Comprehensive Guide to Ketamine Therapy & Esketamine Tolerance

If you’re exploring ketamine treatment in Colorado, you’ve likely heard stories of people finding rapid relief from depression, even after years of trying other medications. But what happens when that initial spark begins to fade? Can your body build a tolerance? Is Spravato™ different? And most importantly: what can you do about it?

Let’s dig into the facts behind ketamine infusions, esketamine nasal spray (Spravato), and what to understand about tolerance, so you can keep getting better.

What Is Ketamine Therapy?

Ketamine therapy is a fast-acting, evidence-based treatment for depression and other mood disorders. Delivered as IV infusions or through Spravato (esketamine) nasal spray, it works differently than traditional antidepressants by rapidly enhancing glutamate signaling and promoting neuroplasticity – your brain’s ability to adapt and form new connections.

At Axis Integrated Mental Health, we started off by offering ketamine infusions. However, it was frustrating to see patients only doing treatment when they could afford it because it was an out-of-pocket cost. They would make some progress but then revert back because treatment was not consistent. To be clear, Ketamine does not "cure" depression. It cannot fix a bad marriage, or a bad job or some of the other life stressors that can contribute to depression. It may provide you with the clarity you need to move to resolve your issues, heal the inflammation and reconnect your logic and emotion. With therapy and support to learn healthier thought patterns and coping skills, you can recover from depression symptoms and go into remission. But we've seen patients do the same thing with therapy only or TMS. The severity of your depression and the physiological reasons behind it are what our board-certified specialists can help you with through a combination of treatments and interventions. We now offer insurance-covered Spravato treatments in Denver, Boulder, and Westminster, and combine it with comprehensive or interventional psychiatric care, therapy, and Deep TMS to support long-term healing.

The Difference Between Ketamine Infusions and Spravato

While both are derived from ketamine, there are some key differences:

• Ketamine Infusions: Administered intravenously (IV) at low doses, typically 0.5mg/kg over 40 minutes.

• Spravato (Esketamine): The S-enantiomer of ketamine, delivered as a nasal spray. It has stronger binding affinity to NMDA receptors (3–4x higher) and is FDA-approved for treatment-resistant depression and major depressive disorder with suicidal ideation. [Coyle, 2018]

Both options can be highly effective, but the right choice depends on your medical history, insurance coverage, and response to previous treatments. At Axis, our psychiatric providers will help determine the best route for you.

Explore more: “Esketamine vs Ketamine. Are They the Same Thing?” →

Can You Build a Tolerance to Ketamine?

In short: yes, it’s possible to develop tolerance to ketamine or esketamine, but it doesn’t mean the treatment has stopped working.

Tolerance refers to needing higher doses over time to achieve the same effect. This can occur with repeated, frequent dosing, especially outside of a structured medical setting. However, it's important to understand that effect and efficacy are two different things. Having a psychedelic experience is not necessary for the brain to undergo synaptogenesis, which many believe is the key to the efficacy of the treatment. Clinical studies show that when spaced and monitored correctly, ketamine’s antidepressant effects remain strong over time.

What to Do If Ketamine Stops Working

If you notice your ketamine treatments feel less effective, don’t panic. There are several clinically supported strategies to overcome this:

• Re-evaluate timing: You may benefit from a booster schedule or temporary pause.

• Consider Deep TMS:  If you're noticing reduced effects from ketamine or Spravato, it may be time to consider Deep TMS is a noninvasive, FDA-cleared treatment that targets the brain directly and can reignite your response to care. At Axis, we often use Deep TMS as a complementary or alternative option when tolerance to ketamine therapy begins to set in.

• Combine with therapy: Research supports enhanced outcomes when ketamine is paired with CBT or trauma-informed therapy.

• Lifestyle factors: Insomnia, nutrition, and burnout can all impact treatment response.

At Axis, we integrate therapy, medication management, and advanced treatments under one roof making it easier to adapt your plan without starting from scratch.

Can I Combine Spravato with Other Forms of Ketamine Therapy? 

Combining Spravato (esketamine) with another form of ketamine, such as IV infusions or lozenges, is not permitted under FDA guidelines and violates the strict safety standards of the REMS (Risk Evaluation and Mitigation Strategy) program. At Axis Integrated Mental Health, patients enrolled in our Spravato program must agree to use only the prescribed esketamine treatment. Mixing forms of ketamine is not only unsafe but also disqualifies a patient from continuing treatment with us and will result in immediate discharge from the program. Our top priority is your safety and adherence to best clinical practices.

What Do Patients Say About Spravato Treatment?

Many patients describe Spravato as a turning point after years of feeling stuck with traditional antidepressants. They often say it helps them feel “more like themselves again” and gives them space to finally heal emotionally. If you’re wondering what it’s really like—from the side effects to the emotional shifts—check out our free ebook, “Ketamine Therapy Through Patients’ Eyes.” It’s filled with honest stories, tips, and reflections from real people who’ve been through Spravato treatment. Download it here and see what they wish they’d known from the start.

Read: “Ketamine Therapy Through Patients' Eyes” →

How We Manage Esketamine Tolerance at Axis

Esketamine (Spravato) has a slightly different tolerance profile than IV ketamine. Thanks to its longer half-life and higher binding affinity, some patients experience longer-lasting results. But for others, symptoms may return if additional interventions or life stressors increase.

At Axis, our esketamine program includes:

• Regular psychiatric reviews to evaluate dose efficacy

• On-site monitoring during each treatment

• Data-driven adjustments using PHQ-9 and GAD-7 scales

• Therapeutic add-ons for neuroplasticity support (like CBT, nutritional psychiatry, and Deep TMS)

Final Thoughts

If you're googling "depression treatment near me" and found this page, we can honestly say that ketamine therapy has been life-changing for so many of our patients. But when it stops feeling effective or you worry about building tolerance, patience and clarity is necessary. At Axis Integrated Mental Health, we walk with you through the ups and downs, using data, science, and a deeply human approach.

Whether you’re just beginning your treatment journey or reevaluating after a plateau, we’re here to help you get better—and stay better.

Frequently Asked Questions

1. How do I know if I’m becoming tolerant to ketamine or Spravato?

2. Can I switch from infusions to nasal spray or vice versa?

3. What are the signs that my dose needs adjusting?

4. Will my insurance cover ketamine therapy in Colorado?

5. Is it safe to take ketamine therapy long-term?