Rafael Maldonado, group leader of the Neuropharmacology Lab of the Department of Experimental and Health Sciences at Pompeu Fabra University, is participating in a review of the importance of the endocannabinoid system in the processes of anxiety, fear and stress. The work highlights the use of cannabinoids as a possible treatment against post-traumatic stress disorders and fragile X syndrome.

The endocannabinoid system acts in all brain regions that are important for processing anxiety, fear and stress. CB1 receptor, the main component of this system, plays a crucial role in these processes. Cannabinoids, both acquired externally, as could be the tetrahydrocannabinol (THC) present in cannabis, and produced naturally by our organism, can bind the CB1 receptor.

Using cannabinoids without side effects

Clinical findings suggest a negative correlation between endocannabinoid (eCB) system activity and anxiety. The use of exogenous cannabinoids as an anxiolytic treatment involves unacceptable side effects. But, what if these secondary effects could be inhibited? Researchers have blocked the pathways involved in the negative side effects related to the administration of cannabinoids obtaining positive results for animal models. The active ingredient of cannabis, THC, enhances fear extinction in humans. By avoiding its side effects, THC could be used as a treatment against post-traumatic stress disorders.

On the other hand, future prospects are not only based on boosting the activity of cannabinoids. Their receptors are also considered as a therapeutic target. Patients with fragile X syndrome suffer mental retardation and anxiety, among others. It has been proved that blocking receptors CB1 and CB2, respectively, reduces cognitive alterations and anxiety in fragile X phenotype rodents.

The complexity of the endocannabinoid system

Exogenous cannabinoids influence anxiety behaviours in a biphasic manner depending on the dose: low doses cause a decrease in anxiety before external stimuli, while high doses cause the opposite effect. While anxiety is elicited by potentially dangerous but unspecific future threats, fear is the response to actual specific threatening stimuli. The endocannabinoid system is also present in the brain regions involved in fear and it plays a key role in the so-called fear-memory, which is the ability to memorize dangerous stimuli.

Apart from the processes of anxiety and fear, the study considers the involvement of the endocannabinoid system in stress situations. This system seems to be affected by stress situations as part of the general alterations they cause to synaptic plasticity. In this case, CB1R is crucial, as its damage due to chronic stress can trigger affective disorders.

Cannabis has been used for centuries as a recreational drug, however the mechanisms of action of its active constituents (cannabinoids) and their endogenous counterparts (endocannabinoids) have only been discovered relatively recently. Cannabinoid receptors are expressed widely throughout the brain and, over the past few decades, the breadth of their influence on neuronal function has become clear, although much still remains to be understood. 

Reference work: Beat Lutz, Giovanni Marsicano, Rafael Maldonado & Cecilia J. Hillard. The endocannabinoid system in guarding against fear, anxiety and stress. Nature Reviews Neuroscience, December 2015. doi:10.1038/nrn4036