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Is Kratom an Herbal Tramadol?

Kratom: Medication mascot, ballicule, and interaction avatars


Kratom is promoted as an

  ❖ Pain reliever

  ❖ Energy booster

  ❖ Mood enhancer



Kratom is an alkaloid extract of the leaves of Mitragyna speciosa, a tree grown in Southeast Asia. Kratom is most commonly obtained as a powder and consumed as a beverage. The tree was named for its leaf, which resembles a mitre (catholic Bishop headdress). Kratom’s principal psychoactive component,  mitragynine (MG), has been banned in six U.S. states. Kratom is still widely available for purchase in the US on the internet and in smoke/vape shops.


The closest prescribable comparison to MG may be the atypical opioid tramadol (Ultram). Tramadol is a weak opioid receptor agonist and SNRI. Although the full pharmacology of mitragynine has not been defined, it appears to be an opioid plus norepinephrine reuptake inhibitor (NRI) with some subtle serotonergic effects. 



Opioid Pharmacology 


MG binds with high affinity to κ-opioid receptors (where it is possibly an antagonist) followed by μ- (agonist) and δ-opioid receptors. The antinociceptive effect of MG and 7-OH-MG is blocked by naloxone (Raffa et al, 2018).


Kratom appears to have all of the characteristics of an opioid including potential for addiction


300 mg/kg of Mitragyna speciosa extract, 75 mg/kg of alkaloids fraction, and 30 mg/kg of MG had antinociceptive activity equivalent to 10 mg/kg morphine and 3 mg/kg oxycodone in rats (Carpenter & Criddle et al, 2016).  


Non-Opioid Pharmacology


Although sedating in high doses, kratom is reportedly energizing in low doses. The stimulant effects of kratom are far more mild than those of synthetic cathinones like bath salts. 


MG interacts indirectly with α2-adrenoceptors, suggesting it is is likely a norepinephrine reuptake inhibitor (NRI). MG suppresses serotonin-induced head-twitch response in mice, suggestive of a 5-HT2A-related action. MG is moderately active in antidepressant tests in mice (Raffa et al, 2018).


Kratom does not target cannabinoid receptors like K2/spice/kush. 


Pharmacokinetics of Kratom


Kratom takes effect after 5–10 minutes, and its effects last 2–5 hours. It is an inHibitor of CYP2D6, CYP3A4, and p-glycoprotein. Although the potency or clinical significance of these effects is not clearly defined, these mechanisms have the potential to increase serum and CNS levels of many prescription medications.


Kratom is not detected on conventional urine drug-screening tests.


Side Effects and Risks


There is currently no evidence that kratom is safe or effective for any therapeutic purpose.  Liver toxicity has been reported. Compared to morphine, it is less constipating and causes less respiratory depression. 


Kratom products are not subject to regulation and may contain contaminants or other psychoactive compounds. The FDA has linked more than 35 deaths to salmonella-tainted kratom. 


The American Kratom Association contends that kratom is not an opioid and compares it to chocolate, cheese, and other substances in its ability to bind to the mu-opioid receptor. 


Kratom Withdrawal


Of kratom users, 43% reported negative adverse events if they abstained for more than 48 hours (Grundmann et al, 2017). Withdrawal symptoms are qualitatively similar to those of opioids (e.g., muscular pain, rhinorrhea, and diarrhea). Other withdrawal symptoms may include lethargy, depressed mood and anxiety.  Overall, kratom withdrawal symptoms are generally milder than observed with chronic opioid/sedative/stimulant users and generally more tolerable and self-manageable without the need for, e.g., buprenorphine (Henningfield et al, 2023).


Kratom Overdose 


Overdose of kratom has been fatal in combination with other drugs.  Kratom toxicity has been described as hyperadrenergic, with cases of hypertension and seizures—consistent with the hypothesis that it is an NRI.  Animal studies found oral LD50s in the range of 200–960 mg/kg for MG, and 200–591 mg/kg for Malaysian total alkaloid extract. Deaths were preceded by restlessness, tremors, and convulsions. Use via the traditional mode of consumption, such as chewing or brewing the leaves as a tea, would require a tremendous amount of kratom to be ingested to prove fatal. However, the currently available pure alkaloid isolates increase risk of fatality (Stanciu & Gnanasegaram et al, 2023). Pharmacokinetic interactions may also contribute to multidrug overdose fatality because MG may inHibit metabolism of the other drugs. Treatment of kratom overdose includes naloxone.


Kratom Dosing


Kratom 1–5 g is a low dose and associated with stimulant effect. Sedative effects are seen with 5–15 g.  Doses in excess of 15 g may mimic an opioid toxidrome.


Thanks to Elizabeth Shumway for helping with this mnemonic. 





Copyright 2024, CaferMed Publishing




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