Phenibut HCl

Phenibut (beta-phenyl-GABA, 4-amino-3-phenylbutanoic acid) is a synthetic derivative of the inhibitory neurotransmitter GABA with a phenyl ring on its beta carbon. Introduced into clinical practice in Russia in the 1960s, it acts mainly at GABA-B receptors, and baclofen is its para-chloro derivative (Lapin, 2001).

Confirm whether the 250MG figure counts the salt or phenibut base; the salt is about 83 percent phenibut by weight.

Published work on phenibut falls into six areas. Each summary below states the model used.

Origin and clinical history

Lapin's review describes phenibut as a tranquilizer and nootropic widely used in Russia for tension, anxiety and fear, for sleep problems and around surgery (Lapin, 2001). A 2020 systematic review analyzed 11 clinical trials with 583 participants and 14 case reports of dependence or intoxication in 16 people.

Adverse events were recorded in 5.66 percent of trial participants, most often somnolence, while the case reports described cardiovascular effects, insomnia, anxiety and agitation, hallucinations and depressed consciousness. The authors flagged that discrepancy and left open the quality of phenibut obtained online and the role of alcohol and other drugs (Kupats et al., 2020). Models: narrative and systematic reviews of human data.

GABA-B receptors and the two enantiomers

Phenibut is used clinically as the racemate. In GABA-B receptor binding, affinity constants were 177 micromolar for racemic phenibut, 92 for R-phenibut and 6.0 for baclofen. In locomotor, forced swimming and tail-flick tests, S-phenibut was inactive at up to 500 mg/kg, R-phenibut was about twice as potent as the racemate in most tests, and the GABA-B antagonist CGP35348 blocked its effects (Dambrova et al., 2008).

In mouse cerebellar slices, phenibut evoked a GABA-B potassium current in Purkinje cells with an EC50 of 1,362 micromolar, against 23.3 for F-phenibut and 6.0 for baclofen (Irie et al., 2020). Models: rodents and mouse brain slices.

The α2δ calcium channel subunit

In rat brain membranes, binding constants at the α2δ subunit of voltage-dependent calcium channels were 23 micromolar for R-phenibut, 39 for S-phenibut and 0.05 for gabapentin, so R-phenibut bound α2δ about four times more strongly than GABA-B receptors. R-phenibut reduced formalin paw-licking responses in a way CGP35348 did not block, and both enantiomers reduced allodynia after sciatic nerve constriction injury (Zvejniece et al., 2015).

A separate team reported gabapentin-site binding near 90 micromolar for both enantiomers and less tactile allodynia in two rat pain models, more so with R-phenibut (Belozertseva et al., 2016). Models: rat brain membranes and rodent pain models.

Rat stroke models

Male rats underwent transient middle cerebral artery occlusion by filament or endothelin-1 and received R-phenibut at 10 or 50 mg/kg for 14 or 7 days. At 50 mg/kg it lessened brain volume loss in the damaged hemisphere in both models and raised BDNF and VEGF gene expression, while sensorimotor tests showed only a trend toward recovery (Vavers et al., 2016). Model: male Wistar and CD rats.

Dependence, withdrawal and poison center reports

A 2023 systematic review of 62 cases from 36 studies found that 86.8 percent obtained phenibut online and 63.2 percent used other substances.

Toxicity cases most often showed altered mental status, somnolence, psychosis and movement disorders, and 48.7 percent required intubation; withdrawal cases most often showed anxiety, irritability or agitation, insomnia and psychosis (Weleff et al., 2023). US poison centers recorded 1,320 phenibut exposures from 2009 to 2019, rising sharply after 2015, when the term could first be coded; 12.6 percent had major effects, and three deaths were reported (Graves et al., 2020). Models: case reports, a systematic review and national poison center data.