Activity of Mitragyna speciosa ("Kratom") Alkaloids at Serotonin Receptors.

Kratom alkaloids have mostly been evaluated for their opioid activity but less at other targets that could contribute to their physiological effects. Here, we investigated the in vitro and in vivo activity of kratom alkaloids at serotonin receptors (5-HTRs). Paynantheine and speciogynine exhibited high affinity for 5-HT1ARs and 5-HT2BRs, unlike the principal kratom alkaloid mitragynine. Both alkaloids produced antinociceptive properties in rats via an opioid receptor-independent mechanism, and neither activated 5-HT2BRs in vitro. Paynantheine, speciogynine, and mitragynine induced lower lip retraction and antinociception in rats, effects blocked by a selective 5-HT1AR antagonist. In vitro functional assays revealed that the in vivo 5-HT1AR agonistic effects may be due to the metabolites 9-O-desmethylspeciogynine and 9-O-desmethylpaynantheine and not the parent compounds. Both metabolites did not activate 5-HT2BR, suggesting low inherent risk of causing valvulopathy. The 5-HT1AR agonism by kratom alkaloids may contribute to the mood-enhancing effects associated with kratom use.

Pharmacological Comparison of Mitragynine and 7-Hydroxymitragynine: In Vitro Affinity and Efficacy for µ-Opioid Receptor and Opioid-Like Behavioral Effects in Rats.

Relationships between µ-opioid receptor (MOR) efficacy and effects of mitragynine and 7-hydroxymitragynine are not fully established. We assessed in vitro binding affinity and efficacy and discriminative stimulus effects together with antinociception in rats. The binding affinities of mitragynine and 7-hydroxymitragynine at MOR (Ki values 77.9 and 709 nM, respectively) were higher than their binding affinities at κ-opioid receptor (KOR) or δ-opioid receptor (DOR). [35S]guanosine 5'-O-[γ-thio]triphosphate stimulation at MOR demonstrated that mitragynine was an antagonist, whereas 7-hydroxymitragynine was a partial agonist (Emax = 41.3%). In separate groups of rats discriminating either morphine (3.2 mg/kg) or mitragynine (32 mg/kg), mitragynine produced a maximum of 72.3% morphine-lever responding, and morphine produced a maximum of 65.4% mitragynine-lever responding. Other MOR agonists produced high percentages of drug-lever responding in the morphine and mitragynine discrimination assays: 7-hydroxymitragynine (99.7% and 98.1%, respectively), fentanyl (99.7% and 80.1%, respectively), buprenorphine (99.8% and 79.4%, respectively), and nalbuphine (99.4% and 98.3%, respectively). In the morphine and mitragynine discrimination assays, the KOR agonist U69,593 produced maximums of 72.3% and 22.3%, respectively, and the DOR agonist SNC 80 produced maximums of 34.3% and 23.0%, respectively. 7-Hydroxymitragynine produced antinociception; mitragynine did not. Naltrexone antagonized all of the effects of morphine and 7-hydroxymitragynine; naltrexone antagonized the discriminative stimulus effects of mitragynine but not its rate-decreasing effects. Mitragynine increased the potency of the morphine discrimination yet decreased morphine antinociception. Here we illustrate striking differences in MOR efficacy, with mitragynine having less than 7-hydroxymitragynine. SIGNIFICANCE STATEMENT: At human µ-opioid receptor (MOR) in vitro, mitragynine has low affinity and is an antagonist, whereas 7-hydroxymitragynine has 9-fold higher affinity than mitragynine and is an MOR partial agonist. In rats, intraperitoneal mitragynine exhibits a complex pharmacology including MOR agonism; 7-hydroxymitragynine has higher MOR potency and efficacy than mitragynine. These results are consistent with 7-hydroxymitragynine being a highly selective MOR agonist and with mitragynine having a complex pharmacology that combines low efficacy MOR agonism with activity at nonopioid receptors.

Metabolism of a Kratom Alkaloid Metabolite in Human Plasma Increases Its Opioid Potency and Efficacy.

Kratom is widely consumed in the United States for self-treatment of pain and opioid withdrawal symptoms. Mitragynine is the most abundant alkaloid in kratom and is a µ-opioid receptor agonist. 7-Hydroxymitragynine (7-HMG) is a mitragynine metabolite that is a more potent and efficacious opioid than its parent mitragynine. 7-HMG contributes to mitragynine's antinociceptive effects in mice, but evidence suggests it may also have a higher abuse potential. This in vitro study demonstrates that 7-HMG is stable in rodent and monkey plasma but is unstable in human plasma. Surprisingly, in human plasma 7-HMG is converted to mitragynine pseudoindoxyl, an opioid that is even more potent than either mitragynine or 7-HMG. This novel metabolite is formed in human plasma to a much greater extent than in the preclinical species tested (mouse, rat, dog, and cynomolgus monkey) and due to its µ-opioid potency may substantially contribute to the pharmacology of kratom in humans to a greater extent than in other tested species.

Percepción de los estudiantes de los programas de Química Farmacéutica, Tecnología en Regencia de Farmacia y Medicina de la Universidad de Antioquia frente al uso terapéutico de los cannabinoides / Perception of the students of the programs of Pharmaceutical Chemistry, Technology in Regency of Pharmacy and Medicine of the University of Antioquia about the therapeutic use of cannabinoids

Resumen Introducción: La planta Cannabis sativa (marihuana) contiene un número aproximado de 60 cannabinoides, de los cuales, el delta-9-tetrahidrocannabinol es el componente más estudiado para ser utilizado con fines medicinales. El conocimiento adecuado por parte de los ciudadanos de esta estrategia terapéutica es un proceso clave para garantizar la aceptación y la buena adherencia al tratamiento. Objetivo: Establecer la percepción que tienen los estudiantes de pregrado de Química Farmacéutica, Tecnología en Regencia de Farmacia y Medicina de la Universidad de Antioquia, en cuanto al uso de los productos de extractos de cannabis como tratamiento medicinal. Método: Estudio observacional de corte transversal, a partir de encuestas a estudiantes a través de un formulario en línea. Resultados: Se aplicaron 374 encuestas, 232 (62%) estudiantes de pregrado de Química Farmacéutica y Tecnología en Regencia de Farmacia y 142 (38%) de Medicina. De los estudiantes, 222 (59,4%) eran del sexo femenino, con una edad promedio de 22,5 años, y 348 (94%) viven en estrato socioeconómico bajo y medio. El 60,2% de los estudiantes dicen tener un conocimiento inadecuado sobre la utilización de la marihuana medicinal, la utilización de cannabinoides medicinales, la reglamentación y la seguridad. Relacionado con la opinión sobre la utilización medicinal, 356 (95,2%) de los encuestados estuvieron de acuerdo. Conclusiones: La mayoría de los estudiantes manifestaron un conocimiento inadecuado sobre la utilización de los cannabinoides terapéuticos. Además, gran parte de los estudiantes están de acuerdo con la utilización de la marihuana medicinal.

Abstract Introduction: Cannabis sativa (marijuana) contains approximately 60 cannabinoids, of which, delta-9-tetrahydrocannabinol is the most studied component to be used for medicinal purposes. Adequate knowledge by citizens of this therapeutic strategy is a key process to guarantee the acceptance and the good adherence to the treatment. Objective: To establish the perception of undergraduate students of Pharmaceutical Chemistry, Technology in Regency of pharmacy and medicine of the University of Antioquia, as regards to the use of cannabis extracts products as medicinal treatment. Method: Observational cross-sectional study, based on surveys to students through an online form. Results: 374 surveys were obtained, 232 (62%) from students of Pharmaceutical Chemistry and Technology in Regency of Pharmacy, and 142 (38%) from Medicine. 222 (59.4%) of the students that were female, with a mean age of 22.5 years, and 348 (94%) live in low and middle socioeconomic strata. 60.2% of students claim to have inadequate knowledge regarding the use of medical marijuana, the use of medicinal cannabinoids, regulation and safety. Related to the opinion of the medicinal use, 356 (95.2%) respondents agreed. Conclusions: Most of the students expressed inadequate knowledge about the use of therapeutic cannabinoids. In addition, the vast majority of students agree with the use of medical marijuana.