CYP1A2 Inhibition and melatonin production, an additional sedative effect?
So, check this out. Kava has been shown in vivo to inhibit the enzymatic pathway CYP 1A2. Russmann et al 2005 found with caffeine application during kava consumption that the clearance rate of caffeine was cut in half. After kava was stopped for 30 days caffeine metabolism increased 100% [1]. This evidence gives us strong indication that kava is a viable CYP1A2 inhibitor in the human body, not just in the lab or in petri dishes.
There are a limited number of drugs that use this pathway, and some endogenous chemicals produced internally by the body. Of these natural chemicals, I would like to focus on melatonin.
Melatonin was first isolated in the late 50s with reported mild sedative effects which plays a primary role in the timing of circadian rhythms, among other functions [2]. Melatonin is produced by the pineal gland during the night [3], and advances sleep onset in adults [4]. After melatonin is produced, and exerts its effect, it begins to be metabolized. Metabolization occurs through 3 separate pathways with the overwhelming majority being with CYP1A2 through the process of hydroxylation [5].
Now, we’ve already covered that kava shows a pretty strong inhibitory affinity for this pathway. My question is, if we manage to reduce the activity of CYP 1A2 would that, in turn, cause the reduction of metabolization of melatonin, and cause an increased or additional sedative effect? Some studies show melatonin levels sky-high in those with weakened expressions of this pathway, indicating that it does make a difference in how chemicals are processed through this enzyme [6]. We can also deduce this change by looking at tobacco consumption. Polycyclic hydrocarbons in tobacco smoke induce CYP1A2, as in it increases the activity, which has shown to cause lower levels of melatonin due to the increased activity of this enzyme [7].
Could this also speak a little towards why kava is routinely consumed after the sun has gone down? Could this speak to why some people find incredible insomnia relief in kava? Maybe, but this is a big maybe, and needs much more information to form fully. There is a paucity of research related to CYP inhibition, melatonin, and increased sedation.
[1] Russmann, Stefan, Bernhard H. Lauterburg, Yann Barguil, Erwan Choblet, Pierre Cabalion, Katharina Rentsch, and Markus Wenk. 2005. “Traditional Aqueous Kava Extracts Inhibit Cytochrome P450 1A2 in Humans: Protective Effect against Environmental Carcinogens?” Clinical Pharmacology and Therapeutics. https://doi.org/10.1016/j.clpt.2005.01.021
[2] Dawson, D., and N. Encel. 1993. “Melatonin and Sleep in Humans.” Journal of Pineal Research 15 (1): 1–12. https://doi.org/10.1111/j.1600-079x.1993.tb00503.x
[3] Skene, D. J., E. Papagiannidou, E. Hashemi, J. Snelling, D. F. Lewis, M. Fernandez, and C. Ioannides. 2001. “Contribution of CYP1A2 in the Hepatic Metabolism of Melatonin: Studies with Isolated Microsomal Preparations and Liver Slices.” Journal of Pineal Research 31 (4): 333–42. https://doi.org/10.1034/j.1600-079x.2001.310408.x
[4] Braam, W., H. Keijzer, H. Struijker Boudier, R. Didden, M. Smits, and L. Curfs. 2013. “CYP1A2 Polymorphisms in Slow Melatonin Metabolisers: A Possible Relationship with Autism Spectrum Disorder?” Journal of Intellectual Disability Research: JIDR 57 (11): 993–1000. https://doi.org/10.1111/j.1365-2788.2012.01595.x
[5] Ma, Xiaochao, Jeffrey R. Idle, Kristopher W. Krausz, and Frank J. Gonzalez. 2005. “Metabolism of Melatonin by Human Cytochromes p450.” Drug Metabolism and Disposition: The Biological Fate of Chemicals 33 (4): 489–94. https://doi.org/10.1124/dmd.104.002410
[6] Braam, W., I. van Geijlswijk, Henry Keijzer, Marcel G. Smits, Robert Didden, and Leopold M. G. Curfs. 2010. “Loss of Response to Melatonin Treatment Is Associated with Slow Melatonin Metabolism.” Journal of Intellectual Disability Research: JIDR 54 (6): 547–55. https://doi.org/10.1111/j.1365-2788.2010.01283.x
[7] Ursing, Carina, Christer von Bahr, Kerstin Brismar, and Sven Röjdmark. 2005. “Influence of Cigarette Smoking on Melatonin Levels in Man.” European Journal of Clinical Pharmacology 61 (3): 197–201. https://doi.org/10.1007/s00228-005-0908-7
So, check this out. Kava has been shown in vivo to inhibit the enzymatic pathway CYP 1A2. Russmann et al 2005 found with caffeine application during kava consumption that the clearance rate of caffeine was cut in half. After kava was stopped for 30 days caffeine metabolism increased 100% [1]. This evidence gives us strong indication that kava is a viable CYP1A2 inhibitor in the human body, not just in the lab or in petri dishes.
There are a limited number of drugs that use this pathway, and some endogenous chemicals produced internally by the body. Of these natural chemicals, I would like to focus on melatonin.
Melatonin was first isolated in the late 50s with reported mild sedative effects which plays a primary role in the timing of circadian rhythms, among other functions [2]. Melatonin is produced by the pineal gland during the night [3], and advances sleep onset in adults [4]. After melatonin is produced, and exerts its effect, it begins to be metabolized. Metabolization occurs through 3 separate pathways with the overwhelming majority being with CYP1A2 through the process of hydroxylation [5].
Now, we’ve already covered that kava shows a pretty strong inhibitory affinity for this pathway. My question is, if we manage to reduce the activity of CYP 1A2 would that, in turn, cause the reduction of metabolization of melatonin, and cause an increased or additional sedative effect? Some studies show melatonin levels sky-high in those with weakened expressions of this pathway, indicating that it does make a difference in how chemicals are processed through this enzyme [6]. We can also deduce this change by looking at tobacco consumption. Polycyclic hydrocarbons in tobacco smoke induce CYP1A2, as in it increases the activity, which has shown to cause lower levels of melatonin due to the increased activity of this enzyme [7].
Could this also speak a little towards why kava is routinely consumed after the sun has gone down? Could this speak to why some people find incredible insomnia relief in kava? Maybe, but this is a big maybe, and needs much more information to form fully. There is a paucity of research related to CYP inhibition, melatonin, and increased sedation.
[1] Russmann, Stefan, Bernhard H. Lauterburg, Yann Barguil, Erwan Choblet, Pierre Cabalion, Katharina Rentsch, and Markus Wenk. 2005. “Traditional Aqueous Kava Extracts Inhibit Cytochrome P450 1A2 in Humans: Protective Effect against Environmental Carcinogens?” Clinical Pharmacology and Therapeutics. https://doi.org/10.1016/j.clpt.2005.01.021
[2] Dawson, D., and N. Encel. 1993. “Melatonin and Sleep in Humans.” Journal of Pineal Research 15 (1): 1–12. https://doi.org/10.1111/j.1600-079x.1993.tb00503.x
[3] Skene, D. J., E. Papagiannidou, E. Hashemi, J. Snelling, D. F. Lewis, M. Fernandez, and C. Ioannides. 2001. “Contribution of CYP1A2 in the Hepatic Metabolism of Melatonin: Studies with Isolated Microsomal Preparations and Liver Slices.” Journal of Pineal Research 31 (4): 333–42. https://doi.org/10.1034/j.1600-079x.2001.310408.x
[4] Braam, W., H. Keijzer, H. Struijker Boudier, R. Didden, M. Smits, and L. Curfs. 2013. “CYP1A2 Polymorphisms in Slow Melatonin Metabolisers: A Possible Relationship with Autism Spectrum Disorder?” Journal of Intellectual Disability Research: JIDR 57 (11): 993–1000. https://doi.org/10.1111/j.1365-2788.2012.01595.x
[5] Ma, Xiaochao, Jeffrey R. Idle, Kristopher W. Krausz, and Frank J. Gonzalez. 2005. “Metabolism of Melatonin by Human Cytochromes p450.” Drug Metabolism and Disposition: The Biological Fate of Chemicals 33 (4): 489–94. https://doi.org/10.1124/dmd.104.002410
[6] Braam, W., I. van Geijlswijk, Henry Keijzer, Marcel G. Smits, Robert Didden, and Leopold M. G. Curfs. 2010. “Loss of Response to Melatonin Treatment Is Associated with Slow Melatonin Metabolism.” Journal of Intellectual Disability Research: JIDR 54 (6): 547–55. https://doi.org/10.1111/j.1365-2788.2010.01283.x
[7] Ursing, Carina, Christer von Bahr, Kerstin Brismar, and Sven Röjdmark. 2005. “Influence of Cigarette Smoking on Melatonin Levels in Man.” European Journal of Clinical Pharmacology 61 (3): 197–201. https://doi.org/10.1007/s00228-005-0908-7