The therapeutic potential of compounds derived from Cannabis sativa is of great interest for the treatment of various diseases. However, the psychoactive effects and, in particular, the cognitive disorders that these substances cause pose a major constraint to the development of new drugs based on compounds derived from this plant.  

Research published on 9 July in PloS Biology has managed to dissociate certain therapeutic effects of cannabinoids from their main side effects. This significant breakthrough identifies new therapeutic targets in the central nervous system and allows the future design of new drugs.

The study has been directed by Rafael Maldonado, head of the Neuropharmacology Laboratory of the Department of Experimental and Health Sciences (CEXS) at Pompeu Fabra University, with Patricia Robledo, a researcher at the Hospital del Mar Research Institute (IMIM) and Xavier Viñals as first author, both members of the laboratory, involving researchers from the IMIM, a centre attached to UPF, UB and UAB.

Cannabinoid receptors and serotonergics combine and form heteromers

This study has shown that in certain brain structures, the molecules responsible for the psychoactive effects of cannabinoids, CB1 receptors, form heteromers (units of two different receptors) with 5HT2A serotonergic-type receptors, which are also targets of great therapeutic interest.

"These heteromers are responsible for some of the psychoactive effects of cannabinoids and, more specifically, of cognitive disorders, anxiety and effects related to social behaviour induced by these psychoactive substances", says Maldonado.

"The interaction between the two receptor systems was described but the mechanism was not known. It is based on the fact that the two receivers are found in the same structures of the brain, the activation of the serotonin receptor 5HT2A releases a type of endocannabinoid and of the loss of the CB1 receptor in mice disrupts activity related to serotonin in the prefrontal cortex of the brain", adds Robledo.

CB1 receptors are responsible for analgesic effects

In contrast, monomeric CB1 receptors, without attaching to the aforementioned serotonergic receptors, are responsible for certain therapeutic actions induced by cannabinoids, such as their analgesic effects.

Therefore, this paper has shown that it is possible to obtain analgesic responses from cannabinoids and, at the same time, prevent harmful, undesired effects on the memory. This is achieved through the use of blocker peptides that act by interfering and separating the CB1 receptors from the heterodimers.

As Robledo explains, "one of the effects of the main psychoactive ingredient of marijuana is the deterioration of the memory, which is limiting the medical use of this substance for pain, nausea or anxiety".

As  Maldonado adds, "the discovery of these heterodimers and the benefit obtained by preventing their formation, opens up new possibilities to design pharmacological tools to enable developing a therapeutic use of cannabinoids to avoid the main known adverse psychoactive effects of these substances".

Reference work:

Xavier Viñals, Estefanía Moreno, Laurence Lanfumey , Arnau Cordomí , Antoni Pastor , Rafael de La Torre,  Paola Gasperini, Gemma Navarro, Lesley A. Howell , Leonardo Pardo , Carmen Lluís, Enric I. Canela, Peter J. McCormick, Rafael Maldonado, Patricia Robledo (2015), " Cognitive Impairment Induced by Delta9- tetrahydrocannabinol Occurs through Heteromers between Cannabinoid CB1 and Serotonin 5-HT2A Receptors",  PLoS Biol 13(7): e1002194. doi:10.1371/journal.pbio.1002194.