I’ve been asked by Nootropics Expert® readers to write about a “Leaky Blood-Brain Barrier”. And the question naturally is what nootropics to use if you suspect you have a leaky brain. You’ll find the answers in this post.
Most of us are aware of “leaky gut” syndrome. It’s long been associated with Celiac disease and Crohn’s disease.
And increased interest in gluten sensitivity has led to food labels featuring ‘gluten free’ and gluten-free products in nearly every category of food you can think of in our supermarkets.[i]
This is a bigger deal than what most people think. The National Institute of Health reports that close to 20% of Americans suffer from a diagnosable mental disorder.[ii]
And serious mental illness causes $193.2 billion in lost earnings each year.
The thing is even if you can name the “diagnosable” mental health disorder, doctors often don’t know the cause.
So you end up with a prescription for some med that doesn’t work. Or it does work but the side effects are horrendous.
Turns out the cause may be a ‘leaky blood-brain barrier’. And if you have a leaky gut, chances are high that you’re dealing with a leaking brain too.
In this post you’ll find natural options for healing a leaky brain.
Table of Contents
What is the Blood-Brain Barrier?
Your brain is protected by a 7 mm thick skull. And is surrounded by cerebrospinal fluid along with a protective membrane called the meninges. This is your primary defense against physical injury like a whack on the head.
This precise control of your brain transports oxygen and nutrients to brain tissues while removing carbon dioxide and other waste.
It also promotes normal hormone and neurotransmitter signaling. And maintains control of the interaction between your brain and the rest of your body.
This allows optimal brain function while protecting your brain tissues from toxins, pathogens and other nasty stuff circulating in your general blood supply.
The Mechanics of your Blood-Brain Barrier
Endothelial cells line the interior of all your blood vessels. But in your brain, the Endothelial cells lining the inside of capillaries are held tightly and sealed together by ‘tight junctions’.[iii]
Tight junctions are made up of a network of claudins and cytoplasmic proteins, such as zonula occludens (ZO), and cingulin.[iv]
But your blood-brain barrier is not just surrounding and encasing your brain in a protective layer. This network of capillaries goes throughout most of your brain. And no brain cell is ever further than ~25 μm (micrometer) from a capillary.[v]
The thing is your blood-brain barrier is more than just a firewall protecting your brain.
Capillaries in select brain regions facilitate the passage of glucose and amino acids across your blood-brain barrier via carriers specific to that molecule.
The bottom-line is a healthy blood-brain barrier is your last line of defense keeping bad things out of your brain. And allowing the good stuff through.
But a leaky blood-brain barrier, just like a leaky gut, can lead to a whole host of problems.
Signs you may have a “Leaky Brain”
But if you’ve tried my suggested nootropic stacks in the past for each of these issues and nothing has worked. It could be a leaky blood-brain barrier.
And if you’re dealing with a leaky gut, chances are you’re suffering from a leaky blood-brain barrier as well.[viii]
A classic example of this is Celiac disease. If you’re dealing with Celiac disease chances are, you’re also suffering from seizures, headache, cognitive impairment, or other psychiatric disease.[ix]
What causes a leaky brain?
I have touched in the past on ‘leaky gut syndrome’ when writing about Psychobiotics and your gut-brain connection.
Recent research shows that a leaky gut is often associated with a ‘leaky brain’.[x]
Problems start with elevated antibodies against occludin and zonulin. Which often leads to leaky brain syndrome.
Lab work can determine if you have elevated levels of antibodies against occludin and zonulin. Blood tests can measure antibodies against these two proteins. Because it it’s left unchecked, tight junctions that seal your gut- and blood-brain barrier are compromised. Resulting in brain and gut permeability.
Research also shows that microRNAs (specifically microRNA-155) are key regulators in inflammation and blood-brain barrier permeability.[xi]
This area of neuroscience has come to be known as the “cytokine model of cognitive function.”[xiii] Elevated proinflammatory cytokines often result in brain inflammation which can lead to anxiety, depression, brain fog, and other autoimmune brain problems.[xiv]
There’s even a “cytokine hypothesis of depression”.[xv]
The bottom-line is inflammation can be the cause of your anxiety, depression, brain fog or some other cognition issue.
If you’ve tried nootropics or meds and have not experienced any relief, it could be inflammation and a leaky blood-brain barrier that is causing your symptoms.
High blood sugar is also a risk factor for developing a leaky blood-brain barrier.[xvii] Get your labs done for fasting blood sugar and Hgb A1C to find out if you’re blood sugar levels are high.
We’ve touched on the gut-brain axis earlier. And with these two linked, it makes sense that a bacterial imbalance and Candida overgrowth in your gut can result in cognition problems and even depression or anxiety.
When Candida gets out of control, it creates a layer in your intestines. Which suppresses the production of neurotransmitters like serotonin.
Antibiotics are often prescribed to treat Candida overgrowth and other bacterial infections. Often leading to yeast overgrowth.
If you find that Candida is out of control, your first option is to eliminate sugar of all forms including desserts, candy, alcohol, and flour. And cut back on refined grains, beans, bread, pasta, white potatoes, and fermented foods.
Best nootropics to fix a leaky blood-brain barrier
If you’re dealing with a leaky blood-brain barrier, nootropics can help tame inflammation and restore the integrity of the tight junctions needed for a healthy blood-brain barrier.
The following nootropic supplements have been clinically proven to help tame inflammation and heal a leaky blood-brain barrier.
You can safely use ALL the nootropics I’ve detailed below in a single nootropic stack at the recommended dosages.
NOTE: each nootropic below contains a live link that will take you to my full review of that supplement. Which includes what it is, where it comes from, why we use it, how it works in your brain, clinical studies, dosage recommendations, side effects and forms or type of supplement to buy.
Berberine – 500 mg 3-times per day
Berberine is a bright yellow alkaloid extracted from plants such as Indian Barberry (tree turmeric), Oregon Grape and goldenseal.
Berberine also decreases proinflammatory cytokines like interleukin-1β, tumor necrosis factor-α and cyclooxygenase-2 mRNA in the hippocampus.[xviii]
Caffeine – up to 200 – 400 mg per day
Caffeine is an adenosine antagonist which influences acetylcholine, epinephrine (adrenaline), serotonin and boosts the use of dopamine. Providing the stimulant effect, you get when consuming caffeine.[xxi]
Caffeine also provides a protective effect by boosting gene expression of brain-derived neurotrophic factor (BDNF).
Studies show that caffeine blocks increase in IgG and fibrinogen and decreases in tight junction proteins occludin and ZO-1, increases in astrocytes activation and microglia density where IgG leakage was present. Protecting the integrity of the blood-brain barrier.[xxii]
Curcumin extract (95% curcuminoids) 750 mg 3-times per day
Curcumin is also a potent antioxidant and helps protect your brain from inflammation.
A study at China Medical University found that Curcumin helps prevent disruption of the blood-brain barrier after a stroke.
The researchers found that Curcumin restored the expression of occludin and ZO-1 proteins which in turn restored the barrier function of the blood-brain barrier.[xxiv]
DHA (Omega-3) – 1,000 mg per day
DHA is an Omega-3 fatty acid which makes up much of the gray matter in your brain. Your brain is about 60% fat. And much of that fat is DHA. It’s a critical part of healthy and fluid brain cell membranes.
DHA can boost brain-derived neurotrophic factor (BDNF), regulate calcium oscillations which are involved in neurotransmitter release, boost mitochondrial function, gene activation, oxidative stress, and reduce inflammatory COX-2 enzymes.
L-Glutamine – 2 – 5 grams per day
We use L-Glutamine to treat a leaky blood-brain barrier because it helps boost your body’s immune response. It increases antibodies to fight against viruses and harmful bacteria.
L-Glutamine also helps tame inflammatory cytokines which can be harmful to tight junctions needed to keep your blood-brain barrier healthy.
And it detoxes your brain from excess ammonia by converting it into other amino acids, sugars, and urea.
Magnesium – 400 mg before bed
Magnesium deficiency is nearly epidemic in our society because it is sorely lacking in our food supply.[xxviii]
The thing is magnesium is the 4th most abundant mineral in your body. And is a cofactor in more than 600 enzymatic reactions.
You need magnesium to produce adenosine triphosphate (ATP) which is your primary source of energy. Magnesium is required for the synthesis of RNA and DNA[xxix], and regulates ion channels which govern the flow of neurotransmitters.
One animal study showed magnesium reduced blood-brain barrier permeability caused by sepsis.[xxx]
Another study showed magnesium supplementation reduced blood-brain barrier permeability caused by high blood pressure.[xxxi]
Resveratrol – 250 mg per day
Resveratrol is a naturally-derived polyphenol antioxidant used to protect your brain from oxidative stress.
One study had 19 Alzheimer’s patients take 1,000 mg of Resveratrol daily for one year. The study found it reduced matrix metalloproteinase-9 (MMP-9) levels in the cerebrospinal fluid by 50%. This MMP-9 decreased when sirtuin1 (SIRT1) is activated.[xxxiv]
High levels of MMP-9 weaken the tight junction of the blood-brain barrier. Conversely, low levels of MMP-9 help maintain a healthy blood-brain barrier.
Another study showed Resveratrol decreased nuclear factor kappaB (NF-κB) and the increased Claudin-5 which strengthened the integrity of tight junctions in the blood-brain barrier.[xxxv]
Vitamin D3 – 4,000 IU’s per day
Vitamin D3, the “sunshine vitamin”, as a nootropic supplement is critical for optimal cognitive health.
But Vitamin D deficiency (hypovitaminosis D) is an undeclared worldwide pandemic affecting nearly 50% of the population on this planet.
Research shows that Vitamin D helps maintain blood-brain barrier integrity by blocking the increased production of reactive oxygen species (ROS), and nuclear factor kappa B (NF- kB) activation. And increases levels of the tight junction proteins occludin, claudin-5 and ZO-1.[xxxvi]
And another animal study showed Vitamin D supplementation reduced blood-brain barrier permeability.[xxxvii]
Several of the B-Vitamins have been clinically shown to help prevent a leaky brain and support the blood-brain barrier.
Vitamin B1 (thiamine) – Thiamine is a required cofactor in the synthesis of acetylcholine, is part of the KREBs cycle that produces adenosine triphosphate (ATP), is needed for the synthesis of myelin, and helps maintain optimal levels of glutamate and GABA.
Thiamine deficiency can be caused by alcoholism, Alzheimer’s Disease, anemia, athletes who reduce food intake, cancer, clogged arteries, Crohn’s disease, diabetes, diarrhea, gastric bypass surgery, consuming large amounts of coffee and tea, and kidney disease. And even a poor diet.
Severe thiamine deficiency (Wernicke encephalopathy) causes damage to the integrity of the blood-brain barrier. Which can quickly be reversed with one week of thiamine supplementation. [xxxviii]
Homocysteine is an inflammatory compound and when levels are excessively high can break the integrity of the blood-brain barrier.
Studies show that supplementing with B6, B9 & B12 will bring homocysteine levels down to normal levels and restore the integrity of the blood-brain barrier.[xxxix]
Leaky Brain Summary
We looked at the causes of a leaky blood-brain barrier. And how to fix it.
We also discovered that if you’ve got a leaky gut, chances are your brain is leaky too. If you fix one, you’ll make great strides in fixing the other.
All the nootropics I’ve detailed above can be used daily as a single nootropic stack if you’re dealing with a leaky brain. Just follow the dosage recommendations and you should be fine.
If this is your first time using any of the above supplements, start with one at a time. Use it for a day or two. And if you don’t experience any problems. Add the next on the list.Heal your leaky brain naturally and watch the symptoms of brain fog, memory loss, chronic fatigue, anxiety, and depression get less and less over time.
[v] Schlageter K.E., Molnar P., Lapin G.D., Groothuis D.R. “Microvessel organization and structure in experimental brain tumors: microvessel populations with distinctive structural and functional properties.” Microvascular Research. 1999 Nov; 58(3):312-28. (source)
[ix] Pennisi M., Bramanti A., Cantone M., Pennisi G., Bella R., Lanza G. “Neurophysiology of the "Celiac Brain": Disentangling Gut-Brain Connections.” Frontiers in Neuroscience. 2017; 11():498. (source)
[xi] Lopez-Ramirez M.A., et. al. “MicroRNA-155 negatively affects blood–brain barrier function during neuroinflammation” The FASEB Journal 6 Mar 2014
[xii] Block M.L., Hong J.S. “Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism.” Progress in Neurobiology. 2005 Jun;76(2):77-98.
[xiii] McAfoose J., Baune B.T. “Evidence for a cytokine model of cognitive function” Neuroscience & Biobehavioral Reviews Volume 33, Issue 3, March 2009, Pages 355-366
[xiv] Perry V.H., “Contribution of systemic inflammation to chronic neurodegeneration.” Acta Neuropathologica. 2010 Sep;120(3):277-86.
[xv] Schiepers O.J., Wichers M.C., Maes M. “Cytokines and major depression.” Progress in Neuropsychopharmacology & Biological Psychiatry. 2005 Feb;29(2):201-17.
[xvi] Kamath A., Chauhan A., Kisucka J., Dole V., Losalzo J., Handy D. Wagner D. “Elevated levels of homocysteine compromise blood-brain barrier integrity in mice” Blood 2006 Jan 15; 107(2): 591–593. (source)
[xvii] Kamada H., Fengshan Y, Nito C., Chan P. “Influence of Hyperglycemia on Oxidative Stress and MMP-9 Activation After Focal Cerebral Ischemia/Reperfusion in Rats: Relationship to Blood-Brain Barrier Dysfunction” Stroke. 2007 Mar; 38(3): 1044–1049. (source)
[xviii] Lee B., Sur B., Shim I., Lee H., Hahm D.H. “Phellodendron amurense and Its Major Alkaloid Compound, Berberine Ameliorates Scopolamine-Induced Neuronal Impairment and Memory Dysfunction in Rats.” Korean Journal of Physiology & Pharmacology. 2012 Apr;16(2):79-89 (source)
[xix] Chen C.C., Hung T.H., Lee C.Y., Wang L.F., Wu C.H., Ke C.H., Chen S.F. “Berberine protects against neuronal damage via suppression of glia-mediated inflammation in traumatic brain injury.” PLoS One. 2014 Dec 29;9(12):e115694 (source)
[xxi] Walker J., Rohm B., Lang R., Pariza M.W., Hofmann T., Somoza V. “Identification of coffee components that stimulate dopamine release from pheochromocytoma cells (PC-12).” Food and Chemical Toxicology. 2012 Feb;50(2):390-8 (source)
[xxii] Chen X., Gawryluk J.W., Wagener J.F., Ghribi O., Geiger J.D. “Caffeine blocks disruption of blood brain barrier in a rabbit model of Alzheimer's disease.” Journal of Neuroinflammation 2008 Apr 3;5:12 (source)
[xxiii] Wang R., Li Y.B., Li Y.H., Xu Y., Wu H.L., Li X.J. “Curcumin protects against glutamate excitotoxicity in rat cerebral cortical neurons by increasing brain-derived neurotrophic factor level and activating TrkB.”Brain Research. 2008 May 19;1210:84-91. (source)
[xxiv] Wang Y.F., Gu Y.T., Qin G.H., Zhong L., Meng Y.N. “Curcumin ameliorates the permeability of the blood-brain barrier during hypoxia by upregulating heme oxygenase-1 expression in brain microvascular endothelial cells.” Journal of Molecular Neuroscience. 2013 Oct;51(2):344-51 (source)
[xxv] Won S., Sayeed I., Peterson B.L., Wali B,, Kahn J.S., Stein D.G. “Vitamin D Prevents Hypoxia/Reoxygenation-Induced Blood-Brain Barrier Disruption via Vitamin D Receptor-Mediated NF-kB Signaling Pathways” PLoS One. 2015; 10(3): e0122821. (source)
[xxvi] Russel K.L., Berman N.E., Gregg P.R., Levant B. “Fish oil improves motor function, limits blood-brain barrier disruption, and reduces Mmp9 gene expression in a rat model of juvenile traumatic brain injury.” Prostaglandins Leukot Essent Fatty Acids. 2014 Jan;90(1):5-11 (source)
[xxvii] Shinto L., Marracci G., Bumgarner L., Yadav V. “The Effects of Omega-3 Fatty Acids on Matrix Metalloproteinase-9 Production and Cell Migration in Human Immune Cells: Implications for Multiple Sclerosis” Autoimmune Disease. 2011; 2011: 134592. (source)
[xxx] Esen E., Erdem T., AKtan D., Orhan M., Kay M., Eraksoy H., Cakar N., Telci. “Effect of magnesium sulfate administration on blood–brain barrier in a rat model of intraperitoneal sepsis: a randomized controlled experimental study” Critical Care. 2005; 9(1): R18–R23. (source)
[xxxi] Euser A.G., Bullinger L., Cipolla M.J. “Magnesium sulphate treatment decreases blood-brain barrier permeability during acute hypertension in pregnant rats.” Experimental Physiology. 2008 Feb;93(2):254-61 (source)
[xxxii] Esen F., Erdem T., Aktan D., Kalayci R., Cakar N., Kaya M., Telci L. “Effects of magnesium administration on brain edema and blood-brain barrier breakdown after experimental traumatic brain injury in rats.” Journal of Neurosurgical Anesthesiology. 2003 Apr;15(2):119-25. (source)
[xxxiii] Li C., Yan Z., Yang J., Chen H., Li H., Jiang Y., Zhang Z. “Neuroprotective effects of resveratrol on ischemic injury mediated by modulating the release of neurotransmitter and neuromodulator in rats.” Neurochemistry International. 2010 Feb;56(3):495-500. (source)
[xxxv] Zhao H.F., Li N., Wang Q., Cheng X.J., Li X.M., Liu T.T. “Resveratrol decreases the insoluble Aβ1-42 level in hippocampus and protects the integrity of the blood-brain barrier in AD rats.” Neuroscience. 2015 Dec 3;310:641-9 (source)
[xxxvi] Won S., Sayeed I., Peterson B.L., Wali B., Kahn J.S., Stein D.G. “Vitamin D prevents hypoxia/reoxygenation-induced blood-brain barrier disruption via vitamin D receptor-mediated NF-kB signaling pathways.” PLoS One. 2015 Mar 27;10(3):e0122821 (source)
[xxxvii] Hajiluian G., Nameni G., Shahabi P., Mesgari-Abbasi M., Sadigh-Eteghad S., Farhangi M.A. “Vitamin D administration, cognitive function, BBB permeability and neuroinflammatory factors in high-fat diet-induced obese rats.” International Journal of Obesity (London). 2017 Apr;41(4):639-644. (source)
[xxxviii] Schroth G., Wichmann W., Valavanis A. “Blood-brain-barrier disruption in acute Wernicke encephalopathy: MR findings.” Journal of Computer Assisted Tomography. 1991 Nov-Dec;15(6):1059-61. (source)
[xxxix] Lehmann M., Regland B., Blennow K., Gottfries C.G. “Vitamin B12-B6-folate treatment improves blood-brain barrier function in patients with hyperhomocysteinaemia and mild cognitive impairment.” Dementia & Geriatric Cognitive Disorders. 2003;16(3):145-50. (source)