Anxiety disorders are the most common psychiatric disorders, and have grown in prevalence and severity in teenagers since the COVID-19 pandemic. Unfortunately, anxiety developed in adolescence often persists into adulthood and can result in worse outcomes, including greater risk of suicide, increased risk of developing another psychiatric disorder and higher health care costs.

Cognitive behavioral therapy (CBT) is a first-line intervention for anxiety, but up to 50% of clinically anxious young people do not achieve full remission at the end of treatment. It is believed that CBT does not work as well in adolescents relative to adults because their brain circuits that regulate fear and anxiety are still underdeveloped.

But what if something as accessible and inexpensive as moderate exercise could help?

Hilary Marusak, assistant professor in the Department of Psychiatry and Behavioral Neurosciences in the School of Medicine, has received a five-year $3.6 million National Institute of Mental Health Biobehavioral Research Awards for Innovative New Scientists (NIMH BRAINS) award to test that hypothesis. NIMH Brains awards are intended to support the research and research career advancement of outstanding, exceptionally productive scientists who are in the early, formative stages of their careers. The awards also seek to assist these individuals in launching an innovative clinical, translational, basic or services research program that holds the potential to profoundly transform the understanding, diagnosis, treatment or prevention of mental disorders.

The study, “Exercise facilitation of adolescent fear extinction, frontolimbic circuitry, and endocannabinoids,” builds on research funded by the NIMH and by a pilot grant from the Office of the Provost that shows acute exercise is a powerful way to activate the endocannabinoid system.

“I’m a runner and I always think about the runner’s high as being associated with endorphins, but recent science shows us that it’s actually cannabinoids that produce some of the beneficial effects of exercise, like reductions in stress, anxiety and pain” said Marusak.

Research in adults has shown that targeting the cannabinoid system with delta-9-tetrahydrocannabinol (THC) – one of the active components of cannabis – can help facilitate fear extinction.

“If you activate this system with a drug during fear extinction or during a cognitive behavioral therapy session, you could help individuals retain that learning so that they come back the next day and they’re not starting over, they’re able to build on the prior session,” said Marusak. “It’s a really promising treatment in conjunction with first line therapies. However, with young people, we don't want to give them THC because we know that it may have detrimental effects on the prefrontal cortex and on brain development in general.”

In Marusak’s study, it is proposed that exercise will target the body’s own natural cannabinoid system — the endocannabinoid system — in adolescents similar to the way THC does in adults.

The new study will recruit 120 adolescents from metro Detroit for a three-day study to see if acute, moderate exercise that activates the endocannabinoid system will help them with “fear extinction” and allow them to better manage their anxiety.

On the first day of the study, participants will undergo fear conditioning, which is a laboratory model of the learning that takes place in fear and anxiety disorders. This is kind of like Pavlov’s dogs, but instead of learning that a neutral cue, like a bell, signals something positive, such as food, the bell signals something negative, like a loud startling sound. Participants will complete this while wearing a virtual reality headset and go through some trauma, psychiatric, substance use and medical history screeners.

On day two, participants will go through fear extinction, which will model what happens during cognitive behavioral therapy wherein anxiety and fear are now reduced. Researchers will then collect biomarkers (blood, saliva, heart rate, etc.) before and after the participant completes either a 30-minute treadmill exercise session or a control condition.

The third day, they'll come back and receive an MRI brain scan.

“We’ll test the integrity of that memory,” said Marusak. “Did exercise actually help them to recall that extinction memory better than the control condition?

“One theory of anxiety disorders is that there is an issue with fear memory maintenance. Fear conditioning is a really nice translational model because we can apply knowledge learned from preclinical studies to help treat common and debilitating disorders in humans. For example, with animal models, we can better look at where fear memories are stored and develop new ways to better regulate fear and anxiety. We can apply that foundational knowledge to humans, which is what we propose to do here.”

The long-term goal is to test this hypothesis first in the lab, which will pave the way for clinical applications.

“Eventually, we could envision bringing children and teens into a clinic and have them do a CBT session, then do a brief bout of exercise such as a treadmill walk or run. This may possibly help therapy be even more effective and/or work quicker or in fewer sessions.”

The multidisciplinary research project draws on experts from around the university and includes Jeanne Barcelona, associate professor of community health in the College of Education; Christine Rabinak, associate professor of pharmacy practice in the Eugene Applebaum College of Pharmacy and Health Sciences; Leslie Lundahl, associate professor of psychiatry and behavioral neurosciences; David Ledgerwood, professor of psychiatry and behavioral neurosciences; Tanja Jovanovic, professor of psychiatry and behavioral neurosciences; Nicholas Mischel, associate professor of psychiatry and behavioral neurosciences; and Krishna Rao Maddipati, professor of pathology in the School of Medicine and director of the Lipidomics Core Facility.     

The project number for this NIH award is MH132830-01.