3rd International Conference of The Society for Interdisciplinary Placebo Studies- SIPS – Harnessing placebo mechanisms for optimal pain management and treatment of alcohol and other drug use disorder (5R13AA028424)

MPIs: Chamindi Seneviratne, MD (UMSOM); Luana Colloca, MD, PhD, MS (UMSON; Contact PI)

Find out more about SIPS 2021: Home (sips-conference.com)

This interdisciplinary, international scientific conference was designed to advance the science of placebo based research and mind-body mechanisms, applying this knowledge to alcohol use and pain disorders. These conditions are interrelated with significant and individually variable placebo effects concerning disease progression and response to treatment. An estimation of placebo effects is difficult to determine in a clinical setting, but the conference aims to provide a collaborative platform to improve knowledge of the placebo effect from an empirical, conceptual and ethical standpoint among researchers, healthcare professionals and external stakeholders.

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Genomic Predictors of Placebo Response in Phase II AUD Trials (5R01AA02629)

PI: Chamindi Seneviratne

Several placebo-controlled double blind studies done on alcohol use disorders (AUD) have revealed that placebo effects complicate the detection of treatment effects for investigational medications. This project explores the utility of genomics to identify placebo responders in phase II AUD treatment trials. The first aim of the project is to examine the changes in patterns of drinking among individuals with AUD during treatment with a placebo. Based on the changes, the effect on the expression of genes (utilizing the entire genome) is explored. Identified changes in gene expression are fine-combed to identify variations in the DNA sequence that may have rendered the individual more susceptible to alcohol. These variations and expression patterns of their genes are examined to determine if they can predict placebo response in populations with AUD and other psychiatric conditions, such as PTSD. The same genetic variations and expression differences are compared to variations and expression in individuals who received an active medication for treatment of their AUD.

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Biomarkers to Measure Treatment Response for Alcoholism (5K23AA020899)

PI: Chamindi Seneviratne

https://clinicaltrials.gov/show/NCT02315885

This study is currently closed for participant enrollment

The primary objective of the project was to develop a novel biomarker combination in serotonin transporter gene (SERT) mRNA expression levels in 5’-HTTLPR-LL genotype carriers to quantitatively predict alcohol consumption levels. Prior studies revealed a 52-HTTLPR allele based difference in drinking severity and a positive association between SERT mRNA expression levels and self-reported alcohol consumption amounts in individuals with LL genotypes. This project focused on validating the 5’-HTTLPR-LL biomarker combination in two stages. In the first stage, adult heavy social drinkers (male and female) with LL and LS/SS genotypes were recruited in equal proportions and given alcohol using a 3×3 diagram balanced Latin square design in a human laboratory. Samples were collected daily and SERT gene expression assays were performed to determine the validity of the proposed biomarker. As well, genome-wide microRNA expression alterations were studied in the presence of varying levels of alcohol to determine which microRNAs regulate 5’-HTTLPR allele-based SERT transcription levels, which will help in identifying new biomarkers for heavy drinking. The second stage consisted of a comparison between the discovered marker and %CDT as well as EtG, and detecting amounts of drinking in previously recorded samples from alcohol dependent individuals by testing the SERT biomarker combination sensitivity.

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Collaborative Projects

Pharmacogenetic Treatment With Anti-Glutaminergic Agents for Comorbid PTSD and AUD (5R01AA024760)

PI: Melanie Bennett, PhD (UMSOM)

Currently accepting participants; ClinicalTrials.gov Identifier: NCT02884908

About 60% of individuals with posttraumatic stress disorder (PTSD) have a comorbid alcohol use disorder (AUD), causing more severe PTSD symptoms, higher rates of psychosocial and medical problems, higher relapse rates, and decreased treatment outcome. Pre-clinical studies revealed that PTSD and AUD share common molecular underpinnings, specifically that adaptations in neurotransmitter systems during alcohol withdrawal share similarities with PTSD cluster B and E symptoms. This causes a cycle of excessive drinking then worsened PTSD symptoms. Anticonvulsant pregabalin, which modulates the effects of gamma-amino butyric acid (GABA) transporters and increases GABA density, has been found to decrease alcohol consumption in AUD with comorbid generalized anxiety disorder, as well as decreases PTSD symptoms. African-American individuals with variants at the SLC6A1 gene promoter region (non-insertion/insertion (NI/I) or insertion/insertion (I/I)) have higher levels of SLC6A1 promoter activity, compared to non-insertion/non-insertion (NI/NI) variants. This study is a double-blind, placebo-controlled 12-week clinical trial utilizing a diverse population of African-Americans of both sexes with differing types of trauma. It tests pregabalin efficacy in reducing AUD and PTSD in two treatment groups (pregabalin and placebo) for two genetic variants (NI/I/II and NI/NI). The study aims to determine if pregabalin-treated AUD patients with NI/I or I/I variants of the SLC6A1 gene are more likely to decrease their alcohol consumption and have their cluster B and E PTSD symptoms reduced than placebo-treated or NI/NI patients.

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1/2 – Pharmacogenetic Treatments for Alcoholism (5R01AA021163)

MPI: David Gorelick, MD, PhD (UMSOM); Henry Kranzler, MD (UPenn)

Closed for participant enrollment; ClinicalTrials.gov Identifier: NCT02354703

Pharmacotherapy is an underutilized approach to treatment of alcohol dependence (AD), which may contribute to effect sizes associated with FDA approved medications for AD. This project aimed to extend findings from a randomized double-blind clinical trial of a serotonin-3 (5-HT3) antagonist, ondansetron, in European-American and Hispanic individuals with AD. The study found that the medication successfully reduced drinking in individuals homozygous for the L allele of the 52-HTTLPR in SLC6A4, a serotonin transport gene. The effect was enhanced in individuals homozygous for the T allele of the 32-UTR SNP in the same gene. Our research addressed important limitations in the study by balancing individuals with the 32-UTR SNP across the LL genotype. This makes it possible to characterize the therapeutic effect of ondansetron enhanced by TT genotypes and compare the effect to their genotypic counterparts (i.e. TG and GG). The study was done with an equal number of European Americans and African Americans, increasing the generalizability of the results. To avoid underestimation of the bi-allelic (L vs S) 52-HTTLPR genotype’s pharmacogenetic effect, our research utilized the tri-allelic genotype (L2 vs S2) of 52-HTTLPR.

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