THC Metabolism Could Influence Cannabis Use Disorder Risk

Summary: Researchers linked differences in THC metabolism to varying effects of cannabis use and the risk of developing Cannabis Use Disorder (CUD). The study, which included young adults with and without CUD, found that genetic differences in THC-metabolizing enzymes can lead to stronger and longer-lasting effects of cannabis, especially among females who metabolize THC more slowly.

This connection between THC metabolism and CUD risk, particularly observed in a younger demographic, underscores the importance of understanding individual physiological responses to cannabis. The findings also suggest potential for targeted interventions and the need for educational programs to inform teens and young adults about their unique risks regarding cannabis use.

Key Facts:

  1. Sex-Specific Effects: Females with slower THC metabolism are at a higher risk for CUD, while males with similar genetic variations report more negative initial effects of cannabis use.
  2. Genetic Influences: About 25% of people have a genetic variant that results in slower THC metabolism, impacting the intensity and duration of cannabis’s effects.
  3. Educational Importance: The study highlights the need for educational programs that address individual differences in cannabis experience and the risks of CUD, particularly among adolescents.

Source: Medical University of South Carolina

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.

This shows a woman and leaves.
Differences in metabolism have been linked to an increased risk for substance use disorder for other drugs but not yet cannabis. Credit: Neuroscience News

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 this CUD and genetics research news

Author: Kimberly McGhee
Source: Medical University of South Carolina
Contact: Kimberly McGhee – Medical University of South Carolina
Image: The image is credited to Neuroscience News

Original Research: Open access.
Evidence for sex differences in the impact of cytochrome P450 genotypes on early subjective effects of cannabis” by Rachel Tomko et al. Addictive Behaviors


Evidence for sex differences in the impact of cytochrome P450 genotypes on early subjective effects of cannabis

Early positive subjective effects of cannabis predict the development of cannabis use disorder (CUD). Genetic factors, such as the presence of cytochrome P450 genetic variants that are associated with reduced Δ9-tetrahydrocannabinol (THC) metabolism, may contribute to individual differences in subjective effects of cannabis.

Young adults (N = 54) with CUD or a non-CUD substance use disorder (control) provided a blood sample for DNA analysis and self-reported their early (i.e., effects upon initial uses) and past-year positive and negative subjective cannabis effects. Participants were classified as slow metabolizers if they had at least one CYP2C9 or CYP3A4 allele associated with reduced activity.

Though the CUD group and control group did not differ in terms of metabolizer status, slow metabolizer status was more prevalent among females in the CUD group than females in the control group.

Slow metabolizers reported greater past year negative THC effects compared to normal metabolizers; however, slow metabolizer status did not predict early subjective cannabis effects (positive or negative) or past year positive effects.

Post-hoc analyses suggested males who were slow metabolizers reported more negative early subjective effects of cannabis than female slow metabolizers. Other sex-by-genotype interactions were not significant.

These initial findings suggest that genetic variation in CYP2C9 and CYP3A4 may have sex-specific associations with cannabis-related outcomes. Slow metabolizer genes may serve as a risk factor for CUD for females independent of subjective effects.

Male slow metabolizers may instead be particularly susceptible to the negative subjective effects of cannabis.

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