Phenobarbital
Also called Phenobarbitone, Luminal, Phenobarb, Fenobarbital, Nunol, Phenylethylbarbiturate
Part of the metabolic pathway of Phenobarbital. See the timeline on the metabolic highway.
Enzymes that break it down: CYP2C19. Wikipedia’s drug infobox says: “Liver (mostly CYP2C19)” (revision 1376696621).
Dosage
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 | 25 mg PW | 50–100 mg PW | 100–150 mg PW | 150–300 mg PW | 300 mg+ PW⚠ The source's own markup is broken here, so this is how a reader of the source would see it. |
| TripSit | – | 50–100 mg TS | 100–150 mg TS | 150–300 mg TS | – |
TripSit dose text
TripSit's factsheet also states its doses as text.
Oral Light: 50-100mg's Common: 100-150mg's Strong: 150-300mg's+ TS
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Duration
| Route · source | Onset | Come-up | Peak | Offset | Total | After-effects |
|---|---|---|---|---|---|---|
| Oral · PsychonautWiki | 15–60 minutes PW | 1–2 hours PW | 4–6 hours PW | 12–24 hours PW | 4–6 hours PW | 1–48 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) - 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 try 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 lead to 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 unsafe to combine barbiturates with stimulants due to the risk of excessive intoxication. Stimulants decrease the sedative effect of barbiturates, which is the main factor most people consider when determining their level of intoxication. Once the stimulant wears off, the effects of barbiturates will be considerably increased, leading to intensified disinhibition as well as other effects. If combined, one should strictly limit themselves to only dosing a certain amount of barbiturates per hour. This combination can also potentially result in severe dehydration if hydration is not monitored. PW⚠ PsychonautWiki lists this combination without a danger rating.
Risks and toxicity
Phenobarbital likely has moderate toxicity relative to dose. However, phenobarbital is potentially lethal when mixed with depressants like alcohol or opioids. Phenobarbital has a higher risk of death or serious adverse effects associated with concurrent depressant use than other drugs such as benzodiazepines. There have been studies linking the use of barbiturates, particularly phenobarbital, with the development of cancer.[12] PW
It is strongly recommended that one use harm reduction practices when using this drug. PW
Tolerance and addiction potential
Phenobarbital is extremely physically and psychologically addictive. Barbiturate withdrawal is medically serious and can potentially cause a life-threatening withdrawal syndrome that can cause seizures, psychosis, and death. Drugs which lower the seizure threshold such as tramadol and amphetamine should be avoided during withdrawal. PW
Tolerance will develop to the sedative-hypnotic effects of phenobarbital after prolonged use. It is unknown exactly how long it takes for tolerance to reach baseline. Phenobarbital presents cross-tolerance with all barbiturates, meaning that after its consumption all barbiturates will have a reduced effect. PW
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 harmless 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
Overdose
Barbiturate overdose may occur when a barbiturate is taken in extremely heavy quantities or concurrently with other depressants. This is particularly dangerous with other GABAergic depressants such as benzodiazepines and alcohol since they work in a similar fashion, but bind to distinct allosteric sites on the GABAA receptor, thus their effects potentiate one another. Benzodiazepines increase the frequency in which the chlorine ion pore opens on the GABAA receptor while barbiturates increase the duration in which they are open, meaning when both are consumed, the ion pore will open more frequently and stay open longer. Barbiturate overdose is a medical emergency that may lead to a coma, permanent brain injury or death if not treated promptly and properly. Barbiturate overdose has an increased frequency of serious adverse effects when compared to other depressants.[13] PW
Symptoms of a barbiturate overdose may include severe thought deceleration, slurred speech, confusion, delusions, respiratory depression, coma or death.[14] PW
TripSit factsheet
- Avoid
- All other CNS depressants. TS
Median lethal dose (LD50) in animals
Quoted from PubChem's Non-Human Toxicity Values, which come from the Hazardous Substances Data Bank (HSDB). PubChem describes them as: “Quantitative non-human toxicity values (e.g., lethal dose) for this compound. The data shown here are mostly for lab animals (e.g., rat, mouse, guinea pig, and rabbit).” and defines the “LD50 (median lethal dose, the estimated amount of a chemical expected to kill 50% of test animals in a single dose)”. PC
| LD50 (as the source gives it) | Reference |
|---|---|
| LD50 rat oral 162 +/- 14 mg/kg PC | O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1249 (via HSDB record 3157) |
| LD50 Rat oral 660 mg/kg /Sodium salt/ PC | O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1250 (via HSDB record 3157) |
| LD50 Rat ip 151 mg/kg PC | Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 1713 (via HSDB record 3157) |
| LD50 Rat sc 200 mg/kg PC | Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 1713 (via HSDB record 3157) |
Testing
Effects
Overview
Phenobarbital, also known as phenobarbitone in British English and by the brand name Luminal, is a long-acting psychoactive drug of the barbiturate class which produces powerful anxiolytic, hypnotic, muscle relaxant and amnesic effects. Phenobarbital is used medically as an anticonvulsant, and occasionally in the short term treatment of insomnia. Phenobarbital works in a similar fashion to benzodiazepines, however barbiturates bind to a distinct allosteric site on the GABAA receptor. PW
CNS depressant that is used mostly for insomnia (In older patients) and epliepsy (in younger patients) And it a very strong narcotic, that can be taken most ways. It's used less as "safer" alternatives have been made (Benzodiazepines). TS
Phenobarbital, sold under the brand name Luminal among others, is a medication of the barbiturate type. It is recommended by the World Health Organization (WHO) for the treatment of certain types of epilepsy in developing countries. In the developed world, it is commonly used to treat seizures in young children, while other medications are generally used in older children and adults. It is also used for veterinary purposes.[1–5] WP
It may be administered by slow intravenous infusion (IV infusion), intramuscularly (IM), or orally (swallowed by mouth). Subcutaneous administration is not recommended. The injectable forms may be used to treat status epilepticus if other drugs fail to achieve satisfactory results. Phenobarbital is occasionally used to treat insomnia, anxiety, and benzodiazepine withdrawal (as well as withdrawal from certain other drugs in specific circumstances), and prior to surgery as an anxiolytic and to induce sedation. It usually begins working within five minutes when used intravenously and half an hour when administered orally. Its effects last for between four hours and two days.[1]
Potentially serious side effects include a decreased level of consciousness and respiratory depression. There is potential for both abuse and withdrawal following long-term use. It may also increase the risk of suicide.[1] WP
It is pregnancy category D in Australia, meaning that it may cause harm when taken during pregnancy. If used during breastfeeding it may result in drowsiness in the baby. Phenobarbital works by increasing the activity of the inhibitory neurotransmitter GABA.[1]
Phenobarbital was discovered in 1912 and is the oldest still commonly used anti-seizure medication. It is on the World Health Organization's List of Essential Medicines.[9]
History
History
The first barbiturate drug, barbital, was synthesized in 1902 by German chemists Emil Fischer and Joseph von Mering and was first marketed as Veronal by Friedr. Bayer et comp. By 1904, several related drugs, including phenobarbital, had been synthesized by Fischer. Phenobarbital was brought to market in 1912 by the drug company Bayer as the brand Luminal. It remained a commonly prescribed sedative and hypnotic until the introduction of benzodiazepines in the 1960s.[15] WP
Phenobarbital's soporific, sedative and hypnotic properties were well known in 1912, but it was not yet known to be an effective anticonvulsant. The young doctor Alfred Hauptmann gave it to his epilepsy patients as a tranquilizer and discovered their seizures were susceptible to the drug. Hauptmann performed a careful study of his patients over an extended period. Most of these patients were using the only effective drug then available, bromide, which had terrible side effects and limited efficacy. On phenobarbital, their epilepsy was much improved: those with the most severe disease had fewer and lighter seizures while some patients became seizure-free. In addition, they improved physically and mentally as bromides were removed from their regimen. Patients who had been institutionalised due to the severity of their epilepsy were able to leave and, in some cases, resume employment. Hauptmann dismissed concerns that its effectiveness in stalling seizures could lead to patients developing a build-up that needed to be "discharged". As he expected, withdrawal of the drug led to an increase in seizure frequency – it was not a cure. The drug was quickly adopted as the first widely effective anticonvulsant, though World War I delayed its introduction in the U.S.[16]
In 1939, a German family asked Adolf Hitler to have their disabled son killed; the five-month-old boy was given a lethal dose of Luminal after Hitler sent his own doctor to examine him. A few days later 15 psychiatrists were summoned to Hitler's Chancellery and directed to commence a clandestine program of involuntary euthanasia.[18]
In 1940, at a clinic in Ansbach, Germany, around 50 intellectually disabled children were injected with Luminal and killed that way. A plaque was erected in their memory in 1988 in the local hospital at Feuchtwanger Strasse 38, although a newer plaque does not mention that patients were killed using barbiturates on site. Luminal was used in the Nazi children's euthanasia program until at least 1943.[20–23] WP
Phenobarbital was used to treat neonatal jaundice by increasing liver metabolism and thus lowering bilirubin levels. In the 1950s, phototherapy was discovered, and became the standard treatment.[24] WP
Phenobarbital was used for over 25 years as prophylaxis in the treatment of febrile seizures. Although an effective treatment in preventing recurrent febrile seizures, it had no positive effect on patient outcome or risk of developing epilepsy. The treatment of simple febrile seizures with anticonvulsant prophylaxis is no longer recommended.[25]
Legal status
- Internationally, phenobarbital is listed in Schedule IV of the UN Convention on Psychotropic Substances.[28] PW
- Australia: Phenobarbitone is listed in Schedule 4, making it a prescription only medicine.[29] PW
- Canada: Phenobarbital is a Schedule IV controlled substance.[30] PW
- Germany: Phenobarbital is controlled under Anlage III BtMG (Narcotics Act, Schedule III). It can only be prescribed on a narcotic prescription form, except preparations which contain up to 10% or up to 300 mg phenobarbital in each dosage form.[31] PW
- Russia: Phenobarbital is a Schedule III controlled substance since 2013. but phenobarbital is also found in the medicines Corvalol or Valocordin, which is dispensed without a doctor’s prescription.[32]
[33] PW - Switzerland: Phenobarbital is a controlled substance specifically named under Verzeichnis B. Medicinal use is permitted.[34] PW
- United Kingdom: Phenobarbitone is a Class B controlled substance.[35] PW
- United States: Phenobarbital is a Schedule IV controlled substance.[36] PW
Names
Phenobarbital is the INN (International nonproprietary name) and phenobarbitone is the former BAN (British Approved Name). WP⚠ Wikipedia itself has flagged this text: citation needed.
Synthesis
Barbiturate drugs are obtained via condensation reactions between a derivative of diethyl malonate and urea in the presence of a strong base. The synthesis of phenobarbital uses this common approach as well but differs in the way in which this malonate derivative is obtained. The reason for this difference is because aryl halides do not typically undergo nucleophilic substitution in Malonic ester synthesis in the same way as aliphatic organosulfates or halocarbons do. To overcome this lack of chemical reactivity two dominant synthetic approaches using benzyl cyanide as a starting material have been developed:[37]
The first of these methods consists of a Pinner reaction of benzyl cyanide, giving phenylacetic acid ethyl ester. Subsequently, this ester undergoes cross Claisen condensation using diethyl oxalate, giving diethyl ester of phenyloxobutandioic acid. Upon heating this intermediate easily loses carbon monoxide, yielding diethyl phenylmalonate. Malonic ester synthesis using ethyl bromide leads to the formation of α-phenyl-α-ethylmalonic ester. Finally, a condensation reaction with urea gives phenobarbital.[37]
The second approach utilizes diethyl carbonate in the presence of a strong base to give α-phenylcyanoacetic ester. Alkylation of this ester using ethyl bromide proceeds via a nitrile anion intermediate to give the α-phenyl-α-ethylcyanoacetic ester. This product is then further converted into the 4-iminoderivative upon condensation with urea. Finally acidic hydrolysis of the resulting product gives phenobarbital.[41–44] WP
A new synthetic route based on diethyl 2-ethyl-2-phenylmalonate and urea has been described.[45] WP
Regulation
The level of regulation includes Schedule IV non-narcotic (depressant) (ACSCN 2285) in the United States under the Controlled Substances Act 1970—but along with a few other barbiturates and at least one benzodiazepine, and codeine, dionine, or dihydrocodeine at low concentrations, it also has exempt prescription and had at least one exempt OTC combination drug now more tightly regulated for its ephedrine content. The phenobarbitone/phenobarbital exists in subtherapeutic doses which add up to an effective dose to counter the overstimulation and possible seizures from a deliberate overdose in ephedrine tablets for asthma, which are now regulated at the federal and state level as: a restricted OTC medicine and/or watched precursor, uncontrolled but watched/restricted prescription drug & watched precursor, a Schedule II, III, IV, or V prescription-only controlled substance & watched precursor, or a Schedule V (which also has possible regulations at the county/parish, town, city, or district as well aside from the fact that the pharmacist can also choose not to sell it, and photo ID and signing a register is required) exempt Non-Narcotic restricted/watched OTC medicine.[46] WP
Pharmacology
Mechanism of action
Phenobarbital acts as an allosteric modulator which extends the amount of time the chloride ion channel is open by interacting with GABAA receptor subunits. Through this action, phenobarbital increases the flow of chloride ions into the neuron which decreases the excitability of the post-synaptic neuron. Hyperpolarizing this post-synaptic membrane leads to a decrease in the general excitatory aspects of the post-synaptic neuron. By making it harder to depolarize the neuron, the threshold for the action potential of the post-synaptic neuron will be increased.[47] WP
Direct blockade of glutamatergic AMPA and kainate receptors are also believed to contribute to the hypnotic and anticonvulsant effect that is observed with phenobarbital.[48]
Pharmacokinetics
Phenobarbital has an oral bioavailability of about 90%. Peak plasma concentrations (Cₘₐₓ) are reached eight to 12 hours after oral administration. It is one of the longest-acting barbiturates available – it remains in the body for a very long time (half-life of two to seven days) and has very low protein binding (20 to 45%). Phenobarbital is metabolized by the liver, mainly through hydroxylation and glucuronidation and induces many isozymes of the cytochrome P450 system. Cytochrome P450 2B6 (CYP2B6) is specifically induced by phenobarbital via the CAR/RXR nuclear receptor heterodimer. It is excreted primarily by the kidneys.[50] WP
Chemistry
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References
- Other Phenobarbital
- Journal / agency Ilangaratne NB, Mannakkara NN, Bell GS, Sander JW. Phenobarbital: missing in action. Bulletin of the World Health Organization. December 2012. doi:10.2471/BLT.12.113183 · PMID 23284189 · PMC3524964
- Journal / agency Brodie MJ, Kwan P. Current position of phenobarbital in epilepsy and its future. Epilepsia. December 2012. doi:10.1111/epi.12027 · PMID 23205961
- Journal / agency National Clinical Guideline Centre (UK). The Epilepsies: The Diagnosis and Management of the Epilepsies in Adults and Children in Primary and Secondary Care: Pharmacological Update of Clinical Guideline 20. January 2012. PMID 25340221
- Other Thomas WB. A Practical Guide to Canine and Feline Neurology. 2003
- Other Marx JA. Rosen's emergency medicine: concepts and clinical practice. 2010
- Other Prescribing medicines in pregnancy database. 3 March 2014
- Other Phenobarbital use while Breastfeeding. 2013
- Other Brenner GM, Stevens CW. Pharmacology. 2013
- Other Engel J. Epilepsy: a comprehensive textbook. 2008
- Other The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). 2023
- Journal / agency Friedman, G. D., Habel, L. A. Barbiturates and lung cancer: a re-evaluation. International Journal of Epidemiology. 1 June 1999. doi:10.1093/ije/28.3.375
- Journal / agency Twyman, R. E., Rogers, C. J., Macdonald, R. L. Differential regulation of gamma-aminobutyric acid receptor channels by diazepam and phenobarbital. Annals of Neurology. March 1989. doi:10.1002/ana.410250302
- Journal / agency Barbiturate intoxication and overdose: MedlinePlus Medical Encyclopedia
- Other Sneader W. Drug Discovery. 23 June 2005
- Other Enersen OD. Alfred Hauptmann
- Other Scott DF. The History of Epileptic Therapy. 15 February 1993
- Other Zoech I. Named: the baby boy who was Nazis' first euthanasia victim. 12 October 2003
- Other Smith WJ. Killing Babies, Compassionately. 26 March 2006
- Other Kaelber L. Kinderfachabteilung Ansbach. 8 March 2013
- Other Binder J. Die Heil- und Pflegeanstalt Ansbach während des Nationalsozialismus. October 2011
- Other Kaelber L. Jewish Children with Disabilities and Nazi "Euthanasia" Crimes. Spring 2013
- Journal / agency López-Muñoz F, Alamo C, García-García P, Molina JD, Rubio G. The role of psychopharmacology in the medical abuses of the Third Reich: from euthanasia programmes to human experimentation. Brain Research Bulletin. December 2008. doi:10.1016/j.brainresbull.2008.09.002 · PMID 18848972
- Journal / agency Pepling RS. Phenobarbital. Chemical and Engineering News. June 2005
- Other Pellock JM, Dodson WE, Bourgeois BF. Pediatric Epilepsy. 1 January 2001
- Other Baumann R. Febrile Seizures. 14 February 2005
- Other various. Diagnosis and management of epilepsies in children and young people. March 2005
- Harm reduction site UN Convention on Psychotropic Substances
- Other Controlled Drugs
- Other Branch, L. S. Consolidated federal laws of Canada, Controlled Drugs and Substances Act. 2022
- Other Anlage III BtMG
- Other Постановление Правительства РФ от 04.02.2013 N 78 “О внесении изменений в некоторые акты Правительства Российской Федерации” - КонсультантПлюс
- Other Государственный реестр лекарственных средств
- Other Verordnung des EDI über die Verzeichnisse der Betäubungsmittel, psychotropen Stoffe, Vorläuferstoffe und Hilfschemikalien
- Other Drugs penalties
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- Other Furniss B, Hannaford A, Smith P, Tatchell A. Vogel's Textbook of Practical Organic Chemistry. 1996
- Journal / agency Adams R. Organic Reactions, Volume 9. 1957
- Journal / agency Adams R, Thal AF. Ethyl Phenylacetate. Organic Syntheses. 1922. doi:10.15227/orgsyn.002.0027
- Journal / agency Meyer GM, Levene PA. Diethyl phenylmalonate. Organic Syntheses. 1936. doi:10.15227/orgsyn.016.0033
- Journal / agency Chamberlain JS, Chap JJ, Doyle JE, Spaulding LB. The Synthesis of 5,5-Alkylphenylbarbituric Acids. Journal of the American Chemical Society. 1935. doi:10.1021/ja01305a036
- Journal / agency Nelson WL, Cretcher LH. The Preparation of Ethyl Phenylmalonate and of 5-Phenyl-beta-hydroxyethylbarbituric acid. Journal of the American Chemical Society. 1928. doi:10.1021/ja01397a029
- Journal / agency Makosza M, Jończyk A. Phase-Transfer Alkylation of Nitriles: 2-Phenylbutyronitrile. Organic Syntheses. 1976. doi:10.15227/orgsyn.055.0091
- Other Preparation of Phenobarbital
- Journal / agency Castagna R, Maleeva G, Pirovano D, Matera C, Gorostiza P. Donor-Acceptor Stenhouse Adduct Displaying Reversible Photoswitching in Water and Neuronal Activity. Journal of the American Chemical Society. August 2022. doi:10.1021/jacs.2c04920 · PMID 35976640
- Other DEA Diversion Control Division
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- Journal / agency Brust JC. Handbook of Clinical Neurology. 2014. doi:10.1016/b978-0-444-62619-6.00008-2 · PMID 25307572
- Journal / agency Löscher W, Rogawski MA. How theories evolved concerning the mechanism of action of barbiturates. Epilepsia. December 2012. doi:10.1111/epi.12025 · PMID 23205959
- Journal / agency Flynn S, Babi MA. Pharmacology and Therapeutics for Dentistry. 2017. doi:10.1016/b978-0-323-39307-2.00012-6
Text and values on this page are quoted from PsychonautWiki (CC BY-SA 4.0), Wikipedia (CC BY-SA 4.0), TripSit factsheets, PubChem (public domain). Each value links to the exact revision it came from.