Subanesthetic-dose racemic (R,S)-ketamine (hereafter referred to as ketamine) is a promising treatment for depression (1–3). The exponential growth in its utilization reflects a shifting landscape in psychiatric care (4, 5). Nevertheless, some individuals receiving antidepressant-dose ketamine report peculiar experiences, including dissociative symptoms—defined as a disconnect between thoughts, emotions, sensations, and the surrounding environment (6–8), altered perceptions of color, and feelings of floating (9, 10). In this context, clinics are actively embracing diverse strategies to optimize the therapeutic potential of ketamine by cultivating an environment that is both positive and supportive for patients (7, 11–13). Strategies include incorporating familial presence, guidance of supportive staff, providing eye masks to reduce light sensitivity, and allowing patients to recline, fostering a relaxed atmosphere to alleviate potential confusion, agitation, or anxiety during ketamine infusion (11). Given the patient-specific nature of these interventions, a crucial element is aligning strategies with individual preferences to tailor each session to unique needs and comfort levels (11, 13–15).

Amongst these strategies, the integration of music and mindfulness during ketamine infusion therapy is a relatively unexplored area. The existing literature on this topic is sparse and leaves a critical gap in understanding the impact of these interventions on the overall ketamine experience, particularly in the context of treating depression (16, 17). Existing studies suggest that combining music or mindfulness with ketamine/esketamine (the S-enantiomer of ketamine) treatments generally reduced distress, provided relaxation, reduced ambient noise, and connected individuals to reality (6, 7, 18–21). Nevertheless, significant variations in individual experiences have been noted; with regard to music, for instance, some studies suggested that individuals found comfort in specific music genres (16, 22), while others felt that music had unpredictable and occasionally negative effects (6). Moreover, a recent randomized, controlled trial investigated the impact of ketamine combined with music and a mindfulness-supportive control condition compared to ketamine alone in individuals with treatment-resistant depression and found that while depressive symptoms were significantly improved in both groups, there were no significant differences between conditions (23). Importantly, the mindfulness component was not standardized and was primarily intended to support relaxation rather than serve as a structured therapeutic intervention.

From a neurobiological standpoint, ketamine rapidly enhances synaptic plasticity by modulating glutamatergic signaling—activating the mechanistic target of rapamycin (mTOR) pathway and increasing brain-derived neurotrophic factor (BDNF) expression—creating a transient window of heightened neural receptivity (e.g., increased connectivity and circuit remodeling) (24, 25). This enhanced plasticity may allow external inputs (such as music and mindfulness) to shape therapeutic effects during infusion. Likewise, psychological models of emotion regulation propose that mindfulness reduces rumination and enhances attention control via neurobiological changes in networks like the insula, cingulate cortex, and prefrontal areas (26). In this context, music therapy during ketamine sessions has been demonstrated to decrease distress and support emotional grounding, facilitating more tolerable experiences (6, 16). Together, these interventions leverage neurobiological and psychological mechanisms, including synaptic plasticity, emotion regulation circuitry, and sensory grounding, to potentially enhance and guide the acute ketamine experience as well as its downstream antidepressant outcomes. Within this framework, the study hypothesis was that adding mindfulness and music would synergistically amplify ketamine-induced synaptic plasticity and emotion regulation, leading to greater reductions in depressive symptom scores and more positive subjective experiences versus ketamine alone.

In addition to music and mindfulness, visual occlusion using eye masks has emerged as a potentially meaningful component of the ketamine experience. Although often used informally to promote relaxation or reduce external distractions, recent findings suggest that eye mask use may alter neural and phenomenological responses during ketamine administration. For example, Farnes and colleagues demonstrated that ketamine infusions administered with versus without eye masks produced distinct profiles of electroencephalogram (EEG) signal diversity and subjective experiences, as measured by the 11-Dimensional Altered States of Consciousness (11D-ASC) scale (27). Specifically, they found that visual occlusion (eyes closed or masked) was associated with stronger correlations between EEG complexity and imagery-related experiences, while eyes-open conditions were linked to higher levels of anxiety and reduced experiences of unity. These findings suggest that light occlusion may influence both the emotional and perceptual dimensions of the ketamine experience and could play an important role in shaping therapeutic outcomes. Despite its routine use in some clinical and psychedelic contexts, eye mask use remains an underexplored variable in ketamine research and warrants further investigation.

To our knowledge, no prior randomized, controlled study has experimentally manipulated the combination of mindfulness, music, and eye mask during ketamine infusion to assess their impact on depressive symptoms using both qualitative and quantitative measures. This study sought to explore the impact of this combined sensory intervention on ketamine therapy for unipolar depressive disorders (primarily major depressive disorder). Forty-three individuals with clinical depression were randomized to receive ketamine infusion plus either a combined mindfulness, music, and eye mask intervention (n=22) or ketamine with no additional interventions during infusion (control group; n=21). A comprehensive assessment protocol, including clinician-rated depression scales, depression-specific questionnaires, and open-ended qualitative descriptions of subjective experiences, was implemented at multiple timepoints. Through both qualitative and quantitative mixed methods analyses, this study sought to study the impact of this combined sensory intervention in the context of ketamine treatment for clinical depression, contributing clinically relevant insights to the evolving landscape of psychiatric care.

To promote a comprehensive understanding of the potential benefits and nuances associated with the integration of combined sensory intervention during ketamine infusion, the outcomes of this study are presented through two distinct lenses: qualitative and quantitative results.

Collectively, the results of this study underscore that integrating mindfulness, music, and visual occlusion (eye mask) into ketamine treatment can profoundly shape the patient experience and enrich the emotional and subjective dimensions of the infusion process. Qualitative analyses showed that participants who received the mindfulness, music, and eye mask intervention during the infusion often described a deeper engagement with the experience, marked by moments of relief, clarity, connection, and even awe—emotional undertones reported less frequently by the control group. Interestingly, quantitative analyses showed that depression scores improved significantly and similarly across both groups at different post-infusion timepoints (24 hours and 5, 12, 21, and 30 days post-infusion), suggesting that combined sensory intervention—including mindfulness, music, and a light-occluding eye mask—did not affect antidepressant response to ketamine as assessed by depression rating scale scores.

Quantitative analyses found no significant differences in depression scale scores between participants who received ketamine with the combined mindfulness, music, and eye mask intervention compared to a control group who received ketamine alone. This aligns with a study of 37 individuals with treatment-resistant depression who underwent 494 sessions of intranasal esketamine (37). In 52% of these sessions, patients listened to their own music via headphones. While the study did not directly contrast participants who listened to music with those who did not, no disparity was found in MADRS or Beck Depression Inventory (BDI) scores between the two groups; notably, however, those who listened to music had reduced anxiety, lower blood pressure, and better tolerance to higher doses. Our quantitative results are also in line with a recent study by Greenway and colleagues (23) who similarly found no significant differences between ketamine combined with music and a mindfulness-supportive control condition (no eye mask), compared to ketamine alone. In their study of individuals with severe, highly comorbid treatment-resistant depression, mindfulness was delivered as non-standardized encouragement to engage in practices such as body scanning and breath awareness. Together, these studies highlight the complexity of parsing the specific contributions of experiential adjuncts to ketamine therapy and point to the need for further trials with larger samples, more structured interventions, and standardized control conditions.

The study hypothesis was that the combined sensory intervention would yield greater reductions in depressive symptoms than ketamine alone, via mechanisms that leveraged ketamine’s neurobiological window of enhanced plasticity (via BDNF upregulation and mTOR pathway activation) and supported emotion regulation processes. Contrary to this expectation, quantitative measures (MADRS, HAM-D) did not differ significantly between groups, though qualitative reports indicated that participants receiving the intervention experienced more tolerable, emotionally grounded, and enriched infusions. This divergence suggests that such adjuncts may primarily influence the subjective quality and integration of the ketamine experience rather than producing large, immediate changes in symptom severity within the measured time frame. However, it should be noted that the modest sample size may have limited statistical power to detect smaller between-group effects in quantitative outcomes.

In this study, all participants (both groups) exhibited significantly reduced MADRS and HAM-D scores 24 hours post-ketamine infusion and at five other post-ketamine timepoints compared to pre-infusion baseline scores. Ketamine’s antidepressant effects have been well-documented in randomized, controlled trials (3). Because all participants and evaluators in this study were aware of the open-label ketamine infusion, the decreased depression scores likely reflect a combination of ketamine’s therapeutic effects and non-specific factors such as patient and rater expectancies, repeated assessment, and social attention from the study team, carefully matched across conditions.

Broadly, the qualitative findings identified a variety of both positive and negative effects for participants of both groups, though predominantly positive experiences were noted. Despite differences in the interventions, participants in both groups experienced similar broad themes (see Table 1 ). This suggests that while a combination of mindfulness, music, and eye mask may enhance certain aspects of the experience, neither was necessary for achieving a robust antidepressant response; furthermore, the core effects of the ketamine infusion were consistent across both groups, aligning with our quantitative findings showing no differences in depression rating scale scores between the groups. Some of these experiences—both positive and negative—have been noted in prior studies exploring the experiential nature of a ketamine infusion without additional interventions. For example, body distortion (38, 39) and sensory alterations (mostly visual) (40) have previously been reported with ketamine infusion and appear to be intrinsic to the drug itself, although they can also be affected by music and mindfulness (12). For instance, a handful of studies exploring the effects of music on ketamine infusion found that hearing music during ketamine treatment altered the treatment experience, with some finding comfort in specific music genres, while others felt that music kept them more connected to the external world (16, 22). Although the previous literature exploring music or mindfulness alongside ketamine is scant and encompasses diverse medical conditions (20), medication combinations, dosages, and order of administration (16), several studies have highlighted the beneficial impact of music in conjunction with ketamine for individuals with mood disorders. Specifically, such studies suggest that music or mindfulness administered in conjunction with ketamine reduced participant distress surrounding dissociative symptoms, providing a relaxing effect that facilitated subsequent treatments (6, 7, 18–21). However, in the current randomized trial, no noteworthy differences were observed across the two groups with regard to adverse events and acute mood states post-infusion. In addition, the use of a light-occluding eye mask in our intervention group may have contributed to participants’ inward focus and modulation of sensory input. Recent findings from Farnes and colleagues (27) demonstrated that visual occlusion during ketamine infusion altered EEG signal complexity and was associated with distinct phenomenological profiles—such as increased visual imagery and reduced anxiety—compared to eyes-open conditions. These effects may help explain participants’ reports of heightened emotional sensitivity in the present study and suggest that eye mask use could be a non-pharmacological means to shape the therapeutic experience.

As noted above, in the present study, both positive and negative experiences were more frequently reported by the combined sensory intervention group. Broadly, participants in the combined sensory intervention group appeared to experience heightened emotional sensitivity, making them more attuned to both positive and negative aspects of their experience. Some of these reactions may have been a direct result of mindfulness techniques; for instance, encouraging participants to note their thoughts or emotions in a non-judgmental way may have made them more likely to notice that they could not ‘control’ their thoughts. Similarly, such noting of the experiential state may have made participants more likely to recognize and label their discomfort, fear, or anxiety and recall it when prompted 30 days later. The inability of participants to select their own music may also have led to discomfort, as personalizing music is often recommended in ketamine therapy (6, 16, 19). An additional exploratory analysis was conducted to explore potential relationships between the qualitative and quantitative findings in this study. The analysis sought to assess whether there were differences in MADRS and HAM-D score changes between participants in the combined sensory intervention group who reported specific themes during the qualitative analysis compared to those who did not, as well as compared to the control group (see Supplementary Figure S6 ). Although the results from this analysis did not reach statistical significance, they may point to potential areas for further research, particularly in studies with larger sample sizes.

From a mechanistic perspective, the heightened emotional responses observed in some participants may reflect a synergistic engagement of neural and psychological systems. Ketamine rapidly reduces amygdala-hippocampal reactivity to negative stimuli and enhances prefrontal-limbic connectivity, creating a neuroplastic window whereby environmental inputs—such as music or mindfulness or eye mask—can exert especially potent effects on emotion processing (e.g., decreased amygdala reactivity to negative images correlates with increased connectivity to the pregenual anterior cingulate cortex) (41). Mindfulness training engages interoceptive and emotion-regulation regions, including the insula, anterior cingulate cortex, and prefrontal cortex, enhancing awareness and labeling of emotional states (42). Concurrently, music stimulates affective subcortical circuits such as the amygdala and hippocampus, anchoring emotional experiences in a sensory context. These interventions may amplify emotional salience during ketamine’s neuroplastic phase, leading to more intense subjective experiences in some individuals. However, inter-individual differences (such as baseline neural connectivity, emotion regulation capacity, or prior mindfulness familiarity) could explain why some participants had stronger emotional reactions than others. For instance, those with greater baseline amygdala-prefrontal coupling might be more sensitive to emotion-laden stimuli post-infusion, making them particularly responsive to music or mindfulness cues. To disentangle these mechanisms, future studies should incorporate neuroimaging (e.g., fMRI, EEG) to elucidate how these interventions modulate brain networks in real time, thus clarifying both common and individual-specific pathways. Such data would strengthen the theoretical contribution, linking changes in neural dynamics to qualitative reports of positive or negative emotional responses.

The present findings serve to highlight a key point regarding the role that therapeutic milieu may play in the psychoactive differences between ketamine and SPs such as psilocybin, lysergic acid diethylamide (LSD), or 3,4-Methylenedioxymethamphetamine (MDMA). This observation underscores the critical need for a multi-disciplinary approach in psychedelic-assisted therapies, where the expertise of psychologists and mental health professionals may influence therapeutic outcomes (7, 16, 19). The concepts of set (mindset) and setting (that is, where the agents are administered) have been implicated in therapeutic outcomes following SPs (43), although direct causal evidence for their impact on therapeutic outcomes remains limited. While correlational data support the relationship between acute subjective experiences and clinical response—for both SPs and ketamine—randomized trials that experimentally manipulate these contextual factors are still underway, and data are not yet available (44, 45). Ketamine is typically administered in standard clinical settings with relatively less focus on set and setting than SPs, which are often delivered in more controlled, supportive environments (46–49). In this context, our study adds to the growing body of research by experimentally manipulating components of the ketamine therapeutic environment—specifically, mindfulness, music, and eye mask—and observing their effects on the subjective experience. Here, mindfulness, music, and eye mask added new dimensions to the ketamine experience, as those who received the combined sensory intervention during ketamine more often reported positive effects, such as connecting to reality and managing negative thoughts, compared to those who received ketamine alone; this suggests that similar interventions may potentially enhance patient adherence to future treatments.

It is important to note that the mindfulness intervention used in this study was limited to a single 20-minute audio-guided session, which likely represents a minimal dose relative to protocols shown to produce robust clinical effects. Brief mindfulness inductions, particularly among mindfulness-naïve individuals, have been shown to yield only modest and often conditional state-level effects (50). This limited exposure may have attenuated potential differences between the intervention and control groups. Future studies may benefit from incorporating extended or repeated mindfulness training protocols, such as those used in Mindfulness-Based Cognitive Therapy (MBCT) (51), to better assess synergistic effects with ketamine. Early evidence drawn from other clinical populations, such as substance use disorders, suggests that more intensive mindfulness interventions delivered in conjunction with ketamine may enhance therapeutic outcomes (20).

Additional limitations should also be noted. First, the sample size was small (n = 43 randomized; 22 in the combined sensory intervention group versus 21 in the controls). A sensitivity power analysis indicated that this sample provided 80% power (α = 0.05, two-tailed) to detect a minimum effect size of Cohen’s d = 0.88. While this suggests adequate power for large effects, smaller but potentially meaningful differences may have gone undetected. Larger, adequately powered trials are needed to confirm and extend these findings. Second, the inclusion of a third group receiving drug placebo would have provided a more comprehensive understanding of ketamine’s effects. Third, individual variability in baseline depression severity, prior exposure to ketamine, and familiarity with mindfulness practices were not systematically assessed or controlled for in the present analyses. These factors may have influenced both subjective experiences and treatment response and should be considered in future work. Fourth, adding brain imaging techniques such as magnetoencephalography or electroencephalography could have helped further elucidate the effects of our combined therapeutic approach. Physiological measures (e.g., heart rate variability, skin conductance) could also offer additional insight into emotional arousal and regulatory processes during and after ketamine infusion. Fifth, the use of open-ended questionnaires, which was useful for gathering data from nearly all participants quickly, may nevertheless have led to variability and missed nuances in responses. Future studies might benefit from semi-structured interviews to better capture the details of the ketamine infusion experience. Sixth, to maintain consistency in our experimental design, the same music and mindfulness tracks were played for all participants. While this standardization facilitated control across participants, it may have reduced the intervention’s effectiveness for some participants, particularly those unfamiliar with mindfulness or who found the provided music less engaging or even discomforting. This variability in personal resonance with the content may have contributed to the mixed qualitative reports; prior work suggests that music tailored to individual preferences may be more effective in shaping ketamine experiences (6). Future research could explore personalized music selection and mindfulness scripts stratified by prior mindfulness experience or individual preference to better match participants’ backgrounds and optimize engagement. Seventh, test-retest interviews were not conducted. Given the acutely evolving ketamine experience and the need to minimize reactivity and burden, these procedures were not feasible within the study design. Future work should incorporate pragmatic approaches to participant validation (e.g., brief theme summaries for confirmation) and, where appropriate, short-interval retest interviews to assess thematic stability. Eighth, data on participants’ engagement in concomitant psychotherapy with external providers during the study period was also not collected. Prior naturalistic research suggests that concurrent psychotherapy may moderate the therapeutic effects of ketamine infusions on symptom reduction, with greater improvements observed among those receiving psychotherapy (52). Future studies should assess and account for such factors to better clarify their potential moderating influence. Finally, the time delay between infusion and participants sharing their experiences was 30 days, which allowed participants to reflect on the most salient aspects of the experience from a more distal, and potentially more crystallized or enduring, vantage point, but it may also have impacted their recollection of events.

In light of the promising subjective outcomes observed, these findings also carry potential implications for clinical practice. Clinicians considering the integration of mindfulness, music, and eye mask into ketamine treatment protocols may benefit from using brief, structured interventions timed to coincide with ketamine’s acute psychoactive window. For example, a 10-15 minute guided mindfulness session initiated shortly before infusion, followed by continuous ambient music throughout the infusion, may offer a feasible and low-burden approach that supports patient comfort and emotional processing, though these may not necessarily enhance quantitative antidepressant outcomes. Implementation in real-world settings may require minimal clinician training in delivering brief mindfulness scripts and access to curated, licensed music libraries; these steps are relatively low-cost and could be incorporated into existing ketamine protocols without substantial workflow disruption. Future research focused on real-world implementation should explore flexible protocols that allow for personalization, such as letting individuals select from a curated set of music genres or mindfulness styles (e.g., body scan vs. breath awareness) based on their preferences or therapeutic goals, while also allowing them to opt out without impacting the core ketamine treatment, as overall antidepressant efficacy appears unlikely to be impacted. Given the absence of significant quantitative effects, combined with the qualitative reports of reduced anxiety and enhanced emotional grounding, such adjuncts should be framed as optional enhancements aimed at improving patient experience rather than as established boosters of antidepressant efficacy.

In conclusion, this first randomized trial to test the impact of experimentally manipulating a combined sensory intervention—including mindfulness, music, and a light-occluding eye mask—during ketamine infusion found that depression scores improved significantly and similarly across both groups—regardless of whether participants received ketamine alone or in combination with mindfulness, music, and eye mask—highlighting ketamine’s robust therapeutic efficacy. However, qualitative data revealed that the combined sensory intervention meaningfully enriched the subjective experience for most—but not all—participants, heightening their awareness of positive emotional states such as deeper engagement, a stronger sense of connection to reality, greater focus on the present moment rather than its strangeness, and even episodes of relief, awe, and spiritual insight. A small number of participants also reported discomfort—an effect that might be mitigated by offering these interventions as an optional component.

Given the limited and largely anecdotal research into ketamine therapy combined with either mindfulness or music or eye mask, these findings are a valuable contribution to the field, laying the groundwork for future investigations in this area aimed at optimizing therapeutic context, integration, and adherence.