This scientific study was written by David Heal PhD, DSc, FRSC, FBPhS, co-founder and Executive Director of DevelRx. Find out more about our team of scientific advisors
There has been an explosion of interest in cannabidiol (CBD) in the last few years with the discovery that this substance, which is synthesized by the cannabis plant, has powerful effects in the brain, yet at the same time it does not produce intoxication or euphoria (“high”).
Although our knowledge about this fascinating molecule is increasing at a tremendous rate, there is still much that we do not know. Part of the reason for gaps in our knowledge is because we have learnt that CBD has not one, but many, pharmacological actions and I am confident that more will emerge as research progresses. It is an exciting journey and I’ll share with you what we know about how CBD works and its effects on the human mind and body.
Chemical structure of cannabidiol (CBD)
Cannabinoids fit into two broad pharmacological classes based on whether or not they have psychotropic (intoxicating and euphoriant) effects. CBD is the most abundant
non-psychotropic cannabinoid and delta-9 tetrahydrocannabinol (THC) is the most important psychotropic cannabinoid. Both chemicals are produced by all parts of the plant but are most concentrated in the leaves and flower buds of the cannabis plant in structures called trichomes. It is important to differentiate between cannabis hemp and cannabis marijuana plants. Although they are both part of the same family, hemp and marijuana plants produce different levels of chemicals; specifically, hemp plants (cannabis sativa L) contain high levels of CBD and very low levels of the psychotropic THC. Conversely, the marijuana cannabis plant produces high concentrations of THC and the most commonly grown varieties are cannabis indica, cannabis sativa and cannabis ruderalis. When the hemp plant is processed and the CBD extracted, it constitutes as much as 40% of the chemicals present in the plant biomass. Although CBD is the most abundant of the cannabinoids present in the hemp plant, over 100 others have been isolated and identified.
The brain and peripheral nervous systems of humans and many animal species synthesize various cannabinoid molecules which act as chemical signals (neurotransmitters) between nerve cells. Because these cannabinoids are produced within the body, they are referred to as “endocannabinoids”. The part of the peripheral and central nervous system that synthesizes and uses them as chemical signals is called the “endocannabinoid system”. This endocannabinoid system in the brain and peripheral nervous system is involved in important physiological and psychological functions including regulation of appetite, pain sensing, mood, memory, fertility, pregnancy, post-natal development and modulating the immune system and immunological responses. The endocannabinoid nervous system “talks” to other nerves and organs in the body by binding and activating specific proteins (receptors) which recognize its chemical signals. You can think of this interaction as a “key and lock”; the endocannabinoid is the key which fits the receptor lock, thereby unlocking it. There are two different types of endocannabinoid receptor, the cannabinoid-1 (CB-1) receptor, which occurs mainly in the brain and the cannabinoid-2 (CB-2) receptor, which occurs mainly in the periphery.
One of nature’s evolutionary coincidences is that plants produce chemicals that interact with the nervous systems of humans and animals when ingested.
CBD and THC are two examples of this coincidental cross-species interaction. The psychotropic effects of the cannabinoids (endocannabinoids that are naturally produced within the brain and plant-derived phytocannabinoids that we ingest) result from activating the CB-1 receptors in the brain. THC activates brain CB-1 receptors and it is the mechanism by which it produces its intoxicating, emotional, perceptual and hedonic effects (“high”). It is also the mechanism responsible for THC’s adverse impact on attention, learning, memory, motor (movement) and cognitive performance. By contrast, CBD does not bind to or activate CB-1 receptors and, as a consequence, it does not have the same intoxicating, perceptual, euphoriant or hedonic effects that are produced by THC that underpin its misuse or abuse by humans. It also explains why ingestion of CBD has no negative impact on attention, learning, memory, motor or cognitive performance.
Numerous placebo-controlled studies have been conducted in human subjects to investigate the potential of CBD for abuse and also its effects on attention, learning, memory, and motor performance. In one study, the psychological and neurological adverse events of CBD were not greater than placebo (dummy pill) at single doses up to 4,500mg and multiple doses up to 750mg/day. The latter dose is more than 10x higher than the recommended maximum daily intake of CBD as a novel food or food supplement. Similarly, several placebo-controlled studies in cannabis-using human volunteers have very clearly shown that CBD does not produce perceptual, emotional or sensory effects in humans and it does not impair attention, learning, memory or motor function.
Just because CBD has no effects on cognition and motor function and is non-intoxicating should not be taken as evidence that this cannabinoid has no effects on brain function or that it does not interact with the human endocannabinoid nervous system. As we will discover later in this review, CBD has many powerful effects on brain function.
CBD has been clinically tested and approved for the treatment of two rare, and extremely severe types of epilepsy in children in the UK, Europe, USA and several other countries.
How does CBD prevent seizures? The short answer is CBD’s mechanism of action is not yet fully understood. This is not an unusual situation with epilepsy drugs, where evidence of their effect on the central nervous system, i.e. preventing seizures, is easy to observe, whereas dissecting the mechanism of action in an organ as complex as the brain is extraordinarily difficult. However, there is good scientific evidence to indicate that CBD’s anti-seizure action is mediated through several mechanisms and it probably interacts with at least 4 different proteins which regulate the excitability of nerves in the brain, they include pores which regulate the excitability of neurons (sodium and TRPV1 channels), a receptor that controls the hyperexcitability of nerves in the brain (GPR55), and CBD also increases the concentration of the inhibitory neurotransmitter, adenosine.
Seizures occur when nerves in the brain signal repetitively and uncontrollably. This is similar to the rhythmic twitching of muscles just before they go into spasm when cramp occurs. Epilepsy drugs prevent seizures either by reducing the repetitive nerve signalling at the point where the seizure starts, or by preventing the spread of the seizure to other areas of the brain.
Seizures are powerful events and as an effective epilepsy drug, CBD’s apparently innocuous behavioural, emotional, perceptual and cognitive profile in humans belies its ability to control the excitability of the brain when it is neurologically dysfunctional during seizures. The inference is that with its multiplicity of pharmacological actions and its ability to reduce brain hyperexcitability, CBD will almost certainly have other effects on brain function. In the next section we will explore some of them.
A substantial number of controlled trials have been performed in humans which indicate that CBD has a beneficial effect on stress and anxiety.
Brain imaging techniques have made an enormous contribution to our understanding of mental disorders and drug treatments. Several imaging techniques are based on the knowledge that blood flow to specific parts of the brain change depending whether they are activated (blood flow increases) or attenuated (blood flow decreases). Using this technique, it has been shown that CBD significantly decreased subjective anxiety and increased mental sedation in a group of patients with generalized social anxiety disorder (placebo was inactive). CBD decreased activity in various brain circuits that control emotion, stress, anxiety and responsiveness to perceived threats, and it increased activation in a brain region linked to a person’s visual awareness of his/her surroundings and environment.
Further evidence for CBD reducing anxiety in neurological disorders comes from a study in subjects with Parkinson’s disease where acute administration of CBD significantly reduced anxiety and stress-induced tremors induced by a simulated public speaking task (an event many people find to be highly stressful).
In another placebo-controlled trial, researchers investigated the effects of single-doses and short-term administration of CBD in drug-abstinent, heroin-dependent individuals and found that CBD reduced drug craving and anxiety in these subjects.
Although most of the studies described here have employed CBD at doses far in excess of those permitted as a daily intake in foods, one study has been performed in patients with anxiety or sleep problems using a low dose of 25 mg/day (the CBD intake recommended in food or supplements is 70 mg/day). On this regimen, almost 80% of subjects reported a reduction in their anxiety and more than 55% reported improvements in sleep. On a cautionary note, a minority of subjects experienced a worsening of their symptoms.
Evidence is emerging that CBD has anti-inflammatory properties when taken orally or applied topically.
CBD’s mechanism, which may be partly mediated by an indirect interaction with the body’s endocannabinoid system, is to reduce the production of the proteins that cause inflammation and increase the ones that reduce it. This effect of CBD has been demonstrated in placebo-controlled trials in human volunteers.
The possible benefits of CBD in osteoarthritis have been demonstrated in a veterinary study in dogs with this painful disease where the researchers found that daily treatment with CBD improved the dogs’ mobility and reduced the level of associated pain. The potential importance of this finding to human health is that osteoarthritis occurs in humans and dogs and suggests that more studies in humans are warranted.
Although the findings are preliminary, a clinical trial has shown that CBD could reduce inflammation in the gut, suggesting that it could be potentially beneficial in treating disorders associated with increased gut permeability such as inflammatory bowel disease.
Neuropathic pain is a sub-category of pain that can occur after a bout of shingles (post-herpetic neuralgia), or for example, it can be caused by nerve trauma or entrapment. Neuropathic pain is often unresponsive to treatment with conventional painkillers. In a small group of subjects, topically applied CBD oil for 4 weeks substantially reduced some of types, of pain and unpleasant sensations caused by peripheral neuropathy when compared to placebo. CBD application produced no side-effects in these subjects.
Lower-back pain represents a different type of pain and it is often treatable with conventional painkillers like aspirin, paracetamol and codeine. When CBD was investigated as add-on therapy to conventional painkillers in a large clinical trial in this indication, it showed no beneficial effect.
What the above findings illustrate is a common disorder like pain is not a single disorder. Rather, it is a complex cluster of different ones. CBD shows therapeutic potential in reducing inflammatory pain and neuropathic pain, but it is not a conventional painkiller.
The description of the findings from recent clinical trials has hopefully provided an overview of the breadth of diseases and disorders that may benefit from CBD in addition to its already proven efficacy in the treatment of some forms of childhood epilepsy.
It neatly brings us back to discuss a very interesting clinical study that was published a couple of years ago. The quality of life for sufferers of epilepsy that is resistant to drug treatment is very low. Subjects with treatment-resistant epilepsy who took CBD for a year experienced a significant improvement in their quality of life that was independent of any change in the frequency or severity of their seizures and associated adverse events. This finding suggests that CBD has a beneficial effect on the mood and quality of life of these epilepsy sufferers that is not directly related to its ability to prevent seizures.
These results reveal one of the important messages, which is differentiating between the direct effects of CBD on medical conditions versus its holistic effect on wellness and quality of life. CBD did not reduce the disease burden in these epilepsy sufferers, but nonetheless, it significantly improved the quality of their difficult lives.
Does CBD interfere with the actions of other drugs is an extremely important safety question. One of the safety concerns about consuming CBD as a novel food was the possibility that CBD could increase the blood levels of medications that people were taking with potentially adverse consequences. This concern arose from test-tube experiments showing that CBD inhibited liver enzymes that break-down drugs and from clinical studies performed during the development of CBD as a treatment for epilepsy.
First, it has to be recognized that the CBD doses producing these effects were 10 to 20x higher than the recommended daily intake of CBD in foods. Second, more recent clinical studies have reported that even at the doses of CBD used to treat epilepsy, its potentiating effect on blood levels of other drugs was overestimated. We conducted an exhaustive analysis of the evidence from test-tube and clinical studies and concluded that when CBD is consumed in the quantities recommended in food or supplements, which are no more than 70mg/day (or about 1mg/kg bodyweight), CBD would not interfere with the actions of other drugs that were being taken.
The term “drugs” is not restricted to over-the-counter and prescription medications, but extends to recreational drugs like alcohol. Those interactions have also been studied in the clinic and have shown that CBD has no clinically significant effect on blood alcohol levels. The same conclusion applies to the interaction between CBD and THC, the major psychotropic cannabinoid in marijuana.
The final point is to dispel the myth that taking CBD will protect individuals against the adverse cognitive, sensory and motor effects produced by THC or alcohol. These interactions have been thoroughly explored in clinical studies and the absolutely concrete finding is CBD will not lessen the adverse effects of either alcohol or THC.
Key to any discussion about the safety of CBD in novel foods is its quality and purity, and its consistency in food products. Part of the legitimate concerns of the UK and European Foods Standards Agencies was the unacceptably low quality of many of the products that were on sale and in some cases their illegal status because they were contaminated by THC and other psychotropic cannabinoids that are controlled drugs.
The Pure Swiss CBD and the Broad Spectrum CBD, which are used by EthicaCBD in the manufacture of its products are of the highest quality and purity.
Pure Swiss CBD is a highly purified CBD isolate (with a minimum 99.4% CBD) that contains negligible concentrations of THC, other psychotropic cannabinoids (CBN) and other
non-psychotropic cannabinoids. It contains a very low level of 0.17% cannabidivarin (CBDV), which is not psychotropic. At greater than 99% purity, the Pure Swiss CBD isolate is on a par with pharmaceutical grade CBD used in the clinical trials that I have discussed. The final CBD concentration in the five Pure Swiss CBD products, Night, Day, Body, Defence and Calm, is 10% with 0.6 – 0.8% added terpenes (aromatic compounds derived from plants) in organic coconut oil. Vitamins, minerals and omega 3 oil are also added to certain of the Pure Swiss CBD oils.
WholePlant – Broad Spectrum CBD is prepared by purifying CBD together with a range of other cannabinoids and other natural chemicals from the hemp plant. This CBD distillate contains a minimum of 95% CBD together with very low levels of some other cannabinoids. The final CBD concentration in the WholePlant – Broad Spectrum CBD Oil is 5% together with 0.9% added terpenes, 0.17% cannabigerol (CBG), 0.02% CBDV, 0.003% THC and 0.001% cannabinol (CBN). The total content of the psychotropic cannabinoids, THC and CBN is less than 0.005% per bottle of CBD WholePlant oil. CBD and CBDV are reputed to have beneficial effects in their own right, and currently, are undergoing extensive laboratory and clinical assessments.
Contaminants in the Pure Swiss CBD and the WholePlant – Broad Spectrum CBD products including pesticides, heavy metals, fungicides, mycotoxins and solvents are well below the safe limits set by UK/European standards.
This overview has hopefully provided a comprehensive description of our current knowledge about CBD. By focusing on findings obtained in clinical studies and wherever possible in placebo-controlled trials, I have attempted to provide a realistic assessment of the possible additional therapeutic applications for CBD. What has to be emphasized is these benefits have been in individuals after diagnosis of a specific disease or disorder by medical professionals and the effects have been produced by doses that are often 10 to 20x higher than the recommended daily intake of CBD in novel foods. I have also described the complexities of even seemingly simple conditions like pain and the very different effects of CBD depending on which type of pain is being treated. This is another reason for caution when discussing the medical benefits of CBD.
As illustrated by the quality of life study in treatment-resistant epilepsy, CBD may have holistic health benefits that are not defined by clinical measures like seizure frequency and severity, but exist nonetheless. CBD in food products may deliver some of those benefits, but those benefits are neither proposed, nor should they be assumed.
For decades the focus of research into cannabis has been on the psychotropic cannabinoids and especially on THC, the chemical in marijuana which is predominantly responsible for its intoxicating effects. The demonstration that CBD was effective in treating some forms of epilepsy has dramatically increased the interest of medical researchers and the public to the potential therapeutic benefits of CBD and several other cannabinoids. Hypotheses about the potential therapeutic benefits of CBD generated on the research bench are now being put to the ultimate test in clinical trials. These are the positive outcomes. However, there is a negative side to the explosion of interest in CBD and it is the plethora of unsubstantiated claims about its health benefits and scare stories about its safety. Moreover, many of the products claiming to contain CBD were of unacceptable quality and in some cases illegal because of their THC content. The UK and European Foods Standards Agencies have now stepped in to ensure that all CBD containing food products comply with what is stated on their labels and the law. You can rest assured that EthicaCBD’s products, Pure Swiss and WholePlant CBD oils meet the highest standards.
EthicaCBD, Unit 7 Bude Business Centre, Kings Hill Industrial Estate, Bude, Cornwall, UK, EX238QN.
