By Maya India Kersey
Published 11:57 EST, November 1st, 2021
In 2020, more than 92,00 Americans died from drug overdoses. This was nearly a 30% increase from 2019, according to a report from the Centres for Disease Control and Prevention. From 2002 to 2017, there was a 22-fold increase in the total number of deaths involving fentanyl and other synthetic opioids and more than a 7-fold increase in the number of deaths involving heroin. Emergency department visits for suspected opioid overdoses rose by 30 percent in the U.S. from July 2016 to September 2017. The opioid crisis was declared a nationwide Public Health Emergency on October 27th, 201728.
Opioid Use Disorder (henceforth OUD), is defined as a problematic pattern of opioid use leading to clinically significant impairment or distress1. Opioid tolerance, dependence, and addiction are all manifestations of brain changes resulting from chronic opioid abuse2.
Symptoms of OUD3:
- Using more of the drugs or using them longer than you intended
- Inability to control or cut down use
- Spend lots of time finding drugs or recovering from use
- Stop or cut down important activities
- Use while doing something dangerous, i.e. driving
- Use despite physical or mental problems
- Become tolerant – need more of the drug or need to take it more often
- Have withdrawal – physical symptoms when you try to stop
The three primary brain regions involved in Opioid Use Disorders
The brain has many sections that are interconnected with one another, forming dynamic networks that are responsible for specific functions such as language, attention, reward, and emotion along with many other functions. There are three regions of the brain that are primarily involved with OUDs. The basal ganglia control the rewarding, or pleasurable, effects of opioid use and are also responsible for the formation of habitual opioid taking. The extended amygdala is involved in stress and responsible for the feelings of unease, anxiety, and irritability that typically accompany opioid withdrawal. The prefrontal cortex is involved in executive function (i.e, the ability to organize thoughts and activities, prioritize tasks, manage time, and make decisions), including exerting control over opioid use. These regions of the brain are easily able to be ‘hijacked’ by addictive substances.
The Basal Ganglia
The basal ganglia are a group of structures located deep within the brain that play an important role in keeping body movements smooth and coordinated. They are also involved in learning routine behaviours and forming habits. Two sub-regions of the basal ganglia are particularly important in opioid use disorders:
- The nucleus accumbens, which is involved in motivation and the experience of reward
- The dorsal striatum, which is involved in forming habits and other routine behaviors9
The Extended Amygdala
The extended amygdala and its sub-regions, located beneath the basal ganglia, controls the brain’s reactions to stress-including behavioural responses, i.e. ‘fight or flight’ and negative emotions such as anxiety and irritability. This region also cooperates with the hypothalamus; an area of the brain that controls activity of multiple hormone-producing glands, such as the pituitary gland at the base of the brain and the adrenal glands at the top of each kidney. These glands control reactions to stress and regulate many other bodily processes10.
The Prefrontal Cortex
The prefrontal cortex is located at the very front of the brain, and is responsible for complex cognitive processes called ‘executive function’. Executive function is the ability to organize thoughts and activities, prioritize tasks, manage time, make decisions, and regulate one’s actions, emotions, and impulses11,12.
|Figure 2:||Figure 3: The three stages of the addiction cycle and the brain regions associated with them.|
Addiction can be described as a repeating cycle with three stages. This cycle involves three key drivers that motivate the neurobiological changes associated with opioid dependence:
- Binge/Intoxication: the stage at which an individual consumes an intoxicating substance and experiences its rewarding or pleasurable effects. Positive emotions are produced, such as euphoria, and are positively reinforcing therefore increase the probability of using the drug in the early stage of addiction.
- Withdrawal/Negative Affect: the stage at which an individual experiences a negative emotional state in the absence of the opioid. It is associated with negative reinforcement because of the desire to consume a drug in order to improve the affective state and to offset the withdrawal symptoms.
- Preoccupation/Anticipation/Craving: the stage at which one seeks opioids again after a period of abstinence.
The three stages are linked to and interconnect to each other, however they also involve different brain regions, circuits, and neurotransmitters, resulting in specific kinds of changes in the brain. A person may go through this three-stage cycle over the course of weeks or months or progress through it numerous times in a day. There may be variation in how people progress through the cycle and the intensity with which they experience each of the stages. Nonetheless, the addiction cycle tends to intensify over time, leading to greater physical and psychological harm12.
The four behaviours central to the Cycle of Addiction:
- Impulsivity: An inability to resist urges, deficits in delaying gratification, and unthoughtful decision-making. It is a tendency to act without foresight or regard for consequences and to prioritize immediate rewards over long- term goals13
- Positive reinforcement. The process by which presentation of a stimulus such as a drug increases the probability of a response like drug taking.
- Negative reinforcement. The process by which removal of a stimulus such as negative feelings or emotions increases the probability of a response like drug taking.
- Compulsivity. Repetitive behaviours in the face of adverse consequences, and repetitive behaviours that are inappropriate to a particular situation. People suffering from compulsions often recognize that the behaviours are harmful, but they nonetheless feel emotionally compelled to perform them; doing so reduces tension, stress, or anxiety13.
Stage 1: Binge/Intoxication: Basal Galangia
The binge/intoxication stage of the addiction cycle is the stage at which an individual consumes the opioid substance. This stage heavily involves the basal ganglia and its two key brain sub-regions; the nucleus accumbens and the dorsal striatum (see above for their functions). In this stage, substances affect the brain in several ways.
The rewarding effects produced by the addictive substances positively reinforce their use and increase the probability of repeated use. The rewarding effects of substances include activity in the nucleus accumbens, including activation of the brain’s dopamine and opioid signalling system. Many studies have shown that neurons that release dopamine are activated by all addictive substances, but particularly by stimulants such as amphetamines, nicotine and cocaine (Figure 4)16. Furthermore, the brain’s opioid system, which includes naturally occurring opioid molecules (such as endorphins, enkephalins, and dynorphins) and three types of opioid receptors (i.e., mu, delta, and kappa), plays a key role in mediating the rewarding effects of other addictive substances, including opioids and alcohol. Activation of the opioid system by these substances stimulates the nucleus accumbens through the dopamine system. Brain imaging studies in humans show activation of dopamine and opioid neurotransmitters during alcohol and other substance use15,16.Studies show that antagonists (chemical substances that bind to and blocks the activation of certain receptors on cells, preventing a biological response) or inhibitors of dopamine and opioid receptors can block drug and alcohol seeking in both animals and humans.
Stimuli associated with addictive opioids can trigger opioid use; frequent use of a substance teaches the brain to associate the rewarding high with other cues in the person’s life, i.e. places where they use substances, the friends they take them with, and paraphernalia that accompany substance-taking. As these
prompts develop in association with the substance, the person may find growingly difficult not to think about using them. Over time, these stimuli can activate the dopamine system on their own and trigger powerful urges to take the substance. These “wanting” urges are called incentive salience and they can persist even after the rewarding effects of the substance have diminished (See fig.5).
Stage 2: Withdrawal/Negative Affect Stage: Extended Amygdala
The withdrawal/negative affect stage of addiction follows the binge/intoxication stage, eventually setting up for future rounds of binge/intoxication. During this stage, a person who has been using alcohol or drugs experiences withdrawal symptoms, the severity of which are dependent on:
- Duration of drug use
- How long the drug stays in your system
- How healthy you are
- Whether you’re quitting ‘cold turkey’ or using other drugs to help you stop taking opioids20
Symptoms commonly include:
- Dilated pupils
- Body aches
- Fast heartbeat
- Rapid breathing
The negative feelings accompanying withdrawal are thought to come from two sources: reduced activation in the reward circuitry of the basal ganglia and activation of the brain’s stress systems in the extended amygdala.
During long-term use, all substances cause disfunction in the brain’s dopamine reward system17. For example, brain imaging studies in humans with addiction have consistently shown long-lasting decreases in a particular type of dopamine receptor; the D2 receptor, compared with non-addicted individuals (see fig.6)18,19. Decreases
in the activity of the dopamine system have been observed during withdrawal from various substances, including stimulants, opioids, nicotine, and alcohol. Interestingly, other studies also show that when an addicted person is given a stimulant, it causes a smaller release of dopamine than when the same dose is given to a person who is not addicted.
These findings propose that people addicted to substances experience a general reduction in the sensitivity of the brain’s reward system both to addictive substances and also to natural pleasant sources, such as food; this because they also depend upon the same reward system and circuits. This explains why those who develop an opioid/substance use disorder often do not derive the same level of satisfaction or pleasure from once-pleasurable activities. This general loss of reward sensitivity may also account for the compulsive increase of substance use, as addicted individuals try to regain the pleasurable feelings the reward system once provided6. At the same time, a second process occurs during the withdrawal stage; the activation of stress neurotransmitters in the extended amygdala.
Studies propose these neurotransmitters play a crucial role in the negative feelings associated with withdrawal and stress-triggered substance use. In both animal and human studies, when researchers use antagonists to block activation of the stress neurotransmitter systems, it had the effect of decreasing opioid intake in response to withdrawal and stress. For example, blocking the activation of stress receptors in the brain reduced alcohol consumption in both alcohol-dependent rats and humans with an alcohol use disorder7. Thus, it may be concluded that an additional motivation for drug and alcohol seeking among individuals with OUDs is to suppress overactive brain stress systems that produce negative emotions or feelings. Research also suggests that neuroadaptations in the endogenous cannabinoid system within the extended amygdala contribute to increased stress reactivity and negative emotional states in addiction21.
The desire to eliminate the negative feelings that accompany withdrawal can strongly persuade
to continue substance use. As previously mentioned, this motivation is strengthened through negative reinforcement, because taking the substance relieves the negative feelings associated with withdrawal, at least temporarily. Of course, this process is a vicious cycle; taking drugs or alcohol to diminish the symptoms of withdrawal that occur during a period of abstinence in fact causes those symptoms to be even worse the next time a person stops taking the substance, making it even more difficult to maintain abstinence.
Stage 3: Preoccupation/Anticipation Stage: Prefrontal Cortex
The preoccupation/anticipation stage of the addiction cycle is when a person may begin to seek opioids again after a period of abstinence. Those with severe OUD may have a very short (hours) period of abstinence. In this stage, an addicted person becomes preoccupied with using substances again; commonly called craving. This stage of addiction involves the brain’s prefrontal cortex; the region that controls executive function. This is essential for a person to make appropriate choices about whether or not to use a substance and to ignore strong urges to use, especially when the person experiences triggers, such as stimuli associated with that substance or stressful experiences.
Go/Stop system analogy:
To explain how the prefrontal cortex is involved in addiction, we can divide the functions of the brain region into a ‘Go system’ and an opposing ‘Stop system’22. The Go system aids decision-making, particularly those that require attention and those involved with planning. People also engage the Go system when they begin behaviours that help them attain goals. Research shows that when substance-seeking behaviour is triggered by substance-associated environmental cues (incentive salience), activity in the Go circuits of the prefrontal cortex increases considerably. This increased activity stimulates the nucleus accumbens to release glutamate, the main excitatory neurotransmitter in the brain. This release encourages incentive salience, which creates a powerful urge to use the substance in the presence of drug-associated cues.
Another role of the Go system is to engage with habit-response systems in the dorsal striatum, contributing to the impulsivity associated with substance seeking. Habitual responding can happen automatically and subconsciously, meaning a person may not even be aware that they are participating in such behaviours. The neurons in the Go circuits of the prefrontal cortex rouse the habit systems of the dorsal striatum through connections that use glutamate (see fig.7).
Abbreviations; PFC – prefrontal cortex, DS – dorsal striatum, NAc – nucleus accumbens, BNST – bed nucleus of the stria terminalis, CeA – central nucleus of the amygdala, VTA – ventral tegmental area.
The Stop system inhibits the activity of the Go system. This system controls the dorsal striatum and the nucleus accumbens, the areas of the basal ganglia that are involved in the binge/intoxication stage of addiction. Specifically, the Stop system controls habit responses driven by the dorsal striatum, and evidence suggests it plays a role in reducing the ability of substance, in other words, it inhibits incentive salience23.
Additionally, the Stop system controls the brain’s stress and emotional systems, and plays an important role in relapse triggered by stressful life events or circumstances. Stress-induced relapse is driven by activation of neurotransmitters in the extended amygdala. As described above, these neurotransmitters are activated during lengthy abstinence during the withdrawal/negative affect stage of addiction. More recent work in animals also implicates disruptions in the brain’s cannabinoid system, which also regulates the stress systems in the extended amygdala, in relapse. Studies show that lower activity in the Stop component of the prefrontal cortex is associated with increased activity of stress circuitry involving the extended amygdala, and this increased activity drives substance-taking behaviour and relapse24.
Brain imaging studies in people with addiction show disruptions in the function of both the Go and Stop circuits24-,26. For example, people with alcohol, cocaine, or opioid use disorders display damage in executive function, including disturbance of decision-making and behavioural inhibition. These executive function deficits mirror changes in the prefrontal cortex and imply reduced activity in the Stop system and greater responsiveness of the Go system in response to substance-related stimuli12.
Different classes of drug affect the brain & behaviour in different ways
The three stages of addiction tend to apply to all addictive substances, however different substances affect the brain and behaviour in different ways during each stage of the addiction cycle. Variations in the pharmacokinetics of various substances determine the duration of their effects on the body and partially account for the differences in their patterns of use. For example, nicotine has a short half-life, which means smokers need to smoke often to maintain the effect. In contrast, THC, the primary psychoactive compound in marijuana, has a much longer half-life. Thus, marijuana smokers do not typically smoke as frequently as tobacco smokers27.
Specifically, opioids attach to opioid receptors in the brain, which leads to a release of dopamine in the nucleus accumbens, causing euphoria (the high), drowsiness, and slowed breathing, as well as reduced pain signalling; this is why they are often prescribed as pain relievers. Opioid addiction typically involves a pattern of:
- Intense intoxication
- The development of tolerance
- Escalation in use
- Withdrawal signs and symptoms
These symptoms include intense negative emotions and physical symptoms. As use progresses, the opioid must be taken to avoid the severe negative effects that occur during withdrawal. With repeated exposure to opioids, stimuli associated with the pleasant effects of the substances
(e.g, places, persons, moods, and paraphernalia) and with the negative mental and physical effects of withdrawal can trigger intense craving or preoccupation with use12.
Maya India Kersey, Youth Medical Journal 2021
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Fig1: Substance Abuse and Mental Health Services Administration (US); Office of the Surgeon General (US). Facing Addiction in America: The Surgeon General’s Report on Alcohol, Drugs, and Health [Internet]. Washington (DC): US Department of Health and Human Services; 2016 Nov. Figure 2.2, Areas of the Human Brain that Are Especially Important in Addiction. Available from: https://www.ncbi.nlm.nih.gov/books/NBK424849/figure/ch2.f2/
Fig2: Front. Psychiatry, 30 August 2019 | https://doi.org/10.3389/fpsyt.2019.00592
Fig3: Substance Abuse and Mental Health Services Administration (US); Office of the Surgeon General (US). Facing Addiction in America: The Surgeon General’s Report on Alcohol, Drugs, and Health [Internet]. Washington (DC): US Department of Health and Human Services; 2016 Nov. Figure 2.3, The Three Stages of the Addiction Cycle and the Brain Regions Associated with Them. Available from: https://www.ncbi.nlm.nih.gov/books/NBK424849/figure/ch2.f3/
Fig4: Substance Abuse and Mental Health Services Administration (US); Office of the Surgeon General (US). Facing Addiction in America: The Surgeon General’s Report on Alcohol, Drugs, and Health [Internet]. Washington (DC): US Department of Health and Human Services; 2016 Nov. Figure 2.5, Actions of Addictive Substances on the Brain. Available from: https://www.ncbi.nlm.nih.gov/books/NBK424849/figure/ch2.f5/
Fig5: Substance Abuse and Mental Health Services Administration (US); Office of the Surgeon General (US). Facing Addiction in America: The Surgeon General’s Report on Alcohol, Drugs, and Health [Internet]. Washington (DC): US Department of Health and Human Services; 2016 Nov. Figure 2.6, Major Neurotransmitter Systems Implicated in the Neuroadaptations Associated with the Binge/Intoxication Stage of addiction. Available from: https://www.ncbi.nlm.nih.gov/books/NBK424849/figure/ch2.f6/
Fig6: Substance Abuse and Mental Health Services Administration (US); Office of the Surgeon General (US). Facing Addiction in America: The Surgeon General’s Report on Alcohol, Drugs, and Health [Internet]. Washington (DC): US Department of Health and Human Services; 2016 Nov. Figure 2.8, Time-Related Decrease in Dopamine Released in the Brain of a Cocaine User. Available from: https://www.ncbi.nlm.nih.gov/books/NBK424849/figure/ch2.f8/
Fig7: Substance Abuse and Mental Health Services Administration (US); Office of the Surgeon General (US). Facing Addiction in America: The Surgeon General’s Report on Alcohol, Drugs, and Health [Internet]. Washington (DC): US Department of Health and Human Services; 2016 Nov. Figure 2.11, Major Neurotransmitter Systems Implicated in the Neuroadaptations Associated with the Preoccupation/Anticipation Stage of Addiction. Available from: https://www.ncbi.nlm.nih.gov/books/NBK424849/figure/ch2.f11/