GLP-1 [music] drugs are everywhere.

>> GLP-1

>> GLP-1s

>> People scramble to get their hands on

GLP-1 drugs.

>> Today, we're going to talk about the

psychiatric effects of GLP-1 [music]

agonists or medications like Ozempic.

And if you're thinking about taking a

GLP-1 agonist, or if you're taking a

GLP-1 agonist, what you should be aware

of because things are a little bit

complicated. Some studies will show

improvements in binge eating. Some

studies will show increases in anorexia.

Some studies will show improvements in

mood. Some studies will show triggering

of depression. And so, what's going on

here? And it turns out that actually all

of that is true, and that's why we need

to dive into it with a little bit more

detail. So, we're going to start off by

doing a quick review of glucagon-like

peptide and what its role is in the

body. So, the first thing to understand

is that GLP is a hormone. So, the

hormones are chemical signals that

travel everywhere in your body,

everywhere that blood exists. Okay. So,

the first thing to understand about

hormones is that they have differential

effects on different parts of your body.

So, let's use a simple example of

hormone, testosterone. So, testosterone

has differential effects depending on

the tissue that it reaches. So, the skin

cells on the top of my head will make me

bald. The skin cells over here will make

me actually grow hair. The skin cells on

my back will also start to grow hair.

So, it causes a differential pattern of

hair growth depending on the target

tissue. When testosterone travels to my

brain, [music] it'll increase my sense

of protectiveness, maybe some degree of

aggression, some degree of

competitiveness. When it travels down to

my scrotum and testicles, it stimulates

sperm production. And so, depending on

where a hormone travels in the body, it

will have a differential effect. And

when it comes to GLP-1 agonists, this

will explain a lot of the contradictory

information. So, next thing we have to

understand about GLP-1s is what is the

role of glucagon-like peptide? Why does

the body secrete it? What is its job?

So, GLP-1 is a satiety hormone. Okay?

So, satiety is to feel sated, to feel

satisfied. So, basically when we eat

something, our stomach stretches,

glucose gets entered into our

bloodstream, and so our body has these

two modes. It has a hungry mode and it

has a no longer hungry or satisfied

mode. And GLP-1 is one of the key

signals that tells our body we are

satisfied. GLP-1 also works in concert

with insulin. So, you can sort of think

about it like in the same way that you

get a food coma from insulin, GLP-1 will

signal to parts of your brain that we

have had enough to eat. I keep seeing

comments, "Dr. K, how do I apply this to

a situation in my life?" That's

literally why we created a coaching

program. Our coaches are certified on an

evidence-based curriculum designed to

help you get unstuck. This involves

analyzing your patterns, increasing

[music] your understanding, and working

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So, if you all are interested, check out

the link in the description below. If we

look at insulin, insulin is focused

primarily on glucose metabolism. So, it

regulates our blood sugar, okay? But

GLP-1 is not related to blood sugar, but

is related to other parts of satiety.

So, GLP-1 travels to this part of our

brain called the ventral tegmental area,

which is where our dopaminergic reward

circuitry is. [music]

So, when we have a craving, that comes

from our dopaminergic reward circuitry,

right? Like I want to eat french [music]

fries. And then I eat french fries, and

then it feels pleasurable. So, eating

food is tied with pleasure. Eating fatty

food, having intense cravings for sugary

food, all of those are tied to pleasure.

And I don't know if you guys have kind

of experienced this, but like hopefully

you know, you can eat a cookie and it

tastes really good and then you eat a

second one, you eat a third one, you eat

a fourth one, you eat a fifth one. And

if you look at the volume of cookies

you're eating, they're actually pretty

small, right? Like you can eat five

cookies and it's not like the same

quantity of food, it's not the same

volume of food as let's say like a big

salad that is like low calories, right?

But as each subsequent cookie you eat

gives you a reduction in your craving

and then your pleasure starts to kind of

go down. A lot of that reduction in your

pleasure is mediated by GLP. So GLP

travels up to your brain and actually

inhibits the pleasure that you get from

eating foods. That same part of your

brain, the ventral tegmental area or

nucleus accumbens, is also where our

cravings come from. So I don't know if

this kind of makes sense. The more you

eat, the less you crave eating unless

you've got something like a binge eating

disorder, right? So does that kind of

make sense? More pleasure you have, so I

have cravings high, pleasure low, and

then as I eat, cravings go down and

pleasure goes up. And the chemical

signal to mediate that shift is a GLP-1.

So the GLPs basically reduce our

cravings and increase our sense of

satiety. So now let's talk about GLPs

and addictions because if we're reducing

our cravings and blunting our pleasure,

then it should have an impact on

addictions, which is absolutely what we

see. This is a study that was used AI to

analyze people talking on the internet

and basically found that people were

reporting when they started GLP-1

agonists like Ozempic that it affects

their substance intake. So it reduces

their alcohol intake, reduces their

caffeine intake, reduces their nicotine

intake, seems to have not a huge effect

on cannabis. And then in terms of

behavioral addiction, seems to reduce

compulsive shopping, impulsive shopping,

but according to some of these reports

may actually enhance pornography usage.

So people become potentially more

addicted to pornography or use

pornography more when they are on GLPs.

So what's going on here? So in order to

understand how GLPs affect addictions,

we have to understand a little bit more

about how they affect the dopaminergic

circuitry, okay? So this gets a bit

complicated. So this is the way that

your dopamine normally works, okay? So

we have some level of dopamine that just

fluctuates throughout our day. I take a

sip of water.

That water's tasty. I get a little bit

of dopamine, okay? And then there are

times where I'm like a little bit bored.

Oh my god, this is boring. Like this guy

is just like rambling on about dopamine.

He's talking about science. Oh my god,

that's so boring. So we get a dip in our

dopamine. So our dopamine just kind of

goes up and down throughout the day. And

then what happens is we sometimes get

something that is addictive.

>> [music]

>> So I eat a donut or I play a video game

or I use cocaine. And [music] in those

three cases, right? Or sometimes all

three all at once.

I get a spike of dopamine. So the way

that GLPs work is by capping the

dopaminergic signal that your brain can

get. So it doesn't affect our day-to-day

dopaminergic stuff, but if we do [music]

something that induces a spike of

dopamine, it kind of caps that, [music]

okay? So the way that you can think

about it is like it doesn't affect the

basic speed of our car, it just lowers

the top speed that my car is capable of

going. I can hit 100 km, but I can't hit

120 or 140 or 150. Now the interesting

thing is that it is the high spikes that

make us addicted to things, okay? So

it's really hard to get addicted to

something that has a low dopaminergic

signal. So the things that are the most

addictive are the things that give us

the biggest spikes. So when my friend

says, "Hey Dr. K, it's great to see you.

Like it it are you having fun at the

party?" I'm like, "Yeah, man, I'm having

fun." He's like, "You want to go into

the bathroom and do some coke?" And I'm

like, "Sure, I'll give it a shot." And

I'm like, "Wow, that's amazing." So when

we get a high spike of dopamine, that is

what triggers neuronal rewiring. So, we

can look at this in other mechanisms

like loot boxes. Why are loot boxes so

addictive? Because the spike in dopamine

that they give us is way higher because

most of the time we get nothing.

Occasionally, we get a big spike, and

then we're like, "Oh my god, I want that

high again." This is why people who play

the lottery and lose lots of money over

the lottery will still continue to play

it because that spike of winning keeps

us coming back. So, now this is

something that's like pretty cool

because the GLP-1, since it prevents the

spike, it prevents us from getting

addicted to things. It's not that

simple, but that's basically the

mechanism that it's blunting, which is

why we see, it's really fascinating,

reductions in a lot of addictive

behaviors, okay? And this is what's kind

of interesting about it. So, now we're

going to tunnel down into specifically

alcohol use. So, here's a study that's

looking at semaglutide or Ozempic on

alcohol use. And what we find is that

[music] people who are on GLP-1s, it

doesn't reduce the number of days that

they drink, okay? So, if I normally have

drinks 3 days a week, I go to happy hour

on Thursday, go to happy hour on Friday,

have a wine night on Saturday. Once I

start my GLP-1, that doesn't [music]

change. I still drink Thursday, Friday,

and Saturday.

But what it changes is how much I drink.

So, if you measure the average alcohol

concentration in the blood before and

after semaglutide, what you find is that

the alcohol concentration is way lower.

The number of drinks that I have [music]

actually drops quite a bit. I still feel

like drinking, right? Oh, like I'll have

a glass of wine. But whereas I used to

have like two, three, four glasses of

wine, now I'm having like one and a half

to two. And if we kind of think about

it, once we understand the

neurochemistry, it sort [music] of makes

sense, because it's reducing my craving.

It is blunting the pleasure that I get

from alcohol. So, I can enjoy a glass of

wine with dinner, but then after you

have that first glass, you're like,

"Man, like top me up. Give me a Give me

a hefty pour, right?" After you have

that second drink, you're like, "Fill it

up all the way, baby. Like, let's go."

As you start to drink a little bit, you

want to drink a little bit more. As you

start to eat one potato chip, you're

like, "Man, that potato chip was really

good. Let me have a second. Let me have

a third. Let me have a fourth." That's

what it blunts, right? Cuz it caps that

dopamine. So, it appears like we've got

pretty decent evidence that it improves

a lot of addictions, alcohol at the top

of the list, maybe caffeine, maybe

nicotine, maybe impulsive shopping,

maybe binge eating, for sure. But, it

may not have much of an effect on

cannabis, and may actually be harmful

when it comes to pornography. Now,

remember that GLPs affect all the

different parts of our brain. And so,

when it affects the emotional parts of

the brain, it appears that it leads to a

lot of mood dysregulation that is not

good. So, it seems to increase feelings

of depression, seems to blunt our

capacity to experience pleasure. And

this is what some people call kind of

the Ozempic personality. This is when

people are on semaglutide, like they

just don't feel like doing stuff. Stuff

doesn't really feel super fun to them.

And that kind of makes sense. So, it

causes some anhedonia. So, anhedonia is

the inability to experience pleasure.

It's one of the hallmarks of depressive

episode. And when people are on

semaglutide, we can see how it can cause

anhedonia because it is capping our

dopaminergic response, right? So, we're

not feeling really excited about stuff.

Like, sure, it caps the cocaine response

and the alcohol response, but maybe it's

also capping the birthday party

response. And since those spikes of

dopamine are what encourage our

behavior, right? Once I get a loot box,

I want to buy another one. Once I go out

and I have a blast, how was your this

party on Saturday night? Oh my god, bro,

it was completely awesome. Some people

were doing in the bathroom. I steered

clear of it, but I still had a great

time. Even if I'm blunting my ability to

have a great time at a party, that'll

then shape my motivation and over time

the Ozempic personality seems to kind of

like contract people's sphere of what

they do. So, there's evidence that it

increases feelings of depression. One

study found that it increased as much as

195%.

So, the risk of depression is

skyrockets, right? So, that's almost a

twofold risk. And it also appears to

increase suicidality by over 100%

according to this one study. And so,

doctors for the past several years have

been noticing that when they start their

patients on GLP-1s, that it seems to be

increasing the risk of depression, can

cause relapses of depression, and what's

even the the scariest thing is that for

people who have had no history of

depression, seems to drastically

increase the risk that they will develop

depression for the first time.

But then there are some studies,

especially things called meta-analyses.

So, this is when we pool together data

from lots of different studies to see if

there's something that kind of floats to

the surface. So, here's an example of a

meta-analysis that basically found that

there's no increased risk of depression.

So, like what's going on, right? So, on

the one hand you have doctors who are

prescribing this medication, who are

seeing people relapse onto depression or

having a a resurgence of their

depression. You're seeing people have

new onset depression, but then you have

some of these big trials that are

showing actually there seems to be no

difference. It doesn't actually increase

risk. So, what's the deal? And this is

where we get to a really fascinating, I

think for me, key finding about GLPs,

which is that the kind of person who

takes it determines how healthy or

unhealthy it is. So, here's a study that

found something really interesting. For

people who were obese and took a GLP-1,

it did not increase their risk of

depression. But, for people who were at

a normal or healthy weight, and if they

took a GLP-1, there is a greater chance

that it increased their risk of

depression. And this is where we have to

get to some like really basic important

stuff about medicine. See, anytime I

prescribe a medication as a doctor,

there's a risk benefit, which is like

duh. But, let's understand something

about depression. So, let's say I'm

morbidly obese, I have a BMI of 30. When

I need a CAT scan, I have to go to the

literally I've had patients who have

this. I'm like 600 lb or 700 lb, and I

don't fit in the CAT scan at

Massachusetts General Hospital. So, I

have to get transported by ambulance to

the zoo because they have a CAT scanner

that will work on me. Imagine

that that is what my life is like. Now,

imagine what what is the impact on my

mood if I am very overweight and I have

to use the zoo's CAT scanner, right? So

shaming, incredibly depressing.

Now, let's say I take semaglutide.

And then what happens is I lose, let's

say 100 lb, 200 lb, 300 lb.

What impact will that have on my mood?

So, what we start to see, this is really

important, is weight loss and a

reduction in obesity has a positive

impact, a huge positive impact on

depression. That's not just because of

the shame of the the zoo CAT scanner,

that's because we don't realize that

adipose tissue, fat tissue, is

hormonally active. So, the greater my

fat tissue, the more insulin resistance

I have, the more inflammation I have.

There are many negative mental health

benefits of being at an unhealthy

weight, let alone the psychological

shame and all that kind of stuff. So,

when we're talking about a risk-benefit,

being able to lose 100 lb, being able to

go outside and go to the beach and

things like that, that will have such a

positive impact on my mental health that

even if from a chemical sense it's

messing with my affect regulation

centers, the gain that I get from the

weight loss for my mental health will

outweigh or balance the risk of messing

up my emotional regulation centers in my

amygdala and my limbic system. Whereas,

if I am at a healthy weight and I just

start semaglutide, I'm not getting some

of those benefits from the weight loss

for my my shame and being able to go to

the beach and things like that cuz I can

already do that. Like I already get sent

to an imaging center instead of the zoo

when I need a cat scan. So, this is why

I think it's really important to like

that that

this is what the study show is that

there is a differential effect of GLPs

on people's mental health. And the more

overweight you are, the more helpful a

GLP is. And the less overweight you are,

the more potentially harmful a GLP is.

And the best place that we see that is

actually when we talk about eating

disorders. So, the first thing remember

is that GLPs go to the ventral tegmental

area that they

blunt the dopaminergic pleasurable

response. So, no surprise that people

with binge eating disorders, right? When

I can't stop myself and I'll eat 6,000

calories in a sitting. And if we think

about what's driving that, it's the

pleasure. It's the dopamine. I feel

addicted. I can't stop. And when we give

people GLPs, it seems like they really

blunt binge eating disorders. So,

people's binge eating goes way down.

Good job. But,

if we look at other kinds of eating

disorders that are not reward based, are

not addictive, are not dopaminergic.

Anorexia is at the top of the list. So,

the the neurochemistry of anorexia is

not related to reward, right? It's not

like people who are anorexic, they

actually feel awful. They feel really

bad. They They're not I've had patients

who were hospitalized with anorexia, who

we have to start we have to put tube we

have to start tube feeds. We have to

sometimes in really scary situations

strap them actually physically restrain

them to get calories inside their body

because they're so malnourished that

their heart is starting to have

arrhythmias. The interesting thing is

when someone is in that bed giving

getting IV fluid or getting

nasogastric tube tube feeds,

they're not high, right? They're not

like pleasurable. They're not like like

this isn't fun for them. Their suffering

is profound. Their suffering is intense.

And even if you you you know, talk to

people with anorexia, what you'll find

is that like the majority of their day

is like suffering. Like they they're

like they have all these cravings that

really want to eat. Their [ __ ] body

wants to eat something, man. Like, "Oh

my god, I want to eat something. The

cravings are so hard. I'm with my

friends and my friend brought a peanut

butter peanut butter and crackers and

and like a girl dinner plate with like

fruit and peanut butter and crackers and

this like triggered me so hard." Their

baseline experience is suffering. And

anorexia conversation for different day

is all about control, trying to exert

control, trying to hammer your body and

the world around you into complying with

your will. That has nothing to do with

dopamine. And so, what we're starting to

see that's really scary is that GLP-1s,

they may help with binge eating

disorders, but they are actually making

anorexia and restrictive eating

disorders potentially way worse. And

they are potentially causing a trigger,

someone who didn't have an eating

disorder, to have eating disorders. So,

here's what's really scary. One of the

risk factors for causing an eating

disorder is weight loss. So, if you are

someone who has certain psychological

vulnerabilities, especially around body

image, right? So, if you're someone who

is at a healthy weight and you have a

lot of body image issues because you

spend a lot of time on the gram, on Tik

Tok, on seeing all these people who have

filtered faces and now you start to feel

a little bit vulnerable, you go on

dating apps but people swipe left. Oh my

god. Right? This is happening all over

the place. So, we have psychological

vulnerabilities in people with

psychological vulnerabilities who lose

weight, this can actually trigger an

eating disorder, okay? So, there's

something called atypical anorexia

nervosa, which has all the features of

anorexia. So, restricted eating, you

know,

body image issues, but they're actually

at a normal weight. So, one of the key

factors of diagnosing anorexia is you

have to be at an unhealthy weight.

That's one of the diagnostic criteria.

But, there are some people who have

atypical anorexia. They have the mind of

an anorexic and the body of someone who

is at a regular BMI or a healthy BMI.

And even as much as a 5% weight loss

can trigger atypical anorexia. So, we

can trigger eating disorders if we

actually lose weight. And here's what's

really fascinating. There's some studies

that show that

patients with binge eating disorders who

go through cognitive behavioral therapy,

the more weight they lose, this is a

binge eating disorder, so they're

usually at a normal weight or

potentially even overweight, the more

weight they lose, the greater their risk

is of developing something like

anorexia. It's insane. So, like if I go

through cognitive behavioral therapy and

I lose 50 lb, my risk of anorexia is

higher than if I lose 25 lb. Right? So,

there's something about the extremity,

I don't know, the severity of like the

rigidity of anorexic thinking where the

more you lose weight, the more it kind

of turns on. And this is what we're

seeing with GLP's is it seems to

exacerbate this risk. And this is where

people are sort of seeing the like the

Ozempic face, right? And the Ozempic

face is like kind of shrunken, um and

there are very like severe cases, case

reports of people who are able to manage

400 to 600 calories a day, are getting

dehydrated with using semaglutide. And I

want y'all to kind of think about this

for a second, okay?

Cuz let's say I'm an anorexic and I want

to lose as much weight as possible. I

hate the fact I look at my my face in

the mirror and I think that I'm obese.

So, in my body there's a war, which is

what anorexics suffer with, okay?

There's a war between like my liver

telling me, "Hey, we're out of calories.

Like we need food." And so there are

strong craving signals that are being

sent to my brain. We are starving, bro.

Give us some food. And that fights

against my control. So, I have

pro-eating signals and anti-eating

signals.

And how does a GLP-1 work? Agonist work?

It reduces my cravings. It reduces It's

a GLP-1 agonist. It tricks my brain into

thinking we just ate. So, now that I've

tricked my brain into thinking that we

just ate, my capacity to restrict my

calories actually increases. So, at the

end of the day, what is the impact of

GLP's on your mental health? We kind of

don't know for sure. Should you take a

GLP-1? I would say this is why we say

talk to your doctor. This is not just

medical legal cover your ass. This is

why what we're seeing with GLP's one

GLP-1's, it is a highly individual

decision based on your risk factors. Do

you have a lot of health benefit to gain

from losing weight? Or are you trying to

do this for cosmetic reasons, right? Are

you struggling with certain addictions?

Do you need to cut down on your alcohol?

But is it porn addiction? And lastly, if

you have a history of mental illness or

even don't have an a history of mental

illness, you should be on the lookout

for things like a rise in depression or

even spike in suicidality. So

potentially amazing drug, but to be used

with caution.