Monday, December 28, 2020

What is responsible for the Mu Opioid Receptor Activity in Kratom? The strong mu opioid agonist 7ohm has been found to be a metabolite.

Up until now the entire Kratom industry has been obsessed with either oxidizing or fermenting leaf like it were tea. We debunked the "strain" myth and realized that it was the color of the dried leaf and not the "vein" color that made a difference. This was because the color was dependent on how it was cured. The 2 main ways are in direct sunlight, or in the shade. Leaf that was allegedly "fermented" (or the attempted failure) or oxidized is red. It was widely believed by processors that this had an effect on the alkaloid profile. It was mainly believed that whatever photooxidation that took place was good enough to explain the opioid effects of Kratom. There was a study published that scored 7ohm's Mu Opioid activity at 8 times Morphine. However, a more recent study showed that although powerful, it was roughly 1/8th of the efficacy as seen in the lab. 

 This study suggests that most, if not all, of the opioid effect from Kratom is a result of a particular enzyme: CYP3A4, which is most abundant in the liver but also found in the stomach, intestines and elsewhere. Hence, it is now believed that 7ohm is metabolized from Mitragynine by the body. So, everything we believed about oxidation and the drying procedure appears to have been either Placebo, or thus far un-explicable by science. It appears as though we are far from being able to draw any logical conclusions on what might facilitate or inhibit this process. We do know: (https://www.medsafe.govt.nz/profs/PUArticles/March2014DrugMetabolismCytochromeP4503A4.htm#:~:text=The%20liver%20and%20small%20intestine%20have%20the%20highest%20CYP3A4%20activity.&text=Potent%20inhibitors%20of%20CYP3A4%20include,John's%20Wort%20and%20glucocorticoids.)

  • CYP3A4 is responsible for the metabolism of more than 50% of medicines.
  • CYP3A4 activity is absent in new-borns but reaches adult levels at around one year of age.
  • The liver and small intestine have the highest CYP3A4 activity.
  • Some important CYP3A4 interactions are due to intestinal rather than hepatic enzyme inhibition (eg, grapefruit).
  • There is considerable variability in CYP3A4 activity in the population.
  • Women have higher CYP3A4 activity than men.
  • Potent inhibitors of CYP3A4 include clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, goldenseal and grapefruit.
  • Inducers of CYP3A4 include phenobarbital, phenytoin, rifampicin, St. John’s Wort and glucocorticoids.

This was recently verified by polling roughly 50 Certificates of Analysis from 2 well known vendors. The results showed absolutely no relationship between effect and levels of Mitragynine or 7 Hydroxymitragynine. In fact the levels of 7ohm were all below .05 and often below .01 regardless of drying method. Higher levels of Mitragynine were not indicative of stronger effects. Also, the vendors polled stated that their most popular strains were consistently between 1.4 and 1.7. They reported "strains" that tested as high as 2.1, but reported that there were no noticeable differences in effect, ie it wasn't perceived as particularly potent.

We looked at 2 reputable vendors who test extensively and have been around longer than 5 year. Consistent with what was theorized in this publication, we found that the average levels found in leaf were minimal across all drying/oxidizing methods. What we did find was that there were much lower levels of Mitragynine in reds vs greens, roughly half. 

What's ironic is that this enzyme is responsible for clearing 65% of known drugs from the blood stream. So, while it seems to be metabolizing the MG into 7ohm, inducing it's production also helps the body remove it from the system. This may explain why the half life is so short and the affinity to which the molecules bind to the Opioid receptor is weak. It could be explained by the G protein pathway that is modulated during binding to the Mu Opioid Receptor. We're not sure exactly which receptor does what, but we do know that opiates and strong opioids have an affinity to the Mu Opioid Receptor. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598159/#sec2title

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