Inhaled low to medium dose CBD may be an effective short-acting fusion agent[5][6].
Larger, sustained doses disrupt mitochondrial networks[1] and result in excessive neural inhibition (though this is also due to receptor binding directly, not just the secondary messenger systems).
Endocannabinoids play a role in fusion-fission cycles, biogenesis and mitophagy, as well as mobility (transport and anchoring). They do this apparently through the mtCB1R, VDAC1 and TRPV4 receptors[2][3], by modulating respiration, apoptosis through Cytochrome C, and calcium homeostasis.
This is relevant because CBD inhibits FAAH, which increases anandamide and 2-AG [4]. But I think the receptor binding effects (of CBD to CB1) are often dominant.
CBD may also have anti-cancer and senolytic activity, which appears in part to be modulated by mitophagy of unneeded mitochondria[3].
(this quote is from reference 2)
In recent years, accumulating findings have evidenced that cannabinoids, a group of endogenous and exogenous (synthetic and plant-derived) psychoactive compounds that bind to cannabinoid receptors, may modulate mitochondrial function and dynamics. As such, mitochondria have gained increasing interest as central mediators in cannabinoids' pharmacological and toxicological signatures. Here, we review the mechanisms underlying the cannabinoids' modulation of mitochondrial activity and dynamics, as well as the potential implications of such mitochondrial processes' disruption on cell homeostasis and disease. Interestingly, cannabinoids may target different mitochondrial processes (e.g., regulation of intracellular calcium levels, bioenergetic metabolism, apoptosis, and mitochondrial dynamics, including mitochondrial fission and fusion, transport, mitophagy, and biogenesis), by modulating multiple and complex signaling pathways.
At a steady state, fusion and fission processes need to be balanced to maintain a functional mitochondrial population [142], [143]. Cannabinoids seem to disrupt this equilibrium via the modulation of CB1R, thus contributing to changes in the mitochondrial morphology and function [16], [52], [56], [106], [131], [142], [143]. For example, Drori et al. (2019) reported that the intraperitoneal administration of AEA or ACEA (10 mg/kg, i.p.) to mice resulted in excessive mitochondrial fragmentation in the kidneys, as evidenced by the increased mitochondrial circularity and decreased perimeter and interconnectivity in micrographs of kidney sections [16]. Interestingly, this effect was not observed in mice lacking CB1R, suggesting that this receptor activation plays an important role in these morphological alterations. Similar findings were also documented in vitro, in HK-2 cells treated with 5 μM AEA or ACEA, as well as in the presence of JZL195, an inhibitor of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), the enzymes responsible for the degradation of AEA and 2–AG, respectively. Moreover, a significant reduction of the phosphorylation at the S637 residue of the mitochondria fission marker DRP1 was observed following in vitro exposure to CB1R agonists, indicating that the cannabinoid-induced mitochondrial abnormal morphology may be mediated, at least partly, by post‐translational modifications of this protein[16]. This low phosphorylation may be the result of reduced activity of PKA, whose activity is inhibited after CB1R stimulation. In fact, cell exposure to H‐89 (a PKA inhibitor) also induced mitochondrial fragmentation and reduced DRP1 phosphorylation, suggesting that PKA inhibition occurs downstream of CB1R activation and upstream of DRP1 dephosphorylation in this cascade [16]. In addition, PKA also inhibits ERK1/2, which has been shown to phosphorylate DRP1 and further promote mitochondrial fission [144], [145].
We can also look at a study with THC showing excessive fission events and network disruption, which again supports the idea that CBD can be used advantageously (CBD being the near pharmacological opposite of THC).
Delta‐9‐tetrahydrocannabinol disrupts mitochondrial function and attenuates syncytialization in human placental BeWo cells
2020
https://www.ncbi.nlm...les/PMC7336740/
THC disrupted mitochondrial function, increased markers of mitochondrial fission and cellular stress in BeWo cells. This was coincident with reduced BeWo cell fusion and secretion of important fetal growth signals, hPL and IGF2. These changes were mediated, in part, via the CB1 receptor in syncytialized BeWo cells.
References
[1] Gross, C., Ramirez, D. A., McGrath, S., & Gustafson, D. L. (2021). Cannabidiol Induces Apoptosis and Perturbs Mitochondrial Function in Human and Canine Glioma Cells. Frontiers in pharmacology, 12, 725136. https://doi.org/10.3...har.2021.725136
[2] Malheiro, R. F., Carmo, H., Carvalho, F., & Silva, J. P. (2023). Cannabinoid-mediated targeting of mitochondria on the modulation of mitochondrial function and dynamics. Pharmacological research, 187, 106603. https://doi.org/10.1...hrs.2022.106603
[3] Huang, T., Xu, T., Wang, Y., Zhou, Y., Yu, D., Wang, Z., He, L., Chen, Z., Zhang, Y., Davidson, D., Dai, Y., Hang, C., Liu, X., & Yan, C. (2021). Cannabidiol inhibits human glioma by induction of lethal mitophagy through activating TRPV4. Autophagy, 17(11), 3592–3606. https://doi.org/10.1...27.2021.1885203
[4] Leweke, F., Piomelli, D., Pahlisch, F. et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry 2, e94 (2012). https://doi.org/10.1038/tp.2012.15
[5] Chan, J. Z., & Duncan, R. E. (2021). Regulatory Effects of Cannabidiol on Mitochondrial Functions: A Review. Cells, 10(5), 1251. https://doi.org/10.3390/cells10051251
[6] da Silva, V. K., de Freitas, B. S., da Silva Dornelles, A., Nery, L. R., Falavigna, L., Ferreira, R. D., Bogo, M. R., Hallak, J. E., Zuardi, A. W., Crippa, J. A., & Schröder, N. (2014). Cannabidiol normalizes caspase 3, synaptophysin, and mitochondrial fission protein DNM1L expression levels in rats with brain iron overload: implications for neuroprotection. Molecular neurobiology, 49(1), 222–233. https://doi.org/10.1...2035-013-8514-7
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