Methamphetamine and the Brain

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Methamphetamine and the Brain

• Steven Shoptaw, Ph.D.
• UCLA Department of Family Medicine
• Sshoptaw_at_mednet.ucla.edu

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Key Points about Methamphetamine and the Brain

• Pharmacology
• Neurobiology
• Psychiatry
• Behavior

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PharmacologyWhat methamphetamine isWhat
methamphetamine does
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Methamphetamine Up Side

• Cheap
• 9-12 h half-life
• Induces euphoria, brightens mood, eliminates
  fatigue, decreases appetite, focuses attention,
  facilitates involvement with sex at the extremes

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Down Sides

• Paranoia
• Skin problems
• Violence
• Sexual dysfunction

• Work and relationship problems
• Neuropsychological problems
• Infectious Disease

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MethamphetamineAcute Physical Effects

• Increases
• Heart rate
• Blood pressure
• Pupil size
• Respiration
• Sensory acuity
• Energy

• Decreases
• Appetite
• Sleep
• Reaction time

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MethamphetamineAcute Psychological Effects

• Increases
• Confidence
• Alertness
• Mood
• Sex drive
• Energy
• Talkativeness

• Decreases
• Boredom
• Loneliness
• Timidity

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MethamphetamineChronic Physical Effects

• Sweating
• Burned lips sore nose
• Oily skin/complexion
• Headaches
• Diarrhea
• Anorexia

• Tremor
• Weakness
• Dry mouth
• Weight loss
• Cough
• Sinus infection

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dopamine reservoir
synapse
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MA or cocaine
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Natural Rewards Elevate Dopamine Levels
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Effects of Drugs on Dopamine Release
Source Shoblock and Sullivan Di Chiara and
Imperato
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DA Transporter Depletion and Recovery
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Partial Recovery of Brain Dopamine Transporters
in Methamphetamine (METH) Abuser After Protracted
Abstinence
3
0
ml/gm
METH Abuser (1 month detox)
Normal Control
METH Abuser (24 months detox)
Source Volkow, ND et al., Journal of
Neuroscience 21, 9414-9418, 2001.
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PET and fMRI Controls (n18) vs MA Abusers
(n17)
Thompson et al., 2004. Neuroscience, 246028-6036.
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Deficits in Word Recall Correlate with
Hippocampal Atrophy
Thompson et al., 2004. Neuroscience, 246028-6036.
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Longitudinal Memory Performance
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20
control
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number correct
baseline
3 mos
10
6 mos
5
0
Word Recall
Word
Picture Recall
Picture
Recognition
Recognition
Simon S. (2004). J Subst Abuse Treat. 2759-66.
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Neurobiological Insults and Meth Dependence
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Low Affinity D1 receptor loop
Prefrontal Cortex
Thalamus
Globus Pallidus
High Affinity D2 receptor loop
Nuc Accumbens
Substantia Nigra
Subthalamic Nuclei
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Important Neuropharm Considerations

• High dose (5-10mg/kg) D2 mediated
• Enters cell via passive diffusion
• Reverse transporters (DAT, 5-HT, NE, VMAT-2)
• Affects transporter trafficking (DAT) by entering
  vesicles
• Leads to abnormal monoamine distribution
• Generates free radicals

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High Dose Methamphetamine

• gt10 fold presynaptic increase of monoamines
• Activates D1 receptor and D2 receptors
• Toxicity to some DA and 5HT pathways, but NOT NE
• Amphet damages DA MA damages DA 5-HT MDMA
  damages 5-HT
• May damage some interneurons, NPY, somatostatin
  and is D-1 sensitive
• If dose starts low and escalates gradually,
  causes tolerance

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Low Dose Methamphetamine

• Low dose (.5-1mg/kg) D1 mediated and is within
  therapeutic dose
• Enters cell by riding plasma-lemnal transporters
• Reverses transporters, largely by blocking uptake
• Mostly D-1 effects, but some D2
• Little or no metabolic problems, so no free
  radicals

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Hep C, Cognitive Deficits, HIV Infection and
Methamphetamine

• Neurocognitive assessment of 430 subjects along
  risk factors
• HIV status
• HCV status
• Methamphetamine dependence
• Global and domain-specific impairments increased
  with number of risk factors
• HCV infection predicted deficits in learning,
  abstraction, motor skills no effects on
  attention, working memory verbal fluency

Cherner et al., 2005
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Psychiatry/Behavior
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Meth, HIV and Psychiatric Illness

• Meth and HIV independently increase risks for
  psychiatric illness
• Psychiatric illness increases risk for meth use
  and HIV transmission
• Effective treatment for methamphetamine abuse and
  psychiatric illness can improve patient outcome
  and may decrease HIV transmission

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Meth and Co-morbidities

• DEPRESSION Primary psychiatric symptom in 1016
  MA users was depression (Rawson et al., 2006)
• 27 reported attempted suicide at least once in
  their lifetime
• Severity of depression greatest in females and
  IDUs
• ADHD High rates of adult ADHD (up to 71 in
  small study) among inpatients (Jaffe et al.,
  2006)
• Treatment of childhood ADHD with stimulants is
  protective against drug dependence for those who
  start medicate early (before age 7 Wilens et
  al., 2003)
• PSYCHOSIS The greater the familial loading for
  schizophrenia, the more likely user is to
  develop MA psychosis and the longer that
  psychosis is likely to last (Chen et al,
  Neuropsychiatric Genetics. 2005 136B8791)

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Meth Use

• Stress
• Demoralization
• CNS inflammation
• Subcortical injury
• Cognitive impairment

Depression
HIV
Impulsivity Hopelessness Carelessness Demoralizati
on Cognitive impairment
Meth Use
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Conclusions

• Pharmacology of methamphetamine has acute and
  chronic effects that differ
• Acute effects are pleasant chronic effects less
  so
• Neurobiology of methamphetamine differs by amount
  used
• Low dose methamphetamine has few deleterious
  effects high dose has many
• Methamphetamine causes gray matter volume loss,
  which corresponds with functional deficits
• Psychiatric co-morbidities can mask or magnify
  problems due related to methamphetamine use
• Need to treat the meth and the psychiatric
  disorders concurrently!