August 07, 2006
Ketamine Lifts Depression Rapidly

While existing antidepressants such as Zoloft, Prozac, and Paxil take weeks to begin working ketamine starts lifting mood within 2 hours.

People with treatment-resistant depression experienced symptom relief in as little as two hours with a single intravenous dose of ketamine, a medication usually used in higher doses as an anesthetic in humans and animals, in a preliminary study. Current antidepressants routinely take eight weeks or more to exert their effect in treatment-resistant patients and four to six weeks in more responsive patients a major drawback of these medications. Some participants in this study, who previously had tried an average of six medications without relief, continued to show benefits over the next seven days after just a single dose of the experimental treatment, according to researchers conducting the study at the National Institutes of Health's National Institute of Mental Health.

This is among the first studies of humans to examine the effects of ketamine on depression, a debilitating illness that affects 14.8 million people in any given year. Used in very low doses, the medication is important for research, but is unlikely to become a widely used clinical treatment for depression because of potential side effects, including hallucinations and euphoria, at higher doses. However, scientists say this research could point the way toward development of a new class of faster- and -longer-acting medications. None of the patients in this study, all of whom received a low dose, had serious side effects. Study results were published in the August issue of the Archives of General Psychiatry.

Imagine living in perpetual depression. What a hell. Though some readers do not have to imagine. You have my sympathy.

The effect is quick and dramatic.

For this study 18 treatment-resistant, depressed patients were randomly assigned to receive either a single intravenous dose of ketamine or a placebo (inactive compound). Depression improved within one day in 71 percent of all those who received ketamine, and 29 percent of these patients became nearly symptom-free within one day. Thirty-five percent of patients who received ketamine still showed benefits seven days later. Participants receiving a placebo infusion showed no improvement. One week later, participants were given the opposite treatment, unless the beneficial effects of the first treatment were still evident. This "crossover" study design strengthens the validity of the results.

"To my knowledge, this is the first report of any medication or other treatment that results in such a pronounced, rapid, prolonged response with a single dose. These were very treatment-resistant patients," said NIMH Director Thomas R. Insel, M.D.

Receptors for the neurotransmitter glutamate are blocked by ketamine and glutamate regulation appears to play an key role in causing depression.

Ketamine blocks a brain protein called the N-methyl-D-aspartic acid (NMDA) receptor. Previous studies have shown that agents that block the NMDA receptor reduce depression-like behaviors in animals.

NMDA receptors are critical for receiving the signals of glutamate, a brain chemical that enhances the electrical flow among brain cells that is required for normal function. Studies indicate that dysregulation in glutamate could be among the culprits in depression. Using ketamine to block glutamate's actions on the NMDA receptor appears to improve function of another brain receptor the AMPA receptor that also helps regulate brain cells' electrical flow.

This result is another clue. Eventually depression will become completely curable and preventable.

Other anti-depressants probably take longer because they act at the beginning of a long chain of causation.

Scientists think the reason current antidepressant medications take weeks to work is that they act on targets close to the beginning of a series of biochemical reactions that regulate mood. The medications' effects then have to trickle down through the rest of the reactions, which takes time. Scientists theorize that ketamine skips much of this route because its target, the NMDA receptor, is closer to the end of the series of reactions in question.

Given that ketamine acts way downstream closer to the final effect of depression it or similarly acting compounds (preferably with fewer side effects) could lift depression while the longer acting compounds build up their effects. For people with severe depression hospitalization or administration of ketamine in clinics might be worth it.

Ravers in settings where people use ecstasy and looking for a new kind of kick have labelled ketamine "Special K" and used it in higher doses. But ketamine has very different effects including paralysis.

At low doses the user may feel euphoric, experience waves of energy, and possibly synaesthesia - sensations such as seeing sounds or hearing colours.

At higher doses the user might become paralysed, experience hallucinations and alternate realities, and a feeling of disassociation giving an 'out of body' experience known as the "K-hole".

Not for casual use.

If you are curious check out the Wikipedia entry on ketamine.

Update: Note that ketamine works for people who fail to get benefit from currently approved anti-depressants. Those who aren't helped by existing anti-depressants probably have tried Selective Serotonin Update Inhibitors (SSRIs) such as Prozac and Zoloft. Well, this result suggests that there are points in the chain of causation where depression can get initiated that are downstream of serotonin receptors and yet upstream of the glutamate receptors. SSRIs won't work with people whose depression gets initiated downstream of serotonin receptors.

Intervention with ketamine might make sense for those people who get no benefit from SSRIs. But ketamine is probably not ideal for them. In most cases the best treatment should act at the earliest stage in the series of events that cause a person to get depressed. Depression has multiple causes. The earliest stage will be different for each different cause.

Share |      Randall Parker, 2006 August 07 08:26 PM  Brain Emotion Alteration

James Bowery said at August 8, 2006 8:25 AM:

Ketamine may be another of those drugs that, because they have abuse potential as "recreational drugs", don't receive serious research.

High doses of anything can have nasty effects and if at lower doses the drug produces what might be called "recreational effects" then the pathway is set up for increased dosage. Blocking euphoria is one way of dealing with this but some euphoria blockers go to far and produce, not depression, but aversive effects that may interfere with the treatment protocol as well and in the opposite direction.

However, given the strong neurochemical link between euphoria and depression, it may be impossible to obtain ketamine's theraputic effects without the euphoria.

PS: I recall a statement by one of John Lilly's associates, maybe Timothy Leary, that "Anyone who takes ketamine twice is insane." This isn't a position he stuck to later in life obviously but it does point to some serious problems if one of the leading advocates of high dose LSD was that averse to high dose ketamine at some point.

Brett Bellmore said at August 8, 2006 4:16 PM:

Pretty impressive; 1200 mg. a day of SAMe got me out of my depression, but it took a month or so before I really noticed much effect, and most of a year before I could skip it for more than a few days without getting depressed again. (I'm up to about a month without before I notice symptoms now, and 400 mg. a day is enough to keep them at bay.) Sure would have been nice to have been bounced out of that pit faster.

Yes, it was hellish; Even after making a deliberate decision not to suicide, I found I had to constantly review my behavior for back door efforts at self destruction, like dangerous driving habits, carelessness around machine tools, a horribly self-destructive diet. There was a "force" within me that was conspiring to achieve my death, even though I'd consciously rejected it.

A darned sneaky force, too.

Randall Parker said at August 8, 2006 7:27 PM:


Glad to hear that you found a way out of the pit and a way to stay out. Keep up the SaMe!

A reliable cure for depression will boost the economy as depressed people become more active and capable of functioning. It'll also put an end to a lot of pointless suffering.

Thomas L Klessig said at August 14, 2006 8:55 AM:

How does one get into a study using Ketamine?
Thomas Klessig

jim hickey said at November 12, 2006 10:00 PM:

Current clinical trials...

After reading this article, taking it very seriously, and being someone that VERY RECENTLY SUFFERED from major depression, I can 1,000% tell you that you will be hearing MUCH, MUCH more about this in the next 2-5 yrs. If you suffer from major depression and have a psychiatrist, I encourage you to ask them to use it off-label and treat you (unless there are reasons that it would be contraindicated). They probably won't because of fear of lawsuits (healthcare in the U.S. is tragically screwed). If they do, I expect that you would feel MUCH better, even after one very small dose treatment. Amazingly better. Just my very honest and INFORMED OPINION.

Good luck!!

Paul said at July 10, 2007 11:07 PM:

I like my picture for the Wikipedia Ketamine page

Dominique Pierce said at October 25, 2007 7:37 AM:

how does one get out of trying to used ketamine?
can you bare the pain of it?

Tim Goodwin said at October 4, 2008 12:12 AM:

Randy, Where can I obtain some of this K.?? I have been stuck in a bad depression on and off for the last few years and have tryed a few different drugs with no positive results...I hate waiting 4-6 weeks to see if the meds will work while suffering with wierd side effects....Help..

Tim Goodwin...

Randall Parker said at October 4, 2008 9:03 AM:


First off, a willing American doctor can inject you with it. I do not know how many doctors will try it on patients. But it is FDA approved for some uses. Hence doctors have access to it.

Another alternative is a Mexican pharmacist.

But this is probably a temporary lift.

Dave said at April 25, 2009 9:38 PM:

I think it is pretty dangerous to suggest that it might be a good idea to take Ketamine if you are depressed. Anyone who has been around people who recreationally use this drug for a few years will know that there is a very dark side to K. Users snorting lines of K, in sub-anasthetic doses frequently show signs of paranoid and depression and there are clear links to psychosis. I have watched a few friends go down this road over the years. I would encourage anyone to do some proper research on the effects of this drug before trying it.


sdf said at March 15, 2010 1:28 PM:

Ok, so Dave says ketamin won't make depressed feel better. Perhaps we need to tell that to the research subjects who improved on it.

It seems people's stigma should override facts. Easy for the healthy to tell the ill to skip a substance. It just goes to show that they've no clue what's going on, with the ill. Like the depressed need to hear sermons on top of their depression. That goes to show society has no clue what many depressed go through. Imagine the hell, to be suffering, with the majority around you having no clue or true empathy, and even telling you to avoid drugs that show promising results for the relief of your suffering. And how many of those will end up actually lobbying against the prescription of potential cures or perhaps guaranteed reliefs because of their ignorance?

Bucky said at November 20, 2010 10:12 AM:

Just to let you know, sdf, you should listen a little to dave. I have been around the music festival scene, which embraces things such as LSD and MDMA. This same group looks down on Ketamine users for the same reason dave mentioned. K users tend to hide away in tents because it can really fuck with your head, more so than a bad LSD trip.

I myself have taken ketamine in one of these settings before. I never got seriously into it, although I was into DXM for a while in high school, mainly because of the stigma and because things got "weird" quick. I felt great and happy, then next thing I know these trees near where I was peeing turned into 3 men in sombreros. I knew they weren't real but they came into my vision every time i looked away from them directly. This only begins to explain the crazy things I saw or thought were happening.

Considering I used MDMA the same weekend, which the few times I've tried it has left me depressed for a week afterwards, I was quite content. It did leave me feeling more balanced, albeit more "strange", for about a few weeks after. In that respect I can see how useful it is. I think Dave's point is that unsupervised K use or K being given to individuals with psychotic disorders could cause more problems than it solves. I myself have battled depression for years, and I understand your point. Just don't believe that K is a magic bullet, and it can be VERY mentally addictive.

depressed old peter said at December 26, 2010 8:03 PM:

It appears to help 1/3 of the depressed folks who can not be helped by SSRIs according to the article.
Ssri's help help about 1/2 of the depressed folks who stick with them for the necessary 2 months.
Alternative SSRIs and other common antidepressants work for another 1/2, very roughly.
Lithium works for a lot of folks but comes with flat affect.
All the drugs come with side effects that differ between drugs and dosage..
All the drugs have a different effect on each individual.
Any absolute statement is to be regarded as suspect.

Lorna said at March 16, 2011 4:57 PM:

I took ketamine recreationally now and then - had an enlightening experience (altho was slightly scary i felt safe throughout) and it cured my depression. At time felt like my brain was defragmenting like a computer, could feel new connections. I did not read anything about the effect of ketamine on depression until after this...was exciting because i knew in myself what had happened, even if i couldnt explain it.This is my experience altho might not work for everyone and might just be co-incidence (but I dont think so). Funny cause i dont feel i need to take it again, i just know my head has got better. Very exciting.

Jeff said at May 31, 2011 1:33 PM:

We are not talking about taking ketamine unsupervised in a festival/rave type setting. Its talking to an educated psychiatrist/doctor who feels one could benefit from this NMDA blocker. - My doctor doesn't feel comfortable doing this off-label but we are looking into someone who will in a controlled and very supervised manner. -I personally have tried well over a dozen medications, ECT, tms, and have been hospitalized. The only med that has helped is the MAOI Emsam - Now MAOI's are part of the glutamate - monoamine connection. Which makes me a prime candidate from the results of the trials that have been done. - I seriously want to help with the stigma that comes with this life sucker. -For those who don't understand this illness, 'Churchill called the BLACK DOG', I would like you to know I looked down on people who had this before it tackled me. I told friends who took medication to exersize and eat better snap out of it. I thought in my mind they were weak. Now 10 yrs later I get that from others and boy is it disheartening cause I know they are giving an uneducated, inexperienced opinion like I did. The facts are its something physically wrong with our brain. Now to save our lives and this can truly be life or death 'very scary'. We need to try every medicine that could be the one. -Just as if you had cancer- This ketamine seems to be the next one, hopefully the last, but I've said that before. (The state won't pay for a vns implant so this is it. If ketamine means going down fighting. Then that's what I'm doing and not waiting yrs for our health system. When you have exausted all other means and want to try for new hope like ketamine. Go find a compassionate doctor they are out there and they will help. You just have to look hard. But dont put all your eggs in the ketamine basket, been there done that. Its just more hope and we could use some of that.

Chris Jay said at July 10, 2012 2:21 PM:

I don`t recommend Zoloft, Celexa, Paxil etc and certainly I don`t recommend ketamine. Why? Click here and you will see.

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