Substance dependence

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Substance dependency
Classification and external resources
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Substance dependency
Classification and external resources

Substance dependence is an adaptive state that develops from repeated drug administration, and which results in withdrawal upon cessation of drug use.[1][2] 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 one 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-IV), substance dependence is redefined as:[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.


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.[7] 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.[7]

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.[8]

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. [9]

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.[10]

DrugMeanPleasurePsychological dependencePhysical dependence

Capture rates[edit]

The percentage of users who reported that they had become dependent to their respective drug at some point.[11][12]

DrugAverage user

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][13][14][15] 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.[16]

Summary of addiction-related plasticity
Form of neural or behavioral plasticityType of reinforcerSources
OpiatesPsychostimulantsHigh fat or sugar foodSexual rewardExerciseEnvironmental enrichment
ΔFosB expression
in the nucleus accumbens
Behavioral Plasticity
Escalation of intakeYesYesYes[5]
YesNot applicableYesYesAttenuatedAttenuated[5]
conditioned place preference
Reinstatement of drug-seeking behavior[5]
Neurochemical Plasticity
CREB phosphorylation
in the nucleus accumbens
Sensitized dopamine response
in the nucleus accumbens
Altered striatal dopamine signalingDRD2, ↑DRD3DRD1, ↓DRD2, ↑DRD3DRD1, ↓DRD2, ↑DRD3DRD2DRD2[5]
Altered striatal opioid signalingμ-opioid receptorsμ-opioid receptors
κ-opioid receptors
μ-opioid receptorsμ-opioid receptorsNo changeNo change[5]
Changes in striatal opioid peptidesdynorphindynorphinenkephalindynorphindynorphin[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.[17]

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.

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.[23] 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.[23][24] Nearly all addictive drugs, directly or indirectly, act upon the brain’s reward system by heightening dopaminergic activity.[25]

Abuse of drugs results in repeated release of high amounts of DA, which in turn affects the reward pathway in multiple ways. Abnormally high levels of DA in the synaptic cleft can induce prolonged, heightened postsynaptic receptor activity, resulting in receptor downregulation. Downregulation of mesocorticolimbic DA receptors can result in a decrease in the sensitivity to natural reinforcers.[23]

Stress response[edit]

See also: Stress response

In addition to the reward pathway, it is hypothesized that stress mechanisms play a role in addiction. Koob 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.[26]


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.[17][26] 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.[18] Evidence shows that this behavior is most likely a result of the synaptic changes which have occurred due to repeated drug exposure.[17][18][26] 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.[17]

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.[27]

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.[28]


Sensitization is the increase in sensitivity to a drug after prolonged use. The proteins ΔFosB (Delta-FosB)and regulator of G-protein signaling 9-2 (RGS9-2) are thought to be involved:

The ΔFosB transcription factor is thought to activate genes that, counter to the effects of CREB, actually increase the user's sensitivity to the effects of the substance. ΔFosB slowly builds up with each exposure to the drug and remains activated for weeks 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 some evidence that ΔFosB even causes structural changes within the nucleus accumbens, which presumably helps to perpetuate the cravings, and may be responsible for the high incidence of relapses that occur in treated drug addicts.[29][30][31][32][33][34][35][36][37][38][39][40][41]

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.[42][43][44][45][46][47][48][49]


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.[50][51][52] 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.[53]

It is sometimes difficult to convince people with substance dependencies to engage in any form of treatment. Family interventions have been highly successful in helping these people accept the help they need.[citation needed]


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.[54]

One of many recovery methods are 12-step recovery programs, with prominent examples including Alcoholics Anonymous, Narcotics Anonymous, Drug Addicts Anonymous[55] 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 buprenorphine - opioid 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).[56]

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.[57][58] 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,[59] dihydrocodeine,[60] dihydroetorphine[61] and even heroin[62][63] 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.[64] 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[64] - 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,[65][66] and clomethiazole to treat alcohol addiction.[67] Bromocriptine and desipramine have been reported to be effective for treatment of cocaine but not amphetamine addiction.[68]

Other pharmacological treatments for alcohol addiction include drugs like naltrexone, disulfiram, acamprosate and topiramate,[69][70] 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.[71][72] 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.[73]

Opioid antagonists such as naltrexone and nalmefene have also been used successfully in the treatment of alcohol addiction,[74][75] 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.[76]

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.[77][78] 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.[79]

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.[80][81][82]

Ibogaine is a hallucinogen (psychotomimetic) that some claim interrupts addiction and reduces or eliminates withdrawal syndromes, specifically in regards to opioids.[83] 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.[84] Another uncontrolled trial showed it reduced tremor by a mild to moderate degree during morphine withdrawal in rats.[85] 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.[86][87] 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.[88] In addition, behavioral treatment such as community reinforcement and family training (CRAFT) have helped family members to get their loved ones into treatment.[89][90]

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.[91]

Acupuncture has been shown to be no more effective than control treatments in the treatment of opiate dependence.[92] Acupuncture, acupressure, laser therapy and electrostimulation[disambiguation needed] have no demonstrated efficacy for smoking cessation.[93]

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.[94]

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]

Evolutionary considerations[edit]

Background on substance dependence from an evolutionary perspective[edit]

An association between the dopamine receptor D2 gene and alcoholism supports a genetic predisposition for alcoholism.[95] There is an association between low rates of alcoholism in Asian populations and a single gene nucleotide change slowing the rate of alcohol breakdown.[96] Speculation on this correlation suggests this single gene nucleotide change may be an adaptation against alcoholism.[96]

Addiction as the result of an evolutionary mismatch[edit]

Substance dependence is hypothesized to be a result of an evolutionary mismatch between the environment to which human hominin ancestors adapted (typically referred to as the environment of evolutionary adaptedness or EEA) and the current environment.[97][98][99] Evidence suggests it was unlikely that prevalence of psychoactive substances was high enough in the EEA to exert selective pressures.[98][99] Thus, psychoactive substances in the current environment hijack the reward pathway in the brain adapted to reinforce certain behaviors.[98][99] These behaviors activate pleasure systems in the brain that reinforce their fitness benefits.[96][98][99] Through repeated usage, drugs displace other rewards, and the reward pathway can no longer distinguish between the positive and negative effects of rewards.[98][99]

The mismatch theory has been explored specifically for alcoholism.[100][101] Alcoholics exhibit traits that are beneficial in some environments but are serious risk factors for alcohol abuse in a modern context.[100][101] Type 1 alcoholism results from abusing alcohol to relieve anxiety.[100][101] In another context, anxiety leading to reward-seeking behavior could be adaptive.[100][101] For instance, anxiety leads primate infants to stay close to their mothers who provide protection and food.[100][101][102] Type 2 alcoholism results from antisocial behavior and impulsivity.[100][101] When food is scarce, solitary behavior can be favored because an individual can forage independently and receive more resources.[100][101] Impulsivity can be favored because it allows access to food and mates, which other less impulsive individuals will not seek out.[100][101][103] Aggressive behavior often results from impulsivity in type 2 alcoholics.[100][101] In a physically competitive environment, aggression could be beneficial.[100][101] These traits are mismatched for our modern environment, however, and function instead as risk factors for alcoholism.[100][101]

The self-perceived survival ability and reproductive fitness (SPFit) theory is a corollary of the mismatch theory.[104] This theory posits that drugs mimic self-perceived power and sexual attractiveness.[104] Since power and sexual attractiveness are basic qualities that lead to reproductive success, drugs are likely to be abused.[104] The distinction between the SPFit theory and other mismatch theories is that other theories highlight pleasure-seeking in addiction, while the SPFit theory states that pleasure is not a significant enough motivator to outweigh the fitness costs of addiction.[104]

Addiction as the result of coevolution with psychoactive substances[edit]

Conflicting research posits that hominins evolved with psychoactive substances, and this coevolution has led to the evolution of pleasure responses from these substances.[105][106] Natural psychoactive drugs induce pleasure responses in humans due to human chemical-ecological adaptations to counteract the effects of plant chemical defense mechanisms.[106] Specific examples of human adaptations to counter plant toxins include liver enzymes, tasting food, olfaction, and vomiting.[106][107] Humans, chimpanzees, and monkeys eat substances such as soil as a method for detoxification.[106] There is also evidence of plant adaptations specifically for human consumption.[106][107] Some psychoactive drugs target human pathogens.[107] For instance, tobacco leaves and nicotine extract can be used to fight helminth infections in livestock.[107] Plants have also evolved chemicals that mimic human neurotransmitters. These examples imply that humans coevolved with psychoactive substances.[106]

Coevolution and mismatch theories are not mutually exclusive.[99][107][108] Humans may have evolved with natural psychoactive substances, but modern psychoactive substances, such as heroin, are far more potent than those likely found in the EEA.[99][107][108] Thus, many modern drugs can still be considered the result of an evolutionary mismatch.[99][107][108]

Evolutionary perspectives on vulnerability to addiction[edit]

An evolutionary perspective can also explain why certain groups in the population are more prone to addiction than others.[98] Impulsivity and risky behaviors are only rewarded when reproductive prospects seem unlikely.[98] This predicts that young men will be most prone to impulsive behaviors like substance abuse because competition for mates and resources is highest at that time.[98] These rates of substance abuse in males should decrease with age as men generally start families and must invest in their offspring's success.[98] As reproductive competition in human females does not vary significantly, there should be fewer impulsive behaviors, like substance abuse, in females because it is more beneficial for them to invest in long-term reproductive success.[98]

Substance abuse variation can also be predicted by environmental differences.[97][98] Impulsivity is only favored in dangerous and unpredictable environments, so it follows substance abuse will be more likely to occur there.[97][98]

Relevance of the evolutionary perspective to treatment and prevention[edit]

The evolutionary perspective can help therapists address the roots of substance dependence issues with their patients and develop long-term solutions.[103] For instance, the SPFit theory proposes psychoactive substances increase self-perceived levels of fitness.[103][104] Therapists using an evolutionary perspective can evaluate what the abuser is seeking when he or she abuses substances, and work towards fixing underlying problems in their patients’ lives.[103]

An evolutionary perspective supports that stopping drug use is the first step of effective treatment.[97] These drugs must also be replaced by natural rewards, like friendship, evoking positive feelings.[97] Because drug use is so heavily tied to emotion, harboring positive emotions should be considered essential to treatment.[97] Recognizing that substance abuse is tied to the evolution of brain systems that are meant to reward social relationships can also influence new methods of treatment.[97] Those who abuse substances often personify addictive substances, and treatment that encourages disentangling oneself from a harmful relationship with substance abuse may help.[97] This is already evident in Alcoholics Anonymous as they encourage gaining control over alcohol.[97]

Anticipating that adolescents, particularly adolescent males, are especially prone to drug abuse can be used to provide programs for these adolescents to direct them towards natural stimuli and away from potentially addictive substances.[97][98] This is especially true for adolescents in marginalized populations, as their environment is more likely to foster impulsive behaviors.[97][98]


Disability-adjusted life year for drug use disorders per 100,000 inhabitants in 2002.
  no data
  less than 40
  more than 440

The most common drug addictions are to legal substances such as nicotine, caffeine, and alcohol.[citation needed]


The phenomenon of drug addiction has occurred to some degree throughout recorded history (see "Opium").[109] 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.[110][111]

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. During and following the American Civil War, the prevalence of caffeine use in the US increased.[112]

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".[112]

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 return 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.[112]

Society and culture[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, caffeine 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]



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    "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. The manual avoids use of the term addiction, which provides the best description of the clinical syndrome."
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    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

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