You may never have heard about kratom (though if you’re a regular reader, you probably have), but there is already a thriving market for this Southeast Asian herb, and groups dedicated to the business of selling kratom. Kratom has also come onto the radar of the FDA and DEA, who would like to regulate it (it currently is essentially unregulated, except as a supplement). This has sparked a controversy over whether and how kratom should be regulated, fueled partly by a lack of clear scientific studies.

So let’s take a close look at what we currently know about kratom.

Mitragyna speciose is a tropical evergreen tree in the coffee family native to Southeast Asia. It produces alkaloid chemicals, mitragynine and 7-hydroxymitragynine (7-HMG), among other compounds. The leaves are traditionally consumed either raw or as a tea, but they can also be smoked, or concentrated into capsules or liquid. The local name for the leaves is kratom or biak. Kratom is used for fatigue, as a pain reliever, and a mood enhancer.

It has been known since 1996 that kratom has opioid effects – mitragynine binds at opioid receptors, which means it has at least some of the effects of opioid drugs like morphine. This is part of the controversy, as the FDA is using this fact as justification for tighter regulation. It is true, however, that mitragynine likely binds only weakly to the opioid receptors, and perhaps to only a subset of receptors.

Mitragynine had > 2- or ~ 16-fold greater affinity for the mu opioid receptor than, respectively, for kappa or delta opioid receptors. Its affinity for the mu receptor was ~ 200-fold less than that for morphine.

This suggests that mitragynine might have less addictive potential than other opiates such as morphine, and may have fewer side effects. However, it may also have less potent benefits as well, which could mean a higher dose is necessary to achieve desired analgesia, which would also increase risks and side effects. This needs to be sorted out in human trials, but that data is limited. A 2017 review of published studies found:

Data analysis suggested that kratom possesses some benefits such as stimulant and sedative effects as wells as antinociceptive effects. It seems to inhibit pro-inflammatory mediator release and vascular permeability and can enhance immunity. In addition, it may be an antidepressant and anorectic. However, kratom can cause intrahepatic cholestasis, seizure, arrhythmia, impair [sic] memory function, coma, and death. Psychological manifestations described are euphoria and feeling relaxed to severe symptoms such as aggression, hostility, and psychosis. Medical manifestations described are polyuria, dry mouth, vomiting, and jerky movements.

There are also case reports of addiction and withdrawl from kratom use.

Of particular concern is the potential for liver toxicity from chronic use. This is often a toxicity that kills drugs in the development stage. Since kratom is being touted specifically for chronic pain, and as an opiate substitute for this, we need to look carefully at chronic toxicity. This may not be easily apparent to users, and the absolute risk might be low, but as kratom use increases cases of liver toxicity will increase proportionally. This is exactly why we conduct toxicity studies before allowing a drug to be sold to thousands or millions of users.

Proponents of kratom often cite its safe traditional use as an argument against regulation (and it is not a good one), but because it is a psychoactive drug it has the potential to be used, and is being used by some, to get a legal high. It produces opiate-like effects of euphoria at high doses, and can also cause similar psychological side effects, like hallucinations. Essentially, traditional use raw or as a tea generally involves low doses, and this does not mean kratom is safe at the higher doses that are likely if it is used as a recreational drug. Traditional use outside of scientific studies is also very poor at detecting statistical risks or long term toxicity, like liver toxicity.

What about the potential for fatal overdose? The FDA’s statements on kratom have emphasized and updated their reports of acute overdose leading to death. These are essentially any death where mitragynine was found in the toxicology. It is not clear in most cases what role the mitragynine played in the death, however in some of the cases mitragynine was the only substance found. The most recent count is 40 deaths associated with kratom (again, not necessarily caused by kratom use).

It is the FDA’s job to protect the public from harmful drugs, so their concerns are understandable. At the other end of the spectrum the Kratom Association denies any overdose or death potential, and that does not make sense or square with the evidence either. At the current time the evidence supports the conclusion that there is overdose potential from kratom, but further study is necessary to evaluate what that potential is. There may be important drug-drug interactions, for example, or susceptible populations due to concurrent illness that need to be discovered.

Animal studies have found that mitragynine at high doses can cause respiratory suppression, but this potential seems to be much less than for morphine or other opiates. Respiratory depression has not been reported clinically in humans, however. One recent review of this and overall kratom safety concluded that there simply is not enough data to reach any firm conclusions.

So where do we stand?

Kratom and its constituents, mitragynine, 7-hydroxymitragynine, and others, should be considered a serious drug. The fact that it is derived from a plant and has a long history of traditional use is irrelevant. The exact same thing can be said of opium. Mitragynine is a drug that acts in the brain with a wide range of effects, related to opioid receptors and other receptors as well, such as monoamine receptors. Kratom components are also Cox-2 inhibitors, which means it has aspirin-like effects.

Drugs have different effects at different doses, some of which are potentially exploitable for benefit, while others are negative side effects. Drugs also have the potential for toxicity, drug-drug interactions, and in this case for addiction, abuse, and withdrawal. There is no reason not to go through the normal process of drug development, identifying active ingredients, studying them, and making a full assessment of their risks and benefits. Often naturally derived chemicals are tweaked to improve their pharmacological profile.

It seems that kratom has a great deal of potential as a source of new drugs. However, so far it seems that the constituents of kratom work through known receptors and pathways. Still, it may have an opiate receptor activity profile that is potentially superior to other opiates in terms of the balance of beneficial effects to harmful side effects.

I do not think that kratom should be classified as schedule 1, which the FDA and DEA did try to do two years ago, but had to back off due to public and political backlash. Schedule 1 is for substances with abuse potential but no legitimate medical use. The problem with this categorization is that it will frustrate scientific investigation, and that is exactly what we need right now.

It may be too late because it is already widely available as an herbal supplement, but kratom should be considered an investigational new drug, and properly scientifically studied. We desperately need more options in treating pain, especially chronic pain, and any addition to our toolkit is extremely welcome.

It would be extremely unfortunate if, rather, kratom continues to develop as an unregulated supplement. That will also impede scientific study, and likely result in unnecessary harm. As the market increases, so will more concentrated and potent forms of the drug, and along with it the abuse potential, toxicity, risk of overdose, and side effects. These markets also promote themselves through anti-establishment conspiracy mongering that harms the entire system.

I understand that there are people currently using reasonable doses of kratom to manage their own chronic pain, and I would not take that away from them. But perhaps they can continue to access a regulated form of kratom, under proper medical supervision, while studies are ongoing. This is not an appropriate drug for the street, however.

In the end the only long term solution is to do the science. We need quality clinical trials to flesh out the risks and benefits.

Posted by Steven Novella

Founder and currently Executive Editor of Science-Based Medicine Steven Novella, MD is an academic clinical neurologist at the Yale University School of Medicine. He is also the host and producer of the popular weekly science podcast, The Skeptics’ Guide to the Universe, and the author of the NeuroLogicaBlog, a daily blog that covers news and issues in neuroscience, but also general science, scientific skepticism, philosophy of science, critical thinking, and the intersection of science with the media and society. Dr. Novella also has produced two courses with The Great Courses, and published a book on critical thinking - also called The Skeptics Guide to the Universe.