
Ketamine blocks bursting in the lateral habenula to rapidly relieve depression - beefman
https://www.nature.com/articles/nature25509
======
Ophelias_Rue
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.

~~~
mabbo
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?

~~~
blobwalker
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.

~~~
Ophelias_Rue
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?

~~~
unixhero
Is enjoyable?

------
rincebrain
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.

------
rhombocombus
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.

------
newnewpdro
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.

~~~
nylonstrung
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

~~~
fragmede
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!

------
Karunamon
Obligatory working scihub link: [http://sci-
hub.tw/https://www.nature.com/articles/nature2550...](http://sci-
hub.tw/https://www.nature.com/articles/nature25509)

------
starpilot
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.

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

~~~
refurb
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.

~~~
Praitor
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.

~~~
nefitty
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.

~~~
jessaustin
_Is it abusive pricing..._

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

------
softbuilder
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](https://en.wikipedia.org/wiki/Habenula)

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

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

~~~
oceanghost
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.

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

~~~
oceanghost
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.

------
aaavl2821
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

~~~
achileas
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/](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).

~~~
aaavl2821
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

------
pdfernhout
Some alternatives for improving depression:
[https://news.ycombinator.com/item?id=15455259](https://news.ycombinator.com/item?id=15455259)

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

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

[https://en.wikipedia.org/wiki/Esketamine#Depression](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/Arketamine#Novel_antidepressant)

[https://en.wikipedia.org/wiki/Hydroxynorketamine](https://en.wikipedia.org/wiki/Hydroxynorketamine)

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

[http://www.cpn.or.kr/journal/view.html?doi=10.9758/cpn.2014....](http://www.cpn.or.kr/journal/view.html?doi=10.9758/cpn.2014.12.1.72)
(2014)

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

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

[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487269/#__sec4...](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487269/#__sec4title)
(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...]

------
lazerpants
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](https://www.nature.com/articles/nature25752)

~~~
jtmcmc
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...

