A chronic neurobiological disease with genetic, social, psychological and environmental risk factors.
Addiction refers to a brain disorder characterized by compulsive engagement in rewarding stimuli despite adverse consequences.
It is a biological process induced by repeated exposure to an addictive stimulus.
Its a biopsychosocial disorder characterized by persistent use of drugs, including alcohol, despite substantial harm and adverse consequences.
Known also as substance use disorder.
Genetics and environmental risk factors each , account for roughly half of an individual’s risk for developing an addiction.
Associated with impaired ability to control drug use, compulsive drug use, and craving for additional drug exposure despite adverse consequences of such behavior.
The use of drugs alters brain circuitry involved in self-regulation and reward processing,and alters brain circuits that process mood and stress.
Addiction manifestations: impaired control over substances or behavior, preoccupation with substance or behavior, and continued use despite adverse consequences.
Addiction is characterized by immediate gratification with short-term reward, coupled with delayed deleterious long-term costs.
Stimulus-driven behavioral responses tend to dominate one’s behavior in an addiction.
Behavioral addiction refers to a compulsion to engage in a natural behavior that is inherently rewarding despite adverse consequences.
Drug and behavioral addictions include alcoholism, marijuana, amphetamine, cocaine, nicotine, opioids, food, chocolate, video games, gambling, and sexual addictions.
Long-term frequent and excessive consumption of high fat or sugar foods can produce a food addiction:chocolate.
Gambling elicits a natural reward which is associated with compulsive behavior, meeting diagnostic criteria for an addiction.
Dopamine is the primary neurotransmitter of the reward system in the brain.
Dopamine helps regulate movements, emotion, cognition, motivation, and feelings of pleasure.
Addictive drugs such as cocaine and amphetamines exert their effects primarily on the dopamine system.
Natural rewards, like eating, and recreational drug use cause a release of dopamine, that reinforce 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 result in high amounts of dopamine, which in turn affects the reward pathway directly through heightened dopamine receptor activation.
Prolonged, high levels of dopamine in the synaptic cleft can induce receptor downregulation in the neural pathway: and can result in a decrease in the sensitivity to natural rewards.
Gambling behavior to meet criteria of an addiction, shows mood modification, compulsivity, and withdrawal.
Neuroimaging studies suggest that gambling activates the reward system and the mesolimbic pathway in particular.
There is a reward cross-sensitization between amphetamine and sexual activity, meaning that exposure to one increases the desire for both, and is clinically as a dopamine dysregulation syndrome.
Certain drugs, such as cocaine, affect cholinergic neurons that innervate the reward system, in turn affecting dopamine signaling in this region.
Chronic addictive drug use causes alterations in gene expression in the mesocorticolimbic projection of the brain: most important transcription factors ΔFosB, cAMP response element binding protein (CREB), and nuclear factor kappa B (NF-κB).
ΔFosB is the most significant biomolecular mechanism in addiction.
The overexpression of ΔFosB in the medium spiny neurons in the nucleus accumbens causes neural adaptations and behavioral effects of increases in drug self-administration and reward sensitization seen in drug addiction, while decreasing sensitivity to aversion.
ΔFosB has been implicated in mediating addictions to many different drugs and drug classes, including:alcohol, amphetaminedps, cannabinoids, cocaine, methylphenidate, nicotine, opiates, phenylcyclidine, and propofol, among others.
Addiction is a disorder of the brain’s reward system.
Addiction arises through the overexpression of DeltaFosB (ΔFosB), a transcription factor, in the D1-type medium spiny neurons of the ventral striatum.
ΔFosB is an inducible gene which is increasingly expressed in the nucleus accumbens as a result of repeatedly overdosing on an addictive drug or overexposure to other addictive stimuli.
Virtually all drugs causing drug addiction increase the dopamine release in the mesolimbic pathway,
The nucleus accumbens is one output of the VTA projections.
The nucleus accumbens itself consists mainly of GABAergic medium spiny neurons.
The nucleus accumbens is associated with acquiring and eliciting conditioned behaviors, and is involved in the increased sensitivity to drugs as addiction progresses.
Hundreds of genes in the cells of the nucleus accumbens (NAc) exhibit histone modifications following drug exposure.
Drug seeking behavior is induced by glutamatergic projections from the prefrontal cortex to the nucleus accumbens.
Drug seeking behavior can be prevented following the inhibition of AMPA glutamate receptors and glutamate release in the nucleus accumbens.
DeltaFosB expression is required for this cross-sensitization effect, which intensifies with the level of deltaFosB expression.
Reward sensitization is a process that causes an increase in the amount of reward assigned by the brain to a rewarding stimulus, such as a drug
Reward sensitization to a specific stimulus, like a drug, an individual’s desire for the stimulus itself and its associated cues increases.
Cue-induced wanting is a a form of craving that occurs in addiction, that is responsible for most of the compulsive behavior that addicts exhibit.
The repeated association of neutral and non-rewarding stimuli with drug consumption triggers an associative learning process that causes these previously neutral stimuli to act as conditioned positive reinforcers of addictive drug use.
The interaction between natural and drug rewards suggests that dopaminergic psychostimulants such as amphetamines and sexual behavior act on similar biomolecular mechanisms to induce ΔFosB in the nucleus accumbens.
Reward sensitization normally occurs with chronically high levels of exposure to the stimulus.
ΔFosB (DeltaFosB) expression in D1-type medium spiny neurons in the nucleus accumbens has been shown to regulate reward sensitization involving drugs and natural rewards.
Dopaminergic psychostimulants, such as amphetamine and sexual behavior act on similar biomolecular mechanisms to induce ΔFosB in the nucleus accumbens and possess bidirectional cross-sensitization effects that are mediated through ΔFosB.
Altered dopamine neurotransmission is frequently observed in the nucleus accumbens following the development of an addictive state.
The projections from the ventral tegmental area (VTA) are a network of dopaminergic neurons that respond when stimuli indicative of a reward are present.
The VTA supports learning and sensitization development and releases dopamine into the forebrain, and release into the nucleus accumbens through the mesolimbic pathway.
The prefrontal cortex, including the anterior cingulate and orbitofrontal cortices, is another VTA output in the mesocorticolimbic pathway.
Additional brain structures involved in addiction:
The basolateral amygdala projecting into the nucleus accumbens, and relates to motivation.
The hippocampus is involved in drug addiction as manipulating cells in the hippocampus alters dopamine levels in the nucleus accumbens and firing rates of VTA dopaminergic cells.
Cross addiction is when one already has an addiction and then starts to become addicted to something different.
If one family member has a history of addiction, the chances of a relative or close family developing those same habits are much higher than one who has not been introduced to addiction at a young age.
Environmental risk factors interact with the individual’s genetic composition to increase or decrease vulnerability to addiction.
The term addiction is frequently misused to refer to other compulsive behaviors or disorders, particularly dependence.
A 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.
Addiction can occur in the absence of dependence.
Dependence can occur in the absence of addiction, although the two often occur together.
Cognitive control, and inhibitory control over behavior, is impaired in both addiction,as well as in attention deficit hyperactivity disorder.
Addicts frequently lack, fear, and avoid emotional intimacy and seek comfort and soothing elsewhere, typically from sources that do not require emotional vulnerability.
Addicts engage in their addiction as an adaptive distraction from their painfully unmet womb-to-tomb emotional dependency needs.
The lifetime prevalence of addictions to alcohol and illicit drugs has been estimated to be approximately 8% and 2–3% respectively.
The lifetime prevalence of prescription drug addictions is around 4.7%.
Addiction is a disorder of the brain’s reward system.
The reward pathway, known as the mesolimbic pathway, or its extension, the mesocorticolimbic pathway, interacts with several areas of the brain.
Signaling events in the brain’s reward center are induced by chronic high-dose exposure to psychostimulants.
Psychostimulants that increase the concentration of synaptic dopamine are amphetamine, methamphetamine, and phenethylamine.
The presynaptic dopamine and glutamate released by psychostimulants, trigger postsynaptic receptors for these neurotransmitters through a cAMP-dependent pathway and a calcium-dependent pathway that ultimately result in increased CREB phosphorylation.
CREB’s transcriptional activity decreases user’s sensitivity to the rewarding effects of the substance is in contrast to ΔFosB’s reward-sensitizing effect,
CREB transcription activity in the nucleus accumbens is implicated in psychological dependence and symptoms involving a lack of pleasure or motivation during drug withdrawal.
Phosphorylated CREB increases levels of ΔFosB.
ΔFosB represses the c-Fos gene with the help of corepressors.
c-Fos repression acts enables the accumulation of ΔFosB in the neuron.
ΔFosB stable form persists in neurons for 1–2 months, accumulating following repeated high-dose exposure to psychostimulants, as noted above.
ΔFosB functions helps control proteins that produces addiction-related structural changes in the brain.
ΔFosB accumulation, with the help of its downstream targets, such as nuclear factor kappa B, induces an addictive state.
Drugs of abuse induce gene expression of DeltaFosB in the nucleus accumbens and chronic acquisition of these rewards result in similar pathologic addictive states through DeltaFosB overexpression.
Overexpression of ΔFosB in the nucleus accumbens is a necessity common for all known forms of addiction.
ΔFosB is a strong positive modulator of positively reinforced behaviors.
ΔJunD, a transcription factor, and G9a, a histone methyltransferase, both oppose the function of ΔFosB and inhibit its expression, and can reduce, or with a large increase block, many of the neural and behavioral alterations that result from chronic high-dose use of addictive drugs mediated by ΔFosB.
Increases in nucleus accumbens ΔJunD expression or G9a expression reduces, or with a large increase can even block, many of the neural and behavioral alterations that result from chronic high-dose use of addictive drugs: alterations mediated by ΔFosB.
ΔFosB has important roles in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.
Drugs of abuse, induce gene expression of ΔFosB in the nucleus accumbens, and chronic acquisition of these rewards can result in a similar pathological addictive state through ΔFosB overexpression.
ΔFosB is the key transcription factor involved in addictions to natural rewards.
ΔFosB in the nucleus accumbens is critical for the reinforcing effects of sexual reward.
The total economic cost to society of addiction is greater than that of all types of diabetes and all cancers combined.
Costs of addiction: direct adverse effects of drugs, healthcare costs such as emergency medical services and outpatient and inpatient care, long-term complications of the addicting substance, the loss of productivity and associated welfare costs, fatal and non-fatal accidents. suicides, homicides, and incarceration.
Addiction develops through transcriptional and epigenetic mechanisms.
Substance abuse disorders occur more frequently in individuals with a comorbid mental health disorder such as depression, anxiety, ADHD, or post traumatic stress disorder.
Early aggressive behavior as a risk factor for substance use.
A majority of mental health patients participate in the abuse of substances: 38% alcohol, 44% cocaine, and 40% cigarettes.
Epigenetic genes and their protein products provide the mechanism through which environmental influences can affect the genes.
Transgenerational epigenetic inheritance is a a phenomenon in which environmental influences on the genes of a parent can affect the associated traits and behavioral phenotypes of their offspring.
Regulators of G protein signaling, particularly RGS4 and RGS9-2, have been implicated in modulating some forms of opioid sensitization, including reward sensitization.
Altered epigenetic regulation of gene expression within the brain’s reward system plays a role in the development of drug addiction.
Addictive drugs are associated with three types of epigenetic modifications within neurons:
histone modifications,
epigenetic methylation of DNA at CpG sites at particular genes,
epigenetic downregulation or upregulation of microRNAs which have particular target genes.
Epigenetic mechanisms play a role in the pathophysiology of addiction.
Some alterations to the epigenome which arise through chronic exposure to addictive stimuli during an addiction can be transmitted across generations.
Epigenome alterations affectthe behavior of one’s children: the child’s behavioral responses to addictive drugs and natural rewards.
Epigenetic alterations implicated in transgenerational epigenetic inheritance include DNA methylation, histone modifications, and downregulation or upregulation of microRNAs.
The inherited behavioral phenotypes resulting from addiction-induced epigenetic alterations and transmitted from parent to children may serve to either increase or decrease the offspring’s risk of developing an addiction.
It arises over time from chronically high levels of exposure to an addictive stimulus: food, cocaine, sexual activity, participation in high-thrill cultural activities such as gambling.
Exposure to high doses of an addictive drug for a long period of time can result in an addiction, even in individuals with a relatively low genetic risk.
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.
Tolerance is the process by which the body continually adapts to the substance and requires increasingly larger amounts to achieve the original effects.
Physical dependence occurs when the body has adjusted by incorporating the substance into its normal functioning as it attains homeostasis. and therefore physical withdrawal symptoms occur upon cessation of use.
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 body aches, anxiety, irritability, intense cravings for the substance, nausea, hallucinations, headaches, cold sweats, tremors, and seizures.
Chronic addictive drug use causes alterations in gene expression in the mesocorticolimbic projection, which arise through transcriptional and epigenetic mechanisms.
The most important transcription factors that produce these alterations in gene expression are DeltaFosB, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and nuclear factor kappa B (NFKB).
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The most important transcription factors that produce these alterations are ?FosB, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and nuclear factor kappa B (NFKB).
DeltaFosB is the most significant biomolecular mechanism in addiction.
Increases in the expression of DeltaFosB through repetitive and excessive exposure to a natural reward induces the same behavioral effects and neuroplasticity as occurs in a drug addiction.
DeltaFosB is the most significant gene transcription factor in addiction since its overexpression in the nucleus accumbens is necessary and sufficient for many of the neural adaptations and behavioral effects that are seen.
DeltaFosB is identified with compulsive sexual activity as an addiction.
The overexpression of deltaFosB in the spiny neurons in the nucleus accumbens is necessary and sufficient for many of the neural adaptations and behavioral effects, such as expression-dependent increases in drug self-administration and reward sensitization, seen in drug addiction.
((FOSB)) The DeltaFosB gene transcription factor, is common to the development of all forms of addictions (dug, behavioral).
ΔFosB expression could be used to diagnose an addiction in humans, but this would require a brain biopsy and therefore is not used in clinical practice.
DeltaFosB overexpression has been implicated in addictions to alcohol, cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others.
DeltaFosB Has important roles in regulating behavior response to natural rewards, such as palatable food, sex, and exercise.
Addiction occurs, and is associated with compulsive behavior changes with the
overexpression of DeltaFosB in the spiny neurons of the nucleus accumbens.
DeltaFosB is used as an addiction biomarker, as its expression in these neurons regulates drug self-administration and reward sensitization through positive reinforcement, while decreasing sensitivity to aversion.
Dopaminergic psychostimulants, such as amphetamine and sexual behavior act on similar biomolecular mechanisms to induce ΔFosB in the nucleus accumbens and possess bidirectional cross-sensitization effects that are mediated through ΔFosB.
A dopamine dysregulation syndrome, characterized by drug-induced compulsive engagement in natural rewards: sexual activity, shopping, and gambling, has also been observed in some individuals taking dopaminergic medications.
ΔFosB inhibitors may be an effective treatment for addiction and addictive disorders.
The nucleus accumbens release of dopamine reinforces many forms of stimuli, including naturally reinforcing stimuli like palatable food and sex.
The dysregulation of the mesolimbic pathway and its output neurons in the nucleus accumbens plays a significant role in the development and maintenance of an addiction.
Addiction from chronic drug use involves alterations in gene expression in the mesocorticolimbic projection.
Increases in nucleus accumbens DeltaJunD expression can reduce or, with a large increase, even block most of the neural alterations seen in chronic drug abuse by the alterations mediated by DeltaFosB.
ΔJunD, a transcription factor, and G9a, a histone methyltransferase, both oppose the function of ΔFosB and inhibit its expression, and can reduce, or with a large increase block, many of the neural and behavioral alterations that result from chronic high-dose use of addictive drugs mediated by ΔFosB.
Environmental factors have been implicated as risk factors for addiction, including various psychosocial stressors: lack of parental supervision, the prevalence of peer substance use, drug availability, and poverty are risk factors for substance use among children and adolescents.
Adverse childhood experiences and various forms of maltreatment and household dysfunction experienced in childhoodhas shown a strong dose–response relationship with numerous health, social, and behavioral problems throughout a person’s lifespan, including substance abuse and addiction.
Children’s neurological development can be disrupted bychronic exposure to stressful events: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.
A child’s cognitive functioning or ability to cope with negative or disruptive emotions may be impaired with chronic stress, and children may adopt substance use as a coping mechanism, particularly during adolescence.
In a study of 900 court cases involving children who experienced abuse: a vast amount of them went on to suffer from some form of addiction in their adolescence or adult life.
Exposure to an addictive drug is the most significant environmental risk factor for addiction.
Adolescence represents a period of vulnerability for developing an addiction, as the incentive-rewards systems in the brain mature well before the cognitive control center.
Adolescents are likely to act on their impulses and engage in risky, potentially addicting behavior.
Adolescents more likely to initiate and maintain drug use, and once addicted they are more resistant to treatment and more liable to relapse.
Individuals who start to drink alcohol at a younger age are more likely to become dependent later on.
Most individuals are exposed to and use addictive drugs for the first time during their teenage years.
Over 90% of those with an addiction began drinking, smoking or using illicit drugs before the age of 18.
Opioid addiction is a chronic, relaxing brain process that affects millions of Americans.
Fewer than 25% of individuals addicted to opioids receive treatment.
Incidence is increasing as are opioid overdoses and particularly those related to prescription drugs.
Behavioral transgressions of social norms make it difficult for patients to receive compassion, even from loved ones.
Opioid agonist therapy with methadone is highly effective treatment.
Buprenorphine hydrochloride is ineffective therapy to treat opioid addiction.
Opioid addiction has a greater than 70% heritable nature, according to twin studies.
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.
Stigma impedes the adequate treatment of people with substance use disorders.
TREATMENT:
Treatments for addiction are integrated with rehabilitation, cognitive behavioral therapy, individual and group psychotherapy, behavior-modification strategies, twelve-step programs, and residential treatment facilities.
Cognitive behavioral therapy, relapse prevention and contingency management, motivational interviewing, and a community reinforcement approaches are effective interventions.
Consistent aerobic exercise, especially endurance exercise prevents the development of certain drug addictions and is an effective adjunct treatment for drug addiction, and for psychostimulant addiction in particular.
Aerobic exercise magnitude by duration and intensity reduces drug addiction risk, by the the reversal of drug induced addiction-related neuroplasticity.
Exercise may prevent the development of drug addiction by altering ΔFosB 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 to those induced by addictions to several drug classes.
Consistent aerobic exercise may lead to better treatment outcomes when used as an adjunct treatment for drug addiction.
Benzodiazepines have the best evidence base in the treatment of alcohol withdrawal and are considered the gold standard of alcohol detoxification.
Pharmacological agents for alcohol addiction include drugs like naltrexone, disulfiram, acamprosate, and topiramate.
These drugs are intended to affect the desire to drink: by directly reducing cravings as with acamprosate and topiramate, or by producing unpleasant effects when alcohol is consumed, as with disulfiram.
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 addiction is a treatable with options including psychotherapy and psychopharmacotherapy or a combination of both.
Cognitive behavioral therapy (CBT) is the most common form of psychotherapy used in treating behavioral addictions.
Cognitive behavioral therapy identifies patterns that trigger compulsive behavior and encourages lifestyle changes to promote healthier behaviors.
CBT does not cure behavioral addiction.
CBT helps with coping with addiction in a healthy way.
There are no effective pharmacological interventions for cannabinoid addiction.
Drugs that act on nicotinic receptors and have been used for treating nicotine addiction include antagonists like bupropion and the partial agonist varenicline.
Physical dependence for opioids is treated using replacement drugs such as suboxone or subutex, both containing buprenorphine, and methadone.
Baclofen has led to successful reductions of cravings for stimulants, alcohol, and opioids, and also alleviates alcohol withdrawal syndrome.
There is no effective pharmacotherapy for any form of psychostimulant addiction.
Only about 10% of people addicted to alcohol, nicotine, or other drugs received any form of treatments, and those that do generally do not receive evidence-based care.
It is estimated at 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.
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.
Almost half of US adults know a family member/close friend who has a drug addiction at some point in their life.