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]
Phenibut was developed in the Soviet Union and was introduced for medical use in the 1960s.[7] Today, it is marketed for medical use in Russia, Ukraine, Belarus, Kazakhstan, and Latvia.[7] 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][10] 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.[11]
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][12] 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]
Tolerance to phenibut easily develops with repeated use leading to dependency.[7][needs update]Withdrawalsymptoms 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.[14]
Phenibut acts as a full agonist of the GABAB receptor, similarly to baclofen.[16][17] 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.[16] (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.[18]
Phenibut also binds to and blocks α2δ subunit-containing VDCCs, similarly to gabapentin and pregabalin, and hence is a gabapentinoid.[19][20] Both (R)-phenibut and (S)-phenibut display this action with similar affinity (Ki = 23 and 39 μM, respectively).[19]
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.[21] The mechanism underlying this putative effect is unclear.[21] Structurally, phenibut can also be considered a derivative of phenethylamine, and some research suggests that phenibut antagonizes the action of phenethylamine.[21]
Pharmacokinetics
Little information thus far has been published on the clinical pharmacokinetics of phenibut.[7] 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.[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.[3][22] 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]
Phenibut is a derivative of the inhibitory neurotransmitter GABA.[7] Hence, it is a GABA analogue.[7] Phenibut is specifically the analogue of GABA with a phenyl ring substituted in at the β-position.[7] As such, its chemical name is β-phenyl-γ-aminobutyric acid, which can be abbreviated as β-phenyl-GABA.[7] The presence of the phenyl ring allows phenibut to cross the blood–brain barrier significantly, unlike the case of GABA.[7] Phenibut also contains the trace amineβ-phenethylamine in its structure.[7]
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).[7][19] 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.[19]
A glutamate-derivative analogue of phenibut is glufimet (dimethyl 3-phenylglutamate hydrochloride).[23]
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.[7] In early publications, phenibut was referred to as fenigam and phenigama.[7][24] The drug has not been assigned an 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]
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]
However, so far, this regulation has not prevented the easy online procurement of phenibut in Germany.[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]
As of 26 August 2020, Italy added phenibut to its New Psychoactive Substances ban list.[27]
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 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
^ abcdDrobizhev MY, Fedotova AV, Kikta SV, Antohin EY (2016). "Феномен аминофенилмасляной кислоты" [Phenomenon of aminophenylbutyric acid]. Russian Medical Journal (in Russian). 2017 (24): 1657–1663. ISSN1382-4368. Archived from the original on 16 September 2017. Retrieved 16 September 2017.
^ abcdefghijklmnopqrstuvOwen 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. PMID26693960.
^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.
^ abcdefghijklmРегистр лекарственных средств России ([Russian Medicines Register]). "Фенибут (Phenybutum)" [Fenibut (Phenybutum)] (in Russian). Archived from the original on 3 March 2009. Retrieved 15 September 2017.
^ abcCohen 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. PMID34550038. S2CID237594860.
^ abSivchik 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
^ abDambrova 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. PMID18275958.
^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. ISSN0040-4020.
^ abcdeZvejniece 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. PMID26234470. S2CID42606053.
^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. PMID26621244.
^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. PMID28726197. S2CID4907409.
^"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.