Respiratory effects of oral mitragynine and oxycodone in a rodent model.

RATIONALE: Kratom derives from Mitragyna speciosa (Korth.), a tropical tree in the genus Mitragyna (Rubiaceae) that also includes the coffee tree. Kratom leaf powders, tea-like decoctions, and commercial extracts are taken orally, primarily for health and well-being by millions of people globally. Others take kratom to eliminate opioid use for analgesia and manage opioid withdrawal and use disorder. There is debate over the possible respiratory depressant overdose risk of the primary active alkaloid, mitragynine, a partial µ-opioid receptor agonist, that does not signal through ß-arrestin, the primary opioid respiratory depressant pathway. OBJECTIVES: Compare the respiratory effects of oral mitragynine to oral oxycodone in rats with the study design previously published by US Food and Drug Administration (FDA) scientists for evaluating the respiratory effects of opioids (Xu et al., Toxicol Rep 7:188-197, 2020). METHODS: Blood gases, observable signs, and mitragynine pharmacokinetics were assessed for 12 h after 20, 40, 80, 240, and 400 mg/kg oral mitragynine isolate and 6.75, 60, and 150 mg/kg oral oxycodone hydrochloride. FINDINGS: Oxycodone administration produced significant dose-related respiratory depressant effects and pronounced sedation with one death each at 60 and 150 mg/kg. Mitragynine did not yield significant dose-related respiratory depressant or life-threatening effects. Sedative-like effects, milder than produced by oxycodone, were evident at the highest mitragynine dose. Maximum oxycodone and mitragynine plasma concentrations were dose related. CONCLUSIONS: Consistent with mitragynine's pharmacology that includes partial µ-opioid receptor agonism with little recruitment of the respiratory depressant activating ß-arrestin pathway, mitragynine produced no evidence of respiratory depression at doses many times higher than known to be taken by humans.

Knowledge gaps in understanding the metabolic and clinical effects of excess folates/folic acid: a summary, and perspectives, from an NIH workshop.

Folate, an essential nutrient found naturally in foods in a reduced form, is present in dietary supplements and fortified foods in an oxidized synthetic form (folic acid). There is widespread agreement that maintaining adequate folate status is critical to prevent diseases due to folate inadequacy (e.g., anemia, birth defects, and cancer). However, there are concerns of potential adverse effects of excess folic acid intake and/or elevated folate status, with the original concern focused on exacerbation of clinical effects of vitamin B-12 deficiency and its role in neurocognitive health. More recently, animal and observational studies have suggested potential adverse effects on cancer risk, birth outcomes, and other diseases. Observations indicating adverse effects from excess folic acid intake, elevated folate status, and unmetabolized folic acid (UMFA) remain inconclusive; the data do not provide the evidence needed to affect public health recommendations. Moreover, strong biological and mechanistic premises connecting elevated folic acid intake, UMFA, and/or high folate status to adverse health outcomes are lacking. However, the body of evidence on potential adverse health outcomes indicates the need for comprehensive research to clarify these issues and bridge knowledge gaps. Three key research questions encompass the additional research needed to establish whether high folic acid or total folate intake contributes to disease risk. 1) Does UMFA affect biological pathways leading to adverse health effects? 2) Does elevated folate status resulting from any form of folate intake affect vitamin B-12 function and its roles in sustaining health? 3) Does elevated folate intake, regardless of form, affect biological pathways leading to adverse health effects other than those linked to vitamin B-12 function? This article summarizes the proceedings of an August 2019 NIH expert workshop focused on addressing these research areas.

Caffeine and cardiovascular health.

This report evaluates the scientific literature on caffeine with respect to potential cardiovascular outcomes, specifically relative risks of total cardiovascular disease (CVD), coronary heart disease (CHD) and acute myocardial infarction (AMI), effects on arrhythmia, heart failure, sudden cardiac arrest, stroke, blood pressure, hypertension, and other biomarkers of effect, including heart rate, cerebral blood flow, cardiac output, plasma homocysteine levels, serum cholesterol levels, electrocardiogram (EKG) parameters, heart rate variability, endothelial/platelet function and plasma/urine catecholamine levels. Caffeine intake has been associated with a range of reversible and transient physiological effects broadly and cardiovascular effects specifically. This report attempts to understand where the delineations exist in caffeine intake and corresponding cardiovascular effects among various subpopulations. The available literature suggests that cardiovascular effects experienced by caffeine consumers at levels up to 600 mg/day are in most cases mild, transient, and reversible, with no lasting adverse effect. The point at which caffeine intake may cause harm to the cardiovascular system is not readily identifiable in part because data on the effects of daily intakes greater than 600 mg is limited. However, the evidence considered within this review suggests that typical moderate caffeine intake is not associated with increased risks of total cardiovascular disease; arrhythmia; heart failure; blood pressure changes among regular coffee drinkers; or hypertension in baseline populations.

Approaches to risk assessment for macronutrients and amino acids.

Risk assessment is a well-established framework for organizing and evaluating diverse, and sometimes conflicting information, to assess the likelihood that agents in the environment may harm human health under known or expected conditions of exposure. Risk assessments are used by regulatory and public health officials to guide judgments and actions regarding the need for risk reduction and the appropriate means to achieve it. These judgments and actions are called risk management, and are guided by law, historical precedent and public health, economic and social concerns. Those in the nutrition community who have been called upon to make recommendations regarding adequate nutrient intakes have long been engaged in the practice of risk assessment. That is, they have assessed the harmful health effects of inadequate intakes and defined intakes likely to avoid such harm. During the past decade attention has turned to the potential health risks of excessive nutrient and nutritional supplement intakes. A recent study released by a committee of the Institute of Medicine illustrates the difficulties in deriving risk-based upper levels of intake for nutrients and nutritional supplements. Amino acids were the subject of extensive discussions by this committee, but in no case was an upper level of intake recommended. It is clear that the extent of scientific investigation of the harmful effects of amino acids has been highly uneven, and that significant questions remain regarding the appropriate methodologies to study such effects.