In aphase I humanclinical trial while under development for the treatment ofepilepsy, CI-966 was assessed at doses of 1–10 mg, 25 mg, and 50 mg.[4] While the 1–10 mg dosages were well tolerated, the 25 mg dose producedmemory deficits and the 50 mg dose was found to produce "a variety of severe neurological and psychiatric symptoms" and "seriouspsychotic adverse effects" of prolonged (several-day) duration and demonstrated "severe adverse CNS symptoms such as memory deficits,myoclonus andtremors,unresponsiveness and subsequent severe psychological disturbances".[2][4][5][6][7] Thepsychotomimetic effects produced by CI-966 are reportedly "similar to those ofschizophrenia" and show "a similarphenotype to that seen with the psychotomimetics that block the effects ofglutamate at theNMDA receptor",[8][9] and the psychiatric effects of CI-966 were also described as resembling those seen in patients withmania in addition to schizophrenia.[4] These research findings were responsible for the discontinuation of the clinical development of CI-966.[2][5][7] In addition, on the basis of these findings, the drug has been characterized as ahallucinogen similarly to the potentGABAA receptor full agonistmuscimol (a constituent of the hallucinogenicAmanita muscaria (fly agaric) mushrooms).[10]
In contrast to CI-966, the marketed selective GAT-1 blocker (andanalogue of CI-966)tiagabine has been found at the dosages in which it has been studied and used to have far lower although non-absent potential for the same adverse effects of the former, including psychotic reactions.[6] This may be due to differences inpharmacology or potency between CI-966 and tiagabine or might be accounted for the possibility that the initial doses of CI-966 studied in humans simply were too high.[2][11] In addition to tiagabine, the marketed anticonvulsantGABA transaminase (GABA-T)inhibitor (and hence also an indirect and non-selective GABA receptor agonist)vigabatrin has also been associated with acute psychotic episodes,hallucinations, and other psychiatric adverse reactions, albeit less commonly.[12][13][14]
^Green AR, Hainsworth AH, Jackson DM (July 2000). "GABA potentiation: a logical pharmacological approach for the treatment of acute ischaemic stroke".Neuropharmacology.39 (9):1483–1494.doi:10.1016/S0028-3908(99)00233-6.PMID10854894.S2CID39073036.
^abcSedman AJ, Gilmet GP, Sayed AJ, Posvar EL (1990). "Initial human safety and tolerance study of a GABA uptake inhibitor, Cl-966: Potential role of GABA as a mediator in the pathogenesis of schizophrenia and mania".Drug Development Research.21 (3):235–242.doi:10.1002/ddr.430210309.ISSN0272-4391.S2CID84577983.
^abWhite HS, Watson WP, Hansen SL, Slough S, Perregaard J, Sarup A, et al. (February 2005). "First demonstration of a functional role for central nervous system betaine/{gamma}-aminobutyric acid transporter (mGAT2) based on synergistic anticonvulsant action among inhibitors of mGAT1 and mGAT2".The Journal of Pharmacology and Experimental Therapeutics.312 (2):866–874.doi:10.1124/jpet.104.068825.PMID15550575.S2CID30717285.
^abArmer RE (February 2000). "Inhibitors of mammalian central nervous system selective amino acid transporters".Current Medicinal Chemistry.7 (2):199–209.doi:10.2174/0929867003375380.PMID10637362.
Borden LA, Murali Dhar TG, Smith KE, Weinshank RL, Branchek TA, Gluchowski C (October 1994). "Tiagabine, SK&F 89976-A, CI-966, and NNC-711 are selective for the cloned GABA transporter GAT-1".European Journal of Pharmacology.269 (2):219–224.doi:10.1016/0922-4106(94)90089-2.PMID7851497.
Phillis JW (September 1995). "CI-966, a GABA uptake inhibitor, antagonizes ischemia-induced neuronal degeneration in the gerbil".General Pharmacology.26 (5):1061–1064.doi:10.1016/0306-3623(94)00270-W.PMID7557251.
Sedman AJ, Gilmet GP, Sayed AJ, Posvar EL (1990). "Initial human safety and tolerance study of a GABA uptake inhibitor, Cl-966: Potential role of GABA as a mediator in the pathogenesis of schizophrenia and mania".Drug Development Research.21 (3):235–242.doi:10.1002/ddr.430210309.ISSN0272-4391.S2CID84577983.
