Neurobiology of Addiction

Issues of Concern

The Addiction Cycle

Based on decades of animal and human research, a scientifically validated neurobiological model of addiction consists of a repeating cycle of 3 distinct stages. This model provides an insightful way to understand the signs of addiction, approaches to treatment, and recovery. The 3 stages include intoxication/binge, withdrawal/negative affect, and preoccupation/anticipation. The cycle length varies among individuals and may occur daily or over months. The intensity with which individuals experience the stages will vary. However, one universal similarity amongst individuals with addictive disorders is that the cycle tends to amplify over time, leading to more significant biological, sociological, and psychological harm. Before exploring these neurobiological stages in depth, it is essential to explore the 4 central behaviors in the addiction cycle: impulsivity, compulsivity, positive reinforcement, and negative reinforcement.

Four Central Behaviors

For most people, initial substance exposure involves impulsivity.[9] Given that most substances produce euphoria or pleasure, the experience will positively reinforce the substance use. This positive reinforcement may make the person more likely to reuse the substance. An alternative reason people utilize substances is to reduce negative feelings such as depression or anxiety. With these individuals, the temporary improvement in negative feelings negatively reinforces substance use. Notably, positive and negative reinforcement can be related to social stimuli instead of the direct use of the substance. An example of positive social reinforcement is peer approval after peer pressure to try a substance. Similarly, individuals can undergo negative social reinforcement by removing social isolation, such as going to the bar for a drink.

The reinforcing impact of substances diminishes with repeated use over time; this is the phenomenon of tolerance.[10] Tolerance typically results in increased or more frequent substance use in chase of the original effect. Tolerance also shifts the individual's emotional baseline, predisposing them to more negative emotions when the substance is absent. This leads to an ongoing withdrawal state in which low mood, anxiety, and physical illness are the baseline. Given the discomfort of the withdrawal state, substance use naturally increases.

A result of increased substance use to avoid withdrawal symptoms is a shift from impulsive to compulsive behavior. Compulsive behavior marks the loss of executive control over substance use and is a hallmark of addiction. Compulsivity also drives the challenges individuals face in the addiction cycle when they attempt to decrease or abstain from substance use.

Intoxication/Binge Stage 

The intoxication/binge stage of the addiction cycle begins when an individual consumes a rewarding substance. Rewarding substances increase the likelihood of eliciting a positive hedonic response. The origins of hedonic tone exist in the basal ganglia.[11] At the hedonic baseline, there is a tonic release of dopamine from the midbrain into the striatum and prefrontal cortex. This tonic level of dopamine only impacts high-affinity dopamine-2 (D2) receptors while minimally interacting with dopamine-1 (D1) receptors. Various signaling molecules can influence the tonic dopamine level, including endocannabinoids, opioids, and gammabutyric acid (GABA). When a rewarding substance is present, the dopaminergic transmission rate increases, and D1 receptors become stimulated. This stimulation of D1 receptors leads to the subjective "euphoria" people experience when first obtaining a rewarding substance.[12]

The reward ultimately activates 2 significant pathways. The mesolimbic pathway involves cross-talk between the ventromedial striatum and the nucleus accumbens (NAcc). The mesolimibc pathway is responsible for the binge stage's reward and positive reinforcement via the direct release of dopamine and opioid peptides. The second pathway is the nigrostriatal pathway involving the dorsolateral striatum; this pathway is directly responsible for controlling habitual motor function and behavior.[13] The activation of these pathways synergistically links the reward with the reward-seeking behavior via dopaminergic transmission.

As the addiction cycle repeats, the firing patterns of dopamine cells transform from responding to novel rewards to anticipating reward-related stimuli.[2] An individual progressively gets a more significant dopamine release from the people, places, and things than the actual substance, leading to motivational urges; this is incentive salience. Studies have shown this dopamine release can persist even after tolerance to the substance has diminished. Incentive salience helps us understand the importance of changing the people, places, or things formerly associated with substance use in treating an individual with an addictive disorder.

Withdrawal/Negative Affect Stage 

The withdrawal/negative affect stage comprises acute and post-acute withdrawal phenomenology. Two primary neuroadaptions neurobiologically define this stage. One adaption arises from within the reward system, where chronic exposure to a reward decreases dopaminergic tone in the NAcc. In addition, the glutaminergic-gabaergic balance in the reward system shifts toward one of increased glutaminergic tone and lessened gabaergic tone. This in-system adaptation leads to diminished euphoria from the reward, reduced tolerance for stress, and increased feelings of agitation while simultaneously decreasing the effects of natural rewards like sex and food. The decreased effects of natural rewards translate to decreased satisfaction in interpersonal relationships at work and home.

The second neuroadaptation in the withdrawal/negative affect stage results from the increased recruitment of stress circuits in the brain. This neuroadaptation is a between-systems process that includes the extended amygdala, often called the "anti-reward" system.[4] The predominant structures in this circuit are the bed nucleus of the stria terminalis (BNST), the central nucleus of the amygdala (CeA), and the shell of the NAcc. The upregulated anti-reward system leads to increased release of stress mediators such as dynorphin, corticotropin-releasing factor (CRF), norepinephrine (NE), orexin, and positive modulation of the hypothalamic-pituitary-adrenal (HPA) axis.

The brain has a buffer for the "anti-reward" system, which includes cannabinoid, nociceptive, and neuropeptide Y neurotransmission.[14][15][16][17] Adjustments in this buffering system may also lead to an increased propensity for addiction. Brain-imaging studies have revealed a decreased density of cannabinoid 1 (CB1) receptors in patients with alcohol use disorder.[18] The clinical consequences of an upregulated "anti-reward" system will present as irritability, anxiety, and dysphoria. The strengthened "anti-reward" system drives chronic withdrawal in patients with addictive disorders.

The desire to remove the negative feelings accompanying withdrawal primes the individual to further intoxication/binge via negative reinforcement. A vicious cycle ensues; taking the substance to lessen withdrawal will lead to worse withdrawal symptoms in the next period of abstinence.

Preoccupation/Anticipation Stage 

The third stage of the addiction cycle is the preoccupation/anticipation stage. This stage occurs during periods of abstinence. The length of this stage varies with the severity of the addiction. In severe addictions, this stage may last only a few hours. The signature of this phase is a preoccupation with using the substance, known as "cravings." The prefrontal cortex (PFC) is the brain region primarily involved in the preoccupation/anticipation stage. The PFC is responsible for executive functioning, including the ability to plan events, manage tasks, and regulate thoughts, emotions, and impulses. Executive function is directly involved in the decision to use substances and can occasionally override strong urges to use a substance.

Researchers have cultivated 2 systems within the PFC to understand its involvement in addiction: a "Go system" and a "Stop system." [19] The Go system involves decisions requiring considerable attention and planning and is heavily activated before beginning goal-directed behaviors. The primary circuitry within the Go system includes the dorsolateral prefrontal cortex and the anterior cingulate, and activity within this circuitry spikes when an individual with a substance use disorder faces substance-associated cues. This increase in activity stimulates the Nacc to release glutamate, promoting a strong urge to use the substance in the presence of drug-associated environmental cues; this, again, is incentive salience. A second function of the Go system is its ability to stimulate habit-response systems in the dorsal striatum via glutamate. Notably, habitual responses are often automatic, making the substance user more impulsive when using the drug.

The Stop system is primarily involved in downregulating the activity of the Go system. The Stop system includes circuits in the orbitofrontal and ventrolateral prefrontal cortex. The Stop system directly influences the dorsal striatum and the Nacc, lessening the impact of incentive salience via the downregulation of habitual responses.[20] The Stop system also controls stress and emotional systems found in the extended amygdala, which is most active during the withdrawal/negative affect stage. Decreased activity in the Stop system leads to increased activity in the stress circuitry of the extended amygdala, which can increase the risk of relapse.

Brain imaging in populations with addictive disorders has revealed an upregulation in the Go system and a downregulation in the Stop system.[21][22] Additionally, brain imaging has revealed that a reduced density in the prefrontal cortex correlates with a shorter relapse time in those with abstinence.[23] These results strengthen the push for an inquiry into treatments targeting the glutaminergic tone of the PFC.

Genetic Contributions (Nature)

Genetics plays a pivotal role in the neurobiology of addiction. Addictive disorders have a 40% to 70% heritable genetic component.[24] Numerous genes contribute to the risk of addiction, each with a unique effect size, and their interplay results in the overall genetic predisposition or protection from addictive disorders. These genes are involved with the brain regions described in the addiction cycle or with the metabolism of a specific addictive substance.

The genes impacting the neurobiological cycle of addiction regulate neurotransmitter expression and regulation in the reward pathway, typically involving dopamine, glutamate, GABA, and opioid peptides. For example, DRD2 regulates dopamine receptor expression and sensitivity, specifically impacting the euphoric effects of the intoxication/binge stage of the addiction cycle.[25] Mutations in DRD2 may predispose an individual to disordered use of various substances, including cocaine, nicotine, and opioids, while also increasing the risk of a behavioral addiction such as pathological gambling.[26]

The enzymes responsible for the metabolization of specific addictive substances also contribute to the genetic risk of addiction. This contribution is seen in individuals with genetic polymorphisms affecting alcohol metabolism. The function of alcohol dehydrogenase encoded by ADH1B and aldehyde dehydrogenase encoded by ALDH2 significantly impacts individual tolerance and vulnerability to alcohol use disorder (AUD).[27] Specific populations possess genetic variants that result in a heightened sensitivity to acetaldehyde, a toxic metabolite of alcohol, which may decrease the likelihood of heavy drinking and AUD. However, the expression of these enzymatic proteins is not a static process.

Epigenetic Contributions (Nurture) 

Epigenetics has a significant and intricate role in the neurobiology of addiction. While genetics provides the blueprint, epigenetics regulates how and when specific genes are expressed or silenced in response to environmental factors, stressors, and drug exposure. Epigenetic modifications, such as DNA methylation and histone modifications, can either predispose to or protect against developing an addiction disorder.[28]

One noteworthy aspect of epigenetics in addiction is its role in modulating neuroadaptations in the addiction cycle. For example, chronic alcohol use can result in DNA methylation, which alters the expression of genes involved in reward pathways, impulse control, and stress responses.[29] DNA methylation, adding a methyl group to a cytosine base, typically results in gene silencing. These epigenetic alterations contribute to the long-lasting neurobiological changes associated with addiction and critically alter the molecular biology of individuals with substance use disorders.

Furthermore, epigenetics offers a promising avenue for therapeutic interventions in addiction medicine. Understanding the epigenetic changes associated with addiction can promote the development of therapies targeted at reversing or mitigating these alterations. Epigenetic-based interventions, such as the inhibition of histone deacetylase by valproic acid, are being explored for their potential to alter addiction-related gene expression patterns and promote recovery.[30] 

Adaptations at the Molecular Level 

The neuroadaptations seen in the addiction cycle are initiated and maintained by molecular and cellular modifications. Interwoven genetic and environmental factors drive the changes found on a molecular level during the addiction cycle. For example, chronic drug exposure in the intoxication/binge stage increases cyclic adenosine monophosphate (cAMP) synthesis and protein kinase A (PKA) activity in the NAcc.[31] Studies indicate that increased cAMP/PKA signaling in the NAcc leads to elevated self-administration of drugs and promotes compulsive drug-seeking behavior.[31] Upregulation of the cAMP/PKA signaling pathway in the NAcc is a vital neuroadaptation for establishing and strengthening the addiction cycle.

Modulated signal transduction pathways lead to altered levels of transcription factor expression. Chronic substance exposure can increase levels of the transcription factor ΔFosB in the NAcc.[32] Elevated ΔFosB increases sensitivity to addictive substances. Some neurobiological models of addiction have identified ΔFosB as the master regulator that drives and sustains addiction.[33] Addiction research has attempted to isolate a drug that downregulates or antagonizes ΔFosB as a treatment.[34] Of particular interest is how the modulation of transcription factors may disproportionately impact adolescents due to the neuroplasticity seen at that stage of development.[35] Thus, early substance use may increase vulnerability to addictive disorders by hastening the neuroadaptions in the addiction cycle.

Significantly, molecular changes in neuronal support cells, such as microglia and astrocytes, impact the addiction cycle. The central alteration is increased toll-like receptor (TLR) expression.[35]

The Role of Neuroinflammation 

Neuroinflammation is a dynamic process that plays a pivotal role in the neurobiology of addiction. Chronic drug exposure can trigger an immune response within the brain driven by microglia and astrocytes.[36] Once considered a secondary consequence of addiction, this neuroinflammatory response is now considered a fundamental element in developing and maintaining addictive disorders. Chronic neuroinflammation in the context of addiction can lead to widespread neural dysfunction and exacerbate the cycle of drug craving and relapse.

The molecular underpinnings of neuroinflammation in addiction are multifaceted. Traditionally associated with the immune system, TLRs have gained prominence in this context. TLR4 can be upregulated by drugs of abuse, contributing to the activation of inflammatory pathways in the brain.[35] This cascade of events can lead to synaptic remodeling, impaired neurotransmission, and a heightened vulnerability to addiction. Notably, emerging evidence suggests that genetic factors may modulate individual susceptibility to neuroinflammation in response to drugs, adding another layer of complexity to the neurobiology of addiction.[37]

Recognizing the significance of neuroinflammation in addiction opens up possibilities for novel interventions. Targeting specific immune signaling pathways or harnessing the brain's endogenous anti-inflammatory mechanisms may offer innovative therapeutic approaches.[36] Addressing the inflammatory component of addiction is a new avenue to disrupt the drug dependence cycle and improve treatment outcomes. 

Clinical Significance

Traditional Diagnostics

Substance use disorders are a profound challenge in modern society and encompass a spectrum of conditions characterized by the recurrent use of substances such as drugs or alcohol despite significant negative consequences. These disorders involve a complex interplay of behavioral, psychological, and neurobiological factors. Traditionally, patients are diagnosed with substance use disorders using the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria.[38] The DSM-5 states that an individual must meet at least 2 of the 11 criteria over 12 months for a substance use disorder diagnosis. The requirements are similar across most substances; notable exceptions include phencyclidine (PCP) use disorder, which does not establish a withdrawal criterion, leaving only 10 criteria, and specific drugs prescribed under a physician's supervision, for which tolerance is not a criterion. The 11 criteria include: 

1. The substance is taken in more significant amounts or over a more extended period than intended.
2. The persistent desire or unsuccessful attempts to reduce substance use.
3. Excessive time spent obtaining, using, or recovering from substance use.
4. Having an intense craving for the substance. 
5. Failure to fulfill significant obligations at work, home, or school related to substance use.
6. Continued use of the substance despite having social and interpersonal conflicts related to the substance use. 
7. Essential activities are reduced or given up related to substance use. 
8. Using the substance in a high-risk or physically hazardous situation.
9. Continued use of the substance despite the knowledge of the psychological and physical adverse effects caused by the substance use. 
10. Tolerance to the substance.
11. Withdrawal symptoms after the substance use is discontinued or withdrawal symptoms are relieved with the continuation of substance use. 

Substance use disorders are classified as mild, moderate, or severe based on how many of the 11 criteria are fulfilled: mild, any 2 or 3 criteria; moderate, any 4 or 5 criteria; severe, any 6 or more criteria. For the patient to be in clinical remission, the patient must meet at least 2 criteria and abstain from substance use for at least 3 months. The remission period from 3 to 12 months is an early full remission; after 12 months, patients are in sustained remission.

Translating the Addiction Cycle to Clinical Practice

While the understanding of the neurobiological effects of addictive substances has increased significantly in recent decades, the translation of these insights into clinical practice has lagged. This lag stems partly from reliance on the DSM-5 criteria to diagnose substance use disorders, which minimizes the underlying neuroscience of addiction.[39]

To bridge this gap, the Research Domain Criteria (RDoC) initiative, spearheaded by the National Institute of Mental Health (NIMH), has been instrumental in funding research that adopts a neuroscience-driven approach to understanding psychiatric diseases.[40] The RDoC paradigm has inspired the development of an Alcohol Addiction RDoC framework that emphasizes delineating specific neuronal circuits involved in addiction processes.[41] The result of this research is the Addictions Neuroclinical Assessment (ANA).[6] The ANA is a clinical tool designed to assess addiction from a neurobiological standpoint. The ANA aims to enhance our ability to diagnose and treat addiction disorders with a more comprehensive understanding of their underlying neurobiological mechanisms.

Addictions Neuroclinical Assessment

The ANA represents a groundbreaking advancement in converting addiction research into a usable clinical instrument. Central to the ANA approach are the 3 pivotal neurofunctional domains of incentive salience, negative emotionality, and executive dysfunction. These ANA domains overlap with the stages of the addiction cycle: the intoxication/binge stage, distinguished by shifts in hedonic tone and incentive salience; the withdrawal/negative affect stage, marked by negative emotional states; and the preoccupation/anticipation stage related to executive function. The ANA assesses these domains by leveraging the power of neuroimaging, genetic testing, questionnaires, and clinical interviews.[6]

The ANA domain of incentive salience is linked to neuroadaptations in the basal ganglia. Incentive salience is the process in which dopaminergic tone becomes hijacked by substance-related cues over the actual substance itself. The clinical manifestation is increased cravings for substances upon exposure to substance-related cues. The central behavior in this domain is positive reinforcement. Clinicians can target this domain from a treatment perspective by transitioning patients to a new environment, such as an acute rehabilitation facility.[42]

The negative emotionality domain correlates with the withdrawal/negative affect stage experienced by individuals with addictive disorders. The central behavior in this domain is negative reinforcement, often described as self-medication.[43] This domain is distinguished by increased anxiety and reduced hedonic tone, which clinically manifests as decreased pleasure in non–substance-related activities such as work and family. Symptoms in this domain are helped by medications targeting neurotransmitters imbalanced in withdrawal states, such as benzodiazepines.

The executive function domain encompasses a spectrum of cognitive processes related to the organization of behavior in pursuit of future objectives. The ANA focuses on subdomains of executive function that are particularly relevant to addiction. These subdomains encompass attention, response inhibition, planning, working memory, behavioral flexibility, and valuation of future events.[6] Discordant executive function plays a pivotal role in addiction by undermining top-down control in the frontal cortex, thereby influencing impulsivity during the intoxication/binge stage and contributing to negative emotional states during withdrawal/negative affect. 

In summary, the ANA enhances our understanding of addiction as a brain disorder that comprises a complex interplay of neurobiological and psychological factors. The ANA highlights the importance of multidimensional information capture, including genetic and neuroimaging data, to advance our understanding of addiction and inform more effective diagnostic and treatment strategies.

Emerging Treatments and Targets 

The neuroadaptations established in the addiction cycle offer a promising target for emerging treatments in substance use disorders. Medications targeting the loss of hedonic tone, excessive incentive salience, overactivation of stress circuitry, and executive dysfunction are in development. Among these innovative mechanisms are histone deacetylase (HDAC) inhibitors, anti-inflammatory medications, and neuromodulators.

HDAC inhibitors have garnered significant attention due to their potential to modulate gene expression and influence addictive behaviors. By altering the epigenetic landscape within the brain, HDAC inhibitors mitigate the long-lasting changes in gene expression associated with chronic substance use and trauma-related stress.[30] Valproic acid, a mechanistic HDAC inhibitor, has reduced alcohol consumption in animal models. Targeting epigenetic changes may be a promising way of reversing addiction-related changes in gene expression.

Anti-inflammatory medications have shown potential in addiction treatment. Chronic substance use can lead to neuroinflammation that contributes to maintaining addictive behaviors. Medications targeting inflammation, such as minocycline and ibudilast, have demonstrated attenuation of alcohol-induced neuroinflammatory processes.[36] Such medications may complement existing treatments and offer new strategies to help individuals achieve and sustain recovery.

There is ongoing exploration of modulating major neurotransmitter systems, such as glutamate, opioid, and endocannabinoid receptors. Neuromodulators aim to restore balance within the reward and motivation circuitry to reduce cravings and the reinforcing effects of drugs. Glutamate plays a role in the preoccupation/anticipation stage of the addiction cycle, and the glutamate modulator N-acetylcysteine (NAC) may positively impact various substance use disorders.[44] A meta-analysis completed in 2017 supported the potential utility of NAC, given its safety profile, over-the-counter availability, and impact on drug cravings.[45] 

Modern neurobiological research has elevated the understanding of why patients respond differently to treatments such as naltrexone. Naltrexone works by antagonizing the mu-opioid receptor encoded by OPRM1.[46] Specific polymorphisms in OPRM1 may predispose to improved efficacy of naltrexone. For example, the A118G polymorphism of OPRM1 influences the reward sensitivity to alcohol, leading to enhanced euphoria. This genetic polymorphism can also predict an increased responsiveness to naltrexone.[47] 

Customizing treatment approaches using individual neurobiology holds great promise for improving the effectiveness of addiction treatment. A future where clinicians can provide more personalized, effective, and compassionate care for individuals with addictive disorders draws closer. Integrating these innovative approaches into clinical practice can transform addiction treatment and offer new hope to those with substance use disorders.

Lessening Negative Attitudes 

Leveraging the neurobiology of addiction is a powerful tool in reducing addiction-related stigma among healthcare providers. A deeper understanding of the biological underpinnings of substance use disorders can help shift attitudes from moral judgment to a more compassionate perspective. Clinical research has consistently shown clinicians foster negative attitudes toward patients suffering from substance use disorders.[48] A systematic review revealed that clinicians who endorsed negative attitudes delivered suboptimal care for patients with substance use disorders.[49] 

By emphasizing the neurobiological aspects of addiction, clinicians can appreciate that substance use disorders are not simply a matter of personal choice or moral failing but rather a result of profound changes in the structure and function of the brain. Studies using neuroimaging techniques, such as functional MRI, have demonstrated how substances like opioids, alcohol, or stimulants can hijack neurological reward systems, making it highly challenging for individuals to control their substance use.

Education about the neurobiology of addiction can highlight the potential for recovery and the effectiveness of evidence-based treatments. When clinicians understand that addiction is a treatable medical condition, much like diabetes or hypertension, they are more likely to approach patients empathetically and provide appropriate care.[50] Combining this neurobiological perspective with comprehensive training on addiction and its treatment can be pivotal in destigmatizing substance use disorders within the healthcare community and ultimately improving outcomes for those in need.

Enhancing Healthcare Team Outcomes

Addictive disorders are highly prevalent in the United States. Given the historical stigma, it is common for people suffering from addictive disorders to avoid medical treatment until an emergency arises. The consequences of addictive disorders have great individual, familial, and societal costs. The vigilance of healthcare providers to screen for addiction has been historically poor despite the preventable consequences. Much of this blindspot is related to traditionally held negative attitudes by healthcare providers toward those with addictive disorders.

Given the current state of addiction and, more specifically, the opioid crisis, a critical agenda among all healthcare professionals is to screen for addictive disorders and make appropriate treatment plans to ensure patients receive the necessary support. Essential to this effort are physicians, physician assistants, nurse practitioners, nurses, pharmacists, social workers, and peer counselors, all of whom can provide direct education, support, and treatment referrals.

Clinicians should assess the patient's level of motivation and respect their stage of change. Treatments can utilize psychosocial supports such as Alcoholics Anonymous (AA) or Narcotics Anonymous (NA). Depending on the addictive disorder, clinicians can consider the possibility of psychotherapy and pharmacotherapy. Caring for this vulnerable population requires an interprofessional approach. By providing support and education, all healthcare team members can contribute to treating and recovering individuals with addictive disorders.