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Crystal Methamphetamine and HIV Infection: Medical and Psychiatric Aspects of a New Epidemic

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Title: Crystal Methamphetamine and HIV Infection: Medical and Psychiatric Aspects of a New Epidemic


1
Crystal Methamphetamine and HIV Infection
Medical and Psychiatric Aspects of a New Epidemic
  • Antonio E. Urbina, MD
  • St. Vincent Catholic Medical Center-Manhattan
  • Kristina Jones, MD
  • New York Presbyterian Hospital
  • Center for Special Studies (HIV)

2
Methamphetamine
  • What is Crystal Methamphetamine?
  • Crystal Methamphetamine is a chemical that has
    stimulant properties.

3
Spread of Methamphetamine Use
4
Epidemiology
  • High prevalence of HIV in patients who use
    crystal MA
  • Shoptaw, et al, J Addict Dis 2002 showed in a CA
    study that 61 of men seeking tx for MA had HIV
    infection
  • 77 of men were white, 17 were Latino
  • All were in their mid 30s and had some college
    education
  • Reported a mean of 66 different partners in 6
    months
  • Persons with HIV were more likely to have
    injected MA, contracted an STD and had more UAI
  • Klitzman, et al Am J Psychiatry 2000 reported
    strong association between MDMA use and high-risk
    sexual behavior
  • 2001 report in MMWR found that in an outbreak of
    130 cases of syphilis in CA, 51 were MSM and 18
    reported use of MA

5
Epidemiology
  • Study of 25 HIV gay men using MA (Semple et al.,
    J Subst Abuse Treat 2002)
  • provided temporary escape from being HIV
  • helps manage negative self-perception and social
    rejection associated with being HIV
  • method of coping with the specter of death

6
Medical Complications
  • Short term effects are similar to those of
    cocaine
  • Mediated through release of DA and NE
  • Tachycardia, HTN, tachypnea, hyperthermia, CNS
    excitation
  • Rhabdomyolysis and cardiovascular events
  • Retrospective review of ER admissions for rhabdo
    reported that 43 used MA ( Richards, J., Am J
    Emer Med 1999)
  • CV responses include vasoconstriction, vasculitis
    and focal myocyte necrosis
  • Intersection between aging HIV population,
    metabolic complications and HIV

7
Medical Complications
  • Cardiopulmonary events associated with long-term
    use include MI and stroke
  • 4 cases of stroke in pts aged 29-45 have been
    documented (Perez, et al. J Emer Med 1999)
  • Smoking of MA is associated with acute pulmonary
    HTN and dilated CM
  • Immunomodulatory activity
  • Impairs CD8 mediated T cell function (House, et
    al Immunopharmacol Immunotoxicol 1994)
  • CD8 cell activity is responsible for early
    suppression of lentiviral replication and viral
    set point
  • Leads to significant bruxism and periodontal
    disease

8
Metabolism
  • MA and related compounds including MDMA
    (Ecstasy) are metabolized by the CYP 2D6
    isoform of the P450 enzyme system
  • Genetic polymorphism
  • 3-10 of white population is deficient in CYP 2D6

9
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10
Drug Interactions with HIV Meds
  • Fatal interactions between amphetamines, their
    analogues (MDMA) and PIs
  • Ritonavir has greater affinity for enzyme than
    amphetamines and results in 3-10 fold increases
    in level of MA
  • Includes all boosted PIs (i.e. lopinavir/ritonavir
    , atazanavir/ritonavir, invirase/ritonavir)
  • Delavirdine is partially metabolized and may have
    similar pharmacokinetic interactions

11
Case Reports
  • One case of HIV patient receiving a combination
    of stavudine, saquinavir, and ritonavir who died
    after injecting MA (Hales,G, et al. Antivir Ther
    2000)
  • Toxicology consistent with overdose
  • Two case reports document fatalities after
    ingestion of ritonavir-containing regimens and
    MDMA (Henry J., Hill IR, Lancet 1999 Baker et
    al, BETA 1997)

12
Neurotoxicity
  • MAs neurotoxic effects are the most devastating
    and potentially permanent sequelae
  • Studies in rats indicate MA accumulates in the
    brain with a brain to plasma of 101 (Melega
    et al, J Pharmacol Exp Ther 1995)
  • Long plasma half life of 12 hours

13
Neurotransmitter Toxicity
  • MA use leads to a reduction in dopamine
    transporter levels (DAT)
  • Study of 15 HIV negative MA abusers using PET
    scans found reductions in DAT levels (Volkow and
    Chang Am J Psychiatry 2001)
  • Neuropsychiatric evidence of impaired motor fx
    and verbal learning
  • 3 subjects DAT levels had ? within range seen
    for low-severity Parkinson disease
  • Extrapyramidal sxs were not seen possibly due to
    young age of subjects

14
Neurotransmitter Toxicity
  • Not known whether ? DAT levels reflect
    irreversible dopamine terminal damage or
    neuroadaptive changes
  • Another study by Volkow and Chang (J. Neurosci
    2001) of former users showed that although DAT
    levels recovered with 12-17 months of abstinence,
    neuropsychological fx did not
  • Neither gross nor fine motor speed improved
  • No improvement in Rey auditory verbal learning

15
Synergy of MA and HIV
  • Clinical features of HIV-related dementia (HAD)
    are those of a subcortical type
  • Psychomotor slowing, apathy and memory deficits
  • Advanced HAD sxs include bradykinesia, altered
    posture and gait and incontinence
  • HAD is a metabolic encephalopathy that involves
    brain cell loss and neuronal dysfunction
  • Supporting neuronal cells (microglial cells,
    macrophages, astrocytes) induce damage by
    secreting inflammatory cytokines that damage
    brain cells
  • Neurons themselves are not directly infected with
    HIV

16
Synergy of MA and HIV
  • Experimental evidence suggests that HIV-1
    proteins gp120 and Tat are toxic to dopamine
    neurons
  • There is overlap in that both MA and HIV target
    dopamine neurons
  • HIV affects the dopamine neurons in subcortical
    structures, particularly the basal ganglia
  • MA targets dopamine in many regions of the brain
    including orbitofrontal cortex, dorsolateral
    prefontal cortices and amygdala

17
Synergy of MA and HIV
  • Some researchers suggest that dopaminergic
    systems are most vulnerable to such combined
    neurotoxicity
  • Researchers (Gravilin et al, J Neurovirol 2002)
    found that exposing feline astrocytes infected
    with FIV to MA increased FIVs ability to
    replicate and mutate by 15-fold.
  • Findings imply that MA use in HIV patients could
    increase prevalence of HIV-related dementia in
    patients who are not receiving ARVs
  • Awaits verification in human studies

18
MA Use and Adherence
  • Adherence to HIV meds slips during acute
    intoxication
  • Weekend warrior approach to using Club Drugs
  • Potential increase for transmission of drug
    resistant HIV

19
CDC Survey Drug-Resistant HIV Among Recently
Diagnosed Patients
MARmutations associated with resistance.
Bennett D, et al. 9th CROI, Seattle, 2002.
Abstract 372.
20
Amphetamines and ED Drugs
  • ED drugs such as sildenafil (Viagra), vardenafil
    (Levitra) and tadalafil (Cialis) are
    metabolized via CYP3A4
  • Dose reduction recommended with concurrent use of
    PIs
  • No significant pharmacokinetic interaction
    between amphetamines and ED drugs
  • Increased prevalence of ED drugs with amphetamine
    intoxication

21
nPEP and MA
  • PEP for consensual sexual exposures
  • May reduce risk by 80
  • Timing and facilitating rapid access access to
    meds (72 hours) are ESSENTIAL
  • Barrier from HCP in administering PEP based on
    context of behavior in which risk occurred
  • MA use/abuse provides counseling opportunity for
    PEP

22
Crystal Meth Effects
  • Euphoria,
  • alertness,
  • well-being,
  • confidence,
  • sexual confidence,
  • sexual enhancement (despite transient impotence
    in many users) / Viagra www.erowid.com

23
Psychiatric Effects/Crystal Meth
  • At higher doses hypomania, grandiosity,
  • Extreme insomnia, irritability,
  • 24-72hrs without sleep,
  • Appetite suppression, weight loss, skin picking
  • 10 frank psychosis,
  • Identical to paranoid schizophrenia
  • Violent behavior (physical and sexual)
  • Nordahl et al J Neuropsychiatry Clinical
    Neuroscience 153 317-324

24
Crystal Meth Withdrawal
  • terrible Tuesday withdrawal
  • depression, irritability,
  • suicidal ideation,
  • carbohydrate craving
  • Long-term use (1-2 yrs?)
  • chronic depression
  • 62 remain depressed 2-5 yrs after abstinence
  • Rawson et al J Addictive Diseases 2002
    21107-19

25
HIV and Crystal Meth
  • Class Amphetamine/stimulant/speed
  • How does it work?
  • 3 main neurotransmitters
  • Serotonin
  • Dopamine
  • Norepinephrine

26
Neurotransmitter Functions
  • Dopamine reward pathway
  • addiction pathway
  • Serotonin mood, sleep, sex, appetite
  • Norepinephrine increases blood pressure, gives
    energy, related to adrenalin
  • American Psychiatric Association Textbook of
    Substance Abuse Treatment 2002

27
Neurotransmitters and Club Drugs
  • Crystal Meth
  • Dopamine and Norepinephrine
  • Ecstasy
  • Dopamine and Serotonin
  • Cocaine
  • Dopamine, Norepinephrine, Serotonin
  • American Psychiatric Association Textbook of
    Substance Abuse Treatment 2002

28
Methamphetamine Causes Release of Dopamine
29
Dopaminergic Neuron
30
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31
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32
Ecstasy MDMA Intoxication
  • Euphoria
  • sensual not sexual
  • but still associated w. unsafe sex
    odds ratio 2.77 Klitzman et al Am J Psychiatry
    20002191-105
  • Danger of seizure esp w. Ritonavir
  • Henry, JA Lancet 1998 3521751-2
  • No paranoia, no violence
  • Long-term depression

33
Localizing Drug Effects NIDA.gov
34
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35
PET studies of drug addiction
Amphetamine-induced dopamine release
Alcohol-induced dopamine release
36
Neurons that make dopamine pleasure-reward
system highlighted. Most drugs of abuse affect
this system
Nestler Figure 8-6
37
BRAIN METABOLISM IN METHAMPHETAMINE ABUSE
Middle Frontal Gyrus
Inf. Temporal Gyrus
Middle Temporal Gyrus
38
Human Brain Areas Corresponding to the Mouse
Brain Areas Damaged by Methamphetamine
Methamphetamine-induced damage to nerve terminals
of dopamine-producing cells occurs primarily in a
brain region called the striatum.
Methamphetamine-induced apoptosis killed off
different types of nerve cells in the frontal
cortex, the hippocampus, and the striatum in
mice.
39
Crystal and HIV
  • Animal research
  • Crystal may increase viral replication in the
    brain by 5-15 fold
  • Gavrilin J Neurovirol 20028240-9
  • Human research
  • Crystal depletes dopamine in the nigro-striatal
    tract Parkinsons disease risk
  • Volkow Am J Psychiatry 2001158377-82

40
Long term Psychiatric Effects
  • In 10 persons, long-term abuse psychoses
    that mimic schizophrenia
  • Cocaine-induced psychosis has a brief duration
    whereas MA may last for several days or weeks
  • Jackson NEJM 1989321907
  • Chronic useMajor Depression
  • California study of 170 former MA abusers, found
    that 62 of subjects reported having depressive
    sx s at baseline and follow-up, while only 7.2
    reported paranoia at followup
  • Rawson et al J Addict Dis 200221107-19

41
Long term cognitive effects
  • Neuropsychiatric effects problems w. manipulating
    information, set shifting, divided attention and
    perseveration (like HIV dementia) Simon et al J
    Addictive Diseases 200221(1)61-73
  • Problems with psychomotor speed, concentration,
    learning and memory
  • n28 many addicts had Attention Deficit as
    children Sim et al J Addictive Diseases
    200221(1)75-89

42
Treatment
  • Psychosis Neuroleptics (Zyprexa, Risperdal)
  • RCT of dopamine agonists Bromocriptine and
    Pergolide (D1/D2 agonist) show no efficacy
  • Moscovitz, J Gen Intern med 199381-4
  • Malcolm et al Drug Alcohol Depend 200060161-8
  • D1 receptors may reduce drug cravings
  • D2 receptors may increase drug cravings
  • Methylphenidate not useful for treatment

43
Crystal and HIV Meds
  • Reported fatality with Crystal
  • 3Tc, Saquinavir, and Ritonavir
  • Hales Antivir Ther 2000519
  • Two reported fatalities with Ecstasy Ritonavir
  • Henry Lancet 1998352 1751-2

44
Treatment of Addiction
  • Treat Substance-Induced psychiatric disorders
  • Wellbutrin (Bupropion) 150mg
  • Celexa 20 mg po od
  • Ambien (Zolpidem) 10mg
  • Depakote for mood stabilization
  • Zyprexa, Risperdal for psychosis/anxiety

45
Treatment of Addiction
  • Motivational Interviewing
  • Harm Reduction
  • Adherence Strategies while using
  • Decreasing other STD transmission
  • Decreasing spread of resistant HIV
  • Gay/Lesbian Centered treatment

46
Crystal and HIV
  • Loss of judgement re safe sex
  • Loss of judgement re safe partners
  • (emotionally, physically)
  • Overconfidence about other STD risk
  • Syphillis outbreak in California
  • MMWR 200150117-20
  • Adherence to HIV meds slips!

47
Websites for HIV/Club Drugs
  • www.nida.gov
  • (National Institute for Drug Abuse)
  • www.erowid.org
  • (pro-drug website w/ pictures)
  • www.hiv-druginteractions.org
  • (drug/herb/club-drug interaction charts)
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