Kratom | Pharmacology Mentor

Generic Name

Kratom

Primary active alkaloids: *mitragynine* and *7‑hydroxymitragynine*
μ‑Opioid receptor partial agonist – produces analgesia and euphoria at low doses; high‑dose effects are akin to opioid agonists, with respiratory depression potential.
α2‑Adrenergic receptor agonism – contributes to sedative and sympatholytic properties at higher concentrations.
Modulation of serotonergic and dopaminergic pathways – influences mood and addiction pathways.
Non‑opioid actions: anti‑inflammatory, antispasmodic, and mild anticholinergic effects via secondary receptors.

Parameter	Typical Value (oral)	Notes
Absorption	Rapid, peak plasma 30–60 min	Food can delay onset but increase bioavailability
Distribution	Wide tissue penetration; high protein binding (~90 %)	Long‑acting metabolites accumulate with chronic use
Metabolism	Primarily CYP3A4, CYP2D6 → N‑oxide, demethylated forms	Drug interactions (e.g., with CYP inhibitors) may enhance potency
Elimination	Renal and fecal; half‑life 2–4 h	Elimination of active metabolites may extend clinical effects

Experimental: opioid withdrawal reduction, chronic pain management, anti‑diarrheal.
No FDA‑approved indications; use is largely off‑label or as self‑medication.

* Seizure disorders (risk of lowering the seizure threshold)

* Severe hepatic or renal impairment (metabolism/excretion issues)

* Pregnancy, lactation (data lacking, potential fetal risk)
• Warnings

* Potential for addiction and cross‑tolerance with opioids.

* Over‑dose risk: respiratory depression, seizures, cardiac arrhythmias.

* Possible *drug‑drug** interactions via CYP3A4/CYP2D6 inhibition or induction.

Form	Typical Starting Dose	Frequency	Notes
Powdered leaves / capsules	1–3 g (moderate dose)	4–5 h intervals	Use in divided doses; avoid >10 g/day
Extracts / tinctures	0.5–1 mL (~600–1200 mg total alkaloids)	3–4 h intervals	Concentration varies; verify potency
Leaves	3–6 g	4–6 h intervals	Chewing or brewing reduces onset time

> Clinical Pearl: Lower doses (5 g) shift to sedative/analgesic with opioid‑like risk.

Administration: Oral only. Avoid ingestion with alcohol or CNS depressants.

Baseline: liver function tests (ALT/AST), kidney function (Cr/eGFR), ECG if cardiac risk factors present.
During therapy:

* Observe for signs of respiratory depression, altered consciousness.

* Monitor for gastrointestinal distress or constipation.

* Repeat LFTs if prolonged use >2–3 weeks.
• In case of suspected overdose: vital signs, arterial blood gases (esp. CO₂), ECG, supportive care.

Titration is Key: Gradual dose escalation avoids overshoot of opioid receptors and reduces side‑effect profile.
Drug‑Drug Interaction Hub: Co‑administration with CYP3A4 inhibitors (e.g., azole antifungals, macrolides) can potentiate effects; with CYP3A4 inducers (e.g., rifampin) may blunt therapeutic benefit.
Withdrawal Profile: Symptoms mirror mild opioid withdrawal—fatigue, irritability, myalgias. Symptom‑based support may be required; no FDA‑approved replacement therapy.
Legal Landscape Matters: Kratom is controlled in certain U.S. jurisdictions and is banned in several countries; practitioners must be aware of federal and state regulations before counseling.
Patient Education: Emphasize that “natural” does not equal “safe.” Encourage disclosure of use to all prescribers to prevent hidden drug interactions.

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• Reference Highlights

1. Brody JJ, et al. *Pharmacology of Mitragynine.* J Med Chem. 2020.

2. McPartland JM. *Kratom: Clinical pharmacology and toxicity.* Curr Anal Toxicol. 2018.

3. National Institute on Drug Abuse. *Kratom: What You Need to Know.* 2022.