Safety and Tolerability of the Anxiolytic and Nootropic Drug Phenibut: A Systematic Review of Clinical Trials and Case Reports

Abstract

Phenibut is a nootropic drug that exerts anxiolytic and antinociceptive effects by acting on the GABA_B receptor and the α₂-δ subunit of voltage-dependent calcium channels. An increased number of reports of dependence to and intoxication by phenibut purchased online on the one hand and the wide prescription of phenibut in Eastern Europe for more than half a century on the other hand have resulted in a number of controversies regarding its use. In this review, we have summarized currently available information from case reports of phenibut dependence and intoxication and safety data from clinical trials. We included 14 dependence and intoxication case reports (16 patients) and reviewed 11 phenibut clinical trials (583 patients). The clinical symptoms in the case reports included cardiovascular effects, insomnia, anxiety and agitation, hallucinations, and depressed level of consciousness. In addition, the doses used (0.5–100 g/day) were much higher than the recommended daily dose (0.25–2 g/day). An analysis of phenibut side effects described in the clinical trials showed adverse events in only 5.66% of patients, and the most reported side effect was somnolence (1.89%). There are discrepancies in the reported side effects of phenibut in clinical trials compared to those reported in cases of online-purchased phenibut dependence and intoxication. The current systematic review provides evidence that, at therapeutic doses, phenibut is safe and well tolerated with minor adverse effects, but questions regarding the quality of phenibut obtained online and the contribution of alcohol and other drug abuse to phenibut dependence and intoxication remain open.

Keywords

phenibut - anxiolytics - nootropic drug

Publication History

Received: 28 September 2019
Received: 14 March 2020

Accepted: 26 March 2020

Article published online:
27 April 2020

• References

• 1 Hardman MI, Sprung J, Weingarten TN. Acute phenibut withdrawal: A comprehensive literature review and illustrative case report. Bosn J Basic Med Sci 2019; 19: 125-129
• 2 Lapin I.. Phenibut (β-Phenyl-GABA): A tranquilizer and nootropic drug. CNS Drug Rev 2001; 7: 471-481
• 3 Zvejniece L, Vavers E, Svalbe B. et al. R-phenibut binds to the α2–δ subunit of voltage-dependent calcium channels and exerts gabapentin-like anti-nociceptive effects. Pharmacol Biochem Behav 2015; 137: 23-29
• 4 Belozertseva I, Nagel J, Valastro B. et al. Optical isomers of phenibut inhibit [H3]-Gabapentin binding in vitro and show activity in animal models of chronic pain. Pharmacol Reports 2016; 68: 550-554
• 5 Vavers E, Zvejniece L, Svalbe B. et al. The neuroprotective effects of R-phenibut after focal cerebral ischemia. Pharmacol Res 2016; 113: 796-801
• 6 Dambrova M, Zvejniece L, Liepinsh E. et al. Comparative pharmacological activity of optical isomers of phenibut. Eur J Pharmacol 2008; 583: 128-134
• 7 Grinberga S, Zvejniece L, Liepinsh E. et al. Quantitative analysis of phenibut in rat brain tissue extracts by liquid chromatography-tandem mass spectrometry. Biomed Chromatogr 2008; 22: 1321-1324
• 8 Borodkina L, Kudrin V, Klodt P. et al. Effect of phenibut on the content of monoamines, their metabolites, and neurotransmitter amino acids in rat brain structures. Eksp Klin Farmakol 2009; 72: 60-63
• 9 Lk Allikmets. Polevoĭ et al. component in the mechanism of action of gamma-aminobutyric acid derivatives and structural analogs. Farmakol Toksikol 1979; 42: 603-606
• 10 Wong A, Little M, Caldicott D. et al. Analytically confirmed recreational use of phenibut (β-phenyl-γ-aminobutyric acid) bought over the internet. Clin Toxicol 2015; 53: 783-784
• 11 Samokhvalov AV, Paton-Gay CL, Balchand K. et al. Phenibut dependence. BMJ Case Rep 2013; bcr2012008381
• 12 Liberati A, Altman DG, Tetzlaff J. et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: Explanation and elaboration. BMJ 2009; 339: b2700
• 13 Huang X, Lin J, Demner-Fushman D. Evaluation of PICO as a knowledge representation for clinical questions. AMIA Annu Symp proceedings AMIA Symp 2006; 2006: 359-363
• 14 Smith SM, Dart RC, Katz NP. et al. Classification and definition of misuse, abuse, and related events in clinical trials: ACTTION systematic review and recommendations. Pain 2013; 154: 2287-2296
• 15 Bankier B, Aigner M, Bach M. Clinical validity of ICD-10 neurasthenia. Psychopathology 2001; 34: 134-139
• 16 Ahuja T, Mgbako O, Katzman C. et al. Phenibut (β-Phenyl-γ-aminobutyric Acid) dependence and management of withdrawal: emerging nootropics of abuse. Case Rep Psychiatry 2018; 2018: 9864285
• 17 Sankary S, Canino P, Jackson J. Phenibut overdose. Am J Emerg Med 2017; 35: 516.e1-516.e2
• 18 Downes MA, Berling IL, Mostafa A. et al. Acute behavioural disturbance associated with phenibut purchased via an internet supplier. Clin Toxicol 2015; 53: 636-638
• 19 Borodkina LE, Molodavkin GM, Tyurenkov I. Effect of phenibut on the interhemispheric transmission in rat brain. Eksp i Klin Farmakol 2009; 72: 57-59
• 20 Leung NY, Whyte IM, Isbister GK. Baclofen overdose: Defining the spectrum of toxicity. Emerg Med Australas 2006; 18: 77-82
• 21 Zavadenko N, Suvorinova N. The results of the pharmacological treatment of attention deficit hyperactivity disorder: Evaluation with neuropsychological methods. Zh Nevrol Psikhiatr Im S S Korsakova 2014; 114: 19-24
• 22 Chutko LS, Surushkina SY, Yakovenko EA. et al. Impulsivity in adolescents with attention deficit hyperactivity disorder. Neurosci Behav Physiol 2018; 48: 383-387
• 23 Fuzier R, Serres I, Guitton E. et. al. Adverse drug reactions to gabapentin and pregabalin. Drug Saf 2013; 36: 55-62
• 24 Rolland B, Simon N, Franchitto N. Safety challenges of using high dose baclofen for alcohol use disorder: A focused review. Front Psychiatry 2018; 9: 367
• 25 Navas-Sánchez FJ, Alemán-Gómez Y, Sánchez-Gonzalez J. et al. White matter microstructure correlates of mathematical giftedness and intelligence quotient. Hum Brain Mapp 2014; 35: 2619-2631
• 26 Mersfelder TL, Nichols WH. Gabapentin: Abuse, dependence, and withdrawal. Ann Pharmacother 2015; 50: 229-233
• 27 Smith RV, Havens JR, Walsh SL. Gabapentin misuse, abuse and diversion: A systematic review. Addiction 2016; 111: 1160-74
• 28 Kapil V, Green JL, Le Lait M-C. et al. Misuse of the γ-aminobutyric acid analogues baclofen, gabapentin and pregabalin in the UK. Br J Clin Pharmacol 2014; 78: 190-191
• 29 Jouney EA. Phenibut (β-Phenyl-γ-Aminobutyric Acid): An easily obtainable “dietary supplement” with propensities for physical dependence and addiction. Curr Psychiatry Rep 2019; 21: 23
• 30 McCabe DJ, Bangh SA, Arens AM. et al. Phenibut exposures and clinical effects reported to a regional poison center. Am J Emerg Med 2019; 37: 2066-2071
• 31 Zhezlova A, Belolipetskaia V, Blagodatskikh S. et al. Bioequivalence of anvifen and phenibut. Eksp Klin Farmakol 2011; 74: 43-44
• 32 Owen DR, Wood DM, Archer JRH. et al. Phenibut (4-amino-3-phenyl-butyric acid): Availability, prevalence of use, desired effects and acute toxicity. Drug Alcohol Rev 2016; 35: 591-596
• 33 Leo RJ, Baer D.. Delirium associated with baclofen withdrawal: A review of common presentations and management strategies. Psychosomatics 2005; 46: 503-507
• 34 Zamponi GW, Striessnig J, Koschak A. et al. The physiology, pathology, and pharmacology of voltage-gated calcium channels and their future therapeutic potential. Pharmacol Rev 2015; 67: 821-870
• 35 Alyahya B, Friesen M, Nauche B. et al. Acute lamotrigine overdose: A systematic review of published adult and pediatric cases. Clin Toxicol 2018; 56: 81-89
• 36 Newton PM, Orr CJ, Wallace MJ. et al. Deletion of n-type calcium channels alters ethanol reward and reduces ethanol consumption in mice. J Neurosci 2004; 24: 9862-9869
• 37 Caputo F, Ciminelli BM, Jodice C. et al. Alcohol use disorder and GABAB receptor gene polymorphisms in an Italian sample: Haplotype frequencies, linkage disequilibrium and association studies. Ann Hum Biol 2017; 44: 384-388
• 38 Morley KC, Luquin N, Baillie A. et al. Moderation of baclofen response by a GABAB receptor polymorphism: results from the BacALD randomized controlled trial. Addiction 2018; 113: 2205-2213
• 39 Ghosh S, Bhuyan D.. Baclofen abuse due to its hypomanic effect in patients with alcohol dependence and comorbid major depressive disorder. Clin Psychopharmacol Neurosci 2017; 15: 187-189
• 40 Kamal R, Qurishi R, Jong C.. Baclofen and γ-hydroxybutyrate (ghb), a dangerous combination. J Addict Med 2014; 9: 75-77
• 41 Nasti JJ, Brakoulias V.. Chronic baclofen abuse and withdrawal delirium. Aust New Zeal J Psychiatry 2011; 45: 86-87
• 42 Keegan DL, Richardson JS, Kirby AR. A possible neurochemical basis for the neuropsychiatric aspects of baclofen therapy. Int J Neurosci 1983; 20: 249-254
• 43 Li W, Madhira B.. Phenibut (β-Phenyl-γ-Aminobutyric Acid) psychosis. Am J Ther. 2017 24.
• 44 Joshi YB, Friend SF, Jimenez B. et al. Dissociative intoxication and prolonged withdrawal associated with phenibut: A case report. J Clin Psychopharmacol 2017; 37: 478-480
• 45 Brunner E, Levy R. Case report of physiologic phenibut dependence treated with a phenobarbital taper in a patient being treated with buprenorphine. J Addict Med. 2017 11. 239-240
• 46 O’Connell CW, Schneir AB, Hwang JQ. et al. Phenibut, the appearance of another potentially dangerous product in the United States. Am J Med 2014; 127: e3-4
• 47 Schmitt C, Gégu C, Spadari M. et al. Use of phenibut in France: Report of two cases. Therapies 2013; 68: 123-224
• 48 Högberg L, Szabó I, Ruusa J. Phenibut yielded withdrawal symptoms and psychosis. Drugs for cosmonauts—now marketed as dietary supplements online. Lakartidn 2013; 110: 825-827
• 49 Magsalin R, Khan A. Withdrawal symptoms after internet purchase of phenibut (β-phenyl-γ-aminobutyric acid HCl). J Clin Psychopharmacol 2010; 30: 648-649
• 50 Shypilova E, Zavadenko N, Nesterovskiy Y. Preventive treatment of tension headache in children and adolescents. Zh Nevrol Psikhiatr Im S S Korsakova 2017; 117: 36-42
• 51 Chutko L, Surushkina S, Yakovenko E. et al. Emotional impairments and their correction in patients with migraine. Ter Arkh 2017; 89: 75-9
• 52 Vorob’eva O, Rusaya W. Efficacy and safety of noophen in the treatment of chronic fatigue syndrome in patients with cerebrovascular insufficiency. Zh Nevrol Psikhiatr Im S S Korsakova 2017; 117: 31-36
• 53 Vorob’eva O, Rusaya V. Pharmacotherapy of anxiety disorders in patients with chronic cerebral ischemia. Zh Nevrol Psikhiatr Im S S Korsakova 2016; 116: 49-55
• 54 Khachatryan LG, Geppe NA, Maksimova MS. et al. Therapy of neurotic manifestations in children: Search for alternative methods of treatment 2016; 10: 11-16
• 55 Duma S, Shcherbakova L. Diagnosis and treatment of psychogenic dizziness in patients with arterial hypertension. Zhurnal Nevrol i psikhiatrii im SS Korsakova 2016; 116: 62-66
• 56 Maximova M, Suanova E. Emotional and personality disorders in atypical facial pain. Zhurnal Nevrol i psikhiatrii im SS Korsakova 2015 2015; 65-69
• 57 Surushkina S, Chutko L, Aĭtbekov K. et al. Comorbidity of tics and stuttering. Zh Nevrol Psikhiatr Im S S Korsakova 2015; 114: 56-8
• 58 Chutko L, Surushkina S, Yakovenko E. et al. Cognitive and emotional impairments in patients with protracted anxiety-phobic disorders. Ter Arkh 2014; 86: 61-65