The Biology of the Blood-Brain Barrier
Follow the inner journey of psychedelics
Before we begin:
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“As long as our brain is a mystery, the universe, the reflection of the structure of the brain will also be a mystery. “
- Santiago Ramón y Cajal
In today’s newsletter you will learn:
How and why brain depends on blood 🩸🧠
Why we have a barrier that separates them ⬅️➡️
How to predict if a molecule will cross the BBB 🔬
Some drug delivery techniques 📦
A Tale of Two Systems
Neuropsychiatric disorders cause human suffering, an issue exacerbated by our public health, social, and existential crises. We can alleviate human suffering by making massive leaps in our understanding of the mind and brain. Psychedelic compounds are poised to fuel this leap. A mountain of magnificent research is emerging about how psychedelics influence the firing and wiring of neuronal networks. However, the brain is a bigger beast than that, and it’s important that this new knowledge rests upon a strong foundation of brain biology. Today, I will tell you about the blood-brain barrier, a river of blood that permeates our brain, delivering life, and psychedelics, to the inner mind.
The Brain
The brain is a complex place. It is made up of roughly 100 billion cells, organized into electrochemical networks through which information runs constantly. Half of the cells in the human brain are neurons, the other half are glial cells. Neurons are the characteristic brain cell, often depicted lighting up like fireflies inside the brain. There are many types of neurons, but they all collect and transmit signals throughout the brain in a circuit-like fashion. Somehow, their interactions form the basis of our memories, thoughts, emotions, and psychedelic trips. The other half of our brain is made of glial cells, of which there are also multiple types. Different glial cell types do different tasks in the brain, such as cleaning up waste, recycling neurotransmitters, insulating neuronal tracts, and a thousand other jobs that keep our brain goop running smoothly.
All of this activity requires a ton of energy. Although our brain makes up 2% of our mass, it accounts for about 20% of our baseline metabolic rate. This means that 20% of the oxygen and glucose we take in from the environment is pumped straight to the dome to make ATP, the primary biological energy currency. ATP produced in the brain mostly fuels neurons, which need a large, steady supply of ATP to produce the nerve impulses that form the basis of our entire existence. Neuronal death occurs almost immediately if glucose and oxygen delivery ceases.
The Blood
Glucose, oxygen, and a sundry of other nutrients are transported to the brain by blood. Unless you’ve only recently come to inhabit a human body, you know that blood runs throughout our entire body, is red, and spills out if you get cut. What you might not know is that blood is full of a bunch of other molecules that are toxic to the brain.
It is not that these molecules are inherently toxic; the brain is just an extremely sensitive tissue. Neurons rely on the movement of ions (electrically charged atoms) across their membrane to generate electrical pulses. Blood contains a lot of ions, and if they leak into the brain, it would mess up the delicate balance required for neurons to fire properly. Ions are one of many ingredients to blood that cannot freely enter the brain. The composition of blood generally reflects what we intentionally put into our bodies (food, drugs, etc.) and what unintentionally gets into our bodies (bacteria, viruses, also drugs, etc.). Fortunately, animals have evolved a gatekeeper to control what gets in and out of our most sensitive organ.
The Barrier Between
A central challenge to having a brain made of brittle, energy-sucking neurons is how to feed them and protect them at the same time. The solution is the blood-brain barrier (BBB), a structure pretty much ubiquitous across the animal kingdom.
The BBB is a network of blood vessels that permeate the brain. It is made of specialized cells that are tightly connected to each other, preventing molecules from leaking through. There are about 375 miles of blood vessels in an adult brain, including about 25 square meters of surface area across which molecules can diffuse. Blood-brain barrier cells are linked up with to a few other cell types inside the brain that help the BBB function properly.
The BBB has two primary functions, let in what the brain needs, keep out what the brain doesn’t need. The BBB brings in what the brain needs using a cornucopia of receptors and transport systems. These systems "catch” molecules in the blood such as glucose and move them into the brain. Small molecules and atoms such as oxygen are small enough to move through the BBB without any help. The BBB keeps out what the brain doesn’t need by a) forming a tight physical seal, b) not having transport systems for certain molecules, and c) pumping out molecules that slip across the membrane. Together, these systems work to maintain an optimal level of homeostasis in the brain.
Psychedelics: Through the blood and over the barrier
So, if the BBB has all of these mechanisms for keeping out non-essential molecules, how come psychedelics can get in? And why can’t other brain disease-fighting drugs get in? Like most things in biology, the BBB ain’t perfect. There is no committee in the BBB deciding if a molecule should enter or not. If a molecule has the right properties to diffuse through the BBB without being shot back out, it’s in. If a molecule can bind to a transport system, it’s also in. Psychedelics mostly fall into the former category, while many other drugs designed to fight brain tumors and other neurodegenerative diseases do not. Let’s break it down further.
To undergo simple diffusion across the blood-brain barrier, molecules need to fit Lipinski’s Rule of 5;
Molecular size less than 500 Da
LogP (measure of solubility in water or lipids) between 1.5-2.5 (soluble in lipids)
Polar surface area below 60-90Å
Less than 5 H-bond donors & less than 10 h-bond acceptors
Low electrostatic charge
Most psychedelics readily cross the BBB because they meet each of Lipinski’s rules. Mescaline however has harder time, because it is fairly hydrophilic (LogP ~0.7), and won’t readily dissolve through the lipid bilayer of BBB cells. Psilocybin does not cross the BBB because its phosphate group makes it highly polar (i.e. also not soluble in lipids), whereas the dephosphorylated psilocin molecule waltzes right in.
Drug Delivery At Your Service
Your new drug doesn’t fit this profile? Researchers have developed a few other ways to deliver therapeutics to the brain. The most obvious way is to force your molecule to meet Lipinski’s Rule of 5, but this comes with the tradeoff of either losing functionality, or making the molecule so bioavailable that it become sequestered in other organs. Another popular way to get drugs across the BBB is to package them into liposomes (lipid bubbles) or nanoparticles (molecular matrices) attached to receptor ligands. All packaged up, the drugs are then shuttled into the brain via BBB’s innate transport systems. Other techniques involve transiently opening or weakening the BBB during the administration of a drug, with the idea that the drug will diffuse in more readily when the BBB is all messed up.
A Final Note
For thousands of years, psychedelics have helped humans chart the connection between the material and ethereal. Now, we can deploy psychedelics to chart the final frontier of our physiology, the connection between the metaphysical mind and the physical brain. Neuronal networks are cool, yes, but if we can master the river of blood that feeds the brain, we can better understand how and where to target therapeutic molecules. With a better map, we won’t be so lost in dealing with the mental health crisis.
From around the psychosphere
🧪 Science:
Curious about how mushrooms grow, and maybe interested in growing them yourself? Don’t pay for an expensive class. Everything you need is already in the psychosphere. That’s all I have to say 😉
⚖️ Society:
Read The Pot Brothers at Law Want You to ‘Shut the Fuck Up’ Around Cops by Troy Farah on Vice.
If you want to read a supreme-r, sicker, spicier substack than this old rag, check out Rave New World by Michelle Lhooq.
💸 Law & Finance:
California Bill SB 519 was debated in the CA State Assembly yesterday, where it passed 5-3. Get the play-by-play in this thread from PsilocybinAlpha:
Tunes for your next flow state:
🔥 Ben Böhmer Live at Kliemannsland
🍯 Poolside - Heat (Full Album)
See you next week for a soothing breakdown of a rad psychedelic paper ✌🏽