Zolpidem
Also called Ambien, Intermezzo, Edluar, Zolpimist, Sanval, Edlular
Part of the metabolic pathway of Zolpidem. See the timeline on the metabolic highway.
Enzymes that break it down: CYP3A4, CYP2C9 and CYP1A2. Wikipedia’s drug infobox says: “Liver through CYP3A4 (~60%), CYP2C9 (~20%), and CYP1A2 (~14%)” (revision 1378287641).
Dosage
The sources disagree here. PsychonautWiki's oral doses for zolpidem are two to four times TripSit's at every level (common dose: 20–30 mg on PsychonautWiki, 5–10 mg on TripSit). Both are shown below exactly as each site publishes them. See the dose table audit.
Oral bands as drawn from PsychonautWiki's ranges below. The table is the source of truth.
When sources disagree, both rows are shown as published. Nothing is averaged or merged.
Oral
| Source | Threshold | Light | Common | Strong | Heavy |
|---|---|---|---|---|---|
| PsychonautWiki | 5 mg PW | 10–20 mg PW | 20–30 mg PW | 30–50 mg PW | 50 mg+ PW |
| TripSit | – | 2.5–5 mg TS | 5–10 mg TS | 10–20 mg TS | 20–30 mg+ TS |
TripSit dose text
TripSit's factsheet also states its doses as text.
Light: 2.5-5mg Common: 5-10mg Strong: 10-20mg Heavy: 20-30mg+ TS
What dose are you on? (self-reported, unverified)
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Duration
Oral, drawn at the midpoint of each PsychonautWiki range.
| Route · source | Onset | Come-up | Peak | Offset | Total | After-effects |
|---|---|---|---|---|---|---|
| Oral · PsychonautWiki | 5–20 minutes PW | 30–60 minutes PW | 1–1.5 hours PW | 2–3 hours PW | 3–6 hours PW | 2–4 hours PW |
TripSit factsheet
Mixing
For best safety practice, don't mix this drug with other depressants.
Why: respiratory depression. PsychonautWiki says:
- “Respiratory depression (also known as hypoventilation) can be described as a reduced urge to breathe that can be fatal depending on its intensity.” (PsychonautWiki, Respiratory depression, revision 150612)
- “... otherwise safe dosages of these compounds can become fatal when combined with even small amounts of other classes of depressant. For example, benzodiazepines combined with opioids are an extremely common cause of fatal respiratory depression. It is therefore strongly discouraged to combine these depressants at any dosage range.” (PsychonautWiki, Respiratory depression, revision 150612)
- “The most common cause of substance-related deaths is the combination of depressants (such as opiates, benzodiazepines, or alcohol) with other depressants.” (PsychonautWiki, Responsible drug use, revision 168206)
- “This combination potentiates the muscle relaxation, amnesia, sedation, and respiratory depression caused by one another. At higher doses, it can lead to a sudden, unexpected loss of consciousness along with a dangerous amount of depressed respiration.” (PsychonautWiki, dangerous interactions table, "Depressants" row, revision 156847)
Quotes from PsychonautWiki, CC BY-SA 4.0.
Acute combinations: what happens when these are taken close together. Entries backed by a medical journal or agency are listed first.
Backed by medical journals
Other documented combinations
- Depressants (1,4-Butanediol, 2-methyl-2-butanol, alcohol, barbiturates, GHB/GBL, methaqualone, opioids, benzodiazepines)- This combination can result in dangerous or even fatal levels of respiratory depression. These substances potentiate the muscle relaxation, sedation and amnesia caused by one another and can lead to unexpected loss of consciousness at high doses. There is also an increased risk of vomiting during unconsciousness and death from the resulting suffocation. If this occurs, users should attempt to fall asleep in the recovery position or have a friend move them into it. PW⚠ PsychonautWiki lists this combination without a danger rating.
- Dissociatives - This combination can result in an increased risk of vomiting during unconsciousness and death from the resulting suffocation. If this occurs, users should attempt to fall asleep in the recovery position or have a friend move them into it. PW⚠ PsychonautWiki lists this combination without a danger rating.
- Stimulants - It is dangerous to combine zolpidem with stimulants due to the risk of excessive intoxication. Stimulants decrease the sedative effect of zolpidem, which is the main factor most people consider when determining their level of intoxication. Once the stimulant wears off, the effects of zolpidem will be significantly increased, leading to intensified disinhibition as well as other effects. If combined, one should strictly limit themselves to only dosing a certain amount of zolpidem every few hours at minimum. This combination can also potentially result in severe dehydration if hydration is not monitored. Furthermore, zolpidem is known to cause an Increased heart rate or an Abnormal heartbeat, which could lead to even more cardiovascular problems. PW⚠ PsychonautWiki lists this combination without a danger rating.
Risks and toxicity
Zolpidem has a low toxicity relative to dose. However, it is potentially lethal when mixed with depressants like alcohol or opioids.[18] PW
Zolpidem has been reported to cause psychosis, delusions and delirium at a significantly higher rate than other hallucinogens like LSD, ketamine, or DMT. There are a large number of experience reports online which describe states of delirium, amnesia, bizarre behavior, sleep walking, driving while impaired and other serious consequences after abusing the drug. In many cases this has resulted in hospitalization, arrests, car crashes, lengthy court cases and even death.[19–24] PW
It is strongly recommended that one use harm reduction practices and have a trip sitter when using this drug. PW
Tolerance and addiction potential
Zolpidem is moderately addictive. A review of 36 human case reports found that reported dependence to zolpidem was lower than that of benzodiazepines.[25] PW
Withdrawal symptoms or rebound symptoms may occur after ceasing usage abruptly following a few weeks or longer of steady dosing, and may necessitate a gradual dose reduction. For more information on tapering from zolpidem in a controlled manner, please see this guide while keeping in mind it is intended for benzodiazepines.[26] PW
Although dependence builds up more slowly than in benzodiazepines, discontinuation from regular recreational doses of zolpidem appear to be as difficult as benzodiazepine discontinuation; it is potentially life-threatening for individuals using regularly to discontinue use without tapering their dose over a period of weeks. There is an increased risk of hypertension, seizures, and death. Drugs which lower the seizure threshold such as tramadol should be avoided during withdrawal.[26]
Dangerous interactions
Although many drugs are safe on their own, they can become dangerous and even life-threatening when combined with other substances. The list below contains some common potentially dangerous combinations, but may not include all of them. Certain combinations may be safe in low doses of each but still increase the potential risk of death. Independent research should always be done to ensure that a combination of two or more substances is safe before consumption. PW
TripSit factsheet
Testing
Effects
Helps with insomnia/sleep, hallucinations through all physical senses, increased or decreased libido, delusions TS
Overview
Zolpidem (also known as Ambien, Intermezzo, Edluar, Stilnoct, Stilnox, Zolpimist, and others) is a non-benzodiazepine hypnotic of the imidazopyridine chemical class which is primarily used in the treatment of insomnia.[1]
Commonly prescribed for insomnia, Ambien (zolpidem) can cause realistic hallucinations similar to those of deliriants, and is very likely to cause amnesia at higher doses. Take care when using this drug, as it tends to lower inhibitions to a level which causes the user to do things they might not normally do when sober.[3]
Zolpidem, sold under the brand name Ambien among others, is a medication primarily used for the short-term treatment of sleeping problems. Guidelines recommend that it be used only after cognitive behavioral therapy for insomnia and after behavioral changes, such as sleep hygiene, have been tried. It decreases the time to sleep onset by about fifteen minutes and at larger doses helps people stay asleep longer. It is taken by mouth and is available as conventional tablets, extended-release tablets, or sublingual tablets.[5–10] WP
Common side effects include daytime sleepiness, headache, nausea, and diarrhea. More severe side effects include memory problems and hallucinations. While flumazenil, a GABAA receptor antagonist, can reverse zolpidem's effects, usually supportive care is all that is recommended in overdose.[5]
Zolpidem is a nonbenzodiazepine, or Z-drug, which acts as a sedative and hypnotic as a positive allosteric modulator at the GABAA receptor. It is an imidazopyridine and increases GABA effects in the central nervous system by binding to GABAA receptors at the same location as benzodiazepines. It generally has a half-life of two to three hours. This, however, is increased in those with liver problems.[5]
Zolpidem was approved for medical use in the United States in 1992. It became available as a generic medication in 2007. Zolpidem is a schedule IV controlled substance in the US under the Controlled Substances Act of 1970 (CSA). In 2023, it was the 54th most commonly prescribed medication in the United States, with more than 11 million prescriptions.[5]
History
History
Zolpidem was used in Europe starting in 1988 and was brought to market there by Synthelabo. Synthelabo and Searle collaborated to bring it to market in the US, and it was approved in the United States in 1992 under the brand name "Ambien". It became available as a generic medication in 2007.[12]
In 2015, the American Geriatrics Society said that zolpidem, eszopiclone, and zaleplon met the Beers criteria and should be avoided in individuals 65 and over "because of their association with harms balanced with their minimal efficacy in treating insomnia." The AGS stated the strength of the recommendation that older adults avoid zolpidem is "strong" and the quality of evidence supporting it is "moderate."[29]
Legal status
- Internationally, zolpidem is a Schedule IV substance under the Convention on Psychotropic Substances.[31] PW
- Australia: Zolpidem is only available by prescription. PW⚠ PsychonautWiki itself has flagged this text: citation needed.
- Canada: Zolpidem is only available by prescription. PW⚠ PsychonautWiki itself has flagged this text: citation needed.
- China: Zolpidem is a controlled Class II psychotropic substances. Prescriptions for psychotropic substances in Class II are generally limited to a 7-day supply.[32]
[33] PW - Germany: Zolpidem is a controlled substance under Anlage III of the BtMG. It can only be prescribed on a narcotic prescription form. There is an exception for oral preperations, containing up to 8,5mg zolpidem per unit, which can be prescribed on a regular prescription form.[34] PW
- Netherlands: Zolpidem is only available by prescription. PW⚠ PsychonautWiki itself has flagged this text: citation needed.
- Russia: In Russia, since 2013, zolpidem is a Schedule III controlled substance.[35] PW
- Switzerland: Zolpidem is a controlled substance specifically named under Verzeichnis B. Medicinal use is permitted.[36] PW
- The Netherlands: Zolpidem is a List 2 substance of the Opium Law.[37] PW
- United Kingdom: Zolpidem has been a class C drug in the UK since 2003. It is illegal to possess (without a legitimate prescription), supply, produce or import.[38] PW⚠ PsychonautWiki itself has flagged this text: citation needed.
- United States: Zolpidem is listed as a Schedule IV drug due to evidence that the drug has addictive properties similar to benzodiazepines. PW⚠ PsychonautWiki itself has flagged this text: citation needed.
Society and culture
Prescriptions in the US for all sleeping pills (including zolpidem) steadily declined from around 57 million tablets in 2013, to around 47 million in 2017, possibly due to concern about prescribing addictive drugs amid the opioid crisis.[39] WP
International travel
Zolpidem is among the agents used in the short-term management of insomnia associated with jet lag, typically at doses of 5–10 mg. Its clinical use, similar to that of other hypnotics, is constrained by the potential for adverse effects and dependence, and guidelines generally recommend limiting treatment duration to short periods, usually under one week.[40] WP
Regulation
For the stated reason of its potential for recreational use and dependence, zolpidem (along with the other benzodiazepine-like Z-drugs) is a schedule IV substance under the Controlled Substances Act in the US. The United States patent for zolpidem was held by the French pharmaceutical corporation Sanofi-Aventis.[15]
Sleepwalking and complex sleep behaviors
Zolpidem has drawn significant media attention due to reports of complex sleep behaviors (CSBs), including sleepwalking, sleep-driving, and other activities performed while not fully conscious. Notable incidents include media reports in the United States concerning events such as Congressman Patrick Kennedy's motor vehicle accident and in Australia following a fatal 20 m fall from the Sydney Harbour Bridge involving an individual reportedly under the influence of zolpidem.[42–46] WP⚠ The source also gives this in other units.
In May 2018, actress Roseanne Barr attributed a controversial remark on Twitter to the effects of zolpidem. Barr's tweet compared Valerie Jarrett, a Black woman and former advisor to Barack Obama, to an ape. The comparison sparked widespread condemnation and led to the cancellation of Roseanne. The incident prompted Sanofi, the manufacturer of Ambien, to issue a public statement clarifying that "racism is not a known side effect" of the medication.[47]
Brand names
As of September 2018, zolpidem is marketed under many brands, examples include: Ambien 5 mg & 10 mg (IR oral tablets), Ambien CR 6.25 mg & 12.5 mg (controlled release tablets), Edluar 5 mg & 10 mg (sublingual tablets), Intermezzo 1.75 mg & 3.5 mg (sublingual tablets), and ZolpiMist 5 mg (oral spray).[50]
Pharmacology
Detection in body fluids
Zolpidem may be quantitated in blood or plasma to confirm a diagnosis of poisoning in people who are hospitalized, to provide evidence in an impaired driving arrest, or to assist in a medicolegal death investigation. Blood or plasma zolpidem concentrations are usually in a range of 30–300 μg/L in persons receiving the drug therapeutically, 100–700 μg/L in those arrested for impaired driving, and 1000–7000 μg/L in victims of acute overdosage. Analytical techniques, in general, involve gas or liquid chromatography.[56]
Mechanism of action
Zolpidem is a ligand of high-affinity positive modulator sites of GABAA receptors, which enhances GABAergic inhibition of neurotransmission in the central nervous system. It selectively binds to α₁ subunits of this pentameric ion channel. Accordingly, it has strong hypnotic properties and weak anxiolytic, myorelaxant, and anticonvulsant properties. Opposed to diazepam, zolpidem is able to bind to binary αβ GABA receptors, where it was shown to bind to the α1–α1 subunit interface. Zolpidem has about 10-fold lower affinity for the α₂- and α₃- subunits than for α₁, and no appreciable affinity for α₅ subunit-containing receptors. ω₁ type GABAA receptors are the α₁-containing GABAA receptors and are found primarily in the brain, the ω₂ receptors are those that contain the α₂-, α₃-, α₄-, α₅-, or α₆ subunits, and are found primarily in the spine. Thus, zolpidem favours binding to GABAA receptors located in the brain rather than the spine. Zolpidem has no affinity for γ₁ and γ₃ subunit-containing receptors and, like the vast majority of benzodiazepine-like drugs, it lacks affinity for receptors containing α₄ and α₆. Zolpidem modulates the receptor presumably by inducing a receptor conformation that enables an increased binding strength of the orthosteric agonist GABA towards its cognate receptor without affecting desensitization or peak currents.[59–65] WP
Like zaleplon, zolpidem may increase slow-wave sleep but cause no effect on stage 2 sleep.[66] WP
A 2004 meta-analysis compared benzodiazepines against nonbenzodiazepines and showed few consistent differences between zolpidem and benzodiazepines in terms of sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia, and daytime alertness.[67] WP
Pharmacokinetics
Microsome studies indicate zolpidem is metabolized by CYP3A4 (61%) CYP2C9 (22%), CYP1A2 (14%), CYP2D6 (<3%), and CYP2C19 (<3%). Less than 1% is excreted in urine unchanged. It is principally metabolized into three metabolites, none of which are believed to be pharmacologically active. The absolute bioavailability of zolpidem is about 70%. The drug reaches peak concentration in about 2 hours and has a half-life in healthy adults of about 2–3 hours. Zolpidem's half life is decreased in children and increased in the elderly and people with liver issues. While some studies show men metabolize zolpidem faster than women (possibly due to testosterone), others do not. A review found only a 33% lower clearance in women compared to men, suggesting the FDA's dosage reduction of 50% for women may have been too large.[5]
Receptor binding · Wikipedia
Binding profile
| Site | Ki (nM) |
|---|---|
| GABAA Benzodiazepine Type Iᶜ | 25 WP |
| GABAA Benzodiazepineᵇ | 26 WP |
| GABAA α₁ (Gamma-aminobutyric acid receptor subunit alpha-1) | 27 WP |
| GABAA α₁β₁γ₂ (GABA A Alpha1 Beta1 Gamma2) | 111.9 WP |
| GABAA α₁β₃γ₂ (GABA A Alpha1 Beta3 Gamma2) | 41 WP |
| GABAA α₂ (Gamma-aminobutyric acid receptor subunit alpha-2) | 160 WP |
| GABAA α₂β₁γ₂ (GABA A Alpha2Beta1Gamma2) | 760.6 WP |
| GABAA α₂β₂γ₂ (GABA A Alpha2Beta2Gamma2)ᵃ | 765 WP |
| GABAA α₃ (Gamma-aminobutyric acid receptor subunit alpha-3) | 380 WP |
| GABAA α₃β₁γ₂ (GABA A Alpha3 Beta1 Gamma2) | 2149.5 WP |
| GABAA α₄β₃γ₂ (GABA A Alpha4 Beta3 Gamma2) | > 10,000 WP |
| GABAA α₅β₁γ₂ (GABA A Alpha5 Beta1 Gamma2) | > 10,000 WP |
| GABAA α₆β₃γ₂ (GABA A Alpha6 Beta3 Gamma2) | > 10,000 WP |
Chemistry
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References
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