Ever wondered what exactly the deal is with the endocannabinoid system? Registered Pharmacist and clinical cannabis consultant, Dr Monica Taing explains.
The endocannabinoid system [ECS] is a comprehensive and complex homeostatic balancing system with diverse potential therapeutic clinical implications in chronic conditions,” said Monica Taing, PharmD, RPh, at the inaugural meeting of Medical Cannabis: Science, Research and Risks, held at Columbia University [in New York City].
Dr Taing, who is a clinical cannabis consultant specialist for hospital systems and academic medical institutions, spoke to meeting attendees about the pharmacokinetic and pharmacodynamic parameters of various cannabinoids and their effects on homeostasis, chronic disease states, dosing, formulation selection and potential drug interactions.
The role of the ECS in homeostasis
“The ultimate function of the ECS is homeostasis, which is returning balance in the body,” Dr Taing told attendees.
“It is the internal biological balancing mechanism of the body and brain.”
Dr Taing used the acronym PREFS to describe the key functions of the ECS in promoting homeostasis: protect, relax, eat, forget, and sleep.
“The ECS changes as we age,” Dr Taing continued.
“It’s different in every person based not only on age, but also on race, gender, and use of pharmacotherapies that can tip the balance away from or help restore homeostasis.”
Basics of the ECS
Dr Taing cited preclinical data showing that the ECS has a profound effect on stress, anxiety, and depressive states at the pharmacologic, biochemical, and genetic levels.
The fundamental pillars of the ECS, consist of the following:
- CB1 and CB2 receptors are G protein-coupled receptors (upon which a majority of other pharmacologic therapies also impact) produced in the body as a result of human evolution.
- CB1 receptors are ubiquitous throughout the body and are predominantly found in the central nervous system, with a high density in certain areas of the brain (eg, cerebel lum, globus pallidus, hippocampus, and substantia nigra),7 whereas CB2 receptors are mainly limited to the periphery, including the immune system.
- Endocannabinoids: N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG) are produced in the body on demand and act as partial agonists at CB1 and CB2 receptors. Activation of these receptors by anandamide and 2-AG has the potential to modulate anxiety/ stress, inflammation, pain perception, and neuropathic pain, among other processes.8,9
- Enzymes produced in the cerebrospinal (uid drive the bio synthesis, degradation, and transport of endocannabinoids and other ligands that act on cannabinoid receptors.10
“It is interesting that CB1 receptors are very minimally, if at all, located in the brainstem,” Dr Taing said.
“This is the pathophysiological reason why it is not physically possible to induce cardiorespiratory depression [solely] with [botanical] cannabis.”
Delta-9-tetrahydrocannabinol (THC) mimics the effects of anandamide and 2-AG and on CB1 and CB2 receptors, and CBD has multimodal activity at CB1 and CB2 receptors as well as at receptors beyond the ECS, Dr. Taing said.11,12
She uses the lock-and-key metaphor for explaining the complex pharmacology of cannabis to patients, where CB1 and CB2 receptors are the locks and cannabinoids (either endogenously produced or exogenously introduced) are the keys.
Preclinical research suggests that anandamide and 2-AG exhibit local effects on cardiovascular physiology (e.g cardiac contractility, platelet activation, endothelial cell activation) as well as positive effects on other cells that contribute to cardiovascular/ atherosclerotic pathologies (e.g monocytes, macrophages, lymphocytes, neutrophils, and other inflammatory cells).
“Understanding the activity of CB1 and CB2 receptors in the ECS, ligands (concentration and duration), as well as enzyme synthesis, release, and degradation is needed to understand the diverse therapeutic clinical implications of medical cannabis use in the treatment of chronic conditions,” said Dr Taing.
Additionally, it is important to consider the entourage effect of cannabis, which is the theory that “terpenes, flavonoids and cannabinoids all work together like a symphony.”
“These components all complement each other so that you can get the maximal effect of the plant,” she added.
Terpenes are essential oils that provide aroma and flavour to the plant, whereas (flavonoids provide pigment and potentially antioxidants.
“In practice, I meet patients who are prescribed the synthetic agent dronabinol and say that it didn’t work for them, and this may be because they are not benefiting from the entourage effect,” Dr Taing noted.
This prescription medication also has a narrow indication and may not address all the issues and symptoms that patients with chronic conditions have, she added.
Dosing and safety
THC produces biphasic effects with low doses mimicking the effects of endocannabinoids in reducing hypothalamic–pituitary–adrenal (HPA) axis activity and anxiety, whereas high doses increase HPA axis function and are anxiolytic.
“Biphasic dosing of THC is the pharmacological rationale behind ‘start low, go slow’ dosing for patients, regardless of whether the patient is using an adjustable or inhalation delivery method,” Dr Taing said.
Patient education is particularly important for those taking edible cannabis, as there is a lag in onset of action, and then an extended duration of action compared with inhaled cannabis.
“When the body is starting to digest and metabolise THC, it will convert it to 11-hydroxy THC, a metabolite that is more potent than the original THC and potentially lasts in the body longer,” Dr Taing noted.
“I have seen so many [reported incidents of] patients who took one bite of a cannabis brownie and they didn’t feel any effect after 15 minutes, and then ate the entire brownie and wound up in the emergency room.”
Even in a cannabis-experienced patient, Dr. Taing suggested starting treatment with a product that has less than 10 percent THC. Then she suggests gradually dose titrating by monitoring for efficacy and the emergence of adverse events.
Monitoring for drug interactions also is essential to care.
“We need to monitor patients taking antidepressants or mood stabilizers for changes in terms of how they feel, their effect, their mood, and any short-term and long-term benefits of cannabis in order to manage the dosing of cannabis as well as dosing of the other prescription medications that they are taking,” Dr Taing explained.
“Striking the right balance in terms of dosing also is important for patients with cardiovascular issues, as the risk for an acute cardiovascular attack is increased for one hour after using cannabis,” Dr Taing said.
Additionally, Dr Taing noted that patient counselling for those who are apprehensive is important to ensure that they are in an optimal environment and mindset to obtain benefit from cannabis treatment.
Dr Taing is on the Board of Directors of Doctors for Cannabis Regulation, is the Director of Research and Clinical Education for Minorities for Medical Marijuana and serves as a Medical Science Liaison for 4Front Ventures.
This article was originally published in the American Journal of Endocannabinoid Medicine (AJEM). Find the original article including reference list here
Breast milk of THC-positive mothers not harmful to short-term health of infants – study
Researchers reported no differences in short-term health impacts such as breathing difficulties or feeding issues.
According to a new study, the breast milk of THC-positive mothers was not found to be harmful to the short-term health of premature infants.
Researchers compared early pre-term infants who were breast-fed from mothers who consumed THC to those who were fed formula or breast milk from non-THC consuming mothers.
They reported that breast milk caused no differences in short-term health impacts such as breathing difficulties, lung development or feeding issues.
The study analysed the medical records of 763 early pre-term babies from 2014 to 2020. Researchers discovered that 17 per cent of the mothers tested positive for THC at the time of giving birth. They also examined post-natal exposure through breast milk.
Researchers found that overall the babies born to mothers who tested positive for cannabis were similarly healthy at the time of their discharge when fed their mothers breast milk in comparison to those who did not receive their mother’s breast milk.
The authors wrote in the abstract: “In our study, we found no evidence that providing [mother’s milk] MM from THC-positive mothers was detrimental to the health of this early preterm population through hospital discharge. A better understanding of longer-term perinatal outcomes associated with THC exposure both in-utero and postnatally via MM would inform appropriate interventions to improve clinical outcomes and safely encourage MM provision for early preterm infants.”
Breast milk from mothers who consume THC is often restricted by neonatal intensive care units because the effects on early preterm infants are unknown. It is thought that the active ingredient can pass through breast milk. Studies have shown that breast milk is a good way to improve pre-term baby outcomes and reduce infection risk along with intestinal issues.
Researchers cautioned women to abstain as the long term effects are still unknown.
THC-positive breast milk
Natalie L. Davis, associate professor of paediatrics at the University of Maryland School of Medicine said: “Providing breast milk from THC-positive women to preterm infants remains controversial since long-term effects of this exposure are unknown.”
She added: “For this reason, we continue to strongly recommend that women avoid cannabis use while pregnant and while nursing their babies. Our study, however, did provide some reassuring news in terms of short-term health effects. It definitely indicates that more research is needed in this area to help provide women and doctors with further guidance.”
“Teasing out the effects of THC can be very difficult to study,” Dr Davis concluded. “We found that women who screened positive for THC were frequently late to obtain prenatal care, which can have a detrimental effect on their baby separate from cannabis use. This is important to note for future public health interventions.”
The study abstract will be presented at the virtual American Academy of Paediatrics National Conference and Exhibition.
“Father of cannabis” Professor Raphael Mechoulam shares new findings at Royal Society of Medicine
The world-renowned cannabis scientist was the first to discover the endocannabinoid system
One of the world’s leading cannabis scientists has shared his latest findings – the discovery of several new compounds which could play a role in managing a wide range of global health issues.
Professor Raphael Mechoulam, is widely regarded as the ‘father of cannabis’ following his discovery of the endocannabinoid system (ECS) in the early 90s.
In a one-off event at the Royal Society of Medicine in London on Monday 11 October, the professor discussed his latest work, including the discovery of new compounds that could play a role in treating brain injury, nicotine addiction and in preventing antibiotic resistance.
The event, which was organised by Integro Clinics, saw medical professionals, scientists and industry experts share their insights on the emerging field of cannabis medicine at the well-established institution.
Prof Mechoulam, shared his findings to a captive audience, attending virtually from his office at the Hebrew University of Jerusalem, in Israel.
His research offers promising potential for the treatment of a wide range of conditions and health issues.
Depression and pain
Cannabidiolic acid (CBDA) and tetrahydrocannabinolic acid (THCA) are found in the cannabis plant before being synthesised to produce CBD and THC and are thought to be more potent.
Prof Mechoulam and his team of researchers recently stabilised CBDA, developing the compound cannabidiolic acid methyl ester (EPM301). According to a study carried out with researchers in Canada, this was found to reduce depression and lower pain in animal models.
Prof Mechoulam explained: “The plant actually doesn’t synthesise either THC or CBD. It synthesises their precursors which are acids.
“These compounds have not been investigated very thoroughly, because they are not stable, but we were able recently to stabilise CBDA by making a methyl ester and with this we have been able to look at the activity of this acid derivative.
“This particular compound, which is present in quite large amounts in the cannabis plant, is of considerable interest.”
Along with anandamide, 2-Arachidonoylglycerol (2-Ag) is one of two primary endocannabinoids which bind with both the CB1 and CB2 receptors.
Researchers have now found that 2-Ag is effective in reducing head trauma following traumatic brain injury, as well as reducing vasoconstriction – the narrowing (constriction) of blood vessels in the brain.
“We saw that 2-Ag when administered to mice lowers the damage [to the brain]… the damage in the control group was 50 percent higher than those that received 2-Ag,” said Prof Mechoulam, who hopes a drug will be developed using 2-Ag as a compound against brain damage.
His team was then able to identify and isolate another “more active” compound, arachidonoyl serine (AraS).
According to Prof Mechoulam, AraS acts similarly to anandamide, but does not bind to the cannabinoid receptors and is “much more potent” in reducing the effects of vessel constriction.
Prof Mechoulam also revealed that AraS can encourage the activity of antibiotics, potentially providing a solution to the major impending health crisis that is increased antibiotic resistance.
“One of the major problems we have in medicine today is that many of the microbes have antibiotic resistance and if we cannot overcome this major problem, we will be back as we were in the 1930s, with microbes that we cannot attack by antibiotics,” he said.
“When microbes are attacked by an antibiotic, one of the ways they resist is by producing a biofilm. Millions of microbes get together and they form a biofilm, which is not attacked by the antibiotic.
“We found that AraS can overcome the microbial resistance of these particular microbes… AraS prevents the biofilm formation by altering the surface of the cell without actually killing the bacteria.
“This may be a very promising way of overcoming microbial resistance.”
Another newly-discovered compound known as oleoyl serine (OS), an endogenous fatty acid produced in the bones, is thought to improve bone formation, reducing and even reversing the effects of osteoporosis.
Prof Mechoulam explained: “The bones we have do not stay the way they are throughout our life, they are broken down all the time by osteoclasts, and at the same time are being rebuilt by osteoblasts. In certain diseases, for example osteoporosis, the osteoclasts work overtime and the osteoblasts cannot promote enough bone formation.”
In a study, mice with osteoporosis symptoms were given OS for 40 days, with results showing that the bones stopped breaking down and began to recover.
Prof Mechoulam and colleagues concluded that OS reduces the effects of osteoporosis, reducing the breakdown of the bone and promoting bone formation.
“We can see now that bones do not continue breaking down and as a matter of fact recover,” he said.
“Most of the drugs that we have for osteoporosis usually just [work to] stop the disease or stop the disease to a certain extent. Very few of the drugs, if any at all, cause the formation of the bone again.”
Earlier this year, a stabilised derivative of OS, H2671 was also shown to exhibit “high efficacy” in reversing the effects of osteoporosis in Prader-Willi syndrome.
Mechoulam’s colleagues in Italy have discovered another endogenous compound, again closely related to anandamide, known as oleoyl glycine (OS).
Using a conditional place preference model [where mice or rats are given the option to go to food with or without nicotine] fellow researchers in Canada found that when mice were given OG, they did not become addicted to the nicotine in their food.
Prof Mechoulam revealed he was “disappointed” that the same model didn’t work with opioid addiction, but OG did prove effective in reducing both nicotine and opioid withdrawal symptoms.
“It turns out that withdrawal and addiction are two different types of response,” he explained.
“Today we know that OG works on nicotine addiction and does not work on opiate addiction, but it does work on nicotine and opiate withdrawal symptoms.”
The authors of the study concluded that morphine withdrawal reactions were accompanied by “suppressed endogenous levels of OG in different parts of the brain.”
Mechoulam and colleagues then stabilised this compound to develop oleoyl alanine which turned out to be “more active” for a “longer period” of time than OG.
He added: “We found that oleoyl alanine is not only more stable, but also a more potent anti-withdrawal molecule than OG, and I am under the impression that this compound should [be developed] to become a drug.”
New course offers expert advice on medical cannabis from doctors and patients
The Sativa Learning course includes insight from doctors and patients
A new online course on prescribing medical cannabis will offer a detailed insight into the industry from both clinicians and patients. Cannabis Health speaks to course creator and CEO Ryan McCreanor.
It will cover a comprehensive list of topics around cannabis as a medicine such as clinical evidence for medical cannabis, the practicalities of prescribing and side effects and contraindications.
The course, which will run online only, will also offer a variety of clinical and patient stories on a select list of conditions such as chronic pain, fibromyalgia, epilepsy, paediatric epilepsy, anxiety and post-traumatic stress disorder (PTSD).
Sativa Learning has already launched a successful online CBD course covering everything from the science behind the cannabinoid to UK regulations.
Ryan got the idea following his return from Canada to his hometown of Northern Ireland where he struggled to find decent quality CBD products. He started his career as a toxicology scientist before working for the Canadian government as an educator and trainer post legalisation in 2018.
“This was a way to bring a level of legitimacy to the industry by developing an accredited expert-led cannabis course,” said Ryan.
“The idea for the platform is that we want to provide education for all avenues of the cannabis industry. The CBD industry was a good place to start as I had a good level of knowledge myself so I put together a lot of the educational content myself.”
He continued: “I wanted to bring in real experts so we partnered with Professor Barnes and Hannah Deacon. All future courses will be CPD-credited. A lot of medical professionals will have to gain a certain amount of CPD points per year so they can take our course and feel comfortable that it is managed to a high started of further learning.”
As well as Hannah Deacon and Prof Barnes, the course also includes expert panels from Dr Dani Gordon who will speak about cannabis and oncology. Other classes will include Dr Elie Okirie speaking about epilepsy and Dr Evan Lewis on paediatric epilepsy. When it comes to the syllabus, the MCCS has put together the content for the cannabis course.
Ryan explained that they selected the conditions they included carefully to give a broad overview of common conditions.
He said: “We picked out 10 of the most common conditions for which cannabis is prescribed. We have fibromyalgia, chronic pain, cancer pain and women’s health issues. The doctors explain how they prescribe for that condition and have a number of patients who speak on camera about their experience.”
When it comes to panel discussions, courses or expert lead videos, it can often feel as if patients are forgotten. Ryan highlighted that this is a key part of the course.
“Not only do we have the doctors educating on cannabis but we have a follow-up with a patient talking about their experience,” he said.
“They discuss what life was like for them before medical cannabis, what their prescription is like and how this changed things for them.
“The industry should be all about the patients so we want to make sure that their voices are heard.”
The course will be fully online, with an option to learn as you go and break and save your progress whenever you are ready. At the end of the course, there will be an exam that will give you a presentation upon a passing grade. The exam is part of the CPD accreditation.
Ryan added: “Some people have blasted through our CBD course in one day where they just sit down and get through it all which can take up to six hours depending on your existing level of knowledge. This course is going to be quite a bit longer but you can do it all in one day or you could do a few hours a night for six months.”
The platform will be available for anyone who wants to learn about cannabis although Ryan explained that it may be more suited towards industry professionals.
He concluded: “There are no barriers to entry. The course is going to be available for whoever wants to learn about cannabis medicine. The language we use is heavily targeted towards the medical professionals as it is aimed at that audience to teach medical professionals about the basics of prescribing.”
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