In the longitudinal study of 150 chronic ketamine users discussed above, increased depression score (Beck Depression Inventory), but not clinical depression, was associated with frequent (daily) current and previous ketamine use. Depression scores were not increased in less frequent (less than three times per week) ketamine users. There have been some pilot studies that have investigated the use of ketamine as an antidepressant in patients with depression and of intravenous ketamine in patients with resistant depression. The results of these preliminary studies are not conclusive, but suggest that ketamine may have a role in this setting.
Neurological and Cognitive Effects
A number of studies have shown that acute Ketamine online use results in impairment of both working and episodic memory; it appears that these effects are greater in men than in women. Long-term ketamine use is also associated with deficits of both long- and short-term memory. Many of these studies involved polydrug users and so it is difficult to be certain that all of the effects seen were due solely to ketamine; however, in a longitudinal study the pattern of ketamine use correlated with memory impairment, with more frequent users more likely to have deficits in short- and long-term memory and pattern recognition tasks.
More recently, imaging studies in ketamine users have been published which demonstrate structural changes in chronic ketamine users. In one study, white-matter volume was assessed using diffusion tensor MRI in 41 individuals with chronic ketamine use and 44 drug-free volunteers. White matter changes were seen in the frontal lobes bilaterally and the left temporoparietal cortex; the frontal white matter changes correlated with estimated ketamine dose. In another report from the same group, voxel-based morphometry in conjunction with statistical parametric MRI mapping was reported in 41 individuals with chronic ketamine use and 44 drug-free volunteers to assess grey matter volume. Decreased grey-matter volume was seen in the left superior frontal gyrus and right middle frontal gyrus in the ketamine users and there was a correlation between the duration/dose of ketamine used and these changes.
There have also been increasing reports of abnormal liver function associated with ketamine use (both recreational misuse and therapeutic use), although not all of these reports have included abdominal pain as a prominent symptom. In a number of these reports, choledochal cysts were found. It appears that generally the common bile duct dilatation and liver function tests improve with ketamine cessation. The cause of these ketamine-related liver effects is poorly understood; however, data from an in vitro study in human hepatoma G2 cells has suggested that S(+) ketamine is directly hepatotoxic.
Neurological and Neuropsychiatric Chronic Toxicity
As summarised at the beginning of this chapter, there is extensive literature describing animal models which have investigated the neurological effects of ketamine. We will now summarise reports from ketamine users and human studies of the neurological and neuropsychological/neuropsychiatric effects of ketamine.
Psychosis and Depression
As discussed above, ketamine is used in animal models of schizophrenia. A number of volunteer studies have also shown that ketamine administration can result in schizophrenia-like positive and negative symptoms. Studies in patients with schizophrenia have shown that ketamine can induce psychotic symptoms, in a similar pattern to patients presenting with schizophrenic symptoms, both in patients treated with antipsychotics and those stabilized off antipsychotic therapy. In one study comparing 20 volunteers who reported acute recreational ketamine use with 19 polydrug using volunteers with no reported ketamine use, the ketamine users had higher scores for schizotypy at baseline and on three-day follow-up. In a longitudinal study of 150 ketamine users, there was a ketamine dose-dependent effect seen with greater delusional and dissociative symptoms in frequent ketamine users that persisted at a one-year follow-up. There have, however, been no studies investigating whether schizophrenia is more common in frequent ketamine users.