WEBVTT 00:00:00.000 --> 00:00:03.160 Welcome back to the Deep Dive. Today we are opening 00:00:03.160 --> 00:00:05.480 up a file that, at first glance anyway, it kind 00:00:05.480 --> 00:00:07.500 of looks like it belongs in some Silicon Valley 00:00:07.500 --> 00:00:09.480 marketing seminar, but it's actually one of the 00:00:09.480 --> 00:00:12.199 most critical and honestly kind of unsettling 00:00:12.199 --> 00:00:14.980 concepts in modern pharmacology. It really is, 00:00:15.039 --> 00:00:17.019 yeah. We're looking at a pretty dense stack of 00:00:17.019 --> 00:00:20.100 research today involving abuse liability studies, 00:00:20.519 --> 00:00:23.899 regulatory guidelines, and some really heavy 00:00:23.899 --> 00:00:26.280 psychological theory from researchers like Robinson, 00:00:26.600 --> 00:00:30.339 Berridge, and Thibault. The headline concept 00:00:30.339 --> 00:00:32.700 here, the thing tying it all together is drug 00:00:32.700 --> 00:00:35.740 liking, which I have to say, when I first started 00:00:35.740 --> 00:00:37.780 reading the source material, it sounded incredibly 00:00:37.780 --> 00:00:39.859 casual to me. It sounds like a social media metric, 00:00:39.960 --> 00:00:42.320 you know, like click here if you like this opioid. 00:00:42.500 --> 00:00:44.299 Right. It does sound a bit trivial, like a Yelp 00:00:44.299 --> 00:00:46.420 review for pharmaceuticals or something. But 00:00:46.420 --> 00:00:48.320 in the context of the sources we have today, 00:00:49.039 --> 00:00:52.039 drug liking is a really rigorous, high stakes 00:00:52.039 --> 00:00:54.939 scientific metric. It is basically the gold standard 00:00:54.939 --> 00:00:57.899 for how we measure the hedonic impact of a substance. 00:00:58.570 --> 00:01:00.390 Ionic meaning the actual pleasure of it, the 00:01:00.390 --> 00:01:03.409 enjoyment, the yum factor, for lack of a better 00:01:03.409 --> 00:01:06.769 term. Exactly. Yeah. The raw, subjective experience 00:01:06.769 --> 00:01:09.730 of pleasure. And our mission for this deep dive 00:01:09.730 --> 00:01:12.689 is to unpack how scientists actually go about 00:01:12.689 --> 00:01:16.129 measuring that pleasure to predict if a drug 00:01:16.129 --> 00:01:20.150 is going to ruin lives. And this is the part 00:01:20.150 --> 00:01:22.530 that really hooked me through. We're going to 00:01:22.530 --> 00:01:25.450 find out why liking a drug might actually be 00:01:25.450 --> 00:01:27.890 completely irrelevant to addiction in the long 00:01:27.890 --> 00:01:30.739 run. That's the liking versus wanting paradox. 00:01:31.159 --> 00:01:32.980 That was the nugget in the reading that just 00:01:32.980 --> 00:01:35.900 stopped me cold. The idea that you can aggressively 00:01:35.900 --> 00:01:38.939 want something, pursue it with every fiber of 00:01:38.939 --> 00:01:40.900 your being, even if you don't actually like it 00:01:40.900 --> 00:01:43.340 anymore. It's a terrifying distinction. It challenges 00:01:43.340 --> 00:01:46.060 basically everything we think we know about human 00:01:46.060 --> 00:01:48.599 desire. But before we get to that kind of existential 00:01:48.599 --> 00:01:50.459 dread, we really have to look at the nuts and 00:01:50.459 --> 00:01:52.500 bolts. Like, how do you even measure liking in 00:01:52.500 --> 00:01:54.480 a clinical lab? Right. Because you can't just 00:01:54.480 --> 00:01:56.620 ask a test subject, hey, was that fun? I mean, 00:01:56.640 --> 00:01:59.109 you could. But that's not data. The FDA needs 00:01:59.109 --> 00:02:01.230 hard numbers, not just anecdotes about a good 00:02:01.230 --> 00:02:05.349 time. Precisely. So imagine you are a pharmaceutical 00:02:05.349 --> 00:02:08.250 company. You've developed a new painkiller, and 00:02:08.250 --> 00:02:10.770 it works great for pain. But you really need 00:02:10.770 --> 00:02:14.189 to know, is this the next OxyContin? Is this 00:02:14.189 --> 00:02:16.610 going to trigger an addiction crisis? You have 00:02:16.610 --> 00:02:18.969 to quantify the high. You need to measure its 00:02:18.969 --> 00:02:21.490 abuse liability. And the tool for that, according 00:02:21.490 --> 00:02:24.620 to these documents, is the VAS. The visual analog 00:02:24.620 --> 00:02:27.080 scale. Yeah, the VAS. It's the standard tool 00:02:27.080 --> 00:02:29.620 of the trade in these environments. Now, most 00:02:29.620 --> 00:02:31.439 people have seen some version of this at the 00:02:31.439 --> 00:02:33.259 doctor's office, I think, like the pain scale, 00:02:33.460 --> 00:02:35.699 the line with the frowny face on one end and 00:02:35.699 --> 00:02:37.580 the smiley face on the other. It's the exact 00:02:37.580 --> 00:02:41.120 same principle, but flipped. So in a lab setting, 00:02:41.340 --> 00:02:44.659 a drug -liking VAS is typically just a 100 -millimeter 00:02:44.659 --> 00:02:47.020 line on a piece of paper or maybe a tablet screen. 00:02:47.479 --> 00:02:50.060 On the far left, it might say strong disliking. 00:02:50.319 --> 00:02:52.759 In the middle, it's neither like nor dislike. 00:02:53.259 --> 00:02:55.699 And on the far right, strong lacking. So paint 00:02:55.699 --> 00:02:58.199 the picture for us here. They give a human volunteer 00:02:58.199 --> 00:03:00.939 a dose of this experimental drug. And then what? 00:03:00.979 --> 00:03:02.699 They just sit there with a clipboard. Basically, 00:03:02.759 --> 00:03:06.699 yes. They wait. And at very specific time intervals, 00:03:06.780 --> 00:03:10.460 say every 15 minutes or every hour, the subject 00:03:10.460 --> 00:03:13.439 has to make a mark on that line. It sounds incredibly 00:03:13.439 --> 00:03:15.659 primitive, doesn't it? Making a mark on a line. 00:03:15.960 --> 00:03:18.180 But it effectively turns a purely subjective 00:03:18.180 --> 00:03:21.400 feeling into a hard number between zero and 100. 00:03:21.780 --> 00:03:25.270 Wow. But the sources list a few variations of 00:03:25.270 --> 00:03:26.770 this, right? There's drug liking, but there's 00:03:26.770 --> 00:03:28.710 also the high VAS. I was trying to parse the 00:03:28.710 --> 00:03:30.310 difference there when I was reading. Is there 00:03:30.310 --> 00:03:32.490 really a meaningful distinction between saying 00:03:32.490 --> 00:03:35.569 I like this and I am high? There is. And it's 00:03:35.569 --> 00:03:37.830 a subtle but really crucial difference in the 00:03:37.830 --> 00:03:40.669 research. High measures the intensity of the 00:03:40.669 --> 00:03:43.789 altered state. So you can be incredibly high, 00:03:43.909 --> 00:03:47.050 disoriented, dizzy, seeing trails, hallucinating. 00:03:47.419 --> 00:03:50.479 but score very low on liking if that experience 00:03:50.479 --> 00:03:53.020 is scary or nauseating. Oh, that makes total 00:03:53.020 --> 00:03:55.479 sense. I can imagine feeling completely altered 00:03:55.479 --> 00:03:57.400 but hating every single second of it, like being 00:03:57.400 --> 00:03:59.080 strapped to a roller coaster you really didn't 00:03:59.080 --> 00:04:00.800 want to ride. You are definitely experiencing 00:04:00.800 --> 00:04:02.780 intense sensations, but you certainly aren't 00:04:02.780 --> 00:04:05.219 liking it. Exactly. And that's why the sources 00:04:05.219 --> 00:04:07.620 emphasize the bipolar nature of some of these 00:04:07.620 --> 00:04:10.500 scales. Bitolar meaning it goes both ways. Right. 00:04:10.520 --> 00:04:13.159 A bipolar scale allows you to go negative. If 00:04:13.159 --> 00:04:15.900 a drug makes you vomit or feel intense anxiety, 00:04:16.259 --> 00:04:19.339 that data point is just as important as the euphoria. 00:04:20.019 --> 00:04:22.259 It tells regulators that the abuse potential 00:04:22.259 --> 00:04:25.300 might be lower because the experience is physically 00:04:25.300 --> 00:04:27.860 or mentally punishing to the user. So if I'm 00:04:27.860 --> 00:04:29.819 a researcher, I'm looking for the drug that scores 00:04:29.819 --> 00:04:33.329 high on, high but low on liking. Or is it more 00:04:33.329 --> 00:04:34.949 complex than that? You're looking for the correlation 00:04:34.949 --> 00:04:37.470 between them. But then there is the third scale 00:04:37.470 --> 00:04:39.730 mentioned in the text, which honestly felt the 00:04:39.730 --> 00:04:43.850 most direct to me. The TDAVAS. Ah, the take drug 00:04:43.850 --> 00:04:46.509 again scale? The TDA. It just cuts through all 00:04:46.509 --> 00:04:48.670 the noise. It's not asking about your feelings 00:04:48.670 --> 00:04:51.129 or your weird sensations. It's literally just 00:04:51.129 --> 00:04:53.639 asking about your future behavior. Given the 00:04:53.639 --> 00:04:56.019 chance, would you do this again? And that is 00:04:56.019 --> 00:04:58.279 very often the most predictive metric they have. 00:04:58.660 --> 00:05:01.240 You might have a subject who says, well, I don't 00:05:01.240 --> 00:05:03.319 really feel high in the traditional sense, and 00:05:03.319 --> 00:05:06.120 I'm not sure I even like this dizziness. But 00:05:06.120 --> 00:05:08.860 when asked, would you take this again, they immediately 00:05:08.860 --> 00:05:12.240 mark a 90 out of 100. See, that's the first hint 00:05:12.240 --> 00:05:14.620 of the problem, isn't it? That strange disconnect. 00:05:15.100 --> 00:05:17.399 Why on earth would you want to take it again 00:05:17.399 --> 00:05:20.360 if you didn't just... rate the experience as 00:05:20.360 --> 00:05:23.240 pleasurable. That seems totally counterintuitive 00:05:23.240 --> 00:05:25.600 to how we usually make decisions in life. You've 00:05:25.600 --> 00:05:27.920 hit the nail on the head. That discrepancy on 00:05:27.920 --> 00:05:30.720 the chart where the take drug again score stays 00:05:30.720 --> 00:05:34.139 incredibly high, even when the liking score drops 00:05:34.139 --> 00:05:35.779 off a cliff that is the shadow of addiction. 00:05:36.319 --> 00:05:40.220 It's the first real scientific clue that something 00:05:40.220 --> 00:05:42.639 other than fun is driving the bus. Let's dig 00:05:42.639 --> 00:05:45.040 into that then, because the source material references 00:05:45.040 --> 00:05:47.160 this theory by Robinson and Barrage called the 00:05:47.160 --> 00:05:50.000 incentive sensitization theory. It sounds super 00:05:50.000 --> 00:05:51.939 academic, but the implications of it are actually 00:05:51.939 --> 00:05:54.500 pretty dark. It is the liking versus wanting 00:05:54.500 --> 00:05:57.139 dissociation. To really understand this, we have 00:05:57.139 --> 00:05:59.540 to look at how we usually view desire in our 00:05:59.540 --> 00:06:02.300 day -to -day lives. We tend to think... I eat 00:06:02.300 --> 00:06:04.019 the cake because I like the taste of the cake. 00:06:04.100 --> 00:06:06.139 I play the video game because I enjoy the game. 00:06:06.300 --> 00:06:09.139 Cause and effect. The pleasure drives the pursuit. 00:06:09.420 --> 00:06:11.939 If the cake suddenly tasted like wet cardboard, 00:06:12.180 --> 00:06:14.939 I wouldn't want it anymore. Right. In a normal 00:06:14.939 --> 00:06:17.240 healthy brain, those two things are intricately 00:06:17.240 --> 00:06:20.360 linked. But Robinson and Barrage argued, and 00:06:20.360 --> 00:06:23.060 this completely shifted the paradigm, that these 00:06:23.060 --> 00:06:25.180 are actually two completely separate neural systems. 00:06:25.579 --> 00:06:28.160 There is a hedonic system, which is the liking. 00:06:28.259 --> 00:06:30.680 That's the yummy feeling. And then there is a 00:06:30.680 --> 00:06:33.939 totally separate incentive salient system, and 00:06:33.939 --> 00:06:36.959 that is the wanting. Incentive salience. That's 00:06:36.959 --> 00:06:38.699 a phrase that kept popping up in the notes. I 00:06:38.699 --> 00:06:40.360 want to make sure we really get this because 00:06:40.360 --> 00:06:43.399 it sounds like dense psychological jargon, but 00:06:43.399 --> 00:06:45.360 it really seems to be the key to the whole thing. 00:06:45.500 --> 00:06:48.339 Let's break it down simply. Think of salience 00:06:48.339 --> 00:06:51.160 as a spotlight. Your brain is constantly scanning 00:06:51.160 --> 00:06:53.519 your environment. When it sees something relevant 00:06:53.519 --> 00:06:55.779 to your survival food, water, or potential mate, 00:06:55.920 --> 00:06:58.720 it shines a massive spotlight on it. It makes 00:06:58.720 --> 00:07:01.120 that specific thing stand out against all the 00:07:01.120 --> 00:07:03.220 background noise of the world. Okay, so I walk 00:07:03.220 --> 00:07:05.160 into a messy kitchen. I don't even notice the 00:07:05.160 --> 00:07:07.480 toaster or the dirty sink, but my brain immediately 00:07:07.480 --> 00:07:09.839 notices the fresh sandwich sitting on the counter. 00:07:10.000 --> 00:07:13.500 The sandwich has salience. Exactly. Now, the 00:07:13.500 --> 00:07:16.319 incentive part means your brain attaches a DOIT 00:07:16.319 --> 00:07:19.930 tag to that spotlight. It's a command. It's not 00:07:19.930 --> 00:07:21.730 a warm feeling of joy. It's a magnetic pull. 00:07:21.970 --> 00:07:23.949 It's the intense feeling you get when you've 00:07:23.949 --> 00:07:25.850 been walking in the desert and you are incredibly 00:07:25.850 --> 00:07:28.389 thirsty and you finally see a glass of water. 00:07:28.730 --> 00:07:31.110 You don't just like the water. You are drawn 00:07:31.110 --> 00:07:33.470 to it. You absolutely need it. So in a healthy 00:07:33.470 --> 00:07:35.290 brain, these two things are synced up perfectly. 00:07:35.490 --> 00:07:37.569 I want the water. I drink the water. I like the 00:07:37.569 --> 00:07:39.670 water. Correct. In a healthy brain, they overlap 00:07:39.670 --> 00:07:43.649 seamlessly. But drugs, specifically the ones 00:07:43.649 --> 00:07:45.689 we're discussing today with high abuse liability. 00:07:46.920 --> 00:07:49.399 They hack this system. They can artificially 00:07:49.399 --> 00:07:52.319 crank up the wanting dial to maximum completely 00:07:52.319 --> 00:07:54.399 regardless of what the liking dial is doing. 00:07:54.519 --> 00:07:56.800 This totally explains that zombie feeling people 00:07:56.800 --> 00:07:59.199 describe in deep addiction or why people say 00:07:59.199 --> 00:08:02.180 they are chasing the dragon, right? Yes, that's 00:08:02.180 --> 00:08:05.000 exactly it. The source literally defines drug 00:08:05.000 --> 00:08:08.279 wanting as the unconscious attribution of incentive 00:08:08.279 --> 00:08:11.360 salience. Note the word unconscious there. You 00:08:11.360 --> 00:08:14.329 don't consciously decide to want it. Your brain 00:08:14.329 --> 00:08:16.170 has physically tagged the drug as being more 00:08:16.170 --> 00:08:18.389 important than food, more important than sleep, 00:08:18.529 --> 00:08:21.430 or even your own safety. It is essentially assigned 00:08:21.430 --> 00:08:24.829 at top survival priority. So when we see a patient 00:08:24.829 --> 00:08:26.569 in these clinical studies who scores the drug 00:08:26.569 --> 00:08:28.990 as totally neutral on enjoyment, maybe it just 00:08:28.990 --> 00:08:30.949 makes them feel tired or slightly nauseous, but 00:08:30.949 --> 00:08:33.970 they score a 100 on take drug. Again, we are 00:08:33.970 --> 00:08:36.210 literally seeing that brain hack happen in real 00:08:36.210 --> 00:08:38.629 time. We are. Their conscious mind is sitting 00:08:38.629 --> 00:08:40.289 there saying, this isn't even fun anymore. I 00:08:40.289 --> 00:08:42.929 actually feel sick. But their primitive survival 00:08:42.929 --> 00:08:47.070 brain is screaming, D, D, D. And here is the 00:08:47.070 --> 00:08:49.309 real kicker of the Robinson and Barrage theory. 00:08:49.789 --> 00:08:52.090 Because physical tolerance builds up, the liking 00:08:52.090 --> 00:08:54.830 almost always fades over time. You need more 00:08:54.830 --> 00:08:56.769 of the drug just to get the same baseline effect. 00:08:57.029 --> 00:08:59.350 But the wanting that sensitization of dopamine 00:08:59.350 --> 00:09:01.429 system actually grows stronger with repetition. 00:09:02.009 --> 00:09:04.730 God, that is tragic. It means the longer you 00:09:04.730 --> 00:09:07.230 use it, the less you actually enjoy it, but the 00:09:07.230 --> 00:09:09.529 more you are completely compelled to do it. It's 00:09:09.529 --> 00:09:11.730 a trap that tightens the more you struggle against 00:09:11.730 --> 00:09:14.529 it. It really reframes our entire empathy for 00:09:14.529 --> 00:09:17.450 addiction, I think. We often judge people thinking, 00:09:17.610 --> 00:09:20.610 why are they choosing to party instead of taking 00:09:20.610 --> 00:09:22.169 care of their family or their responsibilities? 00:09:22.529 --> 00:09:25.309 But if you understand this dissociation, you 00:09:25.309 --> 00:09:27.429 realize they aren't partying at all. The party 00:09:27.429 --> 00:09:30.110 ended years ago. Now they are just servicing 00:09:30.110 --> 00:09:33.100 a... broken survival mechanism in their brain. 00:09:33.259 --> 00:09:35.320 It's mechanical. That's the word that keeps coming 00:09:35.320 --> 00:09:37.720 to my mind. It's not a moral failing. It's mechanical. 00:09:38.000 --> 00:09:40.320 It's like a software glitch where the purchase 00:09:40.320 --> 00:09:42.700 button is just permanently stuck down. It is 00:09:42.700 --> 00:09:45.210 a mechanical glitch. And this brings us nicely 00:09:45.210 --> 00:09:47.049 to the actual chemicals themselves. The source 00:09:47.049 --> 00:09:49.789 material provides this sort of rogues gallery 00:09:49.789 --> 00:09:52.990 of substances that light up these specific systems. 00:09:53.149 --> 00:09:54.509 Yeah, let's run through that chemical landscape. 00:09:54.730 --> 00:09:57.110 It's mostly the usual suspects, but there are 00:09:57.110 --> 00:09:59.309 definitely some nuances here that surprised me. 00:09:59.370 --> 00:10:01.490 At the top of the liking charts, we have the 00:10:01.490 --> 00:10:05.110 major stimulants. Cocaine, amphetamines, MDMA. 00:10:05.309 --> 00:10:07.629 Right, these are the heavy hitters. Because they 00:10:07.629 --> 00:10:10.500 work so directly on dopamine. And while we just 00:10:10.500 --> 00:10:12.519 said dopamine is mostly about the wanting system, 00:10:12.700 --> 00:10:16.500 in the very initial stages, these drugs flood 00:10:16.500 --> 00:10:19.639 the system so hard and so fast, they trigger 00:10:19.639 --> 00:10:22.200 massive liking scores too. They basically force 00:10:22.200 --> 00:10:25.299 the brain to perceive intense euphoria. Then 00:10:25.299 --> 00:10:29.220 we have the depressants, opioids, benzos, alcohol. 00:10:30.009 --> 00:10:32.370 Different mechanism there, but a very similar 00:10:32.370 --> 00:10:34.950 result on the VAS scores. Opioids, for instance, 00:10:35.049 --> 00:10:37.750 mimic our internal endorphins. The liking here 00:10:37.750 --> 00:10:39.850 is often described by subjects as a warm blanket, 00:10:40.009 --> 00:10:42.490 a total removal of physical pain and mental anxiety. 00:10:42.789 --> 00:10:45.049 The score goes up simply because the suffering 00:10:45.049 --> 00:10:47.730 goes down so drastically. But I noticed the source 00:10:47.730 --> 00:10:49.950 spent a specific amount of time discussing ADHD 00:10:49.950 --> 00:10:52.600 medications. methylphenidate, which most people 00:10:52.600 --> 00:10:54.879 know as Ritalin, and lisdexamphetamine. This 00:10:54.879 --> 00:10:57.340 is a very sensitive and highly researched area. 00:10:57.539 --> 00:10:59.139 We have millions of people, including millions 00:10:59.139 --> 00:11:01.159 of children, taking these drugs therapeutically 00:11:01.159 --> 00:11:04.000 every single day. But chemically speaking, methylphenidate 00:11:04.000 --> 00:11:06.200 is actually very similar to cocaine in how it 00:11:06.200 --> 00:11:08.440 blocks dopamine transporters in the brain. Okay, 00:11:08.500 --> 00:11:10.519 so this is the obvious question then. If the 00:11:10.519 --> 00:11:13.789 chemistry is that similar, Why isn't every kid 00:11:13.789 --> 00:11:16.730 with an ADHD prescription turning into an addict? 00:11:16.950 --> 00:11:19.509 Why aren't we seeing that incentive salience 00:11:19.509 --> 00:11:22.529 hijack happen to everyone taking these meds? 00:11:22.570 --> 00:11:24.750 That's where the clinical pharmacologic assessment 00:11:24.750 --> 00:11:27.309 comes in, which was mentioned in the text referencing 00:11:27.309 --> 00:11:31.149 Volko and Swanson's work. It turns out liking 00:11:31.149 --> 00:11:34.370 and the subsequent wanting cascade depends incredibly 00:11:34.370 --> 00:11:37.429 heavily on speed. Speed of onset, like how fast 00:11:37.429 --> 00:11:40.240 it hits you. Yes. The rate of rise. Yeah. If 00:11:40.240 --> 00:11:42.759 you swallow a pill and the dopamine levels in 00:11:42.759 --> 00:11:45.080 your brain rise slowly and steadily over an hour, 00:11:45.200 --> 00:11:48.679 the brain doesn't register that sudden bang of 00:11:48.679 --> 00:11:50.460 incentive salience. It helps you focus. It does 00:11:50.460 --> 00:11:52.840 its therapeutic job, but it doesn't trigger the 00:11:52.840 --> 00:11:55.179 high VAS at all. So it's basically the difference 00:11:55.179 --> 00:11:57.519 between slowly walking up a hill and being shot 00:11:57.519 --> 00:12:00.120 out of a cannon. Exactly. But if you were to 00:12:00.120 --> 00:12:02.580 take that exact same pill, crush it up and snort 00:12:02.580 --> 00:12:05.000 it. You bypass the slow release mechanism entirely. 00:12:05.159 --> 00:12:07.480 You turn the hill back into a cannon. Right. 00:12:07.919 --> 00:12:10.159 The chemical hits the brain in seconds instead 00:12:10.159 --> 00:12:13.940 of hours. That rapid unnatural spike is what 00:12:13.940 --> 00:12:16.399 triggers the liking and the wanting. That's why 00:12:16.399 --> 00:12:18.539 the abuse liability studies referenced in our 00:12:18.539 --> 00:12:20.820 sources are so heavily focused on formulation. 00:12:21.379 --> 00:12:24.139 The drug companies are asking, can we make a 00:12:24.139 --> 00:12:27.179 pill that works therapeutically but is physically 00:12:27.179 --> 00:12:30.500 impossible to crush or inject? Can we make the 00:12:30.500 --> 00:12:33.720 delivery so slow that it's boring to the brain's 00:12:33.720 --> 00:12:36.250 reward system? It's an engineering problem. They 00:12:36.250 --> 00:12:38.470 are trying to figure out how to deliver the medicine 00:12:38.470 --> 00:12:41.350 without accidentally ringing the euphoria bell. 00:12:41.570 --> 00:12:44.090 That is the ultimate goal of modern pharmaceutical 00:12:44.090 --> 00:12:46.269 formulation. They want the purely therapeutic 00:12:46.269 --> 00:12:49.149 effect without the high abuse liability. Now, 00:12:49.169 --> 00:12:51.110 there was one inclusion in the list of substances 00:12:51.110 --> 00:12:53.250 that actually made me check my own desk. I'm 00:12:53.250 --> 00:12:55.870 literally holding a cup of it right now. Caffeine. 00:12:55.889 --> 00:12:59.309 Huh. Yes. The drug of commerce. The source explicitly 00:12:59.309 --> 00:13:02.129 says caffeine increases drug -liking scores, 00:13:02.330 --> 00:13:05.470 but it uses a very specific kind of funny qualifier. 00:13:05.590 --> 00:13:07.990 It says it increases them limitedly. That word 00:13:07.990 --> 00:13:10.009 limitedly is doing a whole lot of heavy lifting 00:13:10.009 --> 00:13:12.409 in that sentence. I was going to say, I definitely 00:13:12.409 --> 00:13:14.950 like my morning coffee. And if I don't have it, 00:13:14.970 --> 00:13:16.909 I absolutely want it. I might even get a headache 00:13:16.909 --> 00:13:19.509 or get cranky. So how is that fundamentally different 00:13:19.509 --> 00:13:22.149 from the addiction mechanisms we just spent all 00:13:22.149 --> 00:13:24.490 this time talking about? It's largely a matter 00:13:24.490 --> 00:13:26.860 of the pharmacological ceiling. You can rate 00:13:26.860 --> 00:13:29.700 a good cup of coffee a high on the liking scale, 00:13:29.759 --> 00:13:33.080 sure. But caffeine has a hard ceiling. If you 00:13:33.080 --> 00:13:35.139 drink 10 cups of coffee, you don't get 10 times 00:13:35.139 --> 00:13:37.860 the euphoria. You get the shakes. You get terrible 00:13:37.860 --> 00:13:39.860 anxiety. You feel like your heart is going to 00:13:39.860 --> 00:13:42.240 explode out of your chest. The disliking scale 00:13:42.240 --> 00:13:44.980 kicks in really hard and really fast. Exactly. 00:13:45.299 --> 00:13:47.820 The negative physical effects override the positive 00:13:47.820 --> 00:13:50.929 ones incredibly quickly. Compare that to cocaine 00:13:50.929 --> 00:13:53.929 or opioids, where the ceiling for wanting is 00:13:53.929 --> 00:13:56.830 virtually non -existent until the user hits toxicity 00:13:56.830 --> 00:14:00.570 or death. Caffeine creates a habit, and it definitely 00:14:00.570 --> 00:14:03.029 has reinforcing properties as noted by Griffiths 00:14:03.029 --> 00:14:06.190 and Woodson in the source material, but it doesn't 00:14:06.190 --> 00:14:08.429 hijack the incentive salience system to the point 00:14:08.429 --> 00:14:10.509 where you'd, you know, rob a bank to get an espresso. 00:14:10.909 --> 00:14:13.649 Usually not, anyway. I mean, maybe on a really 00:14:13.649 --> 00:14:16.899 rough Monday morning. Fair point, yeah. But generally 00:14:16.899 --> 00:14:19.700 speaking, society doesn't collapse due to caffeine 00:14:19.700 --> 00:14:22.440 wanting. So we have the tools with the VAS. We 00:14:22.440 --> 00:14:24.820 have the core theory with liking versus wanting. 00:14:24.940 --> 00:14:27.600 And we have the chemicals. I want to zoom out 00:14:27.600 --> 00:14:30.460 to the real world application of all this. The 00:14:30.460 --> 00:14:32.500 source mentions that these measures are core 00:14:32.500 --> 00:14:35.779 outcome measures for opioid abuse liability laboratory 00:14:35.779 --> 00:14:38.200 assessment studies. That's quite a mouthful of 00:14:38.200 --> 00:14:40.360 a phrase, but it basically just means this is 00:14:40.360 --> 00:14:42.620 the gauntlet. The gauntlet for new drugs before 00:14:42.620 --> 00:14:45.940 they hit the pharmacy. Yes. Before any new opioid 00:14:45.940 --> 00:14:48.740 or sedative hits the market, the FDA usually 00:14:48.740 --> 00:14:51.460 requires these human abuse potential studies. 00:14:51.820 --> 00:14:54.500 And here is the truly fascinating part about 00:14:54.500 --> 00:14:56.820 these studies. Who do you think the actual test 00:14:56.820 --> 00:14:59.799 subjects are? I assumed it was just random healthy 00:14:59.799 --> 00:15:02.039 volunteers, maybe college students looking for 00:15:02.039 --> 00:15:04.419 extra cash on the weekend. No, you actually can't 00:15:04.419 --> 00:15:06.440 use random people. A random person might not 00:15:06.440 --> 00:15:08.500 even know what a high feels like, or they might 00:15:08.500 --> 00:15:11.379 just feel sick and confused by the drug. The 00:15:11.379 --> 00:15:14.000 regulatory guidelines, like those from the IMPACT 00:15:14.000 --> 00:15:16.879 -T group mentioned in the text, strongly recommend 00:15:16.879 --> 00:15:19.860 using recreational drug users. Really? So they 00:15:19.860 --> 00:15:22.080 specifically recruit people who already have 00:15:22.080 --> 00:15:24.460 extensive experience with illicit drugs? They 00:15:24.460 --> 00:15:26.759 do. They need connoisseurs, in a way. They need 00:15:26.759 --> 00:15:30.080 people who can clearly distinguish between, I 00:15:30.080 --> 00:15:32.500 feel a little dizzy, and I feel exactly like 00:15:32.500 --> 00:15:35.580 I just took OxyContin. They need people whose 00:15:35.580 --> 00:15:38.710 brains are already somewhat... tuned to recognize 00:15:38.710 --> 00:15:41.970 these specific subjective effects. That is wild, 00:15:42.070 --> 00:15:45.309 wanted, professional drug taster. But logically, 00:15:45.429 --> 00:15:46.929 it makes total sense. You need someone with a 00:15:46.929 --> 00:15:49.929 refined palate to grade the wine, so to speak. 00:15:50.110 --> 00:15:52.330 It sounds strange to the layperson, but it's 00:15:52.330 --> 00:15:55.190 absolutely vital for public safety. If these 00:15:55.190 --> 00:15:57.950 highly experienced users take the new experimental 00:15:57.950 --> 00:16:00.269 drug and say, whoa, this feels exactly like my 00:16:00.269 --> 00:16:02.450 favorite street drug, and their Take Drug Again 00:16:02.450 --> 00:16:05.370 score is a solid 100, that drug is in serious 00:16:05.370 --> 00:16:07.440 trouble. It will either be rejected entirely 00:16:07.440 --> 00:16:10.200 or put under the very strictest regulatory controls. 00:16:10.440 --> 00:16:13.120 A firewall, a human firewall against the next 00:16:13.120 --> 00:16:16.159 epidemic. It is. But, and here is where the science 00:16:16.159 --> 00:16:18.399 is getting even more sophisticated lately. We 00:16:18.399 --> 00:16:20.379 talked earlier about how wanting is unconscious, 00:16:20.720 --> 00:16:22.840 right? Right, the unconscious attribution of 00:16:22.840 --> 00:16:25.440 incentive salience. So if I ask a subject in 00:16:25.440 --> 00:16:27.779 a lab, do you want to take this again? They might 00:16:27.779 --> 00:16:30.360 just lie to me. Or honestly, they might not even 00:16:30.360 --> 00:16:32.750 realize that they want it yet. Conscious filtering, 00:16:33.009 --> 00:16:35.049 like they think, I shouldn't want this, so I'll 00:16:35.049 --> 00:16:37.450 be good and say no. Or maybe they're just bored 00:16:37.450 --> 00:16:40.509 and want to go home. Exactly. The explicit verbal 00:16:40.509 --> 00:16:43.210 answers can be flawed. That's why the source 00:16:43.210 --> 00:16:46.210 brings up implicit measures, specifically referencing 00:16:46.210 --> 00:16:49.129 the work by Tibble and colleagues. These are 00:16:49.129 --> 00:16:51.350 tests designed to bypass the conscious talking 00:16:51.350 --> 00:16:54.169 mind entirely. How do you do that? Are they reading 00:16:54.169 --> 00:16:56.490 their minds with electrodes? Close, actually. 00:16:56.610 --> 00:16:58.970 You measure the physical reactions they can't 00:16:58.970 --> 00:17:01.440 consciously control. Things like raw reaction 00:17:01.440 --> 00:17:04.279 times or eye tracking. For example, they use 00:17:04.279 --> 00:17:06.319 something called a visual probe task. How does 00:17:06.319 --> 00:17:08.319 that work? You sit the subject in front of a 00:17:08.319 --> 00:17:10.720 screen and you flash two images for just a fraction 00:17:10.720 --> 00:17:13.680 of a second. One is a completely neutral object 00:17:13.680 --> 00:17:16.279 like a stapler or a chair, and the other is a 00:17:16.279 --> 00:17:19.480 picture of the drug or drug paraphernalia. Then, 00:17:19.640 --> 00:17:22.660 using highly sensitive cameras, you track exactly 00:17:22.660 --> 00:17:25.440 how fast their eyes snap to the drug. Oh, the 00:17:25.440 --> 00:17:28.640 spotlight again. The incentive salience spotlight. 00:17:28.920 --> 00:17:32.690 The spotlight. Exactly. If your eyes involuntarily 00:17:32.690 --> 00:17:34.990 jump to the image of the drug in 200 milliseconds, 00:17:35.349 --> 00:17:38.250 your brain is clearly assigned it incentive salience. 00:17:38.529 --> 00:17:40.490 Even if your mouth just told the researcher, 00:17:40.549 --> 00:17:41.970 I have absolutely no interest in that stuff. 00:17:42.089 --> 00:17:44.410 That is incredibly high tech. It's basically 00:17:44.410 --> 00:17:47.369 a lie detector for the lizard brain. It perfectly 00:17:47.369 --> 00:17:49.809 reveals what the organism actually prioritizes 00:17:49.809 --> 00:17:51.950 at a survival level completely, regardless of 00:17:51.950 --> 00:17:53.970 what the person thinks they prioritize. It catches 00:17:53.970 --> 00:17:56.730 that raw wanting signal before the liking or 00:17:56.730 --> 00:17:59.259 disliking conscious thought. even has time to 00:17:59.259 --> 00:18:01.980 fully form in the prefrontal cortex. Man, this 00:18:01.980 --> 00:18:04.019 whole deep dive has really shifted my perspective 00:18:04.019 --> 00:18:06.960 on this. I started off today thinking drug liking 00:18:06.960 --> 00:18:09.920 was just a dry administrative data point, just 00:18:09.920 --> 00:18:13.099 a mandatory box to check on an FDA form. But 00:18:13.099 --> 00:18:16.359 it's actually this profound window into the silent 00:18:16.359 --> 00:18:18.960 battle happening inside our own heads. It really 00:18:18.960 --> 00:18:21.240 is. I think it helps us deeply understand that 00:18:21.240 --> 00:18:24.400 severe addiction isn't just about someone stubbornly 00:18:24.400 --> 00:18:27.119 seeking pleasure. It's about a fundamental chemical 00:18:27.119 --> 00:18:29.539 error. and how the human brain assigns value 00:18:29.539 --> 00:18:32.079 and priority to things. We have the liking system, 00:18:32.220 --> 00:18:33.880 the innocent part of us that just wants to feel 00:18:33.880 --> 00:18:36.400 good, to be happy and comfortable. And then we 00:18:36.400 --> 00:18:39.380 have this wanting system, this dark engine room 00:18:39.380 --> 00:18:41.839 of survival that can just get completely hijacked 00:18:41.839 --> 00:18:44.559 and run totally off the rails. And the true tragedy 00:18:44.559 --> 00:18:47.910 of addiction is simply Those two systems getting 00:18:47.910 --> 00:18:50.630 violently divorced from one another. The engine 00:18:50.630 --> 00:18:52.349 is running at full speed, burning everything 00:18:52.349 --> 00:18:55.269 up, but there's no destination anymore. It really 00:18:55.269 --> 00:18:57.769 makes you think about our own lives, even completely 00:18:57.769 --> 00:19:00.730 outside the realm of heavy pharmacology. The 00:19:00.730 --> 00:19:03.109 source is focused on drugs, obviously, but this 00:19:03.109 --> 00:19:06.109 incentive salience machinery is humming away 00:19:06.109 --> 00:19:09.130 in all of us all day long. It's literally how 00:19:09.130 --> 00:19:11.210 we survive. That's the lingering thought that 00:19:11.210 --> 00:19:13.880 stuck with me, too. We live in a modern world 00:19:13.880 --> 00:19:16.799 that is practically explicitly designed to trigger 00:19:16.799 --> 00:19:19.779 that exact wanting system. Oh, absolutely. Social 00:19:19.779 --> 00:19:23.200 media algorithms, infinite scrolling feeds, hyper 00:19:23.200 --> 00:19:25.920 palatable sugary foods, frictionless buy now 00:19:25.920 --> 00:19:28.579 buttons. They're all just trying to hack that 00:19:28.579 --> 00:19:31.380 spotlight, aren't they? Exactly. The algorithms 00:19:31.380 --> 00:19:33.720 are essentially optimizing for digital wanting. 00:19:34.299 --> 00:19:36.339 They don't actually care if you authentically 00:19:36.339 --> 00:19:38.700 like the content. They don't care if the content 00:19:38.700 --> 00:19:41.339 makes you angry or depressed or deeply jealous, 00:19:41.380 --> 00:19:44.359 just as long as you keep scrolling. As long as 00:19:44.359 --> 00:19:47.420 your personal take drug again metric, or in this 00:19:47.420 --> 00:19:50.420 case, the open app again metric, stays artificially 00:19:50.420 --> 00:19:53.599 high. That's a haunting parallel. We might be 00:19:53.599 --> 00:19:57.039 literally clicking a button called like on our 00:19:57.039 --> 00:20:00.039 phones, but are we actually liking it or are 00:20:00.039 --> 00:20:02.339 we just stuck in a chemically engineered loop? 00:20:03.059 --> 00:20:06.099 Right. Are you genuinely pursuing pleasure and 00:20:06.099 --> 00:20:09.579 enrichment or are you just blindly satisfying 00:20:09.579 --> 00:20:12.019 a compulsion that was programmed into your dopamine 00:20:12.019 --> 00:20:15.400 system by a brilliant software engineer or a 00:20:15.400 --> 00:20:17.779 specific chemical structure? That is definitely 00:20:17.779 --> 00:20:19.559 a question to ask yourself the next time you 00:20:19.559 --> 00:20:21.480 find yourself doom scrolling at two in the morning 00:20:21.480 --> 00:20:23.579 or reaching for that third donut without even 00:20:23.579 --> 00:20:25.420 thinking. Are you liking? Are you just wanting? 00:20:26.119 --> 00:20:28.519 Well, on that cheerful and mildly terrifying 00:20:28.519 --> 00:20:31.150 note, we're going to wrap it up. Thanks for joining 00:20:31.150 --> 00:20:33.170 us for this deep dive. It was a fascinating one. 00:20:33.250 --> 00:20:33.849 See you next time.