What Is Dissociation—and Is It Necessary for the Antidepressant Effects of Ketamine and Spravato?

One of the most common questions we hear from patients receiving ketamine or Spravato treatment is whether they are “supposed” to dissociate. Some patients experience a significant sense of detachment from their body or surroundings, changes in their perception of time and space, or the feeling that they are observing themselves or their thoughts from a distance. Others experience only subtle perceptual changes, while some patients experience very little dissociation at all. This naturally raises an important question: Is dissociation necessary for ketamine or Spravato to work as an antidepressant?

Some view dissociation as a temporary side effect of ketamine and esketamine treatment rather than an essential component of their antidepressant effects. This perspective is supported by evidence that meaningful improvement in depression can occur even in the absence of significant dissociation. At the same time, a growing body of research suggests that the relationship between dissociation, altered states of consciousness, and therapeutic response may be more complex, raising important questions about whether these subjective experiences may play a role in treatment for at least some patients.

A newly published 2026 study in the Journal of Psychiatric Research adds an interesting piece to this discussion. Researchers examining patients with treatment-resistant depression found that those who responded to repeated subcutaneous esketamine treatment experienced significantly greater overall dissociation, particularly derealization, than patients who did not respond. However, the study does not establish that dissociation caused the antidepressant response, nor does it demonstrate that a patient must dissociate in order to improve.

What Does “Dissociation” Actually Mean?

The word dissociation can sound concerning, especially for someone considering ketamine treatment for the first time. In the context of medically supervised ketamine or Spravato treatment, dissociation generally refers to a temporary alteration in the way a person experiences themselves, their body, or their surroundings. Patients may describe feeling unusually light or as though their body is floating. Time may seem to move differently, music can become more immersive, the surrounding environment may feel distant, or thoughts and emotions may seem easier to observe from an outside perspective.

Researchers commonly divide dissociation into several components. Derealization refers to an altered perception of the outside world, in which the environment may temporarily seem distant, dreamlike, or unreal. Depersonalization describes a sense of separation from oneself or one’s body, sometimes described as observing oneself from a distance. These effects are temporary and occur while ketamine or esketamine is pharmacologically active.

It is also important to recognize that not every unusual or altered experience produced by ketamine fits neatly under the term “dissociation.” Patients may experience changes in their perception of time, vivid imagery, emotional openness, a sense of psychological distance from their problems, or changes in how they relate to memories and emotions. The authors of the new study point out that commonly used dissociation scales may not fully capture this broader range of altered states of consciousness.

Why Does Ketamine Cause Dissociation?

Ketamine primarily affects the brain’s glutamate system, including activity at NMDA receptors. This mechanism is very different from traditional antidepressants such as SSRIs and SNRIs. At the doses used to treat depression, ketamine can temporarily alter communication between brain networks involved in sensory processing, self-perception, emotion, memory, and awareness. The resulting experience can vary considerably from one patient to another.

An important distinction is that the biological mechanisms believed to contribute to ketamine’s antidepressant effects are not necessarily the same thing as dissociation. Ketamine influences glutamate signaling and downstream processes involved in synaptic plasticity and neural connectivity. Dissociation can occur alongside these pharmacologic effects, but whether the subjective experience itself contributes to therapeutic improvement remains an open scientific question. This distinction helps explain why a patient may potentially receive meaningful antidepressant benefits without experiencing an intense dissociative state.

Does More Dissociation Mean a Better Antidepressant Response?

Research examining this question has produced mixed results. Some studies have found associations between the intensity or particular characteristics of ketamine-induced dissociation and subsequent antidepressant improvement, while others have found little or no meaningful relationship. This inconsistency has led researchers to question whether dissociation contributes directly to therapeutic effects, simply accompanies them, or perhaps serves as a marker of an individual’s sensitivity to ketamine.

The new 2026 study, titled Dissociation and antidepressant response to subcutaneous esketamine: A clinical study, examined this question in patients with treatment-resistant depression receiving up to eight weekly treatments with subcutaneous esketamine. Dissociation was measured using the Clinician-Administered Dissociative States Scale (CADSS), while depression was evaluated using the Montgomery–Åsberg Depression Rating Scale (MADRS) and Beck Depression Inventory-II (BDI-II). Patients were considered responders if they experienced at least a 50% reduction in their MADRS score by the end of treatment. Of the 30 patients initially enrolled, 23 completed all eight sessions and were included in the final analysis.

The results were intriguing. Patients who ultimately responded to esketamine experienced significantly higher overall dissociation scores than nonresponders across the treatment period. The difference was particularly pronounced for derealization, which was significantly higher among responders. Depersonalization and amnesia also tended to be higher among responders, although those differences did not reach statistical significance.

At first glance, these findings might seem to suggest that greater dissociation leads to a better antidepressant response. However, another finding from the study makes the picture considerably more complicated. When the researchers examined changes within individual patients, they found no significant relationship between the intensity of dissociation and subsequent changes in depression symptoms as measured by MADRS or BDI-II. In other words, responders tended to dissociate more than nonresponders as a group, but a more dissociative individual treatment session did not reliably predict greater improvement in depression afterward.

Association Does Not Mean Dissociation Is Necessary

This distinction is important because the study does not demonstrate that dissociation is necessary for esketamine to work, nor can it establish that dissociation itself caused patients to improve. There are several possible explanations for the association. Dissociation could potentially contribute to therapeutic response, but it is also possible that people who are biologically more responsive to ketamine are simply more sensitive to some of its subjective effects. In that case, dissociation could function more as a marker of sensitivity to the medication rather than being the mechanism responsible for improvement.

The study also had important limitations. The final analysis included only 23 patients and was a secondary exploratory analysis rather than a trial specifically designed to determine whether dissociation causes antidepressant improvement. The researchers also used a dose-escalation protocol, which makes it difficult to completely separate the effects of medication exposure, dissociation, and clinical response. The authors therefore appropriately characterize the findings as exploratory and emphasize the need for larger prospective studies.

There is also evidence pointing in the opposite direction. The paper discusses a much larger analysis of the TRANSFORM-1 and TRANSFORM-2 trials involving 576 patients receiving intranasal esketamine. That analysis did not find evidence of a clinically significant relationship between dissociation scores and antidepressant outcomes during the four-week induction period. Differences in route of administration, dosing, study populations, and how subjective experiences are measured could potentially contribute to these conflicting results.

Taken together, the research suggests that the relationship is probably more nuanced than either “dissociation is required” or “dissociation doesn’t matter.”

You Do Not Need to “Chase” Dissociation

From a clinical standpoint, patients should not assume that treatment has failed simply because they did not experience significant dissociation. Likewise, an intense dissociative experience does not guarantee that someone will have an antidepressant response. For this reason, we do not believe the goal of treatment should simply be to produce the most intense experience possible.

The effectiveness of ketamine or Spravato should ultimately be judged by what happens outside the treatment room. We want to know whether depression is improving, suicidal thinking is decreasing, motivation is returning, patients are reconnecting socially, and functioning at home or work is improving. We also look for changes in emotional flexibility, resilience, interest, and the ability to engage more fully with everyday life. Those changes are much more clinically meaningful than how unusual or intense an individual treatment session feels.

Our Perspective at Innerbloom

In our experience at Innerbloom Ketamine Therapy, we have seen patients experience meaningful antidepressant responses across a wide range of subjective treatment experiences. Some patients dissociate significantly, while others experience relatively mild perceptual changes. We have also seen patients experience substantial improvement in their depression despite having very little dissociation during treatment. For that reason, I do not consider dissociation necessary for ketamine or Spravato to produce an antidepressant response, and I would never conclude that a treatment was unsuccessful simply because a patient remained relatively grounded throughout the session.

At the same time, after treating many patients with ketamine and Spravato, I don’t think we should automatically dismiss the subjective experience as an irrelevant side effect. In particular, it is my opinion that dissociation and the broader altered state produced by ketamine may offer an additional therapeutic benefit for certain patients struggling with anxiety, trauma, and PTSD. This is a clinical observation and hypothesis rather than something that has been definitively established by research, but it is an aspect of treatment that I believe deserves further study.

One possible explanation is that the altered state can temporarily change the relationship a person has with difficult thoughts, emotions, and memories. Patients with trauma can understandably develop deeply conditioned emotional responses to certain memories or triggers. A thought, situation, place, or memory may immediately produce fear, anxiety, shame, hypervigilance, or another powerful emotional response. During a ketamine experience, some patients describe being able to think about difficult experiences while feeling somewhat psychologically removed from them. Instead of being completely immersed in the memory and its associated emotions, they may feel as though they are observing it from a different vantage point.

That psychological distance may potentially be therapeutic. It may allow someone to revisit an experience without automatically producing the same emotional response that has accompanied it for years. Some patients describe seeing a past experience from a different perspective, developing greater compassion toward themselves, or recognizing that a traumatic memory belongs to their past rather than their present. We do not yet know precisely what these experiences mean neurobiologically or how much they contribute to long-term clinical improvement, but they may represent an important area for future research, particularly when ketamine treatment is combined with appropriately trained psychotherapy.

Where Ketamine-Assisted Psychotherapy May Fit In

This possibility is also one of the reasons we offer ketamine-assisted psychotherapy (KAP) at Innerbloom. If ketamine temporarily creates greater psychological flexibility or distance from deeply ingrained emotional patterns, psychotherapy may provide an opportunity to work constructively within that state and during the period following treatment.

This does not mean that every ketamine session needs to include psychotherapy, nor does it mean that every patient needs to have a profound psychological experience. Ketamine has antidepressant properties as a medication in its own right. However, for some patients—particularly those whose depression is intertwined with trauma, anxiety, rigid negative beliefs, or longstanding emotional patterns—the psychological component of the experience may deserve greater attention.

For the new 2026 study, patients did not receive preparatory psychotherapy before esketamine administration or participate in a structured integration process afterward. The authors discuss the possibility that future research should pay greater attention to psychological support, treatment environment, and the subjective experience associated with ketamine-based therapies.

Every Ketamine Experience Is Different

Another important point for patients is that treatment experiences can vary tremendously, even within the same person. A patient may experience significant dissociation during one infusion and relatively little during another. A Spravato session may feel profound one week and relatively uneventful the next. The subjective intensity of treatment can be affected by dose, route of administration, individual biology, medications, anxiety, expectations, treatment environment, and many other factors.

This variability is another reason patients should avoid judging the success of treatment based on what happens during a single session. Sometimes patients become concerned when an early treatment feels intense and a later treatment does not, wondering whether they have developed a tolerance or whether the medication has stopped working. A less intense subjective experience does not necessarily mean the treatment has stopped producing therapeutic effects. Treatment response is better evaluated longitudinally by looking at symptoms, function, safety, quality of life, and the patient’s overall trajectory.

So, Is Dissociation Necessary?

Based on the evidence available today, we cannot say that dissociation is necessary for the antidepressant effects of ketamine or Spravato. Patients can improve without substantial dissociation, and the intensity of an individual treatment experience should not be used as a simple measure of whether the medication is working.

At the same time, emerging research challenges the idea that dissociation should always be viewed as nothing more than an unwanted side effect. This new study found that patients who responded to subcutaneous esketamine experienced greater overall dissociation and, specifically, greater derealization than nonresponders. However, dissociation did not reliably track subsequent improvements in depression symptoms within individual patients, and the researchers emphasize that larger prospective studies are needed before these findings can be translated into clinical recommendations.

The most scientifically accurate conclusion at this point is that the relationship between ketamine’s subjective effects and its therapeutic effects remains unresolved. Ketamine is unusual among psychiatric medications because it can produce both rapid neurobiological effects and, in many patients, a powerful temporary alteration in conscious experience. We are still learning how these two components interact and whether particular aspects of the experience contribute to clinical improvement.

At Innerbloom, our focus is not on making every patient dissociate. Our goal is to provide treatment in a safe, supportive environment and carefully evaluate whether it is creating meaningful improvement in the patient’s life. For some people, the medication’s biological antidepressant effects may be the most important component of treatment. For others—particularly patients dealing with trauma, anxiety, or deeply entrenched emotional patterns—the altered state itself may provide an additional therapeutic opportunity. Future research will hopefully help us better understand when, why, and for whom that experience matters.