Temperature and pH-Dependent Stability of Mitragyna Alkaloids

Abstract

Mitragynine (MG) is the principal psychoactive alkaloid in kratom. The drug produces a variety of dose-dependent effects that appeal to recreational drug users and individuals seeking therapeutic benefits in the absence of medical supervision. In light of documented intoxications, hospitalizations and fatalities, MG and other alkaloids from Mitragyna speciosa are of growing importance to the forensic toxicology community. However, the chemical stability of these compounds has not been thoroughly described. In this report, the stability of MG, 7-hydroxymitragynine (MG-OH), speciociliatine (SC), speciogynine (SG) and paynantheine (PY) are investigated. Short-term stability of the Mitragyna alkaloids was determined over a range of pH (2–10) and temperature (4–80°C) over 8 hours. Liquid chromatography--quadrupole/time-of-flight mass spectrometry was used to estimate half-lives and identify degradation products where possible. The stability of MG and other alkaloids was highly dependent on pH and temperature. All of the Mitragyna alkaloids studied were acid labile. Under alkaline conditions, MG undergoes chemical hydrolysis of the methyl ester to produce 16-carboxymitragynine. MG-OH was the most unstable alkaloid studied, with significant drug loss at 8 hours experienced at temperatures of 40°C and above. No significant drug losses were observed for MG in aqueous solution (pH 2–10) at 4, 20 or 40°C. Diastereoisomers of MG (SC and SG) demonstrated even greater stability. These findings are discussed within the context of the identification of Mitragyna alkaloids in toxicological specimens.

Kratom: A systematic review of toxicological issues

“…Although alkaline hydrolysis at moderate temperature was effective for the hydrolysis of 7‐hydroxymitragynine, it significantly degraded 9‐ O ‐demethylmitragynine. These results are consistent with previously published literature that suggests that Mitragyna alkaloids are acid labile, and to a lesser extent alkaline‐labile (Basiliere & Kerrigan, 2020c; Manda et al, 2014; Ramanathan et al, 2015).…”

“…Two recent studies have also described the detection and quantification of 7‐hydroxymitragynine in blood, urine, and tissues using liquid chromatography‐quadrupole time‐of‐flight‐mass spectrometry (LC‐Q/TOF‐MS;Basiliere et al, 2018; Basiliere et al, 2020). Although simultaneous identification of 7‐hydroxymitragynine might be desirable due to its increased affinity for the mu opioid receptor, its concentration in biological samples is influenced by its stability (Basiliere & Kerrigan, 2020c; Kamble et al, 2020). 7‐Hydroxymitragynine is also particularly susceptible to adduct formation using electrospray ionization (M + 18, m/z 433; Kikura‐Hanajiri et al, 2009) although this can be mitigated using ammonium acetate as a mobile phase additive instead of formic acid or ammonium formate (Basiliere et al, 2018).…”

Refined Prediction of Pharmacokinetic Kratom-Drug Interactions: Time-Dependent Inhibition Considerations

“…We speculate that mitragynine undergoes bioactivation in the microsomal incubations to form reactive species causing TDI ( Figure 5). The quinolizidine moiety on mitragynine is known to undergo oxidative dehydrogenation (Kamble et al, 2019;Basiliere and Kerrigan, 2020), which could form an imine intermediate and inactivate CYP3A by covalently binding to (a) nucleophilic residue(s) on the enzyme (Li et al, 2014). Dehydrogenation of mitragynine could also generate a highly electrophilic, 3-methylindolenine-like species as proposed for several 3alkylindole-containing compounds, including 3-methylindole, zafirlukast, and SPD-304 (Sun and Yost, 2008;Li et al, 2014).…”

Mitragynine: A review of its extraction, identification, and purification methods

“…All of the Mitragyna alkaloids studied were acid labile. Under alkaline conditions, mitragynine undergoes chemical hydrolysis of the methyl ester to produce 16-carboxymitragynine (Basiliere and Kerrigan, 2020), which inarguably decreases the mitragynine yield.…”