There are definitely exceptions, that's true. Usually there's an interesting pharmacological reason why though.
For instance, SSRIs have this property, because for those drugs, the tolerance is the treatment effect. The tolerance has downstream effects on things like BDNF that are thought to be the true mechanism behind their efficacy. But this is also clear from the phenomenology observed, i.e people see improvements with a delayed effect.
This drug is very pharmacologically simple though. It's an extremely selective agonist for the 5-HT-4 receptor, and its effects are mostly acute, it seems(though due to a longish half-life it does take some time to reach steady-state with once daily dosing).
Now, I'm genuinely curious: does anyone know of a drug which,
1. Has acute psychoactive effects
2. Retains those effects under chronic same-dose usage
3. And the perceived effect can not be explained by correction of a rebound effect(i.e one cup of coffee in the morning might wake you up the same, but is it really, or is it just correcting an overly tired, mild withdrawal state associated with chronic use?).
Not sure about the pharmacology, but I want to say methylphenidate (Ritalin)?
I have severe ADHD, so I'm taking a pretty high dose daily, and I haven't noticed diminishing effects nor rebound. My dose hasn't changed in years either.
Ooh, ritalin is a fascinating and intricate one. I also have severe ADHD, and I've also noticed this somewhat paradoxical fact about ritalin.
I think the comparison between ritalin and strattera can be quite illuminating here.
Ritalin is an NDRI(norepinephrine and dopamine reuptake inhibitor). It binds to and and inhibits DAT(dopamine transporter) and NET(norepinephrine transporter). This causes neurotransmitter to remain in the synaptic cleft for longer. It also acts on some interesting serotonin receptors.
Now, for ADHD treatment, you typically want to increase dopaminergic neurotransmission specifically in the prefrontal cortex(PFC), which is the part of the brain that's underdeveloped in ADHD.
Stranglely there's very little DAT in the PFC, but it turns out NET also works for dopamine, and NET does what DAT would normally do in this part of the brain. So inhibition of NET is clearly crucial to ritalin working.
This is where strattera comes in. Strattera is a selective inhibitor for NET with no appreciable effect on DAT. So strattera ups dopamine in the PFC, but not in the brain's reward centre. Helps your ADHD, but it doesn't make you high.
And the interesting thing with strattera is that it sort of has this same property that SSRIs have in that it has a delayed onset of effect Where it gets more and more effective over time. I believe there are some studies tying this to rewiring in the PFC, but don't quote me on that.
But ritalin literally works starting with the first dose. You get that sudden motivation to actually do stuff and so on.
So I actually think ritalin has at least two different modes of operation, one acute and one chronic. And it's the latter that's doing all the real work, the former is just a transitory kick in the butt, so to speak.
Thanks for taking the time to explain, very informative! I've been meaning to look into the mechanisms of Ritalin for a while buuuut ADHD.
Strattera is really interesting, I've heard of it but I don't think it's available in my country. I'll ask my psych about it. We also don't have Vyvanse here, which my psych thinks would suit me better, as I'm currently on 162mg/day (of Concerta).
Have you tried Strattera? How does it compare to Ritalin for you?
For instance, SSRIs have this property, because for those drugs, the tolerance is the treatment effect. The tolerance has downstream effects on things like BDNF that are thought to be the true mechanism behind their efficacy. But this is also clear from the phenomenology observed, i.e people see improvements with a delayed effect.
This drug is very pharmacologically simple though. It's an extremely selective agonist for the 5-HT-4 receptor, and its effects are mostly acute, it seems(though due to a longish half-life it does take some time to reach steady-state with once daily dosing).
Now, I'm genuinely curious: does anyone know of a drug which,
1. Has acute psychoactive effects 2. Retains those effects under chronic same-dose usage 3. And the perceived effect can not be explained by correction of a rebound effect(i.e one cup of coffee in the morning might wake you up the same, but is it really, or is it just correcting an overly tired, mild withdrawal state associated with chronic use?).
I actually can't think of any.