00:02:07.080Good. We will get right into it today on AMA All-Around Medications and Supplements. So
00:02:13.500So first question, before someone takes any medication or supplement, how do you think that they should define what the problem is in a way that increases the odds that they look for and pick interventions that actually benefit them and reduce risk opposed to at best waste money and at worst cause other harm that they don't know about?
00:02:36.080You know, I think this is actually one of the biggest challenges from a sort of mental model standpoint is plaguing most people when they think about supplements in particular, but I think also, frankly, pharmaceuticals.
00:02:47.740So people are, I think, typically defining the problem at the wrong level of abstraction.
00:02:53.960So they'll say things like, I want to be healthier or I want more energy or I want to pursue better longevity.
00:03:01.680And the challenge is that those are not really actionable problem definitions. They're vague, difficult to measure, very difficult to falsify, and things like that. So I would suggest that we reframe this discussion around what would be actionable metrics or actionable parts, right?
00:03:19.500So one would be a metric that can be studied. Two would be a threshold against which you would
00:03:25.000measure. And then I think a third potential one would be a time horizon. So what am I measuring?
00:03:30.740What level tells me that there's a problem and by extension, a solution? And when do I expect
00:03:38.100that to happen? And so if you can't come up a priori with some sense of those things, you're
00:03:43.320probably not in a good spot to start anything. So for example, let's use a tangible example.
00:03:49.680Instead of saying my cholesterol is bad, you would say my ApoB is 130 milligrams per deciliter. I
00:03:55.740want to get it below 60 milligrams per deciliter, and I'd like to do that in the next six months.
00:03:59.980Instead of saying, you know, my sleep is bad, you might say it takes me 60 minutes to fall asleep
00:04:04.320on, you know, four or five nights a week, and I want to make that under 10 minutes to fall asleep
00:04:11.560within two months. So that's a real problem definition. The next question is the counterfactual.
00:04:18.280What happens if I do nothing? Does this problem meaningfully increase risk, reduce quality of life,
00:04:23.820or create some downstream consequence? So I think this question is important because it separates
00:04:29.060real problems from things that merely feel actionable. And it matters because poor problem
00:04:35.540definition almost guarantees some sort of false positive. So if the problem is vague, almost
00:04:40.500anything can look like it helped. You sleep a little better one week, your energy is a little
00:04:45.200better on Tuesday, one lab improves a little, and now you're telling yourself a story. And we all
00:04:50.880do this. I mean, we're storytelling machines. And I think that's how people end up taking things for
00:04:56.100years without ever knowing if they've solved anything real. So I think the rule here could
00:05:02.400be pretty simple, right? Do not start with the molecule, start with the problem. Define tightly
00:05:07.940enough that you could actually be proven wrong. So if you can't state the metric, the threshold
00:05:12.960and the timeline, and even the consequences of doing nothing, you're not really making an
00:05:18.140intervention decision. You're, you're probably impulse shopping on, you know, your favorite
00:05:21.900website. And when looking at different medications and supplements, how do you think about and maybe
00:05:28.800classify the quote unquote job that they would do? And based on that classification, does it
00:05:37.200change the evidence threshold you like to see and how much risk you're willing to tolerate?
00:05:43.880Well, once the problem is defined, I think the next question is asking, okay, what is the purpose
00:05:51.500of that intervention? And again, it matters because it requires different standards. So
00:05:57.640if you don't classify this job as you describe it correctly, you're very likely going to apply
00:06:03.180the wrong evidence threshold and accept the wrong amount of risk. So I think we could put these into
00:06:08.920four buckets, disease treatment, symptom relief, risk reduction, and I hate the term, but I think
00:06:17.780we just need to use it and it's optimization. So they might sound sort of similar on the surface,
00:06:23.100but they're actually quite, quite different. So if the, if the quote unquote job is disease
00:06:26.980treatment, the bar is high, right? Does this improve the disease in a meaningful way? And of
00:06:33.380course, here you would be willing to accept more downside because the underlying problem is serious
00:06:38.020and the counterfactual is strong. Presumably, if you have a disease and you do nothing,
00:06:43.120the disease will get significantly worse. But at the same time, you're going to want stronger
00:06:47.000evidence, ideally hard outcome trials, or at least some well-validated surrogate endpoint,
00:06:52.520not just a compelling story. Now, if the job is symptom relief, the question is a bit different.
00:06:58.180Does the person actually feel or function better? And here we're dealing with something that's
00:07:04.080subjective. You may be willing to frankly tolerate placebo risk because if the symptoms
00:07:09.820meaningfully improve and the downside is low, that could still be a reasonable trade-off.
00:07:14.880If the job is risk reduction, you're treating something that a person can't feel almost by
00:07:20.860definition. So the evidence bar again here needs to be pretty high. That usually means hard outcomes
00:07:25.920when available, or again, at least a very validated surrogate marker. And again, not all biomarkers
00:07:32.200are equal here. ApoB is a very well-validated surrogate biomarker, whereas some vague
00:07:40.180inflammatory marker or heavy metal is not necessarily going to be in that category as
00:07:46.740someone's pontificating about detoxifications or something like that.
00:07:50.860If the job is optimization, then I think skepticism should go up, right?
00:07:55.860This is where error rates are highest.
00:07:57.900The person is usually starting from a relatively healthy baseline, and the expected effect is often small.
00:08:03.920The claims are usually made in a mechanistic way, and there's generally no objective way to determine whether the supplement or medication is benefiting you, making your ability to basically fool yourself enormous.
00:08:18.660So I think the challenge and probably the reason we're even doing this episode is in part because most of the longevity interventions are really optimizations masquerading as risk reductions.
00:08:31.160They kind of borrow the language of prevention, aging, healthspan, resilience, longevity, but the actual evidence that they put forth looks much more like speculative optimization interventions rather than true risk reduction.
00:08:43.500And I think this distinction really matters, right? This classification should change both
00:08:47.840your evidence threshold and your risk tolerance. I think the more serious and concrete the problem,
00:08:53.460the more downside you may be willing to keep, as I said, and the more speculative the goal,
00:08:58.300the less downside you should be willing to tolerate. So I guess to summarize that,
00:09:02.500if you're looking at disease treatment, you want to demand strong evidence, but you'll accept more
00:09:06.220risk. If you're looking at symptom relief, you prioritize the actual lived benefit, but watch
00:09:11.240for placebo and noise and factor in the unknowns about safety. Risk reduction, you're going to
00:09:16.360have to look at validated surrogates or hard outcomes, although the latter tends to be
00:09:19.900challenging. And if it's about optimization, you're going to default into a skeptical state,
00:09:25.360especially around safety. So Peter, let's double click on one of the things you briefly mentioned
00:09:31.020there, which is kind of evidence when looking at medications and supplements. So when people
00:09:36.160are evaluating how they're thinking about a medication and supplement for themselves,
00:09:39.940what are common ways that you see people confuse the different tiers of evidence and how can people
00:09:47.880prevent that in practice so how can people be a little bit more aware so when they're looking at
00:09:52.980various claims they start to understand how good those claims are thank you for listening to today's
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