How Long-Term Benzodiazepine Use Leads to Cognitive Impairments

Summary: Mouse study reveals synaptic loss associated with a daily sleep-inducing dose of diazepam for several weeks leads to cognitive impairments. However, the effect was reversible after discontinuing benzodiazepine use.

Source: LMU

Benzodiazepines are effective and widely used drugs for treating states of anxiety and sleep disorders. While short-term treatments are considered safe, their long-term intake can lead to physical dependence and, particularly in the case of older people, to cognitive impairments.

The mechanisms by which benzodiazepines trigger these changes had previously been unknown. Researchers led by Jochen Herms and Mario Dorostkar from LMU’s Center for Neuropathology and Prion Research and the German Center for Neurodegenerative Diseases (DZNE) have now been able to demonstrate in an animal model that the active ingredient leads to the loss of neural connections in the brain.

A key role is played by immune cells of the brain known as microglia. Benzodiazepines bind to a specific protein, the translocator protein (TSPO), on the surface of cell organelles of the microglia. This binding activates the microglia, which then degrade and recycle synapses—that is, the connections between nerve cells.

Experiments carried out by the scientists showed that the synapse loss in mice that had received a daily sleep-inducing dose of the benzodiazepine diazepam for several weeks led to cognitive impairments.

This shows diagrams from the study
Diazepam alters dendritic spine density and dynamics in vivo. Credit: The researchers

“It was known that microglia play an important role in eliminating synapses both during brain development and in neurodegenerative diseases,” say Dr. Yuan Shi and Mochen Cui, co-authors of the study.

“But what really surprised us was that such well-researched drugs as benzodiazepines influence this process.” When diazepam treatment was discontinued, the effect persisted for some time, but was ultimately reversible.

In the opinion of the researchers, the study could have effects on how sleep disorders and anxiety are treated in people at risk of dementia. “Drugs that are known to have no binding affinity to TSPO should be preferred where possible,” say the authors.

About this neuropharmacology research news

Author: Press Office
Source: LMU
Contact: Press Office – LMU
Image: The image is credited to the researchers

Original Research: Closed access.
Long-term diazepam treatment enhances microglial spine engulfment and impairs cognitive performance via the mitochondrial 18 kDa translocator protein (TSPO)” by Yuan Shi et al. Nature Neuroscience


Long-term diazepam treatment enhances microglial spine engulfment and impairs cognitive performance via the mitochondrial 18 kDa translocator protein (TSPO)

Benzodiazepines are widely administered drugs to treat anxiety and insomnia. In addition to tolerance development and abuse liability, their chronic use may cause cognitive impairment and increase the risk for dementia. However, the mechanism by which benzodiazepines might contribute to persistent cognitive decline remains unknown.

Here we report that diazepam, a widely prescribed benzodiazepine, impairs the structural plasticity of dendritic spines, causing cognitive impairment in mice. Diazepam induces these deficits via the mitochondrial 18 kDa translocator protein (TSPO), rather than classical γ-aminobutyric acid type A receptors, which alters microglial morphology, and phagocytosis of synaptic material.

Collectively, our findings demonstrate a mechanism by which TSPO ligands alter synaptic plasticity and, as a consequence, cause cognitive impairment.

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  1. Honestly, I’m so fed up with these terror articles. First of all, leave the mice and pigs and dogs and rabbits alone. We are a different species, experiment on us or simulated computer models if they want the truth. Secondly, at this rate, stop making all psychotropic and associated medications including those for pain. Anything addictive will be abused,then sold by someone’s idiot, American teenager and end up on the black market, dark web or Mexican Cartels bc he ran out. Those who really needed the medication will be cut off bc of doctors real fear or,more likely,thus the paranoia of being sued and refusing to stand up to the FDA on behalf of their patients truly in need. Every medication that has ever helped me has been made impossible to procure. Not bc it’s unavailable but because my own doctors are terrified to prescribe it. It’s not about the patients, it’s about the money. Always will be. I blew the AMA for not standing the FDA.

  2. Doctors are afraid to prescribe these medications in usa thanks to the government oversight and doctors in training are taught not to prescribe them they are very useful for many conditions without causing problems stated in this article these medications have been taken for many years by many PEOPLE who still have all their mental capacity some even more so thanks to these medications

  3. I’m taking clonazepam because about 7 years ago I suddenly started sleep walking and, most disturbingly, sleep DRIVING. I have driven my vehicle TWICE (that I know of) whilst fully asleep, and would have driven more had my wife not stopped me. The Klonopin has essentially eliminated those night adventures, so I’m OK with taking it. I’ve asked my neuro repeatedly if taking it long-term will have any detrimental effects and he has told me no. I am fully aware of the dependency, and I suppose if I were ever to be given the green light to taper the dosage to zero, it would be over a very long time period. I will be showing him this article, asking him about the research, and specifically asking him about the potential for cognitive impairment. I’m 60 and so far I feel good, but I sure don’t want to be entering my 80s with some drug-induced dementia that I could have avoided starting now. I can always just lock my truck keys away somewhere each night so I can’t sleep-drive, right?

    1. I BLAME (not “blew”, thanks spellck, LOLOL) the AMA for not standing up to the FDA.

    1. My father took Valium for at least a year, had a psychotic reaction and committed violent suicide

  4. Their so-called study. What a crock of bull. I have taken Xanax for 20 years without problems increasing or decreasing the amount. Xanax is a bene but its an anesthetic not an antidepressant. Its only purpose is for sleep, not depression, anxiety, stress. An anesthetic is what they knock you out for surgery. So of course it will make you sleepy if you take it during the day and try to function. Yes it calms the mind, but it does it by putting it to sleep. No buts about it, it is not, nor ever was, supposed to be taken during the day. Maybe I’m different because I just don’t see the whole withdrawal fears you people are talking about. If I don’t have it I don’t sleep. End of story. I lost my sleep 20 years ago and have no hope of every getting it back, so that makes me a lifer, but I’m ok with that. Any minor side affects l sometimes will experience pale in comparison to not sleeping. That’s hell, truly hell. It’s like falling into black hole. Each day slows down to every minute feeling like 3-4. Slow motion, true cruelty. Unfortunately at the behest of the far left commies they want to vilify Xanax, just like they did natural codine. And at the same time vilify melatonin (don’t you know it’s dangerous now). All a crock of bull with the end game to be people at each other’s throat. From some of the stories I have read, I know you understand the evils of Big Pharma. They are fully loaded to push new drugs on the market. You know old drugs with a different name. Just add a little of this & call it new & charge a fortune. I don’t understand why it supposedly takes months to detox from Benes. Xanax is just not a problem. Sure I get a little nervy, but anyone who doesn’t sleep for 3-4-5 days is going to become a zombie. What completely amazes me is I can go 5-6 days without sleep & be more alert than someone who didn’t sleep well last night. Really. I know I’m unique, but come on, you can hardly function because you lost a couple hours sleep. I’m calling baby on that one. However I feel for all of you who deal with depression, anxiety, stress. I was once prescribed Valium some 40 years ago & took 2-3 pills & tossed the rest down the toilet. Told the doc it was a bitch pill & wasn’t gonna take it. Out of the meds you guys refer to Xanax is the safest, but unfortunately for you it’s a sleeping pill & just should not be taken during the day. Good luck to you all, hang in, better days will soon be on the horizon & you can all give Big Pharma the finger & your uncaring docs will be calling & begging you to come in. I can’t wait till the day I can watch all of them getting fired. I just hope that day my siatic hip won’t be crippling me, so I can physically jump up and down.

    1. This study was looking at Valium (diazepam), NOT Xanax (alprazolam). These 2 benzodiazepines aren’t even in the same sub-class with each other either. Xanax is a short-acting benzo & Valium is a long-acting benzo. In drug-mechanism and behavior experiments like this, you really cannot legitimately compare these 2 drugs to each other in that way. And anyway, you’re already far more likely to see side effects over the long-term with daily use of LONG-ACTING benzos, like Valium, than you are with Xanax, based purely on the metabolic half-life of each drug (we’re talking abt hours vs days here!).

  5. I am sure I have brain damage, and I am all of these things, I am also pycho who has over 143 different disorders, I am an encyclopedia full of random insults that only relate to unrelated individual experiences. I am all the attributes pertaining to every repeated suggestion I get on the daily, as such, an ongoing reminder, that I am, every negative aspect of everything in exactly every moment. My health is the worst, and I’m a racist also, the list grows everyday according to my smartphones magical suggestions of me as a huge drug user, and I am sure of this combined is somehow true…my ass.

    1. I agree. It’s all blown out of proportion. As usual. I’m sorry for the animals that have to suffer before the FDA makes it’s decisions to make *us* suffer. It’s not like these are new, experimental drugs come to market.

    2. Xanax is for panic attacks, although it functions for several purposes like most psych meds.

  6. i stopped cold turkey feb 15 2022 after 57 years pretty much daily use in the name of modern medicine. doctors said i needed them and never to stop cold turkey. how and why did i start in the first place? my mother decided in all her human wisdom that since as she put it to me they helped mommy and thus when i was being a fussy baby would crumble up a piece of one and sprinkle it in my baby bottle which made little jonny a bit less of a pain in the ass. as little jonny reached about age 3 the ladies in the small Midwestern community i lived would ridicule and scold my mother because on trips to town she would lead little jonny down the street with a dog collar and leash. her reply was she had no choice as little jonny tended to break loose from her grip and run wildly and blindly into traffic so it was the only way tk ensure my safety. around age 10 in 1972 my grade school class had a informational visir from the county sheriff with a big peice of posterboard with various types of “dope” taped to it and guess what? right at the top was a little blue pill with a v cut out in the middle. my heart leaped as i discovered mommas little helpers were dope. little jonnys wheels started turning and later that evening when everyone was asleep little jonny slipped to the kitchen cabinet where mommy kept those pretty blue pills and consumed a handful. what the hell i figured if mommy said they were okay and the police said they made you feel good what would a few extra hurt, mom wouldn’t notice being as the miners welfare insurance sent mom a big bottle of 200 each month. mom took jonny to the hospital because for some reason he was walking around in his sleep pissing in corners and bumping into walls.our rural physician decided to prescribed little jonny his own “scrip” of those little blue pills leading up to today 50 something years later as i sit here trying to make my fingers type as the phone screen keeps going in and out of focus and fingers that seem to move awkwardly on their own from the nerve damage and tell this to everyone hoping now people will realize what i have been trying to say for years and was too emotionally and mentally numb to put into words. god bless all

    1. I honestly don’t know if this study will “trigger” many to be scared of prescribing these medications. It seems that good intentioned, but poorly thought out “studies” have a rather damning effect on the medical community at large (ex: the fear of prescribing pain relief like Opioids or Fentanyl). I feel that studies must be languaged in a way that promotes the positive effects of the medication instead of waging fingers every time any drug could be construed as “addictive or dangerous”. In otherwords, while the side effects should be mentioned, they should not give a medical professional “red flags” if prescribed. As if they do issue these medications, groups aren’t going to scream “crisis and addiction” like buzzwords to be shaming and marginalizing groups whose very quality of life can be profoundly affected if these medications were suddenly placed on some blacklist and no longer able to be issued.

      The medical community is in crisis right now due to the overwhelming addiction of US Citizens to opioids and pain medications. And to add oxygen to that flame, now the COVID-19 and subsequent mutations are putting those in the front lines and stretching them to their breaking point. But the question remains. There are MANY who benefit from these medications and have been so for many years, why suddenly is the moral high ground called for those who choose to overdose and addict themselves?

      Is it the doctor’s fault is YOU choose to overdose? Is it the doctor’s fault if suddenly a medication that has been a gold standard of treatment has been deemed “addictive and dangerous”? And now due to som well meaning, but paranoid group, now because of a “study” the groundwork has been laid to eventually remove the medication from the USP (United States Pharmacopeia) thus cutting millions who DO take their medication properly and refuse to become addicted? What about them? Why do patients have to suffer because of ignorance, fear, and paranoia?

      So many questions, but so few answers as many of these medicines find themselves suddenly unable to be distributed, and/or doses that are non therapeutic and non beneficial? This almost seems less “in the name of science” and more “let’s get them on something else that WE feel, not the patient should have” Not what works for you and YOUR body, but what committees, panels, and algorhythms dictate is good for you.

      In conclusion, this is the sad future of medicine, more half baked studies that point fingers, and less whole person healing for the patient. More getting involved in what you doctor and you decide what is right for you, and less positive outcomes because “We know what is better for you”. Meaning politicians, computer software, and committees. Not based on skill, experience, or judgement of medical professionals. If this is your future, it’s truly in your hands, just as the lives of overdose and drug abuse citizens are in their hands. Which is where it should be, not in the hands of people who decry moral superiority and “we have to do something”. Those kind of people rarely have your interests in mind and their only interest is winning the overdose epidemic for a few, while making MANY other suffer due to draconian laws, overblown fears, and padded reports that show those who are not medical personnel the “dangers” firing them to action, while suppressing the benefits and therapeutic effects of said medications.

      1. Sounds like yourommy Dearest could have used some antipsychotic medication. Or Lithium
        I’m sincerely sorry for your sad childhood. I thought I had a tough one…Mine was a cakewalk. Be kind to yourself.

  7. My adult 31 yr old son , Brian has such extreme anxiety and panic attacks,with diagnosed mood disorder, has been hospitalized 14 times in patient, had 12 ECTs (Electroconvulsive Therapy,suicidal ideations and actual attempts and PTSD with night terrors, his psychiatrist first put my son on Ativan 1 mg 3 cs a day or as needed. But because Ativan was time release his doctor switched it to Xanex .5 mg as needed. For someone like my son who shakes with fear constantly, who stays in his room all the time, sweaty hands, crotch and feet the Benzodiazepines help him very much. My son also takes 150 mg Seroquel for night terrors, Prozac & Abilify too. There is no cure for my son but whatever meds can help Im all for it and to keep him safe.

    1. Yup.I hear you. As a ten, I was in a facility with kids in similar states of mental instability. I saw up close how badly they suffered,observing parents suffering,too, helpless.They had to try many medications until they found the combinations that relieved the suffering of the afflicted. To jeaprodize this treatment is an’s tough enough to get these meds prescribed *today*. Doctors are afraid of their own shadows..when do they ever listen to their patients,anymore?

  8. I understand your needs to remove Valuable Medications off the Market. Whole this happens we turn to street drugs. Remove Hydrocodone one must rely on the Mexican Cartel for the Green pain pills. All you geniuses even took the Alchagol our of liquid Hydroxyzine. So disgusting as a Blood Transfusion Recipient I have to add Alcohol to my Liquid Atarax. MGP Morton Grove Pharmaceuticals was attacked by the FDA so they quit making Hydroxyzine. These people at the FDA are Evil People! Wait until they get sick and need meds the they get watered down pain pills from their CVS false flag Medication!

  9. My son is a vet, the VA Dr prescribed Valiums (Benzodiazepines), it’s been 6 Damn years, now I learn that Benzos are Valiums, now he is addicted to Long-Term Benzos, which are for short-term use meaning 4-6 weeks. Why couldn’t Dr. Solivan (Stockton clinic) know that? Now I am tapering my son off of (30mg Valiums) after firing Dr. Cecile Solivan, can I sue, the VA says yes, I spoke to 30 Attorneys they aren’t interested in chump change so my son has to suffer Anxiety Attacks, possible seizures due to Incompetance, Rebound Anxiety. As the caregiver & father I am PISST! My son went thru many days of pain, Anxiety, screaming in pain, I left messages with his Dr Solivan, I had my son in pain, screaming asking Dr Solivan for help, the idiot refused to call back, I called her Supervisor and went thru same shit, no calls back. Absolutely nothing happen to these Drs, still working enjoying life, getting guaranteed pay from VA and not earning there pay! I am also a vet, which really means nothing, I can’t even get the Damn VA to pay for medication for my son that was ok ordered 6 months ago from community care. I have complained, complained & complained I was told by community care (Lou)that he should get his $50.50 reimbursement ,
    But I have heard that several Damn times, still the VA does nothing to this Viet Nam era vet. Uppa you Ass, we aren’t paying you! The VA White House won’t do anything either, it’s alllll Bullshit with the VA. Joseph Arsanis 80 yrs old and tired of useless VA and their shit!

    1. Every medication comes with an information sheet one ought to read to under stand what one is putting in ones body

  10. Amino acid as protein end product and michontondria the power house where combustion chamber metabolism takes places. I really want autonomous and get on top of my game as an apprentice physician.
    Lady diazepam for treating spasm is an offices press release oh it needs not be published. Bye Benzoate…

  11. I completely understand the side effects of benzodiazepines. But hindsight is 20/20. No I am not a physician but personally I have been battling with depression, anxiety, and severe PTSD. I personally feel you must way the benefits vs the side effects. What people do not understand is there is also side effects that can happen with medications that treat depression and anxiety. What some don’t understand is many drugs are being prescribed as of label to much. Physicians to often jump to prescribe neurological drugs that work for things not studied allot. As for any neurological drug these can be dangerous
    I personally am repin the side effects of many drugs used to treat depression and anxiety. Yes, responsibility does fall on patients but a lot falls on these physicians. Just because it worked once for another different patient doesn’t mean it will work for you.

      1. Or life saving, depending on individual circumstance and diligent physician monitoring. I’d have already been eaten alive with PTSD and the serious symptoms and effects of chronic of hyper vigilance.

      2. Not for me. I take .25 in PM to get, finally, 5-6 hrs.of sleep a night. I’m 68. I went years, on 0-4 hrs a night. Then get 10 for 1 night. And start the cycle again. No sleep will bring on dementia, suicide, heart disease, suicide and cognition problems faster than dementia.
        I’m sorry if you or a loved one abused and got hooked; but I didn’t do that to you or to whomever you lost to the drug.

    1. My mother couldn’t breathe very well due to emphasema. She would panic. This medication was the only thing that would calm her. Her doctor at first wanted to put her on antidepressants but they didn’t help her panic attacks. She was 75 and doctor was worried she would become addicted. Really?

  12. This study purported to show the mechanism by which benzodiazepines allegedly diminish cognitive function in people. However, they used a dose of 5mg diazepam (Valium) per kilogram in the experimental mice. In a person weighing 150 pounds, this is about 340mg per dose. This is an enormous dose about 10 times that considered to be the maximal daily dosing. Also, different benzodiazepines have differing affinities for peripheral (ie,TSPO) versus central benzodiazepine receptors. For example, both clonazepam and diazepam have high affinity for central receptors, but clonazepam has much lower affinity for TSPO. Benzos in general have been blamed for cognitive loss. Are those with high TSPO affinity worse than others? Does this happen at clinical doses? Interesting results, but the study generates more questions than it answers.

  13. Antipsychotics cause brain shrinkage and with ect it’s worse. I have much to say about any dr. who doesn’t care of being downright cruel to someone. Please talk about the bad affects of antipsychotics.

    1. I’d literally bet $1000 a pharmaceutical company paid for this private college study because they “just happen to have” a new drug they doesn’t do what they claim benzos do

  14. Not sure if this is a mistake but diagram is not a benzodiazepine it’s a barbiturate

      1. So the research team doesn’t know the difference between a barbituate and benzodiazepine model but somehow do know the chemical differences, how they react, long term use in a short term study, etc?

    1. Research team knows nothing. Benzos are extremely valuable therapeutic medications. The industry is rigged to sell designer psychotropic cocktials to unsuspecting patients in grave need of relief and stability. Benzos accomplish this. I took lorazapm (2mg x 4doses) daily for 15 years and it changed (saved) my life. I am bi-polar w/anxiety and OCD. Lorazepam (Ativan) is the only med that helped me after being a Guinea pig for numerous (60+) new “miracle” designer drugs for many years. My doctor recently retired and all of a sudden, no provider would prescribe my lorazepam. So I am self medicating but not doing nearly as well as when i took the benzo. Health care is broken. Doctors are broken. Nurse practitioners are not doctors. R&D is broken. Btw, the study says “sleep-induced dose for mice”. This is not a comparable therapeutic dose for human adults. Every drug has side affects. OTC drugs and maintenance drugs can do alot more harm than benzos, short or long term. Benzos are wonder drugs!

      1. Todd yeah benzodiazepines serve a purpose for many conditions older doctors know this and they have and continue to new doctors are being taught not to prescribe them what a shame because government wants to tell a doctor and patient what is good for them some people who want to be judge and jury should have to experience the agony of chronic pain 24/7 for day after day week after week year after year then see how many pain medications and other medications that help they are ready just to have a half normal life so my body my choice really needs to come back

  15. This article completely misleads readers to believe benzodiazepines are safe.

    As stated: While short-term treatments are considered safe, their long-term intake can lead to physical dependence and, particularly in the case of older people, to cognitive impairments

    Please review what is happening via website where members share information related to benzo withdrawal and recovery.

    Far too little has been written about the horrors withdrawal causes. People are choosing suicide because they CANNOT get off of Benzos. The Betty Ford Hazeldon centers won’t even allow admission if a patient is using benzoyl, as they know it takes way too long to complete withdrawal and recovery so insurance won’t cover the treatment. Check out the Ashton Protocol for helping to get off benzoyl. The process is hell, and then when intake gets to 0mg, shit really hits the fan for withdrawal.
    I helped my wife thru this taking several YEARS. During this time she was incapable of taking care of a plant, Thank God she didn’t have a job or kids to take care of.

    1. That’s awful I hope she is ok now. I have been taking Lorazepam for about 9 years for anxiety. I would like to stop it and I am scared to death of the withdrawals. I really don’t know where to start to do this.

    2. That’s awful I hope she is ok now. I have been taking Lorazepam for about 9 years for anxiety. I would like to stop it and I am scared to death of the withdrawals. I really don’t know where to start to do this. Where does anyone go for help?? Doctor just wants to prescribe me another pill Lexapro.

      1. Over the years, I have worked with my doc to regulate the dose. No more than 3mg and as low as 1 mg over the course of 10+ years. I can’t stress the importance of a skilled psychiatrist in charge of this regimen. And make sure you have your records. General practitioners only know for sure that the feds are counting the number of pills prescribed with little to no interest in the reason

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