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SUBSTANCE-RELATED
DISORDERS
Marcelino V. Ostrea Jr.,M.D.
Historical Background
Substance abuse
Major public health problem throughout the world.
Dangerous Drugs Board and the Antinarcotics Group
of the Philippine National Police
Estimated that 1.8 million of the 80 million Filipinos
were regular drug users while 1.6 million others are
casual users.
Historical Background
International Narcotics Control Board
Methamphetamine Hydrochloride or Shabu
MOST POPULAR DRUG OF ABUSE IN THE
PHILIPPINES.
1.8 million drug users nationwide,
1.2 million young generation (15 to 29yrs.)
More in MALES at 12 to 1 ratio.
Often SINGLE, EMPLOYED or SELF EMPLOYED.
6 to 12 years of education, from urban area.
Historical Background
………Although the sequelae of addiction,
such as cirrhosis, psychopathology, trauma,
and infection, generally receive proper
medical attention, patients’ primary addictive
problems often go untreated.
Drug Addiction
 WHY DO PEOPLE ABUSE
1. GENETICS
2. PERSONALITY PROFILE
3. ENVIRONMENT
4. NEUROBIOLOGY
5. OTHER FACTORS
DRUGS?
Drug Addiction

Genetics
◦ Genes that influence initiation of drug use are
RELATED to ANTISOCIAL PERSONALITY TRAITS
◦ Genetic factors for initiation of use are largely the
SAME for all class of drugs except opiates.
Tsuang et al. 1999
Drug Addiction

Genetics
 Strongest genetic influences on the risk of drug
abuse are the SAME genes that influence
initiation of drug use.
 Once drug use is initiated, the factors that
influence the transition from initiation to
repeated use, abuse, or dependence are largely
NON GENETIC unique to each individual.
(Kendler et al.1999,2000; Sigvardsson et al, 1996; Tsuang et al. 1999).
Personality Profile

Personality Antecedent
◦ ANTISOCIAL PERSONALITY traits in a
person’s biological parents predict an increased risk
of early-onset alcohol and substance abuse.
◦ ANTISOCIAL PERSONALITY traits in a
person’s own childhood and adolescence predict
early onset of substance abuse.
Cadoret et al. 1995
Personality Profile

Personality Antecedent
◦
◦
◦
◦
High novelty seeking
Low self-directedness
Low cooperativeness
Personality disorders characterized by an
inability to delay gratification
◦ Carry high risk of co-morbid substance abuse
leading to both early initiation of drug
experimentation and frequent transition to
substance abuse or dependence.
Neurobiology of Substance Abuse
PSYCHOPHARMACOLOGY
OF REWARD AND
DRUGS OF ABUSE
THEORETICAL ASPECTS OF
ADDICTION

POSITIVE REINFORCEMENT
◦ Something special in the drug that elevates the
mood above the ordinary.
◦ The drug is viewed something that satisfies the
individual like sexual gratification, is simply a
source of enjoyment.
SUBSTRATES OF POSITIVE
RE-INFORCEMENT

The most clearly identified elements of brain reward
circuitry are the Mesolimbic Dopamine System (“Pleasure
Center”) and its primary target neurons in are;
1.
2.
3.
4.

VTA
NAC
VENTRAL PALLIDUM
MEDIAL PREFRONTAL CORTEX.
Dopamine as the “pleasure neurotransmitter”.
Dopaminergic Pathway:
Dopamine Hypothesis of
Psychosis
Dopamine Hypothesis of
Psychosis

Hyperdopaminergic activity of the
mesolimbic pathway induces positive
symptoms of psychosis.
◦ hostility
◦ delusions
◦ hallucinations
disorganization
◦ grandiosity
- excitement
- suspiciousness
- conceptual
SUBSTRATES OF POSITIVE
RE-INFORCEMENT

Factors that trigger mesolimbic dopamine
neurons to release dopamine.
“Natural Highs”




Endorphins
Anandamide
Acetylcholine
Dopamine
“Drug-induced high”
morphine/heroin
marijuana
nicotine
cocaine & amphetamine
Mesolimbic Dopamine Pathway
Psychopharmacology of Reward
Mesolimbic Pathway
Drugs affecting the mesolimbic
dopaminergic neurons.
Amphetamine
GABA
Alcohol
Opiod
Dopamine
Cocaine
Nicotine
Acetylcholine
Hallucinogens
Serotonin
Glutamate
Cannabis
PCP
Stimulants:

Rewarding effects of stimulants are medicated
through the mesolimbic dopamine system.
◦ DA neurons (ventral tegmental area) projections to NAc, v.
pallidum and medial prefrontal cortex.

Reinforcing properties of cocaine and amphetamine
are associated with their increase synaptic DA levels
◦ Cocaine increases synaptic DA by binding to DAT &
inhibiting activity.
◦ Amphetamine increases synaptic DA by actions on
vesicular monoamine transporter causes release of DA.
Johanson & Fischman 1989; Kosten 2002
Pharmacology of Cocaine
Dopamine
Cocaine
Pharmacology of Cocaine
Dopamine
Repeat cocaine use can lead
to REVERSE TOLERANCE such as
ACUTE PARANOID PSYCHOSIS.
Pharmacology of Amphetamine
Stimulants:

Cocaine & Aamphetamine also have
actions on NE and 5-HT neurons, and all
of these neurotransmitters are
important targets for medication
development.
Rothman et al. 2000
Stimulants:

Neurobiological effects of CHRONIC
STIMULANT ABUSE:
◦
◦
◦
◦
Decreased postsynaptic DA receptors
Reduced DA function
Reduced CBF & cortical perfusion
Alterations in glucose metabolism
◦ Increased GM in early withdrawal
◦ Decreased GM in late withdrawal.
Stimulants:

Neurobiological effects of chronic
stimulant abuse:
◦ Impairments in verbal learning, memory, and
attention.
◦ Neuropsychological deficits was due to reduction
in cerebral blood flow.
◦ DAT reduction is also assoc. with psychomotor
impairment in methamphetamine abusers.
Signs and symptoms of stimulant
intoxication:

Behavioral and Psychological Abnormalities:
◦
◦
◦
◦
◦
◦
◦
Euphoria or blunted affect
Hypervigilance
Interpersonal sensitivity
Anxiety, tension, and anger
Stereotyped behaviors
Impaired judgement
Bruxism - Grinding together of the teeth
Signs and symptoms of stimulant
intoxication:

Physical manifestations:
◦
◦
◦
◦
◦
◦
◦
◦
Tachycardia or bradycardia
Dilated pupils
Elevated or low blood pressure
Sweating or chills
Nausea or vomiting
Evidence of weight loss
Psychomotor agitation or retardation
Muscle weakness, respiratory depression, chest pain,
cardiac arrhythmia
◦ Confusion, seizures, dyskinesias, dystonias, coma
Treatment of stimulant intoxication:

Acute Episodes:
 Medical & Psychiatric stabilization
 Delirium of seizure control
 Respiratory support & control of blood pressure,
temperature, arrhythmias
 Control of agitation, aggressiveness, & paranoid psychosis
Acute Cocaine toxicity typically subsides within 1 - 2 hours.
Acute Amphetamine toxicity may persist for several hours.
Indications for Pharmacotherapy:

Treatment of Comorbid Primary Psychiatric Disorders:
 Major depressive disorder
 Bipolar disorder
 Schizophrenia

Treatment of Comorbid Substance Use Disorder
 Alcohol dependence (disulfiram or naltrexone)
 Opioid dependence (methadone)

Treatment of Stimulant-Induced Mental Disorder (if severe
& persistent)
 Cocaine / Amphetamine withdrawal (desipramine)
 Cocaine induced Psychotic disorder (neuroleptics)
 Cocaine induced Mood disorder (Tricyclic or SSRI)
Treatment of stimulant intoxication:

Psychotherapy
1. Motivation for abstinence
2. Development of a rewarding, drug-free lifestyle
3. Avoidance of relapse
Marijuana

Cannabis Sativa (Marijuana)
◦ Smoked to deliver psychoactive substances,
cannabinoids
◦ Especially THC DELTA-9-TETRAHYDROCANNABINOL
◦ THC interact with brain’s own cannabinoid
receptor (CB1) to trigger DOPAMINE RELEASE
from mesolimbic reward system.
Marijuana

Cannabis Sativa (Marijuana)
◦ effect in the body is centered mainly in the
CENTRAL NERVOUS SYSTEM;
1. Increased sense of well-being & euphoria;
2. Impaired short term memory;
3. deterioration in the capacity to carry out tasks that
require multiple mental steps to reach a specific goal
“temporal disintegration”
Marijuana

CB1 Receptor Distribution in the Brain.
◦ BASAL GANGLIA – highest distribution.
◦ Molecular layer of the cerebellum.
◦ Pyramidal layers of the
◦ Hippocampus
◦ Dentate gyrus,
◦ Layers I & VI of cortex
◦ NAc & Ventromedial striatum
◦ Brain stem areas – lowest level

No evidence of CB2 receptor presence in the
neural membrane.
Herkenham et al. 1990
Marijuana

Functional significance of the endogenous
cannabinoid system.
◦ Pain perception
 CB1 & CB2 receptors are both involved in
perception of peripheral pain.
 CB1 involved in the control of inflammatory pain.
 Potentiate morphine anesthesia
 Centrally acting analgesics
Marijuana

Functional significance of the endogenous
cannabinoid system
◦ Appetite and reward
 endogenous cannabinoid system controls hormonal
appetite
 Play a role in control of hypothalamic function.
Di Marzo et al. 2001
Marijuana

Functional significance of endogenous
cannabinoid system.
◦ Immune Modulation
 Endogenous cannabinoids and THC have been shown
to be anti-inflammatory effect, possibly through
the inhibition of the production and action of tumor
necrosis factor alpha and other acute-phase
cytokines
 CB2 receptors involvement in the immune system.
Klein et al. 2000
Marijuana

Cannabis and Neuroimaging.
◦ Those who started using marijuana before age 17,
had a smaller brain
◦ Smaller % of cortical gray matter
◦ Larger % of white matter volume
◦ Males who started using marijuana before age
17 had significantly higher CBF
◦ Male & females who started younger were
physically smaller in terms of weight & height,
especially males
◦ Wilson et al. 2000
Marijuana Dependent

Treatment Approach
 Specialized therapeutic support
 Brief individual & extended group
intervention
 Provide continued access to aftercare
support to prevent relapsed
Alcohol (C2H6O).
Ethanol or beverage alcohol – organic molecule
 Carries little chemical information in its
structure but generates myriads effects in
CNS & PNS
 Alcohol dependence

◦ “pharmacogenetic disease” in which “disease”
causing agent (alcohol) interacts with genetic
background of the “host” (human) to produce
the manifestations of the “disease”.
Alcohol

Factors that influence Alcohol Dependence:
1. GENETIC
2. ENVIRONMENT
◦ ….as the concentration of ethanol in the brain is
increased, the action of ethanol spread from a
limited number of targets to involve multiple
molecular site of action.
◦ differentiate ethanol from other drugs (morphine)
that are limited in their spectrum of action by
specific receptor interactions.
Alcohol

Molecular interactions that mediate effects of
ethanol
◦ Before - disordering of neuronal membrane bulk
lipids.
◦ Current knowledge – ethanol’s biophysical
(amphipathic) properties may well affect
protein-lipid and protein-protein interactions
or disruption of scaffold systems devoted to
bringing together protein complexes.
Pawson & Scott 1997
Alcohol

Molecular interactions that mediate effects
of ethanol.
1. GABAA Receptor System
2. NMDA Receptor System
3. Serotonin Receptors
4. Nicotinic Cholinergic Receptors
 Role of Receptor-Gated Ion Channels & Certain
G Protein-Coupled Receptors in Reinforcing
Properties of Ethanol
Alcohol

GABA Receptor System
◦ Ethanol increase the action of the inhibitory
neurotransmitter GABA at the GABAA
receptor
1. SEDATIVE
2. ANTICONVULSANT
3. ANXIOLYTIC
4. INCOORDINATING effects of ethanol
Whiting et al. 1999
Alcohol

N-methyl-D-aspartate (NMDA) Receptor
System
◦ Ethanol is a potent inhibitor of NMDA
receptor function.
◦ Sedative, anticonvulsant, anxiolytic, and
incoordinating effects of ethanol
◦ Explained by ethanol’s inhibition of the NMDA
receptor system and by potentiation of activation
of the GABAA receptor.
Whiting et al. 1999
Alcohol

Serotonin Receptors & Nicotinic Cholinergic
Receptor System
◦ Conc. of ethanol that produce moderate
intoxication (25 mM) potentiate effects of
serotonin (5-HT) at 5-HT3 subtype of 5-HT
receptor.
◦ Possible role of this receptor in the reinforcing
and/or intoxicating effect of ethanol
Sung et al. 2000
Alcohol

Neuroadaptations leading to craving for
alcohol.
◦ NMDA receptors may exert a tonic
INHIBITORY CONTROL OVER FIRING OF
MESOLIMBIC DOPAMINERGIC neuron
resulting in decreased dopamine release which is
observed after alcohol withdrawal.
Rossetti et al.1991
Alcohol

Neuroadaptations leading to craving
for alcohol.
◦ Withdrawal from ethanol also generates a
DECREASE in the firing of
DOPAMINERGIC neurons in the
VENTRAL TEGMENTAL area of the
brain stem and a decrease in the release
of dopamine from these neurons.
Bailey et al. 1998; Rossetti et al. 1991
Alcohol

Neuroadaptations leading to craving for
alcohol.
◦ Ethanol withdrawal was reported to be
associated with decreased activity of 5-HT
neurons and 5-HT release in the NAc and
may contribute to SLEEP DISTURBANCE
& DEPRESSION.
Weiss et al. 2001
Alcohol Withdrawal
Early-onset withdrawal – starts within 24 hrs,
often within 6 to 8 hrs after blood alcohol level
fall.
 Characterized by:

◦ Autonomic hyperactivity (tacchycardia,
hypertension, diaphoresis, tremor, fever)
◦ Sleep disturbance
◦ GIT manifestation (anorexia, nausea & vomiting)
◦ Psychological manifestations (poor conc.
Impaired memory, hallucinations, agitation, anxiety)
◦ Neurological signs ( seizures)
Alcohol Withdrawal

Late-onset withdrawal – occurs more than 24 hrs,
after the last drink and assoc. with more serious
symptoms
Seizure usually occur within 24 hrs of the
withdrawal syndrome and are not part of Delirium
Tremen nor are they considered epilepsy. Typically
GENERALIZED AND TONIC-CLONIC. Don’t
require long term prophylactic anticonvulsant treatment.
 No Prophylactis TX
 If seizure occurs later than 24 hours. Investigate
other cause ex. Subdural hematoma

Delirium Tremens
Develops within 24 to 72 hrs. after the
onset of abstinence (usually not later than 7
days).
 Manifestations:

1.
2.
3.
4.
5.

High fever
Marked confusion (delirium)
Severe autonomic hyperactivity
Anxiety
Agitation & Mental fluctuation
Syndrome usually DISAPPEARS BY 3
TO 5 DAYS.
Treatment of Delirium Tremens
1.
2.
3.
4.
5.
6.
7.
Intravenous fluid replacement
Parenteral thiamine 100mg/day
Treat hyperthermia
Sedate with IM or IV diazepam
Control seizure (benzodiazepines or
phenytoin)
Treat psychosis with neuroleptic
(haloperidol).
Physical restraint if necessary.
ECTASY
Methyl-1-(3,4-methylenedioxyphenyl)2aminobutane (MDMA).
 Known as Adam, XTC, and X
 Synthetic amphetamine analogue
with stimulant properties.

Methyl-1-(3,4-methylenedioxyphenyl)2aminobutane (MDMA)

MDMA
◦ Principal desired effect is profound feeling
of relatedness to the rest of the world.
◦ Most user experience this feeling as a
powerful connection to those around them.
◦ Alters perception of time and decreased
inclination to perform mental and physical
tasks.
Methyl-1-(3,4-methylenedioxyphenyl)2aminobutane (MDMA)

MDMA
◦ Although the desire for sex can increase, the
ability to achieve arousal and orgasm is greatly
diminished in both men and women.
◦ Common aftereffects is similar the amphetamine
withdrawal.
Methyl-1-(3,4methylenedioxyphenyl)2aminobutane (MDMA)

Severe immediate effects:
◦
◦
◦
◦
◦
◦
◦
◦
◦
◦
Altered mental status
Convulsions,
Hypo-hyperthermia,
Severe changes in blood pressure
Tachycardia
Coagulopathy
Acute renal failure
Hepatotoxicity
Rhabdomyolysis
Death
Methyl-1-(3,4-methylenedioxyphenyl)2aminobutane (MDMA)

Mechanism of action.
◦ INDIRECT SEROTONERGIC
AGONIST.
◦ Taken up by serotonergic cell through an
active channel and induce release of
serotonin stores.
◦ Also blocks reuptake of serotonin
◦ It inhibits synthesis of new serotonin
◦ (subsequent doses diminished high & worsening
of drug’s undesirable effects such as psychomotor
restlessness & teeth gnashing)
Methyl-1-(3,4-methylenedioxyphenyl)2aminobutane (MDMA)

Mechanism of action.
◦ Damage serotonin system which
may be permanent causing lasting
neuropsychiatric disturbances.
◦ Functional brain imaging studies are
consistent with significant and lasting
damage to serotonergic structures.
Substance Abuse

Summary:
◦ Genetics
 Genes that influence initiation of drug use.
 Transition from initiation to repeated use,
abuse, or dependence are largely NONGENETIC
factors.
Substance Abuse

Summary:
◦ Personality profile
 antisocial personality traits in a person’s biological
parents and in person’s own childhood and
adolescence predict early onset of substance abuse.
 High novelty seeking, low self-directedness, and low
cooperativeness have impulse personality disorders
characteriized by inability to delay gratification, carry
a high risk of comorbid substance abuse.
Substance Abuse

Summary:
◦ Neurobiological
 POSITIVE REINFORCEMENT
 “Pleasure Center” Mesocorticolimbic Dopamine
System and its primary target neurons in the
VTA, NAc, ventral pallidum and medial prefrontal
cortex.
 Dopamine “pleasure neurotransmitter”.
Thank you
Marcelino V. Ostrea Jr.,M.D.
Stimulants:
Methamphetamine & Cocaine



Repeated, frequent drug use produces disruptions in
homeostatic mechanism and leads to
neuroadaptations that may provide the
neurobiological basis for consequences such as
addiction or the compulsive use of cocaine or
amphetamine.
Intermittent exposure – lower the threshold for
developing stimulant psychosis.
Chronic exposure – results to tolerance, or
decrease in the effects of stimulant drugs, and may
result in neurotoxicity.
Stimulants:
Methamphetamine & Cocaine

Addiction – compulsive drug seeking
and drug taking, with a loss of control
over drug use.
◦ one factor believed to increase likelihood of
relapsed is exposure to sensory cues
associated with drug taking.
Stimulants:
Methamphetamine & Cocaine

Neurochemical Basis of Addiction:
◦ Functional imaging studies show that cocainerelated cues are associated with increased
activity of the:
1. Basolateral amygdala
2. Cingulate cortex
3. Orbitofrontal cortex
◦ Sensory cues mediates association between
environmental stimuli & drug effects
London et al.1999
Stimulants:
Methamphetamine & Cocaine

Neurochemical Basis of Addiction:
◦ Frontal cortical structures mediating decision
making & impulse inhibition, which are closely
linked with NAc, amygdala, & VTA, appear to be
affected by chronic stimulant exposure
Jentsch and Taylor 1999
Stimulants:
Methamphetamine & Cocaine

Tolerance – larger doses are needed
to produce an effect that previously
was obtained at a lower dose.
◦ Little evidence to support longer-term
tolerance to cocaine’s and amphetamine’s
reinforcing effects.
Stimulants:
Methamphetamine & Cocaine

Dependence – presence of withdrawal
symptoms on termination of drug use.
◦ Stimulants do not produce adaptations in areas
mediating somatic and autonomic function and
therefore are not associated with physical
withdrawal symptoms.
◦ Withdrawal symptoms primarily characterized
by DISORDER OF MOOD.
Weddington et al. 1990
Stimulants:
Methamphetamine & Cocaine

Neurochemical Basis of Dependence:
A DEFICIT OF CENTRAL
SEROTONIN TRANSMISSION during
stimulant withdrawal is consistent with the
hypothesized etiology of clinical depression.
Haney et al. 2001
Stimulants:
Methamphetamine & Cocaine

Neurochemical Basis of Neurotoxicity:
◦ Repeated and toxic doses of
methamphetamine increase GLUTAMATE
efflux in the striatum which underlies the
neuron-damaging effects.
Abekawa et al 1994
Stimulants:
Methamphetamine & Cocaine

Neurotoxicity
◦ Postmortem analyses of methamphetamine
abusers revealed decreased neural level
of striatal dopamine, tyrosine
hydroxylase, and dopamine
transporters in the caudate nucleus and
putamen (striatum).
Wilson et al. 1996
Stimulants:
Methamphetamine & Cocaine

Conclusion:
◦ Acute administration of stimulant drugs have
similar subjective, reinforcing, and discriminative
stimulus effects.
◦ Repeated exposure results in sensitization or
tolerance to certain effects, depending on the
dosage and pattern of drug administration.
◦ Cocaine’s effect are relatively shorter compared
to methamphetamine.
◦ Cocaine inhibits the reuptake of dopamine,
whereas amphetamine both inhibits dopamine
reuptake and promotes dopamine release.