Phenobarbital

5-ethyl-5-phenyl-1,3-diazinane-2,4,6-trione

Overview

Phenobarbital belongs to Depressants.

Key safety note: Phenobarbital, like all barbiturates, has a low therapeutic index and, unlike benzodiazepines, no ceiling on respiratory depression: the gap between an effective and a life-threatening dose is small, and it narrows further with tolerance and when the drug is combined with alcohol, opioids or benzodiazepines.[2]
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.
  • Calming, sedation and drowsiness. Reduced anxiety and, at higher doses, sleep.
  • Impaired coordination, slurred speech, slowed thinking and memory, and a 'hungover' sluggishness the next day (long half-life).
  • With regular use: tolerance to the sedation, physical dependence, and a dangerous withdrawal (agitation, tremor, seizures) on stopping.
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 and by injection (IV/IM), clinician-prescribed and titrated. Figures below are clinical context, NOT a recreational guide.. Phenobarbital is dosed to effect and to blood levels because of its long half-life and narrow safety margin. There is no safe recreational dose: barbiturates have no ceiling on respiratory depression and are especially lethal with alcohol or opioids. Because of tolerance and dependence it must never be stopped abruptly after regular use.

Dose ranges

Adult anticonvulsant maintenance

≈1–3 mg/kg/day (often ≈60–180 mg once daily), titrated to blood level

Neonatal seizures (clinical)

IV loading then maintenance, specialist-dosed

Status epilepticus (later-line)

IV loading dose, specialist-administered

Duration

onset

Oral ≈30–60 min, slower CNS entry than thiopental

total

Very long (half-life ≈53–118 h): once-daily dosing

after effects

Daytime sedation/'hangover'. Withdrawal on cessation after regular use

Chemical & Physical Properties
FormulaC12H12N2O3
Molar mass232.24 g/mol
StateSolid
Melting point174 °C
Boiling pointNot reported
DensityNot reported
Vapor pressureNot reported
pKa7.3
LogP1.47
Solubilityless than 0.1 mg/mL at 14 °C (NTP, 1992), 1110 mg/L (at 25 °C), 1 g soluble in: about 1 L water . 8 mL alcohol. 40 mL chloroform. 12 mL ether. About 700 mL benzene. Solluble in alkali hydroxides and carbonates.
Refractive indexnα 1.557, nβ 1.620, nγ 1.667
Identifiers & Synonyms
CAS50-06-6
CAS (enantiomer)
PubChem CID4763
InChIKeyDDBREPKUVSBGFI-UHFFFAOYSA-N
InChIInChI=1S/C12H12N2O3/c1-2-12(8-6-4-3-5-7-8)9(15)13-11(17)14-10(12)16/h3-7H,2H2,1H3,(H2,13,14,15,16,17)
SMILESCCC1(C(=O)NC(=O)NC1=O)C2=CC=CC=C2

Synonyms

  • Phenobarbitone
  • Luminal
  • Phenobarb
Pharmacodynamics & Biochemistry

Phenobarbital (Luminal) is the oldest antiseizure drug still in use and the prototypical long-acting barbiturate. It is a positive allosteric modulator of the GABA-A receptor: it binds a distinct barbiturate site and prolongs the time the receptor's chloride channel stays open in response to GABA, deepening inhibition throughout the brain. At higher concentrations it can open the chloride channel directly, independent of GABA: a property that gives barbiturates, unlike benzodiazepines, no ceiling to their CNS and respiratory depression. It also directly blocks excitatory AMPA/kainate glutamate receptors, which adds to its anticonvulsant effect. Its defining feature outside the brain is potent induction of hepatic drug-metabolising enzymes (CYP3A4, CYP2C9, CYP2C19 and UGTs). By speeding the breakdown of many other drugs, phenobarbital lowers the levels and efficacy of warfarin, oral contraceptives, many antiepileptics, corticosteroids and others: one of the most clinically important enzyme-induction interactions in medicine. Phenobarbital is almost completely absorbed orally (bioavailability >95%) and is very long-acting, with a half-life of roughly 53–118 hours, allowing once-daily dosing but also causing accumulation. It is metabolised in the liver (mainly CYP2C9, with CYP2C19/2E1), and about a quarter of a dose is excreted unchanged by the kidney, which is why alkalinising the urine speeds its removal in overdose.

Biological targets

  • GABA-A
Pharmacokinetics
BioavailabilityOral >95%
TmaxNot reported
Half-life≈53–118 h
VdNot reported
Protein bindingNot reported
MetabolismHepatic CYP2C9 (also CYP2C19/2E1). Strong enzyme inducer
ExcretionRenal (~25% unchanged, alkaline diuresis increases clearance)
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.

180 mg/kg (rat, oral)

Phenobarbital, like all barbiturates, has a low therapeutic index and, unlike benzodiazepines, no ceiling on respiratory depression: the gap between an effective and a life-threatening dose is small, and it narrows further with tolerance and when the drug is combined with alcohol, opioids or benzodiazepines. Overdose produces a progressive 'slowing' of the body: sedation, slurred speech and incoordination giving way to coma, hypotension, hypothermia and fatal respiratory depression. There is no specific antidote (flumazenil does not reverse barbiturates). Management is supportive, with airway/ventilatory support, activated charcoal, urine alkalinisation and, in severe cases, haemodialysis. Regular use causes physical dependence, and abrupt withdrawal is dangerous: a barbiturate withdrawal syndrome resembling severe alcohol withdrawal (tremor, agitation, seizures and delirium) that can be fatal and must be managed with a slow taper. Historically barbiturates were a leading cause of accidental and suicidal drug death, which is why benzodiazepines largely replaced them.[2]

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.
Interactions & Contraindications

Drug interactions

Drugs cleared by induced liver enzymes (warfarin, oral contraceptives, many antiepileptics, corticosteroids) Strong hepatic enzyme induction (CYP3A4/2C9/2C19, UGT) lowers the levels and efficacy of warfarin, oral contraceptives, many antiepileptics and corticosteroids: a major, wide-ranging interaction.[2]
Alcohol, Opioids, Benzodiazepines Additive, potentially fatal respiratory depression.[2]

Contraindications

Significant respiratory depression or acute severe asthma severe respiratory disease or respiratory depression.[2]
Acute intermittent or related porphyria[2]
Kidney or liver impairment severe hepatic impairment.[2]
Known hypersensitivity to the drug marked sensitivity to barbiturates.[2]
Combining with alcohol or other CNS depressants[2]
Usage & Context
  • A long-standing antiseizure medicine: used for generalised tonic-clonic and focal (partial) seizures, a first-line choice for neonatal seizures, and a low-cost WHO essential medicine still widely used for epilepsy in lower-resource settings.
  • Also used for status epilepticus (as a later-line option) and in the management of alcohol and sedative/barbiturate withdrawal. Historically it was a common sedative and sleeping pill (Luminal) before benzodiazepines.
  • Encountered in overdose and, less often, in misuse for sedation.
Sources & Evidence

Further Information