Entourage effect and therapeutic CBD: Isolated or in combination with other compounds?

Some countries have begun processes to legalise cannabis extracts, and in cases like Epidiolex in the U.S., those products seem here to stay. Governments generally accept oils with high cannabidiol content (CBD) and a very low level of THC, the psychoactive component of the plant. It is precisely due to this reduction of the element that causes euphoria in the consumer, that many governments have been permissive in showing support for medicinal cannabis as a treatment. However, researchers warn that only using CBD will mean that patients do not obtain all of the therapeutic potential of the cannabinoid, as this appears to be more effective when administered in combination with all the elements in the plant.

Science backs up the effectiveness of the entourage effect

According to various studies, the true potential of cannabis resides in what is known as the "entourage effect", a term coined in 1999 by the Israeli researcher Raphael Mechoulam, who suggested that secondary compounds in cannabis, for example, terpenes, can increase the beneficial effects of THC and thus reduce the anxiety induced by its psychoactivity.

Also, in accordance with the U.S. researcher Ethan B. Russo, a neurologist who has spent a long time studying cannabis compounds and their role on the body, it is possible to take advantage of this entourage effect in order to treat pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungi and different infections. In his 2010 research study "Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects" he outlines how the different cannabis compounds have an impact on the mechanisms of each of them. Several years later, other studies have shown that the effects of cannabinoids are increased or reduced by these secondary effects. Even small quantities of terpenes (fragrant oils that give cannabis its smell) can make a big difference.

According to this term, all of the molecules that comprise the plant, act together in order to function much better from a medical point of view. It has been shown that lots of cannabinoids, ketones, esters, lactones, alcohols, fatty acids, steroids and terpenes (the latter are the "ingredients" that contribute smell and taste to vegetables) have great medicinal potential only when they work together and not when they do so individually. However, they do not always all act at the same time; but rather, they change according to different combinations.

In some way, modifying the way in which they combine, changing "the recipe", will also mean that the effects on the consumer are different. It is essential to understand this chemical variety, to then afterwards, create policies regarding medical cannabis. It is not at all useful to prescribe one or two medicines based on a cannabis compound if these medicines will only be one hundred percent effective on certain people.

Cannabis has a wide range of chemical compounds. Scientists have identified more than 100 cannabinoids and other elements that also have therapeutic and regulating effects and which can all be used, combined to a greater or lesser extent, to treat a number of diseases.

For example, terpenes block some cannabinoid receptors in the brain while they encourage connections between others. So far as anyone knows, it seems that these molecules affect the way that the brain receptors accept THC and CBD, as well as offering their own therapeutic benefits.

Cannabis diversity: it's all in the strain

Each cannabis strain has a different composition, that is, different levels and combinations of cannabinoids, terpenoids, flavonoids and so on. This is why each strain causes a psichoactivity of its own, sativas tending to be cerebral and euphoric while indicas are generally narcotic, sedative and physical.

A terpene such as myrcene can reduce the brain's resistance to generate chemical processes when it is under the influence of cannabinoids. In turn, pinene helps to combat the side effects of THC, so it can be used in the medical sector safely. The combination between several terpenes such as pinene, myrcene, and caryophyllene help to combat anxiety.

The mix between the terpenes linalool and limonene and the cannabinoid CBG helps the treatment of staphylococcus infections. THC combined with CBN strengthens sedative effects. Linalool and limonene, along with CBD, could be used as anti-acne treatments. These are only some of the possible examples of the synergies that could be created between different marijuana compounds and they are only scratching the surface of all the combinations available to us, an endless amount of medical possibilities that could change the lives of millions of people.

In 1985 the United States approved Marinol (dronabinol), a medicine containing pure THC that was devised to alleviate the side effects of chemotherapy. After testing it on patients, though, many of them reported they preferred the plant to Marinol on grounds that the effect of isolated THC was too strong and unpleasant. That was when the medical community began to become aware that other components could have a more important role than what was previously thought.

The entourage effect is a discovery that, although known about for years, has barely been taken into consideration. On the contrary, attention has always been paid to the effects of THC, with many people referring to it in order to criticise cannabis.

Each cannabis strain has a different composition that results in a psychoactivity of its own

Things are not black and white

Medicines based solely on CBD have gradually been gaining momentum over the last few years. Arguably, the so-called "CBD wave" started with the case of Charlotte Fiji, an American girl that suffers from Dravet's syndrome (refractory epilepsy) and who is still alive thanks to a CBD-rich cannabis strain called Charlotte's web. Following an improvement in her condition, the therapeutic properties of CBD started to make the headlines, and bank seeds like Dinafem Seeds engaged in breeding programs for the creation of the cannabidiol-reach strains available on the market today. Progress has been such that we now have different THC/CBD ratios that allow to address every patient's needs. These range from strains like Dinamed Plus CBD, with just 1% THC and up to 20% CBD, to strains with a 1:1 ratio (THC/CBD) like Bubba Kush CBD.

On the other hand, although there are cases like that of Charlotte Figi, other parents claim that CBD oil alone is not helping their children. Brian Wilson, former president of New Jersey, moved to Colorado in 2014 with his son, who suffers from Dravet syndrome. He explains that CBD is a "very important element in the mix, but only a part of it," and adds that he has no real control on the child's crisis until he gives him oil with a little THC, in addition to the CBD. He explains that other people do well with the mixes that do not have a specific ingredient and, therefore, he believes that this type of medicine should be created on an individual basis, as that there is not and should not be a unique and magic recipe for everyone.

But while evidence supports the benefits of the entourage effect, this is not a black and white issue. Because researchers have not yet been able to synthetize and recreate the full spectrum of cannabinoids and other elements in the cannabis plant, it is still not possible to develop a drug that contains them all, aside from the plant itself. This is why cannabinoids are treated separately even if they're not as effective as when combined with other cannabinoid and non-cannabinoid substances - but at least this allows to recreate and standardize them as any other drug.

In cases like that of Epidiolex, the drugs based on a single cannabinoid have proved effective, and are the closest thing to a pharmacological cannabis treatment we have so far. The main problem with using the unprocessed cannabis plant as a treatment is that patients cannot control the cannabinoid dose they take. Hopefully, though, further research and investment will result in better outcomes, allowing to make the therapeutic properties of cannabis available to patients just like any other drug.