New research show how tobacco may worsen brain-related outcomes in cannabis users

A new study suggests that people who use both cannabis and tobacco have elevated levels of a key enzyme in their brain compared to people who only use cannabis. This finding may offer a biological explanation for why combining these substances is often linked to more severe mental health symptoms and greater difficulty quitting. The research was published in the journal Drug and Alcohol Dependence Reports.

The high rate of co-use between cannabis and tobacco products has long been a concern for public health experts. Studies have shown that individuals who use both substances often report worse clinical outcomes, including higher rates of depression and anxiety, when compared to those who use cannabis alone. Researchers from McGill University sought to understand the potential brain mechanisms that could be driving this difference.

The scientific team focused on the body’s endocannabinoid system, a complex cell-signaling network that helps regulate mood, appetite, and memory. A key component of this system is a naturally produced compound called anandamide. Lower levels of anandamide have been associated with poorer mental health, including increased symptoms of anxiety and depression.

The amount of anandamide in the brain is controlled by an enzyme called fatty acid amide hydrolase, or FAAH. The job of FAAH is to break down anandamide. When FAAH levels are high, more anandamide is broken down, leading to lower overall levels of this beneficial compound. The researchers proposed that tobacco use might increase FAAH levels, providing a reason for the negative outcomes observed in people who co-use cannabis and tobacco.

To investigate this possibility, the researchers recruited 13 participants who were regular cannabis users. They then divided these individuals into two groups based on their tobacco use. The first group consisted of five people who used both cannabis and at least one cigarette daily. The second group was made up of eight people who used cannabis but had no current tobacco use.

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The two groups were closely matched on several characteristics, including age, sex, and patterns of cannabis consumption, such as how long they had been using and how much they used per week. This matching was done to help ensure that any observed differences in the brain were more likely related to tobacco use rather than other factors.

Each participant underwent a sophisticated brain imaging procedure known as positron emission tomography. This technique allows scientists to visualize and measure the activity of specific molecules in the living human brain. To measure FAAH levels, the researchers injected participants with a special imaging agent called [11C]CURB, which is designed to bind directly to the FAAH enzyme.

By tracking this imaging agent, the scanner could produce a map showing the concentration of FAAH in different parts of the brain. The researchers focused their analysis on six brain regions known to be rich in both cannabinoid and nicotine receptors, including the prefrontal cortex, hippocampus, and cerebellum. They also accounted for each participant’s sex and a common genetic variation that is known to influence FAAH levels.

The results of the brain scans revealed a distinct difference between the two groups. The individuals who used both cannabis and tobacco had consistently higher levels of the FAAH enzyme across all brain regions examined. The difference was statistically significant in two areas: the substantia nigra, a region involved in reward and movement, and the cerebellum, an area critical for motor control and cognitive functions.

A similar, though not statistically significant, trend was observed in the sensorimotor striatum. The magnitude of the difference in the substantia nigra and cerebellum was considered large, indicating a substantial biological effect. These findings provide the first direct evidence in humans that co-using tobacco is associated with higher FAAH activity than using cannabis alone.

The researchers also explored whether the amount of substance use was related to FAAH levels. They found a positive correlation between the number of cigarettes smoked per day and the level of FAAH in the cerebellum. This means that individuals who smoked more cigarettes tended to have higher concentrations of the enzyme in that brain region. In contrast, the team found no significant association between the amount of cannabis used and FAAH levels.

The study’s authors suggest that these elevated FAAH levels could be the mechanism underlying the poorer clinical outcomes seen in people who co-use. Higher FAAH would lead to lower anandamide, which in turn is linked to mood and anxiety problems. This offers a neurobiological pathway that could explain why this group often experiences greater mental health challenges and more severe withdrawal symptoms.

The researchers acknowledged several limitations to their study. First and foremost, the sample size was very small, meaning the results should be considered preliminary. Larger studies are needed to confirm these findings and to determine if the same pattern holds true in other brain regions.

Additionally, the study did not include a group of people who only used tobacco or a control group of non-users. Without these comparison groups, it is difficult to determine if the increased FAAH is due to tobacco use itself or a specific interaction between tobacco and cannabis. The study also did not directly measure participants’ levels of depression or anxiety, so it could not draw a direct line between FAAH levels and clinical symptoms.

Future research is needed to address these points. Scientists recommend conducting larger studies that include groups of tobacco-only users and healthy controls. Such studies could clarify the independent and combined effects of cannabis and tobacco on the endocannabinoid system. Connecting these brain measurements with clinical assessments of mood and anxiety would also be an important next step.

Despite its preliminary nature, this research opens up a new avenue for understanding the risks of combining cannabis and tobacco. If confirmed, the findings could point toward new therapeutic strategies. Medications that inhibit the FAAH enzyme are already under development, and this work suggests they might one day be a useful tool for treating cannabis use disorder, especially for the large number of individuals who also use tobacco.

The study, “A preliminary investigation of tobacco co-use on endocannabinoid activity in people with cannabis use,” was authored by Rachel A. Rabin, Joseph Farrugia, Ranjini Garani, Romina Mizrahi, and Pablo Rusjan.