In a phase I human clinical trial while under development for the treatment of epilepsy, CI-966 was assessed at doses of 1–10 mg, 25 mg, and 50 mg. While the 1–10 mg dosages were well-tolerated, the 25 mg dose produced memory deficits and the 50 mg dose was found to produce "a variety of severe neurological and psychiatric symptoms" and "serious psychotic adverse effects" of prolonged (several-day) duration and demonstrated "severe adverse CNS symptoms such as memory deficits, myoclonus and tremors, unresponsiveness and subsequent severe psychological disturbances". The psychotomimetic effects produced by CI-966 are reportedly "similar to those of schizophrenia" and show "a similar phenotype to that seen with the psychotomimetics that block the effects of glutamate at the NMDA receptor", and the psychiatric effects of CI-966 were also described as resembling those seen in patients with mania in addition to schizophrenia. These research findings were responsible for the discontinuation of the clinical development of CI-966. In addition, on the basis of these findings, the drug has been characterized as a hallucinogen similarly to the potent GABAA receptor full agonist muscimol (a constituent of the hallucinogenic Amanita muscaria (fly agaric) mushrooms).
In contrast to CI-966, the marketed selective GAT-1 blocker (and analogue 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. This may be due to differences in pharmacology 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. In addition to tiagabine, the marketed anticonvulsant GABA 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.
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^ abcSedman, Allen J.; Gilmet, Gregory P.; Sayed, Albert J.; Posvar, Edward L. (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.
^ abWhite, H. S. (2004). "First Demonstration of a Functional Role for Central Nervous System Betaine/ -Aminobutyric Acid Transporter (mGAT2) Based on Synergistic Anticonvulsant Action among Inhibitors of mGAT1 and mGAT2". Journal of Pharmacology and Experimental Therapeutics. 312 (2): 866–874. doi:10.1124/jpet.104.068825. ISSN0022-3565. PMID15550575.
^Ferrie CD, Robinson RO, Panayiotopoulos CP (1996). "Psychotic and severe behavioural reactions with vigabatrin: a review". Acta Neurol. Scand. 93 (1): 1–8. PMID8825264.
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): 219–24. 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): 1061–4. doi:10.1016/0306-3623(94)00270-W. PMID7557251.
Sedman, Allen J.; Gilmet, Gregory P.; Sayed, Albert J.; Posvar, Edward L. (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.