Evolution of the endocannabinoid system

How can medical marijuana work for so many different conditions?

Marijuana activates a mechanism in us called the endocannabinoid system, first described in 2011 by scientists from Hebrew University. They wrote:

Raphael Mechoulam

”Changes in endocannabinoid levels and/or CB2 receptor expressions have been reported in almost all diseases affecting humans, ranging from cardiovascular, gastrointestinal, liver, kidney, neurodegenerative, psychiatric, bone, skin, autoimmune, lung disorders to pain and cancer”

They went on to say:

“modulating CB2 receptor activity holds tremendous therapeutic potential in these pathologies.”

Marijuana is being used to treat an astonishing variety of problems, from acne to cancer. While political interference has prevented clinical trials, a mountain of evidence shows the promise of cannabis medicine. For traumatic brain injury, hospital records show that the mortality rate dropped by 80%, if the patient had THC metabolites in their blood. A similar reduction in mortality was found for pancreatitis:

”The [cannabis exposed] group had significantly lower inpatient mortality compared with the non-cannabis group (odds ratio 0.17, 95% confidence interval, 0.06–0.53).

The cannabis exposed patients also had less kidney injury, less cardiovascular shock, fewer incidents of acute respiratory distress, less gut paralysis, less need for tube feeding, shorter length of stay and lower inflation adjusted charges. So the kidneys, heart, lungs, gut, and stomach all did better, if the patient tested positive for marijuana.

How is this possible? How can one group of medicines help with problems as diverse as brain injury and pancreatitis, let alone “almost all diseases affecting humans”?

A body-wide protective system

The answer that Pacher and Mechoulam gave is that cannabis activates a body-wide protective system. Although plant cannabinoids are not chemically related to the body’s own, endogenous cannabinoids, they twist themselves into similar shapes, so they can imitate our animal “endocannabinoids” for receptor transmission purposes.

Endocannabinoids are an ancient chemistry that evolved in nerve cells as part of the response to certain kinds of stress. This protective response had its power extended twice, with the CB1 and CB2 receptors. So this is a simple story of three steps — the cell chemistry, then CB1, and CB2.

Of course, step 1 — cell chemistry — represents maybe 300 million years of evolution. Actually, it’s not a step at all, it’s just our earliest hazy snapshot, from 555 million years ago. That’s the age of the oldest fossil that’s clearly bilateral like us — clearly not round like a jellyfish. The endocannabinoid system was well developed by that time.

Step 1) Endocannabinoid chemistry within the cell

The way we think about this system is somewhat backward, because its parts were discovered in the opposite order to how they evolved. The plant chemicals were discovered first. They led us to the receptors they bind to, which led to the body’s own signaling chemicals. So “cannabinoids” are defined as any chemicals that activate the CB1 and CB2 receptors. But our animal cannabinoids do a lot more than that, and their other functions are much older. The endocannabinoids were important players in cell chemistry long before CB1 and CB2 evolved. We share this cell-level use of cannabinoids with the jellyfish.

Hydra Vulgaris, the most primitive animal that has nerves. It uses endocannabinoids, but doesn’t have CB1 or CB2 receptors.

Jellyfish have nerves, with synapses like ours. Their nerves use cannabinoids like ours, but they don’t have CB1 and CB2 receptors. So by looking at what we have in common with them, we can see the oldest parts of our endocannabinoid system. This base layer is mostly intracellular. Endocannabinoids were used within nerves to manage their problems with oxidation and inflammation. Nerves have big problems with both of these.

Oxidative damage is a special issue for nerves, for two reasons. First, they run hot. The brain is 2% of the body by weight but uses 20% of its energy. As if that wasn’t enough, the main excitatory neurotransmitter, glutamate, interferes with oxidation management. Glutamate is a signal that can kill the receiver.

Inflammation is the second problem. It causes nerves to send a false signal, so we get phantom pain. Even worse, inflammation leads to cell death, and the nervous system is so interconnected that if a few nerves in your neck get pinched and inflamed, you can lose the use of your arm. In evolutionary terms, that makes you meat for the crows. Other cells can just die but nerves have to be protected.

Endocannabinoids are produced in response to both inflammation and oxidative stress. The chemical reaction that creates them is triggered when calcium levels rise, and both inflammation and oxidative stress cause calcium to rise. If calcium gets too high, mitochondria will kill the cell. Endocannabinoids have direct chemical effects and they act as a broadcast signal, that says “if calcium doesn’t come down, we’re all dead”.

As chemicals, endocannabinoids compete for a precursor with prostaglandins, the main drivers of inflammation. They can be converted to prostaglandins to increase inflammation.They inhibit production of inflammatory hitmen like TNF-alpha and interfere with production of amyloid-beta.

As intracellular signals, they stabilize mitochondria, protect against oxidation, close calcium channels, and manage ion channels involved in things like sensing heat, pain, and nausea. We inherit all this from the common ancestor of jellyfish and kings.

In the years since our ancestral line diverged from the cnidarians, the signaling function has steadily expanded. For example, vertebrates have PPAR receptors, located around the cell nucleus. They manage genes involved in things like reproduction, metabolism, and programmed cell death. After a brain injury, cannabinoids can cause the growth of new nerves by stimulating PPAR receptors.

These ancient and more modern intracellular effects explain why a lot of cannabis medicine does not rely on CB1 and CB2 (acne , arthritis, …). The activist Debbie Wilson calls this the “cellular healing layer”.

2) CB1 and the neural net

CB1 evolved just before the first vertebrate, and appears in all vertebrates that have been tested. CB1 is a very powerful receptor that can affect nerves and their health in many ways. More importantly, it changes the structure of the nervous system.

CB1 recognizes cannabinoids outside the cell, so when a cell produces cannabinoids, its neighbors can notice and respond. This allows a cooperative response to the stresses that cause cannabinoid release. In particular, when a vertebrate nerve gets too many glutamate messages, it produces cannabinoids. These are recognized by CB1 receptors upstream, on the nerves that are sending the glutamate, and they become less active. CB1 can also inhibit the release of all the other neurotransmitters — serotonin, dopamine, acetylcholine and the rest.

In this prototypical case, CB1 signaling and glutamate signaling go in opposite directions — cannabinoids are “retrograde transmitters”. The mathematics of neural networks tells us that this kind of feedback is necessary for effective learning in a neural net.

With CB1, individual nerves can reconfigure the neural net to protect themselves, which allows for a larger and more flexible nervous system. A case can be made that CB1 has been critical for the development of the brain itself.

Insects and jellyfish don’t have CB1 receptors. Their nerves are quite similar to ours, in fact, cannabinoids are the only neurotransmitters that we have and insects don’t. Over hundreds of millions of years, no bug or jellyfish or worm has evolved anything close to the vertebrate brain. Only one invertebrate, the octopus, has anything comparable. The large nervous system belongs almost exclusively to the animals that have CB1.

There were many genetic advances in the early days of vertebrate evolution. CB1 is not the only thing going on, but CB1 plays a critical role. It is the primary brake on runaway glutamate signaling. If you have brakes you can drive a bigger truck.

Nerves firing in the brain of a fish as it swims.

3) CB2 and the whole body

Each animal has a gene that codes for its version of CB1. Shortly before our ancestors crawled onto land, a “gene duplication event” occurred, and a fish was born with an extra copy, CB2. Variations of CB2 are found in some fish and all of the four-limbed land animals.

While CB1 can only express itself on nerves and a few related cell types, CB2 receptors are found throughout the body. Their role in the immune system is particularly important. In general, when CB2 receptors on immune cells are stimulated, the cell slows down and reduces inflammatory signaling. CB2 puts a brake on runaway immune process, similar to what CB1 does for the nervous system.

CB2 receptors take on different functions in other parts of the body. They have different effects in different tissues, but their behavior is consistent because the signals — the endocannabinoids— are produced in response to inflammation or oxidative stress. The receptor’s job then, is to mobilize an appropriate response to stress in a neighbor. So in the bones, stimulating CB2 causes the bone to grow stronger, but in a tumor, stimulating CB2 can trigger programmed cell death. Growth and death are very different effects. What they have in common is they are both appropriate responses to stress among neighboring cells.

Everything about you

Given this history, the broad reach of cannabis medicine should not be a surprise. The endocannabinoid system has been involved in cell protection for 600 to 800 million years. Everything about you that is different from a sponge evolved with endocannabinoids doing inflammation and oxidation control.
With CB1 and CB2, the endocannabinoids became a channel for communication between cells. This system has developed so that by now it manages communication between brain regions, tissues and whole organs.

Two litters of mouse pups, both born six days earlier. On the day of their birth, the ones to the right were given a drug that blocks CB1 signaling. Despite the mother’s efforts, they did not learn to eat. They also do not seek physical contact. Three are already dead, these last two died the next day.

At human conception, when the sperm meets the egg, the new cell immediately releases cannabinoids, deactivating other sperm and helping prevent multiple fertilization. Additional cannabinoid signaling negotiates the gamete’s journey to the uterus and implantation on the uterine wall. When you were a single cell, you relied on cannabinoid signaling to navigate your world.

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