Phenibut: Indications, Mechanism of Action, and Side Effects

Indications

Phenibut (chemical name 4-amino-3-phenylbutyric acid) is a structural analog of GABA with central nervous system depressant and anxiolytic properties, commonly used to treat anxiety, insomnia, and alcohol withdrawal. In Russia, Phenibut is widely used to relieve tension, anxiety, and fear, improve sleep in psychosomatic or neurotic patients, and as preoperative or postoperative medication. It is also used to treat disorders characterized by weakness and depression, as well as post-traumatic stress, stuttering, and vestibular disorders. However, Phenibut is not approved or regulated by the FDA and is only marketed as a nootropic or cognitive enhancer.

Mechanism of Action

Phenibut's primary mechanism of action is believed to be a GABA-B receptor agonist, acting primarily at GABA(B) receptors and to some extent at GABA(A) receptors. It also stimulates dopamine receptors and antagonizes β-phenylethylamine (PEA), a putative endogenous anxiogenic substance. In addition, it has a high affinity for voltage-dependent calcium channels of the α 2 δ subunit, thus possessing gabapentinoid activity - and to a lesser extent GABA-A agonist activity. The psychopharmacological activity of phenibut is similar to that of baclofen, a para-chloro derivative of phenibut.

Side Effects

Phenibut has adverse side effects related to intoxication, withdrawal, and addiction, some of which may be life-threatening and require hospitalization and intervention. Common adverse reactions to phenibut include: sedation, somnolence, nausea, irritability, agitation, anxiety, dizziness, headache, and allergic reactions such as rash and itching. Long-term use may cause liver damage, and liver function monitoring is recommended during long-term use. Non-alcoholic fatty liver disease (NAFLD) occurs when the dose is ≥7000 mg/day.

Phenibut intoxication is usually dose-related, although many factors may cause users to experience toxic manifestations at lower doses. The latter may include individual differences, concurrent intake of other drugs and alcohol, as well as product purity and duration of use. Reports of phenibut poisoning cases range widely and the duration of use varies. Phenibut overdose may present with symptoms ranging from sedation and decreased consciousness to agitation, delirium, and psychosis. Often, these symptoms are accompanied by mydriasis, hypothermia, seizures, hypertension, and tachycardia or bradycardia. Currently, there is no specific treatment for phenibut poisoning, and recommended interventions include supportive care and symptom management. Typically, phenibut overdose symptoms clinically resolve within hours to days (depending on dose and history of phenibut use), but sequelae of poisoning may persist for weeks or months.

In addition to the potential for toxicity from overdose, phenibut also presents severe withdrawal symptoms, which are the most common and almost inevitable consequence of long-term use and tolerance. According to reports, 95.7% of acute phenibut withdrawal cases require therapeutic intervention. Phenibut withdrawal symptoms include insomnia, anger, psychomotor agitation, anxiety, tremor, myalgia, palpitations, and even delirium and hallucinations. Some cases of withdrawal can be particularly severe, including episodes of psychomotor agitation that are unresponsive to pharmacological intervention. For example, intake of up to 5000 mg/day of the drug over a one-month period resulted in a severe withdrawal syndrome 3 days after the last dose. The patient failed to respond to all pharmacological interventions, including diazepam, dilozepam, lorazepam, haloperidol, promazine, and even baclofen (a GABA agonist previously used to successfully treat phenylbutyric acid withdrawal). Despite these measures, the patient's condition worsened, resulting in the onset of catatonic episodes. Only after the haloperidol was replaced first with olanzapine and then with risperidone did the patient's condition improve.

References:

[1] BILL J. GURLEY  Igor K. Phenibut: A drug with one too many “buts”[J]. Basic & Clinical Pharmacology & Toxicology, 2024, 135 4: 409-416. DOI:10.1111/bcpt.14075.

[2] LIGA ZVEJNIECE . R-phenibut binds to the α2–δ subunit of voltage-dependent calcium channels and exerts gabapentin-like anti-nociceptive effects[J]. Pharmacology Biochemistry and Behavior, 2015, 137: Pages 23-29. DOI:10.1016/j.pbb.2015.07.014.

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