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bannedPosts t1_j8tngcw wrote

Receptor binding and conformational dynamics is highly complex. Just because two chemicals bind at the same site, doesn't mean they elicit similar outcomes. Rarely do chemicals bind to only one site either.

The serotonin hypothesis of depression will just not die. 2022 - "The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations."


rjmsci OP t1_j8tpods wrote

I think quoting the Moncrieff paper is a mistake here - that's an article with an agenda. Depression is not caused by lowered serotonin activity, sure, but compounds that primarily modulate the serotonin system do relieve it. It's up to the field to unravel the mechanisms behind this. Do these intracellular 5ht2as kick off pathways that surface receptors don't? How do different serotonin agonists affect these receptors? This is exactly the kind of research the field needs to answer these questions.


The-Crawling-Chaos t1_j8u9m24 wrote

> Depression is not caused by lowered serotonin activity, sure, but compounds that primarily modulate the serotonin system do relieve it.

Which isn’t surprising when their response rate is only ~10% higher than the placebo- controlled response rates for depression of ~40% on average.

source 1 Source 2 Source 3 (another Moncrieff)


peer-reviewed-myopia t1_j8wac9x wrote

I think it's a mistake to say compounds that primarily modulate the serotonin system relieve depression.

Considering the delayed 'time of effect' of the therapeutic actions of compounds targeting the serotonin system, it's clear the adaptive structural / functional changes are not specific to serotonergic signaling — be it at the synaptic, or intracellular level.

For example, underlying these changes in plasticity are interactions with the BDNF system, as pretty much all effective antidepressant therapies lead to increases in levels of BDNF mRNA.

There are plenty of other systems at play, and they interact via a variety of feedback mechanisms to regulate the circuits involved in affective behaviors.


nickyfrags69 t1_j8x8ysr wrote

>but compounds that primarily modulate the serotonin system do relieve it

That's not necessarily accurate though. First off, Ketamine has a much higher success rate, suggesting at the bare minimum that other mechanisms can relieve depression without touching serotonin receptors. Second, most of the benefit of SSRIs seem to be indirect/downstream, which is why they take so long to kick in.


km89 t1_j8ukh6r wrote

Coming from a place of total ignorance here, is there any explanation for why SSRIs work so well, assuming serotonin isn't correlated with depression?


AeonDisc t1_j8v0vnw wrote

Isn't the success rate of treating depression with SSRI's actually rather low?


69tank69 t1_j8uqnie wrote

We don’t fully know. But some research has gone into looking at serotonin boosting Neuro plasticity with conventional anti depressants triggering the 5HT1A. Unfortunately checking mechanisms deep in the brain are very difficult to do but if your interested in that side I would consider reading some articles on the Neuro plasticity hypothesis of depression


bannedPosts t1_j8ytvrk wrote

There's no explanation - aside from wishful thinking - SSRIs do not work any better than placebo. In fact, the most reliable predictor of efficacy is believing they will work. If your doc can sell it, it might work. Sounds like religion to me. If, and I say if, SSRIs worked as advertises they would work in a few days not months / years. No other class of drugs enjoys more apologists than SSRIs.


km89 t1_j8yvud9 wrote

I would very much like to see data on this.


ERSTF t1_j90l9bf wrote

I did not know this. Would love to see the data. As an ignorant myself. What is best for treating depression?


FUNNY_NAME_ALL_CAPS t1_j8trnm6 wrote

Interesting, might also explain why SSRIs are known to blunt psychedelic effects.

This also seems to suggest 2A agonism is at least partially related to neuroplastic effects, which would definitely hamper efforts in creating "trip free" derivatives.

I wonder how this relates to 5-HT2A-mGlu2 heterodimers.


hallgod33 t1_j8wtwpw wrote

Trip-free derivatives already exist, like bromo-LSD is used for cluster migraines. Shulgin invented a boatload of non-psychedelic analogues to the classical psychedelics.


FUNNY_NAME_ALL_CAPS t1_j8x2ez3 wrote

As far as I'm aware 2-bromo-LSD doesn't have antidepressant efficacy. There are now a few substances that labs believe are non-psychoactive and retain antidepressant efficacy, but they base this off mouse head twitch response and they have yet to be validated in humans.


hallgod33 t1_j8x3mjs wrote

True that, a lot of Shulgin's work will never be peer reviewed so its hard to elucidate which compounds are providing the effects through human models. And the human models are self-reported and all that. But there are non-psychoactive preparations of a bunch of classical psychedelics that provide anti-depressant effects. What makes it non-psychoactive and effective is hard to pinpoint but Shulgin had a lot of raw data available for anyone interested to explore.


Nae-yer-no t1_j8vx3ak wrote

We are always tripping. What we perceive as reality is really a controlled persistent hallucination.


Duelist_Shay t1_j8w6r40 wrote

It has to be a hallucination, I don't remember the world being this terrible as a kid


SkippingLegDay t1_j8w583p wrote

There's a theory that mildly depressed people actually view the world for how it truly is. You must be very happy!


Tight-Caterpillar-25 t1_j8u0r4m wrote

It's a strange question to lead the article because high levels of serotonin can cause hallucinations and will cause serotonin syndrome. We don't all have serotonin syndrome because the homeostatis of neutrotransmitters is tightly controlled.


joxeloj t1_j8zfd9h wrote

Serotonin releasing agents are not psychedelic hallucinogens, and hallucinations that might occur during serotonin syndrome are most likely true hallucinations, not psychedelic hallucinations.


Tight-Caterpillar-25 t1_j914jff wrote

MDMA is both a serotonin releasing agent and a psychedelic off the top of my mind.


joxeloj t1_j91oxkx wrote

Have you ever done any of these drugs? Metabolic conversion to MDA (which has some 5-HT2A agonist properties) can create some extremely minor psychedelic effects towards the end of the roll as serotonin levels fall but it's not in the same ballpark as any legitimate psychedelic. There's a reason the empathogen/enactogen classification was created.


Tight-Caterpillar-25 t1_j9229il wrote

So it’s a serotonin releasing agent that has psychedelic effects?


joxeloj t1_j926kd1 wrote

MDA has mild psychedelic effects, because it has some agonist activity at 5-HT2A receptors. If you take enough MDMA occasionally those effects can bleed through towards the tail end of the roll. Very mild visuals at most. Related drugs like 5-MAPB are pure empathogens without psychedelic effects. Methamphetamine at high doses has empathogen effects without psychedelic effects as well. Serotonin release does not induce psychedelic effects. Phenethylamine 5-HT2A agonists can.

Empathogenic effects arise from serotonin release and involve a sense of profound empathy for oneself and others, desire to socialize, anxiety reduction, euphoria, etc while remaining relatively cognitively intact and without meaningful changes in visual perception. These drugs are usually stimulating to some extent. Psychedelic effects arise from biased 5-HT2A agonism and involve vivid, colorful visual hallucinations composed of repeating patterns, loss of sense of self, thought loops, etc without implicit euphoria or anxiolytic effects and in many cases without stimulating effects. Very different experiences.


messopotatoesmia t1_j8vtzj7 wrote

To answer the headline... Oil smokes and burns when it's hot - why aren't our cars always billowing smoke?

(Because your brain isn't a sponge in a bowl of soup).


Johnnyring0 t1_j8xjb3j wrote

Many things can bind to a single type of receptor. When I studied psychopharmacology in college there were a lot of great analogies, one of which comparing a receptor to a lock, and a molecule that binds a key. However, a traditional lock and key is too simple, imagine a lock that can sense every part of the key (a full 360 / 3-D analysis). Since there is so much variability in different molecules, with polarity/charge, etc. A lock and key is far too simple of an analogy, but if you can imagine a mind blowing, highly complex version, you can get closer. And rather than the lock opening a door or something, imagine it turning on a machine. But based on how the lock is turned (or activated) it can change the function of the machine, or turn the machine off/on/partially on/off, etc. Completely changing the function of the machine based on what is needed.

A receptor can be activated in so many varying degrees, and each variation causes it to do something different within the cell. There are so many different cascading mechanisms within the cell based on how the receptor is activated. Serotonin does something very different than psilocybin to that receptor, and thus activates a different cascade of activation within the cell.

Here is a basic image of a signaling cascade within a cell from a single receptor. Notice how there are multiple pathway possibilities from a single receptor within the cell.


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Adept-Confection-186 t1_j9qir1a wrote

I wish there were more studies about how drug use can damage neurons and can cause these conditions in the first place.