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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.

READ MORE  CBD dominant cannabis does not influence driving skills - study

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.

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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.

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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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Insight

CBD dominant cannabis does not influence driving skills – study

Participants showed no signs of impairment when it came to driving but they did test positive for trace levels of THC

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A study suggests that CBD-dominant cannabis does not influence the skills associated with driving such as reaction time, concentration, time perception or balance.

The Swiss study examined CBD and THC dominant cannabis flowers to see if they impacted on neurocognitive or psychomotor skills.

Some of the participants were given a CBD dominant strain that had a 16.6:0.9 per cent ratio, and others were given a placebo.

After inhaling the cannabis, participants were asked to undergo the Vienna Test System TRAFFIC. This measures reaction time, behaviour in stressful situations, concentration and performance. They also took further tests to determine their fitness to drive, three separate balance tests and coordination along with vital signs such as blood pressure and pulse.

Driving and cannabis

The participants showed no signs of impairment when it came to driving but they did test positive for trace levels of THC in their blood. The blood tests were taken 45 minutes after consuming the CBD dominant cannabis.

The authors noted that the slight change in THC levels within the system would potentially place patients in violation of traffic safety laws.

The researchers noted: “This finding suggests that higher CBD concentrations cause a negative allosteric effect in the endocannabinoid system, preventing the formation of such symptoms. Nevertheless, it is recommended that consumers refrain from driving for several hours after smoking CBD-rich marijuana, as legal THC concentration limits may be exceeded.”

Driving and THC tests

When it comes to THC and roadside testing, new research revealed that THC levels in blood and saliva are poor measures of impairment.

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Researchers analysed a range of studies on the relationship between driving performance and Tetrahydrocannabinol (THC) concentrations in blood and saliva.

The researchers took data from 28 different publications that involved ether ingested or inhaled cannabis. They characterised the relationships between blood and saliva THC concentrations, driving performance and skills such as reaction time or concentration.

When it came to infrequent cannabis users, there were some significant correlations between blood and oral levels of THC and impairments were observed. However, It was noted that these relationships were ‘weak.’

There was no significant relationship noted for the more regular consumers.

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Epilepsy

CBGA may be ‘more potent’ than CBD against seizures in Dravet syndrome

Dr Lyndsey Anderson said there is more to explore when it comes to creating more treatment options for Dravet syndrome.

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Athletes: A row of test tubes containing CBGA oil with a doctors white gloved hand holding one up to the light

Scientists say they have found the ‘Mother of all cannabinoids’ which may help to reduce seizures in Dravet syndrome.

A new study on mice from the University of Sydney found that three acidic cannabinoids found in cannabis reduced seizures in Dravet syndrome, an intractable form of childhood epilepsy.

The three cannabinoids are cannabigerolic acid (CBGA), cannabidivarinic acid (CBDVA), cannabigerovarinic acid (CBGVA). All three but CBGA in particular “may contribute to the effects of cannabis-based products in childhood epilepsy” noted the researchers and were found to potentially have ‘anticonvulsant properties.”

The study marks the first time that three acidic cannabinoids were found to potentially help reduce seizures for Dravet syndrome.

Speaking with Cannabis Health News, the lead author of the study, Dr Lyndsey Anderson, said: “We found that CBGA exhibited both anticonvulsant and pro-convulsant effects. CBGA was more potent than CBD against febrile seizures in a mouse model of Dravet syndrome. We also found that a combination of CBGA and clobazam was more effective than either treatment alone. Additionally, we found that CBGA was anticonvulsant in the maximal electroshock acute seizure model, a model for generalized tonic-clonic seizures.”

She added: “CBGA did, however, present some proconvulsant effects. The frequency of spontaneous seizures in the mouse model of Dravet syndrome was increased with a high dose of CBGA. Also, CBGA was proconvulsant in the 6-Hz acute seizure model, a model of focal, psychomotor seizures.”

Although CBGA shows promise, Dr Anderson also stressed that it needs more research before it can replace CBD. She cautioned that Dravet syndrome patients may still need to proceed with caution.

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“Artisanal cannabis-based products are believed to reduce seizures in Dravet syndrome patients,” she said. “As these oils contain rare cannabinoids like CBGA, it is possible CBGA then contributes to the anticonvulsant effects of these artisanal cannabis oils. However, there were proconvulsant effects observed with CBGA, suggesting that Dravet syndrome patients may need to proceed with caution. The proconvulsant liability of CBGA would need to be addressed before it replaced CBD as an anticonvulsant.”

What is CBGA?

Sometimes referred to as ‘the mother of all cannabinoids,’ CBGA is the precursor molecule to many different cannabinioids including CBD and THC. It is thought to help some diseases such as colon cancer, metabolic disease and cardiovascular disease. It is a non-intoxicating cannabinoid much like CBD.

Dr Anderson explains that more research is needed to explain how the three cannabinoids work together.

“We don’t know how they work together yet,” she said. “We found that CBGA, CBDVA and CBGVA were all individually anticonvulsant against thermally induced seizures in the mouse model of Dravet syndrome. We did not investigate whether a combination of these three cannabinoids would result in a greater anticonvulsant effect than either cannabinoid alone. Future work will definitely explore this possibility.”  

CBGA future research

This isn’t the end of the research into CBGA for Dravet Syndrome. Dr Anderson said there is more to explore when it comes to creating more treatment options for Dravet syndrome.

 

She said: “Next on the horizon for this research is to explore whether the anticonvulsant properties of CBDVA and CBGVA translate to other seizure types including spontaneous seizures in the mouse model of Dravet syndrome. Additionally, we have extensively interrogated the anticonvulsant potential of individual cannabinoids and identified ten with anticonvulsant properties.”

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“We are now interested in investigating what happens when we combine these anticonvulsant properties. It remains an open possibility that greater anticonvulsant effects are achieved when the cannabinoids are administered in combination.”

The study was recently published in the British Journal of Pharmacology (DOI: 10.1111/bph.15661)

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Epilepsy

CBD-enriched cannabis oil may reduce seizures in children with West syndrome

Four of the eight children had less than half the seizures they had before the trial.

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Seizures: A black and blue x-ray of a brain on a black background

A new study on CBD-enriched cannabis oil for seizures involving eight children revealed that electroencephalogram (EEG) abnormalities improved by 20 to 80 percent.

The study on seizures, published online, examines if CBD-enriched cannabis oil used as an add-on therapy could help children with condition that causes spasms. It found that four of the eight children in the trial had less than half the seizures they had before the trial.

The researchers reviewed the experiences of eight West syndrome children who were refractory to anti-seizure medications between May 2020 and March 2021. The children were aged between sixteen to twenty-two months and each received a dose of 25:1 CBD to THC as an add-on therapy.

Seizure decrease

The participants record a mean of 63 seizures per day with the lower rate recorded as 31 and the higher amount recorded as 79.

At the follow-up appointment, two of the patients reported a 75 percent to 99 percent decrease in frequency. A further two children recorded a 50 percent decrease while one patient did not experience any changes at all.

The authors wrote: “The index of EEG (electroencephalogram) abnormalities improved between 20 per cent and 80 per cent in seven patients concurrently with the reduction in seizures.”

“Tolerability among those patients experiencing fewer seizures was good and, overall, “adverse effects were mild and transient.”

Epilepsy seizures

West syndrome is a form of epilepsy. According to Epilepsy Action UK, West syndrome happens in about one in every 2,5000 to 3000 children. This means that about 350 to 400 children will develop the syndrome each year in the UK.

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In 9 out of every 10 children, the first seizures will take place in the first year between three to eight months of age. They may happen in clusters or runs rather than singularly. The children may go on to develop learning difficulties as a result of the syndrome.

Earlier studies

A new study published this month shows that CBD transdermal gel may help to reduce seizures and improve children’s quality of life.

The study, Safety and Tolerability of Transdermal Cannabidiol Gel in Children With Developmental and Epileptic Encephalopathies, was conducted in Australia and New Zealand. It involved 40 children with Developmental And Epileptic Encephalopathies (DEE). The authors noted that the DEEs were the most severe type of epilepsy typically beginning in childhood.

The non-randomised, clinical trial involved CBD gel being applied twice a day for six and a half months on children aged three to eighteen. The gel had a CBD content of 125 to 500 mg.

The researchers found that the gel helped in response to facial impaired awareness seizures potentially reducing them to 44.5 percent. It also helped to reduce tonic-clonic seizures where the muscles violently contract by 22.5 percent. Overall, the seizures in 33 participants were reduced by 43.5 percent.

The children also recorded improvements in alertness, alongside the seizure reduction.

Read More: Study on CBD gel shows potentially positive effect seizures

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