**5. Conclusions**

Besides CB1 and CB2, we identified TRPA1 as a target receptor of THC that increases intracellular calcium levels and drug uptake in RASF. Although RASF cytokine production was not altered at relevant concentrations, THC might nevertheless be an important adjunct therapy option in RA, although endocannabinoid degradation inhibitors might be even more suitable, since endocannabinoids only elicit psychotropic effects at high concentrations [76], making the side effect profile more benign compared to THC. THC, on the one hand, might increase effective drug concentrations in target cells when adminis-

tered with an antirheumatic drug (as demonstrated by PoPo3 uptake). On the other hand, THC might be used to treat comorbidities in RA and, in fact, it has been shown that THC ameliorates depression, sleep disturbances and pain [77,78]. The influence of THC on RA comorbidities might be mediated by the sympathetic nervous system, since CB1 receptors control sympathetic outflow centrally and peripherally [9,79]. TRP channels in the nervous system increase excitability and neurotransmission [80], and, therefore, it might be possible that these channels also mediate the release of soluble mediators by peripheral cells, such as fibroblasts or tyrosine hydroxylase positive cells [81] that are increased in chronic inflammation. Although speculative, THC might trigger the release of catecholamines from tyrosine-hydroxylase-positive cells or RASF via TRPA1 activation, which would increase the sympathetic tone and provide anti-inflammatory effects via β adrenoceptor signaling [82,83]. While TRPA1 activation is the main mechanism by which RASF are modulated by THC, PBMC also respond to CB1 or CB2 stimulation [84]. Since THC reduced TNF at a physiological concentration of 1 μM [85], it might be a cannabinoid-receptor-driven effect. In addition, endocannabinoid levels might be increased by THC [86] in co-culture, since RASF and lymphocytes contribute to their production [29,49] and they might also be responsible for the observed inhibitory effects. In addition, THC's complex effects on the immune response (e.g., differentiation, intracellular signaling and activation of immune cells) might also support its use in chronic inflammatory conditions, such as RA.

**Author Contributions:** Conceptualization, T.L.; methodology, T.L., S.S. and C.K.; validation, T.L., S.S., C.K. and G.P.; formal analysis, T.L., S.S., C.K. and G.P.; investigation, T.L., C.K. and S.S.; resources, G.P.; data curation, T.L., S.S., C.K. and G.P.; writing—original draft preparation, T.L.; writing—review and editing, T.L. and G.P.; visualization, T.L.; supervision, T.L. and G.P.; project administration, T.L. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by an unlimited gran<sup>t</sup> by the HILLER foundation.

**Institutional Review Board Statement:** The study was conducted in accordance with the Declaration of Helsinki and approved by the local ethics committee of Düsseldorf (2018-87-KFogU and 2018-296-KFogU).

**Informed Consent Statement:** Informed consent was obtained from all subjects involved in the study.

**Data Availability Statement:** The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

**Acknowledgments:** We thank Birgit Opgenoorth for excellent technical assistance.

**Conflicts of Interest:** The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
