However, multiple other NMDA receptor antagonists, including memantine, lanicemine, rislenemdaz, rapastinel, and 4-chlorokynurenine, thus far have failed to demonstrate sufficient effectiveness for depression. Furthermore, animal research indicates that arketamine, the enantiomer with a weaker NMDA receptor antagonism, as well as (2R,6R)-hydroxynorketamine, the metabolite with negligible affinity for the NMDA receptor, but a  potent alpha-7 nicotinic receptor antagonist may have antidepressive action. It is now argued that NMDA receptor antagonism may not be primarily responsible for the antidepressant effects of ketamine. Molecular targets
Ketamine principally acts as an antagonist of the NMDA receptor, an ionotropic glutamate receptor. The S(+) and R(–) stereoisomers of ketamine bind to the dizocilpine site of the NMDA receptor with different affinities, the former showing approximately 3- to 4- fold greater affinity for the receptor than the latter. As a result, the S isomer is a more potent anesthetic and analgesic than its R counterpart.Ketamine may interact with and inhibit the NMDAR via another allosteric site on the receptor.With a couple of exceptions ketamine actions at other receptors are far weaker than ketamines antagonism of the NMDA receptor (see the activity table to the right).Although ketamine is a very weak ligand of the monoamine transporters (Ki > 60 μM), it has been suggested that it may interact with allosteric sites on the monoamine transporters to produce monoamine reuptake inhibition. However, no functional inhibition (IC50) of the human monoamine transporters has been observed with ketamine or its metabolites at concentrations of up to 10,000 nM.
Urinary and liver toxicity
Urinary toxicity occurs primarily in people who use large amounts of ketamine routinely, with 20–30% of frequent users having bladder complaints. It includes a range of disorders from cystitis to hydronephrosis to kidney failure. The typical symptoms of ketamine-induced cystitis are frequent urination, dysuria, and urinary urgency sometimes accompanied by pain during urination and blood in urine. The damage to the bladder wall has similarities to both interstitial and eosinophilic cystitis. The wall is thickened and the functional bladder capacity is as low as 10–150 mL.Management of ketamine-induced cystitis involves ketamine cessation as the first step. This is followed by NSAIDs and anticholinergics and, if the response is insufficient, by tramadol. The second line treatments are epithelium-protective agents such as oral pentosan polysulfate or intravesical (intra-bladder) instillation of hyaluronic acid. Intravesical botulinum toxin is also useful.Liver toxicity of ketamine involves higher doses and repeated administration. In a group of chronic high dose ketamine users, the frequency of liver injury was reported to be about 10%. There are case reports of increased liver enzymes involving ketamine treatment of chronic pain. Dependence and tolerance
Although the incidence of ketamine dependence is unknown, some people who regularly use ketamine develop ketamine dependence. Animal experiments also confirm the risk of misuse. Additionally, the rapid onset of effects following insufflation may increase potential use as a recreational drug. The short duration of effects promotes bingeing. Ketamine tolerance rapidly develops, even with repeated medical use, prompting the use of higher doses.