Hippocampal subfield differences in people with and without recreational ketamine use: Insights from multi-modal neuroimaging

Background and aims: Recreational ketamine use has increased globally and is associated with psychiatric and cognitive concerns. The hippocampus in preclinical models shows damage and working-memory disruption with repeated dosing. However, whether specific hippocampal subregions may differ in people with chronic ketamine use remains unclear. In Taiwan, ketamine is predominantly consumed by smoking ketamine mixed with tobacco, producing smoking-related behavioral profiles like non-ketamine tobacco use participants (TUs). We therefore examined individuals with urine-confirmed ketamine as the only detected substance who reported predominantly smoking-administered recreational use (KUs) and used TUs as controls. This study aimed to: (1) characterize ketamine-use patterns and psychiatric symptoms; (2) compare working-memory and affective-behavioral measures between KUs and TUs; (3) quantify group differences in hippocampal subregion volumes; and (4) assess group differences in functional connectivity (FC) of identified subregions and relationships with neurotransmitter receptor distributions. Design: Cross-sectional case-control study with cognitive testing and neuroimaging. Setting: Community-based recruitment in Taiwan. Participants: 58 KUs (44 males; mean age = 21.00 ± 4.57) and 73 TUs (52 males; mean age = 24.34 ± 5.86). Measurements: Ketamine-use patterns (Addiction Severity Index), psychiatric symptoms [Symptom Checklist-90-Revised (SCL-90-R)], working-memory (N-back), affective-behavioral measures [Barratt Impulsiveness Scale (BIS-11), Buss and Perry Aggression Questionnaire (BPAQ), Sensitivity to Punishment and Sensitivity to Reward Questionnaire (SPSRQ)], hippocampal subfield volumes (FreeSurfer) and functional connectivity (FC) of identified subregions (seed-based analysis). Spatial correspondence with N-methyl-D-aspartate (NMDA) receptor density was evaluated using JuSpace. Findings: Heavier ketamine use was associated with greater psychological distress [Global Severity Index (GSI) r = 0.343, P = 0.011], particularly anxiety (r = 0.457, P < 0.001) and hostility (r = 0.442, P < 0.001). Although self-reported impulsivity, aggression and reward/punishment sensitivity did not differ between groups, KUs showed reduced accuracy under higher working-memory load [2-back: F(1, 124) = 4.16, P = 0.04, partial η² = 0.03; 1-back: F(1, 124) = 8.10, P = 0.005, η2 = 0.06]. KUs displayed reduced left hippocampal volume [F(1, 119) = 4.23, P = 0.04, η2 = 0.03], most marked in the hippocampal-amygdaloid-transition-area [HATA; F(1, 119) = 10.52, P = 0.002, η2 = 0.08]. KUs also showed increased FC between left HATA and frontal, cingulate, temporal, subcortical, insular and cerebellar regions (P < 0.05, AlphaSim corrected), which correlated with NMDA-receptor distributions (z = 0.30, P = 0.005, false discovery rate corrected). Conclusions: Recreational smoking-administered ketamine use appears to be associated with dose-dependent psychiatric symptoms, load-dependent working memory impairment, selective hippocampal subregion volumetric differences and altered network connectivity aligned with N-methyl-D-aspartate- (NMDA) receptor distribution.