**6. Conclusion**

new targets and biomarkers [95]. Among the experimental models emerges the *Danio rerio (Zebrafish*), a small fish, because it has the facility of genetic manipulation and the biology of its development [96]. *Zebrafish* is particularly useful for measuring changes in the development of the nervous system [97], and its measures of sensorimotor plasticity, emotional function, cognition, and social interaction have been used to characterize the adverse effects of drug abuse such as Δ9-THC [98, 99] due to phylogenetic analyzes, which reveal the endo-

Tolerance and cross-tolerance tests for cannabinoids are also performed *in vivo*, although studies indicate that not all effects of cannabinoids are developed during these tests, for example, adrenocorticotropic hormone (ACTH) secretion is not observed in rodents during these tests, indicating low reliability and the need for greater improvement *in vivo* methods

There are several computational methods; among them, homology modeling is being used in cannabinoid studies [103], considering that the drugs utilized during the withdrawal syndrome of *C. sativa* act at a symptomatic level. The resolution of the crystalline structure of the CB1cannabinoid receptor is recent [19], and this fact favored *in silico* studies that evolve toward the planning of molecules that act as selective agonists of this receptor, mainly studies related to better understanding of the interaction and the relation structure-activity of

cannabinoid system as highly conserved between *Zebrafish* and mammals [100].

used in this sense [101, 102].

168 Recent Advances in Cannabinoid Research

**Figure 12.** Chemical structure of Stemphol.

**5.2.** *In silico*

Studies on cannabinoids were stimulated after the characterization and structural elucidation of Δ9-THC in the 1960s, and later on, the discovery of the cannabinoid system represented by CB1/CB2 receptors and binding substances to these receptors. Many *in vitro*, *in vivo,* and *in silico* trials have been developed in the last decades, and advances mainly regarding the mechanism of addiction, abuse, and withdrawal syndrome have been achieved. However, with the use of cannabinoid-based drugs and the chemical development of synthetic cannabinoids, further studies into these mechanisms are relevant, especially considering that Δ9-THC is a low-efficacy cannabinoid compared to the "new cannabinoids."

It is expected in the future that the investigations will deepen the knowledge on the mechanisms of the cannabinoids, especially those that cause chemical dependence, both as cannabinoid system and as noncanabinoid physiological systems. In this way, it is possible to increase the knowledge about the different classes of these substances and, therefore, favor the development of new models and improvement of the tests currently used in the studies related to *C. sativa*.
