Introduction
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,
although there is often dependence on study conditions. In cats classified
as "anxious" or "passive," phenibut reduced the fear response and increased
aggression in a confrontational situation, while it had no effect on aggressive
cats. In normal cats, it lead to "positive emotional symptoms" [2]. In mice,
phenibut increased social behavior [9]. In rats, phenibut decreased some
of the physiological responses to stress, including the elevation of glucocorticoid
levels [10]. Phenibut has also been reported to decrease the fear response
caused by electrical stimulation and counteract the anxiogenic effect of
the beta-carboline DMCM [2, 11]. Studies in rats examined the behavioral
properties of phenibut when it was administered locally into different parts
of the brain, and it usually lead to a reduction of anxiety in one or more
models [12-16].
The results of animal models don't always pan out in the real world, however,
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].
Side effects and suggested use
Phenibut has low acute toxicity. Reported LD50s (dose required to kill 50%
of laboratory animals) are 900 mg/kg i.p. in mice, 700 mg/kg i.p. in rats,
and 1000 mg/kg in rats (method of administration not given) [2, 34]. Chronic
administration of 50 mg/kg did not have teratogenic effects in rats [34].
In clinical studies, no signs of toxicity have been reported, and side effects
are few. Some report drowsiness, but this effect is not nearly as likely
or severe as with benzodiazepines [2].
One should be aware of the potential for drug interactions when taking phenibut.
In many cases, it will decrease the threshold dose and potentiate certain
actions of a drug. It amplifies some of the effects of anesthetics (ether,
chloral hydrate, and barbiturates), diazepam, alcohol, and morphine [2, 35-36];
it would also presumably have an interaction with related drugs, such as
other opiates and GHB. In contrast, taking phenibut with some other drugs,
such as stimulants, will more than likely just blunt their effect.
In humans, the plasma half-life after a 250 mg oral dose of phenibut is 5.3
hours, and most of the administered drug is excreted unchanged [2]. Reported
dosages used in clinical studies range from 250 to 1500 mg daily, usually
divided among three doses [2, 37]. Feedback indicates that the ideal dose
may be in the higher end of this range.
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.
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