The Japanese have long been engaged in a quest to understand severe fatigue. Severe fatigue is an issue the Japanese apparently take fairly seriously. In fact, Watanabe and Tanaka begin their overview of the causes of severe, chronic fatigue by referring to exhaustion so complete and so intractable – called Karoshi in Japan – that some die of it.
Fatigue is more than an medical issue for the Japanese; it’s an economic issue as well.
The Japanese approach severe fatigue from both a medical and an economic standpoint. Fatigue, the authors point out, impedes efficiency and reduces productivity. From an economic standpoint, then, it makes sense to find ways to recover from severe fatigue and perhaps even avoid it in the first place. The economic impact of fatigue has been used to justify spending yen on it for decades.
Frontier studies on fatigue, autonomic nerve dysfunction, and sleep-rhythm disorder, Masaaki Tanaka1, Seiki Tajima2, Kei Mizuno3, Akira Ishii1, Yukuo Konishi, Teruhisa Miike, Yasuyoshi Watanabe. J Physiol Sci (2015) 65:483–498.
In this review paper the Japanese summarize their understanding of the tie-in between fatigue and nervous system problems in ME/CFS. (Please note that many of these same problems have been found in fibromyalgia.) They assert that they have:
- Identified the brain regions and neurotransmitter pathways responsible for the production of fatigue
- The elucidation of molecular and neural mechanisms of fatigue
- The development of several animal models of fatigue
- The invention of methods/treatments to treat fatigue (this is not addressed)
Autonomic nervous system
The Japanese have found that the autonomic nervous system plays an important role in producing fatigue. Both studies of acute (transient) and chronic (long lasting) fatigue indicate that increased fatigue is associated with increased activity of the “fight or flight” (sympathetic nervous system). Furthermore this increase in sympathetic nervous system activity is a direct result of decreased parasympathetic nervous system (“rest and digest” ) activity. (A similar pattern is found in fibromyalgia.)
Alterations in the brain’s autonomic network appears to be responsible for the autonomic nervous system imbalance seen. This network consists of the frontal and prefrontal cortices, the anterior cingulate cortex, the insula, hypothalamus, amygdala and some others, with an emphasis on the anterior cingulate cortex. (Many of these brain regions will show up in the Japanese core theory of reduced “facilitation” seen later.)
As mental fatigue increases the brain begins to lose control of autonomic nervous system functioning
One of the ways the Japanese learned about fatigue is by driving the nervous systems of healthy controls into exhaustion by having them do complex cognitive tasks for hours. Functional magnetic resonance imaging (fMRI’s) indicate that as the healthy controls became more fatigued the parts of their brains involved in mental processing begin to disengage themselves. Two core regions, in particular, the prefrontal cortex and the anterior cingulate cortex, shut down.
As these regions begin to shut down they also begin to lose control of autonomic functioning. In particular, they begin losing the ability to activate the parasympathetic nervous system and tone down the sympathetic nervous system. Remember, this happened in healthy controls; it appears to be a normal consequence of severe fatigue.
The Japanese believe the same process is happening in people with ME/CFS but is obviously not being caused by long periods of intense mental effort. Instead, they believe damage to the prefrontal cortex; an important locus of both executive and autonomic nervous system functioning in the brain, is the cause. With the inhibitory brake of the prefrontal cortex gone, the sympathetic nervous systems of people with ME/CFS react to the slightest stimuli leaving them tired and wired.
A Postexertional Malaise Test
The Japanese have been so taken by the autonomic nervous system contributions to fatigue that they’ve designed the first test they believe that can accurately measure mental fatigue. This simple sixteen-minute test involves having the participants have their eyes open and then closed for three minutes, followed by a 4-minute cognitive test, followed by two more periods of having their eyes open and then closed. During this time an EEG is done.
Once the cognitive test begins sympathetic nervous system activity will spike, but once the test is over, the parasympathetic nervous system should step in to shut the sympathetic nervous system down, and return the brain and body to a rested state. The Japanese found that the failure of the parasympathetic nervous system to activate after the cognitive test was done was highly correlated with fatigue. This suggests they’ve produced a test that measures mental postexertional malaise.
Another perhaps unique measure of PEM came after a maximal exercise test. When the Japanese used actigraphy to measure movement they found that the maximal exercise test threw the ME/CFS patients (but not the healthy controls) circadian rhythms off.
Circadian rhythms are important for sleep, body temperature, and many other processes. In fact, the Japanese have found that when they combined sleep deprivation with altered circadian rhythms they could reproduce ME/CFS.
The autonomic nervous system has shown up in their (and Western) sleep studies as well. They have found that decreased “vagal tone”; i.e. reduced parasympathetic nervous system activity during sleep keeps people with ME/CFS from fully resting during sleep.
Facilitation Breakdown
The Japanese attribute the source of fatigue in ME/CFS to a breakdown in what they call the facilitation system in the brain. As we become fatigued the facilitation system jumps in to increase the signals coming from the primary motor cortex to the muscles. This increased “drive” from the motor cortex prompts the muscles to work harder and activates more and more of them so that activity can proceed.
The Japanese believe a broken facilitation system stops ME/CFS patients from recruiting the muscles they need to overcome fatigue
Using the facilitation circuit to overcome fatigue and keep on working and moving, however, comes at a cost. This circuit relies upon the excitatory factor glutamate. That’s fine for shorter periods but constant glutamate activation produces high levels of factors that produce inflammation and oxidative stress. The Japanese believe that over time these inflammatory factors cause damage to the facilitation system. As it becomes damaged our fatigue increases, and our ability to reduce that fatigue decreases.
An inhibition circuit is also present which the authors believe is designed to turn off the facilitation system and return the brain and body to rest. It does this by producing an alarm signal (severe fatigue or other unpleasant sensations) which cause us to stop the movement and rest.
Once the damage to the facilitation system has occurred, the inhibition circuit stays on pretty much full time. The result of that, of course, is unremitting severe fatigue.
Later studies suggested that the inhibition circuit can become “classically conditioned” as well. When the brain is presented with an environment that it associates with fatigue an alarm will come on – producing, ironically, more sensations of fatigue in order to return the body to rest. (The classical conditioning of this response was demonstrated in healthy controls, by the way.)
Conclusion
The authors believe three things have happened in ME/CFS
- the facilitation circuit that allows us to surmount fatigue has been damaged.
- the inhibition circuit which prevents the facilitation circuit from operating is turned on full bore.
- classical conditioning produces another fatigue inducing factor.
The Japanese believe a similar fatiguing process may be occurring in multiple sclerosis as well.
Their view of the fatigue, then, in ME/CFS is different and similar to that found in the West. They discount the idea that aerobic energy production or muscle functioning is damaged but fully believe that inflammation and oxidative stress are causing mitochondrial problems and damaging the neurons in ME/CFS patient’s brains. They also believed they’ve identified a key network in which this happens.
Given the Japanese penchant for work, it’s perhaps not surprising that overwork and stress loom large as contributing factors in their hypothesis. They propose that continued activation of the facilitation system without rest can result in permanent damage to the system.
While the Japanese go to some pains to illustrate that the same processes occur in both acute and chronic fatigue, no attention is given to the possibility of acute, infectious onset. So far as I can tell, they have also not, interestingly enough, demonstrated reduced activation of the muscles by the motor cortex in ME/CFS – a core feature of their hypothesis.
Their introduction of classical conditioning will probably raise some hackles but it was demonstrated in healthy control and appears to be an inherent part of being human. The Japanese appear to view it as an important but secondary feature which becomes significant only after the initial damage has been done.
Ultimately, the Japanese hope to use symptomatic, historical, physical, laboratory, behavioral, physiological, molecular imaging, and neuroimaging data to identify those at risk for ME/CFS and to identify ways to prevent it from occurring in the first place.
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what do they suggest one do to recover?
Good question! I don’t know.
My little suggestion, work at healing all the different nervous systems in any way you can that will not cause extra damage. I have been thinking on these lines for awhile and am looking at alternative medicine. The first thing I have come up with is Mullein (a herb). I have bought it in tablet form and it seems to be helping calm my nervous systems. I ran out a several weeks ago and now I am all tense and tight and exhausted (though I did have a mild stroke two weeks ago)). However, before I ran out of the tablets I was starting to feel much better.
Coincidentally, I just read, yesterday, some information about Cerebral Palsy, in which tight and dysfunctional muscles are the way they are because of brain damage. My first thought, obviously, was, what if the tight and dysfunctional muscles in FM are that way because of brain damage?
It does not surprise me that the damage might be an outcome of severe chronic cognitive stress, which was certainly true in my case for years leading up to succumbing to FM. But do other people get FM and CFS without this pre-condition?
Here is another hypothesis: there seems to be numerous factors implicated in the onset of FM or CFS, which can be present in different combinations in different people. But what if the pre-condition that makes all victims vulnerable in the first place, is a “muscle control” brain dysfunction similar to that in Cerebral Palsy, only not as obvious?
I have commented before that every practitioner seems to have a favourite “cause of FM” depending on their own area of specialty. One will say it is thyroid related; another will say “leaky gut”; another will say “infections” or toxic substances; another will say “stress”, and so on. Recently I encountered one who argues that FM victims just always had bad posture and didn’t use their muscles properly – especially, for example, the abs and core muscles! But what if that was the result of the automatic control of those muscles, by the brain, being disabled from birth?
I like it Philip! I like it an awful lot….Do you have a link by chance? Thanks for sharing that.’
I didn’t put it in because I couldn’t remember exactly what study it was but some times ago a study did suggest that the primary motor cortex was not activating the muscles properly.
I really don’t know why that didn’t make a huge impression on the research community.
Hmmmm, well all the docs I have seen since birth say I have had cms since birth. They just didn’t have a name for it in the 50s.Then in ’98 Me cfs came to stay. I have often wondered about the brain conection with us.
There are ballet dancers and athletes who have developed ME-CFS. They are well-known for both good posture and proper, trained use of muscles. In the case of dancers, particularly the core muscles.
So that hypothesis does not appear valid.
Does not explain top athletes with ME/CFS and FM, like many Olympians and me, an ex powerlifter, now in her 50s.
My Kaiser doctor recommended I work out more to reverse my fatigue. She said it would boost my metabolism and energize me. So I went to the gym after work.
My CFS was at a 4 or 5, although I was unaware that I had it at the time; 3 years later I could no longer make it through my workday and was forced to leave my job. Of course I could only train every 3 days for an hour or so. I found the 3 minute rest between 20 second long sets OK. Overall, it made me feel worse instead of better, so I quit 8 months later after my 2nd Masters (50+) bench press competition (I won both). Also deadlifted 275 lbs.
I never noticed any issue with my abs and core, even when my CFS was at a 1 or 2 on the 0-10 scale a few years later. Strength was still there, but that extra 30 lbs hid the 6 pack, and being ‘lazy’, I was only doing a few sets of abs, not the 20+ sets (to hit it from all directions) of my 20s.
Some of the previous research you posted shows that CFS is from a EBV viral infection that has progressed (escaped?) from being semi-dormant in the (now fatty and scarred) liver and gone to the musxles and brain, and sometimes the spinal fluid and/or vagus nerve for the CFS version. Also that CFS, FM, MS, Lupus, and a bunch of other diseases are related to the same virus (but perhaps different mutations?), as per the April 2018 Cincinnati EBV study, so why aren’t researchers building on that?
And joint funding the research, so they get a lot of money? It seems like they do not read each other papers nor ever collaborate much.
Cort seems to read them all and needs to play ‘matchmaker’ if he wants to see true progress in his lifetime.
This is interesting stuff and fits me. The main problems I have are a low tolerance for stress and post exertional malaise. I have noticed a conditioning effect myself, but as described here, this effect is the icing on the terrible tasting cake rather than the central problem.
Yes, indeed, the icing on the cake. The way you can tell that is true is that in healthy people it’s present too – but it doesn’t show up as a problem because they don’t deal with unremitting fatigue. Only when you have this unremitting fatigue would it show up…
I have cerebellar atrophy and have had each knee replaced. #1Nov.2012 #2 Feb.2015. I have life limiting fatigue. Common in ataxia, cerebellar atrophy.
The “excitatory factor of glutamate” seems to have some similarities with Dr. Amy Yasko thoughts CFS. Has anyone had success with her program?
Katie Reid, PhD, has TED talk on how her daughter had apparent autism, hard to function, then she eliminated glutamate, MSG and other glutamate forming sources and daughter became normal. Strict diet restrictions seemed to curre her daughter, so maybe glutamate or biome related. More study is clearly needed. See for example: https://www.youtube.com/watch?v=iL4SD5f2toQ
In Japan way back in the 80s they called ME/CFS “Drunken Man’s Disease” and of course excessive fatigue produces similar symptoms to alcohol. This research sounds like an extension of the 1980’s observation. Is the brain affected? Yes. Tired and wired, sleepless nights, rapid flicking sensations or spasms in my brain which is far worse at night. That enervating exhaustion which permeates everything you do. Lets hope this leads to more understanding.
Glutamates? How does one control that?
It’s funny I was just thinking how uncoordinated I feel, how like a drunken man walking. I hope I don’t look that way (lol)
Hi Cort,
I too have had since 1979 CFS & fibromyalgia and that drunken feeling also. I have not heard this from anyone yet until you mentioning it! If I turn to quickly some days I miss a step or fall down. Other wise I look normal to people:)
Glutamate has been the topic of many ME/CFS Researchers….Chenney, Golstein, Yasako, etc.
The article discusses permanenet damage not good but I feel it needs to be tested further.
I just want them to study all the subsets for once as different people have different symptom clusters.
Money needs to be spent…
Hi Cort, I know you have had Dan Nueffer write on this blog, but this Japanese model is very close to his ANS Rewire theory, which I thought was quite interesting. I am currently taking the program but in early stages. I agree however the above doesn’t really touch on the infectious trigger aspect. Dan has a view that Viral triggers can also cause the ANS to become deregulated. If people can remember the sensations of getting a viral flu for example, that does make sense. Alongside the viral drien fatigue you can feel ‘stressed’ and hyperaroused at times, and then deeply fatigued at others, as if the system is going from one extreme to the other.
Anyway I am very happy to see the Japanese taking this seriously with proper research spend. Aside from the terrible human suffering cost, there is also a considerable economic cost which is no doubt a huge burden, and makes the stupid UK CBT model which attempts to be cost effective – a joke.
Thanks S – good luck with Dan’s program. Please let us know how it goes.
Yeah, Justin, I was going to say pretty much the same thing. Also, the Gupta Programme that’s been around for a long time (I know – I purchased it years ago and tried it but didn’t like the constant repetition of that script). I give kudos to Ashok Gupta though for, like Dan Nueffer, helping himself recover and then working hard on developing a program to help people with CFS/FMS heal. I watched Dan’s four free introductory videos (thanks to Dan’s article here), and was impressed with his heavy, in-depth research and plan of recovery. I also want to purchase his ANS Rewire program, but living on Social Security, it may be some months before I can do that. I had acute onset of CFS in ’97 due to what seemed to me to be a viral infection; I’d had an awful flu a few months before. I immediately developed the severe “flight or fight” symptoms that were horrific, and the “rest and digest” never kicked in, at least for many months, and then only minimally. With this hot, humid weather setting in now, I’m relapsing big time and it’s so frustrating. I love to garden, but I’m not doing as well this summer. Thanks for this article on Japanese research and theories. In the meantime, we keep sloggin’ along. All the best, Judith
Any luck with Roy Katz? I’m guessing he was able to provide some guidance like having your doctor contact him.
I just wanted to touch base with you.
Hopefully my email replies didn’t get shuffled to your spam folder
I strongly believe that the quite remarkable results in chronic pain regional syndrome, fibromyalgia, depression, anxiety, and very very likely me/cfs with the use of intravenous ketamine backs up the Japanese research.
Ketamine is a traditionally anesthetic drug that acts as an NMDA partial agonist and directly target the glutamate system in the brain. Seemingly taming the out of control glutmate action.
Although I guess the Japanese have not recommended the use of intravenous ketamine based on their research, few therapies have come close to its remarkable results in these conditions. Ketamine seems to reset the brain and bring it out of the state of hyperarousal.
The protocol for chronic pain and fibromyalgia is for a series of up to 6 four hour ketamine infusions spaced within a 10 day window. Since all the above conditions seem to be caused by glutamate excitotoxicity, ketamine works very well on all of them.
Based on the promising clinical results of intravenous ketamine, it appears that the “damage” the Japanese describe can be reversed. Nothing has had the dramatic results in treating chronic pain and/or depression as ketamine (and other agents that work on the glutmate system in a similar manner)
I think the brain’s demand for energy coupled by the fact that it cannot store ATP nor borrow ATP from other parts of the body make it highly susceptible to oxidative damage. Under the late researcher, Dr. Rich van Konynenburg’s model, the astrocytes in the brain cannot recycle glutamate to gaba without sufficient energy, or ATP molecules. ATP production can be disrupted by insufficient glutathione levels which seem to be low across the board in me/cfs patients.
Dr. van Konynenburg’s model suggested that the condition becomes chronic because of a negative feedback loop between low glutathione and low levels of methyl B-12.
It seems that one extra negative feedback loop is the state of chronic hyperarousal and sympathetic nervous system activation that continues to drive accelerated oxidative stress further placing a demand on glutathione and ATP. Again, if Rich van Konynenburg was right, then low energy production in the brain results in glutamate excitoxicity leading to
The Japanese could push healthy people into this state by forcing extreme mental exertion. ME/CFS patients are more susceptible because biochemically they cannot produce energy as well as healthy individuals (possibly because of polymorphisms in the genes that affect methylation).
I highly highly recommend patients look into intravenous ketamine as a treatment for fibromylagia, depression, anxiety, and very possibly ME/CFS.
Intravenous ketamine works on the most treatment resistant individuals and is very well tolerated by the most sensitive people. It is one perhaps the safest anesthetic agent and much smaller doses are administered for these conditions (as opposed to ketamine dose used in surgery).
Because ketamine is cleared out of the system quickly after administration and its therapeutic effects (when it works) endures long after the drug has cleared out of the system – there is no issue with side effects. Patients may need to return every few weeks or months for a “booster”infusion. But the effect of ketamine appears to become more enduring after more administrations of the treatment (when the proper protocol is used) as opposed to developing dependency, tolerance and so many other bad things with daily use of pyschotropic drugs.
Many people with chronic pain have either been able to greatly reduce or eliminate their use of pain killers because of the therapeutic effect of ketamine.
It is important to note that chronic benzodiazepine users do not appear to respond well to ketmamine. According to many ketamine clincs in the nation, benzo users should be tapered off their benzo drug before administration of ketamine.
In animal models, ketamine is shown to stimulate rapid production of new neural connections in the brain.
It seems that a drug that directly intervenes in the glutamate system, like ketamine, seems to be a very promising mode of addressing the issues the Japanese research suggests.
If ketamine works for a person, relief is experienced extremely rapidly – within days (and often on the same day) of the first infusion.
Look for a local ketamine clinic for the treatment of chronic pain near you. I believe the Pain Management Clinic in Austin Texas is one of the most reasonable there is in the nation – only $250 per 4 hour infusion.
since L-glutamine supposedly crosses the blood brain barrier, it was recommended to me that i should take the pure power, 3 grams at a time dissolving in mouth, 2 – 3 times a day, being sure my body has adequate Vitamin C & B6. My $ is very limited, fatigue gigantic, and unsure this is a good way to go i have only tried this a few times to no detriment. Is there literature to backup this protocol?
Thank you for your great work!
Chris,
I tried googling “Pure Power” and I am not sure if this is what you meant? What is the name of the product? I am very interested.
I know for Pain I am using Organic Turmeric one capsule after breakfast and one after dinner also with organic ashwagandha which a holistic Dr. recommended and this is the first time in over 3 decades that this really helps me 75%-85% plus stretching after I wake up still in bed about 5-10 min. Bringing up my legs toured my chest while flexing neck tours the knees. You can make up your own routine as
you like.
So I can walk when I get up.
I just did some research on Ketamine and came up with this:
http://local.soberrecovery.com/Risks_and_Side_Effects_of_Ketamine_Redding_CA-r1298750-Redding_CA.html
which is not to say it won’t work… also saw that some doctors are charging many thousands $$$, not good!
Check out Health Rising’s Fibromyalgia Ketamine Resource Center for more. Ketamine can be very helpful in the right person. It would probably be best, though, to get access to it in a academic setting – a University hospital or a clinic you can trust.
The best from Ketamine is yet to come; hopefully it will show up in easier to use, more effective drugs. Drug companies are working on them.
Thanks Stephen for that great summary. I too am jazzed at the possibilities that ketamine and the drugs it is inspiring the drugs companies to develop offer and will offer in the future.
Some people might want to check out our Fibromyalgia Ketamine Resource Center for more on Ketamine. Ketamine, by the way, was the key element in the “resurrection cocktail” Dr. Goldstein developed over 20 years ago for ME/CFS.
Thanks Cort!
Dr. Goldstein may have been ahead of his time on this!
Not to scare people off, the intravenous administration of ketamine by an anesthesiologist or nurse anesthetist in a controlled setting is very different in effect than using the street drug. Intravenous infusions contain a much smaller amount of ketamine and are dripped slowly as opposed to being ingested all at once with the street drug – which of course has danger written all over it.
Not sure if the next generation of pharmaceuticals will work as well as intravenous ketamine in terms of bioavailabilty and (so far it appears) avoidance of extreme side effects, drug dependency etc. But we’ll see. If anything, insurance will be covering it more and more. So in the not so distant future, I think it will be available to all.
Thanks for the link to your Fibromyalgia Ketamine Resource Center!
As one nurse anesthetist told me, the administration of ketamine for treating depression and chronic pain is “like microwaving a pizza” compared to the intensity and risks of anesthetizing someone for surgery.
Anesthesiologist and nurse anesthetists have been using ketamine safely in surgery since the drug was developed in the 1960’s.
I was told by a nurse anesthetist that for depression they only use 1/10th of the ketamine that is used in surgery. I imagine more is used in chronic pain and fibromyalgia.
The only new thing about ketamine is it’s therapeutic application for these conditions.
Ketamine healed my depression. I was treated for about 18 months every 3 weeks. I stopped due to the pandemic. I had hour long IV. I am still healed. I get blue, but not that deep unrelenting feeling of walking thru a mud flat.
I have FM, RA and chronic Lyme/babesia. Ketamine really didn’t help me with the fatigue nor the pain. I think you have to have longer sessions. I can’t afford them any longer. I found the mild psychotropic sessions pleasant and spiritual. I miss them.
If I sleep well, my mornings and early afternoons are pretty energetic. I walk my dog daily for about 60-90 minutes, speed varies on energy level. But around 2pm a heavy blanket of fatigue hits, I get the drunken feeling (or I think of it as a bad case of daily jet lag) I then have to rest horizontally.
I do things to help my BDNF for my brain. Food, etc. And I’m trying acupuncture / Chinese herbs for the FM.
I have also purchased a Continuous Glucose Monitor (NutriSense app) to lose weight and to just have personal feedback on what food causes my blood sugar to spike. I’ve lost 8 pounds since mid-November. More importantly, it has helped me lose carb & sugar cravings. I’m starting to feel overall calmer and comfortable in my skin. It was interesting to see metformin discussed in a recent article. I prefer the CGM over taking meds.
This is so interesting to me as in the 4 years I have been so ill, the ONLY time I felt well was for a period of about 2 days following surgery. I don’t know what anaesthetic was used, but for those two days following the surgery I was elated to feel so good. But then slowly over the following days I declined and was wracked with pain and housebound with exhaustion once again. Could this be the same situation as the Ketamine ?
Also interesting is my vitamin B12 level has since becoming ill been sky high, which I have read means one perhaps is not absorbing it. It made me think about the gene issues and methylation problems that can arise. I am homozygous for MTHFR C677T, COMT V158M, COMT H62H and VDR Bsm and although I am not versed on the ins and outs of this I do know that with this combination there is likely methylation problems. Does anyone know if Dr. Amy Yasko consults via Skype as I’d be interested in looking into this. I’m in the UK and we are limited with doctors who are knowledgable in this area to say the least.
Check out Health Rising’s Ketamine Resource page and read the blog on Dr. Ginerva Liptan – she found out about ketamine and FM when her FM patients came back from surgery saying their FM symptoms had temporarily disappeared. It’s quite a trick to feel better after surgery! When she looked into their cases she found their anesthesia had included ketamine….
Interesting video interviewing a young physician who has fibromyalgia. The video shows his doctor talking to him about his symptom response to ketamine. His pain markedly diminished as his ability to void his bladder markedly improved.
http://www.rsdfoundation.org/en/fibro.htm
Ketamine is, among other things an NMDA-sensitive receptor ANTagonist (i.e., reduces neuronal excitation via that receptor that can be activated by glutamate and aspartate). Although there are reports of ketamine producing a beneficial therapeutic effect relatively quickly, ketamine is NOT generally well tolerated – its effects can resemble those of PCP (“Angel Dust”), and other experimental drugs that have a similar mechanism (use-dependent antagonism of NMDA-sensitive receptors) generally have the same liability (see studies of “MK-801” aka “Dizocilpine”). My point is: Caution – ketamine can produce unpleasant effects, and is unlikely to prove to be a panacea
Intravenous ketamine appears to be extremely well tolerated even by the most sensitive people. However, any other administration of ketamine, intramuscular injections or oral injestion seems to be associated with high incidence of nausea and vomiting and “bad psychedelic trips.” Ketamine is an anesthetic drug and should only be administered intravenously (slow drip) by an expert, i.e. an anesthesiologist.
Some irresponsible doctors trying to get on the ketamine bandwagon will try to suggest that intramuscular shots of the drug is okay. But this does not appear to be the case at all.
I can personally attest that I can not tolerate any drugs that affect the central nervous system, but I tolerated intravenous ketamine very well. One hour after receiving a one hour infusion, I was able to go out to lunch at a restaurant. The psychedelic effects of the drug dissipate within 30 minutes or less after receiving a one hour infusion.
The effects of ketamine appear to be more than just a bandaid or masking of symptoms as the drug only has a 2.5 hour half life – the drug is rapidly cleared out of the system. If it works, what remains appears to be a real therapeutic effect.
Much more needs to be investigated about why it works so well in these conditions like chronic pain and fatigue. It’s not a panacea. But it does highlight the etiological nature of the conditions that it helps.
And I forgot to mention that the Pain Management Clinic in Austin said that the Medicare and some other insurers will cover ketamine for chronic pain.
Because of the Clinic in Austin has scaled up their operations, they are able to be cost efficient, only charging $250 per 4 hour infusion if insurance doesn’t cover it.
My Aunt will be getting a few infusions this month with the Clinic in Austin for fibromyalgia. If her experience is good, then I’ll be able to recommend it to others who can make their way to Austin, Texas.
Thanks Stephen. Looking forward to the report.
Stephen: I would very much like to hear how it goes with your Aunt. If this is really as great as everyone is saying it is, again why is it so difficult getting access to it? Grrr, so frustrating. I can see how this would be so controversial, but I’m tired of not having access to tried and proven ways of feeling better!
Martinigal:
I responded below regarding the benzodiazepines.
I think truly think the real controversy should be that doctors allow patients to take benzos for long periods of time. Ketamine has been used safely as an anesthetic drug since the 1960’s. Intermittent IV infusions so far have not caused problems with drug dependency or tolerance. Ketamine is cleared quickly out of the system after infusion and any potential chance of nausea can be prevented by the proper measures at the start of treatment.
Your first step will probably be beginning a long taper off of Klonopin before beginning treatment with ketamine.
The Ketamine Advocacy Site (geared toward ketamine for treatment resistant depression) has an article about “Getting the Most Out of Treatment” – it states that taking a daily high dose of a benzo drug (2 mg of Klonopin is high dose), your doctor may recommend reducing the dose before starting ketamine treatment:
http://www.ketamineadvocacynetwork.org/getting-the-most-out-of-treatment/
Dr. Abreau of the Portland Ketamine Clinic has posted a comment on this page of the Ketamine Advocacy website regarding chronic benzo usage and ketamine:
http://www.ketamineadvocacynetwork.org/forums/topic/benzodiazepines-make-ketamine-useless/
You’ll need to scroll down to see Dr. Enrique Abreau’s comment
Other ketamine clinics such as the Boston Mind Care recommend weaning off benzos before beginning ketamine treatment:
http://www.bostonmindcare.com/faq
To me the controversy is chronic benzo usage. Benzos are particularly nasty drugs to withdraw from so stay tuned for my blog on Cort’s sight about benzos and information pointing to the resources you may need to withdrawal off (if you choose to do so).
And if I forget to update you regarding my Aunt’s response to ketamine, make a note to yourself and follow up with me within a month or so.
I like their theory. My CFS was triggered by unrelenting work and stress (an earlier EBV infection probably contributed).
Seems to be very common triggers for most of us
It’s interesting to hear people refer to Dan Nueffer’s theory. I believe Dan had mentioned there is quite a similarity between symptoms of me/cfs and benzodiazpine withdrawal syndrome. Benzodiazepine withdrawal seems to lead to glutamate overstimulation.
Perhaps benzo withdrawal is yet another route to reaching the chronic fatigue state the Japanese researchers describe. I can say my personal experience with benzodiazpine withdrawal backs this up.
Klonopin and other benzos appear to be a dead end drug at best and a nightmare for many chronic users because it causes downregulation of the gaba receptors (necessary for calming the mind and body) and increases calcium channel activity once dependency and tolerance develops. This varies greatly from person to person, but tolerance to the drug seems to be the rule not the exception. Obviously some people will fare better than others with chronic use of benzos. But no one will know how well or how terribly bad they’ll fare when first taking a benzo. Short term use is no problem for vast majority of people. Long term use seems to be bad across the board.
According to Dr. Raymond Armstrong, (who has helped hundreds of people get off benzos for many years) Klonopin users may not understand that the drug has about a 12 hour effective half life for most people (shorter than the 18 hour half life attributed to the drug in most literature).
I know a lot of me/cfs patients take Klonopin regularly, and may not understand that they are experiencing interdose withdrawal symptoms.
Given the 12 hour half life of the drug, concentrations of the drug drop by 50% every 12 hours. Very few chronic benzo users can tolerate more than a 50% drop which leaves your brain in a state of hyperarousal. In my experience, when I am in a withdrawal state (not necessarily cold turkey withdrawal) my tolerance to exercise and stress go way down. If I stay regulated on the drug as I taper down, I am much more functional.
I can say my chronic fatigue got dramatically worse with Klonopin due to tolerance/withdrawal effects and excess sedation of the drug. Not to mention worsening anxiety and depression.
A psychiatrist who had been with the VA for 20 years told me we now know that long term use of benzos increase depression and anxiety and worsen sleep. I believe Dr. Nancy Klimas said that benzos worsen sleep.
Twice a day dosing is necessary in most instances to avoid interdose withdrawal.
The best way to taper off benzos is using a liquid oil based (like almond oil – benzos are not water soluble) compound and reduce by 2.5% a week for a 40 week long taper.
I was fortunate enough to find Dr. Raymond Armstrong who assists people in tapering off benzos. I met with Dr. Armstrong in San Antonio where he practices emergency care medicine. He has worked with me over the phone for weeks now.
He has seen people without ME/CFS go from non-functioning to back to life once they are regulated on the correct dose amount and schedule. He suffered from benzo withdrawal himself in the 1970’s after getting off Valium abruptly. He thought he was doomed for life.
A lot of people may not realize that the worsening of their condition is actually attributable to their drug. It’s very difficult to know what is going on. Your body may be demanding more of the drug without you being aware of it.
Dr. Armstrong himself just thought he was “developing all sorts of new psychiatric disorders” when he was actually experiencing benzo withdrawal syndrome.
I was placed on Klonopin originally for anxiety resulting from difficulty sleeping. My physician at the time said not to worry about drug dependency issues and prescribed a year’s worth of the drug.
Currently the legislature in Massachusetts has proposed a bill that would (1) require physicians to get a patient’s consent in writing warning of the risks of chronic benzo use, and (2) requiring the Department of Health in Massachusetts to promulgate a standardized protocol to safely withdrawal those patients who want to get off benzos (i.e. not forcing the patient to undergo a cold turkey withdrawal)
Here is the proposed legislation:
https://malegislature.gov/Bills/189/House/H4062
Here is an article about the politics and legislative process concerning the bill:
http://www.madinamerica.com/2016/04/massachusetts-benzodiazepine-bill-hearing/
I am reaching out to all lawmakers in the State of Texas to push for similar legislation.
Your drug may be greatly exacerbating your problems without even knowing it.
Stephen:
I’m not able to get exactly what you are saying about the relationship between
chronic benzo use and Fibromyalgia. I have been taking 2 mg of klonopin for years
now and, although I’m supposed to be taking 2 mg am and 1 mg pm, I’ve been skipping
the PM dose for years. So I do go for 24 hours on my dose of Klonopin. Are you saying
that I’m in a constant state of withdraw which could be mimicing the symptoms of
Fibromyalgia and that I may not have it at all? That if I could get off of the Klonopin
my Fibromyalgia may go away?
Thanks for your thoughts.
Martinigal:
For every psychotropic drug, including benzos like Klonopin, there are 1,000 different responses a person could have to the drug.
With benzos, one of the biggest issues is drug dependency. So far, there is no smoking gun predictor for whether a person will have a mildly difficult time getting off these drugs or whether they will have an extremely difficult time getting off. Although, people who take the drug and initially have no response to it whatsoever seem to be in safe territory – it doesn’t affect them one way or another.
The information regarding the half life characteristics of the drug (how long before your body clears out half of the concentration of the drug), as well as, one’s ability to tolerate a substantial drop in the concentration of the benzo in their system varies from person to person.
But according to Dr. Raymond Armstrong who has assisted hundreds of people in getting off benzos (and other psychotropic drugs, for most people the half like of Klonopin is 12 hours. And in his experience most people cannot tolerate more than a 50% reduction of the drug in their system over a day’s time.
Of course Fibromyalgia exists independent of benzos such as Klonopin.
To answer your question if you are in a constant state of withdrawal:
That all depends on (1) where your threshold tolerance level is for the drug (i.e. what’s the lowest concentration of the drug in your system before you experience withdrawal symptoms), and (2) how quickly you clear out the drug from your body.
Assuming you clear out half of the drug in your system in a period of 12 hours, than means your concentration of Klonopin will be reduced by a factor of 75% in a 24 hour period. For example, the 2 mg of Klonopin taken in the AM would be reduced in your system 12 hours later to 1 mg, and then another 12 hours later the drug would drop another 50% down to 0.5mg (of course that is assuming the drug is operating on a 12 hour half life in your system).
If your tolerance threshold for Klonopin is above 0.5mg, then you will not be experiencing any interdose withdrawal symptoms. Of course 2mg of Klonopin is a high dose – roughly equivalent to 40 mg of Valium.
The big question is do the benefits of the drug for you outweigh the detriments. Benzos are potent central nervous system depressants. Long term use is often associated with increasing depression, anxiety, and worsening sleep (benzos extend the time you spend in light sleep but decrease the amount of deep sleep you get), and excessive daytime sedation.
Prolonged use of benzodiazepines significantly changes the brain’s structure and functioning. Initially GABA (the brain’s calming substance) is enhanced by benzos, and the brain’s output of excitatory neurotransmitters, including norepinephrine, serotonin, acetyl choline and dopamine is reduced. These neurotransmitters are necessary for alerntess, muscle tone, coordination, memory, emotional responses, endocrine gland hormones, heart rate, blood pressure control and other functions.
Besides the brain, additional receptors for benzos are located in the colon, kidney, blood cells and adrenal cortex. As a result, many body systems can be impaired by benzos.
Chronic use of benzos down-regulate and modify GABA receptors, which in turns causes dependence. With continued use, the calming effect of GABA is diminished while the excitatory neurotransmitter Glutamate is increased.
Calcium-Channels are located in the central nervous system, muscles, nerve cells, in the myelin that shield the nerve endings, while protecting the nerve cells of the brain. Calcium-channel activity is increased by prolonged use of benzos, and the up-regulation is linked to an increase in neuropathy pain.
So benzos (and especially withdrawal from benzos) are linked with an increase in pain symptoms.
Withdrawal of the drug can result in the GABA receptors becoming hypoactive, producing symptoms far worse than what the patient originally sought treatment for. If benzos are suddenly stopped or reduced too rapidly, the calcium floods into the cell. This can cause intense withdrawal symptoms and be life threatening due to risk of seizures.
Anyone seeking to withdrawal off of benzos should do a very slow titration of the drug (I probably will be posting a blog about this on this website soon).
In my estimation, because of all the above, long term use of benzos is never appropriate. At best, benzos are a dead end drug. They are a band aid that should only be used for a few days tops because you never know your risk for dependency.
I think properly withdrawing off a benzodiazpine may be a necessary step in recovering from fibromyalgia.
I have posted about the very promising potential of ketamine for the treatment of chronic pain conditions like fibromyalgia.
It is very important to note that numerous providers of ketamine have noted that ketamine does not seem to be effective in the vast majority of chronic benzo (like Klonopin) users. They are not yet sure why this is the case, but the most reputable ketamine clinics in the nation strongly recommend withdrawing off a benzodiazepine before starting treatment with ketamine to ensure that the ketamine will work.
Withdrawing off a benzo is easier said than done. But my blog will shed some light on how to go about this.
Doctors are far too quick to prescribe long term use of benzodiazepines. I think the next epidemic to hit the country after
Also very very important since you are dealing with pain. While taking Klonopin you absolutely need to avoid taking opiates as the combination of these drugs is exceptionally dangerous.
http://www.desmoinesaddictiontreatment.com/rehab-guide/dangers-of-using-benzodiazepines-with-opiates/
Correction, I should have stated in my above example, “If your tolerance threshold is below (not above) 0.5 mg of Klonopin, then you will not be experiencing any withdrawal.
But again if you have been taking 2 mg of Klonopin per day for a very long time, your withdrawal threshold is likely above 0.5 mg.
I don’t want you to confuse acute “cold turkey” withdrawal with much milder interdose withdrawal. The symptoms would be much milder than from a complete discontinuance of the drug.
Likely you experience the drug’s most powerful effects within the first few hours of taking it. Over the remainder of the day, the drug’s effects are likely to diminish.
You should take note whether or not you are experiencing more symptoms during the hours leading up to your next dose.
If you are interested in tapering off Klonopin, I would contact compounding pharmacist Roy Katz.
He is an authority on benzo withdrawal.
He can work with your doctor or recommend one.
http://www.customrx.com/
Oh, God! Wow, Stephen, that’s a LOT of information to take in. I’m going to print out your comment(s) and carefully re-read them. I’ve been on Klonopin 1.0 mg, with 200 mg. gabapentin (restless legs, works really well) at night since probably 1999 or thereabouts. Cheney encouraged use of Klonopin back then and said it was “neuro-protective,” as did a neurologist I went to for a brief time in Houston, TX. My neurologist here in NY recently told me to get off Klonopin because benzos have been implicated in dementia/Alzheimers, but she could only tell me “decrease it slowly.” It’s worked so well for me to help me sleep and nothing else had. Based on what you’ve said here (and thank you for sharing this, BTW!!), and my neurologist’s comments, I will try and lessen my dose over time. I don’t know how to measure “2.5%/wk” diluted in oil! How do you figure that out? If I crush my tablets, it seems difficult to get an accurate measurement like that. I do not suffer any significant sedation on Klonopin. However, it may be responsible, based on your comments, for my daytime worsening of ANS and other symptoms. I’d never even considered, or knew, that. Ugh! Another challenge coming up! Thanks again, Stephen. (I guess…LOL). 😛 Judith
Judith, you should not do this on your own.
My first advice is contact compounding pharmacist Roy Katz with Custom Rx Compounding Pharmacy
http://www.customrx.com/
He will know what to do. Have Roy contact your physician, and let Roy direct the taper. He is an authority on benzo withdrawal. He even may recommend a physician for you.
Benzos are deceptive in that they will increase overall sleep duration but will often lower or eliminate the time spent in deep sleep.
That is why fatigue expert, Dr Nancy Klimas has said that “Valium like drugs” (this includes Klonopin ) can worsen sleep.
http://www.prohealth.com/library/showArticle.cfm?libid=13462&site=articles
Also, intravenous ketamine seems to be perhaps the most exciting treatment for depression, chronic pain including fibromyalgia, and perhaps fatigue because it calms down the nervous system. If administered properly, intravenous ketamine can have a therapeutic effect for weeks or months (long after the few hours the ketamine is actually in your system).
Unfortunately a number of ketamine clinics have found that chronic use of benzos like Klonopin can negate the therapeutic effect of ketamine.
That reason alone may be a good one for tapering off or substantially reducing your dose of Klonopin.
Call Roy and take it from there. Don’t do it alone.
Chronic benzo use in a lot of people is associated with increased anxiety and depression, worsening sleep.
As people get older the risks associated with benzos increases – increased risk of falls and delirium in the elderly.
And as you mentioned, there is a potential link to dementia.
I wish doctors wouldn’t make speculations about long term use of potent drugs like benzos, that they are “neuroprotective”
The evidence seems to point in the opposite direction. They are essentially nervous system depressants. Gabapentin is also a nervous system depressant but doesn’t seem to pose the same level of risk as benzos (of course depending on your dose of Gabapentin)
Of course, no one should be forced off a drug that they think is helping them. But often this is really difficult to know given the unknowns of long term side effects.
If this investigative reporter’s personal account is true then it highlights how destructive long term use of Ambien was for her and how getting off Ambien and getting treated with ketamine saved her life.
https://vanwinkles.com/ketamine-treatment-chronic-insomnia-trauma-therapy-celia-farber
This hits a chord for me. In the 4 years I have been ill the ‘only’ time I have actually felt well was for 2 days following surgery. I was out for 5 hours during surgery and don’t know what anaesthesia was used, but now I’m wondering was it Ketamine ? I remember the joy of feeling ‘normal’ for those brief two days following the operation and this was with the pain of the incision and surgery, I couldn’t care less about the pain of that, the sheer happiness of being relieved of the ME/CFS symptoms was wonderful. Beyond depressing when after 2 days the symptoms all worked their way back. I wonder if this is available here in the UK? I doubt it.
Karin, it’s probably no coincidence that you felt normal for a couple days after surgery.
Dr. Liptan, a fibromyalgia patient herself, noticed that many of her patients noticed substantial pain reduction for weeks after having surgery. After following up, the only common denominator for these patients was that they all received ketamine as part of their anesthesia.
I suspect that the same benefits occur in ME/CFS. Ketamine is also a powerful antidepressant even in the most treatment resistant people.
When considering ketamine treatment, only choose intravenous ketamine administered by an anesthesiologist or nurse anesthetist under a physician.
Some doctors may want to give intramuscular ketamine injections. Don’t do that. It doesn’t appear safe or well tolerated – nausea, vomiting, and bad psychedelic trips are common with this irresponsible administration of ketamine.
So intravenous is the way to go.
Also important, if you are taking a benzo drug, you may need to taper off it before starting the ketamine to give the ketamine the best chance of working.
And finally, ketamine clinics have found that multiple infusions of ketamine (2.5 to 4 hours each) up to 6 infusions performed within a 10 day period is crucial for a more prolonged therapeutic outcome.
I hope you can find assistance in the UK. If not, you may need to travel to the states. With a doctor’s referral, you can get treated at the Pain Associates clinic in Austin, Texas. They charge $250 per infusion which is a bargain.
My aunt may be going there for treatment soon, so I’ll know a bit more after that.
Thanks for that info Stephen and please be sure to come back to this thread and update us on how your Aunt does with it. Fingers crossed for her.
200 mg of Gabapentin according to the most conservative doctors is a baby dose and should be fine.
1 mg of Klonopin however is quite potent for most people. That is concerning especially for seniors.
Tell Roy Katz that I referred you. I don’t get anything out of it. But I like the guy. From a compounding pharmacy perspective he can do anything!
Judith, I’m in Houston. Feel free to email me
stephen.lacorte@gmail.com
Very interesting article. Even though I’ve been diagnosed with fibromyalgia, central sensitivity, hypermobility syndrome and more my thoughts keep going back to ME/CFS. I find myself wondering if I have all of these or if they’re just simular. The brainfog has gotten so bad that I’m too tired to analyze it anymore. But the pain is higher. Why can’t doctors just take care of us?
I think there are plenty of overlaps between these diseases and some people have all of them.
I love the fact that they feel they have come up with a test to show postexertional fatigue, particularly for mental tasks. My kids, now adults, have suffered with this for years and I think very few people beyond the patients themselves, attentive caregivers, and a few experts in the field really get this and how very real and debilitating such fatiguing is! I would so love to see a test that could be easily done that would prove it and become part of a standard workup for CFS!!
This is a theory I could subscribe to given my cfs history. I developed cfs after repeated bout with over-training syndrome caused by a competitive sport training. That would be the classical conditioning version of cfs. As for the sudden onset, that could be explained as the damage on the frontal/singulate cortices from inflammation and oxidative stress caused by viral infection, just as the Japanese researchers noted.
Stephen I’m catching up on posts and am wondering how your aunt is doing after the ketamine. I have family in Austin although the fibro aspect for me pales in comparison to fatigue so it wouldn’t be a priority rx until more evidence for fatigue relief appears. Also, how is glutamate that may be a cause for worsening fatigue related to glutamine that is good for leaky gut, do you know?
I think fibromyalgia and chronic fatigue are so closely related that it may be worth a try especially if you are dealing with depression too.
Ketamine has been effective in treating not only pain, but also depression, bi-polar depression, anxiety and PTSD.
If your nervous system feels riled up, that can always cause fatigue. If you’re dealing with that, there’s a good chance ketamine could help.
It might be worth a closer look even if your fatigue overshadows pain for you.
My aunt just saw a nurse practitioner who specializes in psychiatry. He thought ketamine would be a good idea for her to try for both pain and depression. So she got a second opinion in favor of it.
I’m not sure if she’s made the appointment yet. But when she texted me a couple days ago, she said she’s planning on doing it.
Glutamate to glutamine recycling in the brain seems to be really important.
Some disagree whether supplementing with glutamine is good or not as it can convert to excess glutamate. But others say glutamine is good for gut health and making glutathione. I guess the jury is still out on that one.
Thanks Stephen – I take glutamine but think I’ll stop for now. I don’t have depression, anxiety etc and my nervous system doesn’t seem revved up at all – it feels asleep!
I thought the idea that your environment can influence fatigue interesting – maybe I should go camping. 🙂
Very much so.
Major sensitivities to mold might be a good place to start looking.
Allergies can make you listless no matter how much sleep you get.
An allergist told me that you can sleep 12 hours a day, but with allergies you can still be tired.
Cort, if you’re seeing this, do you notice if you’re more tired when you stay in one place, or are you never in one place long enough to know? 🙂
I don’t have allergies Stephen, at least not the sinus sniffling kind, but would like to get tested for food sensitivities. One doctor told me just to go on an elimination diet but since I’m quite sure if it’s a problem it’s only a small part, it would be impossible to know what was what. In the recent fibro summit some doctors said the ALCAT test was very good and that IgG levels aren’t, but in researching ALCAT I see it has a lot of controversy surrounding it. It’s hard to know who/what to believe.
Check out Vitamin B12 deficiency. Many crossover symptoms with CFS/FM. Many who are on daily or every two day’s injections have found their CFS/FM improving or even reversing.
High levels in the blood does not necessarily mean high levels in the cells. Few doctors ever test ‘active’ (plasma) B12 levels, only serum or for Pernicious Anaemia. Whilst B12 deficiency is always present in PA, PA is not always present in B12 deficiency.
Also, whilst ‘160’ is viewed an ‘acceptable’ level it is at the very lowest end of the range & is most certainly not Optimum – which would be 700+. B12 deficiency is very much dismissed by the Medical Profession as being of no importance, yet many of our modern diseases, like CFS, FM, MS, Parkinson’s, Ataxia & gait/balance issues, & even dementias, etc, and anything that requires nerve involvement, can potentially be linked to an underlying B12 assimilation issue. Vegans & vegetarians will always be deficient if they are not supplementing in some way (although most oral B12 is very poorly assimilated).
Interesting. I have noticed studies on autonomic problems coming from Japan, South Korea and China. (I have an autonomic disorder, so that’s what I tend to read.) And these are only the studies that have been translated and published in English. There must be more research that doesn’t get translated.