In this post, we cover the science behind a highly controversial concept: “leaky brain.” Read on to see which factors are proposed to protect or improve the state of the blood-brain barrier and whether any are supported by evidence.
A scientist named Paul Ehrlich made an accidental discovery about 100 years ago. He was injecting blue dye into animals to study their physiology, when he realized that the dye wouldn’t pass into their brains. When he injected dye directly into the animals’ brains, it wouldn’t pass into the rest of their bodies .
Ehrlich realized that the blue dye he was using had reached a seemingly impenetrable obstacle. He concluded that the brain is protected from the bloodstream with this special membrane, which later became known as the blood-brain barrier .
Like the gut barrier, the blood-brain barrier is lined with one layer of cells that separate the blood from the brain. It only allows a few substances like oxygen, hormones, and certain cytokines in, while blocking out others .
“Leaky brain” was coined as a non-medical term for increased blood-brain barrier permeability .
This term is still relatively new and research is sparse. The whole theory is theoretical and it has yet to be verified in proper human studies. Findings are still mostly limited to cell culture or brain tissue studies [2, 1].
That said, limited research has linked a compromised blood-brain barrier with “brain fog” or cognitive dysfunction, chronic fatigue, anxiety/depression, neurodegenerative diseases, and other neurological conditions. There’s not enough evidence to support any of these associations [2, 1].
If your goal is to increase the integrity of your blood-brain barrier to improve your neurological issues – including those of cognitive problems, mood imbalances, or serious inflammation – it’s important to talk to your doctor, especially your symptoms are significantly impacting your daily life.
Your doctor should diagnose and treat the condition causing your symptoms.
Remember that the existing evidence does not suggest “leaky brain” causes any disorder. Complex disorders always involve multiple possible factors – including brain chemistry, environment, health status, and genetics – that may vary from one person to another.
Therefore, you may try the strategies listed below if you and your doctor determine that they could be appropriate. Read through the approaches we bring up and discuss them with your doctor before trying them out. This is particularly important if you plan to take any dietary supplements.
Most of the lifestyle, dietary, and supplement factors listed in this article rely on animal and cellular data. These findings can’t be applied to humans. Clinical research is needed before the safety and effectiveness of any approach listed in this post is determined.
Additionally, changes in brain physiology are not something that people can change on their own with the approaches listed below. Instead, the factors listed here are meant to reduce daily stress and support overall brain health and well-being.
Finally, have in mind that none of these strategies should replace what your doctor recommends or prescribes.
As the permeability (“leakiness”) of the blood-brain barrier can increase as a result of many diseases, the most important thing is to work with your doctor to address any potential underlying health condition.
Here are some potential underlying issues your doctor may take into account:
Infections and toxins can damage the blood-brain barrier. It is therefore important to resolve and clear these infections accordingly.
High levels of homocysteine disrupt tight junction function and cause BBB dysfunction .
Read this post to learn more about testing for and lowering homocysteine levels.
There is currently no conventional treatment for increased blood-brain barrier permeability or “leaky brain,” since doctors don’t yet have clear criteria to make this diagnosis.
The only medically-accepted therapeutic approach that can be used to increase the int the blood-brain barrier integrity are glucocorticoids (synthetic cortisone) .
Glucocorticoids are generally the treatment for certain autoimmune disorders. Some research suggests that they can improve blood-brain barrier integrity in patients with multiple sclerosis .
Stress is hypothesized to induce “leaky gut” and overall inflammation. In addition, acute stress activates brain mast cells that secrete proinflammatory cytokines that disrupt the BBB. Stress also has many other detrimental health effects. Look to find ways to de-stress on a daily basis [10, 11].
Chronic sleep loss decreases glucose transport across the BBB, increases inflammation, and impairs BBB permeability. Plus, getting enough quality sleep supports overall brain health and general wellness .
Poor brain circulation reduces the amount of oxygen and nutrients available to the brain. Studies suggest that this may increase oxidative stress. Some scientists claim that when oxidative stress is increased in glial cells and pericytes, the blood-brain barrier and its tight junctions may become damaged [13, 14].
High calorie and high-fat diets are proposed to increase “leaky gut,” which might cause LPS (a bacterial toxin) to enter the bloodstream. LPS aside, eating more calories than you need (especially from fast food and sugar) is known to be harmful in the long run. It can cause obesity and other health issues .
Directly tied to overeating, some scientists think that obesity-induced inflammation can also cause problems in the blood-brain barrier (BBB) .
People who are overweight should aim to lose extra pounds to improve their overall health, but this step might support brain health too.
Anecdotally, anti-inflammatory diets are claimed to support brain health by reducing inflammatory food triggers. This approach isn’t backed by science.
The blood-brain barrier is also sealed by tight junction proteins that resemble those in the gut. They are also proposed to be regulated by the protein called zonulin, suggesting that they may – in theory – be disrupted by gluten. This is purely hypothetical, though [18, 19].
Supplements have not been approved by the FDA for medical use and generally lack solid clinical research. Regulations set manufacturing standards for them but don’t guarantee that they’re safe or effective.
Additionally, supplement-drug interactions can be dangerous and, in rare cases, even life-threatening. That’s why it’s so important to consult your healthcare provider before supplementing and let them know about all drugs and supplements you are using or considering.
Here are some supplements to discuss with your doctor that are being researched:
When mitochondria are damaged, reactive oxygen compounds might leak out into the cells and damage them. ALCAR is claimed to help repair the BBB by reversing the mitochondria decay caused by oxidative damage, but this hasn’t been proven in humans .
Some researchers hypothesize that Alpha-lipoic acid may prevent immune cells from invading the brain and damaging BBB, based on studies in rats with experimental allergic encephalomyelitis. Human data are lacking .
In rats, GPC partially reverses the changes in BBB caused by damage to brain vessels. Human studies are missing .
In rats with a severe form of brain stroke that involves brain bleeding, a component extracted from Angelica sinensis, Z-ligustilide, seemed to reduce brain swelling and strengthen the BBB .
Astragalus is often used in Chinese herbal remedies. Researchers have theorized that injecting an astragalus extract through IV to rats that have suffered stroke might strengthen the blood-brain barrier compared to the control group of animals .
They found that astaxanthin decreased inflammatory molecules and protected the BBB in rats that had brain bleeding, but human studies are needed .
Apigenin is a color compound naturally found in plants. Administration of apigenin in rats suffering from brain injury and bleeding in the brain blocked inflammatory proteins (TLR4 and cytokines) and increased tight junction proteins .
A mix of vitamin B12, vitamin B6, and folate in a small study of patients with mild cognitive impairment was posited to make the BBB stronger and improve the overall condition of their health. These findings haven’t been replicated .
In mice that were fed a diet with a lot of fats, bitter melon extract prevented leaks in the brain and excessive activity of brain immune cells and decreased the concentration of inflammatory proteins .
Butyrate is often produced by bacteria in the gut .
In healthy mice, the lack of necessary butyrate-producing bacteria in the gut weakened the blood-brain barrier .
If germ-free mice (healthy mice that previously had no bacteria in the gut at all) are given those bacteria afterward, their BBB becomes stronger .
Injections of citicoline into mice with traumatic brain injury strengthened the BBB and partially reduced brain swelling .
Collagen (type IV) is hypothesized to be important for BBB structure and function of the cell that forms it .
Curcumin in a nanoparticle format was reported to improve the state of the BBB better than traditional curcumin .
Supplementation appears to be protective in animals in cases where the blood-brain barrier is disrupted because of inflammation from a high-fat and high-calorie diet. This hasn’t been verified in humans .
Also, sun exposure typically increases vitamin D3 levels, but we don’t know how it affects the BBB.
Ellagic acid decreased BBB permeability in rats with traumatic brain injury .
Chemicals obtained from ginseng were also able to support the development of new nerve cells after stroke in rats .
In mice, pre-treatment with Goji fruit extract (10 mg/kg/day) before they experienced stroke prevented the leaks in the BBB and reduced glial cell inflammation .
The animals that drank hydrogen-rich water had fewer leaks from the brain and lower MMP 9, which the authors interpreted as an improvement in the state of the BBB .
The use of hydrogen water in humans is highly controversial and remains unproven.
Have in mind that glycyrrhizin can have detrimental health effects, especially in people prone to heart problems. It’s typically removed from supplements nowadays, as in Deglycyrrhizinated Licorice (DGL).
It seems to restore the proper function of the BBB in rats with experimental diabetes .
It also made the BBB stronger in pregnant rats that had high blood pressure .
In a cell-based study, melatonin pre-treatment protected rat brain blood vessel cells taken from inflammatory molecules .
Melatonin is also thought to be anti-inflammatory and is being researched for its broader effects on the brain .
Methylene blue decreased the level of damage to the BBB by blocking the production of nitric oxide. Methylene blue is often contaminated with impurities and industrial methylene blue shouldn’t be ingested .
In a rat model of brain bleeding, oxaloacetate protected the BBB through blocking glutamate from damaging the BBB and brain .
Treatment of mice after stroke with pterostilbene protected against the BBB damage and brain swelling by decreasing the concentration of dangerous oxygen types .
Resveratrol is an antioxidant .
It is being researched for stabilizing the BBB and protecting it from damage .
In rats that have Alzheimer’s disease, resveratrol blocked MMP9 activities and increased the level of claudin-5, strengthening the BBB and protecting it from destruction .
Rosmarinic acid protected against blood-brain barrier damage permeability in diabetic rats after stroke by lowering inflammation .
If Sulforaphane is given to rats before induction of a stroke, it prevents the destruction of brain blood vessels and the BBB by increasing the level of the antioxidant proteins Nrf2 and HO-1 [74, 75, 76].
Sulforaphane also reduced BBB dysfunction by decreasing inflammation proteins in animals.
The following hormonal factors and neurotransmitters are theoretical. They aren’t backed up by solid science. We bring them up for informational purposes.
Glutamate is an important neurotransmitter and the most abundant one in the brain. However, overstimulation of glutamate receptors in the brain might break down the blood-brain barrier, according to some animal and cell-based studies .
Read this post to learn more about these enzymes and factors that may affect them.
Typically, glutamate in the blood does not cross the blood-brain barrier. But anecdotally, some people with a leaky blood-brain barrier report brain symptoms in reaction to dietary free glutamate. Scientific research is lacking to back up this link.
With the exception of monosodium glutamate, most foods that are high in glutamate are also high in histamine-like substances. It is unclear whether the reaction comes from the glutamate or the histamine-like substances. Human studies are needed.
Substances that block glutamate receptors, such as memantine, are used as a treatment for neurological diseases that also involve high glutamate levels and, possibly, a leaky blood-brain barrier . These include Alzheimer’s, vascular dementia, and Parkinson’s disease.
Nonetheless, it’s unclear how glutamate blockers affect BBB integrity. Clinical trials are required.
GM6001, also known as Ilomastat or galardin, is an experimental broad-spectrum inhibitor of matrix metalloproteinases. Its safety and effectiveness in humans haven’t yet been investigated .
Another group of synthetic MMP inhibitors, BB-1101 and BB-94, also helped repair the damage to BBB in mice that had their BBB damaged by lipopolysaccharide (a bacterial toxin) .
In rats with an injury to brain blood vessels, treatment with a protein involved in blood vessel activity, angiotensin Ang(1-7) protected their BBB .
Ang(1-7) blocked MMP9 and increased the concentration of TIMP-1 in the rats with brain injury and protected BBB from more damage .
However, angiotensin – as part of the renin-angiotensin-aldosterone system – raises blood pressure and abnormal levels can be detrimental.
Progesterone is available with a doctor’s prescription, and it is FDA-approved for specific indications.
It’s unknown if some supplements can disrupt the blood-brain barrier. This hasn’t been researched in humans.
Also, in some cases, increasing the permeability of the BBB is desired – especially if the goal is to get certain substances into the brain.
Animal studies and cellular research is investigating:
- Andrographis/Andrographolide – and whether it can disrupt the layer of brain blood vessel cells when added into cell culture .
- L-Arginine, which might force the blood-brain barrier to open up .
- Zinc in rats with epilepsy .
On the other hand, the addictive tobacco compound nicotine seems to make the BBB less strong by re-shuffling blood-brain barrier proteins responsible for keeping it together .
You can read about the introduction to the blood-brain barrier and possible causes of “leaky brain” in Parts 1 and 2.
- Part 1: Introduction to the Blood-Brain Barrier, Causes of Leaky Brain, and Resulting Diseases
- Part 2: Factors and Disease States That Cause Leaky Brain
- Part 3: What Is a “Leaky” Blood-Brain Barrier & Can You Improve it?
- Part 4: Can Genetics Impact a “Leaky” Blood-Brain Barrier?