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The science of the endocannabinoid system

Ever wondered what the deal is with the endocannabinoid system? Registered Pharmacist Dr Monica Taing explains.

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The ultimate function of the ECS is homeostasis, which is returning balance in the body.

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.” 

Cannabinoid pharmacology 

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).

Monica Taing, PharmD, RPh

“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 

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How THC and CBD work together in the brain – new study

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How THC and CBD work together in the brain – new study

New findings on how CBD and THC – the psychoactive compound in cannabis – affect the brain when administered together, could help to develop new cannabinoid therapeutics, scientists say.

A study has investigated the impact on the brain of CBD and THC, both as separate entities and when co-administered.

Researchers at University College London (UCL) analysed data from previous studies, including one which used functional Magnetic Resonance Imaging (fMRI) technology to measure brain activity in participants taking CBD and THC.

For the first time, they explored the response of the striatum region of the brain – a major part of the motor and reward systems. This is a critical component of numerous aspects of cognition, including motor and action planning, decision-making and motivation.

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One study compared inhaled cannabis containing 8 mg THC, 8 mg THC + 10 mg CBD and a placebo. It showed strong disruptive effects of both THC and THC + CBD on connectivity in the associative and sensorimotor networks.

However it also identified a “specific effect of THC” in the limbic striatum network which was not present in the THC + CBD condition.

In a second study, testing oral 600 mg CBD versus placebo, CBD increased connectivity in the associative network, but produced only relatively minor disruptions in the limbic and sensorimotor networks.

The study concludes that THC “strongly disrupts striato-cortical networks” but that this effect is mitigated by the co-administration of CBD.

It states: “Oral CBD administered has a more complex effect profile of relative increases and decreases in connectivity.

“The insula [part of the brain implemented in diverse functions including emotions and self-awareness] emerges as a key region affected by cannabinoid-induced changes in functional connectivity, with potential implications for understanding cannabis-related disorders, and the development of cannabinoid therapeutics.”

This is the first report in human subjects of data from THC, THC + CBD and CBD use achieved “using a unified set of analysis methods, and with all comparisons performed in a placebo-controlled, double-blind design”.

Read the full report here.

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Five new cannabis studies to have on your radar

The latest scientific papers exploring cannabis and its impact on health and society.

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Five new cannabis studies to have on your radar

Get up to date with the latest cannabis-related research from across the globe.

Over the past few weeks, we’ve seen papers published around inaccurate labelling, the effects of cannabis on Covid-19, the impact of legalisation in Uruguay and how cannabis users might require more sedation during medical procedures.

Read on for five significant studies to dive into.

Lower Covid-19 severity among cannabis users

A recent study has discovered an association between lower Covid-19 severity and cannabis use among hospitalised patients.

The researchers aimed to assess whether current cannabis users hospitalised for Covid-19 had different outcomes compared to non-users through a retrospective analysis of 1,831 patients admitted to UCLA Medical Centre in California.

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Analysis of the data found that cannabis users had significantly better outcomes compared to non-users, shorter hospitalisation, lower ICU admission rates and less need for mechanical ventilation.

Interestingly, the researchers also found that active users had lower levels of inflammatory markers upon admission than non-users.

The authors of the study concluded: “This retrospective cohort study suggests that active marijuana users hospitalised with COVID-19 had better clinical outcomes compared with non-users. However, our results need to be interpreted with caution given the limitations of a retrospective analysis.

“Prospective and observational studies will better help elucidate the effects of marijuana use in COVID-19 patients.”

Cannabis users require more sedation for endoscopy

According to new research, patients who use cannabis required higher levels of sedation during gastric endoscopies than non-users.

As cannabis is legalised in more places and usage continues to rise, researchers in Canada said clinicians should be aware of patients’ cannabis consumption and prepare themselves for increased sedation and the risks that come with it.

The authors of the study conducted a prospective cohort study of 419 adult outpatients undergoing endoscopic procedures at three Canadian centres. Procedures were conducted under conscious sedation, which leaves the patient relaxed and comfortable but partially conscious during the procedure.

Cannabis use was associated with increased odds of requiring higher total sedation during gastroscopy, an endoscopic procedure that begins with the insertion of a tube and camera through the throat.

Legalisation not associated with increased cannabis use among young people

A recent study from researchers in Uruguay found that the use of cannabis following legalisation decreased among teenagers.

Uruguay was the first country in the world to legalise and regulate recreational cannabis. Since legalising the drug in 2016, the country is now regarded as a pioneer, paving the way for other countries like Canada, Mexico and Malta.

Using data from cross-sectional surveys of secondary students in Uruguay and Chile, the study evaluated changes in the prevalence of past-year, past-month and any risky and frequent cannabis use following the enactment and implementation of cannabis legalisation

“The legalisation of recreational cannabis in Uruguay was not associated with overall increases in either past-year/past-month cannabis use or with multi-year changes in any risky and frequent cannabis use among young people,” the authors stated in the paper’s abstract.

Current cannabis labelling system “doesn’t tell you much”

Labels like indica, sativa and hybrid—commonly used to distinguish one category of cannabis from another—tell consumers little about what’s in their product and could be confusing or misleading, suggests a new study of nearly 90,000 samples across six states in America.

Published on 19 May in the journal PLOS One, the research constitutes the largest analysis to date of the chemical composition of cannabis products.

It finds that commercial labels “do not consistently align with the observed chemical diversity” of the product. The authors are now calling for a “weed labelling system” akin to the Food and Drug Administration’s “nutrition facts panel” for food.

“Our findings suggest that the prevailing labelling system is not an effective or safe way to provide information about these products,” said co-author Brian Keegan, an assistant professor of Information Science at CU Boulder.

“This is a real challenge for an industry that is trying to professionalise itself.”

Cannabis dependence treatment is effective in tackling common co-morbidities

Earlier this month, Australian researchers released a paper looking into the effectiveness of cannabis dependency treatment on common co-morbidities, including mood, sleep and pain problems.

The researchers found that the treatment helped decrease anxiety, stress and sleep disturbance among the cohort of 128 cannabis-dependent participants.

The analysis used data from a 12-week double-blind placebo-controlled trial testing the effectiveness of the cannabis-based medicine nabiximols against placebo in reducing illicit cannabis use.

The researchers found that there was “no evidence” that nabiximols treatment is a barrier to reducing co-morbid symptoms. In fact, they found that the treatment reduced illicit cannabis use and improved comorbidity symptoms, even when participants were not able to achieve abstinence.

 

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Research finds cannabis consumers may require more sedation

Consumers required higher levels of sedation during endoscopic procedures than non-users

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Research finds cannabis consumers may require more sedation

Experts have highlighted the need for doctors to be more aware of their patients cannabis use, as research suggests consumers may require higher levels of sedation.

As cannabis is legalised in more places and usage continues to rise, researchers in Canada said clinicians should be aware of patients’ cannabis consumption, and prepare themselves for increased sedation and the risks that come with it.

It comes as a new study has associated cannabinoid use with increased odds of requiring higher total sedation during gastric endoscopies – a procedure that begins with the insertion of a tube and camera through the throat – than non-users.

The authors of the study conducted a prospective cohort study of 419 adult outpatients undergoing endoscopic procedures at three Canadian centres.

Procedures were conducted under conscious sedation, which leaves the patient relaxed and comfortable but partially conscious during the procedure.

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Researchers did not examine its impact on propofol sedation, which is more commonly used in the UK and US so more research would be needed to determine the wider impact of cannabis use on sedation.

“Patients didn’t have increased awareness or discomfort during procedures, but they did require more drugs,” said Yasmin Nasser, MD, PhD, lead researcher on the study and assistant professor at Snyder Institute for Chronic Diseases at the University of Calgary.

Each patient completed two questionnaires, one before the procedure about their cannabis use and another afterwards, indicating their awareness and comfort level during the procedure. The questionnaires were analysed along with details about the use of the sedatives midazolam, fentanyl and diphenhydramine during the procedure.

Cannabis use was associated with increased odds of requiring higher total sedation—defined as more than 5 mg of midazolam, or more than 100 mcg of fentanyl, or the need for diphenhydramine.

Interestingly, cannabis use was not associated with higher use of sedation during colonoscopy. Researchers said this could be because gastroscopy generally requires more sedation than colonoscopy due to the irritation caused in the upper part of the gastrointestinal tract.

Cannabinoid use was not independently associated with fentanyl use or adverse events, nor was it associated with intra-procedural awareness or discomfort, the authors found.

This study looked at whether patients were users or non-users of cannabis, but did not examine the timing, quantity or route of cannabis intake prior to the procedure. Researchers say these variables could be the basis for future studies.

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