KRATOM LEGALITY:
What Is Kratom?
Kratom is a herbal substance that is used for its stimulant effects. It is typically brewed into a tea as dried leaves, or the fresh leaves are chewed. The dried leaves can also be crushed and smoked. In addition, kratom comes in pill form, tinctures, extracts,selzters, vape pens and more.
Kratom has no approved medical uses in the United States, but people do report using it to manage opiod withdrawal symptoms and cravings, for pain management, to address mental health concerns and to combat fatigue. (3)
Some people may take kratom in smaller doses to stay awake, alert, and more social. In higher doses, it is often taken to get a “high” similar to that associated with an opioid drug.it can produce a calming sense of euphoria, which also makes it an addictive substance with a high potential for drug dependence.
In low doses it can make a person more talkative. It can also increase energy and alertness-therefore, acting as a stimulant substance, In higher doses, kratom can cause sedation and opioid-like effects.
Side effects of kratom use may include the following: (4)
Hallucinations, delusions, mental confusion, nausea, itchiness, dry mouth, sweating, loss of appetite, increased urination, constipation.
Kratom is potentially addictive. It can cause physical dependence and withdrawal symptoms, including cravings, sleep disturbances, anxiety, restlessness, lethargy, tremors, muscle pain, and nausea. Long-term use pf kratom can also lead to unhealthy wight loss, anorexia, and insomnia.
STATS ON KRATOM USE& ABUSE
Just under 1% of people over the age of 12 in the United States used kratom in 2020, which equates to 2.1 million people. Kratom abuse is most common in adults; ages 26 and older, with 1.8 million adults using kratom in 2020 compared to 286,000 young adults and teens between the ages of 18 and 25, and 48,000 adolescents between the ages of 12 and 17(5)
SIGNS OF KRATOM USE MAY INCLUDE THE FOLLOWING
Talkativeness, high energy, alertness, restlessness, sociability, heightened sexual desire. In higher doses, it can have the opposite effects.
SIGNS OF USE AT HIGHER DOSES
Drowsiness, euphoria or a dreamlike state, calmness, loss of motor coordination, giddiness, blushing.
Kratom is more commonly used in the Asia Pacific region of the world than in the United States. There are even several countries that classify kratom as a medical herbal substance with some properties, particularly in traditional Eastern medicine.
in Southeast Asia, kratom is used to wean people of heroin. It is also used as an antidiabetic, intestinal deworming agent, antidiarrheal, cough suppressant, and wound poultice.
There are anecdotal reports of using kratom to self-regulate pain and as an opioid. There are recreational and no known medical uses for kratom in modern medicine, however. Use of the substance, at least in the USA, is typically considered to be for recreational and nonmedical purpose.
FDA and Kratom. U.S. Food and Drug Administration (FDA). https://www.fda.gov/news-events/public-health-focus/fda-and-kratom. September 2019. Accessed April 2022. Kratom Drug Profile. European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). https://www.emcdda.europa.eu/publications/drug-profiles/kratom_en. Accessed April 2022. Kratom. National Institute on Drug Abuse (NIDA). https://nida.nih.gov/drug-topics/kratom. Accessed April 2022. Kratom. Drug Enforcement Administration (DEA). https://www.dea.gov/factsheets/kratom. Accessed April 2022. Key Substance Use and Mental Health Indicators in the United States: Results From the 2020 National Survey on Drug Use and Health. Substance Abuse and Mental Health Services Administration. https://www.samhsa.gov/data/sites/default/files/reports/rpt35325/NSDUHFFRPDFWHTMLFiles2020/2020NSDUHFFR1PDFW102121.pdf. October 2021. Accessed April 2022. Notes from the Field: Unintentional Drug Overdose Deaths with Kratom Detected – 27 States, July 2016-December 2017. Centers for Disease Control and Prevention (CDC). https://www.cdc.gov/mmwr/volumes/68/wr/mm6814a2.htm. April 2019. Accessed April 2022. Drugs of Concern. Drug Enforcement Administration (DEA). https://www.dea.gov/taxonomy/term/311. Accessed April 2022.
Why isn’t Kratom Legal Everywhere?
Kratom is widely recognized as an addictive drug with serious side effects.
While it is not currently controlled in the Untied States, kratom was listed as a “drug of concern” by the DEA in June 2020. It has the potential to be placed on the Controlled Substances List.(7) The FDA has thus far found kratom to have no potential therapeutic benefits.
Kratom can cause some significant symptoms when used for an extended period. These symptoms include drug dependence and withdrawal along with the potential for addiction and fatal overdose.
When combined with other substances, kratom can especially be dangerous. Long-term kratom use can also lead to weight loss, muscle pain, darkening of skin pigmentation, liver damage, and potential breathing issues.
Kratom is an unregulated substance, which means it can be difficult to know exactly what in the product you are buying or using. Because it is unregulated, this increases the potential risks of using kratom.
Comparative Analysis of the Prodrug Effects of Codeine and Mitragynine
In pharmacology, the concept of a pro-drug is pivotal for understanding how certain compounds exert their effects not directly, but through their metabolites. Two notable examples of such pro-drugs are codeine and mitragynine, both of which exhibit weak agonistic properties at the human µ-opioid receptor (MOR) but undergo biotransformation in the body to form significantly more potent metabolites. This post compares the pro-drug effects of codeine and mitragynine, focusing on their metabolic conversion and the resulting pharmacological implications.
CODEINE AND ITS METABOLIC TRANSFORMATION
Codeine, a naturally occurring alkaloid found in opium, is widely used as an analgesic and antitussive. Its primary mode of action is mediated through the µ-opioid receptor, where it exhibits relatively weak agonistic activity. However, codeine’s therapeutic efficacy is largely dependent on its metabolic conversion to morphine, which occurs predominantly in the liver.
The enzyme responsible for this conversion is cytochrome P450 2D6 (CYP2D6). Once ingested, codeine undergoes O-demethylation by CYP2D6 to produce morphine, a much more potent agonist of the µ-opioid receptor. Morphine’s affinity for the µ-opioid receptor is approximately 200-fold greater than that of codeine, explaining the significant increase in analgesic potency after codeine is metabolized. Morphine, in turn, is further metabolized into morphine-6-glucuronide, a metabolite that is even more potent than morphine in binding to the µ-opioid receptor.
MITRAGYNINE AND ITS BIOCONVERSION
Mitragynine, the principal alkaloid found in the leaves of Mitragyna speciosa (commonly known as kratom), shares a similar pharmacological trajectory with codeine in terms of its pro-drug nature. Mitragynine itself is a weak agonist at the µ-opioid receptor, exerting minimal opioid-like effects. However, upon ingestion, mitragynine undergoes bioconversion into 7-hydroxymitragynine, a metabolite with significantly enhanced potency at the µ-opioid receptor. 7-Hydroxymitragynine, in turn is further metabolized to the once again even more potent form known as Mitragynine pseudoindoxyl in human plasma.
The enzyme CYP3A4 plays a crucial role in this bioconversion process. Research indicates that approximately 13.25% of mitragynine exposure is converted to 7-hydroxymitragynine. This transformation is critical because 7-hydroxymitragynine has an affinity for the µ-opioid receptor that is up to 17 times greater than that of morphine, making it one of the most potent naturally occurring opioids.
COMPARATIVE ANALYSIS OF CODEINE AND MITRAGYNINE
Both codeine and mitragynine serve as quintessential examples of pro-drugs, and their pharmacological effects heavily relying on metabolic activation. Despite their weak initial interaction with the µ-opioid receptor, their respective metabolites—morphine and 7-hydroxymitragynine—exhibit profound opioid activity, leading to significant analgesic effects and, in some cases, abuse potential.
The key difference between these two compounds lies in the extent of their metabolic activation and the resulting potency of their metabolites. Morphine, which is derived from codeine, is a potent opioid that is still within the therapeutic range for clinical use. On the other hand, 7-hydroxymitragynine, derived from mitragynine, not only surpasses morphine in potency but also raises concerns regarding its potential for abuse and addiction, given its highly potent agonistic activity at the µ-opioid receptor.
Moreover, variability in CYP2D6 enzyme activity among individuals can lead to significant differences in the manner in which codeine is metabolized. For example, individuals who are poor metabolizers of CYP2D6 may experience limited analgesic effects from codeine, whereas ultra-rapid metabolizers may be at risk of morphine toxicity. Similarly, the bioconversion of mitragynine to 7-hydroxymitragynine appears to be equally subject to interindividual variability at CYP3A4.
CONCLUSION
In conclusion, the pro-drug effects of codeine and mitragynine underscore the importance of metabolic transformation in the pharmacodynamics of opioid compounds. Both codeine and mitragynine are weak µ-opioid receptor agonists whose true pharmacological impact is realized only after conversion to their respective, much more potent metabolites—morphine and 7-hydroxymitragynine. Understanding these processes not only provides insight into their therapeutic applications but also highlights the potential risks associated with their use, particularly in the context of opioid dependence and abuse. As research continues to evolve, especially regarding the bioconversion of mitragynine, monitoring and evaluating the implications of these potent metabolites in both clinical and non-clinical settings.
SOURCES
Hiranita, Takato, Abhisheak Sharma, Francisco Leon Oyola, Samuel Obeng, Morgan E. Reeves, Luis F. Restrepo, Avi Patel, et al. 2020. “Potential Contribution of 7‐Hydroxymitragynine, a Metabolite of the Primary Kratom ( Mitragyna Speciosa ) Alkaloid Mitragynine, to the μ‐Opioid Activity of Mitragynine in Rats.” The FASEB Journal 34 (S1): 1–1. https://doi.org/10.1096/fasebj.2020.34.s1.05180.
Kamble, Shyam H., Samuel Obeng, Francisco León, Luis F. Restrepo, Tamara I. King, Erin C. Berthold, Siva Rama Raju Kanumuri, et al. 2023. “Pharmacokinetic and Pharmacodynamic Consequences of Cytochrome P450 3A Inhibition on Mitragynine Metabolism in Rats.” The Journal of Pharmacology and Experimental Therapeutics 385 (3): 180–92. https://doi.org/10.1124/jpet.122.001525.
Ortiz de Montellano, Paul R. 2013. “Cytochrome P450-Activated Prodrugs.” Future Medicinal Chemistry 5 (2): 213–28. https://doi.org/10.4155/fmc.12.197.
Vora, A., and M. Y. Nadkar. 2015. “Codeine: A Relook at the Old Antitussive.” Journal of The Association of Physicians of India 63 (4): 80–82. https://www.academia.edu/download/100046374/19_dc_codeine_a_relook_at.pdf.