The Mechansim Behind the Powerful Antidepressant Effects of Ketamine Revealed

[rocknroll714]

News coverage:

Secrets of 'Magic' Antidepressant Revealed

ScienceDaily (Aug. 20, 2010)

Yale researchers have discovered how a novel anti-depressant can take effect in hours, rather than the weeks or months usually required for most drugs currently on the market. The findings, described in the August 20 issue of the journal Science, should speed development of a safe and easy-to-administer form of the anti-depressant ketamine, which has already proven remarkably effective in treating severely depressed patients.

The Yale scientists found that, in rats, ketamine not only quickly improves depression-like behaviors but actually restores connections between brain cells damaged by chronic stress.

"It's like a magic drug -- one dose can work rapidly and last for seven to 10 days," said Ronald Duman, professor of psychiatry and pharmacology at Yale and senior author of the study.

Ketamine traditionally has been used as a general anesthetic for children, but a decade ago researchers at the Connecticut Mental Health Center found that, in lower doses, the drug seemed to give patients relief from depression, Duman said. In these initial clinical studies, which have been replicated at the National Institute of Mental Health, almost 70 percent of patients who are resistant to treatment with all other forms of antidepressants were found to improve within hours after receiving ketamine. However, its clinical use has been limited because it has to be delivered intravenously under medical supervision and in some cases can cause short-term psychotic symptoms. It has also been used as a recreational drug, known as "Special K" or sometimes just "K."

So Duman, colleague George Aghajanian and the Yale team set out to map the molecular action of the drug in the prefrontal cortex of rats that could lead to potential targets for a safer and more easily used drugs. The team discovered that ketamine acts on a pathway that rapidly forms new synaptic connections between neurons -- a process called "synaptogenesis."

"The pathway is the story. Understanding the mechanism underlying the antidepressant effect of ketamine will allow us to attack the problem at a variety of possible sites within that pathway," Aghajanian said.
The team identified a critical point in the pathway, the enzyme mTOR, which controls protein synthesis required for new synaptic connections. There are already promising leads on ways to sustain the initial rapid effect of ketamine by intervening at specific downstream targets.

An estimated 40 percent of people suffering depression do not respond to medication. And many others only respond after many months or years of trying different treatments. The authors note that ketamine also has been tested as a means to rapidly treat people with suicidal thoughts, a benefit usually not seen until weeks of treatment with traditional antidepressants.

Other Yale authors of the paper are Nanxin Li, Boyoung Lee, Rong-Jian Liu, Mounira Banasr, Jason M. Dwyer, Masaaki Iwata and Xiao-Yuan Li.

National Institute of Mental Health, the Connecticut Mental Health Center and Yale University School of Medicine funded the work.

Source: http://www.sciencedaily.com/releases...0819141913.htm

And the study itself:

mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists

Nanxin Li, Boyoung Lee, Rong-Jian Liu, Mounira Banasr, Jason M. Dwyer, Masaaki Iwata, Xiao-Yuan Li, George Aghajanian, Ronald S. Duman*
Science 20 August 2010; Vol. 329. no. 5994, pp. 959 - 964
DOI: 10.1126/science.1190287

The rapid antidepressant response after ketamine administration in treatment-resistant depressed patients suggests a possible new approach for treating mood disorders compared to the weeks or months required for standard medications. However, the mechanisms underlying this action of ketamine [a glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonist] have not been identified. We observed that ketamine rapidly activated the mammalian target of rapamycin (mTOR) pathway, leading to increased synaptic signaling proteins and increased number and function of new spine synapses in the prefrontal cortex of rats. Moreover, blockade of mTOR signaling completely blocked ketamine induction of synaptogenesis and behavioral responses in models of depression. Our results demonstrate that these effects of ketamine are opposite to the synaptic deficits that result from exposure to stress and could contribute to the fast antidepressant actions of ketamine.

Source: http://www.sciencemag.org/cgi/conten...t/329/5994/959

[Jamshyd]

Thank you, this is fascinating.

In my own experience self-medicating with it, there seems to be two distinct things going on:

a. The immediate "reset button" phenomenon which many people report, and which I assume is the one being targeted here. It can be used to "reprogram" the self out of depressive stints... I'd say this is more akin to psychedelic therapy but seems to have a more physiological basis behind it; and secondly,

b. A more "background" cumulative mood-balancing effect of repeated administration of small doses. The closest I can compare it to is the "buzz" that one gets from large doses of gabapentin (but still very different and not as inebriating). This seems to work through the activation of a secondary or indirect mechanism and only occurs through controlled repeated administration of small (10 - 25mg) doses over the course of at least 3 days. This effect seems to last for a very long time after the last dose is taken once it is achieved.

I had confirmation about these effects from several people who have gone about systemically investigating it.

[MurphyClox]

I knew that Jamshyd would be the first one to respond

[Jamshyd]

^

Does anyone know what was used to block the mTOR signaling in that study?

And does anyone know what effects, if any, do the -racetam drugs have on this signaling?

[MurphyClox]

Gimme some hours and I'll see what I can do (if nobody beats me to it ). Going to bed right now

[Astavats]

Here it is (zipped/no password); http://www.multiupload.com/MJ7MZW1OVH

The topic sounds interesting not to mention it's been sometime since I've read G. K. Aghajanian's work - a pleasant surprise.

[/navarone/]

I read somehwere that chronic use can cause some form of temporary retardation tho I always had the impression that it had some major beneficial effects on my depression especially because it would relieve my stress related mental impairments way more than any other pharm or street drug and started to contemplate about its therapeutic use.
Seems I wasn't so wrong, now lets just wait for the DEA to ease up their minds...

BTW could this advantage be attributed only to ketamine or even to others NMDA antagonists?

[vecktor]

Ketamine seems to be most valuable as an antidepressant when it is used intermittantly as a kind of shock therapy.

mTOR inhibition by rapamycin has been associated with longevity, and so enhancement of mTOR would likely to do the opposite.

I am not convinced by the evidence presented so far regarding this mechanism.

[seep]

Any NMDA antagonist dose that isn't profoundly narcotizing will lower a person's latent inhibition. The net effect of that may indeed lift a depressive brain fog. Or it may exacerbate an already existing psychotic process (and so it'll probably be contraindicated for anyone with a hx of psychosis or with a "4" at the end of their DSM code (e.g. 296.34, 296.44, 296.54, 296.64, etc).

[raybeez]

^

Does anyone know what was used to block the mTOR signaling in that study?

And does anyone know what effects, if any, do the -racetam drugs have on this signaling?

I thought the mTOR aspect was the coolest part. I work with mTOR a lot (but not all in the context of neuropharmacology). Typical molecules that signal in an mTOR dependent manner are amino acids (classically L-Glutamine) and growth factors (Insulin, insulin-like growth factor (IFG) neuronal growth factor (NGF) epithelial growth factor (EGF) etc).

mTOR is the point of convergence between most of the pathways that cells use to tell if their in nutrient rich environments or starving to death, and feeds into the decision making pathways of whether or not a cell lives or dies.

[/navarone/]

^

Does anyone know what was used to block the mTOR signaling in that study?

And does anyone know what effects, if any, do the -racetam drugs have on this signaling?

From what I read one of the most common mTOR inhibitors is rapamycin, a naturally occuring immunosuppressant drug discovered as a products of some bacterium samples from Easter Island (LOL...IDK why but LOL).

About the racetams I don't really know but considering that racetams increase communication between neurons through improved acetylcholine function and possibly through ion channels/carriers effects, in the absence of stress factors that should ease synaptogenesis even more.
Also you just reminded me of a funny coincidence that I almost forgot about. Back in my pushing days when I needed to make a few more bucks I used to cut ketamine with piracetam in a 5 to 1 ratio LOL. I eventually ended up sniffing it myself many times and surprisingly (especially when I popped a few more piracetam pills with it) the high was slightly less confusional easing my introspection a bit more. The comedown felt somehow a bit 'refreshing'.

[Jamshyd]

I will have more to post in a bit, but I just need to tell everybody here that this piece of news coincided with me taking a new, far more rigidly structured regime of "Ketamine therapy" and it is working like a miracle. Only a day before I received my Ketamine (in medical vials this time, so I can calibrate doses with efficiency), I was halfway between insane and suicidal, and generally plagued with all manner of physical and emotional pain.

Today, I feel ok. "OK"... oh my god, if only I could use this word to describe myself more often...

What is so interesting is the predictability of the effectiveness of this procedure. This would be my fifth or so time performing this procedure (last time being more than a year ago), and it has worked just like all the previous times down to the T (Vector is sort of correct in that this is a once-in-a-while thing rather than a maintenance). All the doses are well below 50mg (most around 12mg), all administered IM. I hope I'll write an updated version of my regimen now that I actually have exact numbers to work with (dose and timing-wise).

I am so, so happy that I am blessed with this lifeline.

[/navarone/]

Grrrrrrr....making me envious since I cannot get a hold on ketamine for the moment and I'm experiencing the worst depression ever with significant traits of avolition, catatonia, anhedonia and mental impairments that make me feel so fucking retarded.
I've stopped any drug since many months (apart from a couple of times where I took some clonazepam) but son after I stopped my heavy drug use I started drinking a lot and smoking way more than I used to. I get wasted pretty fucking often even if the morning after I feel even dumber but eventually the stress builds up so rapidly that i find myself opening another bottle few days after.
I'm wondering if DXM might have some similar potentials since it is not a controlled substance over here and I would feel more comfortable with it costs much less and i wouldnt have to take further risks since I already have some drug issues in my criminal record.

Neways interesting post Jamshyd..keep it up with updates.

[Jamshyd]

^ You're in Italy, right?

Someone recently told me that Ketamine is OTC in some parts of Romania. If I were you, I'd save up a bit and take the next train to bucharest....

[monstanoodle]

Great stuff Thanks for posting this.
I had heard the theory about it restoring cell connections but always wondered by what process it was able to do this, so yay ^_^

Cheers again!

[Gup]

I read somehwere that chronic use can cause some form of temporary retardation tho I always had the impression that it had some major beneficial effects on my depression especially because it would relieve my stress related mental impairments way more than any other pharm or street drug and started to contemplate about its therapeutic use.

Sir--

NMDA Antagonists are known to have neurotoxic effects in animal models; analogous effects in humans are possible but not known with certainty. However, I thought you might be interested in the following article:

Antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor, including phencyclidine (PCP) and ketamine, protect against brain damage in neurological disorders such as stroke. However, these agents have psychotomimetic properties in humans and morphologically damage neurons in the cerebral cortex of rats. It is now shown that the morphological damage can be prevented by certain anticholinergic drugs or by diazepam and barbiturates, which act at the gamma-aminobutyric acid (GABA) receptor-channel complex and are known to suppress the psychotomimetic symptoms caused by ketamine. Thus, it may be possible to prevent the unwanted side effects of NMDA antagonists, thereby enhancing their utility as neuroprotective drugs.

"NMDA antagonist neurotoxicity: mechanism and prevention", Science, Vol 254, Issue 5037, 1515-1518

[atara]

In particular, 5-ht2a agonists, like psilocin and LSD, seem to inhibit the formation of Olney's lesions. Since they're generally a good combo with Ketamine anyway...

[ebola?]

NMDA Antagonists are known to have neurotoxic effects in animal models

. . .at anesthetic doses, and if IIRC, with repeated administration. It's unclear how this generalizes to humans taking recreational or sub-recreational doses, but there appears to be a great deal more doubt surrounding the in vivo relevance of this toxicity than that of entactogens.

ebola

[raybeez]

Sir--

NMDA Antagonists are known to have neurotoxic effects in animal models; analogous effects in humans are possible but not known with certainty. However, I thought you might be interested in the following article:

Just to clarify some points about ketamine neurotoxicity: all of the evidence for NMDA-neurotoxicity points towards this affecting the developing brain only (children not adults).

1a. Olney's lesions have only ever been observed in rats, and this is theorized to be a result of the higher metabolic rate of rodent's brains compared to primate's brains (approximately two fold) [1].
1b. Olney's lesions demonstrated in rats are only really apparent in neonatal animals of an age equivalent to children under the age of 2. Older animals show evidence of neuronal death, but not Olney's lesions [1].

2. Olney's lesions have never been observed in the brains of primates. Ketamine-induced neuronal cell death HAS been observed, but only in the brains of newborn primates (both in vitro [2] and in vivo [3,4], or primate fetuses [4]. Primates older than 35 days did not have ketamine-induced neuronal cell death, even when given 24 hours of continuous anaesthetic levels of IV ketamine [4].

3. This data seems to correlate with human children -- a subset of data from an epidemiological study in children who received ketamine + one or more additional anaesthetic (but not ketamine alone) found increased rates of learning disabilities [5].

4. There are many many studies showing NMDA-antagonists prevent neurotoxicity in the adult brain secondary to cerebral ischemia, traumatic brain injury, or chemical neurotoxins (like MDMA). I won't bother citing since there are many (and some provided above in this thread)

Ref 1 (excellent FDA review on the animal toxicity data, and the relevance to the use ketamine in children. They conclude that the data does not warrant cessation of ketamine use in children age 2+ until further primate studies are done)
Ref 2 ( neurotox in newborn primate neurons in vitro)
Ref 3 (neurotox in newborn rhesus monkeys)
Ref 4 (neurotox in rhesus monkeys of 3 different age groups)
Ref 5 (epidemiological study of childhood anaesthesia and learning disabilities)

[vecktor]

^ there is a UK study that shows some level of lasting cognitive impairment in recreational ketamine users. for what thats worth: lack of proper control group, exposure to other substances etc etc.

[Jamshyd]

^ If I'm thinking of the same study you're refering to, then that study was some shrink's way of getting his diploma by saying, with scientific jargon, that Ketamine gets you buzzed. A fantastic example of the art and science of reinventing the wheel.

As for Olney's Liesons, I can't help but feel that someone is actually being PAID to go online and disseminate this utter bullshit "information" becaise of the utter vigour with which its poponents keep chiming in. Just look at "Gup" for example - s/he registered on BL for the sole purpose of remidning us of OLs, in case we with our hole-pierced ratty brains forget. Ketamine, like tea and candy, has its dangers. But these certainly don't seem to be along the lines of "holes in your brain".

[Phener]

What's interesting is Olneys lesions certainly don't stop its MANY uses in modern medicine including children.

[ebola?]

I want to start a band called "Onley's Legions".

[Gup]

As for Olney's Liesons, I can't help but feel that someone is actually being PAID to go online and disseminate this utter bullshit "information" becaise of the utter vigour with which its poponents keep chiming in. Just look at "Gup" for example - s/he registered on BL for the sole purpose of remidning us of OLs, in case we with our hole-pierced ratty brains forget.

It was this subject -- which showed up in a search for some depression-related keywords I have forgotten -- which drew me to this site for the first time. I have great hope in its ability to reduce human suffering, as current antidepressants are grossly inadequate. But a chronic condition such as depression implies long-term use, and we must be especially careful.

Adult humans may not exhibit the types of visible morphological changes in animals, but I am still concerned that there may be some kind of cellular stress there. Hence my interest in protective substances.

[Jamshyd]

^ I understand. But now that I am done with my session I am convinced, once more, that this is a sort of thing that needs to be done only once everywhile, for the positive effects last long after the last dose (= weeks, I imagine longer with proper training or psychotherapy).

A few notes off the top of my head that I have learnt thus far:

- The doses required are small enough for this to be considered "ULD", as 12mg as a singular dose is more than enough.

- The antidepressant effect takes several doses to kick in (usually around day 2 of continuous use). While the initial dose can in fact produce euphoria (the reason this drug is recreational), the truly antidepressant effect (contentment) only occurs later, and it seems that it works even better with smaller than larger doses.

- No stomach cramps, no renal issues, no cognitive defects (at above mentioned doses). And most notable: no tolerance-accrual whatsoever (at least at the 7-day point).

- The staggered-timing of doses is crucial. In my case, said timing seems to be exactly around 30 mins.

- Entheogenic experiences are still possible if a higher dose is taken at any point, and do not seem to affect the process badly as long as they are followed through by staggered (and preferably tapered) followup doses.

- I can say with confidence that I believe Ketamine has at the very least 2 different effects on 2 different systems (one excitatory, and one inhibitory) which aren't mutually-exclusive, however the body seems to answer back with the opposite of each in its respective system, and opposites of the drug effect and body reaction ARE synergistic, which means that a harmonic overlap of the two (drug: excitatort - body: inhibitory and vice versa) must be maintained.

The above point is probably strange, and maybe even a bit koo-koo sounding. When I do a writeup, I'll try to elaborate on it.