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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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Journal Club: The CANPAIN trial in focus

This edition of the Journal Club focuses on the recently announced CANPAIN trial.

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The latest issue of the Journal Club, by Grow Pharma, focuses on the recently announced CANPAIN trial.

Introduction

On the 1st of November 2018, the Home Office announced that cannabis-based medicinal products (CBMPs) were to be moved from Schedule 1 to Schedule 2 status in the misuse of drugs regulations, reflecting the view that these agents possess medical utility.

One of the conditions where the scientific literature contains evidence for the utility of medical cannabis is chronic non-cancer pain. Chronic non-cancer pain is also an often-cited reason for patients taking cannabis for medical purposes. Collecting further data on the effectiveness and tolerability of medical cannabis is key in order to potentially pave the way for its approval as an NHS treatment in the future.

Feasibility study

Prior to commencing the CANPAIN trial, a feasibility study will be conducted, with a minimum of 100 patients recruited and followed across a 3-month period. This has been granted REC approval and will aid in establishing likely rates of patient recruitment, duration of participant enrolment in the study, the demographic and geographic spread of patients, patient acceptability of data collection and identify any issues with technological and drug delivery logistics.

The CANPAIN clinical trial

If the feasibility study is successful and no changes are required then the CANPAIN study will be a pragmatic non-randomised, non-blinded real-world trial of the safety, tolerability and effectiveness of a CBMP for the treatment of chronic non-cancer pain compared against matched controls receiving standard of care pain management.

The study could run for 3 years but there will be an interim analysis after 12 months with a planned sample size of at least 5000 participants per group, with each patient completing a minimum of 12-months treatment. The CBMP used will be an 8:8 (8% THC, 8% CBD) balanced flower inhaled by steam using a handheld device with flow counting and Bluetooth connectivity.

The CANPAIN study will consist of an initiation visit (or call) to allow screening and baseline data to be collected and then a follow up visit (or call) every three months thereafter, until the end of the trial.

The primary end-point will be the difference in pain intensity scores among patients in the CBMP group compared to matched controls.

Secondary end-points will include quality of life, sleep, general well-being, and changes in concomitant medication intake. Safety and tolerability of the treatment regimen will also be monitored.

Grow Pharma and IPS pharma are to be the distribution partners for the CANPAIN trial launched by LVL Health alongside partners Aurora Cannabis Inc, Celadon Pharmaceuticals and RYAH group.

Pain consultants who would like to become involved in this clinical trial can contact LVL Health at [email protected]

To sign up to the Journal Club mailing list, click here

 

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What you should know about cannabis and drug interactions

Juicy Fields explores the important considerations of combining cannabis medication and products with drug treatments.

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Juicy Fields: What you should know about cannabis and drug interactions

You have probably read or heard something along the lines ‘consult your physician before taking cannabis if you are on any prescription pills.’ That statement consists of wise words that you should adhere to at all times.

Prescription pills can interact with cannabis, foods, beverages, supplements, and even with each other, leading to mild or severe side effects. Consequently, without sounding redundant, always consult your doctor to avoid such incidents.

What is a drug-drug interaction?

A drug or medication interaction occurs when a person takes a combination of drugs (2 or more) that are incompatible with each other. In such cases, one of the drugs interferes with the other(s) by countering or accelerating their effects. This may lead to drug inefficiency, severe side effects, and sometimes the loss of life.

How does cannabis interact with other drugs?

P450 enzymes metabolize all drugs before they are available in the consumer’s system. The Cytochromes P450 are a group of enzymes responsible for metabolizing many compounds. These enzymes are primarily located in the liver but can also be found in cells throughout the body in small quantities.

There are more than 50 enzymes under the P450 class, but only six are responsible for metabolizing 90% of prescription drugs. These enzymes include CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. Cannabinoids, THC and CBD, in particular, inhibit or induce the function of these Cytochrome P450 (CYP450) enzymes.

This interferes with enzymatic function, which affects the concentration of certain drugs. Cannabinoids play three prominent roles in drug interactions.

  1. Victims: cannabinoid levels are affected by the presence of another drug.
  2. Perpetrators: the cannabinoids affect the levels of other drugs
  3. Overlapping other drug’s effects: cannabis and other drugs have similar effects on a consumer.

Cannabinoids as drug interaction victims

Ketoconazole, a potent antifungal agent, is a CYP3A4 inhibitor. This enzyme metabolises THC and CBD. Elevated levels of these cannabinoids lead to an increase in the psychoactive effects of THC and adverse side effects of CBD, such as drowsiness and elevated levels of liver enzymes like transaminase. The same results may be experienced with CYP3A4 inhibitors like Verapamil and Macrolides.

CYP2C9 is a P450 enzyme that metabolizes THC and not CBD. Cotrimoxazole, amiodarone, and fluoxetine are classes of drugs that, when consumed, are likely to inhibit the metabolism of THC, leading to increased psychoactive effects. Below is a breakdown of the different classifications of prescription drugs and how cannabis interacts with each of them.

Cannabis interactions with different classes of drugs

Blood thinners

Blood thinners or anticoagulants like warfarin work by preventing blood clots in the body. Combining this class of drugs and cannabis is not advised. THC and CBD can increase warfarin levels in the body by inhibiting the CYP2C9 enzyme. A high warfarin content in the body leads to excessive bleeding that can be fatal.

Benzodiazepines 

Cannabis can interact with benzodiazepines, including Clobazam. The drug is used to treat seizures in Lennox Gastaut syndrome patients. CBD increases the levels of Clobazam by three times through the inhibition of the CYP2C19 enzyme.

Bronchodilators

Bronchodilators are used in opening up airways of patients with lung-related conditions, such as asthma and chronic bronchitis. The drugs become less effective when taken in tandem with cannabis (smoking). This is because cannabis speeds up the metabolism of bronchodilators by 40%.

Psychiatric drugs

Mental health and pain are the leading causes of the sudden rise in medical cannabis consumption. The prevalence of these two conditions is alarming as they are among the top contributors to the global burden of health.

Medical cannabis interacts with psychiatric medications, specifically tricyclic antidepressants like dothiepin and imipramine. The combination may lead to increased heart rate and elevated blood pressure. It may lead to confusion, hallucination, and aggressiveness in severe cases.

Immunosuppressants

Studies suggest that CBD is a potential therapeutic option for kidney transplant patients. The cannabinoid is a natural immunosuppressant and immunomodulator. There are limited documented interactions between medical cannabis and immunosuppressants; however, consult a physician before self-medicating cannabis while taking this classification of drugs.

OTC painkillers

The majority of Over-the-counter pain medications have minimal interaction with cannabis. Drugs containing acetaminophen/paracetamol pose a slight risk of causing liver damage when used with cannabis. Cannabis is a potent analgesic compound that can be utilized to replace OTC drugs. It offers a better, natural alternative with minimal side effects.

Opioids

Medical cannabis has numerous therapeutic and medicinal applications that can benefit millions of patients. One significant contribution that the plant can offer is helping in the fight against the abuse of opioids. Replacing opiates with cannabis reduces the number of fatalities attached to the overdose of opiates.

CBD, in particular, inhibits the function of the CYP2B6, CYP3A4, and other cytochrome P450 enzymes to increase the levels of morphine, oxycodone, and methadone in the body.

While this may be beneficial when opiates are taken in low doses, high doses may lead to excess opiates in the system, leading to an overdose. Additionally, both opioids and cannabis have depressant effects and may significantly compromise the central nervous system when combined.

Antibiotics

There are no recorded interactions between cannabis and antibiotics. Studies available indicate that combining the two may enhance the effectiveness of the antibiotics. Before combining the two, seek advice from a physician.

Take away

Cannabis can interact with different drugs, from opioids to sedatives. Cannabinoids can be the victims of the interactions, whereby their levels of availability in the system are affected by other drugs, such as Ketoconazole.

As perpetrators, cannabinoids inhibit or induce the functioning of P450 enzymes, resulting in the acceleration or delay of the metabolism of drugs. In other instances, cannabis has similar effects as prescription drugs, so the effects overlap.

Medical cannabis is legal in most parts of the world. The plant is easily accessible and is marketed as a potential therapeutic agent for a myriad of conditions. Yes, studies have proven that it does help with pain, mental health issues, mood regulations, inflammation, appetite, and many more diseases. What is usually left out is that cannabis can and does interact with prescription pills.

Before self-medicating with cannabis, always consult a qualified physician, preferably one with medical cannabis expertise. The doctors are best placed to advise on whether you should include cannabis into your treatment regime or not.

Leading crowdgrowing platforms like JuicyFields’, are making medical cannabis accessible for more and more people. You too can join the platform and start making profits with every harvest.

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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.

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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