From Wikipedia, the free encyclopedia
| Addiction and dependence glossary |
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- addiction – a brain disorder characterized by compulsive engagement in rewarding stimuli despite adverse consequences
- addictive behavior – a behavior that is both rewarding and reinforcing
- addictive drug – a drug that is both rewarding and reinforcing
- dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake)
- drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose
- drug withdrawal – symptoms that occur upon cessation of repeated drug use
- physical dependence – dependence that involves persistent physical–somatic withdrawal symptoms (e.g., fatigue and delirium tremens)
- psychological dependence – dependence that involves emotional–motivational withdrawal symptoms (e.g., dysphoria and anhedonia)
- reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them
- rewarding stimuli – stimuli that the brain interprets as intrinsically positive and desirable or as something to approach
- sensitization – an amplified response to a stimulus resulting from repeated exposure to it
- substance use disorder – a condition in which the use of substances leads to clinically and functionally significant impairment or distress
- tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose
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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 activity, participation in high-thrill
cultural activities such as gambling, etc.).
ΔFosB, 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 ΔFosB's role in addiction have
demonstrated that addiction arises, and the associated compulsive
behavior intensifies or attenuates, along with the
overexpression of ΔFosB in the
D1-type medium spiny neurons of the
nucleus accumbens. Due to the causal relationship between ΔFosB expression and addictions, it is used
preclinically as an addiction
biomarker. ΔFosB 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. In the United States, the total economic cost to society is greater than that of all types of
diabetes and all
cancers combined. These costs arise from the direct adverse effects of drugs and associated healthcare costs (e.g.,
emergency medical services and
outpatient and inpatient care),
long-term complications (e.g.,
lung cancer from smoking
tobacco products,
liver cirrhosis and
dementia from chronic
alcohol consumption, and
meth mouth from
methamphetamine use), the loss of productivity and associated
welfare costs, fatal and non-fatal
accidents (e.g.,
traffic collisions), suicides, homicides, and incarceration, among others. 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,
opioid 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. Addiction can occur in the
absence of dependence, and dependence can occur in the absence of
addiction, although the two often co-occur.
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.
Behavioral addiction
The term
behavioral addiction 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 ΔFosB 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 ΔFosB 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; ΔFosB
expression is required for this cross-sensitization effect, which intensifies with the level of ΔFosB 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 video games 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.
Risk factors
There are a number of genetic and environmental risk factors for developing an addiction that vary across the population. Genetic and environmental risk factors each account for roughly half of an individual's risk for developing an addiction; the contribution from epigenetic risk factors to the total risk is unknown.
Even in individuals with a relatively low genetic risk, exposure to
sufficiently high doses of an addictive drug for a long period of time
(e.g., weeks–months) can result in an addiction.
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 (less than 1%) confer much greater additional risk in the development of the disease.
Genome-wide association studies
(GWAS) 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.
Cross addiction is when already has a predisposed 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.
In a recent study done by the National Institute on Drug Abuse, from
2002 to 2017, overdose deaths have almost tripled amongst male and
females. In 2017, 72,306 overdose deaths happened in the U.S. that were
reported.
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 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
(NIDA) 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 individual's life and opportunities of
professional help.
If one has friends or peers who engage in drug use favorably, the
chances of them developing an addiction increases. Family conflict and
home management is also a cause for one to become engaged in drug or
alcohol use.
Age
Adolescence represents a period of unique vulnerability for developing an 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 (~7,800 new users per day); among them, 54.1% were under 18 years of age. In 2011, there were approximately 20.6 million people in the United States over the age of 12 with an addiction. Over 90% of those with an addiction began drinking, smoking or using illicit drugs before the age of 18.
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
NIDA cites early aggressive behavior as a risk factor for substance use. A study by the
National Bureau of Economic Research
found that there is a "definite connection between mental illness and
the use of addictive substances" and a majority of mental health
patients participate in the use of these substances: 38% alcohol, 44%
cocaine, and 40% cigarettes.
Epigenetic factors
Transgenerational epigenetic inheritance
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
transgenerational epigenetic inheritance, 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 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).
The general classes of epigenetic alterations that have been implicated in transgenerational epigenetic inheritance include
DNA methylation,
histone modifications, and
downregulation or upregulation of
microRNAs. With respect to addiction, more research is needed to determine the specific
heritable
epigenetic alterations that arise from various forms of addiction in
humans and the corresponding behavioral phenotypes from these epigenetic
alterations that occur in human offspring. Based upon preclinical evidence from
animal research,
certain addiction-induced epigenetic alterations in rats can be
transmitted from parent to offspring and produce behavioral phenotypes
that decrease the offspring's risk of developing an addiction.
More generally, the heritable behavioral phenotypes that are derived
from addiction-induced epigenetic alterations and transmitted from
parent to offspring may serve to either increase or decrease the
offspring's risk of developing an addiction.
Mechanisms
Chronic addictive drug use causes alterations in
gene expression in the
mesocorticolimbic projection. The most important
transcription factors that produce these alterations are
ΔFosB,
cAMP response element binding protein (
CREB), and nuclear factor kappa B (
NF-κB). ΔFosB is the most significant biomolecular mechanism in addiction because the
overexpression of ΔFosB 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. ΔFosB 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. ΔFosB has been implicated in mediating addictions to many different drugs and drug classes, including
alcohol,
amphetamine and other
substituted amphetamines,
cannabinoids,
cocaine,
methylphenidate,
nicotine,
opiates,
phenylcyclidine, and
propofol, among others.
ΔJunD, a transcription factor, and
G9a, a
histone methyltransferase, both oppose the function of ΔFosB and inhibit increases in its expression. Increases in nucleus accumbens ΔJunD 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 that result from chronic high-dose use of
addictive drugs (i.e., the alterations mediated by ΔFosB).
ΔFosB 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 ΔFosB in the nucleus accumbens, and chronic acquisition of these
rewards can result in a similar pathological addictive state through
ΔFosB overexpression.
Consequently, ΔFosB is the key transcription factor involved in
addictions to natural rewards (i.e., behavioral addictions) as well; in particular, ΔFosB 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
ΔFosB in the nucleus accumbens and possess bidirectional cross-
sensitization effects that are mediated through ΔFosB. 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.
ΔFosB 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.
Reward system
Mesocorticolimbic pathway
ΔFosB accumulation from excessive drug use
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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 ΔFosB in the nucleus accumbens is a necessary common factor in essentially all known forms of addiction; ΔFosB 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
Neural and behavioral effects of validated ΔFosB transcriptional targets in the striatum
Target
gene
|
Target
expression
|
Neural effects
|
Behavioral effects
|
| c-Fos |
↓ |
Molecular switch enabling the chronic
induction of ΔFosB |
–
|
| dynorphin |
↓ |
• Downregulation of κ-opioid feedback loop |
• Increased drug reward
|
| NF-κB |
↑ |
• Expansion of NAcc dendritic processes
• NF-κB inflammatory response in the NAcc
• NF-κB inflammatory response in the CP |
• Increased drug reward
• Increased drug reward
• Locomotor sensitization
|
| GluR2 |
↑ |
• Decreased sensitivity to glutamate |
• Increased drug reward
|
| Cdk5 |
↑ |
• GluR1 synaptic protein phosphorylation
• Expansion of NAcc dendritic processes |
Decreased drug reward
(net effect)
|
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.
ΔFosB (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. During the development of an addiction, the repeated association of otherwise neutral and even 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 (i.e., these stimuli start to function as
drug cues).
As conditioned positive reinforcers of drug use, these previously
neutral stimuli are assigned incentive salience (which manifests as a
craving) – sometimes at pathologically high levels due to
reward sensitization – which can
transfer to the primary reinforcer (e.g., the use of an addictive drug) with which it was originally paired.
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
ΔFosB in the nucleus accumbens and possess a bidirectional
reward cross-sensitization effect that is mediated through ΔFosB. In contrast to ΔFosB'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.
Neuroepigenetic mechanisms
Altered
epigenetic regulation of
gene expression within the brain’s reward system plays a significant and complex role in the development of drug addiction. Addictive drugs are associated with three types of epigenetic modifications within neurons. These are (1)
histone modifications, (2)
epigenetic methylation of DNA at
CpG sites at (or adjacent to) particular genes, and (3) epigenetic
downregulation or upregulation of
microRNAs which have particular target genes.
As an example, while hundreds of genes in the cells of the nucleus
accumbens (NAc) exhibit histone modifications following drug exposure –
particularly, altered acetylation and methylation states of
histone residues – most other genes in the NAc cells do not show such changes.
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,
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.
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.
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
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 (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
β-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 addicted individual'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 ΔFosB 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.
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.).
Australia
The prevalence of substance abuse disorder among Australians was reported at 5.1% in 2009.
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.
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.
