Wow, that sounds pretty incredible. Part of what makes it sound promising to me is the extent of the "no free lunch" aspect: anecdotal reports of not just cardiac issues in humans and dogs but increased brain fog (mitigated with feed consumption...?), blunted emotions, inability to get drunk (maybe a plus?), accelerated cell death, psychosis and hallucinations - in exchange for, allegedly, reversing Alzheimer's and repairing lifelong brain damage:

>One report of a person who gave ISRIB to their grandmother who had terminal stage Alzheimer's. She began to remember everyone. But died after 4 months (this may have been from old age and her type 1 diabetes).

>One anecdotal report of a short course of ISRIB permanently fixing some prefrontal cortex brain damage in a Russian guy, caused by a car crash when he was a child. The repair to the brain was confirmed by MRI scans taken before and after the ISRIB treatment.

Plus a pretty clear mechanism of action. Definitely sounds like it's worth significant study.

I mentioned this in another thread [1] but this idea of "no free lunch" is nothing more than a human aberration. There are many things in life that are free lunches, including drugs you put in your body but we as humans have such an overriding need to balance the scales of life we conveniently overlook them.

Pattern recognition is helpful to a certain extent in life but we should be careful applying it arbitrarily and try to be aware of when we are doing it.

I took a host of weird nootropics when I was younger. The most experimental was NSI-189. My experience is plenty of these drugs were gratis lunches but I wasn't enrolled in a study and don't have hard numbers to show you.

[1] https://news.ycombinator.com/item?id=29800869

The scariest (potential) downside to nootropics to me is an increased risk of cancer. Because if your normal cells are healthier, cancerous cells are also healthier. As a younger person, cancer is less of a risk so nootropics are less of a risk too.

So I was curious, with that in mind, where the free lunch drugs are? As in, which ones did you enjoy most and why stop taking them?

In my opinion, a free lunch drug is something like lion's mane, a mushroom, which depending on the study we're looking at can induce neurogenesis, improve cognitive function and reduce anxiety. [1]

It's something I still take today.

I'm clinically prescribed modafinil for ADHD, which has immeasurably improved my life. I can guarantee I would not be employable as an SRE today without it. Low dose modafinil (50 mgs) is a free lunch for me and, if you believe the anecdotes, for tons of redditors out there. At the dose I recommend, it's all upside (I feel I must emphasize for me with a clinical diagnosis).

Those are the two I have extensive experience with that I see no downside to regular consumption of.

[1] https://www.reddit.com/r/MushroomSupplements/comments/h090ry...

Yes, that's a real risk. Check out this thread, which /r/Nootropics has wisely kept stickied for a while: https://www.reddit.com/r/Nootropics/comments/pbz9mx/warnings.... It's an anecdotal report of nootropic use not necessarily inducing cancer but potentially making cancer spread much more aggressively.

One definitely shouldn't try nootropics without very thoroughly studying the risks. I sometimes take certain (seemingly) low-risk ones, like racetams combined with choline supplements. (For example, oxiracetam + alpha-GPC.)

> So I was curious, with that in mind, where the free lunch drugs are?

Nothing in life is "free lunch", not even free lunch. At the very least you have to expand time to fetch it, eat it and deal with a slightly increased risk of food poisoning afterwards.

But that is often times a very fitting metaphor when comparing the upside of a lot of drugs to their downside: It does not have to be free, to be free. If you have an infection that would otherwise kill you, an effective antibiotic is close enough to free to be a no-brainer.

The idea behind the no free lunch principle is that if a small molecule drug exists that can realistically be biologically produced in humans (ie not penicillin) we would probably have evolved that ability already, because we're very well optimized by now.

I don't think so, we don't even produce vitamin B12. The "no free lunch" only applies to things we already produce, like we already produce dopamine so getting more will have consequences for healthy people or we would have evolved to produce more.

The no free lunch idea is mostly a question of trade offs. For example Humans naturally produce antibiotics, however prescribing them in large numbers could be very risky potentially significantly compromising everyone’s immune system worldwide.

That said, it’s very possible for diseases to have very simple cures that people simply aren’t producing enough of. Evolution is great at population level optimizations over time, but it can really suck for individuals.

You can’t just evolve to produce any random molecule especially anything with actual chemical complexity. Scores of extremely complex enzymes are needed to produce cholesterol and pretty much all small molecule steroids we produce are derivatives of it. Plants have a vast repertoire of enzyme pathways to produce many small molecules which they can mix and match quickly to produce compounds of great chemical complexity but humans cannot.

Evolution is not going to evolve longer-life genes beyond a certain point. Something's going to kill you: disease, accidents, predators. Any gene that would, for example, help humans to live to 200 in the wild is useless. If it did evolve, it could mutate into a broken state and never be missed.

The phrase "no such thing as a free lunch" comes from economics — the study of making choices when your resources are finite. The insight conveyed by this phrase is that there's always some opportunity cost (the cost of the next-best-thing you could be doing, instead of eating the free lunch).

If you are not using it in that context, it loses its insight value. There is presumably some energy cost to the cell actually manufacturing the protein, but it's entirely possible that's the whole cost of the "lunch", and it is a price readily paid. Or it might not! That's really up to biology now, as you say.

The phrase comes from saloons in the United States providing free food, but requiring purchasing of drinks. You can't get"something for nothing". (And if you do there is a hidden cost or an externality.)

https://en.wikipedia.org/wiki/There_ain%27t_no_such_thing_as...

Agreed that it’s not a given that you can never get a free lunch, just that it’s rare.

Also I don’t think you’re painting yourself as a picture of confidence that you just took unapproved mind altering drugs and have come out of it with no issues so you’re logical or anything.

The idea of the Monkey’s Paw / Deal With The Devil when it comes to medicine has a strong pull.

The belief that cures of terrible diseases would come with a terrible price makes it easier to deal with the fact that we don’t have those cures yet.

I was debating whether or not to post some of those self-experiments.

I'm aware of a couple more forums where people tried ISRIB and still claim to have lasting problems from it. One group was led by professional chemists who seemed like they knew what they were doing when it comes to testing and validating the product was pure.

It's amazing what people can access now, but self-experimentation with these compounds is a terrible idea.

Developed a weird dementia at 39. Doctors Spent 2 years trying every prescription drug they could think of. Almost everything made matters worse. In some cases drastically. Complete nightmare. Those are with approved ones. Scary to try experiential.

Eventually learned it was a blood disorder and a simple blood thinner was the answer.

Wow. It sounds like you're better and hope you're better! That's an incredible story. Good on you for not giving up. You just lit a fire under my butt.

Which blood disorder?

Factor 5 Leiden. I clot easily. So mini strokes. Turns out tiny clots don’t show up on MRIs.

Very interested in this. So your c-reactive protein, d-dimer (sp?), etc etc showed negative? How did you find the clots? When you say "tiny", in medical terms do you mean mili or micro meters (I think that's right).

You might like the #1 book on Amazon under cardiology currently. Its thesis is cholesterol has nothing to do with heart diseases, its all in the clots. Good detail of the clotting process and relatively understandable.

Had a Pulmary embolism. Was gasping for air and coughing up flecks of blood. At the Er the Blood work was perfect. D-dimer, everything. Genetic testing came back positive later on. So they put on blood thinners. A few days later my dementia was gone. Was solving complex programming problems with ease once more.

Every time I try and go off them all the symptoms come back. So it was this that micro-clots was determined.

Also when drawing blood nurses kept complaining that my blood clots to fast.

How did you learn it was a blood disorder?

> It's amazing what people can access now, but self-experimentation with these compounds is a terrible idea.

I think it depends what the alternative is. If you have something like Alzheimer’s and no other alternatives, maybe self-experimentation is not such a bad idea.

Reminds me a bit of cerebrolysin self-experiments I've read. It can either permanently make you smarter or permanently give you brain damage. Or both, perhaps.

(For anyone unaware, it's a bunch of neuropeptides harvested from pig brains that you typically either inject or - fittingly, due to the source - snort directly into your brain through your nose.)

"Smarter" do you mean neuroregenesis? As I understood it's used post stroke to try to reverse some of the damage.

If we pair ISRIB with pig heart transplants it's a side-effect free way to boost cognitive function though.

Totally side effect free if we ignore the risk of stroke from cardiopulmonary bypass (at least 0.5%), infection of the chest cavity (0.5-3% incidence of mediastinitis after median sternotomy), anesthesia complications, post op pulmonary embolism, pneumonia, UTI, etc.

I think that's the joke.

Open heart surgery - let alone replacement - isn't likely to be side effect free in our lifetime. A detached sternum is also a side effect, after all, requiring a couple months to recover to basic function...

Perhaps a similar molecule can be found instead which does not have this problem. Or another compound can be added to prevent heart damage.

It's probably going to be interpreted as cynical b/c it's HN but I do honestly believe that solving heart function will be lot easier than solving cognitive decline, and a win on cognitive decline is huge news (hopefully not paired with not pig hearts, but it's a reasonable proof of concept).

I guess it depends on how long the bad effects on the heart last after taking ISRIB. If it keeps lingering, you may need new pig hearts over time. Or.. Just keep taking ISRIB and just schedule a yearly pig heart transplant.

There we have it, yet another way to get those prion diseases...

Sounds very cyber punk.