Despite limited scientific information, the DEA announced their intention to classify kratom, Mitragynine and 7-hydroxymitragynine as Schedule I on the Controlled Substance Act in 2016. Shortly after, a major push-back consisting of 23,000 written pleas from the general public, legislators and scientific community members challenged the DEA’s decision. For the first time in history, the DEA withdrew their intention to schedule a substance.


Today, though Kratom is not a controlled substance under federal law in the US, there is little information about its pharmacological profile and therapeutic potential. But that may be about to change.

Pain reliever, stimulant, religious sacrament


Kratom, also known as Mitragyna speciosa, is a tree native to Thailand, Malaysia and other areas of South East Asia. The leaves of this tree have been utilized for many years by laborers for their stimulant effects and their ability to invigorate workers in harsh conditions. In addition to its stimulant-like properties, Kratom is also used as a replacement for opium due to its euphoric and sedative effects, with extracts also used to alleviate opioid withdrawal symptoms. Kratom preparations have also been used for socioreligious reasons in the region.


Today, kratom plant materials and extracts are widely available on the internet. They are, however, banned in six US states: Alabama, Arkansas, Indiana, Tennessee, Vermont and Wisconsin. Moreover, they are illegal in many countries, including Australia, Myanmar, Denmark, Lithuania, Malaysia, Poland, Sweden, Thailand and Vietnam.


Between 2011 and 2017, forty-four deaths were linked to Kratom, although people who died from kratom use typically have different substances in their system, or have underlying health conditions. As a result, synthesizing safe and effective derivatives of the plant is paramount as the commercially available products tend to have much higher levels of 7-hydroxymitragyne than those found in nature.



An atypical opioid


Mitragynine is the major alkaloid in kratom and is a relatively low potency mu-opioid receptor (MOR) agonist. However, it is metabolized by the liver to 7-OH-mitragynine, approximately 40-times more potent as an MOR agonist. Notably, analgesia in animals appears to be driven primarily by 7-OH-mitragynine.


Unlike most opioids, however, Mytraginine and its major metabolite are biased agonists at MOR with relatively limited recruitment of β-arrestin, which has been hypothesized to improve their safety profiles.


Indeed, unlike most opioids, Mitragynine and kratom do not cause significant respiratory depression in rodents, which may explain why there has yet to be a reported overdose death from kratom alone. In addition, Mitragynine – unlike codeine, for example – does not produce emesis or general shortness of breath.


From a 2020 Endpoints News article:


‘They don’t turn on the receptor as fully as morphine might, [Kures CEO Dr. Andrew] Kruegel said, so you can’t get a better high from just increasing the dose. Additionally, McCurdy and Kruegel’s work suggests that the drug is metabolized in the liver into a slightly different compound before it has its effect, meaning you can’t get a better high from injecting it.


“No matter how much you take, you have a ceiling,” Kruegel said. “That’s probably a major explanation for people who are taking kratom and not dying in droves.”’



A safer analgesic and opioid maintenance therapy


One of the leading therapeutic indicators of kratom is its analgesic effect. One study of Kratom users in Malaysia showed that 90% were using kratom as a substitute for opioids, with 84% reporting that kratom eased their opioid withdrawal symptoms. A US study found that a majority (68.9%) of kratom-users reported that they used kratom as a means of reducing or stopping NPO/heroin use and 64.1% used kratom to substitute NPO/heroin.


Mitragynine may also be a promising alternative to traditional opioid maintenance therapy.


The first study to explore its effect on morphine withdrawal symptoms was done using Zebrafish. By adding morphine to the water for two weeks, the researchers used a CEP and showed that mytragynine attenuated the majority of withdrawal behaviours.





While opioids are indeed effective for most forms of acute pain, they are associated with a variety of adverse effects, including risk of addiction, constipation, and respiratory depression, the latter being the main cause of death among opioid users. Of individuals prescribed at least 1 day of opioids, 6% are still taking them 1 year later. Moreover, it is estimated that 8-12% of individuals prescribed opioids for chronic pain ultimately develop opioid use disorder.

There are notable drawbacks to existing opioid maintenance therapies as well. In addition to respiratory depression and high abuse potential, methadone, a full mu-opioid receptor agonist, significantly impacts cardiovascular function and can induce life threatening arrythmias.

Therefore, by developing a potentially safer and more widely available alternative for both pain management and opioid maintenance therapy, ATAI and Kures are poised to address two key factors underlying the opioid epidemic.

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