LONGECITY

The scenario:

You have trouble paying attention. You feel brain-fogged and slow.

You're first prescribed a stimulant for ADD (D-Amphetamine/Dexedrine).

This is amazing! Your concentration is great, you're swift, and feel highly intelligent.

Over time though, the effects go away. You slowly drift from your enhanced state, to a level hardly above your original baseline.

For whatever reason, you quit taking the drug. Things become even worse than before you started the drug. You're even more brain-fogged, and even slower than baseline. The drug is doing the opposite of what you wanted to do!

This might sound familiar.

Here is how I understand what's happening:

This decrease in effectiveness is due, in part, to the down-regulation of dopamine receptors in your brain.

It's a feedback mechanism for our brain to regulate the monoamines/neurotransmitters within it.
But our brain often over compensates, and things become worse after cessation. Effects may last a long time.

So if agonists are giving short-term benefit and resulting in long term negative effects, why wouldn't we simply use antagonists?

An antagonist would cause short-term negative effects, but result in long-term positive effects through up-regulation. (Provided you are looking to treat an illness (such as depression) that stems from a lack of monoamines.

And if this is true, couldn't agonists work better over the long-term for brains that are overproducing monoamines, like schizophrenia, or OCD?

And that leads me to this question:

Do I totally have this wrong? I know it's oversimplified, but is what I'm saying fundamentally wrong? I know to some degree I must be wrong, because no 19 year old can outsmart dozens of huge drug companies and the field of neurology.

I just don't understand why down-regulation isn't considered in long-term treatment or nootropic enhancement.
Edited by rbgilbert06, 16 April 2013 - 12:06 AM.

I would assume that such things would be incredibly hard to market first of all.

"You should pay for this pill, it'll make you feel terrible! But the withdrawal is awesome!"

Secondly, the effects would only last as long as the up-regulation would, it wold not forever up regulate as far as I know.

I could see how this may work, with true dedication, in a healthy patient... However in someone with a disorder, I feel as though this may make things MUCH worse, even if it is short term.
Edited by Southern_Lights, 16 April 2013 - 12:45 AM.

I've read of some people using the antipyschotic quetiapine (seroquel) to resensitize themselves to dopamine with some success. Apparently it has a 6 hours half life so you can use it just at night as a sleep pill and thus not have to endure the dulling antipychotic effects all day, and it would still work for upregulation of DA receptors. One potential issue is prolactinemia, but I dont think ive read reports of that. Now I dont know if all this has any real validity.
Edited by daouda, 16 April 2013 - 12:51 AM.

Southern_Lights pretty much summed it up. Up and downregulation are temporary phenomena. There's no guarantee you'd be increasing whichever signalling route you're aiming for from a net perspective.

The one exception I can think of is the use of low-dose naltrexone, which seems to work for some individuals in upregulating opioid receptors. Nonetheless, it's still not a common treatment, and neurological pathways are not particularly susceptible to this route.

Psychiatrists sometimes prescribe short courses of anti psychotics probably for this reason.

Perhaps, rather than an antagonist, it may be worth using a non-active DA receptor blocker? That way you don't have as intense anti-dopaminergic effects (still some) but you'll cause a slow upregulation of DA receptors. I was thinking of this recently, as I personally feel that I need more DA receptors considering how much dopaminergic agonists help me.

Have you read about the dopamine modulating effects of the uridine stack? It also increases dopamine receptor densities.. and removes brain fog.

Suppressing DA and NE have horrible effects on your mental health, motivation, energy level and ability to feel pleasure. Also suppressing DA will cause an increase in prolactin which has negative hormonal effects (boner problems). Taking these drugs for long enough to upregulate DA would be disasterous (even people with schizophrenia don't want the side effects with the benefit of less severe positive symptoms). And finally theres the risk of Parkinson symptoms....

And now suddenly I don't want to do any of that, and do want to take Uridine. Uridine here I come.