Assessment of abuse liability and respiratory effects of mitragynine and 7-hydroxymitragynine in rats

Kratom (Mitragyna speciosa) is a natural product ubiquitously available in most US states with little, if any, regulation. Many use kratom to self-treat pain and opioid dependence, yet scientific evidence is lagging. Between 2011 and 2017 there were 1807 kratom exposures reported to poison control centers in the United States. Most of them occurred in the last two years (65 %) and resulted in a serious medical outcome (51.9 %). There is a pressing need to evaluate the safety of the active components found in the kratom plant, as the adverse effects reported to poison control centers could be attributed to any of the 40+ alkaloids identified within kratom. Among these alkaloids, mitragynine is the most prevalent in the plant, while 7-hydroxymitragynine, a minor alkaloid with a strong affinity for the mu-opioid receptor, has also been identified. This study aims to evaluate both the potential for abuse and the impact on respiratory parameters of mitragynine and 7-hydroxymitragynine.In jugular catheter-implanted male and female Sprague Dawley rats, intravenous (i.v.) self-administration for the opioid agonist remifentanil (1 μg/kg/infusion), was established and animals were trained on a multi-component paradigm in which different doses were available at each component. Once remifentanil response was stable, remifentanil was substituted for the test compounds (mitragynine, 7-hydroxymitragynine, and fentanyl). Respiratory experiments were conducted using a within-subjects design and included a 7-day drug washout period between sessions on a separate cohort of male and female rats. Respiratory frequency, tidal volume, and minute ventilation were measured, both pre and post-drug administration, using whole-body plethysmography in unrestrained animals. When mitragynine was substituted for remifentanil, mitragynine suppressed remifentanil-associated lever responses. However, either 7-hydroxymitragynine or fentanyl substitution maintained responding on the remifentanil-associated lever. This same profile was observed in respiration experiments in which mitragynine failed to produce respiratory depression, but 7-hydroxymitragynine resulted in respiratory depression similar to fentanyl. These results are in agreement with the in vitro and in vivo literature indicating mitragynine has low abuse potential and does not result in respiratory depression. However, 7-hydroxymitragynine may be subject to abuse liability and respiratory depression.