Dear Editor,Cannabinol interactions with the melatonergic pathwayI read with interest the recent article by Anderson and colleagues highlighting the suppression of cytochrome P450 (CYP)1A2 by cannabinol, thereby upregulating melatonin availability [1]. As CYP1A2, like CYP2C19, can ‘backward converts’ melatonin to its precursor N-acetylserotonin (NAS) via O-demethylation [2], it will be important to investigate cannabinol effects on the NAS/melatonin ratio. NAS is brain-derived neurotrophic factor (BDNF) mimic, via the activation of the BDNF receptor tyrosine receptor kinase (Trk)B [3], indicating that some of the benefits of cannabinol in cancer and other proliferative conditions may be mediated by decreasing the proliferative effects of NAS at TrkB and increasing the tumor apoptotic effects of melatonin, with potential significant consequences in proliferative conditions, such as cancer and endometriosis [4,5], which are powerfully regulated by the aryl hydrocarbon receptor (AhR), the major inducer of CYP1A2. This is given some support by cannabinol utility in a number of cancers [6], as well as in neurodegenerative conditions where the regulation of the melatonergic pathway is an important treatment target [7]. The association of cannabinol with the melatonergic pathway may therefore be a significant aspect of core pathophysiological processes across diverse medical presentations.Cannabinol also directly regulates mitochondrial function, including mitophagy [8]. As melatonin is produced within mitochondria and the AhR is also expressed on mitochondria where it regulates function [7], cannabinol has significant impacts on core processes of energy and oxidant production [8]. Cannabinol analogues also enhance mitochondrial function, indicating scope for pharmaceutical development [9], including via mitochondrial melatonergic pathway regulation. Cannabinol induces an M2-like macrophage phenotype, which previous data links to macrophage melatonin production and autocrine effects [10], indicating that the cannabinol regulation of CYP1A2 and the AhR thereby upregulating the melatonergic pathway may be important to how immune cells modulate pathophysiological processes.The article by Anderson and colleagues therefore will therefore contribute to driving future research of core processes and novel treatments that are relevant across diverse medical presentations.Yours FaithfullyGeorge AndersonHead of ResearchCRC Scotland & London.References1. Anderson, Lyndsey L et al. “Preclinical Evidence for a Drug-Drug Interaction Between Cannabinol and Melatonin.” Basic & clinical pharmacology & toxicology  vol. 136,1 (2025): e14120. doi:10.1111/bcpt.14120.2. Mokkawes, Thirakorn et al. “Melatonin Activation by Human Cytochrome P450 Enzymes: A Comparison between Different Isozymes.” Molecules (Basel, Switzerland)  vol. 28,19 6961. 6 (2023), doi:10.3390/molecules28196961.3. Jang, Sung-Wuk et al. “N-acetylserotonin activates TrkB receptor in a circadian rhythm.” Proceedings of the National Academy of Sciences of the United States of America  vol. 107,8 (2010): 3876-81. doi:10.1073/pnas.09125311074. Anderson, George. “Tumor Microenvironment and Metabolism: Role of the Mitochondrial Melatonergic Pathway in Determining Intercellular Interactions in a New Dynamic Homeostasis.” International journal of molecular sciences  vol. 24,1 311 (2022), doi:10.3390/ijms240103115. Anderson, George. “Endometriosis Pathoetiology and Pathophysiology: Roles of Vitamin A, Estrogen, Immunity, Adipocytes, Gut Microbiome and Melatonergic Pathway on Mitochondria Regulation.” Biomolecular concepts  vol. 10,1 133-149. (2019), doi:10.1515/bmc-2019-00176. ALSalamat, Husam A et al. “Cannabis and cancer: unveiling the potential of a green ally in breast, colorectal, and prostate cancer.” Journal of cannabis research  vol. 6,1 24. (2024), doi:10.1186/s42238-024-00233-z7. Anderson, George. “Physiological processes underpinning the ubiquitous benefits and interactions of melatonin, butyrate and green tea in neurodegenerative conditions.” Melatonin Research vol 7, 1 (2024), doi: 10.32794/mr112500168. Gugliandolo, Agnese et al. “Transcriptome Highlights Cannabinol Modulation of Mitophagy in a Parkinson’s Disease In Vitro Model.” Biomolecules  vol. 13,8 1163. (2023), doi:10.3390/biom130811639. Liang, Zhibin et al. “Fragment-based drug discovery and biological evaluation of novel cannabinol-based inhibitors of oxytosis/ferroptosis for neurological disorders.” Redox biology  vol. 72 (2024): 103138. doi:10.1016/j.redox.2024.10313810. Muxel, Sandra Marcia et al. “NF-κB drives the synthesis of melatonin in RAW 264.7 macrophages by inducing the transcription of the arylalkylamine-N-acetyltransferase (AA-NAT) gene.” PloS one  vol. 7,12 (2012): e52010. doi:10.1371/journal.pone.0052010