Introduction

Observations that specific brain regions are important in specific behavioral patterns have been known at least since the remarkable case of Phineas Gage,¹ and the ways that use of alcohol and other substances can negatively impact behavior has been noted for centuries (or even millennia). What was missing until recent decades has been a comprehensive understanding of the neurobiological underpinnings of addiction; yet, this knowledge is essential for clinicians and patients.

Advances in neuroscience research at the anatomical, electrophysiological, and neuroimaging levels have all contributed to establishing central nervous system models that help to explain the signs, symptoms, and course of addictive disorders in the context of relevant environmental contributing factors. Both obvious and counter-intuitive aspects of addiction can now be understood through research into the neurobiology of decision-making, choice, habit formation, and brain development. This evolving and growing body of work can be intimidating for clinicians and patients, but exploration of the basic concepts can help to reduce the mystery of addictive behaviors and provide frameworks for prevention and treatment of substance use disorders (SUDs).

Although there are multiple frameworks through which to view and consider addiction (a term corresponding to the definition of moderate to severe SUD in DSM 5),² including philosophical and psychosocial frameworks, most researchers in addiction medicine consider addiction to be a chronic, relapsing, but treatable biopsychosocial disorder of the brain. What this means is that the clinical components of addictive disorders are reflected in changes to specific brain neurotransmitter systems and functional networks, knowledge of which can help clinicians ground their practice in neuroscience. Shared effects of various substances are apparent for major neurobiological models of addiction, such as those delineated by Koob and Volkow,³ but it is also important to understand unique neurobiological effects of different classes of drugs.

In this review, we focus on the key elements of addiction and describe neurobiological underpinnings of these features. A full review of neurobiology is beyond the scope of this overview. Instead, we focus on the major maturational and neuroplastic processes that underlie the onset and natural history of SUD both in general populations, where SUDs may improve without access to formal treatment, and in treatment-seeking cases, which tend to have a chronic, relapsing course. We then describe the alterations in brain circuitry that help explain the loss of control over drug use in those who have developed an addiction as they relate to the three stages of the addiction cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation (or craving).⁴ We lastly describe areas where future research is needed to fill in gaps in knowledge.

Onset and Natural History of Substance Use Disorders

The science of human development underpins our understanding of the onset of SUD.⁵ Environmental factors that influence an individual’s risk for substance use and developing an SUD include not only substance exposures themselves but also characteristics of the family, neighborhood, school, and cultural context in which the individual grows up and lives. These environmental influences interact in complex ways with genes as well as brain maturation.⁶ Propensity to use substances may arise prior to the first use of alcohol, nicotine, or other substances. Early-life environments that are stressful have been demonstrated to increase subsequent likelihood of use of substances and SUD, in both preclinical (animal) and clinical research.⁷ For example, the Adverse Childhood Experiences (ACES) retrospective cohort study of primary care patients (N=~8600) demonstrated that patients who reported more early childhood abuse and neglect experiences were more likely to report using substances during teen or adult years, to have an SUD, and to have initiated drug use at an early age.⁸

While a complete, mechanistic explanation is not fully developed, it is apparent that genetic factors underlie significant risk for substance use disorders,⁹ and that interactions of biology and the environment play a key role in these trajectories from early childhood toward SUD in the teens and in adult life. Epigenetic modifications of gene expression have been shown to link early developmental adversity to sensitivity to stress and associated behavioral disorders.¹⁰ Importantly, altered brain development associated with adverse environments can sometimes be ameliorated.¹¹ A study in rural Georgia of participants in a prevention trial found a strong correlation between number of teen years in poverty and diminished volume of brain structures that contribute to academic functioning, social development, learning, memory, mood, and stress reactivity (left dentate gyrus, CA3 subfield of the hippocampus, and left amygdala) by the early 20s among those who were in the study control group.¹² In contrast, those volumetric declines were not seen in those in the group whose families had received an experimental family-focused intervention when they were in middle school (i.e. early adolescence).¹² These results support the premise that family-based interventions may mitigate the developmental impacts of what otherwise would be a toxic social environment (poverty), even without changing other aspects of that environment.

Interventions as early as the prenatal and infancy periods have also been demonstrated to improve later behavioral, cognitive, and health outcomes. For instance, large randomized studies show that providing guidance to low-income, first-time mothers during pregnancy and in the first two years of a child’s life through home visitation by nurses can have a range of lasting positive impacts on the child—not only reduced abuse and neglect but also reduced substance use onset and improved cognitive and behavioral outcomes into the teen years.¹³ These and other longitudinal, prevention intervention studies document the importance of risk factors for the onset of substance use and the potential benefits of effective interventions that successfully address such risk factors.¹⁴

A key question is why substance use so typically starts during adolescence, a period of risk for many behavioral concerns.^5,6 Developmental neuroscience has documented that brain development is uneven, with limbic structures involved in emotional responsivity and reward maturing earlier than prefrontal cortical areas involved in decision making, impulse control, and judgment (see Figure 1).¹⁵ Circuitry of the prefrontal cortex does not completely reach maturity until the mid-20s.¹⁶ One result of this developmental mismatch is an increased propensity for risk-taking among youth.¹⁷ While this can be seen as developmentally appropriate, since this time of life is when an individual is challenged to become independent from parents and fashion their self-identity, the propensity for novel experiences and risk-taking can have very negative outcomes. The uneven maturation of the adolescent brain also increases susceptibility to environmental influences dominant during the teen years, such as peer influence.¹⁸ The hazards are compounded by the fact that, since it is not fully mature, the adolescent brain is more vulnerable to lasting effects of substance use, including increased risk of addiction.¹⁹ The risk for developing a SUD is highest for those who initiate substances in the early teens, and addiction is most likely to begin in the late teen years.²⁰

Figure 1:

_{Right lateral and top views of the dynamic sequence of gray matter maturation over the cortical surface. The side bar shows a color representation in units of gray matter volume. The following regions were selected for analyses in each hemisphere: A, precentral gyrus and primary motor cortex; B, superior frontal gyrus, posterior end near central sulcus; C, inferior frontal gyrus, posterior end; D, inferior frontal sulcus, anterior end in the ventrolateral prefrontal cortex; E, inferior frontal sulcus in the dorsolateral prefrontal cortex; F, anterior limit of superior frontal sulcus; G, frontal pole; H, primary sensory cortex in postcentral gyrus; I, supramarginal gyrus (area 40); J, angular gyrus (area 39); K, occipital pole; L–N, anterior, middle, and posterior portions of STG; O–Q, anterior, middle, and posterior points along the inferior temporal gyrus anterior end.}

_{(Reproduced from Gogtay N, Giedd JN, Lusk L, et al. Dynamic mapping of human cortical development during childhood through early adulthood. PNAS. 2004;101(21):8174–8179.)}

Most substance use begins with tobacco, alcohol, and then cannabis—before other substances like cocaine or opioids are used. Most who misuse opioids have already used these so-called “gateway substances” during adolescence.^21,22 While multiple studies attest to overlapping onset of substance use,^23,24 neurobiological gateway mechanisms for nicotine have the most evidence. By increasing midbrain dopamine neurons’ firing rate, nicotine can amplify the reinforcing effects of other substances and non-drug rewards (see below).^22,25

Because of the complex interacting biological, psychosocial, and developmental risk factors and various protective factors that may mitigate them (such as attentive parenting and strong social supports), only a subset of people who use drugs—even in their teen years—go on to develop an SUD.^26,27 For instance, using DSM-III-R or DSM-IV definitions, retrospective U.S. national studies have estimated that about 9% of cannabis users will ever develop cannabis dependence, with higher rates for those with early onset, frequent use, or use of more potent forms of cannabis. Similarly, 15–23% of alcohol users develop alcohol dependence, 17–21% of cocaine users develop cocaine dependence and 32–67% of tobacco users develop nicotine dependence.^26,27

Of those who develop an SUD, many report current remission of their symptoms. Over 20 million persons in the USA report being in recovery from problematic substance use; most of these persons either did not avail themselves of formal treatment or it was inaccessible to them, yet they may have years or decades without symptoms of SUD.^28–30 In some cases, SUDs resolve on their own as a result of maturation or because of changing life circumstances or environments—the famous desistence of opioid use among Vietnam war soldiers returning to the U.S. is one example.³¹ However, a recent longitudinal study following 11 early cohorts of the annual Monitoring the Future study found that the majority of high school seniors who had reported SUD symptoms when surveyed in the late 1970s or early 1980s still reported SUD symptoms more than three decades later, at age 50—indicating a long-term course for many SUDs that emerge early in life (i.e. in the teen years).³²

Among persons admitted to treatment for SUD (especially severe SUD), a chronic, relapsing course is well documented.^2,33,34 Use of substances in the year following treatment interventions varies but has been estimated to be 40–60%,³⁵ with longer studies suggesting multiple cycles of heavy use, periodic abstinence, interspersed with incarceration for many.^33,34,36,37 While treatment is a broad predictor of remission,^28,35,36 the underlying chronic, relapsing pattern remains and may be understood based on the neurobiology of the addiction cycle (Figure 2).^38,39

Figure 2:

_{The three stages of addiction: Binge/Intoxication, the stage at which an individual consumes an intoxicating substance and experiences its rewarding or pleasurable effects, primarily involves basal ganglia structures; Withdrawal/Negative Affect, the stage at which an individual experiences a negative emotional state in the absence of the substance, involves stress hormone responses and the extended amygdala; and Preoccupation/Anticipation, the stage at which one seeks substances again after a period of abstinence, involving interactions of the prefrontal cortex, the extended amygdala, and the basal ganglia.}

_{(Reproduced from U.S. Department of Health and Human Services (HHS), Office of the Surgeon General, Facing Addiction in America: The Surgeon General’s Report on Alcohol, Drugs, and Health. Washington, DC: HHS, 2016.)}

_{Notes: Blue represents the basal ganglia involved in the Binge/Intoxication stage. Red represents the extended amygdala involved in the Negative Affect/Withdrawal stage. Green represents the prefrontal cortex involved in the Preoccupation/Anticipation stage. Not shown is the neurotransmitter norepinephrine which is also activated in the extended amygdala during withdrawal. 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.}

Neuroplastic Changes in Addiction and the Addiction Cycle

Among the changes apparent with chronic drug intake is the formation of tolerance and physical dependence. While not synonymous with addiction, tolerance and dependence develop when the body adapts to the frequent presence of an exogenous substance by counteracting its intracellular signaling responses, such as the levels of adenyl cyclase, and by dialing down its own related endogenous signaling system—endorphins and dynorphins in the case of opioid drugs, or downregulating cannabinoid CB1 receptors in the case of cannabis, and so on. The resulting tolerance is the need for increasing doses of the drug to produce the desired effect; and the resulting physical dependence leads to the emergence of withdrawal symptoms when the drug is interrupted. While tolerance and withdrawal (i.e. physical dependence) are typically part of addiction, many substances, including multiple prescription medications, may produce dependence and tolerance without producing addiction. Furthermore, the severity and duration of withdrawal symptoms depend on the specific drug consumed.

Addiction, per se, arises when the individual loses control over use of the substance (i.e. spending a great deal of time using a substance, using larger amounts than intended, etc.). It is driven by the formation of associations between the drug and environmental as well as internal cues that trigger craving, or incentive salience; neurobiological changes that lead to intensified dysphoria during withdrawal, as well as increased preoccupation with the drug; and reduction of self-inhibitory control over drug taking despite, in many cases, an awareness that the drug has assumed too much importance and is harming health and other aspects of the individual’s life like relationships, school, or work.^2,38–41

As displayed in Figure 2, three areas of the brain are critical for these processes: the basal ganglia, the extended amygdala, and the prefrontal cortex.³⁸ Changes to circuits in these brain areas play key roles in three repeating stages of the addiction cycle, respectively: binge/intoxication, the acute rewarding and reinforcing effects upon taking the drug; withdrawal/negative affect, the unpleasant physical and emotional symptoms associated with a period of abstinence; and preoccupation/anticipation, craving the drug in response to internal and external cues. Dynamic relationships across these three stages help explain patterns of heavy consumption, followed by abstinence (can be brief or extended), and then recurrent use to alleviate negative internal states or in response to anticipatory motivation. Classes of substances differ in how they produce their effects, especially in the binge/intoxication phase, as well as in how and to what extent they disrupt the relevant circuits, but the overall patterns are consistent across substances.

Binge/intoxication.

Either immediately or soon after taking a drug (rapidity depending on the substance’s specific properties and mode of administration), the individual experiences rewarding euphoria (i.e. positive reinforcement) and, in the case of a person with dependence or addiction, relief from withdrawal symptoms (i.e. negative reinforcement). The exact neurobiological correlates of experienced pleasure or the drug “high” are debated and may differ for different substances (see Future Directions, below), but well understood is the role of dopamine signaling in neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAC) in building associations between drug-taking and reward, reinforcing those associations each time drug-taking is repeated, and reinforcing associations between the drug and internal and external cues.⁴² Multiple preclinical studies in rodents have identified the neuronal and neurochemical actions of drugs on this dopaminergic VTA-NAC circuit (see Koob and Volkow⁴ for a full description of these pathways). While the mechanisms of action vary by drug, enhancing dopamine activity in the basal ganglia is responsible for the reinforcing properties of all substances whose misuse can result in addiction.

When an association between dopamine and positive reinforcement was first discovered in rodent studies in the 1970s,^43,44 it was believed that dopamine was the neurotransmitter responsible for rewarding feelings that drive drug seeking. Over subsequent decades, dopamine came to be thought of as the “pleasure chemical,” and this idea was expressed widely in the media and popular science explanations of drug addiction. In the past two decades, the science of dopamine has departed from this popular conception with the discovery that dopamine has more to do with reinforcement learning and motivated goal-seeking, and probably not drugs’ hedonic effects, which engage other neurotransmitter systems including endogenous opioids and cannabinoids.⁴⁵ Dopamine signaling in the basal ganglia controls the salience of cues (external or internal) that engender action.⁴⁶ It is released in the NAC both in anticipation of rewards and when rewards exceed expectation, and it is diminished when rewards do not materialize or are less than expected.

The development of incentive salience is a crucial neuroplastic response to natural rewards such as food and one that is hijacked by drugs. Through conditioning and expectation of reward, a memory is formed that will incentivize behaviors to consume the reward (e.g. food or drugs). The conditioned memories that drive incentive salience towards conditioned stimuli are fundamental to survival but also facilitate the development of an addiction. When drugs are repeatedly administered, dopamine comes to be released when the individual encounters or experiences the cues associated with the drug prior to its consumption, energizing the behaviors to obtain it.⁴⁷ Incentive salience has the motivational effect of driving drug-seeking during the anticipation/preoccupation phase (described below).

Depending on the class of drug, dopaminergic signaling in the basal ganglia may be enhanced through several different mechanisms including: direct or indirect increases in activity of VTA-dopamine neurons, increasing terminal dopamine release, blocking dopamine reuptake, or enhancing the post-synaptic actions of dopamine on NAC neurons. An additional neuroplastic mechanism shared among most drugs with their repeated administration is the increase of the ratio of the glutamate receptor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, to that of the N-methyl-D-aspartate (NMDA) receptor, which results in enhanced excitatory transmission onto VTA-dopamine neurons.^48,49 See Box 1 for summaries of the specific mechanisms of action of major drug classes.

Another important component of the binge/intoxication stage is release of both dopamine and glutamate (an excitatory neurotransmitter) in the dorsal striatum, which is implicated in behavioral reinforcement.^63,64 This is another mechanism through which learning processes contribute to the development of compulsive drug use. Indeed, addiction is sometimes compared to a well-learned skill, one that is difficult to unlearn (see Future Directions below).

Withdrawal/Negative Affect.

Koob and Volkow highlight the importance of negative emotional states and memories in the addiction cycle, based on both the expressed responses of human subjects and from fMRI studies correlated with amygdala and hippocampus activation during craving episodes.⁴

As the drug leaves the system and its acute effects wane, an individual who has developed an addiction may experience not only the physical symptoms of withdrawal, which are usually relatively short term, but also protracted negative emotional withdrawal symptoms that are part of the long-lasting adaptations in addiction. The negative emotional state during the withdrawal stage of the addiction cycle is caused by increased sensitivity of the extended amygdala to stress, mediated in part through enhanced corticotropin-releasing factor (CRF), norepinephrine, and dynorphin signaling. The feelings of stress caused by this activity in the extended amygdala, compounded in some cases by intense physical symptoms of drug withdrawal, are one reason why it is incorrect to think of people with addiction as simply hedonically driven, motivated by the euphoria or high caused by drug intoxication. To a significant degree, people with addiction are motivated to experience relief, to escape the stress and suffering of withdrawal, which in many cases can be intense or even unbearable.

Preoccupation/Anticipation

A core feature of SUD, especially the more severe forms (i.e. addiction), is craving, sometimes described as an overwhelming need and urgent compulsion to use a substance after a period of abstinence (short or long).^2,40,41 This preoccupation/anticipation stage in the addiction cycle involves reciprocal interaction of the dopaminergic pathways of the prefrontal cortex, the brain area most associated with goal-directed behaviors, self-inhibition, and judgment, with both the extended amygdala and the basal ganglia.

Signaling in dopaminergic and glutamate connections between the prefrontal cortex and basal ganglia motivate drug seeking in response to cues. Inhibitory connections between the prefrontal cortex and the dorsal striatum that have been weakened by chronic substance use let the habitual response—taking the drug—win out. These weakened inhibitory signals are especially powerless in the face of the dysphoric feelings generated by the stress neurotransmitters in the extended amygdala. This shift in the balance of what are colloquially called the “Go” and “Stop” systems coordinated by the prefrontal cortex helps explain addiction’s chronic, relapsing course.⁶⁵

Future Directions

Much is known about the neurobiology of addiction, at least in broad terms—including the development of incentive salience and compromised self-inhibition that underpins compulsive drug use. But there are areas where our knowledge remains limited. One, oddly enough, is the neurobiology of pleasure itself. Greater understanding that dopamine has to do mainly with reinforcement but not with hedonic perception has left a gap in our understanding of just what is pleasurable about rewards. Some research points to so-called “hedonic hotspots” in the orbitofrontal cortex, insula, NAC, ventral pallidum, and pontine parabrachial nucleus that have been identified in conjunction with “liking” in animal models.⁶⁶ Liking here is distinguished from the anticipatory (and dopamine-related) signal of “wanting.” Activity in hedonic hotspots during pleasurable experience involves endogenous opioid, endocannabinoid, and orexin (but not dopamine) signaling,⁴⁵ and how different drugs interact with these hotspots remains to be seen. But it is almost certainly the case that the neurobiology of pleasure, including the drug high, will not be a simple story of one neurotransmitter flooding the brain with good feelings.

Another gap in our understanding is the neurobiology of recovery from addiction. We understand how the brain changes when an SUD develops, but we still know very little about how the brain restores balance among the systems disrupted during active drug use. Longitudinal clinical research suggests that stable recovery is more likely with lengthy periods of supported abstinence.^34,67 Yet, susceptibility to relapse even after years of abstinence is not rare, strongly indicating that some neuroplastic changes, for instance learned associations between drugs and reward that were formed during the development of the disorder, weaken only very gradually. Addiction is often likened to riding a bicycle: You may not have ridden one in years; yet, if you get on one, you’ll be able to ride it quite well. Among the many avenues of addiction treatment research being pursued, one is to find ways of identifying and weakening those learned associations between a drug and its craving-inducing cues.⁶⁸ It may also be the case that different drug use disorders may have different long-term impacts on those who have recovered from them, and it is likely the case that individual differences will play a role. There could be many neurobiological trajectories of recovery.

Conclusions

The medical framing of addiction as a chronic, relapsing brain disorder has been slow to win adherents outside of medicine, and studies show that even clinicians cling to stigmatizing views that see people with addiction as bad or weak.⁶⁹ The medical framing has been crucial to research explicating addiction neurobiology and has been essential to developing effective treatments, such as those that currently exist for opioid use disorder. However, since learning mechanisms are so central to the processes that make drug use compulsive in people with addiction, some critics argue that the medical framing is overly reductive and pessimistic, and even disempowering to persons who may hear “brain disorder” or “brain disease” and assume that it somehow means non-treatable or incurable, which is not the case.^{70, 71} These terminological (and in some cases, philosophical) questions will continue to be fruitful areas of debate and inquiry. If anything, framing addiction as a learned behavior (as well as a disease) helps make the case for greater societal and healthcare investment in prevention: It may be the case that the surest way to keep people from riding bikes is to keep them from learning to ride them in the first place.

Addiction occurs in a minority of people who use drugs repeatedly, a result of a combinations of biological and psychosocial risk factors. The pathways to addiction involve changes to neurocircuits in limbic and prefrontal regions, and some of these neuroplastic changes may be slow to resolve or “change back” even with months or years of abstinence, warranting calling addiction a chronic brain disorder with high risk of relapse. This understanding of addiction has been crucial to marshalling biomedical research to find and develop treatments. Educating the public, policymakers, and clinicians about the efficacy of these treatments is a crucial part of eroding the stigma that has prevented their wider adoption.

Summary

The neurobiological underpinnings of addiction, a chronic relapsing brain disorder, are increasingly understood through advancements in neuroscience. Research across anatomical, electrophysiological, and neuroimaging levels reveals central nervous system models explaining addictive disorders' signs, symptoms, and progression within environmental contexts. This understanding encompasses decision-making, choice, habit formation, and brain development, offering frameworks for prevention and treatment of substance use disorders (SUDs). While diverse perspectives exist, a prevailing view in addiction medicine considers addiction a biopsychosocial disorder, emphasizing the role of neurotransmitter system and functional network alterations. Shared and unique neurobiological effects across various substances necessitate a nuanced approach.

Onset and Natural History of Substance Use Disorders

Individual risk for SUDs arises from complex interactions between genetic predispositions and environmental influences. Early-life stress, encompassing family dynamics, sociocultural context, and adverse childhood experiences, significantly elevates SUD risk. Genetic factors contribute substantially, with epigenetic modifications linking early adversity to stress sensitivity and behavioral disorders. However, early interventions, such as family-focused programs and prenatal/infant support, demonstrate potential for mitigating adverse developmental impacts. Adolescence presents heightened vulnerability due to uneven brain maturation, with limbic structures maturing earlier than prefrontal cortical regions responsible for impulse control and judgment. This developmental mismatch, coupled with increased risk-taking and susceptibility to peer influence, enhances the likelihood of substance initiation and subsequent addiction. The transition from initial substance use to SUD varies; while many users do not develop addiction, a subset experiences a chronic, relapsing course, often characterized by periods of remission interspersed with relapse, even after treatment.

Neuroplastic Changes in Addiction and the Addiction Cycle

Chronic drug use leads to tolerance and physical dependence—physiological adaptations counteracting drug effects and inducing withdrawal symptoms upon cessation. Addiction, however, surpasses simple dependence; it involves loss of control over substance use, driven by incentive salience, intensified dysphoria during withdrawal, preoccupation with the substance, and impaired self-inhibitory control. Three key brain regions—the basal ganglia, extended amygdala, and prefrontal cortex—mediate the addiction cycle’s three stages: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. These stages illustrate a cyclical pattern of substance use, abstinence, and relapse.

Binge/Intoxication

This stage involves the acute rewarding effects of drug use, primarily through dopamine signaling in the ventral tegmental area (VTA)-nucleus accumbens (NAC) pathway. Dopamine's role extends beyond simple pleasure, encompassing reinforcement learning and motivated goal-seeking. Repeated drug administration strengthens associations between drug-taking and reward, enhancing cue-driven drug seeking. Neuroplastic changes, such as altered AMPA/NMDA receptor ratios in the VTA, further solidify these associations. The dorsal striatum's involvement in behavioral reinforcement contributes to compulsive drug use.

Withdrawal/Negative Affect

This stage is characterized by negative emotional states and withdrawal symptoms. Increased sensitivity of the extended amygdala to stress, mediated by heightened CRF, norepinephrine, and dynorphin signaling, contributes to the dysphoria experienced. This negative reinforcement drives continued drug seeking to alleviate discomfort, highlighting the complex interplay of pleasure and distress in addiction.

Preoccupation/Anticipation

This stage centers on craving, driven by interactions between the prefrontal cortex, extended amygdala, and basal ganglia. Weakened inhibitory signals from the prefrontal cortex to the dorsal striatum allow habitual drug seeking to dominate. The dysphoria generated by the extended amygdala further fuels this compulsive behavior.

Future Directions

Future research should focus on elucidating the neurobiology of pleasure and recovery from addiction. While dopamine's role in reinforcement is established, the precise neurobiological mechanisms underlying the hedonic effects of drugs remain to be fully characterized. Understanding the brain's restoration of balance following abstinence is crucial, as is identifying the mechanisms underlying relapse vulnerability, even after extended periods of abstinence. The possibility of diverse neurobiological recovery trajectories necessitates further investigation.

Conclusions

Addiction's medical framing as a chronic, relapsing brain disorder is vital for research and treatment development. However, it’s crucial to avoid overly simplistic or stigmatizing interpretations. Recognizing the learned aspects of addiction emphasizes the importance of prevention. Effective treatments exist, and broader dissemination of this knowledge is essential to reducing stigma and improving outcomes.

Summary

For decades, a comprehensive understanding of addiction's neurobiological underpinnings has been lacking, despite the long-recognized link between specific brain regions and behavioral patterns, as well as the impact of substance use on behavior. Recent advancements in neuroscience, encompassing anatomical, electrophysiological, and neuroimaging studies, have yielded central nervous system models that explain addictive disorders. These models integrate the signs, symptoms, and progression of addiction within the context of environmental factors. This knowledge is crucial for clinicians and patients to improve the prevention and treatment of substance use disorders (SUDs). Addiction, considered a chronic, relapsing, but treatable biopsychosocial disorder, manifests as alterations in specific brain neurotransmitter systems and functional networks. While shared neurobiological effects exist across various substances, unique effects of different drug classes must also be understood. This overview focuses on key elements of addiction and their underlying neurobiological mechanisms, emphasizing maturational and neuroplastic processes relevant to SUD onset and progression.

Onset and Natural History of Substance Use Disorders

The onset of SUDs is intricately linked to human development. Environmental influences, encompassing family dynamics, socioeconomic factors, and cultural context, interact with genetic predispositions and brain maturation to shape an individual's risk. Early-life stressors significantly increase the likelihood of substance use and SUD development. Genetic factors also contribute significantly to SUD risk. Epigenetic modifications resulting from adverse environments influence stress sensitivity and behavioral outcomes. However, interventions can mitigate these negative effects; for example, family-focused interventions during adolescence may lessen the impact of poverty on brain development. Early interventions, starting prenatally or during infancy, can improve long-term behavioral, cognitive, and health outcomes. The typical onset of substance use during adolescence is linked to the uneven maturation of the brain. Limbic structures related to emotion and reward mature earlier than prefrontal cortical areas responsible for decision-making and impulse control, leading to increased risk-taking behaviors. This developmental mismatch, coupled with the adolescent brain's vulnerability to environmental influences and the lasting effects of substance use, significantly elevates the risk of addiction. Early initiation of substance use is a strong predictor of SUD development. Although many who misuse substances do not develop SUDs, a significant portion do and will experience varying courses of the disorder—some achieving remission naturally, while others face chronic relapse despite treatment. The likelihood of relapse after treatment is significant, reflecting the chronic and relapsing nature of many SUDs.

Neuroplastic Changes in Addiction and the Addiction Cycle

Chronic drug use leads to tolerance and dependence. Tolerance necessitates escalating drug doses to achieve the desired effect, while dependence results in withdrawal symptoms upon cessation. While tolerance and withdrawal are often associated with addiction, they do not define it. Addiction is characterized by a loss of control over substance use. This loss of control stems from neuroplastic changes in the brain, specifically within the basal ganglia, extended amygdala, and prefrontal cortex. These areas are integral to three stages of the addiction cycle: binge/intoxication (acute rewarding effects), withdrawal/negative affect (unpleasant physical and emotional symptoms), and preoccupation/anticipation (craving and drug-seeking). The binge/intoxication stage involves dopamine signaling in the ventral tegmental area (VTA) to the nucleus accumbens (NAc), reinforcing drug-taking behavior and strengthening associations between drug use and reward. This process involves incentive salience—the association between cues and drug seeking. Withdrawal/negative affect is characterized by increased stress sensitivity in the extended amygdala, leading to negative emotional states that drive drug-seeking behavior. The preoccupation/anticipation stage involves interactions between the prefrontal cortex, the extended amygdala, and the basal ganglia, fueling craving and compulsive drug-seeking despite negative consequences.

Future Directions

Despite substantial progress, significant gaps remain in our understanding of addiction's neurobiology. Research into the neurobiology of pleasure itself is one crucial area. While dopamine's role in reinforcement is understood, its precise role in the hedonic experience of reward requires further investigation. Another critical area is the neurobiology of recovery. While longitudinal studies suggest that prolonged abstinence correlates with stable recovery, the mechanisms of brain restoration and the long-term effects of addiction on recovered individuals require additional study. Finally, the continuing debate about the appropriate framing of addiction—as a learned behavior or a disease—reflects ongoing questions about the best ways to conceptualize addiction to guide both research and treatment. Addressing such complexities is essential to reduce the stigma surrounding addiction and to increase understanding among the public, policymakers and clinicians about the best approaches to treatment and prevention.

Summary

Since the Phineas Gage case, the link between brain regions and behavior has been evident. However, a complete understanding of addiction's neurobiological basis is a more recent development, crucial for both medical professionals and those struggling with addiction. Neuroscience advancements have provided models explaining addiction's symptoms and progression, considering environmental factors. While multiple perspectives exist, addiction is largely viewed as a chronic, treatable brain disorder impacting neurotransmitter systems and brain networks. This overview will explore addiction's key elements and their neurobiological underpinnings, focusing on brain maturation and neuroplasticity in the addiction cycle's three stages: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation.

Onset and Natural History of Substance Use Disorders

Understanding the onset of substance use disorders (SUDs) requires knowledge of human development. Environmental factors like family dynamics, community, school, and culture significantly influence an individual's risk, interacting with genetic predispositions and brain maturation. Stressful early-life experiences increase the likelihood of substance use and SUDs. Studies like the Adverse Childhood Experiences (ACE) study reveal a strong link between childhood trauma and later substance use. Genetic factors also play a critical role, with epigenetic modifications potentially linking early adversity to stress vulnerability and behavioral issues. However, the effects of adverse environments can sometimes be mitigated. Interventions, even as early as pregnancy and infancy, can positively impact later outcomes, reducing substance use and improving cognitive development.

Adolescence is a high-risk period for substance use due to uneven brain development. Limbic structures involved in emotions and reward mature earlier than the prefrontal cortex, responsible for decision-making and impulse control. This imbalance increases risk-taking behaviors and vulnerability to peer influence. The adolescent brain's immaturity makes it particularly susceptible to lasting effects from substance use, increasing addiction risk. Early substance use (in the early teens) significantly increases the risk of developing an SUD, with addiction often beginning in the late teens. Most substance use begins with tobacco, alcohol, and then cannabis, often preceding the use of other substances. Nicotine, in particular, plays a crucial role in this progression, potentiating the reinforcing effects of other substances and rewards. Despite the various risk factors, only a fraction of those who use substances develop SUDs. Many individuals achieve remission without formal treatment, demonstrating the complexity of the issue. Conversely, longitudinal studies show that for many, SUDs persist for decades. Those seeking treatment often experience a chronic, relapsing course, with high rates of relapse even following treatment.

Neuroplastic Changes in Addiction and the Addiction Cycle

Chronic drug use leads to tolerance and physical dependence. The body adapts to the substance, counteracting its effects, requiring increased doses for the same outcome. Dependence manifests as withdrawal symptoms upon cessation. While these are often part of addiction, they are not synonymous with it. Addiction involves a loss of control over substance use, driven by associations between the drug and environmental cues, triggering cravings. The brain regions critical to this are the basal ganglia, extended amygdala, and prefrontal cortex. These areas are involved in the three stages of the addiction cycle: binge/intoxication (basal ganglia), withdrawal/negative affect (extended amygdala), and preoccupation/anticipation (prefrontal cortex). While specific mechanisms vary by substance, the overall patterns are consistent.

The binge/intoxication stage involves the rewarding effects of the drug, driven largely by dopamine signaling in the VTA-NAC pathway. This pathway reinforces associations between drug use and reward. Dopamine's role, however, is not simply pleasure, but rather reward learning and motivated behavior. Repeated drug use alters this pathway, increasing the salience of drug-related cues and driving cravings. The withdrawal/negative affect stage involves the unpleasant physical and emotional symptoms experienced during abstinence. Increased stress sensitivity within the extended amygdala is a central component, driving drug-seeking behaviors. The preoccupation/anticipation stage is characterized by cravings and compulsive drug-seeking, involving interactions between the prefrontal cortex, extended amygdala, and basal ganglia. Weakened inhibitory signals from the prefrontal cortex contribute to the chronic, relapsing nature of addiction.

Future Directions

While much is known about addiction neurobiology, some areas require further exploration. One is the neurobiology of pleasure itself. The focus has shifted from dopamine as the sole pleasure chemical to understanding its role in reward learning. Other neurotransmitters, like endogenous opioids and cannabinoids, are implicated in hedonic effects. Research on “hedonic hotspots” in the brain offers further insight into the neurobiological mechanisms of pleasure. Understanding the neurobiology of recovery from addiction is another key area. While long-term abstinence improves outcomes, relapse remains a significant concern, indicating the persistence of neuroplastic changes. Research is needed to identify and target these changes to enhance treatment effectiveness. It may also be that different drug use disorders have different effects on those who have recovered from them, and individual differences in recovery paths require further investigation.

Conclusions

Viewing addiction as a chronic brain disorder has been pivotal in research and treatment development. While this medical model has advanced understanding and improved treatments, it also raises important questions about the overall understanding of addiction. Some criticize its potential to be seen as overly deterministic, implying incurability. Therefore, emphasizing addiction’s learned components alongside the medical view can help to promote more effective prevention strategies. Addiction affects a small portion of those who use drugs. The combination of biological and psychosocial factors contributes to its development, leading to alterations in brain circuits. These neuroplastic changes can persist even after prolonged abstinence, and public awareness campaigns are needed for wider adoption of existing, effective treatments.

Summary

Scientists have known for a long time that certain parts of the brain are involved in our actions and that drugs can change how we act. But until recently, we didn't fully understand how addiction works in the brain. This is important for doctors and for people struggling with addiction. New research helps explain addiction and shows ways to prevent and treat it. Addiction is a brain problem, but it's also affected by things outside of the brain, like our family and friends.

Onset and Natural History of Substance Use Disorders

Lots of things can affect whether someone starts using drugs and becomes addicted. This includes their genes and their experiences growing up, like whether their family was supportive or if they lived in a difficult place. Stressful childhoods often make it more likely that someone will use drugs. Even before trying drugs, some kids might be more likely to use them than others. Luckily, good things in a child's life, like having helpful parents and good friends, can help to lessen the risk of drug use.

The teenage brain isn't fully developed. The part that controls emotions grows faster than the part that helps us make good decisions. This makes teens more likely to take risks, including trying drugs. Because their brains aren't fully grown, teens are more likely to become addicted if they start using drugs. Most people who become addicted start using drugs as teenagers, and it's most likely to start in their late teens. Most people who use drugs don't become addicted, but for those who do, it can be a long-term problem. Some people get better without any help, but for many, addiction is a cycle of using drugs heavily, then stopping for a while, and then starting again.

Neuroplastic Changes in Addiction and the Addiction Cycle

When people use drugs a lot, their bodies get used to them. This means they need more and more drugs to feel the same effects (tolerance) and they experience bad things when they stop using (withdrawal). Addiction is more than just tolerance and withdrawal, though. It’s about losing control over drug use and having strong cravings.

Three important parts of the brain are involved in addiction: the basal ganglia (involved in reward and pleasure), the extended amygdala (involved in stress and negative feelings), and the prefrontal cortex (involved in decision-making and control). When people take drugs, the basal ganglia release dopamine, a chemical that makes us feel good and reinforces the behaviour of taking the drug. When they stop, the extended amygdala makes them feel stressed and bad (withdrawal). The prefrontal cortex helps control our behaviour. But in addiction, this area is weakened, making it harder to stop using drugs, even when people want to.

Future Directions

Scientists still have lots to learn about addiction. For example, we don't fully understand what makes certain things pleasurable. We also don't know exactly how the brain recovers from addiction. While many people recover from addiction without treatment, those who receive treatment have a better chance of recovery. We know that addiction involves learning, which means there could be ways to help people "unlearn" these harmful behaviors.

Conclusions

Addiction is a serious problem, but it's a treatable one. It's important to remember that people with addiction aren't bad; they have a brain problem. Understanding how addiction affects the brain helps us develop better ways to prevent it and treat it. We need to help people understand this and reduce the stigma surrounding addiction.