The Entourage Effect in Cannabis

What is the first thing that comes to mind when you hear the words “cannabis,” “weed,” or “marijuana”? For many people, the most immediate association will be to the THC molecule.

One of the most well-known acronyms on the planet, THC is basically synonymous with being high. It’s the main active ingredient in cannabis plants, and strains with high levels of it tend to make recreational users quite enthusiastic.

Although THC usually takes the spotlight, there is a reason cannabis use is so wildly popular beyond its recreational aspect. Over the last few years, another active molecule called CBD has also been making a name for itself due to its medicinal properties.

Other than these two, cannabis plants boast a plethora of active compounds with an astounding array of effects, both on the mind and body. Their functional diversity and mutual interactions are known as the “entourage effect.”

What is the Entourage Effect?

The entourage effect has been studied for some time in cannabis, as well as in other psychoactives such as magic mushrooms. Also known as the “ensemble” effect, it’s the phenomenon of combinations of compounds causing unique effects – more so than just the sum of their parts.

The two main compounds in cannabis plants, THC (Δ9-tetrahydrocannabinol) and CBD (cannabidiol), are both cannabinoids; they bind to cannabinoid receptors in the brain, mainly the CB₁ and CB₂ receptors. The action of THC and CBD on these receptors produces quite distinct effects, however, that also appear to synergize when ingested together.

Aside from these two, cannabis plants host a variety of other cannabinoids plus an array of completely different chemicals called terpenes. To get an idea of how this consortium of compounds interacts, we need to understand how each molecule affects us individually.

Effects of THC

THC carries out most of the psychoactive function of cannabis. It mimics the action of an endogenous ligand called anandamide, causing changes in the levels of neurotransmitters such as dopamine and norepinephrine. This leads to the two main psychological effects of THC – euphoria and anxiety.

The euphoria manifests in many ways: as a positive change in mood, humor, excitement about concepts and details, appreciation for art, and heightened sensitivity to stimulation, to name a few. It is likely the main reason so many people consume cannabis recreationally.

On the flipside, however, we have anxiety. It is the most commonly reported side effect of smoking cannabis, but cannabis is also consumed to reduce it in people who suffer from anxiety disorders. A likely explanation comes from the correlation of anxiety levels and the amount of THC ingested. This research by Dr Susan Stoner at the University of Washington reports that at low dosages, THC reduces anxiety, while at high dosages, it increases it.

These psychological effects go hand in hand with the physiological ones. Cannabinoid receptors can be found all over the cardiovascular system, including the heart muscle and in the walls of blood vessels. It appears that higher doses of THC cause it to mainly activate CB₁ receptors, creating a net negative impact on the cardiovascular system. Because THC lowers blood pressure, the heart has to work up to 30% harder in order to compensate.

Effects of CBD

The “younger brother” of THC, CBD has been rapidly gaining popularity as a therapeutic compound among individuals suffering from medical and psychological issues. Its concentrations in cannabis flowers are commonly quite low due to decades of cross-breeding for recreational use which favored THC content. However, hemp plants have not been modified for this purpose, so CBD is normally extracted from them.

As it’s non-psychotropic, the heavy regulations governing possession and use of THC don’t apply to CBD, meaning that research into its effects is also less restricted. A wave of studies conducted over the last few decades indicate that this cannabinoid can help manage chronic pain and inflammation, anxiety, insomnia, tobacco addiction, opioid dependency, cardiovascular disease risk and recovery, epilepsy, psychosis, and even cancer. Seems like quite a powerful substance indeed.

However, that’s not all it can do. When ingested together with THC, CBD seems to actually balance out the experience by diminishing the psychotropic side-effects of THC’s functioning. Researcher Adie Wilson-Poe states: “We specifically see that CBD protects against the paranoia and anxiety and the racing heart that THC produces.” This is an important part of the entourage effect of cannabis.

CBD appears to do this partly by blocking out some of the CB₁ receptors so THC doesn’t activate them as strongly. But CBD has a diverse mechanism of action, and it’s possible that its effects on other receptors also contribute to its anxiolytic function.

As Wilson-Poe explains, “CBD has at least 14 distinct mechanisms of action in the central nervous system […] it does a little bit of something at a whole bunch of places, and we probably can’t attribute the anti-paranoia or anti-anxiety effects just to CB₁ occupancy.” This THC/CBD entourage effect has been demonstrated by a study that showed, in terms of anxiety, a much better tolerance to the amalgam of the two compounds than to THC alone.

Other Cannabinoids

Aside from THC and CBD, there are numerous other cannabinoids present usually in trace amounts in different strains of cannabis grown worldwide. They include CBN (cannabinol), CBG (cannabigerol), CBC (cannabichromene), CBL (cannabicyclol), CBV (cannabivarin), and their combinations and derivatives.

Although these compounds haven’t received gratuitous scientific attention, we are familiar with some basic aspects of their functioning. They are either mildly psychoactive or non-psychoactive, and some seem to reduce the psychoactivity of THC in much the same way CBD does, by blocking off some of the CB₁ receptors. It’s also fair to say that they likely exert their own entourage effects on THC, but due to their miniscule concentrations, these are hard to pinpoint and understand.

One of the more interesting compounds of the bunch is CBC. This cannabinoid binds poorly to CB₁ receptors, but has an affinity for other receptors such as TRPV₁ and TRPA₁. Binding to these receptors triggers a release of natural endocannabinoids such as anandamide and keeps them active in the bloodstream for a longer time. The effects are therapeutic, helping with pain management and inflammation, and are even potentially anti-cancerous.

Another potentially relevant compound is a very recent addition to the lineup of known cannabinoids–THCP (Δ9-tetrahydrocannabiphorol). Isolated recently and serendipitously by a team of Italian researchers, this molecule is apparently many times more potent than THC. Its synergistic effects with CBD will probably be discovered as we delve deeper into understanding cannabinoids. The discovery of THCP after decades of studying the cannabis plant only tells us about how much more there is to learn.

Terpenes

And now for a completely different category of compounds found in cannabis–terpenes. These molecules are spread throughout the Earth’s flora; they are responsible for the aromas emitted by many plant species. And, while they are mostly thought of in these terms as far as cannabis goes too, science shows that their function goes beyond the mere fragrances marijuana aficionados can admire.

About 100 different base terpenes and many more variations have been discovered in cannabis so far. Their concentrations and proportions will influence the specific scent that every strain boasts, but they also add to the strains’ unique “characters.” A THC-only high is generally considered unspecific; terpenes are considered to be partly responsible for modulating the effect of THC and creating distinct psychoactive effects.

A few of the main terpenes include limonene, myrcene, pinene, caryophyllene, linalool, eucalyptol, terpineol, and borneol. On their own, these substances can act as antifungal, antibacterial, and anti-carcinogenic agents, sedatives, gastric regulators, immune system stimulators, energy boosters, and focus enhancers, just to name a few functions. It is quite possible that their entourage effects reflect these features too.

Is the Entourage Effect Real?

All things considered, we still don’t have a full understanding of the entourage effect in cannabis. The reality is that science has so far not devoted significant attention to examining the properties of cannabinoids and terpenes and, crucially, their potential synergies. Only in the last decade have we been starting to see an emergence of interest in these “other” compounds, with the entourage effect still remaining a novel idea.

A classic study that is mostly credited for bringing the cannabis entourage effect to the eye of the scientific community is Ethan Russo’s 2011 extensive publication ‘Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects.’ In this paper, Russo describes the chemical basis for synergies between THC and CBD, and the purported synergies of various terpenes with these cannabinoids.

Just a few interesting potential entourage effects he details include:

• The interaction between THC and pinene, wherein the latter may help better retain memory while under the effect due to the increase in acetylcholine levels that it counters THC’s effect with; 
• A combination of CBD and caryophyllene, both of which have been found to be effective in battling addiction;
• The interaction of CBD, linalool, and limonene, which all have anxiolytic properties and may work together to create a highly potent potion against anxiety.

Of course, as we’ve seen, these chemical interactions are usually not just a matter of adding the compounds to each other, as they can have complex and conflicting mechanisms of action. This is why it’s important that more research be done into the entourage effect in cannabis.

The Future of the “Other” Compounds

If the cannabis entourage effect gets further scientific validation and once the interactions of cannabinoids and terpenes are better understood, we can set out on a path of leveraging the healing powers of these compounds for creating more effective, less harmful, and highly personalized medicine. While some medicinal cannabis users can now find certain strains that are better suited to treating their issues, the hope for the future is that everyone will have access to exactly the cannabis compound cocktail they need.

Some pharmaceutical companies are already hard at work making that future a reality. They are analyzing vast amounts of cannabis genomic data in hopes that they can detect the genetic markers associated with the chemical data and patient outcomes. And, while there is also some pushback to this emerging field, viewed by some as not much more than an attempt to capitalize in the booming green industry, it’s clear that cannabis is more than just THC and CBD, and that the remaining substances have their distinct and potentially therapeutic biological properties and interactions.

All that’s left is for the science to catch up and show just how much the sum of the parts and the whole differ.