Phenobarbital
Phenobarbital is a long-acting barbiturate that functions as a nonselective central nervous system depressant1, producing potent anxiolytic, hypnotic, muscle relaxant, and amnesic effects. It is used medically as an anticonvulsant for the management of most seizure disorders except absence seizures2. Compared to other barbiturates, it is distinguished by its extremely slow elimination rate and prolonged duration of action1. It is classified as habit-forming1.
Contents
Dosage & Duration
Dosage
Duration
Subjective Effects
The experience is dominated by nonselective central nervous system depression, producing heavy sedation and sleepiness that build steadily and persist for an unusually long time owing to phenobarbital's status as the longest-acting barbiturate. The character of the intoxication resembles alcohol, with drowsiness, cognitive dulling, and impaired coordination rather than any notable sensory alteration. At high doses the depressant effects deepen dangerously, progressing toward respiratory depression, unconsciousness, and coma.
Physical
Pronounced sedation and muscle relaxation define the body load, accompanied by dizziness and unsteady coordination. In overdose, breathing slows, blood pressure and body temperature fall, and the pupils constrict, with severe poisoning capable of ending in circulatory collapse, respiratory arrest, and death.
Cognitive
The headspace is heavy and clouded, marked by slowed thinking, reduced inhibitions, and impaired memory formation; recall of the period under the drug's influence can be patchy or absent at higher doses.
Suppressions
Reagent Testing
Loading reagent data
Pharmacology
Pharmacodynamics
Phenobarbital acts primarily as a positive allosteric modulator at GABA-A receptors, binding at the barbiturate site to extend the duration of chloride ion channel opening and thereby enhancing inhibitory neurotransmission.345 It also directly blocks glutamatergic AMPA and kainate receptors, which is believed to contribute to its anticonvulsant properties.5 Additional targets include NMDA receptors, neuronal nicotinic acetylcholine receptors (α4 and α7 subunits), and possibly voltage-gated calcium channels.
Pharmacokinetics
Phenobarbital has an oral bioavailability of approximately 90%,6 with peak plasma concentrations reached 8 to 12 hours after oral administration. It is metabolized hepatically, primarily through hydroxylation and glucuronidation, with CYP2C19 as a major metabolic enzyme.78 Phenobarbital is a potent inducer of multiple cytochrome P450 isozymes; CYP2B6 is specifically induced via the CAR/RXR nuclear receptor heterodimer.9 It exhibits low protein binding (20 to 45%)10 and is excreted primarily by the kidneys, with an elimination half-life ranging from approximately 53 to 118 hours.8
Dangerous
Highest riskThese combinations are considered extremely harmful and should always be avoided. Reactions to these drugs taken in combination are highly unpredictable and have a potential to cause death.
Caution
Use cautionThese combinations are not usually physically harmful, but may produce undesirable effects, such as physical discomfort or overstimulation. Extreme use may cause physical health issues. Synergistic effects may be unpredictable. Care should be taken when choosing to use this combination.
Tolerance
Barbiturates
Harm Potential
Addiction & Dependence
Psychological
HighHigh psychological addiction potential with compulsive redosing commonly reported.11 Long-acting barbiturates have moderate to high abuse potential.11
Physical
Extremely HighExtremely physically addictive with life-threatening withdrawal potential.1 Abrupt discontinuation in dependent individuals may cause seizures, psychosis, and death.1 Medical supervision is essential for discontinuation.
Toxicity
Respiratory depression is a primary toxicity concern at high doses and in overdose, potentially progressing to Cheyne-Stokes respiration, apnea, and respiratory arrest.1
CNS depression ranging from sedation to coma occurs in a dose-dependent manner; severe overdose can produce EEG patterns mimicking brain death, though this is usually reversible with treatment.1
Phenobarbital is a potent cytochrome P450 enzyme inducer; severe liver failure is a contraindication for use, suggesting potential hepatic burden in those with compromised liver function.1
Acute renal failure may occur in massive overdose as a consequence of shock and circulatory collapse rather than direct nephrotoxicity.
Overdose can cause bradycardia, hypotension, lowered body temperature, and circulatory collapse; typical shock syndrome may develop in severe cases.1
Psychosis Risk
Psychosis is not typical during intoxication but may occur during withdrawal in physically dependent individuals.14 Withdrawal-induced psychosis can be severe and life-threatening.14
Seizure Risk
Phenobarbital is an anticonvulsant that suppresses seizures during use. However, abrupt discontinuation in dependent individuals may paradoxically trigger severe, potentially life-threatening seizures.1 Drugs which lower the seizure threshold should be avoided during withdrawal.
History & Culture
Discovery and Early Development
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.15 By 1904, Fischer had synthesized several related compounds including phenobarbital. The
Legality
International
UN Convention on Psychotropic Substances 1971 (Schedule IV)21
By Country
References
Source Pages
Citations
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- (n.d.). Revisiting phenobarbital for epilepsy: Large gaps in knowledge still exist, but we may be underestimating its clinical value. https://pmc.ncbi.nlm.nih.gov/articles/PMC529354/1
- Lewis CB, Patel P, & Adams N. (2024). Phenobarbital. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK532277/1
- Richardson RJ, Petrou S, & Bryson A. (2024). Established and emerging GABAA receptor pharmacotherapy for epilepsy. Frontiers in Pharmacology. https://doi.org/10.3389/fphar.2024.13414721
- Nardou R, Yamamoto S, Bhar A, Burnashev N, Ben-Ari Y, & Khalilov I. (2011). Phenobarbital but Not Diazepam Reduces AMPA/kainate Receptor Mediated Currents and Exerts Opposite Actions on Initial Seizures in the Neonatal Rat Hippocampus. Frontiers in Cellular Neuroscience. https://doi.org/10.3389/fncel.2011.0001612
- (2001). P-hydroxylation of phenobarbital: relationship to (S)-mephenytoin hydroxylation (CYP2C19) polymorphism. Clinical Pharmacology and Therapeutics. https://pubmed.ncbi.nlm.nih.gov/11294510/1
- (n.d.). Phenobarbital Oral Solution USP CIV. DailyMed. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=037c7532-7688-44fd-8c76-d25e8adf5fb5&type=display1234
- (1999). The Nuclear Orphan Receptor CAR-Retinoid X Receptor Heterodimer Activates the Phenobarbital-Responsive Enhancer Module of the CYP2B Gene. Molecular and Cellular Biology. https://pmc.ncbi.nlm.nih.gov/articles/PMC109151/1
- (n.d.). Phenobarbital Sodium Injection — DailyMed (setid ffcaa218). DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a2141
- (6 January 2023). Sezaby- phenobarbital sodium injection. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8c7d0402-4977-4c25-bc4b-11db91339e9a12
- (n.d.). Antiepileptic Overdose — PMC 6996662. https://pmc.ncbi.nlm.nih.gov/articles/PMC6996662/1
- (n.d.). Phenobarbital — IARC Monographs Volume 79 (2001). https://www.inchem.org/documents/iarc/vol79/79-06.html1
- (n.d.). Withdrawal Syndromes — StatPearls (NCBI Bookshelf). https://www.ncbi.nlm.nih.gov/books/NBK459239/12
- (December 2005). The history of barbiturates a century after their clinical introduction. Neuropsychiatric Disease and Treatment, 1(4), 329–343. https://pubmed.ncbi.nlm.nih.gov/18568113/1234
- (2003). One hundred years of barbiturates and their saint. Journal of the Royal Society of Medicine. https://pmc.ncbi.nlm.nih.gov/articles/PMC1079678/12
- Yasiry Z, & Shorvon SD. (December 2012). How phenobarbital revolutionized epilepsy therapy: The story of phenobarbital therapy in epilepsy in the last 100 years. Epilepsia, 53(Suppl 8). https://doi.org/10.1111/epi.1202612
- Kaelber L. (n.d.). Kinderfachabteilung Ansbach. University of Vermont. https://www.uvm.edu/~lkaelber/children/ansbach/ansbach.html1
- Wayne King. (April 19, 1989). Abbie Hoffman Committed Suicide Using Barbiturates, Autopsy Shows. The New York Times. https://stealthiswiki.com/library/wayne-king-abbie-hoffman-committed-suicide-using-barbiturates-autopsy-shows1
- (n.d.). Heaven's Gate | UFOs, Mass Suicide, New Religious Movement, Cult & Marshall Applewhite. Encyclopaedia Britannica. https://www.britannica.com/topic/Heavens-Gate-religious-group12
- (n.d.). Barbiturates drug profile — European Union Drugs Agency (EUDA). https://www.euda.europa.eu/publications/drug-profiles/barbiturates_en1
- (n.d.). Phenobarbitone (Aspen) — Schedule 4: Prescription Only Medicine. https://www.healthdirect.gov.au/medicines/brand/amt,929843011000036105/phenobarbitone-aspen1
- (n.d.). Controlled Drugs and Substances Act — Schedule IV (Barbiturates). https://laws-lois.justice.gc.ca/eng/acts/C-38.8/section-sched95660.html1
- (2019). Anlage III BtMG. https://www.gesetze-im-internet.de/btmg_1981/anlage_iii.html1
- (n.d.). Список психотропных веществ (Список III) — Фенобарбитал (Government Decree No. 78, Feb 4 2013). https://www.consultant.ru/document/cons_doc_LAW_136206/99b9c00551ec8df9db44dea714007a82d2595d3d/1
- (n.d.). Misuse of Drugs Act 1971, Schedule 2 Part II — Class B Drugs (5,5 disubstituted barbituric acid). https://www.legislation.gov.uk/ukpga/1971/38/schedule/21
- (n.d.). 21 CFR § 1308.14 — Schedule IV Controlled Substances. https://www.law.cornell.edu/cfr/text/21/1308.141
Further Reading
Automated synthesisInformation aggregated and synthesized using an autonomous workflow built by Josie Kins.
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