Fentanyl Overdoses Including Kratom

[Data Contributor]

Fentanyl Overdose Deaths Including Kratom​

Why do we see an abundance of adverse reports that include kratom and fentanyl?​

Kratom is traditionally used for its stimulant and opioid-like effects. The pharmacology of kratom is complex, involving a range of active compounds, with mitragynine and 7-hydroxymitragynine being the most prominent. These compounds interact with opioid receptors in the brain, producing sedation, pleasure, and decreased pain, especially at higher doses. We’re going to focus specifically on the 115 adverse events, including deaths, reported between 2019-2023 to the FDA involving kratom & fentanyl. There are more instances when the search is expanded to other opioids and this essay may speak to these toxicities as well.

The Cytochrome P450 (CYP450) enzymes are a large family of enzymes that play a crucial role in the metabolism of drugs and the processing of endogenous compounds (like hormones and fatty acids) in the body. These enzymes are primarily found in the liver, but they are also present in other tissues such as the intestines. They are responsible for catalyzing the oxidation of organic substances, which is a key step in the metabolic breakdown and elimination of various compounds (aka, “metabolization” or “biotransformation”).

When discussing the potential role of kratom in overdose deaths, particularly in the context of poly-drug use including substances like fentanyl, it's crucial to understand the role of the Cytochrome P450 (CYP450) enzyme system, specifically CYP3A4, and CYP2D6.

CYP3A4, CYP2D6 and Drug Metabolism (This is key)​

1. CYP3A4 Function: CYP3A4 is one of the key enzymes in the CYP450 system, responsible for metabolizing around 50% of all drugs. It's found primarily in the liver and the intestinal tract. The enzyme plays a crucial role in the detoxification and clearance of various substances from the body, including fentanyl.
2. CYP2D6 Function: CYP2D6 is also another key enzyme involved in the metabolization of opioids and other pharmaceutical drugs. It was shown in a pharmacokinetic study on burn patients that those with CYP2D6 variations had increased serum fentanyl concentrations due to the impaired clearance.
3. Impact of Inhibition: Inhibition of CYP3A4 and/or CYP2D6 can lead to increased blood levels of drugs that are normally metabolized by these enzymes. This is because the inhibited enzyme cannot effectively break down the drug, leading to accumulation, and possible toxicities.

Kratom and CYP3A4 & CYP2D6 Inhibition​

1. Kratom's Effect on CYP3A4: Research has shown that kratom, or more specifically, certain compounds in kratom, can inhibit the activity of CYP3A4 in both the intestines and the liver. This means that when kratom is consumed, it can reduce the metabolic activity of CYP3A4 on a systemic level.
2. Kratom's Effect on CYP2D6: Mitragynine is a potent reversible inhibitor of CYP2D6 activity as shown in human pharmacokinetic studies.
3. Consequences of Concurrent Drug Use: If a person takes another drug that is metabolized by CYP3A4 (like fentanyl) or CYP2D6 (like codeine, fentanyl, hydrocodone, oxycodone and tramadol) alongside kratom, the inhibited enzyme may lead to reduced metabolism and clearance of that drug. This can result in higher, potentially dangerous levels of the drug in the system.

Kratom and Fentanyl Interaction​

1. Increased Fentanyl Levels: Fentanyl is a potent synthetic opioid, significantly stronger than morphine. It's metabolized by CYP3A4 and partially by CYP2D6. When kratom inhibits these enzymes, fentanyl is not adequately metabolized, leading to elevated levels in the bloodstream.
2. Risk of Overdose: Elevated levels of fentanyl can easily lead to overdose, given its high potency. Overdose symptoms can include severe respiratory depression, unconsciousness, and death.

Conclusion:​

The consumption of kratom may contribute to overdose deaths, particularly in the context of poly-drug use involving substances like fentanyl, through its inhibition of CYPs 3A4 and 2D6. This interaction can lead to elevated levels of other drugs in the system, increasing the risk of overdose and its associated complications. It's a potent example of how herbal compounds can have significant, sometimes dangerous, interactions with pharmaceutical drugs, underlining the importance of understanding and monitoring such interactions, especially in contexts of substance abuse or poly-drug use.


Sources:

FDA. FEARS “Federal Adverse Event Reporting System”. Deaths Including Kratom and Fentanyl.2023.

Tanna, Rakshit S., Dan-Dan Tian, Nadja B. Cech, Nicholas H. Oberlies, Allan E. Rettie, Kenneth E. Thummel, and Mary F. Paine. 2021. “Refined Prediction of Pharmacokinetic Kratom-Drug Interactions: Time-Dependent Inhibition Considerations.” The Journal of Pharmacology and Experimental Therapeutics 376 (1): 64–73. https://doi.org/10.1124/jpet.120.000270

Grimsrud, Kristin N., Xenia Ivanova, Catherine M. Sherwin, Tina L. Palmieri, and Nam K. Tran. 2019. “Identification of Cytochrome P450 Polymorphisms in Burn Patients and Impact on Fentanyl Pharmacokinetics: A Pilot Study.” Journal of Burn Care & Research: Official Publication of the American Burn Association 40 (1): 91–96. https://doi.org/10.1093/jbcr/iry053

Kamble, Shyam H., Abhisheak Sharma, Tamara I. King, Francisco León, Christopher R. McCurdy, and Bonnie A. Avery. 2019. “Metabolite Profiling and Identification of Enzymes Responsible for the Metabolism of Mitragynine, the Major Alkaloid of Mitragyna Speciosa (kratom).” Xenobiotica; the Fate of Foreign Compounds in Biological Systems 49 (11): 1279–88. https://doi.org/10.1080/00498254.2018.1552819

Chakraborty, Soumen, Rajendra Uprety, Samuel T. Slocum, Takeshi Irie, Valerie Le Rouzic, Xiaohai Li, Lisa L. Wilson, et al. 2021. “Oxidative Metabolism as a Modulator of Kratom’s Biological Actions.” Journal of Medicinal Chemistry 64 (22): 16553–72. https://doi.org/10.1021/acs.jmedchem.1c01111

Todd, D. A., J. J. Kellogg, E. D. Wallace, M. Khin, L. Flores-Bocanegra, R. S. Tanna, S. McIntosh, et al. 2020. “Chemical Composition and Biological Effects of Kratom (Mitragyna Speciosa): In Vitro Studies with Implications for Efficacy and Drug Interactions.” Scientific Reports 10 (1): 19158. https://doi.org/10.1038/s41598-020-76119-w

Tanna, Rakshit S., Nadja B. Cech, Nicholas H. Oberlies, Allan E. Rettie, Kenneth E. Thummel, and Mary F. Paine. 2023. “Translating Kratom-Drug Interactions: From Bedside to Bench and Back.” Drug Metabolism and Disposition: The Biological Fate of Chemicals, June. https://doi.org/10.1124/dmd.122.001005

Brogdon, Hazel D., Mackenzie M. McPhee, Mary F. Paine, Emily J. Cox, and Amy G. Burns. 2022. “A Case of Potential Pharmacokinetic Kratom-Drug Interactions Resulting in Toxicity and Subsequent Treatment of Kratom Use Disorder With Buprenorphine/Naloxone.” Journal of Addiction Medicine 16 (5): 606–9. https://doi.org/10.1097/ADM.0000000000000968

Coonan, Erin, and William Tatum. 2021. “Kratom: The Safe Legal High?” Epilepsy & Behavior: E&B 117 (April): 107882. https://doi.org/10.1016/j.yebeh.2021.107882

 

[charlie]

I think kratom vendors should offer free Narcan to customers with a warning that mixing kratom with fentanyl and other drugs can be extremely deadly. People who are most at risk:

1) Those using kratom because there drug of choice is unavailable.
2) Those using kratom to withdrawal from harder drugs, but are likely to return to those drugs.
3) Those using kratom to potentiate their drug of choice (most dangerous combo).
4) Those using kratom but accidentally or mindless take a pill they think is Xanax (which is risky itself) but is actually adulterated with fentanyl.
5) Those who are in active addiction with a loss of control and take whatever they can get their hands that particular day.

These are fellow society members who deserve our attention. Writing them off as they would of died anyway without kratom, and that kratom only can save the deserving are not solid public health policies.

 

[Administrator]

I think kratom vendors should offer free Narcan to customers with a warning that mixing kratom with fentanyl and other drugs can be extremely deadly. People who are most at risk:

1) Those using kratom because there drug of choice is unavailable.
2) Those using kratom to withdrawal from harder drugs, but are likely to return to those drugs.
3) Those using kratom to potentiate their drug of choice (most dangerous combo).
4) Those using kratom but accidentally or mindless take a pill they think is Xanax (which is risky itself) but is actually adulterated with fentanyl.
5) Those who are in active addiction with a loss of control and take whatever they can get their hands that particular day.

These are fellow society members who deserve our attention. Writing them off as they would of died anyway without kratom, and that kratom only can save the deserving are not solid public health policies.

Agreed.

If a vendor of this botanical states they care about their customers, this should be mandatory. Some proponents (not all) say "POLY-PHARMACY" as if this were a reason to completely ignore the customers they may actually be putting in danger.

If you sell kratom, you should include Narcan if you care about your customers, and truly do think that poly-drug use is a main factor in these adverse event reports. Put that money where that mouth is

 

[charlie]

 

[Administrator]

Read the paper but never scrolled to the bottom to see that figure. THANK YOU!

Suriaga, Armiel A., Ruth M. Tappen, Christopher R. McCurdy, and David Newman. 2023. “Increased Risk of Mitragynine Drug Intoxication Is Associated with Opioid Use: A Retrospective Analysis.” https://doi.org/10.2139/ssrn.4495146.

 

[charlie]