What Ketamine Therapy Is
Interestingly, ketamine is on the World Health Organization (WHO) essential list of medications (those that satisfy the priority health care needs of the population) and is used in pediatric settings with great safety data.
Ketamine can be administered in a few ways:
Intravenous (IV) infusion (the most studied form)
Intranasal spray (esketamine, sold as Spravato, the only FDA-approved version for depression)—significantly more expensive but is more likely to be covered by insurance
Sublingual liquid and lozenges
More convenient oral formulations being researched for wider accessibility (Silberbauer et al., 2026)
What makes ketamine so effective comes down to how it works in the brain.
How Ketamine Therapy Works
Ketamine quickly produces noticeable changes in mood, perception, and brain function, which is why it's become a more common component of severe and treatment-resistant depression treatment.
It targets a biological reality that conventional antidepressants cannot: structural changes in the way the brain is wired. Ketamine works through several mechanisms, the primary one being the blocking of NMDA receptors in the brain. This triggers a cascade of effects, including enhanced neuroplasticity, the brain's ability to change and adapt—temporarily loosening entrenched neural patterns and creating a window where new ones can form if the right inputs are present (Antos et al., 2024).
Why does this matter? In depression, the number and strength of synaptic connections between neurons—junctions at which brain cells communicate—measurably decline. Standard antidepressants alter neurotransmitter levels related to mood, like serotonin, norepinephrine, or dopamine, but often take several weeks to produce noticeable improvement. This can feel like an especially long time for someone who is really struggling, which is why it’s especially helpful in suicidality.
Beyond NMDA receptor blockade, ketamine also acts on other receptor systems, including opioid receptors, which may contribute to its antidepressant and analgesic effects, though this secondary mechanism is still being studied (Antos et al., 2024).
At sub-anesthetic doses, ketamine's dissociative properties, the sense of detachment from one's thoughts, feelings, and surroundings, may also be therapeutically meaningful, particularly in PTSD. This dissociative state appears to help dampen the fear response and may support the processing and consolidation of traumatic memories, making them less emotionally activating over time.
However, these same dissociative effects carry real risks if the experience is not closely monitored in a clinical setting, which is one reason supervised administration is considered essential.
Who Ketamine Therapy Helps
For those living with treatment-resistant depression (TRD), suicidal ideation, PTSD, and chronic pain, the pursuit of effective, reasonably low-risk treatments can be a frustrating trial-and-error experience, which is where ketamine therapy comes in.
These experiences often come with significant anxiety, trauma, or chronic pain, and ketamine makes sense for people who need rapid intervention.
Overall, ketamine is best suited for people who have run out of conventional treatment options and require the quicker effects it can provide. It’s not a standalone treatment and works best alongside other therapies, particularly psychotherapy (known as KAP, or ketamine-assisted psychotherapy).
On the other hand, several groups either require further safety screening or are considered poor candidates for ketamine therapy:
People with psychosis or schizophrenia
Active or uncontrolled cardiovascular disease
Uncontrolled hyperthyroidism
Active substance use disorder, particularly to alcohol, benzodiazepines, or dissociatives
Pregnancy
History of mania or bipolar disorder
Raised intracranial pressure or active brain lesions
Severe liver disease
Additionally, lifestyle factors, such as sleep quality, stress response, and gut health, shape the internal environment of the body and how well it responds to treatments like ketamine.
Your nutritional status, especially B vitamins, amino acids, and omega-3 fatty acids, is central to making neurotransmitters. Adequate stores of nutrients are an essential foundation upon which any neurological intervention, like ketamine treatment, can take hold. This includes enhanced neuroplasticity.
Common Uses
At lower doses, ketamine has expanded beyond its anesthetic origins to treat:
Treatment-resistant depression and bipolar depression
Suicidal ideation
Chronic pain
We’ll take a closer look at what the currently available evidence has to say about ketamine in these scenarios and others in the following sections.
What the Evidence Supports
Treatment-Resistant Depression (TRD)
Nearly 30% of people living with major depressive disorder don’t respond effectively to two or more antidepressants, making alternative strategies essential—in which case, ketamine has become one of the most important options (Dodd et al., 2021).
For example, a comprehensive systematic review of 83 published reports confirmed substantial, rapid, and temporary antidepressant and anti-suicidal effects of ketamine across a wide range of study designs, and a meta-analysis found that said antidepressant effects peak at 24 hours after a single dose, with repeated dosing effectively maintaining the initial response (Walsh et al., 2021; Kryst et al., 2020).
Both IV ketamine and esketamine (ketatmine) nasal spray can reduce depression severity, but they differ in terms of how quickly and by how much. IV ketamine usually offers faster initial responses, while intranasal ketamine spray (called esketamine) shows more improvement in subsequent uses.
A large meta-analysis of 24 trials representing 1,877 participants found IV racemic ketamine to be more effective and better tolerated than esketamine nasal spray for both unipolar and bipolar depression (Bahji et al., 2021).
When compared to electroconvulsive therapy (ECT), which induces short seizures in the brain and has long been considered the last resort for TRD, a meta-analysis of six trials found that ECT may be better at reducing acute depression severity, but ketamine has a better side-effect profile, highlighting the importance of individualized treatment decisions (Rhee et al., 2022).
That said, ketamine's antidepressant effects are rapid but not permanent, and the best strategies for sustaining them through maintenance treatment are still being figured out. This is why ketamine is so frequently used alongside mental health therapy versus on its own for best results.
Suicidal Ideation
IV ketamine offers antidepressant and antisuicidal effects in treatment-resistant patients. Its quicker action makes it ideal in short-term situations where waiting weeks for a medication to work isn't an option, but the antisuicidal effects from one single dose are short-lived (Feeney et al., 2021).
Bipolar Depression
Researchers have examined maintenance ketamine infusions in patients with treatment-resistant bipolar depression, finding that depression and suicidality scores decreased greatly after an initial course. Ongoing maintenance infusions helped continue these benefits (Haikazian et al., 2025).
Chronic Pain
A Cleveland Clinic study of over 1,000 patients found low-dose ketamine infusions helped 20-46% of patients achieve meaningful improvements in functioning, sleep, and pain management lasting up to six months (Tankha et al., 2025). It comes with low tolerance risk, can be administered outpatient, and requires no anesthesia.
Chronic pain remains an off-label use.
Where the Evidence Is Limited
Post Traumatic Stress Disorder (PTSD)
A University of Florida study suggests that ketamine may help people with PTSD better process trauma while simultaneously improving depression, anxiety, sleep, and quality of life (Almog et al., 2025).
Researchers are also exploring combining ketamine with trauma-informed therapies to deepen its effects.
Alcohol Abuse
In a double-blind placebo-controlled phase 2 trial, ketamine infusions combined with psychological therapy increased days of abstinence from alcohol at a six-month follow-up compared to other conditions (Grabski et al., 2022).
Other Uses
Anxiety disorders, OCD, and eating disorders are also being actively studied, though the evidence base there is at an earlier stage.
Safety and Regulation
There is a significant regulatory difference between FDA-approved esketamine and off-label IV ketamine.
Esketamine was approved for treatment-resistant depression in 2019 and for major depressive disorder in 2025, and carries warnings for:
Dissociation
Sedation
Elevated blood pressure
Respiratory depression
Hallucinations
Bladder and kidney damage with long-term use, and
Tolerance
It can only be dispensed in certified healthcare settings with at least two hours of post-dose monitoring.
For off-label IV ketamine, the framework is less clear.
The DEA classifies it as a Schedule III controlled substance, but physicians have broad prescribing flexibility and no equivalent drug safety program exists.
Additionally, during ketamine treatment, the neuroplasticity window opens and it is only as useful as how directive the administrator chooses to be with their inputs. Without integration (therapeutic, somatic, relational), it’s essentially like doing a hardware upgrade with no software installation, which can leave patients hanging and potentially be harmful in their recovery.
Finally, the number of ketamine clinics has grown faster than regulation can keep up. A significant portion of ketamine is also filled by compounding pharmacies, where quality, strength, and purity can vary (Food and Drug Administration, 2023). Telehealth prescribing adds further safety concerns around unsupervised home use.
The Experience
Individual experiences with ketamine depend largely on the dose and delivery method. Generally speaking, here is what you might expect in a clinic.
Ketamine is administered via IV while you sit in a reclining chair, sometimes with an eye mask. Shortly after the infusion is started, you enter a dissociative state, or a sense of detachment from your body and surroundings. Some people describe this as though they’re floating.
Note that this dissociative state is what people also call the "K-hole" in recreational use, which can reportedly feel very scary to some, and can happen even at low doses. This is why it’s so critical to have professional supervision to help reground you and ensure that you get the safest, most comfortable experience possible.
Additionally, depending on the dose, you may experience a spectrum of mild to deeply intense visual, emotional, or sensory experiences. The dissociative effects typically wear off within 30 to 60 minutes after the treatment stops.
You’ll be monitored afterward, and it’s unsafe to drive yourself home—someone else must drive you. Many people report feeling calmer, more relaxed, or experiencing an uplifted mood, which might last 24 hours after treatment.
Protocols for ketamine infusions vary depending on purpose and provider, but are generally spread out over several weeks. Once initial induction is complete, maintenance doses vary, and individual infusions may be recommended every few weeks or as needed for symptoms. Remember that there is no established regulatory protocol for off-label uses.
The Future of Ketamine Therapy
Research on ketamine is headed in a few concrete directions:
Standardized maintenance protocols through larger randomized trials
Head-to-head comparisons of IV ketamine versus esketamine
Oral ketamine as a more accessible delivery route
Ketamine in combination with psychotherapy for PTSD
Scientists are also studying a ketamine metabolite called hydroxynorketamine, which appears to produce antidepressant effects without the dissociative properties of ketamine and fewer side effects, risks, and recreational abuse potential (Highland et al., 2021).
Takeaway
While not a standalone treatment, ketamine therapy is a genuinely useful possibility for many people with treatment-resistant depression, and potentially other urgent mental health conditions. In the right clinical scenario and with good medical oversight, it offers a meaningful shift worth taking seriously.
