Gaboxadol, also known as 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP) and by its former developmental code names Lu-2-030, MK-0928, and OV101, is a GABAA receptor agonist related to muscimol which was investigated for the treatment of insomnia and other conditions like Angelman syndrome but was never marketed. At lower doses, the drug has sedative and hypnotic effects, and at higher doses, it produces hallucinogenic effects. It is taken orally. The drug acts as a potent and selective partial agonist of the GABAA receptor, the major signaling receptor of the inhibitory endogenous neurotransmitter γ-aminobutyric acid (GABA). However, it acts as a preferential supra-maximal agonist at extrasynaptic δ subunit-containing GABAA receptors. In contrast to GABAA receptor positive allosteric modulators like benzodiazepines and Z drugs, gaboxadol is an orthosteric agonist of the GABAA receptor, acting on the same site as GABA rather than at an allosteric regulatory site. As a result, gaboxadol has differing effects from benzodiazepines and related drugs. Gaboxadol is a conformationally constrained synthetic analogue of GABA and of muscimol, an alkaloid and hallucinogen found in Amanita muscaria (fly agaric) mushrooms. It has greatly improved drug-like properties compared to these compounds. Gaboxadol was first described by Povl Krogsgaard-Larsen and colleagues in 1977. It was assessed in clinical studies for various uses in the 1980s, but was not found to be useful. In the 1990s and 2000s, gaboxadol was repurposed for treatment of insomnia and completed phase 3 clinical trials for this indication. However, development was discontinued for safety and effectiveness reasons in 2007. Subsequently, gaboxadol was repurposed again for treatment of Angelman syndrome and fragile X syndrome, but was later abandoned completely.
Use and effects Gaboxadol produces sedative and hypnotic effects at lower doses and hallucinogenic effects at higher doses. It has also been reported to produce mood elevation and sometimes euphoria.
Hypnotic effects Gaboxadol has been assessed in clinical studies at doses ranging from 10 to 160 mg. It was studied in clinical trials for treatment of insomnia specifically at doses of 5 to 20 mg. The drug's effects at a dose of 10 mg were anecdotally described by Povl Krogsgaard-Larsen as similar to having drunk two or three beers. It was found to be limitedly effective for improving sleep at doses of 5 and 10 mg, but was more effective at doses of 15 to 20 mg. Higher doses for insomnia were precluded by a narrow therapeutic index and high rates of psychiatric adverse effects at such doses. Gaboxadol has been found to decrease sleep onset latency, increase sleep duration, increase slow wave sleep (SWS) and slow wave activity (SWA), preserve sleep architecture, not affect REM sleep, and improve subjective sleep quality and daytime functioning. The drug was found to allow people to fall asleep and stay asleep whilst exposed to continuous recorded stream of road traffic noise, a model of transient insomnia. SWS decreases with age, especially in men, and gaboxadol was found to substantially compensate for the reduction in SWS in elderly men. The drug was also studied in experimental sleep restriction and was found to increase SWS and improve daytime functioning, for instance symptoms of sleepiness and fatigue, despite equal total sleep durations. Gaboxadol's hypnotic and other effects have been found to be much stronger in women than in men. As circulating gaboxadol levels are only slightly higher in women than in men, this is likely to be due to sex differences in GABAA receptor function rather than body weight differences. The greater effects of gaboxadol in women than men may specifically be due to different levels of sex hormones and/or of progesterone-derived neurosteroids like allopregnanolone. These neurosteroids are GABAA receptor positive allosteric modulators, including of gaboxadol-sensitive δ subunit-containing GABAA receptors, and may interact synergistically with gaboxadol. There was no tolerance to the hypnotic effects of gaboxadol after 5 days of repeated administration in animals. Similarly, it maintained effectiveness in short-term clinical studies in humans. However, gaboxadol was subsequently found to be initially effective in improving sleep in insomnia but showed reduced effectiveness after 1 month. In addition, gaboxadol showed mixed effectiveness at the assessed doses of 10 to 15 mg in two large 3-month clinical trials for insomnia. The effects of gaboxadol on sleep differ from those of widely used GABAA receptor positive allosteric modulators like benzodiazepines and Z drugs, which have been found to disrupt rather than enhance SWS and SWA despite improving sleep onset and duration. In addition, unlike such agents, gaboxadol caused no rebound insomnia on discontinuation and produced no next-day residual symptoms. While dissimilar from GABAA receptor positive allosteric modulators, the effects of gaboxadol on sleep are similar to those of the related GABAA receptor agonist muscimol and of the GABA reuptake inhibitor tiagabine. Although gaboxadol was found to be effective in the treatment of insomnia and uniquely able to improve SWS, it was found to have less robust effects on traditional hypnotic effectiveness measures like sleep onset and duration at the evaluated doses compared to zolpidem. In addition, it was more effective for improving sleep maintenance than for improving sleep onset. Gaboxadol was developed for the treatment of insomnia, in which disruption of SWS is not the main feature. The effects of gaboxadol in people with sleeping problems specifically involving impaired SWS have largely not been studied and are unknown.
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