Ketamine is a fascinating medication because it does not fit neatly into a single category. It was originally approved as an anesthetic in 1970, but over the decades, researchers and clinicians have found that it may have therapeutic effects across a wide range of conditions, including acute pain, procedural sedation, chronic pain, status epilepticus, asthma emergencies, treatment-resistant depression, anxiety disorders, PTSD, and OCD.
A recent narrative review in The Journal of Clinical Pharmacology offers a helpful framework for understanding why ketamine is dosed so differently depending on the condition being treated. The authors propose that ketamine-responsive conditions may fall into three broad categories based on what is happening in the glutamate/NMDA receptor system.
This review helps explain why ketamine for depression does not look like ketamine for anesthesia and why the goal of treatment is not simply to “feel the ketamine,” but to create the right biological and psychological conditions for change.
Ketamine Is Not One-Size-Fits-All
Ketamine is best known as an NMDA receptor antagonist. NMDA receptors are part of the glutamate system, one of the brain’s major excitatory signaling systems. However, ketamine’s effects are complex. It also interacts with opioid, dopamine, serotonin, inflammatory, and neuroplasticity pathways.
The review organizes ketamine use into three general categories:
- Conditions where glutamate activity is relatively normal and ketamine is used for a short-term effect, such as anesthesia, procedural sedation, or acute pain.
- Conditions where there appears to be excessive NMDA/glutamate activity, such as status epilepticus, status asthmaticus, traumatic brain injury, or certain chronic pain states.
- Conditions involving impaired neuroplasticity, such as treatment-resistant depression, anxiety disorders, PTSD, and OCD.
Each category uses ketamine differently. For anesthesia or procedural sedation, ketamine is usually given as a brief bolus. For severe neurologic, respiratory, or chronic pain conditions, it may be given as a continuous infusion over days. For depression and anxiety, the goal is usually repeated low-dose treatments over time.
What Does the Research Say About Ketamine for Depression and Anxiety?
For treatment-resistant depression, the most extensively studied IV ketamine dose remains 0.5–1 mg/kg, which has become the foundation of most modern ketamine treatment protocols. Although researchers continue to explore lower and higher dosing strategies, a large meta-analysis of 49 randomized controlled trials found that doses at or above 0.5 mg/kg generally produced greater antidepressant effects than lower doses. This finding supports the dosing range commonly used in many ketamine clinics today.
What about electroconvulsive therapy (ECT), long regarded as one of the most effective treatments for severe depression? A large randomized trial found that ketamine was non-inferior to ECT for treatment-resistant depression, with similar overall outcomes, better tolerability, and fewer cognitive side effects. Some studies still suggest ECT may yield higher response rates in certain patient populations, particularly those with severe or psychotic depression, though the difference between the two treatments may be smaller than previously believed.
Studies involving patients with generalized anxiety disorder and social anxiety disorder found that ketamine doses of 0.5–1 mg/kg were more effective than lower doses, and that improvements could often be maintained through weekly or twice-weekly treatments. Particularly interesting was the finding that after three months of maintenance treatment, approximately one-quarter of patients remained in remission even after treatment had stopped, suggesting that ketamine may produce lasting changes for some individuals rather than simply temporary symptom relief.
Fewer studies and clinical trials are available for PTSD and obsessive-compulsive disorder (OCD) than for depression. For PTSD, five of six clinical studies demonstrated meaningful improvement in symptoms, although one larger trial did not find ketamine to be superior to placebo. For OCD, two placebo-controlled studies found that ketamine significantly improved symptoms. Interestingly, researchers did not find a clear dose-response relationship between 0.5 mg/kg and 1 mg/kg, suggesting that higher doses may not necessarily provide additional benefit for OCD.
Ketamine for Depression Is About Neuroplasticity
In mental health treatment, ketamine is not used as an anesthetic. The doses are much lower than anesthetic doses, and the goal is different.
For depression and anxiety, ketamine appears to create a window of heightened neuroplasticity. Neuroplasticity is the brain’s ability to form, reorganize, and strengthen connections. In depression, anxiety, PTSD, and OCD, the brain can become stuck in rigid patterns: repetitive negative thoughts, fear loops, avoidance, rumination, hopelessness, or emotional shutdown.
Ketamine may help loosen those patterns. Research suggests that ketamine and its metabolites may increase brain-derived neurotrophic factor, or BDNF, which plays an important role in synaptic growth and adaptation. In simpler terms, ketamine may help the brain become more flexible.
At Innerbloom, this aligns with what we often see clinically. Many patients do not describe ketamine as simply “making them happy.” Instead, they often describe a shift in perspective. Some patients feel more distance from old thought patterns. Others report that painful memories feel less fused with their identity. Some describe feeling more connected to themselves, their loved ones, or a sense of possibility.
Why Repetition Matters
One key point from the review is that psychiatric dosing is typically intermittent and repeated. A single ketamine treatment may provide relief for several days, but for many patients, lasting improvement requires a series of treatments.
This is why many depression protocols include an induction series followed by maintenance treatments when appropriate. The purpose is not to keep someone in a dissociated state. Rather, it is to repeatedly support neuroplasticity while the patient builds healthier patterns outside of treatment.
In our clinical experience, patients who do best often treat ketamine as part of a broader healing process. That may include therapy, medication management, sleep improvement, reduced alcohol or cannabis use, exercise, mindfulness, journaling, relational work, or addressing medical contributors to mood symptoms.
Our Provider Perspective: The Experience Matters
One opinion we hold strongly as ketamine therapy providers is that the setting matters. Ketamine is not just a molecule entering the bloodstream. It is also an experience unfolding within a person’s nervous system.
A calm room, thoughtful preparation, skilled monitoring, music, eyeshades, safety, and trust can all influence how a person moves through treatment. The medication may be pharmacologic, but the healing process is deeply human.
At Innerbloom, we have seen that patients often benefit from preparation before treatment and integration afterward. Preparation helps patients understand what to expect and reduces fear. Integration helps patients make sense of insights, emotions, memories, or shifts that arise during treatment.
This is especially important because ketamine can bring up material that is emotional, symbolic, confusing, or difficult to put into words. Without support, patients may leave with an interesting experience but little lasting change. With support, the experience can become part of a larger therapeutic process.
Ketamine, Spravato, and Treatment-Resistant Depression
The review also discusses esketamine, the active ingredient in Spravato. Spravato is the FDA-approved nasal spray form of esketamine for treatment-resistant depression. Unlike IV ketamine, which is used off-label for depression, Spravato has a formal FDA approval pathway and must be administered in a certified medical setting with monitoring.
This distinction is important. Both IV ketamine and Spravato target glutamate/NMDA-related pathways, but they differ in route, regulation, dosing, insurance coverage, and clinical logistics.
At Innerbloom, we value both approaches. Some patients are interested in IV ketamine because of its long history in research and clinical practice. Others are better suited for Spravato because of insurance coverage, regulatory structure, or psychiatric referral pathways.
The key point is that ketamine-based treatments should be individualized. Treatment-resistant depression is not a single disease process. Some patients have prominent anxiety. Others have trauma, bipolar-spectrum features, OCD symptoms, chronic pain, grief, medical contributors, or long-standing nervous system dysregulation. The best treatment plan considers the whole person.
What This Paper Helps Clarify
One of this review’s most useful contributions is explaining why ketamine dosing varies so widely across conditions.
For acute pain or sedation, the goal is immediate symptom control.
For severe conditions involving NMDA overactivity, such as status epilepticus or certain chronic pain syndromes, the goal may require prolonged infusions at higher doses.
For depression and anxiety, the goal is not simply to block NMDA receptors in the moment. Rather, the goal is to promote neuroplasticity over time.
That helps explain why psychiatric ketamine treatment is usually lower-dose, intermittent, and paired with psychological support.
What We Still Do Not Know
Ketamine research is promising but incomplete. The evidence is strongest for anesthesia, acute pain, procedural sedation, and depression. Evidence for anxiety, PTSD, OCD, and many other off-label indications is still developing.
We also know that ketamine’s effects cannot be explained by NMDA antagonism alone. Its metabolites, inflammatory effects, and downstream neuroplasticity pathways may all play important roles.
As providers, we believe it is important to hold both truths at once: ketamine can be profoundly helpful for some patients, and it should still be approached with humility, medical oversight, and careful patient selection.
Final Thoughts
Ketamine is not just “a stronger antidepressant.” It represents a different way of thinking about mood disorders. Rather than targeting only serotonin, norepinephrine, or dopamine, ketamine appears to influence glutamate signaling and neuroplasticity.
For many patients with treatment-resistant depression or anxiety, that difference matters. It may help explain why some people who have tried many traditional medications still respond to ketamine-based therapy.
At Innerbloom, we view ketamine as a catalyst. It may help create a window in which the brain is more flexible, the nervous system is more open, and new perspectives become possible. But the deeper healing often comes from what happens around the medicine: preparation, safety, support, integration, and the patient’s own willingness to engage in change.
References:
Anand, Amit, et al. “Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression.” The New England Journal of Medicine, vol. 388, no. 25, 2023, pp. 2315–2325. https://doi.org/10.1056/NEJMoa2302399.
Glue, Paul, and Ben Beaglehole. “Ketamine Dosing Across Clinical Indications: A Narrative Review Organized by Proposed NMDA-Related Mechanisms.” The Journal of Clinical Pharmacology, vol. 66, no. 6, 2026, e70225. https://doi.org/10.1002/jcph.70225.
Spravato [Prescribing Information]. Janssen Pharmaceuticals, revised 2025. U.S. Food and Drug Administration, https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/211243s016lbl.pdf.
Zarate, Carlos A., et al. “A Randomized Trial of an N-Methyl-D-Aspartate Antagonist in Treatment-Resistant Major Depression.” Archives of General Psychiatry, vol. 63, no. 8, 2006, pp. 856–864. https://doi.org/10.1001/archpsyc.63.8.856.
About the Author
Dr. Rivas is a ketamine specialist and board-certified acute care and trauma surgeon with over 12 years of experience in ketamine administration. Before founding Innerbloom Ketamine Therapy in 2022, Dr. Rivas served on the frontlines of emergency and trauma medicine in Santa Maria, CA, and Austin, TX. Dr. Rivas applies his extensive medical expertise to provide safe, evidence-based ketamine treatments for mood disorders, including depression, anxiety, PTSD, and chronic pain. His passion lies in helping patients find relief and rediscover hope through personalized, compassionate care.
Newy: Bridging the Gap Between Ketamine Treatment and Everyday Wellness
A supplement formulated by Dr. Rivas for enhanced brain and mood support. The formula pairs especially well with ketamine therapy by helping extend and enhance the neuroplasticity effects. That said, the ingredients are equally effective on their own, so it’s a supportive option whether or not someone is undergoing ketamine treatment. Learn more about how Newy supports cognitive function detoxification and cellular repair.
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