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The entourage effect: Why understanding it is a lifetime’s work

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Imperial College London’s Medical Cannabis Research Group has evaluated existing research surrounding the entourage effect

The entourage effect is one of many buzzwords in the cannabis sector right now but what is it and what could it mean for the medical cannabis landscape? Cannabis Health speaks to one of the leading scientists in the cannabis space, Dr Mikael Sodergren, to find out.

The main components of the cannabis plant, delta-9-tetrahydrocannabinol (simply referred to as THC) and cannabidiol (CBD) are the most well-known and well-researched compounds found in the cannabis plant.

However, the plant contains far more than these two constituents alone. Scientists have discovered hundreds of other active compounds that may play a significant role in the body’s response to cannabis-based medicines.

Scientists around the world are working to understand this phenomenon which could explain why many patients claim to experience heightened benefits from taking extracts containing a broad spectrum of cannabinoids, as opposed to isolated THC or CBD.

The entourage effect, which was first named in 2003, can be confused with a similar occurrence known as ‘synergy’. This is when two or more active compounds produce a combined effect greater than that produced by one compound alone.

The entourage effect differs as it brings inactive compounds into the equation. These chemicals fail to produce an effect on the body when delivered on their own but may enhance the benefits when delivered with an active compound such as THC or CBD.

A recent literature review from Imperial College London’s Medical Cannabis Research Group evaluates the existing research surrounding the entourage effect to inform the university’s ongoing and future work.

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According to Mikael Sodergren, principal investigator of the research group, scientists are only scratching the surface of this complex phenomenon and he hopes the review will help his team carry out “as pure an experiment as possible” as it moves forward with its research.

Dr Mikael Sodergren, principal investigator of Imperial College London’s Medical Cannabis Research Group. Photo: Daniel Jones

“This is a review of what’s available out there in the literature; preclinical data for the most part,” Dr Sodergren tells Cannabis Health.

“We did this to understand the landscape; what experiment models people use and what combination people have used before.

“It lays the context for the work that we have been doing for the last six months to a year.”

The existing data, according to Dr Sodergren, is mixed. The review highlights various research papers that suggest the existence of the entourage effect.

For example, one study comparing the effects of purified cannabinoids and botanical extracts of cannabis suggests that terpenoids could enhance the effects of THC.

Another study, using a rat model of neuropathic pain, found that oral treatment with a cannabis extract containing multiple cannabinoids and other minor components displayed greater efficacy than the cannabinoid given alone.

However, despite this “compelling” data which suggests that the entourage effect is a true phenomenon, there is also contradictory evidence.

Some investigators have published evidence suggesting that delivering certain compounds in combination produces little to no additional benefits.

For instance, a 2019 study examining the entourage effect of six common terpenoids found that the compounds did not alter the function of THC. Other studies came to similar conclusions, in some cases finding that compounds delivered alone had better effects than when delivered in combination.

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One thing is clear; the entourage effect needs much more research, however with over 120 cannabinoids and as many as 200 different terpenes found in the cannabis plant, understanding how these compounds work together is not a simple task.

Dr Sodergren explains: “It’s not easy to set up experimental models in which you can really determine these effects with great accuracy.

“If you were to look at all the different permutations of these cannabinoids (i.e. the different combinations that could lead to a certain effect), you’re faced with a number that you can’t investigate because it’s too high.

“There are millions and millions of different permutations, so it becomes a research project which is longer than a lifetime.”

Dr Sodergren believes that the discovery of new synergistic and entourage effects could play an integral role in personalising cannabis-based medicine for different patients.

“What is it that we need to understand about these medicines in order to refine them to a point where we can not only give maximum benefit to a whole population but more importantly personalise them to certain individuals for whatever biomarker we choose to use?

“For that, we need to understand what all of these compounds do in isolation and in combination, and that is a 50-year global research project.”

With such a complex topic to unpack, the first steps will be answering simple questions about the efficacy of different cannabinoids and how they interact with each other.

As these questions begin to be answered through experimental models and clinical trials, Dr Sodergren believes cannabis medicines could be opened up to a broader range of patients.

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“Once we know the best proportions of cannabinoids for treating pain on a population basis, then we can turn that into more of a pharmaceutical or drug development pipeline, which NICE understands.

“The key to getting everyone access to [medical cannabis] is through science and data. While it is good to hear anecdotally that it works for some people, that’s not how we get everyone in this country treatment.

“It’s through rigorous science, applying that science and clinical practice, and evaluating it. That’s how you get it done, and that’s what we’re doing.”

Epilepsy

CBGA may be ‘more potent’ than CBD against seizures in Dravet syndrome

Dr Lyndsey Anderson said there is more to explore when it comes to creating more treatment options for Dravet syndrome.

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Seizure: A row of test tubes containing CBGA oil with a doctors white gloved hand holding one up to the light

Scientists say they have found the ‘Mother of all cannabinoids’ which may help to reduce seizures in Dravet syndrome.

A new study on mice from the University of Sydney found that three acidic cannabinoids found in cannabis reduced seizures in Dravet syndrome, an intractable form of childhood epilepsy.

The three cannabinoids are cannabigerolic acid (CBGA), cannabidivarinic acid (CBDVA), cannabigerovarinic acid (CBGVA). All three but CBGA in particular “may contribute to the effects of cannabis-based products in childhood epilepsy” noted the researchers and were found to potentially have ‘anticonvulsant properties.”

The study marks the first time that three acidic cannabinoids were found to potentially help reduce seizures for Dravet syndrome.

Speaking with Cannabis Health News, the lead author of the study, Dr Lyndsey Anderson, said: “We found that CBGA exhibited both anticonvulsant and pro-convulsant effects. CBGA was more potent than CBD against febrile seizures in a mouse model of Dravet syndrome. We also found that a combination of CBGA and clobazam was more effective than either treatment alone. Additionally, we found that CBGA was anticonvulsant in the maximal electroshock acute seizure model, a model for generalized tonic-clonic seizures.”

She added: “CBGA did, however, present some proconvulsant effects. The frequency of spontaneous seizures in the mouse model of Dravet syndrome was increased with a high dose of CBGA. Also, CBGA was proconvulsant in the 6-Hz acute seizure model, a model of focal, psychomotor seizures.”

Although CBGA shows promise, Dr Anderson also stressed that it needs more research before it can replace CBD. She cautioned that Dravet syndrome patients may still need to proceed with caution.

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“Artisanal cannabis-based products are believed to reduce seizures in Dravet syndrome patients,” she said. “As these oils contain rare cannabinoids like CBGA, it is possible CBGA then contributes to the anticonvulsant effects of these artisanal cannabis oils. However, there were proconvulsant effects observed with CBGA, suggesting that Dravet syndrome patients may need to proceed with caution. The proconvulsant liability of CBGA would need to be addressed before it replaced CBD as an anticonvulsant.”

What is CBGA?

Sometimes referred to as ‘the mother of all cannabinoids,’ CBGA is the precursor molecule to many different cannabinioids including CBD and THC. It is thought to help some diseases such as colon cancer, metabolic disease and cardiovascular disease. It is a non-intoxicating cannabinoid much like CBD.

Dr Anderson explains that more research is needed to explain how the three cannabinoids work together.

“We don’t know how they work together yet,” she said. “We found that CBGA, CBDVA and CBGVA were all individually anticonvulsant against thermally induced seizures in the mouse model of Dravet syndrome. We did not investigate whether a combination of these three cannabinoids would result in a greater anticonvulsant effect than either cannabinoid alone. Future work will definitely explore this possibility.”  

CBGA future research

This isn’t the end of the research into CBGA for Dravet Syndrome. Dr Anderson said there is more to explore when it comes to creating more treatment options for Dravet syndrome.

 

She said: “Next on the horizon for this research is to explore whether the anticonvulsant properties of CBDVA and CBGVA translate to other seizure types including spontaneous seizures in the mouse model of Dravet syndrome. Additionally, we have extensively interrogated the anticonvulsant potential of individual cannabinoids and identified ten with anticonvulsant properties.”

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“We are now interested in investigating what happens when we combine these anticonvulsant properties. It remains an open possibility that greater anticonvulsant effects are achieved when the cannabinoids are administered in combination.”

The study was recently published in the British Journal of Pharmacology (DOI: 10.1111/bph.15661)

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New York regulators vote to allow home grow for medical cannabis patients

The new regulations would allow medical cannabis patients and carers in the state a safe, cost-effective way to access their medication

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New York: The statue of Liberty against a blue sky and the skyline of New York city

The proposed regulations would allow medical cannabis patients and carers in New York to grow up to six plants, indoors or outdoors, for therapeutic use.

New York cannabis regulators voted unanimously for the proposed regulations which would not only allow qualified patients to grow their own plants.

According to a slide from the Cannabis Control Board presentation, patients would be allowed six plants each but carers with more than one patient,  can “cultivate 1 additional cannabis plant for each subsequent patient.”

The new regulations would impose a duty on patients to ensure no one under the age of 21 can access the plants or any products cultivated from them.

Landlords would also have the option to prohibit their tenants from growing cannabis on their property if they chose. The products must not be processed using anything other than alcohol.

The regulations will now have a 60-day public commentary period before review.

Tremaine Wright, chair of the Cannabis Control Board (CCB) said: “We are proud to present those proposed regulations. The home cultivation of medical cannabis will provide certified patients with a cost-effective means of obtaining cannabis through personal cultivation while creating a set of standards governing the conduct and activities relating to the personal cultivation of cannabis.”

In a press release, the CCB also gave an update on the expungement of cannabis convictions. “Approximately 203,000 cannabis-related charges are presently being suppressed from criminal background searches and are in process of being expunged, adding to the approximately 198,000 records that were expunged as part of the first round of cannabis expungement following legislation enacted in 2019.”

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New York recreational market

Earlier this year, New York. It would become the 16th US state to legalise recreational cannabis creating thousands of jobs and tax revenue. The bill was signed into law by Governor Andrew Cuomo in March.

The law would allow for possession of up to three ounces of marijuana for personal use. It would allow licensed dispensaries to sell cannabis products to those over 21.

Neighbouring states who have already legalised marijuana, including New Jersey and Massachusetts, meant that New York citizens were leaving to access cannabis losing tax revenue in the process.

It is expected that home grow for recreational users will follow the proposed regulations for medical cannabis patients but only after the new market is established.

Read more: California governor signs Ryan’s Law to allow medical cannabis use in hospitals

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CiiTECH announces new CPD-accredited training course

It aims to support and encourage UK pharmacists, physicians and nurses.

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Ciitech academy
The course aims to support and encourage UK pharmacists, physicians and nurses.

Cannabis healthcare company CiiTECH has been awarded CPD accreditation for its academy course, which aims to support and encourage UK pharmacists, physicians and nurses.

CiiTECH’s Cannabis Science and Therapeutics course has had tremendous success after launching the course earlier this year.

The new and innovative course offers an interactive digital platform with a 12 chapter syllabus comprising of medical cannabis, CBD knowledge and information, specifically catered for healthcare professionals in the UK.

Industry experts in the UK could potentially face serious challenges if the trainers in question who are both recommending, and dispensing information are not up to the required standards in the field.

People currently working in the industry, such as pharmacy professionals will feel more secure and confident after taking the course. With such an array of knowledge from the experts, they are better able to recommend, treat and understand benefits and causes of their patients.

Besides all the learning and comprehensive information, simple FAQ questions by patients can be simply downloaded to have at hand as an ongoing reference.

The CBD industry is an extremely fast growing market, people are becoming more and more aware of benefits and common usage. It’s said that by 2025 the market in the UK only will be worth over £3 billion.

This means that clinics and pharmacies must be sourcing trustworthy information to their customers.

This course is aimed at filling an education gap in the market, by covering several points in intricate detail, from plant history to dosing, and patient care. A lot of occupations in the UK require an on going learning process each year, with positive results overtime, leading to a greater service in the industry.

“Through years of experience serving UK customers with our portfolio of CBD brands it was abundantly clear that the level of misinformation was enormous and confusing for everyone involved,” says Clifton Flack, CEO and founder of CiiTECH.

“Formal education is always important but with little to no existence in the UK we could not see a better way to help lead the industry than to establish our own online academy and give healthcare professionals the opportunity to not only learn about cannabis therapeutics but to earn further education points at the same time.”

Flack adds: “With the rise in UK cannabis prescriptions and CiiTECH’s long awaited move into the THC medical cannabis arena, now is the time to increase professional education and it is exactly why we have embarked on this education journey. CiiTECH is fast becoming the UK’s one stop shop for all your cannabis needs; research, education, consumer brands.”

CiiTECH collaborated with Medical Cannabis Mentor to produce the course and prepare it for CPD certification.

Joe Dolce, founder and CEO of Medical Cannabis Mentor, comments: “The course synthesises the most up-to-date scientific research and clinical guidelines in an engaging format to help professionals make informed treatment decisions.”

The course can be found on https://cpduk.co.uk/ or for pricing and registration visit:  https://ciitech.academy

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Cannabis Health is a journalist-led news site. Any views expressed by interviewees or commentators do not reflect our own. All content on this site is intended for educational purposes, please seek professional medical advice if you are concerned about any of the issues raised.

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