Transcript BioPsychoSocial Approaches to Addiction - CSAM

CSAM-SCAM
Fundamentals
BioPsychoSocial
Approaches to
Addiction
Presentation by: Kathryn J. Gill PhD
-Associate Professor, Psychiatry
Department, McGill University
-Psychotherapist and Researcher,
Addictions Unit, McGill University
Health Centre
Disclosures/Warnings
Fundamentals: BioPsychoSocial
Approaches to Addiction




No current funding from pharmaceutical
or medical device companies
Psychotherapist at the Addictions Unit,
McGill University Health Centre, and in
private practice
Tenured professor, McGill University with
undergraduate, graduate and postgraduate teaching duties
Addiction research funded by Canadian
Institutes of Health Research
https://muhc.ca/addictions_unit/profile/addictions
-unit
[email protected]
Overview




Alcohol, drugs, new psychoactive
substances
Addiction –What are the signs and
symptoms? How does it develop?
What are the effects of drugs/alcohol on the
brain? What are the implications for
treatment?
Vulnerability to addiction - the roles of
genetics and environment
http://www.emcdda.europa.eu/
Addictions Unit
Department of Psychiatry
McGill University Health Centre
6 new substances — 25I-NBOMe, AH-7921, methoxetamine, MDPV,
4,4′-DMAR and MT-45 are currently undergoing risk assessment
Harms related to substance use disorders
(SUD)
Social Effects
• family violence/child neglect
• isolation/lack of social support
• job loss, legal issues, poverty
• increased emergency room visits
Physical/Brain Effects
• HIV, HCV
• liver toxicity, sleep problems
• neurocognitive & brain deficits
(decrease in receptors, neurotransmitters)
• increased depression, anxiety,
psychosis
(Keil et al., 2015; Goldstein et al., 2011; McClure et al., 2009
Costs of SUD in Primary Care (Quebec)
(Gill et al., 2016)
$7,000
$6,000
+68%
$5,000
+34%
+145%
$4,000
$3,000
$2,000
$1,000
$972
$1,303
$1,984
$4,854
$2,871
$4,827
$0
Other
a)
SU-RC
SUD+
$7,000
$6,000
-10.3%
$5,000
$4,000
+90.2%
-8.5%
$3,000
Average annual
per patient RAMQ
costs (± SEM) for
medical services
(a) and
pharmaceuticals
(b) at two time
points over a 3
year period for SURC and SUD+
groups
$2,000
$1,000
$2,791
$2,553
$3,079
$5,855
$4,228
$3,792
$0
Other
SU-RC
T1
b)
T2
SUD+
N=2794
Addiction –
What are the
signs and
symptoms?
How many started the day with a cup of
coffee or tea this morning?


What drug did you consume?
 Xanthines – caffeine and/or theophylline
Do you think coffee and tea are addictive?
 regular use leads to subjective sensation of needing a
lift/energy/break + preference for caffeinated forms
 strong pharmacological effects - increases alertness,
energy, concentration via brain adenosine receptors
 produces physical dependence. Withdrawal symptoms
(headache, fatigue, nausea, poor concentration,
irritability, increased muscle tension begin 12–24 hours
after stopping; peak by 20–48 hours)
Reinforcing complex - coffee
Warmth
conditioned cues
 Colour, smell, taste
 Taking a break
 Pick me up – stimulant
 Reduction in withdrawal – fatigue, headache

Tobacco Smoking
Single largest preventable cause of illness and mortality in the world
Many of you have patients that are
current smokers
What drug are they consuming?
nicotine +
 harmane/norharmane (known to inhibit brain

enzymes that regulate the level of the
neurotransmitters dopamine and serotonin
acetaldehyde (effects neurotransmitter release)
 preservatives, pesticides, mould retardants,
humectants, polycyclic aromatic
hydrocarbons (carcinogens)

Why can’t they just stop?
Pleasure and Reward
Reinforcing Complex - tobacco
smell, taste
 sound (lighter or match)
conditioned cues
 cigarette shape & colour
 cigarette package
 oral sensations, inhalation/exhalation (calming)
 pharmacological effects of tobacco smoke
 time out, taking a break
 relief from withdrawal (anxiety, fatique)

Rewarding Effects of Tobacco
Primary effects of tobacco constituents
Pleasure
EEG desynchronization
Arousal, enhanced
attention, improved
task performance
Muscle relaxation
Increased levels of catecholamines,
vasopressin, growth hormone, ACTH,
cortisol, prolactin, beta-endorphin
Decreased spinal reflexes
Reduced hunger
Increased metabolic rate, Lipolysis,
increased free fatty acids LDL, HDL
Heart rate acceleration,  BP
coronary vasoconstriction
Reduced anxiety,
depression
? May be due to compounds in smoke
that inhibit Monoamine Oxidase?
Physical Dependence Withdrawal Discomfort
Tobacco Withdrawal
Irritability, restlessness,
hostility
Difficulty concentrating; impaired
task performance
Drowsiness
Sleep disturbance
Anxiety
Headaches
Hunger, weight gain
Cravings or strong urges to smoke
Depression
- Smoking is correlated with a history of childhood depression
and smoking cessation is associated with increased depressive
episodes. (Niemelä et al., Childhood antecedents of being a cigarette smoker
in early adulthood, 2009)
- Smoking is very high among those with anxiety, mood and
personality disorders, as well as psychosis and all forms of
substance dependence
Why is it difficult to quit?
"He stated he could give up smoking
with ease, and in fact had done so
hundreds of times"
(Mark Twain)
Why it is Difficult to Quit
High Availability – Legal, relatively socially acceptable
cheap, readily available - difficult to avoid cues, nonintoxicating – no deficits in performance
Conditioning - Exposure to conditioned cues
repeated hundreds of times per day (oral stimulation,
inhalation, exhalation), associated with many activities
Complex Pharmacological Effects
short duration of action, rapid acute tolerance –
promotes repeated self-administration, strong
physiological dependence with unpleasant withdrawal
long delay to negative medical consequences (lung,
larynx, stomach, pancreatic cancers), cardiovascular
disease
Extrapolate to other drugs of abuse
(alcohol, cocaine, heroin, cannabis)

Many of the factors that make smoking a
difficult habit to quit apply equally to other
drugs of abuse
+ + strong intoxication and/or euphoria
 + ++ cortical suppression after chronic use
(impaired control of impulsivity, decision
making, planning)

What are the
effects of
drugs/alcohol
on the brain?
The brain is hard-wired to
respond to drugs of abuse
Drugs of abuse resemble/activate or disrupt
natural neurotransmitters in the brain
Anandamide is an endogenous cannabinoid with a much
shorter half-life, as well as lower efficacy and binding affinity
for CB1 receptors in the brain compared to exogenous THC
Animal Studies
Drug Exposure has significant effects on:






Release of neurotransmitters (DA, glutamate,
GABA…)
Structure of neurons and circuits (spine density,
#synapses)
Stress hormones and underlying brain structures
Gene expression (striatum and frontal cortex)
Epigenetic modification of genes - transgenerational
(Vassoler)
current research looking at ways to reverse stress and
epigenetic effects – focus on neuroplasticity
Human Studies -Brain Imaging
Positron Emission Tomography - PET
Dopamine Pathways
striatum
frontal
cortex
hippocampus
substantia
nigra/VTA
nucleus
accumbens
Functions
•attention, arousal
•reward (motivation)
•motor function
•decision making
Serotonin Pathways
Functions
raphe
•mood
•memory processing
•sleep
•cognition
Issues with Dopamine-related Theory of
Reward
“Theory - drugs produce pleasure via dopamine release,
and addiction may result from neurobiological changes
to the dopamine system”
Dopamine ≠ Pleasure or Euphoria



Not all drugs of abuse release dopamine in humans (inconsistent
imaging data). DA blockers or depletion do not affect euphoria or
the high in humans, no therapeutic value
Preclinical studies show that dopamine firing and release become
tied to the cues preceding drug use – not the actual drug
decreased DA D2 receptors following chronic drug abuse have
been found, but not consistently. However Low D2 receptors may
predict poor treatment response to behavioural therapy
Dopamine and Incentive Motivation



the mesolimbic dopamine pathway, which includes
the NAcc, amygdala and hippocampus, is relevant for
drug reward and for drug-related memories and
conditioned responses
Current hypothesis is that dopamine mediates the
‘incentive motivational’ value of reward
Dopamine neurons label environmental stimuli with
appetitive value, predict and detect rewards and
signal motivating events leading to increased
dopaminergic activity in response to salient cues
Dopamine receptors (PET)
PET images of D2
receptors and glucose
metabolism in the brain
With chronic cocaine
abuse, there is
decreased dopamine D2
receptors and decreased
activity in the OFC,
which is linked to
compulsive behaviour
and disinhibition
(Volkow & Li, 2004)
Alcohol-induced suppression of brain
activity (PET Scan)
Thanos et al., 2008 (Alc Res Health, 31:233-237)
Recovery of function in chronic alcoholics
Volkow et al.
(Am J
Psychiatry, 151:
171-183, 1994)
Effects of chronic cocaine on the brain - PET
High activity
Non-user, normal brain
Cocaine Abuser (10 days)
Low activity
Cocaine Abuser (100 days)
From Volkow et al. Synapse 14:169-177
Drug-induced reduction of activity in the prefrontal (PFC) and
orbitofrontal cortex (OFC) have effects on memory, decision
making, inhibitory control, judgement, planning and behavioural
control
(Dysfunction of the prefrontal cortex in addiction: neuroimaging
findings and clinical implications. Goldstein & Volkow, 2011)
2016
Discussion –
What are the implications of
frontal cortical dysfunction in
terms of treatment planning?
disorganization
cognitive, attentional and memory deficits
low motivation
less compliant to treatment/medication regimens
poor emotional regulation and decision making
Diagnostic
Criteria for a
Substance Use
Disorder
Fundamentals: BioPsychoSocial
Approaches to Addiction
Addiction Definition – ASAM + CSAM
“Addiction is a primary, chronic disease of
brain reward, motivation, memory and
related circuitry. Dysfunction in these
circuits leads to characteristic biological,
psychological, social and spiritual
manifestations. This is reflected in an
individual pathologically pursuing reward
and/or relief by substance use and other
behaviors…”
DSM-5 ** Diagnostic Criteria For
Substance Use Disorder (SUD)
A maladaptive pattern of substance use, leading to
clinically significant impairment or distress, as
manifested by 2 of 11criteria, occurring within a
12 month period

Impaired control, compulsion to obtain and take
the substance

Detrimental effects on users and their close
relations

Development of tolerance and withdrawal
** Diagnostic and Statistical Manual of Mental Disorders,
APA, 5th edition
DSM-5 Diagnostic Criteria
1) use of larger amounts or
longer period than intended
2) unsuccessful efforts to cut
down or control use
3) long time spent obtaining
or recovering from effects
4) craving
5) failure to fulfill major role
obligations
6) continued use despite
persistent social problems
caused by the substance
7) social, occupational, or
recreational activities
given up
8) repeated use in
hazardous situations
9) continued use despite
persistent physical/
psychological problems
caused by the substance
10) tolerance
11) withdrawal
Sedative/Hypnotic and Anxiolytic
Withdrawal
Two (or more) of the following developing after cessation of
alcohol use that has been heavy and prolonged






autonomic hyperactivity (e.g., sweating, pulse rate
>100), increased hand tremor
psychomotor agitation and/or anxiety
insomnia
nausea or vomiting
transient visual, tactile, or auditory hallucinations or
illusions
generalized tonic-clonic seizures
Are some
people more
vulnerable to
addiction?
Vulnerability – Transition from use to
abuse to dependence?
USE


REGULAR HEAVY

ABUSE


DEPENDENCE

availability, cultural norms, sources of
recreation/pleasure, drug expectancies,
same-sex siblings
peer influences, family attitudes
(modeling), high risk taking behavior,
sensation seeking
family disruption/divorce
familial antisocial personality disorder
familial substance abuse (chaos, shame,
violence, poverty, fetal exposure)
familial mental illness (genetic factors,
neglect, abuse, poor parental monitoring)
Familial Risk Factors …
genetic + intrauterine exposure + socialization +
maltreatment + culture (traditions, religion, values)
Parental substance dependence is associated with more
risk factors including:




mental illness in the parents
impaired parental monitoring and control
higher genetic loading
more disruptive adverse childhood events (family
violence, neglect, physical and sexual abuse, foster
care)
http://www.cdc.gov/ace/
Adverse Childhood Experiences (ACE) –
within first 18 years of life
≥ 4 ACE categories = 4-12x  risk of SUD
1.
2.
3.
4.
5.
6.
7.
8.
9.
Emotional abuse
Physical abuse
Sexual abuse
Emotional/physical neglect
Mother treated violently
Household substance abuse
Household mental illness/suicide attempt
Parental separation or divorce
Incarcerated household member
Is there a
genetic
vulnerability to
addiction?
COGA – Collaborative Study on the
Genetics of Alcoholism



Nine-centre study to detect and map genes for
alcoholism (multiplex pedigrees)
Measuring multiple related factors (alcoholism,
alcohol metabolism, brain waves, personality
traits, biochemical measures such as MAOB
COGA has reported associations between
alcoholism and the GABAA gene clusters on chr 4
(Edenberg et al. 2004), chr 5 (Dick et al., 2006) (Song et
al. 2003; Dick et al. 2004) and chr 15
GABAA Genetics (Kumar et al., 2009)




GABARA2 - a single SNP in the α2 subunit was
associated with alcohol dependence in a large
multigenerational pedigree (Edenberg et al 2004)
Replicated in separate independent studies
(Agrawal et al 2006; Bauer et al 2007; Soyka et al
2008)
in some studies the GABARA2 has been linked to
anxiety scores, ethanol withdrawal severity and
sensitivity to alcohol
COGA has suggested that alcoholism (and
comorbid anxiety) MAY be related to a CNS
dysregulation of the GABA system
Other candidate genes under
investigation

alcohol/drug metabolism (ADH, ALDH, CYP4502E1)

GABA (α2, γ3, rho subunits of GABAA , GAD2)

MAO (promoter VNTR), COMT, nicotinic CHRNA4

Dopamine (receptors D2 , D3 , D4) + DAT)

Serotonin (TPH1, TPH2, 5HT2A, 5HT1B + 5HTT)

Opiate receptor OPRM1 (C118G, A118G
polymorphisms)
Genetic & Epigenetic Factors
 It
is highly likely that genetic and
epigenetic factors affect the transition
from use to abuse
 For example, genes products could
modify initial responses to drugs, rate of
acute and chronic tolerance
development, conditioned responses to
cues, as well as the likelihood of
developing physical dependence and
the severity of withdrawal reactions
Fundamentals: BioPsychoSocial
Approaches to Addiction
Addiction Risk (and Resilience)
 availability,
cost, route, rate of onset,
efficacy, tolerance, physical dependence
 Genetic
s, family environment, co-morbid
psych/med disorders, abuse/trauma
 Occupation,
drug policy, peer group,
culture, poverty, lack of opportunity
The End
Extra discussion slides
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Alcohol related conditions (ICD-9)
Psychosis, alcoholic 291
Polyneuropathy, alcoholic 3575
Cardiomyopathy, alcoholic 4255
Gastritis, alcoholic, w/o haemorrhage 5353
Cirrhosis, fatty, alcoholic 5710
Hepatitis, acute, alcoholic 5711
Cirrhosis, liver, alcoholic 5712
Damage, liver, alcoholic, unspecified 5713
Foetal alcohol syndrome - Alcohol affecting foetus via placenta or breast milk 7607
Abnormal findings, alcohol in blood level 7903
Poisoning by alcohol 908
Personal history mental problems V11
Health problems in family V614
Examination, for medico legal reasons V704
Special screening for alcoholism V791
Drug related conditions (ICD-9)
Psychosis, drug 292
Polyneuropathy, due to drugs 3576
Pregnancy, complicated by drug dependence 6483
Pregnancy, management affected by suspected damage to foetus from drug 6555
Reaction and intoxication, drugs, specific to newborn 7794
Syndrome, drug withdrawal in new born 7795
Poisoning by hormones and other synthetic substitutes 962
Poisoning by Opiates and related narcotics 965
Poisoning by Sedatives and hypnotics 967
Poisoning by other central nervous system depressants and anaesthetics 968
Poisoning by psychotropic agents 969
Poisoning by central nervous system stimulants 970
Poisoning by drug primarily affecting the autonomic nervous system 971
Poisoning by other and unspecified drugs 977
Pimozide Effects in Humans
Brauer & DeWit
1997 –
The D2 antagonist
pimozide did not
change the
subjective effects of
amphetamine in
human subjects
Lack of efficacy of D2 antagonists
(antipsychotics) on cocaine addiction
• Three double-blind RCTs evaluated olanzapine for
cocaine dependence – no positive results (Hamilton,
2009;Kampman etal.,2003; Reidetal.,2005)
• Aripiprazole reduced cocaine use (Meini, 2011), but was
shown to increase self-administration of smoked
cocaine(Haney etal.,2011).
• Meta-analysis of RCTs related to antipsychotics for
cocaine or amphetamine dependence, found no efficacy
over placebo (Kishi et al.,2013)
Phytocannabinoids (from POT)
Endocannabinoids (eCB)
2-AG
Hanus, 2009
Burns et al. (2007) [18F]MK-9470, a positron emission
tomography (PET)tracer for in vivo human PET brain
imaging of the cannabinoid-1 receptor.
Definition of Disease/Disorder
A
disease/disorder is an abnormal condition of
an organism that impairs bodily functions,
associated with specific symptoms and signs.
 It may be caused by external factors, such as
infectious agents, or it may be caused by a
wide variety of internal dysfunctions (such as
genetic mutations, autoimmunity, cancer cells,
breakdown of a tissue/organ).
 In human beings, "disease" is often used more
broadly to refer to any condition that causes
pain, dysfunction, distress, social problems,
and/or death.
– Cocaine Metabolism I –
 Normally cocaine is degraded by plasma or liver
esterases to Benzoylecgonine (50-70% of the cocaine is
metabolized to this form). It is inactive on dopamine
uptake, but has minor vasospastic effects
 In the presence of alcohol, cocaine is degraded by
carboxyl esterase to another metabolite
COCAETHYLENE – a pharmacologically active cocaine
metabolite
 Compared to cocaine it has equal affinity for the
dopamine transporter, lower LD50, greater effects on
blood pressure and heart rate, greater hepatotoxicity
(based on studies in cell culture and animals), and a
longer half-life (~2 hours)
28
– Behavioural, biochemical and molecular changes induced by –
chronic crack-cocaine inhalation in mice: The role of dopaminergic and
endocannabinoid systems in the prefrontal cortex.
Results:






Mice in the crack-cocaine group exhibited hyper-locomotion and “escape jumping” that increased with drug exposure (blue)
Levels of AEME were higher than levels of cocaine
Expression levels of ΔFosB were upregulated in the crack-cocaine group and levels of CREB were downregulated
CB1 receptors and cannabinoid degradation enzymes were downregulated
Expression levels of receptors D1, D2, D3 and TH were significantly upregulated in the crack-cocaine group (red)
There was a significant increase in DAT expression in the PFC of crack-cocaine mice, and a reduction in the levels of dopamine,
DOPAC and HVA
Areal, L. B., Rodrigues, L. C., Andrich, F., Moraes, L. S., Cicilini, M. A., Mendonca, J. B., . . . Pires, R. G. (2015). Behavioural, biochemical and molecular changes induced by chronic crack-cocaine
inhalation in mice: The role of dopaminergic and endocannabinoid systems in the prefrontal cortex. Behavioural Brain Research, 290, 8-16. doi: 10.1016/j.bbr.2015.04.036
– Behavioural, biochemical and molecular changes induced by –
chronic crack-cocaine inhalation in mice: The role of dopaminergic and
endocannabinoid systems in the prefrontal cortex.
Discussion:
 The data demonstrate neurochemical changes in the dopaminergic and
the endocannabinoid systems of the crack-cocaine exposed mice, and the
authors suggest:
 AEME concentration was significantly higher than cocaine and its neurotoxic potential is
much greater; this may be cause for the phenotypic differences observed between
cocaine use and crack-cocaine use
 The downregulation of CB1 receptors and cannabinoid degradation enzymes – which
may have be due to a crack-cocaine-induced increase in levels of anandamide – are
possibly the cause of the deceased levels of dopamine and its metabolites in the PFC
and further the significant increase of dopamine receptors and tyrosine hydroxylase
 They conclude that crack-cocaine addiction should be treated differently from cocaine
addiction and indicate a potential candidate for some of crack’s addictive properties,
though suggest that further research is required
Varenicline: Efficacy
Smokers treated with 1
mg Varencline, 150
mg Bupropion SR, or
placebo twice daily
over 12 week period
Jorenby et al. 2006