How Ketamine Therapy Works and What to Expect

Ketamine therapy works primarily by blocking a receptor in the brain called the NMDA receptor, which triggers a cascade of changes that can relieve depression within hours rather than the weeks required by conventional antidepressants. The experience during a session typically involves altered perceptions of time and sensation, mild dissociation, and often a feeling of calm or peace. But the gap between that simple summary and what actually happens in your brain, in your body, and in a treatment room is worth understanding before you walk through the door.

What Ketamine Does in the Brain

Most antidepressants work on serotonin, norepinephrine, or dopamine. Ketamine takes a fundamentally different path. It blocks NMDA receptors, which are involved in how nerve cells communicate using the neurotransmitter glutamate. That blockade sets off a chain reaction: the brain ramps up production of proteins needed to build and strengthen connections between neurons, particularly in the prefrontal cortex, the region involved in mood regulation and decision-making. Research in animal models has shown that ketamine rapidly increases the density and function of synaptic spines in the prefrontal cortex, essentially helping the brain rebuild wiring that chronic stress and depression have degraded.¹ This process of new synapse formation appears to depend on a growth factor called BDNF and a signaling pathway called mTOR.²

Ketamine also reshapes how different brain regions talk to each other during and after treatment. Imaging studies show that it decreases connectivity in parts of the medial prefrontal cortex while increasing it in other areas.³ The “default mode network,” a circuit that tends to be overactive in depression and is linked to rumination, gets disrupted by ketamine. Changes in the connectivity between specific brain areas have even been shown to predict how much a person’s depressive symptoms will improve after a series of infusions.⁴ So the drug is not just flipping a mood switch. It is restructuring neural circuitry in ways that can be measured on brain scans.

What a Session Actually Feels Like

If you have never taken a dissociative drug, the experience can feel strange. At subanesthetic doses used for depression, the most common perceptual changes involve distortions of time and physical sensation. You might feel like time is slowing down or speeding up, that your body is floating or heavy, or that sounds and textures are unusually vivid. Analysis of patient experiences during IV infusions found that the strongest effects involved these perceptual disturbances, but also identified phenomena not captured by standard clinical rating scales, including a sense of disinhibition and a feeling of deep peace.⁵ Most patients describe the overall dissociative intensity as mild to moderate rather than overwhelming.

The psychological content of a session matters, too. Qualitative research on ketamine-assisted therapy has found that preparation of mindset supports therapeutic benefit. Patients who came in with clear intentions, an attitude of openness, and a sense of safety with their therapist tended to report better experiences. External cues like music influenced the session, sometimes facilitating what patients described as a spiritual journey. But there are also cautions: some participants found that trauma surfaced unexpectedly, and letting go of control left them feeling vulnerable afterward.⁶ This is one reason most clinicians emphasize integration sessions afterward, where you process whatever came up during the treatment with a therapist.

The dissociative effects themselves appear to play a role in the antidepressant response, though the relationship is not straightforward. Research has found that one type of dissociative experience, depersonalization (feeling detached from yourself), was associated with reduced threat-related brain activity, while dissociative amnesia was associated with increased threat-related brain activity.⁷ In other words, different aspects of the dissociative experience point the brain in different directions, and the therapeutic benefit seems linked to the quality of the altered state, not just its intensity.

Routes of Administration

There is no single way to receive ketamine therapy, and the route of administration affects how much drug reaches your bloodstream, how quickly the effects begin, and how intense they are. The main options available in clinical settings break down as follows:

Intravenous (IV): A slow drip over about 40 minutes, typically at a dose of around 0.5 mg/kg. This is the most studied route for depression and has the highest and most predictable bioavailability. Most clinical trial data come from IV infusions.
Intranasal esketamine (Spravato): The FDA-approved nasal spray uses esketamine, one of ketamine’s two mirror-image forms. It is administered in a certified clinic and the patient is monitored for at least two hours. Nasal bioavailability of ketamine has been estimated at roughly 45%, the highest among non-injection routes.⁸
Intramuscular (IM): An injection into the muscle, sometimes used in ketamine-assisted psychotherapy programs. Onset is fast, typically within a few minutes.
Sublingual lozenges or tablets: Dissolved under the tongue at home or in a clinic. Bioavailability is lower, estimated at around 30%.⁸ These are often prescribed by telehealth services for at-home use.

The three main delivery models in the United States are in-person clinics offering off-label racemic ketamine (the mix of both mirror-image forms), clinic visits for FDA-approved esketamine, and telehealth services prescribing off-label racemic ketamine for home use, typically as lozenges.⁹ Esketamine has been found to be about 1.5 times more potent as an anesthetic than arketamine (the other mirror form) and was approved by the FDA in 2019 for treatment-resistant depression when used alongside a conventional antidepressant.¹⁰

How Well It Works for Depression

The hallmark of ketamine for depression is speed. Traditional antidepressants take weeks to reach full effect. Ketamine can produce measurable improvement within hours. In a randomized controlled trial comparing a single IV ketamine infusion to midazolam (a sedative used as an active placebo), ketamine produced significantly greater reductions in depressive symptoms at 24 hours. When patients received repeated infusions, the response rate doubled, with about 59% of participants meeting response criteria. The median number of infusions needed before someone responded was three.¹¹

This speed is especially relevant for suicidal ideation. A double-blind, placebo-controlled trial found that about 63% of patients receiving ketamine reached full remission of suicidal thoughts by day three, compared to about 32% on placebo. The effect was strongest in patients with bipolar disorder. At six weeks, remission rates in the ketamine group remained high but were no longer statistically different from placebo, highlighting that the acute benefit can fade without follow-up treatment.¹² A large nationwide cohort study found that ketamine prescription was associated with a 35% lower rate of suicidal ideation in the first week and continued to show reduced rates at six months and beyond.¹³

A meta-analysis comparing ketamine to various control conditions found it significantly outperformed placebo, esketamine, and midazolam for reducing suicidal ideation on the first day of treatment.¹⁴ That last comparison is worth noting: midazolam produces sedation and some subjective effects similar to ketamine, so it is used in trials to help separate the pharmacological antidepressant effect from the general experience of receiving an infusion.

Ketamine for PTSD

Depression is the most studied indication, but ketamine is also being explored for post-traumatic stress disorder. A randomized clinical trial comparing IV ketamine to midazolam found that a single ketamine infusion produced a rapid and significant reduction in PTSD symptom severity at 24 hours. The reduction held up even after accounting for comorbid depression, suggesting ketamine has a direct effect on PTSD symptoms rather than just improving mood.¹⁵ A systematic review and meta-analysis of ketamine for PTSD found significant improvements in PTSD symptoms by the end of treatment courses lasting one to four weeks, though the statistical significance was clearest at the endpoint rather than after a single session.¹⁶

A large retrospective study of ketamine-assisted psychotherapy, where patients received an average of four guided ketamine sessions (intramuscular or sublingual) along with psychotherapy integration visits, found lasting and effective results for depression, anxiety, and PTSD symptoms at three and six months.¹⁷ This format, combining the ketamine experience with structured therapy, is gaining traction as a way to leverage the drug’s ability to open a window of psychological flexibility.

Maintenance Treatment and the Durability Problem

The biggest practical challenge with ketamine therapy is that the antidepressant effect often fades. A single infusion might produce relief lasting days to a couple of weeks. This has led clinicians to explore maintenance regimens: regularly scheduled follow-up doses intended to sustain improvement over months or longer. One trial found that after patients responded to repeated infusions, weekly maintenance infusions held depressive symptoms stable without further deterioration.¹¹

Evidence on maintenance strategies is still relatively early. A systematic review described ketamine’s antidepressant effects as “rapid yet often transient” and noted that different strategies for prolonging them appear promising but are not well characterized.¹⁸ More recently, a systematic review of maintenance protocols found that regular, fixed-interval dosing schedules had lower relapse rates (about 27%) compared to variable or as-needed dosing schedules (about 46%).¹⁹ So the schedule seems to matter, and simply waiting for symptoms to return before re-dosing may not be the best approach.

Side Effects During Sessions

The most common side effects during a ketamine infusion are the dissociative and perceptual changes already described, along with nausea, dizziness, and a temporary rise in blood pressure. A study of over 2,300 infusions in 138 patients found that blood pressure peaked about 40 minutes into the infusion, with an average increase of about 16 points systolic and 11 points diastolic. Severe hypertension occurred in about 1% of infusion sessions and was more common during the first three treatments. Older patients and those with a history of high blood pressure were more likely to experience significant blood pressure spikes, and every patient with pre-existing hypertension experienced a surge at some point during treatment.²⁰ Another study found smaller mean increases, about 7 points systolic and 6 points diastolic, which resolved within 30 minutes of the infusion ending.²¹ The range in reported values likely reflects differences in patient populations and dosing protocols, but the takeaway is that blood pressure monitoring during infusions is standard for good reason.

These acute side effects are generally transient. Most clinics will monitor you for one to two hours after treatment, and you should not drive for the rest of the day.

Bladder Concerns and the Dose Question

If you have read about ketamine and bladder damage, that concern comes primarily from the recreational use literature. Frequent recreational ketamine users are at substantially increased risk of a condition called ketamine-induced cystitis, with regular use raising the risk of bladder symptoms three- to fourfold.²² Long-term recreational users can develop progressive symptoms from urinary urgency and frequency to severe bladder pain, reduced bladder capacity, and in extreme cases ureteral stricture and kidney failure.²³ The damage can sometimes be irreversible.²⁴

The critical difference is dose and frequency. Recreational users typically consume far higher quantities and far more often than someone receiving clinical treatment. Therapeutic doses for depression are subanesthetic and administered at most a few times per month. While bladder effects at therapeutic doses have not been extensively studied over very long time frames, the existing clinical trial literature has not flagged bladder damage as a problem at therapeutic levels. That said, anyone on a long-term maintenance protocol should be aware of the theoretical risk and mention any urinary symptoms to their provider.

Addiction Potential

Ketamine can be addictive, full stop. It produces pleasant and unusual subjective states, and recreational dependence is well documented. The relevant question for someone considering therapeutic use is whether the clinical setting and dosing regimen carry meaningful risk. A systematic review of patients treated with ketamine for depression found that the vast majority did not develop signs of tolerance to the antidepressant effect or dependence on the drug, though a small number of patients were reported to show clear signs of one or both.²⁵ A review of the prescribing literature concluded that misuse risks for therapeutic ketamine are comparable to those of other commonly prescribed medications with abuse potential, like stimulants or benzodiazepines, and that prescribing decisions should weigh the same risk-benefit considerations.²⁶ The risk is real but manageable with appropriate clinical oversight. At-home prescribing models with less supervision naturally carry more risk than monitored in-clinic infusions.

Who Should Not Use Ketamine

Not everyone is a candidate. Key contraindications include:

History of psychosis or mania: Ketamine can worsen psychotic symptoms.
Uncontrolled high blood pressure: Because ketamine raises cardiovascular tone, poorly managed hypertension is a significant concern. A recent heart attack or stroke is also a contraindication, though patients with controlled blood pressure or a remote history of cardiovascular events may be candidates with specialist clearance.
Severe liver disease: Ketamine is metabolized by the liver, and impaired function could lead to dangerous accumulation.
Active substance abuse: Particularly ketamine itself, but active addiction to other substances is also a flag.
Pregnancy: Animal data raise concerns about fetal neurotoxicity.

These are drawn from clinical guidance for ketamine prescribing.²⁷ If you are taking benzodiazepines or lamotrigine, you should also discuss this with your provider. Evidence suggests both may reduce ketamine’s antidepressant effectiveness.²⁸ That does not mean you cannot use ketamine while on those medications, but it might reduce how well it works.

Insurance Coverage and Cost

Cost is one of the biggest practical barriers. An IV ketamine infusion session typically runs several hundred dollars out of pocket, and most insurance plans do not cover it. A review of health insurance formularies in Ohio found that intravenous ketamine was not covered by any Marketplace or Medicaid plan for depression, while intranasal esketamine (Spravato) was on the formulary of most Marketplace plans and all Medicaid plans.²⁹ The irony here is that IV ketamine may be more cost-effective and possibly more efficacious than esketamine, but the lack of patent protection on racemic ketamine means there has been less commercial incentive to push for insurance coverage. If you have insurance, checking whether esketamine is on your formulary is a reasonable first step, since the clinical infrastructure for its delivery is now well established.

Ketamine in Older Adults and Adolescents

Most ketamine trials have focused on working-age adults, so the evidence for other age groups is thinner. A systematic review covering both adolescents and older adults found that ketamine appeared safe and well-tolerated in both populations, with ten of thirteen studies observing rapid antidepressant effects. But the authors cautioned that the small number of studies and their generally low quality limit firm conclusions.³⁰

A pilot study specifically looking at late-life treatment-resistant depression found that 88% of older participants completed the acute infusion phase, and about 48% met response criteria. Importantly, cognitive function, often a concern with any treatment in older adults, actually improved during the treatment course. Blood pressure increases and dissociation were transient and did not force anyone to discontinue.³¹ In a separate randomized study, subanesthetic ketamine given alongside electroconvulsive therapy in elderly patients reduced the rate of ECT-related cognitive impairment compared to propofol alone, without affecting the antidepressant response rates of ECT itself.³²

Predicting Who Will Respond

One of the frontiers in ketamine research is figuring out, before treatment begins, which patients are most likely to benefit. Researchers have been looking at a wide range of potential biomarkers, from brain imaging and electrical activity patterns to immune markers and stress hormone levels.³³ One specific finding is that activity in a brain region called the pregenual anterior cingulate cortex, measured during emotional tasks before treatment, predicts how much someone’s depression will improve after a ketamine infusion. Higher activity in that region was associated with better outcomes.³⁴

None of these biomarkers are ready for routine clinical use yet. No one is going to scan your brain before your first infusion to decide whether to proceed. But the research signals a future in which ketamine treatment could be better targeted rather than tried broadly and hoped for the best. For now, the practical predictor is response to the first few sessions: the trial data suggest that if you have not responded by the third infusion, the odds of responding to continued treatment at the same dose decrease.

How Ketamine Compares to Psychedelics

Ketamine is sometimes grouped with psychedelics like psilocybin and MDMA, but the pharmacology is quite different. Ketamine acts primarily on the glutamate system through NMDA receptor blockade, while classical psychedelics like psilocybin act on serotonin receptors. Yet research has identified a surprisingly convergent downstream story: both ketamine and serotonergic psychedelics appear to produce a surge in glutamate activity that strengthens synaptic connections and increases BDNF levels, the same growth factor involved in ketamine’s mechanism.³⁵ Both drug classes also produce acute changes in brain network activity that may initially create psychoactive effects and later sustain more subtle improvements in how brain networks operate, though the relationship between the subjective experience and the antidepressant outcome remains unclear.³⁶ The practical distinction for patients right now is availability: ketamine is legal and widely accessible through clinics, while psilocybin therapy is still restricted to a handful of jurisdictions and clinical trials.

1
PubMed Central. Signaling pathways underlying the rapid antidepressant actions of ketamine
2
PubMed Central. A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists
3
PubMed Central. Ketamine effects on default mode network activity and vigilance: A randomized, placebo-controlled crossover simultaneous fMRI/EEG study
4
PubMed Central. Anterior default mode network and posterior insular connectivity is predictive of depressive symptom reduction following serial ketamine infusion
5
PubMed Central. Acute psychoactive effects of intravenous ketamine during treatment of mood disorders: Analysis of the Clinician Administered Dissociative State Scale
6
PubMed. Understanding the Experience of Ketamine-Assisted Therapy and the Importance of Context
7
PubMed Central. Ketamine’s acute effects on negative brain states are mediated through distinct altered states of consciousness in humans
8
PubMed. Plasma concentration profiles of ketamine and norketamine after administration of various ketamine preparations to healthy Japanese volunteers
9
PubMed Central. Caution Is Warranted in Prescribing Ketamine for Mental Health
10
PubMed Central. Ketamine, Esketamine, and Arketamine: Their Mechanisms of Action and Applications in the Treatment of Depression and Alleviation of Depressive Symptoms
11
PubMed. Single, Repeated, and Maintenance Ketamine Infusions for Treatment-Resistant Depression: A Randomized Controlled Trial
12
BMJ. Ketamine for the acute treatment of severe suicidal ideation: double blind, randomised placebo controlled trial
13
PubMed Central. Suicidal ideation and suicide attempt following ketamine prescription in patients with treatment-resistant depression: a nation-wide cohort study
14
Translational Psychiatry. A meta-analysis of the effects of ketamine on suicidal ideation in depression patients
15
JAMA Psychiatry. Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder: A Randomized Clinical Trial
16
PubMed Central. Effectiveness of Ketamine for the Treatment of Post-Traumatic Stress Disorder – A Systematic Review and Meta-Analysis
17
PubMed Central. Ketamine-Assisted Psychotherapy Provides Lasting and Effective Results in the Treatment of Depression, Anxiety, and Post-Traumatic Stress Disorder at 3 and 6 Months: Findings from a Large Retrospective Effectiveness Study
18
The Lancet Psychiatry. Maintenance ketamine treatment in treatment-resistant depression: a systematic review
19
PubMed. Efficacy and safety of ketamine maintenance therapy in treatment-resistant depression: A systematic review of treatment protocols and clinical outcomes
20
PubMed. Blood pressure changes during ketamine infusion for the treatment of depression
21
PubMed. Cardiovascular effects of repeated subanaesthetic ketamine infusion in depression
22
PubMed Central. Ketamine-Induced Cystitis: A Comprehensive Review of the Urologic Effects of This Psychoactive Drug
23
PubMed Central. Pathophysiology, clinical presentation, and management of ketamine-induced cystitis
24
PubMed Central. Ketamine bladder syndrome: an important differential diagnosis when assessing a patient with persistent lower urinary tract symptoms
25
PubMed. Is there a risk of addiction to ketamine during the treatment of depression? A systematic review of available literature
26
PubMed Central. Non-parenteral Ketamine for Depression: A Practical Discussion on Addiction Potential and Recommendations for Judicious Prescribing
27
AJN The American Journal of Nursing. Ketamine as a Mental Health Treatment
28
International Journal of Neuropsychopharmacology. Pharmacodynamic Interactions Between Ketamine and Psychiatric Medications Used in the Treatment of Depression: A Systematic Review
29
Journal of Psychiatric Practice. Formulary Coverage of Esketamine and Ketamine for Depression in Ohio Health Insurance Marketplace and Medicaid Plans
30
PubMed. The effectiveness, safety and tolerability of ketamine for depression in adolescents and older adults: A systematic review
31
PubMed Central. Intravenous Ketamine for Late-Life Treatment-Resistant Depression: A Pilot Study of Tolerability, Safety, Clinical Benefits, and Effect on Cognition
32
PubMed Central. Subanesthetic dose of ketamine for the antidepressant effects and the associated cognitive impairments of electroconvulsive therapy in elderly patients-A randomized, double-blind, controlled clinical study
33
PubMed Central. Neurobiological biomarkers of response to ketamine
34
International Journal of Neuropsychopharmacology. Predicting Antidepressant Effects of Ketamine: the Role of the Pregenual Anterior Cingulate Cortex as a Multimodal Neuroimaging Biomarker
35
PubMed Central. Ketamine for Depression: Advances in Clinical Treatment, Rapid Antidepressant Mechanisms of Action, and a Contrast with Serotonergic Psychedelics
36
International Journal of Neuropsychopharmacology. Ketamine and Serotonergic Psychedelics: Common Mechanisms Underlying the Effects of Rapid-Acting Antidepressants