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Ketamine and its analogs are known to have a rapidly developing and profoundly durable (some even say permanent) tolerance, and I find this is often glossed over, especially when studies don't evaluate it over a long enough time period

I think Ketamine itself isn't a real solution but hopefully some of the isolated metabolites will be

Yeah, I would hope that we find more durable solutions.

I know some people have been on it for an extended interval without any sort of tolerance problem, which is how I initially heard about it firsthand, so it's one more of those strange biochemistry things that's inconsistent, because of course it is.

The interesting thing, to me, would be figuring out what the method of action is for the effect, in order to replicate it in other drugs, but we'll see.

(I'm also curious whether repeating the dense dosages would be effective again for me now, over a year later, or whether the tolerance would be, indeed, permanent.)

I'm curious about whether you've tried to push the dosages into more psychedelic ranges and whether that had an effect? Many researchers seem to think that at sub-dissociative levels the effectiveness is less, as the _experience_ of that state is what alleviates the depression, not the chemical (so to speak).

Most sub-dissociative levels were probably with nasal sprays; I can assure you, this was definitely dissociative levels every time, via IV.

We tried increasing the dosage, which made the dissociation more potent, but had no improved psychiatric benefits for me.

> tolerance. I find this is often glossed over

This was specifically and prominently addressed by the article:

>> However, at 25 days the effects had levelled out.

>> The study's authors suggest it could offer an effective rapid treatment for people severely depressed and at imminent risk of suicide and could help in the initial stages of treatment, as most anti-depressants take four to six weeks to become fully effective.

They see it as a bridge treatment which is temporarily useful until anti-depressants kick in. Because, as it said, after 25 days the benefits begin diminishing... which sounds perfectly reasonable and has the added benefit of reducing the risks of addiction.

I think the durability of that tolerance was what the parent was pointing out.

As in, it's potentially only useful as a bridge treatment once. If you decide to lapse your long term anti-depressant after several months and suddenly need another bridge treatment as you ramp back up again, the durability of the tolerance from your initial ketamine treatment would prevent it from being useful the second time.

The supplement and drug industries are constantly finding ways to provide chemistry that will be most specific and bio-available. While this certainly has benefits, I worry that by bypassing precursors, we also often bypass important regulatory steps the body uses to avoid damage.

The idea that taking something that fixes a symptom, but then creates a permanent tolerance, makes me think that getting that chemical too directly in the past may have caused the tolerance that caused the initial symptom.

Your story reminds me of "Flowers for Algernon" (https://www.amazon.com/dp/B003WJQ74E). If you haven't read it, you might enjoy it for the parallels.

I've considered picking that up a couple of times from very positive reviews, but I'm rather concerned from having heard what the overall mood is at the end of the novel.

Ironically, perhaps when I find a sufficiently effective combination again, I'll give it a look. Thanks!

This easily explained: Ketamine seems to repair some kind of cell damage, thereby increasing neural plasticity.

That is a huge asset, but long endured depressions leave many unhealthy neural circuits over the years. These have be unlearned one by one, which takes time.

Ketamine increases freedom of thought and emotion, but you still need a goal and long-term plan to precisely target and unwork all the patterns that circle back to depression.

Luckily the entrypoint away from happiness is discernable and it is bittersweet: giving up, thereby reducing stress. Which is sweet at first, but turns into hell fast.

Neuroprotective behavior is one of the theories I've heard about ketamine's efficacy, as well as lithium's, but that doesn't explain the immediate gross improvement, just the eventual semi-permanent tolerance in some cases.

In my case, while it was effective, I was a much more productive and healthy person than I'd ever been, cleaning up lots of mess and accumulated dross I'd never been able to convince myself to go through, more physical activity, more consistent eating...but then it all abruptly came crashing down, eventually, so either the learned behaviors have quite a thresholding behavior, or it's a more complex mechanism.

Humans feature meta-cognition. I suspect you felt better and more relaxed due to the mechanism, and that in turn gave you another big boost by showing you that you are still capable to feel and act different.

That reminds me of the short story "Beginner's Luck" By Poi Lass.

It is part of a series examining what happens to people that discover they have a minor super-power.

  It was...possibly the single worst experience of my life,
  feeling that slip away, and now having recent 
  crystal-clear memories of how much that fog had been
  complicating my life.

I should warn you that the overarching theme of this story aligns almost perfectly with this comment.

http://web.archive.org/web/20061112225415/http://www.subreal...

Imho, dissos are for short term depression fixing, you need them psychedelics to open your mind for long term.

Just for a little anecdotal evidence: I ate some psychedelic mushrooms multiple times about 8 years and and haven't been depressed since. I was previously diagnosed with clinical depression and took a moderate amount of Seroquel for it. I haven't taken anything since and I've been great.

counter anecdote i know massive amounts of people who have taken psychedelics that are depressed.

similarly for ketamine.

Without specifying the relative proportion of those who went up, in your experience, along with the massive amount of people who went down, your counter anecdote is weakly armed.

I think either case is weak. Parroting Leary here seems appropriate - set and setting are just as important as dosage when it comes to these substances.

I think this is really what I'm trying to say - that these anecdotes about psychedelics curing / not curing depression to be profoundly useless.

Seroquel for clinical depression, really? I thought it only was used to treat psychotic episodes (I’ve taken it for that specifically).

Oh well, you learn something new every day.

The doctor thought I might also be bipolar or something but wasn't sure which is why it was chosen.

I've heard it being used as an augment for people who have trouble with other treatments, or if they're also looking for synergies with the other effects of it.

A couple of antipsychotics or even more esoteric drug types are used (off-label and otherwise) for antidepressant effects, often at dosages lower than they'd usually be thought to be effective for whatever the primary usage would be. Why does it work? Ask again in 50 years, maybe.

- Seroquel (off-label)

- Adderall/Ritalin for people with drive problems

- Wellbutrin is a smoking addiction aid, antidepressant, and SAD-specific antidepressant (because why not, biochemistry)

- Strattera is nominally an ADHD med but has been using it as an antidepressant off-label for at least 15y (source: I was given it for that, then)

- Abilify is on-label used as an anti-psychotic, anti-depressant augment, and Tourette's med, because again, why not

- Also, one thing a lot of people don't realize is that you don't want to mix a unipolar antidepressant with untreated bipolar, because surprise, side effects may include P(manic episodes) approaching 1, so the options for each of those can sometimes overlap and sometimes not

Biochemistry is really weird, and neurochemistry is one of the densest places for it in the body.

Where I live (Sweden), there are rigid restrictions on what a psychiatrist can prescribe, in the sense that off-label prescriptions aren’t a thing what so ever.

What you said makes perfect sense to me. My reply was just me being surprised by someone who apparently got an antipsychotic for clinical depression alone (... which turned out to not be the case, but yeah...)

Seconded. Try mushrooms, acid, or DMT. Maybe mushrooms if it’s your first time. Watch some trip report videos on YouTube to get an idea of what you’re in for.

It doesn’t “cure” depression... it’s more like it gives you an audience with... something... that then tells you exactly what you need to know about life, the universe, and everything. It’s up to you to then make sense of it, integrate, and execute, which can in itself be difficult for people.

It’s not a cure, it’s a debugger for your brain.

Ketamine is itself a psychedelic.

With all psychedelics, it's very important to integrate the insights you gain during the experience back in to your ordinary life, or they are likely to fade.

It's also important to use psychedelics constructively: with a constructive intention, with an experienced sitter that you trust, in a safe setting. There are lots of other things one can do to prepare. I'd recommend reading "The Secret Chief Revealed" and "The Psychedelic Explorer's Guide".[1][2]

[1] - https://www.amazon.com/Secret-Chief-Revealed-Myron-Stolaroff...

[2] - https://www.amazon.com/Psychedelic-Explorers-Guide-Therapeut...