Psychopharmacological Perspectives and Diagnosis of Substance Use Disorder

1. Introduction

Addiction is the recurrent use of mood-altering substances, such as alcohol and other drugs, despite their adverse health and psychosocial consequences. The interplay among genetic, psychosocial, and environmental factors influences the development and manifestations of the disorder [1]. For some individuals, becoming physiologically dependent on a certain substance is likely to be a developmental process. Individuals may start with a positive attitude towards a substance, begin to practice using it, become regular users, progress to being heavy users and finally become dependent on it. While developing a positive attitude towards a certain substance, for instance, cigarettes and beginning to experiment with it, may be strongly related to exposures to smoking by other family members [2], becoming heavy smoker, on the other hand, is more strongly related to frequent exposures to peer smoking and being able to access cigarettes readily [3].

Addiction, which was once viewed mainly as a moral failing or character fault, is now considered as a chronic illness of the brain characterized by clinically significant impairments in health, social function, and involuntary control over drug use [4, 5]. Although the mechanisms may be different, addiction, like most physiological disorders, is chronic, subject to relapse, and influenced by genetic, developmental, psychosocial, and environmental factors. Addictive substances exert significant influences on the brain that may affect thoughts, emotions, and behaviors. Substances of abuse have powerful effects on the brain and produce euphoria (extreme pleasure) which provokes users to seek those substances repeatedly despite the risks for significant harms.

As individuals continue to misuse alcohol or other substances, neuroadaptations occur due to progressive changes in the structure and function of the brain. Neuroadaptation compromises brain function and eventually results in the transition of an individual from controlled, occasional substance use to chronic misuse, which can be difficult to control. These brain changes may persist long after an individual stops and produce a continuous or periodic craving for the substance that can lead to relapse: More than 60 percent of people treated for a certain substance use disorder experience relapse within the first year after completion of treatment [6], and some may remain at increased risk of relapse for many years.

Much of our knowledge about the effects of substance use and misuse on the brain as well as the development of addiction comes from the study of laboratory animals. Neurobiological studies in animals have examined both the immediate effects (acute impact) of addictive substance in the brain right after ingestion and the long term or chronic impact of drug use to understand, at the most basic level, the mechanisms through which substance use alters brain structure and function and facilitates the transition from occasional use to misuse, addiction, and relapse. Although the animal models do not fully reflect the human experience, animal studies help researchers investigate addiction and related behavioral changes under highly controlled conditions that may be difficult or unethical to replicate in humans [7].

To supplement the work in animals, a growing body of substance use research has been conducted with humans. The use of brain-imaging technologies, such as magnetic resonance imaging (MRI) and positron emission tomography (PET) scans for studying the effects of alcohol and drugs on the human brain have significantly advanced the current knowledge of SUD by allowing researchers to see inside the living human brain. Using these technologies, researchers can investigate and characterize the biochemical, functional, and structural changes in the brain which result from addictive substances and find out how such changes may ultimately contribute to substance use, misuse, and addiction [8]. Animal and human studies are integrated and inform each other for a more complete picture of the neurobiology of addiction [9].

The structural and functional changes caused by using drugs can be long-lasting and can lead to harmful behaviors seen in individuals who continued to abuse drugs. Although the initial decision to try a drug of choice is mostly voluntary, eventually, as drug abuse takes over or an individual transforms from occasional user to heavy user, his/her ability to exert self-control may become seriously affected. Brain imaging studies conducted on drug-addicted individuals typically revealed that physical changes have been observed in the areas of the brain that are critical to judgment, decision making, learning, memory, and self-control. Scientists believe that these changes alter the way the brain works and may help explain the compulsive and destructive behaviors of addiction [10].

Susceptibility for addiction varies from individual to individual as for any other diseases. This depends on the amount and level of risk factors a person has. The more the risk factors the greater the chance that taking drugs will lead to abuse and addiction. No single factor determines whether a person will become addicted to drugs. The overall risk for addiction is influenced by the biological makeup of the individual including sex or ethnicity, developmental stage, and the surrounding social environment such as home, school, and the neighborhood.

Individuals with mental disorders are at greater risk of drug abuse and addiction than the general population [11]. A growing body of research reveals that SUDs and many psychiatric disorders share comparable neural mechanisms. There are several clinical resemblances and symptom overlaps between SUDs and affective disorders [12]. Epidemiological studies revealed that co-occurring substance abuse and psychiatric problems are common in clinical practice. SUDs and a variety of mental illnesses have similar changes in the dopamine-mediated reward system as well as different neurotransmitter systems such as GABA, and serotonin [10]. According to recent findings from neuroimaging research, similar abnormalities in frontal-limbic brain circuitry are implicated in SUDs and depressive disorders. Individuals with SUDs have been found to have lower frontal metabolism and anterior cingulate activation [13, 14]. Depressive symptoms are typically observed after acute and chronic drug withdrawal due to anomalies in the CRF and HPA axis, as well as alterations in catecholamines, serotonin, GABA, and glutamate systems [15]. Hence, chronic stress-induced neuroadaptations in brain stress system and reward pathways may increase the susceptibility to self-administer the substances of abuse and predispose or reveal a vulnerability to psychiatric conditions, SUDs, or both [16, 17].

The influence of home and family environment is usually most important in childhood. Children who are exposed to parental substance use early in life are more likely to develop SUD in their future life through behavioral modeling [18, 19, 20]. It is more likely that parents or older brothers or sisters who abuse alcohol or drugs can increase other children’s risks of developing drug problems [21]. In addition, children with poor social skills and poor academic achievement may be at more risk of developing drug problems in school [22].

The route of administration of the substance being used is also a potential factor that may influence the progress of an individual from a regular user to a heavy user or abuse. For instance, as both smoked and injected drugs enter the brain fast and produce a powerful rush of pleasure, smoking a drug or taking it through the vein increases its addictive potential. This intense high feeling of pleasure (euphoria), however, can gradually fade away and a rebound effect of agitation or low feelings may occur. Then, these feelings develop into cravings and drive individuals to recurrent drug abuse to recapture the high pleasurable state which can worsen the risk of developing addiction [23].

The age of the onset of drug use is another potential factor that increases the likelihood of drug abuse by individuals. Although starting drugs at any age can eventually lead to addiction, early substance use is a strong indicator of problems ahead related to substance abuse and addiction [24]. Research findings have shown that people who start taking drugs at an early age are more likely to be at increased risk for adult substance dependence [25]. The part of the brain, the prefrontal cortex, which is responsible for assessing situations, making sound judgment and decisions, and keeping our emotions and desires under control is still maturing during adolescence. The fact that this critical part of an adolescent’s brain is still a work-in-progress puts young people at increased risk of making poor decisions regarding trying drugs for the first time and/or continuing drug abuse thereafter. Adolescents at this stage are developing judgment and decision-making skills which may limit their ability to assess risks accurately and make sound decisions about using drugs. Therefore, introducing drugs while the brain is still developing may have profound and long-lasting results concerning drug addiction. Early use of psychoactive substances changes the structure and functions of the brain which can lead to addiction and other serious problems [26]. Thus, preventing early use of alcohol or other drugs may reduce the risk of progressing to later abuse and addiction.

Interindividual differences in addiction risk are mostly determined by genetic variation. The impact of genetic variation on total addiction risk has been estimated to be 50% in studies focusing on variability across identical and nonidentical siblings [27]. The largest study to date on 1.2 million people that looked at common genes in alcohol and nicotine use identified genes involved in dopaminergic and glutamatergic neurotransmission, transcription and translation, and brain development [28]. They also revealed that a crucial genetic component of SUDs appears to impact a vulnerability to disorders with pathological symptoms via a general-purpose underlying mechanism.

Besides these common genetic characteristics, genetic variants that are mainly unique in a particular drug have been found. The most well-known genetic variants are those that code for the alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) enzymes, which cause poor alcohol metabolism and protect against alcoholism [28]. Like other complex biobehavioral disorders, addiction is a polygenic disease involving multiple genes and genetic networks [29, 30]. Genetic research has aided our understanding of addiction-related neurobiological processes. Addiction-related gene variations can increase the risk of drug misuse and addiction by altering neurotransmitter systems, drug metabolic pathways, and brain circuitry. For example, genetic polymorphisms in the nicotinic acetylcholine receptor subunits expressed in the medial habenula are linked to development of withdrawal symptoms [31] and are at least partially accountable for the genetic predisposition or vulnerability to tobacco addiction [32, 33]. This has demonstrated that the habenula is involved not just in nicotine addiction, but also in the unpleasant emotional states associated with the long-term use of numerous drugs of abuse [29], such as alcohol [30] and opioids [34].

Epigenetic factors are a diverse set of transcriptional tuning processes that generate and sustain gene expression–mediated physiological outcomes in response to environmental inputs [13]. Plasticity is at work in the transition to compulsive drug use, changing the physiology of the brain to produce addictive states. Physiologically, the rewiring of brain reward circuitries, particularly dopamine neurons in the ventral tegmental area (VTA), is thought to cause vulnerability to relapse after periods of attempted abstinence from drugs of abuse such as cocaine use. The same enzyme that attaches serotonin to Histone 3 can also catalyze the attachment of dopamine to H3 — a process, known as dopaminylation, which may control drug-seeking behavior [35]. Cocaine-induced transcriptional plasticity in the midbrain is mediated by histone H3 glutamine 5 dopaminylation (H3Q5dop). As a result, long-term cocaine use alters neuronal circuits in the brain’s reward system, necessitating a consistent intake of the drug for the circuits to function normally. To make the proteins for those changes, certain genes must be turned on and off, and this is an epigenetic mechanism activated by dopamine acting on H3, not a change in DNA sequence. Epigenetic mechanisms provide a convergent regulatory framework within which the plasticity required to produce an addicted state can emerge and then remain long after drug use has stopped [36, 37].

2. The addiction cycle

There are many theories and models of addiction. While some of the theories and models present their theoretical approaches at an individual level, some explain the addictive behavior in terms of population or group interaction and influence. It is also important to note that many theories of addiction are complex and have evolved over time and therefore may overlap across one or more explanatory domains or perspectives.

The learning theory of addiction is relatively a broad category that emphasizes the importance of associations among cues, responses, and positive (pleasant) or negative (noxious) reinforcers. Among the specific models and theories under this category are operant learning, classical conditioning, and drug withdrawal theory [38, 39]. Moreover, the incentive sensitization theory of addiction also incorporates aspects of learning theory as it proposes that repeated exposure to drugs and drug-associated cues capitalizes on neuroplastic changes in mesocorticolimbic circuits and classical conditioning to make drugs and drug paired stimuli more motivationally salient [40, 41] .

The drive theories of addiction explain that addiction involves the development of powerful drives reinforced by homeostatic mechanisms. The drive theory is part of the disease model of addiction [42] and states that addiction is the result of pathological changes in the brain that produces overpowering urges. These changes that result in impairments may involve a structural or functional abnormality in the CNS [42]. Among the goal-focused theories of addiction are positive reward theories, acquired need theories, pre-existing need theories, and identity theories. These theories mainly explain addiction in terms of an individual’s behavior that satisfies one’s physiological or psychological needs, pleasure, and aspects of self-identity [43, 44, 45, 46, 47].

Other theories such as cognitive control theory [48], executive dysfunction theory [49, 50, 51], self-regulation theory [52], self-determination theory [53, 54], and implementation intentions theory [55, 56], describe addiction as a failure of individual’s strategies, ability or skills to self-control or to counteract impulses and motives underlying the addictive behavior. The biological theories describe that addiction involves specific neural circuitry or mechanisms [57, 58, 59, 60, 61, 62] and is primarily a brain disease’ characterized by dysfunction of neural pathways such as those that subserve executive function. The Reflective Choice Theories focus on the individual’s decisions, preferences, and actions that are made based on reasons and analysis. Therefore, according to these theories, addiction is a rational choice made by individuals in favor of the benefits of the addictive behavior over the costs. The Inhibition dysfunction theories suggest that addiction is an ongoing dysregulation of the ability to inhibit a rewarded behavior due to impairment of impulse controlling mechanisms [63]. In other words, addiction involves impairment of the inhibitory system of the brain regions related to features of response selection, inhibition, and motivation of compulsive behaviors associated with drugs. The hedonic homeostatic dysregulation theory also states that addiction is a cycle of escalating dysregulation of the brain reward systems that gradually increases and facilitates the act of compulsive drug use and a loss of control over drug-taking behavior, which are the basic concepts that underlie the addiction cycle [64].

Drug addiction is a disorder that is chronically relapsing and manifested in terms of compulsive behavior to seek and consume the drug, significant loss of ability to control and limit drug intake, and the emergence of negative and distressful emotional states such as irritability, anxiety, and dysphoria. Drug addiction is conceptualized as a three-stage cyclic disorder that consists of impulsivity and compulsivity and involves neuroplastic changes in the brain reward, stress, and executive functions [64, 65]. Impulsivity often dominates the early stages of the cycle and compulsivity dominates the terminal stages. The three stages are considered to interact with each other, become more intense, and eventually lead to the pathological state known as addiction.

Drug addiction is an excessive drug-taking behavior in which individuals compulsively seek and take drugs and lose their ability to control in limiting their drug intake. One of the multiple motivational mechanisms that drive such behavior is the development of a negative emotional state when access to the drug is prevented or discontinued, which results in dysregulation of hedonic homeostasis [64]. At the neurobiological level, two neuroadaptive models, sensitization and counteradaptation, have been hypothesized to contribute to the changes in motivation for drug-seeking and compulsive use (hedonic homeostatic dysregulation) and the neurobiological mechanisms, such as the mesolimbic dopamine system, opioid peptidergic systems, and brain and hormonal stress systems [64]. While sensitization has been conceptualized to be a shift in an incentive-salience state since it involves a progressive rise in the effect of a certain drug due to its frequent administration (21), counteradaptation hypotheses (20), on the contrary, were closely related to hedonic tolerance and involve the reduction of dopaminergic and serotonergic neurotransmission in the nucleus accumbens during drug withdrawal (22). Critical neurobiological sites with specific neurotransmitters and hormones have been identified that may regulate the hedonic dysregulation and provide the substrates that convey both vulnerabilities to, and protection against drug addiction. Dysregulation of key neurochemical elements in both reward and stress systems, such as decreases in dopamine and opioid peptide functions in the ventral striatum and recruitment of brain stress systems known as corticotropin-releasing factor (CRF) in the extended amygdala is hypothesized to produce the negative emotional state that initiates a condition of negative reinforcement [66]. An individual who uses a drug impulsively starts using it compulsively when a shift has occurred from positive reinforcement driving the motivated behavior to negative reinforcement driving the motivated behavior. Impulsivity and compulsivity often coexist in the different stages of the addiction cycle. This occurrence reflects the role of dysregulated reward and stress systems in the negative emotional states associated with the withdrawal/negative affect and preoccupation/anticipation stages of the addiction cycle that drive drug-seeking behavior [67].

The addiction cycle becomes more severe and well-established as a person continues substance use and as it produces dramatic changes in the functioning of certain brain areas that reduce the person’s ability to control his or her substance abuse. Three neurobiological circuits have been recognized to have empirical value for the study of the neurobiological changes associated with the development and persistence of drug addiction linked to the three-stage cycle (Figure 1). The key elements of the ventral tegmental area and ventral striatum are the focal points for the binge/intoxication stage and mediate the acute reinforcing effects of drugs of abuse. Acute withdrawal symptoms such as increased anxiety and dysphoria are associated with the second stage, the withdrawal/ negative affect stage, and are most likely the results of disruption in the function of the extended amygdala reward system and the recruitment of the brain stress neurocircuitry [68]. The preoccupation/anticipation (craving) stage is a widely distributed network and involves the stress-induced processes at the central brain stress systems in the basolateral amygdala, the orbitofrontal cortex–dorsal striatum, prefrontal cortex, and the hippocampus. The prefrontal cortex is mainly responsible for executive functions like organizing thoughts and activities, prioritizing tasks, managing time, and making important decisions, including limiting substance consumption [65].

This three-stage model of addiction is largely attributed to the extensive works of George Koob [69] and his colleagues and is supported by several animal and human research findings which provide useful means to understand the aspects and symptoms of addiction and design prevention, intervention, and treatment strategies [70]. It is worth noting that the three stages of addiction being discussed do not have absolute temporal distinctions that some components of addiction such as craving, conditioned cued craving, incentive-salience related craving, craving linked to withdrawal, etc. appear at many places in the addictive process and that the impacts of these aspects of craving and their neural basis remain to be further elucidated.

3. DSM-5 substance use disorder

Drug abuse, substance-related problems, and substance use disorders (SUDs) have all been viewed in different ways throughout history and cultures. How drug use and SUDs are conceptualized and how symptoms manifest and are interpreted are all influenced by culture. Sociocultural beliefs can influence how people approach and behave when it comes to substance use and misuse. Individuals’ assumptions regarding potential drug-related problems are shaped in large part by their culture [130]. While in some cultures alcohol use was heavily controlled and was allowed only for ceremonial purposes [131], acculturation, on the other hand, has made significant contribution to accelerated abuse of alcohol and use of illegal drugs among certain groups of people [132, 133].

Although the characterization of substance problem syndromes as medical diseases or disorders has a long history, drug abuse and inebriety were historically regarded from a moralistic perspective [134]. Attempts to define and refine diagnostic criteria for SUDs began in the mid-twentieth century and are still ongoing. Research has identified some limitations in the existing diagnostic criteria for SUDs, which can help with the conception of future classification systems [135].

According to modern theories of substance dependence, chronic substance use can cause neuroadaptations in brain systems involved in reward, motivation, emotional regulation, inhibitory control, and tolerance/withdrawal, all of which can lead to compulsive drug use behavior [136]. Illicit drug usage has been documented all over the world with the highest estimates in Europe, North America, and Australasia. Regular use, “problem drug use,” and drug addiction are less commonly measured, although they are critical to quantify in order to determine disease burden and risk factors for illicit drug use [137]. To better understand the harms associated with illicit drug dependency, future research should focus on collecting better estimates of mortality and morbidity.

Substance use and SUDs follow standard epidemiological age-related trends, with an onset often in late adolescence or early adulthood, showing peak prevalence in emerging adulthood, and then a decline. Although substance abuse is less common among older persons, often has a greater impact when it does occur, making it a public health concern [137]. A careful review of the population-based empirical literature reveals the importance of considering substance use in the context of development, with specific developmental aspects linked to the origin, course, and resolution of the problem.

SUDs are defined and thought of in a variety of ways. They have a lot in common with other chronic, recurrent diseases like diabetes or high blood pressure from a public health standpoint. Chronic diseases with significant behavioral health components may necessitate a lifelong commitment to manage and control. Many professionals believe that SUDs are inherently progressive. To put it another way, if these diseases are not treated, they tend to worsen over time. This chronic disease viewpoint has sparked significant controversy. For example, there is abundant evidence that many people, especially those suffering from the most severe kinds of addiction, follow a chronic, relapsing, escalating cycle. However, many people with SUDs seem to “recover” without undergoing professional therapy. This pattern, however, does not apply to everyone who has been diagnosed with a SUD. Many persons with milder, earlier-stage SUDs do not relapse and their substance-related problems do not progress [138]. Some experts, on the other hand, contend that, despite their history of chronic substance abuse, these individuals may not have been suffering from a severe SUD. Because of the great degree of individual variability in the course of addiction, it appears imprudent to employ a single treatment approach for all people diagnosed with the illness [138]. Despite age-related norms, significant individual course variability seems to be observed and contemporary statistical approaches have found numerous unique prototypic courses that appear to differ in their factors and outcomes. Research on substance use and misuse from a lifetime perspective has significant implications for the design and implementation of successful, developmentally informed diagnosis, prevention, and intervention programs [136].

The Diagnostic and Statistical Manual of Mental Disorders (DSM) is a classification manual for mental illnesses. It establishes a classification system for clinicians, insurance providers, researchers, and policymakers to utilize during diagnosing, researching, and treating mental illness. The 4th edition (DSM-IV) of the DSM, which had been in use for almost a decade, was replaced in 2013 by the 5th edition (DSM-5) [134, 135]. This version included organizational modifications as well as significant revisions to the diagnostic criteria for nearly every DSM-IV disorder. Some SUDs had just minor wording modifications, while others had significant criterion revisions. Some disorders have been added to and some removed from the list [136].

The transition from DSM-IV to DSM-5 has relevance in a multitude of settings, and it is essential for diagnosing and treating mental illness and SUD, as well as medical billing procedures and mental health research. Furthermore, if the modifications result in significant changes in the estimate of illness burden in the United States, they may be relevant to policymaking [136]. Every year, the National Survey on Drug Use and Health (NSDUH) gathers data on substance abuse and mental health from roughly 70,000 occupants of households and noninstitutional group quarters (e.g., shelters, rooming houses, and dormitories) as well as civilians residing on military bases. The NSDUH data give current, relevant information on the nation’s substance use and mental health status to the drug use and mental health prevention, treatment, and research communities. Stakeholders and policymakers can utilize this data to learn more about the disease burden, temporal patterns, and repercussions of substance abuse and mental illness, as well as identify high-risk groups [136]. Professionals in the United States currently rely extensively on the diagnostic method outlined in the DSM-5 for diagnosing substance use disorders [136]. Many nations throughout the world use the 11th edition World Health Organization’s (WHO, 2016) International Statistical Categorization of Diseases and Related Health Problems version 10, (ICD-10).

According to the DSM-5, SUDs are a type of a class of disorder (substance-related disorders) that are “associated to the use of a drug of abuse (including alcohol)”. Although there are changes at various levels in the shift from DSM-IV to DSM-5 for SUDs, the core criteria stay the same [134, 135, 139]. However, there have been changes at the category/class level (see Table 1 for the specific disorders considered within the overall group of disorders), substance level (which substances are considered “drugs of abuse”), disorder level (the template of criteria that is applied, with some deviations, across all substances), and individual criteria level (the number and types of symptoms needed to meet criteria for a disorder) [140]. Changes in relation to categorization refer to a disorder’s “class,” which is used in the DSM to designate groups of related disorders (e.g., personality disorders and anxiety disorders). The DSM-5 includes several revisions to the classification system, one of which is the classification of SUDs. SUDs were classified as substance-related disorders in the DSM-IV, which contained solely substance/drug-based illnesses. Gambling disorder has been added to this classification in DSM-5, and the section has been renamed Substance-Related and Addictive Disorders [136]. Changes from DSM-IV to DSM-5 in the types of substances assessed have been minor, but some reclassification has occurred. Based on empirical evidence since they have similar mechanisms of action (boosting synaptic dopamine), symptom profiles, consequences, and prognoses, cocaine (including crack) and amphetamines have been merged with other stimulants (except caffeine) into a distinct stimulant class [140].

The merging of substance abuse disorder and substance dependency disorder into a single SUD is a fundamental alteration in the criteria for substance use disorders from DSM-IV to DSM-5. DSM-5 has combined what had previously been considered as two distinct and hierarchical disorders (substance abuse and substance dependence) into a single construct, SUD, classifying it as mild, moderate, or severe, with the severity of an addiction based on how many of the established criteria are met. Diagnosis of SUD requires two out of eleven criteria to be met in a 12-month period. In addition, the DSM-5 has included a craving criterion to replace the abuse criterion associated with recurring substance-related legal difficulties (e.g., arrests for substance-related disorderly conduct). Due to low endorsement, poor fit with other items, and poor discrimination of this item (nearly everyone endorsing the legal criteria also endorsed other criteria), the legal problems criterion was omitted (see Table 2) [136, 141]. The majority of cases that met DSM-IV abuse criteria will not receive a DSM-5 diagnosis since they do not meet the minimum two-criterion threshold for a mild SUD. Most DSM-IV abuse cases will now be classified as mild SUD if they also endorsed two dependence criteria, but those who endorsed multiple (i.e., two or three) abuse criteria and two to three dependence criteria will now be classified as moderate SUD [137]. DSM-IV dependence cases that met three dependence criteria and no more than two abuse criteria will be classified as moderate SUDs in DSM-5, whereas nearly all cases that met four or more dependence criteria will be classified as severe SUDs [140]. The withdrawal dependence criterion is another criterion that has undergone some changes in DSM-5. Unlike other criteria, withdrawal symptoms are unique to the substance’s physiological action (see Table 2). Withdrawal is manifested by (1) a person experiencing the substance’s characteristic withdrawal symptoms, or (2) a person taking the same or a closely comparable substance to avoid the substance’s unique withdrawal symptoms in both DSM-IV and DSM-5. Except for cannabis, the DSM-IV and DSM-5 withdrawal criteria remain intact [136].

For that category of substances, the DSM-IV requires the endorsement of one or more symptoms (out of four, at any time) and no history of substance dependency (see Table 2 for the specific criteria) [136]. In addition, in order to meet the substance dependence criteria, three or more symptoms (out of seven) have to be confirmed in 12-month period. According to DSM-IV diagnostic hierarchy standards, people who met both substance abuse and substance dependence criteria for a particular substance were labeled as having substance dependence alone. The objective of this was to highlight the severity of dependence as compared to the abuse diagnosis [136].

The separate abuse and dependence disorders have been eliminated from DSM-5 for several reasons: (1) the separation has little guidance for treatment; (2) the separation created “diagnostic orphans” (those who endorsed two dependence symptoms but no abuse symptoms and hence did not meet any diagnostic criteria); (3) the hierarchical structure did not follow the expected relationship between abuse and dependence (that abuse was largely a less severe symptom of dependence); and (4) the division caused the abuse diagnosis to suffer from substantial reliability problems [136, 140, 142, 143].

A cluster of symptoms related to cannabis withdrawal has been uncovered in research undertaken following the release of the DSM-IV, and this new information has been included in the DSM-5 [2]. The presence of three or more symptoms occurring within one week of stopping severe and persistent cannabis use is known as cannabis withdrawal syndrome. (1) irritability, anger, or depression; (2) nervousness or anxiety; (3) sleep problems (e.g., insomnia or unpleasant/vivid dreams); (4) decreased appetite or weight loss; (5) restlessness; (6) depressed mood; and (7) at least one physical symptom that causes considerable discomfort such as abdominal pain, shakiness/tremors, sweating, fever, chills, or headache, are all possible symptoms [136].

The severity Criteria were another significant change between the two versions of diagnostic criteria. The DSM-IV did not directly measure the severity of SUDs, though dependence was generally thought to be more severe than abuse, and patients who were diagnosed with dependence did not obtain an abuse diagnosis even if the criteria for abuse were met [136]. A symptom count-based severity indicator has been added to DSM-5, with two to three symptoms classified as mild, four to five symptoms categorized as moderate, and six or more symptoms categorized as severe. A study found that a simple symptom count was as successful at evaluating severity as more advanced algorithms [144], prompting the establishment of a severity index [136].

4. Conclusion

Addiction is caused by the brain’s gradual adaptation of neuronal activity to long-term drug exposure, which results in fundamental neuroplastic changes. The extended amygdala (EAc) is a network made up of the central amygdala and the stria terminalis’ bed nucleus. This important location is in charge of controlling drug cravings and seeking behaviors [147]. Drug addiction signifies a three-stage intense dysregulation of motivational circuits due to a combination of excessive incentive salience and habit formation [148], reward deficits and excessive stress, and impaired executive function [64, 80, 126].

Changes in dopamine and opioid peptides in the basal ganglia are involved in the rewarding effects of drugs of abuse, the development of incentive salience, and the development of drug-seeking habits in the binge/intoxication stage. In the withdrawal/negative affect stage, decreases in the function of the dopamine component of the reward system, as well as recruitment of brain stress neurotransmitters like corticotropin-releasing factor and dynorphin in the neurocircuitry of the extended amygdala, lead to an increase in negative emotional states and dysphoric and stress-like responses. The dysregulation of critical afferent projections from the prefrontal cortex and insula, particularly glutamate, to the basal ganglia and extended amygdala, causes craving and executive function deficiencies in the preoccupation/anticipation stage [68].

Almost all addictive substances have the common property of increasing mesolimbic dopamine function. The mesolimbic dopamine (DA) pathway by which the DA cells in the ventral tegmental area (VTA) projecting into the nucleus accumbens (NAc) seems to be crucial for drug rewards. Most psychostimulants such as cocaine [149] amphetamine [150] narcotic analgesics [151], nicotine [152], alcohol [153], and phencyclidine [150] stimulate dopamine transmission in the nucleus accumbens [151], the main area of the ventral striatum. A couple of other dopamine pathways the mesostriatal (DA cells in substantia nigra [154] projecting into dorsal striatum) and the mesocortical (DA cells in VTA projecting into frontal cortex) are recently recognized to have a contribution to drug reward and addiction. Alcohol and other substances of abuse are fundamentally rewarding in that they are consumed by humans or self-administered by laboratory animals. As a result, individuals exposed to drugs, though small in percentage, will become addicted and move from controlled drug use to compulsive and uncontrolled drug consumption despite adverse consequences.

The three stages involving the different neurochemicals and regions of the brain are integrated and feed each other producing strong drives for substance seeking. The addiction cycle tends to intensify over time and progress to greater physical and psychological harms. People with such disorders may have distorted thinking and abnormal behaviors as a result of changes in the brain’s structure and functions. Brain imaging studies on people who frequently use psychoactive substances show marked changes in the areas of the brain that are linked to judgment, decision making, learning, memory, and behavioral control, which can last long after the period of intoxication.

Even though there are no specific biological markers of substance abuse disorders currently on use, there are a number of intriguing neurobiological aspects of substance abuse disorders that can help in the diagnosis of substance use, misuse, and SUD. An impaired reward system, overactive brain stress systems, and compromised orbitofrontal/prefrontal cortex function are some of the major neurobiological changes in the brain revealed in both human and animal studies which are quite relevant for the diagnosis of substance use, misuse, and SUD [155]. Although addictive substances have common properties, there are still considerable variabilities among classes of drugs in terms of primary and long-term physical and psychological effects, mechanisms of action, development of tolerance, and withdrawal. Differences in the availability, cost, legality, marketing, and cultural attitudes towards addictive substances and their use also influence which substances are used, and the development of dependence upon them. Thus, the study of substance use disorder and addiction must take these factors into account, while at the same time noting the similarities across drug classes.

Conflict of interest

The authors declare no conflict of interest.