KETAMINE INFUSION THERAPY AT SOUTH SHORE KETAMINE CENTER

Ketamine, initially developed in the 1960s by Dr. Calvin Stevens, was originally intended as a safer alternative to phencyclidine (PCP), a dissociative anesthetic. It was first synthesized by Parke-Davis (now a part of Pfizer). Ketamine quickly found use in the medical field as an anesthetic due to its ability to induce a trance-like state while maintaining vital functions.

Throughout the 1970s and 1980s, ketamine gained popularity in veterinary medicine. Its unique properties, including rapid onset and relatively short duration, made it a valuable tool. However, ketamine's dissociative effects led to its recreational use, earning it the moniker "Special K" in party circles. Concerns over abuse potential led to its classification as a Schedule III controlled substance in the United States in 1999.

Side effects, such as elevated blood pressure and heart rate, prove advantageous in maintaining adequate cardiac output, particularly in cases of head injuries where preserving cerebral perfusion is critical. As a result, ketamine swiftly found application in emergency and wartime medicine. It also carved a niche in "procedural sedation," particularly for children in emergency departments, where high doses are used to facilitate rapid procedures like resetting dislocated joints. Notably, ketamine doses for procedural sedation can be substantial, often ranging from 2 to 5 mg/kg.

Ketamine's remarkable safety profile allows for its use in patients with asthma and airway disease. Consequently, the World Health Organization (WHO) has classified ketamine as an essential medicine for many decades, reflecting its enduring and extensive applications.

Studies in the early 2000s, including those by Dr. John Krystal and Dr. Carlos Zarate, demonstrated that ketamine could rapidly alleviate symptoms of depression, even in individuals who had not responded to traditional antidepressants.

In 2019, the U.S. Food and Drug Administration (FDA) approved a ketamine-derived nasal spray called SPRAVATO® (esketamine) for treatment-resistant depression, marking a significant milestone in recognizing ketamine's therapeutic potential.  Ketamine infusion therapy clinics began to appear across the United States and around the world, offering treatments for mood disorders and chronic pain. Scientific investigations continue to explore ketamine's mechanisms of action and its applications in treating various conditions, from bipolar disorder to post-traumatic stress disorder.

Ketamine infusion therapy has rapidly evolved as an innovative treatment option for individuals facing treatment-resistant conditions. It offers the promise of rapid relief and a renewed sense of hope for those who have exhausted other treatment avenues. As research and clinical experience continue to grow, ketamine infusion therapy's role in modern medicine is likely to expand further. 

Ketamine infusion therapy utilizes racemic ketamine in sub-anesthetic doses of racemic ketamine. This means ketamine is administered at levels below what's needed for anesthesia. It's a safe and effective approach that provides rapid relief for conditions like depression, anxiety, PTSD, and chronic pain. 

Treatment-Resistant Depression (TRD):
Approximately 50-70% of patients with TRD experience a significant reduction in depressive symptoms after a single ketamine infusion. The rapid antidepressant effects can begin within hours to days after treatment. However, the duration of the antidepressant response is variable, with some individuals experiencing sustained relief while others require maintenance infusions.

Suicidal Ideation:
Ketamine has demonstrated rapid reduction in suicidal ideation. In some studies, up to 50-60% of patients with suicidal ideation experienced a significant decrease after ketamine treatment.

Bipolar Disorder:
Research on the use of ketamine in bipolar disorder is less extensive than in depression. Ketamine may be more effective for managing the depressive phase of bipolar disorder, but the response rates can vary widely.

For Pain Disorders:

The efficacy of ketamine for chronic pain conditions is variable, with response rates ranging from 20% to 70% depending on the pain condition. Ketamine is often considered when other pain management approaches have failed or when patients are unable to tolerate traditional pain medications.

Complex Regional Pain Syndrome (CRPS):
Ketamine therapy delivers substantial pain relief in CRPS patients, with response rates around 60-70%. Ketamine infusions are sometimes used as a primary or adjunctive treatment in CRPS cases.

Ketamine primarily acts on the central nervous system (CNS) and its effects are mediated by several mechanisms:

NMDA Receptor Antagonism: Ketamine is a potent antagonist of N-methyl-D-aspartate (NMDA) receptors in the brain. By blocking these receptors, ketamine reduces the transmission of pain signals and affects neural pathways involved in mood regulation. This is a key mechanism behind its use in both pain management and mood disorders.

Glutamate Modulation: Ketamine's blockade of NMDA receptors leads to increased levels of glutamate, a major excitatory neurotransmitter. This excess glutamate promotes the release of brain-derived neurotrophic factor (BDNF), which is believed to contribute to the antidepressant effects of ketamine by enhancing synaptic plasticity and neurogenesis.

Affecting Other Neurotransmitters: Ketamine's action on the CNS also affects other neurotransmitter systems, including serotonin, dopamine, and norepinephrine, which play roles in mood regulation and pain perception. These interactions contribute to its antidepressant and analgesic effects.

Rapid Onset: Ketamine infusion therapy is known for its rapid onset of action, often producing noticeable effects within hours to days, making it particularly valuable in managing acute symptoms of severe depression and suicidal ideation.

Individual Variability: It's important to note that individual responses to ketamine can vary widely. Factors such as genetics, metabolism, and the specific condition being treated can influence how a person responds to ketamine infusion therapy.

• Active psychosis or severe mental illness.

• Uncontrolled hypertension.
• Severe cardiovascular conditions.
• Recent heart attack.

• Elevated intracranial pressure (e.g., from head injury or tumors).

• Active substance use disorder, especially opioids or stimulants.

• Pregnancy (unless benefits outweigh risks).
• Allergy/hypersensitivity to ketamine.

• Severe liver or kidney dysfunction.

• Medications with potential interactions.

• Age-related cognitive concerns, especially in older adults.

Ketamine infusion therapy, like any medical treatment, can interact with other drugs, potentially leading to adverse effects or reduced efficacy. Here are some major drug interactions to be aware of when considering ketamine infusion therapy:

Central Nervous System (CNS) Depressants:
Combining ketamine with other CNS depressants, such as alcohol, benzodiazepines (e.g., diazepam, alprazolam), or opioids (e.g., morphine, oxycodone), can result in increased sedation and respiratory depression.

Monoamine Oxidase Inhibitors (MAOIs):
Ketamine may interact with MAOIs, potentially leading to a hypertensive crisis, serotonin syndrome, or other adverse effects. Patients should have a sufficient washout period before starting ketamine therapy if they have been on MAOIs.

Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs):
Ketamine may enhance the effects of SSRIs and SNRIs, potentially increasing the risk of excessive serotonin activity. Careful monitoring and potential dose adjustments may be necessary when combining ketamine with these medications.

Antipsychotic Medications:

Ketamine may interact with antipsychotic drugs, leading to an increased risk of sedation, confusion, and hallucinations. Dosing adjustments or close monitoring may be required when using ketamine alongside antipsychotics.

Sympathomimetic Agents:
Ketamine can increase heart rate and blood pressure, and when used with sympathomimetic agents like amphetamines or cocaine, there may be an additive effect on cardiovascular stimulation.

Anticonvulsant Medications:
Ketamine may lower the seizure threshold, increasing the risk of seizures when used with certain anticonvulsant drugs. Close monitoring is essential for individuals taking anticonvulsants.

Antiarrhythmic Medications:
Ketamine may have proarrhythmic effects, so patients taking antiarrhythmic medications should be closely monitored for any changes in heart rhythm.

CYP450 Enzyme Inhibitors and Inducers:
Ketamine is metabolized in the liver by cytochrome P450 enzymes. Drugs that inhibit or induce these enzymes can affect the pharmacokinetics of ketamine. Dosing adjustments may be necessary when ketamine is used alongside drugs that affect these enzymes.

It's essential for healthcare providers to review a patient's complete medication list, including over-the-counter drugs and supplements, to identify potential drug interactions before starting ketamine infusion therapy. Adjustments to medication regimens and careful monitoring can help manage and mitigate these interactions, ensuring the safety and efficacy of treatment.

Common side effects include dizziness, nausea or vomiting, changes in blood pressure and heart rate, and alterations in perception, such as vivid dreams or hallucinations. Some individuals may experience dissociation, a feeling of being disconnected from their body or surroundings, which is a hallmark effect of ketamine. In addition, cognitive impairments, including confusion and difficulty concentrating, can occur during and after treatment, especially at higher doses. While these side effects are generally transient and resolve as the drug clears from the system, they underscore the importance of receiving ketamine infusion therapy in a controlled medical environment under the supervision of trained healthcare professionals who can monitor and manage any adverse reactions.

Ketamine can have negative effects, especially when taken outside clinical setting and in different amounts. According to the 2020 Global Drug Survey, which involved over 20,000 people, around 15.9% had used ketamine in the last year. This was a significant increase compared to the year before (Global Drug Survey, 2021). For comparison, in 2015, only 4.6% of survey participants said they had used ketamine.  While overdosing on ketamine alone is rare, it can still cause problems when used recreationally. People are more likely to have accidents when using ketamine outside of medical settings compared to when it's used under supervision. Ketamine can make you feel disconnected from your surroundings, there have been reports of sexual assaults where people couldn't give consent or defend themselves against attackers. In recreational settings, ketamine is often used alongside other drugs like MDMA, cocaine, and GHB. This increases the risks associated with drug use in these environments.

Ketamine metabolism primarily occurs in the liver, where it undergoes enzymatic transformation, resulting in various metabolites, with norketamine being the most prominent. These metabolites are eventually excreted through urine. Typically, in the blood, ketamine and its metabolites are detectable within minutes after administration, with peak levels achieved during the infusion. After discontinuation, the drug and its metabolites begin to decline, with a half-life ranging from 2 to 4 hours. In urine, ketamine and its metabolites are detectable for a relatively short period, typically within 1 to 3 days after administration, and up to 14 days with repeated use. Detection in hair is less common, as ketamine is not known to readily incorporate into hair follicles, making hair testing less reliable for detecting ketamine use. The majority of detection and monitoring efforts are focused on blood and urine samples due to their reliability in assessing recent ketamine exposure.