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flaminate_strutching t1_jbuvhzu wrote

Reply to comment by ZalmoxisRemembers in MDMA appears to confer resilience in a rodent model of chronic social defeat stress by chrisdh79

That’s the research that’s being done now. Because these substances have been illegal for decades even for research, there are still a lot of unanswered questions.

Hopefully, though. Especially since we’re getting more sure that depression doesn’t really have anything to do with serotonin and that SSRIs don’t ultimately improve overall quality of life for people with depression.

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Wavelength_Finder t1_jbvrs71 wrote

I will confirm. SSRIs did everything but improve my quality of life. In fact, all my physical issues got worse which in turn made my psychological go into silent hill mode, fog and everything.

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PoopIsAlwaysSunny t1_jbvyvbr wrote

Plus they literally cause suicidal ideation.

Or the therapy that gets people SSRIs causes suicidal ideation .

I certainly never thohhht about suicide until someone drugged me half to death and asked me every week if I was thinking about suicide.

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tyler1128 t1_jbv5v7y wrote

That's a bit of a stretch in the second paragraph. It is clear that serotonin is not the beginning and end for depression, but rather is a factor in many cases. SSRIs don't help much for some people, but they do have a statistically significant improvement over placebo at helping reduce the symptoms of depression in some. Given worse depression is correlated with worse QoL generally, at least in severe cases, they can help some people. The do have nasty side effects though as well.

For myself, I'm pretty much impotent unless I stimulate myself in specific ways that don't generally apply in the case of sex.

I'm personally pretty excited about the future of depression and other mood disorder treatment past the serotonin hypothesis, and including psychedelics and other such drugs. I myself am actually legally prescribed ketamine for ketamine-assisted psychotherapy as of a few months ago.

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PolyDipsoManiac t1_jbv7j9i wrote

SSRIs are almost worthless and it’s an embarrassment that we’ve relied on them for so long.

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tyler1128 t1_jbv9a78 wrote

I don't disagree with the sentiment. They are not by any metric highly successful drugs nor is the side effect profile negligible. We also can't let personal experience cloud our analysis. They are not almost worthless in data. Here's a relatively modern meta-analysis: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889788/. They are usually on the lower end of of the spectrum of the four main classifications that most anti-depressants fall into: MAOIs, tricyclics, SSRIs and SNRIs. They also are usually on the lower end of the spectrum in terms of tolerability. Tricyclics and irreversible MAOIs are generally more effective, but also more "dirty drugs" meaning a lower specificity in action. Some irreversible MAOIs are still used as drugs of last resort in treatment resistant depression, but they are fairly dangerous comparatively.

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MervinWervin t1_jbya9x4 wrote

>Some irreversible MAOIs are still used as drugs of last resort in treatment resistant depression, but they are fairly dangerous comparatively.

They're definitely more side-effect & interaction heavy but a lot of providers are unduly afraid of them. The dietary restrictions are pretty overblown unless you're chowing down on artisanal cheese or chugging soy sauce. A lot of the drug interactions aren't absolute either as long as you start very low and monitor closely when going up - I was able to safely take a low dose of adderall when plenty of providers would act like being in the same room as it while on MAOIs causes instant death.

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NoNumbersAtTheEnding t1_jbvd97q wrote

It seems, however, tat most of the role serotonin plays in depression has more to do with its relationship with glutamate than any specific function of serotonin itself.

That is to say that too much glutamate activity is linked to depression symptoms and certain serotonin receptors modulate glutamate levels in the brain. So by increasing serotonin activity, you can decrease glutamate activity and this helps with depression symptoms in some people.

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tyler1128 t1_jbvfq1w wrote

NMDA antagonists are of interest, but not because of the NMDA receptor blockade. It's because of the increase in neuroplasticity they many induce, for still not well understood reasons. This is believed to be part of both ketamine and psychedelic therapy, but we really don't understand it well.

It's also worth noting that psychedelics and MDMA are also believed to work mostly through the serotonergic system, with traditional psychedelics being partial HT-2a and HT-2b agonists. MDMA is a serotonin reuptake inhibitor and releasing agent, as well as the other amphetamine effects. Serotonin is still believed to be the main cause of the empathogenic and mild hallucinogenic effects of MDMA, but it isn't an agonist or antagonist, just a re-uptake inhibitor and releasing agent. This means it floods neurons with more serotonin than usual through two separate mechanisms.

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NoNumbersAtTheEnding t1_jbvn89g wrote

I don’t know why you brought up dissociatives. Those NMDA receptors - whilst yes, typically activated by glutamate, are located on GABAergic neurons, preventing the release of GABA in to the synapses.

Additionally the effects of psychedelics are more closely linked to changes in endocrine hormone distribution and GABA, glutamate and acetylcholine balance. The 5-HT2A, 2C and 1A receptor complexes which are thought to be the starting point for psychedelic effects all regulate the distribution of these compounds, along with dopamine and norepinephrine. Many do not seem to understand that inhibition of the NMDA receptor is a core mediator of effects from classical psychedelics. The activation of the 5-HT2A receptor directly prevents the activation of any NMDA receptors located on the same neuron.

It is also worth noting that SSRIs stimulate neuroplasticity and neurogenesis as well - through the same mechanism (inhibition of mTOR, mGlu2,3,7 and various cortisol functions and subsequent release of NGF and BDNF in to various brain regions).

MDMA does this as well, although the dose and frequency makes the poison. Same can be said, perhaps more surprisingly, about other amphetamines such as methamphetamine and mixed amphetamine salts. All these compounds are also capable of producing neurotoxicity as well, however this effect is only paradoxical with methamphetamine. The neurotoxicity of MDNA and things like Adderall appears to disconnected from the direct effects of the chemicals themselves (even in high doses, MDMA injected straight in to the brain does not cause toxicity - for example)

Also as of like, last month, “we don’t know how psychedelics induce this neuroplastic change” is an outdated statement. They trigger a highly novel mechanism through penetration of the cell membrane, rather than activating surface receptors. Similar to how dopamine receptors server different functions depending on their location on or within the cell, so too do serotonin receptors.

I have a lot more I want to say but I am high as balls right now. I will leave this by saying that it is unlikely that the NMDA receptor plays any role whatsoever on the antidepressant effects that have been discovered in ketamine and DXM. In fact, despite both being dissociatives with similar MoAs, it is likely the antidepressant effects are being cause by entirely different mechanisms from eachother (DXM with sigma-1 activation, ketamine has a strong link with its stimulation of adenosine release and AMPA receptor activation).

SSRIs also cause downregulation of certain serotonin receptors, namely 5-HT1A, which tends to be over active in people with anxiety and has even be speculated to play a role in the development of neural inflammation in chronic amphetamine, nicotine and alcohol abusers. It also regulates the distribution of glutamate and stress hormones like cortisol, vasopressin and epinephrine. But since having too much glutamate is linked to neural inflammation and excitoxicity, it is likely that this mechanism plays a strong role in their effects

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tyler1128 t1_jbx6pvv wrote

I brought dissociatives up as I thought that was where you were talking to bringing up NMDA receptors.

You are right that all of these things affect more than just the the primary target, that being the reuptake, release, agonism/antagonism of the primary receptor target. Any drug affecting a monoamine neurotransmitter is going to have downstream effects on others, and many receptors have specific action on regulating feedback loops on the other neuorotransmitters.

I was really only speaking to the direct effect for brevity if nothing else. I'm also aware that the down-regulation of the serotonergic system over time is considered a likely part of the antidepressant mechanism of SSRIs. In general, I agree with pretty much everything you said.

> "Also as of like, last month, “we don’t know how psychedelics induce this neuroplastic change” is an outdated statement"

I hadn't seen that. Mind linking the paper? Sounds like an interesting read.

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NoNumbersAtTheEnding t1_jc5gv3u wrote

I opened this notification while I was rather busy but I’mma find the paper when I have the time/tomorrow if I forget before going to sleep.

Feel free to respond again calling me out if I don’t do that. I just have ADHD and autism so it’s easy for stuff like this to slip my mind

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flaminate_strutching t1_jbv7l7s wrote

Do you have any links to the studies that found a connection between serotonin and depression? Or that demonstrate long-term improvement in quality life with SSRIs?

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Timely-Huckleberry73 t1_jbvgzht wrote

As far as I know all studies (certainly most studies) that have found antidepressants as “effective treatments” for depression are much shorter than the durations for which antidepressants are typically prescribed. Most studies last a few months at most. The evidence for long term effectiveness is lacking, however, there is certainly evidence of long term harm.

https://pubmed.ncbi.nlm.nih.gov/21459521/

Unfortunately there is insufficient data on long term outcomes because such studies would be expensive to conduct and the results of such studies would almost certainly be harmful to the extremely lucrative sales of antidepressants.

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Lurkernomoreisay t1_jbvnp01 wrote

Flaminate was likely referring to :

More that studies have shown that after decades, there is still no evidence that depression is caused by low seratonin levels https://www.sciencedaily.com/releases/2022/07/220720080145.htm

That anti-depressants have questionable benefit to a significant number of patients.

> Antidepressants seem to have minimal beneficial effects on depressive symptoms and increase the risk of both serious and non-serious adverse events -- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418603/

Meta-studies showing that SSRI use was not beneficial in the long term. (Not beneficial as in harmful to long-term health)

> Outcome reporting was less thorough during follow-up than for the intervention period and only two trials maintained the blind during follow-up. All authors concluded that the drugs were not beneficial in the long term. -- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839490/

-- I agree on the Ketamine and Psychedelics.

Ketamine treatment has done wonders for myself, and several of my friends.

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tyler1128 t1_jbvtybq wrote

I never said it wasn't questionable benefit to many people, I explicitly said that. We can cite study after study or meta-analysis after meta-anaylsis, but the fact is, SSRIs score above placebo in statistical significance more often than not, opinion on them notwithstanding. I work in I guess tangent to the field of epidemiology, but I write software for use by epidemiologists for after market drug effect statistical analysis, on algorithms we use to do that. SSRIs are well above placebo, doesn't matter whether you can cite criticism of them or not, and non-SSRI antidepressants almost all work on the serotoninergic system to some level. Ketamine and bupropion are examples that don't directly, or ketamine at all, but ketamine's MOA is not fully understood beyond that we believe the neuroplasticity change to be significant. Ketamine's acute antidepressant effects last well beyond the length of the drug or known medically relevant metabolites being in your system.

Unfortunately, people who had bad experience with SSRIs really love to make that known even if they know barely beyond an iota of knowledge in the actual science. Even if this is /r/science. And it's really frustrating.

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Cnudstonk t1_jbyjvvb wrote

I had help from them. but it didn't save my job. psilocybin, mdma, ketamine, all made ssri's look like a joke.

better than placebo/not lethal is the lowest bar possible. ssri also wrecked a multi year weight loss journey. It's trash.

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tyler1128 t1_jbzv8dq wrote

Same, I have a mixed relationship with them. Sadly ketamine therapy has not been the breakthrough for me some people have had, though it has absolutely helped.

I'm very optimistic about the future of the field of psychiatry though with the movement beyond just the stuff that has helped somewhat but has been far from a cure for the last 40 or so years.

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