What is the American Society of Addiction Medicine?


The American Society of Addiction Medicine (ASAM), founded in 1954, is a professional medical society representing over 6,000 physicians, clinicians and associated professionals in the field of addiction medicine.


ASAM is dedicated to increasing access and improving the quality of addiction treatment, educating physicians and the public, supporting research and prevention, and promoting the appropriate role of physicians in the care of patients with addiction.

Refer to Addiction Psychiatry, Addiction Psychology, Addiction Medicine, American Academy of Addiction Psychiatry, Addictive Personality, Addiction Vulnerability, Addiction-Related Structural Neuroplasticity, and American Society of Addiction Medicine.

What is Addiction-Related Structural Neuroplasticity?


Addiction is a state characterised by compulsive engagement in rewarding stimuli, despite adverse consequences. The process of developing an addiction occurs through instrumental learning, which is otherwise known as operant conditioning.

Neuroscientists believe that drug addicts’ behaviour is a direct correlation to some physiological change in their brain, caused by using drugs. This view believes there is a bodily function in the brain causing the addiction. This is brought on by a change in the brain caused by brain damage or adaptation from chronic drug use.

In humans, addiction is diagnosed according to diagnostic models such as the Diagnostic and Statistical Manual of Mental Disorders, through observed behaviours. There has been significant advancement in understanding the structural changes that occur in parts of the brain involved in the reward pathway (mesolimbic system) that underlies addiction. Most research has focused on two portions of the brain: the ventral tegmental area (VTA) and the nucleus accumbens (NAc).

The VTA is the portion of the mesolimbic system responsible for spreading dopamine to the whole system. The VTA is stimulated by ″rewarding experiences″. The release of dopamine by the VTA induces pleasure, thus reinforcing behaviours that lead to the reward. Drugs of abuse increase the VTA’s ability to project dopamine to the rest of the reward circuit. These structural changes only last 7-10 days, however, indicating that the VTA cannot be the only part of the brain that is affected by drug use, and changed during the development of addiction.

The nucleus accumbens (NAc) plays an essential part in the formation of addiction. Almost every drug with addictive potential induces the release of dopamine into the NAc. In contrast to the VTA, the NAc shows long-term structural changes. Drugs of abuse weaken the connections within the NAc after habitual use, as well as after use then withdrawal.

Refer to Addiction Psychiatry, Addiction Psychology, Addiction Medicine, American Academy of Addiction Psychiatry, Addictive Personality, Addiction Vulnerability, Addiction-Related Structural Neuroplasticity, and American Society of Addiction Medicine.

Structural Changes of Learning

Learning by experience occurs through modifications of the structural circuits of the brain. These circuits are composed of many neurons and their connections, called synapses, which occur between the axon of one neuron and the dendrite of another. A single neuron generally has many dendrites which are called dendritic branches, each of which can be synapsed by many axons.

Along dendritic branches there can be hundreds or even thousands of dendritic spines, structural protrusions that are sites of excitatory synapses. These spines increase the number of axons from which the dendrite can receive information. Dendritic spines are very plastic, meaning they can be formed and eliminated very quickly, in the order of a few hours. More spines grow on a dendrite when it is repetitively activated. Dendritic spine changes have been correlated with long-term potentiation (LTP) and long-term depression (LTD).

LTP is the way that connections between neurons and synapses are strengthened. LTD is the process by which synapses are weakened. For LTP to occur, NMDA receptors on the dendritic spine send intracellular signals to increase the number of AMPA receptors on the post synaptic neuron. If a spine is stabilised by repeated activation, the spine becomes mushroom shaped and acquires many more AMPA receptors. This structural change, which is the basis of LTP, persists for months and may be an explanation for some of the long-term behavioural changes that are associated with learned behaviours, including addiction.

Research Methodologies

Animal Models

Animal models, especially rats and mice, are used for many types of biological research. The animal models of addiction are particularly useful because animals that are addicted to a substance show behaviours similar to human addicts. This implies that the structural changes that can be observed after the animal ingests a drug can be correlated with an animal’s behavioural changes, as well as with similar changes occurring in humans.

Administration Protocols

Administration of drugs that are often abused can be done either by the experimenter (non-contingent), or by a self-administration (contingent) method. The latter usually involves the animal pressing a lever to receive a drug. Non-contingent models are generally used for convenience, being useful for examining the pharmacological and structural effects of the drugs. Contingent methods are more realistic because the animal controls when and how much of the drug it receives. This is generally considered a better method for studying the behaviours associated with addiction. Contingent administration of drugs has been shown to produce larger structural changes in certain parts of the brain, in comparison to non-contingent administration.

Types of Drugs

All abused drugs directly or indirectly promote dopamine signalling in the mesolimbic dopamine neurons which project from the ventral tegmental area to the nucleus accumbens (NAc). The types of drugs used in experimentation increase this dopamine release through different mechanisms.

  • Opiates:
    • Opiates are a class of sedative with the capacity for pain relief.
    • Morphine is an opiate that is commonly used in animal testing of addiction.
    • Opiates stimulate dopamine neurons in the brain indirectly by inhibiting GABA release from modulatory interneurons that synapse onto the dopamine neurons.
    • GABA is an inhibitory neurotransmitter that decreases the probability that the target neuron will send a subsequent signal.
  • Stimulants:
    • Stimulants used regularly in neuroscience experimentation are cocaine and amphetamine.
    • These drugs induce an increase in synaptic dopamine by inhibiting the reuptake of dopamine from the synaptic cleft, effectively increasing the amount of dopamine that reaches the target neuron.

The Reward Pathway

The reward pathway, also called the mesolimbic system of the brain, is the part of the brain that registers reward and pleasure. This circuit reinforces the behaviour that leads to a positive and pleasurable outcome. In drug addiction, the drug-seeking behaviours become reinforced by the rush of dopamine that follows the administration of a drug of abuse. The effects of drugs of abuse on the ventral tegmental area (VTA) and the nucleus accumbens (NAc) have been studied extensively.

Drugs of abuse change the complexity of dendritic branching as well as the number and size of the branches in both the VTA and the NAc. By correlation, these structural changes have been linked to addictive behaviours. The effect of these structural changes on behaviour is uncertain and studies have produced conflicting results. Two studies have shown that an increase in dendritic spine density due to cocaine exposure facilitates behavioural sensitisation, while two other studies produce contradicting evidence.

In response to drugs of abuse, structural changes can be observed in the size of neurons and the shape and number of the synapses between them. The nature of the structural changes is specific to the type of drug used in the experiment. Opiates and stimulants produce opposite effects in structural plasticity in the reward pathway. It is not expected that these drugs would induce opposing structural changes in the brain because these two classes of drugs, opiates and stimulants, both cause similar behavioural phenotypes.

Both of these drugs induce increased locomotor activity acutely, escalated self-administration chronically, and dysphoria when the drug is taken away. Although their effects on structural plasticity are opposite, there are two possible explanations as to why these drugs still produce the same indicators of addiction: Either these changes produce the same behavioural phenotype when any change from baseline is produced, or the critical changes that cause the addictive behaviour cannot be quantified by measuring dendritic spine density.[citation needed]

Opiates decrease spine density and dendrite complexity in the nucleus accumbens (NAc). Morphine decreases spine density regardless of the treatment paradigm. Either chronic or intermittent administration of morphine will produce the same effect. The only case where opiates increase dendritic density is with chronic morphine exposure, which increases spine density on pyramidal neurons in the orbitofrontal cortex. Stimulants increase spinal density and dendritic complexity in the nucleus accumbens (NAc), ventral tegmental area (VTA), and other structures in the reward circuit.

Ventral Tegmental Area

There are neurons with cell bodies in the VTA that release dopamine onto specific parts of the brain, including many of the limbic regions such as the NAc, the medial prefrontal cortex (mPFC), dorsal striatum, amygdala, and the hippocampus. The VTA has both dopaminergic and GABAergic neurons that both project to the NAc and mPFC. GABAergic neurons in the VTA also synapse on local dopamine cells. In non-drug models, the VTA dopamine neurons are stimulated by rewarding experiences. A release of dopamine from the VTA neurons seems to be the driving action behind drug-induced pleasure and reward.

Exposure to drugs of abuse elicits LTP at excitatory synapses on VTA dopamine neurons. Excitatory synapses in brain slices from the VTA taken 24 hours after a single cocaine exposure showed an increase in AMPA receptors in comparison to a saline control. Additional LTP could not be induced in these synapses. This is thought to be because the maximal amount of LTP had already been induced by the administration of cocaine. LTP is only seen on the dopamine neurons, not on neighbouring GABAergic neurons. This is of interest because the administration of drugs of abuse increases the excitation of VTA dopamine neurons, but does not increase inhibition. Excitatory inputs into the VTA will activate the dopamine neurons 200%, but do not increase activation of GABA neurons which are important in local inhibition.

This effect of inducing LTP in VTA slices 24 hours after drug exposure has been shown using morphine, nicotine, ethanol, cocaine, and amphetamines. These drugs have very little in common except that they are all potentially addictive. This is evidence supporting a link between structural changes in the VTA and the development of addiction.

Changes other than LTP have been observed in the VTA after treatment with drugs of abuse. For example, neuronal body size decreased in response to opiates.

Although the structural changes in the VTA invoked by exposure to an addictive drug generally disappear after a week or two, the target regions of the VTA, including the NAc, may be where the longer-term changes associated with addiction occur during the development of the addiction.

Nucleus Accumbens

The nucleus accumbens plays an integral role in addiction. Almost every addictive drug of abuse induces the release of dopamine into the nucleus accumbens. The NAc is particularly important for instrumental learning, including cue-induced reinstatement of drug-seeking behaviour. It is also involved in mediating the initial reinforcing effects of addictive drugs. The most common cell type in the NAc is the GABAergic medium spiny neuron. These neurons project inhibitory connections to the VTA and receive excitatory input from various other structures in the limbic system. Changes in the excitatory synaptic inputs into these neurons have been shown to be important in mediating addiction-related behaviours. It has been shown that LTP and LTD occurs at NAc excitatory synapses.

Unlike the VTA, a single dose of cocaine induces no change in potentiation in the excitatory synapses of the NAc. LTD was observed in the medium spiny neurons in the NAc following two different protocols: a daily cocaine administration for five days or a single dose followed by 10-14 days of withdrawal. This suggests that the structural changes in the NAc are associated with long-term behaviours (rather than acute responses) associated with addiction such as drug seeking.

Human Relevance


Neuroscientists studying addiction define relapse as the reinstatement of drug-seeking behaviour after a period of abstinence. The structural changes in the VTA are hypothesized to contribute to relapse. Once the molecular mechanisms of relapse are better understood, a pharmacological treatment may be developed to prevent it.

Relapse is the biggest problem for recovering addicts; an addict can be forced to abstain from using drugs while they are admitted in a treatment clinic, but once they leave the clinic they are at risk of relapse. Relapse can be triggered by stress, cues associated with past drug use, or re-exposure to the substance. Animal models of relapse can be triggered in the same way.

Search for a Cure for Addiction

The goal of addiction research is to find ways to prevent and reverse the effects of addiction on the brain. Theoretically, if the structural changes in the brain associated with addiction can be blocked, then the negative behaviours associated with the disease should never develop.

Structural changes associated with addiction can be inhibited by NMDA receptor antagonists which block the activity of NMDA receptors. NMDA receptors are essential in the process of LTP and LTD. Drugs of this class are unlikely candidates for pharmacological prevention of addiction because these drugs themselves are used recreationally. Examples of NMDAR antagonists are ketamine, dextromethorphan (DXM), phencyclidine (PCP).

What is Addiction Vulnerability?


Addiction vulnerability is an individual’s risk of developing an addiction during his or her lifetime. There are a range of genetic and environmental risk factors for developing an addiction that vary across the population.

Genetic and environmental risk factors each account for roughly half of an individual’s risk for developing an addiction; the contribution from epigenetic (inheritable traits) risk factors to the total risk is unknown. Even in individuals with a relatively low genetic risk, exposure to sufficiently high doses of an addictive drug for a long period of time (e.g. weeks-months) can result in an addiction. In other words, anyone can become an addict under particular circumstances. Research is working toward establishing a comprehensive picture of the neurobiology of addiction vulnerability, including all factors at work in propensity for addiction.

Refer to Addiction Psychiatry, Addiction Psychology, Addiction Medicine, American Academy of Addiction Psychiatry, Addictive Personality, Addiction Vulnerability, Addiction-Related Structural Neuroplasticity, and American Society of Addiction Medicine.

Three-Factor Model

Accepted research now shows that some people have vulnerabilities to addiction and has established a three-factor standard for vulnerability to drug addiction: genetic factors, environmental factors, and repeated exposure to drugs of abuse. Being vulnerable to addiction means that there exists some factor which makes one individual more likely to develop an addiction than another individual. Additionally, many in the science community agree that addiction is not simply just a result of desensitised neural receptors but also a corollary of long-term associated memories (or cues) of substance use and self-administration. Vulnerability to addiction has both physiological and biological components.

Genetic Factors

Contemporary research in neurobiology (a branch of science that deals with the anatomy, physiology, and pathology of nervous system) of addiction points to genetics as a major contributing factor to addiction vulnerability. It has been estimated that 40-60% of the vulnerability to developing an addiction is due to genetics. One gene in particular, the D2 subtype of dopamine receptor, has been studied at length in association to substance addiction. The D2 receptor responds to the chemical dopamine which produces rewarding and pleasurable feelings in the brain. Through mice studies, agreeing contemporary research has shown that individuals with a deficiency in this dopamine receptor exhibit not only a preference for and increased consumption of alcohol over their genetically normal peers, but also compensated levels of the cannabinoid receptor type CB1.

This suggests that both of these genetic factors work together in the regulation of alcohol and cocaine in the brain and in the normal regulation of dopamine. Individuals with this genetic deficiency in the D2 dopamine receptor may be more likely to seek out these recreational pleasure/reward producing substances as they are less receptive to the natural “feel good’’ effects of dopamine. This naturally occurring deficiency is one of the most studied genetic vulnerabilities to substance abuse across the field. Recent studies show that GABA also plays a role in vulnerability to addiction. When alcohol is consumed it affects GABA by mimicking its effects on the brain, such as basic motor functions.

Additionally, genetics play a role on individual traits, which may put one at increased risk for experimentation with drugs, continued use of drugs, addictions, and potential for relapse. Some of these individual personality traits, such as impulsivity, reward-seeking, and response to stress, may lead to increased vulnerability to addiction.

Environmental Factors

A major environmental factor that increases vulnerability to developing addiction is availability of drugs. Additionally, other environmental factors come into play, such as socioeconomic status and poor familial relationships, and have been shown to be contributing factors in the initiation (and continued use) of drug abuse. Neurobiology again plays a role in addiction vulnerability when in combination with environmental factors. The main risk of chronic stressors contributing to vulnerability is that they can put the brain in a compromised state. External stressors (such as financial concerns and family problems) can, after repeated exposure, affect the physiology of the brain.

Chronic stress or trauma has been shown to have neuroadaptive effects such that the brain can essentially physically “rewire” itself to accommodate for the increase in cortisol produced by the stressors. Evidence has also shown that a great amount of stress hinders your prefrontal functioning as well causes an increased limbic-stratal level responding. This can lead to low behavioural and cognitive control. Additionally, when the brain is put under severe stress due to repeated drug use, it has been shown to be physiologically altered. This compromised neural state plays a large role in perpetuating addiction and in making recovery more difficult.

Repeated Exposure

Repeated exposure to a drug is one of the determining factors in distinguishing recreational substance use from chronic abuse. Many neurobiological theories of addiction place repeated or continued use of the drug in the path of addiction development. For example, researchers have theorized that addiction is the result of the shift from goal-directed actions to habits and ultimately, to compulsive drug-seeking and taking.

In other words, repeated, deliberate use of the drug plays a role in the eventual compulsory drug-taking and/or habitual drug-taking associated with addiction. Another theory suggests that through repeated use of the drug, individuals become sensitised to drug-associated stimuli which may result in compulsive motivation and desire for the drug.

Additionally, a third neurobiological theory highlights the changes in brain reward circuitry following repeated drug use that contributes to the development of addiction such that addiction is conceptualised as being a progression of allostatic changes in which the addicted individual is able to maintain stability but at a pathological set point. Experience-dependent neural plasticity is a hallmark of repeated drug exposure and refers to the adaptation of the brain due to increased levels of the drug in the body. In this sense, repeated exposure falls under the both physiological vulnerability and behavioural/psychological vulnerability to addiction.

Although many variables individually contribute to an increased risk of developing a substance use disorder, no single vulnerability guarantees the development of addiction. It is the combination of many factors (e.g. genetics, environmental stressors, initiation and continued use of the drug) that culminates in the development of this disorder.


Previous research has examined the increased risk of substance use initiation during adolescence. Many factors have been identified as being associated with increased risk of substance use during this period of development including individual differences (e.g. negative affect, decreased harm avoidance, and low motivation for achievement), biological (e.g., genetic predisposition and neurological development), and environmental factors (e.g. high levels of stress, peer influences, availability of substances, etc.). Rat studies provide behavioural evidence that adolescence is a period of increased vulnerability to drug-seeking behaviour and onset addiction.

The mesolimbic dopamine system of the brain is undergoing reorganisation and functional changes during adolescence. Rat studies have demonstrated that adolescents have tendencies and abilities to drink more than adults due to minimal disruption to their motor functions and also due to minimal sensitivity to sedation. As a result, it is more susceptible to become addicted in the wake of drug use during this developmental period. Overall, social, behavioural and developmental factors in adolescence make individuals more liable to drug seeking behaviour, and as a result, addiction.

Epigenetic Factors

Transgenerational Epigenetic Inheritance

Epigenetic genes and their products (e.g. proteins) are the key components through which environmental influences can affect the genes of an individual; they also serve as the mechanism responsible for transgenerational epigenetic inheritance, a phenomenon in which environmental influences on the genes of a parent can affect the associated traits and behavioural phenotypes of their offspring (e.g. behavioural responses to environmental stimuli). In addiction, epigenetic mechanisms play a central role in the pathophysiology of the disease; it has been noted that some of the alterations to the epigenome which arise through chronic exposure to addictive stimuli during an addiction can be transmitted across generations, in turn affecting the behaviour of one’s children (e.g. the child’s behavioural responses to addictive drugs and natural rewards).

The general classes of epigenetic alterations that have been implicated in transgenerational epigenetic inheritance include DNA methylation, histone modifications, and downregulation or upregulation of microRNAs. With respect to addiction, more research is needed to determine the specific heritable epigenetic alterations that arise from various forms of addiction in humans and the corresponding behavioural phenotypes from these epigenetic alterations that occur in human offspring. Based upon preclinical evidence from animal research, certain addiction-induced epigenetic alterations in rats can be transmitted from parent to offspring and produce behavioural phenotypes that decrease the offspring’s risk of developing an addiction [note 1]. More generally, the heritable behavioural phenotypes that are derived from addiction-induced epigenetic alterations and transmitted from parent to offspring may serve to either increase or decrease the offspring’s risk of developing an addiction.

Note 01:

  • According to a review of experimental animal models that examined the transgenerational epigenetic inheritance of epigenetic marks that occur in addiction, alterations in histone acetylation – specifically, di-acetylation of lysine residues 9 and 14 on histone 3 (i.e. H3K9ac2 and H3K14ac2) in association with BDNF gene promoters – have been shown to occur within the medial prefrontal cortex (mPFC), testes, and sperm of cocaine-addicted male rats.
  • These epigenetic alterations in the rat mPFC result in increased BDNF gene expression within the mPFC, which in turn blunts the rewarding properties of cocaine and reduces cocaine self-administration.
  • The male but not female offspring of these cocaine-exposed rats inherited both epigenetic marks (i.e. di-acetylation of lysine residues 9 and 14 on histone 3) within mPFC neurons, the corresponding increase in BDNF expression within mPFC neurons, and the behavioural phenotype associated with these effects (i.e. a reduction in cocaine reward, resulting in reduced cocaine-seeking by these male offspring).
  • Consequently, the transmission of these two cocaine-induced epigenetic alterations (i.e. H3K9ac2 and H3K14ac2) in rats from male fathers to male offspring served to reduce the offspring’s risk of developing an addiction to cocaine.
  • As of 2018, neither the heritability of these epigenetic marks in humans nor the behavioural effects of the marks within human mPFC neurons has been established.