UC San Diego has received a $12.3 million, five-year grant from the National Institute on Drug Abuse, part of the U.S. National Institutes of Health, to launch Brain-Focused Research on Antiretrovirals and Methamphetamine, or Brain-FRAMe. The multidisciplinary program will examine how to improve HIV treatment and protect brain health among people living with HIV who also have an active methamphetamine use disorder. Researchers will study clinical care, viral control, neurocognitive function, immune activity and the biological mechanisms that connect substance use with damage to the central nervous system.

Methamphetamine use is closely linked to HIV transmission because the stimulant can impair judgment, increase sexual risk-taking and contribute to behaviors associated with exposure to the virus. The drug may also influence immune pathways that affect susceptibility to infection. Once HIV is established, ongoing methamphetamine use can make treatment more difficult by disrupting engagement with health services, adherence to daily medication and management of coexisting psychiatric and medical conditions. These challenges are particularly serious because HIV infection and methamphetamine exposure can each affect the brain, while their combined effects may amplify inflammation, vascular injury and cognitive dysfunction.

“Methamphetamine is a stimulant, and users may lose their judgment and engage in risky behaviors,” said Igor Grant, MD, a co-investigator, professor of psychiatry at UC San Diego School of Medicine and director of the HIV Neurobehavioral Research Program. He noted that the drug also changes immune mechanisms in ways that may make infection more likely. For people already living with HIV, methamphetamine use has been associated with problems involving mood, impulsivity, memory and executive function. Disruption of the blood-brain barrier, the specialized vascular interface that regulates movement of molecules and immune cells into the brain, may further expose neural tissue to inflammatory signals and toxic substances.

The Brain-FRAMe program will test whether combining long-acting injectable antiretroviral therapy, or LAI-ART, with medication treatment for methamphetamine use can provide a more effective alternative to relying exclusively on daily oral pills. Long-acting antiretrovirals are designed to maintain therapeutic drug concentrations over extended periods, reducing the number of medication-taking decisions required from patients. The addiction-treatment strategy will combine long-acting injectable naltrexone with oral bupropion. By integrating treatment for HIV and substance use, investigators hope to improve viral suppression while reducing methamphetamine exposure and creating conditions that support neurological recovery.

The clinical work will be embedded in the Owen Clinic, UC San Diego’s HIV-care program, where researchers will collaborate with clinicians attempting to engage patients in sustained treatment. “There are people who are going to continue to use methamphetamine and who have HIV infection, and who typically have not been included in care, or who have been very difficult to maintain in care, and have been excluded from research,” Grant said. “We want them to get treatment. This study addresses a population that nobody has addressed before.” The approach is intended to study a population often underrepresented in clinical trials because unstable substance use, psychiatric illness, housing insecurity or inconsistent access to care can make conventional research protocols difficult to complete.

Participants will be followed for 52 weeks by four interconnected research teams. The Clinical Implementation Team will examine how LAI-ART and medication treatment for methamphetamine use can be delivered within a primary-care HIV clinic, while also evaluating barriers to adoption, patient retention and the practical requirements of integrating multiple therapies. The Neurobehavioral Phenotyping Team will track psychiatric symptoms, cognition and neuromedical status over time. These assessments may help determine whether improved viral control and reduced stimulant exposure correspond with changes in attention, memory, mood, decision-making and other measures of brain function.

A third group, the Biophenotyping and Pharmacology Team, will investigate how methamphetamine use and addiction treatment influence the way the body absorbs, distributes and eliminates antiretroviral drugs and other medications. Researchers will analyze blood and cerebrospinal fluid to measure drug exposure and investigate viral reservoirs that may persist despite treatment. HIV reservoirs consist of infected cells containing viral genetic material that can remain dormant and evade standard antiretroviral therapy. Understanding drug penetration and viral persistence in the central nervous system could clarify why viral control in blood does not necessarily eliminate infection from tissues such as the brain.

The Basic Science Mechanisms Team will focus on the cellular and molecular processes that drive brain dysfunction and repair. Its work will examine how metabolic pathways regulate immune-cell activity, inflammation and the integrity of the blood-brain barrier. Methamphetamine can alter cellular energy use and activate inflammatory responses, while HIV and antiretroviral exposure may affect overlapping biological systems. By analyzing these interactions, researchers hope to identify mechanisms that explain neurological vulnerability and potential recovery. A dedicated Data Integration and Analysis Group will combine clinical, behavioral, pharmacological, virological and laboratory findings, allowing the program to evaluate treatment effects across multiple biological levels rather than relying on viral load or symptom scores alone.

Mariana Cherner, PhD, professor of psychiatry at UC San Diego School of Medicine and the program’s contact principal investigator, said the five-year effort is designed to improve both clinical care and brain health by working directly within the HIV-care system. The study’s leadership includes Scott Letendre, MD, and David Grelotti, MD, at UC San Diego School of Medicine, and M. Cecilia Marcondes, PhD, at San Diego Biomedical Research Institute. The broader team includes specialists in psychiatry, neurology, pharmacology, virology, immunology, implementation science and public health from UC San Diego, UC Riverside and San Diego Biomedical Research Institute. By bringing these disciplines together, Brain-FRAMe aims to establish a model for treating HIV and methamphetamine use as biologically connected conditions. If successful, the program could provide evidence for more flexible HIV-care strategies, improve durable viral suppression, reduce neurological complications and offer a blueprint for addressing substance use among people who have historically been difficult to retain in treatment.

Subject of Research: HIV infection, methamphetamine use disorder, long-acting antiretroviral therapy, brain health and viral reservoirs

Article Title: UC San Diego Launches $12.3 Million Program to Study Brain Health in People With HIV and Methamphetamine Use Disorder

Web References: https://health.ucsd.edu/care/hiv/

Image Credits: UC San Diego Health Sciences

Keywords: HIV, human immunodeficiency virus, methamphetamine, substance use disorder, antiretroviral therapy, long-acting injectable ART, naltrexone, bupropion, viral suppression, HIV reservoirs, blood-brain barrier, neuroinflammation, brain health, virology, pharmacology, UC San Diego

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