The Wonders of the Amino-Acid: Phenyl-GABA
Introduction:
Phenyl-GABA is a derivative of the neurotransmitter GABA that crosses the blood-brain
barrier [1]. The amino-acid GABA does not readily cross the blood-brain-barrier
and as such has little effect on insomnia. Phenyl-GABA was developed in Russia,
and there it has been used clinically since the 1960's for a range of
purposes. Phenyl-GABA 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, Phenyl-GABA is similar to GABA, baclofen (p-Cl-Phenyl-GABA), 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.
Phenyl-GABA is a GABA receptor agonist and also causes the release of GABA. Similar to baclofen, Phenyl-GABA is an agonist at GABA(B) receptors, although it does have some effect on GABA(A) receptors as well [2]. It is possible that Phenyl-GABA 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, Phenyl-GABA may share some similarities and differences with it. When Phenyl-GABA 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 Phenyl-GABA [2, 7]. Phenyl-GABA 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 Phenyl-GABA [8], but it does not look as though this has been followed up on.
Effects of Phenyl-GABA
Anxiety reduction. Phenyl-GABA is effective in many animal models of anxiety,
although there is often dependence on study conditions. In cats classified
as "anxious" or "passive," Phenyl-GABA 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, Phenyl-GABA increased social behavior
[9]. In rats, Phenyl-GABA decreased some of the physiological responses to stress,
including the elevation of glucocorticoid levels [10]. Phenyl-GABA 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 Phenyl-GABA 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, Phenyl-GABA 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 Phenyl-GABA to diazepam (Valium), which has pronounced anxiolytic properties, and piracetam, which has weak anxiolytic properties. One study found Phenyl-GABA 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, Phenyl-GABA is commonly used to treat many neuroses, including post-traumic stress disorder, stuttering, and insomnia. In double blind placebo-controlled studies, Phenyl-GABA has reportedly been found to improve intellectual function, improve physical strength, and reduce fatigue in neurotic and psychotic patients [2].
Nootropic effects. Although Phenyl-GABA does not meet all the requirements of a nootropic, it does have many similarities to piracetam. In mice, Phenyl-GABA 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. Phenyl-GABA 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, Phenyl-GABA was ineffective in the water maze and shuttle box tests, while piracetam was [18]. Other research supports the idea that Phenyl-GABA 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 Phenyl-GABA shares with nootropics is neuroprotection. Multiple animal studies have indicated that Phenyl-GABA administration increases resistance to the detrimental effects of edema on mitochondria and energy production in the brain [20-22]. Phenyl-GABA 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]. Phenyl-GABA also protects dopaminergic neurons, and improved the condition of patients being treated with antiparkinsonic drugs [25].
Other effects. Phenyl-GABA 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]. Phenyl-GABA has been reported to reduce motion sickness, and used in the treatment of alcohol and morphine withdrawal [2, 26]. One study indicated that Phenyl-GABA increased resistance to heat stress and improved working capacity in humans [27].
Some studies indicate that Phenyl-GABA has anti-arrhythmic properties in humans [28-29]. It also has other cardioprotective properties [30-31]. Finally, Phenyl-GABA showed promise in experimental models of gastric lesions [32-33].
Side effects and suggested use
Phenyl-GABA 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 Phenyl-GABA. 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 Phenyl-GABA 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 Phenyl-GABA 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.
References: Available upon request
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