A single injection of an extremely low dose of THC significantly reduced anxiety-like behavior in mice subjected to chronic stress, with improvements still evident three weeks after treatment, according to a new study published October 12.
The study, published in the peer-reviewed Journal of Molecular Neuroscience, was conducted by researchers Meitar Grad, Hadas Volkov and Noam Shomron of Tel Aviv University in Israel. Researchers found that a THC dose of just 0.002 milligrams per kilogram of body weight produced measurable behavioral improvements in mice exposed to conditions designed to mimic aspects of major depressive disorder.
The researchers subjected mice to five weeks of chronic mild stress, including social isolation and unpredictable environmental stressors. At the beginning of the third week, some mice received a single THC injection, while others received a placebo solution. A separate group of mice that did not undergo the stress protocol served as controls.
Three weeks after treatment, researchers evaluated anxiety-like behavior using an elevated plus maze, which measures how willing mice are to explore exposed areas. Stressed mice treated with THC entered the open arms significantly more frequently than their untreated counterparts, exhibiting behavior comparable to mice that had not undergone chronic stress.
A second behavioral assessment, known as the open field test, also showed a trend toward reduced anxiety-like behavior among THC-treated mice, although the difference between treated and untreated stressed mice did not reach statistical significance.
Beyond the behavioral findings, researchers examined changes in gene expression in the hippocampus and frontal cortex, regions of the brain involved in memory, emotional regulation and stress responses.
They identified changes in several genes associated with neuronal development, synaptic signaling and the body’s response to stress, including Elmod1, Gsk3β, Sgk1 and Nr3c1. The findings suggest that ultra-low-dose THC may influence biological pathways involved in regulating anxiety and maintaining neuronal connections.
The researchers emphasized that the dose was approximately 1,000 to 10,000 times lower than conventional doses used in previous animal studies.
Unlike earlier research involving repeated THC administration, the new findings indicate that a single treatment may be sufficient to produce measurable behavioral effects weeks later, after THC has cleared the animals’ systems.
The researchers also noted that the effects of ultra-low-dose THC appear to depend on the condition of the brain. Previous studies have associated similarly small doses with cognitive impairments in healthy young mice, while finding protective effects in animals experiencing neurological damage or age-related decline.
The new study involved only male mice, and the findings have not been established in humans. Researchers measured anxiety-related behavior rather than demonstrating that THC treated depression itself.
In the stressed mice, however, the behavioral improvements were accompanied by changes in genes involved in the body’s stress-response system, including reduced Gsk3β expression and alterations in Elmod1 expression that remained detectable several weeks after the single THC injection.
