Kratom-Based Opioids Are Potent Painkillers, But Due To Lack Of Beta-Arrestin-2 Recruitment Combined With Delta Opioid Antagonism The Risk Of Addiction, Withdrawal, Tolerance, And Overdose Is Very Low
Practically all pharmaceutical opioid painkillers, including popular drugs such as Hydrocodone and Oxycodone, are derivatives of the natural Opium alkaloids Morphine and Thebaine. Essentially, scientists take the original structure of natural Opium alkaloids and change the molecular structure to create different drugs. The primary natural alkaloids in Kratom, Mitragynine and 7-hydroxymitragynine, can be altered by scientists in the same way to create synthetic Kratom-based drugs, and this has the potential to lead to a new generation of safer pharmaceutical opioid painkillers. Scientists investigated this topic via an in-depth study on the Kratom derivate Mitragynine Pseudoindoxyl, and found that indeed synthetic Kratom derivatives can be potent painkillers while simultaneously leading to little withdrawal, tolerance, and addiction as well as having practically zero overdose risk. Simultaneously, the scientists found that the natural Kratom alkaloids Mitragynine and 7-hydroxymitragynine are just as miraculous, as will be explored in this article.
Mitragynine Pseudoindoxyl is a powerful synthetic Kratom derivative that can be produced from Mitragynine or 7-hydroxymitragynine via a series of chemical reactions. To give an idea of how potent Mitragynine Pseudoindoxyl is, it has a dissociation content (Ki) of 0.087 at the mu-opioid receptor, whereas Mitragynine and 7-hydroxymitragynine have a Ki of 7.24 and 13.5 respectively. A lower Ki means higher binding affinity at the receptor. For example, Oxycodone has a Ki of 18, while the much stronger synthetic opioid Oxymorphone has a Ki of 0.78. That being said, binding affinity is only one part of the equation for the potency of a drug, with the ability of the drug to produce a biological response also being critically important, so it cannot be simply said that Mitragynine Pseodindoxyl is about as potent as Oxymorphone, nor can it be simply said that Mitragynine Pseudoindoxyl is stronger than 7-hydroxymitragynine, and indeed 7-hydroxymitragynine is relatively stronger in terms of painkilling effects.
A scientific study found that Mitragynine Pseudoindoxyl has a much different effects profile than any Morphine-like opioid. First off, Mitragynine Pseudoindoxyl failed to recruit beta-arrestin-2, which is an intracellular protein that plays a critical role in opioid tolerance development as well as suppression of noradrenaline and respiration. In the same study, Endomorphin-2, which is an endogenous opioid that is similar to Morphine, recruited plenty of beta-arrestin-2. In other words, Mitragynine Pseudoindoxyl does not build tolerance as fast, nor suppress respiratory depression as much as Morphine-like opioids since it recruits very little beta-arrestin-2.
Importantly, the natural Kratom alkaloids Mitragynine and 7-hydroxymitragynine recruit just as little beta-arrestin-2 as Mitragynine Pseudoindoxyl, making them safer than Morphine-like opioids for the same reason.
Studies on mice confirmed these results. Within 5 days the mice developed strong tolerance to the painkilling effects of Morphine, while tolerance for Mitragynine Pseudoindoxyl developed much more slowly, and after 29 days the tolerance build-up was still not complete and in-fact began to plateau. In other words, Mitragynine Pseudoindoxyl causes tolerance build-up at a rate which was at least 6 times slower than Morphine, and there was no sign of full tolerance development, only limited tolerance. This is critically important for pain management patients, since it means Kratom-based pharmaceuticals not only cause a tolerance build-up which is many times slower than Opium-based pharmaceuticals, but also the tolerance build-up is only partial even with chronic use.
Another spectacular result is that physical dependence and withdrawal in the mice was very low after 5 days of Mitragynine Pseudoindoxyl, while 5 days of Morphine caused heavy physical withdrawal.
Additionally, the rewarding properties of Morphine were found to be very high in the mice, quite similar to Cocaine, while the rewarding properties of Mitragynine Pseodoindoxyl were practically nil. This means that psychological addiction to Kratom-based opioids is extremely low compared to Opium-based opioids, and therefore patients who take Kratom-based opioids are far less likely to abuse their medication.
One of the most important results is that Mitragynine Pseudoindoxyl caused practically no respiratory depression, while respiratory depression from Morphine was around 50%. This indicates that Kratom-based opioids are much safer than Opium-based opioids, and are essentially not capable of causing overdose from respiratory depression.
Simultaneously, the ability of Mitragynine Pseudoindoxyl to block pain signals, which is called antinociception, was found to be 1.5-3 times stronger than Morphine. For perspective, Mitragynine was found to be 66 times weaker than Morphine, while 7-hydroxymitragynine was found to be 5 times stronger than Morphine, at least in terms of the ability of these alkaloids to block pain.
Thus, Mitragynine Pseudoindoxyl, and the natural alkaloids Mitragynine and 7-hydroxymitragynine, are basically a miracle. Kratom-based opioids can provide pain killing effects on par or stronger than Morphine, while simultaneously leading to practically no respiratory depression, a much slower tolerance build-up, relatively little psychological addiction, and little physical withdrawal. Basically, Kratom-based opioids have the desired opioid painkilling effects with very little of the dangerous side-effects found in Opium-based opioids.
It seems that this is due to Kratom-based opioids being unable to recruit beta-arrestin-2. This study also notes that the mu-opioid agonist/delta-opioid antagonist profile of Kratom-based opioids may be important in separating the painkilling effects from the typical negative opioid side-effects, whereas Opium-based opioids are generally agonists at both the mu and delta opioid receptor.
The scientists who conducted this study conclude by saying that Kratom-based opioids can clearly be the basis for a new generation of synthetic pharmaceutical opioids that have potent painkilling properties with little addiction, tolerance, withdrawal, and overdose risk.
This brings up the critical question, why are Kratom-based opioids not being prescribed to pain management patients when such incredible scientific evidence exists? Certainly, if Kratom-based opioids replaced Opium-based opioids in the pharmaceutical industry many lives could be saved based on this evidence.
Finally, it is important to note that Mitragynine and 7-hydroxymitragynine have essentially the same general properties as Mitragynine Pseudoindoxyl, since these natural Kratom alkaloids also fail to recruit beta-arrestin-2 and are mu-opioid agonists/delta-opioid antagonists. Although the scientists who created this study are focusing on creating new pharmaceutical drugs, which could be fruitful, it could be argued that no synthetic Kratom-based opioids are even needed since natural Kratom leaf already has the same properties of being a potent painkiller while having low risk for addiction, withdrawal, and tolerance, as well as practically no overdose risk.