Gaboxadol

{{Short description|Chemical compound}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox drug | Verifiedfields = verified | verifiedrevid = 457288866 | image = Gaboxadol structure.svg | image_class = skin-invert-image | width = 175px | image2 = Gaboxadol 3D ball-and-stick structure.png | image_class2 = bg-transparent | width2 = 175px

| tradename = | pregnancy_AU =  | pregnancy_US =  | pregnancy_category = | routes_of_administration = Oral<ref name="Sorbera_2004" /><ref name="AdisInsight" /> | class = GABAA receptor agonist; Sedative; Hypnotic; Central depressant; Hallucinogen

| legal_AU =  | legal_CA =  | legal_UK =  | legal_US =  | legal_status =

| bioavailability = ~92%<ref name="ShadleRainakrishnanGargano2006" /> | protein_bound = <2%<ref name="Frlund_2013" /><ref name="Chu_2009" /> | metabolism = Glucuronidation mainly via UGT1A9<ref name="Frlund_2013" /><ref name="KrogsgaardLarsen_1984" /> | metabolites = Gaboxadol-''O''-glucuronide<ref name="Frlund_2013" /> | onset = 20–60 minutes (peak)<ref name="Frlund_2013" /><ref name="Deacon_2007" /><ref name="KrogsgaardLarsen_1984" /> | elimination_half-life = 1.5–2.0 hours<ref name="LundHelboeMengel2006" /><ref name="HoehnSaric_1983" /><ref name="Madsen_1983">{{cite journal | vauthors = Madsen SM, Lindeburg T, Følsgård S, Jacobsen E, Sillesen H | title = Pharmacokinetics of the gamma-aminobutyric acid agonist THIP (Gaboxadol) following intramuscular administration to man, with observations in dog | journal = Acta Pharmacologica et Toxicologica | volume = 53 | issue = 5 | pages = 353–357 | date = November 1983 | pmid = 6659963 | doi = 10.1111/j.1600-0773.1983.tb03434.x | quote = The dose-group mean values of k correspond to an elimination half-life of 1.39 hr and 1.33 hr after the dose of 10 or 20 mg THIP-monohydrate, respectively. }}</ref> | duration_of_action = | excretion = Urine (84–93%; mainly unchanged, partially glucuronidated (34%))<ref name="Frlund_2013" /><ref name="Chu_2009" /><ref name="KrogsgaardLarsen_1984" /><ref name="Schultz_1981" />

| IUPHAR_ligand = 4322 | CAS_number_Ref = {{cascite|correct|CAS}} | CAS_number = 64603-91-4 | ATC_prefix = None | ATC_suffix = | PubChem = 3448 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB06554 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 3330 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = K1M5RVL18S | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D04282 | ChEBI = 34373 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 312443 | synonyms = GBX; THIP; 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol; Lu-2-030; Lu-02-030; MK-0928; MK0928; OV101; OV-101; HLX-0206; HLX0206

| IUPAC_name = 4,5,6,7-tetrahydroisoxazolo[5,4-''c'']pyridin-3(2''H'')-one | C=6 | H=8 | N=2 | O=2 | SMILES = O=C1/C2=C(\ON1)CNCC2 | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C6H8N2O2/c9-6-4-1-2-7-3-5(4)10-8-6/h7H,1-3H2,(H,8,9) | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = ZXRVKCBLGJOCEE-UHFFFAOYSA-N }}

'''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.<ref name="AdisInsight" /><ref name="Wafford_2006">{{cite journal | vauthors = Wafford KA, Ebert B | title = Gaboxadol--a new awakening in sleep | journal = Current Opinion in Pharmacology | volume = 6 | issue = 1 | pages = 30–36 | date = February 2006 | pmid = 16368265 | doi = 10.1016/j.coph.2005.10.004 }}</ref><ref name="Sorbera_2004">{{cite journal | vauthors = Sorbera LA, Castaner J, Silvestre JS | title = Gaboxadol | journal = Drugs of the Future | volume = 29 | issue = 5 | pages = 0449 | date = 2004 | doi = 10.1358/dof.2004.029.05.803754 | url = http://access.portico.org/stable?au=pjbf78x8shw | access-date = 19 June 2025 | url-access = subscription }}</ref><ref name="Brickley_2018">{{cite journal | vauthors = Brickley SG, Franks NP, Wisden W | title = Modulation of GABA A receptor function and sleep | journal = Current Opinion in Physiology | volume = 2 | pages = 51–57 | date = 2018 | doi = 10.1016/j.cophys.2017.12.011 | doi-access = free | url = http://spiral.imperial.ac.uk/bitstream/10044/1/55616/2/Brickley%20et%20al.Curr%20Opin%20Physiol%20revised.Dec%202017.pdf | archive-url = https://web.archive.org/web/20190427075651/http://spiral.imperial.ac.uk/bitstream/10044/1/55616/2/Brickley%20et%20al.Curr%20Opin%20Physiol%20revised.Dec%202017.pdf | access-date = 5 October 2025 | archive-date = 27 April 2019 }}</ref><ref name="Morris_2013">{{cite magazine | vauthors = Morris H | title = Gaboxadol | date = August 2013 | url = http://harpers.org/archive/2013/08/gaboxadol/ | magazine = Harper's Magazine | access-date = 2014-11-20 }}</ref> At lower doses, the drug has sedative and hypnotic effects, and at higher doses, it produces hallucinogenic effects.<ref name="Sorbera_2004" /><ref name="KrogsgaardLarsen_2006" /><ref name="Morris_2013" /> It is taken orally.<ref name="Sorbera_2004" /><ref name="AdisInsight" />

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).<ref name="Sorbera_2004" /><ref name="Wafford_2006" /> However, it acts as a preferential supra-maximal agonist at extrasynaptic δ subunit-containing GABAA receptors.<ref name="Wisden_2019" /><ref name="Wafford_2006" /> 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.<ref name="Atack_2010" /><ref name="Sorbera_2004" /><ref name="Wafford_2006" /> As a result, gaboxadol has differing effects from benzodiazepines and related drugs.<ref name="Atack_2010" /><ref name="Sorbera_2004" /><ref name="Wafford_2006" /><ref name="Wisden_2019" /> Gaboxadol is a conformationally constrained synthetic analogue of GABA and of muscimol, an alkaloid and hallucinogen found in ''Amanita muscaria'' (fly agaric) mushrooms.<ref name="Sorbera_2004" /><ref name="Wafford_2006" /><ref name="Johnston_2014" /><ref name="RiveraIllanes_2024">{{cite journal | vauthors = Rivera-Illanes D, Recabarren-Gajardo G | title = Classics in Chemical Neuroscience: Muscimol | journal = ACS Chemical Neuroscience | volume = 15 | issue = 18 | pages = 3257–3269 | date = September 2024 | pmid = 39254100 | doi = 10.1021/acschemneuro.4c00304 }}</ref> It has greatly improved drug-like properties compared to these compounds.<ref name="Wafford_2006" /><ref name="Johnston_2014" /><ref name="KrogsgaardLarsen_2004" /><ref name="Morris_2013" />

Gaboxadol was first described by Povl Krogsgaard-Larsen and colleagues in 1977.<ref name="Sorbera_2004" /><ref name="Morris_2013" /><ref name="KrogsgaardLarsen_1977" /> It was assessed in clinical studies for various uses in the 1980s, but was not found to be useful.<ref name="Wafford_2006" /><ref name="Wisden_2019" /><ref name="KrogsgaardLarsen_2006" /><ref name="Morris_2013" /> In the 1990s and 2000s, gaboxadol was repurposed for treatment of insomnia and completed phase 3 clinical trials for this indication.<ref name="Sorbera_2004" /><ref name="KrogsgaardLarsen_2006" /><ref name="Wisden_2019" /><ref name="Roth_2010" /> However, development was discontinued for safety and effectiveness reasons in 2007.<ref name="AdisInsight" /><ref name="Frlund_2013" /><ref name="Wisden_2019" /><ref name="Morris_2013" /> Subsequently, gaboxadol was repurposed again for treatment of Angelman syndrome and fragile X syndrome, but was later abandoned completely.<ref name="AdisInsight" /><ref name="Brickley_2018" /><ref name="Heussler_2021">{{cite journal | vauthors = Heussler HS | title = Emerging Therapies and challenges for individuals with Angelman syndrome | journal = Current Opinion in Psychiatry | volume = 34 | issue = 2 | pages = 123–128 | date = March 2021 | pmid = 33395098 | doi = 10.1097/YCO.0000000000000674 }}</ref><ref name="Shapiro_2023" />

==Use and effects== Gaboxadol produces sedative and hypnotic effects at lower doses and hallucinogenic effects at higher doses.<ref name="Sorbera_2004" /><ref name="KrogsgaardLarsen_2006">{{cite book | vauthors = Krogsgaard-Larsen P, Frølund B, Liljefors T | chapter = GABAA Agonists and Partial Agonists: THIP (Gaboxadol) as a Non-Opioid Analgesic and a Novel Type of Hypnotic1 | title = GABA(A) agonists and partial agonists: THIP (Gaboxadol) as a non-opioid analgesic and a novel type of hypnotic | volume = 54 | pages = 53–71 | date = 2006 | pmid = 17175810 | doi = 10.1016/s1054-3589(06)54003-7 | series = Adv Pharmacol | isbn = 978-0-12-032957-1 | quote = In cancer patients and also in patients with chronic anxiety (Hoehn‐Saric, 1983) the desired effects of Gaboxadol were accompanied by side effects, notably sedation, nausea, and in a few cases euphoria. The side effects of Gaboxadol have, however, been described as mild and similar in quality to those of other GABA‐mimetics (Hoehn‐Saric, 1983). This combination of analgesic and anxiolytic effects of THIP obviously has therapeutic prospects. [...] }}</ref><ref name="Morris_2013" /> It has also been reported to produce mood elevation<ref name="Lloyd_1983">{{cite journal | vauthors = Lloyd KG, Morselli PL, Depoortere H, Fournier V, Zivkovic B, Scatton B, Broekkamp C, Worms P, Bartholini G | title = The potential use of GABA agonists in psychiatric disorders: evidence from studies with progabide in animal models and clinical trials | journal = Pharmacology, Biochemistry, and Behavior | volume = 18 | issue = 6 | pages = 957–966 | date = June 1983 | pmid = 6351106 | doi = 10.1016/s0091-3057(83)80021-5 | quote = Recently interest has taken hold on the possibility that GABA systems may play a role in affective disorders. The major impetus for this effort has been the demonstration that one GABA agonist (progabide) has antidepressant qualities (see below) and that another GABA agonist (THIP) is mood elevating (Krogsgaard-Larsen, personal communication). }}</ref> and sometimes euphoria.<ref name="KrogsgaardLarsen_2006" /><ref name="Schoedel_2009" />

===Hypnotic effects=== Gaboxadol has been assessed in clinical studies at doses ranging from 10 to 160{{nbsp}}mg.<ref name="Wafford_2006" /><ref name="Morris_2013" /> It was studied in clinical trials for treatment of insomnia specifically at doses of 5 to 20{{nbsp}}mg.<ref name="Sorbera_2004" /><ref name="Atack_2010" /> The drug's effects at a dose of 10{{nbsp}}mg were anecdotally described by Povl Krogsgaard-Larsen as similar to having drunk two or three beers.<ref name="Morris_2013" /> It was found to be limitedly effective for improving sleep at doses of 5 and 10{{nbsp}}mg, but was more effective at doses of 15 to 20{{nbsp}}mg.<ref name="Atack_2010" /><ref name="Wisden_2019" /><ref name="Sorbera_2004" /><ref name="Reuters2007" /> Higher doses for insomnia were precluded by a narrow therapeutic index and high rates of psychiatric adverse effects at such doses.<ref name="Reuters2007" /><ref name="Lundbeck_2007" />

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.<ref name="Wafford_2006" /><ref name="Sorbera_2004" /><ref name="Dijk_2019">{{cite book | vauthors = Dijk DJ, Landolt HP | chapter = Sleep Physiology, Circadian Rhythms, Waking Performance and the Development of Sleep-Wake Therapeutics | title = Handbook of Experimental Pharmacology | volume = 253 | pages = 441–481 | date = 2019 | pmid = 31254050 | doi = 10.1007/164_2019_243 | isbn = 978-3-030-11270-7 | quote = Agonists of the extra-synaptic GABAA receptor such as gaboxadol, also known as THIP, reliably induce SWS and SWA in healthy participants at baseline, in a model of transient insomnia (traffic noise, Dijk et al. 2012), a model of sleep onset insomnia (Mathias et al. 2001), a circadian phase advance model (Walsh et al. 2007), older participants (Lancel et al. 2001) and insomnia patients (Lankford et al. 2008). Interestingly, the effects of gaboxadol on sleep are much stronger in women than in men (Dijk et al. 2010b; Ma et al. 2011; Roth et al. 2010). | doi-access = free }}</ref><ref name="Walsh_2009" /> 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.<ref name="Morris_2013" /><ref name="Dijk_2012">{{cite journal | vauthors = Dijk DJ, Stanley N, Lundahl J, Groeger JA, Legters A, Trap Huusom AK, Deacon S | title = Enhanced slow wave sleep and improved sleep maintenance after gaboxadol administration during seven nights of exposure to a traffic noise model of transient insomnia | journal = Journal of Psychopharmacology | volume = 26 | issue = 8 | pages = 1096–1107 | date = August 2012 | pmid = 22002961 | doi = 10.1177/0269881111421971 }}</ref> SWS decreases with age, especially in men, and gaboxadol was found to substantially compensate for the reduction in SWS in elderly men.<ref name="Wafford_2006" /><ref name="KrogsgaardLarsen_2002" /><ref name="Morris_2013" /><ref name="Mathias_2005">{{cite journal | vauthors = Mathias S, Zihl J, Steiger A, Lancel M | title = Effect of repeated gaboxadol administration on night sleep and next-day performance in healthy elderly subjects | journal = Neuropsychopharmacology | volume = 30 | issue = 4 | pages = 833–841 | date = April 2005 | pmid = 15602499 | doi = 10.1038/sj.npp.1300641 }}</ref> 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.<ref name="Walsh_2009" /><ref name="Walsh_2008">{{cite journal | vauthors = Walsh JK, Snyder E, Hall J, Randazzo AC, Griffin K, Groeger J, Eisenstein R, Feren SD, Dickey P, Schweitzer PK | title = Slow wave sleep enhancement with gaboxadol reduces daytime sleepiness during sleep restriction | journal = Sleep | volume = 31 | issue = 5 | pages = 659–672 | date = May 2008 | pmid = 18517036 | pmc = 2398757 | doi = 10.1093/sleep/31.5.659 }}</ref>

Gaboxadol's hypnotic and other effects have been found to be much stronger in women than in men.<ref name="Dijk_2019" /><ref name="Roth_2010" /><ref name="DijkJamesPeters2010">{{cite journal | vauthors = Dijk DJ, James LM, Peters S, Walsh JK, Deacon S | title = Sex differences and the effect of gaboxadol and zolpidem on EEG power spectra in NREM and REM sleep | journal = J Psychopharmacol | volume = 24 | issue = 11 | pages = 1613–1618 | date = November 2010 | pmid = 19487320 | doi = 10.1177/0269881109105788 | url = }}</ref><ref name="Lankford_2008" /><ref name="MaDijkSvetnik2011">{{cite journal | vauthors = Ma J, Dijk DJ, Svetnik V, Tymofyeyev Y, Ray S, Walsh JK, Deacon S | title = EEG power spectra response to a 4-h phase advance and gaboxadol treatment in 822 men and women | journal = J Clin Sleep Med | volume = 7 | issue = 5 | pages = 493–501A | date = October 2011 | pmid = 22003345 | pmc = 3190849 | doi = 10.5664/JCSM.1316 | url = }}</ref> 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.<ref name="Roth_2010" /><ref name="DijkJamesPeters2010" /><ref name="MaDijkSvetnik2011" /> 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.<ref name="DijkJamesPeters2010" /><ref name="MaDijkSvetnik2011" /><ref name="Roth_2010" /><ref name="González-FloresSánchezGarcía-Juárez2004">{{cite journal | vauthors = González-Flores O, Sánchez N, García-Juárez M, Lima-Hernández FJ, González-Mariscal G, Beyer C | title = Estradiol and testosterone modulate the anesthetic action of the GABA-A agonist THIP, but not of the neurosteroid 3alpha,5beta-pregnanolone in the rat | journal = Psychopharmacology (Berl) | volume = 172 | issue = 3 | pages = 283–290 | date = March 2004 | pmid = 14685643 | doi = 10.1007/s00213-003-1649-x | url = }}</ref> These neurosteroids are GABAA receptor positive allosteric modulators, including of gaboxadol-sensitive δ subunit-containing GABAA receptors,<ref name="CarverReddy2013">{{cite journal | vauthors = Carver CM, Reddy DS | title = Neurosteroid interactions with synaptic and extrasynaptic GABA(A) receptors: regulation of subunit plasticity, phasic and tonic inhibition, and neuronal network excitability | journal = Psychopharmacology (Berl) | volume = 230 | issue = 2 | pages = 151–188 | date = November 2013 | pmid = 24071826 | pmc = 3832254 | doi = 10.1007/s00213-013-3276-5 | url = }}</ref> and may interact synergistically with gaboxadol.<ref name="DijkJamesPeters2010" /><ref name="CarverReddy2013" /><ref name="SmithShenGong2007">{{cite journal | vauthors = Smith SS, Shen H, Gong QH, Zhou X | title = Neurosteroid regulation of GABA(A) receptors: Focus on the alpha4 and delta subunits | journal = Pharmacol Ther | volume = 116 | issue = 1 | pages = 58–76 | date = October 2007 | pmid = 17512983 | pmc = 2657726 | doi = 10.1016/j.pharmthera.2007.03.008 | url = }}</ref><ref name="PinnaUzunovaMatsumoto2000">{{cite journal | vauthors = Pinna G, Uzunova V, Matsumoto K, Puia G, Mienville JM, Costa E, Guidotti A | title = Brain allopregnanolone regulates the potency of the GABA(A) receptor agonist muscimol | journal = Neuropharmacology | volume = 39 | issue = 3 | pages = 440–448 | date = January 2000 | pmid = 10698010 | doi = 10.1016/s0028-3908(99)00149-5 | url = | hdl = 11380/1248311 | hdl-access = free }}</ref>

There was no tolerance to the hypnotic effects of gaboxadol after 5{{nbsp}}days of repeated administration in animals.<ref name="Wafford_2006" /><ref name="Lancel_2000">{{cite journal | vauthors = Lancel M, Langebartels A | title = gamma-aminobutyric Acid(A) (GABA(A)) agonist 4,5,6, 7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol persistently increases sleep maintenance and intensity during chronic administration to rats | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 293 | issue = 3 | pages = 1084–1090 | date = June 2000 | doi = 10.1016/S0022-3565(24)39335-8 | pmid = 10869413 }}</ref> Similarly, it maintained effectiveness in short-term clinical studies in humans.<ref name="Roth_2010" /> However, gaboxadol was subsequently found to be initially effective in improving sleep in insomnia but showed reduced effectiveness after 1{{nbsp}}month.<ref name="Atack_2010" /><ref name="Lankford_2008" /> In addition, gaboxadol showed mixed effectiveness at the assessed doses of 10 to 15{{nbsp}}mg in two large 3-month clinical trials for insomnia.<ref name="Frlund_2013" /><ref name="Roth_2010" />

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.<ref name="KrogsgaardLarsen_2004">{{cite journal | vauthors = Krogsgaard-Larsen P, Frølund B, Liljefors T, Ebert B | title = GABA(A) agonists and partial agonists: THIP (Gaboxadol) as a non-opioid analgesic and a novel type of hypnotic | journal = Biochemical Pharmacology | volume = 68 | issue = 8 | pages = 1573–1580 | date = October 2004 | pmid = 15451401 | doi = 10.1016/j.bcp.2004.06.040 | quote = Similar [sleep] results [relative to gaboxadol] have been obtained with muscimol, with the GABA uptake inhibitor Tiagabine [65], and with the glia-selective GABA uptake inhibitor, THPO (Fig. 2) [66] [...] }}</ref><ref name="Wafford_2006" /><ref name="Dijk_2010">{{cite journal | vauthors = Dijk DJ | title = Slow-wave sleep deficiency and enhancement: implications for insomnia and its management | journal = The World Journal of Biological Psychiatry | volume = 11 | issue = Suppl 1 | pages = 22–28 | date = June 2010 | pmid = 20509829 | doi = 10.3109/15622971003637645 }}</ref><ref name="Johnston_2014">{{cite journal | vauthors = Johnston GA | title = Muscimol as an ionotropic GABA receptor agonist | journal = Neurochemical Research | volume = 39 | issue = 10 | pages = 1942–1947 | date = October 2014 | pmid = 24473816 | doi = 10.1007/s11064-014-1245-y | quote = The effects of THIP on sleep resembled those reported earlier for muscimol and were dissimilar from those induced by benzodiazepine modulators of GABAA receptors [45]. }}</ref> In addition, unlike such agents, gaboxadol caused no rebound insomnia on discontinuation and produced no next-day residual symptoms.<ref name="Atack_2010" /><ref name="Wisden_2019" /><ref name="Boyle_2009">{{cite journal | vauthors = Boyle J, Wolford D, Gargano C, McCrea J, Cummings C, Cerchio K, Lines C | title = Next-day residual effects of gaboxadol and flurazepam administered at bedtime: a randomized double-blind study in healthy elderly subjects | journal = Human Psychopharmacology | volume = 24 | issue = 1 | pages = 61–71 | date = January 2009 | pmid = 18985628 | doi = 10.1002/hup.986 }}</ref> 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.<ref name="KrogsgaardLarsen_2004" /><ref name="KrogsgaardLarsen_2002" /><ref name="Johnston_2014" /><ref name="Wafford_2006" /><ref name="McDonald_2007" />

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.<ref name="Walsh_2009">{{cite journal | vauthors = Walsh JK | title = Enhancement of slow wave sleep: implications for insomnia | journal = Journal of Clinical Sleep Medicine | volume = 5 | issue = 2 Suppl | pages = S27–S32 | date = April 2009 | doi = 10.5664/jcsm.5.2S.S27 | pmid = 19998872 | pmc = 2824211 }}</ref><ref name="Ebert_2009">{{cite journal | vauthors = Ebert B | title = Discontinued drugs 2007: central and peripheral nervous system drugs | journal = Expert Opinion on Investigational Drugs | volume = 18 | issue = 2 | pages = 109–123 | date = February 2009 | pmid = 19236259 | doi = 10.1517/13543780802687371 }}</ref><ref name="Wafford_2008">{{cite journal | vauthors = Wafford KA, Ebert B | title = Emerging anti-insomnia drugs: tackling sleeplessness and the quality of wake time | journal = Nature Reviews. Drug Discovery | volume = 7 | issue = 6 | pages = 530–540 | date = June 2008 | pmid = 18511929 | doi = 10.1038/nrd2464 }}</ref> In addition, it was more effective for improving sleep maintenance than for improving sleep onset.<ref name="Roth_2010" />

Gaboxadol was developed for the treatment of insomnia, in which disruption of SWS is not the main feature.<ref name="Atack_2010" /><ref name="Ebert_2009" /> The effects of gaboxadol in people with sleeping problems specifically involving impaired SWS have largely not been studied and are unknown.<ref name="Atack_2010" /><ref name="Wafford_2008" />

===Hallucinogenic effects=== Gaboxadol was assessed at supratherapeutic doses of 30 to 45{{nbsp}}mg and compared to the Z drug zolpidem in drug users during its development for treatment of insomnia.<ref name="Morris_2013" /><ref name="Roth_2010" /><ref name="Schoedel_2009">{{cite journal | vauthors = Schoedel KA, Rosen LB, Alexander R, Wang J, Snavely D, Murphy MG, Chodakewitz J, Mengel H, Romach MK, Sellers EM | title = Poster Session I (PI 1-89): PI-44: A single-dose randomized, double-blind, crossover abuse liability study to evaluate the subjective and objective effects of gaboxadol and zolpidem in recreational drug users | journal = Clinical Pharmacology & Therapeutics | volume = 85 | issue = S1 [Supplement: Abstracts of the 2009 Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics. National Harbor, Maryland, USA. March 18–21, 2009] | pages = S9–S36 (S22–S22) | date = 16 January 2009 | doi = 10.1038/sj.clpt.2008.283 | issn = 0009-9236 }}</ref> At these doses, gaboxadol produced euphoria and hallucinogenic effects such as dissociation, perceptual changes, and hallucinations.<ref name="Morris_2013" /><ref name="Roth_2010" /><ref name="Schoedel_2009" /><ref name="Reuters2007" /> The rates of such psychiatric adverse effects were 15% with placebo, 38% with 15{{nbsp}}mg, 72% with 30{{nbsp}}mg, and 88% with 45{{nbsp}}mg gaboxadol.<ref name="Lundbeck_2007" /> It showed less euphoria and misuse potential, more negative and dissociative effects, and fewer sedative effects than zolpidem in these individuals.<ref name="Schoedel_2009" /> At a dose of 60{{nbsp}}mg twice daily in an early study, gaboxadol was described as producing effects including dizziness, vomiting, somnolence, and strong sedation.<ref name="Wafford_2006" /> High doses of gaboxadol have also been reported to produce delirium, amnesia, and loss of consciousness.<ref name="Morris_2013" />

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 40{{nbsp}}mg and powerful hallucinogenic effects occurring at a dose of about 65{{nbsp}}mg of the zwitterion.<ref name="Morris_2013" /><ref name="Thulin_2013" /><ref name="Morris2018-S02E07">{{cite episode | title = A Fungal Fairy Tale | issue = 7 | date = 9 January 2018 | credits = Morris H | series = Hamilton's Pharmacopeia | season = 2 | url = https://www.youtube.com/watch?v=snM7RsUZtaE | publisher = Vice Media | network = Viceland }}</ref><ref name="MorrisKrogsgaard-Larsen2021">{{cite podcast | title = PODCAST 36: An Amanita Christmas with Dr. Povl Krogsgaard-Larsen | date = 25 December 2021 | url = https://www.patreon.com/posts/podcast-36-with-60339541 | website = The Hamilton Morris Podcast | publisher = Patreon | host = Hamilton Morris | time = ~48:00, ~2:07:30 | access-date = 14 February 2025 | quote = [Morris:] [...] they did produce enough [gaboxadol] [...] to conduct a number of self-experiments, some at very high doses. He experienced extremely dramatic psychedelic effects at those high doses. [...] I have a written report—I mentioned that I had a friend [...] [a]nd he took a very, very large dose of [gaboxadol] [...] it was 63 mg of the zwitterion. [...] It's you know very, very dramatic hallucinogenic effects. He describes his entire reality being fragmented. [...] }}</ref><ref name="MorrisGallimore2022">{{cite podcast | title = POD 65: Dr. Andrew Gallimore on DMTx and Reality Switch Technologies | date = 29 December 2022 | url = https://www.patreon.com/posts/pod-65-dr-andrew-76525101 | website = The Hamilton Morris Podcast | publisher = Patreon | host = Hamilton Morris | time = 1:02:16–1:04:33 | access-date = 21 March 2025 | quote = [Morris:] I've used high doses of gaboxadol and that is as psychedelic as anything else. It's different, of course. It's a different type of experience entirely. But that same sort of proliferation of ideas and perceptual disturbances is very much present. It is not in any way analogous to a benzodiazepine. It's something that is visionary and completely alien and strange. [...] It's worth trying. Not because it's enjoyable or good. It's also not bad either. [...] the most intense gaboxadol experience of my life was in Japan. [...] [I was like] at night I'm gonna take gaboxadol at a high dose to knock myself out. And I'd taken gaboxadol at lower doses many many times before and I'd had mild effects from it. [...] [Due to jet lag] I was much more awake and alert and unintentionally had one of the most intense psychedelic experiences of my life taking this stuff that I was thinking was just going to knock me out. [...] I spent the entire night in this visionary state trying to figure out a way to lose consciousness but instead I was hyperconscious [...] }}</ref><ref name="RoganMorris2024">{{cite podcast | title = Joe Rogan Experience #1136 | date = 26 June 2018 | host = Joe Rogan | publisher = The Joe Rogan Experience | website = YouTube | url = https://www.youtube.com/watch?v=HM8WDZIhs3M | archive-url = https://web.archive.org/web/20250927172104/https://www.youtube.com/watch?v=HM8WDZIhs3M&pp=ygUbaGFtaWx0b24gcGhhcm1lY29wZWEgYW1hem9u | archive-date = 27 September 2025 | quote = [Morris:] [Gaboxadol is] every bit as powerful as ayahuasca or something like that, but completely different. [...] it's something that's been experienced by relatively few people, so you don't even have this spiritual or metaphorical vocabulary for it. [...] So I took a high dose I believe it was 45 [mg], but don't quote me on that, of [gaboxadol]. [...] And it was unbelievable. I mean, I couldn't fathom the intensity of what I experienced. It was, you know, just this rushing sense of becoming a passive observer in my own consciousness and seeing all of my thoughts produced by someone else that were racing at a speed that was so fast that I found it physically dizzying and had to lay down. And I felt as if the acceleration was pushing me toward an ultimate state that was sleep and that sleep and death represented the ultimate state of consciousness. [...] [I had this] transformative existential trip accidentally [...] [Rogan:] Did you ever recreate that kind of experience? [Morris:] No, because it was, it was a bit much, I would say. And I know people that have taken even more, and it turns into just your entire visual field transforming into rotating cubes where each face of the cube represents a different aspect of your life, your future, your past, your present, you know, really dramatic stuff. [...] | access-date = 5 October 2025 | url-status = bot: unknown }}</ref> Morris has described hallucinogenic effects he experienced with gaboxadol as follows:<ref name="Magazine_2013">{{cite magazine | vauthors = Magazine H | title = Writers Go in Search of a Good Night's Sleep, by Harper's Magazine | date = 23 July 2013 | website = Harper's Magazine | url = https://harpers.org/2013/07/writers-go-in-search-of-a-good-nights-sleep/ | access-date = 4 October 2025 | quote = “I heard about gaboxadol and decided I had to try it,” writes Hamilton Morris of a rare chemical remedy for insomnia that, though it is nowhere near being approved by the U.S. Food and Drug Administration, could be an improvement over Ambien, Valium, and Xanax. But what really appeals to Morris is the hallucinogenic delirium gaboxadol is said to induce. The intrepid reporter scores some: “In my darkened bedroom,” he writes, “I could hear otherworldly music emanating from the motor of a box fan, the white-noise buzzing slowing, taking on the character of an electric viola, the room’s various shadows animated by strange movements as if cast by a flickering candle—but none of this proved distracting.” Morris finds that gaboxadol is indeed the perfect hypnotic. }}</ref><ref name="Morris_2013" />

: "The next night I increased the dose to 35mg sublingually, and it was then that gaboxadol's relationship to muscimol became manifest. In my darkened bedroom I could hear otherworldly music emanating from the motor of a box fan, the white-noise buzzing slowing, taking on the character of an electric viola, the room's various shadows animated by strange movements, as if cast by a flickering candle — but none of this proved distracting. Once again I fell into an all-consuming slumber."<ref name="Magazine_2013" /><ref name="Morris_2013" />

He has also reported other qualitative accounts of the hallucinogenic effects of gaboxadol.<ref name="MorrisKrogsgaard-Larsen2021" /><ref name="MorrisGallimore2022" /><ref name="RoganMorris2024" /> Morris has stated that gaboxadol is every bit as powerful as a hallucinogen as serotonergic psychedelics like ayahuasca, but is qualitatively completely different.<ref name="RoganMorris2024" /><ref name="MorrisGallimore2022" />

==Side effects== Side effects of gaboxadol include dizziness, sedation, somnolence, headache, nausea, vomiting, and tachycardia, among others.<ref name="Wafford_2006" /><ref name="Lu_2025">{{cite journal | vauthors = Lu C, Geng Y, Guan X, Meng Y, Zhu M, Zhao Y | title = Adverse events of pharmacological interventions for insomnia disorder in adults: a systematic review and network meta-analysis | journal = Frontiers in Psychiatry | volume = 16 | date = 2025 | pmid = 40704033 | pmc = 12283787 | doi = 10.3389/fpsyt.2025.1461166 | doi-access = free | article-number = 1461166 }}</ref><ref name="Lundbeck_2007" /><ref name="PharmaTimes2007" /><ref name="Reuters2007" /><ref name="HoehnSaric_1983" /> It has also been reported to produce giddiness, depersonalization, impaired concentration, confusion, muscle twitches, and bradycardia.<ref name="Korsgaard_1982" /><ref name="HoehnSaric_1983" /> In clinical studies for insomnia, gaboxadol has been found to be generally well-tolerated for up to 12{{nbsp}}months.<ref name="Roth_2010" /> At high doses, it can produce hallucinogenic effects and delirium.<ref name="Morris_2013" /><ref name="Roth_2010" /><ref name="Schoedel_2009" /><ref name="HoehnSaric_1983" />

==Overdose== Gaboxadol has been studied at doses as high as 120 to 160{{nbsp}}mg in small clinical studies, without serious toxicity reported.<ref name="Morris_2013" /><ref name="Korsgaard_1982" /><ref name="Mohr_1986" /> Overdose of gaboxadol in humans can produce symptoms including hallucinogenic effects, euphoria, strong sedation, somnolence, dizziness, vomiting, delirium, amnesia, and loss of consciousness.<ref name="Morris_2013" /><ref name="Roth_2010" /><ref name="Schoedel_2009" /><ref name="Reuters2007" /><ref name="Lundbeck_2007" /><ref name="Wafford_2006" />

The median lethal dose (LD50) of gaboxadol in mice is 80{{nbsp}}mg/kg intravenously, 87 to 145{{nbsp}}mg/kg intraperitoneally, and greater than 320{{nbsp}}mg/kg orally.<ref name="US4278676" /><ref name="PubChem" /><ref name="Löscher1982">{{cite journal | vauthors = Löscher W | title = Comparative assay of anticonvulsant and toxic potencies of sixteen GABAmimetic drugs | journal = Neuropharmacology | volume = 21 | issue = 8 | pages = 803–810 | date = August 1982 | pmid = 7121752 | doi = 10.1016/0028-3908(82)90068-5 | url = | quote = }}</ref><ref name="ZhongJohnsonWu2016">{{cite journal | vauthors = Zhong W, Johnson CM, Wu Y, Cui N, Xing H, Zhang S, Jiang C | title = Effects of early-life exposure to THIP on phenotype development in a mouse model of Rett syndrome | journal = J Neurodev Disord | volume = 8 | issue = | article-number = 37 | date = 2016 | pmid = 27777634 | pmc = 5069883 | doi = 10.1186/s11689-016-9169-2 | doi-access = free | url = | quote = According to a THIP patent report, the LD50 in mice is [>]320 mg/kg orally, which is 2.2 times higher than i.p. (LD50 145 mg/kg) [23].}}</ref> For comparison, the LD50 of muscimol in the same species has been reported to be 5.6 to 7{{nbsp}}mg/kg intravenously, 2.5 to 12{{nbsp}}mg/kg intraperitoneally, and 22{{nbsp}}mg/kg orally.<ref name="Löscher1982" /><ref name="PubChem-Muscimol">{{cite web | title=Muscimol | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/4266 | access-date=18 May 2026}}</ref><ref name="US4278676" /><ref name="TheobaldBüchKunz1968">{{cite journal | vauthors = Theobald W, Büch O, Kunz HA, Krupp P, Stenger EG, Heimann H | title = Pharmakologische und experimentalpsychologische Untersuchungen mit 2 Inhalsstoffen des Fliegenpilzes (Amanita Muscaria) | trans-title = Pharmacological and experimental psychological studies with 2 components of fly agaric (Amanita muscaria) | language = German | journal = Arzneimittelforschung | volume = 18 | issue = 3 | pages = 311–315 | date = March 1968 | pmid = 5696006 | doi = | url = https://scholar.google.com/scholar?cluster=7165244348805609044}}</ref> These findings indicate that gaboxadol has considerably lower lethal potency or toxicity compared to muscimol.<ref name="US4278676" /> Gaboxadol is said to have low toxicity in various animal species and to be well-tolerated in acute and chronic toxicological studies in rats, dogs, and baboons.<ref name="Moroni_1982" /><ref name="Krogsgaard-LarsenChristensen1980">{{cite book | vauthors = Krogsgaard-Larsen P, Christensen AV | date = 1980 | chapter = Chapter 5. GABA Agonists and Antagonists | title = Annual Reports in Medicinal Chemistry | publisher = Elsevier | volume = 15 | pages = 41–50 | isbn = 978-0-12-040515-2 | doi = 10.1016/s0065-7743(08)60366-8 | quote = Clinical studies in progress with THIP (14), which is well tolerated by rats, dogs, and baboons, are expected to provide more information about the therapeutic usefulness of GABA agonists. }}</ref><ref name="Krogsgaard-LarsenArnt1979">{{cite book | vauthors = Krogsgaard-Larsen P, Arnt J | chapter = GABA receptor agonists: relationship between structure and biological activity in vivo and in vitro | title = GABA—Biochemistry and CNS Functions | series = Advances in Experimental Medicine and Biology | publisher = Springer US | publication-place = Boston, MA | volume = 123 | date = 1979 | isbn = 978-1-4899-5201-1 | pmid = 390994 | doi = 10.1007/978-1-4899-5199-1 | pages = 303–321 | quote = THIP is a relatively non-toxic compound in mice and dogs, and it seems to penetrate easily into the brain after peripheral administration (V. Christensen, unpublished results). [...]}}</ref><ref name="MeldrumHorton1980">{{cite journal | vauthors = Meldrum B, Horton R | title = Effects of the bicyclic GABA agonist, THIP, on myoclonic and seizure responses in mice and baboons with reflex epilepsy | journal = Eur J Pharmacol | volume = 61 | issue = 3 | pages = 231–237 | date = February 1980 | pmid = 6767614 | doi = 10.1016/0014-2999(80)90125-9 | url = }}</ref> Its specific LD50 values in these species do not appear to have been reported.<ref name="PubChem">{{cite web | title=Gaboxadol | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/3448 | access-date=18 May 2026}}</ref>

==Interactions== Gaboxadol is metabolized exclusively via glucuronidation and is not appreciated metabolized by cytochrome P450 enzymes, and hence would not be expected to interact with cytochrome P450 inhibitors or inducers.<ref name="Deacon_2007" />

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''.<ref name="Johnston_2014" /><ref name="Skerritt_1983">{{cite journal | vauthors = Skerritt JH, Johnston GA | title = Diazepam stimulates the binding of GABA and muscimol but not THIP to rat brain membranes | journal = Neuroscience Letters | volume = 38 | issue = 3 | pages = 315–320 | date = August 1983 | pmid = 6314189 | doi = 10.1016/0304-3940(83)90388-9 }}</ref> In addition, gaboxadol did not show synergistic effects in combination with alcohol or benzodiazepines ''in vitro'' or ''in vivo'' in animals.<ref name="Miller_2013" /><ref name="Storustovu_Si_2003">{{cite journal | vauthors = Stórustovu S, Ebert B | title = Gaboxadol: in vitro interaction studies with benzodiazepines and ethanol suggest functional selectivity | journal = European Journal of Pharmacology | volume = 467 | issue = 1–3 | pages = 49–56 | date = April 2003 | pmid = 12706454 | doi = 10.1016/s0014-2999(03)01603-0 }}</ref><ref name="Voss_2003">{{cite journal | vauthors = Voss J, Sanchez C, Michelsen S, Ebert B | title = Rotarod studies in the rat of the GABAA receptor agonist gaboxadol: lack of ethanol potentiation and benzodiazepine cross-tolerance | journal = European Journal of Pharmacology | volume = 482 | issue = 1–3 | pages = 215–222 | date = December 2003 | pmid = 14660025 | doi = 10.1016/j.ejphar.2003.10.007 }}</ref><ref name="SanchezEbert2006" /> Similarly, gaboxadol was studied in combination with the Z drug zolpidem in humans and was found to have limited interaction with it.<ref name="LundNielsenWesnes2006">Lund, J., Nielsen, G., Wesnes, K., & Mengel, H. (2006, January). Gaboxadol has little or no effect on cognitive and psychomotor tests compared to zolpidem and the two compounds have limited potential for interaction in healthy subjects. In Sleep (Vol. 29, pp. A41-A41). https://sleepmeeting.org/wp-content/uploads/2018/10/abstractbook2006.pdf#page=71</ref>

==Pharmacology== ===Pharmacodynamics=== Gaboxadol acts as a potent and selective GABAA receptor partial agonist.<ref name="Sorbera_2004" /><ref name="Wafford_2006" /> In contrast to GABAA receptor positive allosteric modulators like benzodiazepines, Z drugs, barbiturates, and alcohol, gaboxadol is an agonist of the orthosteric site of the GABAA receptor and the same site that the neurotransmitter γ-aminobutyric acid binds to and activates.<ref name="Sorbera_2004" /><ref name="Wafford_2006" /> Whereas the related GABAA receptor agonist muscimol is a highly potent partial agonist of the GABAA-ρ receptor (GABAC receptor), gaboxadol is a moderately potent antagonist of this receptor.<ref name="Johnston_2014" /><ref name="Johnston_2005">{{cite journal | vauthors = Johnston GA | title = GABA(A) receptor channel pharmacology | journal = Current Pharmaceutical Design | volume = 11 | issue = 15 | pages = 1867–1885 | date = 2005 | pmid = 15974965 | doi = 10.2174/1381612054021024 }}</ref> Unlike muscimol, it is not also a GABA reuptake inhibitor to any extent, and it does not inhibit the enzyme GABA transaminase (GABA-T).<ref name="Christensen_1982" />

The drug shows functional selectivity at the GABAA receptor relative to GABA itself, activating GABAA receptors of different α subunit compositions with varying efficacies.<ref name="Frlund_2002" /><ref name="Ebert_2001">{{cite journal | vauthors = Ebert B, Mortensen M, Thompson SA, Kehler J, Wafford KA, Krogsgaard-Larsen P | title = Bioisosteric determinants for subtype selectivity of ligands for heteromeric GABA(A) receptors | journal = Bioorganic & Medicinal Chemistry Letters | volume = 11 | issue = 12 | pages = 1573–1577 | date = June 2001 | pmid = 11412984 | doi = 10.1016/s0960-894x(01)00184-6 }}</ref><ref name="Krogsgaard-LarsenFrølundKristiansen2001">{{cite book | vauthors=Krogsgaard-Larsen P, Frølund B, Kristiansen U, Ebert B | chapter=Ligands for the GABAA receptor complex | title=Glutamate and GABA Receptors and Transporters | publisher=CRC Press | date=4 October 2001 | isbn=978-0-429-09545-0 | doi=10.1201/9780203299388-15 | pages=248–286}}</ref> Its {{Abbrlink|Emax|maximal efficacy}} 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.<ref name="Frlund_2002" /><ref name="Ebert_2001" /><ref name="Krogsgaard-LarsenFrølundKristiansen2001" /> Moreover, gaboxadol has been found to act as a supra-maximal agonist at α4β3δ subunit-containing GABAA receptors, low-potency agonist at α1β3γ2 subunit-containing receptors, and partial agonist at α4β3γ subunit-containing receptors.<ref>{{cite journal | vauthors = Brown N, Kerby J, Bonnert TP, Whiting PJ, Wafford KA | title = Pharmacological characterization of a novel cell line expressing human alpha(4)beta(3)delta GABA(A) receptors | journal = British Journal of Pharmacology | volume = 136 | issue = 7 | pages = 965–974 | date = August 2002 | pmid = 12145096 | pmc = 1573424 | doi = 10.1038/sj.bjp.0704795 }}</ref><ref>{{Cite journal | vauthors = Orser BA | title = Extrasynaptic GABAA Receptors Are Critical Targets for Sedative-Hypnotic Drugs | journal = Journal of Clinical Sleep Medicine | volume = 02 | issue = 2 | date = 2006-04-15 | pages = S12–S18 | doi = 10.5664/jcsm.26526 | language = en | issn = 1550-9389 | doi-access = free }}</ref><ref name="Johnston_2014a">{{cite journal | vauthors = Johnston GA | title = Muscimol as an ionotropic GABA receptor agonist | journal = Neurochemical Research | volume = 39 | issue = 10 | pages = 1942–1947 | date = October 2014 | pmid = 24473816 | doi = 10.1007/s11064-014-1245-y }}</ref> Its affinity for extrasynaptic α4β3δ subunit-containing GABAA receptors is 10-fold greater than for other subtypes.<ref>{{cite journal | vauthors = Rudolph U, Knoflach F | title = Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes | journal = Nature Reviews. Drug Discovery | volume = 10 | issue = 9 | pages = 685–697 | date = July 2011 | pmid = 21799515 | pmc = 3375401 | doi = 10.1038/nrd3502 }}</ref> 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.<ref>{{cite journal | vauthors = Mortensen M, Ebert B, Wafford K, Smart TG | title = Distinct activities of GABA agonists at synaptic- and extrasynaptic-type GABAA receptors | journal = The Journal of Physiology | volume = 588 | issue = Pt 8 | pages = 1251–1268 | date = April 2010 | pmid = 20176630 | pmc = 2872731 | doi = 10.1113/jphysiol.2009.182444 }}</ref> 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.<ref name="Johnston_2014a" /> Mice with the GABAA receptor δ subunit knocked out are unresponsive to the hypnotic effects of gaboxadol.<ref name="Wisden_2019">{{cite book | vauthors = Wisden W, Yu X, Franks NP | chapter = GABA Receptors and the Pharmacology of Sleep | volume = 253 | pages = 279–304 | date = 2019 | pmid = 28993837 | doi = 10.1007/164_2017_56 | isbn = 978-3-030-11270-7 | title = Handbook of Experimental Pharmacology }}</ref><ref name="WinskySommerer_2007">{{cite journal | vauthors = Winsky-Sommerer R, Vyazovskiy VV, Homanics GE, Tobler I | title = The EEG effects of THIP (Gaboxadol) on sleep and waking are mediated by the GABA(A)delta-subunit-containing receptors | journal = The European Journal of Neuroscience | volume = 25 | issue = 6 | pages = 1893–1899 | date = March 2007 | pmid = 17408425 | doi = 10.1111/j.1460-9568.2007.05455.x }}</ref> Because of its preferential agonism of extrasynaptic GABAA receptors, gaboxadol has been referred to as a "selective extrasynaptic GABAA agonist" or "SEGA".<ref name="Walsh_2008a">{{cite journal | vauthors = Walsh JK, Mayleben D, Guico-Pabia C, Vandormael K, Martinez R, Deacon S | title = Efficacy of the selective extrasynaptic GABA A agonist, gaboxadol, in a model of transient insomnia: a randomized, controlled clinical trial | journal = Sleep Medicine | volume = 9 | issue = 4 | pages = 393–402 | date = May 2008 | pmid = 17765013 | doi = 10.1016/j.sleep.2007.06.006 }}</ref><ref name="McDonald_2007">{{cite journal | vauthors = McDonald LM, Sheppard WF, Staveley SM, Sohal B, Tattersall FD, Hutson PH | title = Gaboxadol, a selective extrasynaptic GABA(A) agonist, does not generalise to other sleep-enhancing drugs: a rat drug discrimination study | journal = Neuropharmacology | volume = 52 | issue = 3 | pages = 844–853 | date = March 2007 | pmid = 17196996 | doi = 10.1016/j.neuropharm.2006.10.009 | quote = In studies from other laboratories, gaboxadol (5.6 mg/kg i.p. training dose) did not generalise to midazolam (Ator, 1991), and rats trained to discriminate lorazepam (1 mg/kg i.p.), midazolam (0.4 mg/kg s.c.) or diazepam (2.5 mg/kg i.p.) from vehicle did not generalise to gaboxadol (Nielsen et al., 1983; Ator and Griffiths, 1986; Rauch and Stolerman, 1987). Gaboxadol showed partial generalisation to pentobarbital (5 or 10 mg/kg i.p. training dose) in two studies (Ator and Griffiths, 1986; Grech and Balster, 1993). The only compound to which gaboxadol has fully generalised is the GABAA agonist, muscimol (1 mg/kg i.p. training dose; Grech and Balster, 1997; Jones and Balster, 1998). [...] For example, zolpidem, indiplon, RS-zopiclone and S-zopiclone were all reported to enhance sleep onset and increase the total duration of sleep (Nakajima et al., 2000; Zammit et al., 2004; Swainston Harrison and Keating, 2005; Thomson Scientific, 2006). Gaboxadol did not affect sleep onset and had no effect on rapid eye movement (REM) sleep, but increased the total duration of slow-wave sleep in rats (Lancel and Faulhaber, 1996), which resembled the changes it induces in human sleep (Faulhaber et al., 1997). Muscimol had similar effects to gaboxadol on sleep in rats, although it also increased REM sleep (Lancel et al., 1996). }}</ref> In contrast to gaboxadol, benzodiazepines and nonbenzodiazepines do not activate δ subunit-containing GABAA receptors.<ref name="Wisden_2019" /><ref name="Deacon_2007">{{cite journal | vauthors = Deacon S, Staner L, Staner C, Legters A, Loft H, Lundahl J | title = Effect of short-term treatment with gaboxadol on sleep maintenance and initiation in patients with primary insomnia | journal = Sleep | volume = 30 | issue = 3 | pages = 281–287 | date = March 2007 | pmid = 17425224 | doi = 10.1093/sleep/30.3.281 | quote = When given orally in healthy subjects, gaboxadol is rapidly absorbed (tmax of 30-60 min) and eliminated (t½ of 1.5 h). More than 95% of the dose is excreted in the urine, mostly unchanged. A glucoronide conjugate is the only metabolite formed in significant amounts. Hence the CYP450 system does not have significant involvement in the metabolism of gaboxadol. }}</ref> On the other hand, alcohol is known to selectively potentiate δ subunit-containing extrasynaptic GABAA receptors analogously to gaboxadol.<ref name="Lobo_2008">{{cite journal | vauthors = Lobo IA, Harris RA | title = GABA(A) receptors and alcohol | journal = Pharmacology, Biochemistry, and Behavior | volume = 90 | issue = 1 | pages = 90–94 | date = July 2008 | pmid = 18423561 | pmc = 2574824 | doi = 10.1016/j.pbb.2008.03.006 }}</ref><ref name="Santhakumar_2007">{{cite journal | vauthors = Santhakumar V, Wallner M, Otis TS | title = Ethanol acts directly on extrasynaptic subtypes of GABAA receptors to increase tonic inhibition | journal = Alcohol | volume = 41 | issue = 3 | pages = 211–221 | date = May 2007 | pmid = 17591544 | pmc = 2040048 | doi = 10.1016/j.alcohol.2007.04.011 }}</ref><ref name="Wallner_2008">{{cite journal | vauthors = Wallner M, Olsen RW | title = Physiology and pharmacology of alcohol: the imidazobenzodiazepine alcohol antagonist site on subtypes of GABAA receptors as an opportunity for drug development? | journal = British Journal of Pharmacology | volume = 154 | issue = 2 | pages = 288–298 | date = May 2008 | pmid = 18278063 | pmc = 2442438 | doi = 10.1038/bjp.2008.32 }}</ref> In addition, neurosteroids and propofol act on extrasynaptic δ subunit-containing GABAA receptors.<ref name="Wisden_2019" /><ref name="Houston_2012">{{cite journal | vauthors = Houston CM, McGee TP, Mackenzie G, Troyano-Cuturi K, Rodriguez PM, Kutsarova E, Diamanti E, Hosie AM, Franks NP, Brickley SG | title = Are extrasynaptic GABAA receptors important targets for sedative/hypnotic drugs? | journal = The Journal of Neuroscience | volume = 32 | issue = 11 | pages = 3887–3897 | date = March 2012 | pmid = 22423109 | pmc = 4620914 | doi = 10.1523/JNEUROSCI.5406-11.2012 }}</ref><ref name="Wafford_2006" />

Gaboxadol shows 25- to 40-fold lower potency as a GABAA receptor agonist than muscimol in ''in vitro'' studies.<ref name="Waszczak_1980" /> Compared to muscimol, gaboxadol binds less potently to α4β3δ subunit-containing GABAA receptors ({{Abbrlink|EC50|half-maximal effective concentration}} = 0.2{{nbsp}}μM vs. 13{{nbsp}}μM), but is capable of evoking a greater maximum response ({{Abbrlink|Emax|maximal efficacy}} = 120% vs. 224%).<ref name="Johnston_2014a" /> Although gaboxadol is far less potent than muscimol ''in vitro'', it is only about 3{{nbsp}}times less potency than muscimol in rodents ''in vivo''.<ref name="Falch_1990">{{cite journal | vauthors = Falch E, Larsson OM, Schousboe A, Krogsgaard-Larsen P | title = GABA-A agonists and GABA uptake inhibitors: Structure-activity relationships | journal = Drug Development Research | volume = 21 | issue = 3 | pages = 169–188 | date = 1990 | doi = 10.1002/ddr.430210304 | issn = 0272-4391 | url = https://onlinelibrary.wiley.com/doi/10.1002/ddr.430210304 | access-date = 4 October 2025 | quote = The anticonvulsant effects of THIP and muscimol have been compared in a variety of animal models. THIP typically is two to five times weaker than muscimol in suppressing seizure activities. | url-access = subscription }}</ref><ref name="Waszczak_1980">{{cite journal | vauthors = Waszczak BL, Hruska RE, Walters JR | title = GABAergic actions of THIP in vivo and vitro: a comparison with muscimol and GABA | journal = European Journal of Pharmacology | volume = 65 | issue = 1 | pages = 21–29 | date = July 1980 | pmid = 7398775 | doi = 10.1016/0014-2999(80)90204-6 | quote = The magnitude of the differences between drug potencies in iontophoretic studies closely paralleled their relative potencies in binding studies, with muscimol approximately 3 times more potent than GABA and 25-40 times more potent than THIP. After systemic (i.v.) administration, however, muscimot was only 3 times more potent than THIP in inhibiting reticulata cell firing, possibly because THIP passes the blood-brain barrier more readily. }}</ref> This is attributed mainly to gaboxadol's much greater ability to cross the blood–brain barrier than muscimol.<ref name="Waszczak_1980" /> 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.<ref name="Moroni_1982" /> Gaboxadol is also more selective than muscimol and has been said by Povl Krogsgaard-Larsen to be much less toxic in comparison.<ref name="Frlund_2002" /><ref name="KrogsgaardLarsen_2004" /><ref name="KrogsgaardLarsen_1981" /><ref name="Morris_2013" /><ref name="US4278676" />

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.<ref name="Sorbera_2004" /><ref name="McDonald_2007" /><ref name="Christensen_1982" /><ref name="Christensen_2012">{{cite journal | vauthors = Christensen T, Bétry C, Mnie-Filali O, Etievant A, Ebert B, Haddjeri N, Wiborg O | title = Synergistic antidepressant-like action of gaboxadol and escitalopram | journal = European Neuropsychopharmacology | volume = 22 | issue = 10 | pages = 751–760 | date = October 2012 | pmid = 22406239 | doi = 10.1016/j.euroneuro.2012.02.001 }}</ref> In rodent drug discrimination studies, gaboxadol has been found to fully generalize with muscimol.<ref name="McDonald_2007" /><ref name="Grech_1997">{{cite journal | vauthors = Grech DM, Balster RL | title = The discriminative stimulus effects of muscimol in rats | journal = Psychopharmacology | volume = 129 | issue = 4 | pages = 339–347 | date = February 1997 | pmid = 9085403 }}</ref> 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.<ref name="Atack_2010">{{cite book | vauthors = Atack JR | chapter = Development of Subtype-Selective GABAA Receptor Compounds for the Treatment of Anxiety, Sleep Disorders and Epilepsy | title = GABA and Sleep | pages = 25–72 | date = 2010 | doi = 10.1007/978-3-0346-0226-6_2 | publisher = Springer Basel | publication-place = Basel | isbn = 978-3-0346-0225-9 | chapter-url = http://link.springer.com/10.1007/978-3-0346-0226-6_2 | access-date = 4 October 2025 }}</ref><ref name="Wafford_2006" /><ref name="McDonald_2007" /><ref name="SanchezEbert2006">Sanchez, C., & Ebert, B. (2006, January). Lack of generalisation between the GABAA receptor agonist, gaboxadol, and the allosteric modulators of the benzodiazepine binding site in the rat drug discrimination procedure. In Sleep (Vol. 29, pp. A243-A243). https://sleepmeeting.org/wp-content/uploads/2018/10/abstractbook2006.pdf#page=273</ref> Similarly, gaboxadol did not generalize with the neurosteroid pregnanolone.<ref name="McDonald_2007" /> On the other hand, gaboxadol has shown partial generalization with the barbiturate pentobarbital.<ref name="McDonald_2007" /> Gaboxadol does not produce self-administration or conditioned place preference in rodents or baboons, suggesting that it lacks rewarding or reinforcing effects and has low addictive potential.<ref name="Vashchinkina_2014">{{cite journal | vauthors = Vashchinkina E, Panhelainen A, Aitta-Aho T, Korpi ER | title = GABAA receptor drugs and neuronal plasticity in reward and aversion: focus on the ventral tegmental area | journal = Frontiers in Pharmacology | volume = 5 | pages = 256 | date = 2014 | pmid = 25505414 | pmc = 4243505 | doi = 10.3389/fphar.2014.00256 | doi-access = free }}</ref><ref name="Vashchinkina_2012">{{cite journal | vauthors = Vashchinkina E, Panhelainen A, Vekovischeva OY, Aitta-aho T, Ebert B, Ator NA, Korpi ER | title = GABA site agonist gaboxadol induces addiction-predicting persistent changes in ventral tegmental area dopamine neurons but is not rewarding in mice or baboons | journal = The Journal of Neuroscience | volume = 32 | issue = 15 | pages = 5310–5320 | date = April 2012 | pmid = 22496576 | pmc = 6622081 | doi = 10.1523/JNEUROSCI.4697-11.2012 }}</ref> This is in contrast to benzodiazepines like diazepam.<ref name="Vashchinkina_2014" /><ref name="Vashchinkina_2012" />

===Pharmacokinetics=== ====Absorption==== The absorption of gaboxadol is rapid and almost complete with oral administration (83–96%).<ref name="Frlund_2013">{{cite journal | vauthors = Frølund S, Nøhr M, Holm R, Brodin B, Nielsen C | title = Potential involvement of the proton-coupled amino acid transporter PAT1 (SLC36A1) in the delivery of pharmaceutical agents | journal = Journal of Drug Delivery Science and Technology | volume = 23 | issue = 4 | pages = 293–306 | date = 2013 | doi = 10.1016/S1773-2247(13)50046-3 | url = https://linkinghub.elsevier.com/retrieve/pii/S1773224713500463 | access-date = 4 October 2025 | quote = Gaboxadol is a bicyclic analogue of the neurotransmitter GABA. Pharmacologically, gaboxadol acts as a selective extra-synaptic GABAA receptor agonists (SEGA) and was the first compound identified in a novel class of sleep agents [68]. The drug development of gaboxadol, with the indication for treatment of primary insomnia, was discontinued in 2007, partly due to the lack of efficacy observed in a large 3-month efficacy and safety study conducted in the United States [65], and partly due to the occurrence of psychiatric side effect at supra-therapeutic doses in an abuse liability study involving drug abusers [69, 70]. Early preclinical studies in rat, mouse, and human have shown that the absorption of gaboxadol is fast and almost complete (84-96 %) [71, 72]. As gaboxadol is a zwitterionic compound with pKa values of 4.31 and 8.13 [46] and a logDpH 7.4 value of -2.37 (unpublished data), the physicochemical data of the compound indicates that the intestinal transport may require the action of one or more membrane transporters. Also, the plasma protein binding of gaboxadol is low (< 15 %) in rodents [73] and less than 2 % in humans [74]. | url-access = subscription }}</ref><ref name="Chu_2009">{{cite journal | vauthors = Chu XY, Liang Y, Cai X, Cuevas-Licea K, Rippley RK, Kassahun K, Shou M, Braun MP, Doss GA, Anari MR, Evers R | title = Metabolism and renal elimination of gaboxadol in humans: role of UDP-glucuronosyltransferases and transporters | journal = Pharmaceutical Research | volume = 26 | issue = 2 | pages = 459–468 | date = February 2009 | pmid = 19082692 | doi = 10.1007/s11095-008-9799-5 }}</ref><ref name="LundHelboeMengel2006">Lund, J., Helboe, T., & Mengel, H. (2006, January). Absorption, metabolism and excretion profile of gaboxadol in humans. In Sleep (Vol. 29, pp. A41-A41). https://scholar.google.com/scholar?cluster=17960150700023416661 https://sleepmeeting.org/wp-content/uploads/2018/10/abstractbook2006.pdf#page=71</ref><ref name="Schultz_1981">{{cite journal | vauthors = Schultz B, Aaes-Jørgensen T, Bøgesø KP, Jørgensen A | title = Preliminary studies on the absorption, distribution, metabolism, and excretion of THIP in animal and man using 14C-labelled compound | journal = Acta Pharmacologica et Toxicologica | volume = 49 | issue = 2 | pages = 116–124 | date = August 1981 | pmid = 7336969 | doi = 10.1111/j.1600-0773.1981.tb00879.x }}</ref> It is a zwitterionic compound and its absorption involves active transport via intestinal transporters such as the proton-coupled amino acid transporter 1 (PAT-1).<ref name="Frlund_2013" /><ref name="Frlund_2011">{{cite journal | vauthors = Frølund S, Rapin N, Nielsen CU | title = Gaboxadol has affinity for the proton-coupled amino acid transporter 1, SLC36A1 (hPAT1)--A modelling approach to determine IC(50) values of the three ionic species of gaboxadol | journal = European Journal of Pharmaceutical Sciences | volume = 42 | issue = 3 | pages = 192–198 | date = February 2011 | pmid = 21112392 | doi = 10.1016/j.ejps.2010.11.009 }}</ref> 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%.<ref name="Frlund_2013" /><ref name="Larsen_2009">{{cite journal | vauthors = Larsen M, Holm R, Jensen KG, Brodin B, Nielsen CU | title = Intestinal gaboxadol absorption via PAT1 (SLC36A1): modified absorption in vivo following co-administration of L-tryptophan | journal = British Journal of Pharmacology | volume = 157 | issue = 8 | pages = 1380–1389 | date = August 2009 | pmid = 19594759 | pmc = 2765307 | doi = 10.1111/j.1476-5381.2009.00253.x }}</ref><ref name="Larsen_2010">{{cite journal | vauthors = Larsen M, Holm R, Jensen KG, Sveigaard C, Brodin B, Nielsen CU | title = 5-Hydroxy-L-tryptophan alters gaboxadol pharmacokinetics in rats: involvement of PAT1 and rOat1 in gaboxadol absorption and elimination | journal = European Journal of Pharmaceutical Sciences | volume = 39 | issue = 1–3 | pages = 68–75 | date = January 2010 | pmid = 19900542 | doi = 10.1016/j.ejps.2009.10.013 }}</ref> However, they may simply delay the absorption of gaboxadol and decrease peak levels.<ref name="Frlund_2013" /> In contrast to the case of the PAT-1, the drug is not a substrate of the proton-coupled di-/tripeptide transporter (PepT-1).<ref name="Frlund_2013" /> The oral bioavailability of gaboxadol is approximately 92%.<ref name="ShadleRainakrishnanGargano2006">Shadle, C., Rainakrishnan, R., Gargano, C., Fu, I., Luo, R., Alexander, R., Agrawal, N., Lates, C., Ballow, C., & Blum, R. (2006). Assessment of dose proportionality, absolute bioavailability, and tolerability of gaboxadol in healthy young adults. ''Sleep'', ''29'', A40–A41. https://scholar.google.com/scholar?cluster=5888484280122284390 https://sleepmeeting.org/wp-content/uploads/2018/10/abstractbook2006.pdf#page=70</ref> Peak levels of gaboxadol are reached 15 to 60{{nbsp}}minutes after an oral dose.<ref name="Frlund_2013" /><ref name="Deacon_2007" /><ref name="KrogsgaardLarsen_1984">{{cite journal | vauthors = Krogsgaard-Larsen P | title = THIP, a specific and clinically active GABA agonist | journal = Neuropharmacology | volume = 23 | issue = 7 | pages = 837–838 | date = 1984 | doi = 10.1016/0028-3908(84)90272-7 | url = https://linkinghub.elsevier.com/retrieve/pii/0028390884902727 | access-date = 22 September 2025 | url-access = subscription }}</ref> Gaboxadol levels increase linearly or dose-proportionally over a dose range of 2.5 to 20{{nbsp}}mg orally.<ref name="ShadleRainakrishnanGargano2006" />

====Distribution==== The distribution of gaboxadol has been studied in rodents.<ref name="Moroni_1982" /> It penetrates the blood–brain barrier and hence is centrally active unlike γ-aminobutyric acid (GABA).<ref name="Wafford_2006" /><ref name="Frlund_2002" /><ref name="HoehnSaric_1983" /> The drug enters the brain in amounts that are 30 to 100{{nbsp}}times higher than those of muscimol given at the same dose in rodents and hence shows greater blood–brain barrier permeability in comparison.<ref name="Moroni_1982" /> In addition, whereas 90% of the muscimol in the brain is in the form of metabolites in rodents, 80% of the gaboxadol in the brain is in unchanged form.<ref name="Moroni_1982" /> It is unknown which transporters are involved in the transport of gaboxadol across the blood–brain barrier or if it simply crosses into the brain via passive diffusion, although the latter may be more likely.<ref name="Frlund_2013" /><ref name="Cremers_2007">{{cite journal | vauthors = Cremers T, Ebert B | title = Plasma and CNS concentrations of Gaboxadol in rats following subcutaneous administration | journal = European Journal of Pharmacology | volume = 562 | issue = 1–2 | pages = 47–52 | date = May 2007 | pmid = 17362924 | doi = 10.1016/j.ejphar.2007.01.017 | quote = Using both methods, we observed that Gaboxadol penetrates the brain extensively. After the initial redistribution of Gaboxadol in plasma and CNS, the concentrations and elimination from these two compartments seemed to follow similar parameters. Since no particular transporters of Gaboxadol over the blood brain barrier have been identified, it is likely that passive diffusion alone can account for the CNS pharmacokinetics. The protein binding that was observed in the present study was below 15%. This is similar to the binding in humans (Lund et al., 2006). When plasma levels are corrected for protein binding, the data further confirm the passive penetration of Gaboxadol in the brain, which is apparent when free plasma and brain levels reach unity after an initial equilibration stage (De Lange et al., 2000). In all, these data, indicate that Gaboxadol readily penetrates the brain and suggest that the concentration determined in the brain is a direct reflection of the concentration available for receptor interaction. }}</ref> The drug is distributed unevenly in the brain in rodents.<ref name="Moroni_1982" /> The volume of distribution of gaboxadol at steady state is approximately 55{{nbsp}}L.<ref name="ShadleRainakrishnanGargano2006" /> The plasma protein binding of gaboxadol in humans is very low at less than 2%.<ref name="Frlund_2013" /><ref name="Chu_2009" />

====Metabolism==== Gaboxadol is metabolized by ''O''-glucuronidation mainly via the enzyme UGT1A9 into gaboxadol-''O''-glucuronide.<ref name="Frlund_2013" /> To a lesser extent, UGT1A6, UGT1A7, and UGT1A8 also catalyze the formation of this metabolite.<ref name="Chu_2009" /> Unlike muscimol, gaboxadol is not a substrate for GABA transaminase (GABA-T) and does not undergo transamination.<ref name="Moroni_1982">{{cite journal | vauthors = Moroni F, Forchetti MC, Krogsgaard-Larsen P, Guidotti A | title = Relative disposition of the GABA agonists THIP and muscimol in the brain of the rat | journal = The Journal of Pharmacy and Pharmacology | volume = 34 | issue = 10 | pages = 676–678 | date = October 1982 | pmid = 6128395 | doi = 10.1111/j.2042-7158.1982.tb04702.x | quote = THIP is a bicyclic analogue of muscimol with a somewhat weaker intrinsic GABA agonist activity. However THIP, in contrast to muscimol, is not substrate for the GABA reuptake process (Krogsgaard-Larsen et al 1977) and has a low toxicity in various animal species. In acute and chronic toxicological studies THIP is well tolerated by rats, dogs, and baboons (Krogsgaard-Larsen & Christensen 1980).}}</ref><ref name="US4278676" /> Similarly, it is not a substrate for glutamate decarboxylase.<ref name="US4278676" /> The drug is said in general to be more resistant to metabolism than muscimol.<ref name="Frlund_2002">{{cite journal | vauthors = Frølund B, Ebert B, Kristiansen U, Liljefors T, Krogsgaard-Larsen P | title = GABA(A) receptor ligands and their therapeutic potentials | journal = Current Topics in Medicinal Chemistry | volume = 2 | issue = 8 | pages = 817–832 | date = August 2002 | pmid = 12171573 | doi = 10.2174/1568026023393525 | quote = The fact that muscimol is a non-specific GABAA receptor agonist [38, 39], a substrate for the GABA-metabolizing enzyme, GABA transaminase [40], and moreover a neurotoxin, makes the compound therapeutically less valuable. [...] Further conformational restriction of the GABA structural element in muscimol has been achieved by incorporating the amino group into a piperidine ring leading to the bicyclic analogue, THIP, a specific GABAA agonist [11]. THIP has been shown to be devoid of the neurotoxic properties of muscimol and, in contrast to muscimol, is metabolically stable. }}</ref><ref name="KrogsgaardLarsen_1981">{{cite journal | vauthors = Krogsgaard-Larsen P, Brehm L, Schaumburg K | title = Muscimol, a psychoactive constituent of Amanita muscaria, as a medicinal chemical model structure | journal = Acta Chemica Scandinavica B | volume = 35 | issue = 5 | pages = 311–324 | date = 1981 | pmid = 6274117 | doi = 10.3891/acta.chem.scand.35b-0311 }}</ref> Gaboxadol-''O''-glucuronide is the only metabolite of gaboxadol formed in significant amounts.<ref name="Deacon_2007" /> Gaboxadol is not metabolized by the cytochrome P450 system.<ref name="Deacon_2007" />

====Elimination==== Gaboxadol is excreted in urine (83–94%) mainly unchanged and partially as gaboxadol-''O''-glucuronide (34%).<ref name="Frlund_2013" /><ref name="Chu_2009" /><ref name="Deacon_2007" /><ref name="KrogsgaardLarsen_1984" /><ref name="Schultz_1981" /> It is taken up from blood into the kidneys via the organic anion transporter OAT1 (SLC22A6), while the glucuronide is effluxed into urine via the multidrug resistance protein MRP4 (ABCC4).<ref name="Frlund_2013" /><ref name="Chu_2009" /> The drug has an elimination half-life in humans of 1.5 to 2.0{{nbsp}}hours.<ref name="LundHelboeMengel2006" /><ref name="HoehnSaric_1983">{{cite journal | vauthors = Hoehn-Saric R | title = Effects of THIP on chronic anxiety | journal = Psychopharmacology | volume = 80 | issue = 4 | pages = 338–341 | date = 1983 | pmid = 6414002 | doi = 10.1007/BF00432116 | quote = THIP, a 4,5,6,7-tetrahydroisoxazolo(5,4-C)pyridin-3-ol, is a muscimol analog which exhibits specific GABA-agonists properties without affecting enzymes involved in the synthesis or the catabolism of the neurotransmitter. It is 5–15-times weaker than muscimol and substantially less toxic. THIP penetrates the blood–brain barrier and has a half-life of 1.5–2 h (H Lundbeck and Company 1981). }}</ref><ref name="Madsen_1983" /> Two{{nbsp}}hours following attainment of peak concentrations, levels of gaboxadol are reduced by about 50% in humans.<ref name="KrogsgaardLarsen_1984" /> In rodents, the half-life of gaboxadol was about twice as long as that of muscimol.<ref name="Moroni_1982" /> Despite this finding however, gaboxadol is shorter-lasting in its effects than muscimol in rats, with durations of up to 3{{nbsp}}hours and more than 5{{nbsp}}hours, respectively.<ref name="Christensen_1982" /> In people with severe renal impairment, circulating levels of gaboxadol were increased by 5-fold, and the renal clearance of gaboxadol was decreased by 34% while that of gaboxadol-''O''-glucuronide was decreased by 50%.<ref name="Chu_2009" />

==Chemistry== Gaboxadol, also known by its chemical name 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP), is a conformationally constrained synthetic analogue of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) and of the ''Amanita'' alkaloid muscimol.<ref name="KrogsgaardLarsen_2006" />

===Properties=== Gaboxadol is a zwitterion, with pKa values of 4.3 (acidic) and 8.3 (basic) and a log P value of –0.61.<ref name="Frlund_2002" /><ref name="Kesisoglou_2016">{{cite journal | vauthors = Kesisoglou F, Balakrishnan A, Manser K | title = Utility of PBPK Absorption Modeling to Guide Modified Release Formulation Development of Gaboxadol, a Highly Soluble Compound With Region-Dependent Absorption | journal = Journal of Pharmaceutical Sciences | volume = 105 | issue = 2 | pages = 722–728 | date = February 2016 | pmid = 26457884 | doi = 10.1002/jps.24674 | bibcode = 2016JPhmS.105..722K | quote = [Gaboxadol] is a zwitterion with pKa values of 4.3 (acidic) and 8.3 (basic) and log P of –0.61. It is dosed as the hydrochloride (HCl) salt. The compound solubility is more than 30 mg/mL in the physiological pH range. }}</ref> It was formulated pharmaceutically as the hydrochloride salt.<ref name="Kesisoglou_2016" /> The compound's solubility is greater than 30{{nbsp}}mg/mL at physiological pH.<ref name="Kesisoglou_2016" />

===Synthesis=== The chemical synthesis of gaboxadol has been described.<ref name="Sorbera_2004" /><ref name="RongChang2007">Rong, L., & Chang, D. (2007). Synthesis of a novel hypnotic, gaboxadol. ''Chinese Journal of Medicinal Chemistry'', ''17''(3), 166–. https://scholar.google.com/scholar?q=intitle%3A%22Synthesis+of+a+novel+hypnotic%2C+gaboxadol%22</ref><ref name="US4278676" /> Its synthesis has been described as tedious, starting with a commercially unavailable precursor, requiring at least 6{{nbsp}}synthetic steps, and having very low yields.<ref name="Morris_2013" /> This has limited the affordability and availability of gaboxadol.<ref name="Morris_2013" />

===Analogues=== Analogues of gaboxadol (THIP) include γ-aminobutyric acid (GABA), muscimol, 4-AHP, thio-THIP, aza-THIP, iso-THIP, THAZ, THPO, piperidine-4-sulfonic acid (P4S), isonipecotic acid, and isoguvacine, among others.<ref name="KrogsgaardLarsen_2004" /><ref name="KrogsgaardLarsen_2002">{{cite journal | vauthors = Krogsgaard-Larsen P, Frølund B, Liljefors T | title = Specific GABA(A) agonists and partial agonists | journal = Chemical Record | volume = 2 | issue = 6 | pages = 419–430 | date = 2002 | pmid = 12469353 | doi = 10.1002/tcr.10040 }}</ref><ref name="Frlund_2002" /><ref name="GrinbergaDamgaardAndersen2016">{{cite conference | vauthors = Grinberga S, Damgaard M, Andersen V, Jensen AA, Krogsgaard-Larsen P, Nielsen B, Waagepetersen HS, Schousboe A, Frølund B | title = Synthesis and Pharmacological Evaluation of Amidine Containing GABAA Receptor Agonists | conference = EFMC International Symposium on Medicinal Chemistry Manchester, UK Aug. 28 - Sept. 1, 2016 | date = 2016 | pages = P278 | url = https://istina.msu.ru/media/publications/article/6f5/7ea/31004876/ISMC-Book-web-1209.pdf#page=231}}</ref> Numerous attempts to develop pharmacologically interesting analogues of gaboxadol have failed over the decades.<ref name="Krogsgaard-Larsen2018" /> This can be attributed to the very strict structural requirements for GABAA receptor binding and activation.<ref name="KrogsgaardLarsen_2006" /> As such, gaboxadol has been described as a unique compound and GABAA receptor agonist.<ref name="Krogsgaard-Larsen2018" />

==History== Gaboxadol was first synthesized and described by the Danish chemist Povl Krogsgaard-Larsen in 1977.<ref name="Sorbera_2004" /><ref name="Morris_2013" /><ref name="Krogsgaard-Larsen2018" /><ref name="KrogsgaardLarsen_1977">{{cite journal | vauthors = Krogsgaard-Larsen P, Johnston GA, Lodge D, Curtis DR | title = A new class of GABA agonist | journal = Nature | volume = 268 | issue = 5615 | pages = 53–55 | date = July 1977 | pmid = 196200 | doi = 10.1038/268053a0 | bibcode = 1977Natur.268...53K }}</ref> It was patented by Krogsgaard-Larsen soon thereafter, with the patent filed in 1978 and granted in 1981 and with the assignee being Lundbeck.<ref name="US4278676">{{cite patent | country = US | number = 4278676 | inventor = Povl Krogsgaard-Larsen | status = patent | title = Heterocyclic compounds | pubdate = 14 July 1981 | gdate = 14 July 1981 | fdate = 19 June 1978 | pridate = | assign1 = H Lundbeck AS | url = https://patentimages.storage.googleapis.com/2b/88/bb/6a13ba350cdb8c/US4278676.pdf | quote = However, unfortunately, muscimol has toxic effects, such as narcotic effects (derealisation and depersonalisation), and the difference between the effective dose and the toxic dose of muscimol is very small (Arzneimittelforschung, 1968, 18, 311-315), which may limit or prevent the therapeutic use of muscimol. Furthermore, it would be highly desirable to provide a substance having a more specific GABA activity than muscimol which, as mentioned above, shows considerable GABA-uptake inhibitor activity in addition to its GABA agonist activity. [...] [Gaboxadol] has been shown to be a well-tolerated substance: [Acute Toxicity (Mice) LD50 mg/kg Table] Thus, [gaboxadol] is considerably less toxic than muscimol. [...] Based on these experiments, [gaboxadol] has been shown to be a potent GABA agonist. [Gaboxadol] is weaker than muscimol but considerably less toxic.}}</ref> The drug was developed via structural modification of muscimol, a constituent of ''Amanita muscaria'' mushrooms.<ref name="KrogsgaardLarsen_2004" /><ref name="Johnston_2014" /><ref name="RiveraIllanes_2024" /> In the early 1980s, gaboxadol was the subject of a series of small pilot clinical studies that evaluated it in the treatment of various medical conditions, but it was not found to be sufficiently useful in these studies.<ref name="Morris_2013" /><ref name="Krogsgaard-LarsenFrølundKristiansen2001" />

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.<ref name="Morris_2013" /><ref name="Krogsgaard-Larsen2018" /><ref name="Miller_2013">{{cite book | vauthors = Miller R | title = Drugged: The Science and Culture Behind Psychotropic Drugs | year = 2013 | publisher = Oxford University Press | series = EBL ebooks online | isbn = 978-0-19-995798-9 | url = https://books.google.com/books?id=k808BAAAQBAJ | access-date = 5 October 2025 }}</ref><ref name="Lancel_1997">{{cite journal | vauthors = Lancel M | title = The GABA(A) agonist THIP increases non-REM sleep and enhances non-REM sleep-specific delta activity in the rat during the dark period | journal = Sleep | volume = 20 | issue = 12 | pages = 1099–1104 | date = December 1997 | pmid = 9493918 | doi = 10.1093/sleep/20.12.1099 }}</ref> 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.<ref name="Wafford_2006" /><ref name="Morris_2013" /><ref name="Faulhaber_1997">{{cite journal | vauthors = Faulhaber J, Steiger A, Lancel M | title = The GABAA agonist THIP produces slow wave sleep and reduces spindling activity in NREM sleep in humans | journal = Psychopharmacology | volume = 130 | issue = 3 | pages = 285–291 | date = April 1997 | pmid = 9151364 | doi = 10.1007/s002130050241 }}</ref> Subsequently, gaboxadol underwent formal clinical development for treatment of insomnia by Lundbeck and Merck.<ref name="AdisInsight" /><ref name="Morris_2013" /><ref name="Sorbera_2004" /> It reached phase 3 trials for this indication by at least 2004.<ref name="Sorbera_2004" /> The drug was expected to be a blockbuster drug for its pharmaceutical developers.<ref name="Saul_2007">{{cite web | vauthors = Saul S | title = Merck Cancels Work on a New Insomnia Medication | date = 29 March 2007 | website = The New York Times | url = https://www.nytimes.com/2007/03/29/business/29sleep.html | archive-url = https://archive.today/20251005022703/https://www.nytimes.com/2007/03/29/business/29sleep.html | archive-date = 5 October 2025 }}</ref><ref name="Miller_2013" /><ref name="Reuters2007" />

In 2007, the development of gaboxadol was terminated by Lundbeck and Merck.<ref name="AdisInsight" /><ref name="Reuters2007">{{cite web | title = Merck, Lundbeck scrap insomnia drug after trials | date = 9 August 2007 | website = Reuters | url = https://www.reuters.com/article/business/merck-lundbeck-scrap-insomnia-drug-after-trials-idUSN28285490/ | access-date = 30 September 2025 }}</ref><ref name="PharmaTimes2007" /> They cited lack of effectiveness in a large 3-month clinical trial, the occurrence of high rates of psychiatric adverse effects at supratherapeutic doses in a misuse liability study with drug users, a frequent incidence of tachycardia at therapeutic doses, and other reasons.<ref name="Morris_2013" /><ref name="Reuters2007" /><ref name="Frlund_2013" /><ref name="Lundbeck_2007">{{cite web | vauthors = Lundbeck | title = Discontinuation of development program for gaboxadol in insomnia: Teleconference 28 March 2007 | date = 28 March 2007 | url = https://www.lundbeck.com/investor/Presentations/Teleconference/Teleconference_gaboxadol_20070328.pdf | archive-url = https://web.archive.org/web/20071017080433/https://www.lundbeck.com/investor/Presentations/Teleconference/Teleconference_gaboxadol_20070328.pdf | archive-date = 17 October 2007 }}</ref> 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.<ref name="Morris_2013" /> This may have resulted in greater concern about potential liability issues.<ref name="Morris_2013" /> Merck was also struggling with recent litigation from its drug rofecoxib (Vioxx), which may have made it further averse to liability.<ref name="Morris_2013" /><ref name="Miller_2013" /> When presented with the data on the hallucinogenic effects of high doses of gaboxadol, a Merck executive remarked "looks like LSD to me!"<ref name="Miller_2013" /> A New Drug Application (NDA) was ultimately never submitted to the United States Food and Drug Administration (FDA).<ref name="Miller_2013" /><ref name="PharmaTimes2007">{{cite web | title = Merck & Co and Lundbeck's sleep drug terminated in Phase III | date = 29 March 2007 | website = PharmaTimes | url = https://pharmatimes.com/news/merck_and_co_and_lundbecks_sleep_drug_terminated_in_phase_iii_989624/ | access-date = 5 October 2025 | quote = The firms said they are discontinuing studies of the because data from recently-completed Phase III studies suggest that the overall clinical profile for gaboxadol in insomnia does not support further development. As a result of this new information, Merck and Lundbeck added that they will not file gaboxadol with the US Food and Drug Administration, or any other regulatory agencies worldwide, and are terminating the project. [...] “new safety data showed a dramatic increase in psychiatric adverse events at doses as low as twice the recommended dose, raising the possibility of real safety issues in sleep-drug abusers.” Although earlier trials showed effectiveness in sleep onset and maintenance, the drug failed to do either in the latest trials, Mr Tooley wrote, noting that a recent sleep lab study failed to show sufficient effects at lower doses. }}</ref><ref name="Reuters2007" /> Many of the companies' employees were said to have been surprised and confused by the discontinuation<ref name="Thulin_2013" /> and the decision is still critically debated.<ref name="Krogsgaard-Larsen2018" />

Journalist and scientist Hamilton Morris published a notable exposé on gaboxadol in Harper's Magazine in 2013, including his self-experimentation with the drug.<ref name="Brickley_2018" /><ref name="Wisden_2019" /><ref name="Morris_2013" /> According to Morris, the discontinuation of gaboxadol's late-stage development may have deprived people with insomnia access to an effective, safe, and non-addictive treatment.<ref name="Morris_2013" /> In addition, Morris has critiqued the pharmaceutical industry as being more interested in selling minimally effective drugs devoid of side effects than medications with real therapeutic effects but a higher risk of litigation.<ref name="Morris_2013" />

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).<ref name="AdisInsight">{{cite web | title = Gaboxadol - Lundbeck A/S | date = 15 March 2023 | website = AdisInsight | url = https://adisinsight.springer.com/drugs/800014543 | access-date = 14 February 2025 }}</ref><ref name="Tirrell_2015">{{cite web | vauthors = Tirrell M | title = Former Teva CEO's new gig at Ovid Therapeutics | date = 16 April 2015 | url = https://www.cnbc.com/2015/04/16/former-teva-ceos-new-gig-at-ovid-therapeutics.html | publisher = CNBC | access-date = 2015-05-06 }}</ref> It was known internally at Ovid Therapeutics under the developmental code name OV101.<ref name="AdisInsight" /> In 2021, development of gaboxadol for Angelman syndrome and fragile X syndrome was discontinued due to lack of effectiveness.<ref name="AdisInsight" /><ref name="Shapiro_2023" /><ref name="Pinto_2021" /> However, another company appears to be continuing the development of gaboxadol for fragile X syndrome.<ref name="Synapse" /><ref name="NCT04823052" /><ref name="NCT06334419" />

Gaboxadol was encountered as a novel designer drug in Canada in the early 2020s.<ref name="Rymill_2025">{{cite journal | vauthors = Rymill S, Candler L, Ramachandran P, Bacev-Giles C, Ngendabanka RJ, Racine S, He N, Ross M, Mohottalage S | title = New psychoactive substances (NPS) identified in Canada: Results of the online NPS survey (2020–2023) | journal = Emerging Trends in Drugs, Addictions, and Health | volume = 5 | article-number = 100178 | date = 2025 | doi = 10.1016/j.etdah.2025.100178 | url = https://linkinghub.elsevier.com/retrieve/pii/S2667118225000091 | access-date = 5 January 2026 | doi-access = free }}</ref>

==Society and culture== ===Names=== ''Gaboxadol'' is the generic name of the drug and its {{Abbrlink|INN|International Nonproprietary Name}} and {{Abbrlink|USAN|United States Adopted Name}}.<ref name="Sorbera_2004" /><ref name="InxightDrugs">{{cite web | title = GABOXADOL | date = 15 February 2008 | website = Inxight Drugs | url = https://drugs.ncats.io/substance/K1M5RVL18S | access-date = 4 October 2025 }}</ref> It is also known by its former developmental code names ''Lu-2-030'' or ''Lu-02-030'' (Lundbeck), ''MK-0928'' (Merck), and ''OV101'' (Ovid Therapeutics).<ref name="Sorbera_2004" /><ref name="AdisInsight" /> In addition, gaboxadol is well known in the scientific literature by its chemical name ''4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol'' (''THIP'').<ref name="KrogsgaardLarsen_2006" /><ref name="Christensen_1982">{{cite journal | vauthors = Christensen AV, Svendsen O, Krogsgaard-Larsen P | title = Pharmacodynamic effects and possible therapeutic uses of THIP, a specific GABA-agonist | journal = Pharmaceutisch Weekblad. Scientific Edition | volume = 4 | issue = 5 | pages = 145–153 | date = October 1982 | pmid = 6292818 | doi = 10.1007/BF01959034 | quote = Compared to muscimol, THIP is generally less potent in the rat. Figure 7 indicates the dose-response-effect of THIP in rats. THIP is active for up to 3 h whereas comparable doses of morphine and muscimol have an effect over 5 h. However, in the rhesus monkey (HILL et al. 1981), the duration of action of THIP is between 4 and 5 h with a maximal effect being reached within 60-90 min.}}</ref>

===Media coverage=== Gaboxadol was covered, along with muscimol and ''Amanita muscaria'', in an episode of Hamilton Morris's ''Hamilton's Pharmacopeia''.<ref name="Morris2018-S02E07" /><ref name="McCarthy_2022">{{cite web | vauthors = McCarthy B | title = The Trippy Truth About Amanita muscaria, the World's Most Famous Mushroom | date = 8 October 2022 | website = DoubleBlind Mag | url = https://doubleblindmag.com/amanita-muscaria/ | access-date = 4 October 2025 | quote = Also of interest is Hamilton Morris’ Pharmacopeia episode on Amanita and his Harper’s article on one of its constituents I didn’t cover here, gaboxadol. }}</ref>

===Notable individuals=== Povl Krogsgaard-Larsen and Hamilton Morris have both self-experimented with gaboxadol.<ref name="Wisden_2019" /><ref name="Morris_2013" /><ref name="Morris2018-S02E07" /><ref name="MorrisKrogsgaard-Larsen2021" /><ref name="MorrisGallimore2022" /> Morris has described gaboxadol as the "perfect hypnotic" and as the "best hypnotic" he'd ever tried, but also found that it produced strong hallucinogenic effects at high doses.<ref name="Wisden_2019" /><ref name="Thulin_2013">{{cite web | vauthors = Thulin L | title = Speaking with Psychonaut Hamilton Morris about sleep | date = 7 August 2013 | website = New York Daily News | url = https://www.nydailynews.com/2013/08/07/speaking-with-psychonaut-hamilton-morris-about-sleep/ | access-date = 4 October 2025 }}</ref><ref name="Morris_2013" /><ref name="Morris2018-S02E07" /><ref name="MorrisKrogsgaard-Larsen2021" /><ref name="MorrisGallimore2022" />

===Grey market use=== Gaboxadol has been obtained rarely from the grey market, for instance from China, for hypnotic and hallucinogenic purposes.<ref name="Morris_2013" /><ref name="Thulin_2013" /><ref name="Morris2018-S02E07" /><ref name="MorrisKrogsgaard-Larsen2021" /><ref name="MorrisGallimore2022" />

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.<ref name="RiveraIllanes_2024" /><ref name="Stebelska_2013">{{cite journal | vauthors = Stebelska K | title = Fungal hallucinogens psilocin, ibotenic acid, and muscimol: analytical methods and biologic activities | journal = Therapeutic Drug Monitoring | volume = 35 | issue = 4 | pages = 420–442 | date = August 2013 | pmid = 23851905 | doi = 10.1097/FTD.0b013e31828741a5 }}</ref> 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.<ref name="RiveraIllanes_2024" /><ref name="Savickaite_2025">{{cite journal | vauthors = Savickaitė E, Laubner-Sakalauskienė G | title = Emerging Risks of Amanita Muscaria: Case Reports on Increasing Consumption and Health Risks | journal = Acta Medica Lituanic | volume = 32 | issue = 1 | pages = 182–189 | date = 2025 | pmid = 40641545 | pmc = 12239171 | doi = 10.15388/Amed.2025.32.1.23 }}</ref><ref name="Hartwig_2025">{{cite journal | vauthors = Hartwig J, Kendrick J, Ahmad G, Cook J, Matthews DB, Sharma P | title = Exploring User Experiences with ''Amanita muscaria'': A Thematic Analysis of Reddit Online Forum Discussions | journal = Substance Use & Misuse | volume = 60 | issue = 7 | pages = 952–961 | date = 2025 | pmid = 40057818 | doi = 10.1080/10826084.2025.2476141 | quote = The commonly reported reason for Amanita muscaria use was to improve sleep. }}</ref> However, muscimol is far less-researched compared to gaboxadol,<ref name="RiveraIllanes_2024" /> and is less selective and said to be much more toxic in comparison.<ref name="Frlund_2002" /><ref name="KrogsgaardLarsen_2004" /><ref name="KrogsgaardLarsen_1981" /><ref name="Morris_2013" /><ref name="US4278676" /> 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.<ref name="MichelotMelendez-Howell2003">{{cite journal | vauthors = Michelot D, Melendez-Howell LM | title = Amanita muscaria: chemistry, biology, toxicology, and ethnomycology | journal = Mycol Res | volume = 107 | issue = Pt 2 | pages = 131–146 | date = February 2003 | pmid = 12747324 | doi = 10.1017/s0953756203007305 | bibcode = 2003MycR..107..131M | url = https://www.davidmoore.org.uk/21st_Century_Guidebook_to_Fungi_PLATINUM/REPRINT_collection/Michelot_etal_A.muscaria_chemistry_biology_toxicology.pdf }}</ref><ref name="Morris2018-S02E07" /> Povl Krogsgaard-Larsen has warned about safety concerns with regard to medicinal use of ''Amanita'' mushrooms.<ref name="Morris2018-S02E07" />

===Legal status=== Gaboxadol is not a controlled substance anywhere in the world. If it had been approved and introduced as a pharmaceutical drug in the United States, it was expected that it would have been designated a Schedule IV controlled substance.<ref name="Miller_2013" /><ref name="Reuters2007" /><ref name="Lundbeck_2007" />

==Research== Gaboxadol was studied in the 1980s by Lundbeck and others in the treatment of a variety of medical conditions,<ref name="Krogsgaard-Larsen2018" /><ref name="Wafford_2006" /><ref name="Wisden_2019" /><ref name="KrogsgaardLarsen_2006" /><ref name="Morris_2013" /> including pain,<ref name="Maugh_1981">{{cite journal | vauthors = Maugh TH | title = Analgesic from mushrooms begins clinical trials | journal = Science | volume = 212 | issue = 4493 | pages = 431 | date = April 1981 | pmid = 7010604 | doi = 10.1126/science.212.4493.431.c }}</ref> anxiety,<ref name="HoehnSaric_1983" /> mania,<ref name="Emrich_1983">{{cite journal | vauthors = Emrich HM, Altmann H, Dose M, von Zerssen D | title = Therapeutic effects of GABA-ergic drugs in affective disorders. A preliminary report | journal = Pharmacology, Biochemistry, and Behavior | volume = 19 | issue = 2 | pages = 369–372 | date = August 1983 | pmid = 6415677 | doi = 10.1016/0091-3057(83)90067-9 }}</ref> schizophrenia and tardive dyskinesia,<ref name="Korsgaard_1982">{{cite journal | vauthors = Korsgaard S, Casey DE, Gerlach J, Hetmar O, Kaldan B, Mikkelsen LB | title = The effect of tetrahydroisoxazolopyridinol (THIP) in tardive dyskinesia: a new gamma-aminobutyric acid agonist | journal = Archives of General Psychiatry | volume = 39 | issue = 9 | pages = 1017–1021 | date = September 1982 | pmid = 6126170 | doi = 10.1001/archpsyc.1982.04290090021005 }}</ref><ref name="Thaker_1987">{{cite journal | vauthors = Thaker GK, Tamminga CA, Alphs LD, Lafferman J, Ferraro TN, Hare TA | title = Brain gamma-aminobutyric acid abnormality in tardive dyskinesia. Reduction in cerebrospinal fluid GABA levels and therapeutic response to GABA agonist treatment | journal = Archives of General Psychiatry | volume = 44 | issue = 6 | pages = 522–529 | date = June 1987 | pmid = 3034188 | doi = 10.1001/archpsyc.1987.01800180032006 }}</ref> epilepsy,<ref name="Petersen_1983">{{cite journal | vauthors = Petersen HR, Jensen I, Dam M | title = THIP: a single-blind controlled trial in patients with epilepsy | journal = Acta Neurologica Scandinavica | volume = 67 | issue = 2 | pages = 114–117 | date = February 1983 | pmid = 6845976 | doi = 10.1111/j.1600-0404.1983.tb04552.x }}</ref> Huntington's disease,<ref name="Foster_1983">{{cite journal | vauthors = Foster NL, Chase TN, Denaro A, Hare TA, Tamminga CA | title = THIP treatment of Huntington's disease | journal = Neurology | volume = 33 | issue = 5 | pages = 637–639 | date = May 1983 | pmid = 6221200 | doi = 10.1212/wnl.33.5.637 }}</ref> and Alzheimer's disease.<ref name="Mohr_1986">{{cite journal | vauthors = Mohr E, Bruno G, Foster N, Gillespie M, Cox C, Hare TA, Tamminga C, Fedio P, Chase TN | title = GABA-agonist therapy for Alzheimer's disease | journal = Clinical Neuropharmacology | volume = 9 | issue = 3 | pages = 257–263 | date = 1986 | pmid = 2872956 | doi = 10.1097/00002826-198606000-00004 }}</ref> It showed poor clinical effectiveness as an anticonvulsant, in accordance with prior animal studies.<ref name="Krogsgaard-Larsen2018">{{cite book | vauthors = Krogsgaard-Larsen P | title=Reference Module in Biomedical Sciences | chapter=THIP/Gaboxadol, a Unique GABA Agonist | publisher=Elsevier | date=2018 | isbn=978-0-12-801238-3 | doi=10.1016/b978-0-12-801238-3.97290-8 | chapter-url=https://linkinghub.elsevier.com/retrieve/pii/B9780128012383972908}}</ref><ref name="Petersen_1983" /> In addition, it had only weak anxiolytic effects in humans and at doses that were accompanied by substantial side effects.<ref name="Krogsgaard-Larsen2018" /><ref name="HoehnSaric_1983" /> On the other hand, gaboxadol was found to be an effective analgesic in some patients and was equipotent to morphine in these individuals.<ref name="Krogsgaard-Larsen2018" /> Moreover, it lacked the respiratory depression and other characteristic adverse effects of morphine.<ref name="Krogsgaard-Larsen2018" /> However, gaboxadol was ultimately not further developed due to its pronounced sedative and other side effects.<ref name="Krogsgaard-Larsen2018" /><ref name="HoehnSaric_1983" />

Later on, in the 1990s and 2000s, gaboxadol was developed for the treatment of insomnia and reached phase 3 clinical trials for this indication.<ref name="Wafford_2006" /><ref name="Sorbera_2004" /><ref name="Faulhaber_1997"/><ref name="Morris_2013" /> However, development was discontinued in 2007 for safety and effectiveness reasons.<ref name="AdisInsight" /><ref name="Frlund_2013" /><ref name="Wisden_2019" /><ref name="Morris_2013" /> Multiple large phase 3 trials were completed and published.<ref name="Wisden_2019" /><ref name="Lankford_2008">{{cite journal | vauthors = Lankford DA, Corser BC, Zheng YP, Li Z, Snavely DB, Lines CR, Deacon S | title = Effect of gaboxadol on sleep in adult and elderly patients with primary insomnia: results from two randomized, placebo-controlled, 30-night polysomnography studies | journal = Sleep | volume = 31 | issue = 10 | pages = 1359–1370 | date = October 2008 | pmid = 18853933 | pmc = 2572741 }}</ref><ref name="Roth_2010">{{cite journal | vauthors = Roth T, Lines C, Vandormael K, Ceesay P, Anderson D, Snavely D | title = Effect of gaboxadol on patient-reported measures of sleep and waking function in patients with Primary Insomnia: results from two randomized, controlled, 3-month studies | journal = Journal of Clinical Sleep Medicine | volume = 6 | issue = 1 | pages = 30–39 | date = February 2010 | pmid = 20191935 | pmc = 2823273 | doi = 10.5664/jcsm.27707 | quote = Gaboxadol is no longer in clinical development for the treatment of insomnia based on an assessment of its overall clinical profile in phase 3 trials, including those reported here, which suggested limited or variable efficacy, and also the occurrence of psychiatric side effects at supra-therapeutic doses in an abuse liability study involving drug abusers.11,12 [...] 11. Lundbeck. Discontinuation of development program for gaboxadol in insomnia. H. Lundbeck website. [...] March 27, 2007. Accessed May 26, 2009. 12. Schoedel KA, Rosen LB, Alexander R, et al. A single-dose randomized, double-blind, crossover abuse liability study to evaluate the subjective and objective effects of gaboxadol and zolpidem in recreational drug users. Clin Pharmacol Ther 2009; 85 (Suppl 1):S22. Abstract PI-44. }}</ref><ref name="Lundbeck_2007" /> As a result, gaboxadol was not approved and will likely never be used as a hypnotic commercially.<ref name="Wisden_2019" /> There has been some further study of gaboxadol as a hypnotic by David Nutt and colleagues after the discontinuation of its development.<ref name="Nutt_2025">{{cite journal | vauthors = Nutt DJ | title = Drug development in psychiatry: 50 years of failure and how to resuscitate it | journal = The Lancet. Psychiatry | volume = 12 | issue = 3 | pages = 228–238 | date = March 2025 | pmid = 39952266 | doi = 10.1016/S2215-0366(24)00370-5 }}</ref><ref name="Nutt_2015">{{cite journal | vauthors = Nutt D, Wilson S, Lingford-Hughes A, Myers J, Papadopoulos A, Muthukumaraswamy S | title = Differences between magnetoencephalographic (MEG) spectral profiles of drugs acting on GABA at synaptic and extrasynaptic sites: a study in healthy volunteers | journal = Neuropharmacology | volume = 88 | pages = 155–163 | date = January 2015 | pmid = 25195191 | doi = 10.1016/j.neuropharm.2014.08.017 }}</ref> The drug was also studied for treatment of major depressive disorder in combination with escitalopram in a phase 2 trial, but was ineffective.<ref name="Pehrson_2015">{{cite journal | vauthors = Pehrson AL, Sanchez C | title = Altered γ-aminobutyric acid neurotransmission in major depressive disorder: a critical review of the supporting evidence and the influence of serotonergic antidepressants | journal = Drug Design, Development and Therapy | volume = 9 | pages = 603–624 | date = 2015 | pmid = 25653499 | pmc = 4307650 | doi = 10.2147/DDDT.S62912 | quote = Another line of inquiry may be drugs that act as agonists at the GABAA-receptor orthosteric binding site. Although preclinical data suggested that the combination of gaboxadol and escitalopram had synergistic antidepressant-like effects in nonclinical models,90 in a clinical trial 5 and 10 mg gaboxadol did not add any benefit over escitalopram treatment alone.91 | doi-access = free }}</ref><ref name="Morris_2013" /><ref name="Kasper_2012">{{cite journal | vauthors = Kasper S, Ebert B, Larsen K, Tonnoir B | title = Combining escitalopram with gaboxadol provides no additional benefit in the treatment of patients with severe major depressive disorder | journal = The International Journal of Neuropsychopharmacology | volume = 15 | issue = 6 | pages = 715–725 | date = July 2012 | pmid = 22008735 | doi = 10.1017/S146114571100112X }}</ref>

Following discontinuation of its development for insomnia, gaboxadol was repurposed by Ovid Therapeutics for treatment of the Angelman syndrome and fragile X syndrome.<ref name="AdisInsight" /><ref name="Brickley_2018" /><ref name="Keary_2023">{{cite journal | vauthors = Keary C, Bird LM, de Wit MC, Hatti S, Heimer G, Heussler H, Kolevzon A, Mathews A, Ochoa-Lubinoff C, Tan WH, Yan Y, Adams M | title = Gaboxadol in angelman syndrome: A double-blind, parallel-group, randomized placebo-controlled phase 3 study | journal = European Journal of Paediatric Neurology | volume = 47 | pages = 6–12 | date = November 2023 | pmid = 37639777 | doi = 10.1016/j.ejpn.2023.07.008 }}</ref><ref name="Bird_2021">{{cite journal | vauthors = Bird LM, Ochoa-Lubinoff C, Tan WH, Heimer G, Melmed RD, Rakhit A, Visootsak J, During MJ, Holcroft C, Burdine RD, Kolevzon A, Thibert RL | title = The STARS Phase 2 Study: A Randomized Controlled Trial of Gaboxadol in Angelman Syndrome | journal = Neurology | volume = 96 | issue = 7 | pages = e1024–e1035 | date = February 2021 | pmid = 33443117 | pmc = 8055330 | doi = 10.1212/WNL.0000000000011409 }}</ref><ref name="Budimirovic_2021">{{cite journal | vauthors = Budimirovic DB, Dominick KC, Gabis LV, Adams M, Adera M, Huang L, Ventola P, Tartaglia NR, Berry-Kravis E | title = Gaboxadol in Fragile X Syndrome: A 12-Week Randomized, Double-Blind, Parallel-Group, Phase 2a Study | journal = Frontiers in Pharmacology | volume = 12 | date = 2021 | pmid = 34690787 | pmc = 8531725 | doi = 10.3389/fphar.2021.757825 | doi-access = free | article-number = 757825 }}</ref> It reached phase 3 and phase 2 clinical trials for these conditions, respectively.<ref name="AdisInsight" /><ref name="Budimirovic_2021" /><ref name="Keary_2023" /> However, development was discontinued for these uses as well in 2021.<ref name="AdisInsight" /><ref name="Shapiro_2023">{{cite web | vauthors = Shapiro L | title = Final trial data support Ovid's decision to stop OV101 program in... | date = 23 August 2023 | website = Angelman Syndrome News | url = https://angelmansyndromenews.com/news/final-trial-data-support-ovid-decision-stop-ov101-clinical/ | access-date = 4 October 2025 }}</ref><ref name="Pinto_2021">{{cite web | vauthors = Pinto V | title = Ovid Stops Development and Testing of OV101 for Fragile X | date = 23 April 2021 | website = Fragile X News Today | url = https://fragilexnewstoday.com/news/ovid-stops-development-testing-ov101/ | access-date = 4 October 2025 }}</ref> Subsequently, another company known as Healx appears to have begun developing gaboxadol under the developmental code name ''HLX-0206'' for the treatment of fragile X syndrome.<ref name="Synapse">{{cite web | title=Delving into the Latest Updates on Gaboxadol with Synapse | website=Synapse | date=13 September 2025 | url=https://synapse.patsnap.com/drug/0ed63c425f3a43d0b7c416b2095171a7 | access-date=7 November 2025}}</ref><ref name="NCT04823052">{{cite journal | title=ClinicalTrials.gov | website=ClinicalTrials.gov | date=7 December 2022 | url=https://www.clinicaltrials.gov/study/NCT04823052 | access-date=7 November 2025}}</ref><ref name="NCT06334419">{{cite web | title=ClinicalTrials.gov | website=ClinicalTrials.gov | url=https://www.clinicaltrials.gov/study/NCT06334419 | access-date=7 November 2025}}</ref>

==References== {{Reflist}}

==External links== * {{MeshName|gaboxadol}} * [https://isomerdesign.com/pihkal/explore/646 Gaboxadol - Isomer Design] * [https://psychonautwiki.org/wiki/Gaboxadol Gaboxadol - PsychonautWiki] * [https://www.bluelight.org/community/threads/gaboxadol.370965/ Gaboxadol - Bluelight] * [https://erowid.org/experiences/subs/exp_Gaboxadol.shtml Gaboxadol Reports - Erowid Experience Vaults - Erowid] * [https://podclips.com/c/2pmbr8 Hamilton Morris Describes Taking Gaboxadol as an 'Unexpected Delirium' - How To Sell Drugs (Episode 3) - Lucy Podcast] * [https://alieninsect.substack.com/p/why-is-the-fly-agaric-psychedelic Why is the Fly Agaric <nowiki>[</nowiki>and Gaboxadol<nowiki>]</nowiki> Psychedelic? - Alien Insect on Drugs (Andrew Gallimore) - Substack]

Category:Abandoned drugs Category:Biased ligands Category:Danish inventions Category:Designer drugs Category:Entheogens Category:Euphoriants Category:GABA analogues Category:GABAergic hallucinogens Category:GABAA receptor agonists Category:GABAA-rho receptor antagonists Category:Hamilton Morris Category:Hypnotics Category:Isoxazolidinones Category:Sedatives Category:Zwitterions