This is a repost making the rounds of the kratom groups on FB. It has no citations, but is in line with studies & abstracts that I've read.

By Brandon Gaggini, Biology major at Sain’t Xavier University (2021)

First, let’s rule out the “accidental” component of an overdose.

Recent research has suggested that the LD-50 of Kratom is equivalent to more than 2 kilograms. [1] Ingesting such an amount within one day would require time and dedication, and would result in a severe intestinal blockage. If one was to mix 2 kilograms into a tea, assuming 6 grams of high quality Kratom are mixed into 8 ounces of liquid, it would result in 17.857 gallons, or 67.596 liters. It takes about 6 liters of water to kill a 165-pound person, so drinking this entire batch would mean ingesting 11.266 times the average levels of water intoxication. [2] If one attempted to inject a commercial extract of Kratom, it would wreak havoc upon the veins as it is derived from raw plant matter. In addition, if one was to somehow smoke 2 kilograms of Kratom, nothing would happen due to its very low bioavailability through the mucus membranes. Therefore, the only routes of administration that are possible with Kratom usage are all associated with various lethal afflictions unrelated to the plant itself, and are incredible difficult to “accidentally” achieve.

Now let’s examine the properties of Kratom.

Kratom, or Mitragyna speciosa, is an Evergreen tree related to the coffee family. It contains many alkaloids, but the main two active components are Mitragynine and 7-hydroxymitragynine. It is estimated that 7-hydroxymitragynine is approximately 13 times stronger than pharmaceutical-grade Morphine. This statistic may seem alarming, however Mitragynine makes up about 66% of the alkaloids while 7-hydroxymitragynine makes up less than 2%. [3]

These alkaloids bind to the opioid receptors of the brain, however, they do not carry the same lethal consequences. This is because Kratom is an “atypical opioid”. Before I further delve into the details, I must explain a crucial aspect of terminology. An opiate is any substance that is derived from Papaver somniferum, also known as the Opium plant. An opioid is any substance that binds to the opioid receptors of one’s brain in a substantial way. Furthermore, just because a substance binds to one’s opioid receptors does not mean that the substance is dangerous. For example, dark chocolate contains a compound known as epicatechin which binds to the delta-opioid receptors and various dairy products contain beta-casomorphins which are groups of peptides with opioid properties. However, these opioid properties are found to be non-addictive. [4] While we are on the topic of misinterpreted definitions, let’s examine the word “overdose”. Technically, an “overdose” simply means taking too much of a particular substance. For example, one can “overdose” on Marijuana but the worst that could possibly happen would be a panic attack, as no one has ever died from Marijuana. Sure, people have died from driving while high, but no one has ever died from Marijuana alone. The word that you want is “fatal overdose”. Now that we’ve established the individual and collective definitions regarding opioid and opiate properties, we can move on to the specific chemical and biological makeup of Kratom and why it is important.

Kratom and its individual alkaloids are partial agonists to the mu-opioid receptors while being antagonists to the kappa and delta-opioid receptors. [5] This is crucial information, simply because the binding to the mu-opioid receptors are known for causing respiratory depression. However, being a partial agonist, the alkaloids immediately release themselves from the mu-opioid receptors after the inital binding. In addition, due to being an antagonist, the alkaloids create a “ceiling effect” in which nausea will occur before an abnormally high dose can be ingested. Furthermore, research has indicated that the alkaloids recruit G Proteins instead of beta-arrestin. This is significant, because recent research has shown that beta-arrestin is responsible for the many side effects present in typical opioids including severe dependence/withdrawal and respiratory depression. [6]

Therefore, it is safe to say that one can not lethally overdose on Kratom. Most likely, other factors were involved. Kratom may have interacted with another drug, either potentiating the other drug or collectively reducing the seizure threshold. It is recommended that benzodiazepines and opioids are avoided, as the FDA’s official toxicity reports indicate that other drugs were involved in all but one Kratom-related fatalities. [7] However in this situation, because the person suffered from endometriosis, the most likely cause of death was severe internal bleeding that may or may not have been worsened by Kratom’s blood-thinning properties.

Kratom is a very safe substance, but the media portrays it in an exaggerated negative light. Follow the facts, and the world will be a much better place.

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https://www.reddit.com/r/kratom/comments/bj8qab/the_science_of_kratom/