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Comment by phreeza | Hacker News Reader

A note for people not familiar with the terminology - "functional connectivity" is a specific technical term that really just means temporal correlation between brain areas, as opposed to "structural connectivity" which refers to the actual neural pathways that are formed between brain areas. If you rephrase the headline as "Serotonin booster leads to increased correlation between activity in different brain areas" it maybe doesn't sound as exciting.

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Oh, that's disappointing. I was hoping for a drug that will finally help me understand how monads are just simply monoids in the category of endofunctors.

Maybe LSD or mushrooms?

This guy monoids.

I'm also disappointed. I hoped it would help me understand palato-alveolar ejective fricatives and how they differ from voiced retroflex lateral approximants.

Back to the drawing board!

I know that you are memeing, but if are interested in category theory and have exp in functional programming; “category theory” for programmers is possibly a good place to start.

It's probably so simple you assume the most straightforward understanding of it couldn't possibly be right.

No, rather in the category of endocrine functors.

There is a drug already for that. Catnip.

The main reason it's not too exciting to me is much simpler. They tested it for 6 days. You can do all sorts of wonderful stuff with a drug for a few days. But for most drugs, the effects simply cease if you keep taking it due to tolerance.

And there doesn't seem to be a huge amount of leeway to up the dose either because it's a laxative.

I think this is a overly pessimistic take.

It would be nice to see a longer term study. And no people shouldn't be buying this in IndiaMart but critical analysis of studies isn't just about being as pessimistic as possible.

It's overly pessimistic as it's not constructive. Instead of asking for longer term studies you declare the effect probably won't last.

There are loads of criticisms one could make of the study and wider hypothesis. But as with all criticism it should be constructive where reasonable.

I would think it's pretty clear that the implication is longer term studies are needed and that people reading can infer that on their own.

It’s the case with many nootropics, for many people, so I don’t think this is especially pessimistic.

The brain adapts to new regimes; that's probably part of the anti-depressive effect of SSRIs, not the acute effects. For that reason, I agree that a study of connectivity over the longer-term would be more convincing.

I'm not quite sure if laxative is the correct description of this drug, even though it's official one. It is used for treatment of constipation in cases where laxatives don't help. I'm not sure if it has any similar effects in non-constipated people as other laxatives have.

> for most drugs, the effects simply cease if you keep taking it due to tolerance

I'm not sure that's the case in the broad sense. As a simple example, blood pressure medicine is taken daily for decades and it just keeps on giving.

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?).

I actually can't think of any.

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.

I hope that rant made sense!

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?

> because it's a laxative

Good news everybody, no more fiber intake required.

Getting neuron pathways that otherwise don't signal between each other to suddenly light up is also basically what LSD does, right?

yes, actually all the improvements mentioned in the article reminiscence me of positive effects of psychedelics. They happen to act on serotonin receptors, too.

Do you mind if I ask you - how have you had an account here since 7/5/12 and you only have 1 karma point? I'm flattered that you're responding to my post.

Nice that you pointed it out, I had no idea about having 0 karma points nor I paid attention to it. Even nice that it flattered you. I just happen to be interested in psychedelics (not that I have ever tried them!). I just noticed that the drug is a 5HT agonist, just like most of the psychodelics are, and I jumped into the comments to see if anybody mentions it. I believe that psychdelics mostly act upon 5HT2a while this substance is for 5HT4 instead.

Hey now, member since 2009 with -2 points.

Just waiting to warm up to the place a bit more before easing into meaningful discussion no doubt ;)

First comment in 13 years! Amazing.

Nice to have ya around. Enjoy your lurking :)

Incredible! I feel like I just discovered a secret level in the world. Fitting that it happened in a post about acid.

Not the parent, but one reason is if they never comment/post. How else would they get karma?

Which I think is the point of person you're responding to. His comment has someone get out of one's ten year silence. Pretty flattering indeed.

Ironically, I would not have understood that if not for your comment.

People like their psydelic experiences

That sounds like a challenge

Does functional lead to structural?

This is what I was wondering. There's the idea of "neurons that fire together wire together" which would imply so. But that's a super reductionist take on a very big field.

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