Have you ever been curious about ketamine? Its origins, the science behind it, and more? Yes, ketamine is known to be an effective treatment for depression, suicidal, anxiety & PTSD, but how does it work? In this blog post, we’ll cover everything you need to know about ketamine and how we at Reset Ketamine approach our treatments. This blog was adapted from a transcript of a talk that Dr. Ko gave.
The current state of mental health calls for more effective treatments of depression such as ketamine.
The Current State Of Mental Health
Modern Allopathic Medicine & The Current State Of Mental Health
If you're having chest pain, suffering from a car accident, or experiencing a stroke, you definitely want to go to the emergency room and get evaluated by a physician. But there are some things we can improve on in traditional allopathic western medicine. One particular arena is mental health. One in four adults suffer from a mental illness and if it's not you then it's probably someone very close to you. If you're not aware of it, that loved one just may not be sharing it with you.
Mental Health Statistics
Depression
According to the World Health Organization, depression surpasses HIV, AIDS, malaria, diabetes and war as the leading cause of disability worldwide. 16.2 million Americans are affected by depression. It's more common in females than males (~8.5% vs. 4.8%). Some studies are also showing that up to 20% of teenagers experience depression before reaching adulthood. In general there's an increasing prevalence of depression in both teenagers and adults. The biggest concern of depression is that it can lead to suicide.
Anxiety
Anxiety is very common. Up to 31% of Americans will have an experience or an episode of it at least once in their lifetime. Nearly two-thirds of Americans are anxious or extremely anxious about their health and safety. There's been an increase of more than a third in general anxiety overall compared to the year 2019.
Post-Traumatic Stress Disorder (PTSD)
PTSD affects 3.6% of Americans and not just veterans. Typically, we think about individuals who have fought in wars, like the Vietnam War. But it's actually something that can happen to any of us who go through a traumatic event. PTSD is much more common in females versus males ~(5.2 % vs. 1.8%) and a lot of it stems from interpersonal violence. The lifetime prevalence of PTSD is about 6.8%.
Mental Health During The COVID-19 Pandemic
The COVID-19 pandemic has greatly affected our mental health. There's increased loneliness and increased isolation. There's more fear of not just getting sick, but there’s also economic and employment uncertainties. Accordingly, there's increasing rates of depression, anxiety, and substance abuse. One news report shows that U.S. cases of depression have tripled during the pandemic. There are reports of mental health worsening 360% since the pandemic.
Traditional Treatment Options For Depression: Not So Great
Traditionally, our treatment options for depression are to use selective serotonin reuptake inhibitors (SSRI). Unfortunately, it's only effective in about 1 out of 3 patients and it can take weeks to months to actually take effect. It also has a lot of side effects, such as loss of libido, weight gain, insomnia, anorgasmia, suicidal ideation, and suicidal thoughts. We need a new shift and another option.This is where ketamine comes in.
From PCP derivative to general anesthetic, how did ketamine come to be a treatment for pain and mood disorders?
Ketamine: A Quick History
The Origin of Ketamine
Ketamine was invented in 1962 by an organic chemist named Dr. Calvin L. Stevens. He was consulting for the Parke-Davis Pharmaceutical Company, which was working on general anesthetics. The original anesthetic was called phencyclidine, also known as PCP. Unfortunately, PCP had a lot of side effects, so they asked Dr. Stevens if he could make a safer anesthetic. He eventually did come up with one called CI-581.
Later, it was renamed ketamine because of the two chemical structures that you can see in the middle, which is a ketone group and an amine group.
Ketamine was first used on humans in 1964. Dr. Edward Domino tested this drug at Jackson Prison in Michigan. 20 inmates volunteered and they received steadily increasing doses of ketamine. What they were describing were these hallucinations, these dream-like states. The volunteers reported feeling “spaced out” or like they were floating.” When the dose of ketamine was progressively increased, it was found to be a very effective anesthetic.
Thus, they called it a “dissociative anesthetic” since the ketamine seemed to dissociate the mind from the body. This is great when you're doing various procedures because it allows the patient to be “disconnected” from a medical or surgical procedure that could cause discomfort to the body.
FDA Approval of Ketamine
Parke-Davis Pharmaceutical applied for the FDA approval, and was approved for anesthesia in children, adults, and elderly during surgical and diagnostic procedures. This was approved in the year 1970, which is when the Vietnam war was going on. Ketamine actually became the most widely used battlefield anaesthetic sedative and analgesic agent. This was due in part because combat medics would be able to give it easily to their fellow soldiers, preservice their respiration (e able to breathe on their own), get effective pain relief, plus the soldiers could still walk to safety. Compared to other medicines like opioids, this was revolutionizing as opioids could cause significant drowsiness and at high doses could inhibit respiration.
Since 1970, ketamine has been used extensively by anesthesiology in the operating room. Then in 1990, there was a landmark article published in the Annals of Emergency medicine. The research was done at Loma Linda University (which is where Dr. Ko was trained). After this study was published, ketamine became a medication commonly used in the emergency department setting.
Ketamine has been used on humans for over 50 years now and is actually on the list of essential medicines by the World Health Organization. Back then, for medicine to qualify to be on the list of essential medicines meant that it's critical for any hospital to have this drug available because of its safety and efficacy.
Now we're going to shift gears and talk about some of the scientific articles.
Review The Evidence: Scientific Articles On Ketamine
Depression
An article titled Antidepressant Effects of Ketamine on Depressed Patients was the first depression and ketamine study published in 2000 by Society of Biological Psychiatry. It was a very small sample size of just 7 patients who had depression. What was unique about it was that it was placebo controlled and double blinded. This means that both the researcher and the subject didn’t know what they're receiving.
If you look at the graph below, the black line with the black circles represents the ketamine, and the one with open circles represents the placebo.
Image source: https://pubmed.ncbi.nlm.nih.gov/10686270/
If you look on the y-axis, you'll see the change in the Hamilton Depression rating scale (HDRS), which is simply just a marker for depression. And what you'll notice is that for patients who received ketamine, their depression scores dropped significantly compared to the placebo.
Suicide
There was another study called Ketamine for Rapid Reduction of Suicidal Thoughts in Major Depression. This was a midazolam controlled, randomized clinical trial. Midazolam is a placebo, but it's not just saline. It actually does have some effect and it makes it a good placebo because the patient will still feel something.
This study, which was double-blinded, was published just three years ago. They took 54 patients to a psychiatric unit where they received 0.5 milligrams of kilograms of IV ketamine versus low doses of midazolam. The researchers were looking at the scale for suicidal ideation. For the patients who were initially in the placebo group, but didn't have an improvement, were switched to ketamine.
You'll notice three lines in the graph below. You have the green line which is the placebo, the red line which is the ketamine group, and then the orange line which is the people who initially received placebo but then later they switched over to ketamine because of the efficacy.
Image source: https://pubmed.ncbi.nlm.nih.gov/29202655/
This is showing that the mean change in the suicidal scores dropped significantly in ketamine compared to placebo and not just one day out but even in the following weeks.
Anxiety
There was this study published in 2017, Ketamine's dose-related effects on anxiety symptoms in patients with treatment refractory anxiety disorders, which involved a small group of 12 patients who've tried multiple medications for anxiety which weren’t effective. These 12 patients had generalized anxiety disorder, social anxiety disorder, or panic disorder and had previously tried antidepressants and psychotherapy. They were each given various ranges of ketamine doses.
What they found after switching to ketamine was that 10 out of those 12 patients or 83% reported a greater than 50% reduction in the Hamilton A score or their fear questionnaire (FQ) score when they received 0.5 or one milligram per kilogram doses. These effects lasted three days, seven days after each dose and the higher the dose, the greater the effect and duration.
PTSD
There was a study for PTSD, published in JAMA Psychiatry, called Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial. It was just a single infusion wherein they took 41 patients. It was another randomized and controlled study looking at ketamine versus midazolam, which is the placebo. (For the non-scientists, just to let you know, when you have a randomized controlled trial, that's really good data and really good evidence to test whether it's different compared to the placebo.)
In this study, the graph below is looking at the score of PTSD. What you'll notice here with the squares versus the triangles is that for ketamine, there was a significant reduction in the PTSD scores compared to the midazolam and it was statistically significant in this study.
This is just one infusion but they're looking at day one day up to seven days so you might be wondering how ketamine works.
What makes ketamine so effective in treating depression?
How Does Ketamine Work?
What we know about ketamine is that it’s working on the glutamate neurotransmitters. Classically, the SSRIs work on serotonin, which is a different neurotransmitter. There's a receptor in your central nervous system (both the brain and the spinal cord) called the N-methyl D-aspartate Receptor (NMDA) and ketamine will go in there and prevent the NMDA receptor from being activated by glutamate. This is what we hypothesize causes the analgesic and anesthetic effects.
When you stop the stimulation of the NMDA receptor by glutamate, the bottom line is that it's going to increase a protein called brain-derived neurotrophic factor (BDNF), protein synthesis, synaptic strength, and synaptogenesis. Synapses refer to the connections between neurons.
What's happening in the graph below is chronic stress and what that could be with depression or chronic pain. If you'll notice, you'll see that this is a model of neurons and if you look at the top A and B compared to C and D is that 24 hours after ketamine administration, ketamine reverses the chronic stress induced structural deficits.
Image Source: Abdallah CG, Adams TG, Kelmendi B, Esterlis I, Sanacora G, Krystal JH. KETAMINE'S MECHANISM OF ACTION: A PATH TO RAPID-ACTING ANTIDEPRESSANTS. Depress Anxiety. 2016;33(8):689-697. doi:10.1002/da.22501
Sometimes, I tell my patients that ketamine treatments are kind of like giving fertilizer to a plant. They've got these trees with the branches weathering and there are fewer leaves. Ketamine seems to act as the fertilizer to help regenerate some of these connections.
The bottomline is there's neuroplasticity, and someone who gets stuck in these chronic ways is just like hardened clay. And the way to change that clay is to heat it up, and if you're able to heat it up then you can make it malleable. Ketamine seems to make the brain more malleable.
Just like clay, our thoughts can also be malleable and more susceptible to positive change.
There's something called the default mode network (DMN) and it refers to this concept of certain portions of your brain that are active when you're daydreaming, resting, or doing nothing. When you're not engaged in tasks, your mind is wandering and these portions of the brain seem to light up. The DMN is related to self-relic, self-reflection, rumination, self-criticism and worry. We believe that the DMN plays a significant role in depression, PTSD, schizophrenia, autism and chronic pain.
What's interesting about ketamine is that it temporarily disrupts activity of the DMN and its relationship to the other portions of the brain. This allows the brain to come up with other alternative rest state activities so if someone has a habitual self-defeating thought, ketamine could allow you to put in new thoughts. If we can give your brain a reprieve from all these negative thoughts, it can be incredibly powerful. You can put in some new beliefs to change your thoughts.
Yes, ketamine is an effective treatment for depression, but it has its cons as well.
Pros And Cons Of Ketamine
Ketamine is very safe, but it does have side effects. It has its pros and it's cons and I want to discuss some of those.
There's something called emergence phenomena, which is kind of like a panic attack or just a lot of fear, that can occur in 10 to 20% of adult patients after ketamine for procedural sedation.That's specifically in the operating room in the emergency room.
Laryngospasm, which is very dangerous, can happen as well. This is when the vocal cords can just close up and shut tight. Ketamine can also cause agitation, nausea, vomiting, elevated blood pressure and pulse.
Ketamine can have some side effects and you need to be really aware of what those are.
In addition, someone had mentioned that ketamine has a really interesting history. It's known to be a drug of recreational abuse. They might call it “Special K”, “Kit Kat”, “Vitamin K”, or “Cat Valium”. People may also talk about going into a ketamine hole or a “k-hole”. And I want to acknowledge that that exists and one study reports annual use to be less than 1.7% in young adults.
In the graph below, on the y-axis, you have the dependence potential, which is the likelihood of getting addicted or depending upon. On the x-axis, you have how dangerous the active dose is over the lethal dose.
Image Source: https://en.wikipedia.org/wiki/File:Drug_danger_and_dependence-small.png
You can see ketamine encircled. Then you have the very high which are heroin, morphine, nicotine. High which are cocaine, alcohol, caffeine. Ketamine is in the lower dependence potential section so it's possible to be dependent on it, but the likelihood of that is low.
Additionally, as far as the active dose/lethal dose, it can be dangerous at certain points. So it's really vital to be receiving the ketamine under physician supervision.
The important thing about ketamine usage is the set and setting. This is the context of how one receives ketamine treatments. So it's going to be very different if someone is getting it in a clinical setting with a trained physician there versus if they're at Coachella Music Festival getting ketamine in a different way. Mindset also matters and this refers to the person's intentions and what their state of being is as they're receiving the ketamine.
Ketamine isn’t for everyone. Unfortunately, it has some contraindications.
Who Shouldn’t Get Ketamine?
Ketamine has some contraindications. If someone has uncontrolled high blood pressure, unstable heart disease, untreated thyroid disease, substance abuse, mania schizophrenia, or previous adverse reactions to ketamine, they would probably not be a good candidate for the treatment.
Before someone receives ketamine with us in Palm Springs, we screen them very carefully and look at their medical records prior to doing any ketamine treatments.
At Reset Ketamine, our approach to ketamine infusions makes us different.
Our Approach To Ketamine Infusion Treatments
We are going to share about what we do in Reset Ketamine that makes us different in our approach.
Before that, let's talk about what health means. I love the definition of health from the World Health Organization, which is a “state of complete physical, mental, and social well-being, not merely the absence of disease or infirmity.” This is where I apply the biopsychosocial spiritual model of medicine.
When we see a human being, we see that they consist of more than just cells, tissues, and organ systems. We have to consider that when we're treating a patient. We also need to look at the psychology of a patient, like what's going on in the conscious and unconscious mind. Additionally, you need to factor in their life experiences and what kind of behaviors are going on. Additionally, social factors play a huge role, such as your relationship with your partner, friends, community, society and earth.
Lastly, and we don't really talk a lot about this in the medical world, but the spiritual component of a human being is also a factor. These are the things that are immeasurable. The example that comes up for me is when someone who passed away, if you weighed them before they pass away and you weigh them right after they pass away, they're gonna weigh exactly the same amount. However, we know that there's something that has changed. That's what I'm referring to when I'm talking about that spiritual component -- the immeasurable part of a human being.
I just want to reiterate that when we're thinking about mood disorders, depression, anxiety, and PTSD we might say things like “it's all just in the mind” or “ don't let it affect you” but it's all connected. Mind, body, and spirit are all connected.
The example that I like to use is if you think about a map. Just like the image below. You have a picture of Arizona and it's a really clearly defined state border. But when you actually go to that border between Arizona and California, there is no red line.
It's all the same and similarly that applies to the mind, body, and spirit of a human being. It's all the same and it's all connected.
How We Do It
At Reset Ketamine, ketamine is just one component of the treatment. The treatment consists of 4 phases:
Preparation - prior to receiving ketamine infusions, we have patients prepare their mind for it. We have some guidelines that we recommend.
Intention - We're very intentional about receiving the ketamine, so I'll ask my patients what their goals and intentions are for the treatment.
Experience - We want our patients to experience the experience of ketamine.
Integration - This is where you're going to gain some insights or lessons on things that you need to change such as habits possibly. So that's like doing the homework based upon the ketamine treatments.
Logistically, here's how we do it for mood disorders:
We do 40 minute infusions
There are typically 6 treatments spread over a 2-4 week time period
Some patients get booster infusions, which can range anywhere from three weeks to three months
Patients who are non-responders (about 17 percent) get no relief from ketamine treatments and we usually know after 4-5 treatments
The other thing to consider is because it's considered off label, meaning it's used for a different indication, that it's not covered by health insurance companies at this time
Reset Ketamine Paradigm
We really blend Eastern/Western philosophies. When I think about ketamine treatments, I think about it more as a catalyst for transformation. We incorporate music, scents, rituals, and have a holistic approach to healing.
Summary
To conclude, under medical supervision, ketamine is a safe medicine that’s been used for over 50 years. How it works is via an NMDA receptor antagonist, it increases BDNF, disrupts the DNF, and allows for increased neuroplasticity.
Ketamine can be rapidly effective in treatment resistant depression, anxiety, PTSD, and suicidal ideation. Some of the limitations are that there's no long-term studies. There is also an abuse potential for ketamine, although it's low. It's not covered by insurance and there are some side effects to be aware of.
Lastly, ketamine can be a catalyst for transformation but it's not a panacea. It's only one part of the solution for these various mood disorders.
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Learn everything you need to know about ketamine from the science behind ketamine, its history, and how it is revolutionizing the treatment of mood and pain disorders in the blog and video.
