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How to Fix a Leaky Blood-Brain Barrier

Written by Helen Quach, BS (Biochemistry) | Reviewed by Nattha Wannissorn, PhD (Molecular Genetics) | Last updated:

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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.

When this protective layer is compromised, the brain is vulnerable to damage from chemicals, inflammatory cytokines, and immune cells. This causes brain fog (cognitive dysfunction), chronic fatigue, anxiety/depression, neurodegenerative diseases, and other neurological conditions.

In this post, we cover ways to protect the blood-brain barrier and repair it if you already suffer from a leaky brain.

How to Fix Leaky Brain at the Root Causes

1) Anti-Inflammatory Diet

Avoid Inflammatory Substances

The lectin avoidance diet is an elimination diet that helps you reduce inflammation and avoid substances that trigger your immune system. By reducing inflammation from foods, you reduce inflammation throughout the body, including the cytokines that disrupt the blood-brain barrier.

Avoiding inflammation from foods is especially important if you have a traumatic brain injury because brain injuries can directly cause leaky gut.

The blood-brain barrier is also sealed by the same tight junction proteins as in the gut. They are also regulated by the protein called zonulin, suggesting that they are disrupted by gluten [1, 2].

Avoid High-Calorie and High-Fat Diets

High calorie and high-fat diets increase leaky gut, which causes LPS (a bacterial toxin) to enter the bloodstream [3].

A leaky gut also damages the blood-brain barrier [4, 5].

Lipopolysaccharides (LPS) in gram-negative bacteria cell walls

2) Normalize Blood Sugar

High blood sugar increases oxidative stress and inflammation, which kills the pericytes and causes a leaky brain [6, 7].

3) Deal with Infections and Toxins

Infections and toxins damage the blood-brain barrier. It is therefore important to kill off and clear these infections accordingly.

4) Reduce Stress

Stress induces leaky gut and induces overall inflammation [3].

In addition, acute stress activates brain mast cells that secrete proinflammatory cytokines that disrupt the BBB [8].

5) Sleep and Circadian Rhythm

Chronic sleep loss decreases glucose transport across the BBB, increases inflammation, and impairs BBB permeability [9].

6) Healthy Brain Circulation

Poor brain circulation reduces the amount of oxygen and nutrients available to the brain. This increases oxidative stress. When oxidative stress is increased in glial cells and pericytes, it damages the blood-brain barrier and the tight junctions [10, 11].

7) Reduce Homocysteine

High levels of homocysteine disrupt tight junction function and cause BBB dysfunction [12].

Read this post to learn more about testing for and lowering homocysteine levels.

8) Reduce Glutamate Levels

Glutamate is an important neurotransmitter and the most abundant in the brain. However, overstimulation of glutamate receptors in the brain break down the blood-brain barrier [13, 13].

In the brain, glutamate is present in balance with GABA. Defects in the enzymes (GAD) that convert glutamate to GABA, such as from autoimmune attacks, increase glutamate levels.

Read this post to learn more about these enzymes and how to optimize them.

Reduce Dietary Glutamate

Typically, glutamate in the blood does not cross the blood-brain barrier. However, many people with a leaky blood-brain barrier may have brain symptoms in reaction to dietary free glutamate.

With the exception of monosodium glutamate, most foods that are high in glutamate are also high in histamine-like substances, so it is unclear whether the reaction comes from the glutamate or the histamine-like substances.

Blocking Glutamate Receptors

Substances that block glutamate receptors, such as memantine, are used as a treatment for neurological diseases that also involve high glutamate levels and leaky blood-brain barriers [14]. These include Alzheimer’s, vascular dementia, and Parkinson’s disease.

9) Lose Weight (If Obese)

Obesity-induced inflammation also causes problems in the blood-brain barrier (BBB) [15].

It is, therefore, important to lose weight to repair the leaky blood-brain barrier.

Supplements That May Help Repair the Blood-Brain Barrier

There are several supplements that may be connected to repairing the blood-brain barrier:

1) Acetyl L-Carnitine

Acetyl L – carnitine (ALCAR) protects mitochondria in the cells [16].

When mitochondria are damaged, dangerous oxygen types leak out into the cells and destroy them. ALCAR helps repair the BBB by reversing the mitochondria decay caused by the oxidative damage [17].

2) Alpha-Lipoic Acid

Alpha-lipoic acid prevents the immune cells from invading the brain and damaging BBB in rats with experimental allergic encephalomyelitis [18].

Lipoic acid stabilizes the blood-brain barrier and preserves BBB integrity by reducing oxidative stress [19, 20].

3) Alpha-GPC

Alpha glycerophosphocholine or alpha-GPC increases the level of the neurotransmitter acetylcholine [21].

In rats, treatment with GPC in the dose of 150/kg per day partially reverses the changes in BBB caused by damage to brain vessels [21].

4) Angelica (Dong Quai) Extracts

In rats with a severe form of brain stroke that involves brain bleeding, treatment with a component extracted from Angelica sinensis, Z-ligustilide, reduced brain swelling and strengthened BBB [22].

5) Astragalus

Astragalus is often used in Chinese herbal remedies. Researchers have found injecting an astragalus extract through IV to rats that have suffered stroke strengthened the blood-brain barrier when compared to the control group of animals [23].

Astragalus, combined with ligustrazine, increased the level of proteins responsible for BBB strength, such as occludin and claudin, and decreased MMP9 [24].

6) Astaxanthin

Astaxanthin decreases inflammation during injuries [25].

It was shown that astaxanthin decreased inflammatory molecules and protected the BBB in rats that had brain bleeding [25].

7) Apigenin

Apigenin is a color compound naturally found in plants. Administration of apigenin in the dosage of 20 mg/kg in rats suffering from brain injury and bleeding in the brain blocked inflammatory proteins (TLR4 and cytokines) and increased tight junction proteins [26].

8) B12-B6-Folate Mix

Treatment with a mix of vitamin B12, vitamin B6, and folate of patients with mild cognitive impairment was shown to make the BBB stronger and improve the overall condition of their health [27].

10) Berberine

In mice with experimental encephalomyelitis and mice with brain injuries, treatment with berberine blocked the activity of MMP9 and reduced inflammation [2829].

11) Bitter Melon

Bitter melon (Momordica charantia) extract protects the blood-brain barrier (BBB) against disruption caused by a high-fat diet [30].

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 [30].

12) Butyrate

Sodium butyrate given to mice with brain trauma reversed the decrease in the concentration of BBB proteins occludin and ZO-1 and prevented damage to nerve cells [31].

Butyrate is often produced by bacteria in the gut [32].

In healthy mice, the lack of necessary butyrate-producing bacteria in the gut weakened the blood-brain barrier [32].

If germ-free mice (healthy mice that previously had no bacteria at the gut at all) are given those bacteria afterward, their BBB becomes stronger [32].

13) Chlorogenic Acid

Chlorogenic acid is found in green coffee beans [33].

Injection with 3 to 30 mg/kg of chlorogenic acid in rats with experimental stroke decreased the level of MMP-2 and MMP-9 [34].

14) Citicoline

Injection of 400 mg/ kg of citicoline into mice with traumatic brain injury strengthened the BBB and partially reduced brain swelling [35].

15) Collagen

Collagen (type IV) is known to be important for BBB structure and function of the cell that forms it [36].

16) Curcumin

In a cell-based study, curcumin increased the concentration of tight junction proteins in mice brain vessel cells. This increase protected them from injury [37].

In a model of rat brain injury, curcumin decreased brain swelling and prevented the disruption of the BBB by increasing an antioxidant protein Nrf2 [38].

Curcumin in a nanoparticle format was reported to improve the state of the BBB better than traditional curcumin [39].

17) Vitamin D3

Vitamin D3 protects the BBB by increasing the level of BBB proteins occludin, claudin-5 ZO-1, and by blocking MMP9 [40].

Vitamin D supplementation appears to be protective in cases where the blood-brain barrier is disrupted because of inflammation from a high-fat and high-calorie diet [41].

However, personally, I’m more in favor of getting sun and calcitriol rather than supplementing with vitamin D3. Read this post to learn why.

18) Ellagic Acid

Ellagic acid decreased BBB permeability in rats with traumatic brain injury [42].

19) Fish Oil

Fish oil in the dose of 15 ml/kg (EPA, DHA) in rats with brain injury made the BBB stronger, decreased the damage to the limbs, and blocked MMP9 [43].

20) Ginseng

In a model of ischemic stroke in rats, a chemical extracted from ginseng, ginsenoside R1, strengthened the BBB that was weakened after stroke [44].

Chemicals obtained from ginseng were also able to support the development of new nerve cells after stroke in rats [45].

21) Goji Fruit

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 [46].

22) Hydrogen

Rats prone to stroke and high blood pressure were given hydrogen-rich water [47].

In animals treated with hydrogen-rich water, fewer leaks from the brain were observed, and MMP 9 concentration was lower, which indicates improvement in the state of the BBB [47].

23) Licorice

Glycyrrhizin, an active component of licorice, protected the BBB from damage in rats with brain injury by blocking inflammatory proteins TNF-α, IL-1β, and IL-6 [48].

It also blocked a protein HMGB1, which is thought to drive traumatic damage in the body [48].

24) Lycopene

In rats with brain bleeding, treatment with lycopene led to less damage to the BBB, protected nerve cells from cell death, and decreased brain swelling [49].

25) Myoinositol

Myoinositol is a molecule that is important for brain function. It can somewhat pass through the blood-brain barrier [50].

It also restores the proper function of the BBB in rats with experimental diabetes [51].

26) Magnesium

In rats with sepsis (severe and life-threatening bacterial infection), magnesium sulfate given in the muscles restored the BBB and prevented brain swelling in rats sick with sepsis [52].

It also made the BBB stronger in pregnant rats that had high blood pressure [53].

Magnesium sulfate could also directly counteract damage to the BBB induced by injection of mannitol in rats [54].

Magnesium also protected the BBB in cases of traumatic brain injury and high blood sugar in rats [55, 56].

27) Melatonin

Melatonin blocks MMP9, an enzyme that causes a leaky blood-brain barrier [57].

In a cell-based study, melatonin pre-treatment protected rat brain blood vessel cells taken from inflammatory molecules [57].

It is known that melatonin is anti-inflammatory, and it is widely used to treat brain disorders [58].

28) Methylene Blue

Methylene blue decreased the level of damage to the BBB by blocking the production of nitric oxide [59].

29) Olive Leaf Extract

Olive leaf extract in the dosages from 50 mg/kg to 100 mg/kg a day reduced BBB permeability and brain swelling in rats with brain stroke [60].

30) Oxaloacetate

Oxaloacetate gathers up glutamate, a molecule important for brain function, but one that also damages the brain if there is too much of it [61].

In a rat model of brain bleeding, oxaloacetate protected the BBB through blocking glutamate from damaging the BBB and brain [61].

31) Parthenolide (Feverfew)

In rats with brain artery blockage, a chemical parthenolide protected the BBB by lowering the content of inflammatory protein and increased the level of the BBB protein claudin – 5 [62].

32) Progesterone

Progesterone lowered inflammation and supported BBB in rats after brain injury [63].

33) Pterostilbene

Pterostilbene is a component of blueberry [64].

Treatment of mice after stroke with pterostilbene in the dosage of 10 mg/kg protected against the BBB damage and brain swelling by decreasing the concentration of dangerous oxygen types [64].

34) Resveratrol

Resveratrol is an antioxidant [65].

It stabilizes the BBB and protects it from damage [65].

In rats, resveratrol protected the BBB by increasing levels of TIMP-1, which reduces activities of MMP9 [66].

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 [67].

35) Rosmarinic Acid

Rosmarinic acid protected against blood-brain barrier damage permeability in diabetic rats after stroke by lowering inflammation [68].

36) Shilajit

Shilajit reduced BBB damage and brain damage as a whole in rats with brain trauma [69].

37) Selenium

Selenium decreased BBB damage during seizures in baby rats, especially in male rats [70].

38) Sulforaphane

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 [71, 72, 73].

Sulforaphane also reduced BBB dysfunction by decreasing inflammation proteins [74].

39) Ursolic Acid

Ursolic acid is a plant component. In rats with bleeding in the brain, it blocked dangerous oxygen species and through this mechanism, prevented nerve cell death and BBB damage [75].

Supplements That May Disrupt the Brain Barrier in Some Circumstances


Andrographis/Andrographolide disrupt the layer of brain blood vessel cells when added into cell culture [76].


L-Arginine can force the blood-brain barrier to open up [77].


Nicotine makes the BBB less strong by re-shuffling blood-brain barrier proteins responsible for keeping it together [78].


Zinc is a popular supplement. But, in rats, chronic zinc treatment led to an increase of convulsions [79].

Do You Have a Genetic Susceptibility to Have a Leaky Brain?

Sometimes blood barrier issues are caused by infections, while other times a combination of genetics and your environment can be the issue.

The key genes that influence the blood-brain barrier include:

  • Matrix metalloproteinases (MMPs)
  • Tissue Inhibitors of Metalloproteinases (TIMPs)
  • Tight junction proteins
  • Genes that control oxidative stress
  • Genes that control inflammation and susceptibility to autoimmunity

There might not be a direct study that tests the effects of each gene, SNPs, or mutations on the strength of the blood-brain barrier. However, we can infer the significance of these SNPs from the gene functions and their association with worsened brain disease/injury outcomes in humans.

Matrix Metalloproteinases


For example, MMP2 gene variants (SNPs) predict to some extent the possible damage done to the brain by ischemic stroke [80, 81].


MMP9 SNPs are strongly associated with obesity [82, 83]:


An SNP of another matrix metalloproteinase, MMP13, was associated with a condition that increased the risk of blood-brain barrier disruption and stroke – leukoaraiosis [84]:


TIMP2 – People with a variant of MMP inhibitor TIMP2, -261G/A, are at increased risk of bleeding in the brain [85].

Tight Junction Proteins


Claudin-5 is a tight junction structural protein. It is important for BBB strength. Variants in this gene are linked to risks of various diseases.

For instance, it was hypothesized that variants of CLDN5 inherited together with the HLA-DQB1 gene (the celiac disease gene) lead to schizophrenia [86].

This was corroborated by another study carried out among the Chinese population. It was shown that an SNP of CLDN5, rs10314, is associated with an increased risk of schizophrenia [87].


Another blood-brain barrier protein, P-glycoprotein, transports necessary chemicals through the BBB and protects it from unwanted molecules because it is selective [88].

ABCB1 is a gene responsible for P-glycoprotein production. The T3435 allele of this gene was associated with an increased risk of major depressive disorder in Japanese people [88].

Oxidative Stress Genes


In newborns, NOS3 in the cells that line the blood vessel in the brain can mitigate nerve damage due to a lack of oxygen during birth (hypoxic-ischemic encephalopathy) [89].

This is a disease of the disrupted blood-brain barrier.

rs2070744 appears to significantly affect APGAR scores (a measure of infant wellness), with the C allele being associated with worse outcome [89].

rs1800779 and rs1799983 are not associated with the difference in hypoxic-ischemic encephalopathy.

However, rs1800779 was associated with leukoaraiosis after ischemic stroke [84].


Mutations in SOD1 are linked to familial ALS [90].

In addition, mice that have defective SOD1 function have the same leaky blood-brain barrier, blood-spinal cord barriers, and neurovascular units as ALS patients [91].


The A allele of rs662 has higher enzymatic activity than the G allele, which lowers the risk of heart disease [92].

This variant is associated with leukoaraiosis (white matter lesions) after stroke, which may be linked to the worsened leaky brain after stroke [84].

Genes That Control Inflammation and Susceptibility to Autoimmunity


ApoE4 promotes blood-brain barrier disruption, whereas ApoE2 and ApoE3 protect the blood-brain barrier [93, 94].

ApoE4 activates an inflammatory pathway in pericytes that disrupt the tight junctions, while ApoE2 and ApoE3 suppress this pathway [94].

Not surprisingly, ApoE4 is also linked to Alzheimer’s disease [95].

Alpha 2-Macroglobulin (A2M)

The C (minor) allele of A2M rs669 SNP is linked with increased risk of Parkinson’s disease and Alzheimer’s disease [96, 97].

In addition, it is also linked to increased risk of complication following tissue plasminogen activator treatment [98].

This also predicts the outcome of post-ischemic stroke [84].


rs2290608 GG is linked to leukoaraiosis post-ischemic stroke [84].

Drugs That Help Protect and Repair the Blood-Brain Barrier

Glucocorticoid (steroid)

Currently, the only conventional therapy to help improve the blood-brain barrier integrity is glucocorticoids (synthetic cortisone) treatments [99].

Glucocorticoids are generally the treatment for autoimmune disorders.

In a cell-based study, glucocorticoid dexamethasone increased TIMP1, occludin, claudin-5, and other anti-inflammatory proteins that help repair the BBB [100, 101, 102].

MMP Inhibitors

GM6001, also known as Ilomastat or galardin, is a broad-spectrum inhibitor of matrix metalloproteinases [103].

In mice with experimental autoimmune encephalomyelitis (EAE) (a multiple sclerosis model), 4 mg of GM6001 stopped the development of the disease [104].

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) [105].


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 [106].

Ang(1-7) blocked MMP9 and increased the concentration of TIMP-1 in the rats with brain injury and protected BBB from more damage [106].

Leaky Brain – Part Three of a Three-Part Series

You can read about the introduction to the blood-brain barrier and causes of the leaky brain in Parts 1 and 2.

Want More Targeted Ways to Combat Inflammation?

If you’re interested in natural and more targeted ways of lowering your inflammation, we at SelfHacked recommend checking out this inflammation wellness report. It gives genetic-based diet, lifestyle and supplement tips that can help reduce inflammation levels. The recommendations are personalized based on your genes.

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About the Author

Helen Quach

BS (Biochemistry)

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