Hippocampal subfield differences in people with and without recreational ketamine use: Insights from multi-modal neuroimaging.
Yi-Hsuan Liu, Chia-Chun Hung, Marc N Potenza, Kun-Hsien Chou, Pei-Lin Lee, Chu-Chung Huang, Chiang‐Shan R. Li, Tony Szu-Hsien Lee, Ching-Po Lin
Addiction January 29, 2026 DOI: 10.1111/add.70331 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Cross-sectional case-control study Peer reviewed |
|---|---|
| Sample size | 131 |
| Population | Recreational ketamine users and tobacco users in Taiwan |
| Topics | Ketamine Esketamine |
| Keywords | N‐methyl‐d‐aspartate receptors Functional neuroimaging Hippocampus Magnetic resonance imaging Recreational substance use Substance‐related disorders Working memory |
| Key findings | Recreational smoking-administered ketamine use is associated with dose-dependent psychiatric symptoms, load-dependent working memory impairment, reduced left hippocampal volume, and altered functional connectivity aligned with NMDA-receptor distribution. |
Abstract
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. Cross-sectional case-control study with cognitive testing and neuroimaging. Community-based recruitment in Taiwan. 58 KUs (44 males; mean age = 21.00 ± 4.57) and 73 TUs (52 males; mean age = 24.34 ± 5.86). 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. 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). 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.
Comparable studies
Other cross-sectional and survey studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| 5-Year Trends in Use of Hallucinogens and Other Adjunct Drugs among UK Dance Drug Users People who use drugs in dance contexts | 2006 | Repeated-measures cross-sectional survey | |
| Preliminary analysis of positive and negative syndrome scale in ketamine-associated psychosis in comparison with schizophrenia Healthy subjects, ketamine abusers, and schizophrenia patients | 2014 | Cross-sectional study | n = 998 |
| Ketamine as a primary predictor of out-of-body experiences associated with multiple substance use Online survey respondents | 2011 | Cross-sectional survey | n = 192 |
| Self-reported prevalence of dependence of MDMA compared to cocaine, mephedrone and ketamine among a sample of recreational poly-drug users Global non-treatment-seeking sample of last year users of MDMA, cocaine, mephedrone,... | 2014 | Cross-sectional survey | |
| Near-Death States Reported in a Sample of 50 Misusers Previous ketamine misusers who reported a ketamine-related near-death experience | 2010 | Cross-sectional survey | n = 50 |
Citations in the library
Cites 18
- Ketamine use: a review Addiction July 21, 2011
- Association of Ketamine With Psychiatric Symptoms and Implications for Its Therapeutic Use and for Understanding Schizophrenia JAMA Network Open May 1, 2020
- Maintenance ketamine treatment for depression: a systematic review of efficacy, safety, and tolerability. The Lancet Psychiatry November 1, 2022
- Brain Changes Associated With Long-Term Ketamine Abuse, A Systematic Review Frontiers in Neuroanatomy March 18, 2022
- Ketamine induces multiple individually distinct whole-brain functional connectivity signatures. Elife April 17, 2024
and 13 more in the library