Assessing Plasma Protein Binding and Lipophilicity of Various Alkaloids Found in Kratom

US consumption of kratom (Mitragyna speciosa) has increased significantly, reaching millions of users. This popularity is attributed to its dose-dependent effects: low doses elicit excitatory effects, while high doses induce sedation similar to opiates. Individuals addicted to opioids who can no longer obtain them through a physician, are increasingly consuming kratom as a perceived safer and natural alternative. Despite being marketed in the US as a safe alternative to traditional medicine, kratom use is perilous, resulting in adverse events – including death – especially in poly-substance use with opioids or benzodiazepines. Between 2016 and 2017, the Centers for Disease Control (CDC) investigated 152 deaths involving kratom. Of these, 60% were determined to be caused by kratom, with only 7 instances of kratom detected as the sole substance in postmortem toxicology. Commercially available kratom is federally unregulated in the US, therefore quality control evaluations are not required. Although mitragynine and 7-hydroxymitragynine have been extensively studied, several other bioactive alkaloids remain underexplored. There is a critical need to better understand the pharmacokinetic properties of these alkaloids. Pharmacokinetic properties will be elucidated using in vitro assays, including lipophilicity and plasma protein binding. Lipophilicity will be assessed to better understand the alkaloids’ ability to cross biological membranes and influence bioavailability. Plasma protein binding will be assessed to determine the binding of kratom alkaloids in human plasma. The binding of alkaloids can indicate how well they transport throughout the body. As more individuals become addicted, suffer from severe side effects, or accidentally overdose, understanding kratom's effects on the body – especially when co-ingested with other substances – will provide regulatory bodies with data to inform consumer safety for this currently unregulated and widely available product.