Cannabidivarin or a step away from the hyped cannabinoids

We live in the age of changes. Rockets with humans onboard conquer space, electric cars ply the streets, and the amazing bionic prosthetics continue changing lives worldwide. A hundred years ago, we couldn’t even imagine that humans can lead a normal life with a biorobotic “heart” that beats like real or with full face transplant. Nevertheless, from a plot of a science fiction movie, the newest developments of modern engineering and medicine have turned into real-life applications designed to change our lives forever.

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It is great to live in the age when you can become a witness of global changes and feel like a small particle in the huge mechanism of the world’s progress. Modern medicine belongs to the industries that are developing with the overwhelming speed changing everything on its way. Diseases and conditions that have never been cured before have found their remedies and stopped to be a sentence for patients with such diagnoses. Side effects accompanying a range of various treatments have decreased in number or disappeared at all. Altogether, the breakthroughs in the world of medicine of the 21st century are confidently moving forward to create a new world - world, where all the people will be healthy. 

A significant contribution to the changes in modern medicine was made by the discovery of promising cannabis compounds - cannabinoids. While having an impressive range of health benefits, these chemicals are believed to become the worthy analogues to modern drugs or even substitute some of them at all. The new therapeutic benefits of cannabinoids continue to be revealed in the world studies, animal and human trials. Simultaneously with the potential applications of the cannabis compounds, scientists all over the globe continue to discover new cannabinoids that can also be beneficial for our health. For the moment, more than a hundred cannabis chemicals with therapeutic benefits for the treatment of a range of diseases or their prevention have been discovered. Even those of us who are far from medicine most probably heard about the two most popular cannabinoids that actually blew the world of science with their appearance. CBD and THC (or cannabidiol and delta-9-tetrahydrocannabinol) have become the most hyped cannabis chemicals making humanity look at cannabis from a different angle. For being for so long, nothing more than just a plant to relax and travel to the world of unicorns on the wings of euphory, cannabis unexpectedly proved itself to be a source of potent medications that could impact different diseases and conditions. 

The current position of the cannabis plant still remains doubtful. The legalisation and adoption issues are the main barriers to the way of its growth. However, based on the scale of potential benefits and the rapid speed of growth and development, most cannabis experts predict the blue-sky scenario for cannabinoids.   

Higher without limits: Cannabis industry predictions for 2020-2025 term

Predictions for the cannabis sector growth are based on market research reports by experts in cannabis exportation, recent market growth statistics, and consumer/patient demand for quality medicinal marijuana. The main question regarding the future of medicinal marijuana is how fast the worldwide cannabis market will expand? According to research, the modern medical cannabis industry is on the stage of higher consumer demand and significant market growth rate statistics. Cannabis market reports and investing briefs indicate that legal cannabis sales of recent years experienced over 40% growth rates primarily due to high consumer demand in the US markets. The global demand for both recreational and medicinal cannabis is predicted to grow consistently with a growth rate of 17%-23% per annum. However, these numbers are quite approximate as medical cannabis production is an entirely new market in each country, and it still can’t be precisely estimated how this lucrative industry will change in the future in one or another country. In addition to this, the growth rates of medical cannabis will be influenced by regulated production processes, which are still subject to changes and potentially long processing times for cannabis farming applications. 

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Many of the cannabis market specialists predict phenomenal growth rates for the cannabis plant once the medicinal benefits of cannabinoids are further established. Also, it is assumed that as cannabis becomes legal to possess, use, cultivate, and travel with on planes, as well as, standardised in dosage forms, significantly more people may feel safer to use cannabis products for a range of different medical conditions. Another barrier to the cannabis way and, at the same time, the factor that may noticeably influence the medical marijuana future is confirmation of the benefits of the cannabinoids. All the therapeutic properties of cannabis, along with side effects and safety risks, need to be further accessed. Most of the scientists working with medicinal cannabis believe that current cannabinoids studies will reveal new potent treatment medications based on THC, CBD, or other prospective cannabinoids.

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The ongoing research projects into the medicinal benefits of using cannabis or cannabinoids medicines are focused on evaluating such conditions as:

  • epilepsy,
  • seizures control,
  • Parkinson’s disease,
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  • PTSD,
  • depression,
  • anxiety,
  • arthritis,
  • pain management,
  • opioids addiction,
  • anorexia,
  • bulimia,
  • fibromyalgia,
  • skin conditions.

It is not the full list of the conditions that can potentially be treated with cannabinoids. With the growing number of studies and research worldwide, along with anecdotal case studies suggesting a plethora of positive effects, the list of cannabinoids potential benefits for our health is constantly changing, replenishing with new therapeutic effects, accompanied by the new diseases that can potentially be treated with these compounds. 

There is also a theory that Baby Boomers and Millennials can help to drive cannabis market growth and its medicinal use. Such an assumption is supported by the fact that the part of the expected growth surges in cannabis market sectors stems from an ageing baby boomer society that is already familiar with cannabis effects since their university days. In addition to this, it is assumed that Millennials can be supporting the freedoms of cannabis use in the way the baby boomers supported fluid relationships in the sixties and seventies. 

As for the countries where cannabis market growth is going to be the greatest, the US is predicted to remain the largest consumer base for medicinal cannabis products. At the same time, increasing demand for cannabis and especially cannabinoids, is expected to continue as more states and countries worldwide legalise the possession, cultivation, and use of marijuana products. It is interesting that global cannabis industry growth is expected not to be limited to medical purposes, but with recreational cannabis sales as well.

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Cannabidivarin: What to expect from the CBD homolog?

Cannabidivarin or CBDV is a natural cannabinoid found in particular types of cannabis plants in Mexico and northwestern India. As its name suggests, this compound is one way or another similar to so well known for us cannabidiol. It is true. Chemically, CBDV is a CBD homolog. The molecular structure of this compound almost wholly matches the CBD’s structure, and the only difference is that the side-chain of CBDV is shortened by two methylene bridges (CH2 units). Such a small difference makes these two compounds different and unique in their health benefits, allowing researchers to investigate the CBDV’s properties in order to find new potential applications of this cannabinoid. 

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Similarly to CBD, CBDV has seven double bond isomers and 30 stereoisomers and doesn’t cause any intoxicating effects on our organism. Due to the lack of psychoactive effects, cannabidivarin is not scheduled by Convention on Psychotropic Substances that significantly simplifies its research and adoption worldwide in contrast to compounds like THC. Researchers state CBDV is similar to CBD and THC, although the full spectrum of its potential health benefits hasn’t been discovered yet as the compound has been highly underrated until the recent past. The more in-depth research and studies of this compound have begun not so long ago with the changes in laws that played a decisive role in this discovery. The legalisation of medical cannabis in a range of countries has triggered research for several new compounds that haven’t been well investigated before. Cannabidivarin that has been waiting in the shadows for more than half a century since the moment of its discovery is an excellent example of changes in global research that has been provoked by the government changes. To date, there are over one hundred cannabis compounds that have manifested their therapeutic benefits and become the objects of interest for global science. Some of these compounds are studied better, while others, like CBDV, just embarked on the road of massive studies and trials. 

Today, the gap between CBD and CBDV is enormous, and this is due to the lack of studies held to reveal and confirm the potential CBDV benefits and clinical uses. Currently, CBD-infused products are grabbing the market share with impressive speed, and the number of products containing CBD oil in its composition exceeds the mark of 21000. Cannabidiol oil is an active component in various face creams, body butter, lip balms and many more, and this is just if considering the cosmetics products. Cannabis experts state that CBD-based cosmetics is a hit among females of all ages. A significant increase in the popularity of CBD products can also be noticed among athletes, wrestlers, and sportspersons like football and baseball players preferring over 30 types of various cannabidiol products for recreational purposes. Such CBD-based products as pain relief creams, balms, terpenes, concentrates, powders, and capsules are in high demand among athletes and are often used before and after the sessions to derive benefit in terms of muscle relaxation.

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CBD edibles such as froggies, gummies, and lollipops are also not far behind other CBD-infused products in terms of popularity. A wide variety of flavours choice, along with mild sweet taste make edibles along with their benefits have made them a popular choice of thousands of users worldwide. CBD gummies are delicious, easy to chew, swallow, and carry, and, of course, beneficial for our health while being a great food supplement that can help to boost our general health and keep us on track in a healthy lifestyle. 

Returning to cannabidivarin, the thirty-years difference between CBD and CBDV discovery, along with the lack of research played a role, not in favour of CBDV. Nevertheless, the giant mechanism of cannabidivarin studies has already been launched, and all we can do is to be more patient to wait for the scientific confirmation and clinical evidence of the health benefits provided by this cannabinoid. What do we have for the moment? There are not so many clinical studies and trials to prove the therapeutic effects of CBDV, although the results we have for today already impress. 

A range of research has demonstrated that CBDV can mostly be found in cannabis indica landrace strains sourced from Africa and Asia. It was also shown that strains that are higher in CBD, in most cases also tend to be higher in CBDV. It was also found that, in many cases, if a cannabis plant has high levels of cannabidiol and cannabidivarin, then it will have low levels of tetrahydrocannabinol (THC).

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As for medical benefits, CBDV has already shown great promise in the treatment of epilepsy and is currently being actively researched. Some of the current studies are focused on the investigation of possible CBDV use as a treatment option for bone repair and nausea. Several leading companies in the cannabis industry such as Otsuka Pharmaceuticals and GW Pharmaceuticals have been interested in the beneficial effects of this cannabinoid and filed a joint patent on a CBDV rich, whole-plant concentrate that they intend to use to treat epilepsy ultimately. Today, we will not find an abundance of research on cannabidivarin. However, based on the results of the studies that have been already held, a list of conditions and diseases that can potentially be treated or alleviated with CBDV is showing up.

CBDV and seizures treatment. According to the results of the research held in 2013, cannabidivarin has manifested its ability to significantly decrease PTZ-induced seizure severity as well as increased latency to the first sign of a seizure. The authors of this study claimed that the obtained results provide the first molecular confirmation of behaviourally observed effects of the non-intoxicating anticonvulsant cannabinoid CBDV, upon chemically-induced seizures. They also mentioned that this confirmation might serve to underscore the suitability of cannabidivarin for clinical development. 

CBDV and epilepsy. The ability of CBDV to cause a beneficial effect on patients with epilepsy diagnoses was among the first properties that attracted global attention to this compound. The study, held in 2014 by the group of Italian researchers investigated the effects of two most well-known cannabinoids - THC and CBD on rats with induced symptoms of epilepsy. It was revealed during the study that both psychoactive and non-psychoactive compounds interacted with the transient receptor TRPV1, which is responsible for detecting and regulating body temperatures as well as producing the pain feeling. Researching CBDV effect on the disease, Italian scientists found that this compound is able to dephosphorylate TRPV1 working in the same way as anticonvulsive medication Capsaicin. Both CBDV and Capsaicin target TRP channels to combat the gradual process by which a normal brain develops epileptogenesis or, as we used to call it - epilepsy. The study also noted that cannabidivarin reduced the strength and length of simulated epileptic seizures in rat brains. It was decided to continue studying CBDV’s effects on TRP channels in order to understand the anticonvulsive abilities of this cannabinoid completely.

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CBDV and nausea. Nausea is the most common and probably the most debilitating side effects among patients undergoing chemotherapy treatment. Among all the existing methods of cancer treatment for patients diagnosed at the first stage, it will most probably be either surgery or radiotherapy treatment. At the same time, at the latest 4th stage, 39% of all patients undergo chemotherapy. According to physicians, chemotherapy is still considered as the best option for the patient in certain cases. 

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While taking into account this statistic, it is vital to improve the quality of the patient’s life maximally and to alleviate the side effects of this procedure. A study performed in 2013 evaluated the potential of THCV and CBDV to produce CB1 receptor inverse agonism symptoms of nausea in rats. The authors of the research concluded that both studied compounds might have therapeutic potential in reducing nausea and be clinically used as potent antiemetic agents.

CBDV and neuropathic pain. While research is still limited, several newer studies are examining the effect of cannabidivarin on pain. The clinical trial stage involving patients with HIV diagnosis and suffering from HIV-related neuropathic pain is ongoing, and the final results are not available. According to some other studies, CBDV could be effective in reducing this type of pain, although further research is necessary to confirm or disprove this hypothesis.

CBDV and autism. Similarly to the situation with other potential uses of CBDV, there is also a lack of studies examining the possibility of this cannabinoid to cause a beneficial impact on autism. Nevertheless, cannabis companies like GW Pharmaceuticals have been interested in this CBDV effect and initiated a range of research to identify the medical applications of the cannabinoid for autism spectrum disorder. Some of the results obtained for the moment claim that the co-administration of CBDV and CBD has a high potential to improve social and cognitive skills. In addition to this, researchers assume that such a combination of cannabinoids can also reduce repetitive and compulsive behaviour. 

CBDV and Rett syndrome. Rett syndrome belongs to neurological disorders and, according to statistics, occurs almost exclusively in women. This disorder is caused by mutations on the X chromosome and is characterised by intellectual disability, repetitive hand movements, and slower brain growth. A study held in 2018 in mice found that cannabidiol may contribute to reversing the atrophy of the brain areas and deterioration involved in Rett syndrome. GW Pharmaceuticals has already initiated research aimed at evaluating the effectiveness of cannabidivarin in the treatment of the disease.

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“Better late than never” or “the sooner, the better?” The ideal legal age for cannabis use

Cannabis is actively becoming a part of our life, thanks to the global legalisation and numerous health benefits. After all the issues and misunderstandings regarding the cannabis plant legality, the next question that appears on the horizon is when it is better to try cannabis products? What age can be considered as the best for cannabis-infused products purchasing to get the maximal benefits and, at the same time, do not cause harm to the health? In Canada, where cannabis was legalised in 2018, the minimum required age for all the cannabis consumers in many provinces is nineteen years. Only being nineteen-years-old or more, people can purchase recreational cannabis. At the same time, in the United States, the required consumers’ age for legal recreational access comprises twenty-one year. Where is the truth and which age is the most appropriate both legally and physically to consume cannabis edibles, vapes, or topicals? 

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According to Canadian researchers from the Memorial University of Newfoundland, the age of nineteen years, officially established by the government is the best age limit for buying adult-use cannabis. Researchers state that when the consumer is nineteen-years-old or older, the negative cannabis impact on his physical health, mental health, as well as on educational environment is minimized. 

While deciding about the most suitable age for cannabis products purchase, the researchers evaluated data from alcohol and tobacco surveys that were held in Canada in 2004-2015 period. Twenty thousand took part in this survey. The most attention of researchers was focused on such parameters as current cigarette use, educational achievements, and self-reported mental and physical health. Such a factor as the employment of the surveyed people wasn’t taken into account as today there is a little evidence on its association with cannabis. Results of the study were twofold. On the one hand, it was demonstrated that respondents who first used cannabis being at least nineteen years old, were less likely to smoke cigarettes later in their life if compared to those people who first used cannabis aged eighteen. However, on the other hand, researchers have found out that respondents who first used cannabis being from twenty-one to twenty-four years old, had higher education levels. Finally, it was also discovered that mental health outcomes were better in respondents who first used cannabis being from nineteen to twenty years old, that can be considered as a support for a minimum age limit of nineteen years. 

Evaluating all the obtained results and considering all variables, researchers came to a common decision that a MAL or minimum age limit of nineteen years seems to be the “threshold” with the minimal negative cannabis influence on the wellbeing of the consumer. According to dr. Hai Nguyen - the lead author of the study, contrary to both the medical community’s support for MAL of twenty-one or twenty-five years and Canadian federal government’s recommendation of eighteen years, the optimal minimum legal age for recreational cannabis use is nineteen years. To control the cannabis use in Canada and, at the same time, undermine the strength of the illicit cannabis market, the federal government recommended a MAL of eighteen years for non-medical cannabis use when the country legalised the drug in 2018. Nevertheless, to date, Alberta is the only province to follow this recommendation. Most Canadian provinces established a MAL of nineteen years, while Quebec raised its MAL to twenty-one years at the beginning of this year.

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Although the study of dr. Hai Nguyen regarding the ideal minimal age of cannabis use helped to dot all the “I’s” for most of the Canadian provinces, the world debates over cannabis MAL are far from finally settled. 

According to some other studies, as younger brains are believed to be more sensitive to drug exposure, the most suitable MAL for cannabis consumption should vary between twenty-one and twenty-five years. In accordance with the results of a nationwide poll conducted in 2018, 27% of Canadians would prefer a MAL of eighteen years, while 26% favoured the higher MAL of twenty-one year. Moreover, there is also an assumption that the results of Nguyen’s study may be inaccurate as the survey was held prior to the legalization of recreational cannabis in Canada, which could significantly influence how individuals use cannabis, alcohol, and tobacco. Thus, even having a recommended age for cannabis use, to properly determine which age threshold suits best for cannabis consumption, more research into other factors is needed. 

Adopted or still controversial? The FDA’s position on cannabinoids

Times are changing and what has been a prohibited weed to relax and hang out with a company of friends has surprisingly transformed into the potent medical agent. All the debatable moments regarding cannabinoids and justification for their use had roots in the past when marijuana was associated with hippies and youth protests. However, a lot of things have changed. Science and medicine don’t stand still and, along with the technological novelties, continue surprising all of us with an absolutely new view on habitual things. Cannabinoids are confidently moving forward becoming “the drugs of the 21st century” and substituting a range of habitual medications. The number of anecdotal evidence from the cannabis users is growing, as well, as the number of the studies and research held to reveal the new properties of cannabinoids or to discover new marijuana compounds that could be beneficial for our health. All together, successful results of the studies of cured diseases without side effects, and the speed of the global cannabis legalisation cannot but rejoice. However, there is often a fly in the ointment, and this case is not an exception. Even several flies if it can be said so. One of the highest barriers on the way to global cannabinoids adoption is the FDA’s position.

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Today, the FDA’s stance on cannabinoids, namely CBD, has been more than clear - it remains prohibited under the Controlled Substances Act even despite a growing number of state-level legalization measures that have been adopted. However, cannabidiol is a kind of exception to this rule. While being one of the leading cannabis components without psychological activity, cannabidiol has made the FDA’s position even more confusing and complicated. Currently, the Controlled Substances Act includes all tetrahydrocannabinols, and similar compounds acting as CB1 receptor agonists. All these chemicals refer to the Schedule 1 controlled substances that mean the federal government considers them having a high potential for abuse and non-applicable for medicinal uses. However, the compounds from the Schedule 1 list don’t include CBD. After the Farm Bill in 2018, hemp-derived cannabidiol was officially removed from the list of the Controlled Substances Act. In addition to this, the passage of the Bill has resulted in legalizing the cultivation of hemp itself. What does it mean for an average consumer? This legislation allows producing and selling the CBD products legally, with the FDA (or US Food and Drug Administration) having the power to regulate all the CBD-infused products and similar to them hemp-derived products as well.

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Another giant step for cannabis-derived CBD policy that was also made in 2018 was the FDA’s approval of Epidiolex drug. It was a historical moment when the FDA had approved the cannabis-derived drug for the first time. Epidiolex is a cannabis-derived oral solution for treating seizures in Dravet syndrome and Lennox-Gastaut syndrome. Moreover, it was the first FDA’s approval of any drug for Dravet syndrome. According to FDA Commissioner Scott Gottlieb, such approval can serve as a reminder that prospective development programs that can properly evaluate active ingredients contained in cannabis may lead to effective medical therapies. He also mentioned that the FDA is committed to such kind of scientific research and drug development. After Gottlieb's speech, the Drug Enforcement Administration (DEA) decided to reschedule the drug from a Schedule 1 controlled substance under the Controlled Substances Act, to the list of Schedule 5 controlled substances. Although the FDA decided that it’s not enough, and appealed to DEA with a letter in which it was mentioned that cannabidiol doesn’t have a significant potential for abuse and thereby could be removed from the Controlled Substances Act. The US Food and Drug Administration also added that CBD does not meet the criteria for placement in any of the Schedules under the Controlled Substances Act. 

After all the debates, in April 2020, the DEA finally officially removed the Epidiolex drug from the Controlled Substances Act completely. The Epidiolex’s manufacturers stated that such a decision would significantly improve patient access to anti-epileptic medicine.

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Nowadays, one of the biggest issues concerning CBD and the FDA’s battle is the massive use of CBD products in foods and various dietary supplements. In accordance with the provisions of the Farm Bill, the FDA has the authority to regulate the use of such hemp-derived cannabinoids as CBD. From the legality point of view, the FDA states that under the Federal Food, Drug and Cosmetic Act, it’s unlawful to introduce food which contains in its composition CBD or THC into interstate commerce, as well as to sell THC or CBD products as dietary supplements, regardless of whether the substances are hemp-derived. Nevertheless, to listen to the feedback on this decision from industry stakeholders and the general public, a year ago, the FDA held a public hearing on the use of CBD products which featured more than a hundred speakers reporting in front of the FDA officials. The comment period was formally closed on July 16, 2019. However, in March 2020, the FDA announced that it would be extending the comment period “indefinitely” allowing the public to continue to provide information in real-time as research progresses in this area. 

The FDA seems to be willing to consider the most sensible reform to its CBD policy, although it is still actively imposing its current rules. Despite the fact that nowadays, CBD products may be legally sold in the US, the FDA maintains strict rules on how all these products can be sold under the Federal Food, Drug, and Cosmetic Act. A month ago, the FDA sent warning letters to two cannabis companies claiming that their CBD products were effective alternatives to opioids, as well as could serve as effective agents to treat opioid addiction. Some studies indeed have indicated that cannabidiol could have the potential to become the effective treatment for opioid use disorder, although there aren’t any CBD products approved by the FDA for this application. The clinical studies examining this CBD potential are still continuing - therefore, the final verdict still may not be imposed. Besides this, the FDA recently warned one CBD manufacturer in the UK for making unproven claims on its website that implied its products could be used to prevent Covid-19. Though the company is based in London, CBD products were listed for sale in the United States, prompting the FDA to issue its warning. Usually, after such warning letters, companies have a certain limited period of time to retract the claims being made with regard to their products. On the last week, one CBD company based in California ignored FDA warnings about misleading medical claims and dietary supplement labelling. As a result of this, the firm has been named in an FTC complaint which seeks a temporary restraining order as well as a preliminary injunction against the business. The full administrative case from the FTC is scheduled to begin no earlier than January 2021.

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In order to avoid FDA warnings and preserve their reputation among customers, CBD companies are advised not to make any medical claims regarding their products. Nowadays, the FDA is moving forward to exploring pathways in order to allow for the marketing of CBD as a dietary supplement. However, until this is solidified and regulated, all the companies selling CBD products should be sure to comply with the current conditions of the Federal Food, Drug and Cosmetic Act.

Bottom line

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To date, the list of cannabinoids that are believed to be beneficial for our health is growing rapidly. New compounds like cannabidivarin show great promise for world science and medicine, manifesting the possibility to look further at our habitual medications and consider absolutely new natural compounds. Health benefits offered by CBDV and other cannabinoids are auspicious, although there are a lot of barriers on the way of these compounds adoption. One of the main hurdles that have to be overcome is the FDA approval of cannabis-based medications. Today, all the discovered cannabinoids and cannabinoid-based products and medications remain in limbo due to the controversial situation with the FDA. Epidiolex is the only drug that has got FDA approval and can be legally prescribed for the treatment of epilepsy. The process of cannabis legalisation is long and complicated, as well as the way to the global adoption of cannabinoid drugs. The possibility of replacing the habitual medications with cannabinoids that have similar effects but don’t cause any harm to our health sounds tempting, although a lot of efforts should be made until these compounds become the integral parts of our life.

Verified by a Healthcare Professional

Anastasiia Myronenko

Anastasiia Myronenko

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.