Pharmacology 101: Kratom, Part 2

Find the first part of this series here.

As mentioned in Part 1 of this series, the two main biologically active alkaloids in kratom are mitragynine and 7-hydroxymitragynine.^1,2 Recall that pharmacokinetics describes the study of the time course of drug absorption, distribution, metabolism, and excretion. With kratom the onset of effects may occur within 10–20 minutes, with full onset within 30–60 minutes after ingestion. Serum levels peak in approximately 1 hour, with a half-life of 23.24±16.07 hours.² Kratom’s effects typically last for 5–7 hours.³ There is still much to be learned about the pharmacokinetics and pharmacodynamics of kratom in the human body at this time.

Adverse Effects

At lower stimulant doses, slight pupil contraction and blushing may occur, as well as anxiety and internal agitation and loss of coordination. At doses from 5–15 g, diarrhea may occur. With doses greater than 15 g, side effects such as sweating, nausea, dizziness, and dysphoria often result, followed by a calmness and dreamlike state. Long-term use of high doses may result in tremor, anorexia, weight loss, seizures, and psychosis. Other side effects include fatigue, insomnia, constipation, dry mouth, frequent urination, and hyperpigmentation of the cheeks. Withdrawal symptoms are nonexistent to mild, despite its opioidlike properties.³

In a 2017 survey with more than 8000 respondents, the most frequently reported adverse effects were nausea, constipation, and dizziness or drowsiness. Diarrhea was also reported and was the only adverse effect that seemed unrelated to the dose. The rate of adverse events was lower in users who reported using doses of 5 g or less compared to users who said they used doses of 8 g or more. More frequent dosing was also associated with a higher rate of adverse reactions.⁴

One report in 2019 found the most common side effects were agitation (18.6%), tachycardia (16.9%), drowsiness (13.6%), vomiting (11.2%), and confusion (8.1%), with other reported serious events including seizure (6.1%), withdrawal (6.1%), hallucinations (4.8%), respiratory depression (2.8%), coma (2.3%), and cardiac or respiratory arrest (0.6%).⁵

The 2020 annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS) noted 1262 case mentions of kratom for the entire year of 2020, of which half (614) were treated in healthcare facilities. The data show 59 patients with no effects, 175 with minor effects, 259 with moderate effects, and 66 with major effects.⁶

Drug-induced liver damage was reported in 11 users in a 2021 case based on data procured using the US Drug-Induced Liver Injury Network (DILIN). The authors called for an awareness of the risk of severe liver injury from kratom.⁷  

Lastly, note that kratom is not regulated, and as a 2020 review noted, “Without regulatory oversight there is little to ensure the authenticity, purity, quality, potency, and safety of commercially available kratom preparations.”⁸ The FDA has issued warnings previously regarding heavy metals detected in kratom products,⁹ as well as contamination with Salmonella bacteria.¹⁰

Addiction, Withdrawal, and Deaths

Unfortunately, kratom use can lead to addiction and withdrawal. Reported withdrawal symptoms include tearfulness, runny nose, inability to work, muscle pain and cramps, muscle spasms and tremor, insomnia, nausea and vomiting and diarrhea, and psychological symptoms of withdrawal, including anxiousness, depressed mood, inability to feel pleasure, restlessness, anger, hostility, and tension.^1,2 Additionally, neonatal abstinence syndrome has been reported in newborns due to exposure in utero.²

In February 2018 the FDA was aware of 44 deaths associated with kratom. However, this may be an underrepresentation of the true number due to a lack of recognition of kratom as a cause of death prior to 2016. Additionally, kratom is not part of routine drug screening tests.² However, in 2019 the CDC released a report saying it found kratom involved in 152 of the 27,338 overdose deaths (0.56%) in the United States between July 2016 and December 2017. According to that report, “In approximately 80% of kratom-positive and kratom-involved deaths in this analysis, the decedents had a history of substance misuse, and approximately 90% had no evidence they were currently receiving medically supervised treatment for pain.”¹¹  

Five deaths were noted in the 2020 NPDS report.⁶ The 2021 report has not yet been released.

Future Research

At the time of this writing there are two trials registered on clinicaltrials.gov with the index term kratom; one from Centre for Drug Research, Universiti Sains Malaysia called “[Kratom] and Pain Tolerence [sic]” and another from the Washington State University College of Pharmacy and Pharmaceutical Sciences titled “Assessing the Pharmacokinetics and Drug Interaction Liability of Kratom, an Opioid-like Natural Product.”

Conclusion

Kratom is a substance that has pharmacological properties that have yet to be harnessed in a fashion proven to be consistently safe and effective. The FDA has not approved kratom for any uses, and reports of adverse events, including death, are increasing. EMS caregivers should be aware of the existence of kratom and its risks.

The views and opinions expressed in this article are those of the author.

References

1. Singh D, Müller CP, Vicknasingam BK. Kratom (Mitragyna speciosa) dependence, withdrawal symptoms and craving in regular users. Drug Alcohol Depend. 2014; 139: 132–7. doi: 10.1016/j.drugalcdep.2014.03.017

2. White CM. Pharmacologic and clinical assessment of kratom: An update. Am J Heal Pharm. 2019; 76(23): 1915–25. doi:10.1093/ajhp/zxz221

3. Warner ML, Kaufman NC, Grundmann O. The pharmacology and toxicology of kratom: from traditional herb to drug of abuse. Int J Legal Med. 2016; 130(1): 127–138. doi:10.1007/s00414-015-1279-y

4. Grundmann O. Patterns of kratom use and health impact in the US—Results from an online survey. Drug Alcohol Depend. 2017; 176(March): 63–70. doi:10.1016/j.drugalcdep.2017.03.007

5. Eggleston W, Stoppacher R, Suen K, Marraffa JM, Nelson LS. Kratom Use and Toxicities in the United States. Pharmacotherapy. 2019; 39(7): 775–7. doi:10.1002/phar.2280

6. Gummin DD, Mowry JB, Beuhler MC, et al. 2020 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 38th Annual Report. Clin Toxicol. 2021; 59(12): 1282–1501. doi:10.1080/15563650.2021.1989785

7. Ahmad J, Odin JA, Hayashi PH, et al. Liver injury associated with kratom, a popular opioid-like product: Experience from the U.S. drug induced liver injury network and a review of the literature. Drug Alcohol Depend. 2021; 218. doi:10.1016/j.drugalcdep.2020.108426

8. Eastlack SC, Cornett EM, Kaye AD. Kratom—Pharmacology, Clinical Implications, and Outlook: A Comprehensive Review. Pain Ther. 2020; 9(1): 55–69. doi:10.1007/s40122-020-00151-x

9. Laboratory Analysis of Kratom Products for Heavy Metals. Published April 3, 2019. www.fda.gov/news-events/public-health-focus/laboratory-analysis-kratom-products-heavy-metals

10. US Food & Drug Administration. Statement from FDA Commissioner Scott Gottlieb, MD and FDA Deputy Commissioner for Foods and Veterinary Medicine Stephen Ostroff, MD, on the ongoing risk of salmonella in kratom products. Published July 2, 2018. https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-and-fda-deputy-commissioner-foods-and-veterinary

11. 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. Morb Mortal Wkly Rep. 2019; 68(14): 326–7. www.cdc.gov/mmwr/volumes/68/wr/mm6814a2.htm

Daniel Hu, PharmD, BCCCP, has Doctor of Pharmacy degree and is a critical care and emergency medicine pharmacist. He is a frequent speaker at conferences and has many publications in peer-reviewed journals.