How can medical marijuana work for so many conditions?
The evolution of the animal cannabinoid system
Marijuana activates a mechanism in us called the endocannabinoid system. It was described in 2011 by scientists from Hebrew University. They wrote:
”Changes in endocannabinoid levels and/or CB2 receptor expressions have been reported in almost all diseases affecting humans”, and “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. Political interference has prevented clinical trials, but a mountain of evidence shows the promise of cannabis medicine. According to hospital records, the mortality rate for patients with traumatic brain injury 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).
It is hard to believe that one group of medicines can help with conditions as different as brain injury and inflammation of the pancreas, but the scope of cannabis medicine is broader still. For brain injury, pancreatitis, and many other problems, cannabinoids help in more than one way. In the pancreatitis study, the cannabis exposed patients had 1) less kidney injury,2) less cardiovascular shock, 3) fewer incidents of acute respiratory distress, 4) less gut paralysis, 5) less need for tube feeding,6) shorter length of stay and 7) lower inflation adjusted charges.
So the kidneys, heart, lungs, gut, and stomach all did better when the patient tested positive for THC. How can this be possible? How can one group of medicines heal in multiple tissues, in “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. They called it the endocannabinoid system, the ECS. It consists of a handful of signaling molecules, receptors that respond to them, and enzymes that create and destroy them. Chemicals from marijuana stimulate this system by imitating the signaling molecules.
We might say that from a practical point of view it doesn’t matter why the ECS is so powerful. The receptors are there, in all of those parts of the body, and we know what they do, so it is what it is. But many people are still skeptical that such a medicine is possible, and knowing why the receptors are there and how they evolved gives us a way to understand what medical marijuana does.
This story spans 600 million years, and has three acts, with roughly 100 million years between one act and the next. The animal cannabinoids — the signaling molecules — evolved first, then the CB1 receptor, and finally CB2.
Act 1: The Animal Cannabinoids
The story begins with the signaling molecules. They’re called endocannabinoids, but I prefer to call them animal cannabinoids, because they’re used by almost all living animals. They’ve been around a long time. In all the animal world, there are only four basic body types. The first three did not use cannabinoids.
All other animals including humans are the fourth type, eumatazoa. Eumetazoa have bodies made of tissues, with separate skin, digestion, and nerves. Eumatazoan nerves have produced cannabinoids from the beginning.
We know that animal cannabinoids evolved more than 555 million years ago, because that’s the age of the oldest fossil that’s clearly bilateral like us, and not round like a jellyfish. By looking at what we have in common with the jellyfish, we can get a picture of what the animal cannabinoid system looked like before our lineages split. The most primitive relative of the jellyfish uses cannabinoids in many of the same ways we do, but it doesn’t have CB1 and CB2 receptors, so those evolved later.
Cannabinoids are defined as chemicals that activate CB1 and CB2, but they do a lot more than that. CB1 and CB2 allow communication between cells. There is a base layer, in which cannabinoids are used inside a single cell. These intracellular functions are the older part, the part we share with hydra.
Base layer: Maintaining balance within the cell
Let’s talk about calcium. Calcium is one of the most tightly regulated chemicals in our biology. Calcium imbalance is a sign of cell stress. It triggers inflammation. If the imbalance continues, the cell will die. Nerve signals work by turbocharging the flow of calcium.
Cannabinoids are produced when calcium levels are high, so the animal cannabinoids are a running measure of recent changes in calcium balance. This means, at the broadest level of generalization, cannabinoids are a signal measuring recent cell stress. They initiate a cascade of actions to restore balance, for example, they close calcium channels, stabilize mitochondria, protect against oxidative damage, manage ion channels that do all kinds of basic things like sensing heat, pain, and nausea, and reduce the reactivity of nerves.
This is the base layer of the endocannabinoid system. A lot of cannabis medicine operates on this level, for example acne, arthritis, epilepsy. CBD does a lot of its work at the base layer. The medical activist Debbie Wilson calls this the “cellular healing layer”.
So that’s what the animal cannabinoids were doing about 600 million years ago. The story since then is about using them as signals, and finding new ways to respond to the signal. The second big step in this evolution occurred about 520 million years ago, in an ancestor of the vertebrates. These animals developed two new kinds of cannabinoid receptor — PPAR and CB1.
PPAR receptors allow cannabinoids to influence how proteins are made from DNA, particularly proteins involved in fat metabolism. THC Acid from raw cannabis gets its effects on metabolic disease and nerve healing by activating PPARs. So the PPARs are a powerful extension of the intracellular healing layer.
Act 2: The CB1 receptor
CB1 is something else entirely. CB1 appears in all vertebrates that have been tested. It is a very powerful receptor, but the most important thing about it is that CB1 recognizes cannabinoids outside the cell. This means that when a cell produces cannabinoids, its neighbors can notice and respond. Since cannabinoids are produced when cells are under stress, CB1 allows cells to cooperate in response to stress.
For example, the nervous system uses a neurotransmitter — glutamate — that causes oxidative damage. Glutamate is literally a message that can kill its receiver; nerves will die if they get too many incoming messages. Glutamate toxicity is involved in stroke, Parkinson’s, and other neurological problems.
But when a nerve experiences oxidative stress, it will produce cannabinoids — that’s inherited from the base layer. With CB1 this becomes a message to the neighboring cells, including the ones that are sending too much glutamate. They respond by slowing down. So by communicating through CB1, individual nerves can reconfigure the neural net to protect themselves. This allows for a larger and more flexible nervous system. CB1 can control the release of all the other neurotransmitters — serotonin, dopamine, acetylcholine and the rest.
CB1 may have been necessary for the development of the brain itself. It is the brake that stops runaway glutamate signaling, and if you have brakes you can drive a bigger truck.
What we know is that insects and jellyfish don’t have CB1 receptors and they don’t have large brains. Their nerves are otherwise quite similar to ours, in fact cannabinoids are the only neurotransmitters that we have, and insects don’t. Yet over hundreds of millions of years, no bug or jellyfish has evolved anything close to the vertebrate brain. Of all the invertebrates, the octopus is the only one with a nervous system comparable to a vertebrate. The large nervous system belongs almost exclusively to animals that have CB1.
Act 3: The CB2 receptor
There is a gene that codes for CB1. The last act, the last big step in the evolution of our cannabinoid system, was the appearance of CB2. It began as a copy of CB1. About 400 million years ago, CB1 was accidentally duplicated, and a fish was born with two copies. All the land vertebrates descend from that fish. The new receptor evolved in its own direction, and now we call it CB2. In humans, CB1 and CB2 are on different chromosomes. The difference is that CB1 is bound and CB2 is free.
The gene for CB1 only expresses itself on nerves and some related cell types. It’s in a restricted genetic space. The CB2 copy landed outside that space, so CB2 receptors are found throughout the body. Courtesy of our nerves, the rest of the body was suddenly given a signaling system that allows coordinated responses to cell stress. As you can imagine, the immune system found many uses for this. In general, CB2 acts to regulate and resolve the immune response. When CB2 receptors on immune cells are activated, the cell slows down and reduces inflammatory signaling. CB2 puts a brake on runaway inflammatory process, similar to what CB1 does for the nervous system.
Outside of the immune system, stimulating CB2 does different things in different tissues, but its behavior is functionally consistent because the signals — the animal cannabinoids — are produced in response to stress. The CB2 receptor’s job then, is to mobilize an appropriate response to stress in a neighboring cell. In the bones, stimulating CB2 causes the bone to grow stronger, but in some tumors, stimulating CB2 triggers programmed cell death.
Think about that. In bones it causes growth, and in a tumor it causes death. Growth and death are very different effects. What they have in common is that under the circumstances, they are both appropriate responses to stress among the neighboring cells.
Everything about you
This is why cannabis medicine has such a broad scope. Our animal cannabinoid system has been involved in cell protection for 600 million years. Everything about you that is different from a jellyfish evolved with cannabinoids already doing stress management. With CB1, cannabinoids became a channel for communication between cells, and with CB2 this channel was made available to tissues throughout the body. In us today, cannabinoids manage communication between brain regions, tissues and whole organs. They manage behavior from feeding to thought. Cannabis is not just medicine, it is a revolutionary medicine.
