131. Sublingual Ketamine, With Dr. Rachel Wilkenson
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Dr. Rachel Wilkenson: [00:00:00] Sublingual ketamine, especially microdosed, is possibly the most effective neuropsychiatric medication I've ever experienced in my 18 years of full time psychiatric practice, working with severely treatment resistant neuropsychiatric cases. I have one case, a woman, who was diagnosed with posterior cortical atrophy.

Dr. Rachel Wilkenson: So the back of her brain was shrinking. She also came with a psychiatric diagnosis of bipolar one disorder, even with the motor gene, she developed a seizure like episodes. So we stopped everything that I had traditionally used and considered ketamine. And to this day, she has returned to her job. She is performing extremely well in the job that she had before she became disabled from posterior cortical atrophy.

Dr. Rachel Wilkenson: And she is able to walk unassisted without a cane. She's able to talk [00:01:00] fluently, including, uh, giving lectures. So she's had a dramatic turnaround and is so excited about her story that she's sharing it with everybody that she can.

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Dr. Sam Sigoloff: So next, I want to welcome back Dr. Mitch Leister and Dr. Rachel, uh, Wilkinson. Thank you so much for coming on and joining me again, uh, I've had so much good reviews of the, the last episode that you and I, Dr. Leister did, and, and about ketamine. So I want to have your, your colleague, uh, that you, you mentioned in the last episode we did, and I want to hear more about the ketamine.

Dr. Sam Sigoloff: Well,

Dr. Mitch Liester: thank you, Sam. Thanks for inviting us both on, and I have to tell you that, uh, Rachel's the brains in this group. She was the one that discovered the protocol we're using, and it's been, Doing it for years before I even learned about it. And she's kind of guided me and helped me through. So I'm really thrilled she's gonna come and talk to you about her experience, uh, which is pretty extensive with the ketamine.

Dr. Rachel Wilkenson: I kind of, you meant . I really appreciate you've been so supportive throughout.

Dr. Sam Sigoloff: How did you first hear about using [00:05:00] ketamine in this way?

Dr. Rachel Wilkenson: Uh, I ran to upload a deal of my patients who stopped making the kind of progress that would allow them to go back into the work setting. They start focus and attention and the ability to problem solve. We call that group of, um, brain functions, executive skills. And I thought at 1st, the best that I could do was to use a long acting stimulant, like, Which I did at first, and that only was effective, I want to say, for about six to nine months with a lot of my serally treatment resistant patients, on top of their other medications to control inflammation.

Dr. Rachel Wilkenson: So they had made progress with sleep and mood stability and just could not advance any further with their cognition. So I went back to the National Library of Medicine, many know it as PubMed. com, where [00:06:00] Archives of almost all the studies across the world are available for free to look through. And I searched for mechanisms to heal brain tissue.

Dr. Rachel Wilkenson: We call that neuroregeneration. And I found academic work surrounding ketamine, which I had heard of in other settings. And was a little bit fearful about. I was trained traditionally, uh, by a very talented psychopharmacologist. And in the traditional world, we had considered ketamine a substance of abuse.

Dr. Rachel Wilkenson: So something that was abused on the streets. So I hadn't really dove into using ketamine until I found that literature about neuroregeneration in animals. And Of around the same time, one of my very talented professors, Dr. Sheldon Prescorn from the University of Kansas came into the city to give a talk on intranasal esketamine or spravato, and he was very positive about it.

Dr. Rachel Wilkenson: I was [00:07:00] impressed and I thought, well, I'd like to give that a try. However, at my clinic. We had so many limitations with staffing. We prioritized the underserved, and so that lends its own challenges in the clinical setting. I didn't have the kind of support needed to provide spravato, which specifically would mean patients had to come into the clinic every dose Wait for two hours after the dose because it was used, uh, quite high doses.

Dr. Rachel Wilkenson: Spravato is 50 percent bioavailable in the intranasal form. IV is 100 percent available and then sublingual is 30 percent available. So it's very potent and the patients need about two hours to have the wear off effect where they feel comfortable going home and they can't drive themselves home and they must be supervised.

Dr. Rachel Wilkenson: By clinical staff for that two hour period. We didn't have a room that they could be supervised in. I didn't have [00:08:00] staff to help them administer the dose. So I started looking for other options and found one paper from the Journal of Clinical Psychiatry on sublingual ketamine and treatment resistant depression.

Dr. Rachel Wilkenson: And it was not exactly the program that I use now, but it gave enough guidance that I had a sense that it could be compounded in sublingual form. Most of the administration, almost regardless of format, including sublingual and IV, are intermittently dosed, so not daily. That's where I started, and then gradually developed the protocol that we use now.

Dr. Rachel Wilkenson: Based on about a year of clinical experience, and I've been prescribing sublingual ketamine for ease of use, cost savings, it's much cheaper than the other forms of ketamine, and after a prolonged period of time, I've learned that Sublingual ketamine appears to be quite safe [00:09:00] in multiple types of patients.

Dr. Rachel Wilkenson: So, I have become very comfortable using it, and I, and Mitch probably knows this too, I see mostly treatment resistant patients. If the standard treatments for psychiatric conditions were to be effective for them, most, at least in my clinic, I work among primary care providers. Would not need my help. So they are treatment resistant to begin with and ketamine is a medicine that I often use now

Dr. Sam Sigoloff: That's amazing. Let's let's get into the PowerPoint that you sent to me and If we could go through all that because I think there's a lot of really great information there as well

Dr. Rachel Wilkenson: Okay, so this is a relatively short slide deck, but it gives you an overview of I've entitled it Sublingual Ketamine, and you'll see Dr.

Dr. Rachel Wilkenson: Leister and my name there at the bottom. I will go through several basic concepts to [00:10:00] build on this idea of using ketamine, um, and then give some case reports as well. So before I start into the case report, we'll go to the disclaimers. You see my credentials there and Dr. Lester's I'm an integrated psychiatrist Embedded in a primary care and internal medicine setting so I manage my own traditional caseload where I see patients face to face Also, I work with the other types of doctors who are not psychiatrists with their psychiatric cases helping them to manage without direct Psychiatric support and that's been going really well.

Dr. Rachel Wilkenson: It's a lot of fun. The doctors are receptive and learning a lot. The standard disclaimer, this is for educational purposes and just an overview next of sublingual ketamine and our agenda for today. So we'll start with the case reports. I'll go over the specifics of the protocol [00:11:00] with pictures of how the medication is prepared and compounded.

Dr. Rachel Wilkenson: And then discuss basic concepts of neuroregeneration and neurodegeneration. We will go over other psychoplastogens briefly, and then I'll outline the background that led to me. Going down this road with ketamine. So I'll start with my case report. I began working with a young person in their twenties on Medicaid, my bread and butter in the clinic is Medicaid patients.

Dr. Rachel Wilkenson: Often they are challenged with poverty and multiple types of illness, not just mental illness. But I chose this case because it's very clear and how it gives an example of the ability of ketamine to help restore cognitive function. This patient was isolating in their room, would not leave their house, behaved as though they were afraid often, even around their own family members.[00:12:00]

Dr. Rachel Wilkenson: They lost the ability to smile, it seemed, according to the patient and the family members. They had no desire to engage in hobbies. They seemed incapable of having joy or fun. They were retreating to self medication through cannabis and alcohol, which is not uncommon. And they had been diagnosed in high school with dyslexia, auditory processing disorder, barely graduated high school, and had a very low sense of confidence.

Dr. Rachel Wilkenson: They had no desire to get a job, were not interviewing for a job, so this is a very sad person brought in by their family. They had engaged with psychiatric care before I met them and been diagnosed with multiple conditions. So, on the next slide, you'll see they were diagnosed with major depressive disorder that learning disability.

Dr. Rachel Wilkenson: I mentioned with dyslexia and auditory processing disorder. Post traumatic stress disorder, cannabis use disorder, and they were impoverished. The [00:13:00] treatments they had tried included serotonergic agents, but those made their anxiety worse and actually caused suicidal thoughts and worsened them. So those medications were discontinued.

Dr. Rachel Wilkenson: And when they came to me, they were already on gabapentin. And bupropion, also known as Welbutrin. The family were very frightened of any medication changes in one sense. They did not want to discontinue the medication the patient was on, because they remembered how bad they were before. However, they also knew the patient was not doing well on the medication.

Dr. Rachel Wilkenson: So, we were challenged with this idea of what else could we do in addition to their current psychiatric medication and not make things worse. The prognosis of this type of patient before I discovered ketamine was very poor. These patients with very high anxiety and little ability to enjoy life, low confidence, [00:14:00] usually meant that they would lead a life of prolonged disability, stay on Medicaid, and struggle with their occupational efforts.

Dr. Rachel Wilkenson: Many times as well, they would not advance in the various stages of their life into relationships, building a family and so forth. So this is a very hopeless looking patient at first. We discussed the option of ketamine. They researched what I gave them. There's a detailed informed consent process we go through because ketamine That I use the sublingual form is off label.

Dr. Rachel Wilkenson: The FDA has not recommended sublingual ketamine. However, they have recommended intranasal S ketamine for treatment resistant depression. Once the family were in agreement to start sublingual ketamine, we worked through that informed consent process and began a low dose. The patient tolerated it fairly well and stayed on a low dose of around 25 [00:15:00] milligrams.

Dr. Rachel Wilkenson: We raised it to 50 milligrams and then waited. This patient did not come in often to the clinic, about every three to six months. And over the course of two years, their presentation really turned around. So next slide, we will discuss what they looked like after two years. After two years, at the age of 23, this patient was reducing cannabis use.

Dr. Rachel Wilkenson: Also using nicotine, no longer using alcohol. They went back to college, uh, did very well, were elevated to the dean's list, won a national award for academic work. And had been accepted at a prestigious program in their area of academic interest in an out of state university. By the time I saw them two years later, I want to say I visited with them probably three to four times over that period.[00:16:00]

Dr. Rachel Wilkenson: Each subsequent visit, they started making eye contact, smiling a little bit, uh, becoming more fluent with their speech and their facial expressions and their. It began to appear at least like they're learning disability was slowly melting away. Family confirmed this. They were also leaving home regularly and we're ready to move out of state and go to college.

Dr. Rachel Wilkenson: They were vibrant and we're helping their parents and their siblings every day on the next slide. I'll just expand their historic diagnoses. Uh, they no longer criteria for they did meet criteria ongoing for generalized anxiety disorder. And they were reducing the doses of both psychiatric medications and the cannabis, like I mentioned.

Dr. Rachel Wilkenson: So, it seems with this patient, like the dose of 50 mg sublingual ketamine was really serving them well. They did not have any suicidal thoughts within weeks of starting the ketamine. [00:17:00] And then the remaining symptoms slowly improved over that two year timeframe. And just in the last one to two weeks, we had our closing visit.

Dr. Rachel Wilkenson: They were very thankful, um, and had learned a lot about psychiatric medications, very confident, made good eye contact and were smiling during the whole, uh, Clinic time that we spent together. So now the prognosis is completely turned around. I believe this patient will do very well. They're excited about their life.

Dr. Rachel Wilkenson: I would estimate if I were following this patient long term, which I can't do because they're moving out of state. that they will continue to taper off of their traditional psychiatric medications, stay on the sublingual ketamine for probably another several years. I do have patients now who've been on ketamine for about three to four years, and they're tapering even off of that ketamine dose after getting off of their old traditional medications and want to see if they're able to [00:18:00] maintain their mental health Basically, with the very strong, uh, pro health lifestyle, clean diet, filtered water, um, enriched social life.

Dr. Rachel Wilkenson: So, their ultimate goal is to come off of almost all synthetic medications. And I support them in that. Obviously, we give them informed consent. With and without treatment and they always know if they start to struggle again that we could restart ketamine So in the next slide, sorry sam. I lost my earbud pause there

Dr. Rachel Wilkenson: in the next slide. You will see a picture of ketamine powder these pictures were sent to me by our compounding pharmacist who's been very Enthusiastic about this project and has said to me and I'm sure to Mitch as well [00:19:00] that they can see visible signs, uh, of the patients improving as they come in to get their medicine from month to month.

Dr. Rachel Wilkenson: So the ketamine powder starts like this next slide here. You see in a beaker, the solidified mixing compound that the ketamine powder will be dissolved in that is melted and then it's mixed together. Here you see the mixing tools on the next slide, and on the next slide, once the mixture is complete, it will be loaded into a pipette and then dispensed in this blue tray of squares, which we call trochies.

Dr. Rachel Wilkenson: Initially, it's a thick liquid, and then this cools to a soft, waxy consistency, which the patients can easily cut down to size. Usually I'll have the patients quarter [00:20:00] it, and the standard dose is 100 milligrams per trochee, 100 milligrams per square. And I will have them start off at about a quarter of that or 25 milligram dose, and we'll go into detail further in just a second.

Dr. Rachel Wilkenson: So next slide there, you see the completed tray where the product has solidified, but there's a machine from the light where you can see that it has hardened. And this is what patients will sometimes put in their refrigerator, carry it around. It can melt, so they know that they have to keep it cool enough not to melt.

Dr. Rachel Wilkenson: Next slide. We will go over the standard sublingual ketamine protocol. So as I mentioned before, each square is approximately 100 milligrams, and it dissolves slowly under the tongue or in the mouth. Often patients will put it between their cheek. and their gum line and just slowly wait for it to melt, which takes [00:21:00] about 20 to 30 minutes.

Dr. Rachel Wilkenson: They began about a quarter trochee every three days for four doses, and that tends to be 25 milligrams and then take that 25 milligrams every other day for four doses. The four doses mark seems to be about what patients need to adjust to the new dose. Uh, and they will notice initially after taking it that they feel a little bit dizzy and then that dizziness subsides and then they raise the dose.

Dr. Rachel Wilkenson: After the second series of four doses, they will start to take the medication daily if they tolerate it. And from that point on subsequent visits, we discuss titrating the dose, increasing the dose. Sorry, my nose is running by 25 milligrams every two to four weeks up to a maximum daily dose. Thanks. Of 175 milligrams a day.

Dr. Rachel Wilkenson: That's the highest I go. Generally, I do have 2 patients on [00:22:00] 200 milligrams and they are both over 6 foot 5 over 250 pounds. The absorption of the ketamine again, sublingual form is between 25 and 30 percent the total dose. So that 175 milligrams, um, I think it's around 50 or so milligrams. Maybe next slide.

Dr. Rachel Wilkenson: Lab monitoring for this medication. So initially with the research that I found on the National Library of Medicine, there were indications that overdose of ketamine led to acute kidney failure. So I watched the kidneys pretty closely, especially when I started this project with our pilot group of patients.

Dr. Rachel Wilkenson: And then palpitations. So heart palpitations, fast heart rate was experienced by some of the patients right after taking the medicine and seemed to escalate to about the 30 minute mark after the dose. And those that had this side effect, [00:23:00] I did not find The heart palpitations to limit the use of the medication.

Dr. Rachel Wilkenson: I mainly saw palpitations in the patients with preexisting cardiac disease. They had palpitations to begin with. The ketamine seemed to make it a little bit worse. Initially I was so cautious. I sent them back to their cardiologists. They already had established care with to get medical clearance. And every single one came back with medical clearance by their cardiologist to continue the treatment.

Dr. Rachel Wilkenson: So the heart patients have done quite well. Patients with pre existing kidney disease, chronic kidney failure, in other words, where, uh, one lab that we watch with doctors called the glomerular filtration rate was around 35, somewhere in there. I'm more cautious with. Those patients can have lower glomerular filtration rates with too high of a dose of ketamine.

Dr. Rachel Wilkenson: So, typically I will reduce the dose and make sure that, uh, their kidney [00:24:00] physicians, their specialists are also monitoring them with me. In a couple cases, especially if patients are not, you know, As good at hydration, not as good at drinking water. We will stop the ketamine and then consider restarting if their kidneys look to be improving.

Dr. Rachel Wilkenson: So by and large, the monitoring of ketamine is pretty easy. We do get baseline labs as we would for any traditional medication. Those would be like a thyroid panel, comprehensive metabolic panel to check the kidney and liver and electrolytes, uh, uh, complete. Blood count. Uh, sometimes I'll also get drug screening on my patients.

Dr. Rachel Wilkenson: We have a lot of cannabis used here in Colorado and I found that There can be an interaction between THC and ketamine, namely increased cardiovascular side effects like heart palpitations and then increased risk of illusions and possibly [00:25:00] visual hallucinations. So ketamine when it Is too highly dosed will cause visual distortions.

Dr. Rachel Wilkenson: I have found borderline psychosis, which we would define as hallucinations and delusions in my field. I personally believe that once the patient has those early signs of psychosis, they've already had a toxic dose. So I do not like high doses of ketamine. And I had to learn that through this project.

Dr. Rachel Wilkenson: Before I started the sublingual ketamine, and I had reviewed the National Library of Medicine literature, I thought that IV ketamine was very similar in efficacy to intranasal, which was very similar in efficacy to sublingual. The difference I thought beforehand was in the time to improvement. I had assumed that the higher dose intravenous was faster to lead to improvement than intranasal.

Dr. Rachel Wilkenson: And then intranasal is faster than sublingual. But what [00:26:00] I have found actually is the low dose, the micro dosing of ketamine over a prolonged period of time, months, has led to the most long lasting, gradual improvements that do not seem to regress. Whereas my patients that we referred out to clinics that did the IV and intranasal, like we couldn't, did not fare as well.

Dr. Rachel Wilkenson: They might have had. Short term improvements in their side. Sorry symptoms. However, that was not long lasting and after their treatment protocols were finished Especially the IV treatment protocols which were very short term and high cost their symptoms of depression Returned moving on the same slide on the ketamine protocol.

Dr. Rachel Wilkenson: I'll make a Notation of pregnancy. So I do not use ketamine in pregnancy. There are no studies out indicating efficacy. I'm not [00:27:00] inclined to believe that it's safe because it can alter blood pressure and blood pressure in, uh, Pregnancy is something that's very closely monitored, especially with the condition we know as preeclampsia, where blood flow is compromised through the placenta.

Dr. Rachel Wilkenson: And this can compromise the baby's access to healthy blood supply. We do get EKGs if necessary on patients with preexisting cardiac disease. If patients report palpitations, I'll also get an EKG, but otherwise most patients tolerate this dosing schedule. There is one group of patients that needs a lower dose.

Dr. Rachel Wilkenson: And for those patients, I continue the same schedule a quarter. Every three days and then every two days, but I use the compounding dose per trochee instead of 100. I'll go down to 25. So it's 1 4th, the standard dose and that group of [00:28:00] patients would be my severe autoimmune disease patients. They're just more sensitive to medication and they do quite well.

Dr. Rachel Wilkenson: It just takes a lower dose initially and eventually they tolerate a higher dose. The cost of ketamine is worth noting, especially sublingually, because it's very affordable. Even for Medicaid patients who are impoverished, especially when they find how well it works for them, many on fixed income are willing to pay the cash price because insurance does not cover this.

Dr. Rachel Wilkenson: It is off label. And locally, I believe the cost started around 25 a month. And now, uh, we have a higher cost of living here in Colorado. I believe the prices have increased up to about 40 a month, especially at the higher dose end.

Dr. Rachel Wilkenson: Moving on. I want to describe several concepts about how the brain has, uh, seemed to work. [00:29:00] Now, brief comment here. Traditional psychiatry has been built on the use of descriptions of symptoms and then grouping of those symptoms into syndromes. And then an assumption that those syndromes are a disease. I believe personally this is our best historic attempt at explaining what's very difficult to understand as far as brain function by how a person is feeling or behaving.

Dr. Rachel Wilkenson: So this is the type of paradigm or pattern of practice that I had to work through to get to ketamine. What do I mean by that? My view of traditional psychiatry is that it's been a very outside in attempt at understanding the brain. Understanding the brain by behaviors of a person or a person's self reported symptoms.

Dr. Rachel Wilkenson: When I encountered Difficulty helping patients [00:30:00] improve their condition beyond what I was trained to do. Essentially, when they became so treatment resistant and all the wizardry of psychopharmacology that I learned in training wasn't enough to help them, I looked at the brain in a different way. I started asking myself, what if a lot of psychiatric symptoms actually begin in the cells?

Dr. Rachel Wilkenson: What if this is an inside the cell problem? And how do we help the brain cells function better? If they're not functioning well. So that is more of an inside out disease pattern understanding. And that's what helped me find ketamine. Initially I had to get through this. understanding of how brain cells get sick, and we call that neuroinflammation.

Dr. Rachel Wilkenson: So in this first slide of concepts, you'll see a description of neuroinflammation, very basic description where cell stress. So brain cell stress leads to this process. [00:31:00] We call glutamate toxicity, which is where the neural hormone glutamate, which is the main activating hormone in the brain rises so much that it causes the cell to be overexcited.

Dr. Rachel Wilkenson: And if that remains uncontrolled, the cell can actually die. If enough cells die, and I'll go on to the next slide here, it can cause brain scarring, which can in some cases be visible on PET scans, certain types of brain scans, and then ultimately this leads to a decrease in a person's ability to function.

Dr. Rachel Wilkenson: Not just psychiatrically in their emotions, but also in neurologic ways, certainly with cognition. So their memory starts to worsen. They're not able to focus. They're not able to problem solve or be useful in the work environment. So I had to understand that process before I understood how we could try to help heal cells.[00:32:00]

Dr. Rachel Wilkenson: In a lot of treatment resistant psychiatric conditions, I believe, especially the more severe kinds like bipolar one disorder and schizophrenia, it's been documented that repeat brain scans will show shrinkage of the brain because of cell loss and the scarring process. So we know cells are struggling and dying, and we did not necessarily know how to help them stabilize or perhaps even regenerate.

Dr. Rachel Wilkenson: Then, uh, ketamine. So I'll move on to the next slide. Ketamine is a neuroregenerative compound, it turns out. This has been shown in animal models. We call it also a psychoplastogen. When I entered medical school in the year 2000, I believe it was at Cambridge, There was a study that showed brain cells could regrow.

Dr. Rachel Wilkenson: They were in the hippocampus, uh, but it was a very exciting time. And now 24 years later, uh, I feel [00:33:00] as though we are entering a different phase of neuropsychiatric understanding. And broadly, I believe the professions will understand together and start to practice in a different way where we expect. More recovery, we have more hope for patients, whereas in the past, patients might have been told the brain cannot heal.

Dr. Rachel Wilkenson: So how does the brain heal with these cycloplastogens? Cycloplastogens, including ketamine, increase a hormone called brain derived neurotrophic factor, or BDNF. This is also referred to, colloquially, as miracle grow for the brain. And it helps brain cells regrow. Make more connections between styles. And I have one case and it's very exciting case of a woman who was diagnosed with posterior cortical atrophy.

Dr. Rachel Wilkenson: So the back of her brain was [00:34:00] shrinking. She also came with a psychiatric diagnosis of bipolar one disorder. She did not tolerate any traditional psychiatric medication, not even one that I commonly use for neuroinflammation called the motor gene, which reduces glutamate inside of cells and raises glutathione.

Dr. Rachel Wilkenson: We tried. Several different psychiatric medications, even with Lamotrigine, she developed, uh, seizure like episodes. So we stopped everything that I had traditionally used and considered ketamine. She's a very intelligent woman, understood the process of informed consent. We started a low dose of ketamine.

Dr. Rachel Wilkenson: And she was one of my patients who did respond like an autoimmune encephalopathy patient or an autoimmune brain disease patient where the immune system starts to attack different parts of the brain. So we used very low doses. She only tolerated 25 milligrams at first. We [00:35:00] started this, I want to say, about four years ago.

Dr. Rachel Wilkenson: So she was one of my first patients on this medication. At the standard period of time that psychiatrists are trained to watch for changes, which would be around three months. So if you start a serotonin med, we kind of wait for changes for three months. She didn't notice anything, but we talked very candidly and realized together that we didn't have many other options.

Dr. Rachel Wilkenson: So we decided to continue the ketamine treatment. Around the ninth month, she started noticing that she was seeing better. Her symptoms neurologically included loss of vision. So when I first met her, she was unable to write. Her script looked like cuneiform in size 200 or something, and she could not walk well and assisted.

Dr. Rachel Wilkenson: She had very distorted visuospatial senses, and she struggled to speak fluently. She would have halting speech and [00:36:00] have word finding problems. So at the ninth month mark, she told me, she said, Doc, all right. So she said, I think I'm seeing better, doctor. We both consider this to be very strange because it's, Really not common to have a patient's vision improve.

Dr. Rachel Wilkenson: She had been following with a neuro ophthalmologist and was doing testing. I want to say every three months and sure enough, her vision had been improving. Her neurologist locally also noticed improving neurologic function as he was following her and we had a conversation about her case. She and I continued the ketamine and about 18 to 24 months into her treatment on the 25 milligrams of ketamine, She started tolerating a higher dose.

Dr. Rachel Wilkenson: We slowly increased around 40 milligrams a day. And then she said, Doc, [00:37:00] I've been disabled for so long. I rely on my elderly mother to help me out at the home. And, uh, I don't see this as sustainable. But I'm feeling so strong in myself. I wonder if I could try to go back to work. And this patient was highly educated, had a doctorate, and was very hesitant and worried for her because I wasn't sure she would be successful, but together we made a plan with an exit strategy if needed.

Dr. Rachel Wilkenson: And she went for it. And to this day, she has returned to her job. She is performing extremely well in the job that she had before she became disabled from posterior cortical atrophy. And she is able to walk unassisted without a cane. She's able to talk fluently, including, uh, giving lectures. And she's able to write extremely well.

Dr. Rachel Wilkenson: Her handwriting is much better than mine. It's perfect [00:38:00] So she's had a dramatic turnaround and is so excited about her story that she's sharing it with everybody that she can. So this is what I have seen clinically, uh, on her MRI scans as well. Her neurologist noted that there appeared to be thickening of the cortex, which I would tend to interpret as regrowth of nervous tissue.

Dr. Rachel Wilkenson: We've had two other neurologists look at her scans just to make sure. You know, we weren't imagining this and they also agree that there's something very interesting and unusual going on. And along with her clinical signs and symptoms, this needs to be, um, investigated further and possibly written about and shared with the profession.

Dr. Rachel Wilkenson: So it's a very exciting case. I never expected. To see anything like this, of course human studies are few and far between at this point. But I would [00:39:00] summarize my experience with this case and over the four years to say that sublingual ketamine, especially micro dosed, is possibly the most effective neuropsychiatric medication I've ever experienced in my 18 years of full time psychiatric practice, working with severely treatment resistant patients.

Dr. Rachel Wilkenson: neuropsychiatric cases. Also on this slide, I just want to point out the picture. On the top, you'll see a neuron. We call it a control, a neuron without ketamine. On the bottom, you'll see the neuron with ketamine, and you'll see a lot more little buds forming. Call these dendrites or little tree like extensions or branches.

Dr. Rachel Wilkenson: that reach out to other neurons. And that's how learning often occurs is when you learn something new, you have new little dendrites, new branches that reach out and touch one another and create networks. So this is an animal model, I believe, [00:40:00] not a human one. We aren't in the tradition of taking brain biopsies on humans and studying them.

Dr. Rachel Wilkenson: But clinically, I believe this is similar to what happened to that patient. Next slide. There are other psychoplastogens that we are starting to research. You may know that in the state of Colorado, psilocybin has been decriminalized. So I've included that in the list. Although I do consider psilocybin to be fairly high risk in my patient population, it is highly serotonin based, and this can lead to an increased risk of schizophrenia and bipolar disorder, emergence of mania.

Dr. Rachel Wilkenson: I do have patients who've developed schizophrenia from excess psilocybin use, and there is certainly a toxicity risk for all, I think, of these, but specifically psilocybin and ketamine. Even ketamine, if you get too high of a dose, can cause psychosis, and what I believe are signs of neurotoxicity. Other [00:41:00] psychoplastogens that may not require Prescription would be lion's mane mushroom.

Dr. Rachel Wilkenson: This you can get over the counter in supplement form. You can also possibly grow it. I know there are some stores here locally that teach patients to, or um, clients. To grow their own, uh, supply. That's a whole other topic, probably for another day. And then tiger milk mushroom. There are probably up to 100 other different mushroom or fungal based compounds.

Dr. Rachel Wilkenson: That help increase secretion of this brain derived neurotrophic factor. And help lead to nervous system or nervous tissue regrowth. Next slide, I'll just briefly describe how I got here. Where the ideas from the protocol came from again, I was working in a setting where there's just tough psychiatric patients, lots of treatment resistance.

Dr. Rachel Wilkenson: The traditional models, the traditional medications were not enough to help them feel [00:42:00] good. I think at one point when I really started this journey, it was about 10 years ago. And I realized as the lead psychiatrist in a community psychiatric clinic, we were getting patients from the Department of Corrections, the state hospitals, even with all my training and all the wizardry with psychiatric medication that I was taught, uh, only 50 percent were responding.

Dr. Rachel Wilkenson: And by response, I don't mean that they were necessarily Good. I think they were less bad, but they had these persisting cognitive problems, signs of neuroinflammation, and they were developing side effects from a lot of their psychiatric medications, which we know can include risk of, uh, insulin resistance, weight gain, metabolic disease.

Dr. Rachel Wilkenson: And in general, psychiatric patients who have severe disease are expected to live 25 years, uh, less. And [00:43:00] the typical non psychiatric patient. Why is that? Is that just because of the mental illness? Or is it because of long term use of psychotropic medications that carry side effects? We don't really understand, but that's a foreboding.

Dr. Rachel Wilkenson: Um, statistic. So these are the clients that I was working with and it motivated me to look beyond the traditional models into neuroscience, asking more inside out questions, like how do we help cells stabilize and then regrow? So, this is then, um, again, the trail that I kind of followed through the National Library of Medicine to find the underpinnings of neuroinflammatory disease, which were glutamate toxicity and cellular scarring and cellular death, and then neuroregeneration with the help of brain derived neurotrophic factor.

Dr. Rachel Wilkenson: And I just want to say, you know, for my colleagues, uh, there's hope for patients who've [00:44:00] struggled with very little progress with traditional psychiatric treatments. We're always learning new things. We are at a very exciting time. These psychoplastogens are being researched in high level academic facilities, like the university of California Davis.

Dr. Rachel Wilkenson: And, uh, I'm so excited to be a psychiatrist right now. So that's my story. And then Mitch listened to me and started his own use of the medication. And has seen very similar results with many of his cases, which has been just a thrill for me. And now I think our little group has expanded to, gosh, Mitch, maybe seven other providers in the community.

Dr. Rachel Wilkenson: And we're hearing about other providers across the country figuring this out too.

Dr. Mitch Liester: Yes, Rachel, we just had an eighth, uh, provider last weekend, uh, psychiatrist called me and asked if I could show him how to, [00:45:00] uh, use the ketamine in this way because he's having some treatment resistant patients and it heard about the good results we're having. So, yes, more psychiatrists are learning about this, not only here in our area, but.

Dr. Mitch Liester: Around the state and other states as well. So it is growing also with Rachel's help We recently published a case report of a patient who had treatment resistant depression and borderline personality disorder Who's totally now in remission no longer meets criteria for either disorder with just 25 milligrams of ketamine daily So there's still a lot to learn but with Rachel's guidance and experience.

Dr. Mitch Liester: We're all learning And our patients have been wonderful at giving us feedback. So we're very excited to see where this is going to go.

Dr. Sam Sigoloff: This is amazing. I mean, everything you've said is just like my, my jaw has just been sitting on the table here. Just like, this is incredible. It truly is amazing, Sam. And

Dr. Mitch Liester: I was just going to say, Rachel, you know, and Rachel's been doing this for a while.

Dr. Mitch Liester: I'm much older and I haven't been doing it for as long as she has, but it's the most exciting thing that I've experienced in my almost four year career in psychiatry. I've never seen results like we're getting with ketamine. [00:46:00] So I'm, I'm eternally grateful to Rachel and to my patients for being willing to try this treatment and to give, uh, ongoing feedback because they continue to teach me about additional benefits this medicine that I wasn't even aware of.

Dr. Sam Sigoloff: Rachel, I have a question for you. You mentioned, and Mitch mentioned this in the last episode I had him on, that it's like miracle growth for nervous tissue. Now, is that only? Let's say central nervous tissue, is that only, um, the brain or could that be central nervous tissue like the spinal column, could that be peripheral nerves, could that be, um, nervous tissue inside of muscles, i.

Dr. Sam Sigoloff: e., you know, like for paresthesias or even for, uh, let's say myocarditis and changes that have happened after people have gotten certain things injected into them. What are your thoughts on that?

Dr. Rachel Wilkenson: I don't know for sure, but my guess would be both the central and the peripheral nervous system would show responsiveness to BDNF or similar growth factors.

Dr. Rachel Wilkenson: We have had observation of several [00:47:00] cases with neuropathy where the neuropathy improved. Neuropathy would be defined as pain in the extremities due to breakdown of the nervous tissue. So this improved over time and was also mirrored by increased function of those nerves. So if there were any types of movement problems that we observed, at least superficially, I don't think anything like severe spinal cord injury that we've been able to follow yet, but certainly more minor cases like, um, Mitch, I believe, had a case of neuropathy in the hand that reversed, and a patient gained sensation and function.

Dr. Rachel Wilkenson: But Mitch, you might be able to clarify your observations. I would say both central and peripheral nervous system benefits.

Dr. Mitch Liester: Yeah, Sam, I've had at least eight patients now spontaneously report that their peripheral neuropathy has improved. This is typically a peripheral neuropathy in the feet and it can involve pain, numbness, um, tingling.

Dr. Mitch Liester: And these are patients who spontaneous report. I wasn't asking about it. And [00:48:00] the other person Rachel was referring to is actually my sister. It was in a motor vehicle accident 30 years ago and had damage to her left ulnar nerve, which comes from the neck down the elbow down to the hand and her pinky finger and ring finger were numb for 30 years.

Dr. Mitch Liester: Her doctor put her on ketamine for a different reason and suddenly she can feel these two fingers for the first time in 30 years. So there certainly can be improvement in peripheral nerves, um, as well as central nervous system nerves, but to what extent is still to be discovered.

Dr. Sam Sigoloff: I'm thinking complex regional pain syndrome, I'm thinking, uh, you know, peripheral neuropathy from diabetes.

Dr. Sam Sigoloff: It seems like those could all be, uh, could have some benefit from this.

Dr. Mitch Liester: Yes, Sam. In fact, my sister has complex regional pain syndrome, which has been shown to respond to IV ketamine. So when her doctor put her on it for, um, put her on the ketamine for CRPS, um, she did report that her feet had been numb for years and she regained feeling in her feet [00:49:00] related to the CRPS. So yes, I think there are many other potential applications.

Dr. Mitch Liester: We just need some bright, uh, physicians to start exploring this and finding out other potential benefits.

Dr. Sam Sigoloff: And, sorry, I don't mean to interrupt again, but I have so many questions. Um, have you used this in patients that have dementia? Have you used this in patients with, uh, autism? Have you used it in patients with, uh, I mean, obviously, depression, PTSD, um, dyslexia, I think you mentioned.

Dr. Sam Sigoloff: Can you, can you run down a list of patients off the top of your head that have improved from these, this medication?

Dr. Rachel Wilkenson: Yeah, Dr. Spigaloff, amazing. When I first started this project, I narrowed my population down to what the FDA had worked with, uh, in indicating scruvato, which is the treatment resistant depression group.

Dr. Rachel Wilkenson: And with comfort and observation over time, I introduced it as an option for some of my most severely treatment resistant patients with other conditions. You mentioned [00:50:00] PTSD, autism, ADHD, dementia. Patients who had essentially no hope had exhausted almost all traditional therapies to this point. And one by one, I would say, uh, the vast majority of psychiatric diagnoses that I have worked with have responded.

Dr. Rachel Wilkenson: It does take longer than traditional therapies. I think that's because it is an intracellular and, uh, actual kind of cellular regrowth. Model versus a hormonal or extracellular modification model, which traditional psychiatry was built on. So it takes, you know, between nine months and three years to see dramatic clinical results.

Dr. Rachel Wilkenson: However, it seems to be long lasting the limitations. I see with ketamine at this time, after four years of working with the sublingual microdosing daily microdosing form would be more advanced. cases of autism, advanced cases of dementia. I don't [00:51:00] see the same kinds of improvements as I do with those early dementias.

Dr. Rachel Wilkenson: That patient case that I, uh, brought up with a posterior cortical atrophy, that is a form of dementia. That's like Alzheimer's at the back of the brain. We usually see it with more academically educated and successful patients. For some reason, their frontal lobes and their medial lobes seem to be a little bit resistant to the inflammatory.

Dr. Rachel Wilkenson: Process, um, patients with diabetes, uh, who've had cognitive problems, memory problems related to diabetic disease. I think diabetes has been very closely related with dementia, and sometimes dementia is called insulin resistance of the brain. So multiple types of neuropsychiatric disease. I struggle even in this moment to think of a psychiatric illness that I have used it on that has not responded.

Dr. Rachel Wilkenson: Um, Mitch, you might have more feedback there, too.

Dr. Mitch Liester: Yes, [00:52:00] just to build on what Rachel's saying, um, one of the joys of using this medicine in people with bipolar disorder is that it does not seem to trigger mania like some of the conventional antidepressants. That has made it much easier and safer to use. I would also add, um, seeing some success in a patient with a traumatic brain injury who had significant improvement.

Dr. Mitch Liester: Um, with the low dose sublingual ketamine. Um, so I think, Sam, there's probably a wealth of, uh, diagnoses or problems that may respond to this treatment. It's just a matter of having more providers utilizing it. Since Rachel and I together may have treated, I don't know, maybe at this point, five to seven hundred patients.

Dr. Mitch Liester: But I think once people start doing clinical trials or have more clinical experience with this, we're going to see a growth of additional, uh, problems that may respond to this treatment.

Dr. Rachel Wilkenson: I want to add one more thing to one of the more dramatic recent findings I've had is the responsiveness of long term schizophrenic cases.

Dr. Rachel Wilkenson: There's this term negative symptoms, so [00:53:00] lack of motivation, lack of, uh, emotional engagement or attunement that usually comes with long term neuroinflammatory disease. That's a hallmark of advanced schizophrenia, you know, people not being able to speak clearly, dress themselves, tend to their hygiene, much less read a book or watch a movie.

Dr. Rachel Wilkenson: Their dramatic cognitive decline is one of the most limiting factors of their disability later in life, especially over like the 7 to 10 year mark of their diagnosis. So I have two cases now that have finally settled down, and by that I mean their inflammation has calmed, they're sleeping well, their hallucinations are under control, where we tried a low dose of ketamine to see if it helped their cognition, and we Something amazing is happening with them.

Dr. Rachel Wilkenson: Uh, the mother caretaker of one in particular said, you know, I haven't even seen my son read in over 15 years. And now he's not [00:54:00] only having deep conversations with me, he asked for an encyclopedia set. And now he's sitting down in his room reading through this encyclopedia. Uh, so we are seeing return of cognition, return of the ability of patients to care for themselves.

Dr. Rachel Wilkenson: Another patient, similar story, but seven year history of schizophrenia again, six months ago, wasn't able to dress himself or keep a daily schedule. Now is dressing himself, keeping a daily schedule, reminding his mother when they leave the house. Uh, asking if she forgot her keys, her money, or her phone. He knows what medications he takes.

Dr. Rachel Wilkenson: He's tending to his hygiene. He's getting bored at home. So we're seeing return of some of these beautiful functions of these brains that were lost due to chronic inflammatory disease. And that's very exciting. That's been after years and years of treatment. So they would not have tolerated ketamine at first.

Dr. Rachel Wilkenson: It would have been too activating. Once [00:55:00] patients seem to be able to sleep well, the other signs of inflammation are stable. Their hallucinations are under control. For example, their mood is stable. Then we add in a low dose of ketamine and both are on 25 milligrams a couple times a week. So really low doses.

Dr. Rachel Wilkenson: And they're showing those improvements within months.

Dr. Sam Sigoloff: That's just absolutely mind boggling. That's just amazing. I mean, this is such a miracle drug. What do you do for your patients that let's say are so Disfunctional or at such a, a low functionality, I guess, um, that they may not be able to keep it in their cheek or their tongue or underneath their tongue.

Dr. Sam Sigoloff: Is there, is there any way that you can help them keep it sublingual rather than swallowing it and not being able to absorb the medication?

Dr. Rachel Wilkenson: You know, I don't think I've ever heard of such a case. I think they all seem to tolerate it. I do have patients complain that the, uh, taste is not that good, but [00:56:00] once they see how well it's working, they're more than willing to inflict the taste on themselves on a daily basis. Mitch, do you have any experience of patients not tolerating the sublingual form?

Dr. Mitch Liester: No, I have not had anybody stop it because of that. Also, some people mentioned the taste, but I've not had anybody stop the medicine because of the taste. Um, and really, if they don't tolerate, it's usually because the dose is just too high. We reduce the dose and they usually find a dose that works fine for them.

Dr. Mitch Liester: And some people, as Rachel mentioned earlier, are able to tolerate very low doses and it works well. I have a couple of patients on six milligrams every three days. And there was a study out of Brazil done about 11 years ago, where they gave people only 10 milligrams. Um, every two to seven days and saw benefits for depression.

Dr. Mitch Liester: So I think the dose response is one of the keys, Sam. And if, if they're not tolerating it, oftentimes it's just too high of a dose.

Dr. Sam Sigoloff: I have a patient who, um, it's not that he doesn't tolerate it. It's that he does what he wants to do. Cause he's, he's [00:57:00] more like a five year old, I would say. And he, he likes it.

Dr. Sam Sigoloff: And then he swallows it.

Dr. Mitch Liester: Well, and that's not necessarily a bad thing. The bioavailability is a little lower. If they swallow it, maybe 20 percent instead of 30%, but they still get the medicines. They just may need. To just the dose over time. So if people swallow it, it's not necessarily a lost cause.

Dr. Sam Sigoloff: Okay.

Dr. Sam Sigoloff: Cause he's, he's already noticed improvement doing it every three days. His caretakers already noticed a great improvement, which is just amazing. Wonderful. What things do you want to leave us with here? As we wrap up towards the end, uh, where can people find you or find your research? Where can people support you if they're able to?

Dr. Sam Sigoloff: Um, and you know, if someone wants to reach out to you, what's a good way to get ahold of either of you. And if you don't want to give your personal email, that's perfectly fine too.

Dr. Rachel Wilkenson: Yeah, Sam, I probably won't give my email or my phone. I'm a single mom. So, um, [00:58:00] Mitch, I'll let you chat about that in a minute.

Dr. Rachel Wilkenson: I would just say, our work is available on ResearchGate. It's a website that archives almost all the research done, even across the world, as an open source. So if you search my name online on ResearchGate, you'll find the research we've done so far. The same is true if you search Dr. Mitch Leister's name on ResearchGate, you'll find all of our work.

Dr. Rachel Wilkenson: Mitch is much better at responding to correspondence, so I will let him share how he would prefer to be contacted.

Dr. Mitch Liester: Sure, and Sam, I'm happy to have people contact me via email. My email address is d r dot l i e S T E R, so it's doctor. leister at proton, P R O T O N dot M E. So if people want to email, uh, with any questions they have or experiences they have, I'm glad [00:59:00] to correspond with them.

Dr. Mitch Liester: And share any information they have.

Dr. Sam Sigoloff: I just want to encourage everybody. If you do reach out to Dr. Leester, uh, please don't ask for specific medical advice. He obviously cannot provide it. You're not a patient of his, but if you're asking for direction or, um, you know, guidance, how can I find a provider?

Dr. Sam Sigoloff: How can I find more research to give to my provider? Uh, if you're able to provide this particular video to your provider and see if that helps them, um, those are the type of questions to be asking. Thank you, Sam. Well, thank you so much, Rachel and Mitch for coming on. I truly appreciate this. This has just been a huge blessing for so many people that y'all have been able to reach out and touch and improve their life.

Dr. Sam Sigoloff: This is just absolutely amazing. Thank you so much. Sam.

Dr. Rachel Wilkenson: Dr. Sigaloff. I've really appreciated this time and it's a great period in history to Work in neuroscience, and I think there's so much hope in the future, far more than I ever imagined. [01:00:00]

Dr. Sam Sigoloff: Well, Dr. Wilkinson, Dr. Leister, thank you so much. And, you know, uh, I pray that you continue to see results like this with patients in the future, and that more patients, uh, throughout the country will see this video and be able to get this type of treatment if needed.

Dr. Sam Sigoloff: If it's the right fit for them. Thank you so much.

Dr. Rachel Wilkenson: Thank you.

Dr. Sam Sigoloff: Just a reminder for everyone out there. Due to uniform of the day, the full armor of God, let's all make courage more contagious than fear.

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