How Plant Compounds Work Together


Back in the early 1960s, a young Israeli medical student clandestinely procured a small amount of marijuana from a friend inside the police department. That one boldly illegal act turned out to be one of the greatest single cannabis transactions in modern history.

“Yes, I broke the law,” said Rafael Mechoulam, the young student who is now a world-famous 87-year-old scientist who has transformed cannabis research. “But I apologized and explained what I was trying to do.”

What Mechoulam was trying to do was figure out what exactly made cannabis psychoactive. His research led him to the discovery in 1963 of cannabidiol (CBD), a major component in the cannabis plant. It was a breakthrough finding, but it was not responsible for the psychoactivity. About a year later, he identified delta-9 tetrahydrocannabinol (THC), the now famous marijuana ingredient that provides the euphoric high. Before 1964, everybody who got high on marijuana had no idea why.

His work in the lab also led to the eventual unearthing of the “entourage effect,” a term coined by Mechoulam in 1988 to describe how all the compounds found in cannabis interact synergistically. Essentially, what Mechoulam and his team of researchers proved is that the whole plant is greater than the sum of its parts.

CBD THC ratio

The entourage effect is key to understanding how cannabis works inside your body and brain.

 According to experts, there are nearly 500 components found in the cannabis plant and less than 15 percent of those components are classified as “cannabinoids” such as CBD and THC. The ratio of CBD to THC varies depending on the strain, with Sativa plants generally having more THC and less CBD while Indica plants have less THC and more CBD. As each of these cannabinoids possess different healing effects, the ratio of CBD to THC entourage effect determines how the plant affects the human body. The other ingredients include amino acids, hydrocarbons, flavonoids, terpenes and a host of other constituents. All of these work in concert to provide therapeutic value.

Here is one simple way to think about it. Taking a vitamin C tablet is good. But eating an entire orange or half a grapefruit is so much better for you. Why? Because of the entourage effect of all the nutrients, fiber, minerals and other compounds found in the fruit.

Terpenes Could Hold the Key to the Future

Aside from cannabinoids, terpenes show the most promise in the advancement of cannabis medicine. “Terpenes are volatile aromatic molecules that evaporate easily and readily announce themselves to the nose,” according to Martin A. Lee, director of Project CBD. “Various researchers have emphasized the pharmacological importance of terpenes, or terpenoids, which form the basis of aromatherapy, a popular holistic healing modality. Marijuana’s compelling fragrance and particular psychoactive flavor are determined by the predominate terpenes.”

Cannabinoids and Terpenes

Terpenes and cannabinoids both increase blood flow, enhance brain activity, and kill respiratory pathogens, among other benefits. According to Dr. Ethan Russo, the synergy between the compounds “could produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections.”

Unfortunately, many marijuana consumers exclusively search for high THC products because of the belief that they have the most band for the buck. True, THC-dense marijuana typically will produce a more potent psychoactive experience. But these folks are missing the bigger picture. Dr. Russo, a Washington psychopharmacologist and cannabis expert, provides this example:

Alpha pinene — a terpene that gives some types of marijuana a distinctive pine aroma —helps preserve a molecule called acetylcholine, which activates memory formation. “So, one main side effect of THC is short-term memory impairment,” Russo says. “People go, ‘Uh … what were you saying?’ That can be prevented if there’s pinene in the cannabis.”

Western medicine practitioners prefer a one-to-one relationship with illness and medication. Isolated treatment works well in synthetic medications. But whole-plant therapies work better using all the ingredients in the herb. A single compound can treat a specific ailment, but cannabis therapy takes advantage of the whole plant to create the entourage effect.

Some cannabis researchers argue that doctors should reject the idea of creating a single potent drug to treat an isolated problem. Instead, they believe that Western medicine should return to a philosophy of treating multiple possible problems with a low dosage of a single, wide-range medication. 

Why We Focus On THC Free Broad Spectrum and Custom Terpene Blends


One of the hot phrases in the cannabis industry right now is the “entourage effect.” Simply put, the thesis is that combining cannabis compounds creates a different physical or psychological impact than a single compound on its own.

While some still question the efficacy of the entourage effect, let me put to bed the question of whether it is real. It is, and there are thousands of data points to back that up.

Before we go further, a little background:

Plants in the Cannabis Sativa L. species, which includes both marijuana and hemp, contain hundreds of different chemical compounds, including cannabinoids and terpenoids, which all interact with the mind and body to various degrees. While two cannabinoids—psychoactive tetrahydrocannabinol (THC) and non-intoxicating cannabidiol (CBD)—have received the most attention among researchers and consumers, more than 100 other cannabinoids have been identified so far. Terpenoids/terpenes, are found in many other plants including spices, herbs, trees and fruits, and are what give cannabis strains their distinctive smells and flavors.

Each cannabinoid and terpene has a specific biochemical effect on the body. The phrase “entourage effect” was first used in the cannabis context in 1998 by a group of scientists that included “the father of cannabis research,” renowned Israeli biochemist Dr. Raphael Mechoulam. More recently, the phrase has been popularized in Dr. Ethan Russo’s 2011 paper Taming THC: Potential Cannabis Synergy and Phytocannabinoid-Terpenoid Entourage Effects, where he investigated the interactions between cannabinoids and terpenes, looking for synergies to treat pain, inflammation, depression, anxiety, addiction, epilepsy, cancer and bacterial infections.

Russo had reported previously in 2008 that: “Good evidence shows that secondary compounds in cannabis may enhance the beneficial effects of THC” as well as reduce THC’s unwelcome side effects. From that, many people have concluded that all of the synergistic effects are beneficial. And from this, they conclude that “full spectrum” oil (the collection of all of the cannabinoids and terpenes from one or more plants) makes for the best cannabis products or cannabis-based medicine. 

So, is full-spectrum oil is always the best solution for cannabis medicine and consumer products? The quick answer is no. Tailored cannabinoid formulations are far more effective and consistent, and will make up a large portion of mainstream adult cannabis consumption in the future.

Over the last three years in our cellular pharmacology lab, we have studied the effects of individual cannabinoids and terpenes on receptor cells, and then measured the activity in those cells when in the presence of a formulation that combines two or more cannabis compounds. Like Mechoulam and Russo, we have found that different combinations result in quantitatively different reactions from the cells. One compound magnifies the effect of another; another compound mitigates the effect of another.

In full-spectrum consumption, different cannabinoids act on several different receptors in the human body at the same time. I call this “chemical chaos.” You are consuming some compounds that are helpful for a condition or achieving a certain state of being, but many of the effects experienced from the whole-plant entourage effect are neither desirable nor necessary. Other cannabinoids can invoke the complete opposite of the desired result. You can try a strain that is “high CBD” or “high THC,” but products infused with whole plants will always be delivered inconsistently because each plant, even from the same strain, has a slightly different combination of compounds. A report in Nature earlier in 2018 found that the cannabinoid content of legal cannabis in Washington state varies systematically across consumer products and even across testing facilities.

Whole-plant consumption effectively throws an unknown and unquantified combination of cannabinoids at every receptor and hopes for the best. It is the ultimate in polypharmacology. The other side of the coin is using a single cannabinoid to target a single receptor like CB-1 (cannabinoid receptor 1) to perform a single activity. This is the approach taken by Big Pharma thus far, ignoring the entourage effect altogether.

Neither extreme is ideal. But between these two poles lies the best way to truly take advantage of the entourage effect: conducting scientific research to determine the best combinations of purified cannabinoids and terpenes to yield known, reliable, consistent effects.

As the body of scientific research grows, a more thorough understanding of the exact synergistic interplay among discrete cannabinoids and terpenes will lead to sophisticated harnessing of the entourage effect. This knowledge will drive the future of cannabis products, developed for specific patient and adult consumer needs and desires.