Better Together - The Entourage Effect in Medical Cannabis
Anastasiia Myronenko is a Medical Physicist actively practicing in one of the leading cancer centers in Kyiv, Ukraine. She received her master’s degree in Medical Physics at Karazin Kharkiv National University and completed Biological Physics internship at GSI Helmholtz Centre for Heavy Ion Research, Germany. Anastasiia Myronenko specializes in radiation therapy and is a fellow of Ukrainian Association of Medical Physicists.
What don’t we know about medicinal cannabis?
To answer this question as briefly as possible - a lot.
A great number of studies has been held to investigate the potential therapeutic benefits of cannabis and its most promising components - cannabinoids. However, there is still a lack of research, human trials, and scientific evidence regarding the effectiveness of cannabinoids and their ability to compete with traditional medications.
Nevertheless, scientists from all over the world predict a great future for cannabis and state that information which is available for us today is just the tip of an iceberg. A wide range of other health benefits of cannabis and its compounds still remain hidden from us, though according to cannabis experts, it is just a question of time. Today, a lot of questions regarding medicinal cannabis remain unanswered, but the knowledge we have has already shaken global medicine and continues its growth and development.
As for perspectives for cannabis compounds, CBD (cannabidiol) and THC (tetrahydrocannabinol) remain the two leaders among more than a hundred different compounds found in the cannabis plant.
These cannabinoids have manifested their effectiveness and therapeutic properties in a range of successful studies, while the growing number of anecdotal evidence from patients continues to build on CBD and THC reputation. The global market of CBD- and THC-based products have gained popularity in wellness and health and is predicted to reach the mark of $24 billion in 2027. What makes this interesting is that, despite the current regulatory issues and a lack of clinical studies, the growth of the cannabis market remains steady. This means that people are ready to accept such changes and look at their treatment from a completely different point of view.
The research investigating cannabis properties and safety of its use is ongoing. Successful results of the studies confirm claimed health benefits of cannabinoids, which in turn, lead to more in-depth research and new opportunities of the cannabis use for medicinal purposes. As a result of successful randomised clinical trials, a cannabis-based pharmaceutical product called Epideolex has got approval from the FDA. The convincing evidence was obtained that pure cannabidiol extracted from the cannabis plant can be effective in reducing seizures in two specific types of epilepsy, Dravet syndrome and Lennox-Gastaut syndrome (LGS). Currently, Epidiolex is under review by the European Medicines Agency (EMA). Besides rare forms of epilepsy, CBD also has the potential to help other epilepsy patients. Moreover, CBD has not stopped at the treatment of epilepsy patients and also shown its benefits for the range of other diseases and conditions.
Multiple sclerosis (MS) is one of the debilitating diseases of the central nervous system. The main reason for the occurrence of this condition is that our immune system starts mistakenly attacking myelin - a special protective layer covering our nerve fibres. Such an attack leads to inflammation, scar tissue, and lesions. As a result, it significantly complicates the transmission of signals from our brain to the rest of the body. Multiple sclerosis remains one of the hot issues nowadays as the number of cases continues growing. Among the countries with the highest prevalence of multiple sclerosis are Canada, Denmark, San Marino, and Sweden. To date, this disease is treated with disease-modifying therapies (DMTs) that are aimed at slowing the multiple sclerosis progression and lowering the relapse rate. However, it was also assumed that CBD could be used to treat multiple sclerosis symptoms and be beneficial for MS patients, along with other medications. This assumption is backed up with the positive results of several controlled scientific studies which have shown the ability of CBD to be effective in treating the symptom of spasticity in patients with multiple sclerosis diagnosis. In some European countries, a medication called Sativex is approved for multiple sclerosis spasticity. Sativex (a.k.a. Nabiximol) contains THC and CBD in its composition and is commercialised in the following countries:
In particular, the UK and Canada were the first counties to make Sativex commercially available.
Today, this drug can be prescribed to MS patients, whose symptoms cannot be relieved by traditional pharmaceuticals. As there are still no multiple sclerosis treatments capable of curing the disease, and many patients wish to avoid intoxicating effects of THC, a growing number of people with MS diagnosis turn to alternative treatments in addition to their current medical programme. Many chose diets and exercise, massage, meditation, acupuncture and tai chi. Nevertheless, CBD alone can also be used to alleviate such common multiple sclerosis symptoms as pain, fatigue, muscle spasticity, and depression, thereby significantly increasing overall patient mobility without providing any psychoactive effects.
However, it is a proven fact that without THC, the effectiveness of CBD is reduced, and the reason for this is the mysterious entourage effect which we will discuss later in this review. It was also concluded that the addition of low doses of THC to a combination drug could help to get the optimal benefit from the treatment for many MS patients. Today, patients undergoing the MS treatment routinely choose EleCeed - a product containing an equal ratio of CBD to THC and several other non-psychoactive cannabinoids to alleviate the symptoms and improve outcomes.
Autism prevalence rates keep rising worldwide. For the period from the 1970s when autism prevalence was one case for 10 000 people, to 2018 when these numbers have grown to one case in 59 children, a lot of things have changed but not in the autism treatment. Currently, research is ongoing to confirm or refute the claim that medical cannabis, cannabidiol, in particular, can be effective in alleviating the symptoms of patients with autism. There is a large number of anecdotal cases regarding CBD use for autism symptoms claiming that even very disabled patients become more interactive after cannabidiol use. As for a more scientifically confirmed approach, results obtained in a range of clinical trials vary from encouraging to inconsistent and additional studies are needed to make a final conclusion. For example, in one of the studies, 53 children received 600mg cannabidiol daily in addition to their treatment for two months. Results of the study showed that:
- 71.4% of patients had less sleep problems
- 47.1% of patients felt reduced anxiety
- hyperactivity symptoms improved in 68.4% of patients
- 67.6% of patients had less self-injury and rage attacks
In another study, held in 2019, behavioural outbreaks of children with autism were improved or much improved in 61% of patients taking CBD. These results are very promising, although additional research and studies should be performed to evaluate CBD benefits for autism and determine the potential risks of long-term CBD treatment. Another thing that should be determined is the role of low dose THC in autism treatment with medicinal cannabis.
Although researchers state they didn’t find promising conclusions, anecdotal evidence continues showing us that patients behaviour improves after treatment with CBD. All the observations of patients with autism who include CBD in their daily treatment are registered and monitored on a long term basis. CBD-based medications such as EleCeed, TheraCeed, and ClaraCeed enable researchers to compare the impact of both format and formulation adjustments on the most common symptoms across autism patients. The primary goal of collecting and analysing these data is to maximise the potential benefit of cannabinoid-based medications as well as to provide caregivers with additional supporting insights.
Today you can find a lot of claims that a few sips of CBD-enhanced coffee or a couple of CBD gummies can significantly decrease your everyday anxiety, although, let’s consider more scientifically-proven facts.
Despite a constantly growing number of statements, most of which don't give us anything that looks like promising effects, there is scientific data which demonstrates us that cannabidiol can treat anxiety disorders as well as general social anxiety.
The effects provided by CBD differ significantly from those of THC, which have been reported to increase anxiety levels in some patients. Results of CBD use for reducing anxiety also differ from most of the prescription anti-anxiety medications, which usually result in minor to moderate amounts of sedation and euphoria. In a range of studies, while taking at doses ranging from 300mg to 600mg, CBD has demonstrated its ability to reduce experimentally induced anxiety in healthy control groups as well as to reduce anxiety in patients with a social anxiety disorder. Although there is another fact which will make you look at most ad campaigns with different eyes - cannabidiol was not found to affect baseline anxiety levels.
What does it mean for us - ordinary consumers?
First of all, it means that while CBD may be effective for people suffering from anxiety disorders, it has not been proven to help individuals with everyday life stresses. Nevertheless, medical cannabis research and the relationship between CBD and anxiety is ongoing, so everything can change. Anyway, it is highly recommended to be guided not only by advertising when choosing CBD for your particular purposes.
CBD and THC are often perceived as a single whole, which is able to treat and alleviate a wide number of illnesses and conditions. However, their action on our organism, and, respectively, the effects these cannabinoids provide differs significantly.
One of the examples of such a difference between two popular cannabinoids is their impact on our mental health. Although high-THC products have been claimed to increase the risk of occurrence of bipolar disorders and psychotic breaks, CBD, vice versa, has been found to be an effective agent in treating schizophrenia.
In studies investigating this cannabidiol ability, the first group of schizophrenia patients were given 800mg CBD per day for four weeks, the second group continued treatment with common antipsychotic medications, and the third group was taking placebo. Results of the research have shown similar improvements in positive and negative schizophrenia symptoms in both groups of patients confirming the claimed CBD effectiveness in this disease treatment. Also, both cannabidiol and antipsychotic drugs demonstrated significantly higher effectiveness in alleviating the schizophrenia symptoms than placebo. In addition to this, CBD has shown significantly less side effects in comparison with amisulpride - an antipsychotic drug which is commonly used for schizophrenia patients treatment. The effectiveness of this cannabinoid together with its maximally reduced risk for patients’ health suggest it could be a preferred method in alleviating the symptoms of schizophrenia disease and its treatment to some pharmaceutical medications with more serious adverse effects.
Currently, research is ongoing to investigate whether the addition of the high-dose CBD to the usual schizophrenia treatment could be beneficial to patients. Nowadays, up to 0.7% of all people worldwide live with a schizophrenia diagnosis. The appearance of a new, more natural drug with effects similar to pharmaceutical medications may significantly improve the wellbeing of these patients, reduce the risk of the disease progression, and improve the most debilitating symptoms of this condition
The ability to reduce both acute and chronic types of inflammation is the trump card of CBD. CBD has potent anti-inflammatory effects when taken orally or topically.
This ability of the cannabinoid was confirmed in a number of studies and trials, showing evidence for CBD’s potential to alleviate inflammation associated with rheumatoid arthritis, colitis, pulmonary inflammation and neuroinflammation. Animal studies investigating the cannabidiol’s effects on arthritis have shown the ability of CBD to reduce inflammation in a rat model. Although the results obtained in a range of studies are promising, additional robust studies on humans are needed to demonstrate the CBD’s effectiveness in the inflammation treatment. Nevertheless, even with the lack of human trials, there are numerous anecdotal cases of cannabidiol’s successful use for different inflammation types. The ability of CBD to reduce inflammation sounds especially promising when it comes to cases when patients need to take opioids for their condition. Opioid crisis remains a problem of a global scale, and there aren’t still any medications which would be able to substitute opioid drugs. Currently, cannabidiol is actively studying as an active agent, which would be able if not substitute opioids completely but at least be prescribed as a part of opioid treatment, thereby significantly reducing the adverse effects of these medications and reduce opioid addiction. For example, for patients with peripheral neuropathy - a condition which involves severe pain in the nerves of limbs, inflammation plays a key role. Most of the patients with this diagnosis are prescribed opioids to control their pain, although medical cannabis has been claimed to be a better alternative. One of the studies investigating this question demonstrated that 62% of patients with peripheral neuropathy decreased their opioid use or even stopped it while taking low-CBD medications.
Today, more and more studies reveal new properties of medicinal cannabis and evaluate its potential use of different conditions starting from anxiety and depression to diseases of a global scale, such as cancer, multiple sclerosis, and rheumatoid arthritis. Some of you may say we already know everything about this plant and there is no reason to continue investigating any other of its properties, although scientists and cannabis experts would argue with such a statement.
There are still a lot of unanswered questions about cannabinoids, and the main “mystery” of beneficial effects of the cannabis plant on our health is how its components interact with each other.
The mysterious entourage effect
How do CBD and THC work together, and can this affect cannabis efficiency?
The entourage effect remains one of the main secrets of the cannabis plant and continues haunting the minds of cannabis researchers all over the globe. The essence of this effect is that the potent therapeutic cannabis effects are a result of the complex interplay between its chemical constituents.
How do they interact with each other and can cannabis owe their unique benefits to the entourage effect? Let’s try to figure it out.
The title of “father of entourage effect” belongs to Raphael Mechoulam - cannabis chemist from Israel. This scientist is world known as the foremost innovator and pioneer of medicinal cannabis research. The term “entourage effect” coined by Raphael Mechoulam describes the way how different compounds of the cannabis plant synergise to influence a wide variety of diseases and conditions in our body. Moreover, the entourage effect implies that cannabis compounds work better together than in isolation. The Mechoulam’s findings were published in 1998, in a study, where Raphael Mechoulam with his team of researchers described the complicated ways in which different components of the cannabis plant seem to work as a single whole to give this plant its unique health benefits.
Today, the therapeutic effectiveness of a variety of cannabinoids was confirmed scientifically. For example, THC is renowned for its ability to reduce nausea, stimulate appetite, and more. Not so long ago, a pharmaceutical drug Marinol made from synthetic THC got approval from the FDA and became officially available for purchase. While this medication is widely used by many patients, a range of studies has shown that its effectiveness differs from the effects of cannabis flower. In contrast to regular cannabis, Marinol drug contains Dronabinol - a synthetic compound created to mimic the THC effects. This medication is approved in the US and is used to alleviate nausea and vomiting in cancer patients undergoing chemotherapy, as well as to treat wasting syndrome in patients with HIV/AIDS diagnosis.
The question is whether synthetically created Dronabinol really can be as effective as natural THC? As expected - no, it can’t. While the main active compound in Marinol is really very similar to THC, it isn’t as effective as whole-plant cannabis in treating many of the symptoms. In addition to this, being produced in a pill form, Marinol is very hard to stomach for patients suffering from nausea or vomiting. It also produces stronger psychoactive effects in comparison with regular cannabis.
Why is it so and which of the “secret elements” of the cannabis plant remains hidden from science? The answer is in the entourage effect.
Since the THC was first isolated by Raphael Mechoulam in 1964, almost five hundred different natural compounds, including cannabinoids, and a variety of terpenes have been discovered in the cannabis plant. Terpenes represent a diverse group of organic compounds that give plants their specific fragrances. In cannabis, apart from giving the plant aromatic properties, terpenes also have medicinal properties. For example, such representatives of terpenes as caryophyllene and pinene are known for their potent anti-inflammatory properties, as well as can be beneficial in managing insomnia, muscle spasms, and more. Some cannabis researchers state the health benefits of terpenes can be more powerful when ingested with cannabinoids.
The current research of the cannabis plant is focused on using a single cannabinoid, either natural or synthetically created, in isolation. Undoubtedly, it may help to understand the full spectrum of the properties of each individual cannabis compound, although cannabis experts state the investigation of the plant as a whole will give us a more holistic picture. This is the main reason why whole-plant cannabis medications are considered as a future of medicinal cannabis.
When we smoke a joint, ingest a tincture or consume cannabis any other way, we get a unique mix of all the cannabis compounds, not just CBD or THC on their own. These chemicals interact with each other, modifying the properties and boosting the effectiveness of other components, acting in synergy. It gives the answer to the question of why synthetic drugs like Marinol can’t provide the same effects as regular cannabis. Understanding the mechanism of entourage effect and its importance is crucial to clearly evaluate all the possibilities of whole-plant therapy. It seems logical to extract particular beneficial compounds from the cannabis plant and make a concentrated medicine. However, the science of the entourage effect makes it clear that whole-plant approaches are more versatile. The simplest example to explain this difference is a comparison of fresh fruits and vegetables to vitamin tablets - even with similar active components in their composition, vitamins can’t be as effective.
The research of the entourage effect is ongoing, although studies seem to confirm Mechoulam’s theory. Research on Marinol has demonstrated that evaluating the positive effects of medical cannabis isn’t as simple as extracting a single compound from the plant. Scientists have observed the entourage effect of the cannabis plant in many different ways. One of the simplest methods to reveal these effects is to study the effects of certain different cannabinoids together. For example, CBD is claimed to counteract the intoxicating effects provided by THC. It is a proven fact that when taken in high doses, THC can generate paranoia, and a study held in 1982, demonstrated that cannabidiol could help to combat these side effects. An interesting experiment to confirm the entourage effect was also performed by cannabis researcher Ethan Russo. It was revealed that a 10mg dose of pure THC usually produces toxic psychosis in roughly 40% of patients. However, a dose of Sativex (medication which contains an equal ratio of THC to CBD) equivalent to 48mg of pure THC produced toxic psychosis in only 4 of 250 participants of the study, thereby confirming the CBD properties to reduce the psychoactive effects provided by THC.
Of course, it can’t get without criticism. As with almost everything when it comes to cannabis research, there is still no consensus, that creates a great number of debates and critics among people among opponents of medicinal cannabis. Mechoulam’s theory wasn’t an exception and has received its fair share of criticism from scientists. However, even some of the cannabis researchers state there isn’t a lot of data to support the existence of the entourage effect in the cannabis plant. In fact, the verdict on the entourage effect depends greatly on whom you ask about this topic. Until the more research goes into this field and the more studies have been performed to confirm this theory, none of us can make solid conclusions and say for sure about the way cannabinoids and other chemicals in the cannabis plant interact with each other.
Can we still take the isolated compounds? And which THC to CBD ratio is the best?
The next question which occurs after getting to know the entourage effect - is whether the cannabis plant compounds work well separately? The research says taking terpenes together with phytocannabinoids may provide additional health benefits.
According to the review of studies published in the British Journal of Pharmacology in 2011, due to the entourage effect, taking terpenes and phytocannabinoids may be beneficial for such conditions as:
- Fungal infection
Cannabinoids like CBD and THC can also be taken separately for these and a range of other conditions, although the effect they provide will differ as they can’t “balance” each other and reduce potential side effects which may occur when taking one or another cannabinoid. For example, people taking THC for alleviating their conditions often feel hunger, anxiety, and sedation after the cannabinoid taking. A range of rat and human studies has shown that taking CBD together with THC may significantly reduce these side effects or even eliminate them. Also, according to the research held in 2018, certain terpenes and flavonoids found in the cannabis plant may provide anti-inflammatory and neuroprotective properties and be beneficial to brain health. Cannabis experts assume that taking these compounds together with cannabidiol could significantly increase its therapeutic potential.
However, the question of the entourage effect and its role in the cannabis plant still remains open. Not all the cannabis components can interact with each other in a beneficial way, and more research is needed to understand which “combinations” of the chemicals will be able to provide the most effective results. A study held in 2019, investigated the influence of the entourage effect on six common terpenes. The chemicals were tested both alone and together, and the researchers found that the effect of THC on CB1 and CB2 receptors of our endocannabinoid system was unchanged by the addition of the terpenes. These results don’t indicate that the entourage effect doesn’t exist and it is possible that terpenes can interact with THC elsewhere in the body or brain, or in a different way. Whether it is better to take THC or CBD alone? To answer this and many other questions for sure, more research is needed.
When considering taking THC and CBD together, it is important to note that cannabis affects every one of us differently and the goals for its use, as well as the results it provides, are different. For example, a person with rheumatoid arthritis or with Crohn's disease who uses medical cannabis for alleviating the symptoms will have a different ratio of CBD to THC than an athlete after intensive workout who uses it to relieve muscle pain.
The first rule for all people who are just getting to know cannabinoids is that there is no one dose or ratio of cannabinoids that works for everyone. It is highly recommended to talk with your healthcare provider if you want to add cannabinoids or other cannabis compounds in your treatment program. It will help you to limit side effects, avoid possible drug interactions, and choose the necessary dose for your particular case. You should also keep in mind that compounds like CBD and THC may have such adverse effects as slow reaction times, dry mouth, fatigue, short-term memory loss, anxiety, diarrhoea, nausea, and weight changes.
As for the dose, it is recommended to start with a low dose and gradually increase it if needed. For CBD, you can start with 5mg and increase it to 15mg, while for THC it is recommended to start with 5mg or less and increase it according to your needs. Regarding the best CBD to THC ratio, there isn’t also a single rule. Some of you may find that taking CBD and THC at the same time works best, while others may prefer using CBD after THC. The number of methods of taking also gives you freedom of choice. You can take CBD and THC in a number of different delivering methods, such as:
All of these methods have their own pros and cons, as well as different bioavailability levels. You should consult your doctor to choose the most suitable method to meet your needs.
The bottom line
Some of us don’t want to try THC but are interested in taking CBD, while for others CBD’s effects may not be enough and they will stop their choice on THC. For some of us taking whole-plant cannabis medications will bring significantly better results, while for others adding different cannabis chemicals to cannabinoids treatment will not make any difference. We all are different and have different needs and preferences.
The question of the entourage effect among cannabis compounds is still unanswered, and it will take time and lots of research to put a final point in this theory. Anyway, while this question remains open, we want to draw an analogy that no matter how strong the soldier is, the platoon will always be stronger. Same is with cannabis - isolated cannabinoids and terpenes may give effective results, although their combination in most cases will provide better and stronger outcomes by strengthening the benefits of each other and reducing side effects.