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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 effects. It is taken orally.
The drug acts as a potent and selective partial agonist of the GABAA receptor, the major cell signaling receptor of the inhibitory endogenous neurotransmitter γ-aminobutyric acid (GABA). However, it acts as a preferential superagonist at extrasynaptic GABRD-containing GABAA receptors. In contrast to GABAA receptor positive allosteric modulators like and , gaboxadol is an orthosteric site agonist of the GABAA receptor, acting on the same site as GABA rather than at an allosteric 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) . 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 for this indication. However, development was discontinued for drug safety and effectiveness reasons in 2007. Subsequently, gaboxadol was repurposed again for treatment of Angelman syndrome and fragile X syndrome, but development for these uses was discontinued as well.
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. (2025). 9783030112707 ISBN 9783030112707 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. Gaboxadol's hypnotic effects have been found to be stronger in women than in men. On the other hand, 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.
There was no drug tolerance to the hypnotic effects of gaboxadol after 5days 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 to not maintain its benefits after 1month. In addition, gaboxadol showed mixed effectiveness at the assessed doses of 10 to 15mg 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 and , 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 effect 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 sleep disorder specifically involving impaired SWS have largely not been studied and are unknown.
According to journalist and scientist Hamilton Morris, the drug can produce strong hallucinogenic effects at high doses similarly to muscimol, with hallucinogenic effects starting at around doses of 30 or 40mg and powerful hallucinogenic effects occurring at a dose of about 65mg of the zwitterion. Morris has described hallucinogenic effects he experienced with gaboxadol as follows:
He has also reported other qualitative accounts of the hallucinogenic effects of gaboxadol. Morris has stated that gaboxadol is every bit as powerful as a hallucinogen as serotonergic psychedelics like ayahuasca, but is qualitatively completely different.
In contrast to the case of γ-aminobutyric acid (GABA) and muscimol, the binding of gaboxadol to the GABAA receptor does not appear to be stimulated by the benzodiazepine and GABAA receptor positive allosteric modulator diazepam in vitro. In addition, gaboxadol did not show synergistic effects in combination with alcohol or benzodiazepines in vitro or in vivo in animals.
The drug shows functional selectivity at the GABAA receptor relative to GABA itself, activating GABAA receptors of different α protein subunit compositions with varying efficacies. Its values at GABAA receptors were approximately 71% at α1 subunit-containing receptors, 98% at α2 subunit-containing receptors, 54% at α3 subunit-containing receptors, 40% at α4 subunit-containing receptors, 99% at α5 subunit-containing receptors, and 96% at α6 subunit-containing receptors. Moreover, gaboxadol has been found to act as a superagonist at α4β3δ subunit-containing GABAA receptors, low-potency agonist at α1β3γ2 subunit-containing receptors, and partial agonist at α4β3γ subunit-containing receptors. Its affinity for extrasynaptic α4β3δ subunit-containing GABAA receptors is 10-fold greater than for other subtypes. Gaboxadol has a unique affinity for extrasynaptic α4β3δ subunit-containing GABAA receptors, which mediate tonic inhibition and are typically activated by ambient, low levels of GABA in the extrasynaptic space. The supra-maximal efficacy of gabaxadol at α4β3δ subunit-containing GABAA receptors has been attributed to an increase in the duration and frequency of channel openings relative to GABA. Mice with the GABAA receptor GABRD knockout mice are unresponsive to the hypnotic effects of gaboxadol. (2025). 9783030112707 ISBN 9783030112707 Because of its preferential agonism of extrasynaptic GABAA receptors, gaboxadol has been referred to as a "selective extrasynaptic GABAA agonist" or "SEGA". In contrast to gaboxadol, benzodiazepines and nonbenzodiazepines do not activate δ subunit-containing GABAA receptors. On the other hand, alcohol is known to selectively potentiate δ subunit-containing extrasynaptic GABAA receptors analogously to gaboxadol. In addition, and propofol act on extrasynaptic δ subunit-containing GABAA receptors.
Gaboxadol shows 25- to 40-fold lower potency as a GABAA receptor agonist than muscimol in in vitro studies. Compared to muscimol, gaboxadol binds less potently to α4β3δ subunit-containing GABAA receptors ( = 0.2μM vs. 13μM), but is capable of evoking a greater maximum response ( = 120% vs. 224%). Although gaboxadol is far less potent than muscimol in vitro, it is only about 3times less potency than muscimol in rodents in vivo. This is attributed mainly to gaboxadol's much greater ability to cross the blood–brain barrier than muscimol. However, it appears to be due to gaboxadol levels being several-fold higher than levels of muscimol with systemic administration of the same doses as well. Gaboxadol is also more selective than muscimol and has been said by Povl Krogsgaard-Larsen to be much less toxicity in comparison.
In animals, gaboxadol has been found to produce sedation, hypnotic effects, motor impairment, muscle relaxation, hypolocomotion, anxiolytic-like effects, antidepressant-like effects, analgesic effects, and anticonvulsant effects. In rodent drug discrimination studies, gaboxadol has been found to fully generalize with muscimol. However, gaboxadol, GABAA receptor positive allosteric modulators like benzodiazepines and Z drugs, and the GABA reuptake inhibitor tiagabine all do not generalize between each other, suggesting that their interoceptive effects are different. (2025). 9783034602259, Springer Basel. ISBN 9783034602259 Similarly, gaboxadol did not generalize with the neurosteroid pregnanolone. On the other hand, gaboxadol has shown partial generalization with the barbiturate pentobarbital. Gaboxadol does not produce self-administration or conditioned place preference in rodents or baboons, suggesting that it lacks reward system or reinforcing effects and has low addictive potential. This is in contrast to benzodiazepines like diazepam.
/ref> It is a compound and its absorption involves active transport via intestinal transporters such as the proton-coupled amino acid transporter 1 (PAT-1). Coadministration of PAT-1 inhibitors like tryptophan or 5-hydroxytryptophan (5-HTP) has been found to decrease the absorptive permeability of gaboxadol by 53 to 89%. However, they may simply delay the absorption of gaboxadol and decrease peak levels. In contrast to the case of the PAT-1, the drug is not a substrate of the proton-coupled di-/tripeptide transporter (PepT-1). Peak levels of gaboxadol are reached 15 to 60minutes after an oral dose.
/ref> Its synthesis has been described as tedious, starting with a commercially unavailable precursor, requiring at least 6synthetic steps, and having very low yields. This has limited the affordability and availability of gaboxadol.
In 1996, a somnologist named Marike Lancel at the Max Planck Institute for Psychiatry studied the effects of gaboxadol on sleep in rodents and found that it had unique positive effects on sleep, such as increased slow wave sleep. In 1997, Lancel and colleagues published the first clinical study of the effects of gaboxadol on sleep in humans and found similar sleep improvements as in rodents. Subsequently, gaboxadol underwent formal clinical development for treatment of insomnia by Lundbeck and Merck. It reached phase 3 trials for this indication by at least 2004. The drug was expected to be a blockbuster drug for its pharmaceutical developers.
In 2007, the development of gaboxadol was terminated by Lundbeck and Merck. They cited lack of effectiveness in a large 3-month clinical trial, the occurrence of high rates of psychiatric at supratherapeutic doses in a misuse liability study with drug users, a frequent incidence of tachycardia at therapeutic doses, and other reasons. Moreover, there was anxiety in the pharmaceutical industry concerning hypnotics at the time owing to bizarre reports of zolpidem (Ambien)-induced delirium that had emerged in the media in 2006. This may have resulted in greater concern about potential legal liability issues. Merck was also struggling with recent litigation from its drug rofecoxib (Vioxx), which may have made it further averse to liability. When presented with the data on the hallucinogenic effects of high doses of gaboxadol, a Merck executive remarked "looks like LSD to me!" A New Drug Application (NDA) was ultimately never submitted to the United States Food and Drug Administration (FDA). Many of the companies' employees were said to have been surprised and confused by the discontinuation and the decision is still critically debated.
Journalist and scientist Hamilton Morris wrote and published a notable exposé on gaboxadol in Harper's Magazine in 2013, including his self-experimentation with the drug. According to Morris, the discontinuation of gaboxadol's late-stage development may have deprived people with insomnia access to an effective, safe, and non-drug addiction treatment. In addition, Morris has critiqued the pharmaceutical industry as being more interested in selling minimally effective drugs devoid of side effects instead of medications with real therapeutic effects but a higher risk of litigation.
In 2015, Lundbeck sold its rights to the molecule to Ovid Therapeutics, whose plan was to develop it for Angelman syndrome (AS) and fragile X syndrome (FXS). It was known internally at Ovid Therapeutics under the developmental code name OV101. In 2021, development of gaboxadol for Angelman syndrome and fragile X syndrome was discontinued due to lack of effectiveness.
The closely related GABAA receptor agonist muscimol, found in Amanita muscaria mushrooms, has been reported to induce sleep in humans similarly to gaboxadol, in addition to its well-known hallucinogenic effects that occur at higher doses. While gaboxadol was never approved for medical use, informal microdosing of muscimol and Amanita mushrooms for improvement of sleep has become increasingly prevalent by the mid-2020s. However, muscimol is far less-researched compared to gaboxadol, and is less selective and said to be much more toxicity in comparison. In addition, Amanita mushrooms contain other pharmacologically active compounds besides muscimol, such as the glutamate receptor agonist and neurotoxin ibotenic acid and the muscarinic acetylcholine receptor agonist and parasympathomimetic muscarine, which are liable to pose toxicity risks as well. Povl Krogsgaard-Larsen has warned about drug safety concerns with regard to medicinal use of Amanita mushrooms.
Later on, in the 1990s and 2000s, gaboxadol was developed for the treatment of insomnia and reached phase 3 for this indication. However, development was discontinued in 2007 for drug safety and effectiveness reasons. Multiple large phase 3 trials were completed and published. As a result, gaboxadol was not approved and will likely never be used as a hypnotic commercially. There has been some further study of gaboxadol as a hypnotic by David Nutt and colleagues after the discontinuation of its development. The drug was also studied for treatment of major depressive disorder in combination drug with escitalopram in a phase 2 trial, but was ineffective.
Following discontinuation of its development for insomnia, gaboxadol was repurposed by Ovid Therapeutics for treatment of the Angelman syndrome and fragile X syndrome. It reached phase 3 and phase 2 clinical trials for these conditions, respectively. However, development was discontinued for these uses as well in 2021. The drug is no longer under development for any indication.
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