A miracle drug sold over the counter

I have an idea for another drug repurposing effort. I think this one could be a blockbuster.

The drug that I’m thinking of is currently predominantly used as a pesticide. It’s very effective at killing insects, but also can easily be used to kill mice, cats, and dogs. But, I don’t want to use it as a pesticide, or really to kill anything at all.

Instead, my plan is to sell it over the counter to any person that asks for it. Young, old, pregnant, not pregnant – literally anyone. I first plan to advertise it as a cognitive enhancer. Once I land that as a bulkhead, I will advertise it for general brain health, and say that regularly taking it will help prevent Alzheimer’s disease and Parkinson’s disease.

I am standing on this soapbox so people can hear me better.

From there, the sky’s the limit. I’ll tell people that it’s a performance enhancing drug in sports, and that it can help you lose weight. I’ll tell asthmatics that it can cure asthma, and people in pain that it will cure their pain. I’ll tell people with ADHD that it’ll help cure their ADHD, and I’ll tell people who are tired that it will make them energetic.  Hell, I’ll even tell mountain climbers that it’ll cure altitude sickness.

The best part? I’m not even going to bother with proper manufacturing controls. This drug literally occurs in leaves, so I’m just going to go outside, pick some leaves, wash them off, stick them in hot water, and sell the leaf water to the public. Good luck stopping me, FDA.

Of course, with me saying this, my game is probably up. I’m talking, of course, about caffeine. Everything I wrote about caffeine above is true.

It is incredibly widely consumed and has been for centuries. A bunch of different plant species have independently figured out how to produce it, including coffee species, tea species, kola, and yerba mate¹. They mostly use it as a pesticide², although there’s some evidence that it also helps attract pollinators ³. For humans to use it, we just have to boil the leaves, which is pretty convenient.

Caffeine does kill dogs, cats, and mice. The lethal dose (LD50) for mice is 185 mg/kg, cats is 80-150 mg/kg, and dogs is 140 mg/kg. This is actually similar to the lethal dose for humans, but the main difference is that for a 3 kg cat, a single Dunkin Donuts large iced coffee would be fatal, while as for humans it’s just called “being in Boston”.

You probably already know that caffeine is a general cognitive enhancer and keeps you awake. Meanwhile, anyone who’s ever taken pre-workout powder knows that caffeine is a performance enhancing drug. And it’s probably not shocking that people with ADHD can use it to focus, given that it’s a stimulant.

But the other claims are true as well. Caffeine does help people lose weight, although that’s hard to separate out from its effect on energy levels. It’s helpful with asthma⁴, altitude sickness⁵, and pain relief⁶. And, shockingly, it does actually have excellent data in preventing Parkinson’s and Alzheimer’s⁷.

I don’t want to just list all the things caffeine can do, though. Instead, I want to make a point.

Caffeine isn’t some one-off wonder drug. Like doxycycline or cyclosporine, it’s one of a number of drugs that affect fundamental pathways that are conserved across the animal kingdom. The reason caffeine has so many effects is because it’d be impossible to do something so fundamental as being a universal pesticide without having a lot of effects.

There are likely other drugs out there like caffeine. Hell, even caffeine is still out there, given that I, a relatively well-educated person, had no idea that caffeine could help my asthma. 

We have made a choice as a society to not pursue drugs like this. The FDA pushes for all drugs to have a straightforward mechanism of action, stringent and repeatable manufacturing, clear indications, and low toxicity in non-human species. This makes for expensive, limited quantity drugs that are useful for one or two indications.

I understand why this happened. The FDA wants to avoid a snake-oil free-for-all, or a repeat of thalidomide, or contamination of the drug supply, or any number of other bad press events. And I want to avoid that as well.

But I do want a world in which it’d be possible to imagine that a pesticide that kills dogs could be taken by the elderly over-the-counter as a prophylactic against dementia. The only drug currently on that list has been grandfathered in. Could we ever add another?

1. Interestingly, they all produce it using the same pathway (although different, species-specific enzymes), even though there are other pathways they could have used. This pathway starts with xanthosine, which comes from xanthine and ribose. Both of these are pretty easily produced from DNA, so it’s probably just easiest to create caffeine that way. 

2. Caffeine inhibits insect phosphodiesterases, resulting in intracellular accumulation of cyclic adenosine monophosphate (cAMP). cAMP is used a lot in intracellular signaling. It also inhibits human phosphodiesterases, which is probably what accounts for its anti-asthmatic and cardiostimulatory effects. It’s much weaker in humans than in insects, though.

3. This mechanism is interesting. It actually appears as if caffeine, in the low concentration that it reaches in nectar, actually helps bees form stronger memories of the specific flowers they got that nectar from. So, bees are more likely to return to those flowers.

4. The mechanism of this gets very tricky, as I mentioned in footnote 2. If you look up the mechanism of caffeine, every source just says “caffeine blocks adenosine receptors, and adenosine promotes sleep”. That’s true, but hardly the only thing caffeine does or that adenosine does. Caffeine affects at least 10 different receptors, including 4 different adenosine receptors. All of these receptors are spread out all over the body.

Now, adenosine is involved in cardiovascular signaling, but caffeine’s effect on asthma is probably because it prevents the phosphodiesterase signaling pathway that eventually leads to inflammation. Administration of caffeine can directly decrease levels of inflammatory molecules like TNF-alpha, which would be what would cause asthma. This is why corticosteroids also decrease asthma.

5. Although the most recent medical reports I’ve found warn people about caffeine at high altitudes, because it has a stronger effect at higher altitudes, similar to how you get more drunk in an airplane. I want to ask them what they think about the Peruvians chewing coca leaves.

6. This might also be due to its anti-inflammatory effects.

7. I’ll probably write another blog post about this because it’s especially surprising. For both Alzheimer’s and Parkinson’s, there are good longitudinal studies that show people who drink caffeinated coffee have lower risk of developing neurodegenerative diseases than people who drink decaf or no coffee at all.

It’s difficult to imagine the causation going the other way. People who develop neurodegeneration tend to have poor quality sleep, so they should be more likely to drink caffeine, not less. And the longitudinal studies that have been done match people up by age, income, and sex, so those other confounders are also out.

But it’s a strong effect: about 50% less likely for PD, and about 30% less likely for AD. So, what’s the cause? Maybe it’s the anti-inflammatory stuff from before, maybe it’s something to do with adenosine, or maybe it’s the inhibition of acetylcholinesterase. Inhibition of acetylcholinesterase was the target for early AD drugs, although they never seemed to work that well.

Or, maybe, it’s the inhibition of adenosine again. This can get especially complicated, as inhibiting adenosine from reaching its receptors also means inhibiting dopamine from reaching adenosine-dopamine complexes, although those are still very poorly understood. Again, it’s very complicated and something I want to explore more.