Kratom veterans often use the phrase ‘less is more’ regarding Kratom dosages. This basically means that Kratom has a maximum optimal dose, and beyond that dose Kratom has no further positive effects. This helps to decrease Kratom tolerance, as opposed to synthetic opioids and opiates which can be dosed more and more, leading to severe addiction.

Also, in general Kratom users can take the same dose every day long term without having to increase it, unlike synthetic opioids and opiates where the dose has to constantly be increased, and eventually synthetic opioids and opiates stop working no matter how much someone takes since full tolerance develops.

Further, there has never been a death in history that has been scientifically proven to be due to Kratom, despite 15 million Americans being regular Kratom users. This is quite the opposite of synthetic opioids and opiates which kill 50,000 people in the United States every year.

The lack of tolerance buildup and the relative safety of Kratom versus synthetic opioids and opiates may have a lot to do with the fact that Kratom contains natural opioid antagonists according to the scientific study ‘Synthetic and Receptor Signaling Explorations of the¬†Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators‘.

In order to understand what this means, it is important to explain the difference between opioid agonists and opioid antagonists. An opioid agonist binds to and activates the opioid receptors, including the mu, delta, and kappa opioid receptors, but in particular the mu opioid receptor, inducing pain relief, euphoria, warmth, etc.

An opioid antagonist on the other hand binds to and blocks the opioid receptors. Opioid antagonists actually block the effects of opioid agonists, making opioid antagonists the antidote to an opioid overdose. Indeed, the opioid antagonist Naloxone has saved countless lives. Naloxone is administered after synthetic opioid overdoses, and it quickly throws all synthetic opioid and opiate agonists off of the receptors, reversing respiratory depression and instantaneously bringing overdose victims back from the brink of death.

Further, it is well known that opioid antagonists like Naltrexone lower opioid tolerance, since opioid antagonists prevent the receptors from being fully activated, giving the receptors a break.

Miraculously, Kratom naturally contains opioid antagonists, including Paynantheine, Speciogynine, and Speciociliatine. These three alkaloids are antagonists at the mu, delta, and kappa opioid receptors, meaning they inhibit the opioid agonist activity of Kratom.

One way to look at this is while Kratom’s primary alkaloids Mitragynine and 7-hydroxymitragynine are powerful mu opioid agonists, the opioid antagonist alkaloids in Kratom help to balance out the opioid agonist effects, leading to less addiction potential, less tolerance buildup, and helping to prevent overdoses.

Further, while Mitragynine and 7-hydroxymitragynine are powerful mu opioid agonists, they are actually antagonists at the delta and kappa opioid receptors. This is quite different than Morphine, which is the prototypical opioid, which is a full agonist at the mu, delta, and kappa opioid receptors.

Beyond this, Mitragynine and 7-hydroxymitragynine are only partial mu opioid agonists, since they only recruit G proteins while failing to recruit Beta-Arrestin, as explained in-depth in a previous article on Kratom Cafe. Beta-Arrestin release is responsible for most of the addiction potential and overdose risk from synthetic opioids and opiates, since Beta-Arrestin release suppresses noradrenaline throughout the body. It is simply a miracle that Kratom activates G proteins, causing powerful pain killing and mood lifting effects, while simultaneously failing to release Beta-Arrestin.

Thus, Kratom is fundamentally different than synthetic opioids and opiates. Whereas Morphine and most other synthetic opioids are full agonists at the mu, delta, and kappa opioid receptors, Kratom’s primary alkaloids Mitragynine and 7-hydroxymitragynine are partial agonists at the mu opioid receptor, while being antagonists at the delta and kappa opioid receptors. Further, the Kratom alkaloids Paynantheine, Speciogynine, and Specioliatine are antagonists at the mu, delta, and kappa opioid receptors, helping to balance out Kratom’s mu opioid agonist effects, which reduces tolerance buildup and prevents overdoses.

In a nutshell, this science perhaps largely explains why Kratom provides powerful painkilling and mood lifting effects, while simultaneously tolerance never completely builds up, less is more meaning there is an optimal maximum Kratom dose beyond which there are no more positive effects, why Kratom has so little addiction potential, and why Kratom has never caused an overdose death.