Phenibut (beta-phenyl- gamma-aminobutyric acid, also spelled fenibut, originally known as phenigamma) is a derivative of the neurotransmitter GABA that crosses the blood-brain barrier [1]. It was developed in Russia, and there it has been used clinically since the 1960's for a range of purposes. Phenibut has both nootropic and anxiolytic (anxiety-reducing) properties, and it is commonly compared to diazepam (Valium), baclofen, and piracetam, and it has similarities to and differences from all of these substances.

Structurally, phenibut is similar to GABA, baclofen (p-Cl-phenibut), and β-phenylethylamine (PEA). GABA is the primary inhibitory neurotransmitter in the brain. The addition of the phenyl ring to GABA allows the compound to more easily cross the blood-brain barrier, but also changes its activity profile [1-2]. Baclofen is a drug commonly used in studies on GABA(B) receptors, and also clinically used to treat severe spasticity of cerebral origin [3]. PEA is a naturally occurring biogenic amine which is similar in structure to amphetamine, and like amphetamine, it is a stimulant that causes the release of dopamine, and also promotes anxiety in high enough amounts.

Phenibut is a GABA receptor agonist and also causes the release of GABA. Similar to baclofen, phenibut is an agonist at GABA(B) receptors, although it does have some effect on GABA(A) receptors as well [2]. It is possible that phenibut has a higher activity at central GABA(B) receptors than peripheral ones [4]. The role of the GABA(B) receptor is not well-established, although research in the last seven years has significantly increased our understanding of this receptor. The most well-established role of GABA(B) receptors is inhibition of the release of some neurotransmitters, and it may also serve as a negative feedback mechanism for GABA release [5-6].

Because of the structural similarity to PEA, phenibut may share some similarities and differences with it. When phenibut is administered along with PEA, it antagonizes many of its effects, such as promotion of anxiety, promotion of seizures, and hyperthermia. This has led some to postulate that antagonism of PEA, rather than the GABA-mimetic activity, may be the important mechanism of action for the anxiolytic effect of phenibut [2, 7]. Phenibut also increases dopamine levels, and it has been postulated that the structural similarity to PEA may play a role in this effect [2].