The HIV+ brain on drugs: Focus on methamphetamine
Effects of HIV and substances of abuse have been studied separately, but what happens when these occur in combination is less well understood. In addition to effects on drug-specific neurotransmitter systems, substances affect cognition and behavior through common neural pathways that include the basal ganglia and prefrontal cortex. These are brain regions that are also preferentially disrupted by HIV. Mechanisms by which abused drugs and HIV may synergize to cause to increased damage can include neurotoxicity resulting from neurotransmitter systems that are affected by both conditions, such as dopamine and glutamate; effects of substances on immune function, cytokine regulation, inflammation and oxidative stress; and damage to brain vasculature (particularly with stimulant drugs).
Users of certain drugs are at increased risk for HIV infection. This is in part a result of unsafe injection drug use practices, but also the outcome of impaired judgment with regard to sexual risk behaviors while under the influence of substances. Alcohol and many commonly abused drugs have been associated with poor decision-making and risky behavior. Methamphetamine stands out among these as a substance that highly enhances sex drive, sexual pleasure and self-confidence, and has thus been significantly implicated in HIV transmission. Moreover, while there are many costs to the individual and to society associated with any substance addiction, chronic methamphetamine use has been most consistently associated with brain dysfunction and neuropsychological deficits.
Methamphetamine acts through effects on a number of neurotransmitters, including serotonin, norepinephrine, GABA and glutamate, and it causes the brain to release large quantities of dopamine. This massive efflux of dopamine is suspected as a cause of brain injury. The resulting neuropsychological deficits are characterized by problems with episodic memory, executive functions, information processing speed and motor ability, with some studies also showing deficits in sustained attention, working memory and verbal fluency. Methamphetamine is metabolized by a liver enzyme called cytochrome P450-2D6 (CYP2D6). There are many common mutations of the gene that codes for CYP2D6 activity, which determine how efficiently methamphetamine is processed. There is recent evidence suggesting that some individuals may be at increased risk for methamphetamine-related brain injury based on this aspect of their genetic makeup.
It has been shown experimentally that, in the presence of HIV, methamphetamine causes even greater dopamine release and cellular damage. As such, it is important to consider the combined synergistic effects of HIV and methamphetamine on brain integrity and cognitive abilities. HIV infection in methamphetamine users has been associated with additive damage to the frontal cortex (Chana et al., 2006) and basal ganglia (Chang, Ernst, Speck, & Grob, 2005). HIV and methamphetamine are thought to have synergistic neuropathologic effects mediated by proteins that activate chemical pathways to cause neuronal death, as well as through neurotoxicity resulting from oxidative stress (Flora et al., 2003) and inflammatory processes that involve brain glial cells (Cadet & Krasnova, 2007). In addition, methamphetamine users may have more difficulty adhering to their antiretroviral medication regimen, resulting in poorer control over the virus and worse neurocognitive outcomes. Our group at the HIV Neurobehavioral Research Program in San Diego was the first to describe additive neuropsychological effects of HIV and methamphetamine. Deficits have been documented in attention/working memory, abstraction and decision-making, episodic memory, working memory, and psychomotor speed. In addition, Hepatitis C virus (HCV) infection is four times more common than HIV, and prevalence is very high among injection drug users. Worldwide, it is estimated that approximately 30 percent of persons with HIV are co-infected with HCV, and there is some evidence that one infection can affect the course of the other. HCV can be an additional source of neurocognitive disturbances. Because it is potentially curable, it is important to encourage at-risk clients to learn their HCV status and be evaluated for treatment.
Besides combining to cause greater neurocognitive problems, HIV, HCV and methamphetamine are each associated with increased prevalence of mental health concerns, particularly depression and other substance abuse. Antisocial personality disorder and attention deficit disorder are also more common among those with methamphetamine dependence than the general population. Thus, care providers ought to evaluate broadly for the presence of mental health issues, substance abuse and cognitive problems that can be targeted to improve quality of life in clients with HIV.
About the author
Mariana Cherner, PhD, graduated with a BA in psychology from Cornell University. She obtained her PhD at the SDSU/UCSD Joint Doctoral Program in Clinical Psychology in 1997, specializing in neuropsychology and behavioral medicine. She completed a clinical psychology internship at the University of Washington, where she also received postdoctoral training in neuropsychology. Dr. Cherner is an Associate Professor In Residence in the Department of Psychiatry at UCSD and director of the Interdisciplinary Research Fellowship in NeuroAIDS, as well as a faculty member in the SDSU/UCSD Joint Doctoral Program in Clinical Psychology. Dr. Cherner has an interest in the role of coexisting conditions such as hepatitis C and stimulant drug (methamphetamine, MDMA) abuse in the manifestation of HIV-associated neurocognitive disorders. Her current research focuses on genetically determined individual differences in vulnerability to brain dysfunction among methamphetamine users with HIV. She conducts her work within the UCSD HIV Neurobehavioral Research Programs, where she is an investigator on a number of federally funded grants related to neuroAIDS. The other focus of her research is in the area of cross-cultural neuropsychology, with a special interest in culturally competent assessment of cognitive abilities and everyday functioning in Spanish speakers. She also participates in training and mentorship of predoctoral students and postdoctoral researchers.
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