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Drug and Review (2015) DOI: 10.1111/dar.12356 (4-amino-3-phenyl-butyric acid): Availability, prevalence of use, desired effects and acute toxicity

DAVID R. OWEN1,DAVIDM.WOOD2,3,JOHNR.H.ARCHER2 & PAUL I. DARGAN2,3

1Division of Sciences, Imperial College London, London, UK, 2Clinical Toxicology, Guy’s and St Thomas’ NHS Foundation and King’s Health Partners, London, UK, and 3Faculty of Life Sciences and , King’sCollege London, London, UK

Abstract Introduction and Aims. There has been a global increase in the availability and use of novel psychoactive substances (NPS) over the last decade. Phenibut (β-phenyl-γ-aminobutyric acid) is a GABAB that is used as an NPS. Here, we bring together published scientific and grey information sources to further understand the prevalence of use, desired effects and acute toxicity of phenibut. Design and Methods. Using European Centre for and Internet snapshot method- ology, we undertook an English language Internet snapshot survey in May 2015 to gather information on the availability and price of phenibut from Internet NPS retailers. To gather information on prevalence of use, desired effects and/or adverse effects, we searched grey literature (online drug discussion forums) and medical literature (PubMed and abstracts from selected International Toxicology conferences). Results. We found 48 unrelated Internet suppliers selling phenibut in amounts ranging from 5 g (US$1.60, £1.01/g) to 1000 kg (US$0.23, £0.14/g). Capsules containing 200–500 mg of phenibut were available in packs of between 6 (US$4.45, £2.80/g) and 360 (US$0.43, £0.27/g). According to the grey literature, phenibut is taken for its and euphoric properties, with tolerance and withdrawal syndromes commonly reported adverse effects. Phenibut is taken orally at an average dose of 2.4 g. Case reports in the medical literature feature users who present to emergency departments heavily sedated or experiencing with- drawal.Therehavebeennoreporteddeathsrelating tophenibutuse. DiscussionandConclusions. Phenibut is readily available in the UK from Internet sites selling NPS. Its desired and adverse effects appear similar to other gamma-aminobutyric acid receptor . [Owen DR, Wood DM, Archer JRH, Dargan PI. Phenibut (4-amino-3-phenyl-butyric acid): Availability, prevalence of use, desired effects and acute toxicity. Drug Alcohol Rev 2015;00:000–000]

Key words: phenibut, GABA, GABAB, availability, recreational drug, NPS, acute toxicity, prevalence of use.

Introduction , notified to the EMCDDA Early Warning System in 2012 [14]. There has been a global increase in the availability and Phenibut is available in its racemic form, but the use of novel psychoactive substances (NPS) over the last GABAB activity is conferred by the R-. decade [1–7]. In , there were 101 new NPS re- R-phenibut has a 10- to 15-fold lower affinity for the ported to the European Monitoring Centre for Drugs GABAB receptor than the structurally similar and Drug Addiction (EMCDDA) through its Early (Kd 25–90 vs 2.5–6 μM). Although its desired effects Warning System in 2014 [8]. ( and anxiolysis) are thought to be mediated Phenibut (4-amino-3-phenyl-butyric acid) is an ana- primarily via GABAB receptors, phenibut also has ac- logue of gamma-aminobutyric acid (GABA) and a tivity at GABAA and receptors [10]. GABAB agonist [10], licenced in for treatment There is limited information on the prevalence of use, of , alcohol withdrawal, stammering and insom- desired effects and acute toxicity of phenibut. Previous nia [10]. It is also used in preclinical experiments to in- studies have demonstrated that it is possible to obtain this fi ‘ ’ vestigate the effect of GABAB engagement in animal information from a range of both scienti cand grey lit- models [11–13]. Phenibut is not licenced within the erature, in a process known as data triangulation , or the USA. The first detection [2–4,15]. The aim of this paper was to use this data of phenibut as an NPS in Europe was in a 2011 seizure in triangulation methodology for phenibut.

David R. Owen MD, PhD, David M. Wood BSc (Hons), MB ChB (Hons), MD, FRCP, FEAPCCT, FBPhS, FACMT, Consultant Physician and Clinical Toxicologist and Service (Clinical) Lead for Medicine, Honorary Senior Lecturer, John R.H. Archer Consultant Physician & Clinical Toxicologist, Paul I. Dargan MBBS FRCPE FACMT FRCP ERT FAACT FBPhS FEAPCCT. Correspondence to Dr Paul Dargan, Clinical Toxicology, Third Floor, Block C, South Wing, St Thomas’ Hospital, Westminster Bridge Road, London SE1 7EH, UK. Tel: +442071885848; E-mail: [email protected] Received 21 June 2015; accepted for publication 22 September 2015.

© 2015 Australasian Professional Society on Alcohol and other Drugs D. R. Owen et al.

Methods containing 200–500 mg in packs of between 6 and 360. The mean price of phenibut powder was US$0.41 (£0.27) Phenibut availability survey per gram from suppliers in the USA and £0.39 (US$0.59) Using the EMCDDA Internet snapshot methodology per gram from suppliers in the UK. The capsules were [16], we undertook an Internet snapshot survey in English more than double the price, at US$0.99 (£0.65) per gram using the searchengines‘google.co.uk’, ‘yahoo.co.uk’ and from suppliers in the USA and £0.87 (US$1.32) per gram ‘metacrawler.com’ in May 2015, using search terms ‘buy from suppliers in the UK. The cost per gram of the powder phenibut’ and ‘buy fenibut’ and ‘buy 4-amino-3-phenyl- was cheaper when it was sold in larger amounts. From UK butyric acid’.Thefirst 100 sites identified were reviewed suppliers, the cost of phenibut was £1.16/g for 10 g, before continuing the searches to exhaustion. Data were £0.46/g for 25 g, £0.30/g for 100 g, £0.23/g for 1 kg and extracted from each individual site only once, irrespective £0.15/g for 1000 kg. From US suppliers, the cost was US of search term. Sites that appeared unable to ship products $1.05/g (£0.68/g) for 10 g, US$0.58/g (£0.38/g) for 25 g, toEuropewereexcluded,asperEMCDDAmethodology. US$0.31/g (£0.20/g) for 100 g and US$0.18/g (£0.12/g) Data were extracted from these Internet sites on the for1kg.Thepricepergramwasalsolowerwhencapsules amount (mass quantity of powder and number and size were purchased in increasing amounts: 60 capsules were of capsules) of phenibut available and cost and converted US$1.92/g (£1.24/g), 180 capsules were US$0.44/g into cost per gram. Additionally, we extracted the appar- (£0.28/g) and 360 capsules were US$0.41/g (£0.27/g). ent country of origin of the Internet site.

User reports Grey information sources From the six Internet forums that were searched, six Using the keywords ‘phenibut’, ‘fenibut’ and ‘4-amino-3- contained reports that met the inclusion criteria. In total, phenyl-butyric acid’, the Internet search engine Google. 105 reports were found, 45 from www.bluelight.org/vb/ co.ukandonlinedrugdiscussionforumsErowid,Drugs content [17], 21 from www.erowid.org [18], 20 from Forum, Bluelight, UK Chemical Research, Grind Fac- www.ukchemicalresearch.org [19], 15 from www.drugs- tor and Personal Power Meditation were searched in forum.com [20], 3 from www.grindfactor.com [21] and May 2015. Relevant information relating to the preva- 1 from www.personalpowermeditation.com [22]. lence of use, desired effects and/or adverse effects was extracted from entries where both a dose and a route of phenibut administration were stated. This information Administration fi was then collated to extract relevant themes identi ed Of the 105 user reports, all but four reported oral admin- through qualitative review. istration of phenibut by direct swallowing. Of the remain- ing four, one user reported nasal insufflation of phenibut powder, and three reported of Published scientific literature phenibut powder. Nasal insufflation was described as PubMed was searched in English using the keywords very painful, causing the nostrils to swell [23]. ‘phenibut’, ‘fenibut’ and ‘4-amino-3-phenyl-butyric acid’ Therewaswidevariationinthesingleoraldosesthatwere for articles that reported on availability, prevalence of use reported. The mean ± standard deviation dose reported or desired and adverse effects associated with recreational was 2.43 ± 1.62 g. The lowest dose reported was 500 mg phenibut use. Abstracts from selected international toxi- (in 3/105 cases), and at this dose, desired effects were still cology conferences (European Association of Poisons apparent. The highest dose reported was 9 g (2/105 cases). Centres and Clinical Toxicologists and North American The onset of desired effects was reported to occur Congress of Clinical Toxicology) from 2002 to 2015 2–4 h following oral ingestion and 20–30 min after rectal were searched using the same keywords. administration, peaking within 4–6h andwithanoverall duration of 15–24 h. Because of this long latency, first- time users often reported taking a repeat dose believing Results that the initial dose had not worked [24]. Phenibut availability Desired effects Forty-eight unrelated Internet suppliers selling phenibut were identified, either direct from the UK (17) or to be The two most commonly reported desired effects were shipped to the UK from USA (25), China (3), Australia disappearance of (36/105) and a of (2) or Canada (1). Phenibut was available as a powder euphoria (34/105). Users reported the former as mak- in amounts ranging from 5 g to 1000 kg and as capsules ing them more talkative and socially confident [24].

© 2015 Australasian Professional Society on Alcohol and other Drugs Phenibut and acute toxicity

Indeed, self- for social anxiety, distinct from 7 weeks, which was then weaned over 24 weeks [29]. recreational use, was commonly reported as a reason for Magsalin describes a 21-year-old man taking phenibut using phenibut. Users also reported that if taken at night, 1 g/day who experienced anxiety and upon phenibut is a strong (16/105 reports). Continued withdrawal, still mild anxiety despite being euphoria the following day (‘afterglow’) was also reported weaned from phenibut [30]. Withdrawal syndromes in- (4/105 reports). Some users (5/105) also reported that cluding psychotic features have also been reported. phenibut caused sexual [25], and 3/105 reported Hogberg described a male taking phenibut 20 g/day for increased enjoyment of music and arts [26]. 2 months, who experienced withdrawal characterised by insomnia with visual and auditory that lasted 7 days [31]. Marraffa describes a 42-year-old fe- Adverse effects male who experienced hallucinations and agitation fol- At least one adverse effect was described in 49 (46.7%) of lowing withdrawal having used phenibut for 7 days [33]. the 105 reports. Common adverse effects reported were Finally, Odujebe describes a 40-year-old man using tolerance (8/105 reports) and withdrawal (5/105 reports). phenibut 1 g daily for several months who experienced in- Tolerance is described as occurring within days, and somnia, agitation and hallucinations on withdrawal [34]. users posted advice to leave 2 weeks in between doses There have also been several reported cases of users [27]. Likewise, withdrawal effects were commonly found unresponsive following phenibut use. Marraffa de- reported after only a few days of consecutive dosing and scribes three patients with altered mental status following described to involve severe rebound anxiety and insom- presumed phenibut ingestion [33]. A 33-year-old female nia [24]. In addition to these adverse effects, presented responsive only to painful stimuli, and a (7/105), balance and co-ordination impairment (7/105), 23-year-old male presented lethargic. Both recovered (6/105), (5/105) and electric shock over 7 h with no treatment. A 59-year-old female taking symptoms in the limbs (2/105) were also reported. phenibut presented with lethargy and experienced two – Regarding interaction with other recreational drugs, tonic clonic seizures. After 12 h, she became agitated there were very few user reports that stated the drugs and required management with . and doses that had been concomitantly used. Four Wong describes a 43-year-old who had taken phenibut fl reports stated that alcohol was co-used with phenibut, 30 g who presented with uctuating agitation and somno- and in these reports, adverse events were not reported. lence. He required benzodiazepines and intubation and Two reports stated that a was co-used, made a full recovery [35]. Downes describes a 20-year- and in one of these reports (1 g used with 2 g old female who presented with reduced consciousness phenibut), the user reported a negative experience [28]. following phenibut 25 g who recovered over 24 h without There were no reports describing chronic toxicity. treatment and a 38-year-old man with agitated following phenibut ingestion who was intubated over- night and awoke with a normal sensorium [36]. Finally, Prevalence of use O’Connell describes a 25-year-old man found minimally responsive after taking phenibut 3 g/day for 4 days, who There have been no population or sub-population studies presented with a depressed level of consciousness but re- that have reported on the prevalence of use of phenibut. covered over 7 h [32].

Published case reports of phenibut adverse events Discussion Four published case reports were found on PubMed; three described withdrawal syndromes [29–31], and one The aim of this paper is to bring together information described acute toxicity [32]. Eight case reports were de- from a range of sources from both the scientificand‘grey’ scribed in four abstracts from North American Congress literature to understand the patterns of availability and of Clinical Toxicology and European Association of Poi- use, desired effects and adverse effects of phenibut. sons Centres and Clinical Toxicologists meetings. Of Using an EMCDDA Internet Snapshot, we have these, six described acute toxicity, and two described with- shown that phenibut is widely available to potential users drawal syndromes [33–36]. In only two cases [35,36] was in the UK from Internet sites that are mainly based in the the presence of phenibut analytically confirmed. All of the UK and USA [37,38]. acute toxicity and withdrawal case reports identified are The most commonly desired effects were euphoria and summarised in Tables 1 and 2, respectively. reduction in social anxiety. Such effects are also seen with Samokhvalov describes a 35-year-old man taking pharmacologically similar GABAB receptor agonists such phenibut 8 g/day who experienced and as baclofen and gamma-hydroxybutyrate (GHB)/ on withdrawal. Phenibut was replaced with baclofen over gamma-butyrolactone (GBL) [39–41]. The adverse

© 2015 Australasian Professional Society on Alcohol and other Drugs D. R. Owen et al.

Table 1. Summary of case reports describing acute phenibut toxicity

Age Case (years) Phenibut Concomitant Analytical number and sex Symptoms Comorbidity exposure /drugs confirmation Reference

1 33 F and abuse NR NR No [33] myoclonic jerking 2 23 M Lethargic NR NR No [33] 3 59 F Lethargic and tonic– Anxiety and NR Opioid, No [33] clonic seizure chronic unspecified 443MAgitation , 30 g in 24 h Nil Powder [35] interspersed with anxiety and confirmed as insomnia phenibut 5 20 F Sedated but delirious Nil 25 g over 24 h Nil No [36] when roused 6 38 M Agitated delirium Delirium NR Alcohol and Phenibut [36] detected in 7 25 M Minimally responsive Alcohol 3g/dayfor and No [32] dependence and 4days depression

NR, not reported.

Table 2. Summary of case reports describing phenibut withdrawal

Age Case (years) Phenibut Concomitant Analytical number and sex Symptoms Comorbidity exposure medications/drugs confirmation Reference

1 35 M Anxiety, anger Depression 8 g/day for Mitragyna No [29] and irritability anxiety 10 months speciosa (‘kratom’) 2 21 M Anxiety, agitation, Restless leg 1 g/day for Nil No [30] irritability and syndrome 10 days insomnia 330MAnxietyandBenzodiazepine 20 g/day for No [31] hallucinations addiction 2 months and (visual and auditory) 4 42 F Hallucinations and Insomnia Dose unspecified Nil No [33] agitation for 1 week 5 40 M Insomnia, agitation Nil 1 g/day for Nil No [34] and hallucinations several months

event profile includes sedation, early tolerance and with- phenibut, 65% of the dose was recovered unchanged drawal reactions characterised chiefly by anxiety and in- in the [10]. The plasma half-life was 5.3 h [10]. somnia. Again, this profile is similar to baclofen and A half-life of 5.3 h is broadly consistent with the re- GHB/GBL [39–41]. However, unlike GHB/GBL, there ports from the grey literature, which suggest a duration have been no reports of deaths associated with the use of action of approximately 15–24 h (i.e. three to five of phenibut. half-lives). There is limited pharmacokinetic information available The use of data from multiple sources, through a pro- on phenibut. In rodents, phenibut is excreted largely cess known as data triangulation, has been demonstrated unchanged in the urine [10]. Consistent with this, in to provide a robust picture of the acute toxicity associated healthy volunteers administered a single dose of 250 mg with NPS [2–4]. Here, we have expanded this to focus

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