Entourage effect: Whole plant cannabis medicine

 

Unlike modern day pharmaceuticals that generally have one single active chemical ingredient, whole plant cannabis extractions typically include THC and CBD, and the other cannabinoids, and more than 400 other trace compounds including terpenes, flavonoids, ketones, esters, lactones, alcohols, fatty acids, and steroids. The effects of all these chemicals working together and regulating each other has been discovered to be much different and effective than the effects of any one chemical compound working alone.

 

The term "entourage effect" was first described in 1998 by Israeli scientists S. Ben-Shabat, and Raphael Mechoulam, when they were working on a novel endogenous cannabinoid molecular regulation route. The “entourage effect,” magnifies or enhances the therapeutic benefits of the plant’s individual components so that the medicinal impact of the whole plant is far greater than individual compounds or isolated cannabinoids on their own.(1)

 

While THC has received most of the attention since being discovered in 1964 by Raphael Mechoulam, recent studies have demonstrated that many of the secondary cannabinoids and non-cannabinoid compounds found in the cannabis plant or its extracts interact synergistically to produce the “entourage effect,” and may enhance the beneficial effects of THC, and reduce THC-induced anxiety, cholinergic deficits, and immunosuppression. Dr John McPartland notes: “Cannabis is inherently polypharmaceutical, and synergy arises from interactions between its multiple components.”​(3)

 

More recent studies on the synergistic contributions of cannabidiol (CBD) and the other phytocannabinoids, cannabidn 

(CBDV), cannabigerol (CBG) and cannabichromene (CBC) have also been shown to produce additional effects of therapeutic interest. 

 

Terpenes, the main class of aromatic compounds found in cannabis that are responsible for cannabis’s smell, have also been proven to interact synergistically with cannabinoids to block some cannabinoid receptor sites in the brain while promoting cannabinoid binding in others. Terpenes are believed to affect many aspects of how the brain takes in THC or CBD, while offering various therapeutic benefits of their own. Cannabis terpenoids and flavonoids may also increase cerebral blood flow, enhance cortical activity, kill respiratory pathogens, and provide anti-inflammatory activity. (2) (3)

 

Ethan Russo, in his review of the cannabis terpenoids: limonene, myrcene, α-pinene, linalool, β-caryophyllene, caryophyllene oxide, nerolidol and phytol found: "Terpenoids share a precursor with phytocannabinoids, and are all flavour and fragrance components common to human diets that have been designated Generally Recognized as Safe by the US Food and Drug Administration and other regulatory agencies. Terpenoids are quite potent, and affect animal and even human behaviour when inhaled from ambient air at serum levels in the single digits ng·mL−1. They display unique therapeutic effects that may contribute meaningfully to the entourage effects of cannabis-based medicinal extracts. Particular focus will be placed on phytocannabinoid-terpenoid interactions that could produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including methicillin-resistant Staphylococcus aureus). (4)

 

Here’s how it works: Chemical teamwork

 

The basic idea of the "entourage effect" is that cannabinoids within the cannabis plant work together, or possess synergy, and affect the body in a mechanism similar to the body’s own endocannabinoid system.

 

This theory serves as the foundation for a relatively controversial idea within the pharmacology community, that in certain cases whole plant extractions serve as more effective therapeutic agents in comparison to isolated single compounds or synthetic cannabis.

 

A central principal underlying the use of botanical plant medicines is that herbs contain many active ingredients, and the primary active ingredients may be enhanced by secondary compounds, and act in synergy, producing beneficial effects that are not obtained from single molecule or synthetic drugs, including mitigating the side effects of dominant active ingredients.  

 

Synergy or the "entourage effect" theory has been expanded to apply to cannabis and its non cannabinoid compounds. Wagner and Ulrich-Merzenich, define the four basic mechanisms of whole plant extract synergy as follows:

 

• Ability to minimise adverse side effects.

• Ability to affect multiple targets within the body

• Ability to improve the absorption of active ingredients

• Ability to overcome bacterial defence mechanisms

 

Minimising adverse side effects

 

Some patients especially those new to cannabis, experience increased anxiety and paranoia that is sometimes associated with the use of cannabis. The "entourage effect" allows certain cannabinoids and non cannabinoid compounds to modulate these negative side effects of cannabis. CBD has a proven ability to modulate negative effects of THC, an in minimising the anxiety associated with THC, lowering feelings of paranoia.  

 

Wagner and Ulrich-Merzenich also reported that the secondary compounds found in cannabis enhance the beneficial effects of THC, while the other cannabinoid and non-cannabinoid compounds found in herbal cannabis can reduce THC-induced anxiety, cholinergic deficits, and immunosuppression. Studies also show that cannabis terpenoids and flavonoids may also increase cerebral blood flow, enhance cortical activity, kill respiratory pathogens, and provide anti-inflammatory benefits.

 

This means that there is no such thing as a bad and good cannabinoid, as the THC and CBD and the other cannabinoids don’t compete with one another, but can work in tandem alongside the other compounds found in cannabis to provide effective therapeutic relief for a wide variety of ailments with minimal side effects.   

 

Affecting multiple targets

 

Terpenoids and cannabinoids have been found to both increase blood flow, enhance cortical activity, and kill respiratory pathogens, including MRSA, the antibiotic-resistant bacteria. Dr. Russo’s article reports that cannabinoid-terpenoid interactions “could produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, 

epilepsy, cancer, fungal and bacterial infections.”

 

Many studies have demonstrated the effectiveness of whole plant cannabis as a therapeutic agent to treat a number of symptoms for example muscle spasms tremors, incontenance, and pain associated with multiple sclerosis. A study conducted by Wilkinson and colleagues determined that whole-plant extracts were more effective than THC alone. Researchers compared 1mg THC against a 5mg/kg cannabis extract with the equivalent amount of single compound THC, and found the whole plant extract to have significantly more antispasmodic effect, and attributed this result to the presence of cannabidiol (CBD),  which helps to facilitate the activity of the body’s endocannbinoid system.

 

CBD inhibits adenosine uptake, FAAH (increasing AEA), release of proinflammatory cytokines (TNF-α, IL-6, IL-1β), and acts as an antioxidant and free radical scavenger more potent than Vitamin C or E. 

 

Improving absorption of active ingredients

 

The "entourage effect" can work to improve the absorption of cannabis and cannabis extracts.  The terpene myrcene for exammple possesses sedating, muscle-relaxing, anti-depressant, anti-inflammatory, and analgesic effects amongst other therapeutic benefits, and also has an effect on the permeability of cell membranes, which allows for the absorption of more cannabinoids by brain cells.

 

The skin is made up of two layers, known as a bi-layer, which makes it difficult for very polar molecules like water and cannabioids to pass through, which can also make them difficult for the body to absorb in isolation.  With the assistance of terpenoids like caryophyllene, absorption of cannabinoids can be increased, and therapeutic benefits achieved. 

 

Overcoming Bacterial defense mechanisms

 

The "entourage effect" also accounts for cannabis extracts and non-cannabinoid constituents to be effective in treating various bacterial infections. Cannabis has long been known to contain antibacterial cannabinoids. All of the five major cannabinoids, cannabidiol, cannabichromene, cannabigerol, Delta (9)-tetrahydrocannabinol, and cannabinol have showed potent activity against a number of methicillin-resistant Staphylococcus aureus (MRSA) strains of clinical relevance.

 

While over time bacteria can develop defence mechanisms, resulting in the effects of antibiotics ultimately becoming resistant to therapies which were previously effective, whole-plant cannabis extracts with non-cannabinoid constituents that also have antibacterial properties, have been found to attack bacteria through different pathways to the cannabinoid pathways, limiting the development of bacterial resistance.

 

Studies: Whole plant cannabis medicines v single molecule synthetic cannabis

 

Most animal studies with cannabidiol (CBD) will show that animals will utilise synthetic, single-molecule CBD produced from chemicals in laboratories. However it is important to consider the entourage effect (or lack thereof) when extrapolating data based on animal studies as 100 milligrams of synthetic single-molecule CBD is not equivalent to 100 milligrams of a CBD-rich whole plant cannabis extract.

 

Nicky Taylor, host of the BBC documentary “Should I Smoke Dope?,” participated in a British study that gave patients pure THC intravenously one day, and then a mixture of THC and CBD intravenously a week later.  Nicky was kept blind to which cannabinoid mixture she was given.  The end result was illustrative of the entourage effect. In the video she reported feeling horrible with just THC, “like being at a funeral.” Yet with the THC/CBD mixture she was unable to contain her laughter throughout the session. THC and CBD appeared more beneficial with less adverse effects which has been shown by other studies.   

 

Whole Plant Cannabis v Dronabinol (synthetic THC) 

 

Dronabinol (marketed as Marinol) containing pure synthetic THC was approved by the FDA in 1985 for treating the side effects of chemotherapy. It was also later approved in Australia by the TGA as a Schedule 8 prescription drug. However, many doctors and patients have found Marinol to be a very poor substitute for whole plant cannabis and cannabis extracts. 

 

As CNN’s Dr. Sanjay Gupta explains: “When the drug became available in the mid 1980s, scientists thought it would have the same effect as the whole cannabis plant. But it soon became clear that most patients preferred using the whole plant to taking Marinol. Researchers began to realise that other components, such as CBD and the terpenes might have a larger role than previously realised.”

 

Whole Plant Cannabis v Purified CBD 

 

A groundbreaking study from Israel titled “Overcoming the Bell-Shaped Dose-Response of Cannabidiol by Using Cannabis Extract Enriched in Cannabidiol,” has documented the superior therapeutic properties of whole plant CBD rich cannabis extract compared to synthetic, single-molecule cannabidiol (CBD). Published in the journal Pharmacology & Pharmacy (Feb. 2015), the study directly challenges the pro Big Pharma notion that “crude” botanical preparations are inherently low grade and less effective than pure, single-molecule compounds.

 

 

The pure CBD tests confirmed the findings of earlier preclinical research, that singe-molecule CBD administration generated a bell-shaped dose-response curve with a narrow therapeutic window.  In stark contrast when wholeplant CBD extract was administered, rather than showing a bell-shaped curve, where a therapeutic effect could only be achieved at a certain concentration of pure CBD, the whole plant CBD rich extract "provided a clear correlation between the anti-inflammatory and anti-nociceptive responses and the dose, with increasing responses upon increasing doses, which makes this whole plant medicine ideal for clinical uses.”

 

 

The Israeli researchers also found that a small amount of CBD in the whole plant extract was all that was needed for significant pain relief compared to a much larger amount of the pure CBD that was required to achieve the same analgesic effect.  Whereas the pure, single-molecule CBD precipitated a dramatic drop in efficacy if more than a specific dosage was administered, an “overdose” of whole plant CBD extract did not undermine its therapeutic potency.  When a greater than optimal dose of the CBD extract was administered, its effectiveness leveled off, suggesting that a therapeutic plateau had been reached.

 

 

The Israeli team concluded: “A lot of research has been made to isolate and characterize isolated single constituents of traditional herbal medicine to find their rationale for therapeutic uses. However, our data together with those of others provide legitimation to introduce a new generation of phytopharmaceuticals to treat diseases that have hitherto been treated using synthetic drugs alone. The therapeutic synergy observed with plant extracts results in the requirement for a lower amount of active components, with consequent reduced adverse effects.” (8)