Cannabinoids, Cannabis Research, History of Medicinal Cannabis
What is “The Entourage Effect” and how does it work?
Apr
What is the Entourage Effect?
What is the Entourage Effect? If you have been researching the benefits of Medicinal cannabis for any length of time you are sure to have come across the term “Entourage Effect” It’s one of those terms that can easily be dismissed with a simplistic definition that the the sum of the parts are greater than the benefits of any individual cannabinoid. But is this really the case? In this article we will go into a bit more detail about the entourage effect, where the term originated and the scientific evidence backing it up. We will also look at the main mechanisms by which the entourage effect work in the body.
Who first coined the term “Entourage Effect” ?
It was Aristotle who first made the observation that ‘the whole is more than the sum of its parts’, but in cannabinoid research the”Entourage Effect” was first used by Shimon Ben-Shabat and Raphael Mechoulam back in 1998 when referring to the biological synergy of cannabinoids, terpenoids and other compounds like flavonoids.
They observed that greater biological effect was achieved from the whole plant working synergistically together than single cannabinoids taken in isolation.
Cannabis contains approximately 420 molecules, including 113 cannabinoids, over 200 terpenes, plus flavonoids, amino acids, proteins, enzymes, fatty acids and sugars, with so much activity and potential interactions between molecules it’s no wonder it’s hard to come to any definitive conclusions regarding the effects of medicinal cannabis.
Research has mainly focussed on tetrahydrocannabinol THC and Cannabidiol CBD
Research has mainly focussed on just two of the main cannabinoids Tetrahydrocannabinol (THC) and Cannabidiol (CBD) scientists initially believed they are the ones that contributed to the pharmacological effects of cannabis but as more research has been done it’s clear that it’s much more complex and the fact is we really don’t understand the full mechanisms of why Cannabis works for so many conditions.
When you try and study a single molecule in isolation you miss the important synergistic effects of the whole plant.
Studying Whole Plant Medicine
Cannabis plants contain molecules and compounds that interact synergistically to create what researchers define as an “entourage effect” that amplifies the therapeutic benefits of the cannabis plant’s individual constituents—so that the medicinal benefits of the whole plant is greater than the sum of its parts.
These synergistic effects were further expanded by neurologist and psychopharmacology researcher Dr Ethan Russo in his seminal paper ‘Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects’. He examines the mysterious world of the cannabis plant, outlining the under-explored potential of the plant’s terpenes, which according to Russo “display unique therapeutic effects that may contribute meaningfully to the entourage effects of cannabis-based medicinal extracts”
Only by studying whole plant extractions can we truly see the potential future of the cannabis plant in a medicinal context.
Review of the Scientific Literature
Dr John McPartland and Ethan Russo also reviewed the scientific literature on medical cannabis and ∆ 9 -tetrahydrocannabinol (THC)
According to Dr. John McPartland,
“Cannabis is inherently polypharmaceutical and synergy arises from interactions between its multiple components.”
“A central tenet underlying the use of botanical remedies is that herbs contain many active ingredients. Primary active ingredients may be enhanced by secondary compounds, which act in beneficial synergy. Other herbal constituents may mitigate the side effects of dominant active ingredients.”
“Good evidence shows that secondary compounds in cannabis may enhance the beneficial effects of THC. Other cannabinoid and non-cannabinoid compounds in herbal cannabis or its extracts may reduce THC-induced anxiety, cholinergic deficits, and immunosuppression. Cannabis terpenoids and flavonoids may also increase cerebral blood flow, enhance cortical activity, kill respiratory pathogens, and provide anti-inflammatory activity.”
What mechanisms cause the Entourage Effect
Three main mechanisms occur with regard to the Entourage Effect
Every mechanism falls into one of three possible groups, Note that we use THC as an example to explain the mechanisms, but not every example of the entourage effect necessarily has to involve THC.
- Pharmacokinetic interactions: When another molecule in cannabis impacts the levels of THC (either in the blood or in the brain).
- Direct pharmacodynamic interactions: When another molecule in cannabis modulates the effects of THC by binding to the same receptor.
- Indirect pharmacodynamic interactions: When another molecule in cannabis modulates the effects of THC by binding to a different receptor.
The Therapeutic effects of the primary active ingredients in cannabis may be synergized and enhanced by other compounds working together or the side effects of the primary active ingredients may be mitigated by other compounds.
Many of the compounds like the aromatics terpenes are potent at ambient air levels, they can have an effect on physiology. They can improves the absorption of cannabinoids, overcome bacterial defense mechanisms and minimizes any side effects.
Pharmacokinetics of the Entourage Effect
Pharmacokinetics describes the absorption, distribution, metabolism, and excretion of a drug within the body. There are many examples where a drug can interfere with one of these processes for another drug. This is the most common type of drug-drug interaction.
The interaction between CBD and THC is one example of the pharmacokinetic mechanism. In vitro, CBD can inhibit the human CYP2C9 enzyme, which is one of the primary enzymes to metabolize THC.
Direct Pharmacodynamic Mechanisms of the Entourage Effect
This can be defined as two molecules from cannabis interacting simultaneously at the same receptor. We can classify these effects as antagonistic, additive, or synergistic.
In a 2016 press release, ebbu reported that they found 8 different terpenes that increase the potency of THC at CB1 and 3 other cannabinoids that increase the effect of THC at CB1.
Indirect Pharmacodynamic Mechanisms of the Entourage Effect
By an indirect mechanism, we mean that two cannabis molecules are interacting through two different receptors.
Examples
- CBD & CBD-A reduce anxiety produced by THC through the serotonin system
- CBD reduces psychosis-like effects of THC through the dopamine system
- Myrcene amplifies sedative effects of THC through the GABA system
- Pinene improves THC-induced memory deficits through the acetylcholine system
Mitigating the psychoactive effects of THC
The side effects of the primary active ingredients may be mitigated by other compounds. In whole plant cannabis CBD mitigates the psychoactivity of THC. In synthetic THC compounds like (Marinol) you do not get these beneficial effects. According to Russo “people often discontinue Marinol due to negative side effects”. In whole plant cannabis, CBD works by blocking some cannabinoid receptors that then reduce the paranoia-producing effects of THC.
What amount of THC causes psychotic-like symptoms
According to Ethan Russo, “The biggest influence in the entourage effect is CBD,”
Giving a concrete example he shows that “ About 10 milligrams of THC can potentially cause toxic psychosis—or THC-induced, psychotic-like symptoms such as delusions—in about 40 percent of people,”
Sativex a multiple sclerosis medication made by GW Pharma “has equal amounts of THC and CBD,” In research studies they discovered that “At amounts of 48 milligrams of THC, only four patients out of 250 exposures had this toxic psychosis. So this is a very important demonstration of this synergy,” he goes on to say that other cannabinoids might have similar synergistic effects that have not been studied yet.
The Entourage Effect and Terpenes
Alpha Pinene and memory formation
Another example of mitigation of side effects is alpha pinene—a terpene that gives some cannabis a fresh pine scent
According to Russo, it might help preserve a molecule called acetylcholine, which has been implicated in memory formation. “So one main side effect of THC is short-term memory impairment,”
This is the reason why the leaves of plants high in pinenes have been used since antiquity in traditional medicine to aid in alertness and memory.
Linalool Modulating Glutamate & GABA neurotransmitters
Linalool may also contribute to the entourage effect, modulating the glutamate and GABA neurotransmitter systems to produce sedative and anxiolytic effects
Myrcene synergizes the antibiotic potential of other terpenes
Myrcene is crucial in the formation of all terpenes and it synergizes the antibiotic potential of other terpenes.
Myrcene terpene also has many therapeutic effects as stated in another study done in 2007 that suggested that synergistically with another terpene, thujone, could very well be used in help to fight symptoms of diabetes. Though the study was primarily tested on mice it is a good example of the robust human trials is needed to better identify the efficacy of this terpene and how it may help patients with conditions like diabetes. Myrcene interacting with the following cannabinoids can produce many medicinal benefits:
- CBD + Myrcene: Decreases inflammation, reduces pain, and fights cancer.
- THC + Myrcene: Reduces pain and relaxes muscles; also acts as a sedative and a “hypnotic.”
- CBG + Myrcene: Fights cancer.
Beta Caryophyellene
Beta-caryophyllene, found in black pepper, oregano, cloves, cotton, and other edible herbs, as well as in various cannabis strains and in many green, leafy vegetables. Can be very well used to treat certain ulcers, and offers a great therapeutic compound for inflammatory conditions and autoimmune disorders. Because it binds directly to the peripheral cannabinoid receptor known as CB2, it is gastroprotective and good for other gastrointestinal complications.
Respiratory side effects from inhaling cannabis smoke
Respiratory side effects from inhaling cannabis smoke may be ameliorated by both cannabinoid and non-cannabinoid components in cannabis. For instance, throat irritation may be diminished by anti-inflammatory agents, mutagens in the smoke may be mitigated by antimutagens, and bacterial contaminants in cannabis may be annulled by antibiotic compounds (McPartland and Pruitt 1997).
Further research is needed to prove the Entourage Effect
There is a lack of detailed research on the Entourage effect. Even though there have been double-blind, placebo-controlled clinical trials of both CBD alone and how CBD and THC work together the focus has not necessarily been on the entourage effect.
This means that politicians, legislators and doctors lack the evidence they need to make good decisions when implementing medicinal cannabis programs and fall back to the excuse that there isn’t enough evidence or proof. It’s left up to patients and activists to fund much needed clinical research.
Why is whole plant cannabis not included in clinical trials.
Clinical trials are very expensive to conduct. Most are paid for by pharmaceutical companies who are researching cannabinoids in order to patent their specific cannabinoid analogue.
This tendency for single cannabinoid research is further compounded by a lack of incentive for drug companies to invest millions into researching something that is still considered a Schedule 1 controlled substance, is impossible to patent, and will bring very little financial return.
Cannabis consists of natural compounds and so many companies are not interested in researching them as they cannot patent compounds that are found in nature and belong to humankind. This is also a big disincentive to investors who may be funding clinical research
Double blind clinical trials and whole plant cannabis
Evidence based medicine operates by the principle that you can only show a direct effect instead of an association if you conduct a properly controlled scientific experiment using two populations. One group taking the medication you want to test and the other taking a placebo.
Almost all double blind clinical trials have not included whole plant cannabis, so any doctor or government agency looking into the benefits of cannabis, trying to work out how to prescribe it or create regulations for it will make their conclusions based on scientific work that has omitted and avoided to test the whole plant.
Investigation into the anti-cancer properties of cannabis and individual cannabinoids
Jeff Ditchfield, founder of Bud Buddies, the non-for-profit organisation that supplies cannabis products to the seriously ill, decided to take action when he saw that there was no impetus to study the effectiveness of whole plant extracts when treating cannabis.
Through a crowdfunding campaign Jeff raised over €35,750 for a study to be carried out at Madrid Complutense University under Dr Manuel Guzmán, Guillermo Velasco and Cristina Sanchez.
The purpose of the study is to “investigate the anti-cancer properties of cannabis and individual cannabinoids, seeking to establish the most effective cannabinoid or combination of cannabinoids. We will also investigate whether whole plant extracts or individual cannabinoids are more effective at treating breast cancer and glioma cell types than individual cannabinoids”.
Israeli clinical research into cannabis and autism
In Israel, home to some of the most ground breaking research into medical marijuana and cannabinoid science, a mother of an autistic son is campaigning to raise funds for the first ever clinical trial into autism and cannabis.
The trial conducted by Adi Aran, has already been approved, but Abigail Dar, mum to 23 year old Yuval, is raising money for more whole plant strains to be included in the study, as she has seen first hand how single cannabinoids are less effective with autistic children.
Abigail says: “It’s going to be the first clinical research about cannabis and autism. And it must work because if they gave clean CBD or isolated cannabinoids, and it didn’t work for autism, it would be devastating. It would be devastating because people wouldn’t bother to read exactly what they gave. They would just read cannabis doesn’t work for autistic people”.
References:
1: Ethan B Russo Br J Pharmacol. 2011 Aug; 163(7): 1344–1364.
Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects’
2: Lester Grinspoon International Journal of Drug Policy Volume 12, Issues 5–6, 1 November 2001, Pages 377-383
On the pharmaceuticalization of marijuana
3: McPartland, John & Russo, Ethan. (2001). J Cannabis Therapeutics. 1. 103-132. 10.1300/J175v01n03_08.
Cannabis and cannabis extracts: Greater than the sum of their parts?
4: Schizophr Res. 2011 Aug;130(1-3):216-21. doi: 10.1016/j.schres.2011.04.017. Epub 2011 May 17.
Cannabis with high cannabidiol content is associated with fewer psychotic experiences.
5: Br J Pharmacol. 2007 Mar;150(5):613-23. Epub 2007 Jan 22.
Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro.
6: Scientific American
Some of the Parts: Is Marijuana’s “Entourage Effect” Scientifically Valid?
7: Shimon Ben-Shabat, Raphael Mechoulam Eur J Pharmacol. 1998 Jul 17;353(1):23-31.
An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity.
8: 3 Mechanisms Of The Cannabis Entourage Effect
10. Eur J Pain. 2014 Aug;18(7):999-1012. doi: 10.1002/j.1532-2149.2013.00445.x. Epub 2014 Jan 13.
A double-blind, randomized, placebo-controlled, parallel group study of THC/CBD spray in peripheral neuropathic pain treatment.
11. Karniol IG Eur J Pharmacol. 1974 Sep;28(1):172-7.
Cannabidiol interferes with the effects of delta 9 – tetrahydrocannabinol in man.
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