Dr. Sherry Walling - 0:00:09
There's a lot of excitement and anticipation about FDA approval for psilocybin and MDMA, but one medication that is already approved that sometimes gets overlooked is ketamine. Earlier on in the season, we had a few episodes in which we talked about ketamine-assisted psychotherapy. But today, our conversation centers around ketamine as in some ways, kind of a standalone experience. Ketamine administered as an infusion, so not administered in the context of an in-session psychotherapy intervention. My guests are Dr. Steven Mandel and his son, Sam Mandel, who is the COO of the business that they share.

Dr. Sherry Walling - 0:00:46
They run the Ketamine Clinics of Los Angeles, and throughout the years, Dr. Mandel has overseen 13,000 ketamine infusions, so their team is well acquainted with the research and the clinical application around how ketamine infusions can help support those who are looking for more resources and different solutions for mental health distress. As always, please remember that this conversation is not intended to be medical or legal advice. It is an interaction between curious minds. We invite your curiosity in this conversation and welcome your feedback, your questions on any of the MINDCURE social media channels, as well as at mindcure.com. Thanks for listening and let's dive in.

Dr. Sherry Walling - 0:01:31
Well, what a treat for me is to get to spend the afternoon with Dr. Steven Mandel and his counterpart and son, COO, Sam Mandel. I would love if the two of you would just say a little bit about your background and how you come to this conversation around mental health and psychedelics.

Dr. Steven Mandel - 0:01:56
Okay, I'll start if you don't mind, Sam. I'm Dr. Steven Mandel. I'm a physician. I was in graduate school in clinical psychology. I had completed four years. I've done all of my clinical work and all of my coursework and all of my major qualifying exams. I was writing my dissertation when I had the opportunity to go to medical school, and I thought that was amazing, and I went and everyone knew I was going to be a psychiatrist.

Dr. Steven Mandel - 0:02:15
But you know what? I became an anesthesiologist and I was board certified. And I did anesthesiology for 30 years quite successfully, working with a medicine called ketamine, which was at that time among the most widely used anesthetics on Earth. And I'll tell you more about ketamine, but I wanted to introduce my partner and co-founder and son and Chief Executive Officer or Chief Operating Officer. Anyway, Sam Mandel. Go ahead, Sam.

Sam Mandel - 0:02:53
I have a really eclectic mix of my background and in particular where mental health is concerned. I have a lot of experience with friends and family since I was young who have suffered from issues with suicide, depression, addiction, and just growing up around it a lot was naturally very interested in it. And I volunteered for Teen Line when I was 12 or 13 years old, which is a suicide prevention hotline teen-to-teen, and that was my first kind of even semiformal training or experience and learning how to support people who are going through a crisis. And I found it very gratifying and I found it very useful in my personal life, and over the years, worked in a lot of different spaces, but always maintained an interest in it. And in the last eight years, I've had the privilege of working alongside Dr. Mandel and serving this community here in LA, and it's been quite a ride.

Dr. Sherry Walling - 0:03:46
So, the two of you run the Ketamine Clinics of Los Angeles and just for a sense of scope, give me a little bit of how many clinics do you run? How many ketamine treatments are you offering in a-- in a year for example?

Sam Mandel - 0:04:01
Yeah, so we've-- we opted to move into a larger space several times instead of opening up multiple locations for a lot of reasons just as far as quality control, logistics of management. There were competitors who were opening up, you know, large chains throughout the country that ended up folding first, compromising on the quality of their care and then completely going under. So, we didn't want to do that, and we were-- we're very dedicated to doing this with a high-- high level of attention to detail. So, we started out in literally an 8x8-foot closet that we were subletting from another doctor where Dr. Mandel and I worked together, and we had a small recovery room adjacent to this closet that patients were treated in. And then we got our own space in Brentwood, which was 1700 plus square feet, and we moved into our current space about three years ago, which is 3600 square feet, and it's a purpose-built facility that's really premier for this use. And now, we're expanding into the adjacent space next door to us to be about 5000 square feet, and that will probably be the final push. The 5000 is a lot in one space and a lot of people.

Sam Mandel - 0:05:04
We have 12 full time staff. We're adding several more in the next month. We'll probably have a team of 15 before the year is over and in one location, 15 in 5000 square feet. We kind of have to take that leap to an additional location sooner than later. And as far as volume, we've done almost 14,000 infusions in the last eight years.

Sam Mandel - 0:05:28
It's been really, really wonderful.

Dr. Sherry Walling - 0:05:32
Well, congratulations on the business growth. It sounds like you're really finding an area of need within the community that you serve. Tell me about the transition from anesthesiology to ketamine. What is it that ketamine is offering to the world that is-- is making it so easy for you to expand your space and really serve so many people?

Dr. Steven Mandel - 0:05:54
So, ketamine is an amazing anesthetic. It was approved by the FDA in 1970. I used it extensively in anesthesia in the 90s. It also became known as a-- or discovered to be a lifter of mood and reversal of the symptoms of PTSD. This was totally counterintuitive. Nobody ever thought of that, and it's not what you expect from an anesthetic.

Dr. Steven Mandel - 0:06:17
Now, just parenthetically in the 80s in another world, Krupinski in Moscow was doing hardcore alcoholics with ketamine. Again, a behavioral indication and having amazing results, which nobody ever noticed because it was Soviet Moscow. Anyway, he's still around, he still does good work. So, I was an anesthesiologist. I had a mobile anesthesia practice surgery, a transition from the operating room in the hospital to outpatient surgical centers.

Dr. Steven Mandel - 0:06:44
I hit it just right. I was very pleased with my mobile anesthesia service. It was thriving but I loved the psychology. I was so very interested in mood disorders, and when I learned the ketamine, which had been discovered for this purpose in the 90s, was actually being validated (inaudible) in 2006 at the National Institute of Health. He took treatment-resistant patients, patients who had not succeeded at any of the other what were considered proper treatments for depression, and he treated them with ketamine and 71% of them were relieved of their depression.

Dr. Steven Mandel - 0:07:24
Well, you take a treatment-resistant population and you have a 71% success rate, it's like, "What the heck is going on here?" That was in '06 and more and more studies were done, but it was just very slow going, and nobody really believed it. In '14, Thomas Insel, who is head of the National Institute of Mental Health at the time, said ketamine is the biggest breakthrough in depression in 50 plus years. Now, Insel is a really serious mainstream psychiatrist and for him to say that, oh my goodness, I gotta try this, and we had some friends and patients who knew people who were-- anesthesia patients who knew people who were depressed or suicidal. You know what? It's the biggest cause of disability in the country.

Dr. Sherry Walling - 0:08:17
In the world, yeah.

Dr. Steven Mandel - 0:08:17
People who are depressed or suicidal. I'm-- I'm smiling while I'm saying it, but it's not funny. It's the biggest problem we have in health in America. So in '14, treating people with ketamine was like really fringy, really crazy, but I had all these data, and I had the tacit go-ahead (inaudible), and I started doing this as freebies in the afternoon in an anesthesia recovery room. And I was so pleased with the results. They were so amazing to see people really transform, and I love doing anesthesia, and I'm good at it.

Dr. Steven Mandel - 0:08:45
But you know what? Anesthesia is facilitating other people being therapeutic. This was being therapeutic.

Dr. Sherry Walling - 0:08:59
Yeah, and it's hard to dispute some of the research efficacy around ketamine and the way that it performs in helping people to feel better. Why do you think we're not sort of seeing ketamine on the front of every newspaper? Like why is this breakthrough kind of in the underground? 'Cause you know I have a PhD in clinical psychology, and I will tell you that my training did not include much conversation about ketamine at all. So what happened?

Dr. Steven Mandel - 0:09:28
Why would it? I mean, come on, first of all real life, we get our drug information. We physicians and we citizens from the people who sell it. The pharmaceutical houses, they give us information about what they have for sale that's profitable. Ketamine is a commodity item. It is not profitable to produce.

Dr. Steven Mandel - 0:09:48
They produce it in very large quantities because it is still among the top ten anesthetics in the world. But there's no one pharmaceutical house that produces it-- at least half a dozen produce it. It's produced widely. It's a commodity item.

Dr. Sherry Walling - 0:10:08
It's sort of cheap, it's-- it's everywhere. It's easy to produce. Everybody makes it.

Dr. Steven Mandel - 0:10:12
Now, if you could sell something with a really, really infinitesimal markup or if you could sell something with 100% or 200% or 300% markup, and if you're paid on how you did this quarter compared to how you do last quarter, what would you be selling, Sherry?

Dr. Sherry Walling - 0:10:29
I'm going for something where I can make bigger margins, Dr. Mandel, as a businesswoman. But as a healer--

Dr. Steven Mandel - 0:10:35
Oh, forget about being competitive. If you want to keep your trouble in the pharmaceutical industry, you're gonna move the high margin stuff or you're gonna lose your job.

Sam Mandel - 0:10:44
Yeah, and one thing that, you know, as far as ketamine being cheap, I mean, that's a criticism that we get from some people who don't better understand what it is that we're providing as well, and ketamine the medicine is cheap, but we're not selling ketamine. We're providing a service. And it's a-- it's a white glove concierge level, pretty complicated service to actually do in a very safe and comfortable way. So, you know, the medical team that has the knowledge and experience and the training and the facility, like any business, we have brick and mortar. We have rent to pay.

Sam Mandel - 0:11:11
We have an internet bill. I mean, we have costs, right, of providing this at a higher level and in a safe environment. But ketamine's patent is up and it's an off-label use as well in addition to being cheap. So, for people to understand that, you know, when a medicine is approved, it's approved for specific indication for a specific population. Ketamine is approved as an anesthetic, but it's off label for depression, and it's very common for psychiatric medications to be prescribed off label. About one in three of all psychiatric medications are prescribed off label in the United States.

Sam Mandel - 0:11:36
It's a very common practice and just means that there's good basis to use it for an indication other than what it was approved for. But that's another reason why insurance companies are not covering it. As they say, "Oh, it's experimental, it's not proven," so there's a lot of politics involved. And as you're mentioning, you know, as a healer and as somebody who's compassionate and who wants to help others, it seems, you know, insane. Our system really isn't set up by the compassionate healer.

Sam Mandel - 0:12:08
It's set up by the dollar. It's unfortunate and it's starting to shift because the evidence and the results are so overwhelmingly positive, and the need is so overwhelmingly great that you're seeing like Blue Cross in Massachusetts starting to cover ketamine. And that's going to become more common, I think, throughout the country, but it's been a long uphill battle.

Dr. Sherry Walling - 0:12:33
Would you walk me through kind of the best practice of ketamine treatment? What does that look like from the patient's perspective, for someone who's thinking, "Oh, I've tried a couple other things. It's not working for me. I'm-- I'm ready to try ketamine." What is-- what does that look like in the-- in the best possible case? And I asked it this way because at least in my community, I live in Minneapolis, and there's a lot of sort of ketamine clinics that have popped up around the community.

Dr. Sherry Walling - 0:12:54
And I think sometimes it's hard for the consumer to know the difference between high-quality care and a place you can go for an afternoon that gives you ketamine and you kind of go home and there's not maybe the follow through that you would like.

Sam Mandel - 0:13:14
Yeah, I'll let Dr. Mandel start and I think we can kind of bounce around back and forth on that one 'cause that's quite an extensive list, I think, that we have here, as far as best practices and super important.

Dr. Steven Mandel - 0:13:24
But that's the heart of the matter. Ketamine is transformative and it's wonderful, and it really is an important healing agent for depression, for suicide, for PTSD, for postpartum depression, for eating disorders, for OCD, for anxiety. It's just remarkable. I'm leaving ketamine now for pain, so if you have one of these afflictions, most of the sufferers that we see are people who are depressed. Either they have major depressive disorder, or they have bipolar disorder, and they're depressed type ones, or they're type twos, and they're primarily depressed. They spend a little bit of time being manic or hypomanic, but they're depressed, so a best practice.

Dr. Sherry Walling - 0:14:05
Yeah, just tell me about how you do it, and why you do it the way that you do it because you believe it's the best practice.

Dr. Steven Mandel - 0:14:12
We qualify patients in advance without any inconvenience in their travel and without any charge to that.

Sam Mandel - 0:14:22
If I could jump in maybe and just clarify what it means to qualify patients, I think, you know, as far as the-- for those who are listening, what does that mean? What does that look like? I think, you know, we-- we have a wonderful carry team, just like really, similarly basic stuff about a business in general, any business. Like when-- when someone calls, we pick up the phone during business hours. I can't tell you how many, you know, places don't do that nowadays.

Dr. Sherry Walling - 0:14:42
That's kind of a radical idea these days actually.

Sam Mandel - 0:14:44
It's like, do I-- do they pick up phone? Is there someone who's kind and professional who answers? Do they-- are they able to answer your questions? Do they treat you well? Like really basic stuff, at least it should be, and it seems like it's a harder thing to find nowadays than it used to be. But beyond that basic stuff, our team really understands the treatment and-- and patients needs.

Sam Mandel - 0:14:59
And they're-- and they're happy to spend as much time as-- as the prospective patient or the caller needs to understand the treatment. If they're a right fit, then we schedule an actual medical intake with somebody for our medical team by phone. Another consultation that's free by phone. To review the treatment history, we get a medical release from the patient, so we can speak with their other treating providers. And we actually check in with that provider and do an intake with them. All again at no charge to understand the patient's treatment history, their needs, if this is a good fit for them, answer the provider's questions 'cause many providers actually don't really know a lot about this treatment even in mental health.

Sam Mandel - 0:15:30
So, we help to educate them, the prospective patient and then also get background to assess if they're a good fit. And we go through this, all before anyone ever steps foot in the-- in the door. We don't do walk-ins. We don't do-- sure if you got a credit card that works, come on by. That-- these are huge red flags that more and more clinics are operating by that is concerning.

Sam Mandel - 0:15:52
Also, you look at the training of this and the staffing model. There's a lot of solo providers out there. There's nothing wrong with being a solo provider, if you have integrity and you're qualified, but we feel with at-- at very soon after a certain level of volume, you need to be able to have a team environment, and you need to have a variety of backgrounds in order to provide this at a high level. And that includes people who have an emphasis on mental health, if you're treating mental health. And also people who have a medical understanding of ketamine as an anesthetic.

Sam Mandel - 0:16:23
You know, one of the things that's really unique about Dr. Mandel here is as he was sharing, you know, everything towards his PhD in psychology, except his dissertation, he's a board certified anesthesiologist, so he understands that dual background of ketamine as an anesthetic and-- and mental health. And if you don't have one person who has the two-in-one, then working collaboratively, if not within the same office, then at least very closely with other offices to work as-- as a team approach is going to give a better, more comprehensive care for the patient. And I actually have a lot more to say about this issue, but I wanna leave room for you Sherry and if Dr. Mandel wants to add to that.

Dr. Sherry Walling - 0:17:04
So, ketamine is delivered in a few different ways, right? There's infusions, there's-- talk to me-- talk to me about this.

Dr. Steven Mandel - 0:17:12
Routes of administration are super important. We were talking before about ketamine being a commodity item of pharmaceutical houses. So, one of the ways pharmaceutical houses get around that is they take a molecule and they tweak it, and then they get a patent for the tweak, and then they have-- they have pricing power for that molecule. Johnson and Johnson did that with Esketamine, which is an isomer of ketamine, and they chose a different route of administration to distinguish themselves from generic ketamine and to make it more acceptable to psychiatrists. And then the route of administration just doesn't work nearly as well. I mean about barely half as well, so it's too bad for them, and it's too bad for the public.

Dr. Steven Mandel - 0:17:52
But they had plenty of margins. They still do this. Spravato is, I guess I shouldn't mention brand name. Esketamine is available and it's-- it's widely used, and it works, but it works about half as well as generic, and it's substantially more expensive. Routes of administration are crucial.

Dr. Steven Mandel - 0:18:11
One of the huge mistakes that physicians make and patients make is to generalize from findings in one route of administration to findings in another route of administration of all the research done in ketamine, and it's now very expensive, many hundreds of studies, more than 98% of them are done on intravenous ketamine. That when we say ketamine does this, ketamine does that, ketamine does this, these characteristics-- that's based on findings from intravenous administration. Ketamine can be given very constructively in the muscle. It can be given sublingually under the tongue. It can be swallowed, put in the tummy, it can be put up the nose.

Dr. Steven Mandel - 0:18:49
It's used that way recreationally and actually also now as ketamine is also administered that way. People put in other orifices for other reasons including vaginal and rectal. It can be applied on the skin, it can be applied in a wound, it can be injected subcutaneously overtime. So, I may have left one or two out, but there are numerous routes of administration, but virtually, all clinics are giving it in the vein, which is what we know about, in the muscle for a variety of reasons that deviating from what has we actually have evidence for, or under the tongue.

Sam Mandel - 0:19:31
Yeah, so we-- we specialize in IV infusions because that is the safest, most effective way of providing it. And as Dr. Mandel mentioned is what the vast majority of all the research is on, and we're evidence-based, and we don't really have any bias except for where the evidence points to. So you know, one of the things that makes ketamine therapeutic is the gradual rate. Over in our clinic, it's 55 minutes long. Most of the research is a 40-minute infusion.

Sam Mandel - 0:19:54
We also give a slightly higher rate and so we have better results. We-- we have an 83% success rate for mental health. Most research is around 71%, so we do a number of things differently that Dr. Mandel has pioneered to help to create a better outcome, and we also really personalize the treatment. We individualize it, so with the research for good reason, you have to give everybody the same exact thing so you can have your results. When you're not a research center and you're a treatment facility, if you have the ability to tailor it to fit the needs of the patient, we are unique individuals and we all do have different needs. And what Sherry needed on her Monday appointment is not necessarily even what Sherry needs on her Wednesday appointment, and so the ability to use not only the science but a little bit of the art in assessing that in clinical judgment, to find that right match is going to produce the best possible outcome.

Sam Mandel - 0:20:41
So, we do IV. We're-- we're fans of it. Also, if-- if there's any, you know, unwanted side effects or anything that's uncomfortable, you can increase or decrease the dose during the infusion, which is something that's pretty unique to IV. We use digital syringe pumps instead of IV bags, which is another thing that we popularized. So, you can really precisely dial in that exact rate, and you can change it not just from one infusion to the next, but even during an infusion.

Sam Mandel - 0:21:10
Because there is a sweet spot in the level of dissociation and the amount of medicine that the patient needs in order to have an optimum outcome. And there is some adjusting that needs to be made. You know, usually at least one adjustment during most infusions, sometimes two, or in rare cases more if necessary, not only for efficacy but also for comfort. So, if somebody is a little bit anxious, if they're having a difficult experience, which can happen at times, we can dial it back a little, and that change is felt very, very quickly with any of the other ROA as we call them, you know, routes of administrations that Dr. Mandel listed. That's really not possible. Once you squirt a bunch of ketamine or any drug into the muscle, it's gone. You can't take it out.

Sam Mandel - 0:21:49
It's like you put too much, you know, hot sauce in your food.

Dr. Sherry Walling - 0:21:52
You're there, you're on the bus.

Sam Mandel - 0:21:56
(crosstalk) I mean that's it and the same goes for-- for the rest, yeah.

Dr. Sherry Walling - 0:21:59
So, this intervention is a little bit different than some of the other psychedelic-supported psychotherapies or psychotherapy that is integrated with MDMA or psilocybin for example, in that the medicine plays a role in a-- in a sort of talk therapy process. They're integrated as one and-- and this doesn't necessarily have a talk therapy component. Is that correct?

Dr. Steven Mandel - 0:22:24
Not really, no. But I want to circle back just for one second to what you were saying about the clinics on the corner of Minneapolis. Many of these are well-meaning practitioners. The biggest factor in the success of this treatment is the set of the clinic and the mental set of the patient, so the setting is super important. If it's a corner office on a busy street with a lot of noise and lots of other kinds of patients are being seen, and there's some hubbub and commotion and the person taking care of you also has to run and answer the phone, regardless of all the-- their intentions and how much they care, you're not likely to have a therapeutical experience. Timothy Leary in '62 way back when-- before there was Kennedy was able to establish the variance is 92% as to physical setting and mental set as determinants of outcome. As for talking therapy, ketamine is like an energizer. By itself, it isn't necessarily intrinsically therapeutic.

Dr. Steven Mandel - 0:23:24
It's intrinsically opening up, liberating, expanding. Without guidance, that need not necessarily have a constructive outcome. Therapy is super important, but the idea that it has to be provided simultaneously is a little farfetched.

Sam Mandel - 0:23:43
I wouldn't go as far as to say though that it's not really therapeutic otherwise either, though 'cause we have a number of patients who don't engage in therapy, and even though we recommend it and it's very valuable and very enhancing, there's still a lot of value to be gained from ketamine as a standalone.

Dr. Steven Mandel - 0:23:59
It can be definitely beneficial guided journeys.

Sam Mandel - 0:24:05
But when you say guided journeys, you're talking about therapy outside of the treatment model. And when you say guided journey, I think for most people listening, it sounds like you're talking about KAP or psychedelic-assisted psychotherapy. And I think we-- what we've seen is there's a lot of value in patients having their ketamine as a standalone treatment and doing the work with the therapist on a separate occasion as opposed to KAP, ketamine-assisted psychotherapy, or other psychedelic-assisted psychotherapy.

Dr. Steven Mandel - 0:24:34
If I said that or I said it that way, I misspoke. I think optimally, the medicine and the therapy are not provided simultaneously. I think optimally, they are provided successively but in coordination. All of our patients, practically all of our patients are there. The therapeutic relationship is established way before they have ketamine and it's sustained way after.

Dr. Steven Mandel - 0:24:51
This is the six-infusion treatment. It's a treatment, not a cure. It really jumpstarts people's ability to do good therapy with their therapist, but to expect somebody to come into a clinic and establish a really deep trusting relationship with another person I just met, and have a strange medicine, and make good use of it all at once all quickly, that's really a stretch. So, it's great if people already have a relationship.

Dr. Sherry Walling - 0:25:26
So just to clarify, in terms of like best practice, here's what you'd recommend. How would you combine ketamine and therapy or would you like, you know, if you're talking with someone who's starting this process from scratch?

Dr. Steven Mandel - 0:25:39
Have really good relationship with the therapist. Good meaning the chemistry is right, you've gotten by the little uncertainties about whether or not to trust this person. You're relaxed and trusting, and you're able to work on the issues that brought you into the treatment in the first place, and then you come in and have your infusions. And that will give you access to why you're driving your life looking in the rearview mirror rather than staying in the present. And those insights will be worked over with you and your therapist, and the traumas you've had in the past, of course, the trauma what happened is immutable. The stories and narratives you have around it are totally plastic and reworkable, and with a therapist who is ketamine savvy or psychedelic savvy, you will be able to integrate the insights and experiences you've had, which are really extralinguistic into your cognitive ongoing process in a way that makes you way more present and way better able to make good choices in the current world.

Dr. Sherry Walling - 0:26:48
I really love that language of being able to integrate those extralinguistic processes into the conscious mind, and I think again, that's some of this really unique offering of using medicine and therapy in this way is that the medicine does its biochemical work, and then there's a process of restoring language or cognitive access.

Sam Mandel - 0:27:10
There's also the biochemical process and then there's the experiential component that patients are going through, and sometimes having a clinician in the room with you doing KAP, you know,  ketamine-assisted psychotherapy, where they're talking through things with you during the process can be very valuable for some patients. We find that most patients are better off with them on a separate occasion, and you know, it's a-- it's a really special and unique opportunity for patients to get an objective perspective on themselves during the infusion to quiet the default mode network, to have an opportunity to get that shutter in the mind quiet, and to have a different view whether it's of past trauma or their past or things they're dealing with now, in a way that's just unaffected or affected differently, you know. And to take that inventory, a lot of really valuable stuff can come up for people to then go take to someone they trust, that they can work through it, and also the level of dissociation that allows for people to reach some of that is often different from the level of dissociation that's best for talking. So, it can be really hard to communicate what's going on while it's going on when you're having that experience and not to say that there isn't value in it and it isn't. There are people doing wonderful work with that.

Sam Mandel - 0:28:20
But again, it's difficult, and it doesn't necessarily-- it's not necessarily optimum for everyone or for most people in our experience.

Dr. Sherry Walling - 0:28:30
Yeah, I'm-- I'm curious about the role of dissociation in the ketamine process 'cause, you know, people subjectively report the ketamine can feel quite dissociative. And again, putting on my clinical psychologist hat, whether this is fair or not, often dissociation is sort of flagged as one of those or we have to-- we have to watch this carefully. We have to be really careful with this. Sometimes, it's a rule out for certain kind of therapies. But here we have a molecule that's inviting dissociation.

Dr. Sherry Walling - 0:28:55
People are sort of marching right into dissociation, and they're having these-- these great outcomes. So, what do you make of that? The role of dissociation in-- in this healing process?

Dr. Steven Mandel - 0:29:10
That's a bunch of different questions, Sherry, but to speak to your concern about inducing dissociation when dissociation is a marker for thinking so disordered, you have to be really be careful about the fragility of the person who is subject to that. The dissociation induced by our medicine, although it may be qualitatively similar, it's entirely different neurologically, it's not something that comes unbidden and over which the-- the patient has no control. It's something that is being induced in order to open up areas of the mind that are usually not accessible to people otherwise. People who do a lot of meditating, people who do a lot of breathwork may have some access to those things who had any medicine, but for most of us, that's elusive. We can reliably produce dissociation.

Dr. Steven Mandel - 0:30:01
The dissociation is unfortunate. It's the same word. It's not the same as the schizoaffective who hears voices and has trouble ignoring them and doesn't believe that-- isn't quite sure if the voices originate in his head or somewhere else, that's dissociation. And it's-- we are using the same word for different experience.

Sam Mandel - 0:30:25
I think it's as simple as, you know, what's the 'cause? That's not a great thing to have happening, just throughout the day and your daily living, but when you go into a clinic, have a ketamine infusion. To be understood. I'll just say again, I don't know why this seems silly, but I think I'm just hungry. But just going back to my hot sauce analogy, you know, it's like if your tongue is burning all the time, like you should really go see an ENT or like somebody and get that looked at, right? But if you've just eaten out hot sauce or spicy food, like maybe not a big deal that your mouth is hot.

Sam Mandel - 0:30:51
I don't know if you just had a ketamine infusion, you should expect to dissociate to a degree, and-- and that's where the art comes into the science, because finding that sweet spot because dissociation is a-- is a scale, right? And finding where you're dissociated enough to have this therapeutic experience, but not so far gone that you don't even know who you are or what you are, that-- that takes a little bit of art in trying to find that because we want people to be moderately dissociated and-- and not so severely.

Dr. Steven Mandel - 0:31:19
It's really-- we're having some discussion today about nuances that I really wanna listen to this tape again because it's very hard to capture this for other people. We've been at this for eight years and we talk about it like every day. So, we've gotten deep into the weeds. But the fact that we can give ketamine incrementally over time, which is part of the route of administration that makes it so nice in adjusting the degree of dissociation as to where this dissociation facilitates the therapeutic transformation that we seek to bring about. I believe that it does.

Dr. Steven Mandel - 0:31:50
There is not good evidence, plus or minus, that it does. But many of us believe that it does, and some of us don't believe it does. Dissociation is not a switch. You dissociate or you're not dissociated. It's a continuum and it ranges from just slightly altered, you know, if I may analogize and it's not the same.

Dr. Steven Mandel - 0:32:11
But if you had half a glass of wine or three quarters of a glass of wine, or two glasses of wine, or three or five, you're dissociated and now you're altered with each--

Dr. Sherry Walling - 0:32:28
There's a degree there of alteration.

Dr. Steven Mandel - 0:32:30
(inaudible) spectrum and it goes as-- as a psychologist, you know, it goes back to your-- your own Freudian constructs of ego and superego. You're really quieting your superego, you're really getting your it to be a little more plastic and a little less bossy. And you really begin to speak out a little without fear of being slapped about by the superego. One of the-- the default mode network is quiet, so all of the belligerent, judgmental voices that so many depressives have that tell them that they're ugly and that the world is horrible and that they're loathsome, those voices really get subdued, and they can start to look at some of the cruel judgments they make about their own selves. And that requires-- I would say, it requires some degree of dissociation.

Dr. Sherry Walling - 0:33:22
And in the other veins of psychedelic therapy, we might use the word non ordinary state, but I haven't heard that word used much with ketamine, and I wonder if that's just a linguistic thing. And if we're just parsing semantics, we can abandon this line of conversation. But I'm just curious about dissociation and non ordinary status or how we put those together.

Dr. Steven Mandel - 0:33:42
Dissociation is one of the non ordinary states.

Sam Mandel - 0:33:45
We know that on a neurochemical level, there's a whole process occurring with neurotransmitters and brain activity. And we know in animal models, there's BDNF going on, you know, with ketamine infusions, just brain-derived neurotrophic factor. We know there's actual physical growth and in certain areas of the brain, hippocampus, prefrontal cortex, where you're actually seeing dendrite density increased, better connectivity, actual better brain function. So, these are processes that are occurring regardless of the person's experience that are very valuable and therapeutic. It seems bizarre to me that people would think, though, that without the added level of dissociation that there isn't even greater advantage to what people are able to realize about themselves, and that insight that they can gain or even just the experience of feeling at peace. and having a genuine sense of calm and peace during the infusion.

Sam Mandel - 0:34:27
That experience is-- is valuable, and I feel strongly about that. And we actually had somebody reached-- reached our recently, and we've had people reached out before, "I want to test this-- this drug we're working on that basically takes away the dissociation and would you be interested in helping us with a pilot study or something like that?" And it's just-- it's weird that dissociation has been demonized since we started.

Dr. Steven Mandel - 0:34:58
That's why we come to the language non ordinary states.

Sam Mandel - 0:35:01
Yeah, well, it's been looked at as-- as a negative side effect, yeah, but it's not a-- it's not a negative side effect in my opinion. I think I can say, in our opinion, it's actually a very great therapeutic benefit. It's just weird to me that people are targeting it in the way that they are, you know. And-- and then you look at the other psychedelics like MDMA and psilocybin key ingredients are active ingredients in ecstasy and-- and magic mushrooms that are, you know, showing very promising preliminary results. These are really altering. These are non ordinary states that people are in.

Sam Mandel - 0:35:28
Go figure that you might have to go somewhere non ordinary to try to disrupt your ordinary.

Dr. Sherry Walling - 0:35:39
I'm glad I asked you the question 'cause that's the point, isn't it? What's happening is not working. So, what are we reset?

Dr. Steven Mandel - 0:35:49
But it's insanity but repeating the same sequence, expecting a different outcome, yeah? You gotta go in non ordinary to get where you want to go.

Dr. Sherry Walling - 0:35:57
One of the things that I wanted to ask you about while I have you on the line is specifically the use of ketamine infusion for suicidality, and one of the things that I and I'm sure you are quite concerned about, is the increase in suicide that we have seen over the last 20 years, and probably especially an increase that we'll see as a result of the COVID-19 pandemic. So, can you just talk specifically about how ketamine can be useful for people who are experiencing suicidal ideations or suicidal depression?

Dr. Steven Mandel - 0:36:31
Ketamine reverses suicidality quickly, rapidly, safely in more than 80% of patients. It's just amazing. In a few settings, people are actually getting ketamine in the muscle in the emergency room when they come in complaining of suicidal ideations. Ketamine works better for suicide than it does for any of the other indications we've discussed and works quicker. And it works more durably, Sherry, for reasons that are really worth a lot of research that we're not going into today. We give ketamine to people and then we reverse their suicidality and many of our patients are suicidal, and we reversed their depression.

Dr. Steven Mandel - 0:37:05
And typically after about three months, we begin to see some decline in moods, some return to a depression. This is-- here's where the research should come in. The suicidality almost never comes back, so the depression comes back. By the way, we restore their benefit to the level it was at their first series with one or two boosters. But the suicidality doesn't come back.

Dr. Steven Mandel - 0:37:32
We have 70 million depressed patients people-- citizens. Of those 70 million, 4% of them die by suicide every year. That's 45,000 people. That's a lot of folks. Each one of those tragedies costs the family and the insurers and the society at large in the aggregate about $1,000,000 per death.

Dr. Steven Mandel - 0:37:49
That's really amazing. On a large scale, that's 45,000. People are taking-- are dying by suicide every year and of those 45,000, 36,000 would likely have their suicidality reversed by ketamine. That's $36 billion that we're squandering on funerals that we could use for better purposes.

Dr. Sherry Walling - 0:38:26
I think that really drives home the point of how desperate we as a society are for access to better interventions. And I think one of the challenges is seeing that we-- we have something that could be helpful, kind of right here in front of us. It's already legal, it's already available, and it's not being talked about maybe as much as it-- it should or it could be.

Sam Mandel - 0:38:48
While it's painful for me and especially with the excitement over psychedelics, other psychedelics which is great, we were excited too, just as much as anyone else, but we hear people say often, "Oh, I can't wait for MDMA" or "I can't wait for psilocybin." And we're like, "Hello, what-- what's-- what is ketamine? A chopped liver?" You know, we have this. We've been doing this for eight years. We're seeing this literally saving lives every day, and we've talked with people, both clinicians who are excited about the future, and also even individuals suffering from depression or suicidal thoughts who are waiting.

Sam Mandel - 0:39:15
And it doesn't make any sense. Ketamine works and it's here today. And it's a 50-year-old medicine, FDA approved. We have an enormous amount of safety and efficacy data on ketamine. We don't have any of the-- anything remotely close to that, or we probably never will have so much data on these other agents that are not yet approved, and it's going to take a long time to accumulate a good amount of information and also to see longer-term studies, and even still will never catch up to something we've had for 50 years now.

Sam Mandel - 0:39:47
So, it's just-- it's a little mind boggling.

Dr. Steven Mandel - 0:39:55
Sherry, it may be that talking about 70 million depressed and 45,000 suicides and saving 36,000 of them and $1,000,000 of suicide, that may be a little abstract. Let me give you a true case study. A lady in her early 60s that came to our clinic and paid for her infusions with the money she was saving for her funeral because she didn't want her kids to have to pay for her funeral. And she was totally relieved of her suicide and of course, way less than the funeral. And with the difference, she took her kids to Europe.

Dr. Sherry Walling - 0:40:33
Thank you for the work that you're doing, and I say that as somebody who has lost someone I love dearly to suicide after going rounds and rounds in traditional mental health care, and so I think that your willingness to be innovative even though it's with a medicine that is well established, and to try to change the conversation around how we care for people is-- is necessary and welcomed. So, thank you for the work that you're doing and excited to see what comes in the future for both of you. Anything you feel incomplete, anything that you'd like to add, or does that feel like an okay place to leave it?

Sam Mandel - 0:41:13
Well, I would love to just add that as far as what people can look for and where to go, I think looking at reviews online, looking at their website, that they're kind and courteous, that they genuinely take an interest in you and what it is that you're looking to have treated, that you have a private room the whole time, that you'll be monitored and you're getting IV infusions, and typically it's six infusions over two to three weeks, that you're going to be monitored. We use pulse ox, blood pressure, EKG, all that. We have eyes and ears on the patient the entire time, and that you feel really comfortable with the people who you're talking to on the phone and in person, that they really care about you, that they're going to keep you safe and comfortable. Those are all really important things to-- to look at and-- and that they answer all of your questions, and you should ask lots of questions. Those are a couple more things that I wanted to mention.

Dr. Steven Mandel - 0:42:03
One third of all psychiatric medicines are written for off-label uses. Virtually, all of them are reimbursed by insurers. This medicine, which saves lives, is generally speaking not yet reimbursed. Virtually, all of our patients have insurance. They pay a lot of premium every month. Their Prozac gets reimbursed, so does their Lexapro and their Wellbutrin, so do many medicines that they take that are off label, but appropriate for them to receive.

Dr. Steven Mandel - 0:42:30
The insurance company pays for those, I think, since their premiums are being checks and being cashed. Insurance company really owes it to these patients to defray their costs for ketamine care.

Dr. Sherry Walling - 0:42:44
So, what's the advocacy there? Is it time to, you know, call our representatives, call our senators? Is it time to complain to our insurance companies? How-- how do we, the people, get the thing that we need?

Dr. Steven Mandel - 0:42:54
All of the above. When-- when the insurance company tells you they have really great stories, "Oh, we'd love to do that, but it's experimental." Well, it isn't experimental, it's an accepted treatment. In fact, this medicine by another form is approved by the FDA by another route of administration. "Oh, it's off label." Well, you reimburse a third of all psychiatric prescriptions that are written off label.

Dr. Steven Mandel - 0:43:15
Why isn't this one of them? That includes your insurers and your representatives. If they're not representing you, you need to have them shape up or step aside for somebody who does.

Sam Mandel - 0:43:30
And also just to be specific about the research, a lot of people say who don't know better or maybe because they have an ulterior motive that this is anecdotal, and there are about 137 studies done today, and anyone can go look at them on clinicaltrials.gov on ketamine for depression, and dozens of them have been peer-reviewed, at least 50 with results published and publicly available. So, there's quite an abundance, much, much more so actually than many, many other drugs that people take every day, and with a much longer-term study and many more indications and varying doses. So, this is-- this is more than just I know, a guy who knows a guy who said ketamine helped him. I invite anyone to just educate themselves on that, if they have any concerns about that.

Dr. Sherry Walling - 0:44:19
All right. Wel,  I want to thank the two of you for your time and your passion, your stories, and your immense level of wisdom and experience. I think it's been a really interesting and helpful conversation, and I look forward to sharing it with the mind curious listeners. So, if people are interested in learning more specifically about the two of you and your work, where's the best place for them to-- to follow you, or to find out more about the work that you're doing in Los Angeles?

Sam Mandel - 0:44:43
Yeah, we have a great website. It's called ketamineclinics.com, it's K-E-T-A-M-I-N-E-C-L-I-N-I-C-S, lots of good stuff on there, and then they can call us as well at 310-270-0625. We're open Monday through Friday 9:00 to 7:00. We answer questions until you don't have anymore to ask.

Dr. Sherry Walling - 0:45:04
Beautiful, thank you so much. Thank you so much for listening. I hope this conversation was enlightening for you. MINDCURE is working to develop a host of products to support people in their healing journey, including iSTRYM, which is a digital therapeutic platform that helps clinics like the Mandels by using artificial intelligence to provide customized integration practices for people who want to augment their healing journey, or better integrate their ketamine experiences into their daily life. For more information about iSTRYM, and other resources, please visit us at mindcure.com.