Just looking at a single bud there are small purple and orange flowers, resin that shines in the light, and small compact leafs. Each of these characteristics are consequences of the bud’s chemical makeup and such small differences can significantly alter its therapeutic and recreational effects. While weed is best known for its cannabinoids, THC and CBD, there are hundreds of other organic compounds that give weed its sticky touch, make strains smell different, and contribute to the overall high sensation.  The two main classes of compounds are the cannabinoids and terpenes, and research suggests that the chemicals which span these two categories may work cooperatively to produce different sensations-- this synergy is termed the entourage effect.

The Entourage Effect

The entourage effect was first coined in 1998 by Dr. Ben-Shabat after noticing different cannabinoid effects when THC was isolated or present in a total extract. This term was then expanded upon by Dr. Russo in 2011 when he reviewed hundreds of medically related research articles and exposed startling differences between isolates and total extracts. The basic idea behind the entourage effect is that some benefits of cannabis are only seen when all of the compounds are present, and may have a significantly reduced effect when isolated. One way to think about this is like a diet. To lose weight and maintain proper nutrient levels, you have to eat a certain amount of proteins, carbohydrates, and vitamins. While some diets suggest a higher protein intake, or a higher fiber intake the best results always occur when these levels are thought about collectively because fat accumulation is a response to all macromolecules. It is not different in cannabis. To produce the strongest high or have the best antitumor response, all of the compounds must be accounted for or the entire system is unbalanced. 

What is the Difference Between Isolates and Total Extracts?

The effects of cannabis are attributed to THC and CBD and their interactions in the endocannabinoid system. To enhance the pharmacological effects of these cannabinoids, companies will take the complete bud-- the total extract-- and isolate the individual compounds. At the end of the purification, the scientists would be left with each component of cannabis, and run experiments with the chemicals in isolation. But, to understand how all of the compounds work together in cannabis, they would use the unpurified form that contains the natural chemical mixture.

What are Some of the Other Compounds and What Do they Do?

While THC and CBD are the most widely known compounds in cannabis, there are 58 other cannabinoids and over 300 different chemical entities that may contribute to the overall effect. Some of the other well known compounds include THCA, THCV, CBN, and myrcene

Tetrahydrocannabinolic Acid (THC-A)

Despite being a common precursor in THC synthesis, the effects of THC-A are under studied. In the body, THC-A can be converted to THC and further produce the well-known effects. However, before conversion, THC-A can bind to particular neuroreceptors and has shown to decrease neural inflammation which makes it a potential therapeutic for neurodegenerative diseases.

Tetrahydrocannabivarin (THCV)

THCV has a similar structure to THC, but produces its own psychoactive effects. Users often turn to strains high in THCV to produce an uplifting or energetic high. THCV has also been shown to reduce anxiety, blood sugar levels, and is being used to study type 2 diabetes.

Cannabinol (CBN)

CBN has similar psychoactive properties to CBD, but is found in very scarce amounts, less than 1%, in cannabis. Its main psychoactive property is a strong sedative effect that can help alleviate insomnia.

Myrcene

Myrcene is part of the terpene family that provides cannabis with its earthy scent. While the effects of myrcene in cannabis is contested, it has been shown to increase the presence of THC in the brain to create a stronger high, and lead to a more sedative high. When THC or CBD are isolated from cannabis, all of these botanical compounds are removed. While many of these compounds have overlapping effects, the combinatorial effects (“entourage effect”) can be much more beneficial to the user.

Is the Entourage Effect Medically Relevant?

Scientists have been studying THC and other cannabinoids to understand their therapeutic potential. However, there is emerging evidence that certain benefits may not appear in isolation. Instead, multiple compounds may have to be used to alleviate pain, increase antitumor efficacy, and produce better anticonvulsants. 

Antitumor effect

While there is extensive preclinical and clinical research suggesting cannabinoids alone produce anti-cancer responses, there has been little research studying multiple compound therapeutics. Dr. Sandra Blasco-Benito compared the antitumor effects of pure THC and total botanical extract. The team found that there was a stronger antitumor response in total extract than THC alone which suggests other compounds in cannabis work with cannabinoids to improve the desired response.  

Pain Relief

Since cannabinoids dampen sensory nerves, cannabis has been offered as a therapeutic for patients suffering from chronic pain. Pure CBD has been tested and marketed as the primary source for pain relief in cannabis, but it has limited benefits.  In 2014, Dr. Gallily compared purified CBD with total extract. While CBD alone is a bell shaped curve-- meaning the beneficial effects stops at a particular dosage, Dr. Gallily found that total cannabis extract-- with similar levels of CBD-- had a linear response. This meant pain relief continued to increase with dosage so patients with higher pain could get a stronger response from larger dosages. An effect like this is only found in total extract supporting the idea that the compounds within cannabis work together. 

Anticonvulsants

Cannabinoids reduce the frequency and severity of individuals suffering from constant seizures. To study these benefits at the intersection of the entourage effect, Dr. Berman used five different total extracts and a non-CBD control on epileptic mice.  All five extracts contained the same amount of CBD but differed in trace molecules, such as THC-A, THCV, and myrcene. While all five extracts produced better results than the non-CBD control, each total extract had different ranges of benefits including a survival rate from 85-100%. Although non-psychoactive molecules appear unessential, differences in these trace molecules can lead to a significant difference in survival rates and, in turn, become more favorable therapeutics.