Ketamine belongs to a class of drugs called "dissociative anesthetics" with a history dating back to the 1960s, notably employed during the Vietnam War due to its unique ability to maintain respiratory drive and blood pressure unlike most anesthetics. Ketamine was FDA-approved for anesthesia in 1970 and demonstrates promising effectiveness in off-label applications such as mood disorders and chronic pain. It helps your brain form new, healthier connections and addresses the root of your issues, instead of simply numbing them.

While ketamine is sometimes abused recreationally, it is considered safe when administered by a qualified healthcare professional. Unlike many other anesthetic medications, ketamine does not suppress the respiratory drive (hinder breathing); rather, it is known to stimulate breathing and may even have bronchodilator effects. This medicine was originally used by American soldiers in the Vietnam War where access to respiratory equipment was limited. Today, it remains widely utilized by the military and is commonly used in emergency departments and operating rooms, particularly for pediatric patients, due to its excellent safety profile. It is crucial to recognize that almost any prescription and nonprescription medications or supplement can pose risks if used improperly. Additionally, the circumstances (set) and environment (setting) in which ketamine is taken can significantly influence patient responses to treatment.

Ketamine consists of two mirror-image molecules called enantiomers: R-ketamine and S-ketamine. While R-ketamine is recognized as a less potent NMDA receptor antagonist compared to S-ketamine, mounting preclinical evidence indicates that R-ketamine may offer more potent and longer-lasting antidepressant effects than S-ketamine, alongside fewer side effects. Ongoing research aims to discern both their shared and distinct functions.

Ketamine works differently than any traditional psychiatric medication available today. It impacts multiple receptors and pathways in the brain and body, influencing neuroplasticity, pain receptors, the immune system, and the microbiome. This comprehensive action makes it a powerful option for treating conditions like depression, anxiety, chronic pain, and more.

• Metabolites: After administration, ketamine is rapidly converted into active metabolites, such as norketamine and hydroxynorketamine, which likely contribute to its pain-relieving and antidepressant effects.

• Neuroplasticity & Synaptogenesis: Glutamate, the brain's primary excitatory neurotransmitter, interacts with NMDA and AMPA receptors. Ketamine blocks NMDA receptors, facilitating glutamate modulation by balancing receptor activity, regulating cell excitability, and improving synaptic communication. This process increases levels of Brain-Derived Neurotrophic Factor (BDNF), enhancing neuroplasticity—the brain’s ability to form and strengthen new neural connections. These changes improve mood, thought patterns, and resilience to stress, particularly in key regions like the Prefrontal Cortex and hippocampus that regulate mood and stress responses.

• Brain Function: Ketamine normalizes the activity of the Default Mode Network (DMN) and Prefrontal Cortex, enhancing the brain’s ability to process thoughts and emotions, making it easier to handle difficult situations. Research shows that ketamine can significantly reduce suicidal thoughts.

• Anti-inflammatory Effects: It has been shown to be primarily anti-inflammatory which is highly protective in states of stress, depression, and pain. Ketamine lowers interleukin 6 (IL-6), tumor necrosis factor (TNF), and nitric oxide levels, which are often elevated in conditions like depression, anxiety, and chronic pain. It also converts neurotoxic quinolinic acid into neuroprotective kynurenic acid, helping to regulate inflammation and support brain function.

• Microbiome Support: By influencing the gut-brain connection, ketamine may help reduce gut inflammation, which has been linked to mood disorders.

• Receptor Activity: Ketamine exerts multifaceted effects, involving various neurotransmitter systems such as monoamines (norepinephrine, dopamine, and serotonin), as well as the opioid mu receptor system. It also interacts with GABA, muscarinic, and nicotinic receptors, as well as L-type calcium channels. These actions help reduce pain, regulate mood, improve cognition, and restore balance in the brain.

• Entropic Brain States: Ketamine can induce entropic brain states at higher doses, increasing brain signal diversity. This helps disrupt repetitive thought patterns, leading to transformative experiences and new perspectives.

Ketamine comes in many forms for medical use:

1. Intravenous (IV) Infusion: 100% bioavailability

2. Intramuscular (IM) Injection: 93% bioavailability

3. Intranasal Spray: 45-50% bioavailability

4. Sublingual (SL) Lozenge: 24-30% bioavailability

5. Other Less Common Forms: subcutaneous, rectal, epidural, oral, inhaled/nebulizer

Bioavailability refers to how much of a drug or substance actually gets absorbed into the bloodstream and becomes available to produce its effects in the body.

Common side effects of ketamine include dissociation, intoxication, sedation, transient high blood pressure, dizziness, headache, blurred vision, anxiety, nausea, and vomiting. We have medications available that can help alleviate many of the side effects.

Ketamine is used to treat depression, anxiety, mood disorders such as bipolar depression, PTSD, OCD, suicidal ideation, postpartum depression, premenstrual dysphoric disorder (PMDD), grief, existential crisis, end-of-life crisis, complex regional pain syndrome (CPRS), complex pain syndrome, fibromyalgia, neuropathic pain, chronic migraines, phantom limb pain, shingles, palliative care, other chronic pain, and more.

Ketamine is not a first-line treatment and is reserved for treatment-resistant conditions. To qualify, patients must meet the following criteria:

• A diagnosis or condition for which ketamine has shown efficacy (e.g., treatment-resistant depression, PTSD, OCD, severe anxiety disorders, suicidality, postpartum depression, end-of-life crisis, certain chronic pain syndromes).

Treatment-Resistant Depression (TRD): Failure to achieve significant symptom relief after trying at least two different antidepressants from different classes at therapeutic doses for an adequate period (typically 6-8 weeks).

Treatment-Resistant Anxiety: Continued severe anxiety symptoms despite trials of multiple therapies (e.g., medications like SSRIs, psychotherapy).

Treatment-Resistant PTSD: Persistent PTSD symptoms despite treatment with trauma-focused therapy and/or medication.

Exclusion criteria for ketamine therapy include:

• History of psychosis

• History of increased intracranial pressure (ICP)

• Current pregnancy

• Uncontrolled hypertension (elevated blood pressure)

• Acute or unstable cardiovascular disease

• Severe kidney disease

• Previous negative response to ketamine

If you have uncontrolled hypertension or cardiovascular disease, we would require you to be assessed and cleared by your cardiologist.

If you have severe kidney disease or transplant, we would require you to be assessed and cleared by your nephrologist.

If you have a history of increased ICP, we would require you to be assessed and cleared by your neurologist.

Each individual's response to ketamine therapy varies. While uncommon, some patients may indeed experience symptom relief after the first treatment and remain free of symptoms without requiring additional sessions. Typically, patients require a "loading series" of six sessions over the first four weeks, usually administered biweekly. Following this initial phase, "booster" infusions are introduced, initially given bimonthly, then monthly, and potentially spaced further apart, depending on symptom severity. . While some may require monthly or more frequent sessions, others can extend intervals to several months. Although patients will likely continue infusions for symptom management, they are typically less frequent than taking a daily pill.

Ketamine and esketamine (Spravato) are both forms of ketamine, but they have some differences:

1. Formulation & Administration: Ketamine can be compounded into various forms for intravenous, nasal, oral, or intramuscular administration. Esketamine is a nasal spray formulation.

2. Chemical Composition: Ketamine is a racemic mixture, meaning it contains both R-ketamine and S-ketamine isomers. You can think of this like having two different "arms". They are both part of the same molecule, but they have slightly different structures, just like two arms might have slightly different shapes. Esketamine only contains the S-enantiomer of ketamine.

3. FDA Approval: Ketamine is FDA-approved for use as an anesthetic agent for both human and veterinary medicine with off-label use for treatment of depression, chronic pain, and various other conditions. Esketamine (Spravato) has been specifically approved by the FDA for the treatment of treatment-resistant depression (TRD) and depressive symptoms in adults with major depressive disorder (MDD).

4. Cost and Access: Esketamine tends to be more expensive and may have stricter access requirements due to its status as a patented medication with FDA approval. Ketamine, being available in generic form and used off-label, may be more accessible and cost-effective for some patients.

Off-label use refers to prescribing a medication for a condition not approved by the FDA. Off-label use is legal and common, especially in situations where alternative treatments are limited, or when there is emerging evidence suggesting potential benefits for a different condition. According to the National Institutes of Health (NIH), off-label use occurs in 21%3 to 32.3%4 of prescriptions overall.

The FDA approval process can cost hundreds of millions to over a billion dollars. According to a study published in the Journal of Health Economics in 2016, the average cost of developing and gaining FDA approval for a new drug was estimated to be around $2.6 billion. Ketamine, an older medication dating back to the 1960s with an expired patent, is now available as a generic drug, resulting in relatively low costs. Limited financial incentives for pharmaceutical companies to seek FDA approval for new uses, combined with insufficient funding, have hindered efforts to advance ketamine's approval for indications like depression, despite its potential benefits.

We aim to provide our patients with a comprehensive understanding of treatment options, including ketamine, so they can make informed decisions with our team. It's important to note that ketamine is not typically the first treatment choice and is considered when other options, such as antidepressants, psychotherapy (including talk therapy, EMDR), TMS, and ECT, have not been successful.

To prepare for your session, consider the following steps:

1. Set Intention: Reflect on what you hope to achieve or gain from the session. Setting clear intentions can help guide your focus and mindset during the experience.

2. Gratitude List: Despite challenges, try to identify a few things you are grateful for. This exercise can shift perspective and positively impact your mood and mindset.

3. Breathwork: Practice deep breathing exercises to help relax your body and calm your mind. Focusing on your breath can also help center yourself and prepare for the session.

4. Ensure a Safe Set and Setting: Choose a comfortable and safe environment for the session. Minimize distractions and create a space conducive to relaxation and introspection.

By following these steps, you can better prepare yourself for the session and optimize your experience.

1. Set: Understanding where the person is mentally and in their lifespan is crucial for therapy. Are they open to change, and how does their mental health impact their life and relationships?

2. Setting: The therapy space should establish trust and consent, ensuring comfort and safety.

It is also important to identify how one's daily environment can either support or hinder progress, affecting their ability to engage in therapy and make positive changes. Examples of these surroundings may include: negative influences from those around you, absence of supportive relationships, difficulty accessing healthcare, unstable living environment, financial problems, and being treated unfairly due to stereotypes. Understanding these factors is crucial for ensuring a safe session and increasing the likelihood of symptom improvement.

Currently, insurance companies do not cover ketamine treatments. However, we can provide a superbill for potential partial reimbursement from your insurance. If you have a health savings account (HSA), you may be able to use it for ketamine infusions. A promising Hawaii senate bill, SB279, aims to mandate Medicaid and insurance coverage for ketamine therapy to treat depression. It has passed the first reading, and we hope it will progress further to enable insurance coverage for ketamine treatments.

We believe in treatment accessibility especially for those that hold marginalized identities and are willing to discuss fee restructuring and learn about your particular financial situation to consider a fee reduction.

After your infusion, it's important to arrange a safe ride home, as you may still be altered from the session and should avoid driving, operating heavy machinery, or making critical decisions.

Each individual’s response to ketamine therapy varies. Ketamine’s onset of action is typically faster than traditional antidepressants, making it a valuable option for those seeking rapid improvement. Some patients may experience symptom improvement after their first treatment, feeling a decrease in symptoms like low mood, hopelessness, and anxiety. However, it's important to understand that not everyone will respond in the same way, and some individuals may take more time to notice changes.

At MindWave Medicine, we approach this differently. Even if instant symptom relief isn’t experienced, ketamine often shifts perceptions, helping individuals approach life’s challenges with a renewed sense of resilience. For many, this brings meaningful benefits over time.

Although less likely, some patients may experience an initial increase in depressive symptoms or even a continuation of suicidal thoughts. This reaction is still considered "normal" and can be attributed to the release of deep-seated emotions. Each person’s life trauma and experiences are unique, and as these unprocessed emotions come to the surface, it can be an essential step in the healing journey, providing an opportunity to work through long-held challenges. Ketamine is not a “magic bullet,” which is why our Preparation and Integration sessions, alongside each individual’s commitment, are so important in providing full support throughout the process. If you experience any concerning symptoms, please reach out to our office or contact a crisis hotline for support.

Yes, it is possible. Just like with many medications, there doesn’t seem to be a way to prevent it. If you notice that your infusions or injections aren’t as effective as before, please communicate with us​. At MindWave Medicine, we follow a protocol that allows us to increase your dose by 10% if it appears to be losing effectiveness, up to the maximum allowable dose.​Based on our training and observations, tolerance may develop in long-term ketamine users approximately once a year. This is why it’s important to begin with the lowest effective dose, helping to reduce the likelihood of needing dose increases over time.​

Firstly, we believe in a non-pathologizing approach that views a person as more than their problems/diagnoses. We believe that everyone ultimately knows themselves best (even if it doesn’t feel like it sometimes) and we all have an inner healing intelligence that we can trust to guide us in the right direction. Every individual is different in how they process the medicine, so doses are specific to the individual. However, every patient starts at 0.5mg/kg according to evidence-based guidelness. We can go up or down from there, based on your feedback. So being honest with your provider is important.

In some cases, with the supervision of their mental health provider, some people have been able to reduce or eliminate their antidepressants, mood stabilizers, &/or anti-anxiety medicines. However, most people do continue to utilize antidepressants in combination with ketamine; they find that the ketamine seems to cause the anti-depressants to work more effectively.

CRISIS SUPPORT SERVICES

If you are (or someone you know is) experiencing an emergency or believe you are a danger to yourself and/or others, please call 911 or go to the nearest emergency room for immediate assistance.

If you or someone you know are experiencing distress or a painful emotion and need support, please contact Hawai’i Cares below. You may also want to contact your medical provider. If you are contacting a medical provider for someone else, please know they are bound by HIPPA laws and will not be able to confirm/deny or follow up with you, but you can always call to share your experience.

For immediate local assistance:

Crisis Text Line Text ALOHA to 741741 If you prefer texting over talking or are deaf or hard of hearing, the Crisis Text Line connects you with a crisis counselor who will invite you to share at your own pace. Hawai‘i CARES (Coordinated Access Resource Entry System) Call 808-832-3100 (Oahu) or 1-800-753-6879 for neighbor islands When you call Hawai’i CARES, you will be connected with a local crisis counselor who will ask a bit about you, what your needs are, and how they can help.

https://health.hawaii.gov/medicalcannabisregistry/