Take-home message:
- gamma-Aminobutyric acid (GABA) is a major neurotransmitter that regulates much of our brain function. It was previously thought that ingested GABA could not cross the blood-brain barrier, but new research suggests that it may be able to.
- Drugs that mimic the action of GABA are numerous, work in a variety of ways, and can have effects ranging from treating epilepsy to causing it.
- GABA supplements have shown some promise in early, small-scale studies, but a lot more research is needed to know if they truly help.
Lately, it seems that GABA supplements are being hawked on the corner of every pharmacy aisle and health food shelf. Marketed to promote relaxation, mental focus and sleep, GABA is even being sold by David’s Tea in the form of GABA guava tea. I found it while trying to buy some matcha powder. I don’t even like guava, never mind guava with a side of inflated claims.
While promotions by influencers like Olivia Culpo and Sarah Couture are pretty standard for any trendy supplement, (regardless of efficacy) the attention GABA has been given by known quacks like Dr. Oz, Joseph Mercola orMike Adams has left me wondering about the science behind, and evidence for, these supplements.
Let’s start with the basics: what is GABA?
gamma-Aminobutyric acid (also written as γ-aminobutyric acid) is a neurotransmitter, specifically the major inhibitory one in all mammal’s central nervous systems (CNS). That means that it’s a chemical that binds to nerve cell receptors and hinders their ability to receive, create or send messages to other nerve cells (neurons).
Functionally, GABA is incredibly important. A lack of GABA leaves your central nervous system with too many neuronal signals and causes conditions like epilepsy, seizures or mood disorders. Meanwhile, too much GABA means not enough brain activity and can lead to hypersomnia or daytime sleepiness.
You can learn more about GABA in this lovely video, and more about neurotransmitters in general in this one, although I’ve said all you’ll need to know for this article.
GABAergic drugs
As the chief inhibitory neurotransmitter in the CNS, GABA and its receptors have been major targets for drug development. Drugs that activate GABA receptors (called agonists) or increase the receptors' sensitivity to GABA (positive allosteric modulators) work to reduce the neuronal signals in the user’s brain, similar to what happens when you sleep. Logically, they include many common sedatives like barbital or Quaaludes, tranquillizers like Valium, Ativan or Xanax and the most commonly used sedative, alcohol.
GABA reuptake inhibitors like Deramciclane have similar effects, as they help to keep GABA in the vicinity of the receptors for longer.
On the flip side, substances that inhibit the activity of GABA (called antagonists) increase brain activity. That only sounds like a good thing. The results are less Scarlett Johansson in Lucy, more uncontrollable seizures and death.
GABA antagonists, like gabazine or bicuculline are only useful when studying seizures or to counteract overdoses of sedatives and tranquillizers. Some GABA antagonists are particularly scary poisons, causing death by disrupting the CNS’s control of basic body functions like breathing.
The class of drugs we’re most interested in, however, are GABA analogues. These molecules are structurally similar to GABA, though they have different targets of action. GABA analogues include some big names you’ve probably heard of: Lyrica and gabapentin.
While both Lyrica and gabapentin are prescribed to stop seizures, treat neuropathic pain, and anxiety disorders, gabapentin is additionally used for the prevention of migraines.
For more on the efficacy and controversy of gabapentin, click here
Gabapentin has been a constant in my life for a few years now, as my mother was prescribed it for diabetic neuropathic pain just a few years after my partner was prescribed it for near constant migraines. I’ve personally seen GABA to be quite effective in its on-label uses, as the evidence shows it to be, but it was recently at the heart of one of the largest court settlements in US history.
The manufacturers of gabapentin were found to have been marketing it extensively for off-label uses like the treatment of bipolar disorder, restless leg syndrome, hot flashes and stopping smoking. While off-label prescribing is not uncommon, and usually fairly safe, there is no evidence that gabapentin is effective for the bipolar disorder it was being prescribed to treat or some of the other conditions for which it's being prescribed.
Presently gabapentin is again making headlines as its use as a recreational drug skyrockets. Many opioid users are misusing gabapentin to extend opioid highs or bypass drugs that block opioids effects, but its status as a non-controlled substance makes it difficult for law enforcement to control its unsanctioned use.
GABA and the Blood-Brain Barrier
GABA drugs are certainly useful, but why do we need all these GABA-receptor-activating or GABA-like molecules in the first place? Why not just give patients GABA?
We have a highly selective membrane that keeps our blood and cerebrospinal fluid (or brain juice, if you will) separate: the blood-brain barrier (BBB). Some molecules, like water, pass through it easily, other things, like bacteria don’t. This membrane also contains special channels to diffuse important molecules one way or the other, like glucose.
It’s a really important border, as drugs that cannot cross into the brain, or do so poorly, have much less of an effect than ones that do. For example, morphine can’t cross the BBB very well, but it’s close relative heroin can! Upon entry to the brain, heroin is converted into morphine, which is why heroin is so much more potent than morphine.
A 1958 study was the first to look at GABA’s relationship with the blood-brain barrier, and it found a lack of one: GABA could not cross the barrier. Later studies in ‘58, ‘71, and ‘88 confirmed the barrier’s impermeability to GABA. The evidence seems all but clear until you throw a few more studies into the mix. Studies done in ‘80, ‘81, ‘82 and ‘02 found that GABA did cross the blood-brain barrier, just in minuscule amounts.
Why the disagreement? Well, a few things. Some studies used a molecule just like GABA in lieu of GABA, assuming the 1 extra OH group featured on 3-hydroxybutyric acid wouldn’t make a difference, but it may have. Since many studies don’t report the type of GABA used, it’s hard to compare results. Some studies administered their GABA by injecting it straight into animal’s body cavities, others by injecting it into veins.
Most importantly, the BBB permeability of GABA has never been studied in humans!
What we do know is that human’s BBB contains transporters for GABA, implying that GABA can enter/exit the brain through these channels. In mice it was found that GABA was removed from the brain 17 times faster than it entered.
This could explain the conflicting study results. It may not be that GABA cannot enter the brain, but just that it’s removed from it very rapidly.
GABA as a Supplement
Even if it cannot cross the BBB however, GABA could still be affecting your brain.
The enteric nervous system (ENS) is the network of neurons that control your gastrointestinal system. The ENS contains many GABA receptors, and GABA itself, and is connected to the brain through the vagal nerve. It’s been proposed that ingested GABA is able to affect the body even without crossing the BBB through its interactions with the ENS.
We don’t know at this point how GABA is affecting the brain, but we have good evidence that it is. Several studies have shown reductions in markers of stress in patients given dietary GABA.
On their own the success stories from the consumers who buy GABA supplements are meaningless but taken along with the research findings, they may just show that there is something to these supplements.
We’ll need a lot more research to know for sure if GABA supplements are helpful or not. That being said, they are expensive (like most supplements) and if you’re not anxious, experiencing insomnia or very stressed out they’re probably not worth it. There don’t appear to be many side effects or drug interactions, but until more research is done I’d tread carefully.
I did ask my partner, who took gabapentin (a GABA analogue) for years if he ever experienced any focusing of his mind or relaxation as the GABA supplements claim. He said a definitive no.
Want a cheaper option for relaxation? Tea. You can even try some GABA tea, a strain of green tea specially fermented to accumulate GABA. Maybe I’ll pick some up... just not that guava flavoured stuff.
