Dosage Equivalency (mg)Onset of Action (hrs)Duration of Action (hrs)Half-Life (hrs)
Alprazolam (Xanax)0.50.5-13.0-4.011.0-16.0
Chlordiazepoxide (Librium)10.0-25.01.0-2.0---5-200 (with active metabolite)
Clonazepam (Klonopin)0.25-0.514.0-8.020-80
Diazepam (Valium)50.54.0-6.0>100
Lorazepam (Ativan)10.5-14.0-6.010.0-20.0
Temazepam (Restoril)15-300.5-14.0-6.09.0-18.0

What are Benzodiazepines?

Benzodiazepines are a class of medications used to treat anxiety disorders, seizures, bipolar mania, muscle tension, sleep disorders, and alcohol withdrawal.

Benzodiazepines are commonly prescribed short-term (such as 2-4 weeks) when initiating antidepressants to reduce the side effects that can occur when initiating them. Benzodiazepines temporarily decrease activity in the brain by promoting the effects of the major inhibitory neurotransmitter, GABA. Each benzodiazepine medication is different as some are more effective at promoting sleep whereas others are more effective at relieving anxiety.

Each medication has a unique pharmacokinetic profile that also determines the onset of action, the duration of clinical action, and abuse potential. The first benzodiazepines were Chlordiazepoxide (Librium, 1959) and Diazepam (Valium, 1963). Alprazolam (Xanax) was the first benzodiazepine approved for panic disorder in 1981.

All benzodiazepines are similar in terms of their chemical structure. That is, they all have a 1,4-benzodiazepine ring system.


How do Benzodiazepines work?

All Benzodiazepines are positive allosteric modulators (i.e., they bind outside of the active site but still influence receptor dynamics) of the GABA-A Receptor. They increase the binding affinity of GABA for its receptor and increase the frequency of opening of the chloride channel embedded within the GABA-A receptor. This leads to increased chloride influx and hyperpolarization of the dendritic portion of neurons bearing GABA-A receptors). Benzodiazepines that preferentially bind to the α1 subunit of the GABA-A receptor are thought to have more sedative/hypnotic (i.e., sleep-promoting) effects while those that preferentially bind to the α2 and α3 subunits of the GABA-A receptor are thought to have more anti-anxiety effects. Below is an illustration of the GABA-A receptor with additional information below it. 

The GABA-A receptor is a ligand-gated ionotropic receptor. The endogenous ligand is GABA and when GABA acts on its binding site it opens chloride ion channels that cause the influx of chloride ions through its central chloride ion channel, resulting in hyperpolarization of the membrane. In other words, the membrane becomes more difficult to depolarize. The GABAA receptor complex is a pentametric transmembrane receptor that comprises five subunits arranged around a central chloride ion channel. Two molecules of GABA have to bind to the GABA binding sites on the receptors situated between the 𝛼 and 𝛽 subunits to open the central chloride ion channel. The GABAA receptor has a number of allosteric sites that bind benzodiazepines, barbiturates, ethanol and various steroid molecules. The illustration above shows the allosteric binding site for the benzodiazepines; it is located between the 𝛾 and 𝛼 subunits. When benzodiazepines bind to this site, they enhance the inhibitory effects of GABA on the GABAA receptor by opening more chloride ion channels. Muscimol is a GABAA receptor agonist drug and will mimic the effects of GABA at the GABAA receptor. On the other hand, bicuculline is a competitive antagonist at the GABA receptor. Interestingly, the GABA-C receptor is also linked to chloride ion conductance, but is bicuculline insensitive. Most investigators believe that it should be classed as a bicuculline-insensitive subtype of the GABAA receptor rather than as a separate type of GABA receptor.

Benzodiazepines have been associated with the following

Tolerance, physical dependence, withdrawal

Abuse potential


Diminished attention

Failure of memory consolidation

Increased risk of falls in the elderly

Increased risk of delirium in the elderly

Important Facts to Know

  • The rate that a benzodiazepine distributes or spreads in the tissue correlates with it’s ability to cross lipid membranes. Therefore, the rate of distribution and the lipid solubility of a benzodiazepine will determine its onset of action. For example, Diazepam has a rapid onset of action due to its rapid absorption and distribution because it is very lipid-soluble. Interestingly, Diazepam has a shorter duration of clinical action than lorazepam after one dose.
  • Exposure therapies for anxiety disorders and PTSD may be less effective with concurrent use of benzodiazepines
  • Oxazepam, Temazepam, and Lorazepam do not undergo phase 1 metabolism in the liver and therefore these agents are preferred for individuals with liver problems
  • Benzodiazepines alone are unlikely to cause respiratory arrest in healthy individuals due to the fact that benzodiazepines, unlike barbiturates, require GABA to be bound to the receptor to function (this means there is a plateau in the clinical effect). That is not to say there is minimal risk, especially if these medications are combined with other sedating drugs.
  • In patients with heart and lung disease (such as COPD, Asthma, and Sleep Apnea) respiratory distress can occur with benzodiazepines and therefore caution is advised. 
  • Prescribing an opioid and a benzodiazepine increases risk of death significantly.
  • Despite claims of neurological damage associated with benzodiazepines, it is unclear how accurate this is. Nonetheless, it remains a possibility. 

Benzodiazepine Withdrawal

Dependence and/or withdrawal symptoms can occur after 4-6 weeks of continuous use of a benzodiazepine (sometimes less). About one-third of long term users experience problems with dosage reduction. While benzodiazepines are very effective anxiolytics, they are meant for short term use (example: when initiating antidepressants or for panic attacks only). Typically, they should be prescribe only for a few weeks. In some cases, long-term use is necessary to control symptoms. Withdrawal symptoms usually last no longer than a few weeks but some may experience withdrawal symptoms for much longer (we call this “protracted withdrawal”).

Symptoms of Withdrawal




Gastrointestinal disturbance


Flu like symptoms

Visual disturbances



Rebound anxiety/insomnia



Decreased memory and concentration




How to Taper Off Benzodiazepines Safely

Unfortunately, there is not an abundance of literature supporting any one taper schedule over another

General idea: Calculate total daily dose of shorter acting benzodiazepine (Xanax/Alprazolam) the patient is taking and then convert to a longer acting benzodiazepine (Valium/Diazepam, Klonopin/Clonazepam, Librium/Chlordiazepoxide) and then slowly taper over the course of months.

  • Prescribe no more than 1-2 week supply of medication at any one time
  • Make it clear that treatment is not long term
  • Encourage CBT, Relaxation techniques, and other psychosocial supports
  • Offer symptomatic relief with medications with low abuse potential (see medications for side effects below)
  • Always address social stressors and comorbid psychiatric illnesses

Example Taper for an individual who takes Alprazolam (Xanax) 4mg TOTAL daily

  1. Alprazolam (Xanax) 4mg total daily is roughly 4mg of Clonazepam (Klonopin) total daily. 
  2. Start patient on 2mg twice daily of Clonazepam (Klonopin)
  3. Reduce the dose by 0.25mg – 0.5mg per day every 2-3 weeks until off. As soon as intolerable withdrawal symptoms appear, either increase the dose back to previous dose and go slower and/or use other medications to help with symptoms
  4. It is important to note that the longer a patient has been taking a benzodiazepine, the longer the taper process (generally speaking but not absolute). 

Medications used to alleviate withdrawal symptoms:

Mirtazapine (Remeron)

Propranolol (Inderal)

Carbamazepine (Tegretol)

Valproic Acid (Depakote)

Duloxetine (Cymbalta)

Amitriptyline (Elavil)

Gabapentin (Neurontin)



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