Evaluation of the rewarding effects of mitragynine and 7-hydroxymitragynine in an intracranial self-stimulation procedure in male and female rats.

BACKGROUND: Kratom (Mitragyna speciosa Korth.) has been used in Southeast Asia for hundreds of years to increase energy, for relaxation, and to diminish opioid withdrawal. Kratom use has recently spread to Western countries. Kratom could potentially be used for the treatment of opioid withdrawal and pain, but more insight is needed into its abuse potential. Therefore, we investigated the rewarding properties of the primary kratom alkaloid mitragynine and its active metabolite 7-hydroxymitragynine, and morphine as a reference drug in male and female rats. These compounds have agonist activity at mu-opioid receptors. METHODS: The compounds were tested in an intracranial self-stimulation (ICSS) procedure, which allows for the evaluation of the rewarding/aversive and sedative effects of drugs. Rewarding doses of drugs decrease the brain reward thresholds, and aversive drug doses have the opposite effect. RESULTS: Mitragynine, 7-hydroxymitragynine, and morphine affected the brain reward thresholds. A high dose of 7-hydroxymitragynine (3.2 mg/kg) increased the brain reward thresholds, whereas an intermediate dose of morphine (10 mg/kg) decreased the reward thresholds. 7-Hydroxymitragynine and morphine affected the response latencies. Five mg/kg of morphine increased response latencies. 7-Hydroxymitragynine tended to increase the response latencies, but the post hoc analyses did not reveal a significant effect. There were no sex differences in the effects of mitragynine, 7-hydroxymitragynine, and morphine on the reward thresholds and the response latencies. CONCLUSIONS: These initial findings indicate that mitragynine and 7-hydroxymitragynine are not rewarding in the ICSS procedure. The present results suggest that these kratom alkaloids do not have abuse potential.

What Has Come out from Phytomedicines and Herbal Edibles for the Treatment of Cancer?

Several modern treatment strategies have been adopted to combat cancer with the aim of minimizing toxicity. Medicinal plant-based compounds with the potential to treat cancer have been widely studied in preclinical research and have elicited many innovations in cutting-edge clinical research. In parallel, researchers have eagerly tried to decrease the toxicity of current chemotherapeutic agents either by combining them with herbals or in using herbals alone. The aim of this article is to present an update of medicinal plants and their bioactive compounds, or mere changes in the bioactive compounds, along with herbal edibles, which display efficacy against diverse cancer cells and in anticancer therapy. It describes the basic mechanism(s) of action of phytochemicals used either alone or in combination therapy with other phytochemicals or herbal edibles. This review also highlights the remarkable synergistic effects that arise between certain herbals and chemotherapeutic agents used in oncology. The anticancer phytochemicals used in clinical research are also described; furthermore, we discuss our own experience related to semisynthetic derivatives, which are developed based on phytochemicals. Overall, this compilation is intended to facilitate research and development projects on phytopharmaceuticals for successful anticancer drug discovery.

Pharmacology and toxicology of α- and ß-Asarone: A review of preclinical evidence.

BACKGROUND: Asarone is one of the most researched phytochemicals and is mainly present in the Acorus species and Guatteria gaumeri Greenman. In preclinical studies, both α- and ß-asarone have been reported to have numerous pharmacological activities and at the same time, many studies have also revealed the toxicity of α- and ß-asarone. PURPOSE: The purpose of this comprehensive review is to compile and analyze the information related to the pharmacokinetic, pharmacological, and toxicological studies reported on α- and ß-asarone using preclinical in vitro and in vivo models. Besides, the molecular targets and mechanism(s) involved in the biological activities of α- and ß-asarone were discussed. METHODS: Databases including PubMed, ScienceDirect and Google scholar were searched and the literature from the year 1960 to January 2017 was retrieved using keywords such as α-asarone, ß-asarone, pharmacokinetics, toxicology, pharmacological activities (e.g. depression, anxiety). RESULTS: Based on the data obtained from the literature search, the pharmacokinetic studies of α- and ß-asarone revealed that their oral bioavailability in rodents is poor with a short plasma half-life. Moreover, the metabolism of α- and ß-asarone occurs mainly through cytochrome-P450 pathways. Besides, both α- and/or ß-asarone possess a wide range of pharmacological activities such as antidepressant, antianxiety, anti-Alzheimer's, anti-Parkinson's, antiepileptic, anticancer, antihyperlipidemic, antithrombotic, anticholestatic and radioprotective activities through its interaction with multiple molecular targets. Importantly, the toxicological studies revealed that both α- and ß-asarone can cause hepatomas and might possess mutagenicity, genotoxicity, and teratogenicity. CONCLUSIONS: Taken together, further preclinical studies are required to confirm the pharmacological properties of α-asarone against depression, anxiety, Parkinson's disease, psychosis, drug dependence, pain, inflammation, cholestasis and thrombosis. Besides, the anticancer effect of ß-asarone should be further studied in different types of cancers using in vivo models. Moreover, further dose-dependent in vivo studies are required to confirm the toxicity of α- and ß-asarone. Overall, this extensive review provides a detailed information on the preclinical pharmacological and toxicological activities of α-and ß-asarone and this could be very useful for researchers who wish to conduct further preclinical studies using α- and ß-asarone.