My lifelong challenges: is it excess glutamate?

[MarkA]

Very happy to have found this forum and community. A quick background on me before I get to a narrative and some questions:

• 45-year old male

• High performance, high achiever type

• Diagnosed (but not treating) ADHD a year or so ago

• Self-diagnosed autistic as well though yet to formally confirm

• Lifelong sufferer of migraines, restless leg, and panic disorder

• Poor sleeper in general with chronic insomnia in more recent years

A bit more of a narrative: I remember having episodes at night between the ages of 2 and 5 where I would wake up with my brain feeling like it was running too fast for me to keep up. My mother would comfort me as I would explain that everything in my mind was big and inflated like a marshmallow and it felt like a rolling pin was being rolled on my brain. In the years that followed I began experiencing regular migraines that would typically follow the resolution of any stressful event or period (e.g., end-of-year school exams). Occasionally they would strike out of the blue. Over the course of my 20s the frequency of migraines reduced from 4x/year to 1x/year. I now experience 1 every 2 years and can stop them in their tracks with Excedrin Migraine.

As a young child I also began having restless leg syndrome, though only learned of it as an actual condition a number of years ago. I would frequently pace the room at night unable to sleep. I often remember waking up with one or both of my arms completely numb and unable to move until I swung or shook them awake, though that stopped at some point in my 20s. More generally, sleep was definitely a challenge growing up. I recall going to bed late and waking up early, always looking over at the clock hoping that it was late enough that I could get out of bed without suffering that day. I was chronically sleep-deprived. I was a constant yawner my entire childhood.

In my late teens I began experiencing panic attacks in the classroom, specifically when asked to read aloud in class, anticipating being called on to answer a question, or worst of all, standing up and presenting. To this day, social panic is a huge issue for me. If I don't self-medicate with propranolol and Xanax, I am very likely to panic when speaking in workplace meetings, including 1-on-1 conversations, which in addition to a huge surge of adrenaline and uncontrollable fear, results in an inability to produce words. It's awful and crippling. My successful career has been reliant on very strategic use of Xanax, which I am extremely careful to never use on back-to-back days or more than 2 to 3 days in a week. In the past I've also had panic attacks on planes and driving on highways and bridges, though that has resolved.

Sleep is also a big challenge for me today. I have restless legs about 10 to 20% of nights. And about 1/3rd of nights will have some form of insomnia (typically in bad stretches of 2 or 3 days); either difficulty falling asleep or waking up in the early morning struggling to get back to sleep. If I wake up after 4AM it's almost impossible to get back to sleep. I'm left wired but tired the next day with my mood and brain processing shot.

I've tried countless forms of therapy, self-talk, breathing exercises, meditation, vagal nerve stimulation, supplements, medications for the panic and insomnia. I have found the only thing that addresses my panic is the Xanax. My research has led me to explore a glutamate excess as an underlying cause of my myriad of life experiences and ongoing challenges. This seems to track given the pattern I have noted for my experiencing restless leg and insomnia: they arise whenever I am particularly stressed from work or have consumed high free glutamate foods like parmesan cheese and tomato sauce. Tart cherry also causes restless leg for me for whatever reason.

Can anyone relate to my experience and share their insights? My main goal is to address my social anxiety and panic, though I would love to have better sleep as well. I am currently considering new medications (guanfacine, clonidine, or memantine), transcranial magnetic stimulation therapy, and ketamine therapy.

Thanks if you read all of this and thanks in advance for any responses.

[Rustsmith]

Mark, I can relate to some of your situations. Thankfully, panic attacks due to public speaking hasn't been one of them. My professional work required frequent presentations, sometimes to very large crowds. I was always able to calm my nerves by telling myself that I knew more about what I was presenting than they did.

Migraines is one thing that we have in common. Mine started when I was in my late 20's and got worse over the years. Some of my problems were due to severe respiratory allergies, but not all of them. I wrote them off as sinus headaches until one hit me one day while I was waiting in the exam room at my allergist. The florescent lights hurt so much that I turned off the lights and laid down on the exam table. When the doctor walked in, she was confused at first, but quickly realized my problem and told her nurse to go get a same of sumatriptain. That seemed like a miracle because my headache was gone before I left the office. I was having about 2 headaches/month, which isn't considered frequent but is still a problem. When I retired, I started seeing a neurologist to try to prevent the headaches, she head me try two different meds. They helped, but didn't prevent my headaches, the headaches just weren't as severe. Her third choice was gabapentin, which as been a godsend for me. They don't know how gabapentin works, but one theory is that it helps reduce glutamate levels in the brain. I haven't had a migraine now in 18 months and the last one was probably due to covid.

As for RLS, I am now 71 and can remember having problems on long airplane flights when I was in my late 20's. I don't know if I had it before then. My RLS is classed as very severe. It includes movement issues in my legs, arms and abs as well as severe insomnia. Like many RLS sufferers, it was the insomnia that drove me to see the sleep doctor who diagnosed my RLS within minutes of walking into the exam room because my feet didn't quit moving. Once I started taking medication (pramipexole and oral iron), my RLS and insomnia went away. It seemed like a miracle until I augmented on the pramipexole 12 months later. That story continues, but isn't relevant to your question.

What is relevant is the recent work by Dr Ferre at the National Institute of Health. He found that low iron levels in the part of the brain that is responsible for both movement and sleep causes the adenosine receptors to stop functioning as the should. Think of the nervous system's receptors as the locks that various neurotransmitters (such as adenosine, dopamine and glutamate) fit into. It seems that these adenosine receptors are doubled up with dopamine and glutamate receptors, such as with a double lock). If the adenosine receptor doesn't "open", the dopamine and glutamate receptors cannot function, which leads to a buildup of dopamine and glutamate. Treating RLS with more dopamine forces the remaining receptors to work harder, but doesn't do anything to address the buildup of glutamate. Glutamate helps to control our wake/sleep cycle, so too much glutamate in the cause of RLS induced insomnia. IF gabapentin is helps reduce our glutamate levels, this allows us to fall asleep.

As for the new medications that you are considering as well as TMS and ketamine, those are not treatments that I have heard of being used to treat RLS or insomnia. I tried memantine to delay the onset of dementia, but did not like the side effects. I looked into TMS and ketamine as depression treatments but didn't try either one because they are both expensive and require regular treatments at a doctor's office. I still suffer from depression and am waiting for magic mushroom therapy to become available in my area in about five months (I live in Colorado where it is now legal).

[MarkA]

Thanks so much for the incredibly informative response. A takeaway for me is that I should consider supplementing with iron as a first step. Both times I did lab work this past year my ferritin levels were 50 and 51. Seems like I have plenty of opportunity to increase that. Is there a target for which you aim?

Is there a specific form of iron you recommend and dosage? I also have a bottle of gabapentin that I was prescribed a while ago for insomnia and anxiety but have been too nervous to try it. Might try that if getting my iron levels up doesn't do the trick.

[MarkA]

Also any thoughts on supplementing with Vitamin E? I've read research indicating that it is associated with improvements in both anxiety and restless leg symptoms.

Unfortunately, general wisdom seems to be that one should avoid supplementing with both iron and Vitamin E unless absolutely necessary given risks of increased prostate cancer risk from Vit E and many forms of cancer from Iron.

[Rustsmith]

I haven't seen any research indicating that Vitamin E can help with RLS. I do know that VIt D helps with many neurological conditions. I had a neurologist test my Vit D and Vit B12 levels and was advised to take both. As for iron supplements, there are risks for everything but since RLS is due to low levels of iron in the brain, the need for an iron supplement seems obvious.

[Frunobulax]

There are contradictory studies to the effect of vitD. Some say supplementation helps, while others say it doesn't. My approach is to grab as much sunlight without blockers as Ican tolerate without getting sunburnt, and I also supplement with D3 and vitamin K2 (K is very important and often not added). Being outside in the sun is probably superior to supplementation.

In general I believe that proper nutrition from fresh, unprocessed ingredients is #1, and supplementation a distant #2.