Cocaine, Stimulants, and MDMA

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Cocaine, Stimulants, and MDMA

• Karen Drexler, M.D.
• Emory University
• Atlanta VA Medical Center

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ASAMs 2008 Review Course in Addiction
Medicine

• ACCME required disclosure of
• relevant commercial relationships
• Dr. Drexler has nothing to disclose.

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Objectives

• The participant will be able to understand
• How chemical structure of stimulants influences
  pharmacology
• Basic neurobiology of stimulant dependence
• How to recognize and manage acute stimulant
  intoxication and withdrawal

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Overview

• Background
• Stimulant- structure and pharmacology
• Neurobiology of stimulant addiction
• Management of acute intoxication and withdrawal
• Relapse Prevention

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Background

• Stimulants have been used by humans for thousands
  of years to increase energy.
• Plant-derived stimulants have been refined and
  new drugs developed to increase potency and
  duration.
• As potency increases negative effects become
  apparent.

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History of Stimulant Use

• 3000 B.C. Ma-Huang
• 0 A.D. Coca leaf chewing and coca tea
• 1860 Cocaine isolated
• 1887 Amphetamine synthesized
• 1914 Harrison Narcotic Act
• MDMA
• 1919 Methamphetamine
• 1930s Benzedrine inhaler
• 1959 Benzedrine banned
• 1980s Crack

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Epidemiology

• Cocaine
• 2nd most widely used illicit drug in U.S.
• Most frequent illicit drug in ED visits
• In 2004 (NHSDA and DAWN)
• 11.2 lifetime use 1.5 past year 0.8 past
  month
• 2.7 lifetime prevalence of dependence
• 19 of drug-related ER visits
• 39 of drug-related deaths

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Cocaine Abuse/Addiction Liability
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Epidemiology

• Synthetic Stimulants
• Non-prescription use peaked at 1.3 in 1985
• In 2004 (NHSDA)
• 6.6 lifetime non-prescription use
• 1.7 lifetime prevalence of dependence
• Methamphetamine
• Most commonly used synthetic stimulant
• In 2004, 59 of users had a use disorder
• Up from 27.5 in 2002.

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Methamphetamine Lab Seizures
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Trends in Illicit Drug Use
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Trends in Methamphetamine Use
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Trends in Drug Use Disorders
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Club Drugs Epidemiology DAWN, July 2001
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Overview

• Background
• Stimulant- structure and pharmacology
• Neurobiology of stimulant addiction
• Management of acute intoxication and withdrawal

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Structure and Pharmacology

• All stimulant drugs share a common basic
  phenylalkylamine structure.
• Additions to the phenyl group tend to increase
  hallucinogenic properties.
• Additions of a methyl group to the nitrogen atom
  tend to increase the stimulant properties.

N
OH
OH
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Stimulant Drugs

• Plant-derived
• Caffeine
• Cocaine
• Ephedra
• Khat

• Synthetic
• Amphetamine
• Methamphetamine
• Methylphenidate
• Mazindol
• Phenylpropanolamine
• Ephedrine
• Pseudoephedrine
• Phenylephrine
• MDA / MDMA

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Clinical Uses of Stimulants
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Cocaine Chemical Properties

• Cocaine HCl
• High melting point (195C)
• Pyrolysis destroys most of the drug
• Soluble in water (EtOHH2O 18)
• Easily dissolved for injection or absorption
  across mucous membranes

• Crack or Freebase
• Low melting point (98C)
• Easy to smoke
• Insoluble in water (EtOHH2O 1001)
• Difficult to dissolve for injection

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Stimulant Chemical Properties

• Most variations on phenylethylamine
• Phenylisopropylamine stimulants have
  stereoisomers
• D-isomers - 3 5 times more CNS activity
• D-methamphetamine potent stimulant
• L-methamphetamine- OTC decongestant

N
OH
OH
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MDMA Properties

• 3,4- Methylenedioxymethamphetamine
• Stimulant, hallucinogenic, empathogenic
• Taken orally as a pill
• 50 mg to 250 mg
• Stacking with other drugs (LSD, DM, ephedra)
• Non-linear kinetics
• Saturation of high-affinity enzymes
• Large increase in response to small dose increase

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Clinical Uses of Stimulants

• Prescription cocaine
• Local anesthetic
• Prescription stimulants
• ADHD
• Narcolepsy
• Weight loss
• Bronchdilation
• Depression, pain

• Parenteral phenylephrine
• Spinal anesthesia
• Antihypotensive
• Terminate SVT
• OTC stimulants
• Decongestion
• Bronchodilation
• None for MDMA

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Methamphetamine

• Brand name Desoxyn
• ADHD 20 25 mg / day
• Obesity 15 mg / day
• Binge 125 mg 1000 mg/dose
• Toxic doses
• 4- 6 mg/kg q2h (3 gm/day)
• 37 loss of dopamine

Segal et al 2003 Neuropsychopharmacology
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Pharmacokinetics

• Smoking and IV
• Reaches brain in 6 8 seconds
• Onset of action and peak occur in minutes
• Rapid decline in effect
• Rapid onset of withdrawal symptoms and craving

• Intranasal and oral
• Slower absorption and peak effect (30 45
  minutes)
• Longer peak effect and gradual decline
• Peak intensity less than smoking or IV
• Alkalinization enhances absorption

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Pharmacokinetics
Smoked
Oral
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Metabolism and Elimination

• Cocaine
• Hydrolysis of ester bonds
• Ecgonine methylester
• Benzoylecgonine
• Cytochrome P450
• Eliminated in urine
• Benzoylecgonine detectable for 3 days
• Acidifying ?s excretion

• Amphetamines
• To metabolites
• Deamination- inactive
• Oxidation- active
• Parahydroxylation- active
• Eliminated in urine-
• Increased by lower pH

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Drug Interactions

• Other stimulants- ? sympathetic activity
• Cardiac arrhythmia
• Hypertension
• Seizure
• Death
• MAOIs- inhibit metabolism of stimulants
• Tricyclics- may block presynaptic uptake
• Cocaine EtOH cocaethylene
• ? cardiac toxicity due to longer half-life

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Stimulant Effects

• Range of effects vary depending on
• Structure
• Dose
• Route of administration
• Duration and intensity of use
• Typical initial doses for desired effects
• 5 to 20 mg of oral amphetamine, methylphenidate
• 100 to 200 mg of oral cocaine
• 15 to 20 mg of smoked cocaine
• 50 to 250 mg of MDMA

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Acute Stimulant Effects

• CNS
• Euphoria (low dose)
• ? energy, alertness
• ? sociability
• ? appetite
• Dysphoria (high dose)
• Anxiety, panic attacks
• Irritability, agitation
• Suspciousness
• Psychosis
• Movement disorders
• Seizures

• Cardiovascular
• ? HR, BP, vascular resistance, temperature
• Acute myocardial infarction (AMI), ischemia,
  arrhythmia
• Stroke
• Pulmonary
• Shortness of breath
• Bronchospasm
• Pulmonary edema

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Acute Stimulant Effects (cont)

• Musculoskeletal
• Rhabdomyolysis
• Renal
• Acute renal failure secondary to myoglobinuria
• Endocrine
• Ketoacidosis in diabetics
• Activation of HPA

• Sexual function
• Increased arousal
• Prolonged erections
• Head and neck
• Chronic rhinitis, nasal septal perforation
• Xerostomia
• Bruxism
• Fetal effects
• Most Category C

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Mechanisms of Action

• All stimulants enhance monoamine activity
• Inhibition of presynaptic monoamine transporters
• Dopamine reward, psychosis
• Norephinephrine physiological arousal
• Sertonin mood elevation, psychosis
• OTC stimulants bind to and activate
  norepinephrine receptors

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Mesocorticolimbic Pathway
Anterior cingulate
Prefrontal cortex
Nucleus accumbens
Ventral tegmental area
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Dopamine (DA)

• Stimulants acutely enhance dopamine activity
• Cocaine, methylphenidate- transporter blockers
• Amphetamines- false substrates
• Stimulants chronically deplete dopamine
• DA activity key in mediating addictive potential
• Fluctuations in mesolimbic DA parallel cocaine
  self-administration
• Stimulant potency correlates with potency for
  binding at DA transporter

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CocaineMicrodialysis in Awake Squirrel Monkeys
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Norepinephrine (NE)

• Stimulants acutely block NE transporter
• ? plasma NE and epinephine
• NE release correlates with subjective and
  physiological stimulant effects
• Ephedrine related compounds stimulate
  alpha-adrenergic NE receptors

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Serotonin (5-HT)

• All stimulants acutely enhance 5-HT activity by
  blocking serotonin transporter
• MDMA ?s 5-HT by blocking transporters
• Cocaine acutely ?s firing in mesolimbic
  serotonergic neurons, but ?s firing in dorsal
  raphe nucleus
• Serotonin appears to play a permissive, but not
  obligatory role in reward

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Other Neurotransmitters

• Endogenous opioid activity
• No direct stimulant effect
• Cocaine indirectly ?s
• Mesolimbic glutamate
• Cocaine ?s
• Amphetamine ?s
• Acetylcholine
• Cocaine ?s
• Sodium channel blockade (cocaine only)

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Overview

• Background
• Stimulant- structure and pharmacology
• Neurobiology of stimulant addiction
• Management of acute intoxication and withdrawal

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DSM-IV Substance Dependence

• / 3 of the following over a 12-month period
• Tolerance
• Characteristic withdrawal
• Larger amounts than intended
• Persistent efforts to cut down or control use
• A great deal of time spent getting the substance,
  taking it, or recovering
• Important activities given up or reduced
• Continued use despite psychological or physical
  problem caused by or exacerbated by use

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Neurobiology of Dependence

• Sensitization of incentive salience
• Drug
• Conditioned cues
• Impairment of inhibition of urges to use
• Chronic effects of drug
• Signal transduction
• Gene transcription

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Mesocorticolimbic Pathway
Anterior cingulate
Prefrontal cortex
Nucleus accumbens
Ventral tegmental area
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Amygdala Limbic Connections
Nucleus accumbens
Amygdala
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Prefrontal - Limbic Inhibition
Orbitofrontal cortex
Nucleus accumbens
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Cocaine craving-related neural activations Men
drug use - neutral
Left
Right
insula
-34 mm
34 mm
anterior cingulate
amygdala
-19 mm
19 mm
-9 mm
9 mm
subcallosal cortex
nucleus accumbens area
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Overview

• Background
• Stimulant- structure and pharmacology
• Neurobiology of stimulant addiction
• Management of acute intoxication and withdrawal

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Initial Evaluation of Stimulant Intoxication

• Drug history
• Physical examination
• Laboratory examination
• Manage basic life support functions
• T 102F Cooling blanket
• T 106F Cool saline hydration, ice water
  lavage
• Remove drug from GI tract
• Activated charcoal or gastric lavage
• If within one hour of ingestion

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Management of Severe Agitation

• Benzodiazepines- first line
• Protect against CNS and cardiovascular toxicity
• Lorazepam 2 4 mg PO or IV q 15 min until sedate
• Repeat every 1 3 hours
• Antipsychotics- second line
• May prevent heat dissipation, lower seizure
  threshold, prolong QTc, increase dyskinesias
• Haloperidol 2 to 10 mg PO, IM or IV q 6 24
  hours
• Avoid physical restraints

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Cardiovascular Effects of Stimulants

• Myocardial ischemia is common.
• Vasoconstriction
• Increased myocardial workload
• Increased platelet aggregation
• Differential - AMI, aortic dissection,
  pneumothorax, endocarditis, or pneumonia
• Arrhythmias
• Due to ischemia, catecholamines, or sodium
  channel blockade

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Management of Chest Pain

• Observe for 12 24 hours
• ECG-
• Low sensitivity (36)
• Low predictive value (18)
• Cardiac enzymes
• Serial CPK- MB or troponin
• 15 of patients with stimulant-induced chest
  pain will have AMI.

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Management of Arrhythmias

• Treat underlying conditions
• AMI
• Electrolyte and acid-base abnormalities
• Hypoxia
• Many will resolve without treatment
• Avoid Class I antiarrhythic drugs
• Follow ACLS guidelines

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Management of Seizures

• Benzodiazepines
• Lorazepam 2 to 10 mg IV over 2 minutes
• Diazepam 5 to 10 mg IV over 2 minutes
• Repeat as needed
• Monitor respirations, intubation available

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Management of Rhabdomyolysis

• Diagnosis requires high suspicion
• Muscle swelling and myalgia often absent
• Plasma CK 5 times normal
• Urinalysis positive for heme without RBCs
• IV hydration urine output 2 ml/kg/hour
• Urine pH 5.6 sodium bicarbonate

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Management of Hypertension

• Benzodiazepines first line
• Lower myocardial oxygen demand
• Lower seizure risk
• If severe hypertension persists
• Alpha-adrenergic blocker
• Phentolamine 2 to 20 mg IV over 10 min
• No beta-adrenergic blockers
• Unopposed alpha stimulation ?s vasoconstriction

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DSM-IV Cocaine Withdrawal

• A. Cessation of (or reduction in) cocaine use
  that has been heavy and prolonged.
• B. Dysphoric mood and two (or more)
• Fatigue
• Vivid, unpleasant dreams
• Insomnia or hypersomnia
• Increased appetite
• Psychomotor retardation or agitation

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Management of Withdrawal

• Most symptoms resolve within 2 weeks without
  treatment
• Hospitalization for suicidality or psychosis
• Pharmacologic treatment not necessary

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Relapse Prevention

• Psychosocial treatment
• Cognitive behavioral therapy (CBT)
• Contingency management (MIEDAR)
• 12-step facilitation- ?
• Motivation Enhancement Therapy- ?
• MATRIX model
• Treat comorbidities

• Pharmacotherapy
• No FDA approved medications
• Antidepressants
• Dopaminergic agents
• Disulfiram
• Anticonvulsants (GVG, topiramate)

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Disulfiram Patients Have Less Cocaine Use
Carroll et al, 2004
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Modafinil Decreases Cocaine Use
Dackis 2005
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Summary

• Stimulants are common causes of drug-related
  morbidity and mortality.
• Chemical structure of stimulants relates to the
  pharmacologic properties.
• Neurobiology of stimulant addiction is related to
  blockade of monoamine transporters.
• Management of acute intoxication and withdrawal
  is symptom driven.
• Relapse prevention is based on comprehensive
  biopsychosocial treatment.

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Acknowledgements

• Emory University
• Clint Kilts
• Leonard Howell
• Robin Gross
• Tim Ely
• Julie Schweitzer
• Colin Quinn
• John Hoffman
• Tracy Faber
• Faheemah Muhammad

• ASAM
• David Gorelick
• Jennifer Cornish
• Jeffrey Wilkins
• Katherine Mellott
• Romana Markvitsa
• Richard Glennon
• Steven Batki