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DRUGS OF ABUSE Part I

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Title: DRUGS OF ABUSE Part I


1
DRUGS OF ABUSEPart I
  • Martha I. Dávila-García, Ph.D.
  • Howard University
  • Department of Pharmacology

2
Definitions
  • I. Drug abuse.
  • II. Drug dependence.
  • A) Psychological dependence.
  • B) Physiological dependence.
  • III. Drug addiction.
  • IV. Drug tolerance.

3
I. Drug abuse
  • Inappropriate and usually excessive,
    self-administration of a drug for non-medical
    purposes.
  • Almost all abused drugs exert their effects in
    the CNS.
  • Drugs with high abuse potential have a tendency
    to induce compulsive drug-seeking behavior.
  • Preoccupation with the procurement and use of the
    drug may be so demanding as to decrease the users
    productivity.
  • In addition, prolonged abuse may cause chronic
    toxicity.

4
II. Drug dependence
  • Repetitive use of substances that produce an
    optimal state of well being because of their
    positive reinforcing effects in the CNS.
  • A) Psychological dependence.
  • B) Physical dependence.

5
II. Drug dependence
  • A) Psychological Dependence
  • Motivational component great subjective need,
    compulsion, drive to get the drug.
  • Will take drug periodically.
  • Although physical dependence for a drug may not
    occur, drug-seeking behavior is present.
  • Habituation Just "like" the drug Drug effects
    serve as positive reinforcers.
  • No tolerance increase.

6
II. Drug dependence
  • B) Physiological Dependence
  • The body needs the drug for normal physiological
    function.
  • Tend to increase dose because of tolerance.
  • Physical withdrawal symptoms (negative
    reinforcement).
  • Predictable group of signs and symptoms resulting
    from abrupt removal of a drug.
  • Psychological dependence is also present.

7
III. Drug addiction
  • The drug-use and drug-seeking behavior of
    dependent individuals is maintained by the
    reinforcing central activity of the drug despite
    its negative social, psychological and physical
    consequences.
  • Physiological effects, including negative
    reinforcers such as symptoms of withdrawal may
    also be involved.
  • High tendency to relapse.

8
IV. Drug tolerance
  • After chronic use, the same amount of drug is
    insufficient to cause the desired effect and
    thus, more drug is used.
  • A compensatory response.

Normal
Tolerance
EFFECT
Drug Dose
9
IV. Drug tolerance
  • A) Innate Tolerance
  • 1. Sensitivity
  • 2. Insensitivity
  • B) Acquired Tolerance
  • 1. Pharmacokinetic or metabolic
  • 2. Pharmacodynamic or functional
  • 3. Learned or behavioral

10
V. Cross-dependence
  • When a drug is administered to achieve the same
    outcome as that of another drug.
  • i.e. heroin Û methadone.
  • In a heroin user, methadone can be substituted
    for heroin in preventing the withdrawal syndrome.

11
VI. Cross-tolerance
  • When an individual has become tolerant to a drug
    and requires higher than normal doses of a second
    drug to have its effects.
  • i.e. Barbiturates Û BDZ.
  • Amphetamine Û cocaine.
  • BARBs or BDZs Û Anesthetics.

12
VI. Cross-tolerance
  • In general there is cross-dependence and
    cross-tolerance between drugs of the same class,
    but not between drugs in different classes.
  • Exceptions
  • There is some cross-tolerance between
    sedative-hypnotics and volatile intoxicants thus
    a person tolerant to barbiturates will require
    more anesthesia than a non-tolerant person.
  • LSD type drugs (tryptamine group) and
    phenylethylamines have cross-tolerance for each
    other but not with other hallucinogens.

13
VII. Co-administration/Co-abuse
  • Many of these drugs are used in combination with
    other drugs from one or more categories.
  • Alcohol is used, for example, with almost
    everything else.
  • Smoking (nicotine intake) is prevalent in
    patients using other drugs.
  • Be aware of the possibility of combination of
    drugs when treating intoxication, withdrawal or
    overdose, each drug will require a specific
    treatment.

14
Because of the diverse character of these drugs,
there is no single reason for their use, nor is
there an addictive personality".
  • IT IS NOT NECESSARY TO HAVE A PREEXISTING
    EMOTIONAL OR PSYCHIATRIC PROBLEM TO BECOME DRUG
    DEPENDENT!!!

15
VIII. Toxicology
  • A) Tissue and organ toxicity
  • - Usual dose vs overdose.
  • - Acute use (respiratory depression - narcotics,
    coma-barbiturates cardiovascular effects and
    seizures-cocainearrhythmias-volatile
    intoxicants).
  • - Chronic use (alcohol, tobacco).

16
VIII. Toxicology
  • B) Psychic toxicity
  • - Acute use (bad trips, flashbacks -
    hallucinogens CNS stimulants).
  • - Chronic use (alcohol, hallucinogens, stimulants
    reality distortion).

17
VIII. Toxicology
  • C) Behavioral toxicity
  • - Amotivational syndrome, loss of productivity
    loss of psychomotor control, accidents,
    violence.
  • - Acute use (alcohol, stimulants, PCP).
  • - Chronic use (alcohol, CNS depressants,
    stimulants, hallucinogens, PCP).

18
VIII. Toxicology
  • D) Associated Diseases
  • - Infections, AIDS, venereal diseases,
    tobacco-related fires, toxicity due to bad
    batches of drug (MPTP, PCP congeners), car
    accidents, big machinery accidents, other
    accidents, violent death.

19
I. Animal Studies
  • A) Drug-self administration
  • Drugs as reinforcers in animals.
  • High correlation with
  • human dependence
  • liability.

20
Morphine/Heroin
  • Self-Administration

21
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II. Brain Reward System
  • Changes in brain function Reward Craving
  • Involve the Dopaminergic System
  • Mesolimbic pathwayVentral tegmental area (VTA),
    medial forebrain bundle, nucleus accumbens and
    the prefrontal cortex.
  • Nigrostriatal pathway Sustantia nigra,
    striatum.
  • Mesocortical pathway VTA, cingulate and frontal
    CTX.
  • Tubero-Infundibular Arcuate N. in hypothalamus.

24
THE DOPAMINERGIC SYSTEM
25
THE MESOLIMBIC DOPAMINERGIC REWARD PATHWAY
26
Tyrosine
Dopamine Synapse
Tyrosine
L-DOPA
DA
27
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Dopamine Reuptake System
29
OPIOIDS or NARCOTICS
  • Morphine, Codeine, Meperidine, Methadone
  • I. Morphine, Heroin, Hydromorphone,Oxymorphone.
  • A. Pharmacology
  • - Heroin is very lipid soluble.
  • - Short half-life (t½ 3 min).
  • - Heroin 6-mono-acetyl morphine morphine

30
OPIOIDS
  • Desirable Effects Euphoria, sedation (wakeful,
    dreamy state "being on the nod"), relief of
    anxiety and various other forms of distress,
    analgesia.
  • Depression of cough reflex.
  • Subjective CNS effects Drowsiness, difficulty
    concentrating, apathy, decreased physical
    activity, lethargy, extremities feel heavy and
    the body feels warm.
  • Undesirable Effects Dysphoria, dizziness,
    nausea, vomiting, constipation, biliary tract
    spasm, urinary retention.
  • Therapeutic uses not related to analgesia

31
OPIOIDS
  • 1). Psychological dependence
  • I.V. use preferred by most users rush or
    high
  • Oral abuse meperidine.
  • Emotional or motivational symptoms, craving.
  • Iatrogenic addiction.
  • 2). Physical dependence
  • May develop on repeated use of therapeutic
    doses.
  • Narcotic Abstinence Syndrome (Withdrawal).

32
OPIOIDS
  • Withdrawal, onset related to time-effect curve
    and t½ of narcotic.
  • 6-8hr drug seeking behavior, restless,
    anxious.
  • 8-12hr Pupils dilated, reactive to light
    increased pulse rate, blood pressure, yawning
    chills rhinorrhea lacrimation gooseflesh
    sweating restless sleep.
  • 48-72 hrs (peak) All of the above plus
    muscular weakness, aches (cramps) and twitches
    nausea, vomiting and diarrhea temperature and
    respiration rate elevated heart rate and blood
    pressure elevated dehydration.
  • Not life threatening, no convulsions, no
    delirium, no disorientation.

33
OPIOIDS
  • B. Concurrent or Substitute use
  • Alcohol, sedatives or amphetamines
  • C. Tolerance
  • Yes, develops to almost effects except
    constipation and pupillary effects.
  • Cross-tolerance and cross-dependence with other
    narcotics (Implication in narcotic addict need
    to increase dose to experience euphoria).
  • High level of tolerance is possible huge amounts
    of drug can be tolerated after chronic use
    potential for overdose if relapse occurs and
    addict resumes with same high level of drug.
  • Implications for chronic administration for pain.

34
OPIOIDS
  • D. Toxicology
  • 1.Tissue and organ toxicity
  • - Heroin lung with acute overdose.
  • - No apparent tissue damage.
  • 2. Psychic toxicity
  • - Acute and chronic drive reduction.
  • 3. Behavioral toxicity
  • - Criminal behavior to obtain drugs.
  • 4. Associated diseases/Death
  • - Unsterile syringes AIDS, hepatitis, SBE,
    malaria, tetanus, localized infections, pulmonary
    infiltration of contaminants. Neuropathies.
    Violent deaths.
  • E. Intoxication/Overdose
  • 1. Disruption of central control of peripheral
    sympathetic activity.
  • - respiratory depression brainstem DEATH
  • - circulatory depression BP
  • - pupils constricted
  • - pulmonary edema
  • 2. CNS depression
  • - drowsiness sedation coma

35
OPIOIDS
  • E. Acute Intoxication/Overdose
  • 1. Disruption of central control of peripheral
    sympathetic activity.
  • - Respiratory depression apnea DEATH
  • - Circulatory depression BP
  • - Pupils constricted
  • - Convulsions with propoxyphene and meperidine.
  • - Arrythmias with propoxyphene.
  • - Pulmonary edema
  • - ? Reflexes
  • 2. CNS depression
  • Euphoria/dysphoria drowsiness sedation
    coma

36
OPIOIDS
  • F. Treatment
  • Narcotic dependence is one of very few cases
    where there are partially effective
    pharmacological therapies.
  • 1. Opioid replacement
  • a. Methadone, Dolophin
  • Long half-life produces a longer but less
    stressful withdrawal (although more prolonged).
  • Onset 24hrs, peak 5-7 days.
  • Lessens the highs and lows of withdrawal.
  • Oral administration.

37
OPIOIDS
Severity of Withdrawal
TIME
38
OPIOIDS
  • b. Clonidine, an agonist at a2 adrenergic
    receptors.
  • Used to block autonomic signs and symptoms of
    withdrawal
  • cramps
  • nausea
  • vomiting
  • tachycardia
  • sweating
  • hypertension

ANS EFFECTS
Clonidine
39
OPIOIDS
  • c. Opiate Antagonists, cause precipitated
    abstinence.
  • Long term maintenance of abstinence
    Naltrexone
  • Longer half-life, oral, 3 times a week.
  • Also used to control and reverse effects of
    therapeutically administered narcotics
    (anesthesia and labor).
  • d. LAAM (L-a-acetyl methadol, methadyl acetate).
  • Structurally similar to methadone. Longer-acting
    opiate. Taken orally in liquid form, lasts 72hrs
    (visits 3 X a week). "take home" medication.

40
OPIOIDS
  • e. Buprenorphine
  • Partial agonists which substitutes for low doses
    of opioids but antagonizes high doses.
  • Can be administered sublingually every 24-48
    hours as an alternative to methadone.
  • Major problem in detoxification and maintenance
    of abstinence is the motivational component of
    the CNS effect, which is responsible for the
    drug craving sensations, also conditional
    dependence and social factors play an important
    role.

41
OPIOIDS
  • II. Codeine
  • Codeine (Methylmorphine) Dihydrocodeine
    Hydrocodone (Dicodid, Hycodan) Oxycodone
    (Percodan).
  • A. Pharmacology
  • administered parentally.
  • "Weak" opioids.
  • Used as a cough suppressants (antitussive) and
    combined with aspirin and acetaminophen as
    painkillers.
  • Dependence liability

42
OPIOIDS
  • III.Meperidine
  • Meperidine (Demorol) Alphaprodine, (Nisentil)
    Fentanyl.
  • A. Pharmacology
  • - Less potent than morphine IM. More rapid
    onset, shorter duration. Similar to heroin.
  • - Used in anesthesiology.
  • - Dependence liability - Same as Morphine

43
OPIOIDS
  • B. Concurrent or substitute use - Yes. Other
    narcotics
  • C. Tolerance Same as Morphine, Cross-tolerance
    with other narcotics
  • D. Acute intoxication/Overdose Similar to other
    narcotics
  • E. Withdrawal Same as Morphine
  • F. Treatment None
  • G. Mechanism of action m opioid receptors

44
OPIOIDS
  • IV. DESIGNER OPIOIDS
  • Heroin-like drug MPPP contained MPTP impurities
    that caused Parkinson's like-symptoms in the
    young adults who used it by destroying DA
    neurons.
  • China White alpha-methyl fentanyl deaths by
    overdose.
  • 6000 times more potent than morphine.

45
OPIOIDS
  • G. Mechanism of action.
  • 1. Anatomy of m opioid receptors nucleus
    accumbens (N. Acc.), ventral tegmental area
    (VTA), caudate, thalamus, cortex, spinal cord.
  • 2. Actions in thalamus
  • 3. Actions in spinal cord Analgesia
  • 4. Actions at Mesolimbic dopaminergic system
    Reward.
  • a. Inhibit the release of GABA at the VTA
  • Desinhibition of DA DA activity

46
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OPIOIDS
48
OPIOIDS
49
CNS DEPRESSANTS
  • I. Alcohol
  • II. Sedative/hypnotics, Anxiolytics
  • All are very addictive and cause withdrawal
    symptoms (mild anxiety, convulsions, seizures).
  • All of these drugs create "lethal potentiation"
    when combined.
  • Anxiolytics

50
Alcohol
  • A. Pharmacology
  • Ethyl alcohol is created after the fermentation
    of the sugar of grains (beer) and fruit juices
    (wine). If distilled, they produce hard liquors
    (Whiskey, Brandy). In between are the fortified
    wines such as port, cherry and muscatel.
  • Intake of alcohol begins during adolescence.
    Ninety percent of high school seniors have tried
    alcohol during their life times and 30 report
    daily use. Chronic abuse occurs much later.
  • Alcohol is readily dissolved in water and lipids
    and thus distributes very evenly throughout the
    body. It crosses the blood-brain-barrier as well
    as the placenta without difficulty.

51
Alcohol
  • 1. Psychological Dependence
  • Drug seeking behavior.
  • 2. Physical Dependence
  • - Hangovers are mini-withdrawals, probably due
    to a rebound of the depressed CNS.
  • Cure for a hangover ? more alcohol
  • ETOH is converted to acetaldehyde, which causes
    all the negative symptoms of hangovers, including
    dehydration, and headaches.

52
Alcohol
  • Withdrawal Syndrome Delirium Tremens
  • Insomnia, tremulousness, REM rebound, reflexes
    are high, weakness, anorexia, orthostatic
    hypotension, sweating, agitation delirium, vivid
    auditory and visual hallucinations convulsions
    and seizures (probably caused by NMDA receptor
    number and hyperexcitability), may generate
    status epilepticus disorientation, paranoid
    delusions, hyperthermia dehydration,
    cardiovascular collapse, risk of death.

53
Alcohol
  • B. Concurrent or substitute use
  • With most other drugs.
  • Tranquilizers potentiate the effects of alcohol.
  • Complications for treatment when there is
    concomitant narcotic addiction.

54
Alcohol
  • D. Toxicology
  • 1. Tissue and organ toxicity
  • Hangovers low blood sugar, dehydration.
  • Acute use irritation of digestive system
  • Chronic use cirrhosis of the liver, alcoholic
    hepatitis, cerebellar syndrome, alcoholic
    dementia, cancer of the mouth, throat and liver,
    vitamin deficiencies. In the fetus, it is a
    teratogen

55
Alcohol
  • Fetal Alcohol Syndrome
  • Children exposed to alcohol in utero may exhibit
    a wide range of developmental disabilities and
    cognitive and behavioral deficits that reflect
    damage to the developing neurons. These effects
    may include mental retardation, attention
    deficit disorders, perceptual problems, memory
    and learning disabilities, and psychomotor
    dysfunction. Fetal Alcohol Syndrome (FAS), which
    is characterized by central nervous system
    impairments, growth retardation and
    characteristic facial dysmorphology is the most
    severe, manifestation of alcohol neuratogenesis.
  • from NIAAA, Alcohol Alert, No. 13 1991

56
Alcohol
  • 2. Psychic toxicity
  • - Korsakoffs Psychosis
  • - Alcoholic dementia
  • - Cerebellar syndrome
  • - Epilepsy
  • - As with other CNS Depressants
  • Sluggishness, difficulty in thought, slowness of
    speech, poor comprehension, deterioration of
    memory and judgement, poor attention span.

57
Alcohol
  • 3. Behavioral toxicity
  • More than half of all homicides are caused by
    alcohol.
  • Overall the actions of alcohol in the CNS are
    very similar to those of other CNS depressants
  • Desinhibition, aggression, loss of psychomotor
    control.
  • Emotional liability, irritability, exaggeration
    of basic personality traits, hostile and paranoid
    ideas.
  • Breakdown of ability to function, loss of
    decorum, quarrelsomeness, deterioration of work
    and family life, poor coordination and lapses of
    judgement favoring accidents, suicidal tendencies.

58
Alcohol
  • 4. Associated diseases
  • - Chronic malnutrition
  • E. Acute Intoxication
  • - Slowed and slurred speech, ataxia, nystagmus,
    drowsiness coma, confusion reflexes are low,
    respiratory depression or apnea, low blood
    pressure death.

59
Alcohol
  • F. Treatment
  • Disulfiram (antabuse) and CCC (citrate calcium
    carbamate) are acetaldehyde dehydrogenase
    blockers.
  • Drinking alcohol with these drugs produces
    increased conc. of acetaldehyde and this make
    person sick. Sometimes tranquilizers and
    antidepressants are given to relieve the anxiety.
    DETOX is best in a hospital setting. AAA to
    prevent relapse.

60
Alcohol
  • ETHANOL (CH3CH2OH)
  • Alcohol dehydrogenase
  • ACETALDEHYDE (CH3CHO)
  • Aldehyde dehydrogenase ½ Disulfiram
  • ACETYL COENZYME A
  • ø
  • energy citric acid cycle
  • ø
  • carbon dioxide water

61
Alcohol
  • G. Mechanism of Action
  • 1. Affects several ion channels
  • a. NMDA receptor allosteric inhibitor.
    Physical dependence/withdrawal. Reinforcement.
    Behavioral desinhibition.
  • b. GABAA receptor allosteric facilitator.
    Tolerance.
  • c. 5-HT3 receptor sedative, antianxiety
    effects
  • d. L-type calcium channel allosteric
    modulator

62
Alcohol
  • 2. CNS Control
  • a. Alcohol effects in the cerebellum disturb
    equilibrium and posture.
  • b. Alcohol effects in hippocampus disturb
    memory formation and retrieval.
  • c. Alcohol in brainstem and medulla disturb
    respiratory centers.

63
CNS DEPRESSANTS

Alcohol
64
Sedative/Hypnotics
  • I. Barbiturates
  • II. Benzodiazepines
  • III. Methaqualone

65
Sedative/Hypnotics
  • Can be procured readily from illicit sources.
  • Patients experience rebound insomnia or anxiety.

  • Gross binges of intoxication that last several
    days. Others ingest large quantities on a daily
    basis and remain chronically intoxicated
  • Physiological consequences resemble those of
    alcohol intoxication.
  • The person may feel a remarkable capability for
    coping with stress and anxiety, a general feeling
    of well being, may feel euphoric and stimulated.
    These latter effects (euphoria and stimulation)
    may be due to inhibition of inhibitory pathways.

66
Sedative Hypnotics
  • I). Barbiturates
  • Used clinically as anticonvulsant, anti-anxiety
    drugs.
  • phenobarbital (purple hearts)
  • pentobarbital (yellow jackets)
  • secobarbital (red devils)
  • amobarbital (blue angels)

67
Sedative Hypnotics
  • II.) Benzodiazepines
  • flurazepam Sleeping pills.
  • flunitrazepam date rape drug.
  • Diazepam (Valium) Tranquilizer.
  • Chlordiazepoxide (Librium) Tranquilizer.
  • Clonazepam anticonvulsant.
  • They all cause sedation and muscle relaxation.
  • Abuse may cause "BDZ-induced aggression".
  • III.) Methaqualone (Quaalude) "Downer", works
    as Valium, seriously abused, very addictive.

68
Sedative Hypnotics
  • .

69
Sedative Hypnotics
  • Readily absorbed when taken orally or after
    parenteral administration.
  • BARBs are more abused than BDZ.
  • BARBs are favorite drugs used for suicide.
  • Tolerance is slow and only partial.
  • Lethal dose is quickly achieved if overdose
    w/BARBs.
  • They are teratogenic if used during pregnancy
    (malformations of the limbs, facial features,
    CNS, heart, skeleton).

70
Sedative Hypnotics
  • 1. Psychological Dependence
  • Preference for short acting vs long acting and
    for those with steep dose-response curves.
  • 2. Physical Dependence
  • 200 mg/day no effect.
  • 400 mg /day, occasional EEG evidence of
    withdrawal, rebound insomnia.
  • 600 mg/day, minor withdrawal.
  • 80mg/day and higher, most patients have delirium
    and seizures.

71
Sedative Hypnotics
  • Withdrawal
  • Minor tremors insomnia (REM rebound) high
    fever clonic blink.
  • 12-16hrs minor symptoms plus abdominal cramps
    nausea and vomiting, o. hypotension Ý deep
    tendon reflexes.
  • 24hrs pronounced weakness, course tremors (the
    shakes), hyperactive reflexes, early illusions
    and hallucinations.
  • 48-72hrs convulsive seizures (rum fits) vivid
    auditory and visual hallucinations (the
    horrors), formication, agitation,
    disorientation, delirium, paranoid delusions.

72
Sedative/ Hypnotics
  • Withdrawal (cont)
  • Hypothermia, dehydration,
  • electrolyte imbalance, exhaustion,
    cardiovascular collapse. Threat to life.
  • Time of onset and symptoms experienced varies
    with CNS depressant use, similar to alcohol
    withdrawal.
  • Additive effect of sedative/hypnotics.
  • Stabilization diazepam, chlordiazepoxide,
    phenobarbital (cross-dependence).
  • Drug tapered off slowly prevention of onset
    (reversible only early in course).
  • Relatively very large doses are needed.

73
Sedative Hypnotics
  • B. Concurrent or substitute use
  • - May be lethal with other depressants.
  • - Alcohol, amphetamines, cocaine. Not likely to
    abuse narcotics, but not vice-versa.
  • C. Tolerance
  • - Both drug disposition and pharmacodynamic
    tolerance exists to most CNS depressants
  • - Tolerance of modest degree - lethal dose not
    greatly increased.
  • - Cross-tolerance with alcohol, anesthetics and
    volatile intoxicants.

74
Sedative Hypnotics
  • E. Acute Intoxication
  • - Pupils are normal BP and respiration are
    depressed nystagmus on lateral gaze tendon
    reflexes depressed ataxia slurred speech
    confusion coma shock. Death
  • F. Treatment
  • Treatment of overdose w/BDZs flumazenil (BDZ
    receptor blocker)

75
Sedative/Hypnotics
  • G. Mechanism of Action
  • Major site of action is at GABAergic synapses.
  • Inhibitory Synapse.
  • GABA-A receptors Cl- Channels.
  • Hyperpolarization.

BARBs
BDZs
GABA AGONISTS
?
?
?
?
?
76
Sedative Hypnotics
  • The GABA receptor is a pentameric structure that
    forms a Cl- channel.
  • The receptor complex includes distinct binding
    sites for benzodiazepines, barbiturates and
    GABA-like substances.
  • GABA transmission exerts an inhibitory effect on
    norepinephrine (NE), dopamine (DA), serotonin
    (5-HT), and acetylcholine (ACh) pathways.
  • Barbiturates
  • Prolong the opening of the channel associated
    with GABA
  • binding, increase conductance.
  • Benzodiazepines
  • Facilitates the activity of GABA to open the
    channel.

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WEB SITES
  • http//165.112.78.61/DrugAbuse.html
  • http//165.112.78.61/Researchers.html
  • http//165.112.78.61/OtherResources.html
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