This brain imaging study (n=10) in healthy participants used magnetic resonance spectroscopy to measure glutamate levels in the nucleus accumbens before and during a single intravenous ketamine infusion (50mg/70kg). Ketamine did not significantly increase overall glutamate levels, but individual changes in glutamate were positively associated with anxious ego dissolution and reduced vigilance.
Ketamine has been shown to modulate glutamate signaling in animals and may therefore have the potential to restore glutamate imbalances in the brain. Impaired glutamate homeostasis has been implicated in mental health disorders such as substance use disorders (SUDs). Thus, we investigated ketamine’s potential to increase glutamate levels in the nucleus accumbens (NAc), a key region for the development and maintenance of SUD. We further examined whether glutamate changes are associated with ketamine’s potential to induce altered states of consciousness. A single intravenous dose of R,S-ketamine (0.71 mg/kg bodyweight) was administered to 10 healthy volunteers over 40 min. Glutamate levels were measured by using a tailored proton magnetic resonance spectroscopy (1H-MRS) sequence in the left NAc on a 3 T scanner, before and during the infusion. Subjective effects were measured by using the Five-Dimensional Altered States of Consciousness (5D-ASC) questionnaire. Glutamate levels were considered from the overall spectrum average (22 min) as well as three shorter, overlapping sub-blocks (each 10 min), to capture the progression of glutamate over time. Mean glutamate levels in the NAc were not significantly altered between baseline and ketamine 1H-MRS measurement. However, glutamate changes were positively associated with anxious ego dissolution and reductions in vigilance. In conclusion, ketamine did not significantly increase glutamate levels across our sample of 10 healthy volunteers, but individual glutamate changes induced by ketamine correlate with anxious ego dissolution and reductions in vigilance, indicating that ketamine-induced glutamate alterations in the NAc underly specific alterations in perception and consciousness.
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Ketamine is a non-competitive NMDA receptor antagonist with recognised neuroplastic and antidepressant effects, and it has also shown promise in substance use disorders (SUDs). A central uncertainty is how ketamine produces these effects at the neurochemical level. The paper notes that ketamine can modulate glutamatergic transmission and that disturbed glutamate homeostasis has been implicated in psychiatric disorders, particularly in corticostriatal circuits involving the nucleus accumbens (NAc), a region important for reward and craving. However, evidence for ketamine’s effects on glutamate in humans remains mixed, and little is known about whether changes in NAc glutamate relate to ketamine’s altered subjective states. The study aimed to test whether a single intravenous dose of ketamine increases glutamate in the left NAc of healthy volunteers, measured with proton magnetic resonance spectroscopy (1H-MRS), and whether any glutamate changes are associated with altered states of consciousness measured using the Five-Dimensional Altered States of Consciousness (5D-ASC) questionnaire. The authors describe this as a pilot study designed to help clarify a possible mechanism relevant to future work in SUDs and other psychiatric disorders.
This was a pilot study conducted in 10 healthy adults aged 18 to 55 years; 5 were female and the mean age was 29.4 ± 6.8 years. Participants were screened for extensive psychiatric, neurological, medical, medication-related, pregnancy-related, and MRI-related exclusion criteria. The study took place at the Psychiatric University Clinic Zurich and had ethics and regulatory approval. Written informed consent was obtained from all participants. The study involved two visits: a screening visit and an infusion/MRS visit. On the study day, participants underwent two identical 22-minute 1H-MRS scans of the left NAc, one at baseline and one during ketamine administration. During both scans they listened to a standardised instrumental music playlist developed for psychedelic-assisted therapy. Before the infusion, participants also completed a 10-minute audio-guided mindfulness-based exercise. Blood pressure was measured before and after infusion, and participants were monitored for 90 minutes afterwards. During the second MRS scan, participants received racemic ketamine (Ketalar) intravenously over 40 minutes at a total dose of 0.71 mg/kg bodyweight. Five participants received a steady infusion, and five received a bolus after 10 minutes of steady infusion, followed by return to the steady rate for the remaining 20 minutes. The bolus was included to assess tolerability and feasibility for a later clinical trial. Subjective effects were assessed one hour after infusion using the 5D-ASC, which covers five main dimensions, 11 subscales, and a global score. Neuroimaging was performed on a 3.0 T scanner using a tailored sLASER 1H-MRS sequence for the left NAc voxel. Glutamate was quantified relative to the unsuppressed water peak. The researchers analysed whole-scan averages and also three overlapping sub-blocks to capture temporal changes during infusion. Spectral quality was assessed using signal-to-noise ratio, linewidth, and Cramér-Rao lower bounds. Statistical analyses included a one-tailed paired t-test for whole-block baseline versus ketamine glutamate, a one-tailed two-way ANOVA for sub-block effects, and Spearman rank correlations between glutamate change and 5D-ASC scores, with Benjamini-Hochberg false discovery rate correction. Baseline glutamate was also explored as a predictor of subjective effects.
Spectral quality was reported as acceptable in all participants: signal-to-noise ratio exceeded 18, linewidth was below 10 Hz, and Cramér-Rao lower bounds for glutamate were below 7%. No scans were excluded for quality reasons, and the average overlap between baseline and ketamine voxels was 77%. At the group level, ketamine did not significantly increase NAc glutamate. In the whole-block analysis, the paired t-test showed no difference between baseline and ketamine (t(9) = -0.24, p = 0.59, d = -0.08, 95% CI [-1.14, 0.58]). Mean glutamate was 8.2 mmol/kg at baseline and 8.3 mmol/kg during ketamine. The sub-block analysis was also null: there was no significant main effect of condition (F(1, 9) = 0.01, p = 0.92), no significant sub-block effect (F(2,18) = 1.95, p = 0.17), and no significant interaction (F(2,18) = 0.51, p = 0.61). Mean glutamate across conditions and sub-blocks ranged from 8.3 to 8.8 mmol/kg. Subjective effects varied substantially across individuals, especially for oceanic boundlessness, visionary restructuralisation, and reductions in vigilance. In the correlation analyses, greater glutamate change from baseline to ketamine was significantly associated with anxious ego dissolution (r = 0.77, p = 0.01) and reductions in vigilance (r = 0.70, p = 0.03). After multiple-comparison correction, only the anxious ego dissolution association remained significant (p corr = 0.04), whereas vigilance did not (p = 0.08). Similar positive associations were found when using absolute glutamate values during ketamine: anxious ego dissolution and vigilance again correlated positively, with corrected p-values reported as significant. Baseline glutamate was not significantly associated with later subjective effects, suggesting the observed relationships were not simply pre-existing traits. The paper notes that the exploratory sub-block results hinted at a subtle glutamate increase, but this was not statistically significant.
The authors interpret the study as the first human investigation of ketamine’s effects on glutamate signalling in the NAc. Their main finding was that ketamine did not produce a significant group-level increase in NAc glutamate in 10 healthy volunteers, contrary to their initial hypothesis. They note that this differs from much of the preclinical literature and some human MRS work in other brain regions, but they argue that the discrepancy may reflect regional specificity, differences between MRS and microdialysis, and the difficulty of measuring small structures such as the NAc. They emphasise that the NAc voxel was small, which reduced signal and required long acquisition times. This may have made it easier for brief or rapidly changing glutamate effects to be averaged out, and the prolonged scan also increased the chance of motion-related distortion. The authors suggest that the exploratory sub-block analysis may hint at a subtle effect that was obscured in the averaged analysis, but they treat this cautiously. Although the group-level neurochemical effect was null, the authors highlight the association between individual glutamate changes and subjective ketamine effects. In particular, greater glutamate increases were linked to more anxious ego dissolution and reduced vigilance. They suggest that elevated NAc glutamate may alter excitatory signalling and disturb mesolimbic-thalamocortical circuits, producing negative depersonalisation-like experiences and clouded consciousness rather than positive or mystical experiences. They also note that music could potentially influence subjective and neural effects, but argue that this was held constant across conditions. The authors place these findings alongside broader ketamine research suggesting that the quality of subjective experience may matter for treatment outcomes, but they caution that dissociation alone may not fully explain response. They also mention work indicating that anxiety and other affective reactions during ketamine administration may be relevant, and that broader psychometric tools than the CADSS may be needed. Key limitations they acknowledge include the very small sample size, the exploratory nature of the study, the methodological constraints of imaging the NAc, and the uncertainty about whether the findings generalise to people with SUDs. They state that the MRS protocol is now being used in a Phase II trial in cocaine use disorder and argue that future studies should clarify the mechanisms behind the glutamate-subjective experience association and whether these effects relate to therapeutic outcomes.
Ten healthy participants (5 female, mean age of 29.4 ± 6.8) aged between 18 and 55 years and with normal level of German language took part in the study. Exclusion criteria included the following: Current or lifetime psychotic, bipolar I or II disorder, history of substance induced psychosis, family history of psychotic, manic, or bipolar disorders, suicide attempts during the last two years, current suicidality, current abuse of psychoactive substances, current severe depression, severe central nervous system related illnesses, increased intracranial pressure, elevated blood pressure (systolic > 140 mmHg, diastolic > 90 mmHg), hyperthyroidism, abnormal electrocardiogram, regular medication intake, pregnancy or lactation, and contradiction to magnetic resonance imaging (MRI). All criteria were checked on an initial screening visit by questionnaires, blood analysis, vital sign assessment, and electrocardiogram. Ten individuals met the inclusion criteria and were included in the present pilot study. This work was performed as pilot study of a clinical trial that was approved by the Cantonal Ethics Committee, Zurich, Switzerland (2022-01859) and the Swiss Agency for Therapeutic Products (Swissmedic). All participants gave written informed consents prior to study participation. The study was conducted at the Psychiatric University Clinic Zurich in Switzerland.
The pilot study consisted of two visits: a screening visit and a visit during which the ketamine infusion and 1 H-MRS measurement were conducted. On the infusion visit, participants arrived at the clinic's MR center in the morning and were instructed to have a light breakfast no later than 3 h before the infusion. All participants underwent two identical 1 H-MRS measurements lasting for 22 min: a baseline measurement and a subsequent ketamine measurement. During both 1 H-MRS measurements, participants listened to a customized instrumental music playlist that was developed for psychedelic-assisted therapy. After the baseline measurement, participants were prepared for the ketamine infusion: a peripheral vein cannula was placed on their forearm and before the start of the infusion, all individuals performed a 10-minute audio-guided mindfulness-based exercise to shift their focus inwards. The ketamine infusion was initiated simultaneously with the 1 H-MRS measurement. Blood pressure was measured before and after the infusion. After the ketamine administration, participants completed the 5D-ASC questionnaire.
Neuroimaging data were acquired on a Philipps Achieva 3.0 T MRI scanner (Philipps Healthcare, Best, The Netherlands), equipped with a 32-channel receive-only phased-array head coil. High resolution structural images were acquired using a T1-weighted Turbo Field Echo MRI scan (repetition time (TR)/ echo time (TE) = 8.1/3.7 ms, duration: 8 min), which were used for the panning of the 1 H-MRS voxel to cover the left NAc (size 8 ×18 x 9 mm 3 ). The 1 H-MRS measurement used a tailored semi adiabatic localization by adiabatic selective refocusing (sLASER) sequencewith partial water suppression for optimal glutamate measurement in the NAc (details to be published elsewhere). Given the small voxel volume used in this study, the metabolite signal of individual spectra was insufficient for reliable alignment. Therefore, the residual water signal was deliberately retained and employed as a reference for frequency alignment during post-processing, thereby improving overall spectral quality. Partial water suppression was achieved using VAPOR (variable pulse power and optimized relaxation delays) interleaved with outer volume suppression pulses. TR was set to 2500 ms, TE to 30 ms and spectral bandwidth to 2000 Hz. A total of 512 transients was acquired in four (for n = 2) or eight blocks (for n = 8) over approximately 22 min. In addition to the 512-transient-average across all timepoints (whole-block average), three partially overlapping windows à 256 transients (approximately 11 min per sub-block) were averaged to investigate dynamic changes in glutamate levels as a function of evolving ketamine effects (Fig.). This approach allowed for the assessment of potential temporal glutamate changes during the infusion, while the chosen time window ensured sufficient signal-to-noise-ratio for reliable metabolite quantification. The MRS acquisition during both baseline and ketamine conditions consisted of 512 transients (captured within 8 distinct MRS blocks for n = 8; or 4 blocks for n = 2). The nominal acquisition time was approximately 22 min. However, due to sequence-related procedures (e. g., frequency adjustment, water reference acquisition, and inter-block intervals), the effective measurement duration was approximately 28 min. During the remaining infusion time, additional test measurements were performed in preparation for the subsequent clinical trial, which are not included in the present analyses. Metabolite concentrations are reported as ratios relative to the unsuppressed water peak and reflect estimated metabolite levels in millimoles per kilogram of brain water, excluding water contained within cerebrospinal fluid. The water signal was acquired in the same block as the metabolites, using the same TR, but center frequency was set to 4.67 instead of 2.67 ppm.
During the 1 H-MRS measurement, racemic ketamine (Ketalar®) was administered intravenously over 40 min at a total dose of 0.71 mg/kg bodyweight. The ketamine dose (0.71 mg/kg) was selected based on prior studies in SUDs, which have demonstrated safety and feasibility at higher doses than those typically used in depression. This dosing approach is further supported by evidence suggesting reduced sensitivity to ketamine in individuals with SUDs, potentially due to cross-tolerance mechanisms involving NMDA receptor adaptations. As this study was conducted in preparation for a clinical trial for cocaine use disorder treatment, dosing followed the protocols applied in this population. Five participants received ketamine at a steady infusion rate. The other five were administered a bolus after 10 min of steady rate. The bolus contained half of the total dose over 10 min, and after the bolus, the infusion returned to steady rate for the remaining 20 min. The bolus administration was included to assess tolerability and feasibility in preparation for the subsequent clinical trial. The bolus was used to achieve a more rapid increase in plasma ketamine levels prior to steady infusion, consistent with pharmacokinetic evidence indicating faster brain distribution compared to continuous infusion alone. Additionally, bolus administration has been associated with more pronounced subjective effects, which may be relevant for therapeutic outcomes. All individuals were monitored for 90 min post infusion to ensure the remission of ketamine induced effects.
One hour after completion of the infusion, all participants filled out the 5D-ASC, a questionnaire consisting of five dimensions (covered by 94 questions) and eleven subscales (covered by 42 questions). Each question is answered on a visual analog scale ranging from 0 to 100 (0 = not more than usual, 100 = much more than usual). The questionnaire assesses the subjective experience of an altered state of consciousness retrospectively and relative to the individual's typical waking condition. In addition to the five dimensions and eleven subscales, the global score was included, representing the mean value of all 94 items. The five dimensions comprise 'oceanic boundlessness', 'anxious ego dissolution', 'visionary restructuralization', 'vigilance reduction', and 'auditive alteration', whereas the 11 subscales include 'experience of unity', 'spiritual experience', 'blissful state', 'insightfulness', 'disembodiment', 'impaired control and cognition', 'anxiety', 'complex imagery', 'elementary imagery', 'audio-visual synesthesia', and 'changed meaning of percepts'.
Spectral data was analyzed using LCModel) and all further analyses were carried out with R (version 4.4.0 for MacOS, R Core Team; Vienna, Austria;) and R Studio (version 2025.09.1 for MacOS, RStudio, Boston, Massachusetts, USA; see). All outcome measures were tested for normality using a Shapiro-Wilk test. Outliers in the glutamate measures were identified using the interquartile range (IQR), a non-parametric outlier method. For both hypotheses, we considered the whole-block average, as well as glutamate levels from three overlapping sub-blocks (Fig.). To test for glutamate increases from baseline to ketamine infusion, a one-tailed paired t-test was computed for whole-block average and a one-tailed two-way ANOVA for the sub-block analysis. Significance level was set to p < 0.05. To test whether glutamate changes are associated with increased subjective effects, a Spearman's rank correlation test was computed. We corrected for multiple comparisons by implementing the Benjamini-Hochberg, also known as False Discovery Rate correction. As an exploratory analysis for both hypotheses and in addition to glutamate changes (Δ glutamate), glutamate levels measured during the ketamine infusion were included in Spearman's rank correlation tests.
Quality of the 1 H-MRS measurement was assessed by signal to noise ratio (SNR), linewidth, measured as full width at half maximum (FWHM), and Cramér-Rao lower bounds (CRLB) for glutamate. For each individual, the SNR exceeded 18, FWHM was below 10 Hz, and CRLB was below 7%, indicating good spectral quality compared to studies using similar voxel volumes. No exclusion based on spectral quality was made. On average, the overlap between the voxel of the baseline and ketamine measurements was 77%. All quality measures for each condition (baseline/ketamine) are reported in Table, separately for whole-block average and sub-blocks. The individual spectra of all subjects for the baseline and ketamine measurement are shown in Figure.
Glutamate levels did not exceed the 1.5 x IQR threshold in any condition, indicating that there were no outliers. Whole-MRS-block average analysis A one-tailed, paired t-test showed no significant increase in glutamate levels (t(9) = -0.24, p = 0.59, d = -0.08, 95% CI [-1.14, 0.58]) during the ketamine administration. Mean glutamate values for baseline were 8.2 mmol/kg (SD = ± 0.6) and 8.3 mmol/kg (SD = ± 0.8) for ketamine condition (Fig.).
A two-way ANOVA was conducted to examine effects of the condition (baseline vs ketamine) and the three sub-blocks on glutamate levels. There was no significant main effect for either condition (F(1, 9) = 0.01, p = 0.92, η 2 = 0.0001) or sub-block (F(2,18) = 1.95, p = 0.17, η 2 = 0.03). The interaction between condition and subblock was not significant (F(2,18) = 0.51, p = 0.61, η 2 = 0.01). Mean glutamate levels across condition and subblock range from 8.3 to 8.8 mmol/kg (Fig.).
Both the five dimensions and the eleven subscales showed substantial variability across the ten volunteers, as illustrated in the radar plots (Fig.and), especially for oceanic boundlessness, visual restructuralization, and reductions in vigilance.
The Spearman's rank correlation test revealed significant correlations between delta glutamate (Δ glutamate i.e., glutamate [ketamine]glutamate [baseline]) and two dimensions of the 5D-ASC: anxious ego dissolution (r = 0.77, p = 0.01) and reductions in vigilance (r = 0.70, p = 0.03) (Fig.). However, only the correlation with anxious ego dissolution survived the correction for multiple comparison (p corr = 0.04), while vigilance did not (p = 0.08). Spearman's rank correlation between 5D-ASC scores and absolute glutamate values during the ketamine measurement led to similar results: anxious ego dissolution and vigilance showed positive correlations (anxious ego dissolution: p orr = 0.04, vigilance: p corr = 0.03) (Fig.). The correlation analysis with the eleven subscales, including the global 5D-ASC score, is shown in Figure. Additionally, an explorative Spearman's rank correlation test between baseline glutamate levels and the five dimensions of the 5D-ASC was performed to test the predictive value of baseline glutamate on ketamine-induced effects. No significant associations were found, indicating that the correlations observed during the ketamine infusion are unlikely to reflect pre-existing associations at baseline.
Quality measures for baseline and ketamine 1 H-MRS measurement in the nucleus accumbens for N = 10. On the left side are the quality measures for the whole-block average (512-signal-average), and on the right side of a sub-block (256-signal-average). P-value for paired t-test and Cohen's d with 95%-confidence interval. Tissue composition of the voxel, reported in % for gray matter, white matter and cerebrospinal fluid.
In order to shed light the mechanisms underlying the therapeutic effects of ketamine, glutamatergic changes in the NAc and their associated phenomenological effects were investigated in a sample of 10 healthy volunteers. The NAc is of particular interest because it integrates glutamatergic inputs from cortical and thalamic brain regions and serves as a neural hub for translating motivational and affective signals into behavior. Therefore, we compared glutamate levels in the NAc measured by 1 H-MRS at baseline and during the sub-anesthetic ketamine, and related ketamine-associated in glutamate concentrations to alterations in consciousness and perception. To our knowledge, this is the first study to assess the modulatory effects of ketamine on glutamate signaling in the NAc of humans. We found that glutamate levels in the NAc did not significantly increase between baseline and ketamine infusion in this sample. However, glutamate levels were positively associated with psychoactive effects of ketamine, specifically anxious ego dissolution and reduced vigilance. Contrary to the first hypothesis, no significant glutamate increases during the ketamine infusion did occur. This held true both for the overall glutamate levels averaged across the full 1 H-MRS acquisition and for the sub-block analysis in which the whole spectrum was divided into three overlapping segments to capture potential glutamate fluctuations. These findings stand in contrast to most of the preclinical studies) and some human pharmacological MRS studiesreporting glutamatergic increases following ketamine administration in other brain regions. However, findings from human MRS studies remain inconclusive, with one study in depressed patients reporting even decreased glutamate levels in the prefrontal cortex (PFC), while others report no significant changes. Several factors may account for this discrepancy. First, different brain regions, such as the anterior cingulate cortex and the PFC, were assessed in the human and rodent studies. More recent studies suggest that ketamine's effects on glutamate are dependent on brain region and synapses, leading even to decreases in glutamate releases at certain hippocampal and cortical synapses. In line with this regional specificity, ketamine-induced increases in glutamate in the NAc of up to 120% have been observed exclusively in rodents, leaving it unclear how this effect translates to humans. Secondly, while human studies quantified glutamate (or glutamine, or both combined) using MRS, the rodent studies relied on microdialysis, which measures metabolites locally within the extracellular space. In contrast, MRS reflects the aggregated metabolite signal from the entire voxel, giving limited ability to distinguish extracellular from intracellular glutamate. Therefore, changes in intra-and extracellular glutamate levels could go undetected, especially in small samples as in this pilot study. This, together with the small voxel size are possible explanations that could have led to the observed null effect. The markedly smaller size of the NAc compared with regions typically examined so far imposes substantial methodological constraints that directly influence both data quality and interpretation. The small voxel dimensions required to capture the NAc inevitably reduce the detectable metabolite signal, forcing considerably longer acquisition times to achieve acceptable SNR. This raises the possibility that transient or rapidly evolving changes in metabolites, such as short-lived increases in glutamate may occur on timescales much shorter than our effective measurement window and could therefore be averaged out and remain undetected in the final spectra. Our exploratory subdivision of the acquisition into 256-transient sub-blocks, despite their expectedly lower SNR and higher fitting uncertainty, offers preliminary hints of a subtle glutamate increase, suggesting that such dynamics may indeed be present but masked in the fully averaged dataset. In addition, the long measurement duration increases susceptibility to subject motion. Motion effects are amplified by the small voxel size: even minimal displacement can move the voxel partially out of the targeted NAc, thereby altering the effective tissue composition and distorting the derived metabolite estimates. While ketamine infusion did not induce significant changes in glutamate in the NAc at the group level, glutamate levels in the NAc were linked to particular subjective effects captured by the 5D-ASC. Greater glutamate increases in response to ketamine were associated with stronger experiences of 'anxious ego dissolution' and 'reductions in vigilance'. Anxious ego dissolution summarizes mostly unpleasant feelings, such as negatively experienced depersonalization, paranoia, cognitive disturbances, and loss of thought and body control. The dimension reductions in vigilance involves experiences of e.g., clouding of consciousness, slowed thinking and motion, and attenuated sensory awareness. Elevated glutamate levels in the NAc may enhance excitatory signaling, leading to stronger experiences on these two dimensions. The positive associations between glutamate changes and reduced vigilance and increased anxious ego dissolution also held true for absolute glutamate levels during the ketamine infusion. This was in line with our expectations, since glutamate changes (Δ glutamate i.e., glutamate [ketamine]glutamate [baseline) and glutamate levels during the infusion (glutamate [ketamine]) correlated strongly in our sample. This is consistent with previous findings where ketamine-dependent glutamate changes in prefrontal regions have been associated with psychotomimetic effects of ketamine, such as negative depersonalization and dissociative amnesia. On a related note, a recent study examining psilocybin-dependent glutamate changes in healthy participants found region-specific associations with ego dissolution. Increased prefrontal glutamate was associated with negatively experienced ego dissolution, whereas reduced hippocampal glutamate was associated with positively experienced ego dissolution, suggesting that substance-induced glutamate alterations and their experiential correlates may be region dependent. Although no study has directly linked glutamate increases in the NAc to anxious ego dissolution or reduced vigilance, evidence from rodent and human studies suggest a plausible mechanism: ketamine-induced glutamate elevations in the NAc may disrupt excitatory/inhibitory balance and interfere with mesolimbic-thalamocortical circuits, leading to altered self-experience and sensory dampening. Our findings suggest that glutamatergic modulation in the NAc during ketamine infusion may be particularly associated with negatively experienced depersonalization, loss of control over body and thought, and clouded consciousness, rather than with unity, positive mood, and heightened insight characteristic of the 5D-ASC dimension 'oceanic boundlessness. 'Additionally, it should be noted that exposure to music may influence subjective experiences during ketamine infusionand potentially modulate neural activity, including glutamate signaling. However, as the same standardized music playlist was presented during both baseline and ketamine measurements for all participants, any potential influence of music was consistent across subjects and conditions. Building on this, the broader literature summarized byemphasizes that the qualitative nature of ketamine's subjective effects may hold meaningful implications for therapeutic outcomes. While dissociative states have frequently been associated with clinical improvement in depression, the robustness of this relationship varies, suggesting that dissociation alone is unlikely to fully account for treatment response. Mystical-type experiences have emerged as potential positive predictors in two studies of cocaine use disorder. However, these experiences remain insufficiently characterized in ketamine research. This gap is partly attributable to the predominant use of the Clinician-Administered Dissociative States Scale (CADSS), which primarily captures dissociative symptoms rather than the broader spectrum of altered states of consciousness. Additional affective dimensions also appear to be relevant: for example, individuals with major depressive disorder who do not respond to ketamine exhibit greater anxiety during the intervention than responders, pointing to the possibility that negative emotional reactivity may interfere with therapeutic mechanisms. Together, these findings indicate that a broader range of subjective experiences, not only dissociation but also mystical qualities and affective responses, may help distinguish responders from non-responders in ketamine-assisted therapy, underscoring the need for more comprehensive psychometric assessment than the CADSS. Considering the sample size (N = 10), our findings should be interpreted as preliminary and exploratory. With this pilot study, we implemented a new 1 H-MRS protocol for a small, rather difficult to measure brain area which has shown to provide good spectral quality. The presented 1 H-MRS protocol is currently implemented in a phase II clinical trial to test ketamine's therapeutic and glutamatergic potential in individuals with cocaine use disorder. It remains to be determined how ketamine's NMDA-receptor antagonism affects the glutamate levels of individuals with SUDs. In this study, ketamine infusion did not produce significant grouplevel increases in NAc glutamate from baseline. Nonetheless, interindividual variability in glutamate changes was associated with subjective experiences marked by increased anxious ego dissolution and reduced vigilance. Future studies should clarify the mechanisms underlying these associations and determine whether glutamatergic modulation can be therapeutically harnessed, as well as whether these subjective experiences contribute to therapeutic outcomes.
Marcus Herdener has received consulting fees from Boehringer-Ingelheimer unrelated to this study. All other authors have nothing to declare.
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