Pharmacological exploitation of the endocannabinoid system: new perspectives for the treatment of depression and anxiety disorders?

 “Animal experiments suggest that drugs promoting endocannabinoid action may represent a novel strategy for the treatment of depression and anxiety disorders.

Because of its analgesic, antiemetic and tranquilizing effects, the herb Cannabis sativa has been used for medical purposes for centuries. In addition, preparations of cannabis, such as marijuana, hashish or skunk, have a long history as drugs of abuse.1 Typical effects of cannabis abuse are amnesia, sedation and a feeling of well-being described as “bliss”.2 In the middle of the last century, Raphael Mechoulam and colleagues identified Δ9-tetrahydrocannabinol (Δ9-THC) as the main psychoactive ingredient of this herb. Today, it is known that Cannabis sativa contains more than 60 substances, such as cannabidiol, cannabinol and cannabicromene, which are referred to as phytocannabinoids.3 Their lipid nature posed a significant obstacle to chemical experiments, which might explain why the discovery of phytocannabinoids occurred late compared to other natural compounds (e.g. morphine was isolated from opium in the XIX century). The molecular structure rendered it likely that Δ9-THC exerts its effects primarily by changing physico-chemical characteristics of cell membranes. Therefore it came as a surprise that specific binding sites could be identified within the mammalian brain,4 followed by isolation and characterization of endogenous binding substances, named endocannabinoids.5 The development of novel pharmacological compounds targeting receptors or ligand synthesis and degradation revealed a number of complex brain functions, which are tightly controlled by the endocannabinoid system. The aim of the present review is to briefly introduce this system and its pharmacology, to discuss its involvement in psychopathology and to illustrate its therapeutic potential.


 Malfunctions in the endocannabinoid system may promote the development and maintenance of psychiatric disorders such as depression, phobias and panic disorder. Thus, CB1 agonists or inhibitors of anandamide hydrolysis are expected to exert antidepressant and anxiolytic effects. Future studies should consider 1) the development of CB1 antagonists that cannot readily cross the blood-brain barrier, 2) shifts in the balance of CB1 vs. TRPV1 signalling, 3) the allosteric site of CB1 receptor and 4) the potential involvement of CB2 receptor in mood regulation. Striking similarities in (endo)cannabinoid action in animals and men render it likely that the new pharmacological principle outlined in the present article may find their way into clinical practice.”

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