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What is Ketamine and How Does it Work?

woman with an eye mask over her eyes

Written by Dr. Ladan Eshkevari, PhD, CRNA, LAc, FAAN.

In This Post:

What is ketamine? Ketamine is a fascinating medication known for its anesthetic, pain-relieving, and mood-elevating properties. Doctors have harnessed the compound in surgery and pain management since the 1960s. Yet, it is far from a mere numbing agent.

Recently, ketamine has served as an incredibly effective remedy for treatment-resistant mood disorders such as depression, PTSD, and suicidality. Experts agree that it is one of modern psychiatry’s greatest tools for patients who have struggled to find relief.

This article explores ketamine forms and usages, including how it works in the brain to unleash its therapeutic benefits and critical safety considerations.

What is Ketamine? An Overview

ketamine molecule

Ketamine is a dissociative anesthetic medicine that provides diverse benefits depending on dosage and administration. Since 1985, the World Health Organization (WHO) has recognized the compound as essential for anesthesia and pain management.

Initially developed in the 1960s and FDA-approved for anesthesia and procedural sedation in 1970, research shows ketamine has a high safety profile with minimal impact on cardiovascular function, respiratory drive, and airway reflexes.

In the last 20 years, ketamine has taken on new medical imperatives. It has become an invaluable tool for “robust and rapid” depression relief, even in patients who fail to respond to traditional pharmaceuticals and therapeutic models.

Clinical evidence indicates the compound can ease:

  • Treatment-resistant depression
  • Post-traumatic stress disorder (PTSD)
  • Suicidality
  • Anxiety disorders

Additionally, recent research reveals the compound may be a powerful tool for diminishing chronic pain conditions, such as:

  • Neuropathic pain
  • Chronic migraines
  • Fibromyalgia
  • Chronic cancer pain

Beyond medical contexts, ketamine is also used as a street drug (“Special K”) for its hallucinogenic effects. Users seek the “K-hole” to enter a trance-like state of disconnection from reality. Unmitigated recreational use can be dangerous, addictive, and deadly in overdose cases.

Ketamine Administration Routes

The main ketamine types fall into five categories: intravenous (IV), subcutaneous (SC), intramuscular (IM), oral, and intranasal (IN).

IV Ketamine

IV ketamine

IV ketamine refers to the intravenous form of the anesthetic drug administered directly into the bloodstream for rapid and potent effects with a nearly 100% absorption rate. Infusions are only FDA-approved for anesthesia and pain relief. However, given its diverse research-backed benefits, practitioners regularly administer IV infusions for off-label use, including depression relief and pain management.

Several studies conclude IV ketamine can rapidly alleviate depressive symptoms, sometimes within hours or days.

Recommended dosage varies depending on the medical application.

  • Anesthesia: Anesthetic doses are usually higher, based on weight, and calculated as mg/kg, and induce rapid unconsciousness.
  • Mood disorder: Subanesthetic doses for treatment-resistant depression and other mood disorders begin at much lower mg/kg and titrates up, again based on weight but also response to the treatment over a 40 to 60-minute session.
  • Pain: The IV ketamine dosage of mg/kg for acute pain usually falls between the mood disorder and anesthesia dosing. For chronic pain, infusions run over 4 hours and are titrated to effect.

The IV advantage:

A significant advantage of intravenous (IV) administration is its real-time dose adjustability. This allows healthcare providers to titrate the amount up or down based on the patient’s immediate experience and needs.

If a patient wishes to deepen their experience, the physician can promptly administer an increased dose, resulting in rapid effects. Conversely, if the patient desires to exit the experience or feels discomfort, the healthcare provider can reduce the amount or discontinue the infusion instantly. This level of control offers a tailored treatment approach, enhancing safety and efficacy.

Ketamine troches (oral)

Troches are tablets specifically designed for oral use under the tongue. These lozenges dissolve slowly in the mouth, releasing the active ingredient over an extended period. Oral ketamine also comes in liquid form.

Mainly used off-label for chronic pain and mental health conditions such as depression and PTSD, troches offer a convenient alternative to intravenous or intramuscular injections.

Medical professionals like psychiatrists and pain management specialists administer and oversee patient use of troches.

Dosages range widely from 25 to 600 mg, depending on the purpose. The duration of effects is variable but tends to be longer than IV administration due to the extended release of the medication. However, oral forms have relatively low bioavailability from 24–32.2%.

Research on this delivery route for depression is in its infancy. A recent meta-analysis concluded that oral ketamine delivered marginal efficacy for major depressive disorder without significant adverse side effects. It called for further research to determine potential uses.

Subcutaneous and intramuscular

Subdermal or subcutaneous (SC) ketamine is injected into the layer of skin or fat just below the surface. Intramuscular (IM) is injected directly into the muscle. Upon administration, IM ketamine generally has a faster onset of effects compared to subcutaneous administration.

IM takes about 5 to 15 minutes to first feel effects, while SC takes 10 to 20 minutes to first feel effects, and full absorption can take up to an hour.

Healthcare providers such as pain management specialists or psychiatrists must administer these injections.

Dosages for subcutaneous and intramuscular forms are patient-specific and are also weight-based as mg/kg. Both have approximately 90% bioavailability. Depending on the individual and the condition, the effects can last several hours.

SC and IM ketamine are still under investigation, but preliminary studies suggest they may be viable solutions for severe depression, bipolar disorder, and pain.

Intranasal (nasal spray)

Intranasal ketamine is specifically formulated for administration through the nasal passages. It comes in a spray form that delivers the drug directly to the mucosal lining of the nose, allowing for quick absorption into the bloodstream within 15 minutes.

Predominantly utilized off-label for chronic pain and mental health issues, intranasal ketamine can be an alternative to more invasive methods like intravenous or intramuscular injections.

Healthcare providers such as psychiatrists, nurses, and pain management specialists typically supervise the use of intranasal sprays. However, patients can also receive prescriptions for at-home use.

Dosages for intranasal sprays can vary widely, with some depression research supporting 25 to 50 mg per application. The duration of effects is also variable but tends to be shorter than ketamine troches due to faster absorption rates. Nasal ketamine experiences typically last about two hours with a 45% bioavailability rate.

Intranasal ketamine research is growing. Studies indicate nasal ketamine can effectively treat depression and chronic pain symptoms. However, scientists must conduct long-term investigations and randomized clinical trials to fully understand its efficacy, along with the optimal doses and protocols.

Another Type of Ketamine, Spravato

woman with depression

In 2019, the FDA approved a ketamine sister compound, “esketamine,” for treatment-resistant depression to be used with an oral antidepressant. Esketamine is a nasal spray under the brand name Spravato.

Esketamine has similar chemical properties to ketamine, acting on the same receptors. However, it has chemical variations that make it more potent.

Patients can only access this esketamine through a prescription. Additionally, they must take the medication at a clinic under medical supervision. Doses are very specific with Spravato at either 56mg or 84mg, the effects take about five to 15 minutes to kick in, and the experience lasts about two hours.

Spravato studies have shown generally positive but mixed results for people who have not responded well to other antidepressants. Most experts agree that nasal sprays are less effective than IV. Spravato’s main advantage is that the spray is easy to administer and is sometimes covered by health insurance.

Avesta’s co-CEO and founder, Dr. Ladan Ashkevari, has worked with ketamine for over twenty years. In her experience with anesthesia, pain management, and alternative medicine, patients consistently experience better results with infusions.

“I believe patients experience better and more lasting results with ketamine IV infusions [compared to nasal sprays], mainly due to better absorption rates.”

IV Ketamine infusions for depression anxiety ptsd chronic pain fibromyalgia CRPS Bethesda MD McLean VA Washington DC

Ketamine for Mental Health Conditions

The Biological Psychiatry journal published the first randomized, double-blinded ketamine study in 2000, showing immediate antidepressant effects from IV infusions.

Since then, decades of research have substantiated the claim that ketamine is an effective treatment for various debilitating mental health conditions, particularly treatment-resistant depression (TRD) and post-traumatic stress disorder (PTSD).

Ketamine’s superpower is giving patients hope they thought was lost when prescription drugs and traditional therapies failed.

Treatment-Resistant Depression Research

  • In a clinical trial of 403 patients, 55% of those who received ketamine treatment experienced at least a 50% improvement in depressive symptoms compared to 41% of patients who received electroconvulsive therapy (ECT). This was the largest comparative trial, conducted from March 2017 to September 2022.
  • A retrospective chart review of patients with TRD found that repeated ketamine infusions produced a 47.2% reduction in depression symptoms, with no evidence of cognitive impairment.
  • Dr. Eshkevari has observed and quantified patient experiences over seven years of administering IV ketamine infusions in Washington, D.C., Maryland, and Virginia. She has found that around 80-85% of patients exhibit significant improvement in depressive symptoms following Avesta’s recommended treatment protocols.

Post Traumatic Stress Disorder (PTSD)

  • A proof-of-concept study from the Icahn School of Medicine tested IV infusions’ effect on 41 chronic PTSD patients. Ketamine significantly reduced symptoms of PTSD and depression 24 hours post-infusion. The findings suggested ketamine is a promising, tolerable treatment for chronic PTSD.
  • A randomized controlled trial of 30 patients with chronic PTSD analyzed results after six infusions of ketamine or a placebo over two weeks. The results showed that ketamine significantly reduced PTSD and depression symptoms, with 67% of participants responding positively to the treatment compared to only 30% in the placebo group; it was also well-tolerated.

Treating Pain with Ketamine

Several studies and case reports have found that ketamine can effectively treat specific chronic pain syndromes such as fibromyalgia and migraines.

Clinical research also indicates that the dissociative anesthetic is promising in treating neuropathic pain, a chronic pain condition resulting from nerve damage or a malfunctioning nervous system.

Chronic neuropathic pain

  • Ketamine Infusions for Complex Regional Pain Syndrome (CRPS): A systematic review of clinical studies for chronic neuropathic pain found that ketamine infusions reduced pain and improved function in patients with CRPS in 13 of 14 studies. The review concluded that ketamine infusion therapy is a promising option for patients with CRPS who have not responded to other treatments.
  • A systematic review and meta-analysis of ketamine for chronic pain: This Journal of Pain Research study found that ketamine led to a statistically significant reduction (28% to 46%) in pain intensity one week and 30 days after treatment. This study called for future large-scale studies to confirm the results.

Fibromyalgia & migraines

  • A prospective observational study on fibromyalgia: This Journal of Clinical and Diagnostic Research study evaluated the effectiveness of escalating ketamine intravenous infusions in reducing pain and disability for fibromyalgia syndrome. The study included 60 patients and showed that the infusions effectively reduced pain and disability in fibromyalgia syndrome.
  • A systematic review and meta-analysis on migraines: A 2021 study published in the Journal of Dental Anesthesia and Pain Medicine reviewed randomized controlled trials (RCTs) investigating ketamine in treating migraine and headache disorders compared to the placebo. The results showed that ketamine was more effective than placebo in reducing pain intensity and headache frequency in patients with migraines.

IV Ketamine Sessions for Depression & Chronic Pain

Chronic pain patients and people suffering from mental health conditions often seek established IV ketamine clinics like Avesta for relief when all else has failed. Upon arrival, they meet with the clinic’s care team, which assesses eligibility and crafts a personalized, evidence-based treatment plan.

Research shows the best practice for IV therapy includes:

  • Six therapy sessions
  • 40-60 minutes per appointment
  • Over two to three weeks

At the start of each treatment, the practitioner checks the patient’s baseline vital signs, such as blood pressure, heart rate, and oxygenation, to establish a foundational understanding of their physiological state. This knowledge helps ensure patient safety and optimal treatment efficacy.

Next, the IV line starts, with the infusion lasting approximately 45 to 60 minutes. During this period, patients relax in Avesta’s private, serene space. Staff intermittently monitor vitals while the patient drifts into the dissociative state with eye masks on, listening to the calming music of their choice.

Patients typically feel antidepressant effects within the first four treatments, offering a glimmer of transformation. However, ketamine is not a magical cure-all. To sustain optimal mental health, Avesta recommends that patients seek therapeutic support in the weeks, months, and years following.

Avesta also guides patients through a maintenance protocol after finishing the initial IV treatment series which is discussed with patients during consultation and adjusted as needed depending on how the patient reacted to the initial induction infusions.

Every patient’s journey is unique.

How Ketamine Works in the Brain

neural networks

Ketamine begins by crossing the blood-brain barrier, plunging directly into the brain’s complex neural network. Once there, it blocks receptors, known as NMDA, and interrupts the usual chatter between nerve cells.

This disruption indirectly boosts levels of a neurotransmitter called glutamate, pivotal in learning, memory, emotion, and sensory processing.

Glutamate’s elevated levels activate another key player, the AMPA receptor, amplifying communication between neurons and reinforcing their connections, a process known as synaptic plasticity.

Amid this cellular activity, ketamine induces various sensations, from dissociation to altered perceptions.

For depression

Ketamine’s impact on NMDA receptors triggers a cascade of reactions within secondary messenger systems. These changes increase the release of Brain-Derived Neurotrophic Factor (BDNF), which helps form new synapses and pathways. Researchers believe this effect plays a significant role in its rapid antidepressant powers.

By blocking the NMDA receptors, ketamine also initiates a chain reaction that eventually results in better neural connectivity and improved mood, often within a short period after administration.

For pain

Ketamine acts directly on the NMDA receptors in the brain and spinal cord to provide relief from chronic pain. Blocking these receptors interferes with transmitting pain signals from the peripheral nervous system to the brain.

This disruption effectively dampens pain sensations, offering an alternative for those who haven’t found relief with other treatments. The result is immediate alleviation of acute pain and potentially resetting the neural pathways associated with chronic pain, providing longer-lasting comfort.

Is Ketamine Safe?

Ketamine is highly safe when administered in a controlled medical environment. However, the compound does carry risks.

Addiction Risk: Ketamine is not physically addictive, unlike opioids. However, people can and do misuse the drug, potentially causing addiction and overdose. This risk is nearly non-existent when used in moderation in structured medical settings.

Cardiovascular Effects: Elevated blood pressure and heart rate can occur during ketamine administration. Practitioners closely monitor patients’ vitals during infusion therapy to ensure they remain in a safe range.

Psychological Effects: Ketamine infusions commonly cause hallucinations and feelings of dissociation, known as the “K-hole”. These effects are expected and can benefit patients by eliciting profound insights. But hallucinations can also be unsettling, so compassionate ketamine clinics like Avesta provide support and care to patients in need.

Avesta calls the experience a “K-home” because patients who feel safe and supported on the dissociative journey often enter a deeper healing space and quickly regain inner balance following the infusion.

Temporary disorientation: Patients commonly feel groggy and disoriented, a sensation akin to feeling slightly drunk for a few hours post-infusion. These effects emphasize the need for a responsible adult to assist the patient post-treatment.

Most of the adverse effects are dose-dependent and subsite shortly after infusions.

The Bottom Line

Ketamine is a multifaceted pharmaceutical with a rich history and an emergent role in treating various conditions. Once viewed solely as a surgical anesthetic, it is now on the front lines of mental health and chronic pain treatment.

To find out if IV infusions are appropriate for your depression, PTSD, anxiety, or chronic pain, we invite you to schedule a free consultation with us today.

If you want to learn more about Avesta Ketamine and Wellness, please review our About Us page and our Ketamine Infusions page.

Ketamine Infusions in Bethesda, MD, McLean, VA and Washington, DC

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