Zolpidem (Ambien, Ambien CR, Sublinox and Stilnox) is a short acting sedative-hypnotic prescribed to treat insomnia. Zolpidem is in the class of imidazopyridines which have similar effects to benzodiazadine drugs because they potentiate gamma-amino butyric acid (GABA) and thus share some pharmacological properties. Zolpidem causes sedation and can cause anterograde amnesia (forgetting the period during the effects) but has very minimal anti-anxiety, muscle-relaxing and anti-convulsant properties.
Introduction to ZolpidemZolpidem’s main therapeutic use is the treatment of insomnia and it is typically prescribed as a short-acting hypnotic alternative to benzodiazepines. Zolpidem is in the class of imidazopyridines which potentiate gamma-amino butyric acid (GABA). Zolpidem works quickly (usually within 15 minutes) to bind to GABAA receptors at the same location as benzodiazepines but more selectively. However due to its short half-life, immediate release forms of Zolpidem can fail to be adequate to maintain sleep for a full night.
Ways of AdministrationZolpidem can be administered several ways but is standardly prescribed in oral formulation, either a regular instant release or an extended release formulation (Eg. Ambien and Ambien CR). Other formulations include sublingual tablets (Edluar and Intermezzo) which are taken by placing them under the tongue and letting them melt and an oral spray (Zopimis) which is applied into the mouth and over the tongue. Zolpidem is to be taken as needed and not more than once per night. Food taken with Zolpidem may inhibit the speed and effectiveness of the drug.
DoseThe recommended initial therapeutic dose of immediate release zolpidem is 5 mg for women and 5 or 10 mg for men, taken immediately before bedtime, ensuring there is at least 7-8 hours before you need to wake up. Zolpiden has not been shown to be safe or effective for use in children.
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Effects of ZolpidemZolpidem causes sleepiness and in patients with insomnia it both shortens the time it takes to fall asleep and extends the duration of sleep. Zolpidem has been shown as effective as benzodiazepines in both shortening the time to sleep onset and prolonging total sleep time in patients with insomnia. Unlike benzodiazepines, zolpidem's hypnotic/sedative effects do not appear to have negative effects on the stages of sleep in normal human subjects and it does not appear to disrupt stages 3 or 4 of deep sleep. A meta-analysis of randomized and controlled clinical studies that compared Z-drugs including zolpidem to benzodiazepines found no consistent differences in time to sleep onset, sleep duration, number of awakenings, sleep quality, rebound insomnia, tolerance, daytime alertness or adverse events. 
After discontinuation the beneficial effects of zolpidem on sleep have been reported to persist for up to 1 week. Improvement in sleep time during 6 months of continuous treatment with zolpidem has been seen without subsequent discontinuation causing withdrawal or rebound difficulties.
Zolpidem has hypnotic and sedative effects because it is an agonist on GABAA receptors, resembling benzodiazepines in effect (but not mechanism) in this way. But zolpidem has been shown to have only weak anticonvulsant effects in experimental animals, whereas its hypnotic/sedative effects seem to mask anti-anxiety effects in various animal models of anxiety. Chronic administration of zolpidem to rodents does not seem to produce tolerance to its sedative effects nor signs of withdrawal upon discontinuation. Chronic zolpidem administration to baboons, however, has been reported to produce both tolerance and physical dependence. And there have been case reports of tolerance to zolpidem's hypnotic effects developing in patients taking high doses of zolpidem for up to several years.
Recreational drug combinations with ZolpidemNo Recreational drug combinations with Zolpidem have been added to this wiki yet.
Dangerous interactions with ZolpidemAs a sedative-hypnotic drug, zolpidem is a central nervous system (CNS) depressant, so taking it with other CNS depressants (e.g. benzodiazepines, opioids, tricyclic antidepressants, alcohol) can cause additive effects and increase the risk of CNS depression.
Medication interactions with ZolpidemBoth mipramine and chiorpromazine have been reported to increase the impairment of alertness zolpidem causes, chlorpromazine has also been observed to add to the impairment of psychomotor performance under zolpidem. Ketoconazole combined with zolpidem may increase its effects and their duration.
Rifampin taken with zolpidem may decrease zolpidem’s effects. 
Potentiators of ZolpidemKetoconazole, a potent CYP3A4 inhibitor, has been shown to increase zolpidem’s Cmax (maximum blood concentration) by 30% and total AUC (overall blood levels) by 70%, to extend zolpidem’s elimination half-life by 30%, and to increase the pharmacodynamic effects of zolpidem.
Different Uses for Zolpidem
Recreational use of ZolpidemZolpidem has the potential for misuse as a drug used to get high rather than medication for treating insomnia. Such misuse becomes more likely with longer term use whether the use is with or without a prescription. But because the sedative effects of zolpidem are far less subject to chronic tolerance effects than are those of benzodiazepines, and because it has very minimal anti-anxiety properties, long term zolpidem use at normal therapeutic levels is thought to present a much lower risk of developing into problematic recreational use than is long term use of benzodiazepines. Recreational misuse tends to occur when physiological drug tolerance leads to inhalation, injection or the drugs is taken for reasons other than medically approved for usually in amounts greater than 5-10 mg.
Using Zolpidem for come down or sleep with stimulant (ab)useUsers of stimulants have long been involved in the misuse of sedative/hypnotics such as Zolpidem as a way to come down or sleep after using methamphetamine or coke.
Using Zolpidem for its hallucinogenic effectsZolpidem has been reported to have a unique ability to elicit vivid visuals and body highs in some users when they resist the drugs hypnotic effects. 
Pharmacology of Zolpidem
GeneralZolpidem is a gamma-aminobutyric acid (GABA) A agonist. It interacts with a GABA-BZ receptor complex but in contrast to the benzodiazepines, which are non-selective and bind to and activate all subtypes of BZ receptor, zolpidem in vitro preferentially binds to the BZ1 receptor with a high affinity ratio of the α5 subunits. Zolpidem’s preferential binding on the BZ1 receptor might be the reason zolpidem has been found to have very minimal myorelaxant (muscle-relaxing) and anticonvulsant effects in animals, and might explain data from clinical studies showing therapeutic level doses of zolpidem do not disrupt stages 3 and 4 of deep sleep in humans.
Zolpidem taken orally in immediate release formulation is rapidly absorbed from the gastrointestinal tract; 5mg and 10 mg doses have Tmax of 1.6 hours (the average time to reach maximum blood concentrations). Zolpidem has a short elimination half-life (T½) in healthy subjects with a mean of 2.6 hours and 2.5 hours for 5mg and 10 mg tablets respectively.
In a single-dose crossover study in 45 healthy subjects administered 5 and 10 mg zolpidem tartrate tablets, the mean peak concentrations (Cmax) were 59 (range: 29 to 113) and 121 (range: 58 to 272) ng/mL, respectively.
Zolpidem undergoes hepatic oxidation by the CYP system to inactive products that are eliminated primarily by renal excretion and in the dose range of 5 to 20 mg demonstrates linear kinetics.
Zolpidem has been shown not to accumulate in young adults following nightly dosing with 20 mg zolpidem tartrate tablets for 2 weeks. 
Targets, Enzymes, and Transporters
Chemistry of Zolpidem
Property Values Systematic (IUPAC) name: N,N,6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide Synonyms: N,N,6-trimethyl-2-p-tolylimidazo[1,2-a]pyridine-3-acetamide, SL-80.0750; zolpidem tartrate, SL-80.0750-23N, Ambien, Intermezzo, Ivadal, Myslee, Niotal, Stilnoct, Stilnox, Tovalt (L-(+)-hemitartrate) Molecular Formula: C19H21N3O; (C19H21N3O)2.C4H6O6 (L-(+)-hemitartrate) Molar mass: 307.40 g/mol; 764.88 g/mol (L-(+)-hemitartrate) CAS Registry Number: 82626-48-0, 99294-97-4 (L-(+)-hemitartrate) Melting Point: 196°C Boiling Point: no data Flash Point: no data Solubility: L-(+)-hemitartrate : 23 mg/mL (water, 20°C); sparingly soluble in alcohol, propylene glycol Additionnal data: pKa 6.2, log P (octanol/water) 2.43 Notes: L-(+)-hemitartrate aspect : white to off white crystalline powder [/center] 
Reagent test results of Zolpidem
The Dangers of Zolpidem
Side Effects and Interactions
Potential Side EffectsThe most common side effects of zolpidem include nightmares, agitation, headache, gastrointestinal upset, dizziness, and daytime drowsiness. Zolpidem has been reported to cause abnormal thinking and behavior changes including decreased inhibition, aggression, extroversion, agitation, bizarre behavious and depersonalization. Hallucinations both visual and auditory have been reported in controlled studies of zolpidem at therapeutic doses (in less than 1% of adults with insomnia but 7% of children treated with zolpidem at bedtime reported hallucinations compared to 0% of those taking placebo).
There have been reports of mild rebound insomnia on the first night after discontinuation of zolpidem at therapeutic doses (5–10mg). It appears to be rare and to take unusual circumstances for tolerance or physical dependence to happen. At therapeutic doses (5–10mg), zolpidem infrequently produces residual daytime sedation or amnesia, and the incidence of other adverse effects (e.g., gastrointestinal complaints or dizziness) also is low. As with the benzodiazepines, large overdoses of zolpidem typically do not produce severe respiratory depression unless other agents (e.g., ethanol) also are ingested  Hypnotic doses increase the hypoxia and hypercarbia of patients with obstructive sleep apnea.
Potential Drug InteractionsCentral nervous system (CNS) depressants including benzodiazepines, opiate/oid drugs, alcohol, other z-drugs, and tricyclic antidepressants can cause additive effects and increase the risk of CNS depression when taken with zolpidem because it a sedative-hypnotic drug so also a CNS depressant. 
It has been established that alcohol taken with zolpidem has an additive effect increasing the adverse effect on psychomotor performance.
Medication interactions with ZolpidemBoth imipramine and chlorpromazine have been reported to have an additive effect when combined with zolpidem which increases the impairment of alertness; chlorpromazine has also been observed to add to the impairment of both alertness and psychomotor performance under zolpidem. Ketoconazole combined with zolpidem may increase its effects and their duration.
Rifampin taken with zolpidem may decrease zolpidem’s effects. 
Sertraline (Zoloft) in combination with zolpidem increases exposure to zolpidem
Fluoxetine (Prozac) in combination with zolpidem increases zolpidem half-life but it hasn’t been shown this causes an additive effect in psychomotor performance
Potential Food Interactions
Physical Health Risks
Next-day Psychomotor Impairment and Impaired DrivingDouble-blind controlled studies have found that zolpidem impairs performance in tests of psychomotor skills (e.g. critical tracking, body sway, divided attention) and highway driving the following morning. This effect is significantly increased when zolpidem is taken in the middle of the night as opposed to a full 8 hours before getting up.
Withdrawal SeizuresZolpidem withdrawal does involve some risk of seizure, especially if zolpidem is abruptly stopped or doses increased beyond normal therapeutic amounts.
Mental Health Risks
Development of Psychiatric Problems, Worsening of depression or suicidal thinking and actionUse of zolpidem at therapeutic doses can cause the worsening of depression and suicidal thinking and actions (including successful suicide attempts). Treatment of insomnia with zolpidem can also seem to cause the development of new psychiatric problems because insomnia can be the symptom of otherwise unrecognized mental health problems. While the risk of these adverse effects are low the consequences can be very serious and therefore it is very important that any increased or new depression, suicidal thinking or other mental health problem while taking zolpidem be treated seriously and discussed with one's doctor.
Memory impairmentZolpidem has been shown to cause antereograde amnesia in controlled studies and via case reports. This amnesia for the time during the drug’s effects appears to be much more likely at doses higher than 10mg. 
Hallucinations and PsychosisThere have been case reports of hallucinations (and some delusions) occurring at normal therapeutic doses of zolpidem as low as 2.5mg. Zolpidem-induced episodes of hallucination typically start shortly after taking zolpidem and last less than half an hour, but episodes of several hours have been been reported and an association with use of antidepressant serotonin reuptake-inhibition medications (SSRIs) suggested. Hallucinations triggered by zolpidem seem to resolve once the medication is stopped and they do not appear to be cases of psychotic illness being triggered or caused. 
Sleep-driving, sleep-eating, sleep-sex and Other Complex BehaviorsLike other sedative hypnotic drugs, zolpidem can cause behaviours such as sleep-driving and other complex behaviours like preparing and eating food, making phone calls, or having sex when not fully awake. These events appear to be more likely to happen when treatment with zolpidem is initiated, with a dose increased, or with a switch made to extended release formulations. Though they do not seem to be dose-dependent but they may be associated with higher blood levels caused by drug interactions or other factors extending the elimination half life of zolpidem. 
Zolpidem may also induce bizarre and compulsive behaviours during sleep which the patient then does not remember when they wake up. Reported cases include zolpidem related self-harm during sleep as serious as self-inflicted gunshot to the head.
OverdoseZolpidem overdose alone, or in combination with CNS-depressant agents causes impairment of consciousness ranging from from sleepiness to coma, and it can endanger both respiration and cardiovascular health. These effects are potentially serious enough to be fatal, though as with benzodiazapines fatal outcomes from overdose almost always involves additional depressant drugs in combination. 
Forms of Zolpidem
Legal Status of Zolpidem
United NationsZolpidem is a controlled substance 21 CFR 1308.14
USAZolpidem is Schedule IV in the U.S. This means it is illegal to sell without a license and illegal to possess without a valid license or prescription
EUZolpidem is available only with a prescription and is a Class C drug under the Misuse of Drugs Act.
History of Zolpidem
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