Gladden longevity — Episode #51

Steve Reiter: Welcome to the Gladden Longevity Podcast with Dr. Jeffrey Gladden, MD, FACC, founder and CEO of Gladden Longevity. On this show, we want to answer three questions for you: How good can we be? How do we make 100 the new 30? And how do we live well beyond 120? We want to help you optimize your longevity, health, and human performance with impactful and actionable information. Now, here's today's episode of the Gladden Longevity Podcast.

Dr. Gladden: I'm here today with physician Dr. Brent Turnipseed and his wife, Andrea Turnipseed, a licensed clinical social worker, to talk about psychological health. Brent is a board-certified psychiatrist. Andrea and Brent work together. They're also involved with Ketamine-assisted Psychotherapy, and they're located in Austin, Texas.

They have a real passion for helping people with anxiety, depression, PTSD, and things of that nature, ADD, and they also are dedicated to making themselves accessible to people through Texas-based insurance plans for people that live in Texas.

That being said, Brent and Andrea, why don't you tell us a little bit about how you moved towards this particular style of practice, incorporating things like ketamine and things like that? Tell us a little bit about how you got to this point.

Andrea Turnipseed: Yeah. Well, we started as a traditional psychiatry practice, and we found that our traditional medicines weren't always working for our clients, and as well as we treat a large variety of people. Since we do take commercial insurance, as part of our passion is making sure that people can all reach the care they need. And so-

Dr. Gladden: So, traditional medicines, let me just interrupt you for a second. What would be some of the traditional medicines that would be most commonly used in psychiatric practice? I think most people are familiar with antidepressants and SSRIs, but maybe you could just talk us through those medications… What you saw was beneficial about them, and where you saw them falling short, that would be helpful.

Brent Turnipseed: Sure. So, yeah, I mean, most of what we treat are mood disorders. So, mood disorders being depression, whether it's bipolar depression, unipolar depression, and all different kinds of anxiety disorders like panic disorder, PTSD, and we use antidepressants to treat those conditions.

SSRIs are the most common class. That's the first step that psychiatrists will recommend. But there's also another class called SNRIs, serotonin-norepinephrine reuptake inhibitors. There are tricyclic antidepressants, which are an older class, but still used in our field.

And then, there are mood stabilizers like lithium and lamotrigine for treating bipolar. And then, there are antipsychotics that treat bipolar disorder, psychotic conditions. And so, while those medications help many people that come to us for help or come to us for our services, it's pretty well known now of all people seeking treatment, let's just say for depression, about one-third never significantly improved despite trying several different kinds of medicines, medication classes, and combinations. And so, we've been having this problem for about the last 30 years.

An epidemic of depression and suicide in the United States. The rates began climbing in the early 1990s, and they hit a peak right before the pandemic. And, of course, they haven't gotten any better since 2020. And so, that epidemic of depression and suicide has really shone a light on the fact that psychiatric medications and treatments fall short for many people. And suddenly, or in the past, let's say five years at least, there's been a resurgence of interest in research in novel types of therapies and drugs. There's been a resurgence or an interest in psychedelics. And also, luckily, there's been a surge of interest in lifestyle habits to optimize brain health so that long-term maybe people don't need to rely on medications quite as much.

Dr. Gladden: So, let me just go back to the traditional medications for a minute. The SSRIs, the SRNIs, and what we're talking about here, there's been this serotonin hypothesis of depression that if serotonin levels are low, then people don't feel as well. And if you boost things like serotonin-norepinephrine, maybe dopamine, and things like that, that people will feel better. That's not just a perfect paradigm or understanding. Can you talk us through a little bit some of the pitfalls of that approach? And also, for people that are on SSRIs, what I understand is what they're doing is they're basically keeping more serotonin in the synapse. They're not allowing serotonin to be taken back up by the neuron that basically sent it out in the first place. But when you saturate the receiving neuron with the serotonin, let's say, it can start to down-regulate its own receptors, so there can be problems then when you try to withdraw the medication to where now people are potentially worse than they were before, and it has to be taken away quite slowly to allow those other receptors to regulate.

There's lots of interest as to whether or not these drugs are actually the right approach in the first place. And so, what I'm gathering and talking with you is that you're taking a little bit more of a comprehensive approach here. Yes, using the medications, but also being open-minded enough to see that there are limitations to the medication. So, as you think about the paradigm for treating depression, anxiety, and things like that, do you feel like the paradigm is fundamentally still not well understood or maybe flawed on some level with the available drugs, or what are your thoughts about that?

Brent Turnipseed: I think we're currently in a time where the paradigm is certainly being questioned and challenged since it appears that it doesn't seem to explain how depression works (let's just say depression), how depression works for so many people. Like I said, we could prescribe Prozac to 10 people that come in our office for depression, and maybe four, at best, out of 10 will improve. So, it's like, what's going on there? If we increased the serotonin level for everybody, why didn't everybody feel better? And it's probably because serotonin alone doesn't explain the pathophysiology of depression. Depression, I think, is a very complex syndrome that could have dozens, if not hundreds, of potential causes, whether they're environmental factors, genetic factors, and I think the medicines, the drugs we have, they've just been a little too simple. I mean, it's nice you're taking a shot, and you're hoping it'll help, but it's not comprehensive enough to potentially address all the underlying causes for someone's depression.

So, again, they do help some people. I think another thing that experts in our field have gotten a better handle on is that SSRIs and other antidepressants are best used in the short term. Short-term - meaning anywhere from six months to 12 months. And luckily, there are increasing guidelines around this that if someone does take an antidepressant, they probably should talk to their prescriber about optimizing their brain health, improving their relationships, whatever the contributing factors are, and aiming to get off that medication nine, 12 months later if they can. Because you alluded to, if you don't, if people stay on these medicines for years, it does change the physiology of how their brain chemistry works. And some people end up being apathetic, mildly, chronically depressed while they're on antidepressants. They may not be suicidal. They may not severely depress, but they certainly aren't feeling very good. And so, we're starting to realize that "Hey, I think the paradigm”, like you mentioned, “I don't know if it's broken, but we need to rethink our whole approach to treating brain diseases and depression."

Dr. Gladden: Yeah. I think that's a good point that you're making. One of the other things that we've gotten into also, and maybe you have as well, won't put you on the spot about this per se, but doing some pharmacogenomics can be helpful, I think, in terms of understanding which individual’s likely to respond to which antidepressant and that thing too. And I think in cardiology, we were guilty of just throwing up people on statins, not realizing that, genetically, some people were actually going to benefit, some people weren't, and some people were going to have some pretty serious consequences. And so, starting to do some pharmacogenomics around that was very enlightening about who needed or would even benefit from a statin, let's say, and who was likely to get side effects. The same was true for certain blood thinners. Certain blood thinners just didn't work in individuals because, genetically, they weren't going to metabolize it properly.

So, I think there's also been a dearth of physician adoption of trying to look for better ways to improve precision in terms of how we select, what we are going to select, if we're going to work inside the typical, we'll call it allopathic paradigm to even do that better. So, I don't know, is that anything that rings true for you guys?

Brent Turnipseed: So, to some extent, so, pharmacogenetic testing has been used, and I guess, it's been in the prime time for psychiatry for maybe the past decade. And a lot of people in our field were very skeptical initially whether or not it could be a useful tool in clinical practice. I, myself, was somewhat skeptical when it first came out. It just seemed hard to believe that this was going to tell us which medicines would and won't work. But you're right, what they do is there are somewhat genes identified to indicate whether or not a person will metabolize a medicine quickly or slowly, whether or not they're more likely to have side effects or tolerate it well, and there's a couple of gene loci I know that can tell whether or not a person's less likely to respond to the whole class of SSRIs.

So, it's not black and white. It's not an absolute science, but I think if a patient says, "I just want to increase my chances that I find a better fit for a medicine." Aside from some trivial costs, they're not too expensive these days, but aside from the cost, I mean, there's no harm in doing it. You and the prescriber might get more information that leads you to a better choice for an antidepressant or a mood stabilizer. But I don't think the science is so specific yet to say: "Ah, if you take this, this will resolve your depression, certainly.

Dr. Gladden: Yeah, no. That's right. It's not an absolute, but it scooches you in the right direction. I think sometimes it can scooch you away from the wrong decision too, which also has value because you can spend six weeks on this drug and six weeks on that drug and six weeks on a drug, and the next thing you're six months in and nothing is working. So, I think that can be helpful too. But it's interesting.

So, in your approach, you understand obviously very well... I'm just restating something here, that really depression and anxiety and things like that, to some extent, are genetically driven. Some people have more of a predisposition, but they're also environmentally driven. And so, it sounds like, in your work, you're focusing a lot on the environment. I don't know if you're doing genetic testing to look at who's prone to depression or anxiety or things like that. Is that something you do too, or is that more of an adjunct thing?

Andrea Turnipseed: Well, we do ask about your history if you have any family members with those things, which helps. And then, we do focus on what you are doing in your lifestyle that's contributing factors. So, that's the environmental factors which might be... We do a screening with your social media use or your media use, and there are people that are using social media eight or nine hours a day, and they're depressed. And so, it's not surprising. So, those are things that we can talk to them about changing and optimizing, working, and setting boundaries with toxic people or work or getting out and getting vitamin D, all of those things we do screen for and ask in addition to like: "Do you have any family members that have ever had depression?"

Dr. Gladden: So, when I think about social media or our phones in general, even texting for that matter, there's a dopamine hit. It's like... And sometimes, when I pick up my phone, it's like: "You know what? I need a dopamine hit right now. I'm just going to go see if this person texted me or whatever.” And I think we probably all do that. And yet, what I hear you saying, and really tell me what... if I get this wrong, but if people are on it nine, 10 hours a day, and maybe it's driven by this desire for those dopamine hits on some level, but maybe they're burning themselves out and ending up disconnecting themselves socially from people when they think they're actually connecting in some way. Talk us through that a little bit. What's actually happening to them?

Andrea Turnipseed: Go ahead.

Brent Turnipseed: One thing I would say is, okay, there are plenty of people that could be on their screens or social media several hours a day and not be depressed. But if you're talking about a person who has depression or has a mood condition or an anxiety disorder and they happen to be using social media to an excessive amount daily and that population with that person, then you might say: "Hey, maybe we might consider reducing your social media use. Maybe it's time for you to get out of the house, get sunshine and actually see real people in real life. So, it's like obesity too. You could have plenty of people who are overweight or obese, and they're not depressed, but if you have a person with depression who also happens to be obese, I'm probably going to quickly focus in on that obesity. I want to find out if they have chronic inflammation. I want to find out what are these contributing factors to why they ended up in our office in the first place with depression.

Andrea Turnipseed: And the question you asked was, like chicken or egg, which comes first? And maybe they were depressed, and they were using social media for a dopamine kick, but it's not a sustainable or healthy dopamine kick. We need to find more natural ways to get your dopamine or your serotonin up. So, we don't know. But if they're coming to see us, then there are a number of things that we could work on optimizing to make their depression improve.

Dr. Gladden: Right. So, Brent, you brought up an interesting point about inflammation because when we talk about paradigms and understanding for things like depression, I've read in numerous places that neuroinflammation is associated with depression. In fact, it's one of the key underlying mechanisms of depression for some groups of people, let's say. And so, in your practice, how do you actually go about assessing that or treating that or going after that, if you will?

Brent: Yeah, no, that's good. Fortunately, there's been a lot more focus in the last decade in our field on inflammation. So, most people think of inflammation; they think of getting an injury like I stubbed my toe, I stepped on a nail, and it's all red and swollen. That's inflammation, right? But we're talking about low-grade chronic inflammation that can be typically caused by a sedentary lifestyle, poor diets, or underlying autoimmune conditions like diabetes, heart disease, et cetera. The controversial question is: how do you best assess for that? I think there probably is not a complete agreement in our field on how to do that. But if you chase the evidence, if you look at articles on PubMed, you know what inflammatory markers seem to correlate most commonly with depression. It tends to be CRP C-reactive protein, some of these other inflammatory cytokines. So, for the listeners, these are molecules that our immune system kicks off in response to inflammation.

So, cytokines like things called tumor necrosis factor-alpha and interleukin one beta, these things are floating through our bloodstream, and they can easily cross what's called the blood-brain barrier. So, they get into the brain, and they can wreak havoc and cause damage to our neurons, and our brain is just not going to work as well.

So, we can do blood draws, we can look for CRP, we can look for these other cytokines, and if they're elevated, then we can talk to the patient, say: "Hey, you've got some good evidence that you've got inflammation, probably, of chronic nature." And so, then, we're going to tailor treatments and recommendations to things that'll hopefully help reduce that inflammation. Some in terms of what medications we might recommend, but others may be a diet change, maybe getting more active walking, things like that.

Dr. Gladden: Yeah, I think that's a good approach. I think neuroinflammation is interesting because aging itself is comprised of increasing mechanisms of inflammation. And so, elderly people are going to be running, typically. I have a tendency to run higher CRPs. And when you end up with senescent cells and the secretory status of senescent cells are, they're elevating TNF alpha, TNF beta, interleukins, et cetera. And so, we end up, as we age, swimming in a sea of inflammatory cytokines, altered intracellular communications, and other contributors to that. And inflammation itself is now one of the currently 14 hallmarks of aging. There was a 15th just added last week. So, do you see in your population that as people age, that they're more prone to depression with this swirling inflammation that's going on? Or do you find that that's not necessarily the case?

Brent Turnipseed: I think it's the case. I wish we had a good battery of tests that everyone could agree on. I wish the science was there for prime time. It would be much more easy to assess and diagnose our patients and give targeted recommendations.

I think now we're just beginning to put the pieces together. But undoubtedly, when you mention inflammation and aging, I mean the first thing that pops into my mind is Alzheimer's, which is the byproduct of a debilitative chronic inflammatory process. So, I mean, these cells are being damaged by all things that contribute to that damage.

One thing I would add to this conversation is now there's a book that came out recently by Chris Palmer, a psychiatrist at Harvard, called Brain Energy. So, on top of the inflammation model, there's this thinking that a lot of brain illness and mental illness may stem from mitochondrial dysfunction, so inflammation may negatively affect mitochondria.

So, long story short, I mean, it's a fun time to be in psychiatry because when I first started my career 15 years ago, we had no idea about almost any of these things. And it felt like a somewhat mildly hopeless endeavor to treat depression because our tools were so limited. And now, it's nice to tell patients at least: "Hey, we have an idea what's going on at a microscopic level or a cellular level of why you're feeling so bad. Sure, there might be psychological reasons, but there are also some actionable biological reasons we can talk about."

Dr. Gladden: Yeah, that's really interesting. We're actually doing something here in the clinic called Brain Frequency, which is a modified form of transcranial magnetic stimulation to reboot the brain. And one of the things that we're doing with the sessions is using molecular hydrogen because it actually depletes the brain of energy and it creates an oxidative stress. It's almost like exercise for the brain when you're putting it through the treatment program for 20 minutes or 30 minutes. And the other thing we're doing is we're giving NMN precursors. So, NAD precursors, like NMN and some other things to, actually boost energetics into the brain. And that seems to be actually improving the outcomes that we're getting because we're trying to get at that mitochondrial piece, balancing the oxidative stress through the hydrogen, and then boosting NAD to boost energy production. So, anyway, we're in that space, trying to figure it out to some extent because I think this is how things get done as you figure them out. Do you guys use anything to boost ATP production in the mitochondria currently? Is that part of your regiments or something you're thinking about, or what's your take on that?

Brent Turnipseed: Yeah, I mean, I know there are probably many things I'm not thinking of, but off the top of my mind, we certainly could recommend precursors to NAD. We could recommend things like CoQ10. We could recommend any of the B-vitamins whereas which are essential for brain function.

The quickest side about NAD. So, NAD an interesting little side story. We're not using it as a treatment in our clinic, but there are several niche clinics around the country that treat substance use and addiction using [inaudible 00:20:15]-

Dr. Gladden: Yes, using IV NAD.

Brent Turnipseed: That's right. And I've had several clinics approach us, saying: "Would we partner with them or recommend their services after patients have ketamine therapy with us?" And the little evidence you can find online or on PubMed, which is very, very little, seems encouraging, but no one's done clinical trials to my knowledge in the last 20 years on NAD for any mood or addiction condition.

So, I mean, considering what we just said about mitochondrial function and how that relates maybe to contributing factors of brain illness, I'm starting to wonder if this could be a fun clinical trial where I can see why patients gravitate towards it. Reportedly, most people feel much better after getting a NAD infusion.

Dr. Gladden: Yeah. Our take on that is, and we've been working with some people to actually measure NAD/NADH levels out of the University of Georgia. So, we can actually measure NAD levels for our clients. And what's interesting is that they just did a trial, a small trial, looking at the benefits of IV NAD versus the precursors like NMN to boost NAD. And what they found is that if you get IV NAD, they're actually measuring both extracellular and intracellular NAD levels, and they're finding that when you get IV NAD. The only thing that ever elevates is the extracellular NAD. It does not increase. NAD itself does not increase intracellular NAD, which is fascinating. And the NAD is broken down very quickly, and some of the breakdown products, adenosine, and some other things seem to be modulating the benefit.

And I think NAD itself can be a neurotransmitter, if I'm not mistaken. And so, there's some benefit there as well. But if you're really trying to improve the energetics of the neuron, I think it's getting intracellular NAD that you're probably going to be after. So, I think using an enamine molecule, maybe with some other molecules attached to it to improve efficacy, could be, quite honestly, a better way.

That being said, in my reading of literature, too, it seems like people that are in real trouble, post-COVID, alcohol addiction going through withdrawal. These people that are in deep, I would say, seem to benefit from the NAD infusions, but we've really shied away from it in the longevity space because we just don't think it has that much benefit. We think there are better ways to go. So, anyway, that might be helpful to you as you think through what you want to do or don't want to do in your own trial there.

Brent Turnipseed: Yeah, this is a novel area of our field now. And, like I said, this book that just came out is just beginning to put the pieces together and touch on it. So, hopefully, in the next five years, we'll see much more movement or evolution in this part of psychiatry and brain health.

Steve Reiter: This episode of the Gladden Longevity Podcast is brought to you by H2, molecular hydrogen in the Gladden Longevity store.

Dr. Gladden: Yeah, Steve, you've heard us talk about this numerous times on the podcast in terms of the benefits of H2 and hydrogen water. We love it. It's really the best way to balance your entire redox system, so it really protects you from free radical damage. I take it every time I get on a flight to protect me from radiation damage when I'm flying, and I use it to rejuvenate my brain in the afternoon.

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So, you brought up ketamine. So, let's talk a little bit about ketamine because that's a hot topic. A lot of people are... we've talked about the fact that the traditional paradigm and the traditional medications available don't really necessarily accurately either describe or treat what's happening and so, in comes ketamine. So, talk to us a little bit about ketamine, your experience with it, and how it's been working.

Andrea Turnipseed: Yeah. So, we got introduced to it about five years ago. And we just gave it a shot as something that might be helpful for our patients with depression, and we paired it with therapy. And it seems to be very effective about 60% of the time for people with treatment-resistant depression, which is huge considering what Dr. Turnipseed just said, that 30% of traditional antidepressants work.

So, we offer it here with doing therapy, and we also have it without therapy for those people that can't afford it with therapy. And it helps get people into that next phase of taking care of themselves and their mind and body with the suggestions that we have about reducing your social media, adding exercise and cutting back on drinking, things like that.

What it does is it's a catalyst for change, and it can help improve mood for the long-term and help them get off of their regimen of several medications, maybe down to one or two or none at all if they're coming in for regular ketamine treatments. So, it's been very helpful for the people that it works for. Now, it doesn't work for everybody. We have to put that out there, but when it does work, it's a really helpful tool in this field.

Dr. Gladden: So, when you talk about doing ketamine with therapy, I assume you're talking about regular counseling or psychotherapy or something of that nature? Is that what we're talking about?

Andrea Turnipseed: Yeah, we start with a preparation session where the therapist and the client meet together and talk about what their goals are and get to know each other, and make sure that they understand how ketamine is going to work for them and what the expectations are. And then they come back for their future sessions, which is about six to eight sessions over three to four weeks. And then, we go into maintenance after that, and the therapist is with them during their session and ketamine...

Dr. Gladden: So, you're doing ketamine twice a week for about four or five weeks, six weeks, is that what you're saying?

Andrea Turnipseed: Twice a week for three to four weeks, yeah.

Dr. Gladden: Three to four weeks. Okay.

Andrea Turnipseed: It depends on the person, and really that's ideal, but given people have jobs and need rides and things like that, it doesn't always work as beautifully as that. But when they come for their sessions, the therapist is there with them, and we help set an intention, and the room is dark, and there's music, and we have eye shades, and the therapist there is there to guide them and help them feel safe, and remind them of anything that maybe they wanted to talk about, but also to ask questions and to record on paper what happened throughout the session. And ketamine generally takes about 45 to 55 minutes for the intense feelings of it, and we block about two hours. So, the second hour is really integrating what just happened or what you just experienced and finding meaning with your therapist. And so, depending on what you're working through, you might have just had an experience that was just calming or meditative in nature, and there may not be that much to talk about.

However, your defenses are down a little bit after doing or receiving ketamine. And so, you might open up a little bit more and get a little bit deeper in your traditional therapy.

On the other hand, you might have an experience that's mind-blowing and really crazy that you saw a dead loved one and you connected with them on a cellular level. And so, we can talk about that, and what that feels like and what you're going to take from that, and how are we going to make changes in our life. And so, what we typically see when somebody comes in and maybe they do two or three sessions, and we're at a good dose, when they come back for their future sessions, they might say: "I actually signed up to join a gym for the first time in three years," and then they start working out. Or: “I called back those friends that have been reaching out, and I set up some dates with them.” And so, it's those little changes that start a snowball effect for bigger changes. And so, that is what's nice about the ketamine for many people in the therapy because the therapist can then reflect that back to the client and saying: "I know you may not be feeling 100% better, but I see you doing 90% better."

Dr. Gladden: So, it's kind of breaking up a log jam that's held them back, if you will. And it's a chance to break through that enough to get a trickle of water going through. And then, you can start to turn into a stream and then a river, hopefully, as the concept, I think.

Andrea Turnipseed: Yes, I refer to it as breaking up the scar tissue. And so, then that way, break up the scar tissue where we've had these patterns in these negative automatic thoughts or behaviors that are not serving us for so long, and we break that pattern up, and then, we can start to integrate these more positive lifestyle changes.

Steve Reiter: So, I assume most of our listeners probably understand what ketamine is, but for those that don't, what is it? How does it work, and why is it proving to be effective? And why wasn't it used 20, 30 years ago when I was in college, in high school? I never heard about it.

Brent Turnipseed: Okay. Okay. No, good. Yeah. We should...

Dr. Gladden: You went to the wrong school Steve, apparently.

Brent Turnipseed: No, it's good. We should speak about some fundamentals. So, ketamine has been around. FDA approved it in 1970 for general anesthesia, so it's an anesthetic. And it wasn't until the late '90s that researchers started getting curious about its mechanism and how it might be used or repurposed for other means in healthcare. And so, researchers at Yale University in the late 1990s, for reasons I won't go into, decided maybe ketamine might be useful in treating depression. And so, they did a trial in 2000. They gave eight patients with refractory depression a subanesthetic dose of ketamine, half a milligram per kilogram infused over 40 minutes, and four of them, within a day or so responded, had a significant response to their depression, which was unheard of because the, first of all, over half of them improved, but the people improved in such a rapid fashion that never happens in our field, minus shock therapy, which most people just aren't signing up in drives to do. So, that [inaudible 00:32:07]-

Dr. Gladden: I actually heard an interview with the guy that ran that trial, and I forget his name, actually. He's a guy on the East Coast that ran that trial. And what was funny was that when the clients came back the next day and said they felt better, they were initially dismissive, like: "Well, you couldn't possibly feel better. I mean, what do you mean you feel better? What does that even mean?" And then, when they came back a couple of days later or whatever: "Yeah, we actually feel better." It's like: "Well, really? You can't feel better. How can you feel better already?" And then, they couldn't believe their own results, which is interesting. So, it just goes to show you what our preconceptions will do for things.

Brent Turnipseed: That might have been John Crystal. So, John Crystal is currently, he's the chair of psychiatry at Yale, and he was one of the lead researchers on that early study, and he speaks a lot about ketamine still.

So, how does ketamine work? Why are we using it in our field? So, it's unique. It's different than anything else we prescribe. It's what we call an NMDA receptor antagonist. So, it blocks receptors in the brain called NMDA receptors. Those receptors modulate a neurotransmitter called glutamate. So, there are all these downstream effects. But the take-home point for listeners to know is that ketamine leads to a surge of what's called BDNF, brain-derived neurotrophic factor, and BDNF causes synaptogenesis. So, when people have chronic stress, chronic depression, the synapses we've been alluding to in talking about with things like inflammation, the synapses, the ways that the junction in which one nerve cell communicates to another, those synapses are not healthy, they're not working properly, and ketamine leads to new connections forming in these synapses.

But ketamine also is powerful; I don't know if people use this label, but I would call it this, ketamine is a powerful immunomodulator. It's leading to a powerful suppression of most of those inflammatory cytokines we just mentioned. So, if you have elevations of CRP, tumor necrosis factor alpha, and studies already have been done looking at this, it's going to potently reduce those cytokine levels. So reducing neuroinflammation. But the other part about what you alluded to, Dr. Gladden, is changing the script when people are stuck, ketamine, and some interesting studies have also shown this. Ketamine allows you to change what is called maladaptive memories.

So, we have kind of neural circuits in our brain that get wired after certain kinds of experiences, whether we're learning something or it's something traumatic, what have you. Well, we've got a script in our mind when we're depressed often that says: "I'm a terrible person. No one loves me and this is why”, right? Well, these are called maladaptive memories, and those behaviors and memories can lead to unhealthy behaviors like substance use or alcohol abuse.

Well, you get ketamine with psychotherapy, and if the person has the intention, "I want to get better, I want to stop drinking," you actually have the ability to wipe the script clean and write a new script, form a new circuit, form a new mix.

Dr. Gladden: So, it's really an increasing neuroplasticity. It's what we're talking about, right? When the BDNF is increasing the ability to create new synapses, which is going to be critical for rewriting the software, if you will, to get this new perspective.

Andrea Turnipseed: And that's why the therapy is important to be together because you have this critical time where we can make an intervention and start making [inaudible 00:35:32]-

Dr. Gladden: When they're neuroplastic and receptive, is what you're saying, because of the increase in BDNF. Okay, nice. And what about glutamate? Glutamate itself is a neuroexcitatory transmitter, if I'm not mistaken. Does that do anything on the depression side, also?

Brent Turnipseed: No. So, it's more complicated than that. You're right. So, if there's too much glutamate in the space, like floating around in our bodies, glutamate can be neurotoxic, and it can be harmful. And so, we just know that ketamine ends up flipping on and off switches changing the flow of glutamate, but all that really matters is the downstream; it leads to a surge of mTOR, mammalian targeted rapamycin. The mTOR stimulates the BDNF. The BDNF stimulates the synaptogenesis.

Dr. Gladden: Okay. So, there are other things that stimulate mTOR, any kind of anabolic growth hormone, growth hormone releasing peptides, testosterone hormone, replacement therapy, all those things will also activate mTOR, weightlifting, blood flow restriction, weightlifting training, and things like that. Interval training it's been shown to increase BDNF. So, I suspect all those things on some level would be helpful. It's just that ketamine you can stick in a vein, and in 40 minutes, you get to where you want to go to some extent. So, yeah, very, very cool. So, what about the people that don't respond, and then what about negative reactions to it? What's the full gamut of what's happening there?

Andrea Turnipseed: Yeah, the people that don't respond, I mean, there are people; what is nice is we are a psychiatric clinic, and so, there are other tools available to us to try different things and make other referrals. There's TMS which you mentioned before, or therapy, and other things. So, we don't give up on them if ketamine doesn't work. Negative reactions... If you have a therapist with you, hopefully, we can... there's no negative reaction, it's just a reaction, and we can understand why did that come to us and make sense of it with you.

If you are doing ketamine alone or without a guide, it could be scary, it could be traumatizing if something were to come up because I don't know if we mentioned ketamine can be psychedelic. It's not psychedelic in the sense that the walls are moving in on you, it's that we put an eye shade on you, and your mind is coming up with visions and things that you [inaudible 00:37:55]-

Dr. Gladden: Imaging his visions.

Andrea Turnipseed: Right. So, you have strong visuals; the sound is different for you. And so, that's why we keep the music. It's a non-lyrical music going. You go through different phases. And so, if you were doing that alone, you might get stuck in a scary spot where maybe you feel like you're going down into a deep dark hole. If you have a therapist there and you might say ‘help’, and the therapist can help you get out of that or to understand it better. And so, if you come out of that... And most people that do ketamine therapy sessions, and if you might label it negative, they still come back because they got something out of it. The health negative reactions maybe, I mean, you might speak to that if there were any concerns, physically.

Brent Turnipseed: I mean, the main contraindication to receiving ketamine is unstable cardiovascular disease. So, unstable high blood pressure, recent heart attack or stroke. Most people tolerate ketamine very well. It has an excellent safety record. It's been around for 50 years. That one benefit is that we know a lot about what works and what doesn't and the shortcomings and limitations of ketamine, but most people feel fine. We haven't mentioned dissociation, so we hinted that it's got these psychedelic effects. So, what do we mean when we're saying that? We mean that it's changing your perception of how you interpret yourself in the world. You feel like you might be transported somewhere else. You know you're at Roots Behavioral Health on one level, but your mind is saying: "I feel like I'm actually floating out in this deep blue space void," and occasionally seeing images of familiar things like people I know or geometric shapes even, or trees or what have you.

People feel like they've become objects, which is common with psychedelics. You can see colors, and the sounds can become richer. So, there's music which guides the experience. The music seems richer because ketamine apparently lights up the auditory cortex. So, it's a very interesting experience. But some people, when they dissociate, when they feel like they're disconnecting from their physical body, some people get the sense that they are teetering on the edge of not existing anymore.

And so, when I say that, that means, some people are worried that they might be about to die. And so, if you feel like you're about to die, that can be very frightening, very, very panic-inducing. So again, if you have a therapist right there to reassure you and say: "You're doing fine, you're on ketamine, you're at Roots Behavioral Health”, you can quickly reassure people. But if people are alone and don't get that reassurance, they might spiral, and they might start screaming and think, "I'm alone. I'm dying. This is terrible. Make it stop," which is a side topic. There are a lot of companies now really marketing the use of at-home ketamine without any direct support or vital signs checking at home. And this all began during COVID. And while we're all about access to care, I don't think ketamine is the right medicine for most people to be taking at home unsupervised when you're dissociating and very confused.

Dr. Gladden: Maybe you can clarify this for me, but I've heard that there's addiction potential for ketamine also, that people can like the effect of it and then do it again, but it takes more to get the same response, and people can end up using some very high doses of ketamine on a pretty regular basis trying to... I've just heard this a little bit anecdotally, but I think there is potentially some addiction potential with ketamine that probably isn't there with things like psilocybin or even LSD or some of the other psychotics. Maybe you can speak to that. Maybe I'm right or wrong; I'm not sure.

Brent Turnipseed: No, no, you're right. So, ketamine is classified as a schedule three controlled substance. So, the federal government recognizes there's some risk and danger of misuse. Is it on the level of things like cocaine causing direct cravings? Probably not, but it does seem like at least what we've observed is if we've ever talked with patients who had at-home ketamine prescriptions from other clinics like ketamine nasal spray or ketamine lozenges, yes. For many people, there's this temptation that "That felt good. That was kind of a fun experience. I'm going to try three squirts or four squirts in my nose instead of two, and I'm going to try it two or three days in a row instead of once a week." If there are safeguard rails around the dose and use, the evidence says it's low risk and fine. But again, if you put it in the hands of people and you don't have these guardrails, there's a temptation for some people to misuse it, and it absolutely can be addictive. So, if they're only receiving their treatment with a therapist or under supervision in a prescriber's office, that risk is significantly mitigated.

Dr. Gladden: Yeah, I think if you're a listener, and you're listening to this, I think ketamine is something that can be extremely helpful, but I think you want to do it in a controlled setting. I think you want to have people around you that can assist you when you need them, people that can help you process what comes up, people that can keep you safe, et cetera. And you don't want to put yourself in a situation where you would be potentially exposed to its addictive potential where you're controlling the trigger, right? I think that would be the safe way to go about it would be to do it with people like the Turnipseeds here. So, yeah.

Brent Turnipseed: We strongly feel that's best practice. Again, I understand why many companies are trying to scale operations and reach thousands of people and just mail them all ketamine. I get it. You want to treat the depression, which has become an epidemic like we've talked about, but I feel like that's probably not the best way to treat most people. And for the docs and the clinics that do have good ketamine clinics or clinics that offer ketamine that are following best practices, they may be undermining the ability of us to offer this medication to people. I mean, the worst case scenario is that the DEA or the federal government restricts ketamine's use, which it has a good use, it has a good purpose for many people, and I'd hate for people who do need ketamine to have that possible