The 2022 United States National Survey on Drug Use and Health finds almost 47 million Americans ages 12 and older lived with a substance use disorder in a single year — a struggle that impacts millions more family members, friends, acquaintances and coworkers.
Like those millions of Americans, Angelica Morales, Ph.D., experienced family members living with substance use disorders and decided to do something about it.
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"Seeing it happen, especially in your own family, makes you wonder why it happens," said Morales, assistant professor of psychiatry in the Oregon Health & Science University School of Medicine. "And I think when I started as an undergraduate at Stanford, and I took neuroscience courses, that's how the two areas melded together. From a neurobiological perspective, I was interested in how this can be relevant for helping us solve the problem of substance use disorders."
During her graduate studies at UCLA, Morales conducted intake interviews with people who had methamphetamine use disorders.
"People were coming to the lab because they used methamphetamine, but I would learn about other alcohol and other drug use that had gone on since they were young," she said. "As I was talking to people, I was wondering if we could make a bigger impact, if we could find interventions at an earlier age before substance use disorders become more severe."
Morales came to OHSU to do her postdoctoral work in the lab of Bonnie Nagel, Ph.D. With Nagel, Morales worked on longitudinal studies — studies that follow people over long periods of time — to find how brain structure and brain activity in adolescence were related to future alcohol use. Five years ago, Morales became a faculty member and is now part of OHSU's Center for Mental Health Innovation. Her laboratory initially focused on using OHSU functional MRI technology to understand the unique effects of binge drinking in young people.
She continued publishing with Nagel and other colleagues, including as lead author on a study published in the journal Alcohol, Clinical and Experimental Research. In the study, participants were given either a drink of alcohol or a placebo, and brain activity was measured in ventral tegmental area and striatum, areas involved in reward processing.
Morales and colleagues discovered that, on average, giving alcohol made these parts of the brain work less in-synch. However, that was not true for all people. "We saw that the effect differed as a function of personality," Morales said. "Young adults who were more into new or intense experiences had the opposite reaction."
Building on these findings, Morales won NIH funding to study how neurobiological differences in response to consuming alcohol impact substance use over time. She was interested in young people who don't smoke every day, but smoke socially when drinking alcohol with their friends.
"The reason it is interesting is, you would think that occasional smokers would find it easy to quit since they are less likely to experience withdrawal symptoms than daily smokers. But, they still find it difficult," she said. "The hypothesis is that drinking alcohol can make some people more impulsive or reduce their cognitive control, and they may be more likely to make risky decisions, like cigarette smoking, when they use alcohol that they wouldn't make if they weren't under the influence of alcohol."
This study is ongoing. It's looking at brain activity when people make decisions. Participants either drink some alcohol or take a placebo and look at images of cigarettes to measure how much they crave smoking. The same people are interviewed again after one year to see if their alcohol, nicotine or other drug use has changed.
Seeking treatment through neurobiology
Meanwhile, Morales is transitioning her research focus into an intervention-based approach. Through lab-based studies, she's investigating how pharmacological and behavioral interventions change neurobiology. She received a 2024 OHSU Faculty Excellence and Innovation Award, which recognizes exceptionally creative early- and middle-stage investigators.
"Ultimately, my goal is to use neurobiology to inform which treatment is best for a person and to reduce substance use disorders in the United States," she said.
She's researching what factors influence the levels of glutamate in the prefrontal cortex, especially in people who use various substances. Glutamate is a type of chemical messenger in the brain, and it has different receptors all over the central nervous system. Preclinical studies show that it might play a significant role in why people keep using substances.
"The preliminary findings show that people who self-reported greater levels of stress had greater levels of glutamate in the prefrontal cortex and greater alcohol use, so we're going to try to see if altering glutamate levels with a pharmacological intervention has the potential to help some people," Morales said.
Morales said she knows there isn't just one answer to the substance use crisis. Her hope, though, is that her research is part of the solution.
"Substance use disorders are very heterogeneous," she said. "There are likely a variety of neurobiological mechanisms that can contribute to a substance abuse disorder. These are going to have to be targeted interventions, because when it comes to the brain and substance use, there isn't a one-size-fits-all answer."
