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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.

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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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Insight

The best ways to take CBD for pain relief

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CBD is becoming a popular tool for pain management, but with so many options out there, how do you know where to start?

With research constantly emerging to support the health benefits of CBD, more and more people are turning to the remedy – especially when it comes to alleviating pain and discomfort.

But how does it actually work? There are several ways to take CBD, each offering various pros and cons – we’ve rounded up some of the best methods. 

Get topical

In terms of pain relief, one of the most common methods is on the skin. Topical products like lotions and balms can be applied to skin over painful joints or bones and are particularly effective when used to relieve symptoms of arthritis.

However, research is still ongoing to determine whether these products deliver CBD below the skin. It is also difficult to pinpoint the exact effect CBD delivers – with many including common over-the-counter ingredients such as menthol, capsaicin and camphor, it’s uncertain whether the positive relief is solely due to CBD, or if these other ingredients play a significant role.  

Several studies have hailed CBD oil as one of the most helpful methods when it comes to relieving pain symptoms, especially when combined with other forms such as topicals. 

Medical nutritionist and health author Dr Sarah Brewer said: “Cannabidiol oil has direct effects on the endocannabinoid system in the brain. This enhances the effects of other brain chemicals, such as serotonin and anandamide, to reduce pain perception. It is also a powerful antioxidant which suppresses inflammation.” 

Something to digest

Another well-known method for using CBD is by mouth. Whether in capsules, food or liquid, CBD that is swallowed is absorbed through the digestive tract. 

Despite its popularity, this method does have its downfalls. Absorption is slow and dosing can be tricky due to the delayed onset of effect (it can take one to two hours to fully have an impact), plus many believe there isn’t enough research into how recent meals and other factors affect consumption.   

But it has been widely reported that after a safe and effective dose has been established, capsules can work for daily use.

While it may not taste particularly pleasant, CBD can also be effectively absorbed directly into the bloodstream by holding liquid from a spray or dropper under the tongue. Research shows effects can the be felt in as little as a few minutes. 

Give the vapors

CBD can also be inhaled via a vaporising, ‘vape’ pen. However, it’s possible that inhalation can carry unknown risks, particularly in those with respiratory issues and ailments such as inflammatory arthritis, and so isn’t widely recommended as a method for use. 

With all methods, the common downfall is wavering dosage guidelines. Measures can change depending on a number of factors including age, weight and reason for use, however resounding guidance from experts is to ‘go low and slow’. Start with just a few milligrams twice a day, and if relief is inadequate after one week, increase the dose by the same amount, in small increments over several weeks if needed. 

It’s clear that more research is needed to determine exact details into these methods, but this is only set to increase as the number of people turning to CBD for pain relief continues to grow. 

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Insight

CBD distillates, isolates & full spectrum – what’s the difference?

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Fresh Bros take you through the more technical side of CBD

With so many CBD products on the market, do you know your distillates from your isolates? The experts at US manufacturer Fresh Bros break it down.

Las Vegas manufacturer Fresh Bros have nearly a decade of experience in the hemp industry.

The team’s aim is to produce innovative formulas that suit personal needs in terms of performance, recovery, relaxation, and overall wellbeing. 

But with so many products on the market Fresh Bros want to help consumers find the best products for their needs.

Here they explain the differences between CBD distillate, CBD isolate, and full-spectrum CBD products, as well as highlighting the key differences between Delta 8 THC and Delta 9 THC.

CBD isolates 

Cannabidiol (CBD) is one of the most researched compounds of all the known phytocannabinoids found in the cannabis plant. 

CBD isolates are, unsurprisingly, isolated forms of CBD. During the extraction process, cannabidiols are removed or filtered out of the hemp plant except for CBD, resulting in a pure product. 

CBD isolate is great for anyone who struggles with the original earthy flavors of other conventional oils or edibles, so if you’d prefer a high-potency CBD product that is tasty, doesn’t contain THC and or any “extra” cannabinoids that are found in a distillate or full-spectrum product — CBD isolate may be the way to go.

CBD distillates

Unlike CBD isolate, CBD distillate (aka broad-spectrum CBD) typically contains an array of cannabinoids, terpenes, vitamins, and fatty acids that are very beneficial to the body. CBD distillate contains only negligible amounts of THC after going through special processing. 

CBD isolate is an incredible healing source, of course, but there are hundreds of other beneficial cannabinoids found in the hemp plant besides CBD – cannabinol (CBN) and cannabigerol (CBG) to name a couple. 

Therefore, if you want to reap all of the potential benefits of CBD without the high, and you don’t mind the stronger taste, CBD distillate may be the best option for you. 

Full spectrum

Full-spectrum CBD products contain all cannabinoids, terpenes, and plant materials – including the naturally occurring small amount of THC in hemp. 

 

Delta 8 THC vs Delta 9 THC

The cannabis plant has more than 120 cannabinoids, but only a fraction of these have really been studied and marketed. Delta 9 THC is the psychoactive compound found in cannabis, and has received a lot of attention over the last few years. 

However, consumers are slowly noticing the lesser-known Delta 8 THC (a less available double-bond isomer of the more common Delta 9 THC, also derived from hemp) due to its unique properties. The main differences between these two types of THC are found in the molecular structures of both, and it’s worth noting that Delta 8 THC is capable of producing a milder, more manageable, and more enjoyable high compared to Delta 9. 

Delta 8 also has added therapeutic benefits and less severe and functionality-impairing side effects.

 

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