diazepam, as with other benzodiazepine drugs, can cause tolerance, physical dependence, substance use disorder, and benzodiazepine withdrawal syndrome. withdrawal from diazepam or other benzodiazepines often leads to withdrawal symptoms similar to those seen during barbiturate or alcohol withdrawal. the higher the dose and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms. withdrawal symptoms can occur from standard dosages and also after short-term use, and can range from insomnia and anxiety to more serious symptoms, including seizures and psychosis. withdrawal symptoms can sometimes resemble pre-existing conditions and be misdiagnosed. diazepam may produce less intense withdrawal symptoms due to its long elimination half-life. benzodiazepine treatment should be discontinued as soon as possible by a slow and gradual dose reduction regimen. tolerance develops to the therapeutic effects of benzodiazepines; for example tolerance occurs to the anticonvulsant effects and as a result benzodiazepines are not generally recommended for the long-term management of epilepsy. dose increases may overcome the effects of tolerance, but tolerance may then develop to the higher dose and adverse effects may increase. the mechanism of tolerance to benzodiazepines includes uncoupling of receptor sites, alterations in gene expression, down-regulation of receptor sites, and desensitisation of receptor sites to the effect of gaba. about one-third of individuals who take benzodiazepines for longer than four weeks become dependent and experience withdrawal syndrome on cessation. differences in rates of withdrawal (50–100%) vary depending on the patient sample. for example, a random sample of long-term benzodiazepine users typically finds around 50% experience few or no withdrawal symptoms, with the other 50% experiencing notable withdrawal symptoms. certain select patient groups show a higher rate of notable withdrawal symptoms, up to 100%. rebound anxiety, more severe than baseline anxiety, is also a common withdrawal symptom when discontinuing diazepam or other benzodiazepines. diazepam is therefore only recommended for short-term therapy at the lowest possible dose owing to risks of severe withdrawal problems from low doses even after gradual reduction. the risk of pharmacological dependence on diazepam is significant, and patients experience symptoms of benzodiazepine withdrawal syndrome if it is taken for six weeks or longer. in humans, tolerance to the anticonvulsant effects of diazepam occurs frequently. dependence improper or excessive use of diazepam can lead to dependence. at a particularly high risk for diazepam misuse, substance use disorder or dependence are: people with a history of a substance use disorder or substance dependence diazepam increases craving for alcohol in problem alcohol consumers. diazepam also increases the volume of alcohol consumed by problem drinkers. people with severe personality disorders, such as borderline personality disorder patients from the aforementioned groups should be monitored very closely during therapy for signs of abuse and development of dependence. therapy should be discontinued if any of these signs are noted, although if dependence has developed, therapy must still be discontinued gradually to avoid severe withdrawal symptoms. long-term therapy in such instances is not recommended. people suspected of being dependent on benzodiazepine drugs should be very gradually tapered off the drug. withdrawals can be life-threatening, particularly when excessive doses have been taken for extended periods of time. equal prudence should be used whether dependence has occurred in therapeutic or recreational contexts. diazepam is a good choice for tapering for those using high doses of other benzodiazepines since it has a long half-life thus withdrawal symptoms are tolerable. the process is very slow (usually from 14 to 28 weeks) but is considered safe when done appropriately. overdose main article: benzodiazepine overdose an individual who has consumed too much diazepam typically displays one or more of these symptoms in a period of approximately four hours immediately following a suspected overdose: drowsiness mental confusion hypotension impaired motor function impaired reflexes impaired coordination impaired balance dizziness coma although not usually fatal when taken alone, a diazepam overdose is considered a medical emergency and generally requires the immediate attention of medical personnel. the antidote for an overdose of diazepam (or any other benzodiazepine) is flumazenil (anexate). this drug is only used in cases with severe respiratory depression or cardiovascular complications. because flumazenil is a short-acting drug, and the effects of diazepam can last for days, several doses of flumazenil may be necessary. artificial respiration and stabilization of cardiovascular functions may also be necessary. though not routinely indicated, activated charcoal can be used for decontamination of the stomach following a diazepam overdose. emesis is contraindicated. dialysis is minimally effective. hypotension may be treated with levarterenol or metaraminol. the oral ld50 (lethal dose in 50% of the population) of diazepam is 720 mg/kg in mice and 1240 mg/kg in rats. d. j. greenblatt and colleagues reported in 1978 on two patients who had taken 500 and 2000 mg of diazepam, respectively, went into moderately-deep comas, and were discharged within 48 hours without having experienced any important complications, in spite of having high concentrations of diazepam and its metabolites desmethyldiazepam, oxazepam, and temazepam, according to samples taken in the hospital and as follow-up. overdoses of diazepam with alcohol, opiates, or other depressants may be fatal. interactions if diazepam is administered concomitantly with other drugs, attention should be paid to the possible pharmacological interactions. particular care should be taken with drugs that potentiate the effects of diazepam, such as barbiturates, phenothiazines, opioids, and antidepressants. diazepam does not increase or decrease hepatic enzyme activity, and does not alter the metabolism of other compounds. no evidence would suggest diazepam alters its own metabolism with chronic administration. agents with an effect on hepatic cytochrome p450 pathways or conjugation can alter the rate of diazepam metabolism. these interactions would be expected to be most significant with long-term diazepam therapy, and their clinical significance is variable. diazepam increases the central depressive effects of alcohol, other hypnotics/sedatives (e.g., barbiturates), other muscle relaxants, certain antidepressants, sedative antihistamines, opioids, and antipsychotics, as well as anticonvulsants such as phenobarbital, phenytoin, and carbamazepine. the euphoriant effects of opioids may be increased, leading to increased risk of psychological dependence. cimetidine, omeprazole, oxcarbazepine, ticlopidine, topiramate, ketoconazole, itraconazole, disulfiram, fluvoxamine, isoniazid, erythromycin, probenecid, propranolol, imipramine, ciprofloxacin, fluoxetine, and valproic acid prolong the action of diazepam by inhibiting its elimination. alcohol in combination with diazepam may cause a synergistic enhancement of the hypotensive properties of benzodiazepines and alcohol. oral contraceptives significantly decrease the elimination of desmethyldiazepam, a major metabolite of diazepam. rifampin, phenytoin, carbamazepine, and phenobarbital increase the metabolism of diazepam, thus decreasing drug levels and effects. dexamethasone and st john's wort also increase the metabolism of diazepam. diazepam increases the serum levels of phenobarbital. nefazodone can cause increased blood levels of benzodiazepines. cisapride may enhance the absorption, and therefore the sedative activity, of diazepam. small doses of theophylline may inhibit the action of diazepam. diazepam may block the action of levodopa (used in the treatment of parkinson's disease). diazepam may alter digoxin serum concentrations. other drugs that may have interactions with diazepam include antipsychotics (e.g. chlorpromazine), mao inhibitors, and ranitidine. because it acts on the gaba receptor, the herb valerian may produce an adverse effect. foods that acidify the urine can lead to faster absorption and elimination of diazepam, reducing drug levels and activity. foods that alkalinize the urine can lead to slower absorption and elimination of diazepam, increasing drug levels and activity. reports conflict as to whether food in general has any effects on the absorption and activity of orally administered diazepam. pharmacology 5 mg valium roche packaging australia diazepam is a long-acting "classical" benzodiazepine. other classical benzodiazepines include chlordiazepoxide, clonazepam, lorazepam, oxazepam, nitrazepam, temazepam, flurazepam, bromazepam, and clorazepate. diazepam has anticonvulsant properties. benzodiazepines act via micromolar benzodiazepine binding sites as calcium channel blockers and significantly inhibit depolarization-sensitive calcium uptake in rat nerve cell preparations. diazepam inhibits acetylcholine release in mouse hippocampal synaptosomes. this has been found by measuring sodium-dependent high-affinity choline uptake in mouse brain cells in vitro, after pretreatment of the mice with diazepam in vivo. this may play a role in explaining diazepam's anticonvulsant properties. diazepam binds with high affinity to glial cells in animal cell cultures. diazepam at high doses has been found to decrease histamine turnover in mouse brain via diazepam's action at the benzodiazepine-gaba receptor complex. diazepam also decreases prolactin release in rats. mechanism of action