Scholarly article on topic 'Phenibut (4-amino-3-phenyl-butyric acid): Availability, prevalence of use, desired effects and acute toxicity'

Phenibut (4-amino-3-phenyl-butyric acid): Availability, prevalence of use, desired effects and acute toxicity Academic research paper on "Clinical medicine"

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Academic research paper on topic "Phenibut (4-amino-3-phenyl-butyric acid): Availability, prevalence of use, desired effects and acute toxicity"

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Drug and Alcohol Review (2015) DOI: 10.1111/dar.12356

Phenibut (4-amino-3-phenyl-butyric acid): Availability, prevalence of use, desired effects and acute toxicity

DAVID R. OWEN1, DAVID M. WOOD23, JOHN R. H. ARCHER2 & PAUL I. DARGAN23

1 Division of Brain Sciences, Imperial College London, London, UK, 2 Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust and King's Health Partners, London, UK, and 3Faculty of Life Sciences and Medicine, King's College 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 (fi-phenyl-j-aminobutyric acid) is a GABAB agonist 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 Monitoring Centre for Drugs and Drug Addiction Internet snapshot methodology, 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 5g (US$1.60, £1.01/g) to 1000kg (US$0.23, £0.14/g). Capsules containing 200-500mg 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 anxiolytic 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 withdrawal. Therehavebeennoreporteddeathsrelatingtophenibutuse. Discussion and Conclusions. 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 agonists. [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

There has been a global increase in the availability and use of novel psychoactive substances (NPS) over the last decade [1-7]. In Europe, there were 101 new NPS reported to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) through its Early Warning System in 2014 [8].

Phenibut (4-amino-3-phenyl-butyric acid) is an analogue of gamma-aminobutyric acid (GABA) and a GABAB agonist [10], licenced in Russia for treatment of anxiety, alcohol withdrawal, stammering and insomnia [10]. It is also used in preclinical experiments to investigate the effect of GABAB engagement in animal models [11-13]. Phenibut is not licenced within the European Union, Australia or the USA. The first detection of phenibut as an NPS in Europe was in a 2011 seizure in

Sweden, notified to the EMCDDA Early Warning System in 2012 [14].

Phenibut is available in its racemic form, but the GABAB activity is conferred by the R-enantiomer. R-phenibut has a 10- to 15-fold lower affinity for the GABAB receptor than the structurally similar baclofen (Kd 25-90 vs 2.5-6 ^M). Although its desired effects (euphoria and anxiolysis) are thought to be mediated primarily via GABAB receptors, phenibut also has activity at GABAa and dopamine receptors [10].

There is limited information on the prevalence of use, desired effects and acute toxicity of phenibut. Previous studies have demonstrated that it is possible to obtain this information from a range of both scientific and 'grey' literature, in a process known as data triangulation [2-4,15]. The aim of this paper was to use this data 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 SEI 7EH, UK. Tel: +442071885848; E-mail: paul.dargan@gstt.nhs.uk

Received 21 June 2015; accepted for publication 22 September 2015.

Methods

Phenibut availability survey

Using the EMCDDA Internet snapshot methodology [16], we undertook an Internet snapshot survey in English usingthe search engines 'google.co.uk', 'yahoo.co.uk' and 'metacrawler.com' in May 2015, using search terms 'buy phenibut' and 'buy fenibut' and 'buy 4-amino-3-phenyl-butyric acid'. The first 100 sites identified were reviewed before continuing the searches to exhaustion. Data were extracted from each individual site only once, irrespective of search term. Sites that appeared unable to ship products to Europe were excluded, as per EMCDDA methodology.

Data were extracted from these Internet sites on the amount (mass quantity of powder and number and size of capsules) of phenibut available and cost and converted into cost per gram. Additionally, we extracted the apparent country of origin of the Internet site.

Grey information sources

Using the keywords 'phenibut', 'fenibut' and '4-amino-3-phenyl-butyric acid', the Internet search engine Google. co.uk and online drug discussion forums Erowid, Drugs Forum, Bluelight, UK Chemical Research, Grind Factor and Personal Power Meditation were searched in May 2015. Relevant information relating to the prevalence 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 was then collated to extract relevant themes identified through qualitative review.

Published scientific literature

PubMed was searched in English using the keywords 'phenibut', 'fenibut' and '4-amino-3-phenyl-butyric acid' for articles that reported on availability, prevalence ofuse or desired and adverse effects associated with recreational phenibut use. Abstracts from selected international toxicology conferences (European Association of Poisons Centres and Clinical Toxicologists and North American Congress of Clinical Toxicology) from 2002 to 2015 were searched using the same keywords.

Results

Phenibut availability

Forty-eight unrelated Internet suppliers selling phenibut were identified, either direct from the UK (17) or to be shipped to the UK from USA (25), China (3), Australia (2) or Canada (1). Phenibut was available as a powder in amounts ranging from 5 g to 1000 kg and as capsules

containing 200-500 mg in packs of between 6 and 360. The mean price of phenibut powder was US$0.41 (£0.27) per gram from suppliers in the USA and £0.39 (US$0.59) per gram from suppliers in the UK. The capsules were more than double the price, at US$0.99 (£0.65) per gram from suppliers in the USA and £0.87 (US$1.32) per gram from suppliers in the UK. The cost per gram of the powder was cheaper when it was sold in larger amounts. From UK suppliers, the cost of phenibut was £1.16/g for 10 g, £0.46/g for 25 g, £0.30/g for 100 g, £0.23/g for 1kg and £0.15/g for 1000kg. From US suppliers, the cost was US $1.05/g (£0.68/g) for 10g, US$0.58/g (£0.38/g) for 25g, US$0.31/g (£0.20/g) for 100g and US$0.18/g (£0.12/g) for 1 kg. The price per gram was also lower when capsules were purchased in increasing amounts: 60 capsules were US$1.92/g (£1.24/g), 180 capsules were US$0.44/g (£0.28/g) and 360 capsules were US$0.41/g (£0.27/g).

User reports

From the six Internet forums that were searched, six contained reports that met the inclusion criteria. In total, 105 reports were found, 45 from www.bluelight.org/vb/ content [17], 21 from www.erowid.org [18], 20 from www.ukchemicalresearch.org [19], 15 from www.drugs-forum.com [20], 3 fromwww.grindfactor.com [21] and 1 from www.personalpowermeditation.com [22].

Administration

Of the 105 user reports, all but four reported oral administration of phenibut by direct swallowing. Of the remaining four, one user reported nasal insufflation of phenibut powder, and three reported rectal administration of phenibut powder. Nasal insufflation was described as very painful, causing the nostrils to swell [23].

There was wide variation in the single oral doses that were reported. The mean ± standard deviation dose reported was 2.43 ± 1.62 g. The lowest dose reported was 500 mg (in 3/105 cases), and at this dose, desired effects were still apparent. The highest dose reported was 9 g (2/105 cases).

The onset of desired effects was reported to occur 2-4h following oral ingestion and 20-30 min after rectal administration, peaking within 4-6h and with an overall duration of 15-24 h. Because of this long latency, firsttime users often reported taking a repeat dose believing that the initial dose had not worked [24].

Desired effects

The two most commonly reported desired effects were disappearance of social anxiety (36/105) and a sense of euphoria (34/105). Users reported the former as making them more talkative and socially confident [24].

Indeed, self-medication for social anxiety, distinct from recreational use, was commonly reported as a reason for using phenibut. Users also reported that if taken at night, phenibut is a strong hypnotic (16/105 reports). Continued euphoria the following day ('afterglow') was also reported (4/105 reports). Some users (5/105) also reported that phenibut caused sexual arousal [25], and 3/105 reported increased enjoyment of music and arts [26].

Adverse effects

At least one adverse effect was described in 49 (46.7%) of the 105 reports. Common adverse effects reported were tolerance (8/105 reports) and withdrawal (5/105 reports). Tolerance is described as occurring within days, and users posted advice to leave 2 weeks in between doses [27]. Likewise, withdrawal effects were commonly reported after only a few days of consecutive dosing and described to involve severe rebound anxiety and insomnia [24]. In addition to these adverse effects, hangovers (7/105), balance and co-ordination impairment (7/105), dizziness (6/105), nausea (5/105) and electric shock symptoms in the limbs (2/105) were also reported.

Regarding interaction with other recreational drugs, there were very few user reports that stated the drugs and doses that had been concomitantly used. Four reports stated that alcohol was co-used with phenibut, and in these reports, adverse events were not reported. Two reports stated that a benzodiazepine was co-used, and in one of these reports (1 g alprazolam used with 2g phenibut), the user reported a negative experience [28].

There were no reports describing chronic toxicity.

Prevalence of use

There have been no population or sub-population studies that have reported on the prevalence of use of phenibut.

Published case reports of phenibut adverse events

Four published case reports were found on PubMed; three described withdrawal syndromes [29-31], and one described acute toxicity [32]. Eight case reports were described in four abstracts from North American Congress of Clinical Toxicology and European Association of Poisons Centres and Clinical Toxicologists meetings. Of these, six described acute toxicity, and two described withdrawal syndromes [33-36]. In only two cases [35,36] was the presence of phenibut analytically confirmed. All of the acute toxicity and withdrawal case reports identified are summarised in Tables 1 and 2, respectively.

Samokhvalov describes a 35-year-old man taking phenibut 8 g/day who experienced anger and irritability on withdrawal. Phenibut was replaced with baclofen over

7 weeks, which was then weaned over 24 weeks [29]. Magsalin describes a 21-year-old man taking phenibut

1 g/day who experienced anxiety and insomnia upon withdrawal, still suffering mild anxiety despite being weaned from phenibut [30]. Withdrawal syndromes including psychotic features have also been reported. Hogberg described a male taking phenibut 20g/day for

2 months, who experienced withdrawal characterised by insomnia with visual and auditory hallucinations that lasted 7 days [31]. Marraffa describes a 42-year-old female who experienced hallucinations and agitation following withdrawal having used phenibut for 7 days [33]. Finally, Odujebe describes a 40-year-old man using phenibut 1 g daily for several months who experienced insomnia, agitation and hallucinations on withdrawal [34].

There have also been several reported cases of users found unresponsive following phenibut use. Marraffa describes three patients with altered mental status following presumed phenibut ingestion [33]. A 33-year-old female presented responsive only to painful stimuli, and a 23-year-old male presented lethargic. Both recovered over 7 h with no treatment. A 59-year-old female taking phenibut presented with lethargy and experienced two tonic-clonic seizures. After 12h, she became agitated and required management with benzodiazepines.

Wong describes a 43-year-old who had taken phenibut 30 g who presented with fluctuating agitation and somnolence. He required benzodiazepines and intubation and made a full recovery [35]. Downes describes a 20-year-old female who presented with reduced consciousness following phenibut 25 g who recovered over 24 h without treatment and a 38-year-old man with agitated delirium following phenibut ingestion who was intubated overnight and awoke with a normal sensorium [36]. Finally, O'Connell describes a 25-year-old man found minimally responsive after taking phenibut 3 g/day for 4 days, who presented with a depressed level of consciousness but recovered over 7 h [32].

Discussion

The aim of this paper is to bring together information from a range of sources from both the scientific and 'grey' literature to understand the patterns of availability and use, desired effects and adverse effects of phenibut.

Using an EMCDDA Internet Snapshot, we have shown that phenibut is widely available to potential users in the UK from Internet sites that are mainly based in the UK and USA [37,38].

The most commonly desired effects were euphoria and reduction in social anxiety. Such effects are also seen with pharmacologically similar GABAB receptor agonists such as baclofen and gamma-hydroxybutyrate (GHB)/ gamma-butyrolactone (GBL) [39-41]. The adverse

Table 1. Summary of case reports describing acute phenibut toxicity

Case (years) Phenibut Concomitant Analytical

number and sex Symptoms Comorbidity exposure medications/drugs confirmation Reference

1 33 F Sedation and myoclonic jerking Opioid abuse NR NR No [33]

2 23 M Lethargic Substance abuse NR NR No [33]

3 59 F Lethargic and tonic-clonic seizure Anxiety and chronic pain NR Opioid, unspecified No [33]

4 43 M Agitation interspersed with somnolence Depression, anxiety and insomnia 30 g in 24 h Nil Powder confirmed as phenibut [35]

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]

cannabis detected in blood

7 25 M Minimally responsive Alcohol dependence and depression 3 g/day for 4days Venlafaxine and mirtazapine No [32]

NR, not reported.

Table 2. Summary of case reports describing phenibut withdrawal

Case (years)

number and sex Symptoms

Phenibut Concomitant Analytical

Comorbidity exposure medications/drugs confirmation Reference

1 35 M Anxiety, anger

and irritability

2 21M Anxiety, agitation,

irritability and insomnia

3 30 M Anxiety and

hallucinations (visual and auditory)

4 42 F Hallucinations and

agitation

5 40 M Insomnia, agitation

and hallucinations

Depression anxiety

Restless leg syndrome

Benzodiazepine addiction

Insomnia Nil

8 g/day for 10 months

1 g/day for 10 days

20 g/day for

2 months

Dose unspecified for 1 week 1 g/day for several months

Mitragyna speciosa ('kratom') Nil

Alimemazine and hydroxyzine

Nil Nil

No No No

event profile includes sedation, early tolerance and withdrawal reactions characterised chiefly by anxiety and insomnia. Again, this profile is similar to baclofen and GHB/GBL [39-41]. However, unlike GHB/GBL, there have been no reports of deaths associated with the use of phenibut.

There is limited pharmacokinetic information available on phenibut. In rodents, phenibut is excreted largely unchanged in the urine [10]. Consistent with this, in healthy volunteers administered a single dose of 250 mg

phenibut, 65% of the dose was recovered unchanged in the urine [10]. The plasma half-life was 5.3h [10]. A half-life of 5.3h is broadly consistent with the reports from the grey literature, which suggest a duration of action of approximately 15-24h (i.e. three to five half-lives).

The use of data from multiple sources, through a process known as data triangulation, has been demonstrated to provide a robust picture ofthe acute toxicity associated with NPS [2-4]. Here, we have expanded this to focus

also on the availability and desired effects to phenibut to provide a more complete picture of the significance of this drug as an NPS.

Conclusion

Phenibut is widely available to potential users from Internet NPS suppliers. Because it was first notified to the EMCDDA as an NPS in 2012, there have been several reports of acute toxicity/withdrawal, which together with reports from users in the grey literature illustrate the potential for significant acute toxicity and dependence potential associated with the use of phenibut. Given the increasing evidence of availability of phenibut in Europe and increasing reports of acute harms associated with its use, there needs to be consideration regarding the legal status of Phenibut in Europe.

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