When I think of cannabis use, I can’t help but think about the stigma and controversy that has been around it for the past few decades, the back and forth arguments between scientists, legal authorities and people who have personal interests in the topic.
I am a postdoctoral neuroscientist who is interested in the biopsychosocial aspects of depression and in my PhD, I explored the role of cannabinoids in depression. More on this later in this blog.
Recent interest in selling and using cannabis supplements as panacea for many ailments, fuelled by anecdotal facts and personal (and often biased) perceptions, contributed to intensifying any pre-existing attitudes about either beneficial or harmful effects of the plant’s use.
But what do we see when we take a moment to look at the existing evidence?
With sufficient scientific evidence, most European countries allow the use of medicinal cannabis for some medical conditions. For example, currently in the UK, there are several cannabis-derived medications which have been approved for conditions like epilepsy, chemotherapy-related sickness in cancer, or muscle spasticity in multiple sclerosis.
And what exactly do we mean by “sufficient scientific evidence”?
Simply, this means that these drugs went through a lengthy process of testing their efficacy and safety starting from studies on cells, then animals (preclinical studies) and lastly on humans (clinical studies), before they could be approved. Several studies have highlighted the beneficial effects of cannabis-derived medications in the treatment of pain and inflammation, and in mental health, e.g., reducing anxiety.
On the other hand, cannabis use has been also linked with increased risk for some psychiatric illnesses, such as psychosis.
So, how does cannabis work?
The main compounds of cannabis plants are ∆9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Inside our brains, and in almost every cell in our bodies, we have designated areas of our cells (receptors) that “recognise” and bind to these external compounds (THC and CBD), which in turn causes cell activation leading to a cascade of cellular responses.
Of course, we do not have these receptors in our bodies so that we can respond to THC and CBD from plants — we produce our own “cannabis compounds” (so-called, endocannabinoids) which exist even if we do not use cannabis. The main endocannabinoids are called anandamide (AEA) and 2-arachidonoyglycerol (2-AG). Altogether, they are part of the endocannabinoid system, which the main role is to keep homeostasis within and between the cells, and is associated with behaviours such as eating, sleeping and relaxing, and of course, they do not “get you high”. These two endocannabinoids were the focus of my PhD, and I will focus on them in this blog.
As I have mentioned before, in my PhD I studied the role of endocannabinoids (AEA and 2-AG) in depression, and especially in the context of inflammation-induced depression.
Now a little bit about depression in the context of inflammation, since this was what primarily ignited my interest in doing this particular PhD. Over the past few decades, clinical studies have shown that increased systemic inflammation (measured in blood) may be a promising biological indicator of depression. This means that when our immune system is inflamed, we may be more likely to develop depression. For those interested in how the increase in systemic (blood) inflammation affects the brain and can lead to fatigue, low mood, loss of appetite and generally behaviours that are seen in depression, you can read more in one of our previous blogs.
As studies continued, I was intrigued by this discovery.
However, what does it have to do with endocannabinoids?
The endocannabinoid system is a homeostatic system which means it is capable of regulating other systems within our body, such as the immune system. As the activity of the endocannabinoid system increases, it reduces inflammation. And this “communication” seems to go both ways. Inflamed cells produce more endocannabinoids, such as AEA and 2-AG, which in turn act as “brakes” on inflammation.
In depression, on the other hand, previous studies suggest there may be reduced activity of the endocannabinoid system, and so in turn, increased inflammation.
The involvement of the endocannabinoid system in both inflammation and depression inspired me to explore more. I was curious and the questions I asked myself were whether increased systemic inflammation increased blood levels of endocannabinoids, and whether individuals with reduced blood endocannabinoids were more likely to develop inflammation-induced depression.
To achieve this, I chose to study patients who received Interferon-alpha (IFN-α) treatment for hepatitis C infection. IFN-α is a protein produced by the activated immune system and it helps to fight the infection. Administered in higher quantities as a medication, it helps fighting viral infections such as hepatitis C and B. However, the downfall of the treatment is the long duration and its side effects which include fatigue and low mood, and, in up to 40% of patients, also depression.
My role was to see the patients throughout their treatment and ask them a series of questions to determine how they were doing and monitor whether they developed depression. During the visits, I also collected their blood samples from which I measured endocannabinoid levels.
As expected, I found that both endocannabinoids increased following IFN-α treatment.
Interestingly and unexpectedly, I found different patterns of change between AEA and 2-AG, where AEA increased later in treatment and remained increased 6 months after the treatment has ended, whilst 2-AG increased at the beginning of therapy and returned to its initial levels 6 months post-treatment.
My findings suggest that AEA and 2-AG are involved in different stages of immunoregulation following IFN-α treatment, where AEA might be involved in chronic inflammation, providing further evidence that targeting endocannabinoids may be of interest as an anti-inflammatory treatment in the future.
However, I did not find any difference in either AEA or 2-AG between individuals with and without IFN-α-induced depression. This may suggest that different biological mechanisms may be involved in inflammation-induced depression compared with classic “psychiatric” depression, or perhaps that any changes in the endocannabinoid system in this subtype of depression may not be captured by blood levels of AEA and 2-AG. If you would like to read more about this study, my research findings have been recently published in Brain, Behaviour and Immunity here.
Research findings can be in agreement with what we already expect or be completely full of surprises, but one thing is for sure: they are true to the facts, and not affected by our personal views, preferences or opinions — or at least that’s the prerequisite.
Although cannabis was legalised for medicinal use in the UK from the 1st November 2018, it can only be prescribed by a specialist and as a last resource, if other treatments fail. The reluctance to prescribe it is fuelled by the lack of robust research as reported by the Department of Health and Social Care, and for many people this means a struggle to get the right treatment, enormous costs associated with it, and even legal consequences. As I write this, there are strong concerns that Brexit will stop the importation of cannabis-derived medications from Europe, with potentially life-threatening consequences for patients.
We are at the beginning of the right path, however, there is still uncertainty around the risks associated with the use of cannabis-derived medication, which can only be dispersed by more clinical trials.
