Welcome back to the Deep Dive. Today we are opening
up a file that, at first glance anyway, it kind
of looks like it belongs in some Silicon Valley
marketing seminar, but it's actually one of the
most critical and honestly kind of unsettling
concepts in modern pharmacology. It really is,
yeah. We're looking at a pretty dense stack of
research today involving abuse liability studies,
regulatory guidelines, and some really heavy
psychological theory from researchers like Robinson,
Berridge, and Thibault. The headline concept
here, the thing tying it all together is drug
liking, which I have to say, when I first started
reading the source material, it sounded incredibly
casual to me. It sounds like a social media metric,
you know, like click here if you like this opioid.
Right. It does sound a bit trivial, like a Yelp
review for pharmaceuticals or something. But
in the context of the sources we have today,
drug liking is a really rigorous, high stakes
scientific metric. It is basically the gold standard
for how we measure the hedonic impact of a substance.
Ionic meaning the actual pleasure of it, the
enjoyment, the yum factor, for lack of a better
term. Exactly. Yeah. The raw, subjective experience
of pleasure. And our mission for this deep dive
is to unpack how scientists actually go about
measuring that pleasure to predict if a drug
is going to ruin lives. And this is the part
that really hooked me through. We're going to
find out why liking a drug might actually be
completely irrelevant to addiction in the long
run. That's the liking versus wanting paradox.
That was the nugget in the reading that just
stopped me cold. The idea that you can aggressively
want something, pursue it with every fiber of
your being, even if you don't actually like it
anymore. It's a terrifying distinction. It challenges
basically everything we think we know about human
desire. But before we get to that kind of existential
dread, we really have to look at the nuts and
bolts. Like, how do you even measure liking in
a clinical lab? Right. Because you can't just
ask a test subject, hey, was that fun? I mean,
you could. But that's not data. The FDA needs
hard numbers, not just anecdotes about a good
time. Precisely. So imagine you are a pharmaceutical
company. You've developed a new painkiller, and
it works great for pain. But you really need
to know, is this the next OxyContin? Is this
going to trigger an addiction crisis? You have
to quantify the high. You need to measure its
abuse liability. And the tool for that, according
to these documents, is the VAS. The visual analog
scale. Yeah, the VAS. It's the standard tool
of the trade in these environments. Now, most
people have seen some version of this at the
doctor's office, I think, like the pain scale,
the line with the frowny face on one end and
the smiley face on the other. It's the exact
same principle, but flipped. So in a lab setting,
a drug -liking VAS is typically just a 100 -millimeter
line on a piece of paper or maybe a tablet screen.
On the far left, it might say strong disliking.
In the middle, it's neither like nor dislike.
And on the far right, strong lacking. So paint
the picture for us here. They give a human volunteer
a dose of this experimental drug. And then what?
They just sit there with a clipboard. Basically,
yes. They wait. And at very specific time intervals,
say every 15 minutes or every hour, the subject
has to make a mark on that line. It sounds incredibly
primitive, doesn't it? Making a mark on a line.
But it effectively turns a purely subjective
feeling into a hard number between zero and 100.
Wow. But the sources list a few variations of
this, right? There's drug liking, but there's
also the high VAS. I was trying to parse the
difference there when I was reading. Is there
really a meaningful distinction between saying
I like this and I am high? There is. And it's
a subtle but really crucial difference in the
research. High measures the intensity of the
altered state. So you can be incredibly high,
disoriented, dizzy, seeing trails, hallucinating.
but score very low on liking if that experience
is scary or nauseating. Oh, that makes total
sense. I can imagine feeling completely altered
but hating every single second of it, like being
strapped to a roller coaster you really didn't
want to ride. You are definitely experiencing
intense sensations, but you certainly aren't
liking it. Exactly. And that's why the sources
emphasize the bipolar nature of some of these
scales. Bitolar meaning it goes both ways. Right.
A bipolar scale allows you to go negative. If
a drug makes you vomit or feel intense anxiety,
that data point is just as important as the euphoria.
It tells regulators that the abuse potential
might be lower because the experience is physically
or mentally punishing to the user. So if I'm
a researcher, I'm looking for the drug that scores
high on, high but low on liking. Or is it more
complex than that? You're looking for the correlation
between them. But then there is the third scale
mentioned in the text, which honestly felt the
most direct to me. The TDAVAS. Ah, the take drug
again scale? The TDA. It just cuts through all
the noise. It's not asking about your feelings
or your weird sensations. It's literally just
asking about your future behavior. Given the
chance, would you do this again? And that is
very often the most predictive metric they have.
You might have a subject who says, well, I don't
really feel high in the traditional sense, and
I'm not sure I even like this dizziness. But
when asked, would you take this again, they immediately
mark a 90 out of 100. See, that's the first hint
of the problem, isn't it? That strange disconnect.
Why on earth would you want to take it again
if you didn't just... rate the experience as
pleasurable. That seems totally counterintuitive
to how we usually make decisions in life. You've
hit the nail on the head. That discrepancy on
the chart where the take drug again score stays
incredibly high, even when the liking score drops
off a cliff that is the shadow of addiction.
It's the first real scientific clue that something
other than fun is driving the bus. Let's dig
into that then, because the source material references
this theory by Robinson and Barrage called the
incentive sensitization theory. It sounds super
academic, but the implications of it are actually
pretty dark. It is the liking versus wanting
dissociation. To really understand this, we have
to look at how we usually view desire in our
day -to -day lives. We tend to think... I eat
the cake because I like the taste of the cake.
I play the video game because I enjoy the game.
Cause and effect. The pleasure drives the pursuit.
If the cake suddenly tasted like wet cardboard,
I wouldn't want it anymore. Right. In a normal
healthy brain, those two things are intricately
linked. But Robinson and Barrage argued, and
this completely shifted the paradigm, that these
are actually two completely separate neural systems.
There is a hedonic system, which is the liking.
That's the yummy feeling. And then there is a
totally separate incentive salient system, and
that is the wanting. Incentive salience. That's
a phrase that kept popping up in the notes. I
want to make sure we really get this because
it sounds like dense psychological jargon, but
it really seems to be the key to the whole thing.
Let's break it down simply. Think of salience
as a spotlight. Your brain is constantly scanning
your environment. When it sees something relevant
to your survival food, water, or potential mate,
it shines a massive spotlight on it. It makes
that specific thing stand out against all the
background noise of the world. Okay, so I walk
into a messy kitchen. I don't even notice the
toaster or the dirty sink, but my brain immediately
notices the fresh sandwich sitting on the counter.
The sandwich has salience. Exactly. Now, the
incentive part means your brain attaches a DOIT
tag to that spotlight. It's a command. It's not
a warm feeling of joy. It's a magnetic pull.
It's the intense feeling you get when you've
been walking in the desert and you are incredibly
thirsty and you finally see a glass of water.
You don't just like the water. You are drawn
to it. You absolutely need it. So in a healthy
brain, these two things are synced up perfectly.
I want the water. I drink the water. I like the
water. Correct. In a healthy brain, they overlap
seamlessly. But drugs, specifically the ones
we're discussing today with high abuse liability.
They hack this system. They can artificially
crank up the wanting dial to maximum completely
regardless of what the liking dial is doing.
This totally explains that zombie feeling people
describe in deep addiction or why people say
they are chasing the dragon, right? Yes, that's
exactly it. The source literally defines drug
wanting as the unconscious attribution of incentive
salience. Note the word unconscious there. You
don't consciously decide to want it. Your brain
has physically tagged the drug as being more
important than food, more important than sleep,
or even your own safety. It is essentially assigned
at top survival priority. So when we see a patient
in these clinical studies who scores the drug
as totally neutral on enjoyment, maybe it just
makes them feel tired or slightly nauseous, but
they score a 100 on take drug. Again, we are
literally seeing that brain hack happen in real
time. We are. Their conscious mind is sitting
there saying, this isn't even fun anymore. I
actually feel sick. But their primitive survival
brain is screaming, D, D, D. And here is the
real kicker of the Robinson and Barrage theory.
Because physical tolerance builds up, the liking
almost always fades over time. You need more
of the drug just to get the same baseline effect.
But the wanting that sensitization of dopamine
system actually grows stronger with repetition.
God, that is tragic. It means the longer you
use it, the less you actually enjoy it, but the
more you are completely compelled to do it. It's
a trap that tightens the more you struggle against
it. It really reframes our entire empathy for
addiction, I think. We often judge people thinking,
why are they choosing to party instead of taking
care of their family or their responsibilities?
But if you understand this dissociation, you
realize they aren't partying at all. The party
ended years ago. Now they are just servicing
a... broken survival mechanism in their brain.
It's mechanical. That's the word that keeps coming
to my mind. It's not a moral failing. It's mechanical.
It's like a software glitch where the purchase
button is just permanently stuck down. It is
a mechanical glitch. And this brings us nicely
to the actual chemicals themselves. The source
material provides this sort of rogues gallery
of substances that light up these specific systems.
Yeah, let's run through that chemical landscape.
It's mostly the usual suspects, but there are
definitely some nuances here that surprised me.
At the top of the liking charts, we have the
major stimulants. Cocaine, amphetamines, MDMA.
Right, these are the heavy hitters. Because they
work so directly on dopamine. And while we just
said dopamine is mostly about the wanting system,
in the very initial stages, these drugs flood
the system so hard and so fast, they trigger
massive liking scores too. They basically force
the brain to perceive intense euphoria. Then
we have the depressants, opioids, benzos, alcohol.
Different mechanism there, but a very similar
result on the VAS scores. Opioids, for instance,
mimic our internal endorphins. The liking here
is often described by subjects as a warm blanket,
a total removal of physical pain and mental anxiety.
The score goes up simply because the suffering
goes down so drastically. But I noticed the source
spent a specific amount of time discussing ADHD
medications. methylphenidate, which most people
know as Ritalin, and lisdexamphetamine. This
is a very sensitive and highly researched area.
We have millions of people, including millions
of children, taking these drugs therapeutically
every single day. But chemically speaking, methylphenidate
is actually very similar to cocaine in how it
blocks dopamine transporters in the brain. Okay,
so this is the obvious question then. If the
chemistry is that similar, Why isn't every kid
with an ADHD prescription turning into an addict?
Why aren't we seeing that incentive salience
hijack happen to everyone taking these meds?
That's where the clinical pharmacologic assessment
comes in, which was mentioned in the text referencing
Volko and Swanson's work. It turns out liking
and the subsequent wanting cascade depends incredibly
heavily on speed. Speed of onset, like how fast
it hits you. Yes. The rate of rise. Yeah. If
you swallow a pill and the dopamine levels in
your brain rise slowly and steadily over an hour,
the brain doesn't register that sudden bang of
incentive salience. It helps you focus. It does
its therapeutic job, but it doesn't trigger the
high VAS at all. So it's basically the difference
between slowly walking up a hill and being shot
out of a cannon. Exactly. But if you were to
take that exact same pill, crush it up and snort
it. You bypass the slow release mechanism entirely.
You turn the hill back into a cannon. Right.
The chemical hits the brain in seconds instead
of hours. That rapid unnatural spike is what
triggers the liking and the wanting. That's why
the abuse liability studies referenced in our
sources are so heavily focused on formulation.
The drug companies are asking, can we make a
pill that works therapeutically but is physically
impossible to crush or inject? Can we make the
delivery so slow that it's boring to the brain's
reward system? It's an engineering problem. They
are trying to figure out how to deliver the medicine
without accidentally ringing the euphoria bell.
That is the ultimate goal of modern pharmaceutical
formulation. They want the purely therapeutic
effect without the high abuse liability. Now,
there was one inclusion in the list of substances
that actually made me check my own desk. I'm
literally holding a cup of it right now. Caffeine.
Huh. Yes. The drug of commerce. The source explicitly
says caffeine increases drug -liking scores,
but it uses a very specific kind of funny qualifier.
It says it increases them limitedly. That word
limitedly is doing a whole lot of heavy lifting
in that sentence. I was going to say, I definitely
like my morning coffee. And if I don't have it,
I absolutely want it. I might even get a headache
or get cranky. So how is that fundamentally different
from the addiction mechanisms we just spent all
this time talking about? It's largely a matter
of the pharmacological ceiling. You can rate
a good cup of coffee a high on the liking scale,
sure. But caffeine has a hard ceiling. If you
drink 10 cups of coffee, you don't get 10 times
the euphoria. You get the shakes. You get terrible
anxiety. You feel like your heart is going to
explode out of your chest. The disliking scale
kicks in really hard and really fast. Exactly.
The negative physical effects override the positive
ones incredibly quickly. Compare that to cocaine
or opioids, where the ceiling for wanting is
virtually non -existent until the user hits toxicity
or death. Caffeine creates a habit, and it definitely
has reinforcing properties as noted by Griffiths
and Woodson in the source material, but it doesn't
hijack the incentive salience system to the point
where you'd, you know, rob a bank to get an espresso.
Usually not, anyway. I mean, maybe on a really
rough Monday morning. Fair point, yeah. But generally
speaking, society doesn't collapse due to caffeine
wanting. So we have the tools with the VAS. We
have the core theory with liking versus wanting.
And we have the chemicals. I want to zoom out
to the real world application of all this. The
source mentions that these measures are core
outcome measures for opioid abuse liability laboratory
assessment studies. That's quite a mouthful of
a phrase, but it basically just means this is
the gauntlet. The gauntlet for new drugs before
they hit the pharmacy. Yes. Before any new opioid
or sedative hits the market, the FDA usually
requires these human abuse potential studies.
And here is the truly fascinating part about
these studies. Who do you think the actual test
subjects are? I assumed it was just random healthy
volunteers, maybe college students looking for
extra cash on the weekend. No, you actually can't
use random people. A random person might not
even know what a high feels like, or they might
just feel sick and confused by the drug. The
regulatory guidelines, like those from the IMPACT
-T group mentioned in the text, strongly recommend
using recreational drug users. Really? So they
specifically recruit people who already have
extensive experience with illicit drugs? They
do. They need connoisseurs, in a way. They need
people who can clearly distinguish between, I
feel a little dizzy, and I feel exactly like
I just took OxyContin. They need people whose
brains are already somewhat... tuned to recognize
these specific subjective effects. That is wild,
wanted, professional drug taster. But logically,
it makes total sense. You need someone with a
refined palate to grade the wine, so to speak.
It sounds strange to the layperson, but it's
absolutely vital for public safety. If these
highly experienced users take the new experimental
drug and say, whoa, this feels exactly like my
favorite street drug, and their Take Drug Again
score is a solid 100, that drug is in serious
trouble. It will either be rejected entirely
or put under the very strictest regulatory controls.
A firewall, a human firewall against the next
epidemic. It is. But, and here is where the science
is getting even more sophisticated lately. We
talked earlier about how wanting is unconscious,
right? Right, the unconscious attribution of
incentive salience. So if I ask a subject in
a lab, do you want to take this again? They might
just lie to me. Or honestly, they might not even
realize that they want it yet. Conscious filtering,
like they think, I shouldn't want this, so I'll
be good and say no. Or maybe they're just bored
and want to go home. Exactly. The explicit verbal
answers can be flawed. That's why the source
brings up implicit measures, specifically referencing
the work by Tibble and colleagues. These are
tests designed to bypass the conscious talking
mind entirely. How do you do that? Are they reading
their minds with electrodes? Close, actually.
You measure the physical reactions they can't
consciously control. Things like raw reaction
times or eye tracking. For example, they use
something called a visual probe task. How does
that work? You sit the subject in front of a
screen and you flash two images for just a fraction
of a second. One is a completely neutral object
like a stapler or a chair, and the other is a
picture of the drug or drug paraphernalia. Then,
using highly sensitive cameras, you track exactly
how fast their eyes snap to the drug. Oh, the
spotlight again. The incentive salience spotlight.
The spotlight. Exactly. If your eyes involuntarily
jump to the image of the drug in 200 milliseconds,
your brain is clearly assigned it incentive salience.
Even if your mouth just told the researcher,
I have absolutely no interest in that stuff.
That is incredibly high tech. It's basically
a lie detector for the lizard brain. It perfectly
reveals what the organism actually prioritizes
at a survival level completely, regardless of
what the person thinks they prioritize. It catches
that raw wanting signal before the liking or
disliking conscious thought. even has time to
fully form in the prefrontal cortex. Man, this
whole deep dive has really shifted my perspective
on this. I started off today thinking drug liking
was just a dry administrative data point, just
a mandatory box to check on an FDA form. But
it's actually this profound window into the silent
battle happening inside our own heads. It really
is. I think it helps us deeply understand that
severe addiction isn't just about someone stubbornly
seeking pleasure. It's about a fundamental chemical
error. and how the human brain assigns value
and priority to things. We have the liking system,
the innocent part of us that just wants to feel
good, to be happy and comfortable. And then we
have this wanting system, this dark engine room
of survival that can just get completely hijacked
and run totally off the rails. And the true tragedy
of addiction is simply Those two systems getting
violently divorced from one another. The engine
is running at full speed, burning everything
up, but there's no destination anymore. It really
makes you think about our own lives, even completely
outside the realm of heavy pharmacology. The
source is focused on drugs, obviously, but this
incentive salience machinery is humming away
in all of us all day long. It's literally how
we survive. That's the lingering thought that
stuck with me, too. We live in a modern world
that is practically explicitly designed to trigger
that exact wanting system. Oh, absolutely. Social
media algorithms, infinite scrolling feeds, hyper
palatable sugary foods, frictionless buy now
buttons. They're all just trying to hack that
spotlight, aren't they? Exactly. The algorithms
are essentially optimizing for digital wanting.
They don't actually care if you authentically
like the content. They don't care if the content
makes you angry or depressed or deeply jealous,
just as long as you keep scrolling. As long as
your personal take drug again metric, or in this
case, the open app again metric, stays artificially
high. That's a haunting parallel. We might be
literally clicking a button called like on our
phones, but are we actually liking it or are
we just stuck in a chemically engineered loop?
Right. Are you genuinely pursuing pleasure and
enrichment or are you just blindly satisfying
a compulsion that was programmed into your dopamine
system by a brilliant software engineer or a
specific chemical structure? That is definitely
a question to ask yourself the next time you
find yourself doom scrolling at two in the morning
or reaching for that third donut without even
thinking. Are you liking? Are you just wanting?
Well, on that cheerful and mildly terrifying
note, we're going to wrap it up. Thanks for joining
us for this deep dive. It was a fascinating one.
See you next time.