Zolpidem
N,N-dimethyl-2-[6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]acetamide
Overview
Zolpidem belongs to Depressants.
Key safety note: Zolpidem's most distinctive hazard is complex sleep behaviour: sleep-walking, sleep-driving, sleep-eating and other activities performed while not fully awake and with no memory afterwards, which can cause serious injury or death, can occur even at recommended doses and after a single dose, and led the US FDA to add a boxed warning in 2019 and to contraindicate the drug in anyone who has previously had such an episode.[5]
Effects
Subjective effects vary. What a substance feels like depends on dose, individual physiology,
mindset, and setting. The points below describe commonly reported effects, not guaranteed, uniform, or
desirable outcomes.
- Rapid drowsiness and sleep onset within about 30 minutes.
- Anterograde amnesia for the period after dosing, and possible next-morning grogginess or impaired driving.
- If sleep is resisted or the dose is high: hallucinations, distorted perception and complex sleep behaviours, with regular use, tolerance, dependence and rebound insomnia.
Dosing & duration
Harm-reduction note: These are commonly cited reference ranges, not a recommendation or a
“safe” dose. Potency, purity, body chemistry, tolerance, and drug combinations vary widely. Start
low, go slow, wait for full effects before redosing, and never assume an unknown product matches these
figures. Missing data is not evidence of safety.
Oral (immediate-release, extended-release and sublingual tablets), prescribed by a clinician and taken immediately before bed. Figures are therapeutic (prescribing) context, not a recreational guide.. Zolpidem is taken immediately before bed only when a full night's sleep (7–8 h) is possible, because of its amnestic and next-morning-impairment effects. The lowest effective dose is used for the shortest time. Women and the elderly are started at 5 mg. It must not be combined with alcohol, opioids or other sedatives, and the user should not drive until fully alert the next day.
Dose ranges
Insomnia: adult men (immediate-release)
5–10 mg at bedtime
Insomnia: women (FDA 2013)
5 mg at bedtime (slower clearance)
Elderly / debilitated
5 mg at bedtime
Extended-release (CR)
6.25–12.5 mg at bedtime
Duration
onset
≈30 min
total
Short (t½ ≈2–3 h)
after effects
Possible next-morning impairment. Rebound insomnia on stopping
Chemical & Physical Properties
| Formula | C19H21N3O |
| Molar mass | 307.39 g/mol |
| State | Solid (usually the hemitartrate salt, white to off-white crystalline powder) |
| Melting point | 193–197 °C (hemitartrate, free base ~196 °C) |
| Boiling point | Not reported |
| Density | Not reported |
| Vapor pressure | Not reported |
| pKa | 5.65 (strongest basic) |
| LogP | 3.02 |
| Solubility | 23 mg/mL in water at 20 °C |
| Refractive index | Not reported |
Identifiers & Synonyms
| CAS | 82626-48-0 |
| CAS (enantiomer) | |
| PubChem CID | 5732 |
| InChIKey | ZAFYATHCZYHLPB-UHFFFAOYSA-N |
| InChI | InChI=1S/C19H21N3O/c1-13-5-8-15(9-6-13)19-16(11-18(23)21(3)4)22-12-14(2)7-10-17(22)20-19/h5-10,12H,11H2,1-4H3 |
| SMILES | CC1=CC=C(C=C1)C2=C(N3C=C(C=CC3=N2)C)CC(=O)N(C)C |
Synonyms
- Ambien
- Stilnox
- Zolpidem
Pharmacodynamics & Biochemistry
Zolpidem (Ambien, Stilnox) is a non-benzodiazepine 'Z-drug' hypnotic of the imidazopyridine class. Although chemically unrelated to the benzodiazepines, it acts at the same target: it is a positive allosteric modulator at the benzodiazepine site of the GABA-A receptor, enhancing GABA's opening of the chloride channel. Its distinguishing feature is subtype selectivity. It binds preferentially to α1-subunit-containing receptors (the ω1/BZ1 subtype), with markedly lower affinity for α2- and α3-containing receptors and negligible affinity for α5. Because the α1 subtype mediates sedation and hypnosis while α2/α3/α5 carry much of the anxiolytic, muscle-relaxant and anticonvulsant action, zolpidem is a comparatively 'pure' hypnotic: strong sleep-inducing effect with relatively weak anxiolytic, myorelaxant and anticonvulsant properties. Its pharmacokinetics suit sleep onset: rapid absorption gives an onset of about 30 minutes and a peak at ~1.6 hours, and a short elimination half-life (~2–3 hours) limits next-day carry-over. It is metabolised in the liver (mainly CYP3A4) to inactive metabolites, so it forms no long-lived active metabolite. Women clear it more slowly than men, the basis for the 2013 FDA recommendation to halve the starting dose in women (see dosing). Zolpidem's α1 preference is well established qualitatively (roughly an order of magnitude higher affinity at α1 than at α2/α3, and little at α5), but a clean, consistently-sourced set of subtype binding constants is not readily verifiable across primary sources, so the selectivity is described here in relative terms rather than with a receptor-binding table.
Biological targets
- GABA-A
Binding & functional measurements
| Target | Measurement | Species |
|---|---|---|
| GABA-A α1β2γ2 receptor | EC50 78 ± 10 nM Emax 100 ± 5% | Human |
| GABA-A α1β2γ2 receptor | Ki 62 ± 7.3 nM | Rat |
| GABA-A α2β2γ2 receptor | EC50 470 ± 110 nM Emax 198 ± 20% | Human |
| GABA-A α2β2γ2 receptor | Ki 408 ± 35 nM | Rat |
| GABA-A α3β2γ2 receptor | EC50 750 ± 160 nM Emax 217 ± 34% | Human |
| GABA-A α3β2γ2 receptor | Ki 975 ± 132 nM | Rat |
Pharmacokinetics
| Bioavailability | Oral ≈70% |
| Tmax | ≈1.6 h |
| Half-life | ≈2–3 h |
| Vd | Not reported |
| Protein binding | ≈92% |
| Metabolism | Hepatic CYP3A4 to inactive metabolites |
| Excretion | Renal |
Toxicology & Safety
Harm-reduction note: Toxicity and risk depend on dose, route, purity, combinations, setting, and individual
health factors. Missing harms should never be interpreted as evidence of safety.
Not reported
Zolpidem's most distinctive hazard is complex sleep behaviour: sleep-walking, sleep-driving, sleep-eating and other activities performed while not fully awake and with no memory afterwards, which can cause serious injury or death, can occur even at recommended doses and after a single dose, and led the US FDA to add a boxed warning in 2019 and to contraindicate the drug in anyone who has previously had such an episode. It also causes next-morning 'hangover' impairment of driving and cognition (worse in women, the elderly and with the extended-release form), anterograde amnesia and, occasionally, hallucinations or paradoxical agitation: especially if the user fights sleep, which is also how it is misused recreationally. Like the benzodiazepines it produces tolerance, physical dependence and a withdrawal syndrome (rebound insomnia and anxiety, and after high-dose or abrupt cessation, delirium and seizures), so it is meant for short-term use (typically 2–4 weeks) at the lowest effective dose. It causes respiratory depression that is dangerous with alcohol, opioids or other CNS depressants, and is best avoided in the elderly (Beers criteria), in sleep apnoea and severe respiratory insufficiency, and in severe hepatic impairment.[5]
Legal Status
Legal note: Legal status can change over time and may vary by country, region, formulation, analogue status,
prescription context, and enforcement practice. Always confirm with current official sources before relying on this section.
US: Schedule IV. UK: Class C (Schedule 4). DE: BtMG Anlage III
Interactions & Contraindications
Drug interactions
Alcohol, Opioids, Benzodiazepines, Gabapentinoids (gabapentin, pregabalin) Additive sedation and respiratory depression, including with sedating antihistamines.[5]
CYP3A4 inhibitors (ritonavir, azole antifungals, macrolides, grapefruit) Ketoconazole, ciprofloxacin, clarithromycin or ritonavir raise zolpidem levels and next-day impairment.[5]
CYP3A4 inducers (rifampicin, carbamazepine) Rifampicin or St John's wort reduce its effect.[5]
Antipsychotics Other sedatives, antipsychotics and sedating antidepressants add next-day impairment.[5]
Other serotonergic drugs Some serotonergic agents (e.g. sertraline) may increase the risk of complex sleep behaviours.[5]
Contraindications
Prior complex sleep behaviour (sleep-walking or -driving) on a Z-drug a prior episode on zolpidem (FDA contraindication, 2019).[5]
Respiratory disease or sleep apnoea severe respiratory insufficiency or sleep apnoea syndrome.[5]
Kidney or liver impairment severe hepatic impairment.[5]
Myasthenia gravis[5]
History of stimulant or substance use disorder history of substance misuse, with caution in the elderly (Beers criteria).[5]
Pregnancy or breastfeeding[5]
No interactions or contraindications listed.
Usage & Context
- A prescription hypnotic for the short-term treatment of insomnia, particularly difficulty falling asleep, taken immediately before bed. Immediate-release, extended-release (CR) and sublingual (including a low-dose middle-of-the-night) formulations exist.
- Intended for short courses (typically 2–4 weeks) at the lowest effective dose. Not for long-term use.
- Misused recreationally for sedation, disinhibition or, when the user resists sleep, hallucinogenic effects. It carries real dependence potential.
Sources & Evidence
- PubChem: Zolpidem (CID 5732) — identifiers & experimental properties
- FDA / DailyMed: Zolpidem tartrate prescribing information — pharmacokinetics & metabolism
- Holm KJ, Goa KL (2000). Zolpidem: an update of its pharmacology, therapeutic efficacy and tolerability in the treatment of insomnia. Drugs 59:865-89.
PMID 10804040 · doi:10.2165/00003495-200059040-00014
- Sanna E, Busonero F, Talani G, et al. (2002). Comparison of the effects of zaleplon, zolpidem, and triazolam at various GABA(A) receptor subtypes. Eur J Pharmacol 451:103-10.
PMID 12231378 · doi:10.1016/s0014-2999(02)02191-x
- Wikipedia: Zolpidem (Ambien/Stilnox) — imidazopyridine Z-drug, α1-preferring GABA-A PAM, complex sleep behaviours, dosing & legal status CC BY-SA 4.0
- DEA Diversion Control Division: Controlled Substance Schedules (zolpidem is Schedule IV)
- Anlage III BtMG (Gesetze im Internet): Zolpidem — ausgenommen orale Zubereitungen bis 8,5 mg je abgeteilter Form (als Base)
- Richter G, Liao VWY, Ahring PK, Chebib M (2020). The Z-Drugs Zolpidem, Zaleplon, and Eszopiclone Have Varying Actions on Human GABAA Receptors Containing γ1, γ2, and γ3 Subunits. Front Neurosci 14:599812.
PMID 33328871 · doi:10.3389/fnins.2020.599812
- Hanson SM, Morlock EV, Satyshur KA, et al. (2008). Structural requirements for eszopiclone and zolpidem binding to the gamma-aminobutyric acid type-A (GABAA) receptor are different. J Med Chem 51:7243-52.
PMID 18973287 · doi:10.1021/jm800889m