Introduction

Cannabis is the most commonly used illicit drug in the UK. To quantify just how common cannabis use is, it is estimated that around 8% of people aged 16-59 use the drug at least once annually. While cannabis is relatively safer compared to other illicit drugs, as it cannot lead to fatal overdose, its regular use is associated with an increased risk of dependency, mental illnesses, cardiovascular problems and infertility, among others.¹ Understanding the neuroscience behind cannabis dependency and withdrawal gives us an insight into why these conditions arise and how they can be treated effectively. Cannabis contains many different active chemicals called cannabinoids. The two that are most well-known and studied are called tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is responsible for the “high” associated with taking cannabis and also its potential for dependency. Withdrawal occurs when the intake of THC-containing cannabis results in unpleasant side effects. 

But how does the brain dictate what goes on during cannabis dependency and withdrawal? This article offers an insight into how brain processes shape these two phenomena. 

Cannabis and the brain: an overview

Cannabis is composed of many different chemicals which interact with the brain. These chemicals are called cannabinoids, and they work on the endocannabinoid system. This system is associated with many different functions, like the development of the central nervous system, motor control, and emotional regulation.²

Cannabinoids are messengers that bind to proteins called receptors to elicit a specific response. Different cannabinoids promote different responses; hence, not all of them cause the “high” associated with cannabis use and, subsequently, its addictive properties. One cannabinoid in particular is known to cause this effect. This cannabinoid is THC, or tetrahydrocannabinol. 

There are two key receptors in the endocannabinoid system: CB1 and CB2 receptors. The answer to why different cannabinoids are responsible for differing responses lies in their ability to bind to these two receptors. THC binds mainly to CB1 receptors, which have been shown to increase the activity of the dopamine pathway (the reward pathway) in the brain, much like many other drugs of abuse.³ 

Cannabis also has many other physical and mental effects, such as:⁴

• Changes in mood
• Changes to perception—for example, colours can appear more vivid
• Cognitive and muscle impairments—for example, trouble concentrating or coordinating muscle movement
• Increased heart rate
• Decreased appetite
• Diarrhoea 
• Nausea and dizziness
• Tiredness

Dependency versus addiction

Although in this article dependence and addiction are used almost interchangeably, it is important to note that these processes are distinct from each other. Dependency is a term used to describe a state in which an individual is physiologically dependent on a specific drug. Dependency, therefore, leads to withdrawal symptoms when the drug is stopped, as the body has adapted its function to being on the drug. 

Addiction is more linked to the psychological aspect of dependence on a drug. It is less well established, as its complex pathology originates in the brain. This distinction is important in medicine as these two conditions are clinically approached differently.⁵ 

In the case of cannabis, addiction and dependence are given the same diagnosis of cannabis use disorder.⁶ 

Mechanisms of dependency

Daily cannabis use is the number one predictor of developing dependency or cannabis use disorder.⁷ Below, we will explore the variables which factor into both physical and mental dependence on cannabis. 

Physical dependence

Consider your taste buds. If you were to eat a bar of chocolate before drinking a sugary fizzy drink, the drink would no longer taste as sweet as it would on its own. 

Your body has evolved to be highly adaptable to its environment. Compensation mechanisms exist all throughout the body to maintain the stability of biological processes. Hence, if you continuously partake in using a substance which has an effect on a specific bodily process, the body adapts and builds tolerance to the substance in order for this specific process to continue in a way that is within a safe range. 

In the context of cannabis, the body can respond to an overload of cannabinoids by, for example, taking away some of the receptors that they bind to. When this happens, you may need to take a larger dose of the drug to feel the same response. At this point, your body is dependent on the drug being present to maintain a normal balance of specific processes. Physical dependence and tolerance are the causes of withdrawal symptoms. 

Mental dependence

Because mental dependence is not yet fully understood, there are many different hypothesised mechanisms for the neuroscience behind it. 

Dopamine system and reward pathways 

Chronic cannabis use is associated with activation of the reward pathway. It is also associated with sensitising this pathway to cannabis cues. What this means is that the brain perceives cannabis as a reward and is inclined to seek it. This is amplified in those who partake in cannabis use chronically, meaning that they wish to seek it more often than someone who uses cannabis less frequently.⁶ 

Habit formation

Some scientists have argued that substance abuse is not just dependent on the reward value of the drug. Instead, it is proposed that dependence is initially a result of goal-directed (reward-driven) behaviour, and after a while, the choice of whether to partake in drug use becomes habitual. This takes fails to acknowledge the complexity of dependence but may be helpful in targeting it.⁸ 

Behavioural and psychological factors

Dependence is a complex process that is a summation of many different moving parts. Your environment, genetics and psychological traits can make you more likely to become dependent on cannabis. These variables cause changes in the brain, which contribute to different perceptions of the drug from individual to individual.⁹ 

Potential factors that increase the risk of cannabis dependence include:¹⁰

• Smoking cigarettes in high amounts
• Mental health conditions like ADHD or conduct disorder
• Taking cannabis at a young age
• Smoking cannabis alone
• Previous positive reactions to cannabis

Withdrawal symptoms and neurobiological basis

Withdrawal symptoms are associated with physical dependence and occur when you stop a drug after being on it for a long time as a regular or heavy user. Withdrawal symptoms differ a lot in their onset and presentation from person to person. This means that factors such as how long and how often you have been using can contribute to the severity of withdrawal symptoms, but this is different for everyone. Some people are less physiologically adaptable than others, and the reversal of the neurological changes caused by regular cannabis use is much easier than for someone who has adapted extensively. Withdrawal is important to consider, as it can lead some to relapse.  

Symptoms

The symptoms associated with cannabis withdrawal include:¹¹

• Irritability 
• Anxiety, nervousness and low mood
• Difficulty sleeping
• Decreased appetite and weight loss
• Abdominal pain
• Shakiness
• Excessive sweating
• Fever
• Chills
• Headache

The neuroscience behind withdrawal symptoms

Changes in the brain caused by chronic cannabis use are linked with causing and setting the intensity of withdrawal symptoms. These changes are reversible but are responsible for the unpleasant side effects associated with abruptly stopping cannabis use. Typically, these changes start to reverse two days after abstinence and take up to four weeks to completely reverse.¹¹

Changes to the endocannabinoid system

Chronic cannabis use results in the desensitisation or downregulation of CB1 receptors in the endocannabinoid system. This means that when cannabis use is abruptly stopped, there are not enough receptors to maintain normal function. Studies have shown that the lower the number of available CB1 receptors in the brain, the more severe the withdrawal symptoms.¹¹

Changes in brain structure 

The cravings for cannabis that arise after abstinence have been shown to be increased as the size of a part of the brain called the amygdala is reduced. The amygdala is responsible for processing emotions like fear, anger and aggression. It is thought that the amygdala is at least partly responsible for the transient, emotional cannabis withdrawal symptoms.¹¹ Changes to the amygdala are hallmarks of early life stress, which explains why those with changes to the brain caused by their environment can experience withdrawal symptoms for longer. 

Changes in brain activity 

In long-term users of cannabis, the brain was shown to have higher activity in specific brain circuits associated with reward. It has also been shown that the brains of chronic cannabis users were extra sensitive to cannabis-associated cues when compared to non-users, and these changes were associated with increased severity of withdrawal symptoms.¹¹ 

Summary 

Cannabis is the most commonly used illicit substance in the UK and many countries worldwide. Along with long-term use of cannabis comes the risk of dependence and consequent withdrawal symptoms when a person decides to stop usage. The neuroscience of both of these conditions is crucial in helping the medical field to better understand their underlying causes, risk factors and treatments. 

The neuroscience behind dependence is highly complex and can vary drastically from person to person. Mentally, dependence is a consequence of cannabis-induced changes to pathways in the brain related to reward perception, learning and decision-making. Frequency and severity of mental dependence incorporate psychological traits, genetics and environment. Physical dependence is caused by your body adapting to being on the drug to maintain the stability of physiological processes. Physical dependence is the cause of withdrawal symptoms. 

Cannabis withdrawal symptoms include mental symptoms like low mood, anxiety, irritability and difficulties sleeping as well as physical symptoms like abdominal pains, fever and excessive sweating. Withdrawal symptoms occur when the brain is reversing brain changes acquired during cannabis dependence. These include changes to the endocannabinoid system, like the desensitisation of CB1 receptors, physical changes to specific brain regions and changes to brain circuits like those responsible for processing reward.