?????????????? Mitragyna speciosa, also known as kratom, is an evergreen plant endemic to arid parts of South East Asia. There, parts of the plant, and especially its leaves, have been used by indigenous peoples in medicine for centuries. Although possessing a long history of use outside of North America, kratom has only started to become a major trend in the United States within the last decade. Traditionally used for its stimulatory and analgesic (pain-relieving) effects, kratom has found increasing interest in the West as an alternative-medicine treatment of opioid dependence (opioid use disorder).,  Research using Google Trends has found the worldwide search volume for ?kratom? exploded by a factor of 10 from 2004 to 2016. In addition to treating opioid use disorder, there are certainly no shortage of people interested in its other pain-alleviating, energy-boosting effects.
?????????????? Despite community consensus in its home countries (e.g. Thailand) that ?kratom use and dependence carry little if any health risks?, there remains to be a complete consensus in clinical literature of its long-term safety and what the bodily responses are to consuming particular amounts of kratom., ,  This has understandably made some people nervous about this ?new drug?, especially since market data shows the majority of purchases in the United States are made online.,  As of 2019 in the U.S., kratom is not approved for medicinal therapeutic use and is simply regulated as a food ingredient. Naturally, this prompts one to ask, ?What does kratom actually do to the brain, and are the effects worth it??
Kratom?s Effects on the Brain
?????????????? One of the most notable effects of kratom is its use as an analgesic. Let?s explore this mechanism first.?????
Like many things, pain occurs from more than just one cause. Classical thinking employs the ?mono-mechanistic? idea that pain comes solely from nerves at the site of an injury passing information along to the brain, where it gets interpreted at pain. While it seems certain that information must be travelling along this ?ascending? route, there is evidence that points to another path going the opposite direction as well.
Research has shown that signals coming from the brain can lessen the intensity of incoming pain signals. Here, neurotransmitters like serotonin are involved which do not play a role in the ascending route. These ?ascending? and ?descending? phenomena interact in the body to produce the sensation of pain, a notion called by one set of authors as a ?multimechanistic? understanding of pain., 
One major method of reducing pain has been to use drugs which activate the opioid receptors of the brain (and other parts of the body). The activation of these receptors lessens the effect of pain from the ascending route, analogous to an antidote ? while the same amount of ?poison? (pain signal) is flowing in, the addition of something else creates an overall lesser effect. The compounds in the drugs which do this are called ?alkaloids?. While there are many different types of alkaloids, their molecular structure typically involves rings of carbon atoms interrupted by a single nitrogen atom. As one can see from the primary active molecules of kratom ? mitragynine and 7-hydroxymitragynine ? that is definitely the case with kratom., 
Figure 1. The structures of the primary active molecules of kratom: A) mitragynine and B) 7-hydroxymitragynine. Reproduced from  without permission.?
Typically, consuming higher amounts of alkaloids only increases the analgesic effect. However, anecdotal reports and surveys have found that changing the dose of kratom consumed leads to very different responses. At small quantities (1-5 g of raw leaves), kratom has been reported to have a stimulating effect, giving the user a burst of energy and the motivation to do work. On the other hand, larger doses (5-15 g of raw leaves) have been reported to have a sedating effect more similar to other opioids like morphine.? Why is this?
Although the precise mechanisms through which kratom affects the human body are still under research, one set of mechanisms which had been suggested proposes that kratom acts via the multi-mechanistic pathways that the sensation of pain also uses.,  Through processes not yet entirely understood, this interaction results in the phenomenon that at low doses, the mitragynine-associated activation of noradrenergic and serotonergic receptors in the descending path dominates, while mitryganine and 7-hydroxymitragynine both activate opioid receptors to produce the classic sedating/analgesic effects.,  These composite actions could be why kratom is associated with less intense negative side-effects like constipation and respiratory depression (slowed breathing) than ?normal? opiates., , 
?????????????? Knowledge of kratom?s existence is starting to spread in North America, although this does not translate into increased knowledge about kratom itself. Although much research is still to be done to elucidate the precise mechanisms by which kratom affects the body, there is neurological evidence to support the effectiveness of kratom as a sedative and analgesic with less intense side effects than other opiates.
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