Ketamine is a medication first approved by the FDA in 1970, primarily used as a surgical anesthetic in hospitals. It has a complex mechanism of action but within the brain it acts primarily on the glutamate system, specifically as an NMDA receptor antagonist1.
At higher doses, ketamine produces a "dissociative" state, characterized by a sense of detachment from one's physical body and the external world, which is accompanied by a variable degree of sensory and cognitive impairment.
Recently, "off-label" use of ketamine has shown to be effective in the treatment of psychiatric conditions, primarily depression1.
Outside of its medical use, Ketamine is also known for its illicit use as a recreational drug. Ketamine does have abuse potential and long term use has been attributed to serious side effects2.
Several studies have found that ketamine can have a rapid and robust antidepressant effect in people with major depressive disorder, particularly in individuals who have not responded to standard antidepressant treatments—a condition known as treatment-resistant depression1234.
Unlike conventional antidepressants that primarily work on serotonin, norepinephrine or dopamine systems, ketamine facilitates neuroplasticity by acting primarily on a different neurotransmitter known as glutamate, specifically the NMDA glutamate receptor. While it is not entirely clear how ketamine works to treat depression, one hypothesis is that it increases neuronal connections in brain regions that are associated with depression, helping to repair neuronal damage associated with chronic stress5.
While conventional antidepressants typically take a few weeks to have a noticeable effect, ketamine's effects typically occur within hours to a few days. The rapid onset of ketamine's antidepressant effects make it especially useful in treating depressed individuals who may be suicidal3.
While the rapid onset of ketamine's antidepressant effects are useful, the antidepressant effect of a single dose typically wanes after a few days or weeks. Therefore it is common to receive additional administrations of ketamine over the course of multiple weeks. Pairing with ketamine treatment with psychotherapy may also reinforce and the antidepressant effects and improve long term outcomes6.
It's important to note that the use of ketamine in the treatment of depression involves off-label use of the drug (with the exception of Spravato) and should only be administered under the supervision of a healthcare provider due to its potential side effects and risk of misuse.
Additionally, while the rapid effects of ketamine for depression are promising, more research is needed to fully understand its long-term effects and potential risks.
Ketamine: A Paradigm Shift for Depression Research and Treatment
Ketamine Assisted Psychotherapy: A Systematic Narrative Review of the Literature
In addition to depression, ketamine is being investigated as a treatment for a variety of other conditions.
Substance Use Disorders: Ketamine may be an effective treatment for certain addiction disorders. Alcohol use disorder is a particularly popular area of research with at least multiple completed examining ketamine's role as a possible treatment. Overall the results are encouraging and pairing ketamine treatment with psychotherapy has produced more favorable outcomes. It is important to note that more research is still needed to determine whether ketamine should be used as a treatment for substance use disorders1.
Anxiety: It is possible that ketamine may be useful to address to anxiety disorders. Studies have shown ketamine's anti-anxiety effects for up to a week following a single treatment, especially at higher doses2.
PTSD: While more data is needed, early studies indicate that a single dose of ketamine can resolve symptoms of PTSD for up to two weeks, with similar efficacy to its use in treating depression3.
Chronic Pain: Ketamine may be useful for treating chronic pain, particularly neuropathic pain. However, more research is needed4.
While ketamine therapy has been shown to be helpful for many people, the high costs of treatment make it inaccessible for many. Ketamine therapy may require three to eight sessions spread over a few weeks with each session typically costing between $300-$800.
The main reason why ketamine therapy is so expensive is that it is often not covered by health insurance plans. While ketamine has been FDA approved since the 1970s as an anesthetic, it has only recently shown to be effective in the treatment of certain mental health conditions such as depression and is therefore prescribed "off-label" in the context of mental health treatment. Typically health insurance providers are reluctant to cover "off-label" prescriptions, often leaving the full cost of treatment up to the patient. Additionally, ketamine therapy sessions are typically longer than traditional medical approintments or therapy sessions. Therefore, a clinician's time is also accounted for in the high cost of treatment.
Before starting ketamine therapy it is worth checking with your health insurance provider to determine if ketamine therapy might still be covered under your plan. It is also possible that you may be able to receive out-of-network reimbursement for ketamine therapy.
Another option is to ask your doctor about Spravato, which is a form of ketamine (eskatamine) that has been FDA approved for treatment resistant depression. Due to the fact that Spravato has been FDA approved for certain types of depression, health insurance companies may be more likely to cover its costs.
When used appropriately under the care of a professional, ketamine is generally well tolerated although more studies are needed. A ketamine experience will temporarily elevate heart rate and blood pressure, so it is important to monitor these before and during a ketamine experience.
Ketamine can be addictive. However, this is rarely a risk when it is prescribed under professional guidelines. The addiction risk becomes much greater when individuals use ketamine over long periods of time and/or at doses different than would be prescribed by a clinician.
Long term recreational use of ketamine has been associated with problems related to cognition and memory1. Extended use of ketamine can also cause serious infections in the bladder and urinary tract1,2. These risks are much greater when ketamine is combined with other drugs, especially alcohol3.
In addition to alcohol, combining ketamine with opioids or sedatives very dangerous and can lead to memory loss, slowed breathing, decreased heart function and even death4.
Black market ketamine is often mixed with other substances which can be harmful or deadly and it is difficult to know the quality or purity of ketamine bought illegally. It is always a good idea to test all ketamine purchased on the black market using test kits and fentanyl strips such as those provided by DanceSafe.
Ketamine can be administered in various ways, including intravenous (IV), intramuscular (IM), intranasal and sublingual routes. The choice of administration route can affect how quickly the drug takes effect and how potent its effects are.
Intravenous (IV): This method involves injecting the drug directly into a vein. IV administration allows for the most rapid onset of effects (1-3) minutes and provides the most control over the dosage since the entire amount of drug enters directly into the bloodstream and can be monitored and controlled in real-time by the the clinican1. This method is often used in a hospital setting for anesthesia and increasingly for the treatment of mental health disorders such as depression.
Intramuscular (IM): With this method, the entire dose of the drug is injected into a muscle (similar to a flu shot). The onset of effects is slightly slower than with IV administration (3-10 minutes)1. One advantage of this approach is that it is easy to administer and doesn't require the patient to be connected to any medical devices for the duration of the experience. However, with this approach the entire dose is administered all at once and is therefore the dosage level is harder to control after the initial administration.
Intranasal: Spravato, the FDA approved version of esketamine is administered under medical supervision as a nasal spray. This approach results in more of the drug getting into the bloodstream than sublingual ketamine, but not as much as IV or IM2.
Sublingual: In this method, the medication is placed under the tongue and absorbed through the oral mucosa into the bloodstream. The onset of effects is slower than IV or IM administration, generally within 15 to 30 minutes3. Given that some of the drug will be swallowed and then metabolized in the liver before entering the bloodstream, the subjective effects are often less potent than the IV or IM routes. Sublingual ketamine is often used in the context "at-home" ketamine services as well as paired with psychotherapy due to to the fact that is easy to administer and its gentler effects allow an individual to engage more directly with a therapist.
There is the most research on IV ketamine as an effective tool to treat depression, but there is also research data indicating the effectiveness of IM and and sublingual use of ketamine as well.
Spravato is the brand name for the drug esketamine, which is a specific part (or enantiomer) of the ketamine molecule. Ketamine's molecular formula is a racemic mixture, meaning it consists of two mirror images or "enantiomers" of the same molecule: "S-ketamine" and "R-ketamine." These enantiomers are mirror images of each other, much like left and right hands. Esketamine (Spravato) is the S-enantiomer of ketamine.
Esketamine was patented by Janssen Pharmaceuticals and has been approved by the FDA specifically for use in treatment-resistant depression, in conjunction with an oral antidepressant.
Spravato is administered as a nasal spray under medical supervision.
As legal ketamine clinics have risen in popularity in recent years, there has also been a dramatic increase in both demand and law enforcement siezure, of black market ketamine. Black market ketamine should not be considered a substitute for pharmaceutical ketamine provided by licensed clinicians. A risk with black market ketamine, which is often sold as a white powder is that it is often not pharmaceutical grade. Furthermore, illegally obtained ketamine may be cut with dangerous and potentially deadly adulterants including fentanyl. It is always a good idea to test your drugs using reactive agent test kits and fentanyl test strips such as those provided by DanceSafe.
Research Finds Major Increase in Seizures of Illegal Ketamine, Sparking Concerns About Risks of Use
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