Substance dependence

From Wikipedia, the free encyclopedia
Jump to: navigation, search
"Drug addiction" and "Addictive drug" redirect here. For other uses, see Addiction (disambiguation).
Substance dependency
Classification and external resources
ICD-10 F10.2-F19.2
ICD-9 303-304
MeSH D019966

Substance dependence is an readaptive state that develops from repeated drug administration, and which results in withdrawal upon cessation of drug use.[1][2] A drug addiction, a distinct concept from substance dependence, is defined as compulsive, out-of-control drug use, despite negative consequences.[1][2] An addictive drug is a drug which is both rewarding and reinforcing.[1] ΔFosB, a gene transcription factor, is now known to be a critical component and common factor in the development of virtually all forms of behavioral addiction and drug addictions.[3][4][5]

Within the framework of the Diagnostic and Statistical Manual of Mental Disorders (DSM), substance dependence is redefined as a drug addiction, and can be diagnosed accordingly:[6]

Substance dependence can be diagnosed with physiological dependence, evidence of tolerance or withdrawal, or without physiological dependence. The DSM-IV does not use the word "addiction" at all.

Addiction glossary[7][8]
addiction – a state characterized by compulsive engagement in rewarding stimuli, despite adverse consequences
reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them
rewarding stimuli – stimuli that the brain interprets as intrinsically positive or as something to be approached
addictive drug – a drug that is both rewarding and reinforcing
addictive behavior – a behavior that is both rewarding and reinforcing
sensitization – an amplified response to a stimulus resulting from repeated exposure to it
drug tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose
drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose
drug dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated drug intake
physical dependence – dependence that involves physical–somatic withdrawal symptoms (e.g., fatigue)
psychological dependence – dependence that involves emotional–motivational withdrawal symptoms (e.g., dysphoria and anhedonia)
(edit | history)

Causes[edit]

Genetic factors[edit]

It has long been established that genetic factors along with social and psychological factors are contributors to addiction. A common theory along these lines is the self-medication hypotheses. 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.[9] 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.[9]

Overall, the data implicating specific genes in the development of drug dependence 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. 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.[10]

GWAS studies represent the newest exploration into discovering associations between 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 dependence may be involved either in adjusting brain behaviour prior to drug experiences, subsequent to them, or both. [11]

Dependence potential[edit]

The dependence potential of a drug varies from substance to substance, and from individual to individual. Dose, frequency, pharmacokinetics of a particular substance, route of administration, and time are critical factors for developing a drug dependence.

An article in The Lancet compared the harm and addiction of 20 drugs, using a scale from zero to three for physical dependence, psychological dependence, and pleasure to create a mean score for dependence. Selected results can be seen in the chart below.[12]

Drug Mean Pleasure Psychological dependence Physical dependence
Heroin 3.00 3.0 3.0 3.0
Cocaine 2.39 3.0 2.8 1.3
Tobacco 2.21 2.3 2.6 1.8
Barbiturates 2.01 2.0 2.2 1.8
Alcohol 1.93 2.3 1.9 1.6
Benzodiazepines 1.83 1.7 2.1 1.8
Amphetamine 1.67 2.0 1.9 1.1
Cannabis 1.51 1.9 1.7 0.8
Ecstasy 1.13 1.5 1.2 0.7

Capture rates[edit]

The percentage of users who reported that they had become dependent to their respective drug at some point.[13][14]

Drug Average user
Alcohol 15.4%
Cannabis 9%
Cocaine 16.7%
Heroin 23.1%
Tobacco 31.9%

Biomolecular mechanism[edit]

Main article: ΔFosB
Part of this section is transcluded from FOSB. (edit | history)

ΔFosB, a gene transcription factor, has been identified as playing a critical role in the development of addictive states in both behavioral addictions and drug addictions.[3][4][5] Overexpression of ΔFosB in the nucleus accumbens is necessary and sufficient for many of the neural adaptations seen in drug addiction;[3] it has been implicated in addictions to alcohol, cannabinoids, cocaine, nicotine, phenylcyclidine, opiates, and substituted amphetamines[3][15][16][17] as well as addictions to natural rewards such as sex, exercise, and food.[4][5] A recent study also demonstrated a cross-sensitization between drug reward (amphetamine) and a natural reward (sex) that was mediated by ΔFosB.[18]

Summary of addiction-related plasticity
Form of neural or behavioral plasticity Type of reinforcer Sources
Opiates Psychostimulants High fat or sugar food Sexual reward Exercise Environmental enrichment
ΔFosB expression
in the nucleus accumbens
[5]
Behavioral Plasticity
Escalation of intake Yes Yes Yes [5]
Psychostimulant
cross-sensitization
Yes Not applicable Yes Yes Attenuated Attenuated [5]
Psychostimulant
self-administration
[5]
Psychostimulant
conditioned place preference
[5]
Reinstatement of drug-seeking behavior [5]
Neurochemical Plasticity
CREB phosphorylation
in the nucleus accumbens
[5]
Sensitized dopamine response
in the nucleus accumbens
No Yes No Yes [5]
Altered striatal dopamine signaling DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD2 DRD2 [5]
Altered striatal opioid signaling μ-opioid receptors μ-opioid receptors
κ-opioid receptors
μ-opioid receptors μ-opioid receptors No change No change [5]
Changes in striatal opioid peptides dynorphin dynorphin enkephalin dynorphin dynorphin [5]
Mesocorticolimbic Synaptic Plasticity
Number of dendrites in the nucleus accumbens [5]
Dendritic spine density in
the nucleus accumbens
No change [5]

Acute effects[edit]

Different types of drugs produce these effects by different methods. Dopamine (DA) is known to play an important role. Dopamine binds to the D1 receptor, a postsynaptic dopamine receptor (as opposed to D2sh, which is presynaptic), triggering a signaling cascade within the cell. cAMP-dependent protein kinase (PKA) phosphorylates cAMP response element binding protein (CREB), a transcription factor, which induces the transcription of certain genes including C-Fos.[19]

Mesocorticolimbic pathway[edit]

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 ventral tegmental area (VTA) consists of dopaminergic neurons which respond to glutamate. These cells respond when stimuli indicative of a reward are present. The VTA supports learning and sensitization development and releases DA into the forebrain.[20] These neurons also project and release DA into the nucleus accumbens,[21] through the mesolimbic pathway. Virtually all drugs causing drug addiction increase the dopamine release in the mesolimbic pathway,[22] in addition to their specific effects.
  • The nucleus accumbens (NAcc) consists mainly of MSNs, which are GABA neurons.[23] The NAcc is associated with acquiring and eliciting conditioned behaviors, and is involved in the increased sensitivity to drugs as addiction progresses.[20]
  • The prefrontal cortex, more specifically the anterior cingulate and orbitofrontal cortices,[19] is important for the integration of information which contributes to whether a behavior will be elicited. It appears to be the area in which motivation originates and the salience of stimuli are determined.[24]
  • The basolateral amygdala projects into the NAcc and is thought to also be important for motivation.[24]
  • More evidence is pointing towards the role of the hippocampus in drug addiction, because of its importance 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.[21]

Role of dopamine[edit]

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.[25] Natural rewards, like eating, as well as recreational drug use cause a release of DA, and are associated with the reinforcing nature of these stimuli.[25][26] Nearly all addictive drugs, directly or indirectly, act upon the brain’s reward system by heightening dopaminergic activity.[27]

Excessive intake of many types of addictive drugs results in repeated release of high amounts of DA, which in turn affects the reward pathway directly through heightened dopamine receptor activation. Prolonged and abnormally high levels of DA in the synaptic cleft can induce receptor downregulation in along the neural pathway. Downregulation of mesocorticolimbic DA receptors can result in a decrease in the sensitivity to natural reinforcers.[25]

Stress response[edit]

See also: Stress response

In addition to the reward pathway, it is hypothesized that stress mechanisms play a role in addiction. Boob and Kreek have hypothesized that during drug use, the corticotropin-releasing factor (CRF) activates the hypothalamic-pituitary-adrenal axis (HPA) and other stress systems in the extended amygdala. This activation influences the dysregulated emotional state associated with drug addiction. They have found that as drug use escalates, so does the presence of CRF in human cerebrospinal fluid (CSF). In rat models, the separate use of CRF antagonists and CRF receptor antagonists both decreased self-administration of the drug of study. Other studies in this review showed a dysregulation in other hormones associated with the HPA axis, including enkephalin which is an endogenous opioid peptide that regulates pain. It also appears that the µ-opioid receptor system, which enkephalin acts on, is influential in the reward system and can regulate the expression of stress hormones.[28]

Behavior[edit]

Understanding how learning and behavior work in the mesolimbic pathway can help understand the action of addictive drugs. Drug addiction is characterized by strong, drug seeking behaviors in which the addict persistently craves and seeks out drugs, despite the knowledge of harmful consequences.[19][28] Addictive drugs produce a reward, which is the euphoric feeling resulting from sustained DA concentrations in the synaptic cleft of neurons in the brain. Operant conditioning is exhibited in drug addicts as well as laboratory mice, rats, and primates; they are able to associate an action or behavior, in this case seeking out the drug, with a reward, which is the effect of the drug.[20] Evidence shows that this behavior is most likely a result of the synaptic changes which have occurred due to repeated drug exposure.[19][20][28] The drug seeking behavior is induced by glutamatergic projections from the prefrontal cortex to the NAc. 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 NAc.[19]


According to authors Trezza, Barrendse, and Vanderschuren (2014) [29] , studies have shown that antisocial personality disorder is highly caused by drug and alcohol addiction (p. 1720). Adults who were diagnosed with antisocial personality disorder started their addiction to drugs or alcohol at an early age (p.1720).

Psychological drug tolerance[edit]

The reward system is partly responsible for the psychological part of drug tolerance.

The CREB protein, a transcription factor activated by cyclic adenosine monophosphate (cAMP) immediately after a high, triggers genes that produce proteins such as dynorphin, which cuts off DA release and temporarily inhibits the reward pathway. In chronic drug users, a sustained activation of CREB thus forces a larger dose to be taken to reach the same effect. In addition, it leaves the user feeling generally depressed and dissatisfied, and unable to find pleasure in previously enjoyable activities, often leading to a return to the drug for another dose.[30]

A similar mechanism, interfering also with the DA system, but relying on a different transcription factor, CEBPB, has also been proposed. In this case, DA release onto the nucleus accumbens neurons would trigger the increased synthesis of substance P which, in turn, would increase the DA synthesis in the VTA. The effect of this positive feedback is suggested to be dampened by repeated substance abuse.[31]

Sensitization[edit]

Sensitization, or reverse tolerance, is the increase in sensitivity to a drug after repeated use. The protein ΔFosB (Delta-FosB) is known to be involved in drug and behavioral sensitization. The regulator of G-protein signaling 9-2 (RGS9-2) is also thought to be involved.

The ΔFosB transcription factor is activating genes that, counter to the effects of CREB, actually increase the user's sensitivity to the effects of the substance. A stable form of ΔFosB slowly builds up with each exposure to the drug and remains activated for 1–2 months after the last exposure—long after the effects of CREB have faded. The hypersensitivity that it causes is thought to be responsible for the intense cravings associated with drug addiction, and is often extended to even the peripheral cues of drug use, such as related behaviors or the sight of drug paraphernalia. There is also very significant evidence that ΔFosB causes behavioral plasticity and structural changes within the nucleus accumbens, which helps to perpetuate cravings and relapses in addicts.[32][33][34][35][36][37][38][39][40][41][42][43][44]

Regulator of G-protein Signaling 9-2 (RGS9-2) has recently been the subject of several animal knockout studies. Animals lacking RGS9-2 appear to have increased sensitivity to dopamine receptor agonists such as cocaine and amphetamines; over-expression of RGS9-2 causes a lack of responsiveness to these same agonists. RGS9-2 is believed to catalyze inactivation of the G-protein coupled D2 receptor by enhancing the rate of GTP hydrolysis of the G alpha subunit which transmits signals into the interior of the cell.[45][46][47][48][49][50][51][52]

Management[edit]

Addiction is a complex but treatable disease. It is characterized by compulsive drug craving, seeking, and use that persists even if the user is aware of severe adverse consequences. For some people, addiction becomes chronic, with periodic relapses even after long periods of abstinence. As a chronic, relapsing disease, addiction may require continued treatments to increase the intervals between relapses and diminish their intensity. While some with substance issues recover and lead fulfilling lives, others require ongoing additional support. The ultimate goal of addiction treatment is to enable an individual to manage their substance misuse; for some this may mean abstinence. Immediate goals are often to reduce substance abuse, improve the patient's ability to function, and minimize the medical and social complications of substance abuse and their addiction; this is called "harm reduction".

Treatments for addiction vary widely according to the types of drugs involved, amount of drugs used, duration of the drug addiction, medical complications and the social needs of the individual. Determining the best type of recovery program for an addicted person depends on a number of factors, including: personality, drugs of choice, concept of spirituality or religion, mental or physical illness, and local availability and affordability of programs.

Many different ideas circulate regarding what is considered a successful outcome in the recovery from addiction. Programs that emphasize controlled drinking exist for alcohol addiction. Opiate replacement therapy has been a medical standard of treatment for opioid addiction for many years.

Treatments and attitudes toward addiction vary widely among different countries. In the US and developing countries, the goal of commissioners of treatment for drug dependence is generally total abstinence from all drugs. Other countries, particularly in Europe, argue the aims of treatment for drug dependence are more complex, with treatment aims including reduction in use to the point that drug use no longer interferes with normal activities such as work and family commitments; shifting the addict away from more dangerous routes of drug administration such as injecting to safer routes such as oral administration; reduction in crime committed by drug addicts; and treatment of other comorbid conditions such as AIDS, hepatitis and mental health disorders. These kinds of outcomes can be achieved without eliminating drug use completely. Drug treatment programs in Europe often report more favorable outcomes than those in the US because the criteria for measuring success are functional rather than abstinence-based.[53][54][55] The supporters of programs with total abstinence from drugs as a goal believe that enabling further drug use means prolonged drug use and risks an increase in addiction and complications from addiction.[56]

Residential[edit]

Residential drug treatment can be broadly divided into two camps: 12-step programs and therapeutic communities. Twelve-step programs have the advantage of coming with an instant social support network, though some find the spiritual context not to their taste. In the UK, drug treatment is generally moving towards a more integrated approach with rehabs offering a variety of approaches. These other programs may use a cognitive-behavioral therapy approach, such as SMART recovery, that looks at the relationship between thoughts, feelings and behaviors, recognizing that a change in any of these areas can affect the whole. Cognitive-behavioral therapy treats addiction as a behavior rather than a disease, and so is subsequently curable, or rather, unlearnable. Cognitive-behavioral therapy programs recognize that, for some individuals, controlled use is a more realistic possibility.[57]

One of many recovery methods are 12-step recovery programs, with prominent examples including Alcoholics Anonymous, Narcotics Anonymous, Drug Addicts Anonymous[58] and Pills Anonymous. They are commonly known and used for a variety of addictions for the individual addicted and the family of the individual. Substance-abuse rehabilitation (rehab) centers offer a residential treatment program for some of the more seriously addicted, in order to isolate the patient from drugs and interactions with other users and dealers. Outpatient clinics usually offer a combination of individual counseling and group counseling. Frequently, a physician or psychiatrist will prescribe medications in order to help patients cope with the side effects of their addiction. Medications can help immensely with anxiety and insomnia, can treat underlying mental disorders (cf. self-medication hypothesis, Khantzian 1997) such as depression, and can help reduce or eliminate withdrawal symptomology when withdrawing from physiologically addictive drugs. Some examples are using benzodiazepines for alcohol detoxification, which prevents delirium tremens and complications; using a slow taper of benzodiazepines or a taper of phenobarbital, sometimes including another antiepileptic agent such as gabapentin, pregabalin, or valproate, for withdrawal from barbiturates or benzodiazepines; using drugs such as baclofen to reduce cravings and propensity for relapse amongst addicts to any drug, especially effective in stimulant users, and alcoholics (in which it is nearly as effective as benzodiazepines in preventing complications); using clonidine, an alpha-agonist, and loperamide for opioid detoxification, for first-time users or those who wish to attempt an abstinence-based recovery (90% of opioid users relapse to active addiction within eight months or are multiple relapse patients); or replacing an opioid that is interfering with or destructive to a user's life, such as illicitly-obtained heroin, dilaudid, or oxycodone, with an opioid that can be administered legally, reduces or eliminates drug cravings, and does not produce a high, such as methadone or buprenorphineopioid replacement therapy – which is the gold standard for treatment of opioid dependence in developed countries, reducing the risk and cost to both user and society more effectively than any other treatment modality (for opioid dependence), and shows the best short-term and long-term gains for the user, with the greatest longevity, least risk of fatality, greatest quality of life, and lowest risk of relapse and legal issues including arrest and incarceration.

In a survey of treatment providers from three separate institutions (the National Association of Alcoholism and Drug Abuse Counselors, Rational Recovery Systems and the Society of Psychologists in Addictive Behaviors) measuring the treatment provider's responses on the "Spiritual Belief Scale" (a scale measuring belief in the four spiritual characteristics of AA identified by Ernest Kurtz); the scores were found to explain 41% of the variance in the treatment provider's responses on the "Addiction Belief Scale" (a scale measuring adherence to the disease model or the free-will model of addiction).[59]

Anti-addictive drugs[edit]

Other forms of treatment include replacement drugs such as suboxone or subutex (both containing the active ingredient buprenorphine) and methadone; these are used as substitutes for illicit opiate drugs.[60][61] Although these drugs perpetuate physical dependence, the goal of opiate maintenance is to provide a clinically supervised, stable dose of a particular opioid in order to provide a measure of control to both pain and cravings. This provides a chance for the addict to function normally and to reduce the negative consequences associated with obtaining sufficient quantities of controlled substances illicitly, by both reducing opioid cravings and withdrawal symptomology. 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,[62] dihydrocodeine,[63] dihydroetorphine[64] and even heroin[65][66] are used as substitute drugs for illegal street opiates, with different drugs being used depending on the needs of the individual patient. Baclofen has been shown successful in attenuating cravings for most drugs of abuse – stimulants, ethanol, and opioids – and also attenuates the actual withdrawal syndrome of ethanol. Many patients have stated they "became indifferent to alcohol" or "indifferent to cocaine" overnight after starting baclofen therapy.[67] It is possible that one of the best, albeit relatively unexplored, treatment modalities for opioid addiction – notoriously the most difficult addiction to treat (and to recover from), having relapse rates of around 23% at four weeks and 57% at twelve months if not on maintenance therapy with a mu-opioid agonist[67] – would be to combine an opioid maintenance agent, such as methadone or buprenorphine, to block withdrawal symptomology, with baclofen, to attenuate cravings and the desire to use, in people who find that they are still using or still craving drugs while on methadone or buprenorphine maintenance.

Substitute drugs for other forms of drug dependence have historically been less successful than opioid substitute treatment, but some limited success has been seen with drugs such as dextroamphetamine to treat stimulant addiction,[68][69] and clomethiazole to treat alcohol addiction.[70] Bromocriptine and desipramine have been reported to be effective for treatment of cocaine but not amphetamine addiction.[71]

Other pharmacological treatments for alcohol addiction include drugs like naltrexone, disulfiram, acamprosate and topiramate,[72][73] but rather than substituting for alcohol, these drugs are intended to reduce 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.[74][75] Additional drugs acting on glutamate neurotransmission such as modafinil, lamotrigine, gabapentin and memantine have also been proposed for use in treating addiction to alcohol and other drugs.[76]

Opioid antagonists such as naltrexone and nalmefene have also been used successfully in the treatment of alcohol addiction,[77][78] which is often particularly challenging to treat. Some have also attempted to use these drugs for maintenance treatment of former opiate addicts with little success. They cannot be started until the patient has been abstinent for an extended period – unlikely with opioid addicts who are not on maintenance with a full or partial mu-opioid agonist – or they will trigger acute opioid withdrawal symptoms. No study has found them to be efficacious treatments in preventing relapse. They do nothing to block craving, and block endorphin and enkephalin, two natural neurotransmitters that regulate one's sense of well-being. An addict must discontinue the drug for just eighteen hours in order to use again.[79]

Treatment of stimulant addiction can often be difficult, with substitute drugs often being ineffective, although newer drugs such as nocaine, vanoxerine and modafinil may have more promise in this area, as well as the GABAB agonist baclofen.[80][81] Another strategy that has recently been successfully trialled used a combination of the benzodiazepine antagonist flumazenil with hydroxyzine and gabapentin for the treatment of methamphetamine addiction.[82]

Another area in which drug treatment has been widely used is in the treatment of nicotine addiction. Various drugs have been used for this purpose such as bupropion, mecamylamine and the more recently developed varenicline. The cannaboinoid antagonist rimonabant has also been trialled for treatment of nicotine addiction but has not been widely adopted for this purpose.[83][84][85]

Ibogaine is a hallucinogen (psychotomimetic) that some claim interrupts addiction and reduces or eliminates withdrawal syndromes, specifically in regards to opioids.[86] Its mechanism of action is unknown, but likely linked to nAchR α3ß4 antagonism. In one animal trial, it was shown to slightly reduce self-administration of cocaine.[87] Another uncontrolled trial showed it reduced tremor by a mild to moderate degree during morphine withdrawal in rats.[88] These finding can not be extrapolated to human beings with any certainty. Research is complicated by the fact that ibogaine is illegal in many developed countries, and a Schedule I substance in the US, and as a result no controlled human trials have ever been performed. A semi-synthetic analogue of ibogaine, 18-methoxycoronaridine was developed, in an attempt to reduce the toxic (ibogaine is significantly cardiotoxic, and several deaths have been reported from its use; because of its illegal, underground nature, it is impossible to know how toxic the drug is) and psychotomimetic effects of the drug.

Behavioral programming[edit]

Behavioral programming is considered critical in helping those with addictions achieve abstinence. From the applied behavior analysis literature and the behavioral psychology literature, several evidence based intervention programs have emerged: (1) behavioral marital therapy; (2) community reinforcement approach; (3) cue exposure therapy; and (4) contingency management strategies.[89][90] In addition, the same author suggest that Social skills training adjunctive to inpatient treatment of alcohol dependence is probably efficacious. Community reinforcement has both efficacy and effectiveness data.[91] In addition, behavioral treatment such as community reinforcement and family training (CRAFT) have helped family members to get their loved ones into treatment.[92][93] Motivational Intervention has also shown to be an effective treatment for substance dependence.

Alternative therapies[edit]

Alternative therapies, such as acupuncture, are used by some practitioners to alleviate the symptoms of drug addiction. In 1997, the American Medical Association (AMA) adopted as policy the following statement after a report on a number of alternative therapies including acupuncture:

There is little evidence to confirm the safety or efficacy of most alternative therapies. Much of the information currently known about these therapies makes it clear that many have not been shown to be efficacious. Well-designed, stringently controlled research should be done to evaluate the efficacy of alternative therapies.[94]

Acupuncture has been shown to be no more effective than control treatments in the treatment of opiate dependence.[95] Acupuncture, acupressure, laser therapy and electrostimulation[disambiguation needed] have no demonstrated efficacy for smoking cessation.[96]

Important phases in treating substance dependence include establishing coping mechanisms to deal with the hardships of withdrawal symptoms. With the correct approaches, the patient can live a healthier life.[97]

Online websites have been a resource to aid in helping people to overcome addictions. These websites act as ways for struggling addicts, family members of addicts, and people who are in the recovery stage to confide in each other (anonymously if they so choose). They provide an alternative way for these people to seek help, support and information. Sites typically include chat rooms, forums, and blogs for members to interact.[citation needed]


History[edit]

The phenomenon of drug addiction has occurred to some degree throughout recorded history (see "Opium").[98] Modern agricultural practices, improvements in access to drugs, advancements in biochemistry, and dramatic increases in the recommendation of drug usage by clinical practitioners have exacerbated the problem significantly in the 20th century. Improved means of active biological agent manufacture and the introduction of synthetic compounds, such as methamphetamine, are also factors contributing to drug addiction.[99][100]

For the entirety of US history, drugs have been used by some members of the population. In the country's early years, most drug use by the settlers was of alcohol or tobacco.[101]

The nineteenth century saw opium usage in the US become much more common and popular. Morphine was isolated in the early nineteenth century, and came to be prescribed commonly by doctors, both as a painkiller and as an intended cure for opium addiction. At the time, the prevailing medical opinion was that the addiction process occurred in the stomach, and thus it was hypothesized that patients would not become addicted to morphine if it was injected into them via a hypodermic needle, and it was further hypothesized that this might potentially be able to cure opium addiction. However, many people did become addicted to morphine. In particular, addiction to opium became widespread among soldiers fighting in the Civil War, who very often required painkillers and thus were very often prescribed morphine. Women were also very frequently prescribed opiates, and opiates were advertised as being able to relieve "female troubles".[101]

During the 1960s, the hippie movement came into being and became a huge influence on US culture. This movement was marked by–among other things–desire for self-discovery, desire for and self-improvement, and desire for a connection to something greater. One of the key ways in which much of the movement sought to satisfy these desires was through experimenting with LSD, which was a legal substance at the time. Laws were later enacted that made LSD illegal, thus making it such that a substantial portion of a large movement were now consuming illicit substances, whereas otherwise most of them were law-abiding citizens. During the same time period, the Vietnam War was underway and creating a lot of mistrust between the US government and its citizens, resulting in some people having a desire to rebel and live outside the laws of their country. Many soldiers in the Vietnam War were introduced to heroin and many developed a dependency to the substance which survived even when they returned to the US. Technological advances in travel meant that this increased demand for heroin in the US could now be met. Furthermore, as technology advanced, more drugs were synthesized and discovered, opening up new avenues to substance dependency.[101]

Society and culture[edit]

Legislation[edit]

Depending on the jurisdiction, addictive drugs may be legal, legal only as part of a government sponsored study, illegal to use for any purpose, illegal to sell, or even illegal to merely possess.

Most countries have legislation which brings various drugs and drug-like substances under the control of licensing systems. Typically this legislation covers any or all of the opiates, amphetamines, cannabinoids, cocaine, barbiturates, benzodiazepines, anesthetics, hallucinogenics, derivatives and a variety of more modern synthetic drugs. Unlicensed production, supply or possession is a criminal offence.

Usually, however, drug classification under such legislation is not related simply to addictiveness. The substances covered often have very different addictive properties. Some are highly prone to cause physical dependency, while others rarely cause any form of compulsive need whatsoever. Also, under legislation specifically about drugs, alcohol and nicotine are not usually included.

Although the legislation may be justifiable on moral or public health grounds, it can make addiction or dependency a much more serious issue for the individual: reliable supplies of a drug become difficult to secure, and the individual becomes vulnerable to both criminal abuse and legal punishment.

It is unclear whether laws against illegal drug use do anything to stem usage and dependency. In jurisdictions where addictive drugs are illegal, they are generally supplied by drug dealers, who are often involved with organized crime. Even though the cost of producing most illegal addictive substances is very low, their illegality combined with the addict's need permits the seller to command a premium price, often hundreds of times the production cost. As a result, addicts sometimes turn to crime to support their habit.

See also[edit]

Questionnaires

References[edit]

  1. ^ a b c Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 364–368. ISBN 9780071481274. The defining feature of addiction is compulsive, out-of-control drug use, despite negative consequences. ... Addictive drugs are both rewarding and reinforcing. ... Familiar pharmacologic terms such as tolerance, dependence, and sensitization are useful in describing some of the time-dependent processes that underlie addiction. ...
    Dependence is defined as an adaptive state that develops in response to repeated drug administration, and is unmasked during withdrawal, which occurs when drug taking stops. Dependence from long-term drug use may have both a somatic component, manifested by physical symptoms, and an emotional–motivation component, manifested by dysphoria. While physical dependence and withdrawal occur with some drugs of abuse (opiates, ethanol), these phenomena are not useful in the diagnosis of addiction because they do not occur with other drugs of abuse (cocaine, amphetamine) and can occur with many drugs that are not abused (propranolol, clonidine). The official diagnosis of drug addiction by the Diagnostic and Statistic Manual of Mental Disorders (2000), which makes distinctions between drug use, abuse, and substance dependence, is flawed. First, diagnosis of drug use versus abuse can be arbitrary and reflect cultural norms, not medical phenomena. Second, the term substance dependence implies that dependence is the primary pharmacologic phenomenon underlying addiction, which is likely not true, as tolerance, sensitization, and learning and memory also play central roles. It is ironic and unfornate that the Manual avoids use of the term addiction, which provides the best description of the clinical syndrome.
     
  2. ^ a b "Substance use disorder". Pubmed Health. National Institutes of Health. Retrieved 12 September 2014. Drug dependence means that a person needs a drug to function normally. Abruptly stopping the drug leads to withdrawal symptoms. Drug addiction is the compulsive use of a substance, despite its negative or dangerous effects 
  3. ^ a b c d Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–637. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. 
  4. ^ a b c Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, Oscar-Berman M, Gold M (2012). "Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms". J. Psychoactive Drugs 44 (1): 38–55. doi:10.1080/02791072.2012.662112. PMC 4040958. PMID 22641964. It has been found that deltaFosB gene in the NAc is critical for reinforcing effects of sexual reward. Pitchers and colleagues (2010) reported that sexual experience was shown to cause DeltaFosB accumulation in several limbic brain regions including the NAc, medial pre-frontal cortex, VTA, caudate, and putamen, but not the medial preoptic nucleus. Next, the induction of c-Fos, a downstream (repressed) target of DeltaFosB, was measured in sexually experienced and naive animals. The number of mating-induced c-Fos-IR cells was significantly decreased in sexually experienced animals compared to sexually naive controls. Finally, DeltaFosB levels and its activity in the NAc were manipulated using viral-mediated gene transfer to study its potential role in mediating sexual experience and experience-induced facilitation of sexual performance. Animals with DeltaFosB overexpression displayed enhanced facilitation of sexual performance with sexual experience relative to controls. In contrast, the expression of DeltaJunD, a dominant-negative binding partner of DeltaFosB, attenuated sexual experience-induced facilitation of sexual performance, and stunted long-term maintenance of facilitation compared to DeltaFosB overexpressing group. Together, these findings support a critical role for DeltaFosB expression in the NAc in the reinforcing effects of sexual behavior and sexual experience-induced facilitation of sexual performance. ... both drug addiction and sexual addiction represent pathological forms of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical changes mainly in the brain's rewarding circuitry. 
  5. ^ a b c d e f g h i j k l m n o p Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. 
  6. ^

    When an individual persists in use of alcohol or other drugs despite problems related to use of the substance, substance dependence may be diagnosed. Compulsive and repetitive use may result in tolerance to the effect of the drug and withdrawal symptoms when use is reduced or stopped. This, along with substance abuse are considered substance use disorders....DSM-IV & DSM-IV-TR:Substance Dependence

  7. ^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 364–375. ISBN 9780071481274. 
  8. ^ Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues Clin Neurosci 15 (4): 431–443. PMC 3898681. PMID 24459410. DESPITE THE IMPORTANCE OF NUMEROUS PSYCHOSOCIAL FACTORS, AT ITS CORE, DRUG ADDICTION INVOLVES A BIOLOGICAL PROCESS: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type NAc neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement 
  9. ^ a b Kendler KS, Neale MC, Heath AC, Kessler RC, Eaves LJ (May 1994). "A twin-family study of alcoholism in women". Am J Psychiatry 151 (5): 707–15. PMID 8166312. 
  10. ^ Clarke, Toni-Kim; Crist, Richard C.; Kampman, Kyle M.; Dackis, Charles A.; Pettinati, Helen M.; O’Brien, Charles P.; Oslin, David W.; Ferraro, Thomas N.; Lohoff, Falk W.; Berrettini, Wade H. (May 2013). "Low frequency genetic variants in the μ-opioid receptor (OPRM1) affect risk for addiction to heroin and cocaine". Neuroscience Letters 542: 71–75. doi:10.1016/j.neulet.2013.02.018. 
  11. ^ Hall, F. Scott; Drgonova, Jana; Jain, Siddharth; Uhl, George R. (December 2013). "Implications of genome wide association studies for addiction: Are our a priori assumptions all wrong?". Pharmacology & Therapeutics 140 (3): 267–279. doi:10.1016/j.pharmthera.2013.07.006. 
  12. ^ Nutt King, Saulsbury , Blakemore (2007). "Development of a rational scale to assess the harm of drugs of potential misuse". Lancet 369 (9566): 1047–53. doi:10.1016/S0140-6736(07)60464-4. PMID 17382831. 
  13. ^ "Marijuana Drug Facts". National Institute on Drug Abuse. January 2014. Retrieved 18 April 2014. 
  14. ^ "Dangerousness of Drugs A Guide To The Risks And Harms Associated With Substance Misuse". National Addiction Center. Retrieved 6 May 2014. 
  15. ^ Hyman SE, Malenka RC, Nestler EJ (2006). "Neural mechanisms of addiction: the role of reward-related learning and memory". Annu. Rev. Neurosci. 29: 565–598. doi:10.1146/annurev.neuro.29.051605.113009. PMID 16776597. 
  16. ^ Steiner H, Van Waes V (January 2013). "Addiction-related gene regulation: risks of exposure to cognitive enhancers vs. other psychostimulants". Prog. Neurobiol. 100: 60–80. doi:10.1016/j.pneurobio.2012.10.001. PMC 3525776. PMID 23085425. 
  17. ^ Kanehisa Laboratories (2 August 2013). "Alcoholism – Homo sapiens (human)". KEGG Pathway. Retrieved 10 April 2014. 
  18. ^ Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM (February 2013). "Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator". J. Neurosci. 33 (8): 3434–42. doi:10.1523/JNEUROSCI.4881-12.2013. PMC 3865508. PMID 23426671. Together, these findings demonstrate that drugs of abuse and natural reward behaviors act on common molecular and cellular mechanisms of plasticity that control vulnerability to drug addiction, and that this increased vulnerability is mediated by ΔFosB and its downstream transcriptional targets. 
  19. ^ a b c d e Kalivas PW, Volkow ND (2005). "The neural basis of addiction: a pathology of motivation and choice". Am J Psychiatry 162 (8): 1403–13. doi:10.1176/appi.ajp.162.8.1403. PMID 16055761. 
  20. ^ a b c d Jones S, Bonci A (2005). "Synaptic plasticity and drug addiction". Current Opinion in Pharmacology 5 (1): 20–5. doi:10.1016/j.coph.2004.08.011. PMID 15661621. 
  21. ^ a b Eisch AJ, Harburg GC (2006). "Opiates, psychostimulants, and adult hippocampal neurogenesis: Insights for addiction and stem cell biology". Hippocampus 16 (3): 271–86. doi:10.1002/hipo.20161. PMID 16411230. 
  22. ^ Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. p. 596. ISBN 0-443-07145-4. 
  23. ^ Kourrich S, Rothwell PE, Klug JR, Thomas MJ (2007). "Cocaine experience controls bidirectional synaptic plasticity in the nucleus accumbens". J. Neurosci. 27 (30): 7921–8. doi:10.1523/JNEUROSCI.1859-07.2007. PMID 17652583. 
  24. ^ a b Floresco SB, Ghods-Sharifi S (2007). "Amygdala-prefrontal cortical circuitry regulates effort-based decision making". Cereb. Cortex 17 (2): 251–60. doi:10.1093/cercor/bhj143. PMID 16495432. 
  25. ^ a b c "Dopamine in Drug Abuse and Addiction: Results of Imaging Studies and Treatment Implications". 
  26. ^ "Drugs, Brains, and Behavior: The Science of Addiction". 
  27. ^ "Understanding Drug Abuse and Addiction". 
  28. ^ a b c Boob G, Kreek MJ (2007). "Stress, Dysregulation of Drug Reward Pathways, and the Transition to Drug Dependence". Am J Psychiatry 164 (8): 1149–59. doi:10.1176/appi.ajp.2007.05030503. PMC 2837343. PMID 17671276. 
  29. ^ Trezza, V (2014). "On the interaction between drugs of abuse and adolescent social behavior". Psychopharmacology 231 (8): 1715–1729. 
  30. ^ AJ Giannini, RQ Quinones, DM Martin. Role of beta-endorphin and cAMP in addiction and mania. Society for Neuroscience Abstracts. 15:149, 1998.
  31. ^ Kovács KA, Steinmann M, Magistretti PJ, Halfon O, Cardinaux JR (September 2006). "C/EBPbeta couples dopamine signalling to substance P precursor gene expression in striatal neurones". Journal of Neurochemistry 98 (5): 1390–9. doi:10.1111/j.1471-4159.2006.03957.x. PMID 16771829. 
  32. ^ Nestler EJ, Barrot M, Self DW (September 2001). "ΔFosB: A sustained molecular switch for addiction". Proceedings of the National Academy of Sciences of the United States of America 98 (20): 11042–6. doi:10.1073/pnas.191352698. PMC 58680. PMID 11572966. 
  33. ^ Chao J, Nestler EJ (2004). "Molecular neurobiology of drug addiction". Annual Review of Medicine 55: 113–32. doi:10.1146/annurev.med.55.091902.103730. PMID 14746512. 
  34. ^ Nestler EJ (December 2005). "The Neurobiology of Cocaine Addiction". Science & Practice Perspectives / a Publication of the National Institute on Drug Abuse, National Institutes of Health 3 (1): 4–10. PMC 2851032. PMID 18552739. 
  35. ^ Conversi D, Bonito-Oliva A, Orsini C, Colelli V, Cabib S (January 2008). "DeltaFosB accumulation in ventro-medial caudate underlies the induction but not the expression of behavioral sensitization by both repeated amphetamine and stress". The European Journal of Neuroscience 27 (1): 191–201. doi:10.1111/j.1460-9568.2007.06003.x. PMID 18184321. 
  36. ^ Perrotti LI, Weaver RR, Robison B, Renthal W, Maze I, Yazdani S, Elmore RG, Knapp DJ, Selley DE, Martin BR, Sim-Selley L, Bachtell RK, Self DW, Nestler EJ (May 2008). "Distinct Patterns of ΔFosB Induction in Brain by Drugs of Abuse". Synapse 62 (5): 358–69. doi:10.1002/syn.20500. PMC 2667282. PMID 18293355. 
  37. ^ Nikulina EM, Arrillaga-Romany I, Miczek KA, Hammer RP (May 2008). "Long-lasting alteration in mesocorticolimbic structures after repeated social defeat stress in rats: time course of μ-opioid receptor mRNA and FosB/ΔFosB immunoreactivity". The European Journal of Neuroscience 27 (9): 2272–84. doi:10.1111/j.1460-9568.2008.06176.x. PMC 2442756. PMID 18445218. 
  38. ^ Wallace DL, Vialou V, Rios L, Carle-Florence TL, Chakravarty S, Kumar A, Graham DL, Green TA, Kirk A, Iñiguez SD, Perrotti LI, Barrot M, DiLeone RJ, Nestler EJ, Bolaños-Guzmán CA (October 2008). "The influence of ΔFOSB in the Nucleus Accumbens on natural reward-related behavior". Journal of Neuroscience 28 (41): 10272–7. doi:10.1523/JNEUROSCI.1531-08.2008. PMC 2653197. PMID 18842886. 
  39. ^ Nestler EJ (October 2008). "Transcriptional mechanisms of addiction: role of ΔFosB". Philosophical Transactions of the Royal Society B 363 (1507): 3245–55. doi:10.1098/rstb.2008.0067. PMC 2607320. PMID 18640924. 
  40. ^ Ulery-Reynolds PG, Castillo MA, Vialou V, Russo SJ, Nestler EJ (January 2009). "PHOSPHORYLATION OF ΔFosB MEDIATES ITS STABILITY IN VIVO". Neuroscience 158 (2): 369–72. doi:10.1016/j.neuroscience.2008.10.059. PMC 2734485. PMID 19041372. 
  41. ^ Kim Y, Teylan MA, Baron M, Sands A, Nairn AC, Greengard P (February 2009). "Methylphenidate-induced dendritic spine formation and ΔFosB expression in nucleus accumbens". Proceedings of the National Academy of Sciences of the United States of America 106 (8): 2915–20. doi:10.1073/pnas.0813179106. PMC 2650365. PMID 19202072. 
  42. ^ Chen JC, Chen PC, Chiang YC (2009). "Molecular mechanisms of psychostimulant addiction". Chang Gung Medical Journal 32 (2): 148–54. PMID 19403004. 
  43. ^ Teegarden SL, Scott AN, Bale TL (May 2009). "Early life exposure to a high fat diet promotes long-term changes in dietary preferences and central reward signaling". Neuroscience 162 (4): 924–32. doi:10.1016/j.neuroscience.2009.05.029. PMC 2723193. PMID 19465087. 
  44. ^ Watanabe H, Henriksson R, Ohnishi YN, Ohnishi YH, Harper C, Sheedy D, Garrick T, Nyberg F, Nestler EJ, Bakalkin G, Yakovleva T (July 2009). "FOSB proteins in the orbitofrontal and dorsolateral prefrontal cortices of human alcoholics". Addiction Biology 14 (3): 294–7. doi:10.1111/j.1369-1600.2009.00155.x. PMC 2828493. PMID 19523044. 
  45. ^ Garzón J, Rodríguez-Muñoz M, López-Fando A, Sánchez-Blázquez P (March 2005). "Activation of mu-opioid receptors transfers control of Galpha subunits to the regulator of G-protein signaling RGS9-2: role in receptor desensitization". The Journal of Biological Chemistry 280 (10): 8951–60. doi:10.1074/jbc.M407005200. PMID 15632124. 
  46. ^ Kovoor A, Seyffarth P, Ebert J, Barghshoon S, Chen CK, Schwarz S, Axelrod JD, Cheyette BN, Simon MI, Lester HA, Schwarz J (February 2005). "D2 dopamine receptors colocalize regulator of G-protein signaling 9-2 (RGS9-2) via the RGS9 DEP domain, and RGS9 knock-out mice develop dyskinesias associated with dopamine pathways". The Journal of Neuroscience 25 (8): 2157–65. doi:10.1523/JNEUROSCI.2840-04.2005. PMID 15728856. 
  47. ^ Garzón J, Rodríguez-Muñoz M, Sánchez-Blázquez P (May 2005). "Morphine alters the selective association between mu-opioid receptors and specific RGS proteins in mouse periaqueductal gray matter". Neuropharmacology 48 (6): 853–68. doi:10.1016/j.neuropharm.2005.01.004. PMID 15829256. 
  48. ^ Bouhamdan M, Yan HD, Yan XH, Bannon MJ, Andrade R (March 2006). "Brain-specific regulator of G-protein signaling 9-2 selectively interacts with alpha-actinin-2 to regulate calcium-dependent inactivation of NMDA receptors". Journal of Neuroscience 26 (9): 2522–30. doi:10.1523/JNEUROSCI.4083-05.2006. PMID 16510730. 
  49. ^ Silverman JL, Koenig JI (August 2007). "Evidence for Involvement of ERβ and RGS9-2 in 17-β Estradiol Enhancement of Amphetamine-Induced Place Preference Behavior". Hormones and Behavior 52 (2): 146–55. doi:10.1016/j.yhbeh.2007.03.017. PMC 2096711. PMID 17493623. 
  50. ^ Hooks SB, Martemyanov K, Zachariou V (January 2008). "A role of RGS proteins in drug addiction". Biochemical Pharmacology 75 (1): 76–84. doi:10.1016/j.bcp.2007.07.045. PMID 17880927. 
  51. ^ Martemyanov KA, Krispel CM, Lishko PV, Burns ME, Arshavsky VY (December 2008). "Functional comparison of RGS9 splice isoforms in a living cell". Proceedings of the National Academy of Sciences of the United States of America 105 (52): 20988–93. doi:10.1073/pnas.0808941106. PMC 2634932. PMID 19098104. 
  52. ^ Traynor JR, Terzi D, Caldarone BJ, Zachariou V (March 2009). "RGS9-2: probing an intracellular modulator of behavior as a drug target". Trends in Pharmacological Sciences 30 (3): 105–11. doi:10.1016/j.tips.2008.11.006. PMC 3394094. PMID 19211160. 
  53. ^ Ball JC, van de Wijngaart GF (1994). "A Dutch addict's view of methadone maintenance—an American and a Dutch appraisal". Addiction 89 (7): 799–802; discussion 803–14. doi:10.1111/j.1360-0443.1994.tb00974.x. PMID 8081178. 
  54. ^ Reynolds M, Mezey G, Chapman M, Wheeler M, Drummond C, Baldacchino A (2005). "Co-morbid post-traumatic stress disorder in a substance misusing clinical population". Drug Alcohol Depend 77 (3): 251–8. doi:10.1016/j.drugalcdep.2004.08.017. PMID 15734225. 
  55. ^ Moggi F, Giovanoli A, Strik W, Moos BS, Moos RH (2007). "Substance use disorder treatment programs in Switzerland and the USA: Program characteristics and 1-year outcomes". Drug Alcohol Depend 86 (1): 75–83. doi:10.1016/j.drugalcdep.2006.05.017. PMID 16782286. 
  56. ^ Nils Bejerot: Swedish addiction epidemic in an international perspective, 1988
  57. ^ Giannini AJ (June 1996). "Alexithymia, affective disorders and substance abuse: possible cross-relationships". Psychol Rep 78 (3 Pt 2): 1389–90. doi:10.2466/pr0.1996.78.3c.1389. PMID 8816054. 
  58. ^ DAA/UK
  59. ^ Schaler, Jeffrey Alfred (1997). "Addiction Beliefs of Treatment Providers: Factors Explaining Variance". Addiction Research & Theory 4 (4): 367–384. doi:10.3109/16066359709002970. ISSN 1476-7392. 
  60. ^ Johnson RE, Chutuape MA, Strain EC, Walsh SL, Stitzer ML, Bigelow GE (2000). "A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence". N. Engl. J. Med. 343 (18): 1290–7. doi:10.1056/NEJM200011023431802. PMID 11058673. 
  61. ^ Connock M, Juarez-Garcia A, Jowett S, et al. (2007). "Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation". Health Technol Assess 11 (9): 1–171, iii–iv. PMID 17313907. 
  62. ^ Marsch LA, Stephens MA, Mudric T, Strain EC, Bigelow GE, Johnson RE (2005). "Predictors of outcome in LAAM, buprenorphine, and methadone treatment for opioid dependence". Exp Clin Psychopharmacol 13 (4): 293–302. doi:10.1037/1064-1297.13.4.293. PMID 16366759. 
  63. ^ Robertson JR, Raab GM, Bruce M, McKenzie JS, Storkey HR, Salter A (2006). "Addressing the efficacy of dihydrocodeine versus methadone as an alternative maintenance treatment for opiate dependence: A randomized controlled trial". Addiction 101 (12): 1752–9. doi:10.1111/j.1360-0443.2006.01603.x. PMID 17156174. 
  64. ^ Qin Bo-Yi (1998). "Advances in dihydroetorphine: From analgesia to detoxification". Drug Development Research 39 (2): 131–134. doi:10.1002/(SICI)1098-2299(199610)39:2<131::AID-DDR3>3.0.CO;2-Q.  Link
  65. ^ Metrebian N, Shanahan W, Wells B, Stimson GV (1998). "Feasibility of prescribing injectable heroin and methadone to opiate-dependent drug users: associated health gains and harm reductions". Med. J. Aust. 168 (12): 596–600. PMID 9673620. 
  66. ^ Metrebian N, Mott J, Carnwath Z, Carnwath T, Stimson GV, Sell L (2007). "Pathways into receiving a prescription for diamorphine (heroin) for the treatment of opiate dependence in the United kingdom". Eur Addict Res 13 (3): 144–7. doi:10.1159/000101550. PMID 17570910. 
  67. ^ a b Kenna GA, Nielsen DM, Mello P, Schiesl A, Swift RM (2007). "Pharmacotherapy of dual substance abuse and dependence". CNS Drugs 21 (3): 213–37. doi:10.2165/00023210-200721030-00003. PMID 17338593. 
  68. ^ Mattick RP, Darke S (1995). "Drug replacement treatments: is amphetamine substitution a horse of a different colour?". Drug Alcohol Rev 14 (4): 389–94. doi:10.1080/09595239500185531. PMID 16203339. 
  69. ^ White R (2000). "Dexamphetamine substitution in the treatment of amphetamine abuse: an initial investigation". Addiction 95 (2): 229–38. doi:10.1046/j.1360-0443.2000.9522299.x. PMID 10723851. 
  70. ^ Majumdar SK (1991). "Chlormethiazole: current status in the treatment of the acute ethanol withdrawal syndrome". Drug Alcohol Depend 27 (3): 201–7. doi:10.1016/0376-8716(91)90001-F. PMID 1884662. 
  71. ^ Giannini AJ, Billett W (August 1987). "Bromocriptine-desipramine protocol in treatment of cocaine addiction". J Clin Pharmacol 27 (8): 549–54. doi:10.1002/j.1552-4604.1987.tb03065.x. PMID 3308977. 
  72. ^ Soyka M, Roesner S (2006). "New pharmacological approaches for the treatment of alcoholism". Expert Opin Pharmacother 7 (17): 2341–53. doi:10.1517/14656566.7.17.2341. PMID 17109610. 
  73. ^ Pettinati HM, Rabinowitz AR (2006). "Choosing the right medication for the treatment of alcoholism". Curr Psychiatry Rep 8 (5): 383–8. doi:10.1007/s11920-006-0040-0. PMID 16968619. 
  74. ^ Bouza C, Angeles M, Magro A, Muñoz A, Amate JM (2004). "Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review". Addiction 99 (7): 811–28. doi:10.1111/j.1360-0443.2004.00763.x. PMID 15200577. 
  75. ^ Williams SH (2005). "Medications for treating alcohol dependence". Am Fam Physician 72 (9): 1775–80. PMID 16300039. 
  76. ^ Gass JT, Olive MF (2008). "Glutamatergic substrates of drug addiction and alcoholism". Biochem. Pharmacol. 75 (1): 218–65. doi:10.1016/j.bcp.2007.06.039. PMC 2239014. PMID 17706608. 
  77. ^ Srisurapanont M, Jarusuraisin N (2005). Srisurapanont, Manit, ed. "Opioid antagonists for alcohol dependence". Cochrane Database Syst Rev (1): CD001867. doi:10.1002/14651858.CD001867.pub2. PMID 15674887. 
  78. ^ Karhuvaara S, Simojoki K, Virta A, et al. (2007). "Targeted nalmefene with simple medical management in the treatment of heavy drinkers: a randomized double-blind placebo-controlled multicenter study". Alcohol. Clin. Exp. Res. 31 (7): 1179–87. doi:10.1111/j.1530-0277.2007.00401.x. PMID 17451401. 
  79. ^ Comer SD, Sullivan MA, Hulse GK (2007). "Sustained-release naltrexone: novel treatment for opioid dependence". Expert Opin Investig Drugs 16 (8): 1285–94. doi:10.1517/13543784.16.8.1285. PMID 17685876. 
  80. ^ Ling W, Rawson R, Shoptaw S, Ling W (2006). "Management of methamphetamine abuse and dependence". Curr Psychiatry Rep 8 (5): 345–54. doi:10.1007/s11920-006-0035-x. PMID 16968614. 
  81. ^ Preti A (2007). "New developments in the pharmacotherapy of cocaine abuse". Addict Biol 12 (2): 133–51. doi:10.1111/j.1369-1600.2007.00061.x. PMID 17508985. 
  82. ^ Urschel HC, Hanselka LL, Gromov I, White L, Baron M (2007). "Open-label study of a proprietary treatment program targeting type A gamma-aminobutyric acid receptor dysregulation in methamphetamine dependence". Mayo Clin. Proc. 82 (10): 1170–8. doi:10.4065/82.10.1170. PMID 17908523. 
  83. ^ Garwood CL, Potts LA (2007). "Emerging pharmacotherapies for smoking cessation". Am J Health Syst Pharm 64 (16): 1693–8. doi:10.2146/ajhp060427. PMID 17687057. 
  84. ^ Frishman WH (2007). "Smoking cessation pharmacotherapy—nicotine and non-nicotine preparations". Prev Cardiol 10 (2 Suppl 1): 10–22. doi:10.1111/j.1520-037X.2007.05963.x. PMID 17396063. 
  85. ^ Siu EC, Tyndale RF (2007). "Non-nicotinic therapies for smoking cessation". Annu. Rev. Pharmacol. Toxicol. 47: 541–64. doi:10.1146/annurev.pharmtox.47.120505.105354. PMID 17209799. 
  86. ^ K.R. Alper, H.S. Lotsof, G.M. Frenken, D.J. Luciano, J. Bastiaans (1999). "Treatment of Acute Opioid Withdrawal with Ibogaine". The American Journal on Addictions 8 (3): 234–242. doi:10.1080/105504999305848. PMID 10506904. Retrieved 16 June 2009. 
  87. ^ S.L.T. Cappendijk, M.R. Dzoljic (1993). "Inhibitory effects of ibogaine on cocaine self-administration in rats". European Journal of Pharmacology 241 (2–3): 261–265. doi:10.1016/0014-2999(93)90212-Z. PMID 8243561. 
  88. ^ S.D. Glick, K. Rossman, N.C. Rao, I.M. Maisonneuve and J.N. Carlson (1992). "Effects of ibogaine on acute signs of morphine withdrawal in rats: Independence from tremor". Neuropharmacology 31 (5): 497–500. doi:10.1016/0028-3908(92)90089-8. PMID 1528400. 
  89. ^ O'Donohue, W; K.E. Ferguson (2006). "Evidence-Based Practice in Psychology and Behavior Analysis". The Behavior Analyst Today (Joseph D. Cautilli) 7 (3): 335–350. 
  90. ^ Chambless, D.L. (1998). "An update on empirically validated therapies" (PDF). Clinical Psychology (American Psychological Association) 49: 5–14. 
  91. ^ Dutcher LW, Anderson R, Moore M, Luna-Anderson C, Meyers RJ, Delaney HD, Smith JE (Spring 2009). "Community Reinforcement and Family Training (CRAFT): An Effectiveness Study" (PDF). Journal of Behavior Analysis of Sports, Health Fitness and Behavioral Medicine 2 (1): 82–93. ISSN 1946-7079. [unreliable source?]
  92. ^ Meyers RJ, Smith JE, Lash DN (June 2005). "A Program for Engaging Treatment-Refusing Substance Abusers into Treatment: CRAFT" (PDF). IJBCT 1 (2): 90–100. ISSN 1555-7855. [unreliable source?]
  93. ^ Smith JE, Milford JL, Meyers RJ (2004). "CRA and CRAFT: Behavioral Approaches to Treating Substance-Abusing Individuals" (PDF). The Behavior Analyst Today 5 (4): 391–403. [unreliable source?]
  94. ^ http://www.ama-assn.org/ama1/pub/upload/mm/21/omss-handbook-final.pdf
  95. ^ Jordan JB (2006). "Acupuncture treatment for opiate addiction: a systematic review". J Subst Abuse Treat 30 (4): 309–14. doi:10.1016/j.jsat.2006.02.005. PMID 16716845. 
  96. ^ White AR, Rampes H, Campbell JL (2006). White, Adrian R, ed. "Acupuncture and related interventions for smoking cessation". Cochrane Database Syst Rev (1): CD000009. doi:10.1002/14651858.CD000009.pub2. PMID 16437420. 
  97. ^ "Treatment Approaches for Drug Addiction", National Institute of Drug Abuse, 09/12/12
  98. ^ Lowinson, Joyce H; Ruiz, Pedro; Millman, Robert B; Langrod, John G (eds) (2005). Substance Abuse: A Comprehensive Textbook (4th ed.). Philadelphia: Lippincott Williams & Wilkins. ISBN 0-7817-3474-6 
  99. ^ Hillman, D.C.A. (22 July 2008). The chemical muse: drug use and the roots of Western civilization. Macmillan. ISBN 978-0-312-35249-3. 
  100. ^ Rinella, Michael A. (23 November 2011). Pharmakon: Plato, Drug Culture, and Identity in Ancient Athens. Rowman & Littlefield. ISBN 978-0-7391-4687-3. 
  101. ^ a b c Casey, Elaine. "History of Drug Use and Drug Users in the United States". www.druglibrary.org. Retrieved 3 January 2014. 

External links[edit]