Self-medicated. A new study suggests that some people suffer from excessive sleepiness due to a naturally occurring compound that acts like a sedative.
Credit: Digital Vision/Thinkstock
Posted on 11/24/2012 11:24:40 PM PST by neverdem
Hitting the wall in the middle of a busy work day is nothing unusual, and a caffeine jolt is all it takes to snap most of us back into action. But people with certain sleep disorders battle a powerful urge to doze throughout the day, even after sleeping 10 hours or more at night. For them, caffeine doesn't touch the problem, and more potent prescription stimulants aren't much better. Now, a study with a small group of patients suggests that their condition may have a surprising source: a naturally occurring compound that works on the brain much like the key ingredients in chill pills such as Valium and Xanax.
The condition is known as primary hypersomnia, and it differs from the better known sleep disorder narcolepsy in that patients tend to have more persistent daytime sleepiness instead of sudden "sleep attacks." The unknown cause and lack of treatment for primary hypersomnia has long frustrated David Rye, a neurologist at Emory University in Atlanta. "A third of our patients are on disability," he says, "and these are 20- and 30-year-old people."
Rye and colleagues began the new study with a hunch about what was going on. Several drugs used to treat insomnia promote sleep by targeting receptors for GABA, a neurotransmitter that dampens neural activity. Rye hypothesized that his hypersomnia patients might have some unknown compound in their brains that does something similar, enhancing the activity of so-called GABAA receptors. To try to find this mystery compound, he and his colleagues performed spinal taps on 32 hypersomnia patients and collected cerebrospinal fluid (CSF), the liquid that bathes and insulates the brain and spinal cord. Then they added the patients' CSF to cells genetically engineered to produce GABAA receptors, and looked for tiny electric currents that would indicate that the receptors had been activated.
In that first pass, nothing happened. However, when the researchers added the CSF and a bit of GABA to the cells, they saw an electrical response that was nearly twice as big as that caused by GABA alone. All of this suggests that the patients' CSF doesn't activate GABAA receptors directly, but it does make the receptors almost twice as sensitive to GABA, the researchers report today in Science Translational Medicine. This effect is similar to that of drugs called benzodiazepines, the active ingredients in antianxiety drugs such as Valium. It did not occur when the researchers treated the cells with CSF from people with normal sleep patterns.
Follow-up experiments suggested that the soporific compound in the patients' CSF is a peptide or small protein, presumably made by the brain, but otherwise its identity remains a mystery.
The idea that endogenous benzodiazepinelike compounds could cause hypersomnia was proposed in the early 1990s by Elio Lugaresi, a pioneering Italian sleep clinician, says Clifford Saper, a neuroscientist at Harvard Medical School in Boston. But several of Lugaresi's patients later turned out to be taking benzodiazepines, which undermined his argument, and the idea fell out of favor. Saper says the new work makes a "pretty strong case."
Based on these results, Rye and his colleagues designed a pilot study with seven patients using a drug called flumazenil, which counteracts benzodiazepines and is often used to treat people who overdose on those drugs. After an injection of flumazenil, the patients improved to near-normal levels on several measures of alertness and vigilance, the researchers report. Rye says these effects lasted up to a couple hours.
In hopes of longer-lasting benefits, the researchers persuaded the pharmaceutical company Hoffmann-La Roche, which makes the drug, to donate a powdered form that can be incorporated into dissolvable tablets taken under the tongue and a cream applied to the skin. One 30-something patient has been taking these formulations for 4 years and has improved dramatically, the researchers report in the paper. She has resumed her career as an attorney, from which her hypersomnia had forced her to take a leave of absence.
The findings are "certainly provocative," Saper says, although they'll have to be replicated in a larger, double-blind trial to be truly convincing.
Even so, says Phyllis Zee, a neurologist at Northwestern University in Evanston, Illinois: "This gives us a new window into thinking about treatments" for primary hypersomnia. "These patients don't respond well to stimulants," Zee says, so a better strategy may be to inhibit the sleep-promoting effects of GABA—or as Rye puts it, releasing the parking brake instead of pressing the accelerator.
The next steps are clear, Rye says: Identify the mystery compound, figure out a faster way to detect it, and conduct a larger clinical trial to test the benefits of flumazenil. However, the researchers first need someone to fund such a study. So far, Rye says, they've gotten no takers.
Did that neurologist think to recommend patients to an endocrinologist to have calcium and parathyroid levels checked?
When I'm forced out of bed before I'm adequately rested, I'm tired all day. I just blew off making the 900 mile drive home for Thanksgiving because my employer sent me to a very expensive security training class, then my niece stole the only sleep day I was going to get for a memorial for her dad. 11 days of forced 6:30 AM starts with work finishing at midnight to 1 AM. I was too burned out to safely drive.
When I'm forced out of bed before I'm adequately rested, I'm tired all day. I just blew off making the 900 mile drive home for Thanksgiving because my employer sent me to a very expensive security training class, then my niece stole the only sleep day I was going to get for a memorial for her dad. 11 days of forced 6:30 AM starts with work finishing at midnight to 1 AM. I was too burned out to safely drive.
Been going on for a while. I think it is caused by an unusual delay after people click “Post” which causes one to either forget that you already posted, or think that it didn’t take and click again. Apparently the software does not have a way to tell that you only clicked “Post Reply” once before multiple “Post” clicks.
By now all old hands presumably know to wait till the browser itself complains of a time out.
It looks like he refers them to the Social Security Administration for a check.
That’s what I was thinking. Great way to get more freebies.
Wonder if they ever considered these people are easily bored?
Thanks again neverdem, your posts contain a ton of interesting info!
Myrddin...if I’m understanding correctly, what you experience with GABA supplementation is the opposite of what it’s ‘sposed to be. Like Ritalin(!?) for hyperactivity - GABA is causing a paradoxical reaction in you. That’s very interesting.
Could it be the source of supplementation that’s “off”? IDK, but I feel for you. There are lists of various GABA-containing foods, I wonder if your reaction to them would be different?
Also, I’m not as up with the research, but I wonder if it’s a GABA problem, or a hyperactive GABA RECEPTOR problem.
I agree with the poster who mentioned checking endocrine function...
just me, but I’d go for blood testing with an eye toward ‘treatment’ with whole food supplements...YMMV.
FRegards,
spank
It is a major principal of meditation to “turn off the noise in your head” before meditating. However, I finally got an interesting hypothesis as to why.
Some people who were very expert at meditation discovered that with extended periods of silence in the head, the mind tends to drift to either an unusual degree of focus, which allows it to consider a narrow situation at hand, ignoring distractions; or the mind becomes very unfocused, a very inspirational state of mind for both creativity and “quantum leaps” in problem resolution.
However, the “internal dialogue” disrupts these shifts in either direction, sticking the mind in the middle, where the mind is involved with the overall situation of a person in the here and now.
This middle position is optimal, they concluded, if you are “being chased by a tiger.” That is, it is survival oriented, far more so than with a state of narrow focus *or* inspiration.
So, in the shadowy past, our ancestors came up with the trick of talking to ourselves, and parents unknowingly indoctrinate their children in this technique to this day, “even though tigers are few and far between these days.”
Thus they concluded, if you use any of the techniques to shut up the internal dialogue, that little bit of mind discipline will give you access to both a strong state of focus, and an inspirational unfocused state.
In practical terms, say if you were doing your SAT test. Just the ability to focus on the test and ignore all the distractions around you might be worth 10-20 IQ points. A much more enhanced ability to concentrate.
Likewise, when faced with an irresolute and complicated problem, or just needing a big shot of inspirational creativity, unfocusing your mind could open the gates.
However, there is more to it than that. The internal dialogue, and the vacillations between a slightly more focused and a slightly more unfocused state of mind are very energy consumptive. A person too skilled with talking to themselves both sounds like an “airhead surfer”, and are exhausted by all the energy used to keep them in that state.
When such people use one of the techniques to control their internal dialogue, the change is dramatic. I knew one such surfer airhead type who applied himself to a technique for a good two week, and he was like a different person.
Not just speaking in coherent sentences, but full paragraphs, and his brain filled with energy and good ideas. He was very pleased with the result, but somewhat apprehensive, because were that rate of improvement to continue, he imagined it would be overwhelming.
He did describe his new ability as like having “a knife switch in his head”, so he could turn his dialogue on or off at will.
Look up "First sleep and Second sleep" for another idea about how we might be wired and why some of us struggle with going back to sleep.
Unless we develop our will and intent, we are ego ruled creatures, slaved to its whims and desires.
In all fairness, most people do not know that they can, and few would be willing to try even if they did know.
There is no motivation unless with are inspired and encouraged by forces beyond ourselves. Otherwise, we live and die, until something comes along and fractures our zeitgeist. Then most people die, and the few that remain either cling to the old ways, or try something new.
Many of us are essentially lazy, often fearful creatures who do little more than necessary.
However, we bore easily and thus there are a few seekers, inventors, explorers and adventurers who will boldly go where others fear to tread, either on their own or by following another's example.
Outside factors can change the nature of things and whether we look outside or inside. For example, I wonder how much has been displaced/lost by the ubiquitous television/idiot box.
” ...who applied himself to a technique...”
What does that mean?
He took the technique seriously and performed it a lot.
Which technique?
What helped him so much?
Any doc worth his/her salt would order standard chemistry tests that include calcium just to have a baseline after getting a chief complaint as well as complete prior medical and surgical history. Parathyroid levels would be checked only if the calcium result is abnormal, possibly only if that calcium result is confirmed by a repeat test.
I wonder how much genetic/epigenetic testing might explain it, what the bill would be and if you could get a definitive answer. It's possible that they could just rule out what they know to test for on a routine basis.
I always thought of GABA as an inhibitory neurotransmitter, but medicine always has something new to teach me.
Coexistence of excitatory and inhibitory GABA synapses in the cerebellar interneuron network.
Disclaimer: Opinions posted on Free Republic are those of the individual posters and do not necessarily represent the opinion of Free Republic or its management. All materials posted herein are protected by copyright law and the exemption for fair use of copyrighted works.