Phenibutan—an Illegal Food Supplement With Psychotropic Effects and Health Risks

Background: Phenibut (β-phenyl-γ-aminobutyric acid) is an analog of the neurotransmitter gamma-aminobutyric acid (GABA). Like abapentin and pregabalin, it inhibits α2-δ–subunits of voltage-dependent presynaptic calcium channels. The potential harm resulting from the use of these gabapentinoids is currently a matter of debate.

Methods: This review is based on pertinent publications retrieved by a selective literature search and on cases reported to the Giftinformationszentrum-Nord (GIZ-Nord), a poison information center at the University of Göttingen, Germany.

Results: Phenibut is a prescription drug in Russia but its production, possession, use, trafficking, or administration is illegal in Germany. The phenibut toxicity syndrome resembles that of gabapentinoids and GABA mimetics: benzodiazepine-like withdrawal symptoms including epileptic seizures, delirium and paradoxical activation have been described, as have cases of abuse and dependence. A few cases of use in the setting of multidrug abuse, and of phenibut-related death, have been described to date in the USA. The GIZ-Nord received 17 inquiries about phenibut, 55 about gabapentin, and 126 about pregabalin over the period 2008–2022. Over the same period, the GIZ-Nord was informed of 1207 cases involving Z substances and 4324 involving benzodiazepines. In the majority of the registered intoxications, including those with phenibut, the symptoms were mild. Overdoses of phenibut (2–100 g) were reported in 15 of the 17 cases; 8 of the persons who had taken an overdose were somnolent. In such cases, observation in intensive care was recommended. Respiratory depression or coma was not encountered in any case, not even in the patient who had taken 100 g of phenibut.

Conclusion: Phenibut causes symptoms resembling those of gabapentinoid and benzodiazepine use. There have been reports of phenibut use in combination with other psychotropic drugs; in particular, its use together with opiates could increase the risk of coma and respiratory depression. No deaths due to phenibut intoxication have been published in Germany or elsewhere in Western Europe, although such cases may have been overlooked, as this drug is still largely unknown to Western medicine.

This article would like to raise awareness of a psychotropic substance, hitherto virtually unknown in Germany and Western Europe, that can be bought online as a food supplement in capsule and powder form: phenibut (β-phenyl-γ-aminobutyric acid) (1, 2), a lipophilic analog of the γ-aminobutyric acid (GABA) (Table, e1, e2), is touted in Western countries on the bodybuilding scene and the Internet as a food supplement with euphoria-inducing and relaxant effects, but which at lower doses (250–500 mg) also has performance-enhancing effects (street names: e.g., “the happy drug,” “the smart pill”). It originated in Russia and has been medically prescribed in former Soviet Union countries since the early 1960s in daily doses of between 250 mg and 2 g as a nootropic (in low doses) as well as a drug for somatoform symptoms of anxiety, sleep disorders, posttraumatic stress disorder, and mild to moderate alcohol withdrawal symptoms (1, 2).

Table

Pharmacotoxicology of the gabapentinoids available in Germany

In the chiral molecule, only (R)-phenibut is pharmacologically active (e2). Since the 1970s, (R)-phenibut has been considered a GABA-B receptor agonist and as significantly weaker than baclofen (dissociation constants [K_D] at the GABA-B receptor for [R]-phenibut versus baclofen: 92 ± 3 μM versus 6 ± 1 3 μM [1, 2]). Only in 2015 was it recognized that (R)-phenibut, like gabapentin und pregabalin, also inhibits α2-δ subunits of voltage-gated calcium channels (2, 3, 4, 5, e3, e4). However, its affinity to these subunits (K_D = 21 ± 7 µM) is lower compared to that of gabapentin (K_D = 0.05 ± 0.01 µM), the weakest gabapentinoid used clinically to date (Table) (2, e5). The Russian literature additionally describes stimulation of the dopaminergic system and beta-phenethylamine (PEA) inhibition (1). PEA is a trace amine in the intracellular synthesis of biogenic amines such as dopamine, noradrenaline, and serotonin, and furthermore acts as an agonist on trace amine-associated receptor (TAAR)-1, which is also activated by amphetamine (e6). Phenibut is virtually unaffected by hepatic metabolism and is excreted unchanged (5, e7, e8, e9).

Since phenibut belongs to the substance class of gabapentinoids (Box 1), the representatives of which, gabapentin and pregabalin, are increasingly discussed with regard to their potential for harm (3, 4, 5, 6), we attempt to classify phenibut accordingly (Box 1).

Box 1

Definition of the gabapentinoid substance class

Methods

This review article is based on a literature search in the PubMed database. The following search terms were used: “phenibut,” “toxicity,” “safety,” “tolerability,” “dependence,” “withdrawal,” “fatalities,” “death,” “intoxication,” “asphyxia,” “hypoxia,” “respiratory depression,” “review.” The search period covered studies that appeared up to 11.11.2023. All studies and reports providing information on the clinical effect, safety, and tolerability of phenibut were included. We also searched the Internet via Google and evaluated inquiries to the Giftinformationszentrum-Nord (GIZ-Nord), a poison information center at the University of Göttingen, Germany, between 2008 and 2022 regarding phenibut, gabapentin, pregabalin, benzodiazepines, and other GABA mimetics (GABA effect enhancers).

Results

We were unable to find any prospective or randomized controlled studies. The following information on phenibut is based on three retrospective epidemiological studies (5, 7, 8), five case reports (9, e7, e8, e12), one case series (10), six narrative reviews (1, 2, 11, 12, 13, e9), and one systematic review, for which only retrospective studies and case studies were considered (14).

The legality of phenibut

In Germany (as well as outside the former Soviet Union), phenibut is not approved as a drug and, as a food supplement, is controlled under the German New Psychoactive Substances Act (Neue-psychoaktive-Stoffe-Gesetz, NpSG) ([15, e13], Appendix 1.1–1.2. “Compounds derived from 2-phenethylamine”). However, so far, this regulation has not prevented the easy online procurement of phenibut. In actual fact, phenibut is banned. In accordance with the NpSG, the ban includes its: production, possession, use, trafficking, or administration. Exceptions can be approved for technical and scientific purposes as well as for use by a public authority. Phenibut is also illegal in Australia, France, the United Kingdom, Italy, Hungary, and Lithuania (15).

Pharmacovigilance, toxidrome, and mortality

In Germany, phenibut has been made subject to pharmacovigilance (e13). To date, there have been no publications in German-speaking countries regarding emergency cases, deaths, or addiction disorders associated with phenibut. The majority of reports come from Russian-speaking countries (1, 2) and the USA (5, 7, 8, 9, 10, 11, 12, 13, 14, e6, e7, e8, e9, e12). Oral overdoses (up to 50 g = 25-fold overdose) cause symptoms that are also typically known in overdoses of GABA mimetic sedatives and hypnotics (in particular, somnolence to coma, falls, respiratory depression requiring intubation [1, 2, 7, 14]). The recommended approach in phenibut intoxication is derived from these (Box 2). As with benzodiazepines and other GABA mimetics, paradoxical cases involving panic attacks, acute psychoses, and severe psychomotor agitation have been described (1, 2, 11).

Box 2

Approach in phenibut intoxication

Between 2009 and 2019, 1320 cases of intoxication (including three deaths) involving phenibut were reported in the USA. Typical symptoms included tachycardia, nausea, stomach cramps, drowsiness, coma, confusion, hallucinations, and severe psychomotor agitation. Mostly young adults were affected. The number of cases of this kind started to rise in 2015 (7). According to a recent study, approximately 50% of registered cases of intoxication involving phenibut required intubation (14). According to that study, phenibut was one element in multidrug use (7, 14). In a few isolated cases, dependent concomitant use of phenibut in patients prescribed opiates has been described (e12). A US online search recently revealed that drug addicts in the USA are now using phenibut—much in the same way as other gabapentinoids (3, 6)—to manage benzodiazepine and opiate withdrawal symptoms (8).

We were able to find quantitative values in three toxicological post-mortem analyses in which phenibut was identified as part of multidrug use, but was not deemed to be responsible for death: phenibut concentrations of up to 64 mg/L were measured in femoral blood (9, 10). In the few deaths described in association with phenibut, concomitant use of various substances, including alcohol and opiates, was documented (7, 9, 10). We were unable to find any post-mortem analyses in which phenibut alone was detected or declared as the cause of death.

Own Internet research

There are reports of enhanced physical and mental performance, euphoria, and alleviation of alcohol and opiate withdrawal symptoms with phenibut. Users report quantities of between 2 and 5 g of phenibut to alleviate withdrawal symptoms of this kind (1 g of this substance currently costs around 1 euro).

Dependence and abuse, withdrawal syndrome and tolerability

Similar to benzodiazepines, gabapentin, and pregabalin, there are reports for phenibut of dependence and withdrawal symptoms, including withdrawal-related epileptic seizures and delirium following abrupt discontinuation of previously regular use (1, 2, 8, 12). Furthermore, phenibut, like other gabapentinoids (e15, e16) and unlike benzodiazepines (e16, e17), appears to have low toxicity and good tolerability (1, 2, 6, 8). Box 3 shows experience with and recommendations on the treatment of phenibut withdrawal syndrome.

Box 3

Treatment of phenibut withdrawal syndrome

Detectability

As yet, there is no point-of-care or laboratory test for the detection of phenibut. For its qualitative detection and quantitative determination, for example in plasma, high-pressure liquid chromatography–mass spectrometry is required (9, 11).

Protective effects

In animal models of ischemia and brain trauma, phenibut was associated with neuro- and cardioprotective effects, which were explained by increased brain-derived neurotrophic factor (BDNF) activity and antioxidant properties (2, e18, e19, e20).

Experience from the Giftinformationszentrum-Nord

Between 2018 and 2022, the GIZ-Nord received 17 reports (nine from women) relating to phenibut. Affected individuals were 20- to 49-year-olds who reported orally consumed quantities of between 750 mg and 100 g. Parenteral use was not reported. In all cases, intoxication was deemed to be mild (n = 5) to moderate (n = 12) (Figure). Even at the 100-g dose, neither respiratory depression nor signs of severe intoxication were observed. In the overdoses (> 2 g, n = 15), somnolence was reported in eight cases and observation on the intensive care unit was recommended. During the period in question, around three times more inquiries were received regarding intoxications with gabapentin, approximately seven times more for pregabalin, roughly 70 times more for Z substances, and 254 times more for benzodiazepines (Figure).

Figure

Cases registered at the GIZ-Nord center in the period 2018–2022

Discussion

Like gabapentin and pregabalin, phenibut inhibits α2-δ subunits of presynaptic voltage-gated calcium channels (VGCC) (e3, e4). These gabapentinoids have GABA-mimetic properties (i.e., they increase ambient GABA or the expression of extrasynaptic GABA-A receptors [e5, e11]), which have not been investigated for phenibut as yet. However, a number of clinical characteristics, such as benzodiazepine-like toxidrome and withdrawal syndrome, as well as the rapid development of tolerance for euphoria (1, 9), suggest GABA-A receptor stimulation. Moreover, phenibut was described as an element in multidrug use (7, 14). This is a pattern of use that also tends to be typical with gabapentin and pregabalin (6, e5, e22). In the few deaths described to date in the USA in conjunction with phenibut, concomitant use of various substances, including alcohol and opiates, was documented as the cause (7, 9, 10). Neuroprotective effects have also been described in animal models with phenibut (2, e18, e20) as well as with pregabalin, gabapentin, and the benzodiazepine midazolam (e23, e24, e25). However, long-term parenteral administration of high doses of midazolam or pregabalin was also associated with neurotoxic effects (e26, e27).

Problematic alliance of opiates, sedatives,

and gabapentinoids

Opiates and opioids have some serious side effects such as the development of dependence, and, with the increase in dose and depending on age, an increased risk of sedative states, falls, accidents, delirium, hallucinations, and respiratory depression (17). Regular use results in the development of tolerance to respiratory depression as well as to the analgesic and euphoric effects (17). It is likely that there are other mechanisms and motives to explain why repeated use of opioids in therapeutic and illegal contexts brings about an increase in dose (17).

The development of hyperalgesia is a characteristic phenomenon in prolonged opiate use, as is the development of an often very unpleasant and painful withdrawal syndrome if the dose is rapidly reduced or discontinued (17). It is assumed that these two phenomena are based on, among others things, the development of pharmacodynamic, oppositional tolerance (Box 4) primarily in the µ- and δ-opioid receptor signaling systems (e29) and could motivate opiate addicts to use additional opiates (3). Opiate addicts tend to seek substances that are also able to attenuate this process and alleviate the suffering caused by hyperalgesia or withdrawal syndrome (1, 3). It is common for opiate addicts to self-medicate with benzodiazepines (4) and other sedatives such as the α2-adrenoreceptor agonist xylazine, which is used for horses in veterinary medicine (street name: “Tranq,” “zombie drug”), and the use of which has been warned against by the Food and Drug Administration (FDA) (18, 19), among others. The synergistic effects of opiates and these sedatives increase the risk for coma, respiratory depression, and death.

Box 4

Oppositional tolerance

Furthermore, pregabalin and gabapentin are particularly attractive to opiate addicts since, in addition to their sedative effects at supratherapeutic doses, they can also reduce the development of tolerance to opiates/opioids in the therapeutic dose range (and in animal experiments possibly even reverse this tolerance) (6, 7, 8). Thus, on the one hand, these substances may help to pare down the opiate requirements for the desired effects, but on the other they could also increase the likelihood of respiratory depression (7, 8). Therefore, sedatives and gabapentinoids have the potential to increase the risk for fatal respiratory depression if additional opiates are misused. To the extent possible, this aspect should be taken into consideration when providing patient information on opiate, gabapentinoid, and sedative prescriptions as well as in the psychoeducation of opiate addicts and polyvalent addicts.

Particularly in countries dealing with opioid crises, such as the USA and Canada (9, 10), sedatives as well as the gabapentinoids pregabalin and gabapentin are increasingly being found to be associated with respiratory depression and deaths due to opioid overdose (11, 12, 13) (Box 4). Despite the rise in fentanyl prescriptions, an opioid crisis in Germany is relatively unlikely due to the vigilant safety systems in place (10), but cannot be ruled out.

A comparison of phenibut and selank

Selank is also a Russian drug and GABA mimetic available as a food supplement. It is an immunomodulatory heptapeptide (a synthetic analog of tuftsin) that was developed by the Institute of Molecular Genetics of the Russian Academy of Sciences (e31). Since the early 1990s, selank has likewise been prescribed as a nootropic and anxiolytic in former Soviet Union countries. Like phenibut, it is currently available online as a food supplement. A GABA-mimetic effect has also been described in animal models through a dose-dependent benzodiazepine-like allosteric modulation of GABA-A receptors (e10, e32) and indirectly through a change in the expression of genes that are involved in, among other things, GABA neurotransmission (e32). An effect on the α2-δ subunits of VGCC has not been investigated as yet. Animal studies suggest that it attenuates withdrawal symptoms, including those of alcohol and opiate withdrawal (e31). There are no known cases of withdrawal symptoms or death associated with selank (e31). The GIZ-Nord has received no inquiries to date relating to selank (Figure).

Conclusion and outlook

Both the literature search and the analysis of the GIZ-Nord data suggest that the use of phenibut is not widespread on Germany’s hard drug scene (particularly among of heroin, synthetic opioid, cocaine, and methamphetamine addicts [e16]). Although the information to date suggests that phenibut appears to have a lower risk profile than gabapentin, pregabalin, and benzodiazepines (e15, e16), phenibut should not be overlooked in post-mortem material from drug-related deaths and in cases of implausible intoxication symptoms in routine clinical practice (especially from opiate substitution therapy) or as a doping agent (13). It is possible that phenibut-associated deaths have remained hitherto undetected, given that phenibut is not yet sufficiently known in the context of potentially fatal multidrug use in Western drug abuse behavior and simple detection methods are lacking.

Acknowledgments

We would like to thank Dr. rer. nat. Rafael Wagner (Dipl.-Chem.), GIZ-Nord, for evaluating cases in the GIZ-Nord database.

Conflict of interest statement

UB is an associate member of the Drug Commission of the German Medical Association (Arzneimittelkommission der deutschen Ärzteschaft, AkdÄ).

NS is a member of the Expert Committee on Narcotic Drugs (Sachverständigenausschuss für Betäubungsmittel) at the German Federal Ministry of Health (Bundesministerium für Gesundheit), member of the “Addiction and Drugs” (“Sucht und Drogen”) Committee of the German Medical Association (Bundesärztekammer), and Chairman of the German Center for Addiction

Issues (Deutsche Hauptstelle für Suchtfragen e.V., DHS).

The remaining authors declare that no conflict of interest exists.

Manuscript received on 10 July 2023, revised version accepted on

9 January 2024.

Translated from the original German by Christine Rye.

Corresponding author
Prof. Dr. med. Udo Bonnet
Klinik für Seelische Gesundheit
Evangelisches Krankenhaus Castrop-Rauxel
Akademisches Lehrkrankenhaus der Universität-Duisburg-Essen
Grutholzallee 21, 44577 Castrop-Rauxel, Germany

Cite this as:
Bonnet U, Scherbaum N, Schaper A, Soyka M: Phenibut—an illegal food supplement with psychotropic effects and health risks. Dtsch Arztebl Int 2024; 121: 222–7. DOI: 10.3238/arztebl.m2024.0003

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