Understanding Cannabinoid Receptors: Why Cannabis Affects Humans

Cannabinoids, as well as their cousins terpenes, are simply the chemicals that provide actual relief to patients by inserting themselves into special receptors in the tissues and cells of the human body.
Dec 16, 2015

Many cannabis consumers are familiar with popular cannabinoids like THC and CBD, the therapeutic chemical compounds that provide a wealth of medicinal relief for dozens of conditions involving pain, inflammation, and nausea.They are among more than 480 natural components found within the cannabis plant.

These special receptors are part of what is known as the endocannabinoid system. This mechanism, which helps modulate many bodily functions — including appetite, sleep, anxiety level, and cognition — is intimately tied to the nervous system and immune system. In fact, particular cannabinoids target specific types of receptors located on the surface of cells in different areas of the body.

This targeting is formally called a binding affinity. Some molecules may feature a relatively low binding affinity that offers poor or moderate efficacy for a patient, while other pairings feature a very strong affinity that, when combined with cannabinoids from high-quality plants, can result in superb medical benefit or psychoactive effects.

Endocannabinoid System / Receptors

Readers have already learned that molecules like cannabinoids and terpenes fit into special receptors within the endocannabinoid system, or ECS. A researcher or doctor would say that molecules like THC and CBD activate particular cannabinoid receptors. These receptors, called CB1 and CB2, work like a lock and key when flooded with cannabinoids, such as after a patient smokes, vaporizes, or ingests cannabis flowers, a concentrate, or an edible.

The endocannabinoid system produces its own cannabinoids. This is the reason it exists, actually. Technically, this system is simply being supplemented when a person consumes cannabinoids, terpenes, or other chemicals from an herb like a cannabis plant that happen to bind with the receptors within this system. In 1992, it was discovered that the ECS produces an endocannabinoid within the brain called anandamide. This internal cannabinoid, which was discovered by Dr. Raphael Mechoulam at Hebrew University in Jerusalem, binds to CB1 receptors in the brain and nervous system and, to a lesser extent, CB2 receptors in the immune system. More about this powerful molecule later.

Many medical professionals and researchers have identified a shortage of endocannabinoids as a condition called endocannabinoid deficiency. It is theorized that a deficiency of these molecules — which are increasingly understood to be critical to good health and homeostasis (balance) within humans — may lead to a variety of diseases related to the immune and nervous systems. These conditions often involve inflammation, pain, and nausea, the side effects of diseases, pharmaceutical drugs, and treatments like chemotherapy.

Cannabinoid Receptors: CB1 and CB2

The CB1 receptor was discovered in 1990, while CB2 was uncovered shortly thereafter in 1993 by a research group at Cambridge University. One source claims that these two receptor types employ significantly different signaling mechanisms. It is known that they are expressed in vastly different ways, including their appearance in various parts of the body (different regions of the endocannabinoid system).

The cannabinoid THC has been shown to possess a very high binding affinity with CB1 receptors located throughout the brain, central nervous system, connective tissues, gonads, glands, and related organs. This is one reason that consumption of cannabis strains and plants containing a high amount of THC result in a relatively potent effect, giving patients significant relief from pain, nausea, or depression while delivering a strong euphoria to lifestyle users. Significant efficacy is gained by those undergoing chemotherapy and patients suffering conditions involving inflammation, like arthritis and lupus.

CB2 receptors, on the contrary, are located throughout the immune system and related organs, like the tissues of the spleen, tonsils, and thymus gland. They are also common in the brain, although they do not appear as densely as CB1 sites and are found on different types of cells. CB2 receptors feature a high binding affinity with the cannabinoid CBD (among others).

This means that consumption of cannabis strains high in CBD will deliver a flood of cannabinoids catering to the functionality of that particular receptor type. Unfortunately, strains high in CBD, regardless of their THC content, are still somewhat rare in legal states and nearly nonexistent on the black markets of prohibitionist areas.

CB2 sites are also found in greater concentrations (density) throughout the gastrointestinal system, where they modulate intestinal inflammatory response. This is why sufferers of Crohn’s disease and IBS gain such great relief from cannabis medicine. It is also a powerful example of how the endocannabinoid system, when supplemented by external cannabinoids (such as from cannabis), can provide such powerful and long-lasting relief for patients of diseases like Crohn’s. Cannabis has been shown to have such great efficacy for this condition that, in nearly half of cases, the kind herb puts the disease into full remission.

Beyond binding affinity, the locations, density, and overall number of cannabinoid receptors are collectively labeled their expression. Researchers discuss how different patients, especially those with particular diseases, may have different expressions of CB1 and CB2 receptors than patients who are not afflicted with these conditions (one example is patients suffering from anorexia).

The expression of cannabinoid receptors in a person is akin to a fingerprint or hairline: It is a highly subjective characteristic of that individual resulting in a range of responses to different cannabis medicines. Some patients prefer a sativa like Durban Poison or Kali Mist, while others gravitate toward an indica such as Kosher Kush or Blue Cheese or lock in on a hybrid like Blue Dream or Sour Diesel.

Receptor Expression

One patient may overexpress a receptor like CB1 (meaning they have more receptors than average) and, as a result, be very sensitive to a cannabinoid like THC. Other patients may underexpress a receptor like CB2, meaning they may be less sensitive to the therapeutic effects of a cannabinoid like CBD and may need to consume it in greater quantities or add other cannabinoids and terpenes to the mix, especially those that target other receptors, like CB1.

Receptor expression pertains not only to variations among individuals, but also to the density of a particular type of receptor within a region of the body. For example, a study published in 2010 in the British Journal of Pharmacology provided further evidence that receptors vary in the desnity with which they appear in various parts of the body, mostly the brain, central  nervous system, and immune system.

“CB1 receptors are highly expressed in the central nervous system (CNS), with low to moderate expression in the [peripheral nervous system].”

Receptors can accommodate a variety of molecular structures, so it’s not a situation of CB1 receptors, for example, accommodating only the THC molecule. These molecular parking spots may have a higher binding affinity for THC than most other cannabinoids and terpenes, but other molecules may also bind with this receptor.


According to a 2012 study published in the journal Progress in Neuro-Psychopharmacology and Biological Psychiatry, a single receptor type can recognize and bind with multiple varieties of molecules. Due to the dearth of research that has been conducted regarding the human endocannabinoid system and is interaction with phytocannabinoids from herbs like cannabis, experts and scientists can currently only speculate regarding the complexity and breadth of this system that is so critical for human health — and is present in all mammals (this is why cannabis studies on primates and rodents yield data that can be effectively extrapolated to humans).

Reported the study:

“The complex molecular architecture of each of the cannabinoid receptors allows for a single receptor to recognize multiple classes of compounds and produce an array of distinct downstream effects.”

Patient Benefit

How does a knowledge of the binding affinity of particular cannabinoids to certain types of receptors within the endocannabinoid system aid consumers? First, patients can become educated about how particular cannabinoids and terpenes offer therapy for targeted diseases and ailments. Those who suffer epilepsy, for example, may prefer a high-CBD, low-THC strain that reduces the incidence of seizures in both children and adults but doesn’t provide so much psychoactive effect that it interferes with one’s school, job, or family life. Common THC-to-CBD ratios of commercial products in legal states are 1:1 and 1:20, although experimentation is occurring with many ratios.

The endocannabinoid anandamide, mentioned earlier, not only functions within the ECS to serve a variety of medicinal functions, but also interacts with phytocannabinoids like THC and CBC. Anandamide has been shown to enhance the effects of THC for a variety of conditions, as well as its euphoric effects. This human-produced cannabinoid also interacts with the cannabinoid CBC to do things like fight cancer, particularly colorectal and breast types.


Put simply, the cannabinoid CBC allows more anandamide to remain in a patient’s system because it inhibits its uptake — meaning it basically improves the immune system’s ability to use its own healthy chemicals, such as anandamide, to rid itself of cancer.

Additional Receptors?

Many researches and scientists speculate that other receptors, beyond CB1 and CB2, may easily exist. A detailed understanding about how cannabinoids and terpenes interact with currently unknown receptor types in the endocannabinoid system could potentially result in cannabinoid therapies targeted at particular diseases and conditions. Until this research is conducted, however, those considering cannabis to treat their condition must rely mostly on anecdotal evidence provided by fellow patients.

The 2012 study cited above concluded that additional cannabinoid receptors, which it labels “sites of action,” likely exist.

“However, the discovery of additional sites of action for endocannabinoids, as well as synthetic cannabinoid compounds, suggests the existence of additional cannabinoid receptors.”

Research Needed

Until cannabis is removed from Schedule I of the Controlled Substances Act, which is the federal government’s way of officially and legally declaring it a dangerous and highly addictive drug, the necessary research to improve patient conditions for dozens of diseases and ailments will be lacking. Congress must allow robust medical research of cannabis, cannabinoids, and terpenes — including human trials — to best serve sick patients and some of the most frail and vulnerable members of society.

To put things in perspective, consider that cocaine and methamphetamines are both Schedule II drugs, meaning they are considered less dangerous than cannabis and can be prescribed by a doctor. Meanwhile, bath salts and heroin both share the Schedule I category with pot. Until eager researchers are permitted to study cannabinoid receptors, including how they bind with cannabinoids and some terpenes, patients will continue to suffer.

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