New Analysis Puts Ketamine Side Effects Under the Microscope
A clinical review published in Psychiatric Times in April 2026 is drawing renewed attention to the side effect profiles and discontinuation rates associated with NMDA receptor antagonists — the drug class that includes both intravenous (IV) ketamine and intranasal esketamine (Spravato) — in patients with treatment-resistant depression (TRD). The analysis urges clinicians to move faster and more deliberately: optimizing doses sooner, switching between agents when needed, and tracking standardized outcome measures like the PHQ-9 to reach remission more efficiently.
For the growing number of patients and families weighing ketamine-based therapies, the review is a useful, if nuanced, reminder that these treatments are not side-effect-free — and that how well a clinic monitors and responds to those side effects may matter as much as the drug itself.
What the Research Actually Shows
NMDA receptor antagonists work by temporarily blocking glutamate receptors in the brain, producing rapid antidepressant effects that can emerge within hours — a meaningful advantage over traditional antidepressants that can take weeks. But that same mechanism drives a distinct set of short-term side effects that set ketamine apart from SSRIs and SNRIs.
The most commonly reported side effects during and immediately after ketamine infusions or esketamine sessions include dissociation (a feeling of detachment from one's body or surroundings), perceptual distortions, dizziness, nausea, elevated blood pressure, and sedation. For most patients, these effects are transient — peaking during the session and resolving within one to two hours afterward. That time-limited quality is one reason ketamine is typically administered in monitored clinical settings rather than taken at home.
Discontinuation rates — meaning patients who stop treatment before completing a course — are a more complicated story. The review highlights that discontinuation can happen for several reasons: intolerable side effects, lack of efficacy, logistical barriers like cost and travel, or simply reaching remission and no longer needing continued sessions. Parsing why patients stop is essential context that aggregate dropout numbers alone can obscure. A high discontinuation rate at a poorly run clinic may signal tolerability problems; the same rate at a well-run clinic may reflect patients who got better and graduated out of treatment.
The clinical guidance embedded in the review focuses on what practitioners can do to improve outcomes: adjusting dosing protocols when a patient isn't responding rather than persisting with an ineffective regimen, considering a switch between IV ketamine and esketamine when one agent isn't working, and using validated depression rating scales to track progress systematically rather than relying on subjective impression alone.
Understanding the Evidence Quality
It's worth noting what kind of evidence a review article like this represents. Clinical reviews synthesize existing literature and expert opinion — they don't generate new trial data. That means the conclusions reflect the current weight of published research rather than a new randomized controlled trial. The existing evidence base on ketamine's side effect profile is reasonably robust for short-term effects, particularly from IV ketamine studies and the esketamine approval trials. Long-term safety data — covering repeated treatment over months to years — remains thinner, and that gap is an honest limitation the field acknowledges.
The push for faster, data-driven decision-making is consistent with what many leading ketamine researchers have advocated for years: that TRD is a serious condition where delayed or inadequate treatment carries its own costs, including ongoing suffering and suicide risk. Optimizing treatment protocols isn't just about minimizing side effects — it's about improving the odds that patients who need relief actually get it within a clinically meaningful timeframe.
What This Means If You're Evaluating Ketamine Therapy
For patients and families in the early stages of exploring ketamine or esketamine treatment, this analysis reinforces several practical realities worth understanding before you walk into a clinic.
Side effects are real but usually manageable. Dissociation and perceptual changes can be disorienting, especially during a first session. That experience varies considerably between individuals — some find it mild or even interesting, others find it deeply uncomfortable. Asking a prospective clinic how they prepare patients for these experiences, and how they support patients during sessions, is entirely reasonable and reveals something important about care quality.
Blood pressure monitoring matters. Ketamine reliably raises blood pressure during administration. Clinics should be checking vitals before, during, and after infusions. If a clinic doesn't have a clear protocol for managing cardiovascular side effects, that's a red flag.
Tracking your response systematically helps. The recommendation to use tools like the PHQ-9 — a standardized nine-question depression severity scale — isn't just for clinicians. Patients who enter treatment with a clear baseline score and track it over a series of sessions are better positioned to have informed conversations with their providers about whether to continue, adjust, or try a different approach.
Discontinuation doesn't always mean failure. If you or a family member stops treatment, context matters enormously. Stopping because side effects were intolerable is a different outcome than stopping because remission was achieved. Understanding the difference helps in evaluating your own experience and in choosing a provider who tracks outcomes carefully enough to know the difference.
The choice between IV ketamine and esketamine involves tradeoffs. Esketamine (Spravato) is FDA-approved for TRD and some forms of major depressive disorder with suicidal ideation, which affects insurance coverage. IV ketamine is used off-label, which means more variability in protocols and typically no insurance coverage. Both have similar side effect profiles at a high level, but delivery method, setting, dosing flexibility, and cost structure differ — and the clinical review's suggestion that providers consider switching between them when one isn't working underscores that they are not interchangeable for every patient.
Key Takeaway for Patients
Side effects from ketamine and esketamine are real, mostly short-lived, and highly manageable in well-run clinical settings — but the quality of monitoring and protocol matters. Before starting treatment, ask your provider how they track your progress over time, how they handle side effects during sessions, and under what circumstances they would adjust your dose or recommend a different approach. A clinic that can answer those questions clearly is one that takes outcomes seriously.
The Bigger Picture
This review arrives at a moment when ketamine clinics are proliferating rapidly across the United States, with wide variation in protocols, oversight, and care quality. The clinical community's call for more systematic, data-driven treatment management is both timely and necessary — but it also places the burden on patients to ask the right questions, since there is no universal accreditation standard for ketamine providers yet.
The original analysis is available through Psychiatric Times and is primarily aimed at clinicians, but patients and caregivers who want to understand the evidence landscape will find it informative. As always, any treatment decision should be made in close consultation with a qualified mental health provider who knows your full medical history.
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