Ketamine blocks bursting in the lateral habenula to rapidly relieve depression | Hacker News Reader

Ketamine blocks bursting in the lateral habenula to rapidly relieve depression

nature.com

148 pointsbeefman77 comments

I know it's anecdotal, but I've been receiving ketamine at a local clinic for a few years for chronic depression and a spinal injury. It has proven too be the most effective treatment I've had for treating depression. As another poster said, it is short lived (around two months) But the release from depression, and back pain is life changing for me.

To go with the article, it is incredibly fast acting. Like same day results, I don't know if it's placebo or the ketamine but I'm happy with it as it gave me life back.

You get this done at a clinic- what's the effects like? I've heard terms like "K-hole" for heavy off-prescription users getting zonked by the stuff. I'm assuming you're taking a light dose? Can you drive yourself home?

I generally leave my clinic about half an hour after my infusion ends, but I'm taking the subway. If I were going to drive I'd probably hang out for 60-90 minutes. The dissociative and psychotomimetic effects wear off pretty quickly. But this depends on dose... my doc used to use higher doses before there was as much research around what works, and back then it would sometimes take a few hours before I felt back to normal in terms of cognitive and motor skills.

I'm in the opposite boat, the dose I receive is fairly high and I'm unable to even stand for around 20 minutes after it ends. There's no way I can drive the day of. As for the events, the feeling of dissociation takes around a day to fade for me. I also have a high deal of cognitive impairment from it, or detachment in my thoughts?

Is enjoyable?

Yes it's at a clinic, and it's not a light dose. It does cause "K-Holes", it'll completely incapacitate you for the day of, and you'll be dizzy and sluggish the day after. So no you can't drive yourself home.

You should not "K-hole" with a clinical dose.

It's a fairly heavy dose where you will k-hole. I get 1ml/kg, I definitely dissociate with it. They hook you up to a crash cart to make sure your blood pressure does not go too high, you put on some eyemasks and headphones and drift into it.

No clinics will recommend driving afterwards. The one I go to won't even allow me to Uber home, I need to arrange a medical transport or have a friend/family member there.

How specific is the dose? Do they calibrate it by weight or body fat or anything?

Body weight. I'm unsure at the moment/can't remember what their metrics are though.

The dose is based off of body weight. Some do it off of "ideal" body weight while others do actual body weight.

Any side-effects? Bladder/urinary issues? What happens to you as it wears off?

During you can suffer from some intense anxiety and strong nausea, so they'll give stuff for that. After the only thing that I notice is that my emotions are put to 11 and I'll just be extremely uncoordinated and exhausted.

I have found it to cause some memory issues for the following couple weeks, but it mostly recovers. It's certainly better than the memory issues when I'm in the throes of depression itself. It also spikes my blood pressure up quite high during treatment.

You feel sorta light headed afterwards. For the weeks after I just notice myself doing more stuff. Waking up early, having lots of energy, just feeling pretty good.

Does your insurance cover it?

Insurance does not cover it unfortunately

Ketamine was both the best and most depressing depression treatment option I've ever tried.

Within a couple of weeks after having had the initial round of six treatments in two weeks, I was the most functional and productive human being I've _ever_ been - things that used to be impossible or utterly agonizing to complete were as trivial as they "should" be, I was enjoying life, it was great.

After a couple of months of periodic booster treatments, over the course of a week, I felt it completely drain out of me, and no variance or repetition of ketamine treatments has been able to reproduce it since. (We spent months varying dosage levels, frequency, and trying a few OTC things that the doctor had seen synergize ketamine response in people before, to no avail.)

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.

It's so exciting that there is now a putative mechanism for this! Ketamine is such a curious drug, and this effect of it is one of the most interesting of all. Knowing the target will allow more focused therapies and possibly a greater understanding of depression in general.

Isn't regular Ketamine use especially bad for the bladder? I recall reading multiple anecdotes from the Erowid ketamine vaults where people lost their bladders due to recreational Ketamine use.

yes https://www.ncbi.nlm.nih.gov/pubmed/27001627

Why is this being downvoted?

As the other poster said, yes. China is dealing with a fairly grim pattern of ketamine abuse cystitis.

https://www.sciencedirect.com/science/article/pii/S187952261...

http://www.bbc.com/news/av/world-asia-china-33472971/inside-...

It's a huge problem for recreational use. Some individuals have trouble with it even with prescription ketamine, but it's not nearly as common. Last time I asked him, my doctor hasn't had any patients who were forced to discontinue treatment because of it.

n=1, but I've been receiving ketamine therapy for about 6 years and have not developed ketamine cystitis.

Are recreational doses significantly higher than prescription doses? Why the difference?

Yes. "Recreational" users rarely suffer from ket bladder - it's people with serious addictions who are ending up in urology clinics. Users are reporting taking anything from 5 to 15 grams per day; even assuming that it's of very low purity, that's still orders of magnitude more than the doses being used to treat depression.

Ketamine is toxic to the bladder at any dose. I haven't found any long term research on this topic.

The research for depression used much lower doses of ketamine than recreational use. One UK clinic was using about 80 mg as a max dose. https://www.oxfordhealth.nhs.uk/news/first-uk-study-of-ketam...

A large recreational dose may be 250 mg.

This is partly because the recreational dose is looking for different effects, so they use more. And because people build up a tolerance.

It’s also a result of ketamine typically being used in the context of other drugs, especially stimulants.

It is in the way that alcohol use is bad for one's liver- the cases where it results in bladder issues are those of abuse where doses massively larger than the therapeutic psychiatric dose are used on an ongoing basis.

"A young adult male taking 1 g of ketamine could expect 85% of the drug to be excreted in the urine within 24 hours, and taking into account the average voiding rate of 6 × 300 mL per day, a urine concentration in excess of 1 mmol/L is theoretically possible, suggesting the scale of in vitro toxicity reported [in the study] and by others in cancer cell lines is relevant clinically,"

For reference, the dosages this is referring to are generally .5mg/kg, which of course is comparatively small

Back of the envelope... 175 lb ~= 80 kg, which means a single medical dose of 40 mg, with effects lasting weeks to months, compared to abuse-levels of 1g per day!

It's not great for your bladder, but it takes a serious ketamine habit to get to that point - I've known people doing a couple of ounces a week or more for several years who were fine, but tolerance builds up enough over time that people can consume some huge amounts on a daily basis - and injecting it intramuscularly makes it even easier to do so.

Those people were using 10-20x a typical recreational dose, daily.

Obligatory working scihub link: http://sci-hub.tw/https://www.nature.com/articles/nature2550...

I have been looking into Ketamine as there is a clinic which administers Ketamine therapy in my area. The disappointing thing is that it looks like the effects are short lived, and one may need "booster" treatments every 4 weeks, at $400 a shot, for years and possibly forever. I hope with this understanding, we come up with something more permanent.

curious: are you based in the US? Would it not be covered by insurance? $400/shot is a lot for Ketamine.

Insurance absolutely does not cover ketamine therapy in the US

$400 is a fairly typical price. The ketamine itself is cheap, but operating a clinic doing off-label infusions that take an hour or two each is expensive. And nope... no insurance in the US that I know of covers it.

Ketamine is a generic drug and dirt cheap. I just checked and it's under $10 for a vial with enough to use in surgery, not even this setting.

The $400 must be the clinic charge. I'm not sure what administration looks like, but a regular doctor's visit is $100-$150 and if the patient needs to stay for a longer period of time until it's safe to release them, $400 doesn't seem that far off of what you'd expect.

That's on the low end. I've looked into it and seen prices on the order of $1000-1500 per treatment. If you filter those out, many metro areas simply have no provider that charges what would seem to be a justifiable price. Abusive pricing is a big problem for this product it seems. Several advocacy sites that I saw that maintain provider lists make note of this.

Is it abusive pricing or are they covering for potential legal issues, etc? It would be great to hear from a clinician with first-hand experience.

Is it abusive pricing...

Medical clinic in USA? Signs point to "yes".

Most of the expense is that it's an IV, so you need a trained nurse to administer and oversee you having it in and out; at least, that's what the doctor who ran the practice I did this at said, and given the cost of ketamine, it made sense.

It's considered off label use, so insurance won't pay for it.

It's not that expensive on darknet markets.

If I was going to use ketamine, I'd prefer to get it from a reputable source.

Reputation is the key service of darknet markets. If you would prefer to pay $380 extra every four weeks, that's your call.

Are darknet markets still easy to get into? I used SR when it was around, with events in the interim I'm a bit more hesitant.

No, they're in a state of flux right now.

Things aren't as stable as there were in the past but the guides and supporting infrastructure has matured. Read around a bit at reddit.com/r/darknetmarketsnoobs (check out the noob bible especially) if you want to learn more.

By reputable I mean manufactured in an approved facility to Health Canada standards (or equivalent). It seems unlikely that some dude on darknet would meet these standards. It's like saying that your local drug dealer has a good reputation because he hasn't killed too many people with fentanyl.

Darknet stores are mostly distributors not manufacturers of pharmacological products. They are usually sourced from corrupt legitimate medical world supply chains. The economic reality is that there is almost no margin in wholesaling some of this stuff. Starting a yet another factory to make off-patent generic drugs would cost more than the probable medium term profits, especially given that you can more easily acquire from an existing producer. More recent / patented / specialized pharma products are probably harder to synthesize. Therefore, you can rest fairly assured a large-scale supplier with good reputation on the darknet markets is selling real stuff. This is true particularly in the case of generic drugs where, like ketamine, there is already zero patent global production.

> corrupt

Yeah, that's the problem. Are you aware that ketamine is sometimes laced with fentanyl?

https://nowtoronto.com/news/why-is-fentanyl-showing-up-in-st...

Not really something I'd be willing to take the chance on, just to save a few bucks.

> rest fairly assured

No you cannot: http://www.bbc.com/news/av/world-asia-china-33472971/inside-...

mentions illegal manufacturing in China early in the article.

Your advice is dangerous.

To be clear, I live in China and have been here for nearly two decades. You read a BBC article reporting translated third party information on the internet.

I don't think DNM's are the place to direct people experiencing severe depression. It's not only K they might find there. This directive is also potentially damaging to the above-ground progress advocates have been fighting so hard to achieve. I don't think I need to go into the safety issues around self-administration, either.

Even assuming the product is safe, using darknet markets also has legal issues. (I don't agree that it should, but it does.) "Overpaying" $380 to be administered a known safe dose of ketamine in a place surrounded by medical professionals and know you're in the clear legally sure sounds like a fair deal to me when the alternative could end up involving an arrest record and possible prison time, even if everything involved with self-dosing goes just fine.

$400/month seems a very cheap price for getting your life back.

I agree that $10/session does sound better. That's what you pay (at most) for LSD, the traditional longer-term anti-depressive and anti-anxiety effect being there as well (3-6 months).

But: You have to buy a test kit (an additional $25/kit) and be extremely well informed about what do to and what not to do. And plan everything in detail and very carefully. Don't expect miracles if you're not serious about it.

Who are you agreeing with? This is really dangerous advice.

as much as I love LSD, it's by no means a safe drug for severe clinical depression. bad trips can easily push someone over the edge, especially if they have suicidal ideation.

ketamine, on the other hand, has a MoA that doesn't depend on how well the trip went. it's also a known quantity to doctors and far safer and more predictable.

please do not encourage severely depressed people to try acid.

$325-$350 - Albuquerque $500-600 - Chicago Area $900 - Seattle $1000 - LA

It's actually cheaper to fly in to the cheapest center. Ketamine as a drug is safe and cheap. Probably somewhere around $5 a vial. But the doctors are taking a risk with their license and you they have to put an IV in you.

From Wikipedia[1]:

>The habenula receives input from the brain via the stria medullaris thalami and outputs to many midbrain areas involved in releasing neurotransmitters, such as dopamine, norepinephrine, and serotonin.

[1 ]https://en.wikipedia.org/wiki/Habenula

This really, really works. I experimented for years with it after reading about trials. I'd be happy to answer questions.

Where did you get it, and how did you administer it?

Ketamine is available both as a veterinary medicine and is used as an emergency anesthetic (usually for setting broken bones) because it doesn't require an anesthesiologist.

Where I obtained it-- Darknet. I used veterinary needles to do an IM injection. There are also analogues that can be snorted.

How is the darknet these days? I used SR when it was around. Is it still that easy?

I wouldn't recommend it at this moment. The powers that be did a pretty good job of knocking a lot of vendors offline-- then the runup in bitcoin made exit scams attractive while simultaneously making it cost a fortune to tumble/transfer.

Did you administer it with IV or intramuscular? If not, it's completely different from how the studies are conducted.

Intramuscular. I'm not willing to set a cath on myself :)

i did some work around ketamine a few years ago and many physicians i spoke with said it was incredibly helpful for their patients. however there are many others who have said it doesnt work for many of their patients. there are many studies that suggest it works and a lot of other unpublished data suggesting maybe it isnt as great

the mechanism of action is also poorly understood, and while this article may certainly be an important mechanism, ketamine is a "dirty" drug with many potentially active components that act in ways we dont understand

ketamine is also a drug that has been fda approved for anesthesia for years. to properly study its effects in depression would require large clinical studies. however, the drug is off patent, and no company will fund this work

other companies have developed "new" drugs that are structurally similar to ketamine, but different enough to patent. in 2015 allergan bought a company called naurex that had a few phase 2 drugs that acted on the NMDA receptor (the main receptor that ketamine is thought to act on, though there are others -- hence it being a "dirty" drug) but with some chemical modifications aimed at getting the antidepressant effects of ketamine without the "bad" dissociative effects. however, several docs i spoke with said that there isnt sufficient evidence that their chemical only gets the "good" effects, and it may actually be less effective than ketamine because they removed some of the chemical structure that moderated depression. the real reason they used a new chemical was so they could patent it

J&J has another similar product, called esketamine, is an enantiomer of ketamine (imagine ketamine occurred in two forms, a left hand and a right hand one. esketamine is just the left hand version without the right hand). they also deliver it intranasally (while the approved ketamine formulation is IV). both of these tactics help extend patent life or exclusivity. they published phase 2 data last december that looked pretty good

these companies will probably aggressively market their drugs as "better" than ketamine because they have "improved" the chemistry, although there are no data to definitively state this. many anesthesiologists currently offer ketamine treatment for depression, though it is not widely reimbursed or offered. i believe some groups reimburse for it though. it can be expensive because you need to be supervised when you take it, so you have to pay for the time of a medical professional to monitor you.

as others have noted though, the effects wear off basically right after you stop taking the drug. some people are studying a protocol where you "jolt" someone into a non-depressed state with ketamine, and then stop ketamine treatment and start treating them with CBT or another form of therapy. jury is still out on whether this works though seems promising

The dirty argument is not a great one, though, because most illnesses (especially depression) cause changes to a number of networks, and not just one particular receptor subtype or subunit of that receptor subtype. I agree that more mechanistic studies (and more clinical studies) need to be done anyways, but having multiple action sites isn't necessarily a bad thing.

As far as the "jolt" and continued therapy with CBT - this is how treating MDD is generally supposed to be done. Policy issues making it difficult aside, the CBT + antidepressant combo is empirically more effective than drugs alone (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3918025/ - there are more but this is a meta-analysis so it captures a lot of data).

I agree, I meant to say that the "dirty" drug is more effective. If we just isolate one mechanism of action (like NMDA receptor antagonism) and make a specific drug for that, you lose all the other off target effects that could be beneficial

I've had Ketamine infusions for treatment resistant depression, and it did nothing for me. After failing a large range of antidepressants, my doctor prescribed buprenorphine (usually used for getting off of opiates). The buprenorphine has helped far more than any of the other medications I've been on, but now I have problems with nausea.

Some alternatives for improving depression: https://news.ycombinator.com/item?id=15455259

Reminder that the FDA seems to fast track the wrong drug:

They gave "breakthrough designation" ( https://en.wikipedia.org/wiki/Breakthrough_therapy ) to Esketamine under pressure from Johnson & Johnson:

https://en.wikipedia.org/wiki/Esketamine#Depression

Although Arketamine seems like it has a lot more responsibility for the antidepressant effect of racemic ketamine:

https://en.wikipedia.org/wiki/Arketamine#Novel_antidepressan...

https://en.wikipedia.org/wiki/Hydroxynorketamine

https://www.ncbi.nlm.nih.gov/pubmed/24316345 (2013)

http://www.cpn.or.kr/journal/view.html?doi=10.9758/cpn.2014.... (2014)

https://www.ncbi.nlm.nih.gov/pubmed/26327690 (2015)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4910398/ (2016)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487269/#__sec4... (2017)

That isn't to say Esketamine doesn't have an antidepressant effect. In light of the fact that Esketamine makes you Trip Balls(tm) while Arketamine doesn't, I like to think of it this way:

You can likely get an antidepressant effect out of Esketamine in the same way that you can get an antidepressant effect out of psychdelics like LSD-25 & Psilocin. However, like those, it could possibly also make depression worse, and unlike Arketamine doesn't seem to represent anything awfully novel. It however also makes me suspect that like with other racemic drugs like Amphetamine, a shifted ratio preparation might make for a better drug overall than isolating the stereoisomers. For example, Adderall contains 75% dexamphetamine, 25% levoamphetamine, in the form of various amphetamine salts (wheras racemic amphetamine contains 50% of each, typically as a single salt.).

[Semi-related: I still don't comprehend why pharmaceutical companies have yet to create a combination preparation of Lisdexamfetamine with something like Lislevoamfetamine, - which I haven't seen synthesized but I don't see anything speaking against it -, in a ratio akin to the one seen in Adderall. The rational behind that ratio seems sound, albeit I'd perhaps go for an 80/20 split instead of a 75/25 split...]

This is actually one of two papers published by the lab in Nature. The papers together go much further than just describing the mechanism of action of ketamine and propose a potential mechanism for a cause of depression.

Kir4.1 paper: https://www.nature.com/articles/nature25752

This is really great. I'm excited to read these fully unpaywalled later. I'm interested to see how they'll test this in humans PET or fMRI scanning perhaps possibly before/after depressed patients taking antidepressants/therapy/ketamine/etc...

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