A genetic difference in THC metabolism may explain why some young adults have negative experiences with cannabis

Differences in how young adults metabolize THC, the main part of cannabis that makes people feel “high,” can influence how they feel after taking the drug as well as their potential risk for developing cannabis use disorder, or CUD.

These findings were recently published in Addictive Behaviors by Medical University of South Carolina researcher Rachel Tomko, Ph.D., and former psychology intern Christal Davis, Ph.D., who is now a postdoctoral fellow at the University of Pennsylvania, as well as other MUSC colleagues and collaborators at the University of Florida and University of Colorado. Tomko and Davis also explored whether the effects of a genetic difference in THC metabolism on future outcomes of cannabis use depend on a person’s sex.

CUD, which affects one in five people who use cannabis, leads to problems such as withdrawal symptoms and cravings when not using cannabis, difficulty reducing cannabis use and a need to consume more of the drug to experience the same effects.

THC metabolism, the process by which this active component gets broken down in your body into psychoactive and inactive components, can be influenced by genetic differences in enzymes. About one in four people have a gene that causes these enzymes to break down THC less effectively than others, which can increase the strength and duration of the effects of cannabis.

Differences in metabolism have been linked to an increased risk for substance use disorder for other drugs but not yet cannabis.

“Unfortunately, we're just beginning to understand some of the effects of how people metabolize and process cannabis,” explained Davis.

For their study, the researchers recruited 38 young adults ages 18-25 with CUD and 16 with a non-CUD substance use disorder. This age group was chosen as they are three times more likely to have CUD than teens or adults over 26 who use cannabis.

“This age group is super important to study because the brain is still developing up through young adulthood,” said Tomko. “So, this is a key time for intervention.”

Blood samples were collected from study participants, and gene variants for THC-metabolizing enzymes were tested. Participants also completed a questionnaire designed to measure their reported positive and negative effects from cannabis use. Based on their gene variant, participants were categorized as either normal or slow THC metabolizers. The researchers then correlated metabolism with the subjective effects reported by the participants.

Davis was surprised by the sex differences evident in the data.

“Looking at our data, we realized very quickly that there were sex-specific effects going on that we couldn't ignore.”

Notably, the study showed that young females with CUD were more likely to be slow metabolizers of THC compared to young females with other (non-CUD) substance use disorders. This suggests that young females who metabolize cannabis more slowly may be at higher risk for developing CUD. When looking at young adult males, the researchers found that those who had a gene variant contributing to slower THC metabolism reported more negative effects during initial cannabis use, like drowsiness, laziness and difficulty concentrating. Overall, participants of both sexes who were categorized as slow metabolizers of THC experienced more negative effects during recent cannabis use.

Although the study recruited young adults, the most important implications of its findings may be for teens. Many young adults who develop CUD start using cannabis in their teens. As the social acceptance of cannabis grows and its perceived risk diminishes, teens may use cannabis more if they are not aware of potential harms.

The study highlights that not all young people who use cannabis experience the drug the same way, and that how people metabolize THC may be one factor that could contribute to risk for CUD. Although slower THC metabolizers experience more negative effects, the experience of simultaneous positive effects may lead them to continue cannabis use regardless of bad outcomes.

“We might think that if you're experiencing negative effects, you don't continue to use, but in the face of positive, rewarding effects, maybe you do,” said Tomko.

Tomko and Davis believe it is important to educate teens about the differences in how people experience cannabis. For example, educational programs targeted to adolescents can improve their understanding of risk factors for CUD. The Just Say “Know” program, led by Lindsay Squeglia, Ph.D., at MUSC, offers presentations and hands-on training to teach middle and high school students about the neuroscience of drug addiction.

Since most people don’t get genetic testing for these potential risk factors, it’s important to understand how these findings can better inform treatment options for people struggling with CUD.

“Our study opens up new hypotheses and options to explore medications that might modify THC metabolism as a potential treatment for cannabis use disorder,” suggested Tomko.

The initial findings from this research may be particularly important in the context of the continual rise in cannabis potency that has been observed over the past couple of decades, as well as the availability of high-potency cannabis products in legal markets.

“The increases in THC levels found in cannabis could mimic some of the more pronounced effects that we see for people who are slower metabolizers,” said Davis. “The effects of cannabis are lasting longer because it's stronger THC.”

With a lack of regulation of cannabis products, combined with an increase in acceptance of cannabis use, additional research to identify risk factors for CUD will be necessary to advise vulnerable groups, like adolescents.

# # #

Research reported in this press release was supported by the National Institute on Drug Abuse and the National Center for Advancing Translational Sciences of the National Institutes of Health under award numbers K24DA038240 and UL1TR001450. The content is solely the responsibility of the authors of the underlying article and does not necessarily represent the official views of the National Institutes of Health. 

About the Medical University of South Carolina

Founded in 1824 in Charleston, MUSC is the state’s only comprehensive academic health system, with a unique mission to preserve and optimize human life in South Carolina through education, research and patient care. Each year, MUSC educates more than 3,200 students in six colleges – Dental Medicine, Graduate Studies, Health Professions, Medicine, Nursing and Pharmacy – and trains more than 900 residents and fellows in its health system. MUSC brought in more than $300 million in research funds in fiscal year 2023, leading the state overall in research funding. MUSC also leads the state in federal and National Institutes of Health funding. For information on academic programs, visit musc.edu.

As the health care system of the Medical University of South Carolina, MUSC Health is dedicated to delivering the highest-quality and safest patient care while educating and training generations of outstanding health care providers and leaders to serve the people of South Carolina and beyond. Patient care is provided at 16 hospitals (includes owned or governing interest), with approximately 2,700 beds and four additional hospital locations in development, more than 350 telehealth sites and nearly 750 care locations situated in all regions of South Carolina. In 2023, for the ninth consecutive year, U.S. News & World Report named MUSC Health University Medical Center in Charleston the No. 1 hospital in South Carolina. To learn more about clinical patient services, visit muschealth.org.

MUSC has a total enterprise annual operating budget of $5.9 billion. The nearly 26,000 MUSC family members include world-class faculty, physicians, specialty providers, scientists, students, affiliates and care team members who deliver groundbreaking education, research, and patient care.

About the SCTR Institute

The South Carolina Clinical & Translational Research (SCTR) Institute is the catalyst for changing the culture of biomedical research, facilitating the sharing of resources and expertise and streamlining research-related processes to bring about large-scale change in the clinical and translational research efforts in South Carolina. Our vision is to improve health outcomes and quality of life for the population through discoveries translated into evidence-based practice. To learn more, visit https://research.musc.edu/resources/sctr