Anxiety disorders are a common reality for many Americans, affecting approximately 15% of the population each year. These disorders often go hand-in-hand with alcohol-related problems, creating a problematic combination that makes treatment difficult and increases relapse rates. Long-term alcohol use and periods of abstinence intensify anxiety and stress sensitivity, perpetuating a harmful cycle of use.
A recent study published in Frontiers in Neuroscience investigated the potential of cannabinoids, specifically cannabidiol (CBD) and a mixture of CBD and tetrahydrocannabinol (THC), to manage anxiety during alcohol withdrawal in mice. This study suggests that the timing of cannabinoid administration is crucial in determining their effectiveness in reducing anxiety.
The primary goal of the study was to assess whether cannabinoids could alleviate anxiety during alcohol withdrawal, potentially reducing relapse rates in people with alcohol use disorders. Previous research has shown that cannabinoids possess therapeutic properties for anxiety and other stress-related disorders, but their effects on alcohol withdrawal-induced anxiety were not well documented. Additionally, since many cannabis users use mixtures of CBD and THC, the researchers wanted to understand how these substances, alone or in combination, affected anxiety during alcohol withdrawal.
Yuval Silberman, associate professor of neural and behavioral sciences and associate dean for interdisciplinary research at Penn State College of Medicine, said, “In recent years, cannabinoids such as CBD and THC have been discussed as potential therapies to improve a variety of mental health disorders, including alcohol use disorder. There are numerous potential reasons why cannabinoids might reduce alcohol consumption. We sought to examine two potentially interactive reasons: reduction in anxiety-like behavior induced by alcohol withdrawal and alterations in the known effects of alcohol on modulating neuroimmune cell activity.”
To conduct the study, the researchers used a sample of 248 adult mice, both male and female, which they exposed to intermittent and chronic ethanol vapor to induce alcohol dependence. The mice were divided into groups and underwent 4- or 24-hour abstinence periods after their last exposure to ethanol vapor. The researchers then treated the mice with a vehicle solution, 10 mg/kg of CBD, or a 3:1 mixture of CBD and THC. Thirty minutes before behavioral testing, the mice were either left unstressed or exposed to restraint stress for 30 minutes. They were then subjected to an open-field test to measure anxiety-like behavior.
In addition to the observed behaviors, the researchers analyzed plasma levels of CBD and THC and performed immunohistochemical analyses of brain tissues to assess changes in neuroimmune cell activity in the central amygdala, a region crucial for regulating anxiety and alcohol consumption.
The results showed that mice in the 4-hour withdrawal period exhibited increased anxiety and spent less time in the center of the open field, while mice in the 24-hour withdrawal period showed less anxiety. At the 4-hour withdrawal time point, both CBD and the CBD blend increased anxiety-like behaviors. However, the CBD blend in the 24-hour withdrawal period increased the time mice spent in the center, suggesting a reduction in anxiety.
Silberman emphasized the importance of timing of administration: “Timing matters. We looked at two short-term alcohol withdrawal time points (4 hours and 24 hours) and found that CBD and CBD:THC increased anxiety at the 4-hour withdrawal time point, whereas CBD reduced anxiety-like behavior at the 24-hour withdrawal time point. The effects of cannabinoids may be different when used alone or in combination.”
The researchers also observed changes in neuroimmune cell activity in the central amygdala, highlighting a decrease in the number of astrocytes and microglia at 4 hours of withdrawal. CBD and the CBD blend normalized these changes, suggesting a possible mechanism by which cannabinoids might influence anxiety during alcohol withdrawal.
Plasma analysis revealed that mice in 24-hour abstinence had higher THC concentrations and faster CBD metabolism compared to control mice. This could partly explain the observed anxiety-reducing effects of the CBD blend in 24-hour abstinence.
Silberman concluded: “Our data showed that mice undergoing alcohol withdrawal achieved higher plasma levels of CBD and THC than mice that had not been exposed to alcohol, even though they all received the same doses originally. This may, in part, explain our findings regarding the timing of withdrawal and cannabinoid exposure.”
While these results are promising, Silberman noted that the studies were conducted in a model of passive alcohol exposure and dependence, and replicating these studies in long-term active self-administration models could provide different results. Additionally, exploring alternative routes of administration and multiple exposures to cannabinoids could yield different results.
The findings underscore the complexity of cannabinoid effects on anxiety during alcohol withdrawal and suggest several areas for future research. For example, better understanding the metabolism of these cannabinoids could provide better therapeutic strategies in the future. Collaboration across laboratories and support from the Penn State Center for Cannabis and Natural Pharmaceutical Products (CCNPP) have been crucial to the progress of this research.
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