Depression will affect many of us in our lifetime. Some of us are genetically predisposed, others become depressed as a result of the hard knocks of life, while many struggle to find an answer as to why they experience low mood. One factor emerging as a possible biological cause is an imbalance in the endocannabinoid system, with studies suggesting it could be both a potential biomarker of depression and a therapeutic target. And with cannabis being the most studied method of stimulating the endocannabinoid system, could compounds in the plant like CBD, be the depression treatment of the future?

Depression will affect many of us in our lifetime. Some of us are genetically predisposed to depression, others become depressed as a result of the hard knocks of life, while many struggle to find an answer as to why they find themselves struggling with low mood.

Depression – A Personal Experience Needs Personalised Medicine

Depression is described as a medical illness causing “feelings of sadness and/or a loss of interest in activities once enjoyed.” It’s unknown how many people are affected, with estimates suggesting that anywhere between 25% – 50% of the population will be depressed at some point in their lives. Either way, even in the 21st century, a stigma still exists, and in the US 80% of people who are clinically depressed are currently receiving no specific treatment. Those that do receive help may be prescribed antidepressants, receive psychotherapy or combination of both.

Due to the unique combination of factors that contribute to each case of depression: a genetic predisposition, chronic or elevated stress levels, illness, bereavement, trauma or medication, it’s generally accepted that a one-size-fits-all approach will only yield moderate effects. As such, scientists and doctors are increasingly exploring a personalised approach, where every aspect of the patient is considered – from their biological makeup to environmental influences.

Endocannabinoid Imbalance – A Cause Of Depression?

The term ‘chemical imbalance’ is often cited as potential cause of depression and mental illness, referring to an over or under production of neurotransmitters such as serotonin and dopamine. But there’s another key neurotransmitter that may also play a part. Anandamide, one of the primary endocannabinoids in the body, has also been found to be dysregulated in cases of depression, with scientists researching how a dysfunctional endocannabinoid system may be involved in depressed states.

The endocannabinoid system (ECS) is a complex network of receptors and cannabis-like ligands (Anandamide and 2-AG) found throughout the body. There are two primary receptors: CB1 which are mostly located in the brain and central nervous system, and CB2 receptors found in the immune system, peripheral nervous system, and gut. The system’s modus operandi is to bring homeostasis or balance to our bodies and minds, and it has been likened to a dimmer switch, turning up and down activity in the body when needed.

In cases of depression and mental illness, scientists are most interested in studying the relationship between the CB1 receptors and the endocannabinoids that activate them. They have observed how the ECS is involved in regulating the activity of neurotransmitters known to be involved in emotional processing such as reward, fear, memory extinction and stress. It would follow then that too much or too little endocannabinoid activity would affect these key factors in mental health and could be possible biomarkers for future vulnerability to depression.

Endocannabinoid Changes Found In Depression

It’s no coincidence that scientists named the first endocannabinoid they discovered, anandamide. Coming from the Sanskrit word for bliss, they knew that the neurotransmitter was intricately linked to feelings of happiness and wellbeing. While anandamide levels are difficult to measure as it is produced on demand, mood enhancing activities such as cardiovascular exercise have been seen to give it a temporary boost.

Not only that, studies show people with a genetic mutation in which they produce less of the enzyme that breaks anandamide down in the body (FAAH), are generally happier and cope with stress better.

2-AG, the other key endocannabinoid, also shows signs of dysregulation in depressed states. In a study carried out on women with depression, 2-AG was found to be significantly lower, with levels further diminishing the longer the depression lasted. 2-AG is further found to be below normal in cases of PTSD.

But it’s not just the endocannabinoids scientists are interested in studying when it comes to depression. Another indication of a fully functioning ECS is the density of the CB1 receptors in the brain.

So far, studies have been carried out on animal models or in post mortems of depressed patients. Unfortunately, it’s not as straightforward as saying that in all instances the ECS is depleted. While across the board, there appears to be changes in CB1 receptor density compared to non-depressed subject, research shows that this density varies depending on the area of the brain.

On rodent models, the act of blocking CB1 signalling brought about depression like symptoms such as reduced interest in rewards such as sex, food, sleep disruption and increased anxiety. The suggestion being that there is a direct link between reduced CB1 density and depression.

However, in another study on depressed mice, increased CB1 density was observed in the Prefrontal Cortex, the area of the brain responsible for decision making, development of personality, and modulating social behaviour. Scientists believe that this heightened ECS activity rather than being the cause of the depression, is the body’s attempt to mitigate the symptoms of depression and chronic stress.

A Balanced ECS – the Body’s Natural Antidepressant

In the academic paperEndocannabinoid Signaling in the Etiology and Treatment of Major Depressive Illness,’ the authors posit that many of the functions of the endocannabinoid system mirror the effects elicited by pharmaceutical antidepressants.

Take for instance the creation of new neurons in the hippocampus, the part of the brain responsible for remembering and processing long term memory and registering fear. It’s long been observed that in depressed patients the hippocampus appears smaller than in healthy subjects, possibly caused by stress hormones impairing the growth of new nerve cells in the area. It has also been noted that patients taking antidepressants experience hippocampal neurogenesis (nerve growth), which scientists believe may be one of the key factors in their mood elevating effect.

Scientists suggest a functioning endocannabinoid system is key to encouraging new cell growth in the hippocampus. Mice which had been exposed to stress had less CB1 receptors in the hippocampus. In another study, rodents with decreased CB1 function had lower levels of  brain-derived neurotrophic factor (BDNF). BDNF has been described as ‘miracle grow’ for the brain, fertilizing existing brain cells and promoting the growth of new neurons. The suggestion being that weak CB1 signalling may impair new hippocampal cell growth, while a healthy endocannabinoid signalling would have the opposite effect.

What About Cannabis?

Turns out that compounds found in cannabis also promote new cell growth in the hippocampus as well as having other antidepressant effects. While one study found that THC increased levels of hippocampal BDNF, the non-psychoactive CBD (Cannabidiol) has also been shown to promote new brain cell growth in the region, which scientists believe may partly account for its overall anti-anxiety effect. This is much in part to CBD’s role as a FAAH inhibitor (the enzyme that breaks down anandamide), which in turn strengthens endocannabinoid signalling.

Not only that, CBD is a partial 5HT1A agonist, meaning it stimulates the serotonin receptor, which researchers believe may explain its reported calming and antidepressant effect.

A further area of interest lies in the discovery of a link between inflammation and depression. Could the anti-inflammatory effects of compounds in the cannabis plant like CBD and THC help quell the inflamed fires that contribute to and perpetuate mental illness?

In the end, science is just confirming what people have known for years – that with the right dosage, cannabis can lift low mood and calm anxiety. The difference being that with the discovery of the endocannabinoid system, we now have more of an idea about why particular compounds in the plant have this effect. The likelihood is that pharmaceutical companies will try and find their own patentable ways of manipulating the endocannabinoid system such as synthetic FAAH inhibitors. But why try and reinvent the wheel when mother nature has given us her own mood lifting, chemical-free solution?


Cecilia J. Hillard, Qing-song Liu (2014). Endocannabinoid Signaling in the Etiology and Treatment of Major Depressive Illness. Curr Pharm Des. 2014; 20(23): 3795–3811.

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