How Does Ketamine Work in the Brain? How Do Ketamine Infusions Work?

Dr. Mark Leeds [00:00] Dr. Ladan Eshkevari, welcome to the podcast.

Ladan Eshkevari, PhD [00:03] Thank you so much. Thank you for having me.

Dr. Mark Leeds [00:06] Thank you. So you are a PhD in physiology and biophysics, a nurse anesthesiologist, and you’ve done research in animal models. You recently retired as a professor from Georgetown Medical Center, and you’ve done a lot of work with ketamine. In fact, I believe you’re the co-founder and CEO of Avesta Ketamine. Yeah, so that’s incredible, and it’s such an interesting field. And I believe you’re serving the residents of Washington, D.C., Virginia, and I think there’s one other location. It’s like three locations.

Ladan Eshkevari, PhD [00:43] Yes, we’re in the D.C. Metropolitan area, so we do have clinics in Washington, D.C., McLean, Virginia, and Bethesda, Maryland, quite near the National Institute of Health.

Dr. Mark Leeds [00:56] Oh, wow. Well, that’s a great area. I mean, that’s where I’m from originally. And yeah, I love visiting there. And so, yeah, tell me about how did you get involved with ketamine?

Ladan Eshkevari, PhD [01:10] Yeah, you know, so for many years, actually 25 years to be exact, I taught all of the anesthetic drugs to our graduate students at Georgetown University. And it was I would say about a decade maybe a dozen years ago or so that as I was putting my lectures together and updating them annually I started seeing more and more the research results of the effects of ketamine as an antidepressant and I think it was an inadvertent finding when researchers were looking at it as a good pain modality, what they found was that it also helped with depression and anxiety. And so right around that time, I had a colleague who was also very interested in helping patients with ketamine for mood disorders. And so she and I got together and we opened the clinic. And soon thereafter, COVID came along. And maybe a couple of years after that COVID came along and we, she decided to take the clinic in a different, that clinic in a different direction. So I actually, at that point started Avesta Ketamine and Wellness and started out with a pain management practice, doing a lot of pain management and mood disorders, and then shifted more to mood, although we still do some pain management as well.

Dr. Mark Leeds [02:51] Yeah, something really interesting about ketamine is that it works for both pain management and for a variety of mood disorders. And, you know, some people might say like, oh, are those related? Are they somehow, you know, it does seem like if something works for depression, anxiety, OCD, PTSD, you start seeing all these things that maybe it also works for chronic pain and maybe neuropathic pain. Is there an explanation for that crossover of why ketamine would work for both things? Is it by the same mechanism or different mechanisms?

Ladan Eshkevari, PhD [03:24] You know, that’s a very interesting question. And the short answer is we don’t know. But the longer answer, just understanding neuroscience, is that they do share a lot of common pathways in the brain, especially the modulating pathways in the periaqueductal gray, which is your own brain’s ability to modulate pain and also address and crosstalk with the amygdala for, you know, where we have fear conditioning and some of those behaviors as well. So we do know that chronic pain patients have similar misfiring, if you will, in the brain, as do patients with depression and anxiety. We just don’t, you know, it hasn’t been completely elucidated exactly where those connections are. But I’ll set an example for you, which is what I used to tell my students was, you know, people, for example, with chronic pain issues over time develop can can actually develop personality disorders, believe it or not. And they score differently on some tests that we do for personality disorders. And then once you can address that chronic pain and the chronic pain goes away slowly over time, whether that’s with injections, surgery, ketamine, what we find is that once we retest those same individuals and the chronic pain has been resolved, they actually start to score more and more towards the normal personality again. So we do know that there are some changes that occur in the brain and it’s not in people’s heads. It actually is physiologic changes that occur in the brain. And so, yes, there is crosstalk and they do they do tend to share pathways, if you will.

Dr. Mark Leeds [05:17] Yeah. And it makes sense that somebody with chronic pain, especially untreated chronic pain or poorly treated might develop a personality disorder because it’s torture, it’s trauma. And we know that trauma can lead to a personality disorder. So yeah, definitely chronic pain is real and people suffer with it. And sometimes they have to suffer with also people telling them it’s in their head or they shouldn’t get a certain kind of treatment, but there’s a variety of chronic pain syndromes caused by all different kinds of things. And people really do suffer with these kinds of medical conditions.

Ladan Eshkevari, PhD [05:53] Yeah, absolutely. You are 100% correct. And we see patients all the time that tell us exactly what you just alluded to, that a lot of their providers don’t really believe that they have chronic pain because there is no, kind of like mental illness, there’s no test. You know, there’s no, you can’t get an x-ray that says, yes, there is a tumor here, or there is stenosis here, or, you know, there is a clogged artery here. Because there’s no test, because it’s not visible necessarily, a lot of, unfortunately, providers also don’t necessarily believe when patients tell them that they have chronic pain, because they can’t find the reason why. Why is it that the central nervous system is misfiring? And if there’s no reason, then it must be in your head, which can be frustrating and actually, in my opinion, make the chronic pain worse.

Dr. Mark Leeds [06:48] Yeah. Yeah. And in a similar situation, there’s patients I’ve been working with in the last few years who are dealing with protracted withdrawal from discontinuing benzodiazepines. And in some cases, I think that you might even call that a pain syndrome. You know, people that develop akathisia and other issues, you know, they often describe it as pain, but it’s not pain in any certain areas, kind of like a maybe pain in their head and their groin area or just pain inside that they can’t really describe where it is exactly, but it’s pain. And I even had one patient that the husband was panicking. He said, we need to find something for our pain. No one will treat our pain because when they went to the hospital, there wasn’t a back or neck injury. It was just pain and she would tell them the story. You know, she went to a hospital, they took her off benzos too quickly and now she’s suffering. And, you know, it’s pain, but pain that they refuse to treat because, you know, they can’t, like you said, they can’t do an x-ray or an MRI and show where is the pain coming from.

Ladan Eshkevari, PhD [07:53] Yeah, there is a lot of misunderstanding around pain and pain management. And I think that’s why those of us who are educators kind of almost at the front lines of teaching the future providers to take pain seriously, to understand the pathways, to understand that there are changes in the central nervous system that we can’t pinpoint and say, this is exactly why. But just because you don’t know the why doesn’t mean that it isn’t happening. And so I think that is something I took very seriously as an educator, teaching our future providers that, you know, pain is real. And, you know, unfortunately, I’m sure you remember, I think we’re about the same age, but in the 80s and 90s, we were like, oh, pain, the fifth vital sign being undertreated, right? And then we over thought it with all these opioids. And now we’re almost like, I feel like the pendulum went all the way back to zero instead of landing somewhere in the middle where we say, yes, there is pain. It is real. It is happening, even if we don’t see it. And yes, opioids aren’t great long term, but what else can we do? You know, and the first the first step in what else can we do is first acknowledge, acknowledge and let the patients know that you hear them, you see them. It is real. We believe you. We hear you. Now let’s think through how to how to manage it. And I think that’s the difficulty. And I think pain management physicians and providers in general do a wonderful job. And I think when, you know, people can’t figure out exactly where their pain is coming from, they start shopping it around because, you know, there are those who don’t necessarily believe that they’re having chronic pain.

Dr. Mark Leeds [09:45] Yeah, that’s true. So one great thing about using ketamine for mood disorders and for pain is that, you know, and you teach pharmacology or you were teaching pharmacology. And when you look at the, you know, this FDA approved literature that comes with all these drugs and there’s pages and pages of adverse effects, adverse reactions and side effects. And I’m sure, you know, you tell your students, you know, learn every single one of these. If you prescribe a drug, you better know what it’s going to do to your patient or what it could do. And it’s overwhelming to learn all that for every single drug. When I first looked at the information for Ketalar, you know, I guess the original approved ketamine in 1950, I thought that it was cut short. I’m like, where’s the full version? I must be looking at like an abbreviated version. Where’s all the adverse effects that can happen? And because it’s like two pages or something like that, it’s very short. Although if you look at Spravato, you know, which is S-ketamine, which is related, I don’t know if the drug is that much more dangerous or if there’s a different, or maybe they’ve like had to document it differently, but there is more stuff in that one about, you know, potential adverse reactions. So, yeah, what do you think about that? I know ketamine, though, is very safe relative to a lot of other drugs, though.

Ladan Eshkevari, PhD [11:04] Yeah, absolutely. You bring up a really great point. And that is what we term here in Washington. And I know you know this term very well, bureaucracy. You know, I think back in the 50s and 60s, when we were doing research on ketamine, and then when it was finally approved, and I think 1970, the package insert on any drug that we took was maybe a page, page and a half, two pages. Now, I think, to your point, something like Spravato, which is literally just the S-enantiomer of ketamine, now has pages and pages of adverse effects. And I think it’s because, you know, of the litigious nature of our society, perhaps, and that, you know, the FDA feels responsible to talk about every single adverse effect that could occur, even if it occurred in one patient. And even if that was, you know, something that was really not even an untoward effect, but just an effect that they weren’t expecting or, And, you know, I don’t want to dismiss it. I think there is a lot of legitimacy to showing, you know, adverse effects to talking through what are some allergic reactions, adverse reactions. But I do, to your point, believe that it’s gone a little bit overboard in terms of any drug, but in particular with Spravato. But you asked about the safety of ketamine, and I’ll tell you, I think ketamine, when provided in a clinical setting where the patient is monitored, it’s the appropriate patient to receive ketamine, I do believe it to be a very safe drug. It has minimal effect on the central respiratory systems, and that’s why it is such a safe anesthetic drug, at least, compared to all of our anesthetic drugs that maintains the CO2 response to oxygen in the respiratory system and to carbon dioxide. And so, you know, it does tend to be very safe. Of course, it has side effects. You know, it has dissociative effects, which some people believe are the actual good effects of it on mood disorders. And then one of the biggest ones we know and we see are its activation at the chemoreceptor trigger zone, which is nausea and vomiting. And so those are, I would say, are the two major. And then some of the minor side effects are it does activate the sympathetic nervous system, which is your fight or flight. So it does increase blood pressure and heart rate. But I have to tell you in my anesthesia practice, since the mid-90s, I have used ketamine in patients. And I’ve never had a patient that had an adverse effect in terms of blood pressure or heart rate when it comes to ketamine. And we used to use pretty hefty doses back then. And now the doses that we use for mood disorders and even for pain management, you know, we’re using smaller doses. And rather than pushing the medication like we do in anesthesia, we’re doing it over time, which does make a huge difference on reducing a lot of those side effects. So I think that’s one of the advantages of doing it like we do in our clinic, the IV method, because it is so easily titratable. You know, if the patient says, you know, I’m starting to feel nauseous, we can always slow it down. Or if the blood pressure shoots way up for whatever reason, we can always stop it, then restart it as opposed to something like Spravato, which then it makes sense that it would have a bigger package insert because once you instill the medication in the nostril, there’s not much you can do about it. It’s already been instilled and you can’t really titrate it. So ketamine is quite safe, but again, done in a controlled clinical setting.

Dr. Mark Leeds [15:16] Yeah. That makes sense. And I think another big deal is that, you know, the danger of a lot of these medications, you know, like what happens to people with the benzodiazepines and the traditional antidepressants and other drugs is a lot of these drugs are made to be taken every day, you know, for long term. Well, benzo should not be taken long term. That’s a big mistake that a lot of doctors made with them. But, you know, like if you get Prozac, the doctor says take it every day and maybe in a month you’ll feel better. And the patient says, well, how long do I take it for? We’ll recheck in a year, basically forever. But with ketamine, as far as I’m aware, most clinics seem to be doing a series of sessions, maybe six sessions over a period of maybe a couple of weeks or a few weeks. And then when you’re done with that, you’re done. So you’re not taking ketamine every day for a year or 10 years or 30 years or whatever. So that would probably contribute, I think, to safety.

Ladan Eshkevari, PhD [16:16] Yeah, absolutely. Now, I’ll tell you know, we do, at least in our clinic, we have found that once patients respond to that series of six or eight that you alluded to, sometimes older patients, they’re not as neuroplastic, so they might need a seventh or eighth. But generally, to your point, after the first six, once patients start to tell us that they feel more functional, feel like they’re less anxious, better mood, we actually, in our clinic, taper them off slowly. So we don’t just do six and say, okay, goodbye, you’re done. We do talk to patients about, okay, now you’ve presumably grown some new neurons or at least some new synapses and connections, which is what we understand, at least in animal models. So now how do we keep these going, right? And so I think that’s one of the things that is really important is, you know, not just doing the six and saying, okay, bye, you’re done. And really tapering patients off slowly and safely. So what do I mean by that? I mean, maybe have the patient, so if they’ve been coming at a cadence of twice a week, for example, have them come back maybe once a week for a couple of more weeks. And then from there, we go to monthly, keep the patient up monthly for a couple of months, maybe three months, and then from there go to boosters as needed. But I’ll tell you one of the most important things that I think we providers in clinics really forget is, and maybe I don’t because I have that, you know, Chinese medicine training, is that you really do have to treat the whole patient and you have to concern yourself with all of the patient. So, and what I mean by that is once we get the patients to treatment number six, and they do very well, and they’re feeling better and more functional, we start talking about, okay, you have these new neurons. Now, we’re going to take you off, taper you off slowly. In the meantime, here’s what you can do. You can start to take some omega-3s, some B vitamins, or please make sure that you eat foods of every color. And that’ll honestly do the trick. I don’t know if, you know, if telling patients to take vitamins makes that much a difference as it does to say, hey, make sure that you get fruits, vegetables, meats. And yes, once in a while, if you have a feel good food that you like, go for it. But really trying to talk to patients about their diet. And then honestly, one of the most important things as a physiologist is moving your body, exercise. So incorporating, excuse me, some exercise every day, whether it’s just walking a block or two, and then making it two to three blocks, and then four or five blocks. Or, you know, if you’re in a very hot climate, or a cold climate, just going to your local mall and walking around, maybe for 1520 minutes, just seeing other people, just being outside amongst people or nature, all of those things really do contribute to a patient’s well-being and maintaining those new neurons that they’ve grown. So I think this six and done is a little bit of a misnomer because ketamine is like any other drug. If you take it for a short amount of time, you stop taking it and you go back to your old system of thinking. Oh, and therapy. We’ll talk about that. But if you go back to your old system of thinking or doing, those neurons are just going to shrink right back. So in order to maintain those connections, I think it’s really important to talk to the patient on how to do that.

Dr. Mark Leeds [20:15] Yeah. Yeah, definitely. And then that brings up something I wanted to ask you about. So when we talk about, you know, growth of neurons, and I think, you know, they call it neurogenesis. And so you have those, those little spindly tree-like things, the dendrites. And so those dendrites reach out. And this is a really incredible thing about the brain is that, you know, maybe we have like 10 or a hundred billion neurons, you know, there’s a certain amount of neurons that we can kind of conceive. Like, you know, we have less, we have less neurons than, than like Elon Musk has dollars, you know, so it’s like a certain amount of neurons, but the incredible thing is like each of those neurons can connect to many, many other neurons, You know, we’re not like computers where it’s binary. It’s not like one connects to two or whatever. Every neuron connects to like tons of them. You know, so maybe there’s like trillions and trillions of connections, you know. So when you think of connections rather than neurons, it’s like unbelievable how complex our brains are, like way more complex than probably any computer. But the thing about like dendritic growth is that I’ve heard people also say that’s also like how you develop negative habits and addictions and bad things and just for example recently I had prescribed a low dose ketamine like a sublingual ketamine to a patient and it’s helping her a lot and I said oh by the way you might be getting some dendritic growth so you know enforce some good habits you know think happy thoughts you know you know because you know we don’t want to go down a negative path. So I think therapy comes in there. Is it you want to do some positive things with that growth?

Ladan Eshkevari, PhD [21:51] Yeah, 100%. I think one of the most important aspects of ketamine is therapy. And really, the way I talk to the patients is, you know, really what I want you to do is start learning how to use your new brain. You know, now we’re growing a new brain, if you will, And our brains are changing constantly, right? We’re turning over cells. We’re having new cell death, new cell growth. And now that we’re really pushing that growth forward in a positive manner and showing you that there is another way of looking at things, now what you need to do is keep propagating that and building even newer connections and really learning how to be more resilient, even against your own self and your own thinking. Because a lot of patients tend to ruminate more on the negative than the positive. And to your point that carrying that positivity and connecting with a therapist who is ketamine informed is one of the most important things that a patient can do to maintain those new neurons. So exercise, diet, and therapy, 100% are, I think, the tripods that really help kind of navigate, help the patient navigate the new brain, if you will, and really anchor it down. So that they can be more resilient against their own thinking, if you will, as they go forward.

Dr. Mark Leeds [23:15] Yeah. Yeah. And I like how you mentioned the omega-3 fatty acids, you know, like you can get those fish oil capsules and those are, you know, great for your brain, for your heart, for treating pain. And I was taking like one a day, I get this big bottle from Costco. And then I heard this guy on a podcast that he said, like whatever dosage he mentioned for taking for depression, it was like double like what I was taking. So I’m like, well, it’s just fish oil. Maybe I should just take two a day. But yeah, those are really good, you know, I think for the brain for supporting brain health.

Ladan Eshkevari, PhD [23:48] Yeah, absolutely. And you know, if you’re, if you can’t take those large capsules or pills, honestly, just adding some fish to your diet. You know, salmon is very high content in omega threes. I know, I don’t know how many people like sardines, no one in my family eats them, but me, but sardines have a lot of omega threes. So I think just adding some fish, seafood to your diet, that’ll really add some omega threes. And then, you know, some of the, some of the more simpler foods like chia seeds, you know, chia seeds are packed with omega threes, they’re a good source of fiber, they’re pretty tasteless. So you know, if you’re averse to fish, switch it or if you’re vegan, swapping in some chia seeds would also do the trick. So those are some of the things that we talk to our patients about in terms of maintaining their new brain, if you will.

Dr. Mark Leeds [24:44] Yeah. Yeah. It’s like getting a new car. So you got to take care of it.

Ladan Eshkevari, PhD [24:47] That’s right. That’s right.

Dr. Mark Leeds [24:49] Yeah. So that’s great. So now somebody comes to you with depression and they take, you know, Prozac, Paxil, Zoloft, Lexapro. And, you know, they’ve been taking it for like 10 years. Like, I would assume that they don’t just suddenly stop it. I mean, it wouldn’t be safe or a good idea to stop those. So can they just keep taking their medication straight through?

Ladan Eshkevari, PhD [25:11] Yeah, you know, we advise them to not change too many things. You know, it’s like too many variables in a research study. You know, if you’re coming to us and you’ve been on Prozac and Lexapro, and those are obviously not working for you, that’s why you’re coming for ketamine, then what we usually advise patients, the first thing we do is we collaborate, we reach out and collaborate with the patient’s prescriber, whoever that is. Sometimes it’s a psychiatrist, sometimes it’s a mental health nurse practitioner, other times it’s their primary care provider. So we usually reach out and let them know that we are adding a new medication, we’re starting to do ketamine therapy. And then if the patient’s goal is to get off the medications, which a lot of times, I’ll be honest with you, Dr. Leeds, it really is, then in that instance, we collaborate with their psychiatrist or their prescriber, whoever that is, to slowly start to taper off as they start to feel better and better with the ketamine. We’ve actually been very successful reaching patients’ goals who do want to get off the medications because a lot of times, especially younger patients, find some of the side effects to be incompatible with young life. You know, a lot of young patients complain about sexual dysfunction, you know, lack of interest in sexuality, which for a young person is very disconcerting. And so if that’s their goal, if the goal of the patient is to get off their medications, which oftentimes it is, we will work with them and their prescriber to slowly taper them off. So but to your point and I’m glad you raised this you know sometimes people get excited to try something new and as they get they start to feel better and better with the infusions you know I worry that sometimes patients try to self you know they go on dr google and they figure out okay this is the good way to the dr google says I should do it so I always caution patients against doing that because, to your point, patients who’ve been on these medications for a long time, it is actually, some are actually unsafe to come off of rapidly causing seizures, things like that. So I do think it’s important to collaborate and get the patients off slowly.

Dr. Mark Leeds [27:32] Yeah, yeah, definitely. It seems like any kind of medication that gets into the brain at all, any kind of, you know, the benzodiazepines, the antipsychotics, antidepressants, even the opioids, anything that gets in alcohol, like whatever gets into the brain, taking it away suddenly after someone’s been taking it for at least more than a few weeks or for a long time is traumatic to the brain and possibly damaging long-term. And so, yeah, tapers have to be done, you know, reducing medication should be done very carefully and gradually.

Ladan Eshkevari, PhD [28:03] Yes, agree 100%. Yeah. And then for the substance use disorder patients, I mean, we would like them to start ketamine therapy once they’re clean and sober, if you will. But, you know, that doesn’t always happen, especially with cannabis. We’re finding, I don’t know what your thoughts are on this, but we’re finding more and more that patients who are addicted to cannabis are probably one of the most intractable addictions that we’re facing now. It’s very difficult and it’s mostly a psychological addiction, much more than a physical one like the benzos or opioids. And we’re finding that’s a real challenge for patients to not do any cannabis while they’re going through their ketamine therapy and we try to reinforce it. But I think that’s a difficult one for patients as well.

Dr. Mark Leeds [29:00] Yeah. Have you seen any success with stimulant addiction, like methamphetamine or cocaine?

Ladan Eshkevari, PhD [29:07] I have not, I have not, I had one patient who, was addicted to meth, and he, stopped treatment short. So he came for two or three treatments, and he enjoyed the experience, but did not allow for us to continue the protocol. He did not come back and, you know, on follow-up, he did not respond. So I think that was a tough one. Cocaine, I have not seen. We haven’t seen anyone, yeah.

Dr. Mark Leeds [29:43] It seems like whether it’s, you know, addiction where a person that is suffering from cravings or OCD, obsessive compulsive disorder, or even, you know, severe chronic pain, it seems like just the experience of, you know, and I’m not sure I’ve never done it before, but maybe the dissociative effect of, you know, your brain and, you know, some part of your brain’s disassociating from other parts of your brain, it seems like that would give you like temporary relief, you know, that maybe the pain is there and you’re aware of it, but maybe it’s not bothering you like how it usually does, like at least for the time.

Ladan Eshkevari, PhD [30:17] Yeah, I agree. And I think if the patient has a good therapist that is SUD, that substance use disorder informed, I think they can really help the patient incorporate that feeling that they get in the ketamine experience, you know, later on with how do I incorporate that, hey, my brain can work in this new and different way. And I can think in this new and different way and maybe think about my addiction in a new and different way. So I think it is an opportunity for sure. And I do know that patients, at least who we’ve treated, quite a few for alcohol misuse, and they definitely have reported a pretty great significant reduction in their cravings. So there is a-

Dr. Mark Leeds [31:05] Yeah, there’s a protocol for that, right, KARE? KARE, the KARE protocol.

Ladan Eshkevari, PhD [31:09] Yes, exactly. Yeah.

Dr. Mark Leeds [31:11] Yeah. Which I think is just ketamine infusion or ketamine treatment plus therapy. And they have like a really, I guess the big deal is that the relapse rate goes way down with that.

Ladan Eshkevari, PhD [31:22] Yes, it does. And, you know, we, in our clinic, again, we really do encourage some vitamin supplementation to really increase that resiliency in the new neurons, just because alcohol is so damaging to the brain, to the neurons and to cardiac cells and the rest of our bodies, because the body doesn’t recognize it and it overwhelms our metabolic system, if you will. So we don’t metabolize it like we do other drugs. So yeah, that’s an interesting model, but definitely combining ketamine with therapy is kind of at the top of that. Yeah.

Dr. Mark Leeds [32:01] With the patients who have benzodiazepine dependence, you know, whether they’re trying to taper very gradually off of the benzos or they, maybe they were encouraged to quit cold turkey or very quickly, inappropriately, and now they have protracted withdrawal and some even develop akathisia. And those patients are really suffering and looking for answers. And ketamine seems like it should help. And although what I’ve heard personally from like from individuals you know they usually say well it didn’t help me I went for one session and didn’t do anything for me so and you know I think it seems like you really need to keep follow through and do multiple sessions to really see the benefits and although patients with benzodiazepine withdrawal they can be very sensitive to almost anything like medications that would should not cause a bad reaction you know well you know they’re just really sensitive, even the tiniest bit of something that, you know, you would never think would affect someone can give them a really bad reaction. So, you know, we have to be careful with them. But it just seems like, you know, based on how ketamine works, it really should help them to feel better. But have you seen any of that, like the benzo tapering or protracted withdrawal patients?

Ladan Eshkevari, PhD [33:13] Yeah, absolutely. We’ve had quite a few of those patients who are either themselves wanting to get off the benzodiazepines or their psychiatrist or mental health nurse practitioner is like, okay, we need to get you off. You’ve been on this for a long time. And I have to tell you, I agree with you a hundred percent. They’re a little bit more challenging because the ketamine experience can be, you know, although it can be pleasant for most people, I think patients who are used to benzodiazepines and kind of that numbing effect of it, I think they’re a lot more sensitive. They’re a lot more sensitized, if you will, to the effect, the dissociative effect of the ketamine. And it can get a little scary. And there is this term on Google that people refer to, oh my God, I’m worried about going in a K-hole. And I always tell patients, there is no such thing as a K-hole. It’s a K-home. It’s your paleo brain. It’s where your brain started way, way, way back billions of years ago. And you’re just going there. That’s it. It’s your home. It’s your paleo brain, nothing to be scared of. It is just another part of you. So those patients in particular could really benefit from a few therapy sessions with a ketamine-informed therapist that can really help them set intention, set expectations, let them know what to expect, and then maybe even be present with, you know, during the first couple of ketamine journeys so that the patient, to your point, that’s so sensitive, can get through it. And then after that, they actually do very well. But on the back end, it does take a little bit more to get them to that maintenance phase and then off. So they are challenging I think every patient whose brain is used to benzos opioids alcohol and some of the other substances you’ve mentioned I think they do pose a challenge but we’re up for that challenge aren’t we

Dr. Mark Leeds [35:25] Oh yeah yeah definitely definitely so now the way ketamine works. And I know a little, but maybe not all of it. And it’s very interesting. It does something with the NMDA receptor, which interestingly, I remember there was a medication that it was new and I never really heard much about it after it came out. It was for Alzheimer’s dementia. It was to slow down the decline. And it was called, it was Namenda. And Namenda worked on the NMDA receptor and which I think it put it in the same category. There’s like that Robitussin, the stuff in Robitussin does the same thing and PCP does the same thing. These things are all kind of in the same family of working on that receptor and doing something. I’m not sure if it blocks or activates, if it’s an agonist, antagonist. And then once it does something with that NMDA receptor, something happens with the neurotransmitters glutamate and GABA. I’m not sure if it increases one, decreases the other. Can you talk a little bit about what happens at the receptor level?

Ladan Eshkevari, PhD [36:31] Yeah, absolutely. So the way that ketamine actually works is it is an antagonist at the NMDA receptor. So it actually blocks glutamate from interacting with its regular receptor, which is NMDA. But what that does, and actually ketamine is also an ionoporic, so it actually causes increase in calcium entering the cell. So it does both. It’s kind of an interesting, it’s a very elegant drug actually in that regard. But then it also, and that kind of sets off that whole sympathetic nervous system, if you will, you know, increasing calcium intercellularly. But as far as the NMDA, it blocks the NMDA receptor from interacting with glutamate. So what it does is there is an, a preponderance for glutamate to kind of build up and almost get shuttled to the AMPA receptors in the pyramidal cells of the brain. And that’s actually where we see the activity of ketamine and its antidepressant effects. So the way I used to describe it to the medical students is, you know, we have a couple of major roads here in the DC area, but wherever you are, I’m sure there are a couple of parallel main roads, right? So let’s say you’re driving down one of your main highways where you are and there is a car accident. So the cars can no longer go down that road. So what happens is, and that’s ketamine, it’s blocking glutamate from interacting. So all the cars, instead of going down this route now, have to get over, usually for us using Waze or Google. But basically in the brain, the glutamate finds itself interacting more with the AMPA receptors where it actually increases the cell’s machinery to kind of lock in and increase protein synthesis and eventually those dendrites that we’ve been talking about. So that’s the main mechanism of action of ketamine when it comes to its antidepressant effects. And I think that was demonstrated in animal models in a 2019 study that was published in science, nature science, which basically demonstrated, you know, they stressed out mice. I think it’s a rodent model. I don’t recall whether it was mice or rats, but regardless, it was a rodent model. And that’s actually how we manifest depression and anxiety in animal models. We cause chronic stress. And so those animals were shown that they’re, then they exposed some to saline and some to ketamine. And what they found was that chronic stress caused the neurons to shrink and some of those dendrites to shrink back and the spines to actually disappear. And then after exposure to ketamine, we saw new growth in those areas. And we believe that’s happening because of the AMPA receptor reacting with glutamate.

Dr. Mark Leeds [39:33] Oh, that’s really, yeah, it’s really interesting. Is GABA involved in there? I might be mixing it up with a whole different thing. Like somehow there’s like a balance of glutamate and GABA that they’re connected somehow.

Ladan Eshkevari, PhD [39:44] Yes. So, you know, and this is kind of all of us in nature. You know, there is a, wherever there is an action, there is a reaction. In Chinese medicine, it’s yin and yang. And in our brain, it’s glutamate GABA. And so at the same time that glutamate is interacting, ketamine is causing this interaction of glutamate, it also does cause downstream effect on the GABA receptors. And that’s where we see that it does actually over time help with anxiety as well. And so that makes good sense. And then actually in the descending pathways of the central nervous system, both in the spinal cord and in the brain, it also interacts with opioid receptors in a very non-addictive sense. So ketamine is, again, a pretty elegant drug interacting with multiple receptors presynaptically and postsynaptically as well.

Dr. Mark Leeds [40:37] Yeah. And as far as I’ve also read that it has anti-inflammatory effects like that. I don’t know. Is that just in the brain or the whole nervous system or the entire body?

Ladan Eshkevari, PhD [40:47] You know, there is some, it’s very interesting with ketamine. There are some studies that have shown that it’s neurotoxic and there’s some studies that have shown that it’s neuroprotective, that it does have some anti-inflammatory effect. So in our clinic, we actually did the research study where we provided IV ketamine, our usual standard protocol of six. And then we also, So at the end, for some patients, it was a double blind. So I didn’t know, neither did any of the providers. So we did either ketamine with saline or ketamine with glutathione, which is an anti-inflammatory. We didn’t find any difference in either group. And what we were going to do is, OK, if we found a difference, the next study we were going to do would be to draw, you know, some blood, some plasma and test it for some of the anti-inflammatory substances. And because we didn’t have it, we had a positive effect. Everyone responded to ketamine. So that’s the good news. We had significant difference from day one to day 28. So we stopped even 14 days after we stopped the ketamine infusions, patients still did well. But there was no intergroup difference. So in our own clinic, we weren’t able to demonstrate a synergistic anti-inflammatory effect. So I think it’s a little bit more complicated, Dr. Leeds, when it comes to inflammation, whether it’s an anti-inflammatory or a pro-inflammatory. In our clinic, we use it a lot for pain management, but my assumption always is that we’re affecting those kind of common pathways, if you will, that we’ve discussed at the beginning of our podcast, but also maybe more on the opioid side versus the anti-inflammatory side. But I’m not positive on that.

Dr. Mark Leeds [42:46] Okay. Yeah. And I mean, we should say that a lot of this is probably, you know, speculative. I mean, it’s not that easy to look at these receptors in the brain and say, you know, look at, you know, I mean, you’re not actually watching these things interacting in a microscope and saying, look, it hit that receptor and it didn’t go to that one. I mean, it’s not easy to study these things. I mean, it’s easy for us to talk about it and say like, oh, look, it blocks that one and activates that one. But to discover how all this stuff works, you know, must be very difficult to come to these conclusions. And then even then it’s speculative to some degree.

Ladan Eshkevari, PhD [43:20] Yeah, 100%. And you know this better than I do. You know, every patient is so different. You know, every brain, I always tell patients, you know, your brain, just like we all have different fingerprints, every individual has an individual fingerprint. I believe the brain to be the same because there is no way even twins there is no way you and another human being have the exact same experiences the exact same sensory inputs at the exact same times and so given that all of our brains are different. It does make it very complicated. It does make it so complicated and not, and no two trauma patients or, you know, depressed patients or anxiety patients, no two brains are identical. And so, you know, that’s why it’s so individual and our treatments have to be almost, it almost pushes us as providers to really try to look at every patient as an individual and, plan something different for each of those individuals. And to your point, at the cellular level, you know, we understand, we are practicing based on evidence, but is the evidence perfect 100%? Do we know this to be 100% true and in fact true, the reality of it? You know, we can’t say with 100% certainty, right? And it’s very difficult to translate animal models to human models, Again, because of that reason, you know, I’ve done clinical research and I’ve done animal research. And, you know, those rats are bred for research. They’re all identical, whereas humans are anything but. So it does it does pose a challenge, but exciting. You know, that’s what makes our practices so fascinating. Yeah,

Dr. Mark Leeds [45:11] And that’s what makes one, you know, with ketamine, it’s so interesting that as you treat people, you can observe additional benefits along the way. You can say like, well, this patient came in for this reason, but they have these other problems and they’ve reported back that they had improvement of something else. And now we may have discovered a possible new use for it. So now one thing I promised I would ask about this, you know, nootropic supplements and drugs, you know, nootropic meaning like a drug or a supplement that makes someone’s brain function better. You know maybe it helps them to focus or calm down or think more clearly and it’s kind of a difficult thing because you know like our brains are like probably you know we have well I don’t know if you I guess the brain is like like like muscles you can build muscles up to a certain degree you know within certain limitations but could you possibly call ketamine a nootropic drug or like what if someone came in and said I’m pretty much doing fine I don’t really feel depressed or anxious or OCD, PTSD, all these different things, no pain or whatever. Like, I feel fine, but I want to think better. I want to like do better at my job. Like maybe they’re a programmer or, you know, something that takes a lot of, you know, mental focus or an author. Can ketamine, is ketamine a nootropic drug or like, would that not be a good idea to think of it that way?

Ladan Eshkevari, PhD [46:31] You know, we don’t utilize it that way. I don’t know, you know, I don’t know, So I’m not going to sit in judgment of whether that’s a good way of thinking about this amazing drug that we have or not. I tell you, that’s not how we utilize it at our clinic. For us, patients do have to have a diagnosis before we will do ketamine therapy. But you know, if someone is really looking to increase, you know, brain growth, they can do, you know, there are some infusions that are very helpful or people, think are helpful, like some of the ATP, you know, promoting, medications like NAD, and yeah. So some of the acetylcysteine. So I think some of those, amino acids might be a little bit more useful, not be a controlled substance. You know what I mean? And so it’s that side of it out. And then, you know, something that really is very and we know this from from physiologists who’ve done exercise physiology, that if you push your brain to an uncomfortable place with exercise, whether it’s the, you know, the Japanese Tabata method or if it’s a HIIT exercise or something like that, you do release mTOR, which is what rapamycin and some of these other medications. Are trying to do. And by doing that, you actually increase synapses in the brain as well. So I think if someone were to come to me and say, hey, I want to have better focus, use my brain differently, I would probably recommend something like that, like a NAD infusion and intense exercise, probably four to five days a week, a short, short spurt versus trying something like ketamine. You know, do I, would I be entirely against it? Absolutely not. Because to our points that we’ve talked about today, you know, every individual brain is different and there might be someone out there or many someones out there that would benefit from the neuroplastic effects of ketamine. Someone who has a, doesn’t have any diagnosis, but I don’t, I don’t, I wouldn’t prescribe for that. You know what I mean? I just wouldn’t. There are other things, you know, as a physiologist, drugs aren’t my first go-to. Your own body aren’t my first go-to.

Dr. Mark Leeds [48:55] Yeah. Yeah. That makes sense. People really, you know, in the field of nootropics, I mean, there are things that are non-controlled that you can get over the counter. Like we said, the fish oil, there’s a nootropic, you know, and so, you know, there’s definitely things that are safe and readily available. But yeah, prescription drugs and definitely controlled drugs, And, you know, even in a clinical setting, we really shouldn’t think of them as being used for treating people that don’t have a diagnosis that would require the use of them.

Ladan Eshkevari, PhD [49:23] Yeah, I agree with you 100%. I mean, I think that’s what makes us licensed providers, right? There is that kind of safety, that line that we don’t really necessarily cross. Now, you know, if there are people out there that recommend it, maybe they’ve had different experiences. Yeah. So maybe they’ve seen it work in several patients. Maybe they have a cohort of athletes that they’ve worked with and they really believe that it works for this group. You know, I’m not negating it, but that wouldn’t be the first thing I would go to.

Dr. Mark Leeds [50:02] Yeah. Well, it is good to know that there are alternatives if someone is just looking for that. Brain growth effect that there’s, you know, they don’t have to, you know, ketamine is not, like you said, not the first thing to go to. There’s a variety of other options that can do the same thing probably just as well or adequately for those patients or people. Yeah. So, yeah. So, oh, one last thing. I don’t want to take up too much more time, but we talked about, or we discussed Lyme disease. And I think that’s one of your, I don’t know if it’s your most recent, but you have a prominent blog post on your website about Lyme disease. And that’s really interesting. Lyme disease is not something I’ve thought about a lot. I mean, it’s not like a major problem in our area. I know in some areas it is, you know, maybe where you are, maybe there’s more deer and woods and deer ticks. But I know that’s in some areas, it’s a major issue and it’s often underdiagnosed. And then even when a person gets treatment, they may continue to have joint or muscle pain, fatigue and some vague symptoms and maybe symptoms that might even be misdiagnosed to something else. And then I started looking up different conditions, like what’s kind of like protracted chronic Lyme disease syndrome or whatever you would call it. And, you know, you find things like Epstein-Barr virus and fibromyalgia and, you know, just other conditions that might fall into that category of like, you know, doctors might say like, oh, you don’t have anything, you’re fine. We already gave you antibiotics for the Lyme disease. You know, you’re imagining it. You know, and like some of these other conditions, you know, people have real symptoms and real pain. But, yeah, can you talk a little bit about like how ketamine can help someone with chronic Lyme disease symptoms?

Ladan Eshkevari, PhD [51:52] Yeah. So, you know, we have used ketamine really successfully in quite a few Lyme patients who have chronic Lyme, if you will. So to us, it almost seems like there is Lyme disease and then there’s a lot of co-infections with the Lyme disease that attack the nervous system. And so, you know, patients end up with really bad headaches or they end up with joint pain chronically. And so what we found is that combining ketamine with something like magnesium that really kind of takes down that central nervous system, kind of calms it down together with a disruptor like lidocaine so that we’re disrupting the pain pathways from firing. And then combining all of that with an anti-inflammatory, like a high dose vitamin C that they’re using in the ICU now, that we’re having really good success treating patients for their pain, but also maybe trying to address a little bit of that inflammation that’s the underlying cause of what’s happening. So even if the Lyme disease itself is resolved, they might have some co-infections that are causing some longer standing inflammation, as well as central nervous system misfiring, you know, with the chronic pain. So we do some of these combination therapies, if you will. And then, you know, it’s very interesting that you raise the anti-inflammatory effects of ketamine in hopes with Lyme’s patients. We also hope that there is some of that happening as well, although we don’t know with certainty that we’re hopefully causing effect, not just disrupting the pain pathways, but combining ketamine with a glutathione or a vitamin C to cause some anti-inflammatory effects as well. So those are some of the combination therapies that we do.

Dr. Mark Leeds [53:45] Yeah. Now you mentioned, I think, you know, I think you mentioned acupuncture and Asian medicine. Is there, I don’t know if that, if that involved in that is like these energy pathways or the flow of energy and the, what do you call those centers in your head and different? The meridians. Yeah, meridians. But there’s another thing like these energy centers in the body. Oh, chakras.

Ladan Eshkevari, PhD [54:14] Chakras. Yeah, that’s Ayurvedic medicine.

Dr. Mark Leeds [54:18] Okay, so chakras is not like, you know, that’s not the same thing. That’s like more, maybe more alternative and outside of the, you know, like you wouldn’t treat chakras. But you might, but what is a meridian?

Ladan Eshkevari, PhD [54:30] So, you know, in Chinese medicine, they believe that or we believe that your your deep organs send their energies or their chi, which is the life force spelled C-H-I-C-I, that your life force or energy from the organs is transmitted more to the surface of your body so that we can diagnose and treat a lot of your illnesses by tapping into your own organs energies. And so those energies all have pathways that bring the energy forward from your own organ. And those are meridians. So every single organ system in Chinese medicine has its own meridians. So you have, for example, the heart meridian, the lung meridian, the kidney meridian. And so those energies we can tap into by inserting needles into that meridian. And every meridian has a few points that are the strong points. There are over 360 points on the human body, but every acupuncturist will probably tap into about 70. And so each of those meridians have some some master points that are used more universally. And those apparently are the more potent points that we can tap into those energies. So that’s basically kind of the theory of these energy fields that bring information to the surface so that we can tap into it.

Dr. Mark Leeds [56:02] Well, it sounds similar to osteopathic medicine where, you know, we talk about like the spinal levels that correspond to different organs. Like I think it’s a T5 maybe on the left that corresponds to the stomach and each organ has like a different place on, you know, on the outside that connects to that organ where you can treat that spinal level.

Ladan Eshkevari, PhD [56:22] Yes, it’s very similar. It’s very similar. Yes.

Dr. Mark Leeds [56:26] Okay. Is that beneficial to do those kinds of treatments like during a ketamine treatment or would you not want to mess with acupuncture and ketamine at the same time?

Ladan Eshkevari, PhD [56:34] You know, it’s interesting you raised that. I’ve often wondered if it wouldn’t be really cool to do like, you know, the master points. There are four, you know, the four gates, as we call them. There is a point on your, between your thumb and your index finger called large intestine four, which is one of the more potent points. And there is a point on your, on your feet, on the surface of your feet between your large toe and your index toe, if you will, your second toe, that is also a master point. So, you know, some and we call when you insert needles into the four, you know, simultaneously, that’s referred to as the four gates, it supposedly opens up your whole energy field and makes you more, it kind of really causes the flow of chi in your body and really helps to move the energetics along, if you will. So I’ve often wondered if for people who are really stuck and for whom ketamine is working, but it’s not working as rapidly or as much as they’d like, I’ve often wondered if it wouldn’t be really cool to do the four points and then start an acupuncture treatment. I haven’t done it. But I’m wondering if that wouldn’t be so cool to combine and then maybe do a study on that. I think it would be fascinating.

Dr. Mark Leeds [57:59] Yeah, that would really be incredible. I think that’s always interesting, the idea of like, taking two things that are not going to interact in a negative way and seeing how if they can synergistically help each other.

Ladan Eshkevari, PhD [58:10] Yeah, absolutely. Because even just putting needles in those four points, a lot of people, you know, without any mind altering drugs, feel that, you know, they feel like an openness, like a release almost. And that’s why I wonder if doing the four points, you know, the four gates, as they’re called, and ketamine together might be like a really cool exercise. I don’t know, maybe a patient will volunteer to do that with me.

Dr. Mark Leeds [58:40] Yeah, definitely. Yeah, yeah, they should, you know, that, and I would definitely be interested to learn more about that and talk about that on a podcast, you know, when you’ve done that study or you have some experience trying it out.

Ladan Eshkevari, PhD [58:51] Yeah, maybe I should, yeah.

Dr. Mark Leeds [58:53] Yeah, yeah, and there’s probably not that many ketamine specialists out there who are also specialists in acupuncture, so you are probably in a unique position to do that study.

Ladan Eshkevari, PhD [59:05] Yeah, it would be very cool, honestly, to combine, and I’ve thought about combining the two, especially for our pain patients. But I haven’t done it only because, A, it’s difficult to, you know, do ketamine therapy, IV therapy, and insert needles and all of that, just logistically, it’s difficult. But, you know, in our recliners that we use for the IV, we could certainly try the four points and see what we get. It would have to be in a special patient that’s open to that. And, you know, patients are already needle phobic enough at the IVs.

Dr. Mark Leeds [59:41] Yeah, that’s true. Yeah. But those are like tiny, tiny needles, right? They’re like, you don’t even really feel them mostly, I think.

Ladan Eshkevari, PhD [59:49] No, they’re 34, usually 34 gauge. And they’re non hollow, unlike our Western medicine needles that are hollow bore intended to draw blood or insert medications into blood, they’re actually solid. They’re not hollow bore, so they don’t cause bleeding or anything like that. Yeah.

Dr. Mark Leeds [1:00:09] Yeah. Well, that’s great. So Dr. Ladan Eshkevari, thank you so much for joining me. This has been a really enlightening and incredible interview and discussion. Thank you.

Ladan Eshkevari, PhD [1:00:20] Thank you so much for having me, Dr. Leeds, and thank you for your time.