The Endocannabinoid System and it’s Role in Anxiety and Depression

The Endocannabinoid System and its Role in Anxiety and Depression

While cannabis has been consumed by humans for both recreational and medicinal purposes for thousands of years, the system through which cannabis compounds interact – the endocannabinoid system – remains widely under-researched. There is growing evidence to suggest that cannabinoid receptors may play a significant role in the development of psychiatric disorders like anxiety, depression, and schizophrenia.

The physiological effects of cannabis use is believed to be largely due to the interaction between cannabinoids produced by the plant and our endocannabinoid system (ECS). The ECS is a collection of receptors, endogenous ligands, transporter proteins, and enzymes. The two most common endocannabinoid receptors are cannabinoid receptor type 1 (CB1R) and cannabinoid receptor type 2 (CB2R).

CB1 Receptors and Anxiety and Depression

CB1R are distributed mainly in the central nervous system and are expressed in the cerebral cortex, hippocampus, amygdala, basal ganglia, striatum and cerebellum. The activation of these receptors has been found to inhibit neurotransmitter release and produces anxiety reducing and antidepressant effects at low doses as well as enhancing the action of classic antidepressants.

Some animal studies have indicated that animals with low levels of endocannabinoid signalling show increased signs of anxiety, depression, and schizophrenia-like behaviours which compare with patients suffering with psychiatric disorders.

Evidence of anxiolytic and antidepressant effects of CB1R activation

A number of studies have aimed to understand the role of CB1R in the progression of anxiety, depression, and other psychiatric conditions. Some mice models have revealed that the blocking of CB1R produces and increases anxiety- and despair-like behaviours as well as reduces food and sustenance consumption. Such behavioural changes are often associated with symptoms of depression in humans.

A recent study in mice revealed further evidence of anxiety- and depression-like behaviour in animals with a total absence of CB1 receptors. The study used “multiple behavioural tests designed to jointly assess depression-related behaviour in mice with partial or total reduction of CB1R.”

Mice with wild type (CB1R +/+), heterozygous (CB1R +/-), and homozygous (CB1R -/-) CB1R genes were subjected to a number of tests including an Open Field (OF) test, elevated plus maze (EPM) test, light-dark box (LDB) test, novelty suppressed feeding test (NSFT), sucrose splash test (SST), and forced swimming test (FST).

The Results

The OF test, in which mice were placed in a 50x 50 x 40 cm black wooden area, recorded anxiety-like behaviour by recording the amount of time the animals spent in the centre of the area. Each mouse was recorded for five minutes. This test revealed no significant difference between mice sub-groups in terms of anxiety-like behaviours.

The EPM test assessed anxiety-related behaviour through various measures when the mice were placed in a cross-shaped platform 40cm above the floor; the platform had two open arms and two enclosed perpendicular arms. The researchers measured the percentage of time spent in open arms, the percentage of entries to open arms, and the latency to leave the central platform for the first time.

This test revealed that CB1R -/- mice spent less time in open arms as well as a non-significant tendency to latency in comparison to CB1R +/+ and CB1R +/- mice, indicating anxiety-like behaviour. CB1R -/- mice also displayed lower total number of entries to both open and enclosed arms indicating lower locomotor and exploratory activity. In addition, CB1R -/- exhibited a smaller number of grooming episodes compared to other groups, which indicates a lower motivation to self-care.

The LDB test involved placing the mice in a construction of two adjoining compartments – one lit and one dark. CB1R -/- mice spent less time in the light compartment, however, the latency to leave the light compartment was also greater in CB1R -/- mice. Additionally, CB1R -/- mice presented fewer transitions between the light and dark compartments, indicating reduced locomotor activity. Overall, the results of the LDB test were considered to indicate anxiety-like behaviour, lower locomotor activity, and alterations in decision-making in CB1R -/- mice.

The NSFT test found that latency to first contact with food and food intake was lower in CB1R -/- mice which may indicate alterations to appetite.

The SST involved the application of a vaporised 10% w/v sucrose solution to the dorsal coat of each mouse. Researchers recorded the time taken by the animal to carry out the first grooming episode and total grooming activity time. CB1R -/- mice presented longer latency to the first grooming episode and fewer episodes of grooming in comparison to CB1R +/- and CB1R +/+ mice. These findings showed a decrease in induced self-care, which indicates apathy-related behaviour in CB1R -/- mice.

The FST demonstrated an increase in latency to immobility in CB1R -/- mice when placed in a glass cylinder containing water. Immobility is interpreted as a parameter related to depressive behaviour by measuring latency and the number and duration of episodes of immobility. The number of episodes and duration of immobility did not differ significantly between CB1R +/+ and CB1R -/- animals, however, longer latency may suggest an increase in the stress response to the test in CB1R -/- mice.


The researchers and authors of this study conclude that, when considered as a whole, these results reinforce existing evidence that CB1R play a significant role in the regulation of mood and anxiety states. It is indicated that the complete absence of CB1R produces anxiety-like behaviour, decreased locomotor activity, decreased appetite and body weight, risk assessment and decreased motivation for self-care. All of these symptoms are often observed in human patients diagnosed with anxiety and depression.

These findings, along with the findings of previous studies, support the continued exploration into the potential impact of therapeutic drugs in the regulation of eCB signalling on anxiety and depression.