Problematic alcohol use places a heavy burden on affected individuals, healthcare systems and society at large. While many of us consume alcohol recreationally, some at-risk individuals will suffer with chronic, relapsing alcohol dependence (AD). Those with AD struggle with binge drinking, and the repeated consumption of alcohol leads to greater tolerance and debilitating withdrawal during abstinence. In some cases, affected individuals will also use illicit substances, such as cocaine or opiates, either whilst drinking or throughout the course of their illness. Unfortunately, pharmacological therapies for those with alcohol or poly-drug substance dependence are limited, along with our understanding of how existing treatments exert their effects in the brain.
One promising pharmacotherapy for AD is the drug naltrexone. Although clinicians primarily use the drug to treat opioid dependence, mixed evidence suggests naltrexone may reduce alcohol consumption in those with AD. This drug inhibits activity of the endogenous opioid system, which, along with dopamine, contributes to the development and maintenance of addiction. However, limited knowledge of the mechanism of action of naltrexone has prevented more targeted treatment of alcohol and substance use.
In response to this knowledge gap, researchers from Imperial College London, the University of Cambridge and the University of Manchester (ICCAM) launched a multi-site study to evaluate new drugs for relapse prevention in addiction. A group of researchers within the ICCAM Consortium were particularly interested in assessing how naltrexone affects brain activity in healthy adults, as well as those with a history of AD and poly-drug substance dependence.
Their study, published last month in Addiction Biology, recruited adults for three groups: healthy controls, those with previous AD and those with former poly-drug substance dependence. They went on to collect functional magnetic resonance imaging (fMRI) data following administration of either naltrexone or placebo. These data were collected when the subjects were ‘at rest,’ lying awake in the scanner but not completing a cognitive task. Importantly, each subject completed fMRI scanning after both placebo and naltrexone administration, which paints a more detailed picture of how these drugs affect brain responses.
Led by first author Laurel Morris from the Department of Psychology, the team then examined the effect of drug manipulation (naltrexone versus placebo) and clinical group on one property of brain activity termed ‘local efficiency.’ This measure describes the degree to which the brain integrates information broadly across many regions, where high local efficiency would indicate less integrated processing. Findings showed that naltrexone reduced local efficiency in the AD group to a level that resembled healthy adults. Interestingly, the poly-drug substance dependence group demonstrated higher local efficiency than healthy controls, but this was unaffected by naltrexone.
Morris highlighted the dissociation of AD and poly-drug substance dependence, stating, “This work helps to demonstrate why and how a single drug can have different effects in different people. This approach is crucial for the development of more specific and targeted treatment in psychiatry.”
Group differences in functional connectivity were also quantified during the placebo condition. Findings showed reduced functional connectivity of a large number brain regions in the AD group, but not the poly-drug substance dependence group, relative to healthy controls. The greatest reductions in connectivity were seen in the temporal, inferior frontal and supplementary motor areas.
Taken together, these findings suggest that naltrexone may normalise elevated local efficiency in individuals with AD but not poly-drug substance dependence. The finding of greater local efficiency and reduced functional connectivity in AD could indicate more clustered information processing, suggests Morris: “[I]f there was a shift towards more clustered networks in AD, we would expect to see reduced long range connections and increased short range connections. Indeed, the three regions showing the most reduced [functional connectivity] were anatomically distant.”
The study provides exciting new insight into the efficacy of naltrexone in AD treatment, and Morris hopes that others will continue to dig deeper:
“Future work should aim to examine how pharmaceutical agents can have different effects in different groups and further characterise the clinical efficacy of naltrexone and other treatments. Psychiatry will likely benefit from a move towards personalised or individualised targeted medicine.”
Written by Maggie Westwater