The Clinician’s Guide to Ketamine Therapy: How Ketamine Works and Scientific Studies | Part 2

Synopsis: In Part 2 of our Clinician’s Guide to Ketamine Therapy, we explore how ketamine works at the neurological level, the range of patient experiences, and the scientific evidence behind its effectiveness. Whether you're new to ketamine therapy or seeking a deeper understanding, this blog gives you the insight needed to better support your patients with confidence.

Key takeaway: Ketamine isn’t just a single-receptor drug—it works across multiple systems to create neuroplastic change. Understanding the mechanism of action, therapeutic experiences, and evidence-based research behind ketamine therapy equips clinicians to use this treatment more effectively and responsibly in their practice.

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Explore how ketamine works, the 4 types of patient experiences, and key clinical studies supporting its use for depression, PTSD, anxiety, and pain.

A Clinician’s Guide To Ketamine Therapy: A 3-Part Series

Welcome to Part 2 of our three-part blog series designed for clinicians seeking a deeper understanding of ketamine therapy. 

Whether you're a budding ketamine therapy specialist, exploring treatment options for your patients, or simply need a refresher on the science and protocols, this series offers a clear and comprehensive foundation.

• In Part 1, we’ll explore the current state of mental health, the historical journey of ketamine, and how this decades-old anesthetic has reemerged as a powerful mental health intervention.

• In Part 2, we’ll take a closer look at how ketamine works, types of patient experiences, and key scientific studies.

• Finally, Part 3 will cover patient selection, dosing strategies, treatment scheduling, and side effect management.

Let’s begin by understanding ketamine’s mechanism of action!

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Prefer listening over reading?  Check out Episode 31 of our podcast: The Clinician’s Guide to Ketamine Therapy: History, Science & Real-World Protocols  and jump to  9:36 to dive right in.

The episode is on Apple Podcasts, Spotify, Overcast, or on your favorite podcast platform. Watch the discussion on YouTube here.

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How Ketamine Works

So, how exactly does ketamine work? What’s its mechanism of action?

We know that ketamine affects the neurotransmitter glutamate. Specifically, it inhibits the N-methyl-D-aspartate (NMDA) receptor, preventing it from being activated by glutamate. Glutamate is one of the most prevalent neurotransmitters in the brain’s synaptic connections—far more abundant than serotonin, norepinephrine, or dopamine. In fact, it’s estimated to account for about 90% of excitatory neurotransmission.

It’s currently hypothesized that by blocking NMDA receptor activity, ketamine produces its analgesic and anesthetic effects

Beyond the NMDA Receptor

What makes ketamine particularly fascinating is that it doesn’t work solely on NMDA receptors. Ketamine also exerts direct and indirect effects on a wide variety of other receptor systems, including:

• Opioid receptors (mu, kappa, delta)

• Dopamine D2 receptors

• Serotonin receptors

• Acetylcholine receptors

• GABA receptors

• Cannabinoid receptors

• Nitric oxide synthase

• Sigma receptors
  

Unlike medications that target a narrow receptor class, such as beta blockers, which typically act on beta-1 or beta-2 adrenergic receptors - ketamine operates across a broad spectrum of pathways. This receptor-wide activity may explain its diverse range of clinical effects.

Reversing Dendritic Damage

Some studies suggest that chronic stress increases glutamate levels, leading to excitotoxicity and damage to surrounding cells. This can cause dendrites to retract, contributing to symptoms of depression and other mood disorders.

Ketamine appears to help reverse this process. It may boost BDNF (brain-derived neurotrophic factor), stimulate protein synthesis, enhance synaptic strength, and promote synaptogenesis. The net effect? 

Greater neuroplasticity—or the brain’s ability to reorganize and form new connections.

As one researcher put it, "Studying neurons to understand consciousness is like studying letters to understand Shakespeare." Still, understanding ketamine’s impact on neuronal function gives us a critical piece of the puzzle.

Ketamine sessions can range from calming and introspective to profoundly mystical—each patient’s experience is unique and often deeply meaningful to their healing process.

Types of Patient Ketamine Experiences

Initially, non-ordinary states of consciousness (NOSC) were viewed merely as side effects of ketamine treatment. But more recent studies suggest these altered states may actually have therapeutic value.

Dr. Eli Kolp explored this idea in a 2014 paper titled Ketamine Psychedelic Psychotherapy: Focus on its Pharmacology, Phenomenology, and Clinical Applications. In his research, he outlined four levels of patient experiences during ketamine therapy, categorized by their phenomenological depth.

Level 1: The Empathogenic Experience

This is the gentlest level—often described as a heightened awareness of the body. Patients may feel relaxed, safe, and emotionally open. Ego defenses soften, making space for feelings of empathy, compassion, love, peace, and even euphoria. Visuals may appear, often colorful and abstract, like those old computer screensavers—soft, swirling patterns that evoke a dreamlike state.

Level 2: The Out-of-Body Experience

At this stage, patients may feel a pronounced separation from their body, along with further ego dissolution. Experiences can range from exploring mythological realms and encountering alien-like beings to seeing deceased relatives or reliving memories from the past—or even glimpses of possible futures. Some report reliving their birth process.

Level 3: The Near-Death Experience

Here, patients often describe a complete departure from bodily awareness, with a strong sense of ego death and loss of identity. They may experience themselves as pure consciousness—simply aware of awareness itself. Others describe a “life review,” where they re-experience past actions and reflect on their impact on others.

Level 4: The Ego-Dissolving Transcendental Experience

This deepest state typically occurs at higher doses. Patients may describe the total dissolution of their sense of self and boundaries between themselves and the universe. There may be feelings of sacredness, interconnectedness, and union with nature, God, or the cosmos. Many liken it to a mystical or spiritual awakening, beyond time and space.

These profound, often ineffable experiences are now thought to play a role in ketamine’s therapeutic effect—offering not only neurochemical change but deeply meaningful psychological transformation.

It should be noted that patients may not experience all of these levels. Experiences can vary from individual to individuals as well as from session to session.

From depression to PTSD to chronic pain, decades of research continue to validate ketamine’s therapeutic potential across a range of mental health and pain conditions

A Review of Scientific Studies

As discussed in Part 1 of this blog series, ketamine was used in operating rooms between the 1970s and 1990s, and expanded into emergency departments in the 1990s. But in the early 2000s, researchers began looking more seriously at ketamine’s potential in treating mental health and chronic pain conditions.

Ketamine for Depression: The Groundbreaking Research

The real turning point came in the year 2000. Dr. Berman and colleagues at Yale published a pivotal study titled Antidepressant Effects of Ketamine in Depressed Patients in the journal Biological Psychiatry.

This was a small, double-blind, placebo-controlled study involving just seven patients with depression. One group received ketamine, while the control group received saline. Despite the limited sample size, the results were significant. Patients who received ketamine showed a robust and rapid reduction in depressive symptoms.

This study was considered groundbreaking. Even though the sample size was small, it opened the door for larger follow-up studies. And since then, more trials although still relatively small have continued to replicate and expand upon these findings.

To synthesize these smaller studies, researchers have conducted meta-analyses. One example is a paper published in the Journal of Affective Disorders by Marcantoni et al. in December 2020. This meta-analysis examined 28 studies across 35 publications and found:

• A strong antidepressant effect peaking around 24 hours after a single infusion

• Benefits that often persisted for up to 7 days

• Evidence that multiple infusions enhanced and prolonged ketamine’s antidepressant effects

Ketamine Infusions vs. ECT

A more recent and much larger study was published in The New England Journal of Medicine in May 2023. The researchers compared IV ketamine to electroconvulsive therapy (ECT) in patients with non-psychotic, treatment-resistant major depression.

ECT has long been considered the gold standard for treatment-resistant depression. But could ketamine be just as effective—without the cognitive side effects associated with ECT?

This randomized controlled trial included 400 patients (200 in each treatment arm). The results? Ketamine was found to be non-inferior to ECT, meaning it was just as effective for reducing symptoms of major depression.

In June 2024, a secondary analysis of that same trial was published under the title: Ketamine vs. Electroconvulsive Therapy for Treatment-Resistant Depression: A Secondary Analysis of a Randomized Clinical Trial. This follow-up suggested that:

Outpatients and individuals with moderately severe or severe depression may consider ketamine over ECT as a viable option for treatment-resistant depression.

Bottom line: The science supporting ketamine for depression is strong and continues to grow.

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Ketamine for Anxiety

Now let’s turn to anxiety disorders.

A 2017 study published in the Journal of Psychopharmacology by Dr. Paul Glue and his team in Australia explored ketamine’s potential for treating anxiety, not just its effectiveness, but also optimal dosing.

The study involved 12 patients with diagnosed anxiety disorders, including generalized anxiety disorder (GAD), seasonal affective disorder, and panic disorder. All participants had previously tried antidepressants and psychotherapy without sufficient relief.

In this study, patients were given varying doses of ketamine:

• 0.25 mg/kg

• 0.5 mg/kg

• 1 mg/kg
  

Here’s what they found:
10 out of the 12 participants - about 83% - reported a 50% or greater reduction in their anxiety scores or fear questionnaire scales after receiving either the 0.5 mg/kg or 1 mg/kg doses.

These improvements were not only observed during the treatment itself but also lasted three to seven days after each dose. With repeated dosing, the benefits persisted and often grew stronger.

The bottom line: Higher doses of ketamine resulted in greater and longer-lasting reductions in anxiety symptoms for this small but meaningful group of patients.

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Ketamine for PTSD

Now let’s look at ketamine for post-traumatic stress disorder (PTSD) or as it’s sometimes referred to, post-traumatic stress injury.

An early study by Dr. Adriana Feder, published in JAMA Psychiatry in 2014, explored whether ketamine could help treat PTSD. This was a single-infusion study involving 41 participants. Patients were randomized to receive either 0.5 mg/kg of ketamine or an active placebo (midazolam).

The results showed a significant improvement in PTSD symptoms for those who received ketamine compared to the midazolam group. While the sample size was modest, it suggested that even a single dose of ketamine could provide meaningful relief.

Later, Dr. Feder and her team conducted a follow-up study to examine the effects of repeated ketamine infusions. In this trial, participants received six sessions of ketamine. Once again, results showed a marked reduction in PTSD symptoms, as measured by the CAPS-5 (Clinician-Administered PTSD Scale) scores, when compared to the midazolam group.

The takeaway? Repeated ketamine infusions may provide sustained relief for individuals with chronic PTSD symptoms. Offering new hope where other treatments may have failed.

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Ketamine for Chronic Pain

Let’s now turn to chronic pain, which affects millions of people and presents a unique challenge in clinical practice. Specifically, we’re referring to neuropathic pain and pain associated with central sensitization.

Some common examples include:

• Complex Regional Pain Syndrome (CRPS), also known as Reflex Sympathetic Dystrophy (RSD)

• Trigeminal Neuralgia

• Fibromyalgia

• Postherpetic Neuralgia

• Peripheral Neuropathy
  

Based on both research and clinical observation, ketamine tends to be less effective for mechanical causes of chronic pain such as osteoarthritis or bone-on-bone knee degeneration and more effective for neuropathic pain syndromes.

One of the more robust analyses we have comes from a 2019 systematic review and meta-analysis by Dr. Orhurhu, published in Anesthesia & Analgesia. This review found that IV ketamine infusions provided relief for up to two weeks after treatment, even after single doses.

It also showed that higher doses and longer treatment durations were associated with greater and more sustained pain relief.

So, what’s the mechanism here? The authors theorize that the intense blockade of NMDA receptors creates a kind of “reset” effect. By interrupting the overactive pain pathways (central sensitization), ketamine can help reverse or reduce neuropathic pain over time through neuroplastic changes.

However, this isn’t a one-size-fits-all approach. The authors recommend IV ketamine for case-by-case use, especially in patients who haven’t responded well to more conventional pain management therapies.

Wondering how much research is out there? There have now been over 140 clinical trials studying ketamine as a treatment for mental health conditions and chronic pain.

Where Research Meets Real-World Application

Understanding ketamine’s mechanism of action, the unique non-ordinary states of consciousness patients can experience, and the growing body of research supporting its use is essential for clinicians working in the evolving fields of interventional mental health and chronic pain treatment.

Now that you’ve built this foundational knowledge, you’re ready for the next step - how to translate it into practice. In Part 3 of this blog series, we’ll explore patient selection, dosing strategies, and more.

Related Questions:
Are the psychedelic or “non-ordinary” experiences part of the healing process?

• Yes. This is something we’re continuing to learn more about. Originally thought to be just a side effect, many now believe that these altered states may actually enhance therapeutic outcomes. Patients often report experiences that range from feelings of empathy and connection to profound spiritual insights and those can be powerfully healing when integrated intentionally.

Is there strong scientific evidence that ketamine helps with depression or PTSD?

• There is. Multiple studies including randomized, double-blind trials show that ketamine can produce rapid and significant reductions in depression and PTSD symptoms. For example, studies by Dr. Berman and Dr. Feder demonstrated clear improvements even after a single infusion, with repeated treatments enhancing results even further.

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In Part 2 of our Clinician’s Guide to Ketamine Therapy, we explore how ketamine works at the neurological level, the range of patient experiences, and the scientific evidence behind its effectiveness. Whether you're new to ketamine therapy or seeking a deeper understanding, this blog gives you the insight needed to better support your patients with confidence.

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