Anyone tried ketamine?

Thomas

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I just did a quick forum search and found that: @redrachel76 said for pain, it stopped working for her. @Misfit Toy also found that it was working well, and then suddenly lost a lot of its effects. @Thomas got negative effects from ketamine.
Yes my experience with IV ketamine wasn't very good. Being on the drug was pleasant but after it left my system the payback was quite uncomfortable and bizarre. But that was just my own personal experience.

If you look at Dr Goldstein's book, he administered ketamine orally, intranasally and even in the eyes (conjunctivally), and he talks about its effects on the trigeminal nerve (which runs to the face, mouth, teeth nasal and sinus cavities). I am not sure if Goldstein also performed ketamine IVs, but I am guessing these might work in a different way to when ketamine is used more locally to target the trigeminal nerve.
Goldstein infused ketamine at least a thousand times according to his own estimation. One thing he did stress time and time again whenever he mentioned his use of IV ketamine for CFS patients was to make sure the drug was mixed in 500 ml of normal saline and infused very slowly over at least 3 hours. Any faster and you ran the risk of adverse effects and in his experience if this occured, the drug would not work for you again. I actually walked out of two pain clinics before finding an appropriate one, because they wanted to infuse me in 45 minutes and declined my request to stretch the infusion to 3 hours. Just a caveat.
 

Sushi

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Furthermore, you might find this old letter from Dr. Goldstein that someone gave me which may help explain his protocol.
Thanks, Thomas. I am still trying to make contact with the doctor who might administer the ketamine IV so this letter from Dr. Goldstein is very helpful.
 

hmnr asg

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hi there,
I had a ketamine infusion for depression. I had a very powerful psychedelic experience during the infusion which i found to be very interesting and in no way frightening. I had no side effects after and I was back at work maybe two hours after the infusion (i did not drive of course).
My fatigue all but disappeared for two days but on the third day it was back. But my mood was elevated and i felt like my mind was working a little bit more efficiently for maybe a month later.
I didnt think it was a treatment for CFS but definitely a very positive experience.

J
 

hmnr asg

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I shared my ketamine story here before:
http://forums.phoenixrising.me/index.php?threads/ketamine-injection.47816/#post-785085

the dose was "0.5mg/kg" and the infusion took about 45 minutes. So pretty fast and it was VERY intense. I had been warned about hallucinations but it did not upset me, in fact it was very pleasant.

ps i have to mention that ketamine can be addictive (im sure you know that, sorry for the platitude)
 

Sushi

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the dose was "0.5mg/kg" and the infusion took about 45 minutes. So pretty fast and it was VERY intense.
Thanks, sorry you only had 2 good days from it. I am reading that Dr. Jay Goldstein recommended infusing it over about 3 hours, so if I can get the doctor to agree, this would be my preference. We'll see, but if I do get the infusion, I'll report back here.
 

nandixon

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This may be too dense for many people, mainly because of some notes I've interspersed to help me remember some things. So it's more to have the information available for research purposes.

I've been looking at the more recent studies on the hydroxynorketamine (HNK) metabolites of ketamine. The effect of ketamine itself is primarily as a NMDA receptor antagonist (an effect HNK does not have, at least not directly). This aspect might be helpful for some people but it's probably not the mechanism by which ketamine works to facilitate energy production in ME/CFS.

Instead, one or both of the two HNK enantiomers (2S,6S)- and (2R,6R)-HNK are likely responsible for this, along with the intermediate metabolite norketamine to a lesser extent. Ketamine is metabolized to these compounds within minutes in the body.

In this 2014 study, (2S,6S)-HNK and also norketamine significantly increased the activation of the Akt/mTOR (mTORC1) pathway. (2S,6S)-HNK was perhaps 200 times more potent at doing this than norketamine which in turn was about 100 times more potent than ketamine itself.

The authors found that this Akt/mTORC1 activation appeared to occur via inhibition of the α7-nicotinic acetylcholine receptor. (Note: The 2R,6R-HNK enantiomer is apparently less active for Akt/mTORC1 purposes in this study's assays than 2S,6S-HNK, but the authors didn't formally look at this so we don't know by how much. 2R,6R-HNK does have a potent and selective ability to inhibit α7-nAChR on the same order as 2S,6S-HNK, though, so it may not be too dissimilar in its ability to activate Akt/mTORC1.)

Next, in this 2016 study, the other enantiomer, (2R,6R)-HNK, was found to be the metabolite of ketamine most responsible for its antidepressant effect. (2S,6S)-HNK also had this capability but required a higher concentration (more than double, it appears).

According to the authors, (2R,6R)-HNK exerts its antidepressant effect by activation of the AMPA receptor.

(Note: In the 2016 study, the authors found that neither 2R,6R-HNK nor ketamine itself affected mTOR, but that appears to be because of the particular methodology used. Several other studies clearly show that ketamine activates mTOR. Being cynical here, the 2016 study seems to have been reported in such a way as to improve the prospects for obtaining a patent on the 2R,6R enantiomer.)

Anyway, when ketamine is used, HNK appears to be mostly responsible for activating the Akt/mTORC1 pathway and apparently does so by inhibition of α7-nAChR, and HNK is also responsible for ketamine's antidepressant effect which occurs via activation of the AMPA receptor. The 2S,6S enantiomer of HNK is apparently better at the former, while the 2R,6R enantiomer appears better at the latter.

However, to add a twist to this, it's been shown that activating the AMPA receptor increases brain-derived neurotrophic factor (BDNF), which then can also activate the Akt/mTORC1 pathway. (Reference) So it's possible that ketamine (via HNK) may actually be activating that pathway through both the α7-nAChR and AMPA receptors.

Akt/mTORC1 is important because I believe the recent Fluge & Mella study is indicating that this pathway is under-activated in ME/CFS, and that may be what's causing the impairment of the PDH complex that was found. Hence, this may be why ketamine can be helpful for some patients (for energy purposes), if only temporarily.

Interestingly, tianeptine (available as a supplement in the US) has a similar mechanism of action to ketamine in that it also simultaneously activates both the Akt/mTORC1 pathway and the AMPA receptor. (Reference)

Unfortunately, tianeptine is not only weaker than ketamine, but also much shorter acting and even more prone to development of tolerance of its effect.
 
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Tunguska

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Sometimes there really is too much information on this forum to process in a day...

There was an attempt at a group buy for Hydroxynorketamine on Longecity but it looks like it fell through.

The biggest question I still have is: what is the half-life of Hydroxynorketamine in the brain? There's a figure of 8+/-4h in the single rat study that comes up, but I couldn't figure out if that was meaningful in people, and another study's graphs seemed to put it closer to Ketamine itself.

My primary concern out of all this for some time is that ampakines with long half-lives lead to AMPA receptor downregulation (basically) from daily use: https://www.ncbi.nlm.nih.gov/pubmed/19141314
(Though cycling or non-daily use probably mitigates the risk: https://www.ncbi.nlm.nih.gov/pubmed/12893840 )

This is actually an advantage for substances like Aniracetam and Tianeptine sodium. Unfortunately the brain half-life of Agmatine appears to be over 12 hours.

Interestingly, tianeptine (available as a supplement in the US) has a similar mechanism of action to ketamine in that it also simultaneously activates both the Akt/mTORC1 pathway and the AMPA receptor. (Reference)
Thanks for linking that. That's from 2016, I hadn't seen that one, though I still maintain its opioid effects dominate in practical usage and I wonder exactly what parts of those effects it shares with other opioids.
 
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nandixon

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@nandixon we should approach a lab about a custom synthesis. Syntharise.com comes to mind.
The US government, interestingly, owns any potential patent rights to hydroxynorketamine (HNK), but so far I don't see where any actual patent has issued yet (in the US). There's just this pending patent application, I believe. (Note that the title of the application refers to the 2R,6R isomer, but if a patent was in fact granted based on the filed application, it would cover all of the different forms of HNK.)

So as of right now it should still be legal to make HNK itself.

For our purposes I think it would be best just to initially try the (racemic) mixture of both the (2S,6S)- and (2R,6R)-HNK together, since that would be less expensive to make and we don't know which, if either, isomer (enantiomer) might be better anyway. HNK has good oral bioavailability and none of the drug abuse risks of ketamine. It may have to be used only intermittently to maintain its effect, though.

I'm hoping that the 2S,6S isomer ends up being the better one for ME/CFS (assuming either work at all), because the NIH already has testing in the works for the 2R,6R isomer as an antidepressant. (See Note below.)

HNK is available now but very expensively ($745 for 50 mg) here. Perhaps elsewhere too.

Note: The NIH put out a request for development of a commercial synthesis of (2R,6R)-HNK in early 2016, I believe. This was apparently fulfilled by November 2016, because the NIH then made a request for clinical trial partners here. There they state that, "Additionally, the researchers have established appropriate salt, crystal and polymorph forms of the agent and multiple methods of synthesis. Full ADME and polypharmacology assessment is complete as well as pre-formulations studies."
 

Tunguska

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I would have been interested in a group buy attempt if the price came down, but unfortunately I just found out it's already considered as controlled substance where I live (sometimes I manage to get technically less legal stuff in even fully declared, but this seems like a bad idea).
 

Charles555nc

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I had ketamine to put me under for surgery, but I have not been able to find a way to get more. Ive read about clinics for depression that can administer ketamine, but its usually too low a dose from what I heard. Im in North Carolina, is there a good way/good doctor to get ketamine near here?

It can actually repair damaged axons in the brain which is why it probably why it helps with depression.
 

Misfit Toy

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I had my compounded at a pharmacy into a nasal spray. I still think it's great but it needs to be administered differently for each different illness.
 
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I had my compounded at a pharmacy into a nasal spray. I still think it's great but it needs to be administered differently for each different illness.
Trialing this now. Don't have the luxury of a home infusion machine and saline, so I'm going for the intranasal equivalent.
 

Tunguska

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So the whole ketamine thing is a puzzle. Daily/bi-daily use effects are explainable, but I just cannot see how a single dose no matter how strong would upregulate AMPA and mTor and "cure" someone for a week that way.

I've had low time to cover ground but the circadian rhythm (not seasonal) is next most interesting related target. If you follow the studies they explain how it can go awry through cells losing synchronization between each other, which kills the amplitude. They reset the rhythm by administering large doses of dexamethasone (glucocorticoid - nothing I can try either). After a period of time they lose synchronization again.

So turns out they already thought about checking ketamine's effects on circadian rhythm: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3161090/
Abstract
Major mood disorders have been linked to abnormalities in circadian rhythms, leading to disturbances in sleep, mood, temperature, and hormonal levels. We provide evidence that ketamine, a drug with rapid antidepressant effects, influences the function of the circadian molecular machinery. Ketamine modulates CLOCK:BMAL1-mediated transcriptional activation when these regulators are ectopically expressed in NG108-15 neuronal cells. Inhibition occurs in a dose-dependent manner and is attenuated after treatment with the GSK3β antagonist SB21673. We analyzed the effect of ketamine on circadian gene expression and observed a dose-dependent reduction in the amplitude of circadian transcription of the Bmal1, Per2, and Cry1 genes. Finally, chromatin-immunoprecipitation analyses revealed that ketamine altered the recruitment of the CLOCK:BMAL1 complex on circadian promoters in a time-dependent manner. Our results reveal a yet unsuspected molecular mode of action of ketamine and thereby may suggest possible pharmacological antidepressant strategies.
I can't tell how that compares to other substances off the bat but I could be reading this crap for the next 3 years, so better off posting.
 
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There was an attempt at a group buy for Hydroxynorketamine on Longecity but it looks like it fell through.
The group buy is still active. A custom synthesis was ordered for the racemic mixture of (2S, 6S) : (2R, 6R) of HNK-6. It will take some months to synthesize. Since we ordered more than we currently need we would be happy about more members. If interested please send an email to hnk6 at tutanota dot com.
 
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I Have Been Using Ketimine Treatment for a couple years now. at first it was every 3 weeks with noticeable decline in feeling on 3rd week before treatment now weather because of increased dosage, consistent treatments or both i am up to 6 weeks in between treatments with 1 week of less effect.

It helps me alot. i feel more energy, tolerate chronic pain better, i tolerate stimulus better, and i feel less stressed out/ anxious for weeks after the treatment. also i like to stretch at the end of treatment cause it makes it less uncomfortable on problem muscles.

a treatment is a single injection. the doctor puts on some music and i drift off for about 40 min. when i come too im still "drugged" and within an hour or 2 i feel it has left my system but i feel noticeably better for weeks.

Im am still trying to figure out what the reasoning is for this prolonged effect. my main theory is it has something to do with glutamate(or glutamine? glutasomthing) flooding hippo campus during treatment.
the reduction in stress and anxiaty also helps cause those can aggrivate main cfs symptoms.
oh yeah it helps with brain fog too!

Just my expirance. too carashed to worry about rechecking what i types hope it was legiable.
 

Tunguska

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@Offset Entity
That's remarkable. I still don't know the reason for the prolonged effect. Have you taken any other drugs that you can compare the ketamine injections to?

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Here's another study from 2017 that got my attention:
https://www.biopsychiatry.com/ketamine-bdnf.pdf
Ketamine induces brain-derived neurotrophic factor expression via
phosphorylation of histone deacetylase 5 in rats
Abstract
Ketamine shows promise as a therapeutic agent for the treatment of depression. The increased expression of brain-derived neurotrophic factor (BDNF) has been associated with the antidepressant-like effects of ketamine, but the mechanism of BDNF induction is not well understood. In the current study, we demonstrate that the treatment of rats with ketamine results in the dose-dependent rapid upregulation of Bdnf promoter IV activity and expression of Bdnf exon IV mRNAs in rat hippocampal neurons. Transfection of histone deacetylase 5 (HDAC5) into rat hippocampal neurons similarly induces Bdnf mRNA expression in response to ketamine, whereas transfection of a HDAC5 phosphorylation-defective mutant (Ser259 and Ser498 replaced by Ala259 and Ala498), results in the suppression of ketamine- mediated BDNF promoter IV transcriptional activity. Viral-mediated hippocampal knockdown of HDAC5 induces Bdnf mRNA and protein expression, and blocks the enhancing effects of ketamine on BDNF expression in both unstressed and stressed rats, and thereby providing evidence for the role of HDAC5 in the regulation of Bdnf expression. Taken together, our findings implicate HDAC5 in the ketamine-induced transcriptional regulation of Bdnf, and suggest that the phosphorylation of HDAC5 regulates the therapeutic actions of ketamine.
Another on this from 2015:
http://www.pnas.org/content/112/51/15755.full
Ketamine produces antidepressant-like effects through phosphorylation-dependent nuclear export of histone deacetylase 5 (HDAC5) in rats

Significance

The rapid antidepressant response is produced by ketamine administration. However, the molecular mechanisms underlying the antidepressant-like action of ketamine remain incomplete. Here we show for the first time to our knowledge that ketamine stimulates the phosphorylation (Ser259/Ser498) and nuclear export of histone deacetylase 5 (HDAC5). As a consequence, myocyte enhancer factor 2 (MEF2) transcriptional activity is enhanced and results in the induction of MEF2 target gene expression. We further show that ketamine down-regulates and, at the same time, phosphorylates HDAC5 to attenuate its repressive influence on transcription in the hippocampus. These studies unveil a previously unidentified role of HDAC5 in regulating neuronal function in response to ketamine, and thus provide the foundation for new approaches for the treatment of major depression.

Abstract
Ketamine produces rapid antidepressant-like effects in animal assays for depression, although the molecular mechanisms underlying these behavioral actions remain incomplete. Here, we demonstrate that ketamine rapidly stimulates histone deacetylase 5 (HDAC5) phosphorylation and nuclear export in rat hippocampal neurons through calcium/calmodulin kinase II- and protein kinase D-dependent pathways. Consequently, ketamine enhanced the transcriptional activity of myocyte enhancer factor 2 (MEF2), which leads to regulation of MEF2 target genes. Transfection of a HDAC5 phosphorylation-defective mutant (Ser259/Ser498 replaced by Ala259/Ala498, HDAC5-S/A), resulted in resistance to ketamine-induced nuclear export, suppression of ketamine-mediated MEF2 transcriptional activity, and decreased expression of MEF2 target genes. Behaviorally, viral-mediated hippocampal knockdown of HDAC5 blocked or occluded the antidepressant effects of ketamine both in unstressed and stressed animals. Taken together, our results reveal a novel role of HDAC5 in the actions of ketamine and suggest that HDAC5 could be a potential mechanism contributing to the therapeutic actions of ketamine.
I've never heard of HDAC5 specifically, and there's no telling if it has any relation to the prolonged effect... But coincidentally I planned on trying a retinoic acid + HDAC inhibitor combo myself in the near future after reading some studies (it's mostly known as a tentative cancer treatment, but it won't stop at that).

[also coincidentally to the study a few posts above, the HDACs including 5 are heavily involved in daily rhythm https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4256363/ ]

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For the record more recently I managed to try Agmatine, IDRA 21 (advertised AMPAkine), and Adamantane (NMDA antagonist, dopamine agonist, possible HDAC inhibitor effects). All of them did something but only the last one was worth anything and very potent but doesn't give a 2-week symptom resolution (unless you have to take an insane dose...).
 
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