Addiction

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Addiction is a brain disorder characterized by compulsive engagement in rewarding stimuli despite adverse consequences. Despite the involvement of a number of psychosocial factors, a biological process - one which is induced by repeated exposure to an addictive stimulus - is the core pathology that drives the development and maintenance of an addiction. The two properties that characterize all addictive stimuli are that they are reinforcing (i.e., they increase the likelihood that a person will seek repeated exposure to them) and intrinsically rewarding (i.e., they are perceived as being inherently positive, desirable, and pleasurable).

Addiction is a disorder of the brain's reward system which arises through transcriptional and epigenetic mechanisms and occurs over time from chronically high levels of exposure to an addictive stimulus (e.g., eating food, the use of cocaine, engagement in sexual intercourse, participation in high-thrill cultural activities such as gambling, etc.). ?FosB, a gene transcription factor, is a critical component and common factor in the development of virtually all forms of behavioral and drug addictions. Two decades of research into ?FosB's role in addiction have demonstrated that addiction arises, and the associated compulsive behavior intensifies or attenuates, along with the overexpression of ?FosB in the D1-type medium spiny neurons of the nucleus accumbens. Due to the causal relationship between ?FosB expression and addictions, it is used preclinically as an addiction biomarker. ?FosB expression in these neurons directly and positively regulates drug self-administration and reward sensitization through positive reinforcement, while decreasing sensitivity to aversion.

As described by two groups of researchers, addiction exacts an "astoundingly high financial and human toll" on individuals and society as a whole through the direct adverse effects of drugs, associated healthcare costs, long-term complications (e.g., lung cancer with smoking tobacco, liver cirrhosis with drinking alcohol, or meth mouth from intravenous methamphetamine), the functional consequences of altered neural plasticity in the brain, and the consequent loss of productivity. Classic hallmarks of addiction include impaired control over substances or behavior, preoccupation with substance or behavior, and continued use despite consequences. Habits and patterns associated with addiction are typically characterized by immediate gratification (short-term reward), coupled with delayed deleterious effects (long-term costs).

Examples of drug and behavioral addictions include: alcoholism, amphetamine addiction, cocaine addiction, nicotine addiction, opiate addiction, food addiction, gambling addiction, and sexual addiction. The only behavioral addiction recognized by the DSM-5 and the ICD-10 is gambling addiction. The term addiction is misused frequently to refer to other compulsive behaviors or disorders, particularly dependence, in news media. An important distinction between drug addiction and dependence is that drug dependence is a disorder in which cessation of drug use results in an unpleasant state of withdrawal, which can lead to further drug use. Addiction is the compulsive use of a substance or performance of a behavior that is independent of withdrawal.

Video Addiction

Neuropsychology

Cognitive control and stimulus control, which is associated with operant and classical conditioning, represent opposite processes (i.e., internal vs external or environmental, respectively) that compete over the control of an individual's elicited behaviors. Cognitive control, and particularly inhibitory control over behavior, is impaired in both addiction and attention deficit hyperactivity disorder. Stimulus-driven behavioral responses (i.e., stimulus control) that are associated with a particular rewarding stimulus tend to dominate one's behavior in an addiction.

Stimulus control of behavior

Cognitive control of behavior

Maps Addiction

Behavioral addiction

The term behavioral addiction correctly refers to a compulsion to engage in a natural reward - which is a behavior that is inherently rewarding (i.e., desirable or appealing) - despite adverse consequences. Preclinical evidence has demonstrated that marked increases in the expression of ?FosB through repetitive and excessive exposure to a natural reward induces the same behavioral effects and neuroplasticity as occurs in a drug addiction.

Reviews of both clinical research in humans and preclinical studies involving ?FosB have identified compulsive sexual activity - specifically, any form of sexual intercourse - as an addiction (i.e., sexual addiction). Moreover, reward cross-sensitization between amphetamine and sexual activity, meaning that exposure to one increases the desire for both, has been shown to occur preclinically and clinically as a dopamine dysregulation syndrome; ?FosB expression is required for this cross-sensitization effect, which intensifies with the level of ?FosB expression.

Reviews of preclinical studies indicate that long-term frequent and excessive consumption of high fat or sugar foods can produce an addiction (food addiction).

Gambling is a natural reward which is associated with compulsive behavior and for which clinical diagnostic manuals, namely the DSM-5, have identified diagnostic criteria for an "addiction". There is evidence from functional neuroimaging that gambling activates the reward system and the mesolimbic pathway in particular. Similarly, shopping and playing videogames are associated with compulsive behaviors in humans and have also been shown to activate the mesolimbic pathway and other parts of the reward system. Based upon this evidence, gambling addiction, video game addiction and shopping addiction are classified accordingly.

How the 'war on drugs' entrenches patterns of drug addiction ...

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Risk factors

There are a range of genetic and environmental risk factors for developing an addiction that vary across the population. Roughly half of an individual's risk for developing an addiction is derived from genetics, while the other half is derived from the environment. However, even in individuals with a relatively low genetic loading, exposure to sufficiently high doses of an addictive drug for a long period of time (e.g., weeks-months) can result in an addiction. In other words, anyone can become an addict under the right circumstances.

Genetic factors

It has long been established that genetic factors along with environmental (e.g., psychosocial) factors are significant contributors to addiction vulnerability. Epidemiological studies estimate that genetic factors account for 40-60% of the risk factors for alcoholism. Similar rates of heritability for other types of drug addiction have been indicated by other studies. Knestler hypothesized in 1964 that a gene or group of genes might contribute to predisposition to addiction in several ways. For example, altered levels of a normal protein due to environmental factors could then change the structure or functioning of specific brain neurons during development. These altered brain neurons could change the susceptibility of an individual to an initial drug use experience. In support of this hypothesis, animal studies have shown that environmental factors such as stress can affect an animal's genotype.

Overall, the data implicating specific genes in the development of drug addiction is mixed for most genes. One reason for this may be that the case is due to a focus of current research on common variants. Many addiction studies focus on common variants with an allele frequency of greater than 5% in the general population, however when associated with disease, these only confer a small amount of additional risk with an odds ratio of 1.1-1.3 percent. On the other hand, the rare variant hypothesis states that genes with low frequencies in the population (<1%) confer much greater additional risk in the development of disease.

Genome-wide association studies (GWAS) are a recently developed research method which are used to examine genetic associations with dependence, addiction, and drug use. These studies employ an unbiased approach to finding genetic associations with specific phenotypes and give equal weight to all regions of DNA, including those with no ostensible relationship to drug metabolism or response. These studies rarely identify genes from proteins previously described via animal knockout models and candidate gene analysis. Instead, large percentages of genes involved in processes such as cell adhesion are commonly identified. This is not to say that previous findings, or the GWAS findings, are erroneous. The important effects of endophenotypes are typically not capable of being captured by these methods. Furthermore, genes identified in GWAS for drug addiction may be involved either in adjusting brain behavior prior to drug experiences, subsequent to them, or both.

A study that highlights the significant role genetics play in addiction is the twin studies. Twins have similar and sometimes identical genetics. Analyzing these genes in relation to genetics has helped geneticists understand how much of a role genes play in addiction. Studies performed on twins found that rarely did only one twin have an addiction. In most cases where at least one twin suffered from an addiction, both did, and often to the same substance.

Environmental factors

Environmental risk factors for addiction are the experiences of an individual during their lifetime that interact with the individual's genetic composition to increase or decrease the his or her vulnerability to addiction. A number of different environmental factors have been implicated as risk factors for addiction, including various psychosocial stressors; however, an individual's exposure to an addictive drug is by far the most significant environmental risk factor for addiction. The National Institute on Drug Abuse cites lack of parental supervision, the prevalence of peer substance use, drug availability, and poverty as risk factors for substance use among children and adolescents.

Adverse childhood experiences (ACEs) are various forms of maltreatment and household dysfunction experienced in childhood. The Adverse Childhood Experiences Study by the Centers for Disease Control and Prevention has shown a strong dose-response relationship between ACEs and numerous health, social, and behavioral problems throughout a person's lifespan, including those associated with substance abuse. Children's neurological development can be permanently disrupted when they are chronically exposed to stressful events such as physical, emotional, or sexual abuse, physical or emotional neglect, witnessing violence in the household, or a parent being incarcerated or suffering from a mental illness. As a result, the child's cognitive functioning or ability to cope with negative or disruptive emotions may be impaired. Over time, the child may adopt substance use as a coping mechanism, particularly during adolescence. A study of 900 court cases involving children who experienced abuse found that a vast amount of them went on to suffer from some form of addiction in their adolescence or adult life. This pathway towards addiction that is opened through stressful experiences during childhood can be avoided by a change in environmental factors throughout an individuals life and opportunities of professional help.

Age

Adolescence represents a period of unique vulnerability for developing addiction. In adolescence, the incentive-rewards systems in the brain mature well before the cognitive control center. This consequentially grants the incentive-rewards systems a disproportionate amount of power in the behavioral decision making process. Therefore, adolescents are increasingly likely to act on their impulses and engage in risky, potentially addicting behavior before considering the consequences. Not only are adolescents more likely to initiate and maintain drug use, but once addicted they are more resistant to treatment and more liable to relapse. Statistics have shown that those who start to drink alcohol at a younger age are more likely to become dependent later on. About 33% of the population tasted their first alcohol between the ages of 15 and 17, while 18% experienced it prior to this. As for alcohol abuse or dependence, the numbers start off high with those who first drank before they were 12 and then drop off after that. For example, 16% of alcoholics began drinking prior to turning 12 years old, while only 9% first touched alcohol between 15 and 17. This percentage is even lower, at 2.6%, for those who first started the habit after they were 21.

Most individuals are exposed to and use addictive drugs for the first time during their teenage years. In the United States, there were just over 2.8 million new users of illicit drugs in 2013, or about 7,800 new users per day. Over half (54.1 percent) were under 18 years of age.

Comorbid disorders

Individuals with comorbid (i.e., co-occurring) mental health disorders such as depression, anxiety, attention-deficit/hyperactivity disorder (ADHD) or post-traumatic stress disorder are more likely to develop substance use disorders. The National Institute on Drug Abuse cites early aggressive behavior as a risk factor for substance use.

Transgenerational epigenetic factors

Epigenetic genes and their products (e.g., proteins) are the key components through which environmental influences can affect the genes of an individual; they also serve as the mechanism responsible for the transgenerational epigenetic inheritance of behavioral phenotypes, a phenomenon in which environmental influences on the genes of a parent can affect the associated traits and behavioral phenotypes of their offspring (e.g., behavioral responses to certain environmental stimuli). In addiction, epigenetic mechanisms play a central role in the pathophysiology of the disease; it has been noted that some of the alterations to the epigenome which arise through chronic exposure to addictive stimuli during an addiction can be transmitted across generations, in turn affecting the behavior of one's children (e.g., the child's behavioral responses to addictive drugs and natural rewards). More research is needed to determine the specific epigenetic mechanisms and the nature of heritable behavioral phenotypes that arise from addictions in humans. Based upon preclinical evidence with lab animals, the addiction-related behavioral phenotypes that are transmitted across generations may serve to increase or decrease the child's risk of developing an addiction.

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Mechanisms

Chronic addictive drug use causes alterations in gene expression in the mesocorticolimbic projection. The most important transcription factors that produce these alterations are ?FosB, cAMP response element binding protein (CREB), and nuclear factor kappa B (NF-?B). ?FosB is the most significant biomolecular mechanism in addiction because the overexpression of ?FosB in the D1-type medium spiny neurons in the nucleus accumbens is necessary and sufficient for many of the neural adaptations and behavioral effects (e.g., expression-dependent increases in drug self-administration and reward sensitization) seen in drug addiction. ?FosB expression in nucleus accumbens D1-type medium spiny neurons directly and positively regulates drug self-administration and reward sensitization through positive reinforcement while decreasing sensitivity to aversion. Specific drug addictions in which ?FosB has been implicated in addictions to alcohol, amphetamine, cannabinoids, cocaine, methylphenidate, nicotine, phenylcyclidine, propofol, opiates, and substituted amphetamines, among others. ?JunD, a transcription factor, and G9a, a histone methyltransferase, both oppose the function of ?FosB and inhibit increases in its expression. Increases in nucleus accumbens ?JunD expression (via viral vector-mediated gene transfer) or G9a expression (via pharmacological means) reduces, or with a large increase can even block, many of the neural and behavioral alterations seen in chronic drug abuse (i.e., the alterations mediated by ?FosB).

?FosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise. Natural rewards, like drugs of abuse, induce gene expression of ?FosB in the nucleus accumbens, and chronic acquisition of these rewards can result in a similar pathological addictive state through ?FosB overexpression. Consequently, ?FosB is the key transcription factor involved in addictions to natural rewards (i.e., behavioral addictions) as well; in particular, ?FosB in the nucleus accumbens is critical for the reinforcing effects of sexual reward. Research on the interaction between natural and drug rewards suggests that dopaminergic psychostimulants (e.g., amphetamine) and sexual behavior act on similar biomolecular mechanisms to induce ?FosB in the nucleus accumbens and possess bidirectional cross-sensitization effects that are mediated through ?FosB. This phenomenon is notable since, in humans, a dopamine dysregulation syndrome, characterized by drug-induced compulsive engagement in natural rewards (specifically, sexual activity, shopping, and gambling), has also been observed in some individuals taking dopaminergic medications.

?FosB inhibitors (drugs or treatments that oppose its action) may be an effective treatment for addiction and addictive disorders.

The release of dopamine in the nucleus accumbens plays a role in the reinforcing qualities of many forms of stimuli, including naturally reinforcing stimuli like palatable food and sex. Altered dopamine neurotransmission is frequently observed following the development of an addictive state. In humans and lab animals that have developed an addiction, alterations in dopamine or opioid neurotransmission in the nucleus accumbens and other parts of the striatum are evident. Studies have found that use of certain drugs (e.g., cocaine) affect cholinergic neurons that innervate the reward system, in turn affecting dopamine signaling in this region.

Summary of addiction-related plasticity

Reward system

Mesocorticolimbic pathway

Understanding the pathways in which drugs act and how drugs can alter those pathways is key when examining the biological basis of drug addiction. The reward pathway, known as the mesolimbic pathway, or its extension, the mesocorticolimbic pathway, is characterized by the interaction of several areas of the brain.

The projections from the ventral tegmental area (VTA) are a network of dopaminergic neurons with co-localized postsynaptic glutamate receptors (AMPAR and NMDAR). These cells respond when stimuli indicative of a reward are present. The VTA supports learning and sensitization development and releases DA into the forebrain. These neurons also project and release DA into the nucleus accumbens, through the mesolimbic pathway. Virtually all drugs causing drug addiction increase the dopamine release in the mesolimbic pathway, in addition to their specific effects.
The nucleus accumbens (NAcc) is one output of the VTA projections. The nucleus accumbens itself consists mainly of GABAergic medium spiny neurons (MSNs). The NAcc is associated with acquiring and eliciting conditioned behaviors, and is involved in the increased sensitivity to drugs as addiction progresses. Overexpression of ?FosB in the nucleus accumbens is a necessary common factor in essentially all known forms of addiction; ?FosB is a strong positive modulator of positively reinforced behaviors.
The prefrontal cortex, including the anterior cingulate and orbitofrontal cortices, is another VTA output in the mesocorticolimbic pathway; it is important for the integration of information which helps determine whether a behavior will be elicited. It is also critical for forming associations between the rewarding experience of drug use and cues in the environment. Importantly, these cues are strong mediators of drug-seeking behavior and can trigger relapse even after months or years of abstinence.

Other brain structures that are involved in addiction include:

The basolateral amygdala projects into the NAcc and is thought to also be important for motivation.
The hippocampus is involved in drug addiction, because of its role in learning and memory. Much of this evidence stems from investigations showing that manipulating cells in the hippocampus alters dopamine levels in NAcc and firing rates of VTA dopaminergic cells.

Role of dopamine and glutamate

Dopamine is the primary neurotransmitter of the reward system in the brain. It plays a role in regulating movement, emotion, cognition, motivation, and feelings of pleasure. Natural rewards, like eating, as well as recreational drug use cause a release of dopamine, and are associated with the reinforcing nature of these stimuli. Nearly all addictive drugs, directly or indirectly, act upon the brain's reward system by heightening dopaminergic activity.

Excessive intake of many types of addictive drugs results in repeated release of high amounts of dopamine, which in turn affects the reward pathway directly through heightened dopamine receptor activation. Prolonged and abnormally high levels of dopamine in the synaptic cleft can induce receptor downregulation in the neural pathway. Downregulation of mesolimbic dopamine receptors can result in a decrease in the sensitivity to natural reinforcers.

Drug seeking behavior is induced by glutamatergic projections from the prefrontal cortex to the nucleus accumbens. This idea is supported with data from experiments showing that drug seeking behavior can be prevented following the inhibition of AMPA glutamate receptors and glutamate release in the nucleus accumbens.

Reward sensitization

Reward sensitization is a process that causes an increase in the amount of reward (specifically, incentive salience) that is assigned by the brain to a rewarding stimulus (e.g., a drug). In simple terms, when reward sensitization to a specific stimulus (e.g., a drug) occurs, an individual's "wanting" or desire for the stimulus itself and its associated cues increases. Reward sensitization normally occurs following chronically high levels of exposure to the stimulus. ?FosB (DeltaFosB) expression in D1-type medium spiny neurons in the nucleus accumbens has been shown to directly and positively regulate reward sensitization involving drugs and natural rewards.

"Cue-induced wanting" or "cue-triggered wanting", a form of craving that occurs in addiction, is responsible for the majority of compulsive behavior that addicts exhibit. These cues create overwhelming short-term urges to engage an addictive stimulus by acting as conditioned reinforcers for the addictive stimulus (a primary reinforcer) that are assigned pathologically high levels of incentive salience ("want").

Research on the interaction between natural and drug rewards suggests that dopaminergic psychostimulants (e.g., amphetamine) and sexual behavior act on similar biomolecular mechanisms to induce ?FosB in the nucleus accumbens and possess a bidirectional reward cross-sensitization effect that is mediated through ?FosB.

In contrast to ?FosB's reward-sensitizing effect, CREB transcriptional activity decreases user's sensitivity to the rewarding effects of the substance. CREB transcription in the nucleus accumbens is implicated in psychological dependence and symptoms involving a lack of pleasure or motivation during drug withdrawal.

The set of proteins known as "regulators of G protein signaling" (RGS), particularly RGS4 and RGS9-2, have been implicated in modulating some forms of opioid sensitization, including reward sensitization.

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Diagnosis

The 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) uses the term "Substance Use Disorder" to refer to a spectrum of use-related conditions. The DSM-5 eliminates the terms "abuse" and "dependence" from diagnostic categories, instead using the specifiers of "mild", "moderate" and "severe" to indicate the extent of disordered use. Specifiers are determined by the number of diagnostic criteria present in a given case. The manual has never actually used the term "addiction" clinically. Currently, only drug addictions and gambling addiction are listed in the DSM-5. Past editions have used physical dependence and the associated withdrawal syndrome to identify an addictive state. Physical dependence occurs when the body has adjusted by incorporating the substance into its "normal" functioning - i.e., attains homeostasis - and therefore physical withdrawal symptoms occur upon cessation of use. Tolerance is the process by which the body continually adapts to the substance and requires increasingly larger amounts to achieve the original effects. Withdrawal refers to physical and psychological symptoms experienced when reducing or discontinuing a substance that the body has become dependent on. Symptoms of withdrawal generally include but are not limited to anxiety, irritability, intense cravings for the substance, nausea, hallucinations, headaches, cold sweats, and tremors.

Medical researchers who actively study addiction have criticized the DSM classification of addiction for being flawed and involving arbitrary diagnostic criteria. Writing in 2013, the director of the United States National Institute of Mental Health discussed the invalidity of the DSM-5's classification of mental disorders:

While DSM has been described as a "Bible" for the field, it is, at best, a dictionary, creating a set of labels and defining each. The strength of each of the editions of DSM has been "reliability" - each edition has ensured that clinicians use the same terms in the same ways. The weakness is its lack of validity. Unlike our definitions of ischemic heart disease, lymphoma, or AIDS, the DSM diagnoses are based on a consensus about clusters of clinical symptoms, not any objective laboratory measure. In the rest of medicine, this would be equivalent to creating diagnostic systems based on the nature of chest pain or the quality of fever.

Most recently, though, the NIH acknowledged advances in identifying biomarkers, noting they outperform traditional phenomenological categories in identifying types of psychosis. As a diagnostic biomarker, ?FosB expression could be used to diagnose an addiction in humans, but this would require a brain biopsy and therefore isn't used in clinical practice.

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Treatment

According to a review, "in order to be effective, all pharmacological or biologically based treatments for addiction need to be integrated into other established forms of addiction rehabilitation, such as cognitive behavioral therapy, individual and group psychotherapy, behavior-modification strategies, twelve-step programs, and residential treatment facilities."

Behavioral therapy

A meta-analytic review on the efficacy of various behavioral therapies for treating drug and behavioral addictions found that cognitive behavioral therapy (e.g., relapse prevention and contingency management), motivational interviewing, and a community reinforcement approach were effective interventions with moderate effect sizes. Preclinical research using a rodent model of cue exposure therapy (CET) show that this type of treatment is more effective in adults compared to adolescents, however that adolescent outcomes can be improved by acute treatment at the time of (CET) with a dopamine 2 receptor agonist.

Clinical and preclinical evidence indicate that consistent aerobic exercise, especially endurance exercise (e.g., marathon running), actually prevents the development of certain drug addictions and is an effective adjunct treatment for drug addiction, and for psychostimulant addiction in particular. Consistent aerobic exercise magnitude-dependently (i.e., by duration and intensity) reduces drug addiction risk, which appears to occur through the reversal of drug induced addiction-related neuroplasticity. One review noted that exercise may prevent the development of drug addiction by altering ?FosB or c-Fos immunoreactivity in the striatum or other parts of the reward system. Aerobic exercise decreases drug self-administration, reduces the likelihood of relapse, and induces opposite effects on striatal dopamine receptor D₂ (DRD2) signaling (increased DRD2 density) to those induced by addictions to several drug classes (decreased DRD2 density). Consequently, consistent aerobic exercise may lead to better treatment outcomes when used as an adjunct treatment for drug addiction.

Medication

Alcohol addiction

Alcohol, like opioids, can induce a severe state of physical dependence and produce withdrawal symptoms such as delirium tremens. Because of this, treatment for alcohol addiction usually involves a combined approach dealing with dependence and addiction simultaneously.

Pharmacological treatments for alcohol addiction include drugs like naltrexone (opioid antagonist), disulfiram, acamprosate, and topiramate. Rather than substituting for alcohol, these drugs are intended to affect the desire to drink, either by directly reducing cravings as with acamprosate and topiramate, or by producing unpleasant effects when alcohol is consumed, as with disulfiram. These drugs can be effective if treatment is maintained, but compliance can be an issue as alcoholic patients often forget to take their medication, or discontinue use because of excessive side effects. According to a Cochrane Collaboration review, the opioid antagonist naltrexone has been shown to be an effective treatment for alcoholism, with the effects lasting three to twelve months after the end of treatment.

Behavioral addictions

Behavioral addiction is a treatable condition. Treatment options include psychotherapy and psychopharmacotherapy (i.e., medications) or a combination of both. Cognitive behavioral therapy (CBT) is the most common form of psychotherapy used in treating behavioral addictions; it focuses on identifying patterns that trigger compulsive behavior and making lifestyle changes to promote healthier behaviors. Currently, there are no medications approved for treatment of behavioral addictions in general, but some medications used for treatment of drug addiction may also be beneficial with specific behavioral addictions. Any unrelated psychiatric disorders should be kept under control, and differentiated from the contributing factors that cause the addiction.

Cannabinoid addiction

As of 2010, there are no effective pharmacological interventions for cannabinoid addiction. A 2013 review on cannabinoid addiction noted that the development of CB1 receptor agonists that have reduced interaction with ?-arrestin 2 signaling might be therapeutically useful.

Nicotine addiction

Another area in which drug treatment has been widely used is in the treatment of nicotine addiction, which usually involves the use of nicotine replacement therapy, nicotinic receptor antagonists, or nicotinic receptor partial agonists. Examples of drugs that act on nicotinic receptors and have been used for treating nicotine addiction include antagonists like bupropion and the partial agonist varenicline.

Opioid addiction

Opioids cause physical dependence, and treatment typically addresses both dependence and addiction.

Physical dependence is treated using replacement drugs such as suboxone or subutex (both containing the active ingredients buprenorphine) and methadone. Although these drugs perpetuate physical dependence, the goal of opiate maintenance is to provide a measure of control over both pain and cravings. Use of replacement drugs increases the patient's ability to function normally and eliminates the negative consequences of obtaining controlled substances illicitly. Once a prescribed dosage is stabilized, treatment enters maintenance or tapering phases. In the United States, opiate replacement therapy is tightly regulated in methadone clinics and under the DATA 2000 legislation. In some countries, other opioid derivatives such as levomethadyl acetate, dihydrocodeine, dihydroetorphine and even heroin are used as substitute drugs for illegal street opiates, with different prescriptions being given depending on the needs of the individual patient. Baclofen has led to successful reductions of cravings for stimulants, alcohol, and opioids, and also alleviates alcohol withdrawal syndrome. Many patients have stated they "became indifferent to alcohol" or "indifferent to cocaine" overnight after starting baclofen therapy.

Psychostimulant addiction

As of May 2014, there is no effective pharmacotherapy for any form of psychostimulant addiction. Reviews from 2015 and 2016 indicated that TAAR1-selective agonists have significant therapeutic potential as a treatment for psychostimulant addictions; however, as of February 2016, the only compounds which are known to function as TAAR1-selective agonists are experimental drugs.

Research

Research indicates that vaccines which utilize anti-drug monoclonal antibodies can mitigate drug-induced positive reinforcement by preventing the drug from moving across the blood-brain barrier; however, current vaccine-based therapies are only effective in a relatively small subset of individuals. As of November 2015, vaccine-based therapies are being tested in human clinical trials as a treatment for addiction and preventative measure against drug overdoses involving nicotine, cocaine, and methamphetamine.

Since addiction involves abnormalities in glutamate and GABAergic neurotransmission, receptors associated with these neurotransmitters (e.g., AMPA receptors, NMDA receptors, and GABAB receptors) are potential therapeutic targets for addictions. N-acetylcysteine, which affects metabotropic glutamate receptors and NMDA receptors, has shown some benefit in preclinical and clinical studies involving addictions to cocaine, heroin, and cannabinoids. It may also be useful as an adjunct therapy for addictions to amphetamine-type stimulants, but more clinical research is required.

Current medical reviews of research involving lab animals have identified a drug class - class I histone deacetylase inhibitors - that indirectly inhibits the function and further increases in the expression of accumbal ?FosB by inducing G9a expression in the nucleus accumbens after prolonged use. These reviews and subsequent preliminary evidence which used oral administration or intraperitoneal administration of the sodium salt of butyric acid or other class I HDAC inhibitors for an extended period indicate that these drugs have efficacy in reducing addictive behavior in lab animals that have developed addictions to ethanol, psychostimulants (i.e., amphetamine and cocaine), nicotine, and opiates; however, as of August 2015 no clinical trials involving human addicts and any HDAC class I inhibitors have been conducted to test for treatment efficacy in humans or identify an optimal dosing regimen.

Gene therapy for addiction is an active area of research. One line of gene therapy research involves the use of viral vectors to increase the expression of dopamine D2 receptor proteins in the brain.

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Epidemiology

Due to cultural variations, the proportion of individuals who develop a drug or behavioral addiction within a specified time period (i.e., the prevalence) varies over time, by country, and across national population demographics (e.g., by age group, socioeconomic status, etc.).

Asia

Australia

The prevalence of substance abuse disorder among Australians was reported at 5.1% in 2009.

Europe

United States

Based upon representative samples of the US youth population in 2011, the lifetime prevalence of addictions to alcohol and illicit drugs has been estimated to be approximately 8% and 2-3% respectively. Based upon representative samples of US adult population in 2011, the 12 month prevalence of alcohol and illicit drug addictions were estimated at roughly 12% and 2-3% respectively. The 12 month and lifetime prevalence of prescription drug addictions is currently unknown.

As of 2016, about 22 million Americans need treatment for an addiction to alcohol, nicotine, or other drugs. Only about 10%, or a little over 2 million, receive any form of treatments, and those that do generally do not receive evidence-based care. One-third of inpatient hospital costs and 20% of all deaths in the US every year are the result of untreated addictions and risky substance use. In spite of the massive overall economic cost to society, which is greater than the cost of diabetes and all forms of cancer combined, most doctors in the US lack the training to effectively address a drug addiction.

Another review listed estimates of lifetime prevalence rates for several behavioral addictions in the United States, including 1-2% for compulsive gambling, 5% for sexual addiction, 2.8% for food addiction, and 5-6% for compulsive shopping. A systematic review indicated that the time-invariant prevalence rate for sexual addiction and related compulsive sexual behavior (e.g., compulsive masturbation with or without pornography, compulsive cybersex, etc.) within the United States ranges from 3-6% of the population.

According to a 2017 poll conducted by the Pew Research Center, almost half of US adults know a family member or close friend who has struggled with a drug addiction at some point in their life.

South America

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Personality theories of addiction

Personality theories of addiction are psychological models that associate personality traits or modes of thinking (i.e., affective states) with an individual's proclivity for developing an addiction. Models of addiction risk that have been proposed in psychology literature include an affect dysregulation model of positive and negative psychological affects, the reinforcement sensitivity theory model of impulsiveness and behavioral inhibition, and an impulsivity model of reward sensitization and impulsiveness.