41 replies to this topic

[Shay]

By now we've probably all heard about Ketamine's power to relieve depression quickly. Now a study finds an interesting clue - "rapid synaptogenesis". I wonder if/how it could be used responsibly in conjunction with other nootropics to magnify their effects? Do any other nootropics do this?

Yale team describes secrets of 'magic' antidepressant

[NR2(x)]

intranasl low doseage; im not going to do it,
It blcoks extrasynptic nmdar which i assume causes the effect, there are better drugs with far lower side effects although they havent reached the market, CP101606 traxiprodil or ifenprodil etc even ibogaine. NR2b antagonist are the next big thing in the pipeline and have very similar pharmacology to ketamine without side effects

Alcohol increase NGF(Nevre growth factor) by a considerable amount and i believe it is by the same means

[medievil]

you have to shoot it in to ya muscle i think, which sucks.

There is one study showing beneficial effects after oral administration:

J Palliat Med. 2010 Jul;13(7):903-8.
Oral ketamine for the rapid treatment of depression and anxiety in patients receiving hospice care.
Irwin SA, Iglewicz A.

Institute for Palliative Medicine at San Diego Hospice, Palliative Care Psychiatry, San Diego, California 92103, USA. sirwin@sdhospice.org
Abstract
Depression is prevalent and undertreated in patients receiving hospice care. Standard antidepressants do not work rapidly or often enough to benefit most of these patients. Here, two cases are reported in which a single oral dose of ketamine provided rapid and moderately sustained symptom relief for both depression and anxiety. In addition, no adverse effects were noted. Further investigation with randomized, controlled clinical trials is necessary to firmly establish the effectiveness of oral ketamine for the treatment of depression and anxiety in patients receiving hospice care. Ketamine may be a promising safe, effective, and cost-effective rapid treatment for depression and anxiety in this population.

And all other human study's:

Biol Psychiatry. 2010 Jan 15;67(2):139-45.
Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression.
aan het Rot M, Collins KA, Murrough JW, Perez AM, Reich DL, Charney DS, Mathew SJ.

Mood and Anxiety Disorders Program, Department of Psychiatry, Mount Sinai School of Medicine, New York, New York. m.aan.het.rot@rug.nl
Abstract
BACKGROUND: A single subanesthetic (intravenous) IV dose of ketamine might have rapid but transient antidepressant effects in patients with treatment-resistant depression (TRD). Here we tested the tolerability, safety, and efficacy of repeated-dose open-label IV ketamine (six infusions over 12 days) in 10 medication-free symptomatic patients with TRD who had previously shown a meaningful antidepressant response to a single dose.

METHODS: On day 1, patients received a 40-min IV infusion of ketamine (.5 mg/kg) in an inpatient setting with continuous vital-sign monitoring. Psychotomimetic effects and adverse events were recorded repeatedly. The primary efficacy measure was change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) score. If patients showed a > or =50% reduction in MADRS scores on day 2, they received five additional infusions on an outpatient basis (days 3, 5, 8, 10, and 12). Follow-up visits were conducted twice-weekly for > or =4 weeks or until relapse.

RESULTS: Ketamine elicited minimal positive psychotic symptoms. Three patients experienced significant but transient dissociative symptoms. Side effects during and after each ketamine infusion were generally mild. The response criterion was met by nine patients after the first infusion as well as after the sixth infusion. The mean (SD) reduction in MADRS scores after the sixth infusion was 85% (12%). Postketamine, eight of nine patients relapsed, on average, 19 days after the sixth infusion (range 6 days-45 days). One patient remained antidepressant-free with minimal depressive symptoms for >3 months.

CONCLUSIONS: These pilot findings suggest feasibility of repeated-dose IV ketamine for the acute treatment of TRD.

Biol Psychiatry. 2009 Sep 1;66(5):522-6. Epub 2009 Jul 9.
Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression.
Price RB, Nock MK, Charney DS, Mathew SJ.

Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA. rprice@eden.rutgers.edu
Abstract
BACKGROUND: Intravenous ketamine has shown rapid antidepressant effects in early trials, making it a potentially attractive candidate for depressed patients at imminent risk of suicide. The Implicit Association Test (IAT), a performance-based measure of association between concepts, may have utility in suicide assessment.

METHODS: Twenty-six patients with treatment-resistant depression were assessed using the suicidality item of the Montgomery-Asberg Depression Rating Scale (MADRS-SI) 2 hours before and 24 hours following a single subanesthetic dose of intravenous ketamine. Ten patients also completed IATs assessing implicit suicidal associations at comparable time points. In a second study, nine patients received thrice-weekly ketamine infusions over a 12-day period.

RESULTS: Twenty-four hours after a single infusion, MADRS-SI scores were reduced on average by 2.08 points on a 0 to 6 scale (p < .001; d = 1.37), and 81% of patients received a rating of 0 or 1 postinfusion. Implicit suicidal associations were also reduced following ketamine (p = .003; d = 1.36), with reductions correlated across implicit and explicit measures. MADRS-SI reductions were sustained for 12 days by repeated-dose ketamine (p < .001; d = 2.42).

CONCLUSIONS: These preliminary findings support the premise that ketamine has rapid beneficial effects on suicidal cognition and warrants further study.

J Clin Psychiatry. 2010 Jul 13. [Epub ahead of print]
Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder.
Diazgranados N, Ibrahim LA, Brutsche NE, Ameli R, Henter ID, Luckenbaugh DA, Machado-Vieira R, Zarate CA Jr.

Experimental Theapeutics, Mood and Anxlety Disorders Program, National Institute of Mental Health (NIMH), and Department of Human Health Services, Bethesda, Maryland, USA.
Abstract
OBJECTIVE: Suicidal ideation is a medical emergency, especially when severe. Little research has been done on pharmacologic interventions that could address this problem. Ketamine, an N-methyl-d-aspartate antagonist, has been reported to have antidepressant effects within hours. We examined the effects of a single dose of ketamine on suicidal ideation in subjects with treatment-resistant major depressive disorder (MDD).

METHOD: Thirty-three subjects with DSM-IV-diagnosed MDD received a single open-label infusion of ketamine (0.5 mg/kg) and were rated at baseline and at 40, 80, 120, and 230 minutes postinfusion with the Scale for Suicide Ideation (SSI), the Montgomery-Asberg Depression Rating Scale, the Hamilton Depression Rating Scale, and the Beck Depression Inventory. The study was conducted between October 2006 and January 2009.

RESULTS: Suicidal ideation scores decreased significantly on the SSI as well as on the suicide subscales of other rating instruments within 40 minutes; these decreases remained significant through the first 4 hours postinfusion (P < .001). Ten subjects (30%) had an SSI score >/= 4 at baseline; all these scores dropped below 4 (9 dropped by 40 minutes and 1 by 80 minutes). For those patients with a starting score below 4 on the SSI, only 1 reached a score of 4. Depression, anxiety, and hopelessness were significantly improved at all time points (P < .001).

CONCLUSIONS: Suicidal ideation in the context of MDD improved within 40 minutes of a ketamine infusion and remained improved for up to 4 hours postinfusion. Future studies with ketamine in suicidal ideation are warranted due to the potential impact on public health.

TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00088699.

J ECT. 2009 Nov 19. [Epub ahead of print]
Rapid Antidepressant Effect of Ketamine Anesthesia During Electroconvulsive Therapy of Treatment-Resistant Depression: Comparing Ketamine and Propofol Anesthesia.
Okamoto N, Nakai T, Sakamoto K, Nagafusa Y, Higuchi T, Nishikawa T.

From the Departments of *Psychiatry, and daggerAnesthesiology, National Center Hospital of Neurology and Psychiatry, Kodaira City and double daggerSection of Psychiatry and Behavioral Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
Abstract
BACKGROUND: Reports of the superiority of the antidepressant effect of ketamine during the conduct of electroconvulsive therapy (ECT) have been limited. We conducted an open-label trial of ketamine to determine whether ketamine as the anesthetic during ECT would provide a greater antidepressant effect than the antidepressant effect obtained with propofol.

METHODS: Between April 2006 and April 2007, 31 inpatients with treatment-resistant depression gave written consent for ECT and to participate in this study. An anesthesiologist who was unaware of the mental symptoms of the subjects assigned them to receive propofol or ketamine anesthetic according to the preferences of the patients, and the patients underwent 8 ECT sessions for 4 weeks. The Hamilton Depression Rating Scale (HDRS) was valuated before ECT and after the completion of the second, fourth, sixth, and eighth ECT sessions.

RESULTS: The HDRS scores improved earlier in the ketamine group, with decreases in HDRS scores that were significantly greater in the ketamine group.

CONCLUSIONS: The results suggested that it is possible to improve symptoms of depression earlier by using ketamine anesthesia.

Edited by medievil, 22 August 2010 - 11:34 AM.

[medievil]

Potential downsides of ketamine:

It appears that the antidepressant effect is mediated by activation of mTOR wich rapidly induces synaptogenesis.

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

Quote:
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.

A quick scan of mTOR on wikipedia reveals this:

Aging



mTOR signaling pathway.[1]
Decreased TOR activity has been found to slow aging in S. cerevisiae, C. elegans, and D. melanogaster.[27][28][29] The mTOR inhibitor rapamycin has been confirmed to increase lifespan in mice by independent groups at the Jackson Laboratory, University of Texas Health Science Center, and the University of Michigan.[30]
It's hypothesized that some dietary regimes, like caloric restriction and methionine restriction, cause lifespan extension by decreasing mTOR activity.[27]
[edit]mTOR inhibitors as therapies

mTOR inhibitors are already used in the treatment of transplant rejection . They are also beginning to be used in the treatment of cancer.[31]
mTOR inhibitors may also be useful for treating several age-associated diseases.

And we also have this:

Hyperphosphorylated tau in the brains of mice and monkeys with long-term administration of ketamine


L.Y. Yeunga, Maria S.M. Waia, Ming Fanb, Y.T. Maka, W.P. Lama, Zhen Lic, Gang Lua, c and David T. Yewa, ,
a School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China
b Institute of Military Medical Sciences, PLA, Beijing, China
c Biomedical Engineering Research Centre, Kunming Medical University, Kunming, Yunnan, China
Received 13 November 2009; revised 11 January 2010; accepted 12 January 2010. Available online 20 January 2010.
Abstract
Ketamine, a non-competitive antagonist at the glutamatergic N-methyl-d-aspartate (NMDA) receptor, might impair memory function of the brain. Loss of memory is also a characteristic of aging and Alzheimer's disease. Hyperphosphorylation of tau is an early event in the aging process and Alzheimer's disease. Therefore, we aimed to find out whether long-term ketmaine administration is related to hyperphosphorylation of tau or not in the brains of mice and monkeys. Results showed that after 6 months’ administration of ketamine, in the prefrontal and entorhinal cortical sections of mouse and monkey brains, there were significant increases of positive sites for the hyperphosphorylated tau protein as compared to the control animals receiving no ketamine administration. Furthermore, about 15% of hyperphosphorylated tau positive cells were also positively labeled by terminal dUTP nick end labeling (TUNEL) indicating there might be a relationship between hyperphosphorylation of tau and apoptosis. Therefore, the long-term ketamine toxicity might involve neurodegenerative process similar to that of aging and/or Alzheimer's disease.

Suggesting that long term chronic use of ketamine can have detrimental effects.

The good news is that the antidepressant effects are semi long lasting and that chronic treatment isnt neceserry.

Maybe its mTOR downregulation that is causing the beneficial effects of ketamine, leaving the antidepressant effect untill mTOR is upregulated again.

If that is the case then occasional "shocktherapy" with ketamine could of benefit for life extension, but thats just gueswork (and maybe wishfull thinking).

It appears that resveratrol also downregulates mTOR.

Edited by medievil, 24 August 2010 - 01:15 AM.

[Algear Linebra]

Suggesting that long term chronic use of ketamine can have detrimental effects.

The good news is that the antidepressant effects are semi long lasting and that chronic treatment isnt neceserry.

Maybe its mTOR downregulation that is causing the beneficial effects of ketamine, leaving the antidepressant effect untill mTOR is upregulated again.

If that is the case then occasional "shocktherapy" with ketamine could of benefit for life extension, but thats just gueswork (and maybe wishfull thinking).

It appears that resveratrol also downregulates mTOR.

You might lose interest in life extension if you use ketamine.

[Ark]

Suggesting that long term chronic use of ketamine can have detrimental effects.

The good news is that the antidepressant effects are semi long lasting and that chronic treatment isnt neceserry.

Maybe its mTOR downregulation that is causing the beneficial effects of ketamine, leaving the antidepressant effect untill mTOR is upregulated again.

If that is the case then occasional "shocktherapy" with ketamine could of benefit for life extension, but thats just gueswork (and maybe wishfull thinking).

It appears that resveratrol also downregulates mTOR.

You might lose interest in life extension if you use ketamine.

Are there any more trails being done for mood disorders using ketmine or produces similar?

[Solarclimax]

Why was my post removed ?

[aLurker]

Why was my post removed ?

Very strange, I read your post earlier and I thought it was really good. :/

[jackdaniels]

Why was my post removed ?

Very strange, I read your post earlier and I thought it was really good. :/

Ditto. However unsurprised it was removed from this forum.

[medievil]

Why was my post removed ?

Very strange, I read your post earlier and I thought it was really good. :/

Ditto. However unsurprised it was removed from this forum.

Id actually say its suprising as imminst was allways lightly moderated .

[aLurker]

Why was my post removed ?

Very strange, I read your post earlier and I thought it was really good. :/

Ditto. However unsurprised it was removed from this forum.

Too bad. To summarize what I read: it was a very intriguing and involving trip report with an addendum about the dangers of long-term drug use. I guess some moderator thought it was a little too pro-ketamine for their taste.

[Solarclimax]

I thought about it, and understand that there's people who are against life extension who might come to this site looking for the first excuse to blemish it. Someone talking about ketamine in a certain light might be all they'd need to convince sheep that may listen to them that imminst allows it's members to condone illegal drug use (even though i technically wasn't). And that maybe Pro life extension folks have enough idiots to deal with without having the anti drug + anti life extension people having something else to moan about. I just thought at the time of posting my experiences that the view of this site was a bit more open minded but i guess you gotta keep up appearances. I think sometimes pretending that i live in a world where most people are open minded and not insane can lead me to be a bit too open for some peoples liking.

I basically was trying to get across from a personal non scientific point of view why ketamine may cause very quick withdrawal of depression. But that also after reading up on and also maybe experiencing potential side effects from ketamine use i concluded that it's best not to use it and that i would not recommend it. I personally feel that's even more responsible than simply saying don't do it because it's illegal. Sometimes people listen to common sense even if they may have disregard for the law.

The argument to this would be, Yes but you give what could appear to be promotional reasons for taking the drug and that gives the wrong impression. I personally think this is a bit too old school for today's society, people just have to google ket or ask their friend about that person they know who takes ket, people don't buy stuff as easily in today's world. Just look at the governments ever crumbling list of reasons why weed is bad, and what people think to that.. If i tell the absolute best experiences you can get, but then say it's still not worth it. IMO that's far better than trying to lie to people and say don't do it, it just makes you dopey and do crazy things, plus it has side effects. When all kids need to do is look up google, ask someone etc, to know I'm lying.

Would be nice if mods could give a reason when they remove posts though.

Thanks for taking an open minded approach to my now removed post, folks.

Edited by Solarclimax, 28 August 2010 - 06:15 PM.

[medievil]

Apperantly, ketamine activates mTOR by this pathway:

Well, according to the study, ketamine acts to produce its antidepressant effects in a manner something like this: NMDAR (NR2B) blockade -> inhibition of GABA interneurons -> disinhibition of AMPAR -> induction of mTOR (as well as several other proteins) -> synaptogenesis; all of which takes place in the prefrontal cortex.

I'm quoting rocknroll from this post:
http://www.bluelight...159&postcount=9

Havent seen the full text myself.

Anyone up to dig up some more info on mTOR? Will take a look one of the days, could be interesting, i'm interested because it appears that mTOR inhibition actually slows aging, yet activation induces rapid synaptogenesis, however as it appears that "shock" therapy works, the downsides of mTOR could be avoided. And are there more downsides/upsides to mTOR?, lets find out.

Also i wonder why the antidepressant effect only lasts for a while and isnt permanent. (or semi permanent).

Edited by medievil, 28 August 2010 - 09:06 PM.

[NR2(x)]

K appears to have low specificity, the mechanism of nmdar blockade is complex but interesting. Basically
NR2b receptors are mainly located extrasynatpically where they mediate apoptic,antimetabolic,anti signal transduction roles however there synaptic conterparts(NR2b) achieve the reverse and achieve long term potentionation. Therefore there is a net increase in metabolism,cell viabaily and signal transduction on blocked(glutamate rebound). The secret is that the mind must remain in association(cant fully block long term potention on the synapes) by the use of low doses.

This is good article, there are more for those interested
The Yin and Yang of NMDA receptor signalling


I would be interested in seeing a map showing the various functions of mTOR, looks to be involved in some critical pathways

[bobman]

Taking ketamine to increase synaptogenesis is about as wise as eating lithium to increase neurogenesis, and it is pretty well documented than antagonist action, either pre-synaptically or at the synapse, increases neurogenesis/upregulation of respectively affected receptor sites.

[chrono]

Would be nice if mods could give a reason when they remove posts though.

Hi, solarclimax! I'm the one who deleted your post invisible yesterday morning. First, please allow me to apologize profusely for my lack of explanation. The reason for this was that I'm out of town this weekend, and have only sporadic and brief dialup internet access at a friend's house. I saw this on my way out the door, and didn't have time to post a proper explanation. I'd hoped to make it back here much sooner, and that perhaps someone else might have mentioned my explanations in recent threads about LSD and MDMA.

Briefly: what I'm doing, at least for the time being, is trying to strike a balance between the freedom to discuss an interesting topic which can be related to cognitive enhancement/nootropics, and the concerns of those who rightly identify that it is very controversial, very tangentially related to life extension, and might give some the wrong impression about what this forum is about.

I'm attempting to achieve this balance by a closer moderation of the focus and tone of these kinds of topics. Most broadly, I'd like contributions to relate to the thread topic, or to cognitive enhancement/neuropharmacology at the most general. That is to say, I'd like to avoid personal experiences (unless perhaps if they're very relevant to cognitive enhancement), detailed discussion of 'recreational' and other subjective effects, and general drug properties/merits and usage. There are many sites and forums already devoted to these, and their inclusion here will decrease the justifiable relevance.

I'm sorry if this policy seems inhibiting to free discussion; I'm aware it's a double standard compared to the way most substances are discussed here, and will offend the sensibilities of some. ImmInst indeed enjoys very light moderation in most areas. But moderators in years past have felt perfectly justified in closing these kinds of threads. What I'm hoping is that, by keeping these discussions highly relevant and somewhat more 'academic' in tone, we'll continue to be able to have them here.

[maxwatt]

K appears to have low specificity, the mechanism of nmdar blockade is complex but interesting. Basically
NR2b receptors are mainly located extrasynatpically where they mediate apoptic,antimetabolic,anti signal transduction roles however there synaptic conterparts(NR2b) achieve the reverse and achieve long term potentionation. Therefore there is a net increase in metabolism,cell viabaily and signal transduction on blocked(glutamate rebound). The secret is that the mind must remain in association(cant fully block long term potention on the synapes) by the use of low doses.

This is good article, there are more for those interested
The Yin and Yang of NMDA receptor signalling


I would be interested in seeing a map showing the various functions of mTOR, looks to be involved in some critical pathways

The proliferation of extra-synaptic receptors is a feature of Huntington's disease which appears to lead to the destruction of neurons, loss of motor control and eventually death. I would be cautious in its chronic use even at low doses.

[Solarclimax]

K appears to have low specificity, the mechanism of nmdar blockade is complex but interesting. Basically
NR2b receptors are mainly located extrasynatpically where they mediate apoptic,antimetabolic,anti signal transduction roles however there synaptic conterparts(NR2b) achieve the reverse and achieve long term potentionation. Therefore there is a net increase in metabolism,cell viabaily and signal transduction on blocked(glutamate rebound). The secret is that the mind must remain in association(cant fully block long term potention on the synapes) by the use of low doses.

This is good article, there are more for those interested
The Yin and Yang of NMDA receptor signalling


I would be interested in seeing a map showing the various functions of mTOR, looks to be involved in some critical pathways

The proliferation of extra-synaptic receptors is a feature of Huntington's disease which appears to lead to the destruction of neurons, loss of motor control and eventually death. I would be cautious in its chronic use even at low doses.

Seems like a vague comparison. I would say it does interfier with motor control but at what dosage i don't know. All i know is. People can sometimes say don't do this because it causes this, so therefore it's best not to do it.

Jumping from a burning building could result in a broken leg, so maybe it's best to burn to death.

I know this isn't what people are saying when they give reasons why something shouldn't be done. I just think it's good for people to open their mind to the possibility that once in a while the bennefit can outweigh the risk. Not saying this idea fits to anything mentioned in this thread.

Binge drinking has been linked to violence and even death. Wine contains alcohol so i would be cautious about drinking whine.
Again not trying to discredit anything previously said. I happen to think this is a very good point

"I would be cautious in its chronic use even at low doses."

Just that not everything is black and white.

[maxwatt]

....
"I would be cautious in its chronic use even at low doses."

Just that not everything is black and white.

No, but caution is not prohibition. Too many people do not adequately research what they are using, and have no idea of what they are getting into.

[NR2(x)]

I would expect ketamine to be useful in treating Huntingtons disease, as blocking the extrasynatpic nmdar's would facilitate neurogensis and block cell apoptosis. I had a look for studies regarding selective nmdar blockers, the first one i found showed no effect, but it was using the maximium dosage tolerable, which would have enduced considerable dissassociation, which would produce negatives that would balance out the positive.

[maxwatt]

I would expect ketamine to be useful in treating Huntingtons disease, as blocking the extrasynatpic nmdar's would facilitate neurogensis and block cell apoptosis. I had a look for studies regarding selective nmdar blockers, the first one i found showed no effect, but it was using the maximium dosage tolerable, which would have enduced considerable dissassociation, which would produce negatives that would balance out the positive.

I'll run that by someone I know in a Huntington's lab.

[maxwatt]

I would expect ketamine to be useful in treating Huntingtons disease, as blocking the extrasynatpic nmdar's would facilitate neurogensis and block cell apoptosis. I had a look for studies regarding selective nmdar blockers, the first one i found showed no effect, but it was using the maximium dosage tolerable, which would have enduced considerable dissassociation, which would produce negatives that would balance out the positive.

I'll run that by someone I know in a Huntington's lab.

I got a reply:

Ketamine does block NMDA receptors. It is thought that Huntington's disease may involve pathologically increased extrasynaptic NMDA receptor signaling.

Therefore, blocking extrasynaptic would be good. However, ketamine does not preferentially block extrasynaptic receptors, it is not selective for this kind of receptor. This is why it isn't a good treatment for huntington's. Synaptic NMDARs are very useful and necessary.

When he refers to "selective" NMDAR blockers, I'm not sure what selective means in this context. Does he mean selectively extrasynaptic receptors? Or a particular kind of NR2 subunit?

[NR2(x)]

Thanks, I understand that low dose NR2b antagonist work rather selectively on extrasynatpic NMDAr in a rather complex manner. Phosphorlyation of the synaptic NR2b will result from mild inhibition, which should allow sufficient long term potention. Low dose NR2b antagonist are working rather well in depression studies, which may support my proposition. I know that Ketamine is dirty

I would be really interested in hearing about selective extrasynatpic nmdar blockers. I understand that nr2b and nr2d or e are linked only in the extrasynaptic postion which may allow an avenue to develop the above drug.

Edited by NR2(x), 13 September 2010 - 05:31 AM.

[maxwatt]

Thanks, I understand that low dose NR2b antagonist work rather selectively on extrasynatpic NMDAr in a rather complex manner. Phosphorlyation of the synaptic NR2b will result from mild inhibition, which should allow sufficient long term potention. Low dose NR2b antagonist are working rather well in depression studies, which may support my proposition. I know that Ketamine is dirty

I would be really interested in hearing about selective extrasynatpic nmdar blockers. I understand that nr2b and nr2d or e are linked only in the extrasynaptic postion which may allow an avenue to develop the above drug.

If we had a good selective extrasynatpic nmdar blocker, we'd have a good treatment for Huntington's an perhaps for several other neurodegenerative diseases. Some very smart people are looking for it.

[NR2(x)]

Depression, ADD, ,parkinson , particularly persuassive development disorders including schizophrenia etc, the holly grail,
basic nr2b antagonists do hold significant potential, i tried CP101606 once which was interesting
Know of any peptides that encourage the movement from extra to synatpic site?

[6etYM45oLl]

Potential downsides of ketamine:

It appears that the antidepressant effect is mediated by activation of mTOR wich rapidly induces synaptogenesis.

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

Quote:
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.

A quick scan of mTOR on wikipedia reveals this:

Aging



mTOR signaling pathway.[1]
Decreased TOR activity has been found to slow aging in S. cerevisiae, C. elegans, and D. melanogaster.[27][28][29] The mTOR inhibitor rapamycin has been confirmed to increase lifespan in mice by independent groups at the Jackson Laboratory, University of Texas Health Science Center, and the University of Michigan.[30]
It's hypothesized that some dietary regimes, like caloric restriction and methionine restriction, cause lifespan extension by decreasing mTOR activity.[27]
[edit]mTOR inhibitors as therapies

mTOR inhibitors are already used in the treatment of transplant rejection . They are also beginning to be used in the treatment of cancer.[31]
mTOR inhibitors may also be useful for treating several age-associated diseases.

And we also have this:

Hyperphosphorylated tau in the brains of mice and monkeys with long-term administration of ketamine


L.Y. Yeunga, Maria S.M. Waia, Ming Fanb, Y.T. Maka, W.P. Lama, Zhen Lic, Gang Lua, c and David T. Yewa, ,
a School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China
b Institute of Military Medical Sciences, PLA, Beijing, China
c Biomedical Engineering Research Centre, Kunming Medical University, Kunming, Yunnan, China
Received 13 November 2009; revised 11 January 2010; accepted 12 January 2010. Available online 20 January 2010.
Abstract
Ketamine, a non-competitive antagonist at the glutamatergic N-methyl-d-aspartate (NMDA) receptor, might impair memory function of the brain. Loss of memory is also a characteristic of aging and Alzheimer's disease. Hyperphosphorylation of tau is an early event in the aging process and Alzheimer's disease. Therefore, we aimed to find out whether long-term ketmaine administration is related to hyperphosphorylation of tau or not in the brains of mice and monkeys. Results showed that after 6 months’ administration of ketamine, in the prefrontal and entorhinal cortical sections of mouse and monkey brains, there were significant increases of positive sites for the hyperphosphorylated tau protein as compared to the control animals receiving no ketamine administration. Furthermore, about 15% of hyperphosphorylated tau positive cells were also positively labeled by terminal dUTP nick end labeling (TUNEL) indicating there might be a relationship between hyperphosphorylation of tau and apoptosis. Therefore, the long-term ketamine toxicity might involve neurodegenerative process similar to that of aging and/or Alzheimer's disease.

Suggesting that long term chronic use of ketamine can have detrimental effects.

The good news is that the antidepressant effects are semi long lasting and that chronic treatment isnt neceserry.

Maybe its mTOR downregulation that is causing the beneficial effects of ketamine, leaving the antidepressant effect untill mTOR is upregulated again.

If that is the case then occasional "shocktherapy" with ketamine could of benefit for life extension, but thats just gueswork (and maybe wishfull thinking).

It appears that resveratrol also downregulates mTOR.

Regarding mTOR stimulation enhancing aging, ketamine only increases mTOR signaling in the prefrontal cortex of the brain. mTOR is present all throughout the entire body. It is highly unlikely that a selective increase in mTOR in the pFC is going to accelerate aging.

As for ketamine inducing hyperphosorylated tau, let's see what doses they used shall we?:

Young Cynomolgus Monkeys or Crab-eating Macaques (Macaca fascicularis) of 3 years old and ICR (imprinting control region) mice of 2 months old were used to set up the long-term animal abusive models. Six monkeys were given daily intravenous ketamine at dose of 1 mg/kg for 6 months. Eighteen mice in total were divided into three groups of six mice each and each animal in each group received daily intraperitoneal ketamine at dose of 30 mg/kg for either 1, 3 or 6 months.

Now let's see how much crab-eating macaques (first quote) and mice (second quote) weigh on average:

Males are considerably larger than females, weighing 5-9 kilograms (11-20 lb) compared to the 3–6 kg (7-13 lb) of female individuals.

About 20 grams but the weight varies from mouse to mouse.

The monkeys would have on average gotten 8 mg/d IV ketamine and the mice 0.6 mg/d IP ketamine. In comparison, we're talking 10-20 mg/d insufflated ketamine for humans. Of course insufflation is not 100% bioavailability like IV/IP and is instead ~40-60%, so we'll say 50% bioavailability -> 5-10 mg/d ketamine -> average = 7.5 mg/d ketamine. Note that the average human body weight is 50-70 kg -> 60 kg.

Now I won't compare mice as they're just too small to get an actually accurate comparison out of, but I will be comparing the monkeys to humans. These monkeys are approximately 7.5x smaller than humans. Thus we'll multiply the dose they got by 7.5x -> 8 mg * 7.5 = 60 mg. A 60 mg IV dose of ketamine is well into the range of dissociation for a human, and for this reason I would say those monkeys got pretty high. In comparison the daily antidepressant dose of ketamine we're talking about is 7.5 mg [100% bioavailability ≈ IV], almost 10x lower. For this reason I don't think there's too much of a risk.

This reminds me of the ridiculous doses used in the MDMA serotonergic neurotoxicity studies a little bit. Though, it's not really a fair comparison as the authors of this study are talking about ketamine abuse, not therapeutic antidepressant use.

In any case, now that you've seen the data properly laid out, you can make your own decision on the matter.

Edited by el3ctr0nika, 21 September 2010 - 12:12 AM.

[Psionic]

Understanding how ketamine works is crucial because of the drug's limitations. The improvement in symptoms, which are evident just hours after ketamine is administered, lasts only a week to 10 days. In large doses, ketamine can cause short-term symptoms of psychosis and is abused as the party drug "Special K."
In their research, Duman and others show that in a series of steps ketamine triggers release of neurotransmitter glutamate, which in turn stimulates growth of synapses. Research at Yale has shown that damage of these synaptic connections caused by chronic stress is rapidly reversed by a single dose of ketamine.
Efforts to develop drugs that replicate the effects of ketamine have produced some promising results, but they do not act as quickly as ketamine. Researchers are investigating alternatives they hope can duplicate the efficacy and rapid response of ketamine.

http://www.scienceda...21004141747.htm
http://news.ycombina...item?id=4615602

http://www.youtube.c...&v=hNsIiq-5354#!

[CaptainFuture]

Within 24 hours, a small dose of Ketamine, significantly increased the number of connections between neurons. Boosting BDNF could be the next key, to treat or prevent depression.

[Psionic]

I am really interested in way how K acts on neural system. Its is something which allow me to increase vastly my short term memory and fast forward learning about ten times from normal. If similar compound will be developed it can mean real breakthrough in nootropics..

[CaptainFuture]

http://www.scienceda...21004141747.htm

"Efforts to develop drugs that replicate the effects of ketamine have produced some promising results, but they do not act as quickly as ketamine. Researchers are investigating alternatives they hope can duplicate the efficacy and rapid response of ketamine."

I'm excited, too.