Kratom products have been historically and anecdotally used in south Asian countries for centuries to manage pain and opioid withdrawal. The use of kratom products has dramatically increased in the United States. More than 45 kratom alkaloids have been isolated, yet the overall pharmacology of the individual alkaloids is still not well characterized. The purpose of this chapter is to summarize in vitro and in vivo opioid activities of the primary kratom alkaloid mitragynine and its more potent metabolite 7-hydroxymitragynine. Following are experimental procedures described to characterize opioid receptor activity; receptor binding and functional assays, antinociceptive assays, operant conditioning assays, and respiratory plethysmography. The capacity of kratom alkaloids to confer tolerance and physical dependence as well as their pharmacokinetic properties are also summarized. The data reviewed here suggest that kratom products and mitragynine possess low efficacy agonist activity at the mu-opioid receptor in vivo. In addition, kratom products and mitragynine have been demonstrated to antagonize the effects of high efficacy mu-opioid agonists. The data further suggest that 7-hydroxymitragynine formed in vivo by metabolism of mitragynine may be minimally involved in the overall behavioral profile of mitragynine and kratom, whereas 7-hydroxymitragynine itself, at sufficiently high doses administered exogenously, shares many of the same abuse- and dependence-related behavioral effects associated with traditional opioid agonists. The apparent low efficacy of kratom products and mitragynine at mu-opioid receptors supports the development of these ligands as effective and potentially safe medications for opioid use disorder. 

In vitro and in vivo pharmacology of kratom.

The use of herbal medicine has considerably grown worldwide in the past two decades. Studies have shown that the prevalence of herbal diet therapy in pregnancy ranged from 1% to 60% in different societies. Many clinical reports have shown that some herbal medicines may have toxic effects on pregnant women and their fetuses because active ingredients of some medicinal plants can readily pass through the biological barriers (e.g., placental barrier). In the present study, we aimed to systematically review the literature to discover potential benefits versus the hazards of herbal therapy during pregnancy. For this purpose, a comprehensive literature review was performed, and after the literature search and selection of the appropriate documents, the desired data were extracted and reported. From 35 articles with a total of 39,950 study population, the results showed that some medicinal plants could cause severe toxicity on mothers and fetuses, in addition to abortion during pregnancy. It was also shown that some plants may lead to developmental abnormalities or fetal death. Findings of this survey showed that some herbal medicines have toxic, teratogenic, and abortive potential, particularly in the first trimester of pregnancy because active ingredients of some medicinal plants are able to pass through the placental barrier and reach the fetus.

Potential benefits versus hazards of herbal therapy during pregnancy; a systematic review of available literature

Kratom (Mitragyna speciosa) consists of over 40 alkaloids, with 2 of them, mitragynine and 7-OH-mitragynine (7-OH-MG) being the main psychoactive compounds. Mitragynine and 7-OH-mitragynine each target opioid receptors and have been referred to as atypical opioids. They exert their pharmacologic effects on the mu, delta, and kappa opioid receptors. In addition, they affect adrenergic, serotonergic, and dopaminergic pathways. Kratom has been touted as an inexpensive, legal alternative to standard opioid replacement therapy such as methadone and buprenorphine. Other uses for kratom include chronic pain, attaining a "legal high," and numerous central nervous system disorders, including anxiety, depression, and posttraumatic stress disorder. Kratom induces analgesia and mild euphoria, with a lower risk of respiratory depression or adverse central nervous system effects compared to traditional opioid medications. Nonetheless, kratom has been associated with both physical and psychological dependence, with some individuals experiencing classic opioid withdrawal symptoms upon abrupt cessation. Kratom use has been linked to serious adverse effects, including liver toxicity, seizures, and death. These risks are often compounded by polysubstance abuse. Further, kratom may potentiate the toxicity of coadministered medications through modulation of cytochrome P450, P-glycoprotein, and uridine diphosphate glucuronosyltransferase enzymes. In 2016, the US Drug Enforcement Administration took steps to classify kratom as a federal schedule 1 medication; however, due to public resistance, this plan was set aside. Until studies are conducted that define kratom's role in treating opioid withdrawal and/or other central nervous system conditions, kratom will likely remain available as a dietary supplement for the foreseeable future. 

Clinical Pharmacology of the Dietary Supplement Kratom ( <i>Mitragyna speciosa</i> )

Kratom (Mitragyna speciosa Korth.) is a tree native to Southeast Asia with dose-dependent stimulant and opioid-like effects. Dried, powdered leaf material is among the kratom products most commonly consumed in the US and Europe, but other formulations also exist including enriched extracts, resins, tinctures, and edibles. Its prevalence in the US remains debated and the use pattern includes self-treatment of mood disorders, pain, and substance use disorders. Most of the adverse effects of kratom and its alkaloid mitragynine have been reported in the literature as case reports or part of surveys necessitating confirmation by clinical trials. Toxicities associated with kratom consumption have focused on hepatic, cardiac, and CNS effects with the potential to cause fatalities primarily as part of polydrug exposures. Kratom may also present with drug-drug interactions primarily through CYP 3A4 and 2D6 inhibition, although the clinical significance remains unknown to date. The variability in composition of commercially available kratom products complicates generalization of findings and requires further investigation by employing clinical trials. Healthcare professionals should remain cautious in counseling patients on the use of kratom in a therapeutic setting. 

Kratom: History, pharmacology, current user trends, adverse health effects and potential benefits.

Breastfeeding Recommendations for People Who Use Substances: AWHONN Practice Brief Number 16.

Kratom is a legal, widely available substance that contains opioid agonist alkaloids. Due to the marketing of kratom as an opioid alternative for treatment of pain, anxiety, depression, or to reduce opioid withdrawal symptoms, the use of kratom has increased among persons in the USA including pregnant women. This systematic review of the peer-reviewed literature regarding kratom in relation to maternal and infant outcomes resulted in analysis of six case reports of prenatal kratom exposure. Maternal and infant withdrawal from kratom exposure was described in each case, resulting in pharmacologic treatment for both mothers and infants.

Outcomes of mothers and newborns to prenatal exposure to kratom: a systematic review.

PURPOSE The purpose of the study was to describe and analyze the experience of women with substance use disorder during pregnancy and parenting to inform health care services that promote recovery. STUDY DESIGN Interviews of pregnant or parenting women with substance use disorder were used in this qualitative descriptive study. METHODS Participants were recruited from two recovery centers serving pregnant or parenting women with substance use disorder. Participants called a study cellphone to speak with the researchers about their substance use and recovery. Four independent reviewers conducted thematic analysis and were facilitated by Atlas.ti qualitative analysis program. RESULTS N = 15 women called the study cellphone; 10 met inclusion criteria and were interviewed. Researchers coded 81 themes with the common occurrence of prior trauma, multiple substances used, stigma and judgment from others, and having children as a motivation to seeking recovery. Co-occurrence of themes of positive social support and the pursuit of recovery was identified. CLINICAL IMPLICATIONS Positive social support co-occurring with recovery supports the need for strengthened social support structures. Health care professionals should intentionally address the culture of caring for pregnant and parenting women with substance use disorder through education, practice, advocacy, and research.

Emily Shores

Papers

Outcomes of mothers and newborns to prenatal exposure to kratom: a systematic review.

Pregnant and Parenting Women's Experiences with Substance Use Disorder.