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)

• 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 30’s 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

• 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”

• 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

• 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

• 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

• 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

• 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)

• 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 10:1
( Melega et al, J Pharmacol Exp Ther
1995 )
• Long plasma half life of ~12 hours

• 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

• 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

• 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

• 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

• 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 FIV’s 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

• Adherence to HIV meds slips during acute intoxication
• “Weekend warrior” approach to using Club
Drugs
– Potential increase for transmission of drug resistant HIV

Prevalence of MAR (%)
1998
(n=257)
1999
(n=239)
2000
(n=299)
Resistance to:
Any drug
NRTI
NNRTI
PI
>2 drug class
5.5
5.1
0.4
0
0
8.8
7.1
2.1
0.8
1.3
10.7
7.7
1.7
3.0
1.3
MAR=mutations associated with resistance.
Bennett D, et al. 9th CROI, Seattle, 2002. Abstract 372.

• 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

• 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

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

• At higher doses: hypomania, grandiosity,
• Extreme insomnia , irritability ,
• 24-72+hrs 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 15:3 317-324

• “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; 21:107-19

• Class: Amphetamine/stimulant/”speed”
• How does it work?
• 3 main neurotransmitters:
• Serotonin
• Dopamine
• Norepinephrine

•
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

•
Crystal Meth:
•
Dopamine and Norepinephrine
•
Ecstasy:
• Dopamine and
Serotonin
•
Cocaine:
• Dopamine, Norepinephrine, Serotonin
American Psychiatric Association Textbook of Substance Abuse Treatment 2002

• Euphoria
• “sensual not sexual”
• but still associated w. unsafe sex odds ratio 2.77
Klitzman et al Am J Psychiatry 2000;21:91-105
• Danger of seizure esp w. Ritonavir
•
Henry, JA Lancet 1998: 352:1751-2
• No paranoia, no violence
• Long-term : depression

NIDA.gov

PET studies of drug addiction
Amphetamine-induced dopamine release
T stat
7.0
Alcohol-induced dopamine release
3.5
7.0
T-value
4.5

Neurons that make dopamine:
“pleasure-reward” system highlighted.
Most drugs of abuse affect this system
Nestler Figure 8-6

Inf. Temporal
Gyrus
Middle Temporal
Gyrus
Middle Frontal
Gyrus

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.

• Animal research:
• Crystal may increase viral replication in the brain by 5-15 fold
Gavrilin J Neurovirol 2002;8:240-9
• Human research:
• Crystal depletes dopamine in the nigrostriatal tract: Parkinson’s disease risk
Volkow Am J Psychiatry 2001;158:377-82

• 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 1989;321:907
• Chronic use=Major 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 2002;21:107-19

• Neuropsychiatric effects problems w. manipulating information, set shifting, divided attention and perseveration (like
HIV dementia)
Simon et al J Addictive Diseases 2002;21(1):61-73
• Problems with psychomotor speed, concentration, learning and memory
• n=28 many addicts had Attention Deficit as children
Sim et al J Addictive Diseases 2002;21(1):75-89

Psychosis: Neuroleptics (Zyprexa, Risperdal)
RCT of dopamine agonists Bromocriptine and
Pergolide (D1/D2 agonist) show no efficacy
Moscovitz, J Gen Intern med 1993;8:1-4
Malcolm et al Drug Alcohol Depend 2000;60:161-8
D1 receptors may reduce drug cravings
D2 receptors may increase drug cravings
Methylphenidate = not useful for treatment

• 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

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

• Loss of judgement re: safe sex
• Loss of judgement re: safe partners
• (emotionally, physically)
• Overconfidence about other STD risk
• Syphillis outbreak in California
•
MMWR 2001;50:117-20
to HIV meds slips!

• 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)