From Pleasure to Pain: The Effects of Cocaine Use Disorder on the Brain
Brooke Berbeco
Illustrations by Mischa Landgarten
Disclaimer: The following article discusses Cocaine Use Disorder and contains detailed descriptions of drug use, overdose, and its effects. If you or someone you know is struggling with addiction, you can call the SAMHSA National Helpline at 800-662-HELP (4357) to find treatment options near you.
Welcome to the Party… or Not?
Yet another party scene flashes across your screen: people dancing and laughing, colorful lights illuminating the room, and thin white lines of powder are being cut across a table with an Amex Black credit card. There’s no question that cocaine use is glamorized in the media — for instance, in images of Jordan Belfort’s rich and wild lifestyle in The Wolf of Wall Street, or the characters of Saltburn at the Cattons’ parties in their luxurious old-money mansion [1, 2]. Throughout these staged moments, cocaine is often portrayed as an exciting party drug that makes people who use it feel like they are on top of the world [1]. Yet, this glamorous representation of cocaine shrouds an opposite reality: cocaine profoundly impacts the human body, particularly the intricate workings of the nervous system [3, 4, 5]. While indigenous communities around the world have valued the coca plant — or cocaine in its natural state — for its stimulating effects for centuries, modern extraction and refinement processes produce cocaine at unprecedentedly high concentrations [6]. As a result, cocaine’s effects are amplified, subjecting those who chronically use cocaine to consequences that manifest in their brain and the rest of their body [6]. Cocaine use may cause a diverse array of behavioral changes, ranging from heightened energy levels or irritability to persistent paranoia and anxiety [7]. Behavioral changes manifest due to cocaine’s ability to disrupt chemical balances in certain brain structures that coordinate our motivational state, known as the reward circuitry; this may lead to Cocaine Use Disorder (CUD) [8]. CUD is a chronic condition marked by compulsive cocaine seeking and usage despite negative emotional, social, or health effects [8]. Understanding the psychological and physiological mechanisms that cocaine targets is key to understanding the origins of CUD and its associated health risks [8, 9].
I’m Getting ‘Nervous’
The nervous system serves as the body’s primary form of communication by transmitting signals through the specialized cells, called neurons, throughout the body [10]. These signals are responsible for transmitting sensory information, coordinating responses to stimuli, and regulating bodily functions. The nervous system consists of the central nervous system — made up of the brain and spinal cord — and the peripheral nervous system, a network of neurons that connects the central nervous system to the rest of the body. Two important subdivisions of the peripheral nervous system are the sympathetic and parasympathetic systems, which work together to maintain bodily equilibrium by regulating involuntary functions such as heart rate and blood pressure [10]. When a person faces perceived threats and stressors, the sympathetic nervous system activates the rapid fight-or-flight response, increasing heart rate, alertness, and breathing [10, 11]. Cocaine also has the ability to activate the sympathetic nervous system, inducing an undue fight-or-flight response [7, 12]. On the other hand, the parasympathetic nervous system — often referred to as the body’s ‘rest and digest’ system — counterbalances the sympathetic nervous system [13]. Communication in nervous systems begins with the production of signals within individual neurons, a process called synaptic signaling [14]. As signals travel down a neuron, they trigger the release of chemicals — known as neurotransmitters — into the synapse or the space between neurons [14]. Once neurotransmitters flow into the synapse, they bind to receptors on an adjacent cell, activating the cell through a cascade of signals [15]. To ensure precise control over synaptic transmission, neurotransmitter signaling must be tightly regulated [16]. One regulatory mechanism of neurotransmitter signaling is reuptake, during which specialized transporter proteins ‘vacuum up’ neurotransmitters from the synapse back into the presynaptic cell that produced them, reducing the neurotransmitter’s ability to bind to adjacent cells and cause downstream effects [16]. But what happens when cocaine, a molecule that inhibits neurotransmitter reuptake, comes into play?
Down to the Powder: Cocaine at the Synaptic Level
Cocaine interferes with neurotransmission, particularly in the brain’s pleasure-inducing reward circuitry [3, 7]. Generally, dopamine reuptake transporters in the reward circuitry carry dopamine — a neurotransmitter implicated in pleasure and motivation — back into the presynaptic neuron. However, cocaine disrupts neurotransmission by inhibiting the reuptake of dopamine from the synapse [7, 17, 18]. By preventing the reuptake of dopamine, cocaine prolongs the neurotransmitter’s signaling effect [7].
Cocaine also accelerates the firing rate of dopaminergic neurons that originate at the ventral tegmental area (VTA) — a brain region that plays a role in reward processing and stress regulation — and project to the nucleus accumbens — the ‘pleasure center’ of the brain [4, 5, 19, 20]. An increase in firing rate of dopaminergic neurons induces a surge in dopamine levels within the nucleus accumbens, creating an immediate and overwhelming sense of euphoria in people who use cocaine [7, 21, 22]. When cocaine is used repeatedly, physical changes occur at the synapse between neurons, which further reinforces drug-seeking behavior in people who use the drug [7, 20, 21, 22, 23, 24]. In part, physical changes at the synapse are due to an increase in the signaling of glutamate, which is a neurotransmitter that plays an important role in learning, memory, and behavior [23, 25].
Long-term cocaine use results in abnormally high glutamate levels in various regions of the brain, including the VTA [26]. An increase in glutamate activity increases the firing rate of dopaminergic neurons in the VTA that ultimately extend into the nucleus accumbens, driving drug-seeking behavior [20, 26]. An increase in glutamate signaling also reduces the sensitivity of dopaminergic receptors in the nucleus accumbens through a process known as downregulation, altering reward processing [20, 27]. By reducing the sensitivity of dopamine receptors, cocaine subsequently reduces affinity to natural, non-drug related rewards [20]. Downregulation of dopamine receptors therefore serves as a central mechanism in reinforcing addiction, as downregulation compels individuals to compensate for reduced pleasure from other sources by seeking out more of the drug instead [20].
Warning: Danger Ahead!
Frequent and extended periods of cocaine use develop an individual’s tolerance to the drug [7]. People who chronically use cocaine require progressively larger drug doses to achieve the same desired effects, potentially driving cocaine dependence. With continued use, individuals may struggle to function without the drug and experience intensified withdrawal symptoms that worsen over time [7]. Of the two million Americans who frequently use cocaine, 1.5 million fit the diagnostic criteria for CUD, or the chronic use of cocaine despite psychological, social, or physical harm [8] For individuals who chronically use cocaine, abruptly stopping cocaine use causes intense withdrawal symptoms such as depression, anxiety, slowed thoughts and movements, as well as paranoia [8, 28]. Detrimental consequences of stopping cocaine use may lead people with CUD to continue seeking cocaine, hoping to avoid the mental and physical anguish of withdrawal [8]. As a result, one’s initial goal of obtaining pleasure becomes replaced with the goal of avoiding a painful withdrawal episode [8, 28]. In addition to tolerance and dependence, chronic cocaine use is associated with chemical and physical alterations to the brain and body [7, 20].
In the case of CUD, prolonged cocaine use can damage the orbitofrontal cortex — a region essential for decision-making and self-awareness [8, 9]. Damage to the orbitofrontal cortex can cloud an individual’s assessment of the consequences of drug use; more broadly, damage to this area can reduce one’s capacity for rational thinking [9]. Individuals with CUD also exhibit a decrease in white matter integrity, which is a measure of the structural health of white matter fibers [29, 30]. White matter mainly consists of nerve fibers coated with an insulating substance called myelin [29]. Myelin coating allows signals to travel quickly across neurons, facilitating rapid communication between cells [29]. Greater white matter integrity is generally associated with increased efficiency of communication in the brain [31]. People with CUD often exhibit a reduction in white matter integrity, possibly due to the way cocaine constricts blood vessels and reduces blood volume in tissues [29, 30, 32, 33, 34, 35]. For people with CUD, reduction in white matter integrity is observed in their corpus callosum, a brain region that facilitates communication between the left and right hemispheres of the brain [33, 34, 35, 36]. Disrupting communication between hemispheres of the brain is associated with a reduced ability to problem-solve and reason effectively [36]. Additionally, cognitive impairments, such as difficulties in decision-making and working memory, are observed in people with CUD who exhibit a lower white matter integrity [33, 34].
Outside of the brain, CUD causes long-term, adverse, and potentially life-threatening effects on the body, particularly to the cardiovascular and respiratory systems [7]. By repeatedly activating an individual’s fight-or-flight response, chronic cocaine use strains our blood vessels, significantly increasing risks of developing heart disease and circulatory damage [12]. In the respiratory system, snorting cocaine can chemically damage cells in the nose and lungs, causing bleeding, infection, and tissue death [7]. Overall, chronic cocaine use wreaks havoc on the brain and body and warrants effective methods of diagnosis and treatment [7].
Treating the Mental and Physical Effects of CUD
People suffering from CUD often face significant barriers to accessing treatment; unfortunately, many individuals with CUD never receive the help they require [8, 37]. Despite an urgent need for effective CUD care, there are currently no FDA-approved pharmacological treatments for CUD [8]. However, various psychosocial treatments have effectively been utilized in CUD treatment, and include counseling, cognitive behavioral therapy, and motivational interviewing [38]. Another psychosocial treatment called contingency management stands out as particularly effective. Contingency management involves rewarding people as they achieve treatment goals by giving them vouchers, which can then be redeemed for goods and services; these vouchers can be exchanged for incentives that may motivate people who use cocaine to abstain from drug use. Additionally, intensive outpatient therapy offers a cost-effective treatment plan that can be uniquely adapted to patient needs, and has been found to be as effective as more expensive inpatient treatments for CUD. Unfortunately, some people do not respond to aforementioned standard addiction treatments, which is reflected in high dropout rates from studies. Promising treatment options for CUD — such as contingency management and cognitive behavioral therapy — underscore the importance of tailored interventions to address the diverse needs of individuals with CUD [38].
While there are ample psychosocial treatment options available for people with CUD, pharmacological interventions may also effectively treat the disorder [38]. Topiramate, a medication commonly prescribed for epilepsy and migraine prevention, has emerged as a promising candidate for treating CUD. Topiramate inhibits glutamate transmission, targeting an underlying neurochemical process involved in cocaine addiction. Clinical trials investigating topiramate’s effectiveness in treating CUD have yielded encouraging results: topiramate significantly reduces both cocaine use frequency and cravings in people with CUD. Moreover, many individuals treated with topiramate have reported that they were able to remain abstinent from cocaine for longer periods of time than they were previously able to. When combined with psychosocial interventions such as cognitive behavioral therapy, topiramate demonstrates increased effects, enhancing treatment outcomes. Although further research is needed to refine dosing strategies and assess long-term efficacy, topiramate offers renewed hope for recovery through integrated approaches to addiction treatment [38]. Through these novel addiction treatments, people struggling with CUD have a chance to move past their addiction.
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