Table 1.

Structural differences: gray matter.

References	N (ketamine vs. controls)	Ketamine subjects (ketamine use-other substance use-comorbid disorders)	Controls	Significant differences ketamine subjects compared to controls	Statistic measure	Correlation
Liu et al. (2016)	181 (124–57)	25% mood disorder, 15.3% anxiety disorder. “Many” ketamine users used other drugs like cannabis or cocaine. Mean ketamine use: not mentioned Route of administration: not mentioned. Use of other drugs: not mentioned. Psychiatric and/or somatic illnesses: not mentioned. Male/female not mentioned Ketamine users performed worse than controls on intelligence and cognitive tasks. Presence of psychiatric or somatic disorder is not mentioned.	Healthy controls	Smaller gray matter volume in: -right orbitofrontal cortex (rOFC) -right medial prefrontal cortex (rMPFC) -left globus pallidus (lGP) -left hippocampus (lH) -right nucleus accumbens (rNAC) Higher gray matter volume in: -left caudate nucleus (lC)	Not reported	-Gray matter volumes in rOFC, rMPFC, rNAC were negatively correlated with ketamine dependence severity. -rOFC, rMPFC, lC, lGP, lH, rNAC volumes correlated with performance in cognitive tests.
Liao et al. (2011)	85 (41–44)	Mean age 26.9 years Male/female 33/8 Mean ketamine use: 2 g/day 3.4 years Ketamine was consumed by snorting Other drugs used in users: 100% Tobacco 73% Alcohol 68% Ecstasy 66% Amphetamine+ caffeine 56% Methamphetamine 20% Marijuana 15% Benzodiazepines 2,4% Heroin 0% Cocaine No history of neurologic disorder or psychiatric illnesses	Drug-free controls Mean age 26.3 years Male/female 34/10 0% Tobacco 20% Alcohol No history of neurologic disorder or psychiatric illnesses	Smaller gray matter volume in 1) left superior frontal cortex 2) right middle frontal cortex	Gray matter volume 1) Left superior frontal cortex: Voxel Z 4.48 2) Right middle frontal cortex voxel Z 4.81 P-cluster level < 0.05	Negative correlation with lower gray matter in left superior frontal cortex (p = 0.011) and right middle frontal cortex (p = 0.009) and duration of ketamine use (months). Negative correlation with lower left superior frontal cortex gray matter volume and estimated lifetime consumption (p = 0.022)
Chesters et al. (2016)	27 (14–13)	Age not mentioned Male/female not mentioned Mean ketamine use: not mentioned Other drugs: MDMA: 100% Cocaine: 100% Amphetamine: 93% Heroin: 50% Route of administration was not mentioned, age and gender were not mentioned. Other psychiatric or somatic disorders not mentioned	Polydrug controls Age not mentioned Male/female not mentioned Used drugs: MDMA: 46% Cocaine: 38% Amphetamine: 23% Heroin: 0% Other psychiatric or somatic disorders not mentioned	Smaller cortical matter volume and smaller cortical thickness in frontal lobe	Freesurfer analysis, p = 0.052, FDR corrected
Wang et al. (2013)	21 (patient cohort)	Age: between 19 and 48 years Mean ketamine use: 1 g/day Route of administration was not mentioned Subjects were mostly below 30 years old, two individuals were above 30. Other drugs: One subject took a combination of ketamine, ecstasy and amphetamine. 1 subject was known to use amphetamine and ecstasy. No history of brain trauma or neurological disease. Psychiatric conditions were not mentioned	No controls	After ketamine addiction duration 1 yr: atrophy spots in superficial white matter of cortex 3 yrs: extension to internal capsule 4 yrs: atrophy spots in basal forebrain, cerebellum, pons and diencephalon; atrophy in small region in frontal, parietal and occipital cortex 5 yrs: atrophy of parahippocampal gyrus 6 yrs: atrophy lesions in corpus striatum. 7 yrs: extension of atrophy in frontal, parietal and occipital cortex. Lesions in midbrain. 10–12 yrs: all lesions as above.	Lesions were not quantifeid	In 1 subject, increased quantity (grams per year) ketamine use correlated with acceleration of cortical atrophy. In 1 subject, high amounts of polydrug (ecstasy, amphetamine, ketamine) correlated with acceleration of atrophy in basal prefrontal gyrus rectus
Hung et al. (2020a)	53 (34 users, 19 non-users)	Ketamine users were divided between adolescent (onset before age 20) onset users and adult onset users (onset after age 20).		1) Lower gray matter volume (GMV) in the left precuneus of ketamine users. The volume was	1) GMV 0.412 cm3 (adolescent), 0.48 cm3 (late onset) 0.51 cm3 (HC)
		Age: 25.33 Mean ketamine use: not mentioned Male/female 26/8 Subjects testing positive on methamphetamine, opioids, ecstasy and marijuana were excluded. Participants had no major medical or neurological illness. The level of education of ketamine users was significantly lower than in the control group.	Age: 25.26 years Male/female 11/8 Participants had no major medical or neurological illness.	lower in the adolescent onset group than in the adult onset group. Lower GMV in the 2) right insula, 3) left inferior parietal lobule, 4) left DLPFC 5) lmOFC	p < 0.001 2) GMV 0.87 cm3 SD vs 1.11 cm3 3) GMV 0.70 cm3 SD = 0.02 vs. 0.82 cm3 SD = 0.03 (p < 0.001) 4) 0.90 cm3 vs. 1.04 cm3 p < 0.001) 5) 0.63 cm3 vs. 0.73 cm3