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Nitric oxide and its possible implication in ME/CFS (Part 2 of 2)
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How Ketamine Defeats Chronic Depression

Discussion in 'Other Health News and Research' started by Waverunner, Oct 5, 2012.

  1. xks201

    xks201 Senior Member

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    When I think of chronic pain I think mainly of hormone deficiencies. And any hormone deficiency can cause chronic pain. This is a great article. I have NEVER responded to any serotonin increasing drugs well. Yet my glutaminergic system is extremely hyperactive. Neuroresearchers are now discovering that the reason these SSRIs and Lithium and whatnot decrease depression is because they modify other factors in the brain like these and increase growth factors and resistance to stress. That is actually their main mechanism of action which is why you don't just take one and wake up a new person for a week. In any event SSRIs still put me to sleep and this sounds like something interesting to try.

    I personally think that in a lot of our cases our adrenaline/stress levels are so high due to low hormone levels and or hypovolemia. I know when I fix my hypovolemia my stress/adrenaline goes down almost completely.
     
    August59, GhostGum and heapsreal like this.
  2. MishMash

    MishMash *****

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    This drug has huge potential benefits for treatment of severe depression, FM, CFS, PTSD, and probably numerous other chronic neuroimmune illnesses. I have read all the literature too. Waverunner, you are right to be excited. This would probably work extremely well for you. It is a potential boon for many of us.

    But it will never see the light of day because it cannot be patented so nobody has any interest in spending big money on long and expensive trials. And as has already been warned: don't take it !! Wait for years and years of official testing for some official body to declare it safe and effective. Or wait for some kind of "guidance" on dosing, when like most drugs, dosing is almost always highly individual and specific. In other words, most of us will be dead, or too old to care, before it is ever approved.

    The kiss of death is that it is used recreationally, mostly by folks in Europe, so by definition the US drug nannies will declare it as having "no medicinal value." Such is the stigma of the Nancy Reagan "just say no" drug wars left over from the 1980s.

    Never mind that Ketamine, not to mention Ecstasy, and medical marijuana have all been found to be effective in treating PTSD in returning Iraq and Afghanistan veterans. To hell with them, the self-appointed morality police of the drug world will decide what you get and don't get. Load up the vets with SSRIs, whose only side effects are suicide and rage fits, plus other new exotic off-label junk that nobody knows the true long term effects of.

    If you are a CFS patient, living in pain and disability day to day, and you have access, legal or otherwise, to drugs such as Ketamine, Ecstasy, or medical marijuana, I highly encourage you to use your own judgement and to experiment if you think it will help you. There are literally millions of people who have used these substances, including our *past four Presidents*, and any potential harm from them will always be highly, highly overstated. Our most hideously destructive drug is alcohol. Not Ketamine, Ecstasy, etc.

    I can assure you, the crazy anti-psychotic, anti-seizure off-label junk (Seroquel, Neurontin, Abilify, etc) being peddled, really aggressively, in doctors offices is no worse than the side effects of these drugs. These so-called "safe drugs" generate massive profits for pharma companies. The companies themselves have no idea what the long-term side effects of these are. But they will decide what is "safe and effective" for you and what is not. CFS patients, save yourselves, because this is an example where, again, nobody really cares about you.
     
    vli, GhostGum, mellster and 1 other person like this.
  3. Marlène

    Marlène Senior Member

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    Poorly managed pain can evolve into chronic disease of the nervous system


    NPR again reports ketamine’s rapid relief of depression. A 28 year old man whose refractory depression began at age 15, after ketamine, says:

    .
    ‘I Wanted To Live Life’

    .
    Stephens himself has vivid memories of the day he got ketamine. It was a Monday morning and he woke up feeling really bad, he says. His mood was still dark when doctors put in an IV and delivered the drug.”Monday afternoon I felt like a completely different person,” he says. “I woke up Tuesday morning and I said, ‘Wow, there’s stuff I want to do today.’ And I woke up Wednesday morning and Thursday morning and I actually wanted to do things. I wanted to live life.”.

    .
    Since then, they treated him with Riluzole that is FDA approved for ALS and has one of the dirtiest side effect profiles I have ever seen in medicine with serious organ toxicity. Ketamine rarely causes mild transient side effects, usually none. It appears the concern is how ketamine is used on the street with potential for abuse. I do not see ketamine abuse in my patients, some of whom are on opioids for pain or Valium family medicines from their psychiatrist. All of those have a greater potential for abuse, also not occurring in my patients. Pain and/or depression can lead to suicide.

    .

    About 18 months ago, researchers at Yale found a possible explanation for ketamine’s effectiveness. It seems to affect the glutamate system in a way that causes brain cells to form new connections.

    .

    Researchers have long suspected that stress and depression weaken some connections among brain cells. Ketamine appears to reverse the process.


    Source: http://painsandiego.com/2012/01/25/...-to-help-pain-care-reform-is-urgently-needed/
     
    MishMash likes this.
  4. Waverunner

    Waverunner Senior Member

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    The drug war has failed on all fronts. Just look at Mexico and how many people there get brutally murdered, kidnapped or abused every year.The war on drugs created these monstrous, invincible drug cartels and the only way to get rid of them now, is by legalizing drugs and destroying their income. Addiction should be treated as what it is, an illness. A crime, that is victimless, is no crime, yet we put people into prison for it.

    There is not justification for banning marijuana but legalizing alcohol, when the first has a lower addiction potential. Everything we do is based on increasing neurotransmitters, opiates or endorphins in our brain (e.g. by eating, exercising, alcohol etc.), yet government prevents us from taking responsibility for our lives. This would be OK, if we all would be healthy, but we are not. So right now, because medicine is not far enough into the future, trying medicine, most of the time is the only way, to find out, if something helps or not.
     
    mellster and MishMash like this.
  5. MishMash

    MishMash *****

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    This is a very brave and compassionate doctor. Any physician who offers pain treatment is going to accused of common drug pedaling. She will be crushed between the greed of the pharma companies and the dogmatic stupidity of our government drug enforcement offiicals. I wonder how many of PR's patients would be helped (or possibly cured) by Ketamine treatment.
     
  6. MishMash

    MishMash *****

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    I agree completely. Without turning PR into a marijuana decriminalization forum, I do think current laws impinge on our rights to seek treatment for a life-altering, intractable illness. Currently 17 states agree with my view of this basic right. The whole drug war is, in fact, a massive failure. I think most Americans would actually agree with that now.

    While in college back in the early 80s, my fraternity house was one big cloud of pot smoke, starting at
    6 pm. Some of the smartest, most ambitious students were owners of large, heavily used bongs. There was also a high amount of binge drinking going on, particularly during the weekend parties.

    After 30 years, what is clear is that the binge drinkers suffered more from the effects of their habits in later years in the form of alcoholism. The stoners moved on to jobs, graduate schools got married, and yeah, eventually gave up pot smoking. As you said, it is innocuous and a victimless crime.
     
  7. Waverunner

    Waverunner Senior Member

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    Just wanted to say this. I read the whole study. One pathway, by which Ketamine produces its beneficial effects is through inhibition of Glycogen synthase kinase 3 (GSK-3). At the end of the study they notice, that a GSK-3 inhibitor may be a possible treatment alternative to Ketamine.
     
  8. Marlène

    Marlène Senior Member

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    @ waverunner

    Thanks for pointing at this!

    Google directed me to next article:

    Neurochem Int. 2012 Jul 10;61(5):666-671. [Epub ahead of print]
    GSK-3 mediates the release of IL-1β, TNF-α and IL-10 from cortical glia.

    Green HF, Nolan YM.
    Source

    Department of Anatomy and Neuroscience, University College Cork, Ireland.
    Abstract

    Neuroinflammation has been shown to contribute to neurodegenerative and psychiatric disorders such as Alzheimer's disease and major depression due to the inappropriate release of pro-inflammatory cytokines from activated microglia. The precise molecular events that mediate cytokine release from glia remain unknown but we suggest that the serine/threonine kinase glycogen synthase kinase-3 (GSK-3) may be involved. The aim of this study therefore was to investigate the effect of lipopolysaccharide (LPS) on expression and activity of the GSK-3β isoform in glia, and to assess if GSK-3 mediates the LPS-induced change in inflammatory cytokine levels in culture medium from rat glial-enriched cortical cultures. GSK-3β was expressed in microglia and astrocytes, and stimulation of these cultures with LPS induced an increase in GSK-3β expression and activity, and in pro-inflammatory cytokine levels in culture media. We show that GSK-3 inhibition using a small molecule inhibitor SB216763 or the mood stabiliser lithium chloride reduced the LPS-induced elevated levels of pro-inflammatory cytokines present in culture media from rat glial-enriched cortical cultures. These results demonstrate a role for GSK-3 as a modulator of inflammatory cytokine levels in the brain, and contribute to a mechanistic insight into neurological disorders in which neuroinflammation is a characteristic feature.

    Copyright © 2012 Elsevier Ltd. All rights reserved.
    PMID:
    22796213
    [PubMed - as supplied by publisher]
    http://www.ncbi.nlm.nih.gov/pubmed/22796213
     
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  9. MishMash

    MishMash *****

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    Interesting. I hope pharma doesn't try and develop GSK-3 as a patentable variant of Ketamine. Probably Ketamine will be declared "unsafe" and billions will be made off of a "me-too" drug.
     
  10. Legolas

    Legolas

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    Below a abstract of a study from cfs specialist dr.Maes who also does some research on depression.

    New drug targets in depression: inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And new drug candidates--Nrf2 activators and GSK-3 inhibitors.

    Maes M, Fišar Z, Medina M, Scapagnini G, Nowak G, Berk M.
    Source

    Maes Clinics@TRIA, 998 Rimklongsamsen Road, Bangkok 10310, Thailand. dr.michaelmaes@hotmail.com
    Abstract

    This paper reviews new drug targets in the treatment of depression and new drug candidates to treat depression. Depression is characterized by aberrations in six intertwined pathways: (1) inflammatory pathways as indicated by increased levels of proinflammatory cytokines, e.g. interleukin-1 (IL-1), IL-6, and tumour necrosis factor α. (2) Activation of cell-mediated immune pathways as indicated by an increased production of interferon γ and neopterin. (3) Increased reactive oxygen and nitrogen species and damage by oxidative and nitrosative stress (O&NS), including lipid peroxidation, damage to DNA, proteins and mitochondria. (4) Lowered levels of key antioxidants, such as coenzyme Q10, zinc, vitamin E, glutathione, and glutathione peroxidase. (5) Damage to mitochondria and mitochondrial DNA and reduced activity of respiratory chain enzymes and adenosine triphosphate production. (6) Neuroprogression, which is the progressive process of neurodegeneration, apoptosis, and reduced neurogenesis and neuronal plasticity, phenomena that are probably caused by inflammation and O&NS. Antidepressants tend to normalize the above six pathways. Targeting these pathways has the potential to yield antidepressant effects, e.g. using cytokine antagonists, minocycline, Cox-2 inhibitors, statins, acetylsalicylic acid, ketamine, ω3 poly-unsaturated fatty acids, antioxidants, and neurotrophic factors. These six pathways offer new, pathophysiologically guided drug targets suggesting that novel therapies could be developed that target these six pathways simultaneously. Both nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activators and glycogen synthase kinase-3 (GSK-3) inhibitors target the six above-mentioned pathways. GSK-3 inhibitors have antidepressant effects in animal models of depression. Nrf2 activators and GSK-3 inhibitors have the potential to be advanced to phase-2 clinical trials to examine whether they augment the efficacy of antidepressants or are useful as monotherapy.
     
  11. MishMash

    MishMash *****

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    It all seems to be converging. It's nice when some scientists actually agree.

    Biogen trying to cash on the Nrf2 activators for big $$$. Trial results for their soon to be approved blockbuster MS drug BG-12.

    Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the nuclear factor (erythroid-derived 2)-like 2 pathway.

    Scannevin RH, Chollate S, Jung MY, Shackett M, Patel H, Bista P, Zeng W, Ryan S, Yamamoto M, Lukashev M, Rhodes KJ.
    Source

    Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142, USA. robert.scannevin@biogenidec.com
    Abstract

    Oxidative stress is central to the pathology of several neurodegenerative diseases, including multiple sclerosis, and therapeutics designed to enhance antioxidant potential could have clinical value. The objective of this study was to characterize the potential direct neuroprotective effects of dimethyl fumarate (DMF) and its primary metabolite monomethyl fumarate (MMF) on cellular resistance to oxidative damage in primary cultures of central nervous system (CNS) cells and further explore the dependence and function of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in this process. Treatment of animals or primary cultures of CNS cells with DMF or MMF resulted in increased nuclear levels of active Nrf2, with subsequent up-regulation of canonical antioxidant target genes. DMF-dependent up-regulation of antioxidant genes in vivo was lost in mice lacking Nrf2 [Nrf2(-/-)]. DMF or MMF treatment increased cellular redox potential, glutathione, ATP levels, and mitochondrial membrane potential in a concentration-dependent manner. Treating astrocytes or neurons with DMF or MMF also significantly improved cell viability after toxic oxidative challenge in a concentration-dependent manner. This effect on viability was lost in cells that had eliminated or reduced Nrf2...
     
  12. Marlène

    Marlène Senior Member

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    Bingo!

    Does anyone know where the VIP vasoactive intestinal peptide could fit in?

    Vaso-active neuropeptides(VNs) – related to glucagon, secretin, insulin – are a super family of small peptide or protein-like molecules, and potential activators of adenylate cyclase (AC), which converts ATP to cyclic adenosine monophosphate (cAMP).
    VNs of particular interest and relevance to ME/CFS were discussed: PACAP, VIP and CGRP. They are widely distributed in the CNS.
    Data does support the notion of VN dysfunction in ME/CFS and symptoms do match the putative targets.

    VPAC2R receptors are dysregulated. There are links to FOXP3 and cAMP metabolism, and the
    state of receptors is crucial for transmission. cAMP is a very important neurotransmitter involved in the transmission of ATP to AMP. cAMP is a secondary messenger and has a key role in cell metabolism. It acts through CREB and ICER proteins and these have a role in CNS
    neuroplasticity, involving cognition, memory etc.

    http://www.iacfsme.org/LinkClick.aspx?fileticket=sHATs4R9uOM=&tabid=512
     
  13. FunkOdyssey

    FunkOdyssey Senior Member

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    Anyone lamenting the unavailability of ketamine might want to explore methoxetamine. It's available from various grey market sources online (just google "buy mxe"), not illegal to buy or possess, and its antidepressant efficacy is widely praised by users. It's very closely related to ketamine, with minor molecular tweaks.

    Here's a link to some discussion from MXE users: http://www.drugs-forum.com/forum/showthread.php?t=176571
     
    vli likes this.
  14. Marlène

    Marlène Senior Member

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    @ funkOdyssey

    Do you happen to know if methoxetamine has an influence on neuroinflammation as well?
     
  15. GhostGum

    GhostGum Senior Member

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    I would go much further than saying no worse to more like that they are much safer than the prescription drugs you mention, cannabis especially, not to mention that it is very likely for most a much better and safer alternative to all opiates for pain.

    There is an interesting article here on an MS sufferer turning his condition around on a cannabis oil,

    http://www.getwokingham.co.uk/news/s/2121275_medical_cannabis_user_says_drug_should_be_legalised

    This is the stuff that needs to be more readily available for medical users, it makes a vast difference compared to what dispensaries typically offer.

    Cannabinoids are probably a new frontier in medicine, the list of potential treatments is huge and already backed up by many studies but of course there is massive resistance because of the huge threat it posses for obvious parties.

    There is a cancer article here,

    http://www.huffingtonpost.com/2012/09/19/marijuana-and-cancer_n_1898208.html

    Guys like Rick Simpson have known about this for decades and been providing and trying to provide terminally ill patients with oil, apparently with very good results.

    There is even a bloke here in Australia who has been doing the same thing for a long time for free,

    http://www.mullawaysmedicalcannabis.com.au/

    You can even apply to him I believe but the waiting list is probably long. He has even selectively bred his plants over the years to reduce THC, which is what can cause the psychological side effects, and increase the cannabinoid content massively; apparently taking an oil is nowhere near as psychoactive anyway.

    Ketamine is interesting but I wholly agree it is totally unrealistic it would ever see the light of day as a treatment for ME, being viewed as a serious drug for pain and its recreational use its like the idea of using MDMA for depression or PTSD, totally scoffed at for reasons of morality and belief over any real scientific validity.
     
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  16. GhostGum

    GhostGum Senior Member

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    MishMash likes this.
  17. Marlène

    Marlène Senior Member

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    I'm going to give it a try and ask a neurologist.
     
  18. MishMash

    MishMash *****

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    Don't know if our foreign PR web forum members have heard about it, but there's going to be a little election in few weeks in the US of A. One candidate is part of a religious cult that believes drinking caffeine, alcohol or anything similarly mind-altering is immoral. Not just for him; but you too!

    The Mormons don't live and let live, folks. Have you ever had them knock at your door..several times a month? Think you are safe in Britain, Australia, continental europe? Think again. They are like zombies. They don't want to eat your brains, they just want you to turn it off. They'll be at your door too soon! It is their mission statement to convert the whole world. This where we get our Presidential candidates.

    Probably if you live in one of those countries, you wonder "why do I care who gets elected over there?" But in fact, whatever the US President dictates pretty much gets rammed down the throats of our allies and friends. Our Mormon candidate has said many times he personally loathes cannabis use, and would continue, or intensify America's absurd war on drugs.

    Do you think the Australian Prime Minister or the British PM would get away with saying, "oh, we are just going to try not slamming all those poor bastards in jail, and see how other ways work out." Our government, State Department, would find a way to put your n**ts in a vise. Sorry to be so indelicate, but it's the way the free world works.

    In this country, we have a huge law enforcement bureaucracy that literally drags sick people out of bed and puts them in jail for taking substances in the privacy of their homes. Finding something to help with chronically debilitating illnesses like ours would be a peril to your freedom, and possibly your life.
     
  19. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    we have plenty of mormons here in Oz. Mostly we just slam the door on them here, there in the category of door to door salesman etc. I dont have any beef with someone being a mormon but do when they try to ram it down peoples throats who dont agree with their beliefs.

    cheers!!!
     
  20. August59

    August59 Daughters High School Graduation

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    Ketamine could possibly be picked by an "orphan" pharmaceutical company such as Jazz Parmaceuticals did with Xyrem (GHB). The downside will probably be the cost though as all orphan drugs tend to be expensive.

    Jazz Pharmaceuticals has moved to somewhere in the Netherlands or Belgium(???) for some reason and I would be willing to bet it has something to do with the crazy ass regulations the FDA placed on Xyrem.
     

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