Update on Kratom

 

 

I started writing about kratom on this blog 7 years ago after I noticed more people having problems with it.  One of the main themes of this blog is that any substance that reinforces its own use is a most important property that cannot be denied at the individual, societal, or medical level.  The most successful approaches to limiting the consequence of excessive use are cultural change, limiting access, and criminal penalties.  Without those deterrents the progression from increased use to commoditization and use on a much larger scale is predictable.  It turns out that this extends beyond addictive compounds to behavioral addictions as well. Examples include gambling, sex and pornography addiction, and social media addiction. Rather than acknowledging this reality – the typical way these problems are approached in the US is rationalization, denial, and inadequate remedies.

The examples available just in the past 2 decades are striking. We entered the 21^st century on the cusp of an opioid epidemic.  That was based initially on more liberal prescribing by physicians of compounds that were highly addictive – but those properties were denied using this medication for maintenance treatment.  They were also sold based on the idea that chronic pain was better treated with opioids and that it was possible to eliminate pain.  From there cannabis was sold as the next great universal cure – even though its medicinal use has been in existence for about 2,500 years.  That led to a confusing decade of state-by-state regulations for so called medical cannabis.  Some of those states considered non-medical use illegal.  Some states took that a step farther by decriminalizing cannabis typically based on personal use.  Other states eventually legalized recreational cannabis.  It is currently legal in 40 of 50 states for medical use, in 24 of 50 for recreational use, and decriminalized in 6 states.

Over the past decade the evidence for medical applications of cannabis have been increasingly sparse.  It appears that the initial hype about it being a miraculous medicinal have not played out and it looks like that approach was established to facilitate a path to legalization. Now that medical applications are vanishing, we see it being sold as an industry and even a source of equity for oppressed minorities.

The next frontier seems to be convenience stores.  About 50 years ago, gas stations in the Midwest began selling bread and milk in addition to gasoline.  In those days they were open longer than most grocery stores and people got accustomed to picking up these necessities at odd hours.  As more people used them the stock expanded to the point where today you can get prepared hot food 24 hours a day at some of these stores.

Some but not all these stores are selling compounds like kratom and other potentially problematic compounds.  Many of these drugs being sold fall into loopholes in state statutes and despite warnings from federal agencies are still available for over-the-counter purchase.  They are not FDA approved prescription drugs, so they are not available though pharmacies.  In the case of kratom 30 of 50 states regulate it to some extent, it is illegal as a Schedule 1 drug and banned in 6 states, and in 20 states it is neither controlled or regulated.  I live in one of the states where it is regulated to some extent and it is available for purchase at gas stations. It is only illegal to sell to a person less than the age of 18 years or possess kratom if you are less than age 18.  Both are considered misdemeanor crimes. 

That brings me to the current update (3) from the Mortality Morbidity Weekly Report (MMWR).  The authors analyze data from the National Poison Data System (NPDS) from 2015 to 2025 and have several outcomes and demographics available from that system.  The system depends on self report so mild cases may be minimized, the type of formulation (leaf versus other formulations) was not available, multiple exposures can be reported so causality may be undetermined and repeat calls and misclassification can occur. 

A further analysis problem is that in many cases there are more drugs present than just kratom.  The authors analyze the data about whether there is single substance or multiple substance exposure leading to the morbidity or mortality event.  The case selection and outcomes of interest are illustrated in the top graphic for this post.  The NPDS database tracks deaths and other outcome categories. Hospital admissions are tracked including psychiatric admissions.  Major, moderate, and minor effects.  Major effects are considered life-threatening or resulting in permanent disability or disfigurement.  Moderate effects are systemic, prolonged and require some treatment but are not life threatening. The authors define serious as lethal, major, or moderate for the purpose of their outcomes.

Kratom exposure rates were calculated per million drug exposures in the NPDS database.  They document a 1200% increase in kratom exposures from 2015 (n=258) to 2025 (n=3434).  Multiple substance exposures exceeded single exposures over the same period.  Males had consistently higher rates of kratom only and multiple drug exposures.  Hospitalizations had similar increases of 1200% increase over the study interval.  There were 233 deaths over the period with 49 (21%) due to kratom exposure alone and 184 (79%) due to multiple exposures including opioids, benzodiazepines, and stimulants.  That last mortality statistic is important because many users believe that kratom is a benign substance.  That belief hinges on the amount of raw material (as leaves) that can be used for effect. Any concentrated form should be viewed as potentially as toxic as any other opioid receptor agonist and easily complicated by the use of any other opioids.

The authors attribute the significant increase in 2025 reports to the availability of concentrated semi-synthetic forms like 7-hydroxymitragynine.  It is important to note that persons with substance abuse disorders are not necessarily risk averse. The progression of any addictive process generally involves using more concentrated or bioavailable forms. That process is not rational – so if you have that kind of problem and know this data – you will not necessarily avoid more potent forms of kratom or avoid mixing them with other intoxicants like opioids or benzodiazepines.  The authors also point out that persons with multiple exposures are more likely to require hospitalizations and have more serious outcomes. 

Total lifetime use of kratom increased from 4 million to 5 million persons between 2019 and 2023 and that increase was across all demographic groups.

The overall impact of increased exposure to a drug that reinforcers it own use is expected.  Over time in every case there will be increasing morbidity and where possible mortality.  The exposure to multiple substances is expected, since people using substances for their reinforcing effects tend to use more, make substitutions, and use by routes that lead to increased bioavailability and impact.  No matter who you are this needs to be remembered at every policy debate.  The ideas about raising more revenue form these kinds of compounds and reducing taxes is a pipe dream.  The societal costs of these compounds are always high.  The more widely available they are – the higher the costs.              

 

 

George Dawson, MD, DFAPA

 

References:

1:  Crocq MA. History of cannabis and the endocannabinoid system
. Dialogues Clin Neurosci. 2020 Sep;22(3):223-228. doi: 10.31887/DCNS.2020.22.3/mcrocq. PMID: 33162765; PMCID: PMC7605027.

2:  Legislative Analysis and Public Policy Association.  Kratom: Summary of State Laws.  January 2026.  https://legislativeanalysis.org/wp-content/uploads/2026/02/Kratom-Summary-of-State-Laws.pdf

3:  Towers EB, Thomas YT, Holstege CP, Farah R. Increases in Kratom-Related Reports to Poison Centers - National Poison Data System, United States, 2015-2025. MMWR Morb Mortal Wkly Rep. 2026 Mar 26;75(11):139-145. doi: 10.15585/mmwr.mm7511a1. PMID: 41886310.

4:  US Food and Drug Administration. Import Alert 54–15: detention without physical examination of dietary supplements and bulk dietary ingredients that are or contain kratom (Mitragyna speciosa). Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration; 2026.  https://www.accessdata.fda.gov/cms_ia/importalert_1137.html

“FDA has seen an increase in the number of shipments of dietary supplements and bulk dietary ingredients that are, or contain kratom, also known as Mitragyna speciosa, mitragynine extract, biak-biak, cratom, gratom, ithang, kakuam, katawn, kedemba, ketum, krathom, krton, mambog, madat, Maeng da leaf, nauclea, Nauclea speciosa, or thang. These shipments of kratom have come in a variety of forms, including capsules, whole leaves, processed leaves, leaf resins, leaf extracts, powdered leaves, and bulk liquids made of leaf extracts. Importers' websites have sometimes contained information about how their products are used.”

5: Substance Abuse and Mental Health Services Administration. National Survey on Drug Use and Health (NSDUH): key resources and tools for NSDUH. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2025. Accessed July 27, 2025. https://www.samhsa.gov/data/data-we-collect/nsduh-national-survey-drug-use-and-health

This reference says nothing about the prevalence of kratom use.

Graphics Credit:

Lead summary graphic was done by me.  Bar graphs of annual outcomes is from reference 3 and open access as an official government publication. 

Kratom - Don't Believe the Hype

The CDC came out with a brief 2 page report on kratom deaths 3 days ago (1). That was all it took for the Twitterati to proclaim that there were many more deaths from alcohol and I suppose there was a post about even more deaths from cigarette smoking but thankfully I missed that one. When I pointed out that it was clearly an addictive drug and lifelong disability (a very significant problem) may be the issue - the defenders of kratom stepped up and talked about how harmless it is and also how it is advantageous for people who cannot afford medication assisted treatment (MAT) (buprenorphine preparations, methadone, or naltrexone extended release injections) for opioid use disorder (OUD). The expected personal attacks and sarcasm followed.

Kratom is an interesting compound because like many psychoactive botanicals there is a history (2). Kratom itself is basically leaf material from the kratom tree (Mitragyna speciosa). The leaves can be smoked or chewed. They can also be dried and powdered. The powdered form is what is typically available for sale. The powder can be packaged in capsules and taken orally, brewed into a tea, or rendered into a syrup and formed into pills. Fresh leaves can be chewed with or without betel nuts. Kratom has been used in Malaysia since the 19th century to “heal opium addiction”. A recent paper referenced a study of kratom users that were using an estimated 4-8 g/day (8). Converting based on typical leaf content means that these users would be exposed to a maximum of 120-180 mg mitragynine and 1.1 - 3.4 mg 7-hydroxymitragynine.   Rӓtsch suggests in his text that “in studies with mice, even extreme dosages of 920 mg/kg did not produce any toxic effects”. He describes “self experiments” in the literature suggesting that kratom can be both stimulating like cocaine and sedating like opium. The only comment on addiction is “The alleged kratom addiction is a Thai cultural phenomenon” (p. 367).  Like most intoxicants in the modern era there is progression to intravenous use.  Although that is currently rare, there are case reports of intravenous use of kratom extracts.

The CDC document describes a series of deaths in 11 states between July 2016 and June 2017 and an additional 27 states from July to December 2017. The data set was from the SUDORS (State Unintentional Drug Overdose Reporting System) and consisted of 27,338 overdose deaths, 152 (0.56%) of which were kratom positive. There is no standard postmortem toxicology protocol and as previously noted that is problematic in determining the drugs present in these analyses. As shown by the table from this report in 91 cases kratom was considered the cause of death, but numerous other substances were present. In seven cases kratom was the only substance noted in postmortem toxicology, but additional substances cannot be ruled out.

A report in the New England Journal of Medicine, looked at 15 cases of death (4) associated with kratom in Colorado. In this series the authors used more rigorous toxicological analysis with high-performance liquid chromatography – mass spectrometry. Whole blood mitragynine concentrations were noted between 16-117 ng/ml and up to 4800 ng/ml. In this series, 14 of 15 deaths had multiple drugs leading the authors to conclude that these deaths were kratom related.  This series of cases illustrates the importance of toxicological analysis and specifically plasma levels of the drug to correlate with various toxidromes and post mortem toxicology.

The leaves of Mitragyna speciosa, contain multiple alkaloids including mitragynine, 7-hydroxymitragynine, paynantheine, speciocilatine, and speciogynine. The crude alkaloid extract consists primarily of 66% mitragynine and 2% 7-hydroxymitragynine. The extraction process may be protective against toxicity for many people that brew the leaves into a tea, chew the leaves, or ingest the powdered leaves as capsules but even then the concentration of these alkaloids may vary from species to species. Counting on an inefficient extraction process for safety is probably not the best idea.  The other property of the raw material is that the alkaloids are mixtures of  opioid receptor agonists and antagonists that may determine the net effect. Searching the way these products are sold there is really not much about concentration of any associated alkaloids other than mitragynine.  The plant itself contains more than 40 unique alkaloids (8).

Until recently, the pharmacology of mitragynine and 7-hydroxymitragynine were unknown. There is research to suggest (5) that opioid receptors mediated the primary effects. Both compounds had binding affinity for the mu opioid receptor (MOR). They were also active in tissue essays and blocked by naloxone.  Some of these effects were inconsistent between laboratory species. Activity was reported at a number of non-opioid receptors as well. The pharmacology of mitragynine and 7-hydroxymitragynine is now well-characterized. Recent studies show that mitragynine is a partial agonist at the human mu opioid receptor (hMOR), and a competitive antagonist at the human kappa opioid receptor (hKOR), and an antagonist at the human delta opioid receptor (hMOR) but with very low potency. The authors studied these compounds against all three human opioid receptors looking at both functional activity (EC50 and IC50) and binding affinities (Ki) and discovered they were consistent across those experiments. They concluded that mitragynine (0.233 μM) And 7-hydroxymitragynine (0.047 μM) had significant binding affinity for hMOR. The remainder of the paper focuses on medicinal chemistry theory, specifically how opioid -like compounds that bias intracellular signaling toward G proteins rather than β-arrestin may be better candidates for opioid analgesics with low addiction potential and better side effect profiles and possibly antidepressant activity. They synthesize a number of analogues and look at their agonist activity at hMOR. The authors conclude that the psychoactive activity of Mitragyna is most likely due to their action at hMOR. They also point out that due to the competitive nature of the alkaloids the gross effects will be due to that balance of agonism and antagonism.

The alkaloid and methanol crude extracts of kratom are both inhibitors of CYP3A4 and CYP2D6 in vitro. No specific components have been identified with this activity and there has been in vivo confirmation (8).

Another paper (6) looks at the “unanticipated toxicity” of kratom. This group looked at the LD50 of mitragynine, 7-hydroxymitragynine, and heroin. The LD50 is a measure of acute toxicity and what single dose will kill half of the research animals. In this case mice were used and the researchers were surprised to find that an intravenous dose of either mitragynine or 7-hydroxymitragynine were as lethal as heroin. No lethal doses were observed for oral dosing in a range of 6.25-50 mg/kg. the lethal intravenous dose was midpoint in that range. Researchers observed that the mice appeared to die from respiratory depression within 10 minutes of direct exposure. In the surviving mice many were noted to have seizures in the first 20 minutes.  In a separate review, the authors point out that with a typical 8 g dose of kratom powder, the levels of 7-hydroxymitragynine, may be too low to cause a pharmacologically relevant effect at the opioid receptor. 

The research on kratom has elucidated receptor activity in opioid receptors. The activity is complex but the mu opioid receptor is clearly involved and is the likely site of the psychoactive effects and the application of opioid substitution in people with addictions. The receptor effect is complicated and likely involves more than the mu opioid receptor. The research also suggests that activity at murine and human opioid receptors are not equivalent. Persons acquiring kratom in the powder form need to consider that the ratio of mitragynine to 7-hydroxymitragynine likely varies with species and source. The 7-hydroxymitragynine is 52 times as potent as mitragynine at the MOR and 13 times as potent as morphine. Products made from extractions will be more potent.

All of this information should create skepticism in prospective kratom users. As addiction psychiatrist I can attest to the fact that it is addicting and with any addiction there is a tendency to escalate the dose. Many people with addictions as noted in the above table are using multiple substances some of which are also agonists at the opioid receptor. If you are considering kratom as a treatment for opioid addiction or chronic pain there are much, much safer and effective ways to proceed.


George Dawson, MD, DFAPA



References:


1. Olsen EO, O’Donnell J, Mattson CL, Schier JG, Wilson N. Notes from the Field: Unintentional Drug Overdose Deaths with Kratom Detected — 27 States, July 2016–December 2017. MMWR Morb Mortal Wkly Rep 2019;68:326–327. DOI: http://dx.doi.org/10.15585/mmwr.mm6814a2External

2: Rӓtsch C. The Encyclopedia of Psychoactive Plants: Ethnopharmacology and Its Applications. Park Street Press. Rochester, Vermont, 2005. pages 366-367.

3: Olsen EO, O’Donnell J, Mattson CL, Schier JG, Wilson N. Notes from the Field: Unintentional Drug Overdose Deaths with Kratom Detected — 27 States, July 2016–December 2017. MMWR Morb Mortal Wkly Rep 2019;68:326–327. DOI: http://dx.doi.org/10.15585/mmwr.mm6814a2

4: Gershman K, Timm K, Frank M, Lampi L, Melamed J, Gerona R, Monte AA. Deaths in Colorado Attributed to Kratom. N Engl J Med. 2019 Jan 3;380(1):97-98. doi: 10.1056/NEJMc1811055. PubMed PMID: 30601742.

5: Kruegel AC, Gassaway MM, Kapoor A, Váradi A, Majumdar S, Filizola M, Javitch JA, Sames D. Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators. J Am Chem Soc. 2016 Jun 1;138(21):6754-64. doi: 10.1021/jacs.6b00360. Epub 2016 May 18. PubMed PMID: 27192616; PubMed Central PMCID: PMC5189718.

6: Smith LC, Lin L, Hwang CS, Zhou B, Kubitz DM, Wang H, Janda KD. Lateral Flow Assessment and Unanticipated Toxicity of Kratom. Chem Res Toxicol. 2018 Nov 16. doi: 10.1021/acs.chemrestox.8b00218. [Epub ahead of print] PubMed PMID: 30380840.

8: Kruegel AC, Grundmann O. The medicinal chemistry and neuropharmacology of kratom: A preliminary discussion of a promising medicinal plant and analysis of its potential for abuse. Neuropharmacology. 2018 May 15;134(Pt A):108-120. doi: 10.1016/j.neuropharm.2017.08.026. Epub 2017 Aug 19. Review. PubMed PMID: 28830758.

9: Post S, Spiller HA, Chounthirath T, Smith GA. Kratom exposures reported toUnited States poison control centers: 2011-2017. Clin Toxicol (Phila). 2019 Feb 20:1-8. doi: 10.1080/15563650.2019.1569236. [Epub ahead of print] PubMed PMID:30786220.

Supplementary:

FDA Guidance On Lead and Nickel Exposure from kratom products:  Link

"Based on these test results, the typical long-term kratom user could potentially develop heavy metal poisoning, which could include nervous system or kidney damage, anemia, high blood pressure, and/or increased risk of certain cancers."

Graphics Credit:

1.  Mitragynine and 7-hydroxymitragynine were done with ChemDoodle.

2.  Table is from the CDC per reference 3 and public domain.