A systematic review of phenibut withdrawal focusing on complications, therapeutic approaches, and single substance versus polysubstance withdrawal.

INTRODUCTION: Phenibut is an unregulated supplement that acts primarily as a gamma-aminobutyric acid type B receptor agonist. Use of phenibut can lead to dependence and subsequent withdrawal when use is stopped. Phenibut withdrawal can cause severe symptoms such as delirium, hallucinations, and seizures. The purpose of this systematic review is to characterize the natural history of phenibut withdrawal and summarize treatment strategies published in the literature. METHODS: A systematic review was conducted using the preferred reporting items for systematic reviews and meta-analyses checklist. English language peer-reviewed articles or conference abstracts in humans describing phenibut withdrawal after cessation of use were included. Databases (Ovid/MEDLINE, Web of Science, and Science Direct) and references of included articles were searched. Case reports were appraised using the Joanna Briggs Institute critical appraisal checklist for case reports. Patient demographics and key outcomes, including withdrawal characteristics and treatment characteristics, were collected into a predefined data collection sheet by six independent reviewers. RESULTS: Search results yielded 515 articles of which 25 were included. All articles were case reports or published conference abstracts. All of the cases (100 percent) involved male patients and the median age was 30 years, (interquartile range 23.5-34 years, range 4 days-68 years). The median daily phenibut dose prior to experiencing withdrawal was 10 g (interquartile range 4.75-21.5 g, range 1-200 g). The shortest duration of phenibut use (2-3 g daily) prior to withdrawal was one week. Withdrawal symptoms occurred as quickly as two hours after the last phenibut dose. Sixteen patients (64 percent) reported progression of withdrawal severity within the first 24 hours of healthcare contact. Seizures were reported in two patients (8 percent), intubation in six patients (24 percent), and intensive care unit admission in 11 patients (44 percent). Withdrawal patterns and outcomes were similar in those using phenibut alone and those with comorbid polysubstance use. Withdrawal treatment strategies varied widely. Only three cases (12 percent) were managed outpatient and all three utilized a phenibut tapering strategy. All patients undergoing medication-assisted abstinence were admitted inpatient for symptom management and received a drug that acts on gamma-aminobutyric acid receptors. The most commonly used medication was a benzodiazepine, reported in 17 cases (68 percent). Nineteen patients (76 percent) required at least two drug therapies to manage symptoms. Baclofen was used in 15 cases (60 percent), primarily in conjunction with gamma-aminobutyric acid type A agonists (12 of 15 cases) or as monotherapy during a phenibut taper (two of 15 cases). Two patients using baclofen monotherapy outpatient, after initial stabilization with multiple drug classes, reported adverse effects. One patient had a seizure and the other experienced recurrent withdrawal symptoms, returned to using phenibut, and was admitted to a hospital for withdrawal symptom management with benzodiazepines. LIMITATIONS: This review is subject to several limitations. Due to the manual nature of article selection, it is possible relevant articles may not have been included. As the entire data set is comprised of case reports it may suffer from publications bias. Outcomes and meaningful conclusions from specific treatment strategies were rarely available because of the heterogeneous nature of case reports. It is possible those reporting only phenibut use were actually using multiple substances. The doses of phenibut a user believed they were taking may be different from what was present in the unregulated product. CONCLUSIONS: Phenibut withdrawal appears to have a range of severity. It is important to recognize that patients undergoing phenibut abstinence may have progressive symptom worsening during early withdrawal. All published cases of abrupt phenibut abstinence were admitted inpatients for symptom management. Benzodiazepines or barbiturates with adjunctive baclofen appear to be the most commonly used drugs for moderate to severe withdrawal. Outpatient management via slow phenibut tapers with or without adjunctive gamma-aminobutyric acid agonist therapy may be successful. However, there is no standard treatment, and consultation with experts (e.g., toxicologists, addiction specialists) experienced in managing withdrawal syndromes is recommended. Significant study is warranted to develop methods of triaging phenibut withdrawal (e.g., severity scoring, inpatient versus outpatient management) and creating optimal treatment regimens.

Seizure Occurring During Baclofen Monotherapy for Phenibut Withdrawal.

OBJECTIVE: Phenibut is a widely available gamma-aminobutyric acid B receptor agonist. When taken chronically, phenibut causes dependence and subsequent withdrawal if stopped. Baclofen, a gamma-aminobutyric acid B receptor agonist structurally related to phenibut, has been used to manage phenibut withdrawal (PW), although baclofen doses for PW are not well defined and may exceed Food and Drug Administration-approved doses. Little data described outcomes from baclofen use. METHODS: This case details a patient who experienced a seizure while on baclofen 10 mg thrice daily as monotherapy for PW and highlights a potential risk of underdosing baclofen as monotherapy in the management of PW. RESULTS: A man in his early 30s with anxiety, depression, and substance use disorder presented to the emergency department by family for lethargy and confusion starting earlier that day. He had been using 25-30 g of phenibut daily for the past 6 months. On arrival, he was hypertensive, tachycardic, tachypneic, and lethargic. The patient received 1 mg of intravenous lorazepam and was admitted to the hospital for presumed PW. His symptoms improved overnight, and he was discharged on 10 mg of baclofen thrice daily. He returned 28 hours later after having a seizure and required intensive care admission in addition to multimodal drug therapy. CONCLUSIONS: Phenibut use is rising, and treatment options for PW, such as baclofen, warrant additional study. Potential risks of underdosing baclofen if used as monotherapy in PW may include seizures as withdrawal progresses. Baclofen's role in therapy may be more appropriate as an adjunct than a cornerstone of therapy. Treatment done in consultation with providers experienced in managing withdrawal such as a toxicologist may help reduce this risk.