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: By mouth[3]
Uncommon: Rectal[3]
Drug classGABA receptor agonist; Gabapentinoid
ATC code
Legal status
Legal status
  • AU: S9 (Prohibited substance)
  • US: Unapproved "New Drug" (as defined by 21 U.S. Code § 321(p)(1)). Use in dietary supplements, food, or medicine is unlawful; otherwise uncontrolled. [4]

Illegal in Alabama[5]

  • RU: Rx-only
Pharmacokinetic data
BioavailabilityWell-absorbed[6]
≥63% (250 mg)[7]
MetabolismLiver (minimal)[6][7]
MetabolitesInactive[6]
Onset of actionOral: 2–4 hours[3]
Rectal: 20–30 minutes[3]
Elimination half-life5.3 hours (250 mg)[7]
Duration of action15–24 hours (1–3 g)[3]
ExcretionUrine: 63% (unchanged)[7]
Identifiers
  • 4-Amino-3-phenylbutanoic acid
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 names Anvifen, Fenibut, and Noofen among others,

intravenously.[6][7]

Side effects of phenibut can include

γ-hydroxybutyrate (GHB).[7] However, at low concentrations, phenibut mildly increases the concentration of dopamine in the brain, providing stimulatory effects in addition to the anxiolysis.[9]

Phenibut was developed in the

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]

Medical uses

Phenibut is used in Russia, Ukraine, Belarus and Latvia as a

diagnostic tests.[6][7]

Available forms

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][8][11] 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.[10]

Contraindications

Contraindications of phenibut include:[6][8]

Phenibut should not be combined with alcohol.[8]

Side effects

Phenibut is generally well-

monitored, due to risk of fatty liver disease and eosinophilia.[6][8]

Overdose

In

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][8] There have been three associated deaths which found Phenibut in the users system but only one of these cases single-handedly included Phenibut.[12]

Dependency and withdrawal

visual and auditory hallucinations, and acute psychosis.[3] Baclofen has successfully been used for treatment of phenibut dependence.[13]

Interactions

Phenibut may mutually potentiate and extend the duration of the effects of other central nervous system depressants including anxiolytics, antipsychotics, sedatives, opioids, anticonvulsants, and alcohol.[6][8]

Pharmacology

See also: Gabapentinoid § Pharmacology

Pharmacodynamics

GABA and analogues
at biological targets[14]
Compound GABAB GABAA
GABATooltip γ-Aminobutyric acid 0.08 0.12
GHB
Tooltip γ-Hydroxybutyric acid		 >100 >100
GABOB
Tooltip 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

affinity for the GABAB receptor than baclofen, and, in accordance, is used at far higher doses in comparison.[15] (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.[17]


Phenibut and analogues
at biological targets[18]
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

affinity (Ki = 23 and 39 μM, respectively).[18]

Pharmacokinetics

Little information thus far has been published on the clinical

elimination half-life was approximately 5.3 hours and the drug was largely (63%) excreted in the urine unchanged.[7]

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.

duration for the oral route has been reported to be 15 to 24 hours (or about 3 to 5 terminal half-lives).[3]

Chemistry

Phenibut is a

synthetic aromatic amino acid. It is a chiral molecule and thus has two potential configurations, as (R)- and (S)-enantiomers.[16]

Structure and analogues

Chemical structures of phenibut and analogues.

Phenibut is a

β-phenethylamine in its structure.[7]

Phenibut is closely related to a variety of other GABA analogues including

GABOB (β-hydroxy-GABA).[7][18] 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.[7] Phenibut is also close in structure to pregabalin, which has an isobutyl group at the β position instead of phenibut's phenyl ring.[18]

A

glutamate-derivative analogue of phenibut is glufimet (dimethyl 3-phenylglutamate hydrochloride).[21]

Synthesis

A chemical synthesis of phenibut has been published.[11]

History

Phenibut was synthesized at the

USSR) by Professor Vsevolod Perekalin's team and tested at the Institute of Experimental Medicine, USSR Academy of Medical Sciences.[7] It was introduced into clinical use in Russia in the 1960s.[7]

Society and culture

Olainfarm's pharmaceutical phenibut sold in Russia.

Other names

Alternate spellings include fenibut and phenybut.

INNTooltip International Nonproprietary Name.[2][6]

Brand names

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

Phenibut is approved in

nutritional supplement".[3][10] It is often used as a form of self-medication for social anxiety.[3]

Recreational use

Phenibut is used

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]

Legal status

As of 2021, phenibut is a controlled substance in Australia,[3] France,[23] Hungary,[24] Italy,[25] and Lithuania.[26][27] 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.[28][29]

As of 14 November 2018, Hungary added phenibut and 10 other items to its New Psychoactive Substances ban list.[30]

As of 26 August 2020, Italy added phenibut to its New Psychoactive Substances ban list.[25]

As of 18 September 2020, France added phenibut to the controlled psychoactive substances list, prohibiting production, sale, storage and use.[31]

In the United States, phenibut is not a Controlled Substance. However, Dietary supplements that contain phenibut are unlawful to introduce into interstate commerce, because phenibut is considered a "New Drug" and any food, supplement, cosmetic, or drug that contains phenibut is therefore misbranded. Alabama placed phenibut and tianeptine into Schedule I status on 2021, first by action of the Alabama Department of Public Health and then followed by the state legislature.[5]

References

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  4. ^ Nutrition, Center for Food Safety and Applied (6 March 2023). "Phenibut in Dietary Supplements". FDA.
  5. ^ a b "HB2, Holmes, Tianeptine and Phenibut added to Schdule I Conrolled Substances". Alabama Pharmacy Association. Archived from the original on 1 June 2021.
  6. ^ a b c d e f g h i j k l m n o p q r s t Ozon Pharm, Fenibut (PDF), archived from the original (PDF) on 16 September 2017, retrieved 15 September 2017
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  8. ^ 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). Retrieved 15 September 2017.
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  24. ^ "39/2018. (XI. 8.) EMMI rendelet Az új pszichoaktív anyaggá minősített anyagokról vagy vegyületcsoportokról szóló 55/2014. (XII. 30.) EMMI rendelet módosításáról" (PDF).
  25. ^ a b "Gazzetta Ufficiale 11/08/20". Lorenzo Arbolino. 11 August 2020. Retrieved 27 August 2020.
  26. ^ "RINKOS RIBOJIMO PRIEMONĖS FENIBUTUI!". ntakd.lrv.lt (in Lithuanian). Archived from the original on 6 October 2021. Retrieved 27 January 2020.
  27. ^ "V-1431 Dėl Lietuvos Respublikos sveikatos apsaugos ministro 2000 m. sausio 6 d. įsakymo Nr. 5 "Dėl Narko..." e-seimas.lrs.lt (in Lithuanian). Retrieved 27 January 2020.
  28. ^ "3.3 Phenibut". Administration Therapeutic Goods Administration. Australian Government Department of Health. 31 October 2017. Retrieved 6 November 2017.
  29. ^ "Mass school overdose investigation focuses on banned Russian drug". ABC News. Australian Broadcasting Corporation. 22 February 2018. Retrieved 22 February 2018.
  30. ^ "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.
  31. ^ Le phénibut interdit en France | Le Généraliste