substance-related disorders

Substance-Related Disorders

Brian Ladds, M.D.

Outline

• A neuro-biological perspective

• Definitions

• Specific substances

Substance Abuse

Why do people use psychoactive substances?

Why do they persist?

Pleasure & Reward Circuit

• Stimulation of this pathway leads to feelings of pleasure

– Dopamine produces these feelings

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

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

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

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

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

Neuro-adaptations

• Neuro-adaptations, esp. in the brain stem, may lead to:

• Diminished effects of a given substance (‘tolerance’)

• Effects upon its discontinuation (‘withdrawal’)

Relapse

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

Definitions

• Additional definitions and concepts

• DSM-IV classification and criteria

Behaviors

• Tolerance

• Withdrawal

• Sensitization

• Craving

• Dependence

• Abuse

Tolerance

• Tolerance develops at different rates for different actions of a drug

– Euphoria caused by cocaine diminishes faster than its cardiostimulant effects

Withdrawal

• The signs and symptoms that occur when a drug is stopped or dose lowered

• Both physiological and psychological processes contribute

Withdrawal

• Can cause secondary problems

– Depression and anxiety from cocaine

– Excito-toxic brain damage from alcohol

Sensitization

• An increase in an effect of a drug upon its repeated administration

• Tends to be seen with the stimulating actions of a drug

Sensitization: Examples

• Cocaine use– Psychotimimetic effects of cocaine

• Alcohol withdrawal– Excitatory changes in withdrawal

• alcohol withdrawal progressively worsens

DSM-IV Definitions

• Substance-Related Disorders

– Substance Use Disorders• Substance Dependence

• Substance Abuse

– Substance-Induced Disorders

Substance-Induced Disorders• Intoxication• Withdrawal• Other

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

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


1. Tolerance

2. Withdrawal

3. The substance is often taken in larger amounts or over longer periods than was intended


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


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

Dependence: Sub-types

• Specify subtype:

• ‘With physiological dependence’– Evidence of tolerance or withdrawal

• ‘Without physiological dependence’– No evidence of tolerance or withdrawal

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


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


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.

Specific Substances

Prevalence

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”)

Alcohol-related disorders

• Alcohol abuse is several times more common in men

• Significant increased risk for accidents, suicide, and violence

Prevalence

• Lifetime prevalence of alcohol abuse or dependence is approximately 8%

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

Etiology

• Psychological Theories

• Socio-cultural Theories

12 grams Ethyl Alcohol

• 12 oz beer

• 4 oz glass wine

• 1.5 oz liquor (80 proof)

Blood Alcohol Level (BAL)

• 0.08 Legal intoxication

• 0.40 Lethal dose, 50% of population (LD50)

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

Alcohol effects on the CNS

• Blackout

• Peripheral Neuropathy

• Cerebellar Degeneration

• Sleep impairment

• Sexual dysfunction

• Mood, Anxiety & Psychotic Disorders

Alcohol effects on the CNS

Wernicke-Korsakoff’s syndrome

• Severe deficiency of thiamine1. Ataxia

2. Amnesia

3. 6th Nerve palsy (opthalmoplegia)

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

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

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

Alcohol Withdrawal, cont.’

– Hallucinations• transient visual, tactile, or auditory

– Grand Mal Seizures• (Later) = 24-72 hours

• Delirium Tremens

• Treatment

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)

Opioids

• Endogenous opioids:

– enkephalins, endorphins

• Mixed agonist/antagonists:

– buprenorphine (Buprenex)

• Antagonists:

– naloxone (Narcan), naltrexone (ReVia)

Opioids

• Prevalence

– Less than 1% with current dependence or abuse

Opioids: Mechanism of Action

• Binding to Mu opioid receptors influences mood & reinforcing effects

• Stimulate the release of dopamine in the Nucleus Accumbens

‘Positive’ Effects of Opioids

• Tranquility

• Euphoria

• Decreased apprehension

Opioids:Some Possible Symptoms

• Apathy and dysphoria

• Analgesia

• Decrease respiration

• Decrease cough reflex

• Constipation

Effects of IV opioids on the body

• Thrombosed veins

• Abcesses

• Hepatitis

• Endocarditis

• HIV and AIDS

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

Clinical Presentation of Opioid Overdose

• Pinpoint pupils

• Decreased respiration; Pulmonary edema– Blue lips, pale skin

• Cardiac arrhythmias

• Seizures

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

Opioids

• Treatment

Cocaine

• Alkaloid of Erythroxylon coca

• One of the most powerful and reinforcing CNS stimulants

• Tends to be used in heavy binges vs. daily

Cocaine

• Prevalence

– Less than 1% lifetime dependence

– Over a million people in U.S.

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

‘Positive’ Effects of Cocaine

• Increased self-confidence

• Sense of alertness

• Sense of well being

• Increased energy

• Heightened sense of pleasure

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

Cocaine: effects on the CNS

• Headache

• Anxiety

• Psychosis

• Sexual dysfunction

Cocaine: effects on the body

• Rhabdomyolysis

• Hyperthermia

• Myocardial ischemia

• Cerebral hemorrhage

• Sudden death

Cocaine Withdrawal

• Dysphoric mood (and 2 or more): 1. Fatigue

2. Vivid, unpleasant dreams3. Insomnia or hypersomnia4. Increased appetite5. Psychomotor agitation or retardation

• Treatment

Other Substances

• Amphetamines

• Hallucinogens

• PCP

• Cannabis

• Inhalants

• Nicotine

Amphetamines

• Dextroamphetamine (Dexedrine)

• Methylphenidate (Ritalin)

• Dextroamphetamine & Amphetamine (Adderall)

• Methamphetamine (Desoxyn)

• Designer amphetamines– 3,4 methylene dioxymethamphetamine (“Ecstacy”)

Hallucinogens

• Natural– psilocybin (‘mushrooms’)– mescaline (‘peyote’)

• Synthetic– Lysergic acid diethylamide (LSD)

Hallucinogens

• Psychosis (‘bad trip’)

• Persisting perception disorder (‘flashbacks’)

• Sympathomimetic effects

Phencyclidine

• 1-(1-phenylcyclohexy-1) piperidine (PCP)

• PCP and Ketamine:– NMDA antagonists– Dopamine activators

• Intoxication

Cannabis

• Hemp plant Cannabis Sativa

• 9-tetra-hydro-cannabinol (THC)

• Most commonly used illicit substance

Cannabis

• Receptors widely dispersed

• Immediate effects

• Long term effects

Inhalants

• Solvents, glue, adhesives, aerosols, and paint thinners, fuels

• CNS depressants

• Dementia– Neurotoxicity

• Medical Effects

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