Benzodiazepines (BZDs) are among one of the most widely prescribed drug classes in the United States. BZDs are a class of psychoactive drugs known for their depressant effect on the central nervous system (CNS). They quickly diffuse through the blood–brain barrier to affect the inhibitory neurotransmitter GABA and exert sedative effects. One of the debilitating side effects of BZDs is their addictive potential. The dependence on BZDs generally leads to withdrawal symptoms, requiring careful tapering of the medication when prescribed. Regular use of BZDs has been shown to cause severe, harmful psychological and physical dependence, leading to withdrawal symptoms similar to that of alcohol withdrawal.
Benzodiazepines (BZDs) are among one of the most widely prescribed drug classes in the United States. BZDs are a class of psychoactive drugs known for their depressant effect on the central nervous system (CNS). They quickly diffuse through the blood–brain barrier to affect the inhibitory neurotransmitter GABA and exert sedative effects. GABA is the most common neurotransmitter in the CNS, and BZDs primarily work on the GABA-A receptor subunit 
. The GABA-A receptor has various subunits, and the most important in this case is the alpha (A) submit unit. The alpha subunit has various isoforms, which dictate a BZD’s effects on the CNS. The A1 subunit is believed to be responsible for the sedative effects and anterograde amnesia, and some of the anticonvulsive impacts of diazepam 
. The A2 subunit isoform mediates the anxiolytic and myorelaxant effects 
. In total, there are six isoforms of the GABA-A subunit. To be specific in terms of binding sites and actions, BZD binds between the alpha and the gamma subunit. It enhances the effect of GABA at the GABA-A receptor, allowing it to exert a more significant effect 
Given their lipid solubility, BZDs have a high volume of distribution in the body, which translates to higher tissue concentrations than blood. After exerting their effect, BZDs are metabolized primarily by the liver and excreted by conjugation, so they should be used in caution in the elderly, smokers, and those with liver disease or damage 
. Due to their rapid onset and immediate symptom relief, BZDs are used for those struggling with sleep, anxiety, spasticity due to CNS pathology, muscle relaxation, and epilepsy. Their sedative effect aids in sleep and insomnia disorders by reducing sleep onset latency. Their CNS depressant effects potently reduce anxiety and abort acute-onset panic and anxiety attacks 
. Benzodiazepines are also incredibly effective at rapidly aborting convulsant activity in those with epilepsy or other seizure disorders 
BZDs gained popularity in the 1960s and 1970s through household names such as The Rolling Stones and numerous Hollywood movies sensationalizing Valium (diazepam). BZDs were encouraged for anyone wanting to calm their nerves and ease their sleep, causing them to rapidly attain favor in society 
. Additionally, given the continual rise of anxiety and sleep-disordered problems over the decades, BZDs remain a regular fixture in the United States today 
. However, with this ongoing, widespread use comes the dark reality of BZD dependence 
Chronic users of the drug class often exhibit reliance with a high risk for abuse. This should provide pause, as BZD discontinuation after chronic use leads to withdrawal symptoms, with heavy users at risk for seizure activity 
. Short-acting BZDs appear to carry more significant risks of adverse effects on abrupt cessation and usually exhibit greater dependence 
. Several factors determine the rate and severity of withdrawal from the hypnotic. These are (1) the duration of use, (2) elimination half-life (short- or long-acting), (3) daily dosage, (4) rate of the taper and (5) the potency of the BZD itself 
. One study found a withdrawal rate of approximately 40% in those using for six or more months with abrupt cessation of long-acting BZDs 
. BZDs should especially be cautioned for use in the elderly, as the medication can lower the seizure threshold, cause gait instability, and balance problems 
. Currently, the number of individuals seeking treatment for complications related to BZD use dependence is rising 
. Therefore, the aim of this review is to highlight the indications for BZD use, the dangers of withdrawal from BZD, concerns regarding the cognitive decline associated with BZD use, and the clinical studies regarding this cognitive decline and treatment of withdrawal symptoms.
2. Benzodiazepine Overuse Pathology, Misuses, and Complications
2.1. The Effects of Benzodiazepine on Cognition
Many studies have examined the effects of benzodiazepines on cognition with varied results. Some of the variations in results may be attributed to cognitive criteria in which each study followed. In a prospective longitudinal study on the effects of psychotropic drugs in the cognition of the elderly, Allard et al. 
found no significant long-term effect of BZD use on cognition. This is supported in a similar study of elderly adults on a BZD for six months with drug discontinuation one month later. The study found no significant cognitive impairment in adults with long-term use of BZD 
. A study of over 2000 older adults assessed the effects of chronic BZD use on cognition 
. Chronic use of BZD leads to a small but significant change in fluid intelligence, while long-term use of BZD correlates with worse cognitive decline when compared to the effects of using a high dosage 
2.2. Side Effects of Benzodiazepine Use
Passaro et al. described an increased risk of falls in elderly hospitalized patients prescribed short-acting BZD . For mothers with BZD use during pregnancy, there is a risk of premature birth and low birth weight. While the study showed some teratogenic effects of BZDs on fetuses, the result is not statistically significant, and some of the malformations seen in fetuses in the study may have been due to the use of other medications such as antidepressants . One of the debilitating side effects of BZDs is their addictive potential. Their relative safety compared to fellow depressants or barbiturates have increased the rate at which they are prescribed . The dependence on BZDs generally leads to withdrawal symptoms, which necessitates careful tapering of the medication when prescribed .
2.3. Misuse of Benzodiazepine
There has been a steady increase in the number of prescribed BZDs in the US 
. Bachhuber et al. 2016 reported an increase in ED visits for overdose and increased overdose death due to BZD use 
. Women are more susceptible to BZD overuse because they are more likely to be prescribed than men 
. Mclean et al. 2011 reported that the diagnosis of anxiety and stress disorders has a higher prevalence in women, which can explain the discrepancies in the prescription for men vs. women 
It has been shown that patients diagnosed with substance use disorder have increased tendencies to misuse BZD compared to the general population 
. Although women are prescribed BZDs more commonly than men, Mchugh et al., 2021 reported no gender-based misuse of BZD in adults with substance abuse disorder 
2.4. Complications of Benzodiazepine Abuse
One of the main categories of people with BZD prescriptions is those with insomnia. Manconi et al. explored the effects of long-term BZD use on sleep architecture and microstructure in those with insomnia. They found significant changes in sleep microstructure in chronic insomnia with high dosage abuse of BZD, but sleep architecture changes were not significant. Long-term use of BZD leads to negative changes in sleep microstructure in patients with insomnia 
2.5. Issues with Clinical Use of Benzodiazepine
In 2018, between 8.3% and 12.8% of BZD users in Switzerland have prescriptions from multiple physicians which resulted in the inability to track the number of prescriptions a patient is given yearly 
. In a survey of British general practitioners, many reported pressures in prescribing BZD to patients and a lack of adequate knowledge on alternative psychological treatment for insomnia 
BZDs are classified either by their duration of action or potency. The difference in these characteristics dictates the clinical applicability of the drugs. Oxazepam, temazepam, and chlordiazepoxide which are low potency benzodiazepines are well tolerated with low toxicity levels. Alprazolam, lorazepam and clonazepam are high potently clinically used to treat panic disorders and serve as adjuncts for treating many other diseases 
. Due to their toxic effect on the central nervous system, appropriate care is necessary with BZD. BZDs lead to long-lasting impairment of episodic implicit memory while it only impairs implicit memory transiently 
. They also lead to disinhibition, impairing the user’s ability to appropriately assess the risky actions or behaviors. Elderly patients in intensive care can develop delirium if they are on a BZD 
Researchers studied the neuroplastic effects of diazepam on mice. Results showed that, compared to wild-type mice, mice on diazepam experienced longer uninterrupted sleep 
. It also reduces the expression of mRNA transcripts such as CaMKIIa, BDNF, GIF, c-fos, NGFIa which are necessary for regulating synapses and plasticity 
. The suppression of CaMKIIa by diazepam has a long-lasting effect leading to a limited neuronal response to changes in intracellular calcium and decreased response by GABA-A receptors 
3. Benzodiazepine Use Dangers
A study analyzing over 1000 cases of oxycodone-related drug abuse deaths showed that BZDs are among the most abused drugs by individuals using multiple drugs of abuse. The study showed that in oxycodone users, combination use with diazepam was the most prevalent . This was further supported by data from Rooney et al. which reported that 54% of abusers of oxycodone are also dependent on a BZD . The study also showed that 64% of heroin users are also abusing BZD .
Abrahamsson et al. investigated the relationship between hypnotic drug overdose versus non-overdose deaths in patients on opioid maintenance therapy. They showed that benzodiazepine increased the incidence of non-overdose death in these patients which may be attributed to its impairment of cognition, sensory, and motor skills and increased risk of fall leading to injuries 
. Despite the increase in risk, less than 13% of the non-overdose deaths were trauma related. A study investigating the prescription of opioids and BZD in veterans showed an increased risk of overdose death in veterans who have prescriptions for both BZD and opioids at the same time 
. The dose of BZD given also positively correlated with increased risk of an overdose death 
In a literature review exploring the relationship between BZD and suicide risk, it stated that although anxiety and insomnia which are often treated with a BZD, it can increase the risk of suicide; several studies in the literature have suggested that BZD use is also involved in increased suicide risk in its users 
. The use and discontinuation of alprazolam within 2 weeks disrupt sleep onset and quality, increasing suicide risks 
4.1. Symptoms of Withdrawal
Regular use of BZDs has been shown to cause serious, harmful psychological and physical dependence, leading to withdrawal symptoms similar to that of alcohol withdrawal. Regular use of BZDs can lead to tolerance, which is the physiologic dependence on the presence of BZDs in the body’s system. This can be linked to addiction as the patient is not just psychologically addicted to the substance, which can be seen with cravings, and physical addiction. Withdrawal, like with alcohol since they exert their effects on similar receptors, can be life threatening. Withdrawal occurs as the BZD concentration in blood and tissue declines, generally causing symptoms opposite to that of the drug’s therapeutic effects. Psychological symptoms include increased excitability, nightmares, anxiety, insomnia, panic attacks, depression, hallucinations, irritability, paranoid thoughts, social phobia, poor memory, poor concentration, delirium, and even psychosis. Physical symptoms include headache, seizures, pain or stiffness in the head and neck region, an altered sensation of limbs, weakness and fatigue, tingling and numbness, muscle twitches, tremors, gastrointestinal symptoms (abdominal distension, nausea, diarrhea, constipation, etc.), appetite and weight changes, unusual smell, and others have been documented 
. These symptoms may last for one to a few weeks after cessation, with duration and severity largely depending upon the amount of time spent chronically taking the BZD, the half-life of the specific BZD, and the daily dose consumed 
4.2. Mechanism of Withdrawal
Symptoms associated with withdrawal occur due to the chronic effect on the GABA-A receptors in the CNS to BZDs. Over time, this causes a neuroadaptive process of both desensitization of the inhibitory function of GABA, sensitization of excitatory glutamine receptors, and possibly sensitization of N-methyl-D-aspartate (NMDA) receptors, along with other receptors. These changes contribute to tolerance to specific BZD and dosage, mediating dependence and later withdrawal 
One of the most well-studied BZDs in the setting of withdrawal is alprazolam. Due to its short half-life, and rapid absorption, alprazolam is distinguished as one of the most rapid-acting BZD with fastest relief of symptomology, increasing its abuse liability 
. Alprazolam is widely used as monotherapy for panic disorder and anxiety and was found superior to other forms of monotherapy for these conditions including other BZD, non-SSRI antidepressants, and buspirone.
4.4. Special Populations and Withdrawal
First, the elderly (over 65 years old) are of extremely high risk due to their predisposition for falls, confusion, insomnia, memory loss, and other psychiatric problems regardless of BZD use.
Secondly, approximately 20% of the children in the intensive care unit given BZD during sedation, more specifically midazolam, have been shown to exhibit withdrawal effects. The severity of the withdrawal sequelae depends on the total dose and duration of infusion and usually presents as agitation, tremors, difficulty sleeping, and inconsolable crying .
Pregnant women and fetuses are at increased risk for adverse effects of withdrawal; they both metabolize BZD slowly, and the drug can cross the placenta to cause concentrations to build up to significant levels in the neonate . While a therapeutic dose has not been proven teratogenic, use during pregnancy has been linked to low birth weight, preterm labor, and intrauterine growth restriction.
4.5. Treatment for Benzodiazepine Withdrawal
There are pharmacological options for treatment in those suffering from withdrawal or wishing to discontinue their chronic BZD use. Many alternate drug therapies have been proposed to reduce the severity of withdrawal, including alpha-blockers (propranolol and clonidine), anticonvulsants (valproic acid, lamotrigine, carbamazepine, and phenobarbital), progesterone, baclofen, and trazodone. Each of these studies received mixed results, with no statistically significant advantage to BZD therapy. The current treatment of choice is to switch the current short-acting BZD for a long-acting alternative then gradually taper the dose to wean the individual off BZD completely 
. Clonazepam has been used in the outpatient setting as a medication for taping the use of BZD. However, no set schedule for a taper has been validated in the current literature.