Substance dependence

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Substance dependency
Classification and external resources
ICD-10 F10.2-F19.2
ICD-9 303-304
MeSH D019966


According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), substance dependence is defined as:


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.[2]


Drugs known to cause addiction include both legal and illegal drugs as well as prescription or over-the-counter drugs, according to the definition of the American Society of Addiction Medicine.[citation needed]

Although stimulants are generally classified as drugs that cause only a psychological addiction, mild physical symptoms might appear when a withdrawal from a stimulant is being done. For example, withdrawing from caffeine causes headaches for most people. But, unlike depressants, which cause heavy physical withdrawal symptoms when stopped, and may cause death when stopped abruptly, deaths from stimulant withdrawals are extremely rare.


Several theories of drug addiction exist, some of the main ones being genetic predisposition, the self-medication theory, and factors involved with social/economic development. There are strong associations between poverty and addiction.[3] It is important to remember that people abuse substances for hundreds of different, individual, almost idiosyncratic reasons.[4][5]

Genetic factors[edit]


Overall, the data implicating specific genes in the development of drug dependence is mixed for most genes. One reason this may be 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.[7]

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. Surprisingly, these studies very infrequently 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 wiring prior to drug experiences, subsequent to them, or both. [8]

Addictive potential[edit]


An article in The Lancet compared the harm and addiction of 20 drugs, using a scale from 0 to 3 for physical addiction, psychological addiction, and pleasure to create a mean score for addiction. Selected results can be seen in the chart below.[9]

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
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
Tobacco 2.21 2.3 2.6 1.8
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 become addicted to their respective drug at some point.[10][11]

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


Researchers have conducted numerous investigations using animal models and functional brain imaging on humans in order to define the mechanisms underlying drug addiction in the brain. Changes to several areas of the brain are thought to be involved.

Acute effects[edit]

Different types of drugs produce these effects by different methods. Dopamine (DA) is known to play an important role. DA 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.[12]

Mesocorticolimbic pathway[edit]

When examining the biological basis of drug addiction, one must first understand the pathways in which drugs act and how drugs can alter those pathways. 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 dopamine (DA) into the forebrain.[13] These neurons also project and release DA into the nucleus accumbens,[14] through the mesolimbic pathway. Virtually all drugs causing drug addiction increase the dopamine release in the mesolimbic pathway,[15] in addition to their specific effects.
  • The nucleus accumbens (NAcc) consists mainly of medium-spiny projection neurons (MSNs), which are GABA neurons.[16] The NAcc is associated with acquiring and eliciting conditioned behaviors and involved in the increased sensitivity to drugs as addiction progresses.[13]
  • The prefrontal cortex, more specifically the anterior cingulate and orbitofrontal cortices,[12] 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.[17]
  • The basolateral amygdala projects into the NAcc and is thought to be important for motivation as well.[17]

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.[18] Natural rewards, like eating, as well as recreational drug use cause a release of dopamine, and are associated with the reinforcing nature of these stimuli.[18][19] Nearly all addictive drugs, directly or indirectly, act upon the brain’s reward system by heightening dopaminergic activity.[20]

Abuse of drugs results in repeated release of high amounts of dopamine, which in turn affects the reward pathway in multiple ways. Abnormally high levels of dopamine in the synaptic cleft can induce prolonged, heightened postsynaptic receptor activity, resulting in receptor downregulation. Downregulation of mesocorticolimbic dopamine receptors can result in a decrease in the sensitivity to natural reinforcers.[18]

Stress response[edit]

See also: Stress response



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.[12][21] Addictive drugs produce a reward, which is the euphoric feeling resulting from sustained dopamine 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.[13] Evidence shows that this behavior is most likely a result of the synaptic changes which have occurred due to repeated drug exposure.[12][13][21] 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 the drug seeking behavior can be prevented following the inhibition of AMPA glutamate receptors and glutamate release in the NAc.[12]

Psychological drug tolerance[edit]



A similar mechanism, interfering also with the dopamine system, but relying on a different transcription factor, CEBPB, has also been proposed. In this case dopamine release onto the nucleus accumbens neurons would trigger the increased synthesis of substance P which, in turn, would increase the dopamine synthesis in the VTA. The effect of this positive feedback is suggested to be dampened by repeated substance abuse.[23]


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.[24][25][26][27][28][29][30][31][32][33][34][35][36]

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.[37][38][39][40][41][42][43][44]

Individual mechanisms of effect[edit]



Depressants such as alcohol, barbiturates, and benzodiazepines work by increasing the affinity of the GABA receptor for its ligand; GABA. Narcotics such as morphine and heroin work by mimicking endorphins—chemicals produced naturally by the body which have effects similar to dopamine—or by disabling the neurons that normally inhibit the release of dopamine in the reward system. These substances (sometimes called "downers") typically facilitate relaxation and pain relief.


Stimulants such as amphetamines, nicotine, and cocaine increase dopamine signaling in the reward system either by directly stimulating its release, or by blocking its absorption (see "Reuptake"). These substances (sometimes called "uppers") typically cause heightened alertness and energy. They cause a pleasant feeling in the body and euphoria, known as a high. Once this high wears off, the user may feel depleted of energy and/or depressed. This can increase the urge for the user to redose, possibly increasing the risk for addiction.






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 or Therapeutic Communities. 12 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. CBT sees addiction as a behavior rather than a disease and subsequently curable, or rather, unlearnable. CBT programs recognize that for some individuals controlled use is a more realistic possibility.[50]



Anti-addictive drugs[edit]

Other forms of treatment include replacement drugs such as suboxone/subutex (both containing the active ingredient buprenorphine) and methadone; these are used as substitutes for illicit opiate drugs.[53][54] 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,[55] dihydrocodeine,[56] dihydroetorphine[57] and even heroin[58][59] 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.[60] 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 60% at four weeks and 97% at twelve months if not on maintenance therapy with a mu-opioid agonist[60] - 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,[61][62] and clomethiazole to treat alcohol addiction.[63] Bromocriptine and desipramine have been reported to be effective for treatment of cocaine but not amphetamine addiction.[64]

Other pharmacological treatments for alcohol addiction include drugs like naltrexone, disulfiram, acamprosate and topiramate,[65][66] 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.[67][68] 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.[69]

Opioid antagonists such as naltrexone and nalmefene have also been used successfully in the treatment of alcohol addiction,[70][71] 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.[72]

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.[73][74] 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.[75]


Ibogaine is a hallucinogen (psychotomimetic) that some claim interrupts addiction and reduces or eliminates withdrawal syndromes, specifically in regards to opioids.[79] 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.[80] Another uncontrolled trial showed it reduced tremor by a mild to moderate degree during morphine withdrawal in rats.[81] 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 evidenced based intervention programs have emerged: (1) behavioral marital therapy; (2) community reinforcement approach; (3) cue exposure therapy; and (4) contingency management strategies.[82][83] 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.[84] In addition, behavioral treatment such as community reinforcement and family training (CRAFT) have helped family members to get their loved ones into treatment.[85][86]

Alternative therapies[edit]



Acupuncture has been shown to be no more effective than control treatments in the treatment of opiate dependence.[88] Acupuncture, acupressure, laser therapy and electrostimulation[disambiguation needed] have no demonstrated efficacy for smoking cessation.[89]

Important phases in treating substance dependence include establishing coping mechanisms to deal with the hardships of withdrawal symptoms. Additionally, precautions should be established with the patient to avoid relapse by designing a treatment plan around the patient's lifestyle. With the correct approaches, the patient can live a healthier life.[90]


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.[91] There is an association between low rates of alcoholism in Asian populations and a single gene nucleotide change slowing the rate of alcohol breakdown.[92] Speculation on this correlation suggests this single gene nucleotide change may be an adaptation against alcoholism.[92]

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.[93][94][95] Evidence suggests it was unlikely that prevalence of psychoactive substances was high enough in the EEA to exert selective pressures.[94][95] Thus, psychoactive substances in the current environment hijack the reward pathway in the brain adapted to reinforce certain behaviors.[94][95] These behaviors activate pleasure systems in the brain that reinforce their fitness benefits.[92][94][95] Through repeated usage, drugs displace other rewards, and the reward pathway can no longer distinguish between the positive and negative effects of rewards.[94][95]

The mismatch theory has been explored specifically for alcoholism.[96][97] Alcoholics exhibit traits that are beneficial in some environments but are serious risk factors for alcohol abuse in a modern context.[96][97] Type 1 alcoholism results from abusing alcohol to relieve anxiety.[96][97] In another context, anxiety leading to reward-seeking behavior could be adaptive.[96][97] For instance, anxiety leads primate infants to stay close to their mothers who provide protection and food.[96][97][98] Type 2 alcoholism results from antisocial behavior and impulsivity.[96][97] When food is scarce, solitary behavior can be favored because an individual can forage independently and receive more resources.[96][97] Impulsivity can be favored because it allows access to food and mates, which other less impulsive individuals will not seek out.[96][97][99] Aggressive behavior often results from impulsivity in type 2 alcoholics.[96][97] In a physically competitive environment, aggression could be beneficial.[96][97] These traits are mismatched for our modern environment, however, and function instead as risk factors for alcoholism.[96][97]

The self-perceived survival ability and reproductive ﬁtness (SPFit) theory is a corollary of the mismatch theory.[100] This theory posits that drugs mimic self-perceived power and sexual attractiveness.[100] Since power and sexual attractiveness are basic qualities that lead to reproductive success, drugs are likely to be abused.[100] 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.[100]

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.[101][102] Natural psychoactive drugs induce pleasure responses in humans due to human chemical-ecological adaptations to counteract the effects of plant chemical defense mechanisms.[102] Specific examples of human adaptations to counter plant toxins include liver enzymes, tasting food, olfaction, and vomiting.[102][103] Humans, chimpanzees, and monkeys eat substances such as soil as a method for detoxification.[102] There is also evidence of plant adaptations specifically for human consumption.[102][103] Some psychoactive drugs target human pathogens.[103] For instance, tobacco leaves and nicotine extract can be used to fight helminth infections in livestock.[103] Plants have also evolved chemicals that mimic human neurotransmitters. These examples imply that humans coevolved with psychoactive substances.[102]

Coevolution and mismatch theories are not mutually exclusive.[95][103][104] 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.[95][103][104] Thus, many modern drugs can still be considered the result of an evolutionary mismatch.[95][103][104]

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.[94] Impulsivity and risky behaviors are only rewarded when reproductive prospects seem unlikely.[94] 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.[94] These rates of substance abuse in males should decrease with age as men generally start families and must invest in their offspring's success.[94] 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.[94]

Substance abuse variation can also be predicted by environmental differences.[93][94] Impulsivity is only favored in dangerous and unpredictable environments, so it follows substance abuse will be more likely to occur in these environments.[93][94]

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.[99] For instance, the SPFit theory proposes psychoactive substances increase self-perceived levels of fitness.[99][100] 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.[99]

An evolutionary perspective supports that stopping drug use is the first step of effective treatment.[93] These drugs must also be replaced by natural rewards, like friendship, evoking positive feelings.[93] Because drug use is so heavily tied to emotion, harboring positive emotions should be considered essential to treatment.[93] 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.[93] Those who abuse substances often personify addictive substances, and treatment that encourages disentangling oneself from a harmful relationship with substance abuse may help.[93] This is already evident in Alcoholics Anonymous as they encourage gaining control over alcohol.[93]

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.[93][94] This is especially true for adolescents in marginalized populations, as their environment is more likely to foster impulsive behaviors.[93][94]


  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").[105] 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.[106][107]

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.[108]



Society and culture[edit]







See also[edit]


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