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Recreational drug kratom hits the same brain receptors as strong opioids

Chemists study the neurochemistry of alkaloids from the Mitragyna plant

by David Kroll, special to C&EN
June 3, 2016 | APPEARED IN VOLUME 94, ISSUE 23

Credit: Shutterstock
Recreational drug users have looked to the kratom plant for an opioidlike high.
Credit: Shutterstock
Recreational drug users have looked to the kratom plant for an opioidlike high.

For recreational drug users looking for an opioidlike high without the legal problems of heroin, fentanyl, and oxycodone, the Southeast Asian plant called kratom (Mitragyna speciosa) has provided an attractive alternative. But, acting on anecdotal reports of people becoming dependent on kratom, six states, including Vermont and Indiana, have banned the sale and use of the herb.

A new study provides some data to support those states’ concerns (J. Am. Chem. Soc. 2016, DOI: 10.1021/jacs.6b00360). A team of researchers shows for the first time that kratom’s primary constituent, mitragynine, and four related alkaloids bind to and partially activate human µ-opioid receptors (MORs), the primary targets of strong opioids in the brain, spinal cord, and gastrointestinal tract.

The most potent of the related alkaloids was the mitragynine oxidation product 7-hydroxymitragynine. Its MOR potency was one-tenth that of morphine, while mitragynine’s was one-hundredth.

“Mitragynine is not a particularly very potent opioid,” says Dalibor Sames, a chemist at Columbia University who led the team. But, he says, it’s possible that the plant provides a high enough dose of the compound to overcome that weak potency. “The plant is designed to be a factory for mitragynine,” Sames says. Mitragynine can amount to almost two-thirds of the alkaloid extract from a kratom leaf, adds Andrew C. Kruegel of Columbia, who is the paper’s first author.

Kelly M. Standifer, professor and chair of pharmaceutical sciences at the University of Oklahoma, points out that the researchers tested the compounds’ potency in nonneuronal cells forced to express the receptors. The molecules could be more potent in actual brain tissue, so these findings may not fully capture the risks of kratom, she says.

Previous studies had suggested the plant itself produced 7-hydroxymitragynine. Sames says the team could detect it by mass spectrometry, but only at very low concentrations. Instead, the team demonstrated that sunlight and oxidizing conditions can convert about half of the mitragynine in solution to 7-hydroxymitragynine. And sunlight alone can convert about 8% of the mitragynine. Therefore, the team concluded that storage conditions can affect the potency of an extract by increasing the amount of the oxidized alkaloid.

Further experiments on the kratom alkaloids showed that when they activate MORs, the receptors turn on pathways independent of a protein called β-arrestin. Previous studies have shown that the β-arrestin pathway mediates many of the undesirable effects of traditional opioids such as constipation, respiratory depression, and the development of tolerance. So drugmakers have been trying to develop opioids that don’t recruit β-arrestin in hopes of finding painkillers with fewer side effects.

Sames noted that their findings could fuel the design of other, safer opioid painkillers.



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Pepper Culpepper (June 3, 2016 2:32 PM)
There are several problems with this article:

1. 7-hydroxymitragynine accounts for as little as 2% of the alkaloids, if that. Each tree and each strain can vary in terms of alkaloidal content. In fact, the kratom trees that Dr. McCurdy grew for his research at Ole Miss didn't even produce mitragynine, rather it produced mitraphylline instead.

2. The claim that "A team of researchers shows for the first time that kratom’s primary constituent, mitragynine, and four related alkaloids bind to and partially activate human µ-opioid receptors (MORs), the primary targets of strong opioids in the brain, spinal cord, and gastrointestinal tract," is NOT new. At all. Pharmacologists have known this for decades.
Istvan (June 4, 2016 3:59 PM)
As for the mitragyine-content of USA-grown kratom trees: Pepper Culpepper is wrong. According the 2009-publication of Leon et al, co-authored by McCurdy (Phytochemical characterization of the leaves of a Mitragyna speciosa chemotype grown in U.S.A;, the Ole Miss tree did produce mitragynine: from an 18 g of concentrated leaf extract several alkaloid fractions were obtained. while mitraphylline was the most abundant (24 mg of pure substance), mitragynine was isolated as well (8 mg) along with 7-hydroxymitragynine (1.2 mg; apparently formed from mitragynine), isomitraphylline (7 mg) and other related kratom alkoids.
Your second comment, however, is valid: the introductory sentence of this news article is misleading. There have been several in vitro and in vivo studies defining opioid receptor-related activities of various kratom extracts and the major alkaloids. Naloxone-antagonism has also been established.
Andrew Kruegel (June 4, 2016 7:05 PM)

It is quite true that the alkaloid content and composition will vary between strains, as we discuss in our paper. However, in our experience with samples of multiple strains obtained from the endemic regions of Mitragyna speciosa, mitragynine has always been by far the dominant alkaloid and occurs in high concentrations. I agree that 7-hydroxymitragynine does not play a significant role in the effects of many strains/extracts, as we were not able to isolate it, but mitragynine is sufficient to induce opioid effects on its own.

Of course the suggestion of opioid activity is not new, but this is the first demonstration of functional activity at the human receptors. All previous studies were either only binding (not functional) or in vivo and tissue studies in non-human species (not necessarily appropriate for demonstrating the actual molecular target).
Susan Ash (June 11, 2016 6:41 PM)
As director of the non-profit American Kratom Association, I thank you for this research and for personally responding, as lead author, to questions and criticism regarding your study. I'd absolutely love to have a conversation with you about this and any future work that might be planned. My contact info is on our website on the media contact page and I will try to find yours!
Istvan (June 5, 2016 1:03 AM)
Are your sure about the lack of mitragynine in the leaves of the Mississippi-grown kratom? A publication by the referred McCurdy-group states otherwise (Leon et al., Phytochemical characterization of the leaves of Mitragyna speciosa grown in U.S.A.)
While mitraphylline was indeed the most abundant alkaloid (24 mg isolated from some 18 g of crude leaf extract), there was a relatively large amount of mitragynine from the same preparation (8 mg); some 7-hydroxymitragynine (1.2 mg) was also isolated.
Nevertheless your 2nd point is valid: the title and the statement are indeed misleading. Kratom's principal mode of action, and the dependence liability associated with it, has been known for two decades.
The title also misguiding by suggesting that'strong' and 'weak' opioids have different receptors...
I recommend reading the recent book edited by RB Raffa and was reviewed here:
Pepper Culpepper (June 4, 2016 3:42 PM)
If kratom does not have side effects as this study shows, then the states claims are NOT founded and kratom should be further researched due to the fact that it does not have the worse side effect which is respiratory depression.
Andrew Kruegel (June 4, 2016 7:11 PM)
We do not show any data regarding side effects in vivo; our studies in cells are only suggestive of a potentially improved side effect profile. More study is certainly needed and is ongoing, both in our labs and those of others. We are hopeful that mitragynine and related alkaloids will prove useful starting points for the development of new opioids with reduced respiratory depression and/or other side effects.
Joanne Thompson (June 10, 2016 10:34 PM)
with all due respect, we don't need any "useful starting points" for any new development. Kratom is perfectly effective and non(or very mildly - especially in comparison to most commercial pharmaceuticals)-harmful to hundreds of people that use it - and have for years as a safe(r) alternative to pharmaceuticals - and all your "starting point" is going to do is commercialize what you can presently literally grow on trees, and make it illegal to get through non-commercial, non-branded, non-refined sources. you're not helping people by promoting commercialization of Kratom, you're ruining Kratom for the people it's already helping for myriad conditions. with all due respect, please stop helping and producing "new" "starting points"... it's not needed and will only cause harm by forcing people that rely on Kratom to use other, less available, less safe, less helpful alternatives, or risk legal consequences for trying to cure pain, depression, and the many other ailments Kratom is helpful or effective at treating (naturally, without any help or "development").

I've personally used Kratom for several years, in small doses, to take the edge off chronic pain and treat my bipolar/depression better than other medications have previously. Recently my doctor convinced me to try a "real" medication, Lamictal, and I was rewarded with a life threatening reaction called "Stevens Johnsons Syndrome". Here's a tip - don't google it while you're eating.

While learning about this specific medication reaction I found out over 200 different medications - including penicillin and normal, over the counter Tylenol, can cause it! I'm done with these insane chemical concoctions and going back to my nice, effective tree leaf for relief. Only just after doing so, I see that it's smattered all over facebook and will probably be illegal in another half dozen states as a result soon. They outlawed it in Asia initially because it interfered with their opium trade, giving the farmers and peasants access to something that made their lives tolerable, and they'll outlaw it here because it gives people an alternative to expensive medications that are far less effective and far more potentially dangerous.
Robert Scanlan (June 4, 2016 4:34 PM)
I am an organic chemistry major, and have had quite a lot of experience with kratom and have even made extracts myself in the lab. It is not news that this is an excellent topic for opioid research and otherwise. The Taiwanese government knew that it was superior to morphine and opium long ago, banning it because it was hurting their taxes on opium. This is obviously going to be a topic of much debate and probably some pharmaceutical companies will not want to further the research due to the fear that the potential product would make traditional opiates like hydrocodone and morphine obsolete. Nontheless it will eventually make it to stage 3 clinical and be on the market (some form of it). In any case it's very interesting to research just in it of itself😊
John Burke (June 9, 2016 12:47 PM)
I believe you mean Thailand, not Taiwan. That's a common mistake. As far as I am aware, kratom is not illegal in Taiwan, nor is there an opium industry.
Pepper Culpepper (June 5, 2016 8:23 AM)
Yes, I've reviewed that publication.

My apologies. I worded that incorrectly. On page 79 of Kratom and other Mitragynines: The Chemistry and Pharmacology of Opioids from a Non-Opioid Source (edited by Robert Raffa) it states:
"The predominant alkaloid in M. speciosa grown in the United States at the University of Mississippi is the oxindole-type mitraphylline [2] and not mitragynine." [1] (Leon et al. 2009).
Kelly Devine (June 5, 2016 10:24 PM)
Where can I find publication stating it does NOT cause respiratory depression? I'm amazed at this discussion! Thanks
Istvan (June 8, 2016 3:45 PM)
I am not aware of any publication stating that 'kratom' does NOT cause respiratory depression. However, there was one study
cited here:
The original study done by Macko et al. using mitragynine, or SK&F 12711 (just one of the chemical constituents of kratom!), concluded that "there was no evidence of severe respiratory depression". In dogs, monkeys and cats, only relatively high intravenous doses produced some respiratory depression (9.2, 9.2 and 4.6 mg/kg, respectively). Other side and adverse effects were also noted at such high doses.
The Macko et al. paper is abstracted here:
Kelly Devine (June 5, 2016 10:25 PM)
Sorry I'm also in search for the publication on the 41 alkaloids, can't seem to find it. Any help is welcome
Istvan (June 8, 2016 3:12 PM)
The alkaloids reported so far (that is until 2014) from Mitragyna speciosa are listed in Adkins et al:
Mitragyna speciosa, a psychoactive tree from Southeast Asia with opioid activity. Curr Top Med Chem. 2011;11(9):1165-75.
The chemical structure of 41 of them are given in the chapter by Cogineni et al. in the Raffa-book mentioned above.
I hope this helps.
Istvan (June 8, 2016 3:16 PM)
You may also find a concise description of kratom here:
To be updated soon...
Jack Burn, PhD (June 8, 2016 6:03 PM)
I take offense athletes then title "Recreational drug kratom."

I have used the herb kratom daily multiple times daily for over 6 years for pain control. This has allowed me to go from being unemployed to hold down a technically demanding full-time job.

I am a Mormon & do not believe in taking substances for recreation.

I find kratom to be superior to NSAIDS or opiate/acetaminophen combinations. Today I take less (by half), not more than when I started.

Also, I find that taking larger amounts leads to very unpleasant side effects (nausea disphoria), perhaps suggesting that there is a complex mixture of compounds that provide a natural safety to this blessed herb.

I am concerned that this is being outlawed without reasonable science to support it. I have seen no believable dangers reported in any peer-reviewed scientific research journals.

I do advocate proper safety in handling & sales (perhaps licensing & taxation like tobacco). I am concerned about sales of concentrated/isolated kratom compounds until there is much more study.

In closing, I urge other like-minded scientists to speak their minds & help prevent an immoral nation-wide ban.

PS: while I a don't advocate taking any substance for recreation,
I think all will agree that kratom much safer than high dose lopermide use that is being reported by the FDA.
Jmcconnor (June 10, 2016 5:44 PM)
It doesn't matter why you are taking it, for medical reasons or recreational reasons. It will still do the same things.
Crystal (June 10, 2016 6:58 PM)
I fully agree with Jack! I am a 41 year old mother of 4 and have dealt with chronic pain for as long as I can remember. My doctor prescribes me three different pain medication; one is an opioid, one is not an opioid base but still a prescription pain killer, and the third is a strong ant-inflammatory. It is extremely difficult to manage my daily lifestyle of full time work and full time house keeping - in general! It is even harder when you are either IN pain or out of your mind because of pain medicine! I have been substituting kratom (a weak strain by all standards) for my opioid pain medicine for about a year now. I couldn't be happier! Not only does it actually ease the pain, but it doesn't have the horrible side effects like the man made drug does! I can function fully all day and still take care of my kids, pets, and house in the evenings! I get an average of 7 hours of sleep a night compared to the 13 hours or more I would sleep when taking the prescription! I find the fact that this is a God given substance to be it's best quality! It's horrible that the government must have their share of any profits and THEY outline our lives, not the other way around. I do not partake in "recreational" drugs; I don't even drink alcohol! So I really do take offense to people calling this a recreational drug! I am sure there are abusers, there are abusers in everything in today's world!!
I do continue learning about kratom, but from what I know from experience it is a wonderful, God given substance!!!
Mary Leonhardt (June 11, 2016 3:13 PM)
Thank you very much, Jake Burns. I was also very annoyed at the title. I am a 72-year-old woman who uses kratom to manage the symptoms of severe Restless Leg Syndrome. Truly, it's given me back my life, without the devastating side effects of the prescription meds available for this condition. Actually, I guess that most people who use it, use it for medical conditions, primarily chronic pain, PTSD, and other anxiety disorders.
z (June 12, 2016 12:51 AM)
I found this to be rather interesting

" Instead, the team demonstrated that sunlight and oxidizing conditions can convert about half of the mitragynine in solution to 7-hydroxymitragynine. And sunlight alone can convert about 8% of the mitragynine. Therefore, the team concluded that storage conditions can affect the potency of an extract by increasing the amount of the oxidized alkaloid."

Usually people argue that drying the leaves in sunlight will actually result in a loss of mitragynine content and so make the leaf less potent. But according to that quote, the loss of mitragynine content is actually a conversion to 7-hydroxymitragynine, which is far more potent and effective in mimicking an opiate. Did I understand this correctly?
Heather ballew (June 14, 2017 3:47 PM)
So....the pharmaceutical industry is just mad that there is an all natural plant with zero side effects that is great at reliving mild to even severe chonic pain without the use of the deadly chemicals the pill pusher (legal drug dealer) docs push onto the American bad

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