Considering that they impair memory formation and can cause anterograde amnesia, it shouldn't be surprising that rates of dementia are higher in long-term users. I believe they can be used to induce dementia-like amnesia in rats to test nootropics, although scopolamine is more commonly used.

An alternate explanation would be that the pathology that the benziodiazepines were treating is what caused dementia. Depression symptoms are correlated with neurodegeneration, and anxiolytics are generally also neurotrophic.

As to mechanism, there is a lot of literature implicating the cholinergic system in dementia-related and Alzheimer's-related neurodegeneration.

I did a quick search of my references on scopolamine to see if benziodiazapine was also mentioned, and found a reference in one of the citation pages. I haven't read it, but it might give you a place to start.

Bishop KI, Curran HV (1998) An investigation of the effects of

benzodiazepine receptor ligands and of scopolamine on conceptual

priming. Psychopharmacology (Berl) 140:345–353

All of these medication including this drug indices damage in the mitochondria and appeared to be sources for the free radical and therefore initiate mental retardation that outcome all of these manifest as a dementia. This drug should be taken out form the market.

I shall attend the Alzheimer Disease's Conference next week so I can post a question regarding this interesting relation between benzodiazepin and dementia. I agree with Akshay that the benzodiazepine use is simply a marker for other conditions like anxiety or neuroticism.

As far as I know lorazepan can impair memory during use and also after stopping as a sequelae. Other problem is that BZPs are frequently used to treat wrongly depression with anxiety so depression wich is associated with dementia is reinforced by a medication that slows down CNS.

As you mention, one possibility is that the “need” for the benzos reflect an underlying dementing process. I would guess that this explains some of the variation. But if these medications cause or accelerate the development of dementia, how do they do it.

I do not think it is enough to say that benzos impair memory formation while they are being taken. The question would still be, after they are withdrawn has the brain been impaired by having taken them. If so, what would be the mechanism.

My shortest answer is that I do not know. But looking back at older literature, it has been observed for years that benzodiazepines (and neuroleptics and certain other sedating medications) impair recover from stroke and other forms of brain damage (J Neural Transplant Plast. 1993 Jul-Sep;4(3):175-92. Basic and clinical studies of pharmacologic effects on recovery from brain injury. Goldstein LB.) The general, and rather vague mechanism typically offered is that they impair neuroplasticity.

So I would suggest what I might call a “meta mechanism”, i.e. a sort of framework whereby one might make potentially testable hypotheses in the following way. The brain does have some capacity to repair itself from certain degrees of damage. This is not as much as we might like but there is always hope of enhancing it. The repair can be via terminal sprouting of axons to replace damaged branches. There is some capacity for remyelination. There is even some capacity for birth of new neurons even though it is not clear that the new neurons contribute much long term. Some experiments have shown that this neuronal birth can be enhanced by certain antidepressants.

So possibly there is a balance of destruction and repair. As we get older, destruction starts winning. Sometimes the destruction, whether by oxidative damage or whatever, can encourage some proteins to crumple into toxic aggregates and tangles. Probably the brain’s restorative abilities can handle some of that. But if the benzos decrease this repair process, even by a bit, over the course of years the brain destruction will be enhanced.

Then you can add to that any direct damage the benzos might cause. I am a little of an oxidative mechanism because some benzos have been shown to be protective in that regard (Korean J Anesthesiol. 2012 February; 62(2): 166–171. Published online 2012 February 20. doi: 10.4097/kjae.2012.62.2.166 PMCID: PMC3284740 Midazolam protects B35 neuroblastoma cells through Akt-phosphorylation in reactive oxygen species derived cellular injury, Won Seog Chong,1 Chang Lim Hyun,2 Min Kyu Park, et al. ). From what I have read there is a lot of complexity with respect to all the different possible actions of benzos. For example, activation of peripheral benzodiazepine receptor (PBRs), which are present also in the CNS though mainly in non-neuronal cells, can inhibit apoptosis in some systems (Bono F, Lamarche I, Prabonnaud V, Le Fur G, Herbert JM (1999) Peripheral benzodiazepine receptor agonists exhibit potent antiapoptotic activities. Biochem Biophys Res Commun 265:457–461). So this would be in the opposite direction. But perhaps apoptosis of damaged glial is helpful in repair.

In any case, my guess would be that mainly benzos slow repair rather than cause overt damage.

Benzodiazeoines may induce mitochondrial alterations, with serious consequences on the synaptic activity of neuronal circuits

Excellent and i agree with your opinion completely.

From a brief NIH search there appears to be some suggestion that in AD patients that there is some correlation between amount of NFT and GABAa receptors.

(An immunohistochemical study of GABAA receptor gamma subunits in Alzheimer’s disease hippocampus: relationship to neurofibrillary tangle progression

Masahiko Iwakiri, MD,1) Katsuyoshi Mizukami, MD, PhD,2)* Milos D. Ikonomovic, MD,3),4) Masanori Ishikawa, MD, PhD,5) Eric E. Abrahamson, PhD,3) Steven T. DeKosky, MD,3),4) and Takashi Asada, MD, PhD.2)

However this article suggests that benzo may possible be protective for AD. Since there are different types of Dementia I would suggest that it is hard to make a direct correlation to benzos and dementia as many of the dementias can not be diagnosed until autopsy. There are allosteric changes in the brain with benzos perhaps there is a sensitivity to those who are predisposed to dementia.

It would seem that on a surface level BZDs would be helpful as they decrease glutamate exitotoxicity?

The BZD does change the ion channels. Could this lead to increase in free radicals as already mentioned.

I've attached a PDF of a 1996 study regarding the inhibition of acetylcholine release by benzodiazepines. I'll follow with files regarding the role of acetylcholine in working memory, dementia, and neurodegeneration.

Also I found an article that might be helpful, but couldn't download it, so here's a citation:

Assunta Imperato, Laura Dazzib, M.Carmen Obinua, Gian Luigi Gessaa, Giovanni Biggiob. Inhibition of hippocampal acetylcholine release by benzodiazepines: antagonism by flumazenil. The European Journal of Pharmacology. 1993;238(1):135-137

This discussion on possible mechanisms is fascinating. However, I'm still not convinced that the association is causal. Certainly benzos can impair short-term memory, but all that I have read on this indicate that it is a transient effect, not effecting long-term memory or brain structure--but I'm certainly open to new information. Clearly people begin taking benzos to treat symptoms, like insomnia, restlessness, anxiety, fear of losing one's capacities, etc -- all of which are more common in early dementia syndromes. So such an association would be certainly expected, even without implicating a causal relationship.

This PDF describes the relationship between 17 beta estradiol, muscarinic acetylcholine receptors, and working memory.

Found this publication on RG - I'm now following the guy I pulled it from

Article Acetylcholine receptors in dementia and mild cognitive impairment

More about nAChR deficit and various dementias.

Such studies are predominantly retrospective and conclusions drawn are not based on a set of controls or carefully selected groups studied over a set course of time under known conditions. I often question the conclusions drawn from these "studies" as those which match the author's expectations rather than true cause and effect.

Could prescribing benzodiazepines be a reaction to behaviors found in dementia patients rather than a cause of those behaviors?

I recall quite a few past retrospective studies that received sensational coverage by the professional and public media only to fade into obscurity once the methodology and conclusions were carefully examined.

The relationship between benzodiazepines and dementia, if confirmed, is far from straightforward. However more information about changes and remodeling of GABA receptors, a target of benzodiazepines, in Alzheimer is coming out. Whether alterations in the density and in the subtypes of GABA receptors form part of a protective or degenerative process is still not known. Below are the links to some papers that may be of your interest. One is our study showing changes in the electrophysiological properties of human GABA receptors in Alzheimer, and changes in the subunit composition that would produce changes to benzodiazepine sensitivity. The second is the same article recommended by Amy Huang below, and the third is an interesting review of GABA receptors in AD.

http://www.ncbi.nlm.nih.gov/pubmed/22691495

http://www.ncbi.nlm.nih.gov/pubmed/19019179

http://www.ncbi.nlm.nih.gov/pubmed/21388375

Anyway, sorry to spam. I haven't been able to figure out how to attach more than one thing at a time. There has been a bunch of work done on ACh, dementia, and memory, as well as anxiolytics and memory, and depression and memory. The way I understand it, increased ACh release (or specific AChR agonism) is correlated to increased cognitive function and some kinds of neuroproliferation. Decreased ACh release (or specific AChR subtype antagonism) is associated with reduced anxiety.

The problem is showing causation, though. Neurodegeneration is correlated with major depressive disorder, and rodent models have been able to induce depression-like behaviors through induced neurodegeneration. Anxiolytics often impair spatial memory and psychomotor ability, both of which are modulated by AChR, but may be neurotrophic. I believe that benzodiazepines act as broad ACh antagonists (although I could be very wrong about that), so they would be expected to reduce anxiety and impair memory. However, whether the initial disorder that required treatment with benzodiazepines caused neurodegeneration that eventually led to dementia, or whether long-term treatment with benzodiazepines inhibits neuroproliferation and leads to dementia is more difficult to pin down.

Anyone want to spend a year or two giving otherwise healthy mice benzodiazepines to see what happens?

Well I do not think it is even necessary to treat mice with this compound. It is very obvious that this substances has cytotoxic effects on the cellular membrane especially on the mitochondrial external and inner membrane!!.

The reference (full text) @ http://www.bmj.com/content/345/bmj.e6231

Benzodiazepines have been associated with increased mortality in a variety of populations (cancer and psychiatric patients are the two extremes of a wide range of clinical populations where such correlations were found). However it's been hard to draw any clear conclusion of what this might be as most of these studies used cross-sectional data collection.

A longitudinal study finding severe cognitive effects such as dementia at a highly increased rate - 50% !!! could be concerning unless the numbers are small, which is actually the case here and other possible confounders/contributors to the outcome have been ruled out , which unfortunately is not the case in the BMJ study.

I was always of the opinion that chronic benzodiazepine intake, which is an iatrogenic low dose dependency, is leading to or triggering dementia at an earlier age. What is well-established is a character change occuring after chronic intake of benzodiazepines, the person becoming forgettable, unreliable, uncritical and superficial always jocund - I would call it a somewhat floppy personality. Experienced physicians can see prima vista whether a person takes benzodiazepines in a chronic fashion. Lüder Deecke, Clinical Neurology

We know that patients with Alzheimer's disease have pathophysiologic changes in their brains more than 20 years prior to the clinical onset of dementia, according to a study published recently in NEJM (see Bateman et al, 2012). In the pre-AD state, many patients present to their providers with symptoms of anxiety and depression. These symptoms are likely to be part of the mild cognitive impairment that precedes AD

(see Petersen, NEJM, 2011). The benzodiazepines are simply markers for the anxiety that is associated MCI and early AD, not a cause of dementia.

The hippocampus has a high percentage of GABA A receptors that express the alpha- 5 subunit. This receptor over activity has been implicated in reducing 'spatial memory' in animals. Alpha -5 knockoput mice do better in the memory tests. However, this is spatial memory that was tested in these studies. All GABA agonists like alcohol, barbiturates and benzodiazepines are known to cause anterograde amnesia. Whether the mechanism is the same, it is difficult to say. The studies that have concluded that benzodiazepines increase the risk of dementia, should definitely take into consideration the bias regarding the primary indication for which they were started in the first place. The confounding factors should be taken into consideration before the final statistical analysis. If that has been done and the results still show an increased risk, then it could be cause for concern.It is a well known fact that in animal studies that drugs that block the GABA- A receptor, enhance memory. However, it surely does not mean that all patients taking benzodiazepines will develop dementia.

Soon or later benzodiazepines will affect on the neuronal and other brain cellular compartment and their activities and therefore most likely initiate developing of the dementia!

There is support for both: for a pathophysiological role of benzodiazepines in the development of dementia and for an increased need to take benzodiazepine drugs in people with preclinical Alzheimer’s disease.

1.) Benzodazepines may contribute to abnormal GABA-A receptor function

A postmortem analysis of human cortical tissue from AD patients and controls reveals an AD-related alteration of GABA-A receptor structure, favoring Alpha-2 (over Alpha1) and Gamma1 over Gamma2 subunits. (Proc Natl Acad Sci U S A. 2012 Jun 19;109(25):10071-6.). These changes are associated with altered functional properties of the GABA-A receptor, ultimately leading to impaired GABAergic signalling in AD (Proc Natl Acad Sci U S A. 2012 Jun 19;109(25):10071-6.). It can be speculated that these changes may in turn increase the incidence of symptoms which require treatment with drugs that facilitate GABA-ergic signalling.

However, chronic benzodiazepine use seems to partly resemble these GABA-A receptor subunit changes observed in AD: Diazepam has been found to downregulate gene expression and/or protein levels of both the Gamma2 subunit (Brain Res Mol Brain Res. 1997 Aug;48(1):164-6) as well as of the Alpha1 subunit (Br J Pharmacol. 1996 Jul;118(5):1103-10.) - the very same subunits that seem to be pathologically reduced in AD. The pathophysiological relevance of these changes is not entirely clear, however, it may contribute to the AD-related abnormal balance of excitatory/inhibitory signalling which has been suggested to be critical to the development of AD pathology and cognitive deficits (Rissmann & Mobley J Neurochemistry 2011 117:613-622).

Interestingly, intact GABA signalling appears to be a necessary factor in the regulation of adult neurogenesis (Nature. 2006 Feb 2;439(7076):589-93). It’s not a far stretch proposing that functional alterations of GABA-receptor signalling (as caused by chronic benzodiazepine use) may negatively interfere with synaptic integration of newborn neurons. Some studies show that application of diazepam may completely abrogate fluoxetine-induced adult neurogenesis in animal models of depression (Biol Psychiatry. 2009 Jul 1;66(1):5-8.).

2.) Benzodazepines may affect neurotrophic signaling

Chronic diazepam use has been linked to profound downregulation of BDNF, transcription factor GIF, c-fos, nerve growth factor induced gene-A, among others (J Neurochem. 2004 Mar;88(5):1059-67.). Impaired neurotrophic regulation due to benzodiazepine use may as well add up to an ongoing yet clinically silent neurodegenerative process and thus facilitate the manifestation of dementia.

Dear David Prvulovic, thanks for your clear explanation and its really so relevant and scientific.

I also think that the role of benzos in AD is more that only a marker. I think that benzos plus alcohole are also in the game. The clearcut Alzheimer is rarely found especially in patients over 65,in these patients a vascular dementia is intermingled with AD what I am saying is that also the vascular element is already in it.The term is microangiopathy. All risk factors for Alzheimer's disease beyond 65th year of age are causes of microangiopathy. This is maybe not so clearly seen by clinicians. What we can do against Alzheimers is not much, but what we can do against microangiopathy is at least something: Asasantin Retard (= Aggrenox)has proven to be 33 % better than plain Aspirin in the second Eur. Stroke study. The trend should be to see the multimorbidity and try to treat the "multi" elements on a single basis. Best wishes! Lüder Deecke, Vienna

Buenas noches,en mi práctica he visto benzodiazepinas,como :Midazolam producen marcados efectos sobre la memoria inmediata,he relacionado mas el uso de benzo,con trastorno cognitivo leve.Si tomamos en cuenta que su uso ha venido en aumento principalmente para el tratamiento de trastorno de ansiedad y de pánico,dicho tratamiento se extiende por un periodo comprendido entre seis meses a dos años,entonces allí si observamos su impacto sobre la esfera cognitiva;por ello actualmente se indica usar en insomnio,medicamentos tales como el Zolpidem,Brotizolam,que no impactan tanto en la memoria.No hablare del mecanismo de acción ya que ya fue explicado anteriormente.Creo que el inicio es este y además cómo escapar de su uso en pacientes con Alzheimer y otras demencias si se presenta clinica de trastorno de ansiendad en comorbilidad.

This is a frustrating topic an one that the media will pervert until everyone is so deathly afraid of them an extremely effective class of medications will be avoided. are there studies that show a link, absolutely. Okay, but are there studies that refute this, you'd better believe it. In fact, the ones refuting the causal connection are often much better regarding their methodological choices.

Personally this topic is as banal as eating a pound of grape nuts cereal. And here is why: the damning evidence against benzodiazepine meds is just as damning for other pharmacological choices (i.e. antipsychotics and sedating antidepressants (trazodone and mirtazapine in particular). The only clear finding is that a person who is drugged up for the bulk of their lives are less mentally/cognitively well of than those who are not. If you want the actual research in favor for and agfains the use of benzos for dementia I have a serious collection and would gladly share them with you however I do not have them on me and  if you truly lust for an empirical answer they are fantastic so please feel free to respond to me and I will send them to you.

Wishing you the best,

Logan Netzer

Does diazepam induce or promote neuro-inflammation on the cell-molecular level?

If we assume that a dementia begins at least a decade before the symptomatic manifestation, the use of benzodiazepine is subsequent to the onset of subclinical disease. This is a sufficient justification for suspending all indications for benzodiazepines, as is currently the case with general practitioners?

It would be an appropriate investigation to assess memory loss in patients with essential tremor treated with or without benzodiazepine, but not by cognitive symptoms or mood disorders.

Yes, long term use of benzodiazepines increases the risk of dementia. Please have a look at the following RG links.

Article Risk of Dementia in Long-Term Benzodiazepine Users: Evidence...

Article Association between Benzodiazepine Use and Dementia: A Meta-Analysis

Article Benzodiazepine Use and Risk of Dementia in the Elderly Popul...

Article Regular Benzodiazepine and Z-Substance Use and Risk of Demen...

Article Benzodiazepine use and risk of dementia: evidence from the C...

Yes, benzodiazepines can leads to demantia, but when it be used for a long time.