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The effects of long-term benzodiazepine use include
drug dependence Substance dependence, also known as drug dependence, is a biopsychological situation whereby an individual's functionality is dependent on the necessitated re-consumption of a psychoactive substance because of an adaptive state that has develope ...
as well as the possibility of adverse effects on cognitive function, physical health, and mental health. Long-term use is sometimes described as use not shorter than three months. Benzodiazepines are generally effective when used therapeutically in the short term, but even then the risk of dependency can be significantly high. There are significant physical, mental and social risks associated with the long-term use of
benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...
s. Although anxiety can temporarily increase as a withdrawal symptom, there is evidence that a reduction or withdrawal from benzodiazepines can lead to a reduction of anxiety symptoms in the long run. Due to these increasing physical and mental symptoms from long-term use of benzodiazepines, slow withdrawal is recommended for long-term users. Not everyone, however, experiences problems with long-term use. Some of the symptoms that could possibly occur as a result of a withdrawal from benzodiazepines after long-term use include emotional clouding, flu-like symptoms,
suicide Suicide is the act of intentionally causing one's own death. Risk factors for suicide include mental disorders, physical disorders, and substance abuse. Some suicides are impulsive acts driven by stress (such as from financial or ac ...
,
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...
,
headaches A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches. Head ...
,
dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...
,
irritability Irritability is the excitatory ability that living organisms have to respond to changes in their environment. The term is used for both the physiological reaction to stimuli and for the pathological, abnormal or excessive sensitivity to stimul ...
,
lethargy Lethargy is a state of tiredness, sleepiness, weariness, fatigue, sluggishness, or lack of energy. It can be accompanied by depression, decreased motivation, or apathy. Lethargy can be a normal response to inadequate sleep, overexertion, overw ...
, sleep problems,
memory impairment Amnesia is a deficit in memory caused by brain damage or brain diseases,Gazzaniga, M., Ivry, R., & Mangun, G. (2009) Cognitive Neuroscience: The biology of the mind. New York: W.W. Norton & Company. but it can also be temporarily caused by t ...
, personality changes,
aggression Aggression is behavior aimed at opposing or attacking something or someone. Though often done with the intent to cause harm, some might channel it into creative and practical outlets. It may occur either reactively or without provocation. In h ...
, depression, social deterioration as well as employment difficulties, while others never have any side effects from long-term benzodiazepine use. Abruptly or rapidly stopping benzodiazepines can be dangerous; when withdrawing, a gradual reduction in dosage is recommended, under professional supervision. While benzodiazepines are highly effective in the short term, adverse effects associated with long-term use, including impaired cognitive abilities, memory problems, mood swings, and overdoses when combined with other drugs, may make the risk-benefit ratio unfavourable. In addition, benzodiazepines have reinforcing properties in some individuals and thus are considered to be addictive drugs, especially in individuals that have a "drug-seeking" behavior; further, a
physical dependence Physical dependence is a physical condition caused by chronic use of a tolerance-forming drug, in which abrupt or gradual drug withdrawal causes unpleasant physical symptoms. Physical dependence can develop from low-dose therapeutic use of certa ...
can develop after a few weeks or months of use. Many of these adverse effects associated with long-term use of benzodiazepines begin to show improvements three to six months after withdrawal. Other concerns about the effects associated with long-term benzodiazepine use, in some, include dose escalation, benzodiazepine use disorder, tolerance and
benzodiazepine dependence Benzodiazepine dependence (BZD dependence) defines a situation in which one has developed one or more of either tolerance, withdrawal symptoms, drug seeking behaviors, such as continued use despite harmful effects, and maladaptive pattern of su ...
and benzodiazepine withdrawal problems. Both physiological tolerance and dependence can be associated with worsening the adverse effects associated with benzodiazepines. Increased risk of death has been associated with long-term use of benzodiazepines in several studies; however, other studies have not found increased mortality. Due to conflicting findings in studies regarding benzodiazepines and increased risks of death including from cancer, further research in long-term use of benzodiazepines and mortality risk has been recommended; most of the available research has been conducted in prescribed users, even less is known about illicit misusers. The long-term use of benzodiazepines is controversial and has generated significant debate within the medical profession. Views on the nature and severity of problems with long-term use of benzodiazepines differ from expert to expert and even from country to country; some experts even question whether there is any problem with the long-term use of benzodiazepines.


Symptoms

Effects of long-term benzodiazepine use may include
disinhibition Disinhibition, also referred to as behavioral disinhibition, is medically recognized as an orientation towards immediate gratification, leading to impulsive behaviour driven by current thoughts, feelings, and external stimuli, without regard for ...
, impaired concentration and memory, depression, as well as
sexual dysfunction Sexual dysfunction is difficulty experienced by an individual or partners during any stage of normal sexual activity, including physical pleasure, desire, preference, arousal, or orgasm. The World Health Organization defines sexual dysfunction ...
. The long-term effects of benzodiazepines may differ from the adverse effects seen after acute administration of benzodiazepines. An analysis of cancer patients found that those who took tranquillisers or sleeping tablets had a substantially poorer quality of life on all measurements conducted, as well as a worse clinical picture of symptomatology. Worsening of symptoms such as
fatigue Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself. Fatigue (in the medical sense) is sometimes associated wit ...
,
insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...
,
pain Pain is a distressing feeling often caused by intense or damaging Stimulus (physiology), stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sense, sensory and emotional experience associated with, or res ...
,
dyspnea Shortness of breath (SOB), known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing discomfort that ...
and
constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The Human feces, stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the ...
was found when compared against those who did not take tranquillisers or sleeping tablets. Most individuals who successfully discontinue
hypnotic A hypnotic (from Ancient Greek, Greek ''Hypnos'', sleep), also known as a somnifacient or soporific, and commonly known as sleeping pills, are a class of psychoactive drugs whose primary function is to sleep induction, induce sleep and to trea ...
therapy after a gradual taper and do not take benzodiazepines for 6 months have less severe sleep and anxiety problems, are less distressed and have a general feeling of improved health at 6-month follow-up. The use of benzodiazepines for the treatment of anxiety has been found to lead to a significant increase in healthcare costs due to accidents and other adverse effects associated with the long-term use of benzodiazepines.


Cognitive status

Long-term benzodiazepine use can lead to a generalised impairment of
cognition Cognition is the "mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought, ...
, including sustained attention, verbal learning and
memory Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembe ...
and psychomotor, visuo-motor and visuo-conceptual abilities. Transient changes in the brain have been found using
neuroimaging Neuroimaging is the use of quantitative (computational) techniques to study the neuroanatomy, structure and function of the central nervous system, developed as an objective way of scientifically studying the healthy human brain in a non-invasive ...
studies, but no brain abnormalities have been found in patients treated long term with benzodiazepines. When benzodiazepine users cease long-term benzodiazepine therapy, their cognitive function improves in the first six months, although deficits may be permanent or take longer than six months to return to baseline. In the elderly, long-term benzodiazepine therapy is a risk factor for amplifying cognitive decline, although gradual withdrawal is associated with improved cognitive status. A study of
alprazolam Alprazolam, sold under the brand name Xanax among others, is a fast-acting, potent tranquilizer of moderate duration within the triazolobenzodiazepine group of chemicals called benzodiazepines. Alprazolam is most commonly prescribed in the ...
found that 8 weeks administration of alprazolam resulted in deficits that were detectable after several weeks but not after 3.5 years.


Effect on sleep

Sleep can be adversely affected by benzodiazepine dependence. Possible adverse effects on sleep include induction or worsening of sleep disordered breathing. Like
alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...
,
benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...
s are commonly used to treat insomnia in the short term (both prescribed and self-medicated), but worsen sleep in the long term. Although benzodiazepines can put people to sleep, while asleep, the drugs disrupt sleep architecture, decreasing sleep time, delayed and decreased REM sleep, increased alpha and beta activity, decreased K complexes and delta activity, and decreased deep slow-wave sleep (i.e., NREM stages 3 and 4, the most restorative part of sleep for both energy and mood).


Mental and physical health

The long-term use of benzodiazepines may have a similar effect on the brain as
alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...
, and is also implicated in depression,
anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...
, post-traumatic stress disorder (PTSD), mania, psychosis,
sleep disorders A sleep disorder, or somnipathy, is a medical disorder affecting an individual's sleep patterns, sometimes impacting physical, mental, social, and emotional functioning. Polysomnography and actigraphy are tests commonly ordered for diagnosing sle ...
, sexual dysfunction, delirium, and neurocognitive disorders. However a 2016 study found no association between long-term usage and dementia. As with alcohol, the effects of benzodiazepine on neurochemistry, such as decreased levels of
serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...
and
norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...
, are believed to be responsible for their effects on mood and anxiety. Additionally, benzodiazepines can indirectly cause or worsen other psychiatric symptoms (e.g., mood, anxiety, psychosis, irritability) by worsening sleep (i.e., benzodiazepine-induced sleep disorder). These effects are
paradoxical A paradox is a logically self-contradictory statement or a statement that runs contrary to one's expectation. It is a statement that, despite apparently valid reasoning from true or apparently true premises, leads to a seemingly self-contradictor ...
to the use of benzodiazepines, both clinically and non-medically, in management of mental health conditions. Long-term benzodiazepine use may lead to the creation or exacerbation of physical and mental health conditions, which improve after six or more months of abstinence. After a period of about 3 to 6 months of abstinence after completion of a gradual-reduction regimen, marked improvements in mental and physical wellbeing become apparent. For example, one study of hypnotic users gradually withdrawn from their hypnotic medication reported after six months of abstinence that they had less severe sleep and anxiety problems, were less distressed, and had a general feeling of improved health. Those who remained on
hypnotic A hypnotic (from Ancient Greek, Greek ''Hypnos'', sleep), also known as a somnifacient or soporific, and commonly known as sleeping pills, are a class of psychoactive drugs whose primary function is to sleep induction, induce sleep and to trea ...
medication had no improvements in their insomnia, anxiety, or general health ratings. A study found that individuals having withdrawn from benzodiazepines showed a marked reduction in use of medical and mental health services. Approximately half of patients attending mental health services for conditions including
anxiety disorders Anxiety disorders are a group of mental disorders characterized by significant and uncontrollable feelings of anxiety and fear such that a person's social, occupational, and personal functions are significantly impaired. Anxiety may cause phys ...
such as
panic disorder Panic disorder is a mental disorder, specifically an anxiety disorder, characterized by reoccurring unexpected panic attacks. Panic attacks are sudden periods of intense fear that may include palpitations, sweating, shaking, shortness of breath ...
or
social phobia Social anxiety disorder (SAD), also known as social phobia, is an anxiety disorder characterized by sentiments of fear and anxiety in social situations, causing considerable distress and impairing ability to function in at least some as ...
may be the result of alcohol or benzodiazepine dependence. Sometimes anxiety disorders precede
alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...
or benzodiazepine dependence but the alcohol or
benzodiazepine dependence Benzodiazepine dependence (BZD dependence) defines a situation in which one has developed one or more of either tolerance, withdrawal symptoms, drug seeking behaviors, such as continued use despite harmful effects, and maladaptive pattern of su ...
often acts to keep the anxiety disorders going and often progressively makes them worse. Many people who are addicted to alcohol or prescribed benzodiazepines decide to quit when it is explained to them they have a choice between ongoing ill mental health or quitting and recovering from their symptoms. It was noted that because every individual has an individual sensitivity level to alcohol or sedative hypnotic drugs, what one person can tolerate without ill health will cause another to develop very ill health, and that even moderate drinking in sensitive individuals can cause rebound anxiety syndromes and sleep disorders. A person who experiences the toxic effects of alcohol or benzodiazepines will not benefit from other therapies or medications as they do not address the root cause of the symptoms. Recovery from benzodiazepine dependence tends to take a lot longer than recovery from alcohol, but people can regain their previous good health. A review of the literature regarding benzodiazepine
hypnotic A hypnotic (from Ancient Greek, Greek ''Hypnos'', sleep), also known as a somnifacient or soporific, and commonly known as sleeping pills, are a class of psychoactive drugs whose primary function is to sleep induction, induce sleep and to trea ...
drugs concluded that these drugs cause an unjustifiable risk to the individual and to public health. The risks include dependence, accidents and other adverse effects. Gradual discontinuation of hypnotics leads to improved health without worsening of sleep. Daily users of benzodiazepines are also at a higher risk of experiencing psychotic symptomatology such as
delusions A delusion is a fixed belief that is not amenable to change in light of conflicting evidence. As a pathology, it is distinct from a belief based on false or incomplete information, confabulation, dogma, illusion, hallucination, or some other m ...
and
hallucinations A hallucination is a perception in the absence of an external stimulus that has the compelling sense of reality. They are distinguishable from several related phenomena, such as dreaming ( REM sleep), which does not involve wakefulness; pse ...
. A study found that of 42 patients treated with alprazolam, up to a third of long-term users of the benzodiazepine drug alprazolam (
Xanax Alprazolam, sold under the brand name Xanax among others, is a fast-acting, potent tranquilizer of moderate duration within the triazolobenzodiazepine group of chemicals called benzodiazepines. Alprazolam is most commonly prescribed in the ...
) develop depression. Studies have shown that long-term use of benzodiazepines and the benzodiazepine receptor agonist
nonbenzodiazepine Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive, depressant, sedative, hypnotic, anxiolytic drugs that are benzodiazepine-like in uses, such as f ...
Z drugs are associated with causing depression as well as a markedly raised suicide risk and an overall increased mortality risk. A study of 50 patients who attended a benzodiazepine withdrawal clinic found that, after several years of chronic benzodiazepine use, a large portion of patients developed health problems including
agoraphobia Agoraphobia is an anxiety disorder characterized by symptoms of anxiety in situations where the person perceives their environment to be unsafe with no way to escape. These situations can include public transit, shopping centers, crowds and q ...
,
irritable bowel syndrome Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by a group of symptoms that commonly include abdominal pain, abdominal bloating, and changes in the consistency of bowel movements. These symptoms may ...
, paraesthesiae, increasing anxiety, and
panic attacks Panic attacks are sudden periods of intense fear and discomfort that may include palpitations, otherwise defined as a rapid, irregular heartbeat, sweating, chest pain or discomfort, shortness of breath, trembling, dizziness, numbness, con ...
, which were not preexisting. The mental health and physical health symptoms induced by long-term benzodiazepine use gradually improved significantly over a period of a year following completion of a slow withdrawal. Three of the 50 patients had wrongly been given a preliminary diagnosis of
multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...
when the symptoms were actually due to chronic benzodiazepine use. Ten of the patients had taken drug overdoses whilst on benzodiazepines, despite the fact that only two of the patients had any prior history of depressive symptomatology. After withdrawal, no patients took any further overdoses after one year post-withdrawal. The cause of the deteriorating mental and physical health in a significant proportion of patients was hypothesised to be caused by increasing tolerance where withdrawal-type symptoms emerged, despite the administration of stable prescribed doses. Another theory is that chronic benzodiazepine use causes subtle increasing toxicity, which in turn leads to increasing psychopathology in long-term users of benzodiazepines. Long-term use of benzodiazepines can induce
perceptual Perception () is the organization, identification, and interpretation of sensory information in order to represent and understand the presented information or environment. All perception involves signals that go through the nervous syste ...
disturbances and
depersonalization Depersonalization is a dissociative phenomenon characterized by a subjective feeling of detachment from oneself, manifesting as a sense of disconnection from one's thoughts, emotions, sensations, or actions, and often accompanied by a feeling of ...
in some people, even in those taking a stable daily dosage, and it can also become a protracted withdrawal feature of the
benzodiazepine withdrawal syndrome Benzodiazepine withdrawal syndrome (BZD withdrawal) is the cluster of signs and symptoms that may emerge when a person who has been taking benzodiazepines as prescribed develops a physical dependence on them and then reduces the dose or stop ...
. In addition, chronic use of benzodiazepines is a risk factor for
blepharospasm Blepharospasm is a neurological disorder characterized by intermittent, involuntary spasms and contractions of the orbicularis oculi muscle, orbicularis oculi (eyelid) muscles around both eyes. These result in abnormal twitching or blinking, an ...
. Drug-induced symptoms that resemble withdrawal-like effects can occur on a set dosage as a result of prolonged use, also documented with
barbiturate Barbiturates are a class of depressant, depressant drugs that are chemically derived from barbituric acid. They are effective when used medication, medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological a ...
-like substances, as well as alcohol and
benzodiazepines Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat co ...
. This demonstrates that the effects from chronic use of benzodiazepine drugs are not unique but occur with other GABAergic
sedative A sedative or tranquilliser is a substance that induces sedation by reducing irritability or Psychomotor agitation, excitement. They are central nervous system (CNS) Depressant, depressants and interact with brain activity, causing its decelera ...
hypnotic drugs, i.e., alcohol and barbiturates.


Immune system

Chronic use of benzodiazepines seemed to cause significant immunological disorders in a study of selected outpatients attending a psychopharmacology department.
Diazepam Diazepam, sold under the brand name Valium among others, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is used to treat a range of conditions, including anxiety disorder, anxiety, seizures, alcohol withdrawal syndr ...
and
clonazepam Clonazepam, sold under the brand name Klonopin among others, is a benzodiazepine medication used to prevent and treat anxiety disorders, seizures, bipolar mania, agitation associated with psychosis, obsessive–compulsive disorder (OCD), and ...
have been found to have long-lasting, but not permanent, immunotoxic effects in fetuses of rats. However, single very high doses of diazepam have been found to cause lifelong immunosuppression in neonatal rats. No studies have been done to assess the immunotoxic effects of diazepam in humans; however, high prescribed doses of diazepam, in humans, have been found to be a major risk of pneumonia, based on a study of people with tetanus. It has been proposed that diazepam may cause long-lasting changes to the GABAA receptors with resultant long-lasting disturbances to behaviour,
endocrine The endocrine system is a messenger system in an organism comprising feedback loops of hormones that are released by internal glands directly into the circulatory system and that target and regulate distant organs. In vertebrates, the hypotha ...
function and immune function.


Suicide and self-harm

Use of prescribed benzodiazepines is associated with an increased rate of suicide or attempted
suicide Suicide is the act of intentionally causing one's own death. Risk factors for suicide include mental disorders, physical disorders, and substance abuse. Some suicides are impulsive acts driven by stress (such as from financial or ac ...
. The prosuicidal effects of benzodiazepines are suspected to be due to a psychiatric disturbance caused by side effects or withdrawal symptoms. Because benzodiazepines in general may be associated with increased suicide risk, care should be taken when prescribing, especially to at-risk patients. Depressed adolescents who were taking benzodiazepines were found to have a greatly increased risk of
self-harm Self-harm refers to intentional behaviors that cause harm to oneself. This is most commonly regarded as direct injury of one's own skin tissues, usually without suicidal intention. Other terms such as cutting, self-abuse, self-injury, and s ...
or
suicide Suicide is the act of intentionally causing one's own death. Risk factors for suicide include mental disorders, physical disorders, and substance abuse. Some suicides are impulsive acts driven by stress (such as from financial or ac ...
, although the sample size was small. The effects of benzodiazepines in individuals under the age of 18 requires further research. Additional caution is required in using benzodiazepines in depressed adolescents.
Benzodiazepine dependence Benzodiazepine dependence (BZD dependence) defines a situation in which one has developed one or more of either tolerance, withdrawal symptoms, drug seeking behaviors, such as continued use despite harmful effects, and maladaptive pattern of su ...
often results in an increasingly deteriorating clinical picture, which includes social deterioration leading to comorbid
alcohol use disorder Alcoholism is the continued drinking of alcohol despite it causing problems. Some definitions require evidence of dependence and withdrawal. Problematic use of alcohol has been mentioned in the earliest historical records. The World Hea ...
and
substance use disorder Substance use disorder (SUD) is the persistent use of drugs despite substantial harm and adverse consequences to self and others. Related terms include ''substance use problems'' and ''problematic drug or alcohol use''. Along with substance-ind ...
. Benzodiazepine misuse or misuse of other CNS depressants increases the risk of suicide in drug misusers. Benzodiazepine has several risks based on its biochemical function and symptoms associated with this medication like exacerbation of sleep apnea, sedation, suppression of self-care functions, amnesia and disinhibition are suggested as a possible explanation to the increase in mortality. Studies also demonstrate that an increased mortality associated with benzodiazepine use has been clearly documented among 'drug misusers'.


Carcinogenicity

There has been some controversy around the possible link between benzodiazepine use and development of cancer; early cohort studies in the 1980s suggested a possible link, but follow-up case-control studies have found no link between benzodiazepines and cancer. In the second U.S. national cancer study in 1982, the
American Cancer Society The American Cancer Society (ACS) is a nationwide non-profit organization dedicated to eliminating cancer. The ACS publishes the journals ''Cancer'', '' CA: A Cancer Journal for Clinicians'' and '' Cancer Cytopathology''. History The society w ...
conducted a survey of over 1.1 million participants. A markedly increased risk of cancer was found in users of sleeping pills, mainly benzodiazepines. Fifteen epidemiologic studies have suggested that
benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...
or
nonbenzodiazepine Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive, depressant, sedative, hypnotic, anxiolytic drugs that are benzodiazepine-like in uses, such as f ...
hypnotic A hypnotic (from Ancient Greek, Greek ''Hypnos'', sleep), also known as a somnifacient or soporific, and commonly known as sleeping pills, are a class of psychoactive drugs whose primary function is to sleep induction, induce sleep and to trea ...
drug use is associated with increased mortality, mainly due to increased
cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
death. The cancers included cancer of the
brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
,
lung The lungs are the primary Organ (biology), organs of the respiratory system in many animals, including humans. In mammals and most other tetrapods, two lungs are located near the Vertebral column, backbone on either side of the heart. Their ...
,
bowel The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascular system. T ...
,
breast The breasts are two prominences located on the upper ventral region of the torso among humans and other primates. Both sexes develop breasts from the same embryology, embryological tissues. The relative size and development of the breasts is ...
, and
bladder The bladder () is a hollow organ in humans and other vertebrates that stores urine from the kidneys. In placental mammals, urine enters the bladder via the ureters and exits via the urethra during urination. In humans, the bladder is a distens ...
, and other
neoplasms A neoplasm () is a type of abnormal and excessive growth of tissue (biology), tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tiss ...
. It has been hypothesised that benzodiazepines depress immune function and increase viral infections and could be the cause or trigger of the increased rate of cancer. While initially U.S. Food and Drug Administration reviewers expressed concerns about approving the
nonbenzodiazepine Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive, depressant, sedative, hypnotic, anxiolytic drugs that are benzodiazepine-like in uses, such as f ...
Z drugs due to concerns of cancer, ultimately they changed their minds and approved the drugs. A 2017 meta-analysis of multiple observational studies found that benzodiazepine use is associated with increased cancer risk.


Evidence of neurotoxicity

In a study in 1980 in a group of 55 consecutively admitted patients having engaged in non-medical use of exclusively sedatives or hypnotics, neuropsychological performance was significantly lower and signs of intellectual impairment significantly more often diagnosed than in a matched control group taken from the general population. These results suggested a relationship between non-medical use of sedatives or hypnotics and cerebral disorder. A publication asked in 1981 if
lorazepam Lorazepam, sold under the brand name Ativan, Tavor among others, is a benzodiazepine medication. It is used to treat anxiety (including anxiety disorders), insomnia, severe agitation, active seizures including status epilepticus, alcoh ...
is more toxic than
diazepam Diazepam, sold under the brand name Valium among others, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is used to treat a range of conditions, including anxiety disorder, anxiety, seizures, alcohol withdrawal syndr ...
. In a study in 1984, 20 patients having taken long-term benzodiazepines were submitted to brain CT scan examinations. Some scans appeared abnormal. The mean
ventricular-brain ratio Ventricular-brain ratio (VBR), also known as the ventricle-to-brain ratio or ventricle-brain ratio, is the ratio of total Ventricular system, ventricle area to total brain area, which can be calculated with planimetry from brain imagining technique ...
measured by planimetry was increased over mean values in an age- and sex-matched group of control subjects but was less than that in a group of alcoholics. There was no significant relationship between CT scan appearances and the duration of benzodiazepine therapy. The clinical significance of the findings was unclear. In 1986, it was presumed that permanent brain damage may result from chronic use of benzodiazepines similar to alcohol-related brain damage. However, alcohol has many off target effects which prelude its toxic effects, including direct organ toxicity, while benzodiazepines are highly selective in their mechanism of action and present with a significantly greater therapeutic index than alcohol. In 1987, 17 inpatient people who used high doses of benzodiazepines non-medically have anecdotally shown enlarged
cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...
spaces with associated
cerebral atrophy Cerebral atrophy is a common feature of many of the diseases that affect the brain. Atrophy of any tissue means a decrement in the size of the cell, which can be due to progressive loss of cytoplasmic proteins. In brain tissue, atrophy describes ...
. Cerebral atrophy reportedly appeared to be dose dependent with low-dose users having less atrophy than higher-dose users. However, a CT study in 1987 found no evidence of cerebral atrophy in prescribed benzodiazepine users. In 1989, in a 4- to 6-year follow-up study of 30 inpatient people who used benzodiazepines non-medically,
Neuropsychological Neuropsychology is a branch of psychology concerned with how a person's cognition and behavior are related to the brain and the rest of the nervous system. Professionals in this branch of psychology focus on how injuries or illnesses of the brai ...
function was found to be permanently affected in some people with long-term high dose non-medical use of benzodiazepines.
Brain damage Brain injury (BI) is the destruction or degeneration of brain cells. Brain injuries occur due to a wide range of internal and external factors. In general, brain damage refers to significant, undiscriminating trauma-induced damage. A common ...
similar to
alcoholic Alcoholism is the continued drinking of alcohol despite it causing problems. Some definitions require evidence of dependence and withdrawal. Problematic use of alcohol has been mentioned in the earliest historical records. The World Hea ...
brain damage was observed. The
CT scan A computed tomography scan (CT scan), formerly called computed axial tomography scan (CAT scan), is a medical imaging technique used to obtain detailed internal images of the body. The personnel that perform CT scans are called radiographers or ...
abnormalities showed dilatation of the
ventricular system In neuroanatomy, the ventricular system is a set of four interconnected cavities known as cerebral ventricles in the brain. Within each ventricle is a region of choroid plexus which produces the circulating cerebrospinal fluid (CSF). The ventric ...
. However, unlike people who consume excessive alcohol, people who use sedative hypnotic agents non-medically showed no evidence of widened cortical
sulci Sulci or Sulki (in Greek , Stephanus of Byzantium, Steph. B., Ptolemy, Ptol.; , Strabo; , Pausanias (geographer), Paus.), was one of the most considerable cities of ancient Sardinia, situated in the southwest corner of the island, on a small isla ...
. The study concluded that, when cerebral disorder is diagnosed in people who abuse high doses of sedative hypnotics, it is often permanent. However, sampling bias limits extrapolation to other populations or contexts, as does the lack of ability to show causation from the observations made. A CT study in 1993 investigated brain damage in benzodiazepine users and found no overall differences to a healthy control group. A study in 2000 found that long-term benzodiazepine therapy does not result in brain abnormalities. Withdrawal from high-dose use of
nitrazepam Nitrazepam, sold under the brand name Mogadon among others, is a Hypnotic, hypnotic drug of the benzodiazepine class used for short-term relief from severe, disabling anxiety and insomnia. It also has sedative (calming) properties, as well as am ...
anecdotally was alleged in 2001 to have caused severe shock of the whole brain with diffuse slow activity on EEG in one patient after 25 years of use. After withdrawal, abnormalities in hypofrontal brain wave patterns persisted beyond the withdrawal syndrome, which suggested to the authors that organic brain damage occurred from chronic high-dose use of nitrazepam. Professor Heather Ashton, a leading expert on benzodiazepines from
Newcastle University Newcastle University (legally the University of Newcastle upon Tyne) is a public research university based in Newcastle upon Tyne, England. It has overseas campuses in Singapore and Malaysia. The university is a red brick university and a mem ...
Institute of Neuroscience, has stated that there is no structural damage from benzodiazepines, and advocates for further research into long-lasting or possibly permanent symptoms of long-term use of benzodiazepines as of 1996. She has stated that she believes that the most likely explanation for lasting symptoms is persisting but slowly resolving functional changes at the GABAA benzodiazepine receptor level. Newer and more detailed brain scanning technologies such as PET scans and MRI scans had as of 2002 to her knowledge never been used to investigate the question of whether benzodiazepines cause functional or structural brain damage. A 2022 study employing florbetapir (18F) PET and MRI to obtain Total Standardized Uptake Value Ratio (SUVR) of brain amyloid load and hippocampal volume (HV), respectively, in a sample of chronic BZD users and nonusers, was conducted in older adults with minor memory/cognitive complaints/issues. After controlling for multiple confounding variables, chronic BZD users were more likely to present with depression, anxiety, and apathy than nonusers, while the MRI subgroup of BZD users were more likely to be females with lower education and greater clinical impairment on the clinical dementia rating scale. The results showed that SUVR of brain amyloid load and hippocampal volume were significantly lower and higher, respectively, in BZD users compared with nonusers. Although short-acting BZDs had a more significant effect on increased HV, the dose and duration of use were not observed to have an effect. Thus, the following study found a beneficial effect associated with BZD use on two significant diagnostic markers of Alzheimer’s disease. A 2018 review of the research found a likely causative role between the use of benzodiazepines and an increased risk of dementia, but the exact nature of the relationship is still a matter of debate.


History

Benzodiazepines, when introduced in 1961, were widely believed to be safe drugs but as the decades went by increased awareness of
adverse effects An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term complic ...
connected to their long-term use became known. Recommendations for more restrictive medical guidelines followed. Concerns regarding the long-term effects of benzodiazepines have been raised since 1980. These concerns are still not fully answered. A review in 2006 of the literature on use of benzodiazepine and nonbenzodiazepine hypnotics concluded that more research is needed to evaluate the long-term effects of hypnotic drugs. The majority of the problems of benzodiazepines are related to their long-term use rather than their short-term use. There is growing evidence of the harm of long-term use of benzodiazepines, especially at higher doses. In 2007, the
Department of Health A health department or health ministry is a part of government which focuses on issues related to the general health of the citizenry. Subnational entities, such as states, counties and cities, often also operate a health department of their o ...
recommended that individuals on long-term benzodiazepines be monitored at least every 3 months and also recommended against long-term substitution therapy in benzodiazepine drug misusers due to a lack of evidence base for effectiveness and due to the risks of long-term use. The long-term effects of benzodiazepines are very similar to the
long-term effects of alcohol consumption The long-term effects of alcohol consumption on health are predominantly detrimental, with the severity and range of harms generally increasing with the cumulative amount of alcohol consumed over a lifetime. The extent of these effects varies depen ...
(apart from organ toxicity) and other sedative-hypnotics. Withdrawal effects and dependence are not identical. Dependence can be managed, with a medical professional of course, but withdrawal can be fatal. Physical dependence and withdrawal are very much related but not the same thing. A report in 1987 by the Royal College of Psychiatrists in Great Britain reported that any benefits of long-term use of benzodiazepines are likely to be far outweighed by the risks of long-term use. Despite this benzodiazepines are still widely prescribed. The
socioeconomic Economics () is a behavioral science that studies the Production (economics), production, distribution (economics), distribution, and Consumption (economics), consumption of goods and services. Economics focuses on the behaviour and interac ...
costs of the continued widespread prescribing of benzodiazepines is high.


Political controversy

In 1980, the
Medical Research Council (United Kingdom) The Medical Research Council (MRC) is responsible for co-coordinating and funding medical research in the United Kingdom. It is part of United Kingdom Research and Innovation (UKRI), which came into operation 1 April 2018, and brings together ...
recommended that research be conducted into the effects of long-term use of benzodiazepines A 2009
British Government His Majesty's Government, abbreviated to HM Government or otherwise UK Government, is the central government, central executive authority of the United Kingdom of Great Britain and Northern Ireland.
parliamentary inquiry recommended that research into the long-term effects of benzodiazepines must be carried out. The view of the Department of Health is that they have made every effort to make doctors aware of the problems associated with the long-term use of benzodiazepines, as well as the dangers of benzodiazepine drug addiction. In 1980, the
Medicines and Healthcare products Regulatory Agency The Medicines and Healthcare products Regulatory Agency (MHRA) is an executive agency of the Department of Health and Social Care in the United Kingdom which is responsible for ensuring that medicines and medical devices work and are accepta ...
's Committee on the Safety of Medicines issued guidance restricting the use of benzodiazepines to short-term use and updated and strengthened these warnings in 1988. When asked by Phil Woolas in 1999 whether the Department of Health had any plans to conduct research into the long-term effects of benzodiazepines, the Department replied, saying they have no plans to do so, as benzodiazepines are already restricted to short-term use and monitored by regulatory bodies. In a
House of Commons The House of Commons is the name for the elected lower house of the Bicameralism, bicameral parliaments of the United Kingdom and Canada. In both of these countries, the Commons holds much more legislative power than the nominally upper house of ...
debate, Phil Woolas claimed that there had been a cover-up of problems associated with benzodiazepines because they are of too large of a scale for governments, regulatory bodies, and the pharmaceutical industry to deal with. John Hutton stated in response that the Department of Health took the problems of benzodiazepines extremely seriously and was not sweeping the issue under the carpet. In 2010, the All-Party Parliamentary Group on Involuntary Tranquilliser Addiction filed a complaint with the
Equality and Human Rights Commission The Equality and Human Rights Commission (EHRC) is a non-departmental public body in Great Britain, established by the Equality Act 2006 with effect from 1 October 2007. The Commission has responsibility for the promotion and enforcement of e ...
under the
Disability Discrimination Act 1995 The Disability Discrimination Act 1995 (c. 50) (informally, and hereafter, the DDA) is an Act of the Parliament of the United Kingdom which has now been repealed and replaced by the Equality Act 2010, except in Northern Ireland where the A ...
against the Department of Health and the
Department for Work and Pensions The Department for Work and Pensions (DWP) is a Departments of the Government of the United Kingdom, ministerial department of the Government of the United Kingdom. It is responsible for welfare spending, welfare, pensions and child maintenance ...
alleging discrimination against people with a benzodiazepine prescription drug dependence as a result of denial of specialised treatment services, exclusion from medical treatment, non-recognition of the protracted
benzodiazepine withdrawal syndrome Benzodiazepine withdrawal syndrome (BZD withdrawal) is the cluster of signs and symptoms that may emerge when a person who has been taking benzodiazepines as prescribed develops a physical dependence on them and then reduces the dose or stop ...
, as well as denial of rehabilitation and back-to-work schemes. Additionally the APPGITA complaint alleged that there is a "virtual prohibition" on the collection of statistical information on benzodiazepines across government departments, whereas with other controlled drugs there are enormous volumes of statistical data. The complaint alleged that the discrimination is deliberate, large scale and that government departments are aware of what they are doing.


Declassified Medical Research Council meeting

The
Medical Research Council (UK) The Medical Research Council (MRC) is responsible for co-coordinating and funding medical research in the United Kingdom. It is part of United Kingdom Research and Innovation (UKRI), which came into operation 1 April 2018, and brings together ...
held a closed meeting among top UK medical doctors and representatives from the pharmaceutical industry between 30 October 1980 and 3 April 1981. The meeting was classified under the
Public Records Act 1958 The Public Records Act 1958 ( 6 & 7 Eliz. 2. c. 51) is an Act of the Parliament of the United Kingdom forming the main legislation governing public records in the United Kingdom. It established a cohesive regulatory framework for public records ...
until 2014 but became available in 2005 as a result of the Freedom of Information Act. The meeting was called due to concerns that 10–100,000 people could be dependent; meeting chairman Professor Malcolm Lader later revised this estimate to include approximately half a million members of the British public suspected of being dependent on therapeutic dose levels of benzodiazepines, with about half of those on long-term benzodiazepines. It was reported that benzodiazepines may be the third- or fourth-largest drug problem in the UK (the largest being alcohol and tobacco). The chairman of the meeting followed up after the meeting with additional information, which was forwarded to the Medical Research Council neuroscience board, raising concerns regarding tests that showed definite cortical atrophy in 2 of 14 individuals tested and borderline abnormality in five others. He felt that, due to the methodology used in assessing the scans, the abnormalities were likely an underestimate, and more refined techniques would be more accurate. Also discussed were findings that tolerance to benzodiazepines can be demonstrated by injecting diazepam into long-term users; in normal subjects, increases in
growth hormone Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in ...
occurs, whereas in benzodiazepine-tolerant individuals this effect is blunted. Also raised were findings in animal studies that showed the development of tolerance in the form of a 15 percent reduction in binding capacity of benzodiazepines after seven days administration of high doses of the partial agonist benzodiazepine drug flurazepam and a 50 percent reduction in binding capacity after 30 days of a low dose of diazepam. The chairman was concerned that papers soon to be published would "stir the whole matter up" and wanted to be able to say that the Medical Research Council "had matters under consideration if questions were asked in parliament". The chairman felt that it "was very important, politically that the MRC should be 'one step ahead'" and recommended epidemiological studies be funded and carried out by Roche Pharmaceuticals and MRC sponsored research conducted into the biochemical effects of long-term use of benzodiazepines. The meeting aimed to identify issues that were likely to arise, alert the Department of Health to the scale of the problem and identify the pharmacology and nature of benzodiazepine dependence and the volume of benzodiazepines being prescribed. The
World Health Organization The World Health Organization (WHO) is a list of specialized agencies of the United Nations, specialized agency of the United Nations which coordinates responses to international public health issues and emergencies. It is headquartered in Gen ...
was also interested in the problem and it was felt the meeting would demonstrate to the WHO that the MRC was taking the issue seriously. Among the psychological effects of long-term use of benzodiazepines discussed was a reduced ability to cope with stress. The chairman stated that the "withdrawal symptoms from valium were much worse than many other drugs including, e.g., heroin". It was stated that the likelihood of withdrawing from benzodiazepines was "reduced enormously" if benzodiazepines were prescribed for longer than four months. It was concluded that benzodiazepines are often prescribed inappropriately, for a wide range of conditions and situations. Dr Mason (
DHSS The Department of Health and Social Security (commonly known as the DHSS) was a ministry of the British government in existence for twenty years from 1968 until 1988, and was headed by the Secretary of State for Social Services. History In 1 ...
) and Dr Moir ( SHHD) felt that, due to the large numbers of people using benzodiazepines for long periods of time, it was important to determine the effectiveness and toxicity of benzodiazepines before deciding what regulatory action to take. Controversy resulted in 2010 when the previously secret files came to light over the fact that the Medical Research Council was warned that benzodiazepines prescribed to millions of patients appeared to cause
cerebral atrophy Cerebral atrophy is a common feature of many of the diseases that affect the brain. Atrophy of any tissue means a decrement in the size of the cell, which can be due to progressive loss of cytoplasmic proteins. In brain tissue, atrophy describes ...
similar to hazardous alcohol use in some patients and failed to carry out larger and more rigorous studies. ''
The Independent on Sunday ''The Independent'' is a British online newspaper. It was established in 1986 as a national morning printed paper. Nicknamed the ''Indy'', it began as a broadsheet and changed to tabloid format in 2003. The last printed edition was publishe ...
'' reported allegations that "scores" of the 1.5 million members of the UK public who use benzodiazepines long-term have symptoms that are consistent with brain damage. It has been described as a "huge scandal" by Jim Dobbin, and legal experts and MPs have predicted a class action lawsuit. A solicitor said she was aware of the past failed litigation against the drug companies and the relevance the documents had to that court case and said it was strange that the documents were kept 'hidden' by the MRC. Professor Lader, who chaired the MRC meeting, declined to speculate as to why the MRC declined to support his request to set up a unit to further research benzodiazepines and why they did not set up a special safety committee to look into these concerns. Professor Lader stated that he regrets not being more proactive on pursuing the issue, stating that he did not want to be labeled as the guy who pushed only issues with benzos. Professor Ashton also submitted proposals for grant-funded research using MRI, EEG, and cognitive testing in a randomized controlled trial to assess whether benzodiazepines cause permanent damage to the brain, but similarly to Professor Lader was turned down by the MRC. The MRC spokesperson said they accept the conclusions of Professor Lader's research and said that they fund only research that meets required quality standards of scientific research, and stated that they were and continue to remain receptive to applications for research in this area. No explanation was reported for why the documents were sealed by the Public Records Act. Jim Dobbin, who chaired the All-Party Parliamentary Group for Involuntary Tranquilliser Addiction, stated that: The legal director of Action Against Medical Accidents said urgent research must be carried out and said that, if the results of larger studies confirm Professor Lader's research, the government and MRC could be faced with one of the biggest group actions for damages the courts have ever seen, given the large number of people potentially affected. People who report enduring symptoms post-withdrawal such as neurological pain, headaches, cognitive impairment, and memory loss have been left in the dark as to whether these symptoms are drug-induced damage or not due to the MRC's inaction, it was reported. Professor Lader reported that the results of his research did not surprise his research group given that it was already known that alcohol could cause permanent brain changes.


Class-action lawsuit

Benzodiazepines spurred the largest-ever
class-action lawsuit A class action is a form of lawsuit. Class Action may also refer to: * ''Class Action'' (film), 1991, starring Gene Hackman and Mary Elizabeth Mastrantonio * Class Action (band), a garage house band * "Class Action" (''Teenage Robot''), a 2002 e ...
against drug manufacturers in the United Kingdom, in the 1980s and early 1990s, involving 14,000 patients and 1,800
law firms A law firm is a business entity formed by one or more lawyers to engage in the practice of law. The primary service rendered by a law firm is to advise consumer, clients (individuals or corporations) about their legal rights and Obligation, respon ...
that alleged the manufacturers knew of the potential for dependence but intentionally withheld this information from doctors. At the same time, 117 general practitioners and 50 health authorities were sued by patients to recover damages for the harmful effects of dependence and withdrawal. This led some doctors to require a signed consent form from their patients and to recommend that all patients be adequately warned of the risks of dependence and withdrawal before starting treatment with benzodiazepines. The court case against the drug manufacturers never reached a verdict;
legal aid Legal aid is the provision of assistance to people who are unable to afford legal representation and access to the court system. Legal aid is regarded as central in providing access to justice by ensuring equality before the law, the right ...
had been withdrawn, leading to the collapse of the trial, and there were allegations that the consultant psychiatrists, the expert witnesses, had a conflict of interest. This litigation led to changes in British law, making class-action lawsuits more difficult.


Special populations


Neonatal effects

Benzodiazepines have been found to cause teratogenic malformations. The literature concerning the safety of benzodiazepines in pregnancy is unclear and controversial. Initial concerns regarding benzodiazepines in pregnancy began with alarming findings in animals but these do not necessarily cross over to humans. Conflicting findings have been found in babies exposed to benzodiazepines. A recent analysis of the Swedish Medical Birth Register found an association with preterm births, low birth weight and a moderate increased risk for congenital malformations. An increase in pylorostenosis or
alimentary tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascular system. T ...
atresia Atresia is a condition in which an orifice or passage in the body is (usually abnormally) closed or absent. Types Anotia Anotia is characterized by the complete absence of the ear and is extremely rare. This condition may affect one or both ...
was seen. An increase in orofacial clefts was not demonstrated, however, and it was concluded that benzodiazepines are not major teratogens.
Neurodevelopmental disorders Neurodevelopmental disorders are a group of mental conditions negatively affecting the development of the nervous system, which includes the human brain, brain and spinal cord. According to the American Psychiatric Association Diagnostic and Sta ...
and clinical symptoms are commonly found in babies exposed to benzodiazepines in utero. Benzodiazepine-exposed babies have a low birth weight but catch up to normal babies at an early age, but smaller head circumferences found in exposed infants persists. Other adverse effects of benzodiazepines taken during pregnancy are deviating
neurodevelopmental The development of the nervous system, or neural development (neurodevelopment), refers to the processes that generate, shape, and reshape the nervous system of animals, from the earliest stages of embryonic development to adulthood. The field ...
and clinical symptoms including
craniofacial Craniofacial surgery is a surgical subspecialty that deals with congenital and acquired deformities of the head, skull, face, neck, jaws and associated structures. Although craniofacial treatment often involves manipulation of bone, craniofacial ...
anomalies, delayed development of pincer grasp, deviations in
muscle tone In physiology, medicine, and anatomy, muscle tone (residual muscle tension or tonus) is the continuous and passive partial contraction of the muscles, or the muscle's resistance to passive stretch during resting state.O’Sullivan, S. B. (2007) ...
and pattern of movements. Motor impairments in the babies are impeded for up to 1 year after birth. Gross motor development impairments take 18 months to return to normal but fine motor function impairments persist. In addition to the smaller head circumference found in benzodiazepine-exposed babies
mental retardation Intellectual disability (ID), also known as general learning disability (in the United Kingdom), and formerly mental retardation (in the United States), Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010).Archive is a generalized neurodevelopmental ...
, functional deficits, long-lasting behavioural anomalies, and lower intelligence occurs. Benzodiazepines, like many other sedative hypnotic drugs, cause apoptotic
neuronal A neuron (American English), neurone (British English), or nerve cell, is an excitable cell that fires electric signals called action potentials across a neural network in the nervous system. They are located in the nervous system and help to ...
cell death. However, benzodiazepines do not cause as severe
apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
to the developing brain as alcohol does. The
prenatal Prenatal development () involves the embryonic development, development of the embryo and of the fetus during a viviparity, viviparous animal's gestation. Prenatal development starts with fertilization, in the germinal stage of embryonic develop ...
toxicity of benzodiazepines is most likely due to their effects on neurotransmitter systems,
cell membranes The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extra ...
and
protein synthesis Protein biosynthesis, or protein synthesis, is a core biological process, occurring inside cells, balancing the loss of cellular proteins (via degradation or export) through the production of new proteins. Proteins perform a number of critica ...
. This, however, is complicated in that
neuropsychological Neuropsychology is a branch of psychology concerned with how a person's cognition and behavior are related to the brain and the rest of the nervous system. Professionals in this branch of psychology focus on how injuries or illnesses of the brai ...
or neuropsychiatric effects of benzodiazepines, if they occur, may not become apparent until later
childhood A child () is a human being between the stages of childbirth, birth and puberty, or between the Development of the human body, developmental period of infancy and puberty. The term may also refer to an unborn human being. In English-speaking ...
or even
adolescence Adolescence () is a transitional stage of human Developmental biology, physical and psychological Human development (biology), development that generally occurs during the period from puberty to adulthood (typically corresponding to the age o ...
. A review of the literature found data on long-term follow-up regarding neurobehavioural outcomes is very limited. However, a study was conducted that followed up 550 benzodiazepine-exposed children, which found that, overall, most children developed normally. There was a smaller subset of benzodiazepine-exposed children who were slower to develop, but by four years of age most of this subgroup of children had normalised. There was a small number of benzodiazepine-exposed children who had continuing developmental abnormalities at 4-year follow-up, but it was not possible to conclude whether these deficits were the result of benzodiazepines or whether social and environmental factors explained the continuing deficits. Concerns regarding whether benzodiazepines during pregnancy cause major malformations, in particular cleft palate, have been hotly debated in the literature. A
meta analysis Meta-analysis is a method of synthesis of quantitative data from multiple independent studies addressing a common research question. An important part of this method involves computing a combined effect size across all of the studies. As such, th ...
of the data from
cohort studies A cohort study is a particular form of longitudinal study that samples a cohort (a group of people who share a defining characteristic, typically those who experienced a common event in a selected period, such as birth or graduation), performing ...
found no link but
meta analysis Meta-analysis is a method of synthesis of quantitative data from multiple independent studies addressing a common research question. An important part of this method involves computing a combined effect size across all of the studies. As such, th ...
of case–control studies did find a significant increase in major malformations. (However, the cohort studies were homogenous and the case–control studies were heterogeneous, thus reducing the strength of the case–control results). There have also been several reports that suggest that benzodiazepines have the potential to cause a syndrome similar to
fetal alcohol syndrome Fetal alcohol spectrum disorders (FASDs) are a group of conditions that can occur in a person who is exposed to alcohol during gestation. FASD affects 1 in 20 Americans, but is highly misdiagnosed and underdiagnosed. The several forms of the ...
, but this has been disputed by a number of studies. As a result of conflicting findings, use of benzodiazepines during pregnancy is controversial. The best available evidence suggests that benzodiazepines are not a major cause of
birth defects A birth defect is an abnormal condition that is present at birth, regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can range from mild to severe. Birth de ...
, i.e. major malformations or
cleft lip A cleft lip contains an opening in the upper lip that may extend into the nose. The opening may be on one side, both sides, or in the middle. A cleft palate occurs when the palate (the roof of the mouth) contains an opening into the nasal cavi ...
or
cleft palate A cleft lip contains an opening in the upper lip that may extend into the nose. The opening may be on one side, both sides, or in the middle. A cleft palate occurs when the palate (the roof of the mouth) contains an opening into the nose. The ...
.


Elderly

Significant toxicity from benzodiazepines can occur in the elderly as a result of long-term use.
Benzodiazepines Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat co ...
, along with antihypertensives and drugs affecting the cholinergic system, are the most common cause of drug-induced
dementia Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...
affecting over 10 percent of patients attending memory clinics. Long-term use of benzodiazepines in the elderly can lead to a pharmacological syndrome with symptoms including
drowsiness Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...
,
ataxia Ataxia (from Greek α- negative prefix+ -τάξις rder= "lack of order") is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in e ...
, fatigue,
confusion In psychology, confusion is the quality or emotional state of being bewildered or unclear. The term "acute mental confusion"
,
weakness Weakness is a symptom of many different medical conditions. The causes are many and can be divided into conditions that have true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, ...
,
dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...
,
vertigo Vertigo is a condition in which a person has the sensation that they are moving, or that objects around them are moving, when they are not. Often it feels like a spinning or swaying movement. It may be associated with nausea, vomiting, perspira ...
, syncope, reversible
dementia Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...
, depression, impairment of intellect, psychomotor and
sexual dysfunction Sexual dysfunction is difficulty experienced by an individual or partners during any stage of normal sexual activity, including physical pleasure, desire, preference, arousal, or orgasm. The World Health Organization defines sexual dysfunction ...
, agitation, auditory and visual hallucinations, paranoid ideation,
panic Panic is a sudden sensation of fear, which is so strong as to dominate or prevent reason and logical thinking, replacing it with overwhelming feelings of anxiety, uncertainty and frantic agitation consistent with a fight-or-flight reaction. ...
,
delirium Delirium (formerly acute confusional state, an ambiguous term that is now discouraged) is a specific state of acute confusion attributable to the direct physiological consequence of a medical condition, effects of a psychoactive substance, or ...
,
depersonalization Depersonalization is a dissociative phenomenon characterized by a subjective feeling of detachment from oneself, manifesting as a sense of disconnection from one's thoughts, emotions, sensations, or actions, and often accompanied by a feeling of ...
,
sleepwalking Sleepwalking, also known as somnambulism or noctambulism, is a phenomenon of combined sleep and wakefulness. It is classified as a sleep disorder belonging to the parasomnia family. It occurs during the slow wave stage of sleep, in a state of ...
, aggressivity,
orthostatic hypotension Orthostatic hypotension, also known as postural hypotension, is a medical condition wherein a person's blood pressure drops when they are standing up ( orthostasis) or sitting down. Primary orthostatic hypotension is also often referred to as ne ...
and
insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...
. Depletion of certain neurotransmitters and
cortisol Cortisol is a steroid hormone in the glucocorticoid class of hormones and a stress hormone. When used as medication, it is known as hydrocortisone. Cortisol is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal corte ...
levels and alterations in immune function and biological markers can also occur. Elderly individuals who have been long-term users of benzodiazepines have been found to have a higher incidence of post-operative confusion. Benzodiazepines have been associated with increased body sway in the elderly, which can potentially lead to fatal accidents including falls. Discontinuation of benzodiazepines leads to improvement in the balance of the body and also leads to improvements in cognitive functions in the elderly benzodiazepine
hypnotic A hypnotic (from Ancient Greek, Greek ''Hypnos'', sleep), also known as a somnifacient or soporific, and commonly known as sleeping pills, are a class of psychoactive drugs whose primary function is to sleep induction, induce sleep and to trea ...
users without worsening of insomnia. A review of the evidence has found that whilst long-term use of benzodiazepines impairs memory, its association with causing dementia is not clear and requires further research. A more recent study found that benzodiazepines are associated with an increased risk of dementia and it is recommended that benzodiazepines be avoided in the elderly. A later study, however, found no increase in dementia associated with long-term usage of benzodiazepine.


See also

*
Long-term effects of alcohol consumption The long-term effects of alcohol consumption on health are predominantly detrimental, with the severity and range of harms generally increasing with the cumulative amount of alcohol consumed over a lifetime. The extent of these effects varies depen ...
*
Benzodiazepine withdrawal syndrome Benzodiazepine withdrawal syndrome (BZD withdrawal) is the cluster of signs and symptoms that may emerge when a person who has been taking benzodiazepines as prescribed develops a physical dependence on them and then reduces the dose or stop ...
*
Benzodiazepine dependence Benzodiazepine dependence (BZD dependence) defines a situation in which one has developed one or more of either tolerance, withdrawal symptoms, drug seeking behaviors, such as continued use despite harmful effects, and maladaptive pattern of su ...


References

{{DEFAULTSORT:Long-Term Effects Of Benzodiazepines Substance dependence Drug rehabilitation Neuropharmacology Substance-related disorders Syndromes Benzodiazepines Long-term Effects Adverse effects of psychoactive drugs