Substance-Related Disorders

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Substance-Related Disorders

• Brian Ladds, M.D.

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Outline

• A neuro-biological perspective
• Definitions
• Specific substances

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Substance Abuse

• Why do people use psychoactive substances?
• Why do they persist?

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Pleasure Reward Circuit

• Stimulation of this pathway leads to feelings of
  pleasure
• Dopamine produces these feelings

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Meso-Accumbens Pathway

• From mid-brain to limbic system and back
• Meso-Accumbens pathway
• From the VTA to the Nucleus Accumbens
• From Nucleus Accumbens back to VTA

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Inputs to the Pleasure/Reward Circuit

• Inputs to VTA and/or Nucleus Accumbens
• from other parts of brain
• using a variety of neurotransmitters
• Glutamate
• GABA
• Opioid peptide neurotransmitter
• Other inputs

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Hijacking the Pleasure Reward Circuit

• This circuit is hijacked by all substances of
  abuse
• All are extremely potent at stimulating this
  circuit
• Pleasure from ordinary activities come to have
  diminished power in this circuit

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Actions of Substances of Abuse

• All substances of abuse increase dopamine effects
  in this circuit
• They do so by acting at
• the VTA, and/or
• the Nucleus Accumbens
• They act to
• increase dopamine release, and/or
• block re-uptake

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Neuro-adaptations

• Upon repeated use, the brain tries to counter-act
  the effects of these substances
• Such neuro-adaptations involve changes in
  structure and function

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Neuro-adaptations

• Neuro-adaptations, esp. in the brain stem, may
  lead to
• Diminished effects of a given substance
  (tolerance)
• Effects upon its discontinuation (withdrawal)

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Relapse

• What triggers a return to use a drug after
  prolonged abstinence?

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Definitions

• Additional definitions and concepts
• DSM-IV classification and criteria

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Behaviors

• Tolerance
• Withdrawal
• Sensitization
• Craving
• Dependence
• Abuse

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Tolerance

• Tolerance develops at different rates for
  different actions of a drug
• Euphoria caused by cocaine diminishes faster than
  its cardiostimulant effects

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Withdrawal

• The signs and symptoms that occur when a drug is
  stopped or dose lowered
• Both physiological and psychological processes
  contribute

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Withdrawal

• Can cause secondary problems
• Depression and anxiety from cocaine
• Excito-toxic brain damage from alcohol

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Sensitization

• An increase in an effect of a drug upon its
  repeated administration
• Tends to be seen with the stimulating actions of
  a drug

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Sensitization Examples

• Cocaine use
• Psychotimimetic effects of cocaine
• Alcohol withdrawal
• Excitatory changes in withdrawal
• alcohol withdrawal progressively worsens

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DSM-IV Definitions

• Substance-Related Disorders
• Substance Use Disorders
• Substance Dependence
• Substance Abuse
• Substance-Induced Disorders

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Substance-Induced Disorders

• Intoxication
• Withdrawal
• Other
• Delirium
• Persisting Dementia
• Persisting Amnestic Disorder
• Psychotic Disorder
• Mood Disorder
• Anxiety Disorder
• Sexual Dysfunction
• Sleep Disorder

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Criteria for Substance Dependence

• A maladaptive pattern of substance use,
• leading to clinically significant impairment or
  distress,
• as manifested by at least 3 of the following 7
  criteria,
• occurring at any time in the same 12-month period

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Criteria for Substance Dependence

• 1. Tolerance
• 2. Withdrawal
• 3. The substance is often taken in larger amounts
  or over longer periods than was intended

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Criteria for Substance Dependence

• 4. There is a persistent desire or unsuccessful
  efforts to cut down or control substance use
• 5. A great deal of time is spent in activities
  necessary to obtain the substance, use the
  substance, or recover from its effects

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Criteria for Substance Dependence

• 6. Important social, occupational or recreational
  activities are given up or reduced because of
  substance use
• 7. 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

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Dependence Sub-types

• Specify subtype
• With physiological dependence
• Evidence of tolerance or withdrawal
• Without physiological dependence
• No evidence of tolerance or withdrawal

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Criteria for Substance Abuse

• A maladaptive pattern of substance use,
• leading to clinically significant impairment or
  distress,
• as manifested by at least 1 of the following
  criteria,
• occurring within a 12-month period

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Criteria for Substance Abuse

• 1. Recurrent substance use resulting in failure
  to fulfill major role obligations at work,
  school, or home
• 2. Recurrent substance use in situations in which
  it is physically hazardous
• 3. Recurrent substance-related legal problems

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Criteria for Substance Abuse

• 4. Continued substance use despite having
  persistent or recurrent social or interpersonal
  problems caused or exacerbated by the effects of
  the substance
• B. The symptoms have never met the criteria for
  Substance Dependence for this class of substance.

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Specific Substances
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Prevalence
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Pharmacokinetic Factors

• Important in determining the misuse potential of
  a drug
• Oral vs. nasal vs. smoked vs. IV
• Cocoa leaves vs. powder cocaine vs. lipophilic
  free-base cocaine (crack)

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Alcohol-related disorders

• Alcohol abuse is several times more common in men
• Significant increased risk for accidents,
  suicide, and violence

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Prevalence

• Lifetime prevalence of alcohol abuse or
  dependence is approximately 8

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Etiology

• Genetics
• 60 monozygotic twins
• 25 of children of alcoholic parent
• risk increases with
• number of alcoholic relatives,
• severity of their illness, and
• closeness of genetic relationship

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Etiology

• Psychological Theories
• Socio-cultural Theories

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12 grams Ethyl Alcohol

• 12 oz beer
• 4 oz glass wine
• 1.5 oz liquor (80 proof)

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Blood Alcohol Level (BAL)

• 0.08 Legal intoxication
• 0.40 Lethal dose, 50 of population (LD50)

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Mechanism of Action of Alcohol

• Alters the fluidity and organization of cell
  membranes throughout the brain
• Alters the function of proteins that transverse
  cell membranes, such as neurotransmitter
  receptors and ion channels
• Binds to GABA-A receptor
• Acts like a glutamate (NMDA) receptor antagonist

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Alcohol effects on the CNS

• Blackout
• Peripheral Neuropathy
• Cerebellar Degeneration
• Sleep impairment
• Sexual dysfunction
• Mood, Anxiety Psychotic Disorders

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Alcohol effects on the CNS

• Wernicke-Korsakoffs syndrome
• Severe deficiency of thiamine
• Ataxia
• Amnesia
• 6th Nerve palsy (opthalmoplegia)

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Alcohol Effects on the Body

• Vitamin malabsorption
• Severe inflammation esophagus stomach
• Pancreatitis
• Bone marrow suppression
• Cancer esophagus, stomach, head, neck
• Hypertension and alcoholic cardiomyopathy
• Fatty liver, alcoholic hepatitis, cirrhosis

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Alcohol Intoxication

• Clinically significant maladaptive behavioral or
  psychological changes
• One (or more) of the following signs
• slurred speech
• incoordination
• unsteady gait
• nystagmus
• impairment in attention or memory
• stupor or coma

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Alcohol Withdrawal

• At least 2 of these, within a few days of
  cessation of (or reduction in) use
• Autonomic hyperactivity (Early)
• Hand tremor (Early)
• Insomnia (Early)
• Nausea and vomiting (Early)
• Psychomotor agitation (Early)
• (Early) within 6-8 hours of last drink

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Alcohol Withdrawal, cont.

• Hallucinations
• transient visual, tactile, or auditory
• Grand Mal Seizures
• (Later) 24-72 hours
• Delirium Tremens
• Treatment

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Opioids

• Opium juice of opium poppy, Papaver Somniferum
• Natural (or synthesized from naturally occurring
  opiates) morphine, heroin (diacetyl-morphine),
  codeine (3-methoxy-morphine), hydromorphone
  (Dilaudid), oxycodone
• Synthetic meperidine (Demerol), methadone
  (Dolophine), pentazocine (Talwin), proproxyphene
  (Darvon)

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Opioids

• Endogenous opioids
• enkephalins, endorphins
• Mixed agonist/antagonists
• buprenorphine (Buprenex)
• Antagonists
• naloxone (Narcan), naltrexone (ReVia)

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Opioids

• Prevalence
• Less than 1 with current dependence or abuse

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Opioids Mechanism of Action

• Binding to Mu opioid receptors influences mood
  reinforcing effects
• Stimulate the release of dopamine in the Nucleus
  Accumbens

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Positive Effects of Opioids

• Tranquility
• Euphoria
• Decreased apprehension

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OpioidsSome Possible Symptoms

• Apathy and dysphoria
• Analgesia
• Decrease respiration
• Decrease cough reflex
• Constipation

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Effects of IV opioids on the body

• Thrombosed veins
• Abcesses
• Hepatitis
• Endocarditis
• HIV and AIDS

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Opioid Intoxication

• Constriction of pupils (except with anoxia from
  severe overdose) and one (or more)
• 1. Drowsiness or coma
• 2. Slurred speech
• 3. Impairment in attention or memory

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Clinical Presentation of Opioid Overdose

• Pinpoint pupils
• Decreased respiration Pulmonary edema
• Blue lips, pale skin
• Cardiac arrhythmias
• Seizures

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Opioid Withdrawal

• 3 (or more)
• 1. Dysphoric mood
• 2. Nausea or vomiting
• 3. Muscle aches
• 4. Lacrimation or rhinorrhea
• 5. Pupillary dilation, piloerection or sweating
• 6. Diarrhea
• 7. Yawning
• 8. Fever
• 9. Insomnia

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Opioids

• Treatment

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Cocaine

• Alkaloid of Erythroxylon coca
• One of the most powerful and reinforcing CNS
  stimulants
• Tends to be used in heavy binges vs. daily

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Cocaine

• Prevalence
• Less than 1 lifetime dependence
• Over a million people in U.S.

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Mechanism of ActionCocaine Amphetamines

• Cocaine binds to the dopamine transporter
  re-uptake protein pump, blocking dopamine
  re-uptake
• Amphetamines can also block this transporter, but
  they principally stimulate the release of dopamine

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Positive Effects of Cocaine

• Increased self-confidence
• Sense of alertness
• Sense of well being
• Increased energy
• Heightened sense of pleasure

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Signs of Cocaine Intoxication

• 2 or more of these
• Tachycardia or bradycardia
• Increased or decreased blood pressure
• Pupillary dilation
• Perspiration or chills
• Nausea or vomiting
• Weight loss
• Psychomotor agitation or retardation
• Muscles weakness, respiratory depression, chest
  pain, or arrhythmias
• Confusion, seizures, dyskinesia, dystonia, coma

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Cocaine effects on the CNS

• Headache
• Anxiety
• Psychosis
• Sexual dysfunction

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Cocaine effects on the body

• Rhabdomyolysis
• Hyperthermia
• Myocardial ischemia
• Cerebral hemorrhage
• Sudden death

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Cocaine Withdrawal

• Dysphoric mood (and 2 or more)
• 1. Fatigue
• 2. Vivid, unpleasant dreams
• 3. Insomnia or hypersomnia
• 4. Increased appetite
• 5. Psychomotor agitation or retardation
• Treatment

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Other Substances

• Amphetamines
• Hallucinogens
• PCP
• Cannabis
• Inhalants
• Nicotine

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Amphetamines

• Dextroamphetamine (Dexedrine)
• Methylphenidate (Ritalin)
• Dextroamphetamine Amphetamine (Adderall)
• Methamphetamine (Desoxyn)
• Designer amphetamines
• 3,4 methylene dioxymethamphetamine (Ecstacy)

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Hallucinogens

• Natural
• psilocybin (mushrooms)
• mescaline (peyote)
• Synthetic
• Lysergic acid diethylamide (LSD)

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Hallucinogens

• Psychosis (bad trip)
• Persisting perception disorder (flashbacks)
• Sympathomimetic effects

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Phencyclidine

• 1-(1-phenylcyclohexy-1) piperidine (PCP)
• PCP and Ketamine
• NMDA antagonists
• Dopamine activators
• Intoxication

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Cannabis

• Hemp plant Cannabis Sativa
• 9-tetra-hydro-cannabinol (THC)
• Most commonly used illicit substance

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Cannabis

• Receptors widely dispersed
• Immediate effects
• Long term effects

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Inhalants

• Solvents, glue, adhesives, aerosols, and paint
  thinners, fuels
• CNS depressants
• Dementia
• Neurotoxicity
• Medical Effects