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Peering into the void – the intriguing world of the endocannabinoid system

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That refreshing wake-up feeling. The rumble in your stomach. The stress-busting power of a deep breath. These momentary passages of everyday life are part of the body’s response to the myriad of molecular interactions going on internally, invisible to the human eye.

The complex cell-signalling endocannabinoid system encapsulates these very interactions, mediating multiple processes at work in your body right now – from the immune response to metabolism (the chemical reactions of life).

The endocannabinoid system is comprised of three major components; the endocannabinoids themselves, the enzymes which break down endocannabinoids and receptors – all interacting in a network of neural pathways and cells.

It is believed that the endocannabinoid system has a crucial role in “essentially all human disease.”

The compound cannabidiol or ‘CBD’ (derived from the cannabis plant) has an interesting part to play in the system, with therapeutic potential for a variety of neurological disorders.

Endocannabinoids are molecules synthesised in the body (endo meaning ‘in’). Their aim is to bind to specific cell-surface receptors and exert a range of physiological effects in the body. For example, stimulating that familiar growl of hunger.

The major endocannabinoids which have been characterised in-depth are anandamide and 2-arachidonoylglyerol (2-AG).

THC is the psychoactive substance in cannabis plants. Cannabidiol (CBD), first synthesised in 1965, can be perceived as THC’s sensible older sibling. While you might not think it is quite as exciting as THC in its effects, I hope to change your mind.

In fact, the cannabis plant has over 60 cannabinoids which are similar to endocannabinoids such as 2-AG. Both CBD and 2-AG are neurotransmitters – chemical messengers which transmit a signal to a key target cell in order to elucidate an effect. Although the exact number is unknown, there are over 200 neurotransmitters in the human body.

The principle purpose of a neurotransmitter is to activate its target receptor. The resulting physiological effect depends on the chemistry of the receptor itself and the specific biochemical pathways involved.

For instance, the neurotransmitter serotonin (also known as the ‘happy’ chemical) binds to 5-hydroxytryptamine (5-HT) receptors, thus regulating a number of processes including memory and learning and muscle contraction.

How exactly does a neurotransmitter such as serotonin reach its target receptor? How does neurotransmission of CBD work after ingestion? To understand this a little more, we will need to dive down to the level of the cell itself…

Cells in the human body come in an array of shapes and sizes and have various components, from the control-centre (the nucleus) to the protein-making machines (known as ribosomes) to the cell surface membrane, which is decorated with receptors. The gaps between cells are known as synapses. Those synapses which use chemical messengers are called chemical synapses.

A neuron is a vital cell of the nervous system, with the ability to transmit information to other cells in order to bring about an effect.

Imagine you are standing on the surface of a neuron cell body – the portion of the neuron which contains its nucleus.  Stretching before you is a longer extension of the neuron, the axon.

If you gaze into the distance, you can see that this axon starts to divide into a multitude of branches. These are the axon terminals.

Curious, you walk down the axon until you stand right at the end of one of these vast branches.

Do you dare to peer down into the void, the synaptic cleft? The neuron on which you stand is ‘presynaptic’ (situated before the synapse). Towering before you is a portion of a gate-like protein (called a voltage-gated calcium channel) with the remainder embedded in the cell surface membrane below you.

You notice that there are more of these gate-like proteins along the other edges of your axon terminal (and all over the axon terminals adjacent to yours). If you look through this voltage-gated calcium channel and across the gap, you can just make out the postsynaptic neuron.

Suddenly, you feel a trembling in the cell beneath you and turn around to see the surface of the long axon behind you rippling, with the rippling coming closer by the second! You hold on to the side of the calcium channel to brace yourself as this rippling reaches the surface below your feet.

Remember the ‘information’ that neurons transmit? This information is an ‘action potential’ or ‘nerve impulse’ (imagined as the ‘rippling’ depicted here) – an electrical signal which will stimulate the calcium channel. In turn, this will enable positively charged atoms known as calcium ions to flow into the neuron.

Fascinated, you watch the channel’s shape shift and alter, clinging on to its side as the influx of calcium ions passes you. There is another trembling in the cell membrane below you and you lie flat, looking over the edge of the axon terminal.

Because of the influx of calcium, sphere-like portions of the membrane – called vesicles – can now release small molecules into the synaptic cleft directly beneath you. These small molecules are neurotransmitters – perhaps serotonin.

You watch as the molecules diffuse across the synapse and bind to receptors dotted along the surface of the postsynaptic neuron. In binding to these receptors, the neurotransmitters are able to stimulate another nerve pulse down the postsynaptic neuron.

Synaptic transmission in the human nervous system.

Now you know how neurotransmitters normally travel between neurons, it will be easier to understand how our particular group of neurotransmitters – the endocannabinoids like 2-AG of the endocannabinoid system (or cannabinoids like CBD) – do so. The way in which endocannabinoids reach their target receptor occurs in a backwards manner, through retrograde signalling.

Indeed, the activation of a postsynaptic neuron by a nerve impulse stimulates endocannabinoids to diffuse across the synaptic cleft to bind to receptors of the presynaptic cells. The receptors bound by anandamide or 2-AG bind are the cannabinoid receptors.

Specifically, these are cannabinoid receptors 1 and 2 (CB1 and CB2), which were first discovered in the nineties. While CB1 is situated abundantly in the Central Nervous System (CNS), CB2 is expressed much more in both the Immune and Peripheral Nervous Systems.

The activation of these two receptors by endocannabinoids has numerous implications for cellular physiology (the activities in the cell which keep it functioning) or cell motility, to name only a couple.

In the last three decades, the endocannabinoid system has been the most studied retrograde system of neurotransmission, with plentiful facets of research seeking to unravel the sheer complexity of the overall system.

While we know the system has implications for multiple physiological processes – from mood regulation to neuroprotection – there is a vast number of unknowns in this area. For instance, although there is a whole collection of evidence presenting the components of the endocannabinoid system as anti-cancer targets, the complex interplay of this system with other biological pathways makes progress challenging, with rigorous testing required.

CBD has been shown to possess anxiolytic (ability to reduce anxiety) antipsychotic (for management of psychosis) and neuroprotective (aiding preservation of neuronal integrity) properties, with the potential to treat several health conditions such as schizophrenia, depression or Parkinson’s.

There is a need for further controlled clinical research on the use of CBD in these areas and its role as an adjunct therapy – given in addition to an existing therapy for a condition such as epilepsy in order to increase effectiveness.

Interestingly, CBD binds to neither CB1 nor CB2 receptors – it is thought that it may instead interact with a receptor not yet discovered! Additionally, it has been proposed that CBD could alter how endocannabinoids interact with CB1/2.

As you read this, research scientists are peering into the synaptic cleft – the void of the unknown – to elucidate the therapeutic potential of the endocannabinoid system and compounds like cannabidiol.

Perhaps next time you feel that niggling rumble of hunger, your thoughts will wonder down to the unseen world of the cell – to the tiny neurotransmitters whizzing across those synaptic clefts in a series of complex biological interactions which might just tell you that it’s time for lunch.

Insight

All female-led CBD company to list on London Stock Exchange

It will be the first multi-brand CBD-focused consumer goods business to list on the LSE.

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South West Brands CEO Rebekah Hall (second right) leads the all-female management team

The multi-brand consumer goods company South West Brands has announced its intention to apply for listing on the London Stock Exchange (LSE).

South West Brands expects to be admitted to the LSE in July and will be the first multi-brand CBD-focused consumer goods business to list on the LSE.

The group develops, licences, and markets CBD brands to consumers across the UK.

It plans to raise equity to continue to develop its existing portfolio of brands and pursue its strategy of adding more assets over the next two years.

Launched earlier this year, the all-female management team brings together extensive experience from both the consumer products sector and the CBD industry, supported by an exemplary board with experience across brand building, marketing, licensing, finance, and cannabis.

Its CEO Rebekah Hall brings almost a decade of experience in investment banking to the role, and helped set up Botanic Lab, the company behind Europe’s first CBD drink in 2018.

Rebekah Hall, CEO comes from a background in investment banking

Hall commented: “This is a key moment in the development of the CBD industry. South West Brands is uniquely placed to take advantage of this growing market and the significant opportunity that exists in branded goods. The time is right to advance consumer products expertise, discipline, and structures that can elevate the industry and consumer experience, ultimately building world class brand assets that utilise CBD.

“Our listing on the London Stock Exchange will enable South West Brands to access the new pool of cannabis investors that has grown in London following the successful admission of a number of cannabis companies in 2021. The Admission will allow the Group to advance to the next stages of its growth plans, and build a suite of strong brands that not only utilise CBD, but drive consumer engagement and product sell-through, something which has been missing in the industry thus far.”

The company has identified key product areas and markets which it will look to build and develop quality CBD brands that address areas of underserved consumer need.

These include: Drinks, Menstrual cycle care, Generation Z Skincare, Sport, Men’s holistic wellness, Menopausal care and 50+ supplements.

As well as Botanic Lab, the South West Brands has two further brands in development that are expected to launch later in the year, including Love,MeMeMe a Generation Z focused beauty and wellness brand, and FEWE, a menstrual cycle care brand.

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Industry

Daniel Gauci – the crowdgrowing pioneer aiming to revolutionise the cannabis industry

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The ‘Gentleman Smoker’ is a stylish, family man  – and cannabis influencer. His mission is to break down stigmas by promoting responsible use of cannabis among its many benefits.

Under this public figure we find Daniel Gauci, CBDO at JuicyFields, a medicinal cannabis crowdgrowing platform that is revolutionising the fast-growing industry.

Today he is with us to talk about his relationship within the cannabis industry and the medicinal resources that offer the world’s most famous green plant.

What is it like to be The Gentleman Smoker? Tell us about the positive and negative aspects.

The Gentleman Smoker came about from the want of promoting the positive aspects of medicinal marijuana from a realistic albeit different perspective.

To break the stereotypes of what a typical cannabis user is and to show that a modern day cannabis user is a professional, responsible person.

I have a vast history with cannabis and most if not all is positive, from positive, personal points of view regarding introspection, mental health and productivity matters to the medicinal benefits within many diseases including ones my children suffer from.

The negative aspects, if I have to view it that way, would be that my private and professional life are now as one, and that my thoughts and motives are there for all to see, but that also has positives.

Many people still deny the health benefits that cannabis has to offer, what do you think about that?

The evidence is there. I am still surprised to hear the claim that there is not enough research, data or studies regarding medicinal marijuana and the benefits that it offers.

There are more than fifteen thousand peer reviewed studies and trials freely available for review and many more recently that focus on the endocannabinoid system that is clearly recognised throughout the medical world, with many clinicians prescribing cannabis for a multitude of treatments.

It does pain me that people can deny something when the information is freely available, however, it is understandable due to the many years of negative propaganda campaigns.

More and more countries are changing their legislation and perception of medical cannabis. Will we ever see a world in which medical cannabis is legislated and socially accepted?

I hope so. However, let us not forget there are places in the world where it is still a crime to be gay or to favor one religion over another.

There are many challenges that marijuana legislation faces but I see them being overcome one by one.

Let us take Europe as an example, the shift for positive legislation has come quick with governments and medicine authorities realising the potential that medicinal marijuana offers not only as medicine for patients but as an industry for the nation.

If we look at the current predicted figures the industry is expected to boom in the coming years, this will only speed up favourable legislation ultimately benefiting the consumer.

If we look back 10 or even 5 years, progress is gaining insatiable momentum that was not predicted by many so soon.

You have a background experience in the pharmaceutical field. Could you list some new medical benefits that can be found in cannabis if research continues?

Everyday I wonder where the research will take us. I read almost weekly of new applications and possible uses that medicinal marijuana can offer.

Not just in relation to cannabinoids but also in relation to terpenes and also the entourage effect, the innovation is truly outstanding.

When I studied pharmacology we touched upon cannabis in relation to the psychoactive elements in relation to the body and mind but since then microbiology and the understanding of chemical relationships has advanced so much I believe that we will keep learning more about this wonderful plant and what she has to offer for many years to come.

The most curious aspect for me is the relationship between the creation of amino acids and the importance of synapse connection in relation to speech. I am very much looking forward to the progress in this particular field of research.

On a personal level, what influence has medical cannabis had on your life?

Cannabis has held a different influence over me at various stages during my life. From one off theory and research to that of actively keeping members of my family alive.

The gap is profound and stretches so far but to narrow in on the practical medical applications in a personal scenario, it would be that of helping to save our baby daughters life.

It showed me how persecution from ignorance was prevalent in many avenues in life, not just in the medical marijuna world. In reflection it influenced me to be a better person, father, husband and member of society.

Having seen with your own eyes the benefits of medical cannabis, what would you say to those who want to try but are not sure about it?

Go and do it and do not waste time. Seek medical expertise prior but do not wait for any condition to worsen. Cannabis, while not 100% safe in all methods and for all people, has very little side effects with very, very high quantities needed for any type of overdosing classification.

Medicinal marijunana can have an immediate effect in certain conditions such as epilepsy and Parkinson’s disease with other conditions and symptoms being alleviated within minutes.

There are numerous resources available that can guide and help you to make an informed decision. Currently we are treating our severely autistic, non verbal son with CBD oil.

The results are proving positive, the studies and trials undergoing currently, particularly in Spain, are very encouraging.

My daughter was treated with high strength (and dosage) of full spectrum THC oil when undergoing chemotherapy for a tumor on her kidney, not only did it help with managing negative side effects of the harsher treatments, we believe also stopped the tumor from growing. (However, we have no medical evidence to present for this claim).

What is the role of JuicyFields regarding the medical cannabis industry?

JuicyFields enables people to support the medicinal cannabis industry by keeping the supply chain within grassroots and community cultivation level operations.

JuicyFields is adamant that the people working within this industry for years, fighting for legislation and research should be the ones to benefit now that legislation is positive and the industry being legalised.

We operate so that the money generated in this industry goes back to the community farmers and cultivators and processors so that they can continue to support themselves and grow, rather than having to sell their lands or businesses to multinational corporations eager to monopolise the industry for profit.

Is crowdgrowing going to change the course of the cannabis industry? How?

I believe so, yes. The other role of JuicyFields is to provide easy access to those wanting to support and invest in the medical cannabis industry.

For those who have looked, it is very expensive and prohibitive to enter. High costs, many licenses, industry knowledge and a highly skilled workforce is required if one were to venture in the industry as a normal business might.

That is where crowdgrowing comes into play. JuicyFields provides a platform that these budding entrepreneurs and investors can not only support the grass roots level cultivators but to also make a profit for themselves without the heavy time and financial commitment usually required.

The cultivation partners on the platform are all vetted to the highest of standards and comply with every regulation required where they operate and beyond.

All with full compliance and cultivation licenses from the relevant authorities and are also insured. This means that crowdgrowers are fully legal and compliant to enter into what is traditionally an exclusive yet very profitable and fast growing industry.

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Fibromyalgia

Fibromyalgia and cannabis: What does the latest research say?

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Fibromyalgia is a condition which causes chronic pain across the body

Cannabis Health rounds up the latest research into the impact of cannabis on fibromyalgia. 

There are thought to be around 1.5-2 million people in the UK currently living with fibromyalgia, a condition which causes chronic pain around the body, muscle stiffness and fatigue.

With no cure for the illness and symptoms severely affecting day-to-day life, research is focusing on therapeutic treatments – including medical cannabis. 

In 2019, research published by Sagy, Schleider, Abu-Shackra and Novak showed that cannabis can help reduce fibromyalgia pain. The study of 367 patients found that pain intensity decreased when treated with medical marijuana, leading the team to state that “cannabis therapy should be considered to ease the symptom burden among those fibromyalgia patients who are not responding to standard care”.

Chaves, Bittencourt and Pelegrini further supported these findings in October 2020, concluding that phytocannabinoids can serve as an affordable yet well-tolerated therapy for fibromyalgia symptom relief and quality of life improvements. 

After the randomised controlled trial, the researchers went as far as to suggest that the cannabinoid therapy “could become an herbal or holistic choice of medicine for treating fibromyalgia as part of Brazil’s public healthcare system”.

A study in Italy, published in February 2020, also demonstrated that medical cannabis improves the efficacy of standard analgesic fibromyalgia treatments. 

Researchers concluded: “This observational study shows that medical cannabis treatment offers a possible clinical advantage in fibromyalgia patients, especially in those with sleep dysfunctions.” 

Published in the Clinical and Experimental Rheumatology journal, the study followed 102 fibromyalgia patients who had not responded well to conventional treatments. These participants were given two forms of medical cannabis oil extracts and researchers then collected data over a six-month period from patients, who self-reported fibromyalgia symptoms, how well they slept, and feelings of fatigue, as well as depression and anxiety levels.

While only a third of fibromyalgia patients reported reduced symptoms of the disease overall, cannabis did improve overall quality of life for some. Fewer symptoms of depression and anxiety were found in around half of patients, too. 

Despite fibromyalgia being more common amongst women – up to 90 per cent of sufferers are female – one study has found that cannabis may provide better pain relief for men.

The preclinical studies, conducted in 2016, compared the analgesic, subjective and physiological effects of active cannabis and inactive cannabis in male and female cannabis smokers under double-blind, placebo-controlled conditions, and measured pain response through the Cold-Pressor Test. 

Among men, active cannabis significantly decreased pain sensitivity relative to inactive cannabis. However, in women, active cannabis failed to decrease pain sensitivity relative to inactive, indicating that in cannabis smokers, men exhibit greater analgesia compared to women.

Researchers concluded: “Sex-dependent differences in cannabis’ analgesic effects are an important consideration that warrants further investigation when considering the potential therapeutic effects of cannabinoids for pain relief.”

While further research is necessary, it is clear to see that medical cannabis can make a huge difference to treatment and relief of pain caused by fibromyalgia.

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