Detecting neuroplastic effects induced by ketamine in healthy human subjects: A multimodal approach

Ketamine has dose-dependent psychoactive effects and, at sub-anaesthetic doses, can produce rapid and sustained antidepressant effects that last beyond the period of drug exposure. Earlier animal and human studies suggest that these lasting benefits may involve neuroplastic changes, including altered synaptic structure, glutamatergic signalling, and resting-state brain network activity. However, evidence in living humans has remained incomplete and sometimes inconsistent, especially for direct in vivo measures of synaptic plasticity. Prior PET work using the synaptic marker [11C]-UCBJ, which targets SV2A, had not shown a clear group-level ketamine effect in humans, and the relationship between synaptic measures and functional MRI findings was still poorly understood. This study set out to use a multimodal PET/MRI approach to examine ketamine’s effects across multiple biological levels in healthy men. The authors aimed to test whether a single intravenous psychedelic dose of ketamine would increase [11C]-UCBJ VT, a putative marker of synaptic plasticity, particularly in mood-regulating regions within the default mode network (DMN), over 1-8 days after dosing. They also examined glutamate and GABA in the anterior cingulate cortex (ACC), regional intrinsic brain activity, and functional connectivity, and explored whether changes in synaptic markers were related to changes in whole-brain activity.

The study was an exploratory within-subject imaging investigation in 11 healthy male participants, mean age 32 ± 10 years. Participants were screened to exclude physical or psychiatric illness, substance misuse, recent ketamine or psychedelic exposure, and MRI/PET contraindications. They abstained from alcohol and illicit drugs during the study period, with urine and breath testing at each visit. Ethical approval was obtained in London, and all participants gave informed consent. Each participant received a single intravenous infusion of racemic ketamine at 1 mg/kg over 40 minutes. This was described as a sub-anaesthetic, psychedelic-like dose that is used clinically and had known antidepressant effects. Vital signs were monitored before, during and after infusion. Psychological effects were assessed acutely with the Brief Psychiatric Rating Scale (BPRS), the Modified Observer’s Assessment of Alertness/Sedation scale, and the 6-item Clinician-Administered Dissociative States Scale (CADSS). Mood and wellbeing were measured at baseline, 1 week, and 4 weeks using the Profile of Mood States (POMS) and Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS). Participants underwent two integrated PET/MRI scans. The first scan occurred about 2 weeks before ketamine, and the second occurred after ketamine, either 1-2 days later in five participants or 7-8 days later in six participants; this timing was chosen to sample possible temporal effects across the post-infusion window. PET imaging used [11C]-UCBJ to quantify SV2A-related binding, with [11C]-UCBJ VT as the primary outcome. The authors focused on pre-specified regions including the dlPFC, vmPFC, ACC, PCC, hippocampus and amygdala. MRI included 1H-MRS to measure glutamate and GABA in the ACC, and resting-state fMRI to assess intrinsic activity and functional connectivity. Due to quality control issues, some MRS GABA data were excluded, and the HERMES sequence was not used in the main analysis. PET data were modelled with a 1-tissue compartment approach. Functional connectivity was calculated from pairwise correlations between ACC and the other regions of interest, with the ACC used as a seed. Intrinsic activity was assessed using ALFF, a measure of low-frequency BOLD signal power. Statistical analysis relied on one-sided linear mixed-effects models for within-subject pre-post changes in PET measures and mood scales, two-sided models for glutamate, Spearman correlations for associations between imaging and behavioural measures, voxel-wise mixed-effects analysis for ALFF, and permutation-based testing for functional connectivity. Multiple comparisons were controlled with Benjamini-Hochberg or Bonferroni corrections as appropriate.

Ketamine was followed by statistically significant improvements in mood measures: POMS scores decreased at 7 days and 4 weeks, and WEMWBS showed a trend towards improvement at 7 days. The extracted text reports POMS changes of M: -15 ± 20 at 7 days (β = -14.82, p = 0.031) and M: -14 ± 15 at 4 weeks (β = -13.91, p = 0.011), while WEMWBS increased by M: 6 ± 9 at 7 days (β = 5.64, p = 0.072). For the primary PET outcome, no statistically significant group-level increase in [11C]-UCBJ VT was detected after ketamine in any region of interest when all 11 participants were analysed. There was, however, a non-significant trend towards higher VT across regions, including the amygdala, where the increase approached significance (M: 7.33 ± 13.44%; β = 1.17; p = 0.066; d = 0.495; BF = 0.837). The extracted text is incomplete at the point where the ACC result is reported, but it indicates a similar trend in the ACC. No significant relationships were found between changes in [11C]-UCBJ VT and long-term changes in WEMWBS or POMS in any analysed region. Ketamine produced a statistically significant increase in glutamate levels within the ACC. The extracted text does not give the exact effect size or p-value in the Results subsection, but the Discussion states that this glutamate increase was particularly pronounced in the 7-8 day group. There was no significant correlation between the ketamine-related change in ACC glutamate and the change in [11C]-UCBJ VT in the ACC (n = 9; ρ = 0.01, p = 0.980). In terms of network measures, ketamine altered ACC functional connectivity: the Discussion specifies that coupling between the ACC and dlPFC became more anti-correlated, while coupling between the ACC and amygdala shifted from baseline anticorrelation towards positive coupling. For whole-brain intrinsic activity, ketamine produced a statistically significant reduction in ALFF only in a small occipital cortex cluster. The exploratory multimodal analysis found a negative relationship between changes in [11C]-UCBJ VT and ALFF, but only in regions belonging to the DMN, indicating that participants with larger increases in the synaptic marker tended to show larger reductions in intrinsic activity. The extracted text does not report any significant correlation between the PET and functional measures at baseline in those same DMN regions.

The authors conclude that a single 1 mg/kg dose of ketamine did not produce a clear group-level increase in [11C]-UCBJ VT in DMN regions 1-8 days later in healthy men. They interpret this as inconclusive rather than negative, noting that the data showed a trend towards increased VT and that a larger, better powered sample may be needed to detect any effect. They also report no difference between the early scan group (1-2 days) and the later scan group (7-8 days) for PET metrics. Their broader interpretation is that ketamine may exert complex and heterogeneous effects across molecular, cellular, and network levels rather than a single uniform neuroplastic response. In contrast to the PET findings, the authors emphasise a robust and sustained increase in ACC glutamate after ketamine, particularly in the later post-dose window. They note that this persistence extends beyond the commonly assumed acute glutamatergic surge and may indicate a longer-lasting shift in excitatory/inhibitory balance in the ACC. They place this within the wider idea that ketamine acts through NMDA receptor antagonism, disinhibition of pyramidal neurons, and downstream synaptic remodelling. Although they did not find a correlation between ACC glutamate and ACC [11C]-UCBJ VT, they argue that the ACC remains a key region in ketamine’s mechanism because it also showed altered coupling with the dlPFC and amygdala. The authors interpret the connectivity changes as a reconfiguration of fronto-limbic circuitry that may be relevant to ketamine’s therapeutic actions, although they stress that this healthy-volunteer study cannot test antidepressant efficacy. They suggest that ketamine may reduce maladaptive ACC-PFC synchrony and alter ACC-limbic interactions in ways that resemble previously reported changes in depressed patients. They also discuss the ALFF findings as evidence of reduced intrinsic activity, albeit limited to a small occipital cluster at the whole-brain level. Their exploratory PET-fMRI analysis is presented as especially informative because it linked increases in the synaptic marker with decreases in intrinsic activity in DMN regions, which they interpret as consistent with ketamine perturbing self-referential network processing. The authors compare their findings with earlier work, including prior [11C]-UCBJ PET studies that were also inconclusive, and they suggest several reasons why group-level PET effects may be hard to detect in humans. These include high inter-individual variability, the possibility that repeated dosing is needed, stronger effects in clinical populations than in healthy volunteers, and limitations of the tracer itself. They acknowledge several important limitations: the very small sample, inclusion of only male participants, the fact that none were naive to classic psychedelics, the varying post-dose scan times, and the limited spatial resolution and biological specificity of [11C]-UCBJ PET. They also caution that the tracer may not cleanly index a single form of plasticity and may be influenced by other presynaptic processes. Overall, they present the study as a proof-of-concept multimodal investigation that offers hypotheses for future work rather than definitive evidence of ketamine-induced synaptic plasticity in healthy humans.