The National Institutes of Health has awarded funding to a University of California, San Diego researcher for a study designed to establish what researchers describe as the first molecular framework for understanding marijuana’s proposed “entourage effect.”
The $126,003 award went to researcher Anna Love for a project titled “Molecular mechanisms of phytocannabinoid-protein interactions in the brain.” The project began in September and is scheduled to run through August 2028 as part of an NIH Pathway to Independence award administered through the National Center for Complementary and Integrative Health.
The entourage effect is the idea that combinations of cannabinoids can produce biological effects that differ from, or exceed, those caused by individual cannabinoids on their own. Despite widespread use of the term, researchers say there is still no clear molecular explanation for how such interactions might occur.
The NIH-funded project will focus heavily on minor cannabinoids, particularly cannabichromene, or CBC, and related compounds, which have received substantially less research attention than THC and CBD.
According to the project summary, Love has already discovered that CBC-type cannabinoids interact with a kinase involved in the chemical modification of anandamide, one of the body’s primary naturally occurring endocannabinoids.
Anandamide normally activates cannabinoid receptors. When phosphorylated, however, it can interact with a different class of receptors known as lysophosphatidic acid receptors. The researchers hypothesize that exposure to certain phytocannabinoids could alter the balance between those signaling systems, potentially affecting pathways involved in pain.
The new research will use biochemical methods and chemoproteomic profiling to identify additional proteins that interact with phytocannabinoids in the brain. Researchers will then examine whether those interactions are specific to individual cannabinoids or emerge when multiple cannabinoids are present together.
The project could help determine whether the entourage effect has an identifiable molecular basis rather than simply documenting differences in outcomes between cannabinoid mixtures and isolated compounds.
Researchers said the work could also uncover previously unknown cannabinoid targets relevant to pain management and provide new insight into how plant-derived cannabinoids interact with the body’s endocannabinoid system.
Love, a postdoctoral researcher at UC San Diego’s Scripps Institution of Oceanography, has previously investigated the production and biological activity of minor cannabinoids. At a 2024 NIH cannabinoid research meeting, her work included CBC and cannabichromenic acid, or CBCA, as well as the potential synergistic effects associated with exposure to mixtures of phytocannabinoids.
The newly funded project builds on that research by moving more directly into the molecular mechanisms behind those interactions.
NIH describes the study as potentially providing the “first molecular framework” for understanding the entourage effect while opening new areas of research into cannabinoid pharmacology and pain management.
