Literature Collection

The leaves of Mitragyna speciosa (kratom), a plant native to Southeast Asia, are increasingly used as a pain reliever and for attenuation of opioid withdrawal symptoms. Using the tools of natural products chemistry, chemical synthesis, and pharmacology, we provide a detailed in vitro and in vivo pharmacological characterization of the alkaloids in kratom. We report that metabolism of kratom's major alkaloid, mitragynine, in mice leads to formation of (a) a potent mu opioid receptor agonist antinociceptive agent, 7-hydroxymitragynine, through a CYP3A-mediated pathway, which exhibits reinforcing properties, inhibition of gastrointestinal (GI) transit and reduced hyperlocomotion, (b) a multifunctional mu agonist/delta-kappa antagonist, mitragynine pseudoindoxyl, through a CYP3A-mediated skeletal rearrangement, displaying reduced hyperlocomotion, inhibition of GI transit and reinforcing properties, and (c) a potentially toxic metabolite, 3-dehydromitragynine, through a non-CYP oxidation pathway. Our results indicate that the oxidative metabolism of the mitragynine template beyond 7-hydroxymitragynine may have implications in its overall pharmacology in vivo.

BACKGROUND: The prevalence of methamphetamine use disorder (MUD) in the United States has risen dramatically in the past four decades and is concentrated in populations such as men who have sex with men (MSM). Despite the public health consequences of MUD, there are no FDA-approved psychopharmacological treatments. Psychosocial treatment alone has been shown to reduce methamphetamine use, but high attrition rates limit treatment efficacy. Promising findings from animal models of MUD using exogenous oxytocin, a social neuropeptide, have set the stage for translational work. Along with unique anti-addiction effects, oxytocin holds a primary role in enhancing social salience and modulating stress. In humans, oxytocin administration, combined with evidence-based psychosocial interventions, may act synergistically to improve addiction treatment outcomes and improve retention rates in current MUD treatment. METHODS/DESIGN: We are conducting a randomized, double-blind, placebo-controlled trial of oxytocin-enhanced motivational interviewing group therapy (MIGT). Oxytocin or placebo 40 IU is administered intranasally in conjunction with six, weekly MIGT sessions. We will recruit 50 MSM, initiating treatment for MUD from specialized community health programs in San Francisco, CA, USA. Individuals will be randomized (1:1) to receive six, weekly sessions of MIGT with or without oxytocin. Our primary outcome is session attendance. Other outcomes of interest include: measures of group cohesion, anxiety, psychophysiology, and stimulant craving and use. DISCUSSION: This will be the first study of oxytocin's effects in humans with MUD. Findings from this novel protocol will attempt to bridge existing animal data with the need for innovative clinical treatments for MUD, inform the growing field of pharmacologically-enhanced psychotherapy, and help to elucidate mechanisms behind oxytocin's potential anti-addiction effects. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02881177 . Registered on 26 August 2016.

BACKGROUND: The p factor represents the overall liability for the development of mental illness. While evidence supporting the p factor in adults has been reported, studies in children are fewer, and none have examined the p factor in children with chronic physical illness (CPI). OBJECTIVE: We aimed to model the p factor in a longitudinal sample of children with CPI using a parent-reported checklist and examine its construct validity against a structured diagnostic interview. METHODS: We used data from 263 children aged 2-16 years diagnosed with a CPI who were enrolled in the Multimorbidity in Children and Youth across the Life-course (MY LIFE) study. The p factor was modelled using the Emotional Behavioural Scales over 24 months using confirmatory factor analysis. Validation of the p factor was set against the Mini International Neuropsychiatric Interview for Children and Adolescents. RESULTS: Factorial evidence supported the p factor, modelled using a bi-factor structure, compared to a standard correlated-factors (i.e., two-factor) structure [Δχ(2) = 9.66(4), p = 0.047]. p factor scores were correlated with the number of different mental illness diagnoses (r = 0.71) and total number of diagnoses (r = 0.72). Dose-response relationships were shown for the number of different diagnoses (p < 0.001) and total number of diagnoses (p < 0.001). CONCLUSION: In this first study of the p factor in children with CPI, we showed evidence of its bi-factor structure and associations with mental illness diagnoses. Mental comorbidity in children with CPI is pervasive and warrants transdiagnostic approaches to integrated pediatric care.

Opioid dependence is an epidemic in the United States, and the percentage of pregnant women who are opioid dependent has increased dramatically in the last decade. Pain management, already a concern for intrapartum and postpartum care, is complicated in the context of opioid dependence. This clinical review surveys the literature on pain management in opioid-dependent pregnant women to summarize current consensus and evidence to guide clinical practice. Points of consensus for pain management in opioid-dependent pregnant women include continual opioid maintenance therapy throughout the pregnancy and the postpartum period; adequate management of acute pain; the contraindication of opioid agonist-antagonists for pain management; and the need for interdisciplinary teams using a multimodal approach to provide optimal care to opioid-dependent pregnant women.

IMPORTANCE: Care management benefits community-dwelling patients with dementia, but studies include few patients with moderate to severe dementia or from racial and ethnic minority populations, lack palliative care, and seldom reduce health care utilization. OBJECTIVE: To determine whether integrated dementia palliative care reduces dementia symptoms, caregiver depression and distress, and emergency department (ED) visits and hospitalizations compared with usual care in moderate to severe dementia. DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical trial of community-dwelling patients with moderate to severe dementia and their caregivers enrolled from March 2019 to December 2020 from 2 sites in central Indiana (2-year follow-up completed on January 7, 2023). Electronic health record screening identified patients with dementia; caregivers confirmed eligibility, including dementia stage. INTERVENTION: The intervention consisted of monthly calls from a trained nurse or social worker and evidence-based protocols to help caregivers manage patients' neuropsychiatric symptoms, caregiver distress, and palliative care issues (eg, advance care planning, symptoms, and hospice) (n = 99). Usual care caregivers received written dementia resource information and patients received care from usual clinicians (n = 102). MAIN OUTCOMES AND MEASURES: The primary outcome was Neuropsychiatric Inventory Questionnaire (NPI-Q) severity score (scores range from 0-36, with higher scores indicating worse patient symptoms). Secondary outcomes included Symptom Management in End-of-Life Dementia scores, caregiver depression (Patient Health Questionnaire-8) scores, caregiver distress (NPI-Q distress) scores, and combined ED and hospitalization events. Outcomes were assessed quarterly for 24 months or until patient death. RESULTS: A total of 201 dyads were enrolled (patients were 67.7% female; 43.3% African American; mean [SD] age, 83.6 [7.9] years); 3 dyads withdrew and 83 patients died over the course of the study, with at least 90% of eligible dyads in both groups completing each of the quarterly assessments. For the dementia palliative care vs usual care groups, mean NPI-Q severity scores were 9.92 vs 9.41 at baseline and 9.15 vs 9.39 at 24 months, respectively (between-group difference at 24 months, -0.24 [95% CI, -2.33 to 1.84]). There was no significant difference in the rate of change in NPI-Q severity from baseline between groups over time (P = .87 for the group and time interaction). There were no significant differences in the secondary outcomes, except that there were fewer combined ED and hospitalization events in the dementia palliative care group (mean events/patient, 1.06 in dementia palliative care vs 2.37 in usual care; between-group difference, -1.31 [95% CI, -1.93 to -0.69]; relative risk, 0.45 [95% CI, 0.31 to 0.65]). CONCLUSIONS AND RELEVANCE: Among community-dwelling patients with moderate to severe dementia and their caregivers, dementia palliative care, compared with usual care, did not significantly improve patients' neuropsychiatric symptoms through 24 months. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03773757.