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Sensi Magazine

Special Report: Entourage Effect

Jul 25, 2018 05:45PM ● By Leland Rucker

As a pharmacist, she began studying how cannabis compounds seem to work in conjunction with one another, and eventually began to use cannabis as part of her treatment regime. “The reason I got involved is because cannabis is a balancer of the body, a homeostatic regulator,” she says. “As a pharmacist, I approach it scientifically. Holistic medicine has a bad rap—you know, rainbows and unicorns. I approach it as hard science.”

Dr. Van’s studies have led her to subscribe to what is commonly known as the “entourage effect,” the concept that chemical substances in cannabis, especially cannabinoids (like THC and CBD) and terpenes (the oils that give different strains of cannabis their distinctive fragrances) work in concert better than when they are isolated from one another. “The question is,” Van asks, “is the whole plant more beneficial than an isolate? Or do isolates work together with each other?”

This whole-plant concept seems to rub against the way drugs and medications are created today, usually by isolating and testing compounds then developing and patenting drugs from those compounds. And with a scarcity of clinical trials in the United States for anything cannabis-related, many scientists are openly skeptical of most entourage-effect claims.

“The lay public has really taken on the notion of the entourage effect, but there’s not a lot of data,” Margaret Haney, a neurobiologist and cannabis researcher at Columbia University, told Scientific American last year. “The cannabis field can say anything—and it does. I’m not against marijuana. I want to study it carefully. We know it can affect pain and appetite, but the large majority of what’s being said is driven by anecdotal marketing. These guys are really trying to make money.”

Wait, What’s a Cannabinoid?

Most plants contain chemical compounds that are used for everything from defense against animals and other organisms to aiding photosynthesis. Those are called “cannabinoids.” Cannabis has more of them than most other plants, some of which seem to deliver opposing effects in users. And some of which you’ve definitely heard of before, even if you’ve never heard the term “cannabinoid” in your life. THC is a cannabinoid more formally known as delta-9 tetrahydrocannabinol, and it’s the one responsible for the plant’s telltale psychoactive effects. CBD, or cannabidiol, is another, and it’s the “it” ingredient causing a stir in health, wellness, and even beauty and skincare circles thanks to its medicinal properties and healing qualities.

Scientists have identified more than 100 other compounds in the cannabis plant, with more still being discovered—THCA, CBDA, CBN, CBG, CBC, CBL, CBE, and CBT among them.
In 1988, scientists also discovered that the human body has an endocannabinoid system, which works to help keep the body in balance, including basic functions like controlling appetite, sleep, cognition and anxiety. The body produces its own cannabinoids (called endocannabinoids) that are similar to those produced by cannabis; both activate CB-1 receptors found in the brain and CB-2 receptors found throughout the rest of the body.
Brian Reid is chief science officer of ebbu, a cannabis technology research company. Like many of his colleagues, he comes from a pharmaceutical background, and he says that they apply the same basic principles in their research. But the company looks to see how different formulations of cannabinoids and terpenes work to create moods. “Where we differ, instead of looking for a single compound for a target, we work with what Mother Nature gives us,” he says, “but we emphasize polypharmaceutical effects, which is what things do to these targets.”

He says pharmaceutical companies generally isolate a component or look for something specific to target. “CBD alone hits many different targets in different ways. That’s one thing pharmaceutical companies sometimes dial out,” he explains. “Some say the entourage effect is many compounds doing one thing. But in some cases, it’s one compound doing many things.”

Reid says that ebbu researchers use chromatography, a process that separates cannabinoids and terpenes into a kind of soup that allows them to test how different combinations affect receptors. “There are a handful of cannabinoids and terpenes that modulate THC and can increase or decrease its potency.” One example, he says, are serotonin receptors, which help modulate moods and feelings. “We can mimic a profile at serotonin receptors, for instance, that works like antidepressant drugs.”

Van used myrcene, a terpene with a citrusy smell that’s also found in mangoes and other fruits, as another example.

Myrcene has been found to increase the amount of THC the body carries to the brain. Finding the right combination or ratio of myrcene and THC could help people sleep or deal with pain. “This is actually hard science,” she says. “These mechanisms are very old.”

“Some say the entourage effect is many compounds doing one thing. But in some cases, it’s one compound doing many things.”
—Brian Reid, ebbu

Dr. Daniela Vergara, an evolutionary biologist researching cannabis genomics at the University of Colorado, is the director of the Agricultural Genomics Foundation, a nonprofit whose goal is to make cannabis science available to everyone. She says that originally their studies led researchers to believe that cannabinoids like THC and CBD were produced by one gene in different forms. “Now we know that they are different genes in very close proximity,” she says.

In fact, they are so close that they seem to originally come from the same ancestor genes, and that’s what makes the entourage effect argument so compelling. “There is no evidence to support this,” she says, “but what I think is going on is that many molecules are produced by the same gene. The entourage effect is all of these compounds working together to make you feel some way. All of these work in synchronicity because they all come from the same ancestors.”

Though the federal government’s official stance on cannabis is that it’s a substance “with no currently accepted medical use,” it has allowed drugs developed by pharmaceutical companies that use chemicals from the cannabis plant or synthesized versions. Sativex, an oral spray that contains both THC and CBD, is sold by UK-based GW Pharmaceuticals to treat pain and spasticity. Marinol, aka dronabinol, uses synthetic delta-9 THC for treatment of nausea and as an appetite stimulant in cancer patients. And GW Pharmaceuticals is in clinical trials for FDA approval of Epidiolex, a treatment for certain epilepsy conditions.

Sativex, which was brought to market in 2010 and combines THC and CBD, has a pretty good history of success. Marinol, which uses synthetic THC, has a more checkered history. “Many patients have found the side effects unpleasant,” Reid says. “There are a lot of data that people don’t like Marinol. I don’t know how hard that evidence is, but it is documented in patients. It appears that whole-plant extracts provide more benefits.”

Vergara says it’s not unusual for plants to produce compounds, but not as many as cannabis. “We do know that CBD appears to counteract the effects of THC,” she says. “We know it does that, which suggests that when you’re taking pure THC, it’s not as effective.”

Ten Millennia of Cannabis Cures

Humans have been experimenting with marijuana as medicine for a long time now, some say at least 10,000 years. And it has been used over the centuries to ease symptoms for many of the same things it’s been recommended for today. In ancient Greece, it was used for earaches and inflammation. A 1621 English clergyman suggested cannabis as a treatment for depression. After it was brought to France from Egypt, it was acclaimed for headache and pain relief and as a sleep aid. And despite the attitude of some scientists who say there is no evidence to support the entourage effect, research continues to indicate otherwise.

“I think the problem is that some physicians aren’t looking at the hard science of cannabis,” Van says. “They’re not paying attention to the pharmacokinetics, which is how the drug affects you, and pharmacodynamics, which is how your body affects the drug.”

She also points out that there is a lot of research if you just look for it. Recent studies in Israel led by Dr. Ari Aran found dramatic improvements using cannabis for some autistic children, and Lehigh Hospital in Pennsylvania is doing its own trial on autistic children. A study published a few months ago offers encouraging signs for Epidiolex. More than 170 people with Lennox-Gastaut syndrome, a rare type of spasticity, were given Epidiolex or a placebo. The Epidiolex subjects experienced a reduction rate of 41 percent while the placebo only worked 14 percent of the time. Reid says that ebbu scientists have been presenting their findings at conventions and are beginning the process of peer review for their research.

All this talk of the entourage effect as a cannabis phenomenon forgets to mention that it’s not a quality unique to cannabis; it’s somewhat unique to all plants. “What’s the best part of an apple?” Van asks rhetorically. “The skin? The meat? We don’t know. The skin is full of nutrients. The meat is full of sugar and fiber. Even the seeds have nutritional value. I still believe that whole food is the answer. I don’t know what’s the best part.”