The Cognitive and Medical Risks of Benzodiazepines

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This article discusses the adverse effects on cognition associated with commonly-prescribed and often over-used benzodiazepines—Xanax (alprazolam), Ativan (lorazepam), and Klonopin. In the short term they impair memory and learning reversibly upon discontinuation. But long-term use significantly increases the risk of developing irreversible dementia. 

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Benzodiazepines are a family of psychoactive drugs “descended” from Valium (diazepam) that function as central nervous system depressants. These drugs work by enhancing the effect of the neurotransmitter GABA (gamma-aminobutyric acid) in the brain and other parts of the central nervous system. GABA is a “relaxing” neurotransmitter that serves to dampen excitatory circuitry, hence the calming effects of benzodiazepines on anxiety and all its associated physiological components. This manifests as a variety of therapeutic effects such as sedation, reduced anxiety, anticonvulsant action, and muscle relaxation. In large doses, the shortest acting benzodiazepines are used as anesthetics. 

They have different equivalent strength in milligrams and different “half-lifes.” The half-life is the amount of time it takes for a given amount in your system to drop to half. If you take just a single lowest dose that is fully-effective for a given purpose, then ¼  of the half-life tells you roughly how long after you take it you will likely feel its anti-anxiety effects wearing off (although this varies from person to person).

Benzodiazepine Equivalency

 Approximately Equivalent Oral Dose, mgHalf-life, hours (effective life)
Alprazolam (Xanax)0.5–112 (3 hours)
Bromazepam (Lexotan)3–620 (5 hours)
Chlordiazepoxide (Librium)10–25100 (1 day)
Clonazepam (Klonopin)0.25–0.534 (9 hours)
Clorazepate (Tranxene)7.5–15100 (1 day)
Diazepam (Valium)5–10100 (1 day)
Flurazepam (Dalmane)15–30100 (1 day)
Lorazepam (Ativan)1–215 (4 hours)
Nitrazepam (Mogadon)2.5–1030 (8 hours)
Oxazepam (Serax)15–308 (2 hours)
Quazepam (Doral)10–2025-41 (8hours)
Temazepam (Restoril)10–2011 (3 hours)
Triazolam (Halcion)0.25–0.52 (1/2 hour)

The proper utilization of benzodiazepines for mental health is in the acute management of short-term anxiety states but they have also long been over-prescribed to treat long-term, true, anxiety disorders. When benzodiazepines are used as the mainstay of such treatment over a long period problems ensue. 

Benzodiazepines are the most commonly prescribed drugs worldwide. In the United States 12.6% of the population reports their use in the prior year. The rapidly increasing number and length of prescriptions is raising concerns of an incipient crisis akin to the opioid epidemic we now face.  Many people have been started long ago on reasonable, very small doses of for example Xanax (alprazolam), say 0.25 mg twice a day as needed. All too often such a prescription will be renewed without limit and without seeking alternatives. And since benzodiazepines are habit-forming (habituation, tolerance, addiction), their effect fades and higher and higher doses are prescribed over the years to maintain the anti-anxiety effect. It is not uncommon, unfortunately, to find people who started years ago on small doses who are now taking 4, 5 even 8 to 15 mg a day. 

Seizures and Death

If even modestly high doses of a benzodiazepine are abruptly discontinued (unavailability, medical reasons) the anxiety that returns is not at the level of the anxiety for which the benzodiazepine was originally prescribed. In proportion to how much the dose has increased over time, the so-called “rebound” anxiety and all its physiological concomitants (heart rate, breathing rate, blood pressure, perspiration and so on) is far greater. This increase is so severe that people usually cannot tolerate it. In other words, habituation has led to an addiction. 

And if the dose is high enough abrupt discontinuation is medically dangerous. If the medication is not slowly tapered, the withdrawal syndrome that ensues is essentially identical to the DTs (delirium tremens) that occurs with abrupt cessation of severe alcohol use. This is because benzodiazepines are 100% cross-tolerant with alcohol (hence their use in medical detox from alcohol): The one can replaced with the other to prevent withdrawal.  The DTs are characterized by:

  • Agitation
  • Sweating
  • Fever
  • Water-electrolyte imbalance
  • Delirium
  • Hallucinations (“pink elephants”)_
  • Rapid heart rate
  • Tremor
  • Severe anxiety
  • Dilated pupils
  • Insomnia
  • Irritability
  • Panting

DTs are also associated with a very high risk of seizures. Shockingly, even with medical treatment, both benzodiazepine and alcohol withdrawal seizures carry with them a 5-15% risk of death. Because of the half-life, such seizures do not occur immediately but rather 2-3 days after cessation (depending on which benzodiazepine is at issue and on individual metabolism), lulling people into a false sense that they are managing okay. Thus many people at risk of such seizures do not seek medical help, and without medical help a seizure of this kind carries with it a 37% risk of death. Indeed, contrary to popular fictionalization, withdrawal from benzodiazepines is far more medically risky than withdrawal from opioids.

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The Influence of Benzodiazepines on Higher Brain Functioning

The addictive capacity and medical risks of being dependent on a benzodiazepine is not the only problem. The long-term use of benzodiazepines on higher brain functioning has been the object of concern and the subject of research for the past quarter century. 

Memory and learning are two critical underpinnings for every human experience in life, from daily routines to clear communication with loved ones and others to higher education to expertise in a job. Although benzodiazepines are effective in reducing anxiety over a short duration, clinical observation and research findings both suggest that they interfere with the neurobiological processes of forming and recalling memories, producing an “anterograde amnesia” which is not entirely reversible upon discontinuation of use. That is to say, the drugs prevent new information from being encoded into memory and once it is learned and consolidated into long-term memory, it can be again lost. However, this not an effect specific to memory—it is simply one part of general cognitive degradation across the following domains:

  • Processing Speed
  • Memory
  • Executive Function 
  • Sustained Attention

A 2022 study in the journal European Addiction Research concluded:

Of long-term benzodiazepine users, 20.7% could be classified as cognitively impaired across all domains, with the largest effects found in the domains of processing speed and sustained attention, and an overall worse performance in women…

Both the severity of these impairments and the risk that they will persist permanently in some noticeable degree after discontinuation appears roughly proportional to the cumulative dose ingested.

Benzodiazepines and the Risk of Dementia

There exists a long-standing concern about the relationship between benzodiazepine use and Alzheimer’s Disease and other forms of dementia. The ongoing and/or residual cognitive impairment they cause raises the obvious concern as to whether they can generate a formally diagnosed dementia. No clear-cut answer has yet been found if the question is framed properly: Do benzodiazepines cause dementia of a specific (e.g., Alzheimer’s) or non-specific kind in individuals who would otherwise not develop it? What makes this question so difficult is that to answer is one must know in advance the baseline risk without benzodiazepines of an individual developing dementia of the Alzheimer’s type. In general this is unknowable except on a population basis.

  1. For any specific individual we do not know the true risk of developing dementia in advance and family history provides only a crude estimate of increased risk
  2. A diagnosis of dementia is quantitative, with a certain threshold of measured impairment required to make it; 
  3. It is plausible that a given degree of dementia will be measured as worse by the concomitant or long-term prior use of benzodiazepines;
  4. Therefore it is difficult to distinguish whether a subject with dementia developed it solely because of benzodiazepine use and never would have otherwise; or developed it sooner and/or more severely because of benzodiazepine use. 

Of course it is likely that people who will develop dementia anyway, and are long term users of benzodiazepines, are likely to have worse dementia, with an earlier onset of noticeable symptoms. In a mixed pool of people who will develop dementia and people who won’t, the use of benzodiazepines by all in this pool will show itself as a statistical increase in the number of people with dementia compared to a matched pool of non-users. But as we cannot foresee who will and who won’t develop dementia anyway, this wouldn’t necessarily mean that everyone in the benzodiazepine pool is at risk.  However, the rational decision in the absence of certainty is to avoid long term use if possible, especially as the non-dementia cognitive risk is certain.

Seeking Safer Treatment

Assuming that medications are required to manage long-term anxiety, and that psychotherapeutic options are inadequate as for true anxiety disorders they often are, there a number of safer pharmacologic options. These include:

  1. Antidepressants. Most antidepressants are equally good at reducing and preventing anxiety as depression.  Indeed, that these medications are called “antidepressants” is an accident of history. The first SSRI was Prozac (fluoxetine). For market purposes, Eli Lily applied to the FDA for Prozac to be indicated for depression and it was approved. But they went back a year later and received the indication for anxiety. Antidepressants in the SSRI category are typically employed first, but for many people antidepressants in other classes prove to work better. None block anxiety in the moment you take them the way sedatives do, but rather they induce long-lasting and complex changes in brain circuitry that re-regulate anxiety and make its appearance more tightly coupled to real, not imaginary, threats. These changes take weeks to be complete. For someone with a longstanding anxiety disorder, and not a brief episode, this is the definitive and best treatment.
  2. Beta blockers. These medications were developed to lower blood pressure. Then they were found to lower the heart rate. Later, it was realized that they reduce anxiety. They are best described as medications that down-regulate the entire fight-flight reflex in all its mental and physical manifestations. They come in long-acting versions for daily use and short-acting versions for anxiety spikes. Propranolol is the most commonly prescribed beta blocker for anxiety.
  3. Gabapentin. This medication has found many uses in medicine. It is prescribed chiefly for nerve pain, but has anti-anxiety, sedative, and to a degree mood-stabilizing properties. It can be used to treat restless legs syndrome as well. However, gabapentin does appear to induce true physiologic dependence in a small subset of people. As it is not categorized as such (it is not a controlled substance), one must know this and be alert for signs of such dependence.
  4. Pregabalin (Lyrica). Perhaps pregabalin ought not be included in this list as it is habit-forming (and controlled) albeit less severely so than benzodiazepines. It works against nerve pain, fibromyalgia and restless legs as well.
  5. Buspirone (Buspar) is a short-acting non-habit-forming purely anti-anxiety agent that often can be used in place of benzodiazepines and in similar fashion.
  6. Hydroxyzine is an anti-histamine with anti-anxiety effects. It is non-habit-forming but sedating.

The possibility of reversing cognitive impairments

The good news is that new research might offer hope to those who have already fallen victim to the cognitive impairments that they experienced due to benzodiazepine use. Most people who stop taking benzodiazepine drugs experience significant improvement in their cognitive function and research shows that some, but not all, show no sign of residual deficit. This finding is especially pertinent for older people who are at greater risk for dementias and for people who already have some degree of cognitive impairment for any reason. 

Stopping Benzodiazepine Use

Most people are aware of the existence of 28-day programs for substance abuse and of 7-day medical “detox” protocols. It is not common for such programs to adequately reduce a benzodiazepine dependence, especially if the doses are high and the use over many years. 7-day detoxes simply remove the medical risk and 28-day programs are too short. The best way to eliminate a benzodiazepine dependence is extremely slowly in tiny steps taking quite a long time. What works best are tiny decrements to which the brain and body can adapt with minimal or undetectable rebound anxiety. For instance someone dependent on 2 mg a day of Xanax can successfully stop by decreasing the dose at a rate of -0.125 mg monthly, or slower. At monthly intervals this will take 16 months, a length of time that is not popularly understood.

Dementia References

Wu CS, Wang SC, Chang IS, Lin KM. The association between dementia and long-term use of benzodiazepine in the elderly: nested case-control study using claims data. Am J Geriatr Psychiatry. 2009; 17(7): 614–620.

Wu CS, Ting TT, Wang SC, Chang IS, Lin KM. Effect of benzodiazepine discontinuation on dementia risk. Am J Geriatr Psychiatry. 2011; 19(2): 151–159.

Gallacher J, Elwood P, Pickering J, Bayer A, Fish M, Ben-Shlomo Y. Benzodiazepine use and risk of dementia: evidence from the Caerphilly Prospective Study (CaPS). J Epidemiol Community Health. 2012; 66(10): 869–873.

Billioti de Gage S, Begaud B, Bazin F, et al. Benzodiazepine use and risk of dementia: prospective population based study. BMJ. 2012; 345:e6231.

Billioti de Gage S, Moride Y, Ducruet T, et al. Benzodiazepine use and risk of Alzheimer’s disease: case-control study. BMJ. 2014; 349:g5205.

Billioti de Gage S, Pariente A, Begaud B. Is there really a link between benzodiazepine use and the risk of dementia? Expert Opin Drug Saf. 2015; 14(5): 733–747.

Imfeld P, Bodmer M, Jick SS, Meier CR. Benzodiazepine use and risk of developing alzheimer’s disease or vascular dementia: a case-control analysis. Drug Saf. 2015; 38(10): 909–919.

Gray SL, Dublin S, Yu O, et al. Benzodiazepine use and risk of incident dementia or cognitive decline: prospective population based study. BMJ. 2016; 352: i90.

Shash D, Kurth T, Bertrand M, et al. Benzodiazepine, psychotropic medication, and dementia: a population-based cohort study. Alzheimers Dement. 2016; 12(5): 604–613.

Richardson K, Mattishent K, Loke YK, et al. History of benzodiazepine prescriptions and risk of dementia: possible bias due to prevalent users and covariate measurement timing in a nested case-control study. Am J of Epidemiol. 2019; 188(7): 1228–1236.

Pariente A, de Gage SB, Moore N, Bégaud B. The benzodiazepine-dementia disorders link: current state of knowledge. CNS Drugs. 2016; 30(1): 1–7.

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