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Does CBD Work?

By: :Alex McMillan 0 comments
Does CBD Work?

Introduction

 

Never in recent memory has a health product captured the attention of the world like the cannabinoid known as cannabidiol (CBD). 1 of over 100 cannabinoids found in the cannabis plant, CBD has become perhaps more famous in recent years than it’s inebriating ‘brother’ molecule tetrahydrocannabinol (THC).  Now it seems everyone from star athletes to Instagram influencers are jumping on the ‘CBD bandwagon’ starting their own brands or advertising CBD products for others. Despite this meteoric rise in popularity as a health supplement the question remains, does CBD work?

 

With anecdotal reports ranging from ‘this is literally a scam’, to ‘CBD changed my life’ it can be hard to determine who is telling the truth is. The truth as always is neither white nor black but a lovely shade of grey. We know from current science that cannabinoids like CBD interact with an existing biological system present in all of us, the endocannabinoid system (ECS) and can produce real, measurable neuro-physiological effects, some of which may be potentially useful in the treatment of human disease. BUT, by way of balance, the ludicrous medical claims made by many proponents of cannabidiol are simply not to be believed.

 

There is not enough evidence. Many brands and individuals that do not know the science are guilty of reading an unsubstantiated claim and then propagating that claim forward – regardless of intention, this is not good for consumers or the cannabis industry as a whole. A good example is the supposed anti-cancer effects of CBD in humans; this has not been proven in a high-quality clinical setting so is for all intents and purposes not true.

 

We must let the science guide the claims we make; there is no other option less we risk lying to people which so much of the supplement industry is already guilty of. Dr. Ed® as a brand was started precisely because of this lack of transparency, our goal is to educate, not to sell. We have written this article to summarise some of the more promising research into CBD or the most relevant whether promising or not, specifically using cannabidiol to treat various diseases or disorders.

 

While we of course cannot touch upon all research, the studies we look at here are diverse looking at a wide variety of disorders. We have broken this article down into 3 main areas which represent the typical path of normal pharmaceutical drug discovery which is; 1) in vitro research: studies using cell lines and cell models 2) in vivo research: studies work using animal models 3) clinical research: studies with human participants. Typically, drugs only proceed to each stage if they are deemed worthy of continued exploration based on the results of the data from the previous stage.

 

 

The Endocannabinoid System

 

The endocannabinoid system (ECS) is a complex and loosely defined signalling system which is only now beginning to be understood. Based on current evidence, the ECS is present in all animals and is affected by diet, sleep, stress and a host of other factors including exposure to our own natural endocannabinoids and phytocannabinoids like cannabidiol (CBD). Its main role appears to be homeostatic in nature and the system constantly balances our physiology in response to external and internal changes (1).

 

The system plays a role in a huge number of biological processes including energy regulation, pain signalling, endocrine control, regulation of the sleep-wake cycle and the stress response to name just a few (2). Understanding how the ECS works and how we can modify its activity may offer tremendous therapeutic potential in the treatment of a wide range of health disorders ranging from mental health issues to pain, nerve damage, metabolic diseases like diabetes and brain disorders like Parkinson’s Disease (3).

 

Put briefly, the ECS is comprised of two parts – endocannabinoids which act as signalling molecules, and cannabinoid receptors which bind these molecules to produce a response.

 

Endocannabinoids are fatty-acid neurotransmitters that act as the signalling molecules of the ECS. They produce most of their effects by acting through cannabinoid receptors. While AEA and 2-AG are the most well studied endocannabinoids, other endocannabinoid-like compounds exist that function in similar ways including oleoyl ethanolamine (OEA) and palmitoyl ethanolamine (PEA). Endocannabinoids share some structural similarity with phytocannabinoids like CBD but generally have less affinity for the cannabinoid receptors. Like their hemp-derived counterparts, endocannabinoids interact with a range of receptors, not just cannabinoid receptors (4).

 

Despite the widely held belief that the ECS comprises only two receptors, CB1 and CB2 (Cannabinoid Receptor 1 and 2 respectively), numerous other receptor types are involved in regulation of the system and also interact with cannabinoids like CBD including GPR55 as well as forms of the serotonin and adenosine receptors. This, along with many other biological markers, suggests the ECS is closely intertwined with other biological systems including the serotonin system (5).

 

For a much more detailed breakdown of the endocannabinoid system in human health read our full piece here. The main take home point from this section is that phyto cannabinoids like CBD interact with an existing biological system present in almost all animals; it is intriguing that our own endocannabinoid system, developed and conserved over millions of years can be so influenced by molecules produced by plants. Although there is a huge amount we do not know about cannabinoids, we do know their (neuro) physiological effects are real and produced at least in part by their interaction with the ECS.

 

 

 

In Vitro Definition

 

‘In vitro’ refers to work performed outside of a living organism and involves studies that use cell lines or other isolated biological material usually in test tubes or petri dishes. In vitro work is the corner stone of most biological science and allows scientists to experiment on different cell types or components with fewer ethical constraints. Almost all drug development begins with extensive in vitro work which allows researchers to determine the basic cellular mechanisms by which drugs work and also allows them to assess toxicity to various types of cells and tissues. In vitro studies usually lay the groundwork for more complex studies in the future; for example, drug target discovery or identification of new receptors, ligands and their behaviour are often the result of in vitro work.

As can be expected, much of the early work into cannabinoids relied on in vitro investigation and our understanding of the major receptors and signalling molecules of the endocannabinoid system has stemmed directly from these types of mechanistic studies. We have not included a summary of in vitro data here as we wished to get into the ‘meat’ of the research which has more immediate relevance to whole systems and thus, us as humans. However, many of the studies we cite and discuss further down this article also include a wealth of in vitro data should you wish to look.

 

 

 

Does CBD Work? – In Vivo Evidence

 

In vivo refers to research work carried out inside or within a living organism and is often referred to as animal research. The term ‘animal research’ will quite rightly evoke strong emotions in some of our readers and with good reason so it is important to clarify what we mean. When we refer to animal research in our writings, we are specifically referring to in vivo studies carried out in animal models with a view to developing drugs and surgical techniques which ultimately benefit humanity a.k.a medical animal research. We are NOT referring to needless testing on animals which would include animal testing in the cosmetic industry which we whole heartedly oppose.

 

As a medical animal researcher, I can assure you that neither myself nor my colleagues take any pleasure in the act itself, it is only the outcome of better medical care for humans that makes that animals ultimate sacrifice worthwhile. Until a viable alternative to medical testing on animals is available, it will continue to be the cornerstone of both basic and advanced medical research. I would also like to take the time to point out to all readers that if you have benefited in any way from medical devices, surgery or drugs then you are the beneficiary of medical animal research.

 

In vivo work is the critical ‘second-step’ before drug testing proceeds to humans and it is incredibly important as it allows us to access how certain interventions i.e. CBD, effect an entire biological system, not just individual cells. Systems are often affected in very different ways to individual cells. Case in point, 1000s of chemicals and compounds both natural and synthetic are anti-cancer when studied in an in vitro setting and every couple of years a new ‘wonder compound’ appears to be discovered. But then, things go quiet because this compound does nothing, at least not what is intended, when introduced to an entire biological system. This happens all the time and is one of the reasons animal research is so important. Promising in vitro drug candidates might end up useless in an animal, or worse, actively harmful. In vivo research gives us a better understanding of how drugs and molecules interact with large systems and also allow us to observe their effects on things like behaviour.

 

 

The brain – seizure disorders, traumatic brain injury and ischaemic event

 

Suppression of neuron firing is one of the ways that the endocannabinoid system (ECS) protects the nervous system from over activity during a seizure. Our own endocannabinoids are produced during seizures and act on cannabinoid receptors in two brain areas namely the hippocampus and neocortex where they dampen seizure activity and neuron cell death (6). Phytocannabinoids like CBD are generally anti-convulsant and are often referred to as ‘circuit breakers’ due to their ability to reduce certain types of seizure. In fact, in June 2018 the FDA approved the use of purified CBD as a drug called Epidiolex to treat two severe forms for epilepsy (expanded in clinical evidence section).

 

The anticonvulsant and neuroprotective effects of CBD have been demonstrated in animal models of epilepsy (7).

 

Cannabinoids also have the ability to protect neurons from a variety of issues resulting from traumatic brain injury (TBI) (8). Data suggest that the endocannabinoids anandamide and 2-AG serve as homeostatic regulators to limit brain damage following brain injury. Furthermore, exogenous cannabinoids given within 4 hours of TBI, have been shown to limit nerve-cell damage in animal models (9).

 

As with seizure and TBI, the body’s levels of endocannabinoids spontaneously elevate during stroke, perhaps indicating a protective response. In animal models of stroke, cannabinoids significantly reduced the size of the damaged area and improved functional outcomes in animals (10). Additionally, in a study of ischemia produced by carotid artery occlusion, CBD demonstrated a protective effect on neuronal death in mice (11).

 

Relevance: Our ECS plays an important role in brain health perhaps especially so during the response to injury. CBD has been shown in animal models to be an anti-convulsant and thus useful in the treatment of epilepsy; it’s approval as an anti-epilepsy drug now confirms this. Its additional neuroprotective effects make it potentially very valuable in the immediate treatment of traumatic brain injury following physical trauma or stroke.

 

 

The brain – mood regulation and anxiety.

 

Studies with specific animal models, usually rats due to their higher intelligence, have shown that under certain circumstances CBD can produce anxiolytic (anti-anxiety) effects (12, 13, 14). However, not much is known about the mechanism by which this is achieved and results between models are not always consistent. For example, one study showed that the anxiolytic effect of CBD only emerged in animals that were experimentally placed into a high level of stress before treatment (15).

 

Below is a fantastic table summarised by Blessing et al, which includes most available pre-clinical CBD and anxiety-like disorders studies; as can be seen from the table, the overwhelming majority of studies report anxiolytic effects. Note that the dose, animal model and route of CBD administration vary between each entry. I have simplified this massively but encourage anyone interested to read the original review which is a very detailed summary of our current understanding of CBD with regards to anxiety disorder treatment (16).

 

Study

Effect

Silveira Filho et al.

No effect

Zuardi et al.

Anxiolytic

Onaivi et al.

Anxiolytic

Guimaraes et al.

Anxiolytic

Moreira et al.

Anxiolytic

Resstel et al.

Anxiolytic

Campos et al.

Anxiolytic

Anxiolytic

Bitencourt et al.

Anxiolytic

No effect before CFC
Anxiolytic following CFC

Campos et al.

Anxiolytic

Resstel et al.

Anxiolytic,
↓ Pressor
↓ Tachycardia

Anxiolytic

Soares et al.

Anxiolytic
Panicolytic

Panicolytic

Long et al.

No effect

1 mg/kg
anxiolytic

No effect

50 mg/kg anxiolytic

Lemos et al.

IP and PL anxiolytic IL anxiogenic

Casarotto et al.

Anticompulsive

Gomes et al.

Anxiolytic

Anxiolytic

Granjeiro et a l.

Anxiolytic, ↓Pressor ↓Tachycardia

Anxiolytic

Deiana et al.

Anticompulsive

Uribe-Marino et al.

Panicolytic

Stern et al.

Anxiolytic
1 and 7 d old fear memories disrupted

Campos et al.

Anxiolytic

Hsiao et al.

↓ REM sleep suppression

Anxiolytic

Anxiolytic

Gomes et al.

Anxiolytic

El Batsh et al.

Anxiogenic

Campos et al.

Anxiolytic

Anxiolytic

Do Monte et al.

Anxiolytic

Campos et al.

Anxiolytic
Panicolytic

Almeida et al.

Anxiolytic

Gomes et al.

Anxiogenic
↑ Tachydardia

Twardowschy et al.

Panicolytic

Focaga et al.

Anxiogenic

Anxiolytic

Anxiolytic

Nardo et al.

Anticompulsive

Da Silva et al.

Panicolytic

 

 

Relevance: Currently available pharmacological treatments include serotonin reuptake inhibitors, benzodiazepines and tricyclic antidepressant drugs to name just a few. These medications are associated with limited response rates and residual symptoms, particularly in PTSD, and adverse effects may also limit tolerability and the likelihood of patients sticking to drug regimes. The substantial burden of anxiety-related disorders and the limitations of current treatments place a high priority on developing novel pharmaceutical treatments; could CBD find its place here? Existing pre-clinical evidence strongly supports the use of CBD in the treatment of anxiety disorders.

 

 

Gut Function

 

In addition to acting as neurotransmitters (molecules which transmit information along nerves), endocannabinoids also act as autocrine and paracrine regulators. For example, in the presence of inflammatory bowel disease (IBD), endocannabinoids interact with various gut receptors on the cells that produce endocannabinoids (autocrine regulation) as well as nearby immune cells (paracrine regulation) to reduce additional infiltration and inflammation caused by said immune cells. CB1 receptor agonism has been shown across a variety of models to be anti-emetic (anti-vomiting) and can reduce nausea. Conversely, antagonism of the CB1 receptor induces emesis. CBD has been shown to produce anti-nausea effects by indirect agonism of serotonin receptors.

 

Relevance: Aside from the emerging role of the ECS in normal healthy gut function, anti-emetic medications are few and far between but are highly sought after in the medical field. CBD may hold promise in this area due to its ‘anti-vomiting’ effects.

 

 

The Sleep Wake Cycle

 

The ECS has the capacity to modulate circadian rhythms and is involved in the regulation of the circadian sleep–wake cycle. The term ‘circadian’ refers to a biological process that occurs naturally on a 24-hour cycle even in the absence of light. Our body clocks are circadian in nature.

 

Plasma concentrations of the endocannabinoid anandamide exhibit a circadian rhythm, which can be disrupted by sleep deprivation. Studies in rodents have shown that The systemic acute administration of CBD appears to increase total sleep time, in addition to increasing sleep latency in the light period of the day of administration (17). However other studies have shown that CBD actually possess waking properties (18).

  

Relevance: Sleep support is one of the most popular reasons that consumers purchase CBD but this particular area remains poorly understood. Some animal studies support the notion that CBD improves sleep time and reduces latency to sleep whereas others have shown a waking effect of CBD – this may be largely dose dependent and location dependent. It should be noted that the waking effects of CBD seem to appear when CBD is injected directly into the brain whereas sleep effects are produced when CBD is introduced into the blood which is much more in line with consumer use of CBD! Either way, CBD has a demonstrable effect on sleeping and waking and users may need to experiment particularly in this area.

 

Appetite – Energy Regulation

 

Administration of AEA, an endocannabinoid, has been shown to stimulate appetite in various rodent models. Additionally, CB1 receptors are expressed in key hypothalamic brain areas associated with energy regulation.


Cannabinoid-dopamine interactions appear to play an important role in feeding and the dopaminergic system is important in controlling reward processing including the rewarding aspect of food. In one interesting study, treatment with cannabidiol reduced total food consumption in animal models whereas the closely related cannabinoid, cannabinol, increased total food consumed (19). Additionally, daily treatment with CBD, reduced body weight gain in rats with CB2 being a possible receptor target for this effect (20) and CBD can also block the feeding response usually seen with appetite-stimulating molecules (21).

 

Relevance: Interestingly one of the more common side effects of CBD is changes to feeding behaviour and weight. While CBD is not typically purchased for weight control, CBD does show appetite reducing effects in vivo which may find some utility in weight control products in the future.

 

 

Pain and Inflammation

 

Cannabinoid receptors are abundant on many types of neuron involved in pain processing pathways in both the brain and spinal cord – they are often found together with opioid receptors (22). Activation of CB1 receptors in these areas has been shown to inhibit pain signals to higher brain regions and modulate pain signals in descending pain pathways (23).

 

Numerous preclinical studies have demonstrated the beneficial effects of cannabinoids, including CBD, in animal models of acute pain, chronic pain, and neuropathic pain, some demonstrating opioid-sparing effects; this is particularly exciting due to the growing opioid addiction issues in the USA and the inherent poor safety record of opioid drugs (24, 25, 26, 27).

 

Although reductions in pain have been reported in numerous animal models, the mechanism(s) for this analgesic effect are still being investigated and are currently not well understood. The observed effects on pain may be linked to anti-inflammatory effects as shown in other rodent models. Ultimately CBD-induced analgesia as well as the compounds effects on inflammation are likely down to a complex interplay of mechanisms - interaction with specific receptors like TRPV1 as well as modulation of inflammatory mediators such as TNF-a are also possible ways in which CBD produces analgesic effect and a combination of multiple mechanisms is likely (28, 29, 30).

 

Relevance: Human studies investigating CBD-induced analgesia (pain relief) in humans are few yet CBD’s potent anti-inflammatory properties have been demonstrated numerous times in rodent studies and this anti-inflammatory behaviour is probably directly linked to observed pain-relieving properties; interestingly, CBD appears to be potentially useful in multiple forms of pain including acute, chronic and neuropathic pain. There is always a need in medicine for analgesic options with low side-effect profiles and CBD may potentially fit that bill providing we have more clinical evidence to warrant its wider use in pain management.

 

 

The HPA Axis

 

The hypothalamic-pituitary-adrenal (HPA) axis is our central ‘stress’ response system and is comprised of an intricate overlap between the central nervous system (CNS) and the endocrine system (hormone system). Endocannabinoids have been shown to influence the activity of the HPA via interaction with CB1 receptors in the hypothalamus (31). The authors summarise that endocannabinoids generally work as negative modulators of HPA signalling and thus aspects of the endocannabinoids system may be useful targets in the treatment of anxiety-like disorders which typically display over-active HPA signalling (32).

 

Relevance: It stands to reason that CBD probably has effects either direct or indirect on the HPA axis due to the presence of CB1 receptors but as of writing very little animal work has been conducted specifically looking at cannabidiol in relation to HPA axis activity. This is certainly worth further investigation as one of the major reported reasons for using CBD is to reduce stress/anxiety – if true, perhaps this occurs, at least in part, by effects on the HPA axis.

 

 

 

Does CBD Work? – Clinical Evidence

 

Clinical evidence is the ‘gold standard’ when it comes to evidencing the effectiveness of a drug or intervention in the treatment of a human ailment or disease. Clinical evidence is usually backed up by a plethora of in vitro and in vivo studies as investment into clinical research is not made until drug candidates are proven to be effective, safe and basics mechanism revealed, in a wealth of in vitro and in vivo models. Clinical evidence naturally stems from clinical research which is a branch of healthcare science that determines the safety and effectiveness of medications, devices, diagnostic products and treatment regimens intended for human use. These may be used for prevention, treatment, diagnosis or for relieving symptoms of a disease.

 

The brain – seizure disorders

 

In June 2018, the FDA approved purified CBD as the drug product Epidiolex (Greenwich Biosciences, Carlsbad, CA, USA) to treat 2 severe forms of epilepsy—Lennox– Gastaut syndrome and Dravet syndrome (33) The anticonvulsant effects of CBD aren’t confined to these rare forms of epilepsy. Anticonvulsant and neuroprotective effects have been demonstrated in animal models of status epilepticus22 and in humans with generalized epilepsy and treatment-resistant epilepsies (34, 35)

 

Relevance: There is no greater evidence for a drug’s efficacy than clinical evidence and creation of a new pharmaceutical medication. CBD has proven interaction with the brain and has been sued for decades (in the form of marijuana) as an ‘off label’ treatment for various forms of epilepsy. While it is still a belief among many that THC is solely responsible for the anti-convulsant effect of cannabis, purified CBD ‘Epidiolex’ proves otherwise.

 

 

The brain – mood regulation and cognitive disorders

 

Aside from pain management, anxiety/stress is the most common reason consumers seek out CBD in the UK. The anxiolytic effects of CBD in humans was first demonstrated in the context of reversing the known anxiety-inducing effects of THC. CBD reduced THC-induced anxiety when given alongside THC but had no effect on baseline anxiety when given by itself (3637).

 

Interestingly, further studies using higher doses supported a lack of anxiolytic effects at baseline (3738) but by contrast, CBD potently reduces experimentally induced anxiety or fear. CBD reduced anxiety associated with a simulated public speaking test in healthy subjects, and in subjects with SAD, showing a comparable efficacy to diazepam (3940). Blessing et al have summarised available clinical data in humans regarding CBD and anxiety disorders in their report which I encourage anyone interested to look at more closely (41).

 

Relevance: CBD doesn’t appear to make a ‘calm person calmer’; instead it shows beneficial effects in contexts of heightened stress, anxiety or fear which may explain why anecdotally CBD has been used to such great effect in those how have conditions like generalised anxiety disorder. Available clinical and preclinical evidence demonstrates CBD’s efficacy in reducing anxiety behaviours relevant to multiple disorders. Human experimental findings support preclinical findings, and also suggest a lack of anxiogenic effects, minimal sedative effects, and an excellent safety profile. Current preclinical and human findings mostly involve acute CBD dosing in healthy subjects, so further studies are required to establish whether chronic dosing of CBD has similar effects in relevant clinical populations. Overall, this review emphasizes the potential value and need for further study of CBD in the treatment of anxiety disorders.

 

  

Pain and Inflammation

 

Despite such widespread use as a purported natural pain reliever, the clinical data surrounding the use of CBD in the treatment of pain is very sparse and while pre-clinical (in vivo) data is promising, very few studies have been conducted in humans. This will surely be addressed in the near future due to the increasing demand for and interest in CBD products. One of the main issues currently in the literature is that human trials, almost without exception, involve the use of THC and CBD, usually given in a 1:1 ratio simultaneously. As such it is hard if not impossible to attribute a specific outcome to one of the compounds specifically.

 

Relevance: The disappointing summary here is that clinical data into the use of CBD specifically in pain management is perhaps one of the most under-studied areas at the moment.  While pre-clinical data suggests CBD is a worthy pain management candidate and anecdotal evidence is strong, clinical evidence involving only the application of CBD and not THC, is almost entirely lacking.

 

 

Final Word

 

CBD, cannabidiol, is not ‘snake oil’. It is a complicated, biologically active molecule that produces a range of neurological and physiological effects primarily, but not exclusively, through interaction with the conserved signalling system that we call the endocannabinoid system. The ubiquitous nature of the endocannabinoid system helps explain why CBD appears to be potentially useful in multiple areas of health and disease. Despite a growing body of pre-clinical studies into the effects of cannabinoids, CBD is only now emerging as a clinically relevant molecule in humans. While clinical research is only just ramping up, the data that is emerging is very encouraging and CBD already forms the basis of an effective treatment for a particularly debilitating form of epilepsy.

 

However, we must remember that despite the often-touted miracle discovery of the endocannabinoid system and CBD’s interaction with said system, this is all still a relatively new area of research and much more work needs to be done in the field before we can draw definitive conclusions about how the system works in its entirety and the full role cannabinoids play in human health. As consumer interest continues to grow, companies, universities and other research bodies are more inclined to invest in deeper investigation and no doubt we will continue to unlock the tremendous potential of CBD and other cannabinoids in the years to come.

 

It is also important to state again that cannabinoids should be viewed with a more holistic approach than traditional pharmaceuticals. As body weight, metabolic health, endocannabinoid system health and numerous other factors affect the outcomes of using CBD, it is unwise to compare yourself to a friend or family member that has used CBD successfully. There is also a huge amount we still do not know about cannabinoids which means experimentation and a bit of ‘tinkering’ is often required. In most cases you need to start the journey from square one, finding what works for you and there are LOTS of places that people trip up ranging from having unrealistic expectations to not increasing their dose and not applying CBD properly. Understanding how CBD works in your body and the best methods for getting CBD into your system is key to the making the most of this compound. Our blog section has an extensive range of guides and FAQs to help you make the most of CBD and to learn more about cannabinoids and human health.

 

Reach out to us on web chat, social media or over email if you have any questions about our products, the science behind CBD or just CBD in general.

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