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Ketamine therapy is gaining significant attention in mental health treatment as a breakthrough option for conditions resistant to traditional medications. Unlike conventional antidepressants that target serotonin, ketamine works through different neural pathways, offering rapid symptom relief—often within hours rather than weeks. This alternative approach shows particular promise for treatment-resistant depression, anxiety disorders, PTSD, and chronic pain conditions, with success rates of 60-70% in patients who haven't responded to standard treatments.

Innerwell offers expert-guided ketamine therapy for mental health—discover our Innerwell ketamine programs.

Ketamine therapy involves using ketamine, a medication traditionally used as an anesthetic, to treat mental health conditions. First developed in the 1960s and approved by the FDA as an anesthetic in 1970, ketamine has a long history of safe use in medical settings. Its unique properties allow it to induce anesthesia while maintaining respiratory function, making it valuable in emergency and surgical settings.

In the early 2000s, researchers discovered ketamine's rapid antidepressant effects, leading to its off-label use for mental health conditions. Off-label prescribing—using FDA-approved medications for non-approved purposes—is common and legal in medical practice when supported by scientific evidence.

What sets ketamine apart from traditional psychiatric medications is its mechanism of action. While conventional medications primarily target serotonin, norepinephrine, or dopamine systems, ketamine affects the glutamate neurotransmitter system.

As an NMDA receptor antagonist, ketamine may disrupt patterns of negative thought and behavior associated with depression, explaining why it works quickly—often within hours—compared to traditional antidepressants that take weeks to show benefits.

These are the mechanisms of action that affect the brain:

The primary mechanism of ketamine's action is as an antagonist of N-Methyl-D-Aspartate (NMDA) receptors. These glutamate-activated ion channels play a crucial role in excitatory neurotransmission in the brain. Ketamine blocks the NMDA receptor channel in its open state, preventing ion conductance and altering glutamate signaling.

This blockade is particularly potent in certain receptor subtypes. GluN2C/D-containing NMDA receptors appear more susceptible to ketamine's effects compared to GluN2A/B-containing receptors. This differential sensitivity contributes to ketamine's unique profile of effects.

Beyond its immediate effects on neurotransmission, ketamine enhances neuroplasticity and synaptogenesis. It increases the production of brain-derived neurotrophic factor (BDNF), a protein that promotes the growth and differentiation of new neurons and synapses.

This enhanced neuroplasticity may explain why ketamine's effects can persist beyond its immediate presence in the body. It potentially "resets" dysfunctional neural circuits involved in depression and other mood disorders.

While ketamine blocks NMDA receptors, it also paradoxically increases glutamate release in certain brain regions. This leads to activation of AMPA receptors, another type of glutamate receptor. This AMPA receptor stimulation triggers molecular cascades that promote synapse formation and strengthen neural connections.

The complex interplay between NMDA receptor blockade and downstream glutamate signaling appears central to ketamine's antidepressant effects.

What Conditions Does Ketamine Therapy Treat?

Ketamine has been proven effective for several conditions, including:

Treatment-Resistant Depression—For patients who haven’t responded to at least two antidepressants, ketamine offers fast relief—helping most of them experience significant improvement, sometimes after just one session.

Major Depressive Disorder (MDD)—Effective not only for treatment-resistant cases but also for broader MDD, with 50–70% response rates and rapid symptom relief.

Anxiety Disorders (GAD, Social Anxiety, PTSD)—Emerging research supports ketamine for anxiety, especially PTSD. Ketamine-assisted psychotherapy (KAP) may deepen emotional processing and introspection.

Bipolar Depression (Not Mania)—Can reduce depressive symptoms in bipolar disorder when carefully managed alongside mood stabilizers to prevent mania.

Obsessive-Compulsive Disorder (OCD)—Some evidence suggests ketamine may quickly reduce obsessions and compulsions by targeting glutamate pathways, though results can vary.

Chronic Pain (CRPS, Migraines, Fibromyalgia)—Ketamine’s pain-relieving effects may benefit chronic pain conditions, especially when depression and pain overlap.

Types of Ketamine Therapy: How is Ketamine Administered 

Ketamine is administered through a variety of routes, such as:

Intravenous (IV) infusion is the most common and well-studied method for ketamine's psychiatric use. Typically, doctors administer a dose of 0.5 mg/kg over about 40 minutes, though dosages may range from 0.1 mg/kg to 0.75 mg/kg depending on patient response and clinical needs.

IV administration provides 100% bioavailability, allowing for precise dosage control and rapid onset of effects. This method requires a clinical setting with medical supervision throughout the infusion.

Intramuscular injections involve administering ketamine directly into a muscle, typically the deltoid or thigh. This method offers rapid absorption similar to IV, though with slightly more variable bioavailability.

IM ketamine is useful when IV access is challenging and provides a practical alternative while maintaining the supervision and safety of a clinical setting.

Sublingual ketamine involves dissolving a lozenge or troche under the tongue, allowing the medication to be absorbed through the oral mucosa. This method offers lower bioavailability (approximately 30%) than IV or IM routes but can be more convenient for maintenance treatments.

Some providers prescribe sublingual ketamine for at-home use between in-office treatments, though this practice varies widely based on provider protocols and patient factors.

Intranasal Esketamine (Spravato®) — FDA-Approved

Esketamine (Spravato®) is a nasal spray formulation of the S-enantiomer of ketamine that received FDA approval in 2019 for treatment-resistant depression. It's administered in a certified healthcare setting with strict monitoring protocols.

It's important to distinguish ketamine from esketamine (Spravato), a related compound with FDA approval for treatment-resistant depression. Both work through similar mechanisms, but esketamine comes as a nasal spray with standardized protocols defined by FDA guidelines.

Oral ketamine tablets have the lowest bioavailability (approximately 20%) due to extensive first-pass metabolism in the liver. This route typically requires higher doses to achieve therapeutic effects.

Some clinics prescribe oral ketamine for at-home maintenance treatment, though this is less common than other methods due to the limited bioavailability and variable absorption.

Rapid Symptom Relief (Hours to Days, vs. Weeks for SSRIs)

Ketamine's most remarkable benefit is its rapid effects, delivering significant symptom relief within hours or days, unlike traditional antidepressants that typically take weeks to work.

For patients in crisis, this quick response can be life-changing and potentially life-saving, particularly for those experiencing suicidal thoughts or severe functional impairment.

Supports Neuroplasticity and Emotional Flexibility

Ketamine promotes neuroplasticity—the brain's ability to form new connections and reorganize itself. This enhanced flexibility may help patients break free from rigid thought patterns and develop healthier cognitive processes.

The neuroplasticity effects may contribute to lasting benefits beyond the immediate drug effects. By promoting the growth of new neural connections, ketamine potentially helps "rewire" dysfunctional brain circuits associated with depression and anxiety.

May Help Break Negative Thought Patterns and Rumination

Many patients report that ketamine helps interrupt persistent negative thinking and rumination. The dissociative experience can provide psychological distance from entrenched thought patterns, offering a new perspective on problems.

This cognitive flexibility can create a window of opportunity for implementing therapeutic techniques and developing healthier thought patterns.

Effective for People Who Haven't Responded to Traditional Treatments

For treatment-resistant depression—defined as failure to respond to at least two adequate trials of antidepressants—ketamine offers hope when other options have failed. Studies show approximately 60-70% of treatment-resistant patients experience significant improvement after ketamine treatment.

This effectiveness in otherwise treatment-resistant cases represents one of ketamine's most important clinical contributions.

Can Accelerate Breakthroughs in Therapy (Especially with Integration Sessions)

Ketamine-Assisted Psychotherapy (KAP) combines ketamine administration with psychotherapy, potentially enhancing the therapeutic process. The altered state ketamine induces can facilitate deep introspection and emotional processing, allowing patients to engage with their thoughts and feelings in new ways.

Many clinicians report that patients can achieve therapeutic breakthroughs more quickly when ketamine sessions are paired with skilled psychotherapy, particularly psychedelic integration therapy that helps process insights gained during ketamine treatments.

Potential Benefits for Suicidal Ideation Reduction

Research shows 55% of patients receiving ketamine experienced a ≥50% reduction in suicidal thoughts within a day. This quick action contrasts sharply with traditional antidepressants, which carry FDA black box warnings about potentially increasing suicidal ideation, particularly in young adults.

This rapid anti-suicidal effect represents one of ketamine's most clinically significant benefits, potentially creating a window of safety during which other therapeutic interventions can be implemented.

Risks and Side Effects of Ketamine Therapy

Common Short-Term Side Effects (Dissociation, Nausea, Dizziness, Increased Blood Pressure)

During and shortly after ketamine administration, patients commonly experience:

Dissociative effects (feeling detached from reality or one's body)

Perceptual disturbances (visual or sensory changes)

These effects typically resolve within hours after treatment, but can be distressing for some individuals. The dissociative experience, while therapeutically valuable for some patients, may be challenging for others, particularly those with a history of dissociative disorders.

Less Common but Serious Risks (Misuse Potential, Bladder Issues with Long-Term High Doses)

The long-term risks of repeated ketamine treatments for psychiatric conditions are still being studied. Concerns include:

Potential for Tolerance or Dependence: While ketamine administered in controlled medical settings appears to have low abuse potential, there are concerns about psychological dependence with repeated use.

Urological Effects: Chronic, high-dose ketamine use has been associated with urinary tract problems, including a condition known as "ketamine cystitis". However, this appears rare at the doses used for depression treatment.

Cognitive Effects: Some studies suggest potential concerns about cognitive effects with long-term use, though research at therapeutic doses is limited.

Who Should Not Use Ketamine Therapy (Contraindications: Active Mania, Psychosis, Certain Cardiovascular Issues)

Ketamine therapy is not appropriate for everyone. Key contraindications include:

Uncontrolled hypertension or serious cardiovascular disease

Patients with a history of psychosis or schizophrenia are typically not considered good candidates for ketamine therapy due to the risk of exacerbating psychotic symptoms. Similarly, ketamine's potential for abuse makes it a cautious choice for individuals with a history of substance use disorders.

The cardiovascular effects of ketamine—primarily increased blood pressure and heart rate—necessitate caution in patients with cardiovascular conditions.

Healthcare providers typically implement several safety measures:

Comprehensive screening and informed consent in ketamine therapy before treatment

Continuous monitoring of vital signs during administration

Careful dose adjustment based on individual response

The FDA has issued specific warnings regarding ketamine products, emphasizing that the drug is safe only when administered in a healthcare facility under supervision. This highlights the importance of proper medical oversight during treatment.

What to Expect During a Ketamine Therapy Session

Pre-Treatment Screening and Medical History Review

Before beginning ketamine therapy, you'll undergo a comprehensive evaluation to determine if you're a suitable candidate. This typically includes:

A thorough review of your medical history

Assessment of current symptoms and previous treatments

Screening for contraindications such as uncontrolled hypertension or certain psychiatric conditions

Discussion of your goals and expectations for treatment

Baseline vital signs and possibly laboratory tests

This screening is essential for safety and helps predict whether ketamine therapy is likely to benefit you.

Setting the Intention: Importance of Mindset and Environment ("Set and Setting")

Many providers emphasize the importance of "set and setting"—your mindset and the treatment environment—in shaping the ketamine experience. You may be encouraged to:

Develop clear intentions for your treatment

Practice relaxation techniques to prepare mentally

Consider what aspects of your condition you hope to address

Create a comfortable environment with elements like eye shades and calming music

This preparation can enhance the therapeutic potential of ketamine and help manage the dissociative effects.

What Happens During a Session (Duration, Monitoring, Dissociative Effects)

When you receive ketamine therapy, especially via IV infusion, you can expect:

Potential dissociative effects, including altered perception and a sense of detachment

Session duration of about 40-60 minutes for the infusion, plus recovery time

The dissociative experience varies widely among patients. Some report a floating sensation, visual or auditory changes, or a feeling of being outside their body. Others describe a dreamlike state or enhanced introspection. These effects are normal and typically fade within a couple of hours after treatment.

Throughout the session, medical staff will monitor your blood pressure, pulse, and oxygen levels while remaining available to provide support if the experience becomes challenging.

Integration Sessions: Processing Experiences After Ketamine Therapy

Many providers incorporate integration sessions after ketamine treatment to help process the experience and translate insights into lasting change. These sessions may involve:

Discussing any insights or emotions that emerged during treatment

Connecting experiences to your therapeutic goals

Developing strategies to maintain improvements

Addressing any challenging aspects of the ketamine experience

Integration support can significantly enhance treatment outcomes by helping patients incorporate the ketamine experience into their overall mental health journey.

Timeline: How Many Sessions Are Typically Recommended?

A typical ketamine therapy protocol might include:

Initial Series: Often six infusions over two to three weeks

Maintenance: Periodic "booster" sessions, usually every four to six weeks

Ongoing Monitoring: Regular check-ins to assess response and adjust treatment

The frequency and duration of maintenance treatment vary widely based on individual response. Some patients maintain improvements with infrequent boosters, while others require more regular treatment.

Your provider will work with you to determine the optimal schedule based on your response and needs.

This is perhaps the number one question most patients considering ketamine may have—and it is understandable as to why. This depends on the dose range, according to Dr. Cooper. 

“At the extreme end of the dose range, ketamine is going to act as a general anesthetic and can put someone to sleep to the point where they're not going to remember the experience and not feel pain,” he says. 

This is more of how it was traditionally used when it was first discovered. “As you look at the lower doses, say, if you go on the opposite end of the spectrum, where you take a low dose of ketamine, it can be a very relaxed feeling,” he says. The effects of this low dose could be compared to a glass of wine, for example, in terms of that relaxation feeling. 

“Most patients describe the feeling of ketamine as very relaxed and open where they feel comfortable talking and communicating about difficult things in their life,” says Dr. Cooper. “In this low-dose administration, it can be thought of as a psycholytic agent where it lowers ego defenses  to allow patients to talk about aspects of their personality, their life and their memories in a little bit more of an easier way than they can without ketamine.”

In the moderate dose range, ketamine tends to be more like a psychedelic where patients may close their eyes and see beautiful colors, geometric patterns and other shapes, especially when they’re listening to music. They may also notice a distinct shift in their perspective. “They might feel that their sense of self is growing larger, or that they feel more connected to their surroundings or to the people around them, as well as a heightened sense of oneness and connectedness to the world,” explains Dr. Cooper. 

As the dose increases from there, ketamine generates sort of almost an out-of-body experience, where a patient may feel like they're outside looking inward in a very peaceful way. “They feel very much a part of the universe and they can even have these visual experiences of watching the universe being constructed and planets coming into existence and quite metaphysical, extraordinary experiences like that,” says Dr. Cooper. 

Ketamine Therapy at Home vs. In-Clinic: Pros and Cons

The key difference between at-home and in-clinic ketamine therapy is the level of supervision and dosing. In-clinic care offers higher doses (including IV), continuous monitoring, and immediate medical support if side effects occur—making it a good fit for more complex cases or those new to ketamine.

At-home therapy, which Innerwell provides, uses lower, safer doses (oral or sublingual) with remote supervision through telehealth. It’s more affordable, easier to fit into daily life, and allows patients to receive treatment from the comfort of home. Innerwell’s app supports mood tracking and ongoing check-ins with the care team between sessions.

The decision between at-home and in-clinic ketamine therapy should consider:

Previous response to ketamine (if applicable)

Comfort level with dissociative experiences

Practical considerations like transportation and schedule

Financial considerations and insurance coverage

Provider recommendations based on your specific condition

Many patients begin with in-clinic treatment to establish safety and efficacy, then potentially transition to at-home maintenance if appropriate for their situation.

Is Ketamine Therapy Safe? What the Research Says

Ketamine's safety profile is well-established from decades of use as an anesthetic. When used at appropriate doses under medical supervision, it has a favorable safety record for psychiatric applications.

Research indicates that ketamine therapy is generally well-tolerated when properly administered. A systematic review of 60 studies found serious adverse events to be rare, with transient dissociation, nausea, and blood pressure changes being the most common side effects.

The FDA approval of esketamine (Spravato®) in 2019 for treatment-resistant depression represented a significant milestone, validating the therapeutic potential of ketamine-like compounds for psychiatric conditions.

Off-label ketamine use refers to prescribing the medication for purposes not specifically approved by the FDA. While ketamine is FDA-approved as an anesthetic, its use for depression and other psychiatric conditions is considered off-label. This practice is legal and common in medicine when supported by scientific evidence.

Long-term outcomes remain an active area of research. Current data suggest that ketamine's benefits typically last days to weeks, with maintenance treatments often needed to sustain improvement. Research on the safety and efficacy of long-term maintenance protocols is ongoing, with particular attention to potential cognitive effects and urinary tract issues with prolonged use.

How to Find a Reputable Ketamine Therapy Provider

When seeking ketamine therapy, be alert to these red flags:

Providers who don't conduct thorough medical screening

Clinics offering "recreational" ketamine experiences rather than medical treatment

Absence of licensed medical professionals

Pressure tactics or guarantees of results

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