Efficacy of Ketamine in the Treatment of Substance Use Disorders: A Systematic Review

Background: Despite advances in behavioral and pharmacotherapy interventions, substance use disorders (SUDs) are frequently refractory to treatment. Glutamatergic dysregulation has received increasing attention as one common neuropathology across multiple substances of abuse. Ketamine is a potent N-methyl-D-aspartate (NMDA) glutamatergic receptor antagonist which has been found to be effective in the treatment of severe depression. Here we review the literature on the efficacy of ketamine in the treatment of SUDs.Methods: A systematic review of the PubMed, Scopus, and ClinicalTrials.gov databases was undertaken to identify completed and ongoing human studies of the effectiveness of ketamine in the treatment of SUDs between January 1997 and January 2018.Results and conclusion: Seven completed studies were identified. Two studies focused on alcohol use disorder, two focused on cocaine use disorder, and three focused on opioid use disorder. Both cocaine studies found improvements in craving, motivation, and decreased cocaine use rates, although studies were limited by small sample sizes, a homogeneous population and short follow-up. Studies of alcohol and opioid use disorders found improvement in abstinence rates in the ketamine group, with significant between-group effects noted for up to two years following a single infusion, although these were not placebo-controlled trials. These results suggest that ketamine may facilitate abstinence across multiple substances of abuse and warrants broader investigation in addiction treatment. We conclude with an overview of the six ongoing studies of ketamine in the treatment of alcohol, cocaine, cannabis, and opioid use disorders and discuss future directions in this emerging area of research

High pT hadron spectra at RHIC: an overview

Recent results on high transverse momentum (pT) hadron production in p+p, d+Au and Au+Au collisions at the Relativistic Heavy Ion Collider (RHIC) are reviewed. Comparison of the nuclear modification factors, $R_{dAu}(pT)$ and $R_{AA}(pT)$, demonstrates that the large suppression in central Au+Au collisions is due to strong final-state effects. Theoretical models which incorporate jet quenching via gluon Bremsstrahlung in the dense partonic medium that is expected in central Au+Au collisions at ultra-relativistic energies are shown to reproduce the shape and magnitude of the observed suppression over the range of collision energies so far studied at RHIC.Comment: 12 pages, 10 figures, Talk given at Hot Quarks 2004: Workshop for Young Scientists on the Physics of Ultrarelativistic Nucleus-Nucleus Collisions (HQ'04), Taos Valley, New Mexico, 18-24 Jul 2004, to be published in J. Phys.

Glial Hsp70 Protects K+ Homeostasis in the Drosophila Brain during Repetitive Anoxic Depolarization

Neural tissue is particularly vulnerable to metabolic stress and loss of ion homeostasis. Repetitive stress generally leads to more permanent dysfunction but the mechanisms underlying this progression are poorly understood. We investigated the effects of energetic compromise in Drosophila by targeting the Na+/K+-ATPase. Acute ouabain treatment of intact flies resulted in subsequent repetitive comas that led to death and were associated with transient loss of K+ homeostasis in the brain. Heat shock pre-conditioned flies were resistant to ouabain treatment. To control the timing of repeated loss of ion homeostasis we subjected flies to repetitive anoxia while recording extracellular [K+] in the brain. We show that targeted expression of the chaperone protein Hsp70 in glial cells delays a permanent loss of ion homeostasis associated with repetitive anoxic stress and suggest that this is a useful model for investigating molecular mechanisms of neuroprotection

Metal-on-Metal Hip Prostheses and Systemic Health: A Cross-Sectional Association Study 8 Years after Implantation

There is public concern over the long term systemic health effects of metal released from hip replacement prostheses that use large-diameter metal-on-metal bearings. However, to date there has been no systematic study to determine which organs may be at risk, or the magnitude of any effect. We undertook a detailed cross-sectional health screen at a mean of 8 years after surgery in 35 asymptomatic patients who had previously received a metal-on-metal hip resurfacing (MoMHR) versus 35 individually age and sex matched asymptomatic patients who had received a conventional hip replacement. Total body bone mineral density was 5% higher (mean difference 0.05 g/cm2 , P = 0.02) and bone turnover was 14% lower (TRAP 5b, mean difference 20.56IU/L, P = 0.006; osteocalcin, mean difference 23.08 ng/mL, P = 0.03) in the hip resurfacing versus conventional hip replacement group. Cardiac ejection fraction was 7% lower (mean absolute difference 25%, P = 0.04) and left ventricular end-diastolic diameter was 6% larger (mean difference 2.7 mm, P = 0.007) in the hip resurfacing group versus those patients who received a conventional hip replacement. The urinary fractional excretion of metal was low (cobalt 5%, chromium 1.5%) in patients with MoMHR, but creatinine clearance was normal. Diuretic prescription was associated with a 40% increase in the fractional excretion of chromium (mean difference 0.5%, P = 0.03). There was no evidence of difference in neuropsychological, renal tubular, hepatic or endocrine function between groups (P.0.05). Our findings of differences in bone and cardiac function between patient groups suggest that chronic exposure to low elevated metal concentrations in patients with well-functioning MoMHR prostheses may have systemic effects. Long-term epidemiological studies in patients with well-functioning metal on metal hip prostheses should include musculoskeletal and cardiac endpoints to quantitate the risk of clinical disease

Interbasin flow in the Great Basin with special reference to the southern Funeral Mountains and the source of Furnace Creek springs, Death Valley, California, U.S.

Interbasin flow in the Great Basin has been established by scientific studies during the past century. While not occurring uniformly between all basins, its occurrence is common and is a function of the hydraulic gradient between basins and hydraulic conductivity of the intervening rocks. The Furnace Creek springs in Death Valley, California are an example of large volume springs that are widely accepted as being the discharge points of regional interbasin flow. The flow path has been interpreted historically to be through consolidated Paleozoic carbonate rocks in the southern Funeral Mountains. This work reviews the preponderance of evidence supporting the concept of interbasin flow in the Death Valley region and the Great Basin and addresses the conceptual model of pluvial and recent recharge [Nelson, S.T., Anderson, K., Mayo, A.L., 2004. Testing the interbasin flow hypothesis at Death Valley, California. EOS 85, 349; Anderson, K., Nelson, S., Mayo, A., Tingey, D., 2006. Interbasin flow revisited: the contribution of local recharge to high-discharge springs, Death Valley, California. Journal of Hydrology 323, 276–302] as the source of the Furnace Creek springs. We find that there is insufficient modern recharge and insufficient storage potential and permeability within the basin-fill units in the Furnace Creek basin for these to serve as a local aquifer. Further, the lack of high sulfate content in the spring waters argues against significant flow through basin-fill sediments and instead suggests flow through underlying consolidated carbonate rocks. The maximum temperature of the spring discharge appears to require deep circulation through consolidated rocks; the Tertiary basin fill is of insufficient thickness to generate such temperatures as a result of local fluid circulation. Finally, the stable isotope data and chemical mass balance modeling actually support the interbasin flow conceptual model rather than the alternative presented in Nelson et al. [Nelson, S.T., Anderson, K., Mayo, A.L., 2004. Testing the interbasin flow hypothesis at Death Valley, California. EOS 85, 349] and Anderson et al. [Anderson, K., Nelson, S., Mayo, A., Tingey, D., 2006. Interbasin flow revisited: the contribution of local recharge to high-discharge springs, Death Valley, California. Journal of Hydrology 323, 276–302]. In light of these inconsistencies, interbasin flow is the only readily apparent explanation for the large spring discharges at Furnace Creek and, in our view, is the likely explanation for most large volume, low elevation springs in the Great Basin. An understanding of hydrogeologic processes that control the rate and direction of ground-water flow in eastern and central Nevada is necessary component of regional water-resource planning and management of alluvial and bedrock aquifers

Enhancing prolonged exposure therapy for PTSD among veterans with oxytocin: Design of a multisite randomized controlled trial.

Posttraumatic stress disorder (PTSD) is the most highly prevalent mental health disorder among U.S. military Veterans. Prolonged Exposure (PE) therapy is one of the most widely used evidence-based treatments for PTSD, but there is substantial room for improvement in outcomes and retention rates. Accumulating data suggest that oxytocin offers a promising pharmacological approach towards achieving this goal. Therefore, the primary objective of this two-site Phase II study is to examine the ability of oxytocin (vs. placebo) administration combined with PE therapy to (1) reduce PTSD symptom severity, (2) accelerate the rate of PTSD symptom improvement, and (3) improve PE adherence and retention rates. To accomplish these objectives, we will employ a randomized, double-blind, placebo-controlled trial and use standardized, repeated dependent measures of change at five time points (baseline, mid-treatment, end of treatment, and 3 and 6 month follow-up). Intranasal oxytocin (40 IU) will be administered directly prior to each PE therapy session. Findings from this study will provide critical new information regarding the efficacy of oxytocin to augment psychosocial treatment for PTSD, as well as information regarding the physiological mechanisms underlying PTSD and positive treatment response. ClinicalTrials.gov Identifier: NCT04228289