If I am mistaken, we do not know why plenty of medications work -- especially those within in the domain of mental disorders.
For example, why does lithium work, amphetamines, etc.? Obviously, we know such medications work, but not the "how"/"why."
Here’s a fun one: we don’t know how general anesthetics work. From ether to desflurane to propofol, they all exhibit similar behavior, but we actually don’t know exactly what that mechanism is.
Anesthesia is weird. I'm an anesthesiologist; believe me, there are tons of weird things about the human body that you learn from throwing various compounds at bodies and seeing what happens. Xenon is an effective (though expensive) anesthetic gas by itself. People of West African descent occasionally (~10-20%, usually on the lower end of that) have a hypersalivatory response to cholinergic stimulation. Drugs that should be fine and got approved but turn out to kill kids disproportionately (rapacuronium).
Much of our practice is derived from "we've been doing this without too many bad effects for a long time with these drugs, so we're going to continue using them rather than try something new unless the new one brings something to the table that's a slam-dunk". Diethyl ether is slow, it smells awful, and it's flammable (and will form explosive peroxides if stored too long), but it's still a good anesthetic. If I had to re-create civilization from scratch, that would be one of the first drugs I tried to make.
In the days before routine pulse oximetry (which, in addition to measuring oxygenation of the blood, is proof of a pulse - it does not work on heart-lung bypass), the fact that the heart was beating was confirmed by using an esophageal or precordial stethoscope. This was typically connected to an earpiece that was molded to the individual user by a simple piece of tubing. Precordial stethoscopes are a neat thing to see; they are just the "bell" part of a stethoscope made out of a decent-sized piece of metal so that the weight would keep it on the patient's chest and prevent it from moving around. I'm told that anesthesiologists who practiced in this era, which was also before each anesthesia monitor had continuous gas sampling of the patient's respirations to determine the concentration of anesthetic agents, could recognize when a patient under halothane (which was also a well-known cardiac depressant, but unlike many other agents had a non-irritating smell and so could be used for pediatric cases without an existing IV, where anesthesia is induced by simply breathing the gas) was getting too deep by the change of the heart sounds. We have a newer, less cardiac-affecting anesthetic now, sevoflurane, which has essentially replaced halothane in developed countries and I would assume most less-developed ones as well (because it's now off-patent and pretty cheap).
Sure, I am not doubting that we have some understanding of some of the mechanisms. We know SSRI's affect serotonin, but not how they work in terms of providing therapeutic relief. My point about amphetamines was the same. We might know that catecholamines are pushed out of the presynaptic neurons, but how/why does that treat conditions like ADHD, Narcolepsy, Binge-Eating Disorder, etc.?
those disorders are often characterized by inappropriate dopamine/norepinepherine levels.
if you push more catecholamines into availability, while also reducing the ability for them to be re-uptaked by their associated transport chains, then the patient begins to edge towards a more normal saturation level of the deficit chemicals.
Trying to remember what a neuroscience friend of mine said; your brain, like your body, tries to reach some sort of homeostasis. Inhibiting the reuptake of serotonin results in there being more serotonin in the brain, resulting in your brain changing somehow to handle this serotonin.
These changes take time to develop, thus the delay on the impact of ssris.
Generally, consistent use of any drug will cause these longer term changes in the brain. Since your body is trying to find homeostasis, these changes reduce the impact of the acute effect of the drug, thus the experience of tolerance. The experience of withdrawal is a side effect of having these changes without the acute effect of the drug.
Those are secondary effects of underlying issues in ADHD, Binge-Eating, etc. The core issue is something not working well, such as in ADHD, the brain may have smaller prefrontal cortex regions (or less connected, etc) and thus have problem with self-regulation. You can sort of work around this by boosting dopamine, but it is working around the issue.
It is akin to an engine that is under powered so we figure you show to press the gas pedal harder (dopamine increases focus/effort/alert, so it is like pressing on the gas.) But the core issue is that the engine is underpowered in comparison to others. And it may be underpowered for a large variety of very specific reasons, including genetics (controlling development, or resistance to stressors), physical trauma, sleep, etc.
My understanding is that is still hypothetical at this point, albeit the leading hypothesis. Personally, I think that ADHD is just an abstraction for a set of behaviors. I am not trying to downplay its severity, it's caused me undue suffering, but my point being that I believe there are multiple etiologies that have fairly similar symptoms.
After all, stimulants have a wide variance in efficacy for people with ADHD, and there are plenty of medications that are even non-stimulants, so I think that should be a sign that there is much more to this disorder(s) than just dopamine and norepinephrine.
But hey, what do I know?
This makes the effects of extra dopamine in the system a side-effect, not the feature. But I'm not a doctor, so I could be wrong on that.
Could it be that catecholamines have a higher affinity for the presynaptic neurons, so we need the dopamine to push it out, at which point there's a chance the norepinephrine can get into the receptor?
NE may be desirable in some subtypes of ADHD because varying mechanisms can cause the same symptomology, its complicated and we don't know enough yet. Dopamine also plays an important role in attention
In no way does dopamine "attach" to NE, so I'm not sure what you're trying to say there
There are receptors for catecholamines both pre and postsynaptically, so it is a misstatement to say that they have an affinity for one or the other.
The way that synaptic release works is generally through vesicular release but in the case of amphetamines what they do is not only stop the reuptake of dopamine or NE from their synapses but they can also cause efflux out of the reuptake transporter.
Generally speaking NE and dopamine are in different neurons but there may be some crossover.
There has been no clinical evidence on SSRIs mitigating the effects if clinical depression, and a lot if anecdata I've seen is that they're very hit-or-miss.
The "why" costs money, resources and an itch for genuine curiosity and ingenuity with mostly negative returns. So it remains unknown, while we focus on the combining 2 or more things we already know and see where that can be sold.
Another observation here is there's a lot of money riding on "pseudo science". See any superfood or beauty products for example. You take a data point that is demonstrated under certain conditions in a controlled environment. Make that single data point a centerpiece of evidence, tack the usual goop on it, market it, label it and place it on the front aisles of Trader Joe's. Now there's a lot of incentive to keep the "why" away from consumers walking those aisles.
Turmeric is sold for like a dollar a pill. It's pure horseshit.
I try my hardest to avoid it due to the associated hepatotoxicity which, to my understanding, is less likely/not observed in other NSAIDs.
Sure, I do agree that NSAID have their own pitfalls. I am sure most, if not all, medications have pitfalls at some intersection between dosage and time. My understand of acetaminophen is that the line between therapeutic help and harm is rather small for compared to many other OTC medications.
Just based off of a few brief searches it is recommended that an adult take no more than 2 tablets every 4 to 6 hours. One tablet is typically 325mg. According to this Harvard Health link [1]:
"For the average healthy adult, the absolute maximum daily dose is no more than 4,000 milligrams (mg) from all sources. But in some people, doses close to the 4,000 mg daily limit for adults could still be toxic to the liver. It's safest to take only what you need, and to not exceed 3,000 mg a day whenever possible, especially if you use acetaminophen often."
So, even with infrequent usage, and by following proper instructions, liver toxicity could still technically occur within just 24 hours of usage. How likely is it? Well, that I have not looked into.
Overall, my point is: why risk even go down that road? Now, I could be wrong (again), but most research I have seen on the topic pertains to pain relief where Tylenol doesn't seem as effective as alternatives. Perhaps for other aliments it's better, but again, that begs the question -- better compared to what else and what are those risks?
[1] https://www.health.harvard.edu/pain/acetaminophen-safety-be-...
[1] https://science.thewire.in/health/paracetamol-650-mg-drug-pr...
I think you're overstating the risk to your liver, it's not even a prescription drug in any country I'm aware of, there are guidelines and dosages stated for a very good reason, sure, but if you're not taking it routinely (rather just to address an occasional issue) it's fine. And if you are you should see a GP, but the outcome might still be that they agree and prescribe a daily dose.
Ibuprofen should be taken with food to mitigate risk of stomach ulcers, but how many people follow that guidance? It's processed by and a toxin to kidneys instead of liver, can result in AKIs/renal failure, at least you have two of those I guess?
Personally I take ibuprofen for a migraine etc., but paracetamol for a fever. Neither is happening frequently, so I don't worry about occasional use within the guidelines/on doctor advice of either of them.
I've been told to avoid NSAIDs "forever", or at least until a gastroscopy has shown my stomach is fully recovered after using ibuprofen strictly within the dose limits. It's a known risk, and lowering the dose just reduces the odds - it doesn't remove the risk.
Acetaminophen/paracetamol overdoses do happen, but they're rare and usually involve significant overdoses rather than minor accidental excess use.
Their ability to bring down fevers etc. also tend to differ depending on source.
Acetaminophen/paracetamol is usually the first recourse in hospitals etc. because as long as you dose it right, the odds it both works and doesn't incur harm are better.
Sorry, I find it hard to understand how you came to this conclusion. Even if taken every 4 hrs for the whole 24h (which is extreme case, rarely one needs more than 2-3 tablets for a pretty nasty fever) it gives us 6 doses per 325 mg = 1950 mg which is well below even the most cautious limit
Fevers are there to kill the virus.
You only need to break them if they get high enough to pose a danger to the brain or other organs.
Which is a lot higher than a low-grade fever.