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Phenibut

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Phenibut
Clinical data
Trade namesAnvifen, Fenibut, Noofen, others[1]
Other namesAminophenylbutyric acid; Fenibut; Fenigam; Phenigam; Phenybut; Phenygam; Phenylgamma; Phenigama; PHG; PhGABA; β-Phenyl-γ-aminobutyric acid; β-Phenyl-GABA[2]
Routes of
administration		Common: Oral[3]
Uncommon: Rectal[3]
Drug classGABAB receptor agonist; Gabapentinoid
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability≥63% (250 mg)[5]
MetabolismLiver (minimal)[6][5]
MetabolitesInactive[6]
Onset of actionOral: 2–4 hours[3]
Rectal: 20–30 minutes[3]
Elimination half-life5.3 hours (250 mg)[5]
Duration of action15–24 hours (1–3 g)[3]
ExcretionUrine: 63% (unchanged)[5]
Identifiers
  • 4-Amino-3-phenylbutanoic acid
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.012.800 Edit this at Wikidata
Chemical and physical data
FormulaC10H13NO2
Molar mass179.219 g·mol−1
3D model (JSmol)
Melting point253 °C (487 °F)
  • O=C(O)CC(c1ccccc1)CN
  • InChI=1S/C10H13NO2/c11-7-9(6-10(12)13)8-4-2-1-3-5-8/h1-5,9H,6-7,11H2,(H,12,13) checkY
  • Key:DAFOCGYVTAOKAJ-UHFFFAOYSA-N checkY
  (verify)

Phenibut, sold under the brand name Anvifen among others,[1] is a central nervous system (CNS) depressant with anxiolytic effects, and is used to treat anxiety, insomnia, and for a variety of other indications.[5] It is usually taken orally (swallowed by mouth), but may be given intravenously.[6][5]

Side effects of phenibut can include sedation, sleepiness, nausea, irritability, agitation, dizziness, euphoria, and sometimes headache, among others.[6][7] Overdose of phenibut can produce marked central nervous system depression including unconsciousness.[6][7] The medication is structurally related to the neurotransmitter γ-aminobutyric acid (GABA), and hence is a GABA analogue.[5] Phenibut is thought to act as a GABAB receptor agonist, similarly to baclofen and γ-hydroxybutyrate (GHB).[5] However, at low concentrations, phenibut mildly increases the concentration of dopamine in the brain, providing stimulatory effects in addition to the anxiolysis.[8]

Phenibut was developed in the Soviet Union and was introduced for medical use in the 1960s.[5] Today, it is marketed for medical use in Russia, Ukraine, Belarus, Kazakhstan, and Latvia.[5] The medication is not approved for clinical use in the United States and most of Europe, but it is sold on the Internet as a supplement and purported nootropic.[3][9] Phenibut has been used recreationally and can produce euphoria as well as addiction, dependence, and withdrawal.[3] It is a controlled substance in Australia, and it has been suggested that its legal status should be reconsidered in Europe as well.[3] In Germany, phenibut is not approved as a drug and, as a food supplement, is controlled under the German New Psychoactive Substances Act.[10]

In a 2023 assessment, the U.S. Food and Drug Administration (FDA) determined that phenibut does not meet the definition of a dietary ingredient, thereby making phenibut supplement products misbranded and illegal for marketing.[11] FDA warning letters had been issued to supplement manufacturers marketing phenibut products as adulterated.[12]

Medical uses

[edit]

Phenibut is used in Russia, Ukraine, Belarus and Latvia as a pharmaceutical drug to treat anxiety and to improve sleep (e.g., in the treatment of insomnia).[5][6] It is also used for various other indications, including the treatment of asthenia, depression, alcoholism, alcohol withdrawal syndrome, post-traumatic stress disorder, stuttering, tics, vestibular disorders, Ménière's disease, dizziness, for the prevention of motion sickness, and for the prevention of anxiety before or after surgical procedures or painful diagnostic tests.[6][5]

Available forms

[edit]

Phenibut is available as a medication in the form of 250 mg or 500 mg tablets for oral administration and as a solution at a concentration of 10 mg/mL for infusion.[6][7][13] In the US, dietary supplements labeled as containing phenibut have been found to contain zero to greater than 1,100 mg of phenibut per serving.[9]

Contraindications

[edit]

Contraindications of phenibut include:[6][7]

Phenibut should not be combined with alcohol.[7]

Side effects

[edit]

Phenibut is generally well-tolerated.[5][7] Possible side effects may include sedation, somnolence, nausea, irritability, agitation, anxiety, dizziness, headache, and allergic reactions such as skin rash and itching.[6][7] At high doses, motor incoordination, loss of balance, and hangovers may occur.[3] Due to its CNS depressant effects, people taking phenibut should refrain from potentially dangerous activities such as operating heavy machinery.[6][7] With prolonged use of phenibut, particularly at high doses, the liver and blood should be monitored, due to risk of fatty liver disease and eosinophilia.[6][7]

Overdose

[edit]

In overdose, phenibut can cause severe drowsiness, nausea, vomiting, eosinophilia, lowered blood pressure, renal impairment, and, above 7 grams, fatty liver degeneration.[6][7] There are no specific antidotes for phenibut overdose.[7] Lethargy, somnolence, agitation, delirium, tonic–clonic seizures, reduced consciousness or unconsciousness, and unresponsiveness have been reported in recreational users who have overdosed.[3] Management of phenibut overdose includes activated charcoal, gastric lavage, induction of vomiting, and symptom-based treatment.[6][7] There have been three associated deaths which found Phenibut in the users system but only one of these cases single-handedly included Phenibut.[14]

Dependency and withdrawal

[edit]

Tolerance to phenibut easily develops with repeated use leading to dependency.[5][needs update] Withdrawal symptoms may occur upon discontinuation, and, in recreational users taking high doses, have been reported to include severe rebound anxiety, insomnia, anger, irritability, agitation, visual and auditory hallucinations, and acute psychosis.[3] Baclofen has successfully been used for treatment of phenibut dependence.[15]

Interactions

[edit]

Phenibut may mutually potentiate and extend the duration of the effects of other CNS depressants, including anxiolytics, antipsychotics, sedatives, opioids, anticonvulsants, and alcohol.[6][7]

Pharmacology

[edit]
See also: Gabapentinoid § Pharmacology

Pharmacodynamics

[edit]
GABA and analogues
at biological targets[16]
Compound GABAB GABAA
GABATooltip γ-Aminobutyric acid 0.08 0.12
GHBTooltip γ-Hydroxybutyric acid >100 >100
GABOBTooltip γ-Amino-β-hydroxybutyric acid 1.10 1.38
Phenibut 9.6 >100
4-F-phenibut 1.70 >100
Baclofen 0.13 >100
  (R)-Baclofen 0.13 >100
  (S)-Baclofen 74.0 >100
Values are IC50 (μM) in rat brain.

Phenibut acts as a full agonist of the GABAB receptor, similarly to baclofen.[17][18] It has between 30- and 68-fold lower affinity for the GABAB receptor than baclofen, and, in accordance, is used at far higher doses in comparison.[17] (R)-Phenibut has more than 100-fold higher affinity for the GABAB receptor than does (S)-phenibut; hence, (R)-phenibut is the active enantiomer at the GABAB receptor.[19]


Phenibut and analogues
at biological targets[20]
Compound α2δ GABAB
Phenibut ND 177
  (R)-Phenibut 23 92
  (S)-Phenibut 39 >1,000
Baclofen 156 6
Gabapentin 0.05 >1,000
Values are Ki (μM) in rat brain.

Phenibut also binds to and blocks α2δ subunit-containing VDCCs, similarly to gabapentin and pregabalin, and hence is a gabapentinoid.[20][21] Both (R)-phenibut and (S)-phenibut display this action with similar affinity (Ki = 23 and 39 μM, respectively).[20]

It is often claimed on websites about nootropics and elsewhere on the internet that phenibut increases dopamine. Three papers published in Russian by Soviet scientists in 1979, 1986, and 1990 report that phenibut increases dopamine in the striatum of rats and in the mouse brain.[22] The mechanism underlying this putative effect is unclear.[22] Structurally, phenibut can also be considered a derivative of phenethylamine, and some research suggests that phenibut antagonizes the action of phenethylamine.[22]

Pharmacokinetics

[edit]

Little information thus far has been published on the clinical pharmacokinetics of phenibut.[5] The drug is reported to be well-absorbed.[6] It distributes widely throughout the body and across the blood–brain barrier.[6] Approximately 0.1% of an administered dose of phenibut reportedly penetrates into the brain, with this said to occur to a much greater extent in young people and the elderly.[6] Following a single 250 mg dose in healthy volunteers, its elimination half-life was approximately 5.3 hours and the drug was largely (63%) excreted in the urine unchanged.[5]

Some limited information has been described on the pharmacokinetics of phenibut in recreational users taking much higher doses (e.g., 1–3 grams) than typical clinical doses.[3][23] In these individuals, the onset of action of phenibut has been reported to be 2 to 4 hours orally and 20 to 30 minutes rectally, the peak effects are described as occurring 4 to 6 hours following oral ingestion, and the total duration for the oral route has been reported to be 15 to 24 hours (or about 3 to 5 terminal half-lives).[3]

Chemistry

[edit]

Phenibut is a synthetic aromatic amino acid. It is a chiral molecule and thus has two potential configurations, as (R)- and (S)-enantiomers.[18]

Structure and analogues

[edit]
Chemical structures of phenibut and analogues.

Phenibut is a derivative of the inhibitory neurotransmitter GABA.[5] Hence, it is a GABA analogue.[5] Phenibut is specifically the analogue of GABA with a phenyl ring substituted in at the β-position.[5] As such, its chemical name is β-phenyl-γ-aminobutyric acid, which can be abbreviated as β-phenyl-GABA.[5] The presence of the phenyl ring allows phenibut to cross the blood–brain barrier significantly, unlike GABA.[5] Phenibut also contains the trace amine β-phenethylamine in its structure.[5]

Phenibut is closely related to a variety of other GABA analogues including baclofen (β-(4-chlorophenyl)-GABA), 4-fluorophenibut (β-(4-fluorophenyl)-GABA), tolibut (β-(4-methylphenyl)-GABA), pregabalin ((S)-β-isobutyl-GABA), gabapentin (1-(aminomethyl)cyclohexane acetic acid), and GABOB (β-hydroxy-GABA).[5][20] It has almost the same chemical structure as baclofen, differing from it only in having a hydrogen atom instead of a chlorine atom at the para position of the phenyl ring.[5] Phenibut is also close in structure to pregabalin, which has an isobutyl group at the β position instead of phenibut's phenyl ring.[20]

A glutamate-derivative analogue of phenibut is glufimet (dimethyl 3-phenylglutamate hydrochloride).[24]

Synthesis

[edit]

A chemical synthesis of phenibut has been published.[13]

History

[edit]

Phenibut was synthesized at the A. I. Herzen Leningrad Pedagogical Institute (USSR) by Professor Vsevolod Perekalin's team and tested at the Institute of Experimental Medicine, USSR Academy of Medical Sciences.[5] It was introduced into clinical use in Russia in the 1960s.[5]

Society and culture

[edit]
Olainfarm's pharmaceutical phenibut sold in Russia.

Other names

[edit]

Alternate spellings include fenibut and phenybut.[2] It is also sometimes referred to as aminophenylbutyric acid.[1] The word phenibut is a contraction of the chemical name of the drug, β-phenyl-γ-aminobutyric acid.[5] In early publications, phenibut was referred to as fenigam and phenigama.[5][25] The drug has not been assigned an INNTooltip International Nonproprietary Name.[2][6]

Brand names

[edit]

Phenibut is marketed in Russia, Ukraine, Belarus, and Latvia under the brand names Anvifen, Fenibut, Bifren, and Noofen (Russian: Анвифен, Фенибут, Бифрен and Ноофен, respectively).[1]

Availability

[edit]

Phenibut is approved in Russia, Ukraine, Belarus, and Latvia for medical use.[3] It is not approved or available as a medication in other countries in the European Union, the United States, or Australia.[3] In countries where phenibut is not a licensed pharmaceutical drug, it is sold online without a prescription as a "nutritional supplement".[3][9] It is often used as a form of self-medication for social anxiety.[3]

Recreational use

[edit]

Phenibut is used recreationally due to its ability to produce euphoria, anxiolysis, and increased sociability,[3] as well as remaining undetected in routine urinalysis. Because of its delayed onset of effects, first-time users often mistakenly take an additional dose of phenibut in the belief that the initial dose did not work.[3] Recreational users usually take the drug orally; there are a few case reports of rectal administration and one report of insufflation, which was described as "very painful" and causing swollen nostrils.[3]

[edit]

As of 2021, phenibut is a controlled substance in Australia,[3] France,[26] Hungary,[27] Italy,[28] Lithuania,[29][30] and Germany[10] where, nevertheless, it is readily obtained online.[31]

In 2015, it was suggested that the legal status of phenibut in Europe should be reconsidered due to its recreational potential.[3] In February 2018, the Australian Therapeutic Goods Administration declared it a prohibited (schedule 9) substance, citing health concerns due to withdrawal and overdose.[32][33]

As of 14 November 2018, Hungary added phenibut and 10 other items to its New Psychoactive Substances ban list,[34] and, as of 26 August 2020, Italy added phenibut to its New Psychoactive Substances ban list.[28] As of 18 September 2020, France added phenibut to the controlled psychoactive substances list, prohibiting production, sale, storage, and use.[35]

In the United States, phenibut is an unapproved drug, but is often misleadingly marketed as a dietary supplement. It is readily available without a prescription.[36][37]

In Alabama, phenibut was made a Schedule II substance at the state level in November 2021.[38]

See also

[edit]

References

[edit]
  1. ^ a b c d Drobizhev MY, Fedotova AV, Kikta SV, Antohin EY (2016). "Феномен аминофенилмасляной кислоты" [Phenomenon of aminophenylbutyric acid]. Russian Medical Journal (in Russian). 2017 (24): 1657–1663. ISSN 1382-4368. Archived from the original on 16 September 2017. Retrieved 16 September 2017.
  2. ^ a b c Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 69–. ISBN 978-1-4757-2085-3.
  3. ^ a b c d e f g h i j k l m n o p q r s t u v Owen DR, Wood DM, Archer JR, Dargan PI (September 2016). "Phenibut (4-amino-3-phenyl-butyric acid): Availability, prevalence of use, desired effects and acute toxicity". Drug and Alcohol Review. 35 (5): 591–6. doi:10.1111/dar.12356. hdl:10044/1/30073. PMID 26693960.
  4. ^ Nutrition, Center for Food Safety and Applied (6 March 2023). "Phenibut in Dietary Supplements". FDA. Archived from the original on 23 May 2023. Retrieved 23 May 2023.
  5. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab Lapin I (2001). "Phenibut (beta-phenyl-GABA): a tranquilizer and nootropic drug". CNS Drug Reviews. 7 (4): 471–81. doi:10.1111/j.1527-3458.2001.tb00211.x. PMC 6494145. PMID 11830761.
  6. ^ a b c d e f g h i j k l m n o p q r s Ozon Pharm, Fenibut (PDF), archived from the original (PDF) on 16 September 2017, retrieved 15 September 2017
  7. ^ a b c d e f g h i j k l m Регистр лекарственных средств России ([Russian Medicines Register]). "Фенибут (Phenybutum)" [Fenibut (Phenybutum)] (in Russian). Archived from the original on 3 March 2009. Retrieved 15 September 2017.
  8. ^ Lapin I (7 June 2006). "Phenibut (beta-phenyl-GABA): a tranquilizer and nootropic drug". CNS Drug Reviews. 7 (4): 471–81. doi:10.1111/j.1527-3458.2001.tb00211.x. PMC 6494145. PMID 11830761.
  9. ^ a b c Cohen PA, Ellison RR, Travis JC, Gaufberg SV, Gerona R (April 2022). "Quantity of phenibut in dietary supplements before and after FDA warnings". Clinical Toxicology. 60 (4): 486–488. doi:10.1080/15563650.2021.1973020. PMID 34550038. S2CID 237594860.
  10. ^ a b "Anlage NpSG - Einzelnorm". www.gesetze-im-internet.de. Retrieved 7 June 2024.
  11. ^ "Phenibut in Dietary Supplements". US Food and Drug Administration. 12 July 2023. Retrieved 14 September 2024.
  12. ^ "FDA Acts on Dietary Supplements Containing DMHA and Phenibut". US Food and Drug Administration. 29 April 2019. Retrieved 14 September 2024.
  13. ^ a b Sivchik VV, Grygoryan HO, Survilo VL, Trukhachova TV (2012), Синтез γ-амино-β-фенилмасляной кислоты (фенибута) [Synthesis of β-phenyl-γ-aminobutyric acid (phenibut)] (PDF) (in Russian), archived (PDF) from the original on 16 September 2017, retrieved 16 September 2017
  14. ^ Graves JM, Dilley J, Kubsad S, Liebelt E (September 2020). "Notes from the Field: Phenibut Exposures Reported to Poison Centers - United States, 2009–2019". MMWR. Morbidity and Mortality Weekly Report. 69 (35): 1227–1228. doi:10.15585/mmwr.mm6935a5. PMC 7470459. PMID 32881852.
  15. ^ Samokhvalov AV, Paton-Gay CL, Balchand K, Rehm J (February 2013). "Phenibut dependence". BMJ Case Reports. 2013: bcr2012008381. doi:10.1136/bcr-2012-008381. PMC 3604470. PMID 23391959.
  16. ^ Bowery NG, Hill DR, Hudson AL (January 1983). "Characteristics of GABAB receptor binding sites on rat whole brain synaptic membranes". British Journal of Pharmacology. 78 (1): 191–206. doi:10.1111/j.1476-5381.1983.tb09380.x. PMC 2044790. PMID 6297646.
  17. ^ a b GABAb Receptor Pharmacology: A Tribute to Norman Bowery: A Tribute to Norman Bowery. Academic Press. 21 September 2010. pp. 25–. ISBN 978-0-12-378648-7.
  18. ^ a b Dambrova M, Zvejniece L, Liepinsh E, Cirule H, Zharkova O, Veinberg G, Kalvinsh I (March 2008). "Comparative pharmacological activity of optical isomers of phenibut". European Journal of Pharmacology. 583 (1): 128–134. doi:10.1016/j.ejphar.2008.01.015. PMID 18275958.
  19. ^ Allan RD, Bates MC, Drew CA, Duke RK, Hambley TW, Johnston GA, et al. (1990). "A new synthesis resolution and in vitro activities of (R)- and (S)-β-Phenyl-Gaba". Tetrahedron. 46 (7): 2511–2524. doi:10.1016/S0040-4020(01)82032-9. ISSN 0040-4020.
  20. ^ a b c d e Zvejniece L, Vavers E, Svalbe B, Veinberg G, Rizhanova K, Liepins V, et al. (October 2015). "R-phenibut binds to the α2-δ subunit of voltage-dependent calcium channels and exerts gabapentin-like anti-nociceptive effects". Pharmacology, Biochemistry, and Behavior. 137: 23–9. doi:10.1016/j.pbb.2015.07.014. PMID 26234470. S2CID 42606053.
  21. ^ Vavers E, Zvejniece L, Svalbe B, Volska K, Makarova E, Liepinsh E, et al. (November 2016). "The neuroprotective effects of R-phenibut after focal cerebral ischemia". Pharmacological Research. 113 (Pt B): 796–801. doi:10.1016/j.phrs.2015.11.013. PMID 26621244.
  22. ^ a b c Lapin, Izyaslav (December 2001). "Phenibut (β-Phenyl-GABA): A Tranquilizer and Nootropic Drug". CNS Drug Reviews. 7 (4): 471–481. doi:10.1111/j.1527-3458.2001.tb00211.x. PMC 6494145. PMID 11830761.
  23. ^ Schifano F, Orsolini L, Duccio Papanti G, Corkery JM (February 2015). "Novel psychoactive substances of interest for psychiatry". World Psychiatry. 14 (1): 15–26. doi:10.1002/wps.20174. PMC 4329884. PMID 25655145.
  24. ^ Perfilova VN, Popova TA, Prokofiev II, Mokrousov IS, Ostrovskii OV, Tyurenkov IN (June 2017). "Effect of Phenibut and Glufimet, a Novel Glutamic Acid Derivative, on Respiration of Heart and Brain Mitochondria from Animals Exposed to Stress against the Background of Inducible NO-Synthase Blockade". Bulletin of Experimental Biology and Medicine. 163 (2): 226–229. doi:10.1007/s10517-017-3772-4. PMID 28726197. S2CID 4907409.
  25. ^ Khaunina RA, Lapin IP (1976). "Fenibut, a new tranquilizer". Pharmaceutical Chemistry Journal. 10 (12): 1703–1705. doi:10.1007/BF00760021. ISSN 0091-150X. S2CID 29071385.
  26. ^ Par [1] Archived 8 May 2021 at the Wayback Machine La liste des substances psychotropes
  27. ^ "39/2018. (XI. 8.) EMMI rendelet Az új pszichoaktív anyaggá minősített anyagokról vagy vegyületcsoportokról szóló 55/2014. (XII. 30.) EMMI rendelet módosításáról" (PDF). Archived (PDF) from the original on 14 November 2018. Retrieved 14 November 2018.
  28. ^ a b "Gazzetta Ufficiale 11/08/20". Lorenzo Arbolino. 11 August 2020. Archived from the original on 2 May 2024. Retrieved 27 August 2020.
  29. ^ "RINKOS RIBOJIMO PRIEMONĖS FENIBUTUI!". ntakd.lrv.lt (in Lithuanian). Archived from the original on 6 October 2021. Retrieved 27 January 2020.
  30. ^ "V-1431 Dėl Lietuvos Respublikos sveikatos apsaugos ministro 2000 m. sausio 6 d. įsakymo Nr. 5 "Dėl Narko..." e-seimas.lrs.lt (in Lithuanian). Archived from the original on 27 January 2020. Retrieved 27 January 2020.
  31. ^ Bonnet U, Scherbaum N, Schaper A, Soyka M (5 April 2024). "Phenibut — an Illegal Food Supplement With Psychotropic Effects and Health Risks". Deutsches Ärzteblatt International. 121 (7): 222–7. doi:10.3238/arztebl.m2024.0003. PMC 11539871. PMID 38377332.
  32. ^ "3.3 Phenibut". Administration Therapeutic Goods Administration. Australian Government Department of Health. 31 October 2017. Archived from the original on 27 March 2020. Retrieved 6 November 2017.
  33. ^ "Mass school overdose investigation focuses on banned Russian drug". ABC News. Australian Broadcasting Corporation. 22 February 2018. Archived from the original on 22 February 2018. Retrieved 22 February 2018.
  34. ^ "EMMI Decree substances or groups of compounds classified as new psychoactive substances". Wolters Kluwer. 1 January 2015. Archived from the original on 8 August 2020. Retrieved 5 August 2020.
  35. ^ "Le phénibut interdit en France | Le Généraliste". Archived from the original on 22 January 2021. Retrieved 28 April 2021.
  36. ^ Penzak SR, Bulloch M (June 2024). "Phenibut: Review and Pharmacologic Approaches to Treating Withdrawal". J Clin Pharmacol (Review). 64 (6): 652–671. doi:10.1002/jcph.2414. PMID 38339875.
  37. ^ Jouney EA (March 2019). "Phenibut (β-Phenyl-γ-Aminobutyric Acid): an Easily Obtainable "Dietary Supplement" With Propensities for Physical Dependence and Addiction". Curr Psychiatry Rep. 21 (4): 23. doi:10.1007/s11920-019-1009-0. PMID 30852710.
  38. ^ "Controlled Substances List; Schedule II, page 70" (PDF). Alabama State Board of Health. 22 February 2024. Retrieved 13 September 2024.
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