In its essence, ketamine is a dissociative anaesthetic that provides short-acting relief for pain. It has been around since the 1950s and was discovered by Parke-Davis and Company in their Detroit laboratory. They were on the hunt for the ideal anaesthetic and gave ketamine the developmental code name CI-581. The earliest clinical research on ketamine was performed on animals before it was then used on prisoners of war as an alternative to phencyclidine (PCP) for anaesthetic purposes. It was not until the 1970s, during the Vietnam War, when ketamine’s use was extended for the purpose of surgical anaesthesia.
Ketamine has a wide range of utilization and can be used operatively at both high and low doses. At low doses, it has been shown to be instrumental in treating mental health and pain disorders, explains Mike Cooper, M.D., Psychiatrist and Medical Director at Innerwell. We all have NMDA receptors throughout our brain that play an integral role in both memory and learning. What ketamine does, Dr. Cooper explains, is antagonize these receptors and blocks a neurotransmitter that binds to these receptors, called glutamate. “Ketamine essentially blocks the binding of glutamate to those receptors, which in turn increases activation of a different kind of receptor called AMPA,” he says. “By increasing activation of AMPA you increase the release of BDNF, or brain derived neurotrophic factor, which is a protein in the brain that increases neuroplasticity.”
What is neuroplasticity? Put simply, neuroplasticity is the ability of our nervous system to shift in response to various stimuli, therefore creating new neuronal connections in the brain, explains Dr. Cooper.
Ketamine is administered through a variety of routes, namely oral, intravenously (IV,) intramuscularly (IM) or intranasally (IN). Here’s a look at how each one works and in which use case one may be preferred over another.
This is perhaps the least expensive and most straight-forward way to administer ketamine, especially when it comes to treating depressed patients, per research published in The Journal of Clinical Psychiatry. The only downside of dosing ketamine orally is that only about 25 percent of the drug actually reaches systemic circulation. This means that doses may have to be higher to achieve the same results that would be needed if the drug was administered via other methods, such as intravenously.
In the operating room, ketamine is typically administered intravenously, since there is simply more literature and decades of research supporting this method. It is also how the very first human trial of ketamine infusion was administered. This is often how ketamine infusion clinics prefer to administer their ketamine, according to Dr. Cooper. Research has shown this route to be quite effective, especially when given slowly in a very low dose of 0.5 mg/kg over the course of 40 minutes (http://ketamineinstitute.com/wp-content/uploads/2016/09/Antidepressant-Effects-of-Ketamine-in-Depressed-Patients-Berman-2000.pdf).
Mental health clinics that offer ketamine-assisted psychotherapy sometimes administer ketamine intramuscularly or injected into the muscle, almost in the same way that a vaccine is administered.
Additional data is accumulating on the intranasal route, which is quite non-invasive and simply involves spraying the medication into the nostrils. In terms of bioavailability, or how well a drug is absorbed in the body, research has shown that intra-nasally is roughly 45 percent, compared to intravenously, which is 100 percent and intramuscularly, which is about 95 percent, according to Dr. Cooper. “These are rough estimates, but they give a general sense of how a practitioner would calculate what dose to give a patient relative to an IV dose,” he says. “So, for instance, if you wanted to give an equivalent dose orally as compared to 90 milligram dose intravenously, you would give 300 mg orally, assuming approximately 30 percent bio available.”
Yes—ketamine is actually one of the safest anesthetics available today, especially in regards to how it preserves the airway reflexes. “You can put someone to sleep with ketamine, but they can still breathe on their own without needing to be connected up to any kind of supplemental oxygen or any kind of airway procedure like an intubation to provide mechanical breathing,” explains Dr. Cooper. This is unique when compared to other anesthetics that put you to sleep. During this process, these anesthetics often suppress a patient’s breathing, which requires them to be intubated in an operating room and provided mechanical ventilation to keep them breathing. With ketamine, on the other hand, the patient continues to breathe even though they're asleep and not feeling pain.
Ketamine is also a very short-acting medication, lasting up to about an hour after its onset. The only real potential downside of ketamine is that it has been shown to increase blood pressure slightly for some patients. Even so, this rise in blood pressure is not to an alarming or concerning degree, notes Dr. Cooper. “While it can increase heart rate a little bit, it is a very physiologically safe medication.”
While, traditionally, ketamine has been used mainly as an anaesthetic, in the last couple of decades, it has been used increasingly in psychiatry after it was found to be helpful in treating depression in a very rapid manner when given intravenously. Practitioners have been using it off-label to treat depression for a long time, however, a certain form of ketamine, called esketamine, under the name Spravato, was FDA approved in 2019 for the clinical treatment of depression.
Recent reviews published in both Pharmacological Reviews and the Australian and New Zealand Journal of Psychiatry have shown ketamine to be impressively effective in the treatment of major depressive disorder as well as in the treatment of post-traumatic stress disorder.
While other depression medications such as sertraline (Zoloft®), paroxetine (Paxil®), fluoxetine (Prozac®) and citalopram (Celexa®), may take many months to work fully, ketamine has been shown to work as rapidly as after one dose, within 24 hours of the first dose, in fact, notes Dr. Cooper.
This is perhaps the number one question most patients considering ketamine may have—and it is understandable as to why. This depends on the dose range, according to Dr. Cooper. “At the extreme end of the dose range, ketamine is going to act as a general anesthetic and can put someone to sleep to the point where they're not going to remember the experience and not feel pain,” he says. This is more of how it was traditionally used when it was first discovered. “As you look at the lower doses, say, if you go on the opposite end of the spectrum, where you take a low dose of ketamine, it can be a very relaxed feeling,” he says. The effects of this low dose could be compared to a glass of wine, for example, in terms of that relaxation feeling.
“Most patients describe the feeling of ketamine as very relaxed and open where they feel comfortable talking and communicating about difficult things in their life,” says Dr. Cooper. “In this low-dose administration, it can be thought of as a psycholytic agent where it lowers ego defenses to allow patients to talk about aspects of their personality, their life and their memories in a little bit more of an easier way than they can without ketamine.”
In the moderate dose range, ketamine tends to be more like a psychedelic where patients may close their eyes and see beautiful colors, geometric patterns and other shapes, especially when they’re listening to music. They may also notice a distinct shift in their perspective. “They might feel that their sense of self is growing larger, or that they feel more connected to their surroundings or to the people around them, as well as a heightened sense of oneness and connectedness to the world,” explains Dr. Cooper.
As the dose increases from there, ketamine generates sort of almost an out-of-body experience, where a patient may feel like they're outside looking inward in a very peaceful way. “They feel very much a part of the universe and they can even have these visual experiences of watching the universe being constructed and planets coming into existence and quite metaphysical, extraordinary experiences like that,” says Dr. Cooper.
The length of time during which ketamine lasts is about an hour long when used for its psychological effects, with only very mild residual effects of the medicine lasting longer than that 60-minute duration period. The official half-life of the medicine, or how long it takes for the medicine in your body to be completely eliminated by 50 percent is an estimated 2.5 hours in adults, per FDA data.
How a ketamine treatment works depends mainly on the model of treatment. If it is an intravenous ketamine clinic, a patient would go to their doctor’s office, often a psychiatrist. Next, they would be connected to an IV and would receive an infusion of ketamine over the course of an hour or two. There may also be a nurse in position to check in with the patient at frequent intervals. “This type of model doesn't usually involve psychotherapy; it is usually the patient in a clinic room getting an infusion of ketamine, almost like chemotherapy,” explains Dr. Cooper.
Another model is called ketamine assisted psychotherapy, where the patient undergoes psychotherapy at the same time as they are having a ketamine experience. Often, this type of model kicks off with a preparation session beforehand where the practitioner seeks to learn and understand more of what the patient is seeking assistance and help with. “Part of the initial intake involves setting an intention for the journey, talking about what it is going to be like for them and helping select the music to play to guide them on their way,” says Dr. Cooper.
This type of ketamine therapy could be provided after they get an intramuscular injection of ketamine, an IV infusion of ketamine, or after they take an oral or sublingual dose of ketamine, according to Dr. Cooper. “The most common route of administration for a patient receiving treatment in the form of psychotherapy is intramuscular injection after which you would lie on the couch in their office and talk about things that come to your mind,” he says. “Often, the psychiatrist will encourage the patient to look inward at their life, put eye shades on, and listen to a music playlist to help guide them on this introspective journey and reflect on their life during the ketamine experience.”
Another type of ketamine-assisted psychotherapy involves the practitioner treating the patient virtually over Zoom. This can allow for a more comfortable experience and may encourage the patient to go more in-depth about their thoughts and past experiences. If a patient chooses to go this route, they would be prescribed ketamine orally in the form of a lozenge or tablet. They would also have a support person or family member present who would be there to help them through potentially difficult aspects of their journey.
During the treatment, the practitioner conducts a medical evaluation that involves assessing the patient's psychiatric history, medical history, and any past experiences with non-ordinary states of consciousness, as well as educating the patient about what the ketamine experience can feel like to them.
The first ketamine experience often starts with a very low dose of the drug, which simulates the feeling of drinking a glass of wine—the patient is relaxed and can get comfortable with the medication. “Some patients choose to remain at a lower dose because they find it very therapeutic and can do a lot of good psychological work at this dose,” says Dr. Cooper. “For patients who feel ready to have a bit more of an intense experience, the doctor can carefully titrate the dose over time so the patient can learn to work with the stronger effects along the way.”
Ketamine is very versatile and there is a great deal of emerging evidence that is showing it to be useful for treating a variety of conditions, especially depression. “Ketamine can be quite beneficial for someone who has depression and has not responded to traditional antidepressant medications like Prozac and Lexapro, or for a patient who's in psychotherapy and has made some progress towards treating their depression and anxiety, but they want to augment their treatment or have a bit more rapid improvement in their symptoms,” explains Dr. Cooper. “Patients who are naturally very introspective and philosophical in general, who would appreciate the kind of inward journey and perspective that they can gain through ketamine, would also be very good candidates for this type of treatment.”
It’s important to recognize that ketamine treatment, while quite extensive and science-backed in its therapeutic abilities, is not for everyone—and determining whether or not it’s right for you is a deeply personal decision that shouldn’t be taken lightly.
If you do decide to try ketamine, it’s also important to recognize that there is no substitute for working with a licensed expert who has been certified and trained in this specialty. Not only can they help prepare you for what to expert and guide you along the journey, but they can also help you better process your experiences and traumas.
If you’re interested in harnessing the power of psychedelics to move beyond what’s been holding you back, sign up and take our patient screener to take the first step towards healing.