In the process of trying to find out why marijuana produces a psychoactive effect, researchers in the 1960s began to figure out a new, all-encompassing aspect the central nervous system, endocrine and limbic (brain) systems called “the endocannabinoid system,” deriving its name from the cannabis sativa plant they were studying.
The scientists figured that humans probably didn’t evolve neuro-receptors just for delta-9 tetrahydrocannabinol or THC, the main psychoactive ingredient in pot. People have been consuming marijuana for almost 5,000 years, but there’s no way there would be enough evolutionary pressure to develop specific receptors just for weed consumption.
Therefore, they theorized, the body must produce its own neurochemicals that are similar to THC that perform some vital function. It wasn’t until the early 1990s that scientists isolated the specific chemicals that make up the endogenous cannabinoid system to confirm the theory.
In confirming that theory, those scientists opened a vast new area of research and opportunity in the medical field. The endocannabinoid system is responsible for a host of vital processes that regulate mood, appetite, healing, memory, sleep, emotion, motor functions and various other functions — functions that go to the very core of what makes us human.
Perhaps the editor of the neuroscience journal Cerebrum said it best in 2013:
“With its complex actions in our immune system, nervous system, and virtually all of the body’s organs, the endocannabinoids are literally a bridge between body and mind.”
How does the endocannabinoid system work?
Half of the endocannabinoid system is a group of specific protein types that form openings in the membranes of mostly nerve cells. Specific types of fat molecules form the other half of the endocannabinoid system, and their function is to fit into the protein openings in the nerve cells, kicking off a cascade of reactions.
Of course, that is a vast simplification, but it’s a good way to understand how not only the endocannabinoid system works, but how the body functions on a molecular level in general. Everything that happens in your body is controlled by a series of keys and locks. When a specific key fits into the right lock, a specific process starts, whether it’s to make your nose run when you breath in pollen, or your stomach secrete acid to digest the pork chop you just ate.
Keys come in the form of messenger chemicals the body releases in response to stimuli. In this case, the “keys,” endocannabinoids, are complex molecules made of fatty acids you get from your diet, especially plant-based fats like coconut oil or olive oil.
Locks come in the form of proteins that sit in the cell membranes to create uniquely shaped openings that only fit a certain kind of key. In the endocannabinoid system, these are called cannabinoid receptors. There are two kinds scientists have identified so far: cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). These are in huge family of proteins called G-protein coupled receptors (GPCR), which include all sorts of different protein-based receptors that handle transmitters throughout the body. Scientists figure there even might be a third kind of cannabinoid receptor in the GPCR family, but whether it exists remains a mystery, as is the nature of the vast majority of GPCRs.
Are endocannabinoids neurotransmitters?
Scientists have only isolated and studied two of the endocannabinoid transmitter chemicals themselves: anandamide (AEA) and 2-arachidonoyl glycerol (2-AG). They are neurotransmitters, meaning they travel between the spaces between neurons (nerve cells) to transmit an impulse along a nerve.
AEA and 2-AG are weird compared with other kinds of neurotransmitters, though.
First, as mentioned earlier, they are fats. Most other neurotransmitter chemicals medical researchers have isolated and studied are made of amino acids or some other water-soluble base. Before the discovery of endocannabinoids and other lipid (fat) signalers, medical researchers didn’t think the brain could work right with loose fat molecules floating around. Cell membranes are made of fat, so fat molecules can pass in and out at any point, which scientists figured would screw up the works on a chemical level.
Weirder still: AEA and 2-AG run backward compared with other neurotransmitters. In nerve fibers — whether in the brain, spinal cord, or elsewhere — neurons are lined up end-to-end so the electrochemical impulse can travel along.
The receiving end of the cell is called the axon and transmitting end is the dendrite. The space in between is called the synapse. In a typical nerve impulse, the dendrite of the neuron receives neurotransmitters from the axon of the previous cell in the chain, which initiates an electrical impulse along the body (soma) of the neuron, which then releases neurotransmitters from the axon of that cell through the synapse to the dendrite of the next cell in the chain and so on.
Endocannabinoids AEA and 2-AG, however, are released from the dendrite and go back toward the axon — the opposite direction of the nerve signal — where they lock into CB receptors to help regulate the flow of other neurotransmitters. An article in the journal Cerebrum described AEA and 2-AG as the “traffic cops” for other neurotransmitters.
Also, because AEA and 2-AG can’t be stored the same way other neurotransmitters (typically made of amino acids) are stored, they are thought to be created on-demand from components floating around in the cell membrane. Because of this, their effects, though powerful and crucial for nerve function, don’t last very long. Once they lock into the CB receptors, they get digested pretty fast.
Recent research, however, has shown that at least AEA can be stored and accumulated in drops of fat in between cells, but scientists have yet to figure out how or why.
What causes the marijuana high?
The main active ingredients in the cannabis sativa plant are delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD), however; there are dozens of cannabinoids in marijuana. These are generally called exocannabinoids or exogenous cannabinoids — “exo” or “exogenous,” means they’re produced outside the body as opposed to “endo” or “endogenous,” meaning they’re produced within the body.
The exogenous cannabinoids produced by cannabis sativa are also known as “phytocannabinoids,” the prefix “phyto” from the Greek for “plant.”
THC is the main psychoactive phytocannabinoid. It fits in the CB1 and CB2 receptors in a similar way to anandamide, but it doesn’t quite stick in the opening right. This means it sort of performs the same function as anandamide, but not 100 percent. This means it’s a “partial agonist” to the CB1 and CB2 receptors.
Because anandamide is crucial to regulating high-order brain function, and the THC hijacks some of its CB1 receptors, a person who consumes THC experiences a shift in his emotions, thoughts, appetite and perceptions.
Cannabidiol does not produce a high; it is a non-psychoactive phytocannabinoid. Cannabidiol interacts with the immune system, pain receptors and other parts of the nervous and endocrine system by mechanisms not well understood, suffice to say this compound seems to have the most medicinal value of all the phytocannabinoids found in the marijuana plant.
But all the phytocannabinoids in marijuana interact to modulate one another, which is why attempts to isolate any specific cannabinoid have met with limited therapeutic success.
For example, chemists isolated THC decades ago for medicinal use in drug called Marinol, which comes in pill form. People report many negative side effects of Marinol (dronabinol), however, including paranoia, anxiety, dizziness, stomachache, vomiting and others.
Researchers theorize that gamut of phytocannabinoids in whole marijuana, when smoked or ingested as edibles produce an “entourage effect” which regulates the total effect of the drug on the body. Again, as with many aspects of the endocannabinoid system, how the entourage effect works is poorly understood.
“The Endocannabinoid System as an Emerging Target of Pharmacotherapy”
P. Pacher, S. Batkai, and G. Kunos
“Cannabinoid Receptors: Where They are and What They do”
“The Endocannabinoid System, Cannabinoids, and Pain”
Perry G. Fine, M.D., Mark J. Rosenfeld, M.S., Ph.D.
Rambam Maimonides Medical Journal
Brain Endocannabinoid System Topic Page
“G Protein Coupled Receptor Structure and Activation”
Brian K. Kobilka
Biochimica et Biophysica Acta
G-Protein Coupled Receptors
Lodish H, Berk A, Zipursky SL, et al.
Molecular Cell Biology. 4th edition.
“Anandamide Compound Summary”
“2-arachidonoylglycerol Compound Summary”
“Cannabidiol Compound Summary”
“THC Delta 9 Compound Summary”
“The case for peripheral CB1 receptor blockade in the treatment of visceral obesity and its cardiometabolic complications”
George Kunos and Joseph Tam
British Journal of Pharmacology
MedTerms Medical Dictionary
“Medical Marijuana (Medical Cannabis)”
Medical Author: Erica Oberg, ND, MPH Medical Editor: John P. Cunha, DO, FACOEP
“Getting High on the Endocannabinoid System”
Bradley E. Alger, Ph.D.
“Fatty Acid Modulation of the Endocannabinoid System and the Effect on Food Intake and Metabolism”
Shaan S. Naughton, Michael L. Mathai, Deanne H. Hryciw, and Andrew J. McAinch
International Journal of Endocrinology
“Evidence for the intracellular accumulation of anandamide in adiposomes”
S. OddiF. FezzaN. PasquarielloC. De SimoneC. RapinoE. DaineseA. Finazzi-AgròM. Maccarrone
Cellular and Molecular Life Sciences
“Lipid Signaling and Synaptic Plasticity”
Nan Sang, Chu Chen