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 beta-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
occuring 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 lead
some to postulate that antagonism of PEA, rather than the GABA-mimetic activity, may be the important mechanism of action
for tha 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]. There
is one report in the literature of serotonergic effects of phenibut [8], but it does not look as though this has been followed
up on. Effects of phenibut Anxiety reduction. Phenibut is effective in many animal models of anxiety phenibut has a mechanism
of action similar to that of many drugs which are known to reduce anxiety in humans. Animal studies have compared the profile
of phenibut to diazepam (Valium), which has pronounced anxiolytic properties, and piracetam, which has weak anxiolytic properties.
One study found phenibut had a tranquilizing effect similar to, but weaker than diazepam. It also caused sedation and muscle
relaxation (whereas piracetam did not), but again these effects were weaker than those caused by diazepam [2]. In Russia, phenibut is commonly used to treat many neuroses, including post-traumic
stress disorder, stuttering, and insomnia. In double blind placebo-controlled studies, phenibut has reportedly been found
to improve intellectual function, improve physical strength, and reduce fatigue in neurotic and psychotic patients [2]. Nootropic effects. Although phenibut does not meet all the requirements of a
nootropic, it does have many similarities to piracetam. In mice, phenibut causes significant improvement on the passive avoidance
test [2]. In this test of memory, animals are put in an undesirable area (such as a lighting situation or height from the
floor that that species dislikes), and then given a negative stimulus (such as a shock) when they exit that area. Their ability
to stay in the original area reflects how well they remember that if they exit it, they will receive the undesirable stimulus.
Phenibut also improves performance on the swimming and rotarod tests and antagonizes the amnestic effect of chloramphenicol
[2]. It also has an antihypoxic effect, a trait commonly seen among nootropics [17]. However, in one study, phenibut was ineffective
in the water maze and shuttle box tests, while piracetam was [18]. Other research supports the idea that phenibut has nootropic
activity similar to that of piracetam, but not as strong [19]. Nootropic activity has also been reported in humans [2], but
it was not specified whether these were healthy adult humans, and they were probably elderly or psychiatric patients. Another trait phenibut shares with nootropics is neuroprotection. Multiple animal
studies have indicated that phenibut administration increases resistance to the detrimental effects of edema on mitochondria
and energy production in the brain [20-22]. Phenibut also normalizes brain energy metabolism changes caused by chronic stress
[23]. It was found to prevent changes in plasma electrolytes caused by cerebral injury [24]. Phenibut also protects dopaminergic
neurons, and improved the condition of patients being treated with antiparkinsonic drugs [25]. Other effects. Phenibut has anticonvulsant activity against some drugs or conditions, but
not others. It also potentiates the action of some other anticonvulsant drugs, and has been used to treat patients with epilepsy
[2]. Phenibut has been reported to reduce motion sickness, and used in the treatment of alcohol and morphine withdrawal [2,
26]. One study indicated that phenibut increased resistance to heat stress and improved working capacity in humans [27]. Some studies indicate that phenibut has anti-arrhythmic properties in humans
[28-29]. It also has other cardioprotective properties [30-31]. Finally, phenibut showed promise in experimental models of
gastric lesions [32-33]. Tolerance develops to many of the
effects of phenibut, although it is reported that it does not develop to the nootropic effect. The first signs of tolerance
may be seen within as little as five days. For this reason, it is commonly used for one to two week periods, or dosage is
increased by 25-30% after two weeks [2]. This makes phenibut ideal for short periods of stress or anxiety, but not ideal for
chronic use. It is possible that taking only one dose daily may partially reduce the development of tolerance. |
