DEVELOPMENT OF GLYCINERGIC THERAPEUTICS FOR ALCOHOL USE DISORDERS

Sandra HelinskiLeave a Comment

  1. Höifödt Lidö1,2, Ph.D., M. Ericson2, Ph.D., B. Söderpalm1,2, M.D., Ph.D.

1Beroendekliniken, Sahlgrenska University Hospital, Gothenburg, Sweden

2Addiction Biology Unit, Dep of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Sweden

 

Alcohol use disorders (AUD) constitute major public health problems and improved pharmacotherapy with different mechanisms of action is needed for treating this heterogeneous disease affecting multiple neurotransmitter systems. Glycine serves a bimodal role in neurotransmission, as an agonist at inhibitory glycine receptors (GlyRs) and as co-agonist at excitatory NMDARs.  The possible role for glycine signaling as therapeutic target for AUD is supported by animal studies showing that GlyRs in nucleus accumbens are access points for alcohol to the mesolimbic dopamine system. Glycine elevates accumbal dopamine levels and decreases ethanol consumption in rats. Thus, glycine may modulate alcohol drinking via GlyRs, or tentatively by a bimodal mechanism interacting with GlyRs and NMDARs. Several glycine-based compounds are under investigation. The strongest drug candidate so far has been Org25935, a non-competitive glycine reuptake inhibitor. Prolonged Org25935 administration decreases relapse-like compulsive drinking and ethanol preference in Wistar rats, and attenuates ethanol-induced dopamine release in nucleus accumbens, without tolerance development. Yet, the resulting phase II RCT aimed to translate these findings to humans failed. The trial was aborted midway as Org25935 demonstrated no benefit over placebo in preventing alcohol relapse. This double-blind, placebo-controlled investigation examined the effect of high-dose glycine treatment with individual dosing (0.12 g/kg/day) using an established laboratory paradigm with alcohol challenge. The study was performed between September 2015 and April 2016. Fifty-six non-treatment-seeking volunteers with AUD were randomized to glycine or placebo treatment for five days. Following baseline assessments subjects were administered a priming dose of alcohol (0.3 g/kg) and self-reported effects on alcohol craving and on the subjective effects of alcohol were collected at several time points. Participants were also exposed to a self-administration period where they were provided with four drinks, each 12 g alcohol. Secondary outcome measures, i.e. cognitive performance and insomnia were recorded pre and post the medication period. The study applied GCP principles and used external monitoring. Data is under analysis. It is hypothesized that glycine reduces the intensity of alcohol craving and that efficacy correlates with baseline s-glycine levels and/or s-glycine increments. Results, study limitations and implications will be discussed.

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