Cannabidiol (CBD) basics
Cannabidiol (CBD) is one of the two dominant cannabinoids in the cannabis species. Since its discovery in 1940 CBD has been subject to investigation for its potential to treat a wide range of symptoms and diseases. Unlike its counterpart THC, CBD lacks intoxicating effects which allows for a broader capacity to prescribe in varied patient demographics.
CBD does not interact with the endocannabinoid system (ECS) in the same fashion as other cannabinoids. Its influence on cannabinoid receptor 1 is established yet many of its therapeutic effects may potentially occur via different mechanisms. CBD is also thought to induce possible therapeutic effects by modulating ion channels, neurotransmitters and a number of other processes in the immune and central nervous systems.
Safety of CBD
Numerous clinical trials from around the world have assessed the safety of CBD at varying doses in a range of settings and diseases. While some side effects have been routinely reported, CBD has largely been shown to be a safe compound, which is one of the key reasons why the Australian Department of Health has proposed low dose CBD formulations be down scheduled to over-the-counter (OTC) medicines.
In 2018 the World Health Organisation’s Expert Committee on Drug Dependence (ECDD) released a critical review on the safety and efficacy of CBD. This was the first time a cannabis-derived substance has been reassessed in this manner since it was restricted under the 1961 Single Convention on Narcotic Drugs.
“The Committee recommended that a footnote be added to Schedule 1 of the 1961 Single Convention on Narcotic Drugs to read: ‘Preparations containing predominantly cannabidiol and not more than 0.2% of delta-9-tetrahydrocannabinol are not under international control.‘”
-Excerpt from Expert Committee on Drug Dependence recommendations
Simply put, this review showed CBD is widely well tolerated with a good safety profile and significant potential therapeutic benefits across a number of indications. Its tendency to few and mild side effects was also noted by the committee.
Given this comparatively benign compound is currently scheduled in the same category as heroin and ecstasy, amending CBD’s scheduling under international law goes a long way in acknowledging the safety and evidenced-based potential CBD exhibits. The finalisation of this change has been delayed numerous times and is now earmarked for December 2020.
On a more local front, the Therapeutic Goods Administration (TGA) has conducted a review on the safety of low dose CBD preparations. The safety review concluded that CBD has potential therapeutic application in some conditions without the supervision of a doctor if restricted to doses <1mg/kg/day.
If Australian scheduling of CBD is amended it’s possible CBD over-the-counter products will be legal from February 2021. Whether or not low dose CBD formulations will be available immediately is another story.
The medicinal possibilities for CBD are vast
The claims cannabinoid medicines are a broadly applicable panacea is generally misrepresented and overemphasised in the media, however, it can’t be ignored that CBD does show promise for a veritable range of symptoms and conditions.
Some of the less lauded conditions CBD is proposed to treat included skin conditions, from acne to psoriasis and even more concerning presentations like MRSA bacterial infections, based on the current preclinical and early clinical evidence. Conditions related to neurological and autoimmune dysfunction such as Alzheimer’s, Parkinson’s, Multiple Sclerosis and Huntington’s disease have also shown positive preclinical and clinical outcomes.
Epilepsy opened the door for CBD’s medicinal potential
Epilepsy is the main condition that has brought CBD oil into the spotlight. Widespread anecdotal reports of success in reducing seizures in treatment-resistant epileptic children sparked compassion in the hearts of many who would’ve otherwise never considered CBD due to the stigma associated with cannabis.
An evidenced-based understanding for the treatment of epilepsy with CBD has been building over the past two decades. Animal studies have shown that CBD may play a role in protecting the brain from seizures. Its action as an anticonvulsant, for specific seizure types, is also acknowledged in the literature, however, mechanisms of action are not yet fully understood.
A study conducted on epileptic children and adults across 12 weeks showed an overall decrease in the frequency of seizures by 63% when CBD was given adjunct to their other antiepileptic medications. Despite some patients withdrawing from the study over the following 36 weeks, data indicated this reduction in seizures was sustained over time. It also indicated patient seizure severity improved by as much as 50-60%, which was also sustained over the 48 week period. Such significant changes pose a potentially dramatic positive impact on the quality of life of patients with otherwise treatment-resistant epilepsy.
A 2018 systematic review pooled data from randomised controlled trials and observational studies and concluded that 48.5% of patients reported more than 50% reduction in their seizures. Other significant findings included increased quality of life scores plus a number of reports of patients being entirely seizure-free or having meaningful increases in seizure-free days.
A significant number of the trials examining CBD’s effects in epilepsy are using the product Epidiolex™. In Australia, this CBD product is being reviewed by the TGA with hopes it will become registered and available under the Pharmaceuticals Benefits Scheme (PBS) soon. This will allow for patients with specific epileptic conditions to be subsidised for this CBD medication, removing a significant financial barrier to access for some.
High doses of CBD can be required in some patients
Compared with other conditions, CBD oil is often administered in much higher doses for epilepsy than for other conditions. However, recent studies of CBD for psychiatric indications (i.e. anxiety, schizophrenia) have also suggested 600 -1000mg per day may be required to see effects. This is likely to differ between patients.
Currently, aside from epilepsy, there have not been any other clinical trials that have defined a therapeutic dose range for CBD and therefore doctors are having to take an approach of starting low and up titrating the dose for each patient. Several observational reports have shown that patients are self-reporting benefits with doses as low as 25mg/day however this has not been systematically evaluated. Further research is still needed.
To make a sweeping generalisation, therapeutic CBD dosing for most common conditions range from 2-20mg/kg/day. However, in the case of epilepsy doses can often reach as much as 20-50mg/kg/day in adults or 10-20mg/kg/day in children. This varies greatly depending on the condition and individual presentation of the patient. For some patients smaller doses divided throughout the day is most appropriate, conversely, certain individuals may benefit from larger appropriately timed doses for the best therapeutic results.
Plenty of potential for CBD in chronic pain
In Australia, approximately 85% of medical cannabis prescriptions relate to chronic pain indications. Currently, approximately 30% of these are for CBD-only products.
Historically when administering medical cannabis for pain, prescriptions often include high THC or equal parts THC:CBD. THC has well-documented analgesic effects and is thought to be synergistically enhanced by the presence of CBD. In other words, products containing a combination of CBD and THC were superior to THC alone in alleviating physical pain in chronic pain patients. Closer to home, the CACOS study has found that patients are reporting improvements in chronic pain intensity potentially as a result of their medicinal cannabis medicines. These results have been observed in patients largely taking THC-containing products.
Conclusive clinical research solely looking at CBD in the treatment of chronic pain is sparse. Nevertheless, potential mechanisms of action behind its pain-relieving effects are being uncovered, supporting patient reports and helping to support a scientific foundation for future human trials.
Human research into the effects of CBD on anxiety often includes small patient cohorts, yet many show statistically significant positive outcomes.
In an experimental study, anxiety was induced in individuals with Social Anxiety Disorder (SAD) through the act of public speaking, a cardinal fear for patients with SAD. These cannabis-naive participants were dosed with 600mg of CBD or a placebo prior to a public speaking task. Both physiological and psychological measurements were recorded to capture subjective experience of anxiety and physical manifestations of anxiety (such as increased blood pressure or perspiration).
Participants with SAD treated with CBD showed significant reductions in anxiety, cognitive impairments and discomfort in relation to their speech performance compared to the placebo group. These outcomes suggest that a single, albeit high, dose of CBD has anxiolytic properties.
Following on from this research, a recent (2019) placebo-controlled study evaluated CBD over 4 weeks in 37 teenagers (18-19 years old). CBD significantly reduced anxiety scores in Japanese teenagers with SAD. Interestingly, of the CBD group, more than 50% chose to engage in some form of treatment (medication or therapy) after the trial, whereas none of the placebo group made such a choice.
In terms of anxiety, we know through brain imaging of SAD patients that CBD affects the limbic and paralimbic regions of the brain. These areas function as processing centres for fear responses and regulate emotion-based behaviours. It is through interacting with these areas of the brain that CBD is thought to potentially influence anxiety and fear responses, alongside other unclear mechanisms.
CBD holds promise for other mental health conditions
Anxiety isn’t the only psychological condition where CBD holds possible therapeutic benefit. Through CBDs ability to regulate processes involved in fear-based memory extinction the compound holds great promise for PTSD sufferers who are prone to re-experiencing fearful memories due to dysregulated memory storage functions.
The greatest number of placebo-controlled clinical trials of CBD have been conducted with a focus on psychosis and schizophrenia. For example, one study showed improved cognitive function in schizophrenia patients with CBD treatment of 800mg/day. More generally, research into CBD for conditions such as depression, bipolar and obsessive-compulsive behaviours are beginning to gain momentum, as is research into the mechanism of action of CBD in these psychological conditions.
Interactions and side effects
As with any prescription drug, there are potential interactions and side effects that must be taken into account when prescribing CBD formulations.
In the process of metabolising drugs and other exogenous compounds, the liver utilises enzymes of the CYP450 family. One of the enzymes in this family that is most often required is CYP3A4, accounting for approximately 60% of the metabolism of pharmaceutical drugs. CBD may interfere and potentially inhibit the action of CYP3A4 and other CYP enzymes. The majority of research supporting these findings has yet to be correlated with human trials, however, it is a risk factor that should be considered especially in cases of polypharmacy with other pharmaceuticals.
Despite CBD being confirmed as safe in a variety of settings, there are still unknown factors and idiosyncratic reactions yet to be uncovered which may influence the metabolism of other drugs or the risk of adverse effects. Abnormal liver function tests have been observed in concurrent use of CBD with specific epilepsy medication. Additionally, changes in serum levels of anti-epileptic drugs have also been reported with the simultaneous use of CBD, highlighting the need for clinical supervision of CBD prescribing.
The potential for interactions with other drugs highlights the necessity to prescribe CBD oils – and medical cannabis formulations more generally – through a lens of personalised medicine. Despite potential interactions, CBD has the promise to work effectively as an adjunct to many conventional treatments and should be prescribed with patient education and ongoing monitoring.
General side effects of CBD include drowsiness, fatigue and gastrointestinal upset or nausea. Most human trials report these side effects regularly, yet individuals often classify them as mild and in many instances tolerable given the efficacy of the treatment. When compared with many other pharmaceutical drugs, the common consensus is side effects of CBD are manageable and balance out in terms of their benefits.
CBD also holds promise in the management of substance misuse and addiction, which is thought to be by reducing cravings and anxiety, and/or by potential pharmacokinetic interactions that interfere with the metabolism of other drugs (i.e. keeping the substance in the system longer so the patient requires less).
As such, there are a number of new clinical trials underway or recently completed that explore this idea in areas such as alcohol use disorder and opioid use disorder. Addiction is a new and exciting area for exploration of CBD and this work is only now transitioning into human studies, so results will be apparent in the coming months and years.
Research more broadly
In Australia, there are quite a number of clinical trials ongoing in the field of medicinal cannabis, many of which are actively looking for eligible participants. These studies encompass a broad range of conditions from mental health and sleep disorders to cancer symptom management and neurological conditions. An up to date list of these studies can be found on the ACR website. Many include THC and CBD formulations, but there are a number focused on CBD-only products.
Finally, ACR is in the process of developing a new prospective observational research study, the Cannabinoid Medicine Observational Study (CMOS), that will assess prescribing patterns, dosing, efficacy and adverse effects of cannabis medicines in Australia across some 20,000 patients. Through this research medical professionals and others in the medical cannabis arena will be able to gain a greater insight into medical cannabis prescribing for specific conditions in Australia.
If you want to find out more about this exciting research or how your clinical practice could become a participating site please contact [email protected].
By Jessica Kindynis