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0:29

It's Lindsay Smith Rogers. Ketamine

0:32

is in the news again. Today,

0:34

Dr. Paul Kim, a psychiatrist

0:36

and director of the Johns

0:38

Hopkins Treatment Resistant S. Ketamine

0:41

Antidepressant Targeted, or Treat Depression

0:43

Clinic, and co-director and psychiatrist

0:46

Dr. Paul Nestat, talk about

0:48

the differences between Ketamine an

0:51

S-chedamine, an FDA-approved medicine for

0:53

treatment-resistant depression. They also talk

0:56

about why chedamine is in

0:58

the news right now and

1:01

the importance of administering S-chedamine

1:03

in a clinical setting as

1:06

part of a broader comprehensive mental

1:08

health strategy. Let's listen. Dr.

1:10

Paul Kim and Dr. Paul Nestat,

1:12

thank you so much for coming

1:14

on public health on call. So

1:16

today we're going to revisit a

1:18

topic that we've talked about before,

1:20

but is trending in the news.

1:22

But first, what are the differences

1:24

between ketamine and S-ketamine? Dr. Kim,

1:26

could you walk us through what

1:28

these two things are and how they're

1:31

used? Sure. Thanks for having

1:33

us on. Difference between ketamine

1:35

and S-ketamine. So when people

1:37

talk about ketamine, it is

1:39

a mixture of both this

1:41

and this R-ketamine. The S-and-R-ketamine

1:43

are mirror images of each

1:46

other. And so while they

1:48

are... chemically same, but they

1:50

are structurally different. So

1:52

like your right and left hand,

1:54

they are very similar. You know,

1:57

they have five fingers, but they're

1:59

mirror images. each other and

2:01

you know you can't superimpose

2:03

them on top of each

2:06

other. And escatamine is just

2:08

a purified form of that

2:10

mixture so they have synthesized

2:13

this one form of cetamine

2:15

and cetamine has been used

2:17

for a very long time

2:19

was in the 70s FDA

2:22

approved for its use as

2:24

an anesthetic and later it

2:26

became popular as a recreational

2:29

drug. Now escatamine on the

2:31

other hand was just recently

2:33

approved by FDA in 2019

2:35

for its use for treatment-resistant

2:38

depression, which really means that

2:40

people who have tried a

2:42

couple of oral antidepressant and

2:45

they did not respond to

2:47

it. So it's approved for

2:49

major depressive disorder with suicidal

2:51

ideation and behavior. The idea

2:54

is that it alleviates suicidal

2:56

thoughts in a more rapid

2:58

way. We've also heard that ketamine, and

3:01

correct me if I'm wrong, but ketamine

3:03

is being used in opioid use disorder,

3:05

and I think there's some confusion about

3:07

whether ketamine is an opioid. You know,

3:10

you mentioned that it was used at

3:12

one point as an anesthetic. Could you

3:14

talk a little bit about that? Yeah.

3:16

So unfortunately, ketamine has... then used sort

3:19

of off label for many different use

3:21

disorders like as you mentioned opioid use

3:23

disorder and PTSD and numerous other disorders.

3:25

But they really haven't been they haven't

3:28

been approved by FDA for those uses.

3:30

And so Ketamine typically isn't considered an

3:32

opioid at all. Although, you know, there's

3:34

some evidence that at a higher dose

3:37

it may bind to the opioid receptor.

3:39

So for those reasons, you know, there's

3:41

concerns about abuse potential and addictive nature

3:43

of ketamine, but it really hasn't. been

3:46

proven to treat opioid use disorder. So

3:48

let's get a little more into the

3:50

details about eschedamine and its use for,

3:52

you said, major depression and treatment-resistant depression.

3:55

So Dr. Nestat, could you talk to

3:57

us a little bit about your research

3:59

and how this is used as part

4:01

of a comprehensive strategy? Yeah, absolutely. So

4:04

eschedamine is one of the newer treatments

4:06

we have for depression. Depression, major depression

4:08

has been a major issue in the

4:10

United States and globally. It's a major

4:13

cause of workplace disability. It's of course

4:15

a contributor to suicide. suicide rates have

4:17

been climbing dramatically for the past 20

4:19

years. So when a new mechanism of

4:22

treating depression was sort of discovered, when

4:24

ketamine was found to be helpful for

4:26

depression, people were very excited. And early

4:28

on, the research was in ketamine, this

4:31

racemic mix of drugs that Dr. Kim

4:33

was describing, and that was found to

4:35

be somewhat effective, although it wasn't studies

4:37

as extensively as S. Ketamine, this purified

4:40

form of ketamine has been cited by

4:42

the FDA in several large what we

4:44

call phase, what we call phase 3.

4:46

trials with multiple sites and found to

4:49

be very effective in treating treatment resistant

4:51

depression depression that hasn't responded to other

4:53

treatments. How it works is generally you

4:55

come in to a hospital or a

4:58

clinic in a supervised setting. and you're

5:00

administered this drug, it's actually given intranasily,

5:02

which means like you might take, like

5:04

Claritin, you sort of squirt it up

5:07

your nose, a doctor's there to monitor

5:09

you. Because it's got potential side effects,

5:11

including things like blood pressure increases and

5:13

nausea, that kind of thing. We do

5:16

it with a doctor present. In our

5:18

clinic at Johns Hopkins, a patient comes

5:20

in, they're monitored via a protocol that

5:22

the FDA set for S. Ketamine, where

5:25

they're there for two hours. Doctor is

5:27

physically present to check blood pressure at

5:29

specified intervals. Make sure blood pressure is

5:31

not having any problems. If someone gets

5:34

nauseous, we have medicines for that. If

5:36

they get a headache, we have medicines

5:38

for that. They're given on the first

5:40

day a relatively low dose to make

5:43

sure that there is no major side

5:45

effects. We use 56 milligrams just for

5:47

contact. And then they come in twice

5:49

a week. for the first month, they

5:52

come in twice a week, they get

5:54

that treatment, we go up if they

5:56

can tolerate it to a dose a

5:58

little bit higher, 84 milligrams, and they

6:01

stay on that dose. After a month

6:03

of getting this treatment for twice a

6:05

week, we're assessing every time they come

6:07

in if their depression is getting better

6:10

or if they're having any side effects,

6:12

and after a month we sort of

6:14

make a decision with the patient where

6:16

they think it's helping. We continue that

6:19

treatment, but we taper it down. We

6:21

go down to once a week for

6:23

a couple of weeks, and then every

6:25

other week, and then every month or

6:28

so, and we taper the treatment down

6:30

because they've gotten over that hump of

6:32

depression. And importantly, they're also taking other...

6:34

medications and other treatments for depression that

6:37

whole time. So vast majority, I think

6:39

almost all of our patients are on

6:41

other treatments as well. They might still

6:43

take an oral antidepressant. They're encouraged to

6:46

be in therapy, specifically things like cognitive

6:48

behavioral therapy, which works synergistically with the

6:50

escutamine treatment. And we have seen remarkable

6:52

results. We've seen people that have been

6:55

depressed and resistant to treatment that treatment

6:57

hasn't been working for decades in some

6:59

cases, seeing good psychiatrists. when we first

7:01

opened the clinic we were seeing a

7:04

lot of people that were in the

7:06

Hopkins Psychiatry program but had been unable

7:08

to reach success in their treatment for

7:10

decades and then they come to this

7:13

program and often they see relatively rapid

7:15

improvement. Not same day, you know, people

7:17

might feel good that first day with

7:20

treatment but really that sustained improvement can

7:22

come within a few weeks by the

7:24

end of the month and then we

7:26

we potentially potentially that with further treatment.

7:29

People tend to do pretty well. We

7:31

rarely do see those side effects of

7:33

high blood pressure, but it can happen.

7:35

And when it does, we're prepared. That's

7:38

why it's so important that someone's in

7:40

a clinically monitored setting. We have what's

7:42

called a crash cart. The medicines that

7:44

can help bring their blood pressure back

7:47

to normal if they need very rarely

7:49

used, but it's important to have. And

7:51

also, because it can be a strange

7:53

experience using this medication, it can be

7:56

helpful for a patient to know there's

7:58

a doctor right there, I think that's

8:00

essential. I worry about when it's given

8:02

an unsupervised setting, but fortunately, S. ketamine,

8:05

this form of ketamine, is regulated in

8:07

such a way that it's only legally

8:09

allowed to be given in a supervised

8:11

setting. Dr. Kim, what is the patient

8:14

experience? of this. So they come to

8:16

the clinic, they are administered the medication,

8:18

and then you said it takes about

8:20

two hours. What happens during those two

8:23

hours? Yeah, so during those two hours,

8:25

the real experience happens during the first

8:27

hour, where they have these dissociative effects.

8:29

So, ketamine is a dissociative anesthetic. And

8:32

so this S ketamine, even at this

8:34

lower dose, also has some dissociative and

8:36

sedative effect. So during that time, you

8:38

know, they sort of feel disconnected from

8:41

themselves. That's what it means to be

8:43

having those dissociative effects. So their thoughts

8:45

that they may have body experience, right?

8:47

So they feel disconnected from their body

8:50

or feel that the speed of the

8:52

time has changed in a certain way.

8:54

The things that they experience during the

8:56

first hour or less, after that a...

8:59

come out of it and they're back

9:01

to their normal self. Is there a

9:03

hallucinogenic effect to this or I'm trying

9:05

to fully understand what you mean by

9:08

they're outside of their body? Are they

9:10

lying down? Are they daydreaming? What is

9:12

that like? Yeah, so there isn't really

9:14

like a true hallucinogenic effect with as

9:17

ketamine, but they just feel a little

9:19

bit out of it. They feel a

9:21

little bit strange, so typically they're not

9:23

seeing... Visions or hearing voices, anything like

9:26

that. Yeah, it's just different is a

9:28

lot of times what the patients tell

9:30

us. They can't quite describe it. And

9:32

what they're actually describing is this common

9:35

effect of these types of medicine, which

9:37

is the dissociative effect. You know, it

9:39

really varies a lot per patient, but

9:41

some patients will describe things like feeling

9:44

if they're in a tunnel or feeling

9:46

if their body is very large or

9:48

very small or just just feeling kind

9:50

of out of it. And remember that

9:53

we're using a much lower dose of

9:55

this drug than someone would use if

9:57

they were using it recreationally. So it's

9:59

not as severe of an effect. Oftentimes

10:02

the first time or maybe first and

10:04

second time they might feel that, but

10:06

after they've had a few treatments, some

10:08

patients bring their laptop and are doing

10:11

work, doing emails, that kind of thing.

10:13

And Dr. Nesta, I also want to

10:15

ask you, sometimes with drugs for depression

10:17

like SSRIs, you know, sometimes people are

10:20

looking to as cadmine because the side

10:22

effects from the side effects from those

10:24

drugs are so... They almost counteract any

10:26

benefit that the patient is getting from

10:29

them. So you mentioned some side effects

10:31

that are happening in the room at

10:33

the time they might get nauseous have

10:35

low blood pressure. Are there any side

10:38

effects that they might have outside of

10:40

the sessions over the time that they're

10:42

using the stroke? That's a great question.

10:44

We get patients asking that all the

10:47

time. It's also worth pointing out that

10:49

most people in SSRIs. Most people use

10:51

SSRIs. don't have any side effects. Some

10:53

people do and they're side effects that

10:56

can be bothersome like dry mouth or

10:58

headache or nausea, but most people do

11:00

pretty well. But yeah, there are people

11:02

that are very sensitive to the side

11:05

effects and and they do look for

11:07

other treatments like Eschedamine. With Eschedamine, the

11:09

vast majority of the side effects you

11:11

might have, or maybe the only really

11:14

dangerous one that we worry about is

11:16

this high blood pressure spike which happens

11:18

during the session. It's why we keep

11:20

them in the hospital for two hours.

11:23

Outside of the treatment session, there's not

11:25

very much that we've ever heard people

11:27

experiencing. The clinical trials didn't find much

11:29

in terms of side effects outside of

11:32

the treatment. It's worth pointing out though

11:34

that... Ketamine, the mixture that includes eschetamine,

11:36

when it's been used recreationally or chronically,

11:38

there are people that have given reports

11:41

of things like bladder problems, whether using

11:43

high doses or very frequent doses or

11:45

using it chronically for years and years,

11:47

they can have things like bladder problems

11:50

and there can be cognitive problems and

11:52

there can be cognitive problems and there's

11:54

even been reports of people that have

11:57

been using it chronically, high dose, chronically.

11:59

and frequently not what happens in a

12:01

supervised treatment setting. We're hearing a lot

12:03

about cadmene in the news. What should

12:06

people know about this? Dr. Nestot. Yeah,

12:08

so when you see cadmene in the

12:10

news, you know, because of the way

12:12

that news... reports things, it's usually on

12:15

extremes. So for a while, Ketamine was

12:17

in the news because it was a

12:19

wonder drug, this miraculous thing that could

12:21

finally treat depression quickly, and it was

12:24

even marketed sometimes in the media as

12:26

being used for things besides suppression, like,

12:28

oh, there's some promising evidence for OCD

12:30

or PTSD or Arachnophobia or whatever, whatever

12:33

you could sell it as. And that's

12:35

unfortunately, what happened sometimes when there's something

12:37

new, people get maybe overexited, there's some

12:39

hype. And then, you know, you know,

12:42

look for places they get ketamine wherever

12:44

they could and these these private businesses

12:46

would pop up and they were marketing

12:48

ketamine and remember this is the recemic

12:51

mixture of ketamine not this purified FDA

12:53

approved version it was being given in

12:55

unsupervised settings with being shipped by the

12:57

mail you could sign up for companies

13:00

that would ship you ketamine maybe they'd

13:02

ship like a scented candle with it

13:04

or something because there would be the

13:06

idea that you'd want to have the

13:09

setting matter that kind of thing and

13:11

because it was unsupervised weren't that well

13:13

assessed before being prescribed the ketamine, there

13:15

was all kinds of bad outcomes. I

13:18

mean, there was diversion, but also, you

13:20

know, when we see a patient in

13:22

our clinic, the first step is a

13:24

long two-hour interview with a psychiatrist where

13:27

we get to know if this patient

13:29

actually has treatment-resistant depression as opposed to

13:31

their demoralized, they're grieving, they're anxious, lots

13:33

of things can look like depression to

13:36

an untrained person. But these people are

13:38

getting it for all kinds of things

13:40

being sent. That created a lot of

13:42

news because of the abuse, the misuse.

13:45

In some cases, unfortunately, really tragic outcomes.

13:47

Of course, the actor Matthew Perry died

13:49

because he was being prescribed a lot

13:51

of ketamine in a way that was

13:54

given unsupervised. It's also in the news

13:56

because it's become popular like in Silicon

13:58

Valley. Right. Famously, Elon Musk for reports

14:00

that he uses Ketamine on a very

14:03

regular basis on his own that his

14:05

doctor gets it to him to administer

14:07

to himself. And people have worried that

14:09

might have chronic effects. Notably, the most

14:12

biggest name in private Ketamine distribution is

14:14

a company called Mindbloom, which has popped

14:16

up all over the country shipping Ketamine.

14:18

And interestingly enough, the co-founder of Mindbloom,

14:21

the wife of the founder and the

14:23

chief engineer, now works. for Doge. And

14:25

so there's all these sort of interactions

14:27

between the ketamine world and things going

14:30

on in the federal government and the

14:32

tech world. So it's in the news.

14:34

And I worry that that might be

14:36

giving patients, potential patients, the wrong idea

14:39

about what this medicine is as opposed

14:41

to what this, I guess you could

14:43

say, what this drug is. The medicine

14:45

that Spravato, which is a brand name

14:48

for us ketamine, is a very different

14:50

animal, supervised and helpful and proven with

14:52

evidence to be effective. And that's also

14:54

a good segue to this question, and

14:57

I'll direct this to you, Dr. Kim.

14:59

So you're doing all this research. What

15:01

more do we need to know about

15:03

Eschedamine? Yeah, I think one of the

15:06

biggest questions that we still have is

15:08

exact mechanism of Eschedamine. We just really

15:10

don't know. You know, it's primarily used

15:12

as an antagonist for this receptor, NMDA,

15:15

but you know, it potentially may be

15:17

acting... at another receptor, as well as

15:19

its metabolite. Eschedamine and ketamine's metabolite might

15:21

also play a role in having this

15:24

anti-depressant effect. So I think that's the

15:26

next step, because what eschedamine and ketamine

15:28

has done is sort of go beyond

15:30

this serotonin model for depression and start

15:33

looking at other possible... ways of treating

15:35

depression. And I think those, I imagine

15:37

those would be the next steps. And

15:39

Dr. Nestau, I'll end with you here.

15:42

Do you think there's other uses for

15:44

these drugs that maybe we haven't looked

15:46

into yet? Well, there are people that

15:48

are doing active trials for other sorts

15:51

of indications. So maybe there is some

15:53

evidence that it potentially could help other

15:55

psychiatric conditions. It's worth pointing out that

15:57

it's also used in the treatment of

16:00

pain, and that's been something that's been

16:02

FDA approved for even longer than for

16:04

depression. But yeah, there's trials going on

16:06

for OCD, there's trials going on for

16:09

PTSD, even for anxiety disorders, and I

16:11

think you alluded to one for opiate

16:13

use disorder earlier in the interview. happening

16:15

but it's important to recognize that those

16:18

are trials that are ongoing they're not

16:20

completed we don't know yet and in

16:22

medicine it's really important that we don't

16:24

jump the gun because we're dealing with

16:27

people's lives. So we don't want these

16:29

drugs being given for things that we

16:31

just have a hunch, they might work,

16:34

you know. They're not 100% benign, they

16:36

require, you know, safe monitoring. So yeah,

16:38

there's certainly potential out there, but right

16:40

now, what we know, Eschedamine works for

16:43

is treatment-resistant depression, and it also can

16:45

work for suicidal thoughts specifically. And so

16:47

we treat those conditions. Well, this has

16:49

really brought a lot of context to

16:52

the headlines. Sure, thanks for having us.

16:54

Yeah, you're welcome. Public Health on Call

16:56

is a podcast from the Johns Hopkins

16:58

Bloomberg School of Public Health, produced by

17:01

Joshua Sharfstein, Lindsay Smith Rogers, Stephanie Desmond,

17:03

and Grace Fernandez Sissieri. Audio production by

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