Individuals with major depressive disorder (MDD) and treatment-resistant depression (TRD) often find limited relief from traditional oral antidepressants, primarily due to their low rates of efficacy or poor tolerability secondary to adverse side effects. As an alternative, low-dose ketamine offers a unique mechanism that enables rapid-acting treatment not only for MDD and TRD but also provides potential benefits for those suffering from post-traumatic stress disorder, substance abuse, and chronic pain. It’s crucial to recognize that ketamine is not a new therapy; it has been used in medical settings for over five decades and is considered an essential medication, particularly in emergency situations where its life-saving potential has been demonstrated.
Initially utilized as an anesthetic in the late 1960s, ketamine was notable for inducing a dissociative state. Over the years, its ability to address psychiatric conditions has been extensively studied, consistently showing its efficacy in alleviating depressive symptoms where other treatments have failed. Despite its long-standing clinical use, many still do not fully appreciate the therapeutic potential of ketamine therapy, often due to misconceptions or a lack of understanding of this pioneering treatment. This article aims to provide a comprehensive guide to the intricacies of ketamine therapy, illustrating that low-dose ketamine is effective, well-tolerated, fast-acting, and holds a significant place in the fields of psychiatry and pain management.
What is Ketamine?
Introduction of Ketamine: Originally synthesized in a laboratory by chemist Calvin Stevens in 1962, ketamine was developed in an effort to create a new and safe anesthetic agent. Interestingly, researchers have discovered that the fungus Pochonia chlamydosporia produces ketamine, perhaps as a protective mechanism against parasitic infections. Meanwhile, its close relative, phencyclidine, occurs naturally in certain plants.
Initial Testing and Approval: Ketamine was first tested on human subjects in 1964, and subsequently approved by the FDA in 1970 for use in anesthesia and procedural sedation.
Recognition as Essential Medication: The World Health Organization includes ketamine on its list of Essential Medications, recognized for its critical use in emergency situations and operating rooms. This list also features other vital medications like penicillin, lidocaine, and morphine.
Approval for Depression Treatment: The FDA has approved esketamine (the S enantiomer of ketamine) for treating treatment-resistant depression in conjunction with an oral antidepressant, as well as for major depressive disorder with suicidal behaviors.
IV Administration: The intravenous (IV) form of ketamine, often considered the gold standard due to its effectiveness and safety, is currently used "off-label" for treating pain and mental health disorders such as depression, anxiety, and post-traumatic stress disorder.
Broad Evidence of Efficacy: Over two decades of research underscore the significant benefits of ketamine in treating both mental health and pain syndromes.
Low-Dose Applications: For managing mood disorders and pain, ketamine is used in sub-dissociative, or low-dose, administrations. It may be used alone or combined with other pain medications and/or antidepressants.
Comparison to Other Treatments: Recent studies have demonstrated that ketamine outperforms Electroconvulsive Therapy (ECT), often regarded as the gold standard for treatment-resistant depression, by showing higher response and remission rates. According to UpToDate, the world's most widely read medical reference, IV ketamine is now recommended over ECT and nasal Spravato for treatment-resistant depression due to its superior efficacy, safety, and fewer adverse effects.
Indications for Ketamine Therapy
Ketamine therapy has been extensively researched for its effectiveness in treating major depressive disorder and treatment-resistant depression. However, the potential applications of ketamine often extend beyond depression. It is used for treating a variety of other disorders, including anxiety, substance abuse (encompassing alcohol, cocaine, and opioids), obsessive compulsive disorder (OCD), posttraumatic stress disorder (PTSD), suicidal ideation, eating disorders, and bipolar disorders.
Many individuals seek alternative treatments such as ketamine therapy to avoid the unpleasant side effects associated with oral antidepressants, such as decreased libido, weight gain, and disruptions in sleep and mood. Therefore, ketamine therapy might be considered an early alternative to traditional antidepressants, rather than being reserved solely for those labeled as treatment-resistant—defined as a lack of satisfactory response to at least two different antidepressant treatments administered at adequate doses and durations.
Depression
After a single infusion, studies have shown a 71% response rate at day one, with peak antidepressant effects occurring at 24 hours.
A remission rate greater than 50% has been observed for depression following ketamine therapy.
The average time to relapse from another depressive episode is approximately three weeks after a single infusion of ketamine. However, multiple infusions, such as a series of six sessions, can extend the duration between recurrent depressive episodes, with symptom relief often lasting many months.
When ketamine therapy is combined with psychotherapy, as practiced at Innerbloom, the effects tend to be more pronounced and enduring. This approach may offer long-term relief from symptoms, reducing the need for recurrent ketamine treatments. In fact, most patients do not require ongoing therapy.
Anxiety Disorders
Individuals with anxiety disorders often have comorbid depression, making ketamine an effective treatment for both conditions.
Studies have demonstrated significant benefits of ketamine for patients with anxiety and treatment-resistant depression. A single infusion of ketamine can alleviate anxiety symptoms within hours, with effects that may persist for up to two weeks.
The standard practice of administering repeated doses, involving six IV infusions, may significantly reduce anxiety levels, with a remarkable response rate of 83% as reported in studies utilizing a low dose range from 0.5 mg to 1 mg per kg.
Post Traumatic Stress Disorder (PTSD)
Many people mistakenly believe that PTSD only affects military personnel with combat experience. However, PTSD can arise from a broad range of traumatic experiences, including sexual assault, serious accidents, natural disasters, and other significant personal traumas.
Approximately one in three individuals who experience a severely traumatic event will develop PTSD.
The lifetime incidence of PTSD ranges between 6-9%, with rates around 13% among U.S. veterans.
Studies have demonstrated that individuals suffering from chronic PTSD can experience relief from symptoms as soon as 24 hours after receiving ketamine treatment.
Remission rates of up to 80% have been reported with repeated ketamine infusions—specifically, six infusions over a twelve-day period for PTSD.
Suicidal Ideation and Behaviors
On average, there are 132 suicides per day, or approximately one death every 11 minutes.
Clinical studies have demonstrated that a single ketamine infusion can significantly reduce suicidal thoughts within just one hour.
Individuals who received ketamine experienced complete remission of suicidal ideation at a rate of 63% by the third day, and these high remission rates (70%) persisted even through the six-week mark. This stands in stark contrast to other acute suicide treatment methods like electroconvulsive therapy (ECT), where only 38% were free of suicidal thoughts after three treatments.
Substance Abuse and Alcoholism
Studies suggest that low-dose ketamine can effectively treat alcohol use disorder (AUD), leading to reduced alcohol cravings and intake.
In this clinical trial, patients who were given three weekly ketamine treatments had significantly more days abstinent from alcohol compared to the placebo group at six month follow-up; 86% of participated were still sober after six months.
Be sure to read testimonials from two Innerbloom patients here and here, who found relief and sobriety after undergoing ketamine therapy.
In some trials, ketamine has shown promise in treating cocaine and opioid use disorders.
Ketamine-assisted psychotherapy may increase abstinence rates and curb cravings, with slightly higher doses thought to be more effective.
Additionally, ketamine may ease opiate withdrawal, reducing the need for other medications to manage symptoms.
One study aimed to assess the impact of ketamine as an intervention to discontinue benzodiazepines in patients with treatment-resistant depression. The study revealed that after a six-session ketamine intervention, 91% successfully discontinued benzodiazepines. Furthermore, 64% remained benzodiazepine-free over a 12-month follow-up, with significant improvements in depression, anxiety, and suicidality observed.
Bipolar Disorder
Studies suggest that ketamine can have significant antidepressant and anti-suicidal effects for patients with bipolar disorder, especially those with treatment-resistant depression.
Even a single low-dose administration can rapidly improve depressive symptoms in bipolar patients.
Repeated administrations have shown to improve mood, cognition, and sleep in approximately 77% of patients.
A study involving 16 bipolar patients who underwent six low-dose ketamine infusions reported response and remission rates of 73.7% and 63.2%, respectively, at 24 hours post-treatment.
However, there are reports of ketamine-induced manic episodes, which have led to the exclusion of patients with bipolar type I disorder and schizophrenia from many ketamine therapy protocols. Some experts argue that excluding these patients is "unfortunate and unwarranted," suggesting ketamine could be beneficial as an adjunctive treatment when mood stabilization is achieved with other medications.
When ketamine is specifically employed for pain treatment, the dosage may be higher than that used for mood disorders, potentially requiring longer infusion times (e.g., 1 hour).
In a study, patients with fibromyalgia who received a single dose of ketamine infusion experienced a significant reduction in pain intensity scores, exceeding 50%.
Ketamine is known for its anti-inflammatory effects, which are believed to play a significant role in the pathogenesis of various pain conditions and disorders, including fibromyalgia.
Contraindications (who should avoid ketamine therapy)
Ketamine therapy is not suitable for everyone, and certain individuals should avoid it due to specific health risks. Contraindications for ketamine include:
Severe Cardiovascular Conditions: Patients with unstable heart disease, including conditions such as congestive heart failure and unstable coronary artery disease, as well as those with uncontrolled high blood pressure or other serious heart conditions, should avoid ketamine therapy.
Psychotic Disorders: Individuals with a history of psychotic disorders, such as schizophrenia, or those currently experiencing the active manic phase of bipolar disorder may find that their symptoms worsen due to the psychotomimetic effects of ketamine.
Uncontrolled Thyroid Disease: Individuals with uncontrolled thyroid conditions, such as hyperthyroidism, should avoid ketamine due to concerns about potential complications like tachycardia and arrhythmias.
Substance Use Disorders: Although ketamine is used in treating certain substance use disorders, it should be avoided in individuals with a history of ketamine abuse due to the potential for misuse and dependence.
Pregnancy: Due to the lack of extensive research on its safety in these populations, ketamine is generally contraindicated for pregnant women.
Severe Liver Disease: Patients with significant liver impairment should avoid ketamine, as it is metabolized by the liver and may exacerbate liver conditions.
Allergy to Ketamine: Individuals who have had previous allergic reactions to ketamine should not undergo ketamine therapy.
Ketamine's Mechanism of Action for Mental Health Disorders
Ketamine is primarily known for its rapid antidepressant effects, which can be significant for treatment-resistant depression as well as other mood disorders. The key mechanisms include:
NMDA Receptor Antagonism: Ketamine is best known as an NMDA receptor antagonist. By blocking these receptors, which are part of the glutamate pathway, ketamine affects neurotransmitter activity, leading to rapid changes in mood and thought patterns. This triggers a cascade of changes in the brain, resulting in increased neuroplasticity—essentially, the brain's ability to reorganize itself by forming new neural connections, which is thought to contribute to mood improvement. This mechanism is different from traditional antidepressants, which primarily target the serotonin system.
BDNF Release: Ketamine promotes the release of Brain-Derived Neurotrophic Factor (BDNF), a protein that plays a critical role in neurogenesis, causing the regrowth and strengthening of broken connections in stressed brains. This enhances the brain's ability to communicate and function optimally.
Reopening of Critical Periods: Recent research indicates that ketamine has the potential to reopen what are known as "critical periods" for social reward learning. Ketamine seems to induce a mental state reminiscent of youthful receptivity, making learning and behavioral changes more accessible and attainable. This parallels the idea that learning a new language is notably easier during one's early years when the mind is more adaptable and open to embracing new concepts.
Anti-inflammatory Effects: Studies suggest that ketamine may have anti-inflammatory effects, which could also contribute to its antidepressant properties, as inflammation is thought to be a factor in some cases of depression.
How Does Ketamine Treatment Alleviate Pain?
Ketamine's effectiveness in pain management is primarily through its action on the central nervous system:
NMDA Receptor Blockade: NMDA receptors are a type of glutamate receptor involved in the transmission of pain signals within the central nervous system. By blocking these receptors, ketamine can dampen the transmission of pain signals to the brain and spinal cord.
Anti-inflammatory Effect: Ketamine has been shown to reduce pro-inflammatory molecules such as Tumor Necrosis Factor (TNF-α), which plays a role in several autoimmune disorders, including rheumatoid arthritis, inflammatory bowel disease (e.g., Crohn's disease), ankylosing spondylitis, and psoriasis.
Central Sensitization Inhibition: After years of chronic pain, often associated with the use of analgesics such as opioids, the nervous system may become hypersensitive to pain signals. Ketamine may help reprocess and "reset" the pain threshold back to a normal level.
Neuroplasticity and Pain Perception: Ketamine induces a process that repairs injured nerve cells and promotes the creation of new neural pathways, potentially altering the perception and processing of pain. Some individuals report developing a new relationship, acceptance, and understanding of their pain. Through this mechanism, incorporating psychotherapy may provide utility, helping individuals achieve lasting effects similar to those observed with ketamine in treating mood disorders such as depression.
The Ketamine Infusion Experience
The purpose of the infusion process is to safely administer ketamine while ensuring the most comfortable experience possible. Some individuals may undergo a dissociative state or "trip," which is a natural part of the process.
It is important to understand that the healing process and antidepressant effects occur after infusions during the neuroplastic process
Some individuals find meaning in their ketamine experiences with new ideas or feelings brought up to the forefront of their mind, which offers them something to work with internally or with a therapist. Others will have an experience filled with random thoughts and imagery that is difficult to understand. Individuals are reassured that it’s normal to have unusual or random experiences, because the healing is caused by structural changing of the brain, such as neurogenesis, which happened days to weeks post infusion.
Some experiences will be very pleasurable, relaxing, and meditative, while others will be challenging; the ketamine experience may bring out subconscious issues such as memories or trauma that can feel overwhelming or emotional.
A challenging trip (rather than the term “bad" trip) can still be very therapeutic, and potentially even more can be gained and used from these tough experiences.
Ketamine's Different Routes of Administration
Intravenous (IV) and Intramuscular (IM)
IV is the preferred route for safety and efficacy.
IV and IM ketamine rapidly alleviate symptoms, often within hours to days, in individuals with treatment-resistant depression.
Studies show IV ketamine has a higher efficacy than oral and nasal forms, with a response rate of 75-80% in treating depression.
IV ketamine ensures 100% bioavailability, allowing for lower doses that minimize side effects.
IV allows for precise control over the infusion, quick adjustment of doses, and immediate treatment of side effects like nausea, hypertension, and tachycardia.
The effects of IV ketamine are predictable and consistent.
The IV and IM forms are the most extensively researched and supported in the scientific community.
Nasal
Nasal ketamine is 40% bioavailable and offers a less predictable experience (i.e., the dose is dependent on the rate of absorption and other patient-specific factors).
There is no ability to stop or reverse the dose; instead, the patient must wait for the effects to "run their course" and wear off.
More treatments are required to achieve remission with nasal ketamine compared to IV ketamine.
Expected response rates for nasal ketamine range between 35-50%.
Key differences between IV ketamine and nasal Spravato
Oral and At-Home Ketamine
Some studies have reported that it takes 4 to 6 weeks to observe any antidepressant effects with oral ketamine, similar to traditional antidepressant medications.
Oral ketamine requires much higher doses and has a greater potential for side effects due to its lower bioavailability of approximately 20%.
When taken at home, patients are not monitored, which increases the risk for abuse or misuse and potentially reduces therapeutic benefits.
Recent reports reveal that more than 50% of Americans misuse at-home ketamine, often accidentally or intentionally using more than the recommended dose.
At Innerbloom, we strongly advise against at-home ketamine use. We've encountered numerous patients who initially sought treatment through online prescribers and experienced alarming and highly ineffective results. Many of these individuals have turned to us after their at-home ketamine experiences failed, seeking our professional and therapeutic guidance.
Types of Responders to Ketamine Therapy
Early Responders: Show improvements after 1 or 2 treatments.
Standard Responders: Experience incremental improvements within 3 or 4 treatments.
Late Responders: May require 5 or more treatments before noticing any benefits. By the sixth infusion, 80% of individuals who respond to ketamine can be identified. For some, a longer course of treatment is required.
Non-responders: 15-20% of individuals do not experience antidepressant effects from ketamine. Non-ketamine treatment alternatives for non-responders include cognitive-behavioral therapy (CBT), electroconvulsive therapy (ECT), eye movement desensitization and reprocessing therapy (EMDR), and transcranial magnetic stimulation (TMS).
Interactions with Medications and Potential Inhibitors of Ketamine
Benzodiazepines and lamotrigine may diminish the effectiveness of ketamine. When possible, patients are requested to refrain from taking these medications on infusion days.
Alcohol can also hinder the antidepressant effects of ketamine. Additionally, some individuals may be sensitive to other substances, such as cannabis, which might interfere with the action of ketamine.
One of the key advantages of ketamine is that it does not compromise breathing, and it can even slightly stimulate heart rate and blood pressure, rather than reducing them to dangerously low levels, as seen with other medications (e.g. benzodiazepines and opioids).
Ketamine has minimal interactions with other medications, allowing for safe co-administration with drugs like antidepressants.
Approximately 5% of patients experience nausea, which may be associated with high dosages and visual stimulation, particularly when individuals do not wear eye shades during their treatments. However, if patients are more prone to nausea or experience it after an infusion, we may opt to use an antiemetic IV medication such as Ondansetron (Zofran).
Rarely some may experience anxiety given the normal emotional response from the medicine; this typically does not require pharmacological treatment, but rather reassurance and sometimes physical touch (e.g., hand holding)
Ketamine is not physically addictive. Chronic and frequent use of ketamine, often associated with at-home use, can lead to psychological addiction.
Recreational abuse of ketamine may cause bladder injury known as interstitial cystitis which is associated with daily high dosages (1+ grams); this can lead to a stiff bladder with decreased volume capacity.
Innerbloom's Philosophy of Care
Ketamine alone may not be sufficient to "cure" depression or other mental health disorders. At Innerbloom, we advocate integrating psychotherapy to foster a more holistic and enduring response.
Ketamine serves as a tool or catalyst for change and transformation, rather than a silver bullet. It can help interrupt negative thought patterns, maladaptive behaviors, or destructive life cycles, promoting a pathway to healing.
Unlike antidepressants, which are typically designed for daily use to treat symptoms, ketamine should be administered sparingly with ample preparation and mindfulness. This series of infusions is aimed at addressing the root cause of problems rather than merely masking or numbing effects. This approach allows patients to regain their footing and implement healthy lifestyle changes.
Preparation, integration, and psychotherapy are crucial to the proper and safe utilization of ketamine, ensuring that it complements a comprehensive treatment plan.
While a series of infusions may propel an individual into a healthy mental state that doesn't require ongoing therapy, others have found ketamine to be an ongoing treatment. For these individuals, the maintenance phase necessitates periodic booster infusions, depending on the duration of their symptom relief.
The Ketamine Infusion Process Explained
Standard Infusion Protocol: Patients generally undergo a series of six or more 40-minute infusions spread over 2 to 6 weeks. To support the treatment's efficacy, it's recommended to schedule 1 to 3 infusions per week. This regimen is complemented by a minimum of three psychotherapy sessions to enhance the psychological benefits of ketamine.
Booster Infusions: For patients who have completed the initial series of six infusions, booster doses are available. These boosters help maintain the therapeutic effects over a longer period and are tailored to individual needs. For further details on the potential need for booster infusions as part of a maintenance phase of care, be sure to read this article.
Minimum Effective Dose: Single infusions are not recommended as they are typically insufficient to gauge the full therapeutic response. A sequence of 4 to 5 infusions is considered necessary to effectively assess a patient's reaction to the treatment and determine whether they are non-responders.
Safety and Monitoring: During each infusion, a dedicated sitter is present to ensure the patient's safety and provide support. This close monitoring is crucial for managing any immediate side effects and enhancing the overall comfort of the patient during the treatment process.
If a booster infusion is needed, the goal is to administer it before symptoms return to their original pre-treatment baseline. By utilizing a well-timed booster, the individual can return to the improved baseline achieved after completing the induction series.
What to Expect After an Infusion
Patients will need a ride home and are encouraged to have a restful day afterward. They should expect to feel back to baseline within about 3 hours, given that the half-life of ketamine is 2.2 hours. However, they cannot drive for at least 12 hours after the infusion.
Rest and hydration are essential following the infusion. Some patients may find it difficult to sleep that night, while others might experience a very restful slumber.
Patients can expect to return to work, school, and their daily routines the next day.
Preparation prior to infusions appears to be beneficial for achieving the proper mindset that allows for a therapeutic response; the goal of preparation is to maximize benefits and avoid potential risks or side effects.
At Innerbloom, preparation begins with the client's first psychotherapy appointment with our ketamine-assisted psychotherapy (KAP) therapist. This includes education, attention to set and setting, and making use of strong support systems while setting intentions.
Integration
Integration refers to what is done after infusions or in between treatment sessions; this includes plans of action and changes in lifestyle in positive ways to achieve long lasting results after ketamine therapy.
Ketamine therapy alone may have beneficial effects, although integration enhances the therapeutic potential of the medicine to achieve long lasting results.
Integration includes self-reflection, developing new healthy routines and daily habits with help from a professional, such as a therapist which may ultimately lead to long-term positive life changes.
At Innerbloom, integration is an integral part of the process and is included in the psychotherapy sessions involved throughout the treatment.
Four Misconceptions About Ketamine
Misconception #1: Ketamine Is Illegal: Ketamine is a Schedule III controlled substance, indicating moderate to low potential for dependence. It is legal when administered by a licensed medical provider, with the DEA regulating its manufacture, sale, and possession.
Misconception #2: Ketamine Is a Horse Tranquilizer: Ketamine is used in both humans and animals, but with different formulations and dosages. Safe for humans when administered by licensed providers, similar to other medications like amoxicillin, Prozac, and ivermectin.
Misconception #3: Ketamine Is “Off Label” Meaning Not Approved by the FDA: Ketamine is FDA-approved as an anesthetic since 1970 and for Treatment-Resistant Depression in nasal spray form since 2019. "Off label" use is common and does not imply ineffectiveness or unsafety; about 20% of pharmaceuticals are used off-label.
Misconception #4: Ketamine Is a Dangerous Party Drug With Widespread Abuse: While ketamine can be abused, it has a long history of safe medical use, especially in emergency and operating rooms. Under medical supervision, it is very safe, but misuse can lead to risks. Medical providers ensure safety and can respond to emergencies, unlike recreational use.
About the Author
Dr. Ray Rivas, a former general and trauma surgeon with over a decade of experience utilizing ketamine, became a ketamine therapy specialist to treat mental health and pain after witnessing its profound impact on his hospital trauma patients and his own mental health. As the founder and medical director of Innerbloom Ketamine Therapy in San Luis Obispo, California, Dr. Rivas applies his extensive medical expertise to provide safe, evidence-based ketamine treatments for mood disorders, including depression, anxiety, PTSD, and chronic pain. His passion lies in helping patients find relief and rediscover hope through personalized, compassionate care.
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