SUBSTANCE-RELATED DISORDERS Marcelino V. Ostrea Jr.,M.D

SUBSTANCE-RELATED DISORDERS

Marcelino V. Ostrea Jr.,M.D.

Historical BackgroundHistorical 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.


International Narcotics Control BoardMethamphetamine 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.


………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 AddictionDrug Addiction

WHY DO PEOPLE ABUSE DRUGS?1. GENETICS2. PERSONALITY PROFILE3. ENVIRONMENT4. NEUROBIOLOGY5. OTHER FACTORS

Drug AddictionDrug AddictionGenetics

◦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 AddictionDrug 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 ProfilePersonality 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 ProfilePersonality 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 Neurobiology of Substance AbuseAbuse

PSYCHOPHARMACOLOGY OF REWARD AND DRUGS OF ABUSE

THEORETICAL ASPECTS OF THEORETICAL ASPECTS OF ADDICTIONADDICTION

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 SUBSTRATES OF POSITIVE RE-INFORCEMENTRE-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. VTA

2. NAC

3. VENTRAL PALLIDUM

4. MEDIAL PREFRONTAL CORTEX.Dopamine as the “pleasure neurotransmitter”.

Dopaminergic Dopaminergic Pathway:Pathway:

Dopamine Hypothesis Dopamine Hypothesis of Psychosisof Psychosis

Dopamine Hypothesis of Dopamine Hypothesis of PsychosisPsychosis

Hyperdopaminergic activity of the mesolimbic pathway induces positive symptoms of psychosis.◦hostility - excitement◦delusions - suspiciousness◦hallucinations - conceptual

disorganization◦grandiosity

SUBSTRATES OF POSITIVE SUBSTRATES OF POSITIVE

RE-INFORCEMENTRE-INFORCEMENTFactors that trigger mesolimbic

dopamine neurons to release dopamine. “Natural Highs” “Drug-induced high”

Endorphins morphine/heroin Anandamide marijuana Acetylcholine nicotine Dopamine cocaine & amphetamine

Mesolimbic Dopamine Mesolimbic Dopamine Pathway Pathway Psychopharmacology of Psychopharmacology of RewardReward

Mesolimbic Pathway

Drugs affecting the Drugs affecting the mesolimbic dopaminergic mesolimbic dopaminergic neurons.neurons.

Amphetamine

Cocaine

Cannabis

Dopamine

GABA

Alcohol

Opiod

Nicotine

Acetylcholine

Hallucinogens

PCP

Glutamate

Serotonin

Stimulants: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 CocainePharmacology of Cocaine

Dopamine

Cocaine

Pharmacology of CocainePharmacology of Cocaine

Dopamine

Repeat cocaine use can lead to REVERSE TOLERANCE such asACUTE PARANOID PSYCHOSIS.

Pharmacology of Pharmacology of AmphetamineAmphetamine

Stimulants: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: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: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 Signs and symptoms of stimulant intoxication: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 Signs and symptoms of stimulant intoxication: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 Treatment of stimulant intoxication:intoxication: Acute Episodes:

Medical & Psychiatric stabilizationDelirium of seizure controlRespiratory 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 Indications for Pharmacotherapy:Pharmacotherapy: Treatment of Comorbid Primary Psychiatric Disorders:Major depressive disorderBipolar disorderSchizophrenia

Treatment of Comorbid Substance Use DisorderAlcohol 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 Treatment of stimulant intoxication:intoxication:

Psychotherapy1. Motivation for abstinence2. Development of a rewarding, drug-

free lifestyle3. Avoidance of relapse

MarijuanaMarijuanaCannabis 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.

MarijuanaMarijuanaCannabis 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”

MarijuanaMarijuanaCB1 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

MarijuanaMarijuana

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

MarijuanaMarijuana

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

MarijuanaMarijuanaFunctional 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

MarijuanaMarijuanaCannabis 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 DependentMarijuana DependentTreatment Approach

Specialized therapeutic support Brief individual & extended group

interventionProvide continued access to

aftercare support to prevent relapsed

AlcoholAlcohol (C2H6O).(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”.

AlcoholAlcoholFactors that influence Alcohol

Dependence:1. GENETIC2. 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.

AlcoholAlcoholMolecular 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

AlcoholAlcohol

Molecular interactions that mediate effects of ethanol.

1. GABAA Receptor System2. NMDA Receptor System3. Serotonin Receptors4. Nicotinic Cholinergic Receptors Role of Receptor-Gated Ion

Channels & Certain G Protein-Coupled Receptors in Reinforcing Properties of Ethanol

AlcoholAlcohol

GABA Receptor System◦Ethanol increase the action of the inhibitory neurotransmitter GABA at the GABAA receptor

1.SEDATIVE2.ANTICONVULSANT3.ANXIOLYTIC4.INCOORDINATING effects of

ethanolWhiting et al. 1999

AlcoholAlcohol

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

AlcoholAlcohol

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

AlcoholAlcoholNeuroadaptations 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

AlcoholAlcohol

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

AlcoholAlcohol

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 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 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 TXIf seizure occurs later than 24 hours.

Investigate other cause ex. Subdural hematoma

Delirium TremensDelirium TremensDevelops within 24 to 72 hrs. after the

onset of abstinence (usually not later than 7 days).

Manifestations:1. High fever2. Marked confusion (delirium)3. Severe autonomic hyperactivity4. Anxiety5. Agitation & Mental fluctuation

Syndrome usually DISAPPEARS BY 3 TO 5 DAYS.

Treatment of Delirium Treatment of Delirium TremensTremens

1. Intravenous fluid replacement2. Parenteral thiamine 100mg/day3. Treat hyperthermia4. Sedate with IM or IV diazepam5. Control seizure

(benzodiazepines or phenytoin)6. Treat psychosis with neuroleptic

(haloperidol).7. Physical restraint if necessary.

ECTASY ECTASY

Methyl-1-(3,4-methylenedioxyphenyl)-2aminobutane (MDMA).

Known as Adam, XTC, and XSynthetic amphetamine analogue with stimulant properties.

Methyl-1-(3,4-Methyl-1-(3,4-methylenedioxyphenyl)-methylenedioxyphenyl)-2aminobutane (MDMA)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-Methyl-1-(3,4-methylenedioxyphenyl)-methylenedioxyphenyl)-2aminobutane (MDMA)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-(3,4-Methyl-1-(3,4-methylenedioxyphenyl)-methylenedioxyphenyl)-2aminobutane (MDMA)2aminobutane (MDMA)

Severe immediate effects:◦ Altered mental status◦ Convulsions,◦ Hypo-hyperthermia,◦ Severe changes in blood pressure◦ Tachycardia◦ Coagulopathy◦ Acute renal failure◦ Hepatotoxicity◦ Rhabdomyolysis◦ Death


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)


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 Substance AbuseAbuseSummary:

◦Genetics Genes that influence initiation of

drug use.

Transition from initiation to repeated use, abuse, or dependence are largely NONGENETIC factors.


◦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.


◦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 youThank you

Marcelino V. Ostrea Jr.,M.D.

Stimulants: Stimulants: Methamphetamine & Methamphetamine & CocaineCocaineRepeated, 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: Stimulants: Methamphetamine & Methamphetamine & CocaineCocaineAddiction – 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: Stimulants: Methamphetamine & Methamphetamine & CocaineCocaineNeurochemical Basis of Addiction:

◦Functional imaging studies show that cocaine-related cues are associated with increased activity of the:1. Basolateral amygdala2. Cingulate cortex3. Orbitofrontal cortex

◦Sensory cues mediates association between environmental stimuli & drug effectsLondon et al.1999

Stimulants: Stimulants: Methamphetamine & Methamphetamine & CocaineCocaineNeurochemical 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: Stimulants: Methamphetamine & Methamphetamine & CocaineCocaineTolerance – 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: Stimulants: Methamphetamine & Methamphetamine & CocaineCocaineDependence – 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: Stimulants: Methamphetamine & Methamphetamine & CocaineCocaineNeurochemical 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: Stimulants: Methamphetamine & Methamphetamine & CocaineCocaine

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: Stimulants: Methamphetamine & Methamphetamine & CocaineCocaine 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: Stimulants: Methamphetamine & Methamphetamine & CocaineCocaineConclusion:

◦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.

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SUBSTANCE-RELATED DISORDERS Marcelino V. Ostrea Jr.,M.D