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The Brain Chemistry Behind Tolerance and Withdrawal

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By Canva© Studio

The Center for Disease Control and Prevention defines substance use disorders (SUDs) as ‘treatable, chronic diseases characterized by a problematic pattern of use of a substance or substances leading to impairments in health, social function, and control over substance use’1. Addiction at times can be incorrectly thought of as ‘a moral failing instead of what we know it to be: a chronic treatable brain disease’2, which results in the body sending signals in the absence of the drug. These signals cause the user to ‘crave’ the substance, much like the body sends signals when we are hungry or tired. These physiological changes are related to our body’s natural messengers, neurotransmitters.

Neurotransmitters are the body’s natural chemical messengers that control bodily functions such as breathing, heartbeat and blood pressure, muscle movement, sleep, digestion, and thoughts and memories3. Some examples of neurotransmitters are dopamine, glutamate, serotonin, norepinephrine, GABA, epinephrine, and histamine. The volume and storage of neurotransmitters within the body is highly regulated. The body can sense when there is too little or too much of a neurotransmitter and responds by creating more or destroying the neurotransmitter.  Any change of this homeostasis can have severe consequences on the body’s ability to react to external stimuli and can be referred to as intoxication4.

The effects experienced by drugs is related to neurotransmitters. Neurotransmitters work on the body by binding to receptors. Neurotransmitters and their receptors work very similarly to a lock and key. The neurotransmitter perfectly fits into a specific receptor just like a key fits into a specific lock.

Some drugs, referred to as agonists, mimic neurotransmitters causing the body to think neurotransmitters are present, when in fact they are not. In our lock and key model, this would be like using an object to pick a lock in the absence of a key.

Some other drugs can increase or decrease the level of natural neurotransmitters in the body resulting in an increased or decreased level of signals. For example, the drugs can ‘copy’ the set of keys, allowing the lock to be opened more freely, or destroy the keys, preventing the lock from being opened.

Other drugs, called antagonists, block the body’s natural neurotransmitters causing no signal even when the stimuli are present. In our model, this would be equivalent to breaking a key off in the lock, preventing future keys from opening the lock (infographic 4). The effects of the drugs can be desirable such as euphoria or relaxation, while others are not desirable, like paranoia or increased blood pressure.

Over time with repeated drug usage, the body will compensate for the imbalance of neurotransmitters to restore the homeostasis. For instance, amphetamine increases the level of dopamine in the body. With chronic amphetamine use, the body recognizes the unnaturally high levels of dopamine.  As a response, the body starts producing less dopamine. If the user then suddenly stops using amphetamine, they can experience side effects of low dopamine in the body, such as lack of motivation, lethargy, moodiness, or difficulty sleeping5. This phenomenon is referred to as withdrawal, and at times, for some substances, can be life-threatening.

Tolerance is similar to withdrawal in that it is also related to the body compensating for the imbalance of neurotransmitters. In the prior example, chronic amphetamine use causes the body to produce less dopamine. However, the ‘high’ experienced by amphetamine use is caused by the unnaturally high level of dopamine. If the body is producing less dopamine naturally, the user will need to take more amphetamine to experience the same ‘high’. This phenomenon is referred to as tolerance. Both tolerance and withdrawal are related to imbalance of the body’s neurotransmitters.

SUDs are more than just the psychological need to use a substance. They are complex diseases which affect the natural chemistry of the user’s body. Due to this complexity, individuals suffering from SUDs are recommended to seek treatment from professionals.



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