocaine use disorder while
at rest, compared to participants without
cocaine addiction
Orbitofrontal Pathways
• Frontal regions are important for regulating
higher-order cognitive functions
o Response inhibition
o Decision making
o Working memory
• Extensive connections with midbrain,
limbic, and subcortical structures
• Increased activation of the pre-frontal
cortex in drug users relative to controls
during fMRIs when drug related cues are
presented
Executive Function Deficits
• Executive functioning deficits are common
in individuals with addictions (executive
control is mediated by frontal regions)
o Motivation
o Craving
o Withdrawal symptoms
• Study
o Increased blood flow activity in
orbitofrontal cortex and striatum in healthy
volunteers while they eat chocolate and
rated eating the chocolate as “very
pleasant”
o No changes in activity when participants
did not find the experience pleasurable
(i.e., were satiated)
Stage Theory of Addiction
- Binge and intoxication
- Withdrawal and negative affect
- Preoccupation and anticipation (or
craving)
*Each stage activates specific neurobiologic
circuits
Stage Theory of Addiction • All addictive drugs trigger the release of dopamine • Repeated environmental stimuli elicit conditioned surges of dopamine release in anticipation of the drug • This repetitive surge in dopamine in anticipation of the drug results in a physiological desire for the drug (i.e., drug craving) • Continued use of drugs results in reduced dopamine release and less pleasurable effects • Lack of drug consumption leads to: o Negative affect o Increased reactivity to stress o Withdrawal symptoms
Timeline
• As the process of addiction progresses
from using drugs to get high to using drugs
to escape dysphoria and withdrawal
symptoms.
• As drug addiction continues, dopamine
down-regulation continues resulting in
impaired functioning of the Orbitofrontal
pathways which results in:
o Poor decision making
o Poor self-regulation
o Poor inhibition of impulsive response
• As a result individuals with addiction
succumb to desire, cravings, and continue
to use drugs despite their intention to stop
and the negative consequences of their
actions.
Challenge to unitary theory of addiction
o Addiction to a drug such as cocaine has
different neurobiological effects than
addiction to other drugs such as opioids
o There may be a high degree of overlap
regarding cellular adaptations with the use
of these drugs. Although different drugs
may produce different behavioural and
psychological effects, they may share core
underlying neurobiological substrates of
addiction.
Dopamine
• Addictive drugs effect dopamine and mesolimbic pathways by:
o activating neurons in the mesolimbic and
projecting systems
o results in increase firing of dopamine-
releasing neurons
o are associated with increased dopamine
levels in extracellular space
o are self-administered
o often result in relapse after detoxification
• Dopamine antagonists block drug effects
(cocaine and amphetamines)
• Patients with Parkinson’s disease have
compromised level of dopamine in the
nucleus accumbens and mesolimbic
pathways and experience reduced effects
of stimulants.
• Complex relationship between dopamine
and other neurotransmitter systems
o Drug addiction is often characterized by
anhedonia (failure to experience rewarding
stimuli) linked to reduced serotonin (i.e.,
based on depression research).
Other systems involved (GABA)
• Opioid receptors located on GABA neurons
in the ventral tegmental are activated,
dopamine cell activity is enhanced and
dopamine is subsequently released in the
nucleus accumbens.
• Opiates increase dopamine by removing
the inhibitory effect of GABA neurons on
dopamine releasing neurons
• GABA agonist: e.g., gabapentin
o Reduce drinking
o Decrease craving
o Improve sleep and affect in participants
with alcohol use disorder
Other systems involved (Glutamate)
• Lower glutamate levels in the forebrain
(dorsal anterior cingulate region) in
participants with alcohol use disorder
• Glutamate signaling in the prefrontal region
has been implicated in nicotine,
amphetamine, cocaine, and opioids
addiction
Brain stimulation methods
*Which interfere with dopamine release and/or cellular functioning in the mesocorticolimbic pathways • Opiate antagonists injected into the nucleus accumbens block the rewarding effects of opiates in rats
Brain stimulation methods (Naltrexone)
*Which interfere with dopamine release and/or cellular functioning in the mesocorticolimbic pathways • A pharmacological treatment for human alcohol and opiate addiction is daily administration of naltrexone – an opioid mu receptor antagonist
Brain stimulation methods (Baclofen)
• Baclofen is a GABA receptor agonist
• Reduced drug-seeking behavior in rats
(controversial in humans) by reducing the
propensity of conditioned stimuli that
induce drug-seeking behaviour
*Mesocorticolimbic dopamine activation
plays a critical role in the rewarding effects
of drugs and, over time, chronic drug use
leads to cellular adaptations.
Cellular Adaptation
*Chronic drug use leads to internal
processing of cells as well as morphological
changes
• Research supports that chronic drug use
leads to enduring changes in:
1. Synaptic plasticity
2. Changes in white and gray matter
3. Up/down-regulation of receptors
4. Changes in internal cellular processing
Rapid Detox (Opiates)
• Chronic use of opiates results in cellular
adaptation and as the opiate receptors
become less sensitive to the drug, tolerance
occurs, followed by withdrawal symptoms in
the absence of the drug.
• Withdrawal symptoms for opiates tend to
be severe and long-lasting (i.e., nausea,
vomiting, chills, insomnia, depression) which
complicates detoxification treatment.
• Detoxification treatments include:
o abrupt cessation (cutting cold turkey),
o tampering with other drugs used to
minimise withdrawal symptoms,
pharmacological substitution (e.g.,
methadone),
o or rapid detox (i.e., a medical procedure
designed to avoid physiological discomfort
of withdrawal whilst under anaesthesia. An
opioid antagonist like naltrexone or
naloxone is administered so the patient can
go with rapid and painless withdrawal)
Rapid Detox (Success)
• Detox session vary in terms of
o Length of hospital stay
o Safety
o Cost
o Pre-evaluation measures
o Follow-up interventions
o Actual detox method
• Typically last 4-6 hours
• Opiate antagonists are generally
prescribed for several weeks to a year
post-detox to reduce cravings and
likelihood of relapse.
• Rapid detox is a medical procedure
(invasive; with risks associated with
anesthesia) so psychological treatment is
often needed to address the emotional and
behavioral aspects of addiction
• Study: Compared relapse rates of 30
opiate-dependent individuals who
underwent rapid detox with and without a
9-month follow-up course of naltrexone:
o 34% of the subjects overall relapsed within
13 months but no significant difference
between treatment with and without
naltrexone.
o More research is needed to understand
the benefits and limitations
Genetic Findings
Family and Twin Findings
• Influenced by both genetic and environmental factors o Genetic factors influence the: • Metabolism • Sensitivity • Effects of drugs • Relatives have increased risk of substance use disorders including: o Alcohol o Cannabis o Cocaine o Hallucinogens o Sedatives o Stimulants o Opiates • Genetic factors account for 40% to 60% of a person’s vulnerability to addiction • Alcohol: Siblings elevated rates of dependence o 50% for men and 25% for women • First-degree relatives of those with opioid, cannabis, or cocaine use disorders have an eightfold increased risk
Environmental experiences
• Determines the specific type of substance an individual will use or misuse • Environmental experiences include: o Age of exposure o Route of administration o Stress o Family o Peers o Community factors
Genetics (Study)
• 3,372 twin pairs
• 10.1% of the sample addicted to at least one
illicit drug (i.e., substance disorders
typically involve the misuse of more than
one substance)
o Monozygotic 26.2%
o Dizygotic 16.5%
o Supporting the genetic influence in
addiction
Heritability
Heritability estimates vary across drugs:
o marijuana .33
o opiates .43
o stimulants .44
o general drug use .34
• slightly higher heritability estimates in twins
for alcohol and marijuana (.56 and .50)
• high degree of comorbidity between
substance use disorders and psychological
disorders including depression, anxiety,
PTSD, and, personality disorders.
Personality traits (predictive)
• Novelty seeking
• Harm-avoidance
• Low cooperation
• Impulsivity
• In childhood, externalizing disorders such
as conduct disorder and antisocial
behaviors are associated with early use of
drugs and alcohol
• Neither family history nor use of drugs or a
combination of genetic risk and exposure
necessarily lead to addiction!
*individuals with this family/genetic history,
who are depressed or possess certain
personality traits that are even higher risk
for substance abuse disorders, particularly
when onset use occurs during adolescence
or childhood. Linkage, candidate, and
genome wide studies are needed to identify
the specific genes linked to substance use
disorder
Linkage Studies (chromosomes)
*Identify specific chromosomes and
chromosome locations that may harbor
susceptibility genes involved in substance
disorders.
• Chromosome 4 (in loci 4q, 4p) has been
linked to alcohol use disorder
• A different locus on chromosome 4 has
been linked to opioid use disorder
• Chromosomes 6, 7, 11, and 17 have also
been linked to opioid use disorders
*There have been conflicting findings, and
they are correlational not causal in nature
3 main Candidate Genes
*Identifying specific genes linked to substance disorder
• two main approaches:
o exploring the role of genes that regulate
neurotransmitter systems
o exploring specific genes associated with
specific genes associated with specific
drugs and their potential role in substance
use disorders
• Genes involved in regulating monoamine
neurotransmitters (dopamine, serotonin,
norepinephrine) that are commonly studied
in the addiction literature include COMT,
SLC6A, and MAO-A genes.
• polymorphisms of COMT (enzyme which
breaks down dopamine; Val158Met) is
associated with lower dopamine levels in
mesocroticolimbic regions of the brain.
occurs in more in individuals with substance
use disorder (controversial). Val158Met is
associated with increased white matter
alterations in the prefrontal cortex and
increased risk of addiction.
• SLC6A gene regulates serotonin levels and
the reuptake process by encoding a
membrane protein involved in serotonin
transporter. Polymorphisms of this gene is
linked to increased risk of substance use
disorders.
• Variants of the MAO-A gene that encodes
enzymes which break down monoamines
have also been implicated in substance use
disorders, including nicotine, opioids, and
other substances.
Alcohol-metabolizing enzymes genes
• Polymorphisms of ADH1B and ALDH2
influence alcohol consumption
o Polymorphism of the ALDH2 gene results
in acetaldehyde not being broken down in
~10% of the Asian population leading to an
aversive response to alcohol consumption
o when carriers of this gene drink alcohol,
the acetaldehyde build up causes
unpleasant side effects, including nausea,
dizziness, skin flushing which significantly
reduces alcohol drinking behaviour.
o ALDH2 is protective against alcoholism but
does not prevent other addictive
behaviours from forming.
Genes (Opioids)
• Dopaminergic system plays an important
role in the rewarding effects of addictive
drugs like opioids.
• DRD4 gene more common in heroin users
(controversial)
• Meta-analyses have concluded variants of
the D2 receptor gene are associated with
several addiction disorders
o Alcoholism
o Cocaine
o Nicotine
o Opioids
• Others include: VEGFR, CLOCK, PDCL2,
NMU, NRSF, IGFBP7, KCNC1, KCN2
Genes (Stimulants)
• Dopamine transporter protein (DAT1)
polymorphisms are associated with crack-
cocaine addiction
*mixed findings overall
*No single gene, or group of candidate gene
have been identified that confer strong and
reliable risk for any substance use disorder
Genome-Wide Association Studies
*observe the entire genome of different
populations to determine whether specific
gene variants are associated with a
particular substance use disorder. genome
wide association studies are able to detect
smaller effects in chromosome regions
• No particular marker is causally related to
“addiction” or to all substance use
disorders
• genes expected to be related to substance
use disorders based on theory and linkage
studies are often not identified in genome-
wide studies
• genes involved in regulating monoamines
(dopamine, serotonin) were not associated
with substance use disorder (those that
were related to cell adhesion molecules
were significant).
Summary of Genetic Studies:
(A) Substance disorders are not caused by a
single gene; multiple genes likely interact
with constitutional (i.e., personality traits)
and environmental factors.
(B) No single gene or group of genes has
been identified as causing a particular
substance disorder and the amount of
genetic variance accounted for by
genetic factors appears to be relatively
small. 95% of the genetic variance
remains unaccounted for, indicating that
most of the genetic risk factors for
addictions have not been discovered.
Neurotransmitter Findings:
• Drugs exert their effects by enhancing
(agonist) or interfering (antagonist) the
brains neurotransmitter systems.
• These effects occur at the level of the
synapse
• Depending on the drug the mode of action
varies
Neurotransmitters (Agonists & Antagonists)
• Opiates attach to opioid receptors and
mimics the effects of naturally occurring
opioids
• Nicotine is an agonist at the level of the
nicotinic receptor (acetylcholine)
• Alcohol is a GABA agonist attaches to a
portion of the benzodiazepine receptor
and enhance the effects of GABA (agonist)
• Alcohol can also have an antagonist effect
by inhibiting the functioning of NMDA
Glutamate receptor which is associated
with the intoxicating effects of alcohol
Neurotransmitters
• Stimulants like cocaine prevents reuptake
of dopamine (to a lesser extent serotonin
and norepinephrine)
• Barbituates and benzodiazepines are
GABA agonists
• Cannabinoids attach to Cannabinoid CB1
receptors that activate second messenger
systems which enhance the release of
dopamine in the midbrain and forebrain
Neurotransmitters (Opioids)
• Receptors for various neurotransmitters
are differentially distributed throughout the
brain and their effects on behaviour differ
based on the brain region of interest it
targets.
• Opioid receptors are located in various
brain regions and include different
subtypes: mu, delta, and kappa
o These receptors are heavily concentrated
in CNS particularly in the locus coeruleus,
brain stem, and spinal cord
o Explains why opiates such as morphine
and oxycotin can impact respiration
Neurotransmitters Modulatory Effects
• It is important to note that
neurotransmitters can have modulating
effects on the dopaminergic system and
are implicated in drug addiction.
• serotonin receptor agonist (psilocybin) on
dopamine receptor (D2) binding found that
serotonin receptor activation helped to
modulate (increase) dopamine release in
the striatum.
• cocaine is associated with alterations in
serotonergic function
• cocaine effects hippocampal GABA and
glutamate synapses by directly modulating
production and degradation of enzymes
that are important to the functioning of the
dopamine system.
• opioids modulate glutamate-releasing
neurons in mesolimbic system and
increase inhibition of GABAergic synapses
• multiple neurotransmitter systems are
involved in chronic use of ecstasy, alcohol
and other substances
Functional Findings (Alcohol substance abuse)
• Children from families with one or both
parents are alcohol-dependant are at
heightened risk for substance use disorders
during adolescence and adulthood and this
risk may be related to early childhood brain
differences
o Smaller volumes of the orbitofrontal cortex
during childhood and adolescence predict
alcohol (and cannabis) use disorder
• Thinner and lower volume of prefrontal
cortex and cerebellum
• Decreased white matter
• Elevated brain activity in fronto-parietal
regions during working memory, inhibitory
control, and verbal learning tasks
• Males with a history of alcoholism have
fewer dopamine receptors in the striatum
which is correlated with alcohol craving
severity
• Increased activation in mesolimbic regions
(striatum, anterior cingulate cortex,
hippocampus, amygdala) in college
students predict future heavy drinking
• Individuals with a family history of
alcoholism showed increase activation in
reward pathways in response to sugar pill
relative to HCs (oral sucrose response
might be an endophenotypic marker of
alcoholism risk).
Pharmacological Treatment
Medications
• Decrease alcohol and drug craving by
blocking dopamine release and neuronal
activity in the mesolimbic regions
o Naltrexone (Opiate receptor antagonist;
FDA approved opioid treatment; blocks
the release of dopamine in the nucleus
accumbens in response to alcohol by
occupying the opioid mu and delta
receptors and reduces cravings; reduced
binding of these receptors in alcohol use
disorder in the right frontal, parietal, and
dorsal lateral precortex linked to higher
levels of cravings)
o Bupropion hydrochloride (Nicotine
receptor antagonist)
o Baclofen (GABA receptor agonist)
o Methadone (Opiate receptor agonist)
o Varenicline (Nicotine receptor antagonist)
• Modafinil improves cognitive and impulse
control
• Disulfiram: used to deter alcohol use by
inhibiting the enzyme that clears
acetaldehyde from the body, resulting in
highly unpleasant physiological reactions
of nausea and vomiting if alcohol is
consumed
*Chicken and the egg. Does addiction or the
morphological and functional brain
changes come first?
Is Tylenol Just as Effective as Oxycodone?
• Despite the opioid crisis. Opioids remain
the first line of defence for severe acute
pain in emergency rooms.
• Are non-opioid medications as effective as
opioids in managing acute pain?
• Study: Experimental groups
o Opioid free (ibuprofen and
acetaminophen- paracetamol)
o 5 mg of oxycodone (opioid) and 325 mg of
acetaminophen
o 5 mg of hydrocodone (opioid) and 300 mg
of acetaminophen
o 30 mg of codeine (opioid) and 300 mg of
acetaminophen
*No difference in pain reduction! this
suggests that ibuprofen + acetaminophen is
a viable alternative to opioids. different
types of pain can be treated with non-
addictive medications than prescription
opioids
Opioids
Extracted from…
Two types…
• Opioids is extracted from poppy seeds and
is a highly effective but addictive pain
reliever
• opioids include:
o Endogenous opioids
§ Enkephalins
§ Endorphins
o Synthetic opioids
§ Heroin
§ Oxycontin (oxycodone)
§ Vicodin (hydrocodone)
§ Sublimaze (fentanyl)
• Oxycodone is the most prescribed in the
US and overdose rates are increasing.
There are individual differences in response
to opioids, not everyone becomes
addictive.
• Opioids systems in the CNS, opioids
occupy and activate opioid receptors (mu,
delta, kappa) and stimulate mesolimbic
pathways
o mu receptors (molecular gate for opioid
addiction) in the VTA stimulate
dopaminergic neurons while activation of
the kappa opioid receptor inhibits
dopaminergic neurons
• Visual cues (videos and pictures) of opioids
activated regions rich in dopamine and
opiate receptors (ventral tegmental area,
mesolimbic system) in participants with
opioid use disorders and these findings
correlate with cravings.
• Cravings and addiction are normal brain
regions which are activated significantly
greater in individuals with substance abuse
• increased activation in the right caudate
while at rest may serve as a biomarker for
opioid relapse
• Naltexone is an opioid receptor antagonists
which reduces activation in the dorsal
striatum in response to heroin related cues
o Reduced drug craving
*These studies show greater activation in
brain regions linked to opioid drug use and
that salient environmental cues are also
activate these same regions. these
neuroimaging findings help explain
how cues can elicit cravings and
conditioned emotional reactions that
increase the risk of relapse.
Safe Injection Sites
• In January 2018, Philadelphia announced
“supervised injection sites”
o Safe place and clean needles to inject illicit
drugs
o Trained staff to administer naloxone
(narcan) a drug that reverses overdose
o They significantly reduce the rate of death,
spread of disease, and refer individuals to
substance abuse treatment
Stimulants
• Stimulants increase arousal in the CNS by
increasing dopamine release
o Cocaine inhibits dopamine reuptake by
binding to dopamine transporter
o Amphetamines induces a reversal of the
transporter causing more dopamine to be
released into the extracellular fluid
• even after abstinence chronic cocaine use
is associated with widespread reductions in
cerebral glucose metabolism in the
prefrontal regions
• at least 50% occupancy of the dopamine
transporter was required to induce a high
• lower functional connectivity in the
midbrain, cingulate, and cerebellum
predicted poor performance on attention
task (chronic cocaine use)
• both drugs and food increase dopamine
neurons in the mesolimbic pathway
• when it becomes more chronic blunting
dopamine release in mesolimbic system
leads to compulsive drug-seeking
behaviour.
*neuroimaging studies support that stimulant
use is initially associated with increased
release and availability of dopamine in
extracellular fluid leading to rewarding
effects of drugs. With chronic use, however, dopamine release is diminished.
Pharmacological Treatment
• Despite the prevalence of cocaine and amphetamine addiction, no pharmacological treatment is available
o Several studies have reported that naltrexone reduces craving in adults addicted to cocaine
Cannabis
- Psychoactive effects attributed to THC (cannabinoid)
- cannabinoid like THC is inhaled or ingested and attaches to CB1 endogenous receptors in brain regions associated with memory, perception, appetite, and motor control.
- High to moderate concentrations of CB1 receptors in the hippocampus, amygdala, cerebral cortex, stratium, globus pallidus, cerebellum, and brain stem
- ~5–10% of the population, worldwide, who regularly use cannabis will develop cannabis use disorder and experience tolerance, craving, and withdrawal.
- mixed findings on structural and functional changes
- longitudinal study shows regular cannabis use in adolsebce and adulthood is associated with abnotmal activity in the fronto-parital region in cannabis users (especially heavy users) and in some cases this pattern of activation corresponded with reduced performance on memory and inhibition tasks
Cannabis functional study
• Under the influence:
o Higher activation in the dorsal striatum,
insula, posterior parietal regions, anterior
and posterior cingulate, and dorsolateral
prefrontal
o participants who decline cannabis use
exhibited activation in different brain
regions leading to 100% accuracy
classification rate (neural signature of
decisions to smoke cannabis)
Medicinal Cannabis
• those who smoke cannabis for medicinal
purposes may have different brain
activation responses
• longitudinal study compared fMRI scans of
medicinal cannabis users after three
months of treatment, improved task
performance was associated with activation
in the cingulate cortex and frontal regions.
Non-medicinal marijuana users have shown
to exhibit decrements in task performance
accompanied by altered brain activation.
Marijuana medicinal users had activations
closer to HCs than non-users.
• cannabis used for medicinal reasons may
normalise brain function back to baseline.
Pharmacological Treatment
• Relapse rate of ~70% for cannabis users
(adults seeking treatment who have
smoked daily for 10 years have relapsed 6
or more times)
• No FDA drugs have been approved
• Chronic cannibals use leads to the
downregulation and desensitization of the
CB1 receptors (i.e., neuroplastic changes)
leads to cannabis dependence
• CB1 antagonists that block the effects of
THC and CB1 agonists which compete with
cannibals for occupying the receptors.
• e.g., dronabinol and nabilone are synthetic
THC and THC agonists that have been
found to reduce cannabis withdrawal
• fatty acid amide hydrolase (FAAH) inhibitor
for treatment for adults is undergoing
clinical trials
• The main form of treatment for cannabis
disorders are psychosocial interventions
Cellular Adaptations
- Synaptic plasticity
- Dendritic size and spines
- Changes in white and gray matter
- Up/down-regulation of receptors
- Changes in internal cellular processing
(1) Synaptic Plasticity
Synaptic Plasticity
• Strengthening or weakening of synapses as
a result of increased or decreased activity
o Receptors change in quality
o Increased or decreased sensitivity or
responsivity to neurotransmitter substances
(Hebb, 1949)
AMPA glutamate receptor (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)
• Drugs of abuse result in up-regulation of
AMPA receptors
o Increase in the number of receptors
• After cessation of abused drug, AMPA
activity remains enhanced
Long term potentiation
• Cocaine use results in LTP in the ventral
tegmental area
• Opioids, Cannabis, and alcohol elicit LTP in
mesocorticolimbic structures
• LTP: Strengthening of synapses based on
recent patterns of activity
(2) Dendritic Plasticity
• Cocaine: Increases dendritic spine density
in the NA
• Alcohol: Decreases dendritic spine density
and alters size and shape of spines
• Opioids: Smaller dendrites, decreased
density of dendritic spines, and reduced
size of neurons and cell bodies of
dopaminergic neurons in VTA
(3) Gray Matter
Gray Matter
• Volume reductions in the prefrontal regions
and mesocorticolimbic structures
• Drug craving is negatively associated with
gray-matter volume
Gray Matter (marijuana)
• Inconsistent findings
o Longitudinal studies are needed!
White Matter
• Reduced white matter in people with
substance use disorders
• Alcohol: Loss of cerebral white matter found
in postmortem and living individuals
o Reduced total brain volume
• Reduced white matter, particularly in the
hippocampus of adolescents
• Cannabis use in adolescents associated
with white matter reduction
• Children exposed to cocaine, tobacco,
marijuana, or alcohol in utero have smaller
head circumference and white and gray
matter!
• Opioid use disorder is associated with white
matter (and gray matter) changes in brain
regions implicated in addiction
(4) Receptors and Transporters
• Decreased density of postsynaptic dopamine receptors (D2) o Study: Reduced D2 receptors in individuals with alcohol use disorder • Reduced dopamine transporter density and reduced dopamine D2 receptors in the striatum of participants addicted to methamphetamine
(5) Glial Cells
Glial Cells
• Stimulants, opioids, and alcohol increase
the expression of glial fibrillary acidic protein
o Protein found in the cytoskeleton of
astrocytes
• Morphological changes in astrocytes that
connect with blood vessels
• Reduction of neurotrophins (BDNF - protein)
Internal Changes • Decrease in the amount of neurofilament proteins o Transport of substances from the soma to the terminal button o Up-regulation of the cyclic adenosine monophosphate (cAMP – second messenger)
CREB
• Reduced phosphorylation of the protein
CREB (cyclic adenosine monophosphate
response element binding protein)
o Initiates intracellular events that lead to
long-term changes in cellular function
cAMP (Opiates)
• Exposure to opiates decreases cAMP levels
• Chronic exposure increases levels of cAMP
levels
• Up-regulation of cAMP increases the firing
of neurons in the locus coeruleus
(norepinephrine)
o Brain’s effort to establish homeostasis?
Sensitivity (Tolerance)
• Larger amounts of the drug are required to
achieve a desired effect
o Long-lasting intracellular, enzymatic, and
genetic changes modulated by CREB may
lead to tolerance
Summary
• prominently involved in addiction is the
dopaminergic system, including the
mesolimbic system and associated
ascending and descending pathways and
connecting prefrontal and subcortical
regions.
• dopamine and other neurotransmitter
systems (i.e., endogenous opioids, GABA,
Serotonin, and glutamate) which play a
poorly understood modulating role in
addiction.
• intercellular transcription factors, such as
CREB and delta FosB, appear to play an
integral role in altering gene expression that
contributes to drug addiction.
• molecular and neuroplastic changes
including alterations in synaptic plasticity,
dendritic size and density of spines, white
and gray matter, and up/downregulation of
receptors contribute to drug craving,
withdrawal, and relapse.
• No single drug addiction genes has been
identified. it is likely a complex interaction
between genetics-environment.
