Caffeine and modafinil shouldn’t be compared, as they have vastly different activity, history of use, and understanding of effects.
This is merely an anecdote, but I was prescribed modafinil for narcoleptic symptoms. Compared to traditional psychostimulants, I found it to be ineffective with a more severe side effect profile. Of course, YMMV.
My brother has narcolepsy, and finds modafinil much better than amphetamines. He says he has zero side effects with modafinil, and it makes him much less jittery than amphetamines.
I have CFS, and sometimes need a stimulant if I must stay awake. I've tried amphetamines, but they make me really jittery and a bit anxious and snappy - I feel "tweaked", and it's not pleasant. By contrast, modafinil keeps me focused and awake, with the only side effect being a small increase in blood pressure.
I've found that the people who say Modafinil does nothing for them are people experienced with high powered stimulants who are expecting the same kick. This is mostly due to a misunderstanding of what the drug actually does.
Modafinil is a "wakefulness" drug. My favorite comparison is the feeling that you get when you have to pee in the middle of the night, and your body sends out that hormone to wake you up. Modfanil just kind of keeps that process going continuously. There is no "high" or any hyperactivity, just an extra layer of wakefulness.
> My favorite comparison is the feeling that you get when you have to pee in the middle of the night, and your body sends out that hormone to wake you up.
Really? I had no idea! Thanks for teaching me something new.
Paradoxical and other unusual effects can occur with any kind of drug. Brain drugs in particular seem to be prone to a wide variance in the effect profile. I speculate that in part it is due to the heavy "reuse" of neurotransmitters for various purposes (neurotransmitters themselves being mostly reused modified amino acids). For example, dopamine modulates motor activity, reward pathways, attention, and error correction, and more. Serotonin modulates smooth muscle, appetite, uterine contraction, mood, visual salience, and more. Both can affect circadian rhythms. NMDA/AMPA and GABA are widely present and are the basic "wires" for excitatory/inhibitory signals, so drugs that affect these can do all kinds of zany things.
Neurotransmitters tend to be context-depended, so when you wash over the whole body with a small molecule which hits in a neurotransmitter-specific rather than context-specific way, you can get some funky effects. Most of the activity comes from the coincidence that there are some domains which correlate well with context: dopamine tends to affect anything resembling taxis, so physical movement, but also goal seeking, prediction, etc.
On top of all that, receptors and enzymes are physical things, and thus different folks have different affinities for transmitters and drugs. Pharmacokinetics - how your body distributes and clears drugs - is a huge variable.
Modafinil in particular is interesting because it's what drug chemists call a "greasy brick" - highly lipophilic, low solubility, to the point where ensuring consistent bioavailability is hard. Cephalon has put in a fair bit of work ensuring a certain particle size and excipient profile (emulsifiers to facilitate absorption) and personally I've experienced quite the difference between name brand and generic, the later often does jack-all for me.
td;dr - small molecules act on broad regions and impact many subsystems at once. Biology is complicated and crufty.
Sorry for off-topic, but: why are there many different neurotransmitters instead of a common single one? (I mean, sure, evolution, there's no "why", but I'm asking from an hypothetic engineering standpoint.)
Neurotransmitters are often synthesized from amino acids. They have different functions in the body, often either inhibiting or exciting the neuron that it targets.
There are a bunch of different aspects to being awake. Caffeine works on adenosine, which has to do with wakefulness. But also things like adrenaline have a different aspect of wakefulness that amphetamines target. Modafinil targets orexin receptors I believe, which involve wakefulness as well as eating.
If anyone tells you they understand the brain - they are lying.
The only certainty we know is it’s located in your head and weighs a few pounds. That’s pretty much it.
The absolute best neuroscience program at the absolute best university would essentially read from an outdated curriculum (which means it’s from the last semester, in neuroscience that’s ancient history), supplemented with current studies, and you will be told that you will not be penalised for using answers from six months ago that have been invalidated now, and are absolutely wrong, but were the textbook dogma last semester.
It's true that we don't know everything there is to know the brain, and critically we have zero idea where consciousness actually comes from; where 'you' exist within your brain.
But we do know a whole hell of a lot of details. A bunch of the different chemicals inside of the brain, how they influence behavior and mood. We know a whole bunch about different receptors and have drugs to modify their behavior. We're now able to use transcranial magnetic stimulation (TMS) to stimulate nerve cells in the brain and are able to use that to help people suffering from depression, OCD, and to help mathematical cognition [1].
Our knowledge is hampered by the difficulty of research in this area. The cost of imaging techniques - specifically SPECT scans which use 5-7 Tesla machines which use liquid helium which is super difficult to work with. This means there's not really a way to test exactly which medication will help a given individual other than to give it to them, but don't mistake that for a total lack of knowledge about how things work. We do actually know the method of action on how those drugs work, which ones are agonists and which ones are antagonist and which don't mix.
Better real-world treatment options would be really awesome! It sucks that we can't do any better. Cheap and better imaging options would really change the status quo and allow better real-world treatment for mental illness. But what we do know takes years, if not decades for a person to learn, so even though things are still changing in the field, even though we can't answer some fundamental questions about consciousness, we understand a whole hell of a lot more than "it's located in your head and weighs a few pounds".
I don’t disagree, there is of course a body of knowledge, which rapid churn implies that we are accreting that at a good pace.
And yet, despite all this, no better treatments that amphetamines have been found for so many cognitive disorders.
100 years old drug, and to prescribe which you don’t even need to know how much the brain weighs.
What is the use to the laity of all this research, if half of the time the answer is stimulants, the other have is SSRI?
I think we will be seeing the most promising area in sleep, because it’s so underserved and you can collect a lot relevant data inexpensively and un-intrusively.
It's quite different in most regards: I'm super-tired all the time, need a nap every afternoon, my endurance is extremely low (lifting a kettle feels like lifting a weight, climbing the stairs feels like climbing a hill) and simple activities tire me out waaay more than they should. If I do anything remotely strenuous, then it does kind of hit me like narcolepsy - within the space of a few seconds I become extremely tired, like I've been drugged, and I have to sleep.
CFS remains a diagnosis of exclusion, and it's quite likely that it's a label that actually represents several conditions, and people are affected to varying degrees - some are bed-bound, for example.
This is merely an anecdote, but I was prescribed modafinil for narcoleptic symptoms. Compared to traditional psychostimulants, I found it to be ineffective with a more severe side effect profile. Of course, YMMV.