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| Other names | 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 |
| Routes of administration | Oral[1][2] |
| Drug class | GABAA receptor agonist;Sedative;Hypnotic;Central depressant;Hallucinogen |
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| Bioavailability | 83–96% (absorption)[3] |
| Protein binding | <2%[3][4] |
| Metabolism | Glucuronidation mainly viaUGT1A9[3][6] |
| Metabolites | Gaboxadol-O-glucuronide[3] |
| Onset of action | 20–60 minutes (peak)[3][5][6] |
| Eliminationhalf-life | 1.5–2.0 hours[7][8][9] |
| Excretion | Urine (84–93%; mainly unchanged, partially glucuronidated (34%))[3][4][6][10] |
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| ECHA InfoCard | 100.059.039 |
| Chemical and physical data | |
| Formula | C6H8N2O2 |
| Molar mass | 140.142 g·mol−1 |
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Gaboxadol, also known as4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP) and by its former developmental code namesLu-2-030,MK-0928, andOV101, is aGABAA receptor agonist related tomuscimol which was investigated for the treatment ofinsomnia and other conditions likeAngelman syndrome but was never marketed.[2][11][1][12][13] At lower doses, the drug hassedative andhypnotic effects, and at higher doses, it produceshallucinogenic effects.[1][14][13] It is takenorally.[1][2]
The drug acts as apotent andselectivepartial agonist of theGABAA receptor, the majorsignalingreceptor of theinhibitoryendogenousneurotransmitterγ-aminobutyric acid (GABA).[1][11] However, it acts as a preferentialsupra-maximal agonist atextrasynapticδ subunit-containing GABAA receptors.[15][11] In contrast toGABAA receptorpositive allosteric modulators likebenzodiazepines andZ drugs, gaboxadol is anorthostericagonist of the GABAA receptor, acting on the same site as GABA rather than at anallosteric regulatory site.[16][1][11] As a result, gaboxadol has differing effects from benzodiazepines and related drugs.[16][1][11][15] Gaboxadol is aconformationally constrainedsyntheticanalogue of GABA and ofmuscimol, analkaloid and hallucinogen found inAmanita muscaria (fly agaric)mushrooms.[1][11][17][18] It has greatly improveddrug-like properties compared to these compounds.[11][17][19][13]
Gaboxadol was first described byPovl Krogsgaard-Larsen and colleagues in 1977.[1][13][20] It was assessed in clinical studies for various uses in the 1980s, but was not found to be useful.[11][15][14][13] In the 1990s and 2000s, gaboxadol was repurposed for treatment of insomnia and completedphase 3clinical trials for this indication.[1][14][15][21] However, development was discontinued forsafety andeffectiveness reasons in 2007.[2][3][15][13] Subsequently, gaboxadol was repurposed again for treatment ofAngelman syndrome andfragile X syndrome, but development for these uses was discontinued as well.[2][12][22][23]
Gaboxadol producessedative andhypnotic effects at lower doses andhallucinogenic effects at higher doses.[1][14][13] It has also been reported to producemood elevation[24] and sometimeseuphoria.[14][25]
Gaboxadol has been assessed inclinical studies at doses ranging from 10 to 160 mg.[11][13] It was studied inclinical trials for treatment of insomnia specifically at doses of 5 to 20 mg.[1][16] The drug's effects at a dose of 10 mg were anecdotally described byPovl Krogsgaard-Larsen as similar to having drunk two or three beers.[13] It was found to be limitedly effective for improving sleep at doses of 5 and 10 mg, but was more effective at doses of 15 to 20 mg.[16][15][1][26] Higher doses for insomnia were precluded by a narrowtherapeutic index and high rates ofpsychiatricadverse effects at such doses.[26][27]
Gaboxadol has been found to decreasesleep onset latency, increasesleep duration, increaseslow wave sleep (SWS) andslow wave activity (SWA), preservesleep architecture, not affectREM sleep, and improve subjectivesleep quality and daytime functioning.[11][1][28][29] 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 transientinsomnia.[13][30] Gaboxadol's hypnotic effects have been found to be stronger in women than in men.[28][21] On the other hand, SWS decreases with age, especially in men, and gaboxadol was found to substantially compensate for the reduction in SWS in elderly men.[11][31][13][32] The drug was also studied in experimentalsleep restriction and was found to increase SWS and improve daytime functioning, for instance symptoms ofsleepiness andfatigue, despite equal total sleep durations.[29][33]
There was notolerance to the hypnotic effects of gaboxadol after 5 days of repeated administration in animals.[11][34] Similarly, it maintained effectiveness in short-term clinical studies in humans.[21] However, gaboxadol was subsequently found to be initially effective in improving sleep in insomnia but to not maintain its benefits after 1 month.[16][35] In addition, gaboxadol showed mixed effectiveness at the assessed doses of 10 to 15 mg in two large 3-month clinical trials for insomnia.[3][21]
The effects of gaboxadol on sleep differ from those of widely usedGABAA receptor positive allosteric modulators likebenzodiazepines andZ drugs, which have been found to disrupt rather than enhance SWS and SWA despite improving sleep onset and duration.[19][11][36][17] In addition, unlike such agents, gaboxadol caused norebound insomnia ondiscontinuation and produced no next-day residual symptoms.[16][15][37] While dissimilar from GABAA receptor positive allosteric modulators, the effects of gaboxadol on sleep are similar to those of the related GABAA receptor agonistmuscimol and of theGABA reuptake inhibitortiagabine.[19][31][17][11][38]
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 tozolpidem.[29][39][40] In addition, it was more effective for improvingsleep maintenance than for improving sleep onset.[21]
Gaboxadol was developed for the treatment of insomnia, in which disruption of SWS is not the main feature.[16][39] The effects of gaboxadol in people withsleeping problems specifically involving impaired SWS have largely not been studied and are unknown.[16][40]
Gaboxadol was assessed at supratherapeutic doses of 30 to 45 mg and compared to theZ drugzolpidem indrug users during its development for treatment ofinsomnia.[13][21][25] At these doses, gaboxadol producedeuphoria andhallucinogenic effects such asdissociation,perceptual changes, andhallucinations.[13][21][25][26] The rates of suchpsychiatricadverse effects were 15% withplacebo, 38% with 15 mg, 72% with 30 mg, and 88% with 45 mg gaboxadol.[27] It showed less euphoria andmisuse potential, more negative and dissociative effects, and fewersedative effects than zolpidem in these individuals.[25] At a dose of 60 mg twice daily in an early study, gaboxadol was described as producing effects includingdizziness,vomiting,somnolence, and strong sedation.[11] High doses of gaboxadol have also been reported to producedelirium,amnesia, andloss of consciousness.[13]
According to journalist and scientistHamilton Morris, the drug can produce strong hallucinogenic effects at high doses similarly tomuscimol, with hallucinogenic effects starting at around doses of 30 or 40 mg and powerful hallucinogenic effects occurring at a dose of about 65 mg of thezwitterion.[41][42][43][44][45] Morris has described hallucinogenic effects he experienced with gaboxadol as follows:[46][13]
He has also reported other qualitative accounts of the hallucinogenic effects of gaboxadol.[43][44][45] Morris has stated that gaboxadol is every bit as powerful as a hallucinogen asserotonergic psychedelics likeayahuasca, but is qualitatively completely different.[45][44]
Side effects of gaboxadol includedizziness,sedation,somnolence,headache,nausea,vomiting, andtachycardia, among others.[11][47][27][48][26][8] It has also been reported to producegiddiness,depersonalization,impaired concentration, andbradycardia.[8] In clinical studies for insomnia, gaboxadol has been found to be generallywell-tolerated for up to 12 months.[21] At high doses, it can producehallucinogenic effects anddelirium.[13][21][25][8]
Gaboxadol ismetabolized exclusively viaglucuronidation and is not appreciated metabolized bycytochrome P450enzymes, and hence would not be expected to interact with cytochrome P450inhibitors orinducers.[5]
In contrast to the case ofγ-aminobutyric acid (GABA) andmuscimol, the binding of gaboxadol to the GABAA receptor does not appear to be stimulated by thebenzodiazepine andGABAA receptorpositive allosteric modulatordiazepamin vitro.[17][49] In addition, gaboxadol did not show synergistic effects in combination withalcohol or benzodiazepinesin vitro orin vivo in animals.[50][51][52]
Gaboxadol acts as apotent andselectiveGABAA receptorpartial agonist.[1][11] In contrast to GABAA receptorpositive allosteric modulators likebenzodiazepines,Z drugs,barbiturates, andalcohol, gaboxadol is an agonist of theorthosteric site of the GABAA receptor and the same site that theneurotransmitterγ-aminobutyric acid binds to and activates.[1][11] Whereas the related GABAA receptor agonistmuscimol is a highly potent partial agonist of theGABAA-ρ receptor (GABAC receptor), gaboxadol is a moderately potentantagonist of this receptor.[17][53] Unlike muscimol, it is not also aGABA reuptake inhibitor to any extent, and it does notinhibit theenzymeGABA transaminase (GABA-T).[54]
The drug showsfunctional selectivity at the GABAA receptor relative to GABA itself, activating GABAA receptors of different αsubunit compositions with varyingefficacies.[55][56] ItsEmaxTooltip maximal efficacy values at GABAA receptors were approximately 71% atα1 subunit-containing receptors, 98% atα2 subunit-containing receptors, 54% atα3 subunit-containing receptors, 40% atα4 subunit-containing receptors, 99% atα5 subunit-containing receptors, and 96% atα6 subunit-containing receptors.[55][56] Moreover, gaboxadol has been found to act as asupra-maximal agonist at α4β3δ subunit-containing GABAA receptors, low-potency agonist at α1β3γ2 subunit-containing receptors, and partial agonist at α4β3γ subunit-containing receptors.[57][58][59] Itsaffinity forextrasynaptic α4β3δ subunit-containing GABAA receptors is 10-fold greater than for other subtypes.[60] 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.[61] 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.[59] Mice with the GABAA receptorδ subunitknocked out are unresponsive to thehypnotic effects of gaboxadol.[15][62] Because of its preferential agonism of extrasynaptic GABAA receptors, gaboxadol has been referred to as a "selective extrasynaptic GABAA agonist" or "SEGA".[63][38] In contrast to gaboxadol, benzodiazepines andnonbenzodiazepines do not activate δ subunit-containing GABAA receptors.[15][5] On the other hand,alcohol is known to selectively potentiate δ subunit-containing extrasynaptic GABAA receptors analogously to gaboxadol.[64][65][66] In addition,neurosteroids andpropofol act on extrasynaptic δ subunit-containing GABAA receptors.[15][67][11]
Gaboxadol shows 25- to 40-fold lower potency as a GABAA receptor agonist than muscimol inin vitro studies.[68] Compared to muscimol, gaboxadol binds less potently to α4β3δ subunit-containing GABAA receptors (EC50Tooltip half-maximal effective concentration = 0.2 μM vs. 13 μM), but is capable of evoking a greater maximum response (EmaxTooltip maximal efficacy = 120% vs. 224%).[59] Although gaboxadol is far less potent than muscimolin vitro, it is only about 3 times less potency than muscimol in rodentsin vivo.[69][68] This is attributed mainly to gaboxadol's much greater ability to cross theblood–brain barrier than muscimol.[68] However, it appears to be due to gaboxadol levels being several-fold higher than levels of muscimol withsystemic administration of the same doses as well.[70] Gaboxadol is also more selective than muscimol and has been said byPovl Krogsgaard-Larsen to be much lesstoxic in comparison.[55][19][71][13]
In animals, gaboxadol has been found to producesedation,hypnotic effects,motor impairment,muscle relaxation,hypolocomotion,anxiolytic-like effects,antidepressant-like effects,analgesic effects, andanticonvulsant effects.[1][38][54][72] In rodentdrug discrimination studies, gaboxadol has been found to fully generalize with muscimol.[38][73] However, gaboxadol, GABAA receptor positive allosteric modulators like benzodiazepines and Z drugs, and theGABA reuptake inhibitortiagabine all do not generalize between each other, suggesting that theirinteroceptive effects are different.[16][11][38] Similarly, gaboxadol did not generalize with theneurosteroidpregnanolone.[38] On the other hand, gaboxadol has shown partial generalization with thebarbituratepentobarbital.[38] Gaboxadol does not produceself-administration orconditioned place preference in rodents or baboons, suggesting that it lacksrewarding orreinforcing effects and has lowaddictive potential.[74][75] This is in contrast to benzodiazepines likediazepam.[74][75]
Theabsorption of gaboxadol is rapid and almost complete withoral administration (83–96%).[3][4][7][10] It is azwitterionic compound and its absorption involvesactive transport viaintestinaltransporters such as theproton-coupled amino acid transporter 1 (PAT-1).[3][76] Coadministration of PAT-1inhibitors liketryptophan or5-hydroxytryptophan (5-HTP) has been found to decrease the absorptivepermeability of gaboxadol by 53 to 89%.[3][77][78] However, they may simply delay the absorption of gaboxadol and decreasepeak levels.[3] In contrast to the case of the PAT-1, the drug is not asubstrate of theproton-coupled di-/tripeptide transporter (PepT-1).[3] Peak levels of gaboxadol are reached 15 to 60 minutes after anoral dose.[3][5][6]
Thedistribution of gaboxadol has been studied in rodents.[70] It penetrates theblood–brain barrier and hence iscentrally active unlikeγ-aminobutyric acid (GABA).[11][55][8] The drug enters the brain in amounts that are 30 to 100 times higher than those ofmuscimol given at the same dose in rodents and hence shows greater blood–brain barrierpermeability in comparison.[70] In addition, whereas 90% of the muscimol in the brain is in the form ofmetabolites in rodents, 80% of the gaboxadol in the brain is in unchanged form.[70] It is unknown whichtransporters are involved in thetransport of gaboxadol across the blood–brain barrier or if it simply crosses into the brain viapassive diffusion, although the latter may be more likely.[3][79] The drug is distributed unevenly in the brain in rodents.[70] Theplasma protein binding of gaboxadol in humans is very low at less than 2%.[3][4]
Gaboxadol ismetabolized byO-glucuronidation mainly via theenzymeUGT1A9 into gaboxadol-O-glucuronide.[3] To a lesser extent,UGT1A6,UGT1A7, andUGT1A8 also catalyze the formation of thismetabolite.[4] Unlikemuscimol, gaboxadol is not asubstrate forGABA transaminase (GABA-T) and does not undergo metabolic transamination.[70] It is said to be more resistant tometabolism than muscimol.[55][71] Gaboxadol-O-glucuronide is the only metabolite of gaboxadol formed in significant amounts.[5] Gaboxadol is not metabolized by thecytochrome P450 system.[5]
Gaboxadol isexcreted inurine (83–94%) mainly unchanged and partially as gaboxadol-O-glucuronide (34%).[3][4][5][6][10] It is taken up from blood into thekidneys via theorganic anion transporterOAT1 (SLC22A6), while the glucuronide iseffluxed into urine via themultidrug resistance proteinMRP4 (ABCC4).[3][4] The drug has anelimination half-life in humans of 1.5 to 2.0 hours.[7][8][9] Two hours following attainment of peak concentrations, levels of gaboxadol are reduced by about 50% in humans.[6] In rodents, the half-life of gaboxadol was about twice as long as that ofmuscimol.[70] In people with severerenal impairment, circulating levels of gaboxadol were increased by 5-fold, and the renalclearance of gaboxadol was decreased by 34% while that of gaboxadol-O-glucuronide was decreased by 50%.[4]
Gaboxadol, also known by its chemical name 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP), is aconformationally constrainedsyntheticanalogue of the majorinhibitoryneurotransmitterγ-aminobutyric acid (GABA) and of theAmanitaalkaloidmuscimol.[14]
Gaboxadol is azwitterion, withpKa values of 4.3 (acidic) and 8.3 (basic) and alog P value of –0.61.[55][80] It was formulated pharmaceutically as thehydrochloridesalt.[80] The compound'ssolubility is greater than 30 mg/mL at physiologicalpH.[80]
Thechemical synthesis of gaboxadol has been described.[1][81][82] Its synthesis has been described as tedious, starting with a commercially unavailableprecursor, requiring at least 6 synthetic steps, and having very lowyields.[13] This has limited the affordability and availability of gaboxadol.[13]
Analogues of gaboxadol (THIP) includeγ-aminobutyric acid (GABA),muscimol,4-AHP,thio-THIP,aza-THIP,iso-THIP,THAZ,THPO,piperidine-4-sulfonic acid (P4S),isonipecotic acid, andisoguvacine, among others.[19][31][55][83] Numerous attempts to develop pharmacologically interesting analogues of gaboxadol have failed over the decades.[84] This can be attributed to the very strict structural requirements for GABAA receptor binding and activation.[14] As such, gaboxadol has been described as a unique compound and GABAA receptor agonist.[84]
Gaboxadol was firstsynthesized and described by the DanishchemistPovl Krogsgaard-Larsen in 1977.[1][13][84][20] It was developed viastructural modification ofmuscimol, a constituent ofAmanita muscaria mushrooms.[19][17][18] In the early 1980s, the drug was the subject of a series of smallpilotclinical studies that evaluated it in the treatment of variousmedical conditions, but it was not found to be useful.[13]
In 1996, asomnologist named Marike Lancel at theMax 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 increasedslow wave sleep.[13][84][50][85] 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.[11][13][86] Subsequently, gaboxadol underwent formal clinical development for treatment ofinsomnia byLundbeck andMerck.[2][13][1][82] It reachedphase 3 trials for this indication by at least 2004.[1] The drug was expected to be ablockbuster drug for its pharmaceutical developers.[87][50][26]
In 2007, the development of gaboxadol was terminated by Lundbeck and Merck.[2][26][48] They cited lack of effectiveness in a large 3-month clinical trial, the occurrence of high rates ofpsychiatricadverse effects at supratherapeutic doses in amisuse liability study withdrug users, a frequent incidence oftachycardia at therapeutic doses, and other reasons.[13][26][3][27] Moreover, there was anxiety in thepharmaceutical industry concerning hypnotics at the time owing to bizarre reports ofzolpidem (Ambien)-induceddelirium that had emerged in the media in 2006.[13] This may have resulted in greater concern about potentialliability issues.[13] Merck was also struggling with recent litigation from its drugrofecoxib (Vioxx), which may have made it further averse to liability.[13][50] When presented with the data on the hallucinogenic effects of high doses of gaboxadol, a Merck executive remarked "looks likeLSD to me!"[50] ANew Drug Application (NDA) was ultimately never submitted to theUnited StatesFood and Drug Administration (FDA).[50][48][26] Many of the companies' employees were said to have been surprised and confused by the discontinuation[41] and the decision is still critically debated.[84]
Journalist and scientistHamilton Morris wrote and published a notable exposé on gaboxadol inHarper's Magazine in 2013, including hisself-experimentation with the drug.[12][15][13] 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.[13] In addition, Morris has critiqued the pharmaceutical industry as being more interested in selling minimally effective drugs devoid of side effects instead of medications with real therapeutic effects but a higher risk of litigation.[13]
In 2015, Lundbeck sold its rights to the molecule to Ovid Therapeutics, whose plan was to develop it forAngelman syndrome (AS) andfragile X syndrome (FXS).[2][88] It was known internally at Ovid Therapeutics under the developmental code name OV101.[2] In 2021, development of gaboxadol for Angelman syndrome and fragile X syndrome was discontinued due to lack of effectiveness.[2][23][89]
Gaboxadol is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name andUSANTooltip United States Adopted Name.[1][90] It is also known by its former developmental code namesLu-2-030 orLu-02-030 (Lundbeck),MK-0928 (Merck), andOV101 (Ovid Therapeutics).[1][2] In addition, gaboxadol is well-known in thescientific literature by its chemical name4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP).[14][54]
Gaboxadol was covered, along withmuscimol andAmanita muscaria, in an episode ofHamilton Morris'sHamilton's Pharmacopeia.[42][91]
Povl Krogsgaard-Larsen andHamilton Morris have bothself-experimented with gaboxadol.[15][13][42][43][44] 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.[15][41][13][42][43][44]
Gaboxadol has been obtained rarely from thegrey market, for instance fromChina, forhypnotic andhallucinogenic purposes.[13][41][42][43][44]
The closely related GABAA receptor agonist muscimol, found inAmanita muscaria mushrooms, has been reported to inducesleep in humans similarly to gaboxadol, in addition to its well-known hallucinogenic effects that occur at higher doses.[18][92] While gaboxadol was never approved for medical use, informalmicrodosing of muscimol andAmanita mushrooms for improvement of sleep has become increasingly prevalent by the mid-2020s.[18][93][94] However, muscimol is far less-researched compared to gaboxadol,[18] and is lessselective and said to be much moretoxic in comparison.[55][19][71][13] In addition,Amanita mushrooms contain otherpharmacologically active compounds besides muscimol, such as theglutamate receptoragonist andneurotoxinibotenic acid and themuscarinic acetylcholine receptor agonist andparasympathomimeticmuscarine, which are liable to pose toxicity risks as well.[95][42]Povl Krogsgaard-Larsen has warned aboutsafety concerns with regard to medicinal use ofAmanita mushrooms.[42]
Gaboxadol is not acontrolled substance anywhere in the world as of October 10, 2025.[50][26][27]
Gaboxadol was studied in the 1980s byLundbeck and others in the treatment of a variety ofmedical conditions,[84][11][15][14][13] includingpain,[96]anxiety,[8]mania,[97]schizophrenia andtardive dyskinesia,[98][99]epilepsy,[100]Huntington's disease,[101] andAlzheimer's disease.[102] It showed poor clinical effectiveness as ananticonvulsant, in accordance with prioranimal studies.[84][100] In addition, it had only weakanxiolytic effects in humans and at doses that were accompanied by substantialside effects.[84][8] On the other hand, gaboxadol was found to be an effectiveanalgesic in some patients and wasequipotent tomorphine in these individuals.[84] Moreover, it lacked therespiratory depression and other characteristic adverse effects of morphine.[84] However, gaboxadol was ultimately not further developed due to its pronouncedsedative and other side effects.[84][8]
Later on, in the 1990s and 2000s, gaboxadol was developed for the treatment ofinsomnia and reachedphase 3clinical trials for this indication.[11][1][86][13] However, development was discontinued in 2007 forsafety andeffectiveness reasons.[2][3][15][13] Multiple large phase 3 trials were completed and published.[15][35][21][27] As a result, gaboxadol was not approved and will likely never be used as a hypnotic commercially.[15] There has been some further study of gaboxadol as a hypnotic byDavid Nutt and colleagues after the discontinuation of its development.[103][104] The drug was also studied for treatment ofmajor depressive disorder incombination withescitalopram in aphase 2 trial, but was ineffective.[105][13][106]
Following discontinuation of its development for insomnia, gaboxadol was repurposed by Ovid Therapeutics for treatment of theAngelman syndrome andfragile X syndrome.[2][12][107][108][109] It reached phase 3 and phase 2 clinical trials for these conditions, respectively.[2][109][107] However, development was discontinued for these uses as well in 2021.[2][23][89] Subsequently, another company known as Healx appears to have begun developing gaboxadol under the developmental code nameHLX-0206 for the treatment of fragile X syndrome.[110][111][112]
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].
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.
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).
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.
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. [...]
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].
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] [...]
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.
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).
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).
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).
[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. [...]
[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 [...]
[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. [...]
"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.
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.
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.
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.
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.
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.
[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.
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.
The commonly reported reason for Amanita muscaria use was to improve sleep.
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
