Pharmacology
DrugBankDescription
A barbituric acid derivative that acts as a nonselective central nervous system depressant. It promotes binding to inhibitory gamma-aminobutyric acid subtype receptors, and modulates chloride currents through receptor channels. It also inhibits glutamate induced depolarizations.
Mechanism of Action
Phenobarbital acts on GABAA receptors, increasing synaptic inhibition. This has the effect of elevating seizure threshold and reducing the spread of seizure activity from a seizure focus. Phenobarbital may also inhibit calcium channels, resulting in a decrease in excitatory transmitter release. The sedative-hypnotic effects of phenobarbital are likely the result of its effect on the polysynaptic midbrain reticular formation, which controls CNS arousal.
Pharmacodynamics
Phenobarbital, the longest-acting barbiturate, is used for its anticonvulsant and sedative-hypnotic properties in the management of all seizure disorders except absence (petit mal).
Metabolism
Hepatic (mostly via CYP2C19).
Absorption
Absorbed in varying degrees following oral, rectal or parenteral administration. The salts are more rapidly absorbed than are the acids. The rate of absorption is increased if the sodium salt is ingested as a dilute solution or taken on an empty stomach.
Toxicity
CNS and respiratory depression which may progress to Cheyne-Stokes respiration, areflexia, constriction of the pupils to a slight degree (though in severe poisoning they may wshow paralytic dilation), oliguria, tachycardia, hypotension, lowered body temperature, and coma. Typical shock syndrome (apnea, circulatory collapse, respiratory arrest, and death) may occur.
Indication
For the treatment of all types of seizures except absence seizures.
Receptor Profile
Receptor Actions
Receptor Binding
History & Culture
1902–1912
The barbiturate class emerged in 1902 when German chemists Emil Fischer and Joseph von Mering synthesized barbital, the first compound of its kind, subsequently marketed as Veronal by Bayer. By 1904, Fischer had synthesized several related compounds including phenobarbital. The drug was introduced to market in 1912 by Bayer under the brand name Luminal, initially recognized for its sedative, hypnotic, and soporific properties.
While phenobarbital's sedative effects were well-established by its 1912 market introduction, its potential as an anticonvulsant remained unknown. The young physician Alfred Hauptmann made this discovery serendipitously when he administered the drug to his epilepsy patients as a tranquilizer and observed a marked reduction in their seizures. Hauptmann conducted a careful extended study of his patients, most of whom had previously relied on bromide—the only available treatment at the time, which offered limited efficacy and caused severe side effects. On phenobarbital, patients showed substantial improvement: the most severely affected experienced fewer and milder seizures, while some became entirely seizure-free. The drug was rapidly adopted as the first widely effective anticonvulsant, though World War I delayed its introduction to the United States.
1939–1943
Phenobarbital became implicated in one of history's darkest chapters when it was employed in Nazi Germany's involuntary euthanasia programs. In 1939, a German family petitioned Adolf Hitler to have their disabled five-month-old son killed; the infant was administered a lethal dose of Luminal after Hitler dispatched his personal physician to examine the child. This event precipitated a broader clandestine program—within days, fifteen psychiatrists were summoned to Hitler's Chancellery and directed to commence systematic involuntary euthanasia. By 1940, approximately fifty intellectually disabled children were killed by Luminal injection at a clinic in Ansbach, Germany. The drug continued to be used as an instrument of the Nazi children's euthanasia program until at least 1943.
1960s–present
Phenobarbital remained a commonly prescribed sedative and hypnotic for nearly five decades following its introduction. However, the emergence of benzodiazepines in the 1960s gradually displaced barbiturates for most sedative and anxiolytic applications due to their improved safety profile. Despite this shift, phenobarbital persists as the oldest continuously used anticonvulsant medication and is included on the World Health Organization's List of Essential Medicines.
Phenobarbital has been involved in several notable deaths throughout its history. In November 1970, an unidentified woman was discovered deceased in Bergen, Norway, in a case that remains unsolved. Known as the Isdal Woman, she died from a combination of burns, phenobarbital, and carbon monoxide poisoning; numerous theories have emerged about her death, with some investigators believing she may have been a spy. British veterinarian Donald Sinclair, who served as the inspiration for the character Siegfried Farnon in James Herriot's "All Creatures Great and Small" book series, ended his life at age 84 by self-administering an overdose of phenobarbital. American activist Abbie Hoffman died on April 12, 1989, after consuming phenobarbital combined with alcohol; residue from approximately 150 pills was detected in his body during autopsy. In March 1997, thirty-nine members of the Heaven's Gate religious group died in a mass suicide in Rancho Santa Fe, California. The members consumed lethal doses of phenobarbital mixed with vodka before lying down to die, believing they would be transported to an alien spacecraft.
Tolerance & Pharmacokinetics
drugs.wikiTolerance Decay
Tolerance to sedative effects typically builds with regular daily use over 1–2+ weeks and decays slowly over several weeks; data are largely clinical experience and user reports rather than controlled studies. Cross-tolerance with other positive GABAA modulators (e.g., benzodiazepines) is partial but clinically relevant. Because of phenobarbital’s long half-life, perceived tolerance may reflect accumulation rather than receptor-level changes.
Cross-Tolerances
Experience Report Analysis
ErowidDemographics
Gender Distribution
Age Distribution
Reports Over Time
Effect Analysis
ErowidEffects aggregated from 4 experience reports (4 Erowid)
Effect Sentiment Distribution
Confidence Distribution
Positive Effects 1
Adverse Effects 0
Form / Preparation
Most common forms and preparations reported
Legal Status
| Country | Status | Notes |
|---|---|---|
| Australia | Schedule 4 | Classified as a prescription-only medicine under the Poisons Standard. Legal for medical use with a valid prescription from a licensed healthcare provider. |
| Canada | Schedule IV CDSA | Controlled under the Controlled Drugs and Substances Act. Available for medical use by prescription, with restrictions on dispensing and record-keeping requirements. |
| Germany | Anlage III BtMG | Controlled under Schedule III of the Betäubungsmittelgesetz (Narcotics Act). Requires a narcotic prescription form for dispensing, with exceptions for preparations containing up to 10% phenobarbital or up to 300 mg per dosage unit. |
| Russia | Schedule III | Classified as a Schedule III controlled substance since 2013. However, phenobarbital remains available in over-the-counter combination medications such as Corvalol and Valocordin, which can be dispensed without a prescription. |
| Switzerland | Verzeichnis B | Specifically named as a controlled substance under Verzeichnis B of Swiss narcotics legislation. Medicinal use is permitted with appropriate authorization. |
| United Kingdom | Class B | Controlled as a Class B substance under the Misuse of Drugs Act 1971. Available for medical use by prescription, with penalties for unauthorized possession and supply. |
| United States | Schedule IV | Controlled under Schedule IV of the Controlled Substances Act. Recognized as having accepted medical use with lower abuse potential than Schedule II-III substances. Available by prescription for seizure disorders and sedation. |
Harm Reduction
drugs.wikiPhenobarbital is a long-acting barbiturate used primarily as an anticonvulsant; it enhances GABAA-mediated inhibition and also dampens excitatory transmission, producing dose-dependent CNS and respiratory depression. Its elimination half-life averages roughly 79 hours (range ~53–118 h), which means effects can accumulate across days; redosing on the same day or consecutive days markedly increases overdose risk. As a strong inducer of multiple CYP isoenzymes, phenobarbital reduces the efficacy of many medications, notably combined oral contraceptives (risk of unintended pregnancy) and warfarin (risk of subtherapeutic anticoagulation), and can lower levels of other antiepileptics; users should avoid assuming familiar medications behave normally while on phenobarbital. Barbiturates carry a narrow therapeutic index: toxic and even fatal blood concentrations overlap with or lie not far above therapeutic levels, making self-titration hazardous; overdose deaths typically result from respiratory depression compounded by hypotension and coma. Combining with other CNS depressants (opioids, alcohol, benzodiazepines, Z-drugs, GHB/GBL, sedating antihistamines, carisoprodol) substantially increases the risk of fatal respiratory depression; this risk persists for days because phenobarbital remains in the body long after the subjective effects fade. Phenobarbital is contraindicated in acute or latent porphyria and should be avoided in significant hepatic impairment; it can precipitate porphyric crises via enzyme induction. Chronic use can cause dependence; abrupt cessation after sustained daily use can provoke severe, potentially life-threatening withdrawal (including seizures)—any stop should be medically supervised and slowly tapered. Avoid driving or tasks requiring alertness for at least 24 hours after dosing (longer with higher or repeated doses), as coordination and reaction time are impaired even when one feels “sober.” If phenobarbital has been used with opioids, naloxone reverses only the opioid component—sedation from phenobarbital may persist and requires airway support and monitoring by professionals. Parenteral phenobarbital must be administered by clinicians; nonmedical IV use (especially of tablet formulations) risks immediate apnea/hypotension and catastrophic local injury; intra-arterial and subcutaneous injection are explicitly unsafe. Use in pregnancy is associated with congenital risks; avoid nonmedical exposure during pregnancy and lactation.
References
Cited References
Drugs.wiki References
- DrugBank: Phenobarbital (DB01174) — PK and half-life
- StatPearls: Phenobarbital — contraindications, CYP induction, OCs/warfarin interactions, overdose ranges
- StatPearls: Barbiturates — enzyme induction profile; CNS depressant interactions; pregnancy risks; porphyria contraindication
- EUDA/EMCDDA Barbiturates drug profile — therapeutic/toxic/fatal blood concentrations; modes of use
- EUDA/EMCDDA Take-home naloxone — reverses opioid respiratory depression only (barbiturates unaffected)