Anxiety and Depression are the most common psychiatric illnesses in the United States, affecting ~40 million people every year. There are seemingly countless antidepressants on the market, falling into several different categories based on their mechanism of action and particular chemical composition. These drugs are incredibly popular; a study from 2016, summarized here, showed that 1 in 6 American adults currently take psychiatric drugs. Antidepressants have helped millions of people world-wide, but they often come with serious side effects. Furthermore, they are not a one-size-fits-all kind of drug; what works for one person won’t work for another, leaving those who are already anxious and depressed on the lookout for something new and more effective.
These conditions are difficult to treat, partly due to the fact that we don’t entirely understand their causes. One potential cause is a failure of new neuron formation in the hippocampus. This part of the brain is responsible for long-term memory formation. Stress affects the ability to generate new neurons in the hippocampus, and this inability has been linked to chronic anxiety and depression. Therefore, some anti-depressants act to increase the generation of new hippocampal neurons, with varying degrees of success.
Cannabis and CBD-based products are gaining popularity for their anxiety relieving properties. Research in animal models has demonstrated the effectiveness of CBD for reducing anxiety, results that are attested to by anecdotal reports by patients. How CBD is able to relieve stress is still under investigation, but a recently released study sheds new light on this question. Researchers were able to show that CBD treatments led to decreased anxiety in chronically stressed mice, and that this was associated with increased neural growth in the hippocampus. This work provides crucial insight into understanding how CBD acts to relieve anxiety and stress.
To perform this research, the authors needed to induce anxiety in their mice. This was done through the use of Chronic Unpredictable Stress (CUS). The mice were subjected to mild environmental stresses at irregular intervals over the course of two weeks. Each day, the mice would also receive an injection of either CBD or a non-active control solution. At the end of the two week period, the mice underwent two tests to assess their anxiety levels. The stressed mice were significantly more anxious than those that hadn’t experience CUS. Further, CBD was able to improve performance on these tests, suggesting a reduction in anxiety in these mice.
CBD is known to interact with the cannabinoid receptors CB1 and CB2. The authors wanted to determine if these receptors were necessary for anxiety relief. In a set of experiments similar to those above, mice were given secondary injections of compounds that block each CB receptor individually. The rationale is that if one receptor is blocked, and CBD is unable to reduce anxiety, then that receptor must be important for CBD’s action. In these experiments, blocking either one led to a reduction in CBD’s effect on anxiety, indicating that they both play a role.
Following the anxiety testing, the researchers dissected out the brains of these mice and looked for markers of neural growth and remodeling in the hippocampus. Mice without CBD treatment had impaired neural growth, and those neurons that did grow had fewer connections as those in unstressed mice. CBD treatment prevented all of these defects in the stressed mice. Interestingly, it was shown that CB1 and CB2, while both important for anxiety relief, affected neuronal growth in different ways. Finally, they found evidence that CBD may be acting, in part, by improving the function of endocannabinoids, chemicals produced by the brain that are similar to THC and CBD.
This is the first paper to look at the long-term effects of CBD on neural growth and remodeling in the hippocampus. Previous work had hinted at these effects, but they used isolated cells grown in culture. This study expands on that work by looking at neurons in their natural environment. Further, this work stands out because of its methodology. Most work in this area focuses on treating mice after inducing anxiety. In this work, they administered CBD treatments while the mice were experiencing stress. Based on these results, the authors conclude that CBD works not by fixing existing damage, but by preventing it in the first place. Had they followed the methods used by others, they would have missed this key conclusion.
Another interesting finding is that CBD may be acting in a similar manner to certain antidepressants. A gene called GSK3β is known to control the generation and maturation of neurons. Some anti-depressants target this gene, turning it off and allowing neurons to grow. The authors found that CBD also inactivated GSK3β, but by an unknown mechanism. Elucidating this mechanism will not only explain the effects of CBD, but will provide more potential targets for a new generation of anti-depressants.
Of course, mice are not people, and so it is hard to say if these same results will extend to humans. However, pre-clinical data like this is often the starting point for the initiation of clinical trials. Given the relative safety of CBD, it is likely that such trials may be underway sooner rather than later.