Kratom

Introduction Overview

Generic Name

kratom

Brand Name

None (herbal product with multiple street names including Thang, Krypton, Kakuam, Thom, Ketum, Biak-Biak, Maeng da leaf, among others)

Dosage Form

capsule, tablet, powder, liquid (tea or extracts)

Drug Class

Herbal product with stimulant and opioid-like effects; classified pharmacologically as an opioid receptor agonist

Pharmacokinetics

Absorption:
Kratom is primarily taken orally in various forms such as capsules, powder, tea, or liquid extracts. Following oral ingestion, animal studies indicate that peak plasma concentrations of mitragynine, the primary active alkaloid, are achieved approximately 1.26 hours post-dose. The onset of psychoactive effects is noted within 10 minutes and can last from one to five hours, depending on dose and formulation. The presence of other plant constituents and the preparation method (e.g., tea versus capsule) can influence absorption kinetics. However, human pharmacokinetic data remain limited, with variability in bioavailability attributed to factors such as gastrointestinal motility, pH, and concomitant food intake.

Distribution:
After absorption, mitragynine is widely distributed throughout body tissues, given its lipophilicity and ability to cross the blood-brain barrier. It binds to opioid receptors in the central nervous system to exert its effects. While detailed human plasma protein binding data are scarce, mitragynine’s distribution volume suggests extensive tissue penetration. There is potential for accumulation with repeated use, though detailed human studies evaluating steady-state concentrations are lacking.

Metabolism:
Kratom alkaloids, mainly mitragynine and 7-hydroxymitragynine, undergo hepatic metabolism primarily via the cytochrome P450 enzyme system. In vitro studies suggest involvement of CYP3A4, CYP2D6, and CYP2C9 isoenzymes. The metabolic pathways likely include demethylation, oxidation, and conjugation reactions. Metabolites have varying degrees of pharmacologic activity, with 7-hydroxymitragynine noted to have a higher affinity for opioid receptors. The extent of first-pass metabolism is significant and contributes to interindividual variability. Concomitant use of CYP inhibitors or inducers may alter kratom's pharmacokinetics, influencing efficacy and toxicity.

Elimination:
Elimination of mitragynine is primarily hepatic, with renal excretion of metabolites. The elimination half-life reported in animal models is approximately 3.85 hours. Human data are limited but suggest a similar elimination profile. Factors affecting liver function can impact clearance, and accumulation may result in prolonged effects or toxicity. There is no well-defined data on the excretion in bile or feces. No formal pharmacokinetic studies in renal or hepatic impairment populations are available, which poses challenges for dose adjustment and safety monitoring.

Dosage Forms

Available Dosage Forms:
- Capsules: Often containing powdered kratom leaf, variable concentrations depending on vendor; commonly available strengths are not standardized.
- Tablets: Pressed powder forms, similarly unstandardized in dosage.
- Powder: Raw dried leaf material ground into powder, used for mixing into drinks or direct consumption.
- Liquid: Kratom tea prepared by steeping leaves or powder; concentrated liquid extracts are also available commercially.

Dosages for Adults and Adolescents:
- No standardized dosing regimen established due to lack of clinical trials and regulatory approval.
- Anecdotal adult doses for stimulant effects typically range from 1 to 5 grams of raw leaf powder.
- Higher doses (5 to 15 grams) are associated with opioid-like sedative and analgesic effects.
- Capsules often contain 500 mg to 1000 mg of powder per unit, with users taking multiple capsules per dose.
- No recommended dosing for adolescents or pediatric populations; usage discouraged due to safety concerns.

Specific Patient Populations:
- Pregnant or breastfeeding women: Safety unknown; use not recommended.
- Patients with hepatic or renal impairment: No dosing data available; caution advised due to metabolism and elimination via liver and kidneys.
- Elderly: No specific dosing guidelines; increased susceptibility to side effects expected.
- Patients with history of substance use disorder or mental health conditions should avoid use due to potential for addiction and psychiatric adverse effects.

Note: The actual kratom dosage and form vary widely due to lack of regulation and standardization. Consumers are exposed to products with inconsistent purity and concentration, complicating safe dosing.

Mechanism Of Action

Kratom primarily exerts its pharmacological effects through activation of opioid receptors, notably the mu (μ), kappa (κ), and delta (δ) subtypes. The principal alkaloid, mitragynine, acts as an agonist at these receptors, with some studies indicating it is approximately 13 times more potent than morphine at the kappa-opioid receptor. This receptor activation accounts for the opioid-like analgesic and sedative effects observed at higher doses. Mitragynine is structurally related to yohimbine and uniquely interacts with multiple receptor types, which contributes to its complex pharmacodynamic profile.

In addition to opioid receptor interaction, kratom alkaloids modulate monoaminergic neurotransmission. Specifically, they affect serotonergic and noradrenergic systems within the spinal cord, contributing to pain modulation and mood effects. Post-synaptic alpha-2 adrenergic receptor stimulation is also implicated, which can enhance analgesia and exert sedative effects. Conversely, antagonistic activity at 5-hydroxytryptamine 2A (5-HT2A) receptors may contribute to mitigation of hallucinogenic properties observed with certain opioids.

The minor alkaloid 7-hydroxymitragynine exhibits a higher affinity for opioid receptors than mitragynine and is believed to be a more potent analgesic agent. Both alkaloids act as partial agonists, which may result in differing efficacy and dependency profiles compared to full opioid agonists. Animal studies indicate that the opioid-receptor-mediated effects of kratom can be reversed by naloxone, underscoring its opioid receptor mechanism.

Clinically, kratom's dual stimulant and depressant effects reflect its dose-dependent receptor engagement—low doses tend to stimulate adrenergic pathways leading to increased alertness and energy, while high doses predominantly engage opioid receptors to produce sedation, analgesia, and euphoria. This complex mechanism makes kratom pharmacologically distinct from conventional opioids and warrants further research to elucidate its full clinical implications.

Pharmacological Actions

Agonist activity at mu-, kappa-, and delta-opioid receptors producing analgesic and sedative effects.
Stimulant effects at lower doses mediated by adrenergic receptor stimulation leading to increased alertness and energy.
Modulation of serotonergic pathways contributing to mood alteration and possible antidepressive effects.
Noradrenergic pathway involvement enhancing analgesic and sedative actions.
Partial agonist behavior possibly leading to reduced respiratory depression compared to full opioid agonists.
Antagonistic effects at 5-HT2A receptors potentially mitigating hallucinogenic side effects.
Induction of CNS depression at higher doses similar to opioid narcotics.
Pharmacological profile suggesting potential for withdrawal and dependence due to opioid receptor interactions.
Influence on gastrointestinal motility resulting in antidiarrheal effects.
Potential antihypertensive effects via peripheral vasodilation.
Local anesthetic properties reported anecdotally but not well studied.

Therapeutic Or Clinical Uses

Management of chronic musculoskeletal pain as an alternative to opioids in some regions.
Relief of opioid withdrawal symptoms, aiming to alleviate craving, anxiety, and physical withdrawal signs.
Self-treatment of diarrhea due to gastrointestinal motility modulation.
Anecdotal use as an anti-inflammatory agent in traditional medicine.
Reported use for anxiety and mood disorders, though lacking clinical validation.
Use as a stimulant to increase energy and sociability at low doses.
Reported antipyretic (fever-reducing) properties in traditional settings.
Use as a local anesthetic for minor procedures in folk medicine.
Promoted for enhancement of sexual function by some users.
Experimental or off-label use in managing fatigue and improving focus.
None are FDA-approved; clinical effectiveness and safety remain scientifically unproven.

Side Or Adverse Effects

Nausea and vomiting, commonly reported with acute use.
Sedation and drowsiness, especially at higher doses.
Dry mouth and increased thirst.
Excessive sweating and urinary frequency.
Constipation due to opioid receptor-mediated gastrointestinal effects.
Itching and skin irritation reported in some cases.
Dizziness and confusion, impacting cognition and motor function.
Dependence and addiction with chronic use, exhibiting opioid-like withdrawal symptoms.
Withdrawal syndrome manifestations including irritability, anxiety, yawning, runny nose, stomach cramps, and diarrhea.
Liver injury with jaundice, abdominal pain, fever, and itching, documented in case reports.
Psychosis including hallucinations, delusions, and confusion in chronic high-dose users.
Cardiovascular effects such as tachycardia and hypotension.
Weight loss, anorexia, and muscle aches linked to long-term use.
Seizures, notably when combined with other substances like modafinil.
Potential contamination risks leading to additional toxicities from adulterated products.

Precautions

Avoid use in pregnant or breastfeeding women due to unknown safety.
Not recommended for children or adolescents given lack of safety data.
Caution in patients with hepatic or renal impairment because of metabolism and elimination pathways.
Contraindicated in individuals with history of substance abuse or opioid dependency without medical supervision.
Avoid concurrent use with other CNS depressants, including opioids, benzodiazepines, and alcohol.
Risk of drug interactions with medications metabolized by CYP450 enzymes (e.g., CYP3A4, CYP2D6).
Consider potential contamination with heavy metals or adulterants; source verification is critical.
Avoid driving or operating machinery due to risk of sedation and impaired motor skills.
Monitor for signs of liver toxicity or allergic reactions during use.
Users should be aware of legal status varying by jurisdiction.
Use under medical supervision is advisable, especially in individuals with pre-existing medical conditions.
Patients should report any adverse events to healthcare professionals promptly.
Due to addictive potential, limit duration of use and monitor for dependency symptoms.
Potential for withdrawal symptoms upon cessation; tapering may be necessary.

Warnings

FDA warnings indicate no approved medical use and potential for serious adverse effects.
Reports of death linked to kratom, often involving polydrug use including opioids and benzodiazepines.
Risk of respiratory depression and CNS depression especially when combined with other drugs.
Possibility of adulterated products containing harmful substances or synthetic opioids.
Kratom's legal status varies by state; possession or use may be illegal in some areas.
Avoid using kratom as a substitute for FDA-approved opioid withdrawal treatments.
Use can cause psychosis or severe psychiatric symptoms in susceptible individuals.
Potential for liver toxicity and failure; immediate medical attention required if symptoms appear.
Risk of seizure with kratom, particularly when combined with interacting drugs.
Dependence and addiction risk similar to traditional opioids.
Use in children, pregnant, or breastfeeding women is strongly discouraged.
FDA advises against using kratom products marketed for opioid withdrawal or other medical claims.
Be cautious in elderly or debilitated patients due to increased sensitivity.
Potential for serious interactions with prescription and over-the-counter medications.

Contraindication

Known hypersensitivity to kratom or its alkaloids.
History of opioid addiction or substance use disorder without medical oversight.
Pregnancy and breastfeeding due to insufficient safety data and potential risks.
Severe hepatic or renal impairment without clinical monitoring.
Concurrent use of other CNS depressants or opioids without medical supervision.
Individuals with psychiatric disorders prone to psychosis or severe mood swings.
Patients with known QT prolongation or cardiac arrhythmias due to risk of exacerbation.
Children and adolescents under 18 years of age.
Known heavy metal poisoning or exposure conditions worsening by kratom contaminants.
Use of medications with narrow therapeutic indices metabolized by CYP450 enzymes involved in kratom metabolism.

Drug Interactions

Potential additive CNS depressant effects when combined with opioids leading to respiratory depression.
Interactions with benzodiazepines increasing sedation and risk of overdose.
Inhibition or induction of cytochrome P450 enzymes (e.g., CYP3A4, CYP2D6) altering metabolism of concomitant drugs.
Increased risk of seizures when combined with proconvulsant agents such as modafinil.
Possible interference with serotonergic agents, posing serotonin syndrome risk.
Interaction with loperamide and other opioids can potentiate opioid-like adverse effects.
May affect metabolism of antidepressants, antipsychotics, and other CNS-active drugs.
Potential interaction with antihypertensive medications causing hypotension.
Avoid use with medications causing QT prolongation due to additive cardiac risk.
Co-administration with monoamine oxidase inhibitors (MAOIs) is not studied but may increase adverse CNS effects.
Drug interactions with immunosuppressants and chemotherapeutics through CYP enzyme modulation.
Concomitant use with alcohol increases risk of CNS depression and liver toxicity.
Potential alteration of blood glucose-lowering medications leading to hypoglycemia or hyperglycemia.
Interactions with herbal supplements sharing metabolic pathways or similar pharmacological effects.

Preparations Of The Drug

Raw dried leaves of Mitragyna speciosa used in powder form for mixing or direct consumption.
Capsules containing powdered kratom leaf from various strains and concentrations.
Pressed tablets formed from compressed kratom powder.
Liquid preparations including traditional kratom tea and concentrated extracts.
Commercially produced kratom extracts with variable mitragynine concentration marketed online.
Adulterated products named like 'Boosted Kratom', 'The Devil’s Kratom', 'Terra Kratom', beyond natural formulations.
Kratom gum made from fresh or dried leaves used traditionally in Southeast Asia.
Some products may be blends with synthetic opioids or other unwanted substances increasing toxicity risks.
Street mixtures like "Krypton" combining mitragynine with tramadol metabolites have been implicated in fatalities.
No standardized pharmaceutical formulations or FDA-approved products available.
Supply chain lacks quality control, resulting in variable potency and contamination risks.
Products are sold as dietary supplements or herbal products but lack regulatory approval.
Packaging often unregulated with false claims regarding therapeutic benefits.
Kratom preparations can differ geographically in alkaloid composition impacting effect profile.