A number of studies show that the endocannabinoid system profoundly influences both hormone secretion and metabolic processes. Animal models have represented the ideal tool for advancing the understanding of the mechanisms of these functions. However, the data derived from early studies were not
always straightforward in the conclusions. The contradictory results had to be largely attributed to the heterogeneous variety of substances, dosages, and routes of administration used in each experimental model. Studies in humans with marijuana or A9-THC were even more contradictory in their conclusions, because no standardization of dose was used and no stringent criteria (i.e., randomization) of patient recruitment were defined in nearly all the experimental models.
However, the generation of CB1_/~ mice and the introduction of CB1 receptor antagonists initially in animal models and later in humans provided a remarkable stimulus to better characterize the functions of the endocannabinoid system in the regulation of hormone secretion and metabolic processes (Fig. 3).
As a general conclusion, the endocannabinoid system appears to play a very important regulatory role in the secretion of hormones related to reproductive functions and to stress responses. These observations have led to some important clinical considerations. High levels of endocannabinoids seem to negatively affect reproduction by acting at different sites. It is therefore possible to speculate about a clinical use of CB1 receptor antagonists to ameliorate gonadotropin pulsatility or to improve fertilization capability. On the other hand, endocannabinoids are important modulators in the physiological response of the HPA axis during repetitive stress conditions and in pathological conditions, such as anxiety, phobias, depression, and posttraumatic stress disorders (16, 147). Moreover, the endocannabinoid system has been proposed as playing an important role in protection against neuro-toxicity and, possibly, certain forms of epilepsy (115, 331, 332). Drugs presumed to increase endocannabinoid tone are therefore currently proposed as a new therapeutical frontier to treat anxiety-related disorders and neurodegenerative diseases (82). The use of drugs acting as antagonists of CB1 receptor should thus be carefully monitored when administered, for instance, to patients with anxiety traits, epilepsy, or neurodegenerative disorders.
The anecdotes regarding the orexigenic properties of marijuana have nowadays been substantiated by an impressive number of reports that make it possible to definitively include cannabinoids in the large family of orexigenic signals. This large body of data provided the basis to establish a novel approach to tackle obesity and related disorders by means, as strongly suggested by the clinical trials with rimonabant, of a CB1 receptor antagonist.
During the last few years, it has become evident that multiple mechanisms of action, not solely limited to the CNS, are involved in the endocannabinoid-mediated control of food intake and energy balance. The full understanding of these modes of action may lead to the identification of the particular types of obesity where treatment with CB1 receptor antagonists work most efficiently. The potential clinical use of rimonabant will also help us to clarify how the endocannabinoid system affects the physiological functions and the pathological diseases related to hormonal secretion and energy balance.
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