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The Extraordinary Endocannabinoid System

A new theory published in a 2016 study states that an endocannabinoid deficiency may be the origin of migraine.[i] The research team was led by none other than Dr. Mechoulam, the godfather of cannabinoids. Let’s work our way forward from the 1960s to understand how plausible this new migraine theory is.

An Israeli scientist, by the name of Dr. Raphael Mechoulam, identified the first cannabinoid, THC, in 1964. CBD was discovered soon after.[ii] “By using a plant that has been around for thousands of years, we discovered a new physiological system of immense importance,” Dr. Mechoulam recalled.

Scientists followed the cannabinoid pathways in the late 1980s and early 1990s and discovered that cannabinoids bind to at least two receptors, appropriately named cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2).


But why do we have these cannabinoid receptors in the first place? What purpose do they serve, besides getting you high?

How the endocannabinoid system affects human health is the focus of Dr. Mechoulam’s life’s work. In 1992, Mechoulam and a team of researchers discovered that smoking ganja was not the only way to activate the cannabinoid receptors. Our bodies make their very own cannabinoids called endocannabinoids, “endo” meaning “from within.” Mechoulam named the first endocannabinoid “anandamide,” after the Sanskrit word for bliss.

Anandamide plays a core role in the feelings of motivation and pleasure. Anandamide helps produce the sense of “runner’s high,” which is just as much of a mechanism of biological survival as it is a feeling of happiness.[iii] The discovery of anandamide opened Pandora’s box. It was the first of many endocannabinoids discovered which began to unravel a prehistoric system that regulates human health: the endocannabinoid system.

Have you ever run into a high guy who said, “This is my medicine, man,” as he finished a joint? His musk would linger with a woody smell, maybe Palo Santo. I always thought that guy, there’s one in every town, was just high. It turns out he was talking about the enormous role that the endocannabinoid system plays in the biological functions of human existence. And to think you scoffed at him.

The endocannabinoid system is responsible for maintaining homeostasis. Dr. Mechoulam wasn’t kidding around when he said “a system of immense importance.” Homeostasis is the ability of the body to maintain equilibrium or stability internally when faced with changes externally. That means everything you think it does.


Cannabinoid receptors are located throughout the entire body and control the immune system, inflammation, energy production, appetite, memory, nutrient transport, stress response, anxiety, the autonomic nervous system, temperature, blood pressure, sleep, and more.[iv] In other words, endocannabinoids balance your health.

Every positive influence that cannabinoids have over migraine is the result of the balancing act of the endocannabinoid system. For example, if too much glutamate is sent between the synapses in the brain, blocking the neurotransmitter pathway, it can trigger a migraine or seizure. This destructive process is called excitotoxicity. It excites cells to death and results in oxidative stress.[v]


Endocannabinoids are the most well-known retrograde messengers, and possibly the only retrograde neurotransmitters, which retroactively send messages back to an overactive nerve, saying, “Slow down, dude, you are sending too much glutamate too fast.”[vi] Endocannabinoids are like your own little cannabis doctor telling your brain that you are overexcited, chill out, slow down, and here is a chill pill before you excite yourself to death. Have you heard a cannabis doctor speak? That’s how they sound.

Because overactive nerves, excitotoxicity, and oxidative stress are involved in neurodegeneration, the endocannabinoid system is under research aimed at preventing oxidative-stress-related conditions, from stroke and traumatic brain injuries to Alzheimer’s and Parkinson’s disease, migraine, and many more.[vii]

According to the medical authority Medscape, “modulation of the endocannabinoid system may be a cure for chronic neurologic and immune conditions.” Migraine is a neurological condition, but a study recently published in the journal Nature Genetics suggested that migraine could also be an immune system disease.[viii] If an endocannabinoid deficiency exists in migraine, immune system function is also likely to go out-of-whack, because endocannabinoids help control the immune system in addition to neurological health.

One night last week, I started to get a bad cold and I took 15 mg of hemp extract. By morning, I was a little tired, but all my symptoms of the cold were gone. Vanished. Yeah, I’m one guy, writing a book on hemp, claiming that hemp cured my common cold. Sure, I’ve never had this happen before, but I acknowledge it could be a placebo effect. However, research shows that cannabinoids can fight off infections with anti-inflammatory activity and can even significantly reduce the replication of powerful viruses such as hepatitis C.[ix] [x]

All you need to do is look at the vast list of auto-immune conditions associated with migraine (e.g., fibromyalgia, lupus, multiple sclerosis, etc.) to realize that a healthy immune system is essential for fighting migraines.

So, the big question is, does an endocannabinoid system deficiency exist in migraine patients? I’m glad you finally asked, you smart cookie you.

A 2008 study published in the journal Neurobiology of Disease found that chronic migraineurs had an endocannabinoid system that functioned at only 50 percent compared to the endocannabinoid function of healthy individuals.[xi] You can imagine that a system of “immense importance” is going to wreak havoc on the human body if it’s only functioning at 50 percent. Your cannabis doc would be like, “I’m giving your endocannabinoid system a grade of F-, dude, your body is out of order.”


You can also bet that the catastrophic problems occurring within the endocannabinoid system didn’t happen overnight. They must have progressed for a long time before the entire system plummeted to half speed. Multiple studies now support this theory, with findings of reduced endocannabinoid levels in the cerebrospinal fluid of migraine sufferers, and endocannabinoid dysfunction in related conditions.[xii]


Fibromyalgia and irritable bowel syndrome (IBS) are two of the most common comorbidities of migraine, and guess what: they are also associated with endocannabinoid deficiency. Most notable about these conditions is that traditional medicine— prescription medication—provides a level of treatment that is pathetic. The drugs are far from adequate.


In the 2016 National Pain Report over 60 percent of fibromyalgia patients said prescription medications “do not help at all.” Only ten percent of patients listed medications as “very effective.”[xiii] Cannabis provides the opposite level of relief, in a good way, with 62 percent of patients claiming cannabis is “very effective” and only five percent saying that it “does not help at all.” It’s no shock that cannabinoids help with conditions that are related to endocannabinoid deficiencies.

How do we know cannabinoids will help with endocannabinoid deficiency? You ask an important question. Cannabinoids bind to the endocannabinoid receptors and produce the same effects. However, it also appears that cannabinoids will help improve the function of the endocannabinoids we already have.


New research found that CBD alleviated the psychotic symptoms of schizophrenic patients as effectively as prescription medications.[xiv] The study, published in the journal Translational Psychiatry, attributed the alleviation of schizophrenia symptoms (anxiety, depression, hallucinations, etc.) to a measurable rise in anandamide signaling or the “bliss” endocannabinoid. This surge of endocannabinoids is one of many examples that prove that the cannabinoids from external sources can help your internal endocannabinoid system.


If endocannabinoids are so important to human health, what would happen if we took them away? If you were an evil drug company, you could try that, on real people. A pharmaceutical company tested out a drug called Rimonabant to see what would happen if they blocked endocannabinoids from binding to CB1 or CB2. Cannabinoids control appetite, so why not block the cannabinoid receptors of thousands of obese people?

The idea of a magic pill that eliminates appetite is alluring. Blocking an entire system that we know very little about is appalling. Rimonabant was being tested to reduce the risk of cardiovascular disease in obese folks but marketed as a weight-loss drug, which after 33 months failed to show any significant improvement in patients.[xv] Rimonabant did, however, significantly increase gastrointestinal, neuropsychiatric, and fatal psychiatric side effects. Four patients committed suicide and the trial abruptly ended.

Four dead people. Four dead people with families and pets and friends. Let’s focus on improving the endocannabinoid system and not blocking or destroying it. The side effects of a weak functioning endocannabinoid system will be vast and this, of course, brings us to oxidative stress.


Endocannabinoid Deficiency, Oxidative Stress, and Migraine

At this point, you may be wondering if it’s oxidative stress or endocannabinoid dysfunction that causes migraine. First, I will say that the official cause of migraine is unknown. Migraine is the most sophisticated defense mechanism, alerted from numerous complex conditions and headache triggers that harm the body, and is more advanced than all of our progress in science combined. That said, what we do know about oxidative stress, endocannabinoids, and migraine is fascinating.

It’s clear that an endocannabinoid deficiency will create oxidative stress if the body loses homeostasis. If the endocannabinoid system goes rogue, you won’t be able to control glutamate, energy production, stress, or any other factors that trigger migraines.

On the other hand, we know that a ton of conditions and nearly all migraine triggers are associated with oxidative stress. Vast amounts of migraine research imply that oxidative stress is the initial culprit. Is there only one “cause” of migraine or are these systems connected?

What is oxidative stress in its simplest terms? Oxidative stress is caused by just about any external force that harms the human body. The endocannabinoid system maintains homeostasis or stability internally when faced with changes externally. Oxidative stress disrupts homeostasis. The endocannabinoid system controls homeostasis. It’s yin and yang.


Yin and yang are not just negative and positive, light and dark, but two forces which are complementary to each other. You can’t have one without the other. (Just think of me as Sensei Jeremy for the next few paragraphs.) The endocannabinoid system controls homeostasis. Homeostasis is maintained by controlling oxidative stress with an antioxidant process called redox, short for the reduction of oxidation.

The processes of oxidative stress and reduction of oxidation happen simultaneously and neither can occur independently, according to The Gale Encyclopedia of Science. The endocannabinoid system is therefore connected to oxidative stress every step of the way. One does not exist without the other. If oxidative stress sounds confusing, that’s because it is, and when you figure it out, you should let scientists know, because they may be able to cure virtually every disease from understanding the exact pathway of oxidative stress.

The concept of something hurting and healing the body at the same time is confusing. It is happening now as you breathe. Every breath of oxygen you take in is turned into energy and left oxidized. This small amount of oxidative stress is no problem because homeostasis controls it with an antioxidant process. It happens simultaneously. Just make sure your body has what it needs to produce enough antioxidants and endocannabinoids.

New research confirms that the endocannabinoid system has a direct connection to oxidative stress. Lab rats were injected with toxins at the University of Bialystok, in Poland. The response was a reduction of antioxidants and an increase in oxidative stress and endocannabinoid activity.[xvi] Something hurts the body, antioxidants are depleted, oxidative stress occurs, and the endocannabinoid system is activated to maintain the equilibrium that we call life.

Growing evidence suggests that these two systems “cross-talk” to maintain homeostasis: “Whereas abnormalities in either system may propagate and undermine the stability of both systems, thereby contributing to various pathologies associated with their dysregulation,” according to research published by the University of Dundee, Scotland, in April of 2016.[xvii] That is a profound statement for migraine sufferers, but right now I’m thinking, “Does the University of Dundee have anything to do with Crocodile Dundee, and whatever happened to that guy?”

It’s like this: a healthy endocannabinoid system is needed to control oxidative stress and the control of oxidative stress is required for a healthy endocannabinoid system. Problems in the endocannabinoid system lead to issues with oxidative stress and vice versa. Yin and yang.

What does this mean for migraine sufferers? Migraine sufferers should be aware of all the triggers that increase oxidative stress, all the methods that increase antioxidants, and all the measures that improve the endocannabinoid system. We are dealing with one system that is interconnected.

As we move forward, the endocannabinoid system will explain how hemp heals migraines and at the same time, we will discuss how to improve those results by decreasing oxidative stress and increasing antioxidants. But first, you now have sufficient evidence to buy some hemp, if you haven’t already. Let’s jump into the different options of cannabinoids and the best ways to use them.