Article by Bolek Kwiek (bmkwawpl@gmail.com)
Introduction
Addiction is a complex yet debilitating disease which has been at the forefront of discussions in scientific, political and social fields for a while. This is because it has widespread effects and severe consequences. A World Drug Report released by the United Nations Office on Drugs and Crime in 2021 (1) outlined an estimated 39.5 million people have some form of drug use disorder. Moreover, addiction can affect people of all ages, sexes, backgrounds, ethnicities, albeit at different rates. Furthermore, by supplying the substances of abuse to addicts, many different criminals, gangs, and cartels are able to fund themselves.
One of the main reasons addiction has become such a problem is that the treatment is difficult and rarely straightforward. Compared with other diseases, addiction carries a large stigma, which means some people won't even seek treatment in the first place. If they do go into treatment, the National Institute of Drug Abuse reports that overall relapse rates for substance use disorders are estimated to be between 40 and 60 percent (2). Additionally, addiction, along with many other psychiatric diseases, often presents itself with comorbidities, further complicating treatment options.
But what actually is addiction?
This is a multifaceted question, and depending on who is asked (neurobiologist, clinical psychologist, sociologist), you will get slightly different answers. Generally it can be defined as ‘a chronically relapsing disorder, characterised by compulsion to seek and take the drug, loss of control in limiting intake, and emergence of a negative emotional state (e.g. dysphoria, anxiety, irritability) when access to the drug is prevented’ (3). This definition is broad, and there are many angles you could begin to tackle when trying to treat addiction. However, for now, we will dissect addiction and its mechanisms through a neurobiological framework.
The contemporary model outlines three distinct stages of addiction that occur in a repeating cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation, Figure 1. Each stage involves different behaviours, brain regions, and neurotransmitters. These stages were identified through research into social psychology, psychiatry, and brain imaging.
Before looking into each stage in detail, here is a brief overview. The binge/intoxication stage occurs right after the administration of the drug, when the person would feel rewarded for taking the drug, and would also start to associate certain related cues with this reward. Just after the high of the drug taking, there is the withdrawal/negative affect stage, where the person would feel the opposite of reward that the high gave. Additionally, they might feel stressed about this. Finally, during extended periods of not taking the drug, known as abstinence, there is the preoccupation/anticipation stage. It has been observed that addicts have a higher tendency to act impulsively and seek out the drug, whilst having less inhibition in stopping this negative habit. It is also important to realise that addiction isn’t just the mere activation of pathways and brain regions, it is also the permanent alterations in brain chemistry: neuroadaptations. Now we will dive into the nitty-gritty of the biochemistry and neurobiology of these stages (4,5).

Binge/intoxication stage
During the stage of binge/intoxication there are two major mechanisms that play a role, first is drug reward. This mechanism is somewhat self-explanatory, the drug makes the user feel good or hedonic. It is unsurprising then, that substances of abuse activate the brain’s reward system. In brief, this system is mediated by the neurotransmitter dopamine, in the mesocorticostriatal pathway. This pathway connects the parts of the brain known as the ventral tegmentum to the prefrontal cortex (Figure 2-Green). These areas of the brain would normally make you feel the feeling of reward, for example after eating a food you enjoy. Therefore in the case of addicts, the mesocorticostriatal pathway is upregulated (5).

Although this dopamine reward pathway is implicated as the main one in this mechanism, it is worth noting that recent research has also pointed towards other systems being involved in the drug reward. These include opioid peptides, γ-aminobutyric acid (GABA), glutamate, serotonin, acetylcholine, and endocannabinoid systems that also act at the level of either the ventral tegmental area or nucleus accumbens. These systems are in charge of things like mood regulation, including stress reactivity and interoception (5). This is just to illustrate that addiction, and the brain, are both very complex and many different systems are hijacked by drugs to change the regular functioning. This complexity is also something we will explore later when looking at the clinical side of addiction because it could be the reason why addiction is very difficult to neatly diagnose and treat.
The second mechanism at play during the binge/intoxication stage of addiction is incentive salience. There can be neutral stimuli which the user starts to associate with the use of a drug, which will cause the neutral cue itself, to stimulate the feeling of wanting to take the drug. For example, a bar doesn’t have to immediately be associated with alcohol. But for someone who frequently drinks at bars, the environment itself can become a trigger. When this person then goes to a bar, even if they didn’t initially plan to drink, the surroundings - which were once neutral - might now stimulate the person to really want to drink alcohol. This phenomenon is called conditional reinforcing. Incentive salience builds on conditional reinforcing because these stimuli are assigned exaggerated importance, compelling someone to actively seek them out. Neurologically, this process of incentive salience is mediated by the mesolimbic dopamine system (Figure 2- Red). It manifests when the previously neutral cue starts to cause this firing in the same neurons (4,5). To draw on the previous analogy, it is when the cue of the bar starts to stimulate the desire for the reward of alcohol.
To summarise these two mechanisms, we have the drug reward mediated by dopamine through the mesocorticostriatal pathway. This pathway makes the person feel good when taking the drug, and becomes dysregulated after chronic drug use. Then we have incentive salience, also mediated by dopamine but in the mesolimbic system, which causes neutral cues to stand out and intensify the addicts’ urge to take the drug.
Withdrawal/negative affect stage
The withdrawal/negative affect stage involves neuroadaptations in the reward system and in the stress response system. The changes in the reward system are called in-system neuroadaptations, and the changes in the stress response system are called between-system neuroadaptations.
For the in-system neuroadaptations, it has been observed that after the chronic administration of substances of abuse, there is a decrease of dopamine transmission in the nucleus accumbens (Figure 2- Blue). This brain area governs the motivation for reward, but also threat response (7). Therefore, the decrease in transmission in the nucleus accumbens aligns with the feelings reported during withdrawal, such as depressed mood, sadness and anhedonia (loss of interest in normally rewarding activities). There have also been other receptors implicated during this stage, for example the increase in GABAergic or NMDA glutamatergic transmission, also in the nucleus accumbens. These neuroadaptations further decrease the functioning of the reward system and contribute to withdrawal (4,5).
The other major neurological system which is affected during this stage is the stress response system. This is called a between-system neuroadaptation, because stress response is not considered to be directly a part of the reward system. Both the hypothalamic-pituitary-adrenal axis and brain stress system in the amygdala are mediated by corticotropin releasing factor (Figure 3). Normally, this would be activated by stressful events, such as if you were being chased by a big scary bear, which would put your body into ‘fight-or-flight’. However in addicts this would be overactivated by the lack of high. Besides corticotropin releasing factor, other stress factors like dynorphin, norepinephrine, and orexin are upregulated. Consequently, patients have reported increased stress and feelings of unease during this stage. This has led to the term anti-reward system being used for this as it causes the patient to actively try to avoid this by taking more drugs.

To summarise, two key neuroadaptations contribute to the withdrawal/negative affect stage. The in-system neuroadaptation that directly affects the reward system: decreased dopaminergic transmission in the nucleus accumbens. And the between-system neuroadaptation on the stress response: increased corticotropin releasing factor in the amygdala and activation of the hypothalamic-pituitary-adrenal axis. These changes result in overwhelming negative emotions during withdrawal, which drive the patient to seek more drugs to alleviate these feelings. This creates a negative reinforcement loop, where the drug taking is motivated by the desire to avoid feeling bad, as opposed to positive reinforcement during the binge/intoxication stage, where a person wants to take drugs to feel good.
Preoccupation/anticipation stage
The last stage identified is the preoccupation/anticipation stage, which occurs in periods of abstinence and is hallmarked by the feeling of craving. The main brain region involved here is the prefrontal cortex, which is considered the region of the brain in charge of executive function. It gives you your ability to plan events, speech, risk processing and is a critical area for conscious perception. Similarly to the previous two stages, research has identified two systems important during this stage, the Go system and the Stop system.
The Go system drives cravings towards the drug, and makes the patient want to go and pursue getting more substances. It relies on the aforementioned idea of incentive salience, where cues associated with the drug are heightened. In the nucleus accumbens, there is increased firing and this makes the user want to take the substance again (5).
On the other hand we have the Stop system, this inhibits us from going ahead with some, especially habitual decisions. Critically, this has been observed to be downregulated in addicts. This system has complex circuitry, but one of the main parts of it is the dopamine receptor in the striatum and it is downregulated (5). Interestingly, it has been observed that patients with the receptor levels at a more normal range tend to have better treatment outcomes and lower levels of relapse (9).
Overall then, the increase in the Go system and decrease in the Stop system lead to the user being more impulsive and more prone to relapsing during a phase of abstinence. Being able to modulate these systems during this stage is extremely important for the treatment of addiction, as it is not enough to simply stop someone taking a drug. A patient needs to maintain not taking the drug and not relapse.
How does this look clinically?
So after a brief explanation of the neurobiology of addiction and how it is most commonly conceptualised in research, how does this actually look in clinical practice? Well, the most common tool doctors and psychiatrists have for the diagnosis of psychiatric diseases, including addiction, is the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). It is a long book that outlines guidelines for how these diseases may manifest and how to diagnose them.
When it comes to the diagnosis of addiction, the doctor asks 11 questions, and depending on what the patient answers, they give a corresponding diagnosis (Table 1). To support this diagnosis, the doctor may conduct blood tests to measure drug levels in the patient's system and assess the overall impact of the drug on the patient’s health. However, it is important to understand that since addiction is classified as a psychiatric disease, the diagnosis primarily comes from the DSM and the other physical exams are only sometimes performed to provide additional information and aid this decision.
 | Yes | No |
---|---|---|
The substance is taken in more significant amounts or over a more extended period than intended  |  |  |
The persistent desire or unsuccessful attempts to reduce substance use | Â | Â |
Excessive time spent obtaining, using, or recovering from substance use | Â | Â |
Having an intense craving for the substance | Â | Â |
Failure to fulfil significant obligations at work, home, or school related to substance use | Â | Â |
Continued use of the substance despite having social and interpersonal conflicts related to the substance use | Â | Â |
Essential activities are reduced or given up related to substance use | Â | Â |
Using the substance in a high-risk or physically hazardous situation. | Â | Â |
Continued use of the substance despite the knowledge of the psychological and physical adverse effects caused by the substance use | Â | Â |
Tolerance to the substance | Â | Â |
Withdrawal symptoms after the substance use is discontinued or withdrawal symptoms are relieved with the continuation of substance use | Â | Â |
Table 1:Â The questions in the DSM-V for diagnosing addiction. If the answer to the questions is 2 or 3 out of 11: Mild, 4 or 5 out of 11: Moderate, 6+ out of 11: Severe. Table reproduced from (10).
Based on this diagnosis, the patient will be assigned a treatment plan. Pharmacological intervention is the first line treatment for addiction (11) whereas psychological intervention is secondary and optional. This begins to shed light on a big gap between research and clinical views of addiction. It is diagnosed through psychological assessment, but immediately treated with pharmacological agents, which have been developed based on neurological principles.
What are we actually treating?
Generally, more effort is required to bridge the gap between addiction research and clinical practice. There have already been some initiatives that have started to address this. For example, the Research Domain Criteria (RDoC) is a framework created and funded by the National Institute of Mental Health (NIMH) in the US to try to help with just this.
In short, the RDoC tries to reframe the conventional view and categorisation of psychopathology into more general domains, that are governed by neurobehavioural functioning. It tries to look at deviations from normal function which then lead to symptoms, as opposed to using symptoms as a way to define pathologies, which is the approach used in the DSM (Figure 4). Importantly, the RDoC framework is not a diagnostic tool like the DSM, instead it aims to get a better understanding of the underlying physiological process going on in psychiatric diseases. The idea behind this is that if we can target neuroadaptations, then we can more accurately return the brain to its regular function. These ideas that the RDoC uses are sometimes referred to as the transdiagnostic approach to psychiatric disease - targeting the core mechanisms behind a disease rather than the symptoms (12,13).

Another noteworthy initiative is the Addictions Neuroclinical Assessment (ANA) which specifically focuses on addiction, unlike the RDoC that focuses on psychiatric diseases in general. It has identified three broad key neuroscience domains that are essential to study in order for research to be of more help clinically. They are incentive salience, negative emotionality, executive function, and as you can maybe already tell, they correspond to the three stages of addiction, binge/intoxication, withdrawal/negative, and preoccupation/anticipation respectively. The ANA wants to integrate both self-reports and behavioural data, as well as neuroimaging and genetic data for multidimensional information. To summarise, the ANA wants to try to research how to treat the overall systems that govern addiction (14,15).
These are just two examples of how this gap between neurological research and clinical application are being bridged. This will hopefully lead to both more accurate and meaningful diagnoses, and more effective and long-term treatment.
Words of caution
In this article, we have looked at the neurobiological framework and how this could be integrated into clinical practice more effectively, which could lead to better treatments. However, as echoed throughout this text, addiction is complex, and what has been presented here is just one angle on how to improve the issue. I wanted to take the last part of this article to shed light on other, very different aspects of addiction that also play a big role. This last section aims to ask more questions than provide answers, so that you, the reader, can get a more holistic view and be able to think critically about the issue.
Stigmatisation of addiction by people, but also caregivers, is not unusual and can cause addicts to feel ostracised, making them not want to seek help. We can come up with the most effective treatments, but if no one seeks to get treated it will not be much help. Perhaps, presenting addiction through a different lens to patients could be helpful. By offering real thought and guidance to an addict instead of just giving them medication and sending them on their way, helps the person feel like they are being cared for. This could lessen stigmatisation and humanise addicts, leading to better overall treatment compliance.
A lot can be said about the accessibility of substances of abuse. Adverts for alcohol or nicotine vapes are commonplace, arguably targeting young people in some cases. It could be argued that this is essentially preying on the addict’s incentive salience to sell these substances. Furthermore, socioeconomic background influences the prevalence of addiction, helping impoverished areas could mean those people are less likely to turn to substances for relief.
Only with a complete view of the scientific knowledge, so that it can be effectively integrated into clinical practice, along with all the social aspects, will more people be able to overcome addiction.
Acknowledgments and Bibliography
Acknowledgments
I would like to thank my good friend Summer Crane for the very helpful and informative conversation on how working with addicts looks like in practice.
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