What are the pharmacologic effects of kratom and why is it available over‑the‑counter?

Kratom: Pharmacologic Effects and Over-the-Counter Availability

Kratom should not be used and must be discontinued due to its opioid-like properties, serious adverse effects including hepatotoxicity, cardiotoxicity, seizures, and deaths, despite being legally available as an unregulated dietary supplement in most U.S. jurisdictions. 1

Pharmacologic Mechanisms

Kratom (Mitragyna speciosa) contains over 40 alkaloids, with mitragynine and 7-hydroxymitragynine as the primary psychoactive compounds that produce complex opioid-like and stimulant effects 2:

• Acts as a partial agonist at mu-opioid receptors and antagonist at kappa- and delta-opioid receptors, creating analgesic and mild euphoric effects 3, 2
• Affects multiple neurotransmitter systems including adrenergic, serotonergic, and dopaminergic pathways beyond just opioid receptors 2, 4
• Produces dose-dependent effects: stimulant properties at lower doses (increased energy, alertness) and opioid-like sedation and analgesia at higher doses 4
• Lower respiratory depression risk compared to traditional opioids, likely due to lack of β-arrestin pathway activation 3

Serious Health Risks

The FDA explicitly warns against kratom use, and multiple serious adverse effects have been documented 1:

• Hepatotoxicity and cardiotoxicity are established risks with kratom consumption 3
• Seizures and neurologic effects occur with chronic use 1
• Physical and psychological dependence develops, with classic opioid withdrawal symptoms (particularly at doses >5-15g daily) requiring gradual tapering rather than abrupt discontinuation 1, 2
• Deaths have been reported in the U.S. and Europe, though typically involving polysubstance use and potentially adulterated products 3, 5

Critical Drug Interactions

Kratom alkaloids are potent inhibitors of CYP2D6 and moderate inhibitors of CYP2C19 and CYP3A4, creating dangerous pharmacokinetic interactions 3:

• Potentiates toxicity of co-administered medications through cytochrome P450, P-glycoprotein, and UGT enzyme modulation 2
• Particularly dangerous with other CNS-active substances, which is the pattern seen in most reported fatalities 5

Why It Remains Over-the-Counter

Despite these risks, kratom remains legally available as a dietary supplement in most U.S. states due to regulatory gaps 2, 5:

• Not FDA-approved for any medical indication and carries FDA warnings against use 1
• DEA attempted Schedule I classification in 2016 but withdrew due to public resistance, leaving it in legal limbo 2
• Sold as an unregulated "dietary supplement" through smoke shops, websites, and the darknet, with no quality control 5
• Adulteration and contamination risks are substantial in Western markets, unlike traditional Southeast Asian use of fresh leaves 3, 5

Common Pitfalls

• Patients may not disclose kratom use when asked about medications, as they view it as a "natural supplement" rather than a drug with opioid-like properties
• Self-treatment of opioid withdrawal is a common use pattern in the U.S., creating a dangerous cycle of substituting one dependency for another 2, 4
• Abrupt discontinuation in chronic users (>5-15g daily) precipitates withdrawal syndrome requiring medical management 1
• Polysubstance use dramatically increases mortality risk, particularly when combined with other CNS depressants or medications metabolized by CYP2D6 3, 5