Psychiatry & Psychotherapy Podcast - Ketamine and Psychedelics with Dr. Michael Cummings

Episode Date: September 25, 2018

On this week's episode of the podcast, I interview Dr. Cummings, a reputable psychopharmacologist, about ketamine. We talk about psychedelics, the research behind it, both the positives and the negatives. We will look at how it is or is not helpful in psychiatric treatments.   (Disclaimer: There are no conflicts of interest to report. Neither Dr. Puder or Cummings is affiliated with any companies in favor of ketamine and other drug companies.) Ketamine Although ketamine has recently become a medication of great interest in psychiatry, it actually is a fairly old medication. It was first synthesized in 1962 and began human trials for anesthesia in 1964. It was finally approved by the FDA as a dissociative anesthetic in 1970. What has piqued interest in psychiatry is that infusion of a smaller dose of ketamine produces a rapid response in terms of reversal of depressed mood, suicidality, and some treatment-resistant depressed patients. The literature is rich (in one sense) as the most recent consensus statement (Sanacora, 2017) looked at seven randomized controlled trials, all of which support a robust antidepressant response and anti-suicide response. The difficulty with those trials is the majority of them lasted only one week. A few of the later trials lasted two to three weeks with two to three infusions per week. So, what's lacking at this point is adequate data regarding long term treatment response and data about transitions to more traditional antidepressant treatments. By listening to this episode, you can earn 0.75 Psychiatry CME Credits. Link to blog. Link to YouTube video. Instagram: dr.davidpuder Twitter: @DavidPuder Facebook: DrDavidPuder

Welcome to the Psychiatry and Psychotherapy Podcast, the podcast to help you in your journey towards becoming a wise, empathic, genuine, and connected mental health professional. I'm your host, Dr. David Puter, a psychiatrist who splits his time practicing psychopharmacology, individual and group psychotherapy, medical director of a day treatment program, medical education research, and teaching, residents, and medical students. So welcome back to the podcast. I'm here with Dr. Michael Cummings. great resource, amazing psychopharmacologist. Dr. Cummings, welcome to the show.

Thank you very much. I'm happy to be back. And today we are going to be talking about ketamine and psychedelics and some of the research, both the positive, what we have research-wise, for these drugs for the use actually of treating psychiatric illness, and some of the limitations. And I'm coming to this personally from a place. of skepticism, you know, like I want to see the evidence first. I know some people I know are kind of jump into it full head first and are really,

really excited about it, but I've been kind of watching the literature. And I'm really excited to hear where Dr. Cummings is. We have no conflicts of interest that we have to report. We do not get any money from drug companies. We don't belong to any pro-psychedelic or pro-ketamine. task force or we don't have clinics set up to make money out of those things. So I think we're hopefully going to be approaching the literature as objectively as possible. So Dr. Cummings.

Okay. Well, why don't we start with ketamine? Although ketamine has recently become a medication of great interest in psychiatry, it actually is a fairly old medication. It was synthesized in 1962 began human trafficking. trials for anesthesia in 1964 and was approved by the FDA as a dissociative anesthetic in 1970. What has piqued interest in psychiatry is that infusion of a sub-anesthetic dose of ketamine has been observed in the last few years to produce a rapid response in terms of reversal

of depressed mood and suicidality in some treatment-resistant depressed patients. The literature is in one sense rich. There have been seven randomized controlled trials of ketamine, all of which support a robust antidepressant response and anti-suicide response. The difficulty with those trials is the majority of them last. one week. A few of the later trials lasted two to three weeks with two to three infusions. What's lacking at this point is adequate data regarding longitudinal treatment response, adequate data about transition to more traditional antidepressant treatments. This area has caught on and has been of great interest largely because of the limitations of our current antidepressants in general.

If you look at most antidepressant trials, about two-thirds of people get a 50% reduction in depressive signs and symptoms. Only about a third of depressed patients actually achieve remission with traditional antidepressants. Yeah, so a couple things you said there that I think, are important to look at maybe in more detail is ketamine given for depression it's i think 0.5 milligrams per kilogram yes usually usually resulting in a plasma concentration of around 70 to 200 nanograms per milliliter um in contrast when it's used for anesthesia the plasma concentrations are more in the range of 2 000 to 3 000 nanograms per milliliter And the second thing to kind of look at a little bit differently is how robust is that transient decrease in depression?

The decrease in depression and suicidality is typically fairly robust but short-lived. There is a fairly rapid decay of the antidepressant response following an infusion. The infusions are typically done over about 40 minutes. 30% of the patients or so will become fairly unresponsive to light verbal stimulation. They then recover, they feel much better, but within a few days, their mood will begin to deteriorate. So within a few days, their mood will start to deteriorate. When I looked at the study comparing two days a week to three days a week, it seemed like those were fairly equivalent in the effectiveness of the ketamine

for the couple weeks that they studied it. Yes. They were. The other limitation of ketamine in terms of an ongoing treatment for depression is, like all NMDA antagonists, these drugs are somewhat psychotomimetic. That is, they can induce psychotic. signs and symptoms. And those do begin to become more prevalent with repeated infusions. So that at this point, we don't have adequate data really telling us how long it would be

safe to continue ketamine infusions and how do you make a transition from ketamine, perhaps, to a more stable, long-lasting treatment. When they talk about ketamine, they talk about it as like a dissociative drug. drug. And I almost wonder, like, are the people who are taking it, are we sending them into a kind of a dissociative state? Is that what's going on? Or do you have any thoughts on? Yeah, we are. Basically, the people who describe their experiences during the ketamine infusion note, indeed a loss of sense of personal boundaries, a sort of sense of union with the universe, often fairly dramatic changes in their thinking.

This drug, after all, is inhibiting the brain's primary activating receptor in methyl deaspartate, blocking the effects of glutamate. That does enhance transiently plasticity. And that may be responsible for the short-term improvement in depressive symptoms. But you are doing that via causing a dissociative state that has some psychotic or psychedelic properties. And indeed, it's those properties that have been responsible for the street use of ketamine. You know, it's also been a drug of abuse for a number of... years, actually since it's an introduction in the 70s, with the street name Special K.

Special K and some other names as well. I think it might be worth talking about the street drug use of it, because I think, you know, when you think about this drug being used on the street, often people are drinking before they use it or they're at some sort of rave, you know, likely not the safest place. And then they use something fairly dissociative. And they can really be out of it. Like if you use a high enough dose, you can lose the ability to hear or see and just kind of be stuck in this sort of frozen state to the observer. Yes.

Indeed, you can produce a delirium, which can be either stuporous or in some cases agitated. People are familiar with a related drug that's used on the street, Fincycladine. Fincycladine causes a more severe dissociation and psychosis, but the effect of ketamine and fincylidine are in the same direction and by the same mechanism. They call it the K-hole. It's when you can't move, you have this depersonalization. And because of it, it's sometimes been called a date rate drug because the person could be very very very vulnerable in this state. How is that different dose-wise than what people are giving for depression?

Typically, the doses that people are using at raves, or indeed the doses used for anesthesia, are about an order of magnitude higher than those used for infusion for treatment of depression. about the peak plasma concentration you'll see with antidepressant infusions of ketamine are about 200 nanograms per milliliter. It's not uncommon for people using the drug either recreationally or, for example, with ICU anesthesia for them to be more at around 2,000 nanograms per milliliter. So a tenfold increase in terms of the drug. level. There still is a risk when people are recovering from the antidepressant infusion,

indeed that they may become agitated or confused or may hallucinate, which is why one of the recommendations for treatment centers using ketamine is that they have adequate expertise in controlling psychomotor agitation and confusion, that they can treat the person if those things occur. During ketamine infusion, about a third of people exposed to ketamine also exhibit a fairly pronounced sympathetic arousal during the initial portion of the infusion with about 30% of patients achieving a heart rate of 180 and a blood pressure of around 130 over 100, so that indeed you would not want to give ketamine to somebody who was in a cardiac fragile status. And indeed, one of the recommendations for ketamine infusion centers is that they,

one, take a good cardiac history and be sure the person is exercise tolerant. And two, that the drug be administered by somebody else, by someone who is A-CLS certified and has access to essentially a crash car. Yeah. So there's two components there. One, the person who is doing this treatment knows how to basically run a code or intubate if needed or kind of give advanced life support. And then two, deal with any sort of psychotic symptoms that could develop potentially. Yes. And have restraints available and have the ability to control someone who has. is in a delirious or psychotic state.

Yes. I was reading, I was actually listening to some podcasts on this, and probably the best one is actually done by a veterinarian. I'll put a link in the show notes or the website for it. And he described how with cats coming off of surgery with ketamine, they try not to put them next to an angry barking dog. They ideally put them in a quiet place, which helps them, which I found interesting.

the correlates of humans and animals? Yes, and indeed you'd want to do the same thing with a human. You'd want a quiet, safe environment so that you did not induce an agitated delirium. Because the person is responsive to the environment, but their interpretation of the environment may not be reality-based and can produce a very agitated response. and some individuals.

Anything more on the sort of mechanism of action and what it's teaching us about depression? I think that what ketamine is offering, perhaps via blockade of glutamate at NMDA receptors, perhaps via downstream mechanisms from that is that in many cases of resistant depression is it is necessary essentially to alter the plasticity of the brain to get a response. This correlates to some extent with electroconvulsive therapy.

They've looked at what is important in ECT in terms of gaining response, and for decades we've thought it was the seizure. They actually now think it may be the post-ictal neuronal suppression period that actually accounts for the therapeutic benefit because that's associated with turning on rapid response genes. There was one small study in which they looked at simply exposing people repeatedly to isofluorane, again, anesthetic agent, causing neuronal suppression repeatedly. And they got an antidepressant response from doing that as well.

So it may be that turning neurons off, transiently can have benefit in terms of resetting them at the DNA level, making them more plastic. That's interesting. You know, I'm thinking about a patient who had a manic episode and shot herself and then was intubated under general anesthesia for a while. Because of that, when the psychiatry team came around to evaluate her, they totally missed that she was having a manic episode. I found out she was having a manic episode about a couple months later when in my partial program, she started going hypomanic and talkative and wasn't sleeping at night. And all of a sudden, as I looked back at the history, it became obvious to me that she was having a manic episode before she shot herself.

So I've wondered how that, I mean, that's kind of off topic, but how the brain, how it's, how it's, slowed the brain down all that anesthesia that she was on. Yeah. In that sense, we are finding that, indeed, ketamine may not be the only anesthetic agent that alters longer-term functioning of neural circuits, although ketamine has certainly become the one that is popular at the moment. I think the major risk in this is not that the drug may not have psychiatric utility. we are still fairly early on and there is a risk, as with most things, that become rapidly popular,

that our use will outrun the data that we have available to guide us. I think that's probably already going on with all these ketamine clinics popping up. I was on a psychiatry board, and they were talking about how often they're started by anesthesiologists, and there's no clear sort of psychiatric evaluation that may precede some of these patients starting. Yeah, which is highly important. Currently, all of the data we have essentially points to treatment of treatment refractory major depression. In many of the ketamine clinics, they're sort of using it to treat all complaints. And the data on other disorders ranges.

from slim to none at all. And I think that, you know, there is a lucrative pull towards these clinics. It's usually cash pay because insurances aren't there yet. And so, you know, what would you say to a patient maybe who stumbles upon this podcast and is considering whether they should do this? I would one say that they should have a very careful psychiatric evaluation, including diagnosis of their mental disorder, a careful review of their treatment history

to be sure that they have essentially received optimal treatment in terms of established long-term treatments. And then if they do decide to pursue ketamine treatment, they should work with a psychiatrist who is well-versed in using ketamine, but also well-versed in using other means to address depression, including access to more traditional antidepressant medications and to psychotherapies. It's clear from the literature that does exist so far

that ketamine is not a cure-all for major depression. It may help jolt a brain that has become resistant to treatment into being more plastic and transiently being, I'm depressed, but it clearly is not a cure for the underlying condition. Yeah, I think my sort of input to patient, if a patient came in and said, this is what I want, I would talk about the gap and we don't know what's going to happen if this treatment is given for six months or one year. I have no idea what that patient's going to look like.

I'll know that probably three to five years from now. I'll see those patients in my clinic. I'll see what they look like, what their story has been. have they had full recovery for the whole time, you know, or do they have persistent issues? Do they have complicating issues from the treatment, right? And so there's a lot there that we don't know. And that would be my hesitancy where I get sort of like, like, wow, okay, this could be really helpful as if, yeah, if they've had multiple full doses of antidepressants, maybe even failed ECT. And it's like, okay, what's next?

you know, is this, this might be something that they could try to see if it works. I don't know if you have any thoughts on that. Yeah, that is largely where I see ketamine at this point is for those treatment refractory cases who haven't responded to other modalities, it may provide a means to enhance treatment response to get the person out of the immediate danger of severe depression and suicidality. But it's not at this point a standalone treatment. One of the other concerns I have,

and I don't know if you have any thoughts on this, is what it would be like to be receiving psychotherapy during this treatment. If it is a dissociative drug, I usually try to get people off of dissociative drugs when they're in psychotherapy. I want their brain to be fully functional. Well, I think in this case,

the psychotherapy would need to follow on after the person's dissociation has dissipated. The good news with ketamine in that respect is the half-life of the parent compound is about two and a half to three hours. The active metabolite nor ketamine or desmethal ketamine, depending on whether you're from England or Germany, is up to around 12 hours so that by the time the person is 60 hours post-infusion. the ketamine is gone. Do you think that there are potentially prolonged dissociative effects even when the medication is gone?

Probably not, at least not with one or two or three exposures. What we have no data about at this point is how many exposures to ketamine are safe in terms of not inducing a more protracted delirium. So in summary, you know, this is something will probably come back. back to in a year, in two years, as bigger studies come out, as there's more experience in this sort of new frontier. And yeah, any other final thoughts on ketamine before we move on to some of the other psychedelics? I think it is promising, perhaps not so much for itself, as it does suggest that if we can discover more useful, perhaps somewhat gentler in MDA,

antagonists, it may provide us a new avenue into treatment of more resistant depressive illnesses. Okay, I know we also wanted to touch on psychedelics. Yes. Where do you want to start with that? Again, somewhat as with the ketamine, these are a drug class of new interest in psychiatry. They, however, have been in use, particularly. in Native American and other indigenous

populations, indigenous populations, for in some cases millennia. Let's talk a little bit about that. How were they used? And how were they helpful for those societies?

They have been used historically, primarily in terms of religious ritual. Often under the guidance of a shaman or a medicine man helping to guide an individual with respect to life issues. All of these drugs, psilocybin, LSD, Anna-Hu-Ska are all essentially very potent 5HT2A serotonin agonists, with many of them also being agonists at other serotonin receptors, they produce a state that in some ways is somewhat like

what we were talking about with ketamine, that is the person has an alteration of their sense of self, a sort of loss of boundaries, a sense of being in touch with the universe in a much larger sense. And indeed, they've become much more influential, fluenceable, suggestible under those circumstances. As they were traditionally used, they were often used only once or very sparingly, essentially as a support to what were ritual-based psychotherapies. And that has been an area of interest in psychiatry that's been dawning is, would these facilitate

some forms of psychotherapy? Of course, again, like ketamine. They've also been prone to being drugs of abuse. I'm old enough that I actually remember the psychedelic era of the late 1960s. Yeah. You know, it's interesting. I worked with a now psychiatrist at the VA, Shannon Remick, on a grand rounds where we looked at some articles on ecstasy and psychotherapy and some of these things. And one of the things that we looked at was, okay, does it damage the brain? And there's some studies of people who had used street ecstasy

and who knows what else. But when they looked at what was actually in the street ecstasy, it wasn't just ecstasy. There was methamphetamines. There was all sorts of other chemicals sort of in those pills, which made it very different

than what could potentially be given at like a pharmaceutical, grade? A lot has to do, as with all drugs, with the dosing and the concentration that is present. When abused, often drugs are used at very high doses, achieving very high concentrations. A good example of permanent change, I'm not sure if you could call it damage or change, but certainly LSD can induce, for example, a persisting hallucinosis. That's essentially the result of a permanent change in receptor status. That usually occurred, however, with repeated very high-dose exposure.

Used more modestly, frankly, at this point, we don't know very easily how to separate the benefits and risks of these drugs. We don't know that much about the risks, although used as they were traditional. Traditionally, they were often very limited exposures in very controlled environments, suggesting that these are drugs that perhaps should be used with caution for therapeutic benefits. They have shown benefits in a variety, mostly of anecdotal studies for everything from depression to anxiety and to even inhibiting the use. of substances of abuse like alcohol. Yeah, specifically like psilocybin.

There's been some studies on cancer patients and does it decrease depression? And for these studies, they'll look at, they'll meet the patient, they'll get to know the patient, kind of build a therapeutic alliance, and then have this sort of event where they take this medication or placebo

and they have the people lie down in a hospital bed and put a eye covering and listen to some light music. And then there's sort of the person there, if they do have any sort of fear experiences that they can talk to. And when I watched some of the video of the patients who had gone through this, it seemed like the patients who had positive experiences also talked about positive experiences they had in the 60s of LSD or different things. Do you have any thoughts on these studies in particular, positive, negative?

They are, well, in terms of their primary results, they typically report positive results. Their limitations are they are typically very small samples, and they lack usually an adequate control group. so that most of our data is still very much anecdotal with respect to the halicinogens and their particular benefits or possible benefits. You know, in contrast to that, though, we do have a wealth of data from traditional cultures that have often used these substances for millennia. It's very clear from those that these drugs used in a very very very important. controlled, very limited manner don't seem to induce ongoing mental disorder.

But again, with those caveats that these are under controlled, much more limited circumstances than would be typical of an abuse situation. And I'll put some links on my website to the studies where they looked at, like there's a a review of all the reviews that have been out that just came out in August 2018. I'll put that one out there. And yeah, I think it's very interesting. I feel like I am sort of underqualified to speak definitively about it. And likely that's because the research is at a very sort of early stage.

Well, in that sense, I think we are, in this case, even at an earlier stage than with the ketamine. in the sense that this may open new routes for treatment by modulation of serotonin receptors in ways that we haven't approached before. It may turn out that the halicinogens themselves may or may not be the right agents to use in the long run, but this may point to a new approach to altering brain plasticity to enhancing treatment. I want to touch base on the placebo aspect because when I was reading the ketamine study,

it seemed like just giving an injection of normal saline, the patient would know, I think. And the same thing is true, I think, with like giving, you know, for the LSD if they were just giving like a sugar pill. Yes. What do you think would be a good placebo? Clearly, you'll have to give the person something that produces some degree of change in level of consciousness. Something like an infused benzodiazepine, for example, might be a possibility.

Clearly, a normal saline placebo or sugar pill orally is not going to be an adequately blinded study since both the halisone. synogens and ketamine produce fairly rapid effects that anyone being exposed to the drug will be aware of. Yeah, I think that's, I think this is a good discussion in general, like how to look at design of studies and placebos. Because if the patient has, sometimes they'll match the placebo that has some similar side effects to the actual medication like Benadryl or benzodiazepine if the medication is sedating. to not allow the patient to know what they're getting.

I recently saw some studies on Botox for depression. And when I read about the placebo, they were just injecting normal saline. Like someone's going to know if the muscle is not having that sort of Botox experience, that they're not getting the actual treatment. Yeah, which indeed those studies then become suspect because particularly in treating mood disorders, the placebo response rate is typically fairly high off and around 30 to 40 percent, so that you really do need to be able to blind both the patient and the person administering the treatment as to whether you're actually giving the compound that you're studying

or you're giving an active comparator placebo. Yeah, and that's another sort of thing of the bias of some. someone who really, really believes in the treatment versus it's at like, you know, why they go multi-sight on some of these studies, because you get away from that sort of charismatic leader who's leading the charge, really believes that this is going to be the next biggest thing. Indeed, our clinical decisions need to be based on data, not belief. Yeah, but what I'm saying is that, what is the effect called when it's like the first

center has a much better effect than the second center. Oh, the Hawthorne effect. The Hawthorne effect. You begin to, if you expect something to happen, you tend to see it whether it actually exists or not. Yeah, and, you know, it's interesting. I run a treatment program and we do research off of it. And I see the energy level that's put into the patients because we're running research. And I'm not sure if it's just a facet of the people who really believe in this paradigm, you know, tend to kind of conglomerate in this group. And so they're just really passionate about what they do. But there is this sort of Hawthorne effect that I see in studies.

And so, you know, when the first several studies come out, we're always sort of thinking through, okay, what's going to happen when this goes to a multi-site study in those other sites where you don't have that charismatic leader? I can tell you that if you look at research in general, if you look at open label studies, the rate of positive findings is about twice that of what you find in randomized control trials. Explain to someone who doesn't quite understand the difference between open label and randomized control trial,

like why that would change so much. Okay. In an open label trial, the patient and the prescriber of the treatment, both know what the patient is receiving, and consequently they can be biased by their beliefs. If you compare those studies to studies in which neither the patient or the prescriber know what the patient got, the rate of positive results is about twice in the open trials, what it is in the control trials. We can fool ourselves, talk ourselves into seeing something that wasn't actually there about half the time.

So in summary, I think that we're probably going to have to return to these topics. You know, as more research comes out, as there's longer-term studies of this stuff, as there's more randomized controlled trials, that's where we really sort of start to get excited about things. With ketamine, I think the randomized controlled trials need to be extended for, I don't know, how many months would you go out? I think they need to do trials that are three, four months, maybe six months in duration to figure out how often the person can receive the treatment, what the long-term effects are. What's the point at which you should say this needs to stop because of long-term effects on the person's brain?

There also needs to be a great deal of study about how do you transition from ketamine infusion to alternative. alternatives, does the ketamine make the person ultimately more responsive to other either pharmacological interventions or psychotherapeutic interventions? We don't yet know the answer to those questions. And then in terms of the psychedelics, where do you see the need of the research the most? I think the need of the research with the psychedelics is to understand more fully what is happening in the brain as a result of of very potent stimulation of 5HT2A receptors and perhaps use that as a jumping off point

to look for other means to modulate or encourage treatment response using those receptor systems, but perhaps without some of the negative effects of the halicinogens. Very good. Well, Dr. Cummings, thank you for coming on again. I really appreciate it. it. And if you're listening to this, if you have any comments, thoughts, follow the show notes

to the social media profiles that I put out there. And that's a good place to put some your thoughts down and engage conversation around this. Dr. Cummings, until next time. Okay. Thank you.