Cannabis compounds have distinct effects on brain connectivity and blood flow, study finds

A new study in rats provides evidence that tetrahydrocannabinol (THC) and cannabidiol (CBD) have opposing effects on brain function—and that combining the two produces more muted changes than THC alone. Published in the Journal of Psychopharmacology, the research used advanced neuroimaging to compare how these cannabis-derived compounds alter patterns of communication and blood flow in the brain.

Cannabis contains a wide range of bioactive compounds, but two of its most studied constituents are THC and CBD. THC is primarily responsible for the euphoric high associated with cannabis use and exerts its effects through the cannabinoid type 1 receptor, found throughout the brain. It is also approved for medical use in treating symptoms such as nausea in chemotherapy patients, spasticity in multiple sclerosis, and chronic pain.

In contrast, CBD does not produce a high and has a very different pharmacological profile. It interacts with multiple systems in the body but does not strongly bind to cannabinoid receptors. Instead, it has shown promise as a treatment for conditions like epilepsy, anxiety, and psychosis. A pharmaceutical-grade form of CBD, known as Epidiolex, is already approved for certain seizure disorders. Research also suggests CBD may reduce neuroinflammation and protect brain cells in neurodegenerative diseases.

There is growing interest in how THC and CBD interact when used together. Products like nabiximols, which contain THC and CBD in roughly equal amounts, are already used to treat multiple sclerosis symptoms. These combination treatments are thought to allow for higher THC doses while limiting unwanted side effects, but the mechanisms behind these interactions remain unclear. The new study sought to shed light on this by examining how THC, CBD, and their combination affect brain connectivity and blood flow using non-invasive imaging.

“We were interested in directly comparing the effects of the two best-known cannabis constituents: cannabidiol (CBD) and tetrahydrocannabinol (THC),” said study author Diana Cash, an associate professor at King’s College London and director of The Brain Centre.

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“CBD, which is non-psychoactive, is often promoted as a treatment for a wide range of issues—from inflammation to stress and insomnia—although the scientific evidence does not always support these claims. THC, on the other hand, is often stigmatized because it is the psychoactive component of cannabis, the one responsible for the ‘high,’ yet it also has recognized therapeutic benefits.”

“We wanted to investigate how these compounds act alone and in combination, as in ‘nabiximols,’ a licensed medication used to treat pain and spasticity in multiple sclerosis. We used rats as an experimental model but applied clinically relevant brain imaging techniques to measure neural connectivity and blood flow. These kinds of controlled studies are difficult to perform in humans due to ethical and practical challenges, such as prior recreational drug use, but of course, animal research also comes with limitations when translating findings to people.”

The researchers used 48 adult male Sprague Dawley rats divided into four groups. Each group received a single dose of either THC, CBD, a THC:CBD combination, or a placebo. The THC dose was 10 milligrams per kilogram, the CBD dose was 150 milligrams per kilogram, and the combination contained both THC and CBD in a ratio similar to that used in nabiximols. About two hours after administration, the rats were scanned using magnetic resonance imaging to assess two key brain functions: resting-state functional connectivity and cerebral blood flow.

Functional connectivity refers to the level of synchrony in activity across different brain regions. It is measured by analyzing patterns in blood oxygenation over time and provides insight into how different parts of the brain communicate. Cerebral blood flow, on the other hand, is a measure of how much blood is reaching different brain areas, serving as a proxy for neural activity and metabolic demand.

The imaging data were analyzed using a combination of graph theory and statistical modeling. This allowed the researchers to examine both overall brain-wide changes and effects within specific neural networks. They also analyzed tissue samples to measure the concentrations of THC, CBD, and their metabolites in the brain and plasma.

The most pronounced effects were seen in the THC group. Rats given THC showed widespread increases in functional connectivity across the brain, especially between cortical regions and between the cortex and the hippocampus and striatum. Graph theory analysis revealed that THC increased both the strength and clustering of connections, suggesting more tightly knit communication within and between brain networks. Cerebral blood flow was also significantly elevated in many regions, including the thalamus, striatum, and cingulate cortex.

The rats given CBD, in contrast, showed a general reduction in functional connectivity. This reduction was not localized to a specific area but was more diffuse across the brain. Unlike THC, CBD did not produce any significant changes in cerebral blood flow. These results suggest that CBD may have a dampening or calming effect on neural synchrony, which aligns with its potential use in treating anxiety and seizure disorders.

“We were somewhat surprised that CBD reduced brain connectivity,” Cash told PsyPost. “However, this is not necessarily a negative outcome—it’s possible that THC-induced hyperconnectivity reflects an overstimulated state, whereas CBD may allow the brain to “reset” or relax. This interpretation is speculative, especially since our work was conducted in rats rather than humans, but it is an intriguing possibility.”

When THC and CBD were given together, the effects were intermediate. Functional connectivity and cerebral blood flow were both elevated compared to the placebo group, but not to the same degree as with THC alone. Seed-based analyses showed that the combined treatment produced some of the same patterns as THC, such as increased connectivity between the striatum and sensorimotor cortex, but the effects were less robust.

Importantly, the researchers observed that CBD seemed to moderate some of THC’s impact on brain activity. This was evident in both the graph theory metrics and the regional analyses. Increases in connectivity and blood flow were smaller in the combination group than in the THC-only group, even though THC levels in the brain were actually higher in the combination condition. This finding supports the idea that CBD can alter THC’s effects, not just by reducing its absorption or metabolism but by actively influencing brain function.

The researchers also used a multivariate statistical approach to identify distinct neural signatures associated with each treatment. This analysis revealed that THC, CBD, and the combination treatment each produced unique patterns across connectivity and blood flow measures. These signatures were consistent enough to differentiate the drug groups and could be useful in future efforts to classify how other cannabis-based compounds affect the brain.

“We found that THC strongly increased both brain connectivity and blood flow, while CBD had no effect on blood flow but significantly reduced connectivity,” Cash explained. “The combination produced an effect somewhat similar to THC, but much weaker—suggesting that CBD can dampen or modulate the effects of THC. This could help explain why traditional cannabis, which contains both compounds, is often reported to produce milder effects compared to newer strains bred for very high THC content.”

“Our results are broadly consistent with several previous studies in both animals and humans, though the literature is quite mixed. One striking aspect we noticed is just how heterogeneous the findings in this field are—likely reflecting differences in methods, models, and populations studied.”

While the findings offer insight into how cannabis compounds affect brain function, there are limitations to consider. The study was conducted in healthy, anesthetized male rats, which means the results may not fully translate to human users or to individuals with medical conditions. The use of anesthesia, although necessary for high-quality imaging, may interact with cannabinoid signaling and affect brain activity in ways that do not occur in awake brains.

Additionally, the study only examined the short-term effects of a single dose. Longer-term studies are needed to understand how repeated use of THC, CBD, or their combination might reshape brain networks over time. There is also a need to study female animals and include disease models to better assess the therapeutic potential of these compounds.

Future research may build on these findings by incorporating additional brain imaging techniques, testing different doses and delivery methods, or examining how other cannabinoids and non-cannabinoid components of cannabis influence brain activity. The researchers note that they are working toward creating a comprehensive database of brain imaging profiles for different drugs. Such a resource could aid in drug development by linking specific brain signatures to therapeutic or side effect profiles.

“The biggest limitation is that our experiments were conducted in animals, and the rats were lightly sedated during imaging to minimize stress,” Cash said. “These factors limit direct generalization to humans. Still, one of our main goals was to establish a framework for comparing the brain effects of different compounds, including synthetic cannabinoids and other psychoactive drugs. In that sense, the study provides a valuable blueprint for future work.”

“We are currently extending this work by profiling a range of drugs that affect the brain. Ultimately, we aim to build a database of brain signatures using advanced imaging techniques, combined with AI and machine learning, to support drug discovery and the development of new therapeutics.”

“We would like to emphasize the importance of using comparable brain imaging approaches in both animal and human studies, to make results more directly translatable,” Cash added. “Standardization of imaging analysis methods across research groups would also help the field move forward more effectively.”

The study, “Acute cannabidiol (CBD), tetrahydrocannabinol (THC) and their mixture (THC:CBD) exert differential effects on brain activity and blood flow in rats: A translational neuroimaging study,” was authored by Eilidh MacNicol, Michelle Kokkinou, Maria Elisa Serrano Navacerrada, Donna-Michelle Smith, Jennifer Li, Camilla Simmons, Eugene Kim, Michel Mesquita, Loreto Rojo Gonzalez, Tierney Andrews, Sally Loomis, Royston A Gray, Volker Knappertz, Benjamin J Whalley, Andrew C McCreary, Steven CR Williams, David Virley, and Diana Cash.