Clinical Assessment of the Drug Interaction Potential of the Psychotropic Natural Product Kratom

Abstract

Oral formulations prepared from the leaves of the kratom (Mitragyna speciosa) plant are increasingly used for their opioid-like effects to self-manage opioid withdrawal and pain. Calls to US poison centers involving kratom exposures increased >50-fold from 2011-2017, one-third of which reported concomitant use of kratom with drugs of abuse. Many of these drugs are eliminated primarily via cytochrome P450 (CYP) 3A and CYP2D6, raising concerns for potential adverse pharmacokinetic kratom-drug interactions. The impact of a single low dose of kratom tea (2 g) on the pharmacokinetics of the CYP3A probe midazolam (2.5 mg) and CYP2D6 probe dextromethorphan (30 mg) were assessed in 12 healthy adult participants after oral administration. Kratom showed no effect on dextromethorphan area under the plasma concentration time-curve (AUC) and maximum concentration (C_max ; geometric mean ratio (90% confidence interval) 0.99 (0.83-1.19) and 0.96 (0.78-1.19), respectively) but a modest increase in midazolam AUC and C_max (1.39 (1.23-1.57) and 1.50 (1.32-1.70), respectively). Lack of change in midazolam half-life (1.07 (0.98-1.17)) suggested that kratom primarily inhibited intestinal CYP3A. This inference was further supported by a physiologically based pharmacokinetic drug interaction model using the abundant alkaloid mitragynine, a relatively potent CYP3A time-dependent inhibitor in vitro (K_I , ~4 μM; k_inact , ~0.07 min^-1 ). This work is the first to clinically evaluate the pharmacokinetic drug interaction potential of kratom. Co-consuming kratom with certain drugs extensively metabolized by CYP3A may precipitate serious interactions. These data fill critical knowledge gaps about the safe use of this increasingly popular natural product, thereby addressing ongoing public health concerns.

Figure 1

Clinical study design. Healthy adults (6 males, 6 females) participated in a two-arm open-label, fixed-sequence, crossover pharmacokinetic kratom-drug interaction study. During the baseline arm, after an overnight fast, participants were administered an oral cocktail consisting of midazolam (2.5 mg) and dextromethorphan (30 mg) as probes for CYP3A and CYP2D6 activity, respectively. During the kratom exposure arm, after an overnight fast, participants were instructed to drink 240 mL of kratom tea, prepared with a low dose (2 g) of Yellow Indonesian Micro Powder (K51), within 10 minutes. Participants were orally administered the same probe cocktail 15 minutes after kratom tea administration. Blood and urine were collected at the indicated times.

Figure 2

Plasma concentration-time profile for (a) midazolam, (b) 1′-hydroxymidazolam, (c) 4-hydroxymidazolam, (d) dextromethorphan, and (e) dextrorphan following a single oral dose of midazolam (2.5 mg) and dextromethorphan (30 mg) administered alone (black and gray symbols) or 15 minutes after kratom tea (2 g) administration (blue and yellow symbols). Symbols and error bars denote geometric means and 90% confidence intervals, respectively.

Figure 3

Effects of a single low dose (2 g) of kratom tea on the C_max, AUC_inf, and t_1/2 of (a) midazolam and (b) dextromethorphan in 12 healthy adult participants following oral administration of midazolam (2.5 mg) and dextromethorphan (30 mg). Solid black lines denote individual values and blue and yellow symbols connected by lines denote geometric means. AUC_inf, area under the plasma concentration-time profile from time zero to infinity; C_max, maximum concentration; t_½, terminal elimination half-life.

Figure 4

Simulated and observed concentration-time profiles of mitragynine (a) training and (b) verification datasets. Overlay of simulated and observed concentration-time profiles of (c) midazolam and (d) dextromethorphan before (black and gray) and after (blue and yellow) mitragynine (surrogate for kratom) administration where inhibition of CYP3A and CYP2D6 were incorporated. Symbols and error bars denote geometric means and 90% confidence intervals, respectively, of the observed data. Lines denote the geometric means, and the shaded regions represent the 5^th and 95^th percentiles of the simulated profile.

Figure 5

Examples of drugs that undergo intestinal CYP3A-mediated metabolism categorized based on the fraction of drug escaping intestinal metabolism (F_g).^– Kratom was assumed not to alter fraction of the dose absorbed unchanged into enterocytes.