substance use/addiction its epidemiology, etiology and pathophysiology

1. Presented By : Dr. Karrar Husain
Moderator : Dr. M. Amir Usmani

2. CONTENTS
1. Introduction
2. Brief history and epidemiology
3. Biology
4. Learning and conditioning
5. Psychodynamic theory
6. Environmental and other factors

3. 1. DSM and ICD
2. Terminology

4.  In DSM 5 substance related disorder are classified in substance related
and addictive disorder.
 Substance related disorder  substance use disorder and substance
induced disorder.
 Substance use disorder in DSM-5 combines the DSM-IV categories of
substance abuse and substance dependence into a single disorder
measured on a continuum from mild to severe k/a substance use
disorder. (only 2 are required).
 Substance induced disorder consist of withdrawal, intoxication, and
other substance induced mental disorder.
DSM 5

5. Substance-Use Disorder
 A. A maladaptive pattern of substance use leading to clinically significant
impairment or distress, as manifested by 2 (or more) of the following,
occurring within a 12-month period:
 1. recurrent substance use resulting in a failure to fulfill major role obligations
at work, school, or home (e.g., repeated absences or poor work performance
related to substance use; substance-related absences, suspensions, or
expulsions from school; neglect of children or household)
 2. recurrent substance use in situations in which it is physically hazardous
(e.g., driving an automobile or operating a machine when impaired by
substance use)
 3. continued substance use despite having persistent or recurrent social or
interpersonal problems caused or exacerbated by the effects of the substance
(e.g., arguments with spouse about consequences of intoxication, physical
fights)

6.  4. tolerance, as defined by either of the following:
a. a need for markedly increased amounts of the substance to achieve
intoxication or desired effect
b. markedly diminished effect with continued use of the same amount of
the substance
 5. withdrawal, as manifested by either of the following:
a. the characteristic withdrawal syndrome for the substance
b. the same substance is taken to relieve or avoid withdrawal symptoms
 6. the substance is often taken in larger amounts or over a longer
period than was intended.
 7. there is a persistent desire or unsuccessful efforts to cut down or
control substance use

7.  8. a great deal of time is spent in activities necessary to obtain the
substance, use the substance, or recover from its effects
 9. important social, occupational, or recreational activities are given up
or reduced because of substance use
 10. the substance use is continued despite knowledge of having a
persistent or recurrent physical or psychological problem that is likely
to have been caused or exacerbated by the substance
 11. Craving or a strong desire or urge to use a specific substance.

8.  Severity specifiers:
Mild : 2-3 criteria
Moderate : 4 or 5
Severe : 6 or more

9. ICD 10
 F10 - F19 MENTAL AND BEHAVIOURAL DISORDERS DUE TO
PSYCHOACTIVE SUBSTANCE USE
 F10.- DISORDERS DUE TO USE OF ALCOHOL
 F11.- DISORDERS DUE TO USE OF OPIOIDS
 F12.- DISORDERS DUE TO USE OF CANNABINOIDS
 F13.- DISORDERS DUE TO USE OF SEDATIVES OR HYPNOTICS
 F14.- DISORDERS DUE TO USE OF COCAINE

10.  F15.- DISORDERS DUE TO USE OF OTHER STIMULANTS,
INCLUDING CAFFEINE
 F16.- DISORDERS DUE TO USE OF HALLUCINOGENS
 F17.- DISORDERS DUE TO USE OF TOBACCO
 F18.- DISORDERS DUE TO USE OF VOLATILE SOLVENTS
 F19.- DISORDERS DUE TO MULTIPLE DRUG USE AND USE OF
OTHER PSYCHOACTIVE SUBSTANCES

11.  Dependence - The repeated use of a drug or chemical substance, with
or without physical dependence. Physical dependence indicates an
altered physiologic state caused by repeated administration of a drug,
the cessation of which results in a specific syndrome.
 Abuse - Use of any drug, usually by self-administration, in a manner
that deviates from approved social or medical patterns.
 Misuse - Similar to abuse, but usually applies to drugs prescribed by
physicians that are not used properly.

12.  Addiction - The repeated and increased use of a substance, the
deprivation of which gives rise to symptoms of distress and an
irresistible urge to use the agent again and which leads also to physical
and mental deterioration.
 Intoxication - A reversible Syndrome caused by a specific substance
that affects one or more of the following mental functions: memory,
orientation, mood, judgment, and behavioral, social, or occupational
functioning.
CTP 9th edition.

13.  Cross-tolerance - Refers to the ability of one drug to be substituted for
another, each usually producing the same physiologic and
psychological effect (e.g., diazepam and barbiturates). Also known as
cross-dependence.
 Codependence - Term used to refer to family members affected by or
influencing the behavior of the substance abuser. Related to the term
enabler, which is a person who facilitates the abuser’s addictive
behavior. Enabling also includes the unwillingness of a family member
to accept addiction as a medical-psychiatric disorder or to deny that
person is abusing a substance.
CTP 9th edition.

15. HISTORY
 Opium has been used for medicinal purposes for at least 3,500 years.
 References to cannabis (marijuana) as a medicine can be found in
ancient chinese herbals.
 Wine is mentioned frequently in the bible.
 Indigenous people of the western hemisphere were smoking tobacco
and chewing coca leaves generations before the arrival of the spaniards.
 In asia, opium smoking was a major problem in the 18th and 19th
centuries, new problems related to opium were seen there and in other
parts of the world after morphine, its most active alkaloid, was isolated
in 1806.

16.  Intravenous (IV) morphine and heroin use began to spread in the early
part of the 20th century.
 Although tobacco use was common by the 19th century, the serious
adverse medical consequences associated with it did not emerge until
the 20th century, when new methods of curing the leaves produced a
mild smoking tobacco, and cigarettes were introduced

17. Medicalizing Excessive Drug Use
 In 1810, Benjamin Rush, suggested that excessive use of alcohol was a
disease.
 in 1835, Samuel Woodward, a pioneer in the establishment of asylums
for the insane, advocated similar asylums for inebriates.
 In 1870, estb. Of The American Association for the Cure of Inebriates
(AACI), dedicated to setting up hospitals for such people, conducting
research, and teaching medical students and physicians how to treat
inebriety.
 Thomas Crothers, the secretary of AACI, saw inebriate asylums as
places to treat all those who used any variety of intoxicant or narcotic to
excess
CTP 9th edition.

18. Burden of problem
 According to WHO there are 2 billion alcohol users, 1.3 billion smokers
and 185 million drug users.
http://www.who.int/substance_abuse/facts/global_burden/en/

19.  There is no National epidemiological data collection system for Alcohol
and Drugs in INDIA.
 Prevalence estimates for alcohol use disorders (12-month prevalence,
%)
 Female (15+ years) - Year 2004 -0.42
 Male (15+ years) - Year 2004 -3.47
 Prevalence estimates for drug use disorders (12-month prevalence, %)
 Female (15+ years) - Year 2004- 0.03
 Male (15+ years) - Year 2004 - 0.24
World Health Organization 2010
Global Burden of Disease (GBD) estimate, 2004.

20. Risk factors
 Men > women, 2:1
 Adults who did not complete high school are more likely than college
graduates to have become dependent on illegal drugs.
 Unemployed : employed.. 2: 1
 Younger age of onset.
 Individuals with a serious mental illness are more than twice as likely
to have used an illegal drug and to have been cigarette smokers.
CTP 9th ed

21. 1- ACUTE EFFECT OF DRUGS ( REWARD CIRCUITS)
2-MECHANISM OF ACTION OF VARIOUS DRUGS
3- CHRONIC EFFECTS OF DRUG
4- VULNERABILITY AND GENETICS

22.  Substance abuse and addiction are complex phenomena that defy
simple explanation or description.
 A tangled interaction of factors contributes to an individual’s seeking
out, using, and perhaps subsequently abusing drugs.
 Since more individuals experiment with drugs than eventually develop
substance abuse problems, great interest persists in understanding
what differentiates these groups.
 Factors that can play a role in drug abuse susceptibility include a
person psychological makeup, biological response to drugs and
environmental situation, and the availability of drugs.

23.  Two biological factors contribute to substance abuse and addiction:
1. The effects drugs of abuse exert on the individual.
2. The biological status of the individual taking drugs .

24. DRUG ACTION
Acute Actions
 What separates drugs of abuse from other psychoactive drugs ?
• One of the most striking features of drug addiction is how few chemicals
are subject to abuse.
• All known congeners of all known chemicals, approximately 30,000,000
chemical substances [Gardner, 2005]. Yet, only approx 100 are addictive.
• What makes these 100 chemicals addictive, while the remaining
30,000,000 chemicals lack this property?

25.  All addictive drugs are subjectively rewarding, reinforcing and pleasurable.
 All addictive drugs (excep) activate reward circuitry of brain -producing
subjective ‘high’ that drug abuser seeks.
 Degree of such activation of the brain’s reward circuitry correlates well
with the degree of subjective high.

26. REWARD CIRCUITS
Stahl’s essential psychopharmacology.

27. The mesolimbic dopamine circuit
 The final common pathway of reinforcement and reward.
 Also k/a “pleasure center” of the brain and dopamine to be the
“pleasure neurotransmitter.
 Natural ways to trigger your mesolimbic dopamine neurons to release
dopamine, ranging from intellectual accomplishments, to athletic
accomplishments, to enjoying a good symphony, to experiencing an
orgasm. These are called as “natural highs”.
 The inputs to the mesolimbic pathway that mediate these natural highs
include a naturally occurring substances - endorphins, anandamide,
acetylcholine, and dopamine itself.

28.  Drugs of abuse also have a final common pathway of causing the
mesolimbic pathway to release dopamine, more explosive and
pleasurable than that which occurs naturally.
 A drug-induced reward causes such wonderful feeding of dopamine to
postsynaptic limbic dopamine receptors that they furiously crave even
more drug to replenish dopamine once the drug stops working, leading
one to be preoccupied with finding drug and thus beginning a vicious
cycle of abuse, addiction, dependence, and withdrawal

29. 0
50
100
150
200
0 60 120 180
Time (min)
%ofBasalDAOutput
NAc shell
Empty
Box Feeding
Source: Di Chiara et al.
FOOD
100
150
200
DAConcentration(%Baseline)
Mounts
Intromissions
Ejaculations
15
0
5
10
CopulationFrequency
Sample
Number
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
ScrScr
BasFemale 1 Present
Scr
Female 2 Present
Scr
Source: Fiorino and Phillips
SEX
Natural Rewards Elevate Dopamine
Levels

30. 0
100
200
300
400
500
600
700
800
900
1000
1100
0 1 2 3 4 5 hr
Time After Amphetamine
%ofBasalRelease
DA
DOPAC
HVA
Accumbens AMPHETAMINE
0
100
200
300
400
0 1 2 3 4 5 hr
Time After Cocaine
%ofBasalRelease
DA
DOPAC
HVA
Accumbens
COCAINE
0
100
150
200
250
0 1 2 3 hr
Time After Nicotine
%ofBasalRelease
Accumbens
Caudate
NICOTINE
Source: Di Chiara and
Effects of Drugs on Dopamine Release
100
150
200
250
0 1 2 3 4hr
Time After Ethanol
%ofBasalRelease 0.25
0.5
1
2.5
Accumbens
0
Dose (g/kg ip)
ETHANOL
Much greater
Activity than any
Other drug of abuse.

31. The reactive reward system
 Addicts act impulsively, automatically, and obligatorily to cues that
lead them to seek and ingest more drug..mediated by reactive reward
system.
 Upon repeated exposure to drugs of abuse, this reactive reward system
pathologically “learns” to trigger drug seeking behavior and
“remembers” how to do this when confronted with internal cues such
as craving and withdrawal and external cues from the environment
such as people, places, and paraphernalia associated with past drug
use.

33.  Connections of VTA DA neurons with the amygdala are involved with
reward learning.
 Once reward learning has been conditioned in the amygdala,
connections of the amygdala back to the VTA DA neuron later
communicate whether anything relevant to the previously rewarding
drug abuse experience is being detected.

34.  Connections of the amygdala with the nucleus accumbens tell the
spiny neurons there that emotional memories have been triggered by
internal or external cues, and instruct these spiny neurons to take
action impulsively, right away, automatically, obligatorily, and without
thought, almost as a reflex action, to find and take more drugs.

35. The reflective reward system
 Includes important connections from prefrontal cortex down to the
nucleus. These connections are the first legs of cortico-striatal-
thalamic-cortical (CSTC) loops.
1. Prefrontal projections from the orbitofrontal cortex may be involved
in regulating impulses,
2. Dorsolateral prefrontal cortex (DLPFC)  analyzing the situation,
and regulating whether it is rational to take an action.
3. Ventromedial prefrontal cortex may try to integrat impulsiveness
from OFC with analysis and cognitive flexibility from DLPFC with its
own regulation of emotions, and come up with a final decision of
what to do.

37.  The reflective reward system is also involved in the will power to resist
drugs.
 When fully developed and functioning properly ..it provide motivation
for pursuing more naturally rewarding experiences such as education,
accomplishments, recognition, financial benefits, career development,
enriching social and family connections, etc

38. Turning reward into goal-directed behavior:
output of the reward system
 The output of the reward system is really just the completion of CSTC
loops starting in the prefrontal cortex.
 Nucleus Accumbens  via GABA-ergic neurons to the ventral pallidum
 via GABA-ergic neurons to the thalamus, and then project back up
to the prefrontal cortex, where behaviors are implemented, such as
learning and activities resulting in long-term rewards or drug-seeking
behavior resulting in short-term rewards.

40.  First time you take a drug, there is immediate pharmacological action
upon the mesolimbic pleasure center……Dopamine is released, pleasure is
experienced and the amygdala “learns” that this is a rewarding experience.
Reward has now been conditioned in the amygdala.

41. • when cues are encountered, the amygdala signals dopamine neurons in the ventral tegmental
area (VTA) that something good is coming ,This leads to dopamine release in the nucleus
accumbens which triggers GABA-ergic input to the thalamus, thalamic input to the prefrontal
cortex, and leads to action such as drug-seeking behavior

42.  But can impulses from the reactive reward system ever be
resisted?
 What is the role of will power over temptation?
 when temptation occurs with the opportunity to ingest drugs arising at
a party, in a bar, or when seeing or feeling drugs or their paraphernalia,
the amygdala anticipates the pleasure that the drugs would bring in by
signaling an impulsive choice to the VTA that urges output from the
nucleus accumbens to engage in behavior that leads to ingesting the
drugs again.
 The OFC in prefrontal cortex is signaling craving and voting for more
drug ingestion as well.

43. When drug anticipation occurs, this signals an impulsive choice to the
ventral tegmental area (VTA) to release dopamine in the nucleus
accumbens, which in turn produces output to engage in behavior that leads
to ingesting drugs again.

44.  Will power can be represented in the reward system as the ability of
prefrontal circuits to become activated and prevent impulses being
expressed as drug-seeking behavior.
 For example, Reflective reward system allows the time to evaluate
whether losing your driver’s license, getting into an auto accident,
losing your job or your relationship is worth becoming intoxicated, and
if the answer is no, can trigger the choice not ingesting the drug.

45. The dorsolateral prefrontal cortex (DLPFC) interprets the various signals and, showing cognitive
flexibility, decides whether to take the action of drug ingestion (5). (B) If the reflective reward
system (prefrontal circuits) is activated, this can prevent impulses (temptation) from being
expressed as behavior.

46. MECHANISM OF ACTION OF VARIOUS DRUGS

47. Nicotine
1. Nicotine directly causes dopamine release in the nucleus accumbens
by binding to alpha 4 beta 2 nicotinic postsynaptic receptors on
dopamine neurons in the ventral tegmental area (VTA).
2. Nicotine binds to alpha 7 nicotinic presynaptic receptors on
glutamate neurons in the VTA, which in turn leads to dopamine
release in the nucleus accumbens.
3. Nicotine also seems to desensitize alpha 4 beta 2 postsynaptic
receptors on GABA interneurons in the VTA; the reduction of GABA
neurotransmission disinhibits mesolimbic dopamine neurons and
thus is a third mechanism for enhancing dopamine release in the
nucleus accumbens.

48. Alcohol
 The pharmacology of alcohol is poorly understood and its mechanism
of action is thought to be somewhat nonspecific.
 Alcohol can have effects on a wide variety of neurotransmitter systems.
 Enhancing inhibitory neurotransmission at GABA synapses and
reducing excitatory neurotransmission at glutamate synapses 
depress CNS neuronal functioning  intoxicating, amnestic, and
ataxic effects.
 Alcohol either act directly mu opiate receptors or indirectly act by
releasing endogenous opiates such as enkephalin…actions on opiate
synapses is thought to be the release of DA in the nucleus accumbens.
 Alcohol may also have some actions on cannabinoid receptors.

49. Opiates
 Act as agonists at mu, delta, and kappa opiate receptors, particularly at
mu sites.
 Opiates act as neurotransmitters released from neurons that arise in
the arcuate nucleus and project both to the VTA and to the nucleus
accumbens and release enkephalin.
 The opiates induce euphoria, which is their main reinforcing property.

50. Stimulants
 The main mechanism of action of cocaine is to block reuptake and
cause the release of monoamines, principally dopamine (DA) but also
norepinephrine (NE) and serotonin (5HT).
 Amphetamine as an inhibitor of the dopamine transporter (DAT) and
also of the vesicular monoamine transporter (VMAT).
 The potential abuse properties of stimulants stem from their ability to
enhance dopamine release in the nucleus accumbens.

51.  Marijuana delivers its active ingredients, the cannabinoids (e.g., THC;
delta-9-tetrahydrocannabinol), which interact with the brain’s own
cannabinoid receptors to trigger dopamine release in the nucleus
accumbens.
 Sedative/ hypnotics are positive allosteric modulators (PAMs) for
GABA-A receptors.

52.  Inhalants : Agents such as toluene are thought to be direct releasers of
dopamine in the nucleus accumbens.
 Phencyclidine and ketamine : act as antagonists of NMDA receptors,
actions at glutamate synapses within the reward system.
 Hallucinogens : The hallucinogens are a group of agents that act at
serotonin synapses in the reward system.

53.  Addictive drugs of different classes act on this brain reward neural
circuit at different points to activate the circuit and produce drug-
induced high.
 Barbiturates, benzodiazepines, cannabinoids, ethanol, nicotine and
opiates act on synapses in ventral tegmental area.
 Amphetamines, cannabinoids, cocaine, opiates and dissociative
anesthetics eg. ketamine and phencyclidine act on synapses in nucleus
accumbens
 Addictive drugs effectively ‘hijack’ brain’s reward circuits, activating
them more strongly than natural rewards, and diverting the drug
addict’s life to pursuit of drug- induced pleasure at the expense of
‘getting off’ on life’s normal pleasures and rewards….to begin with
anyway!

54. CHRONIC EFFECTS OF DRUG

55. NEUROADAPTATIONS IN SUBSTANCE
DEPENDENCE
 Chronic drug and alcohol use produces numerous neurobiological
changes in several brain regions.
 These changes occur at virtually every level of information processing,
ranging from neurotransmitters and receptors to intracellular signaling
pathways and regulation of gene expression to long-term structural
changes that alter synaptic plasticity.
 These changes ultimately could alter entire neural networks with
impact on motivation, emotion, decision making, and other cognitive
processes.

56. From: Nestler - Transcriptional and Epigenetic
Mechanisms of Addiction
http://az9194.vo.msecnd.net/pdfs/100401/EB10L5.pdf

57. From: Nestler - Transcriptional and Epigenetic
Mechanisms of Addiction
http://az9194.vo.msecnd.net/pdfs/100401/EB10L5.pdf

58. From: Nestler - Transcriptional and Epigenetic Mechanisms of Addiction
http://az9194.vo.msecnd.net/pdfs/100401/EB10L5.pdf

59. VULNERABILITY AND GENETICS

60.  why does one person become dependent on drugs while another,
exposed to the same environment and experiences, does not?
 There is likely to be a genetic component to substance abuse and
addiction.
 That is, inherited differences among individuals affect their response to
drugs.

61.  The children of alcoholic parents are at higher risk for developing
alcoholism and drug dependence than are children of nonalcoholic
parents.
 The higher risk for alcoholism manifests itself even when children are
adopted by nonalcoholic families soon after birth. Dependence on
other drugs also shows a familial pattern.
 Numerous studies of laboratory animals have revealed genetically
transmitted differences in the reinforcing effects of alcohol and various
drugs, such as cocaine and opioids, and show that genetic factors
powerfully influence sensitivity to toxic effects.

62.  Studies of boys adopted soon after birth have shown higher rates of
alcoholism among those whose biological fathers were alcoholics than
among those whose biological fathers were not.
 Some adoption studies point toward subtypes of alcoholism among
men: One is a later-onset disorder that is less severe and far more
sensitive to environmental factors (type I OR low risk), and the other is
associated with early-onset, antisocial behavior and criminality in the
biological fathers and a stronger genetic basis for the increased
vulnerability (type II OR high risk).

63. High risk and low risk children and adolescents
 HR children have :
 smaller (slower maturing) brain areas
- Frontal BRAKES
- ANT CING
 Less mature connecting WHITE matter tracts - reduced white matter
being associated with greater impulsivity.
 ALTERED EMOTIONAL REACTIVITY AND REACTION TO SOCIAL
CUES. Deficits in recognizing anger and fear recognition difficulties
in recognizing and responding appropriately to others emotions and
thoughts------ >> More asocial and drinking helps them to become
more prosocial which is highly rewarding.

64.  Hypo-activation in high risk subjects for Recognition of Angry &
Fearful faces  inability to recognize these emotions may lead to
increased risk taking behavior.
 HR respond differently to alcohol Greater CNS “stimulation”….greater
reinforcing effect of alcohol; BUT……HR receive less warning of
intoxication.
 HR young adults receive increased CNS reinforcement from alcohol
…but lower negative signals of intoxication  frequent drug use and
bingeing.

65. P300
 A P300 event-related potential (ERP) is a brief electrical wave in the
EEG, reflects active stimulus processing that is affected by attention
and memory and is genetically mediated
 Measure of the way the brain pays attention and discriminates
between potentially important and non-important stimuli.
 Marker of CNS hyperexcitability - lower amplitude of P300 associated
with generalized disinhibition, associated with the early onset of a
number of deviant behaviors
 Several studies: HR children have demonstrated reduced P300
amplitude
 Differences not always replicable in adults (Gandhi & Benegal, 2004)
Benegal V, Jain S, Subbakrishna DK, Channabasavanna SM. Psychiatr Genet. 1995;5(4):49-56.
Iacono and McGue, 2006; Porjesz and Rangaswamy, 2007

66. ‘Reward Deficiency’ as a Driving Force in
Addiction
 In 1996, Blum et al. proposed that many aspects of addiction are driven
by a chronic basal deficiency in brain reward.
 The fundamental notion : that drug addicts are either born with or
acquire a deficiency state in the dopaminergic brain substrates of
reward and turn to addictive drug use to remedy this reward deficiency.
 ‘IF this be so, then our goals are really two- fold: first, to rescue addicts
from the clutches of their addictions, and second, to restore their
reward systems to a level of functionality that will enable them to
function appropriately.
Gardner (2011) In, Clark MR, Treisman GJ (eds): Chronic Pain and
Addiction. Adv Psychosom Med. Basel, Karger, 2011, vol 30, pp 22–60

67. Genetics
 Heritability estimates for nicotine, alcohol, and drug addiction are in
the range of 50% to 60%.
 In general, it appears that environmental factors have a stronger effect
on initiation, whereas genetic factors play a larger role in the transition
from regular use to the development of addiction.
(Heath et al., 1997;Tsuang et al., 1998;Kendler et al., 2003;Li, 2006)
(Vink et al., 2005).
The Genetic Basis of Addiction, Chad Epps and Elizabeth
Laura Wright

68.  Genetics of Alcohol Dependence
 Polymorphisms in the alcohol metabolizing enzymes are the most strongly
associated genetic variants that influence alcohol consumption and
alcohol dependence.
 Protective role for the deficiency of ALDH2 in alcohol dependence
 Several known genetic variants cause amino acid changes in these proteins
and alter enzymatic activity.
 ADH1B*2, or rs1229984, diminishes ADH1b enzymatic activity several fold,
and ALDH2*2, or rs671, results in a nearly inactive enzyme (Edenberg,
2007). These genetic variants reduce the probability of heavy alcohol
consumption and the development of alcohol dependence.

69.  The mechanism by which variants of these enzymes influence the risk
of developing alcohol dependence is hypothesized to be through an
elevation of acetaldehyde levels after drinking, leading to facial
flushing, nausea, and other adverse reactions.
(Enoch, 2008

70.  Genetic influences for other Drug Addictions
 Endogeneous opioid system clearly plays a role in addiction, and an
amino acid change in the μ opioid receptor (OPRM1) displays
functional changes with up to threefold variation in the affinity of the
receptor to bind beta-endorphin.
 However, a large scale meta-analysis does not demonstrate that this
variant alters the risk of developing addiction.
(Bond et al., 1998).
(Arias et al., 2006).

71.  Studies of Nicotine Dependence
 The most robust genetic finding that alters the risk of developing heavy
smoking is in the chromosome 15q25 region, which contains the α5, α3,
and β4 nicotinic receptor subunit gene cluster (CHRNA5, CHRNA3,
CHRNB4).
 Variation in an independent group of nicotinic receptors is also
associated with the development of heavy smoking and nicotine
dependence. The nicotinic receptor gene cluster on chromosome 8 that
includes the α6 and β3 nicotinic receptor subunit gene cluster
(CHRNA6, CHRNB3) is correlated with smoking behavior.

72.  The importance of nicotine metabolism and variation in the CYP2a6
region on chromosome 19 was recently reinforced by the GWAS meta-
analysis studies in which variants in this region were associated with
number of cigarettes smoked per day.
(Thorgeirsson et al., 2010; Tobacco and Genetics Consortium,
2010).

73.  The chromosome 15 variant in the α5 nicotinic receptor, which
influences the development of nicotine dependence, has also been
independently shown to contribute to the occurrence of alcohol and
cocaine dependence.
 The minor allele is correlated with an increased risk for nicotine
dependence is associated with a decreased risk for alcohol and cocaine
dependence.
(Grucza et al., 2008; Chen et al., 2009; Sherva et al.,
2010)

75.  Drug use, whether occasional or compulsive, can be viewed as behavior
maintained by its consequences.
 Any event that strengthens an antecedent behavior pattern can be
considered a reinforcer of that behavior. In that sense, certain drugs
reinforce drug-taking behavior.
 Drugs can also reinforce antecedent behaviors by terminating some
noxious or aversive state such as pain, anxiety, or depression.
 In some social situations, the use of the drug can be reinforcing if it
results in special status or the approval of friends.

76.  Each use of the drug evokes rapid positive reinforcement, either as a
result of the rush (the drug-induced euphoria), alleviation of disturbed
affects, alleviation of withdrawal symptoms, or any combination of
these effects.
 The paraphernalia (needles, bottles, cigarette packs) and behaviors
associated with substance use can become secondary reinforcers, as
well as cues signaling availability of the substance, and in their
presence, craving or a desire to experience the effects increases.

77.  With socially acceptable substances, such as tobacco, use becomes so
woven into the matrix of daily functioning that some users are
reminded of the substances when performing ordinary tasks.

78. Classical Conditioning
 Opioid and alcohol withdrawal phenomena can be conditioned to
environmental or interoceptive stimuli.
 For a long time after withdrawal (from opioids, nicotine, or alcohol),
the addict exposed to environmental stimuli previously linked with
substance use or withdrawal may experience conditioned withdrawal,
conditioned craving, or both.
 The most intense craving is elicited by conditions associated with the
availability or use of the substance, such as watching someone else use
heroin or light a cigarette or being offered some drug by a friend.
 Cues induce memories of drug-induced euphoria are more important
for stimulating craving and in predisposing to relapse.

79. Withdrawal Syndromes and Negative
Reinforcement
 Aversive withdrawal phenomena and negative reinforcement is equally
important, or even dominant in substance use.
 Eg …in people who become dependent on benzodiazepines in the
course of treatment for anxiety syndromes, when drug use is
interrupted, some seem to experience a reappearance of the original
symptoms, whereas others have new distressing symptoms indicating
withdrawal. The use of benzodiazepines alleviates both kinds of
aversive states.
 The alcoholic, the heavy smoker, and the heroin user may experience,
simultaneously or sequentially, relief of withdrawal, a sense of ease,
and perhaps alleviation of dysphoria and depression after taking
substance.

81.  According to classic theories, substance abuse is :
1. A masturbatory equivalent(some heroin users describe the initial
“rush” as similar to a prolonged sexual orgasm),
2. A defense against anxious impulses, or a manifestation of oral
regression (i.e., dependency).
 Recent psychodynamic formulations relate substance use as a
reflection of disturbed ego functions (i.e., the inability to deal with
reality).

82.  As a form of self-medication, alcohol may be used to control panic,
opioids to diminish anger, an amphetamines to alleviate depression.
 Some addicts have great difficulty recognizing their inner emotional
states, a condition called alexithymia(i.e., being unable to find words to
describe their feelings).

84. Stress, drug use and addiction
 Stress activates the same brain [reward] systems responsible for the
positive reinforcing effect of drugs
 It increases physiological sensitivity to drugs
 It increases desire to improve mood with drugs after exposure to stress.
 Stress more strongly predicts drug use when there is a psychiatric
disorder, poor parenting, family dysfunction, and adverse
neighborhood characteristics.
 Stress, lack of social supports, and poor coping skills predict early onset
and escalation of drug use, relapse, and treatment resistance.

85.  Interestingly, Post-Traumatic Stress Disorder (PTSD) often precedes
drug use in girls, but occurs more often after drug use in boys.
 Girls are at increased risk for substance abuse when exposed to the
stressors of family violence and alcoholism.
 Preventive Implications: Sex differences should be taken into
account in identifying factors that contribute to drug use and in the
development of a prevention or treatment plan.

86. • Children exposed to stress and conflict in the home are more likely to
Manifest high levels of aggressive behavior, the strongest predictor of
later drug use and other risk behaviors
 Girls are influenced by peers differently than boys:
 More likely to use drugs if friends & partners are using or introduces
drugs to them.
 Concerns about peer approval, depression and body image – all
interrelated – increase susceptibility to drug use in girls.

87. Mental Health Problems
 Mental Health Disorders are strongly linked to drug use and
dependence.
 Internalizing Disorders (PTSD, Depression, Anxiety disorders, Bipolar
disorder)
 Brain responses are heightened in response to drugs.
 Tendency to self-medicate the anxiety & depression this process causes
drug use.

88. Mental Health Problems
 Externalizing Disorders (Conduct Disorder, Attention Deficit
Hyperactivity Disorder, Oppositional Defiant Disorder, Antisocial
Personality Disorder)
 Low level of arousal in these disorders is related to an insensitivity to
consequences and a need for more stimulation.
 Heightens risk for continued drug use to relieve symptoms.
 Tend to be resistant to substance abuse treatment.

89. Personality & Temperament
 A difficult temperament
and certain personality
characteristics are
consistently related to
heightened risk for drug
use.
 Impulsivity
 Aggressiveness
 Sensation or novelty-seeking
 Negative affect
 Impaired judgment
 High activity level
 Risk taking tendencies
 Lack of regard for negative
consequences
 Lack of pain avoidance
responses
 Abnormal levels of arousal in
response to stress.

90.  Normal adolescence is characterized by greater reward anticipation,
sensitivity, and sensation seeking—particularly social rewards (e.g.,
peer regard, gains in social status).
 It follows that adolescence is the period during which drug use onset is
most common.
 And, therefore, that adolescents with especially high levels of any
combination of these traits are at heightened risk.
 Preventive Implications: These traits can be redirected through
psychosocial means to decrease risk for drug use. Prevention programs
must be designed to specifically redirect this developmental track.

91.  Social Cohesion = attachment to and satisfaction with the
neighborhood
 Involves trust and support for one another in a community
 Maintains norms for positive social behavior
 Associated with lower drug use and lower drug-related mortality
 Discrimination and social exclusion have profound negative effects :
Physical and mental health disorders, including drug use and
dependence.

92.  Substantial evidence indicates that changes in price and availability can
alter the consumption of alcohol and tobacco.
 Increase in sales outlets or an extension of sales hours increases the
availability of alcohol, consumption tends to increase.
 When the cost of either alcohol or tobacco is increased in relation to
disposable income (e.g.,by increased taxes), consumption decreases.

93.  Availability and Health Professionals.
 physicians, dentists, and nurses have far higher rates of dependence on
DEA-controlled substances, such as opioids, stimulants, and seda-tives,
than other professionals of comparable educational achievement.

94. Thank you

95.  Stahl’s essential psychopharmacology.
 CTP 9th edition.
 DSM 5
 ICD 10
 Kaplan and sadock synopsis of psychiatry 10th ed.
 The Genetic Basis of Addiction Chad Epps and Elizabeth Laura Wright,