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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) Methamphetamine • What is Crystal Methamphetamine? – Crystal Methamphetamine is a chemical that has stimulant properties. Spread of Methamphetamine Use 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 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 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” 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 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 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 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 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) 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 10:1 (Melega et al, J Pharmacol Exp Ther 1995) • Long plasma half life of ~12 hours 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 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 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 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 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 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 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 CDC Survey: Drug-Resistant HIV Among Recently Diagnosed Patients Prevalence of MAR (%) 1998 (n=257) 1999 (n=239) 2000 (n=299) Any drug 5.5 8.8 10.7 NRTI 5.1 7.1 7.7 NNRTI 0.4 2.1 1.7 PI 0 0.8 3.0 >2 drug class 0 1.3 1.3 Resistance to: MAR=mutations associated with resistance. Bennett D, et al. 9th CROI, Seattle, 2002. Abstract 372. 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 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 Crystal Meth Effects • • • • • • Euphoria, alertness, well-being, confidence, sexual confidence, sexual enhancement (despite transient impotence in many users) +/= Viagra www.erowid.com Psychiatric Effects/Crystal Meth • • • • • • • 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 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; 21:107-19 HIV and Crystal Meth • • • • • • Class: Amphetamine/stimulant/”speed” How does it work? 3 main neurotransmitters: Serotonin Dopamine Norepinephrine 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 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 Methamphetamine Causes Release of Dopamine Dopaminergic Neuron Ecstasy MDMA Intoxication • 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 Localizing Drug Effects NIDA.gov PET studies of drug addiction Amphetamine-induced dopamine release T stat 7.0 3.5 Alcohol-induced dopamine release 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 BRAIN METABOLISM IN METHAMPHETAMINE ABUSE 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. Crystal and HIV • 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 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 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 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 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 Treatment 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 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 Treatment of Addiction • • • • • • ‘Motivational Interviewing’ Harm Reduction Adherence Strategies while using Decreasing other STD transmission Decreasing spread of resistant HIV Gay/Lesbian Centered treatment 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 2001;50:117-20 • Adherence to HIV meds slips! 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)