Basics & Fundamentals

The Endocannabinoid System

If you only learn one thing about why cannabis actually works on humans (and dogs, cats, fish, birds … basically every vertebrate), make it this: the endocannabinoid system (ECS). It’s the reason cannabis isn’t some random alien plant—it’s a plant that speaks your body’s own language.

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What Exactly Is the Endocannabinoid System?

The ECS is a vast signaling network that helps your body maintain homeostasis—i.e., keeps everything in balance when the world throws stress, injury, or change at you.

It has three core parts:

1. Endocannabinoids – tiny signaling molecules your body makes on demand from fats in your cell membranes. The two best-studied:

   • Anandamide (AEA) – nicknamed the “bliss molecule”

   • 2-Arachidonoylglycerol (2-AG)

2. Cannabinoid Receptors

   • CB1 – mostly in the brain, spinal cord, and nerve endings (this is why THC feels psychoactive)

   • CB2 – mostly on immune cells, bones, gut, and skin (this is why CBD is so good for inflammation)

3. Enzymes that build and break down the endocannabinoids

   • FAAH breaks down anandamide

   • MAGL breaks down 2-AG

Think of it like Wi-Fi for your body: the endocannabinoids are the signal, CB1/CB2 are the routers, and the enzymes are the on/off switch.

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When and How Was It Discovered?

Most people think the ECS was found because of cannabis. That’s half-true—it was found because scientists were trying to figure out how THC works.

Timeline:

• 1964 – Raphael Mechoulam (the “grandfather of cannabis research”) in Israel isolates THC for the first time. Mechoulam & Gaoni, J Am Chem Soc, 1964

• 1988 – Bill Devane and Allyn Howlett at St. Louis University discover the first cannabinoid receptor (CB1) in a rat brain using radioactive synthetic THC. Devane et al., Mol Pharmacol, 1988

• 1990 – The first CB1 receptor is cloned (Matsuda et al., Nature, 1990)

• 1992 – Raphael Mechoulam’s lab discovers anandamide, the first endocannabinoid, in pig brains. Devane et al., Science, 1992

• 1993 – CB2 receptor discovered in immune cells (Munro et al., Nature, 1993)

• 1995 – 2-AG discovered (Mechoulam & Sugiura labs)

By the mid-90s scientists realized we didn’t evolve cannabinoid receptors because a plant exists—we evolved them because we make our own cannabinoids. The plant just happens to make analogs that fit the same lock.

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Where Is the ECS and What Does It Actually Do?

It’s literally everywhere:

• Brain & nervous system → mood, pain, memory, appetite, sleep, neuroprotection (Di Marzo et al., Nat Rev Drug Discov, 2015)

• Immune system → turns inflammation up or down as needed (Turcotte et al., Cell Mol Life Sci, 2016)

• Digestive tract → gut motility, appetite, nausea (Sharkey & Wiley, Eur J Pharmacol, 2016)

• Skin → wound healing, oil production, itch (Bíró et al., Trends Pharmacol Sci, 2009)

• Bones → bone formation and resorption (Idris & Ralston, Nat Med, 2010)

• Reproductive system → implantation of embryos, sperm motility (Wang et al., Nat Med, 2006)

• Cardiovascular system → blood pressure regulation (Pacher et al., Pharmacol Rev, 2020)

In short: the ECS is one of the body’s master “tone” systems, like the thermostat that keeps everything from running too hot or too cold.

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Clinical Endocannabinoid Deficiency?

A growing hypothesis (backed by some solid correlational data) is that many hard-to-treat conditions—migraine, fibromyalgia, IBS—may be linked to low endocannabinoid tone. Russo, E.B., “Clinical Endocannabinoid Deficiency Reconsidered,” Cannabis Cannabinoid Res, 2016

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Key Scientific Papers Worth Reading (open access or easy to find)

1. Mechoulam & Parker – “The Endocannabinoid System and the Brain” Annu Rev Psychol, 2013 → Great overview

2. Di Marzo & Piscitelli – “The Endocannabinoid System and Its Modulation by Phytocannabinoids” Nat Rev Neurosci, 2015 → The gold-standard modern review

3. Pacher et al. – “The Endocannabinoid System as an Emerging Target of Pharmacotherapy” Pharmacol Rev, 2020 → 340+ pages of everything we know​

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The Take-Home Message

Your body is quietly making its own cannabis-like molecules every single day to keep you balanced. The plant we call cannabis just happens to produce compounds (THC, CBD, etc.) that can push the same buttons—sometimes gently (CBD), sometimes like mashing the whole control panel (high-dose THC).

That’s why cannabis can feel so “natural” to so many people: it’s not introducing a foreign drug. It’s speaking a language your body already knows.