Sunday, April 14, 2019

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.



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