**6. Conclusions**

Growing evidence has revealed that the ECS modulates direct olfactory processes such as odor sensitivity or olfactory learning and memory. Across different brain olfactory areas, the ECS appears to play an essential role in the control of synaptic transmission and plasticity, but also in the regulation of vital behaviors that depend on olfaction, such as the feeding state of the individual (Figure 1; [59]). However, the physiological impact of the endocannabinoid-mediated plasticity, the contribution of CB1 receptors during other olfactory-dependent behaviors, and the contribution of each olfactory brain region (e.g., OE, MOB, PC) during specific behaviors remain to be elucidated. Furthermore, the role of other components of the ECS in olfactory processes is less clear, such as the role of CB2 receptors, which are described to be present in the OE [27]. This highlights the importance of continuing with this exciting line of research. To the same extent, there is a lack of direct evidence about the participation of other olfactory-related structures in cannabinoid-mediated effects, for example, the olfactory tubercle (OT). In fact, the OT is a target of different hormones and local modulators regulating feeding behavior and motivation [48]. Thus, it is reasonable to think about a potential cross-link between cannabinoid signaling and hormonal regulation in olfactory related behaviors taking place in the OT.

Besides the studies regarding the functions of the ECS in primary olfactory structures, it is important to take into account that CB1 receptors are present and modulate associated olfactory areas (i.e., amygdala, orbitofrontal cortex, hippocampus or periaqueductal gray; [41–44]), suggesting that olfactory processing that involves the control of different brain structures might also be modulated by the ECS. In humans, the main psychoactive compound of cannabis has been shown to induce an increase in olfactory perception and disturbs odor discrimination and pleasantness [60–62]. Furthermore, a recent study shows that cannabis consumption could also affect other neurotransmitter systems in olfactory structures [63]. One of the main characteristics of the CB1 receptor's activity is its bimodal activity: the cell-type of where it is expressed can lead to opposite effects (e.g., CB1 in GABAergic cells promotes satiety while in glutamatergic cells it induces hunger) [64]. This bimodal action could also be present in olfactory processes considering the pattern of expression of the CB1 receptors, but future research is needed to clarify this crucial point.

The interconnectivity between olfactory areas, together with the tight ECS-control of various types of cells and subcellular locations, makes the determination of the different roles of CB1 receptors in the olfactory system very complex and challenging. A better understanding of such interactions will result not only in a significant advance for neuroscience, but could also lead to novel human-based studies targeting specific populations. Interestingly, alterations of ECS functioning have been shown to contribute to the development of neurological and neuropsychiatric disorders in which loss of smell represents the early stages of the disease [65–68]. All of this information could provide the rationale to propose a combined use of olfactory manipulations with ECS-based pharmacotherapy to potentially treat pathological conditions.

**Figure 1.** Main functions regulated by the cannabinoid signaling described in the primary olfactory-dependent structures. The endocannabinoid system controls various functions that depend on the olfactory areas involved. The colors in the boxes indicate which structure is involved in the associated function. The scheme also shows how the different localization of the cannabinoid type-1 (CB1) receptor potentially modulates the flow of olfactory information from early sensory coding to more complex computations, and is modulated by peripheral signals, resulting in behavioral outputs. GL: glomerular layer; GCL: granular cell layer; the olfactory cortex includes both the anterior olfactory nucleus and the piriform cortex, ECS: endocannabinoid system.

**Author Contributions:** Conceptualization, E.S-G.; Writing-Original Draft Preparation, G.T.; Writing-Review & Editing, P.G., G.M. and E.S.-G.; Supervision, E.S.-G. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by Fondation pour la Recherche Médicale (FRM, FDT20170436845) (to G.T.); The Basque Government (ITI230-19), Red de Trastornos Adictivos, Instituto de Salud Carlos III (ISC-III) and European Regional Development Funds-European Union (ERDF-EU; gran<sup>t</sup> RD16/0017/0012), MINECO/FEDER, UE (SAF2015-65034-R) (to P.G.); EU–FP7 (PAINCAGE, HEALTH-603191), European Research Council (Endofood, ERC–2010–StG–260515; CannaPreg, ERC-2014-PoC-640923, Micabra) (to G.M.); Ikerbasque (The Basque Foundation for Science) and MINECO (Ministerio de Economía y Competitividad) PGC2018-093990-A-I00 (to E.S.-G.).

**Conflicts of Interest:** The authors declare no conflict of interest.
