GABA-B function in alcohol dependence
Research type
Research Study
Full title
GABA-B receptor function in alcohol dependence: a study of the effects of 2 doses of baclofen and placebo on objective and subjective measurements of brain function
IRAS ID
168987
Contact name
Anne Lingford-Hughes
Contact email
Sponsor organisation
Imperial College
Duration of Study in the UK
2 years, 0 months, 1 days
Research summary
Research Summary
There are several developing lines of evidence suggesting a significant role for γ-aminobutyric acid type B (GABA-B) in addiction and its treatment. We wish to investigate the sensitivity of brain GABA-B receptors in alcohol addiction, as part of our MRC programme of research in neurotransmitters in alcohol and opiate addiction (NOAA). This present study furthers our previous research in healthy volunteers by investigating the effects of Baclofen in abstinent alcohol dependent individuals
Summary of Results
This research was investigating the effects of a medication called baclofen in individuals with alcohol dependence and healthy controls. Baclofen works at a brain receptor called the GABA-B receptor and it may be useful in the treatment of alcohol dependence. We wanted to determine whether the function of this receptor may be different in those with alcoholism, as this may have an impact on the dose of the medication required to be effective in treating this disorder. The study was conducted in 2 parts. Part 1 was a study of the effects of 2 doses of baclofen and placebo on objective and subjective measurements of brain function. We as-sessed the pharmacokinetics (blood levels) and pharmacodynamics (effects of the medica-tion on physiology and subjective experience) of baclofen to provide insight into GABA-B sensitivity in this patient group, relative to controls.
Methods. Male healthy volunteers (controls, n=12) and abstinent alcohol dependent individu-als (n=8) received single oral doses of baclofen (10, 60 or 90mg) or placebo (dummy pill). Measures were recorded at baseline and for up to 6 hours after dosing, including plasma baclofen, plasma growth hormone (GH), and questionnaires to measure subjective experi-ence (Subjective High Assessment Scale; SHAS, and biphasic alcohol effects scale; BAES).
Results: As expected, we found a relationship between the dose given and the response (higher doses resulted in higher blood levels, and increased subjective response relative to lower doses). We also found that blood levels of baclofen did not differ between alcohol de-pendent and control groups who were given the same dose of baclofen. However, we found that subjective measures of drug effect were substantially different between groups. There was a blunted response to baclofen in the alcohol group relative to controls; the growth hor-mone response that was observed in controls following 60mg baclofen was absent in the al-cohol group, and the subjective experience of baclofen (e.g. feelings of sedation and alcohol-like effects) as measured by the SHAS and BAES questionnaires was largely absent in the alcohol group.
Conclusions: This suggests that those with alcohol dependence have significantly lower GABA-B receptor sensitivity, and this may explain why high baclofen doses are requested and tolerated in the treatment of alcohol dependence. These findings have implications for choice of dose in future clinical trials in alcohol dependence. This research has been pub-lished and the full details can be found here: https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fu2790089.ct.sendgrid.net%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agbebd-2Fr7k2hoipaRSxik15EZlqGQ7N0TctgeA6xoKjYe3dK91Z1pJYGNcGL-2Bjoz7-2BUA-3D-3Dqrr2_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YK8Wca6oVfMfrMpMyDvqEqmcOGG-2F-2BwhH63ssEWE-2Fj5C69t5FlIPv6R1m-2FJB7tHEgLpTKkihaBNdxTqigJVUfrTlPFeIwsBL0gzuxVspUgwfiJ2cWGcUnd7E2rNB1M7fzXTYeVecLlTjEa99cS6hZOrZjSjh1Z-2BUtaXAKS79y11WPw-3D-3D&data=05%7C01%7Capprovals%40hra.nhs.uk%7C21596f83e2114d0cc75208da5f3d6cf8%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C637927014664505293%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=gkxMVMntdUAbE0ByPMam9%2BGEaCN8txZRGFRYhl91sYI%3D&reserved=0 In addi-tion, the blood tests that were developed and validated by the Imperial Toxicology Unit to measure plasma baclofen levels has also been published and the full details can be found here: https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fu2790089.ct.sendgrid.net%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agbYmQsGrKhqntA-2FbTU5g6kdFB1Qw2z3vUFyFonOrMhgLee99G_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YK8Wca6oVfMfrMpMyDvqEqmak915WT2wvKxUPJeCebSe-2F0-2B3XU8xbB0V-2Fp7JG1QoSf-2BFwcCT48z6ZSPksmChDFXP00sAaRxh4P-2BRS14HadCERYDzMi3leDW8fxtDTrN7Up5Djr75DTADDxPX3PggPvTOmTYoQGNN3V7Eoc-2FSUIR7g-3D-3D&data=05%7C01%7Capprovals%40hra.nhs.uk%7C21596f83e2114d0cc75208da5f3d6cf8%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C637927014664505293%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=NSIZjXIkS%2B1SXZgM%2BE8cnmyC8RUXQKU2%2FtpxOpLV7RM%3D&reserved=0Part 2 of the study was a randomised, double-blind study investigating the effects of baclofen on brain function, as measured by MRI neuroimaging to determine whether baclofen works to normalise certain brain processes that are associated with addiction and relapse, including reward and emotional brain circuitry. 8 abstinent alcohol dependent participants were recruit-ed for this part of the study, with 7 completing it. Each participant had two brain scans at least one week apart, after taking a single dose of either placebo or 60mg baclofen. Unfortunately due to the delays caused by Covid-19 and the resulting staff shortages it was not possible to complete this brain imaging part of the study, but we will make an assessment as to whether the data collected from the 7 individuals can be analysed and published accordingly.
REC name
London - West London & GTAC Research Ethics Committee
REC reference
15/LO/1000
Date of REC Opinion
27 Jul 2015
REC opinion
Further Information Favourable Opinion