Neuroresilience with Natural Products: a Path to Improving Whole Person Health - PROJECT SUMMARY Resilience is defined as the ability to resist, adapt to, recover, or grow from a challenge or stressor. A classic stressor is pain, particularly chronic pain, which afflicts millions of people worldwide. This debilitating condition often leads to a cascade of downstream adverse effects, particularly sleep disruption, which perpetuate a vicious cycle of neurological conditions that include anxiety, depression, social withdrawal, substance misuse, and harmful behaviors. These negative effects on daily life further lead to lost productivity and increased health care costs. Conventional medical treatments, including opioids, are typically accompanied by unacceptable side effects, which only enhance this vicious cycle. Accordingly, patients often turn to complementary and integrative health modalities, including botanical products, to mitigate or eliminate their use of opioids and improve their quality of life. A botanical that increases resilience to pain-induced adverse effects represents an innovative modality that could help address this widespread public health problem. Such a potential botanical is the increasingly popular kratom [Mitragyna speciosa (Korth.) Havil. (Rubiaceae)], which has been touted as a safe alternative to opioids. Rigorous scientific evidence from preclinical studies supports select kratom alkaloids as interacting with opioid receptors, and our clinical pharmacokinetic (PK) studies involving a well-characterized kratom product administered to healthy adults demonstrate that at least seven alkaloids are bioavailable. However, knowledge gaps remain regarding other molecular targets, dose- and time-response relationships, PK nonlinearities, and sleep-related pharmacodynamic (PD) endpoints. In response to RFA-OD-24-014, we have assembled an outstanding transdisciplinary and diverse team of investigators with expertise in natural products chemistry, neuropharmacology, PK/PD, chronic pain, clinical research methods, and sleep science to generate the most critical data needed for future full-scale efficacy trials of kratom as a new modality to improve resilience to chronic pain-induced adverse effects. We will test the central hypothesis that kratom promotes resilience to these effects using an innovative approach that integrates data generated from an established mouse model of chronic pain (AIM 1); a dose-escalation in-laboratory PK study of two commonly used kratom formulations involving healthy adult participants (AIM 2); and a controlled in-laboratory study involving patients with chronic lower back pain to assess quality of life, including objective measures of sleep (AIM 3). These complementary AIMS are interwoven with physiologically based PK (PBPK) and PBPK/PD modeling to gain further mechanistic insight, inform the dose and frequency of administration, and assess the concentration-response relationship of kratom in both mice and humans. Accomplishment of the proposed studies will help pave a path for improving whole person health for tens of millions of people.
