Introduction 

Anxiety is a common term used to describe fear or worry over problems that we encounter in our lives. However, anxiety disorder is a medical term describing a mental health condition that may not be temporary and can worsen with time if it is not monitored. It is an overestimation of a perceived threat or the false appraisal of danger in a situation that leads to overprotective responses.¹ Anxiety disorder was reported as the most common mental health disorder in 2019, with around 501 million people in the world being diagnosed with an anxiety disorder. Anxiety disorders can be classified into generalised anxiety disorder, panic disorder, social anxiety disorder, and phobia-related disorders. Common symptoms of anxiety disorders include psychological symptoms, such as feelings of fear, panic, distress, irritability, difficulty concentrating, and uncontrollable or obsessive thoughts, and physical symptoms, such as shortness of breath, heart palpitations, restlessness, cold or sweaty hands, tensed muscles, nausea, dryness of the mouth, numbness, and insomnia .¹ Common treatments for anxiety disorders include medications and psychotherapy.¹ This article will illustrate the neuroscience behind how medical cannabis may relieve anxiety symptoms.

Understanding anxiety

Most symptoms of anxiety are mediated by the sympathetic nervous system via the well-known fight-or-flight response . When your body detects a stressor (the cause of stress), this signal is first received by the hypothalamus (part of the brain that senses body energy stores), which activates the SAM system or sympathetic adrenal medulla system, a short-term response to stress.² Upon activation of the adrenal medulla, the hormone adrenaline is produced and released. At this stage, your heart rate, blood pressure, and breathing rate increase, and your muscles and blood vessels become constricted. Anxiety disorders persist for a longer time and activate a chronic response to stress called the hypothalamic pituitary adrenal axis or HPA axis.² Here, the hypothalamus stimulates the pituitary gland, which further stimulates the adrenal cortex to release the stress hormone cortisol. Cortisol increases indicate the level of stress in your body by increasing blood glucose and metabolism in the body.² These stress response processes are activated to provide your body with more energy to either fight or flee from the stressor. Normally, the HPA axis would switch off when the stressor is no longer present, however, this does not occur and those affected by anxiety disorders are constantly under a state of high alarm. 

The HPA axis involves three brain structures, the amygdala, the hippocampus, and the prefrontal cortex.² The amygdala is an important brain structure for the processing of fearful stimuli, and due to its close location to the hippocampus (responsible for memory), recollecting fearful memories could invoke the fear experienced at the time of trauma as well.² The amygdala and hippocampus are part of the limbic system, which is central to the regulation of emotions.² The limbic system is connected to the prefrontal cortex, responsible for information processing, decision-making, problem-solving, and other important cognitive abilities.^1,3 

Neurotransmitters are chemical signals that allow the nerve cells in the brain to communicate with the rest of the body. Serotonin is responsible for regulating mood, appetite, and sleep. Noradrenaline or norepinephrine is responsible for alertness and attention, and GABA (gamma-aminobutyric acid) reduces the activity rate of brain signals. Low levels of serotonin, GABA, and noradrenaline are associated with anxiety.

The endocannabinoid system (ECS) and anxiety 

The endocannabinoid system (ECS) is involved in the regulation of sleep, mood, cognition, appetite, and immune function.⁴ ECS includes cannabinoid receptors CB1 and CB2, endogenous cannabinoid molecules (anandamide and AG-2) and enzymes which synthesise and degrade these molecules. CB1 receptors are mainly found in the central nervous system and govern the release of neurotransmitters and the activation of neurons.⁴ The CB2 receptors are mostly found in the peripheral immune system and in the microglia cells of the central nervous system that play an important role in neuroinflammation.⁴ 

Anandamide and 2-AG endocannabinoids are lipid signalling molecules that have been found to act on CB1 receptors in the amygdala and prefrontal cortex, which regulates emotions of fear and anxiety.^4,5 Low doses of endocannabinoid action on CB1 receptors reduce anxiety levels, whereas high doses of endocannabinoids increase anxiety levels.⁵ 

In fear, endocannabinoids play a role in the reconsolidation and extinction of fearful memories.⁵ 

How medical cannabis works on anxiety

Cannabis or Cannabis sativa is a plant that produces two well-known cannabinoids, tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is a psychoactive component, whereas CBD does not produce an intoxicating effect. Plant-based cannabinoids (phytocannabinoids), like THC and CBD, have been found to regulate anxiety through the ECS, which is why medical cannabis has been investigated for its therapeutic effects on anxiety. 

THC acts on the CB1 receptors to produce a sense of euphoria and relaxation; however, high THC doses can trigger anxiety, fear, and panic. 

CBD acts on the 5-HT1A receptors, which produce the same effect as serotonin (mood regulation), and on the GCPRs, which produce the same effect as GABA (relaxation). 

Studies suggest CBD has anxiety-reducing effects in doses between 500 mg to 800 mg per day; however, due to limited research, CBD cannot be confirmed as an effective treatment for relief from symptoms of anxiety disorders. Furthermore, there is less evidence to support the use of THC-dominant products for the treatment of anxiety.⁴ THC doses of 20 to 50 mg per day have been found to cause adverse effects like sedation, depersonalisation (feelings of being outside your own body), and heightened or altered sensory perception.⁴ 

Evidence regarding the efficacy of medical cannabis is generally low-quality due to the lack of large clinical trials solely focused on its effect on anxiety symptoms.⁶ A recent study found THC-induced anxiety can be reduced with the joint action of d-limonene, an essential oil commonly found in citrus fruits and naturally present in cannabis, which can help diminish the risks related to THC use in medicines. Continued efforts in research are being made towards eliminating risks and making medical cannabis products safer for public use. 

Summary 

Anxiety disorder is a chronic condition where an overestimation of a perceived threat or the false appraisal of danger in a situation leads to overprotective responses by the individual. Common symptoms of anxiety disorders include psychological symptoms, such as feelings of fear, panic, distress, and physical symptoms, such as shortness of breath, heart palpitations, restlessness, cold or sweaty hands, tensed muscles, nausea, and insomnia. Anxiety disorders persist long-term and activate a chronic response to stress by the body called the hypothalamic pituitary adrenal axis or HPA axis. It causes the release of the stress hormone cortisol, and high levels have been linked to symptoms of anxiety. Low levels of neurotransmitters, including serotonin, GABA, and noradrenaline, are associated with anxiety. 

The endocannabinoid system (ECS) consists of endogenous cannabinoids (anandamide and AG-2), and CB1 and CB2 cannabinoid receptors. ECS is involved in the regulation of sleep, mood, cognition, appetite, and immune function. Low doses of endocannabinoid action on CB1 receptors reduce anxiety levels, whereas high doses of endocannabinoids increase anxiety levels. Cannabis or Cannabis sativa is a plant that produces two well-known cannabinoids, tetrahydrocannabinol (THC) and cannabidiol (CBD). THC acts on the CB1 receptors to produce a sense of euphoria and relaxation, however, high doses can trigger anxiety, fear, and panic.CBD has been found to act on the 5-HT1A receptors, which produce the same effect as serotonin (mood regulation), and on the GCPRs, which produce the same effect as GABA (relaxation). Therefore, the use of medical cannabis products must be taken with caution and within the limits of safe usage. 

To conclude, due to the low-quality evidence, the efficacy of medical cannabis on anxiety symptoms remains inconclusive and research efforts are being made to ensure medical cannabis can be safely administered for public use.