a different post with a different topic, although it is related to my last post somehow. And very lengthy. (Sorry for that.) The more I read about the chemical plant called "brain" in regard to dopamine synthesis, the more I think we're on to something here. If you don't know what I mean, search for "The beer experiments" and "artificial sweeteners" here at the WED board. Both threads are rather old, I think from 2006 and 2004, but IMO "must reads". Even if they are incorrect, they open a way of thinking about influencing the disease that I never considered before. When reading them, and more stuff about the GABA/glutamate balance, I experienced something like the "magic eye" effect where you suddenly see the picture and can't understand why you missed it before, because it appears to be completely obvious. Some facts that I knew for a long time, combined with a few facts that I read about just recently, suddenly fell into place and fit together. It is a wild theory, granted. But I hope it's interesting nevertheless
Some parts of this post were clearly inspired from these two threads. I hope to add something by putting it all together somewhat differently. I'm going to start with a layout of what I've learned about WED during the last year, then I will follow up with some wild thoughts which you may or may not find interesting. Some of the thoughts may be considered controversial - fire away if you don't like them. And do excuse my english, it's not my first language.
I must add that I have absolutely no background in pharmacology or chemistry, so feel free to bash me wherever I'm wrong. I do have some experience in WED, unfortunately, even though it was diagnosed just 4 years ago - since then I went quickly through increasing doses of dopamine agonists (and massive augmentation, taking up to 2mg/d ropinirole and later 1mg/d sifrol), gabapentin/lyrica, opioids and benzodiazepines. While my WED symptoms where pretty severe without medication when I started ropinirole, now my sleep is just as bad with a combination of an opioid and a benzodiazepine. Which explains why I have plenty of time and even more motivation to think about this disease, given that virtually all my nights include some, or rather many, sleepless hours. Yes, yes, I will stop my lamentations right here and come to the point.
Treating WED symptoms
=====================
Let's start with a review what works for some WED patients.
1. L-Dopa and Dopamine agonists, activating dopamine receptors and working somewhat like real dopamine. Works for almost everybody, at least for some time.
2. Gabapentin, Pregabalin and the like, designed to work like GABA, but apparently working somewhat differently.
3. Benzodiazepines: Enhancing the GABA neurotransmitter via modulation of the GABA receptor.
4. Opioids: Enhancing the natural dopamine production of the brain.
5. Iron infusions: Supply one of the ingredients for dopamine production. Suspected to work for patients whose ferritin levels are "too low" for the natural dopamine production, whatever that means. (One of the topics I'm going to investigate next.)
Also there seems to be a correlation with conditions that usually decrease the amount of dopamine receptors: Nicotine/drug consumption, obesity/food addictions (chocolate, or binge eating in general). Note that this is a natural reaction to increased dopamine levels: Oversupply of dopamine will decrease the number of receptors in the long term. Also augmentation in WED symptoms is linked to a reduced number of dopamine receptors, caused by an oversupply of dopamine [agonists]. (More on that later.)
Another issue is the balance between GABA and glutamate levels. Glutamate stimulates, GABA calms, and a lot of WED patients have high glutamate levels. If the latter is linked to WED symptoms, this would explain why drugs like Gabapentin and Pregabalin work for WED patients, but not always and only to a limited degree.
Did I get it right so far? Then let's start with the things I'm less sure about.
We have two primary ways to deal with WED: Increasing the amount of dopamine or dopamine agonists (DAs), or enhancing the GABA neurotransmitter. So what exactly is the connection between those two? I've read that GABA inhibits dopamine release. Do these substances work in competition, meaning that increasing either quantity will help WED symptoms? That would explain why a combination of dopaminergic therapy (DAs or opioids) and GABA-transmitter active drugs (Benzodiazepines or Gabapentin/Pregabalin) often works better than a single substance.
Augmentation and impulse control disorders
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Augmentation is _the_ biggest problem in WED treatment.
(Attention. The speculations start here. Even though I think there is some solid evidence that supports them.)
What exactly happens if the symptoms get worse and worse? I think that the most plausible explanation is the oversupply/receptor reduction cycle: Some substances work in the short term by increasing the dopamine levels, but worsen the symptoms in the long term by reducing the number of receptors. Alcohol abuse, obesity and smoking are correlated to WED, causing many people to conclude that these things increase the risk of WED. However, I think they've got it wrong: There is a dopamine deficiency first, causing many patients to seek remedies that increase dopamine (including nicotine, alcohol and chocolate). This works for some time, but at some point the WED symptoms resurface (already a sign of augmentation?), and they have to take up WED medication, usually DAs - again inviting further augmentation. Symptoms vary, and people will mix freely available remedies and prescription drugs (again, usually dopamine agonists). Some unfortunate people realize that activities that increase the dopamine levels "naturally" (e.g. stuff not requiring a prescription) include excessive gambling, sex/***** addiction, punding and binge eating. Sounds familiar? This is called a impulse control disorder (ICD) and very familiar among people taking dopamine agonists. The theory is that the dopamine agonists invite ICDs. But perhaps this is just an advanced state of dopamine dysregulation? Maybe these people simply look for some way to increase dopamine levels? This would explain why ICDs occur at varying dosages of dopamine agonists. In any case, the net result is augmentation, again.
Taking a step back from WED, we observe that this is the usual cycle for an addiction: We ingest something that produces dopamine, the reward system learns that we feel good if we do that, we repeat the process, after some iterations the number of receptors dwindles and we suddenly experience cravings whenever the substance is not present. More potent substances and higher volatility (shorter half-life of the substances) lead to faster addiction. But we WED patients have an imbalance first, without ingesting any (legal or illegal) substance! So we look for remedies, and tadaam! we take up smoking, drinking, gambling or drugs. If it relieves the symptoms, we start a long-term "treatment" of our symptoms. The result is the same: Augmentation and/or addiction. (Me, I did start with increasing quantities of alcohol whenever I couldn't sleep. After some time I needed a regular dose of alcohol every evening. I was never an alcoholic though - when the WED was diagnosed and I started on ropinirole, I quit the drinking immediately, and without problems. The drinking habit resurfaced when augmentation occurred and I once again couldn't sleep. However, when I became aware of the possible connection I stopped my wine consumption, and currently I drink alcohol only on rare occasions. Of course the sample size of 1 may not be enough to convince you.) The difference between augmentation and addiction seems to be the volatility of the dopamine level, i.e. duration of the oversupply: Classic drugs will give a very short dopamine kick, causing cravings and addiction very fast. DAs with a reasonably long half-life will decrease the dopamine receptors just the same, but without the high volatility in dopamine levels and therefore (usually) without addiction. They do cause withdrawal symptoms if discontinued though.
I was convinced that WED should not be treated with dopamine agonists (or only very carefully with small doses) for some time, but this was because of the high risk of impulse control disorders. But if my reasoning is true, augmentation may just be a likely complication that is just as severe. Why the hell did we start to treat all those WED patients with dopamine agonists?
Can augmentation be reversed? I am told that a decrease of the number of dopamine receptors may be reversed if taper the additional dopamine. This is very hard to achieve for WED patients, because the more severe cases will not sleep if we stop the dopamine-enhancing drugs. I'm on thin ice here, but it seems that opioids or gaba-enhancing drugs have less potential for augmentation because they stimulate the dopamine production of the body, instead of simply supplying a dopamine-like substance. So switching from to DAs to opioids or GABA-enhancing drugs may at least reduce the risk of augmentation. Maybe a natural restoration of receptors can be achieved - I think I've read that this usually happens to (non-WED) smokers and dopamine-related drug addicts once they stop smoking/taking the drugs. This would have a beneficiary effect on the WED, but not cure it completely - my theory is still that there was a dopamine deficiency that started the cycle.
Let's dwell on this thought a bit more, because I think this is an important point. If we can find and fix the reason for the initial dopamine deficiency, we have a chance to stop augmentation and maybe even gradually taper the medication, reversing the effects of augmentation. If we can't find the reason, then we can't taper - because the initial deficiency is still there and contributes to the augmentation cycle. (Technically we _can_ taper, but the sleep deprivation would be pretty much unbearable for the duration of time required to restore the number of dopamine receptors sufficiently to be noticeable.) Could this be the difference between idiopathic and secondary cases? We label cases as "secondary" if we find a reason for a dopamine deficiency, and if we can eliminate the deficiency (e.g. treat low ferritin levels by iron injections) then WED symptoms subside. We may still need medication because of augmentation (lower number of receptors). We label cases as "idiopathic" if we can't find the reason for the dopamine deficiency. Since we can't find the reason, we treat the WED with DAs, hence augmentation starts. The symptoms get worse, more medication, more augmentation. The more severe the initial deficiency, the faster the augmentation cycle.
To put it in other words: There are "healthy" and "unhealthy" ways to increase dopamine levels. I assume that healthy people have a natural balance between the substances used to fabricate dopamine. WED patients have some imbalance here - if balance can be enhanced by eliminating the cause (e.g. iron infusions if there was a ferritin deficiency), I call this "healthy" and there is hope that the balance can be restored and maintained for a long time. If an increase of dopamine levels is achieved by different means (dopamine agonists, or the food and drugs we talked about), this will result in a fluctuation of the dopamine levels, starting the augmentation cycle. This is the "unhealthy" option, because it does reduce the symptoms, but aggravates the disease.
Proper WED treatment
====================
The summary so far: Augmentation is a likely result of improper WED treatment. But I assumed that there is a reason for an initial dopamine deficiency in the first place before augmentation takes place. Some people find and fix the reason (permanently or temporarily, through dietary measures or medical intervention like iron infusions), and WED is history. But the more probable outcome is that these people "treat themselves" with unhealthy dopamine-increasing measures (drinking alcohol, smoking and such) or start taking medication, both resulting in augmentation. We can break the augmentation cycle (and maybe even reverse it gradually) if we find the reason for the initial deficiency.
So what are candidates for this initial deficiency? We may have temporary or permanent causes. Temporary causes (triggers) may be certain food ingredients or medication that influence the dopamine balance. Augmentation kicks in, we start WED medication, and when we stop the triggering substance we have to continue the medication because of the augmentation. In theory, if the medication is taken in a way to maintain a constant dopamine level then there shouldn't be any more augmentation. As for permanent causes, dopamine synthesis is a very complex procedure with a lot of ingredients. If there is a deficiency in just one of the ingredients, we may experience WED symptoms.
This explains the fact that there is an extremely wide range of substances that will relieve or worsen WED symptoms. To elaborate: A lot of experimental results seem to be paradoxical, stuff that helps some patients will aggravate the symptoms for other patients. Take chocolate. A lot of people claim that WED symptoms really take off if they eat chocolate. I can't confirm this, in fact I think eating large amounts of chocolate has helped me find sleep after I woke up because of my legs doing a "dancing with the stars" impression. Another classic example is aspartame, I've read thoughts that this may be due to a fragile balance between phenylalanine and tyrosine. I have no clue if this is correct, but some people report that aspartame worsens their WED symptoms. Other people claim that diet coke (which contains caffeine and aspartame) relieves their WED symptoms. Some people observe no effect.
I have two explanations:
(a) Long term use and augmentation vs. short term use. (You saw that coming, right?) A lot of people don't specify if something helps in the long term or if they just started. Remember, short-term dopamine increase equals augmentation equals long-term aggravation. (I always felt that smoking relieved my WED symptoms somewhat. However, public opinion is that nicotine worsens WED symptoms. It is quite possible that smoking contributed to my augmentation, although I experienced augmentation before I took resumed smoking after a 10-year break.)
(b) Chemical balance. (Now it gets interesting.) The factory in our brain depends on a balance of ingredients for a lot of different processes. Say we have a balance between two proteins/amino acids/vitamins A and B, both required for natural dopamine production. Assume that a severe imbalance (too much or not enough of either substance) hampers the dopamine production. (There may be more than two substances involved, but this doesn't matter for this line of reasoning.) Say food F contains large amounts of a substance C that is processed into A. For people who have a deficiency of A, eating the right amount of F will restore the balance and help them. For people with a deficiency of B, eating F will increase the imbalance between the substances, which may or may not worsen the symptoms. For people with a good balance of A and B, digesting F has the potential to create an imbalance and introduce new or increased symptoms. Unfortunately the body sometimes adapts to higher levels of substances, so over time F may lose efficiency because the rate of of conversion from C into A is slowed over time. (Again, medication losing efficiency. But this time not from augmentation.)
Now, what's the lesson here? I'm no specialist, but it seems like a good idea to me to experiment if there are substances that affect my symptoms, for good or worse, and if the effect is temporary (symptoms return to normal even though I still use this substance) or permanent. A permanent effect indicates I may have found the cause (or one of many causes) for a deficiency. A temporary effect may mean that I have found a "unhealthy" way to produce dopamine - well, I'm not advocating the usual suspects like drugs, more stuff like sweeteners, vitamins, certain amino acids, iron, zinc and the like, where permanent changes are rare once taking the supplement is discontinued. These are things were one would either expect no reaction (if we missed the cause for the deficiency) or an improvement (if we hit). Also, I wonder if doctors have a way to check the chemical balance of the brain and detect candidates for imbalances. The aim is of course to find something that can be taken long-term without side effects, fixes the imbalance and allows us to stop the augmentation first and perhaps gives us a chance to taper medication. (Again, like measuring ferritin and administering iron if the levels are low).
Mind you, a few weeks ago I've read about a guy who claims to control his WED by avoiding a ridiculous amount of foods and beverages. I thought this was total bull, and that he probably never was a severe case. Now I'm not so sure this is true...
Checking the pieces of the puzzle
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I said a lot of things fall in place if I'm right.
* The theory explains augmentation,
* the varying efficiency of WED medication among patients,
* the loss of medication efficiency after some time, and
* why WED is correlated with obesity, smoking and the like.
* It gives a reason why the symptoms usually get worse over time, but there are caseswhere the symptoms retreat to some degree.
* It accounts for the difference between idiopathic and secondary WED, and why iron infusions work well for some patients, but has no effect on other patients.
* It explains why WED runs in families, because vitamin or protein deficiencies are often hereditary.
How did this start?
===================
If you don't want to read about musings from an experiment with sample size 1 (me), skip to the next paragraph.
My line of reasoning didn't come out of nowhere. My aunt, who also has WED, told me about a condition called pyroluria or pyrrole disorder, which is supposed to cause a vitamin b6 and zinc deficiency. AFAIK it is somewhat in the area of "alternative medicine" - which I am wary about, because there a lot of charlatans making huge amounts of money with so-called medication or devices that do nothing but to invoke the placebo effect. Yes, there are also areas of alternative medicine that have merit. Anyway, the description of the symptoms caught my eye, because it linked some characteristics that I have but never thought they may be linked to WED, most notably a disability to remember dreams. Let's be precise here: I used to remember dreams shortly after waking up when I was a child, or teenager. (Of course I forgot the contents of most of these dreams, sometimes within seconds after waking up. But I did remember that I dreamt something.) The dreams stopped some years ago. Can't tell when this started, could be the start of the DA medication, but it may have started earlier. (Not later.) Then came many years where I would remember the occasional nightmare (maybe once or twice a year), but apart from that I never, ever remembered dreaming, even immediately after waking up. When I switched to tilidin, there was a surprise: Suddenly I had vivid, strange dreams again - but only for a few days. At this time I first really noticed the lack of previous dream memory. About 5 months later I heard about pyroluria - during this timespan I had exactly one nightmare. (That one had me jumping in my bed, with cold sweat and an inability to get back to sleep.) I consulted my neurologist and he encouraged me to try a b6 supplement, even though he called the role of B6 in dream memory and dopamine production "unclear" - which I interpreted as "no solid evidence, but there might be a connection". So I started taking a vitamin B compound, and indeed I started to remember a few dreams about two weeks after starting the supplements. They are still rare, but they are there.
Recently I found a placebo controlled study that vitamin b6 supplementation will improve vivid dreaming, speculating on absence of dream memory as strong indicator for vitamin B6 deficiency. (Search for "Effects of pyridoxine on dreaming: a preliminary study.") The b6 dose I took was way below what was used in the study (I took something like 10mg/d where the study worked with 0, 100mg and 250mg per day), but I still found the reappearence of dreams remarkable.
Other notable symptoms are amnesia (check -I do have trouble remembering things, which I'm told is a common symptom for sleep disorders), and a weak immune system (I was often sick with flu-like symptoms, and it took me longer to recover than most other people) an permanently enlarged spleen without obvious reasons (which I have), cold hands and feet (check), bad skin (check) and knee pain (check). Of course the list is longer (and I do have a few of the other things, but most of them I haven't). As I said I'm sceptic - find a list of symptoms that is long enough and half the population will have a few of the symptoms (another trick of the charlatans).
Then I googled on vitamin B6 and zinc. Well, guess what: Both do have a role in dopamine synthesis, and pyridoxal phosphate (which is the active form of vitamin B6) has a role in the GABA synthesis too.
Even more, there is a distinction between the classical WED periodic limb movement (PLMS) when sleeping (which I developed about 6 years back, at age 35), the twitching with an uncontrollable urge to move the legs (which followed roughly 18 months after the first observation of PLMS) and the inability to sleep even though being tired (which I have since I finished high school). The latter is also attributed to pyroluria, or vitamine B6 deficiency - resulting in low GABA levels. Pyroloria or not, according to a recent study at John Hopkins university ("Restless Legs Syndrome, Insomnia And Brain Chemistry: A Tangled Mystery Solved?"), high glutamate levels are common for WED patients and cause the inability to sleep, even though the twitching was controlled by the WED medication. I later stumbled upon a recommendation (on german wikipedia) that people with high glutamate levels should digest roughly 0,5mg vitamin B6 per kilogram body weight to help lower the glutamate levels. (That's way above 10mg/d.) That caught my attention.
I am still not convinced that there is such a thing as pyroluria, but if the lack of dream memory is really an indicator of a B6 deficiency, then I may have that deficiency (whatever the reason) and this might well explain my initial restless legs symptoms.
I realized that I may have high glutamate levels too, since the description match my sleep problems as a young adult perfectly: I was unable to sleep even though I was tired. Leg movement and later twitching followed later, worsening the problem. However, the inability to sleep vanished suddenly when I started taking DAs (ropinirole, later pramipexole): I often felt kinda wired (pumped up, stimulated) for most of the day, but 10-20 minutes after taking my DA all the wiredness vanished and I became extremely sleepy and tired. When I went to bed, I slept within seconds after turning off the light. When I later increased the DA dosage, the sleepiness often persisted for the whole day or for the better part of the day. Dopamine agonists apparently reduce the glutamate level quickly, and the half-life of ropinirole (5-6 hours) and pramipexole (8-12 hours) is short enough to explain this effect, which was more noticable with ropinirole. I got a rotigotine patch but discontinued it after a month because I was tired all day long. After dumping the DAs I had all world of sleep problems, but after a few weeks (I was taking Gabapentin and Lyrica at the time) just one problem seemed to be left: The twitching and urge to move the legs. Very recently they reappeared - I'm now taking tilidin and clonazepam, but am in the process of tapering the clonazepam because it doesn't work as well as I (and my doctor) hoped. The inability to sleep has returned about two weeks ago: I feel wired all day long, even after taking the evening dose of clonazepam (tilidin is round the clock). (But this may be an effect of the tapering - we'll see if this changes.)
More circumstantial evidence of some, say, unusual dopamine balance: I am highly reward-driven. Even as a child, I excelled only wherever I had success and fun (in and out of school), and I stank wherever I had no fun or no success.This hasn't changed. Luckily I have a job that I really love, otherwise I would be in deep trouble... There are more indications, but let's not get into that.
Most recently I experienced increased WED symptoms shortly after I started to drink protein shakes to speed up my weight loss - some shakes containing aspartame, other shakes containing casein, both containing an extensive cocktail of (other) amino acids. It may be pure coincidence, but hey, if my hunch about brain chemistry is right such a amino acid cocktail certainly has the potential to affect my symptoms.
Conclusion
==========
Unfortunately, there is no happy end. I have not found the cure for my disease, these ideas are a recent development.
It is quite possible that I'm completely wrong. See, I had an accident about 10 years ago when a car missed me biking at full speed - the result was a massive concussion and a blackout of about 20-30 minutes. Such an event has certainly the potential to cause some permanent damage, right? Maybe my WED has nothing to do with brain chemistry.
Still, I think the facts come together nicely. I have identified two possible deficiencies (vitamin B6, and perhaps zinc), which could be responsible for a dopamine deficiency. I will experiment with high doses of vitamin b6, and perhaps zinc for good measure, to check if this has any effect on both my dreams and my WED. I will discontinue the use of protein shakes and artificial sweeteners for a while. I will talk to my doctor about all this, and check if other measures designed to lower the glutamate levels help in any way. And if it doesn't work, then I will continue my research to identify other probable substances which could cause WED that I may have a surplus or deficiency in.
What if I do have success, and the B6/zinc supplements help? Then there is no guarantee that these supplements do anything for you.
Maybe only 0,1% of the WED patients suffer from a vitamin B6 deficiency as initial WED cause. Stll, we would have switched these 0,1% of the patients from "idiopathic" to "secondary" - and doctors would know that they should ask WED patients if they remember any dreams.