The Neuroscience of Addiction - Application to Clinical Practice (2024)

In addressing Substance Use Disorders (SUDs), a significant public health concern, it becomes important to explore the neuroscience of addiction and translate these insights into clinical practice. This approach is crucial, as SUDs are deeply entrenched in the fundamental biological drive to seek pleasure and avoid harm.

This article examines the neuroscientific perspective on how substances such as alcohol, cannabis, and others influence the brain’s reward system, triggering a cascade of neuroadaptations contributing to the development of addiction.

While we focus on substance addiction in this article, the principles apply to other disorders of addiction, such as pathological gambling and internet addiction disorder.

NEUROSCIENCE OF PLEASURE AND PAIN

Like all conscious entities, humans have evolved within their psychological framework to inherently gravitate towards positive stimuli and avoid negative ones, a tendency deeply structured to avert pain and pursue pleasure.

This pursuit of pleasure, instinctual and hereditary, aligns with Freud’s pleasure principle, a cornerstone of psychoanalytic theory.

The pleasure principle posits that the fundamental human drive to seek pleasure and avoid pain is an unconscious force that persistently influences behaviour.

Freud asserted that this principle operates throughout an individual’s lifespan, subtly directing actions and moulding subjective experiences.

Unlocking the Neurobiology of Freud’s Psychoanalytic Theories – Neuropsychoanalysis | Part 1 of 4

This drive for pleasure is considered a primary motivator in the development of human behaviour, exerting a significant influence on individuals’ choices and actions in pursuit of hedonic fulfilment. [Cieri & Esposito, 2019]

This adaptive behaviour, while critical for survival, also predisposes individuals to the risk of addiction.

Across species, the response to rewarding stimuli (like food and sex) and aversive stimuli (such as pain and threats) is remarkably conserved.

In terms of pain and reward dynamics, the pleasure principle aligns with the opponent-process theory (OPT) of emotion. [Borsook et al., 2016]

This theory suggests that hedonic tone results from valuationally opposite reward and aversion processes that regulate emotional and motivational homeostasis.

According to the OPT, repeated activation of one process can lead to its attenuation and the concurrent intensification of the opponent process.

This concept is central to the neurobiological model of addiction proposed by Koob and colleagues, which underscores the intricate interaction between the reward and stress systems within the brain, which we will cover later. [Koob et al., 2014]

The model suggests addiction as a disorder of hedonic homeostasis, wherein the chronic pursuit of pleasure via substance use paradoxically results in heightened stress and diminished reward sensitivity. This dysregulation fuels compulsive drug-seeking behaviour and a challenging addiction cycle, mediated by the brain’s reward pathways, including dopamine neurotransmitter systems. These pathways, altered by substances of abuse, drive the excessive pursuit of pleasure and the neglect of potential harm.

Human innovation has led to the extraction and refinement of substances that are more compelling than natural rewards.

High-strength alcoholic beverages, cigarettes, and technologically advanced drug delivery systems, such as syringes and vaping devices, provide potent stimuli that can overpower the brain’s reward system.

Additionally, modern chemistry has introduced new, highly potent psychoactive substances, including synthetic opioids and cannabinoids, which can influence reward pathways more robustly than ever before, significantly increasing the risk of addiction.

Common substances leading to SUD include alcohol, tobacco, caffeine, cannabis, methamphetamine, heroin, and cocaine.

The availability of highly addictive drugs, combined with certain environmental factors (such as stress and peer influence) and individual vulnerabilities (including mental health conditions, chronic pain, genetic predisposition, age, and gender), significantly impact the likelihood of substance experimentation and the development of SUDs.

IS ADDICTION A DISEASE? THE BRAIN DISEASE MODEL OF ADDICTION (BDMA)

The brain disease model of addiction (BDMA) is an influential framework for understanding addiction. This model posits that addiction stems from neurobiological changes in the brain that alter reward anticipation and perception, cognitive control, and memory.

By conceptualising addiction in this way, the BDMA helps diminish stigma and shifts the blame away from individuals by recognising addiction as a result of these underlying brain alterations. [Volkow et al., 2016]

According to the BDMA, the structural and functional changes in the brain make relapse common, illustrating how individual vulnerabilities and environmental stressors contribute to the risk of addiction.

While the disease model of addiction can help shift the discourse from a moral to a medical perspective, it may not be the sole method for achieving a non-moralistic view of addiction.

Medical terminology alone does not always remove the stigma; in some instances, it could perpetuate it.

Conversely, non-disease models, which may risk reviving moral judgments by attributing addiction to character flaws, often overlook the intricate interplay of biological and social factors influencing addictive behaviours.

For some, categorising it as a psychiatric disorder may inadvertently perpetuate segregation and stigma, reinforcing the notion that the disease is an inextricable part of the individual’s identity.

While a diagnostic label can offer clarity and a path to treatment, the journey to overcome a chronic illness like addiction can be both complex and seemingly unrewarding. [Frank and Nagel, 2017]

DEFINITIONS - SUBSTANCE USE DISORDER | ADDICTION | ABUSE | DEPENDENCE

Varying definitions of substance-related disorders have evolved, reflecting advancements in our understanding of addiction and its complexities.

Substance addiction, commonly known as drug addiction, is a chronic relapsing disorder characterised by compulsive drug seeking, a loss of control in managing intake, and withdrawal symptoms upon cessation.

Classified as a chronic disease, drug addiction affects a significant portion of the population. It is associated with numerous secondary health issues, societal challenges, and a decline in work ethic, all carrying substantial societal costs.

The National Institute on Drug Abuse (NIDA) describes addiction as …

A chronic, relapsing brain disease that is characterized by compulsive drug seeking and use, despite harmful consequences. It is considered a brain disease because drugs change the brain – they change its structure and how it works. These brain changes can be long lasting, and can lead to the harmful behaviors seen in people who abuse drugs. [NIDA]

From a diagnostic perspective, the term addiction is now encompassed by theterm substance use disorders.

The abuse and dependence classifications of the DSM-IV were intended to be related yet distinct clinical syndromes. [American Psychiatric Association. (2000)]

Abuse was defined as a maladaptive pattern of use leading to clinically significant impairment or distress over a 12-month period.

Dependence was defined as continued substance use despite behavioural impairment or distress in the same 12-month period.

In 2013, DSM-5 combined what was previously conceptualised as two separate and hierarchical disorders (substance abuse and substance dependence) into one construct, defining substance use disorders on a range from mild to moderate to severe, with the severity of addiction depending on how many of theestablished criteria apply.

The DSM-5 outlines Substance Use Disorder (SUD) as a chronic relapsing neuropsychiatric disorder with three core characteristics: [American Psychiatric Association, 2013]

Compulsive seeking and taking of drugs
Loss of control and craving in limiting intake
Emergence of negative emotion states (e.g. dysphoria, anxiety, and irritability) and stress

DSM‐5 diagnostic criteria for substance use disorder: [American Psychiatric Association, 2013]

A problematic pattern of substance use leading to clinically significant impairment or distress, as manifested by at least two of the following, occurring within a 12‐month period:

The substance is often taken in larger amounts or over a longer period than was intended.
There is a persistent desire or unsuccessful efforts to cut down or control the substance use.
A great deal of time is spent in activities necessary to obtain the substance, use the substance, or recover from its effects.
Craving, or a strong desire or urge to use the substance.
Recurrent use of the substance resulting in a failure to fulfill major role obligations at work, school, or home.
Continued use of the substance despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the substance.
Important social, occupational, or recreational activities are given up or reduced because of use of the substance.
Recurrent use of the substance in situations in which it is physically hazardous.
Use of the substance is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance.
Tolerance, as defined by either of the following:

A need for markedly increased amounts of the substance to achieve intoxication or desired effect.
A markedly diminished effect with continued use of the same amount of the substance.

11. Withdrawal, as manifested by either of the following:

The characteristic withdrawal syndrome for the substance.
The substance (or a closely related one) is taken to relieve or avoid withdrawal symptoms.

NEUROBIOLOGY OF ADDICTION

To understand the mechanisms underlying addiction, it is essential to explore the concept of the reward cascade, as addiction, fundamentally a conditioned behaviour, hinges on the process of reward consolidation.

Without the reinforcement provided by rewards, the learned behaviours that characterise addiction would not take hold.

The neuroscientific understanding of addiction is intricate, with the Reward Cascade being a central component.

The Reward Cascade:

Dopamine (DA) is central to the reward mechanisms triggered by drugs of abuse, as every substance known for its addictive potential has been shown to increase levels of DA in the brain.

The mesolimbic dopamine pathway, extending from the ventral tegmental area (VTA) of the midbrain to the forebrain regions such as the Nucleus Accumbens (NAc), amygdala and medial prefrontal cortex (mPFC), is the crucial component of the brain reward and reinforcement system.

These substances initially influence DA neurons within the ventral tegmental area (VTA).

The subsequent impact of this interaction is the release of DA in the nucleus accumbens (NAc), a core region of the brain’s reward system.

The elevation of DA by these drugs is not uniform but varies depending on their molecular targets and the specific pharmacological effects they impart.

Repeated use of addictive drugs leads to significant neuroadaptations across several neurotransmitter systems.

Glutamatergic, GABAergic, opioidergic, endocannabinoid, cholinergic, serotonergic, and noradrenergic systems undergo changes that influence the brain’s affective and hedonic pathways and its aversive response circuits.

Neurotransmitter systems and their effects on DA modulation: [Volkow et al., 2019]

Endogenous opioid system and its effects:

Modulates the mesolimbic DA system, assigning hedonic values to rewards and aiding decision-making.
Opiates increase DA indirectly by inhibiting GABAergic interneurons in the VTA.
Mu opioid receptors (MOR) on NAc neurons are linked to the rewarding effects of opioids and analgesia.
Delta opioid receptors (DOR) are implicated in analgesia, anxiolysis, and kappa opioid receptors (KOR) associated with dysphoric responses associated with addiction.

The endogenous cannabinoid system (ECS) interaction:

Modulates neurotransmitter systems such as GABA, glutamate, and DA in the mesolimbic pathway.
CB1 receptor activation in cortical glutamatergic afferents inhibits DA release in the NAc, affecting reward behaviours.
Cannabinoids act differently on GABA and Glu terminals due to variations in CB1 receptor-to-vesicle ratios.
Both CB1 and MOR activation on GABA neurons can stimulate DA release by disinhibiting ACh, whereas activation on ACh interneurons could decrease DA levels in the accumbens.
Cannabinoids like 2-archidonoylglycerol (2-AG) can disinhibit substantia nigra GABA-A neurons, leading to an increase in DA.

Medicinal Cannabis – Psychopharmacology and Clinical Application

Glutamate and GABA:

The activity of DA neurons is regulated by local and long-range glutamatergic (excitatory) and GABAergic (inhibitory) inputs from multiple brain regions, including the prefrontal and orbitofrontal cortex and the rostromedial tegmental nucleus.

Glutamatergic inputs to dopamine (DA) neurons in the ventral tegmental area (VTA) and medium spiny neurons (MSNs) in the nucleus accumbens (NAc) play a role in behavioural adaptations associated with reward sensitivity and habit formation, hallmarks of addiction.

Excitatory glutamate stimulates NMDA receptors in the interneuron, resulting in GABA release.

GABA, in turn, inhibits dopamine release from the mesolimbic pathway. Thus, the glutamatergic pathway acts as a break in the mesolimbic dopamine pathway.

The glutamatergic system plays an essential role in learning through NMDA-dependent pathways, essentially reinforcing the learned associations between drug use and positive reinforcement.

Concurrently, the GABAergic system inhibits action potential transmission, providing a modulatory balance that can be disrupted by addictive substances.

This complex interplay is crucial to our broader understanding of addiction and will be explored in more detail later in this article.

Neuromodulatory inputs such as norepinephrine, serotonin, acetylcholine, neuropeptides (oxytocin, neurotensin, orexin), and hormones (insulin, leptin) also influence DA neuron activity.

ROLE OF DOPAMINE IN LEARNING, BEHAVIOUR AND ADDICTION

Dopamine (DA) is one of the oldest neurotransmitters and is central to the phenomena of addiction, influencing behaviour and cognition.

In the mammalian brain, dopamine accounts for 80% of catecholamine content, signifying its place as the dominant neurotransmitter. [Costa and Schoenbaum, 2022]

Dopamine’s presence and function are incredibly conserved across the animal kingdom, indicative of its fundamental role in life processes.

Dopamine’s evolutionary journey began around 600 million years ago, correlating with the emergence of motility in multicellular organisms.

The architectural design of the basal ganglia in vertebrates is remarkable. It is characterised by dual output pathways that contrast with the singular direct pathway found in simpler species with less complex nervous systems.

The emergence of a secondary or indirect pathway in vertebrates signifies a significant evolutionary advance.

This indirect pathway is integral to the nuanced and precise response selection for higher cognitive processes. This evolution of the basal ganglia’s indirect pathway is believed to be foundational to the sophisticated cognition observed in mammals, including humans, reflecting the intricacy of neural development through evolutionary history. [Keeler et al., 2014]

The axiom “To think is to move” underscores dopamine’s pivotal role in initiating and controlling movement. [Keeler et al., 2014]

THE STRUCTURAL ORGANISATION OF DA NEURONS:

In mammals, the majority of brain dopamine is produced by neurons in the ventral midbrain, particularly within the ventral tegmental area and the substantia nigra.

Humans possess approximately 135,000 dopaminergic neurons in the substantia nigra and 40,000 in the ventral tegmental area.

These neurons project to three principal regions, forming 3 key DA pathways:

Mesocortical – projecting to the cortex
Mesolimbic – projecting to the nucleus accumbens (ventral striatum)
Nigrostriatal – projecting to the dorsal striatum

Beyond these pathways, dopaminergic projections extend to the amygdala, olfactory tubercle, hippocampus, and cerebellum.

The Dopamine Hypothesis of Schizophrenia – Advances in Neurobiology and Clinical Application

The striatum’s dense dopamine innervation is a crucial component of the basal ganglia circuit, which plays an important role in the development of addictive behaviours.

Within the striatum, 95% of neurons are striatal projection neurons (SPNs), the vast majority of which are Medium spiny neurons (MSNs). These act as the principal interface between dopamine reward signals and functionally diverse cortico-basal ganglia circuits.

These MSNs are categorised into two groups based on dopamine receptor expression with differing functions:

D1R-positive (direct pathway)
D2R-positive (indirect pathway).

FUNCTIONS OF DA:

Dopamine modulates many critical functions across various brain regions. [Klein et al., 2019]

THEORIES OF ADDICTION

Research has highlighted 3 principal theories elucidating the neurobiological underpinnings of addictive behaviours, each positing divergent mechanisms of dysfunction within the brain’s reward circuitry. [Luijten et al., 2017][Patrono et al., 2016]

1. Reward Deficiency Syndrome (RDS) Theory: [Blum et al., 1996]

The Reward Deficiency Syndrome (RDS) model posits that individuals with hypodopaminergic traits require additional external stimulation to attain feelings of satisfaction or pleasure.
This model further contends that these hypodopaminergic characteristics are predisposed by genetic factors responsible for maintaining dopamine homeostasis, leading to an inherent difficulty in activating the brain’s reward pathways and resulting in a chronic underactivation of these neural circuits.
This hypoactivation is theorised to result in diminished pleasure derived from typical rewarding stimuli.
Consequently, addictive behaviours, such as substance use or gambling, are initiated as compensatory mechanisms to stimulate these underactive reward centres, particularly the ventral striatum (VS), in an attempt to mitigate this reward deficiency.

2. Impulsivity Theory / Hedonic Dysregulation Theory [Koob, 2000]

This theory contrasts with RDS by positing that addiction stems from an excessively active brain reward system rather than a deficiency, as suggested by Reward Deficiency Syndrome (RDS).
This heightened reward reactivity leads individuals to experience intense responses to reward cues, driving novelty-seeking, impulsivity, and ongoing substance-seeking behaviour.
Addiction is seen as the result of a “top-down vicious circle” where an imbalance in the hedonic state propels the transition from casual drug use to addiction.
The progression into addiction involves three stages: “preoccupation/anticipation,” “binge/intoxication,” and “withdrawal/negative affect,” which intensify over time and disrupt the hedonic balance. (See later)
“Sensitisation” contributes to addiction by shifting towards an “incentive-salience” state where initial use is for pleasure and subsequent use is driven by negative reinforcement—to avoid withdrawal discomfort.
The model highlights the evolution from impulsivity in early drug use to compulsivity in later stages, with craving being central to the addictive process.
The interaction of the three stages exacerbates hedonic dysregulation, leading to full-blown addiction, characterised by an overpowering urge to use drugs despite obligations, an increasing need for larger drug quantities, and significant withdrawal effects.

3. Incentive Sensitisation Theory: [Berridge, 2004]

According to this theory, “Liking” and “Wanting” are distinct processes within the reward system, each following separate neural pathways.
Chronic drug use induces neurological changes in the reward system, sensitising it to drugs and related cues.
This sensitisation amplifies the incentive value of drug-related stimuli, leading to a state where users of the drug “want” the substance despite diminished “liking” or pleasure derived from its use.
The imbalance between “wanting” (driven by incentive-sensitisation) and “liking” contributes to the development of addictive behaviours.
Dopamine (DA) projections to the nucleus accumbens (NAc) and striatum are implicated in “wanting,” enhancing the motivational aspect of rewards.
In contrast, DA’s role in “liking,” associated with pleasure and hedonic appreciation, does not involve direct projections to the NAc and neostriatum.
Associative learning from conditioned (CS) and unconditioned stimuli (US) involves memory comparisons that influence this reward processing.
Further cognitive processing is necessary for the conscious awareness of pleasure and motivation, which underlies the emotional components of “liking” and “wanting.”

A fourth theory, the habit learning theory, was proposed. This theoryposited that addiction develops along a temporal continuum, integrating features from three distinct theories: aberrant motivation, hedonic dysregulation, and aberrant learning.

While “wanting” and “liking” – aspects of drug reward associated with appetitive and hedonic components – traditionally function independently, this theory suggests they are part of a sequential process.

4. Habit Learning Theory [Everitt & Robbins, 2005]

The habit-based learning theory posits that the evolution of addiction is linked to the transition from “liking” a substance to “wanting” and eventually “seeking” it compulsively, reflecting a shift from conscious reward-driven behaviours to automatic habits.
The theory delineates a “transitionality” in addiction, shifting from desire to need, leading to substance use despite negative consequences.
Instrumental learning is divided into “goal-directed behaviour,” which is quickly acquired and flexibly deployed guided by outcomes, and “habit learning,” which is slowly acquired, stimulus-bound, and inflexible, driven more by preceding stimuli than consequences.
Drug addiction represents the endpoint of a sequence of transitions starting from voluntary, rewarding substance use to habitual, compulsive behaviour.
Gradual loss of control and the shift in stimulus-response dynamics are central to the transition from goal-directed to habitual drug-seeking behaviour.
The capacity of a substance to serve as a conditioned reinforcer increasingly dictates the pattern of drug-seeking/taking actions, signifying the entrenchment of habit-based learning.
It begins with aberrant habit learning during casual drug use, followed by hedonic dysregulation, and culminates in an aberrant salience-incentivisation driving drug intake.

DOPAMINE PATHWAYS INVOLVED IN ADDICTION

1. MESOCORTICAL PATHWAYS: CORTICO-STRIATAL CIRCUITS IN ADDICTION

One key finding in the pathophysiology of addictive behaviours is a dysfunction of the cortico-striatal reward pathways, including the ventral striatum (VS) and the medial prefrontal cortex (mPFC). [Volkow et al., 2019]

These circuits include corticostriatal circuits crucial for reward processing and cognitive control, midbrain pathways, and thalamic-cortical circuits that play roles in craving and addiction behaviours.

These circuits form parallel loops, connecting different PFC areas with various striatum subregions, and are implicated in cognitive aspects, impulsivity, compulsivity, and reward processing in addiction.

Research demonstrates varying brain activation in response to rewards in addicted individuals. [Luijten et al., 2017]
Discrepancies in reward-processing abnormalities are reported, with some studies finding reduced activity, others finding increased activity, or some finding no difference in the ventral striatum (VS) compared with non-addicted individuals.
Functional MRI research reveals a pattern of reduced activation in the striatum during reward anticipation in individuals with gambling disorder (GD) and substance use disorder (SUD).
During the reward outcome phase, individuals with SUD exhibit heightened VS activation, whereas those with GD show decreased activation in the dorsal striatum.

2. The Mesolimbic Pathway and Its Role in Seeking Behaviour

There is good evidence that psychostimulants, opiates, ethanol, cannabinoids and nicotine increase dopamine transmission in the nucleus accumbens in particular. [Pierce & Kumaresan, 2006]

The mesolimbic dopamine system arises from the ventral tegmental area (VTA) projecting to the nucleus accumbens and plays a crucial role in directing goal-oriented behaviours. [Alcaro et al., 2007]

This system increases the stimuli’s salience or importance, effectively making them desired incentives. It drives organisms towards seeking behaviours that enhance survival and away from detrimental ones.

3. THE NIGROSTRIATAL PATHWAY

The nigrostriatal pathway, with dopamine neurons in the substantia nigra projecting to the dorsal striatum, is critical for translating recurring reward signals into habits.

The dorsal striatum is classically segregated into a medial aspect, the dorsomedial striatum (DMS), and a lateral aspect, the dorsolateral striatum (DLS).

Classic studies have shown that the DMS is associated with goal-directed actions while the DLS is related to habitual actions. [Lipton et al., 2019]

This pathway is involved in action-outcome learning, which is essential for adaptive behaviour but can contribute to the formation of habitual behaviours associated with addiction.

When we look at living creatures from an outward point of view, one of the first things that strike us is that they are bundles of habits (James, 1890).

Behavioural automaticity, as articulated by William James in his seminal work “Habit,” is a cornerstone of human behaviour. It is crucial for conserving cognitive resources, allowing us to allocate attention to new and complex tasks.

The more of the details of our daily life we can hand over to the effortless custody of automatism, the more our higher powers of mind will be set free for their own proper work. (James, 1890).

Habit is thus the enormous fly-wheel of society, its most precious conservative agent. It alone is what keeps us all within the bounds of ordinance…[Lipton et al., 2019]

THE PATHOPHYSIOLOGY OF THE SHIFT FROM VENTRAL TO DORSAL STRIATUM IN ADDICTION

Dopamine neurons encode differences between expected and actual rewards in the goal-directed system and between chosen actions and habits in the habit system, thus contributing to the formation of adaptive and maladaptive behaviours such as those seen in addiction.

Interestingly, dopamine NAc neurons often show heightened activity not during the reward itself but in anticipation of it. This anticipatory activation also extends to aversive stimuli, highlighting dopamine’s role in preparing for significant events, both positive and negative.

The transition from goal-directed (voluntary use) to habitual (compulsive drug seeking) behaviours to compulsions or addictions is characterised by a neurobiological shift from the ventral to the dorsal striatum. [Lipton et al., 2019]

Goal-directed behaviour is characterised by its reliance on attention, flexibility, and sensitivity to the current value of rewards. It requires a higher cognitive engagement to adapt to changing circ*mstances.

In contrast, habitual behaviour operates on a stimulus-response mechanism, showing less dependence on the immediate value of rewards and more on automaticity and routine.

The transition from goal-directed to habitual behaviour, and potentially to compulsive actions or addiction, is described as a continuum. This progression is marked by a strengthening of stimulus-response associations and a diminishing relevance of the outcome of actions.

Although this shift is generally considered bidirectional, allowing for a return from habitual to goal-directed behaviours, in extreme cases of addiction, reverting fully to non-addictive behaviours may be uncertain.

Goal-directed actions adjust quickly to changes in reward value. In contrast, habitual behaviours require significantly more trials to extinguish, particularly evident in the context of addiction, where behaviour becomes compulsive and resistant to negative consequences.

To summarise, the neural dynamics between goal-directed and habitual behaviours are orchestrated through differential activation within the striatum, beginning with initial habits linked to the ventral striatum’s action valuation and transitioning progressively to the dorsal striatum.

As behaviours evolve from goal-directed actions initially centred in the dorsomedial striatum (DMS) to more automatic, habitual actions in the dorsolateral striatum (DLS), there is an increased engagement of dorsal-striatal circuits, particularly under conditions of prolonged drug administration, enhancing drug-seeking behaviours that rely increasingly on the dopaminergic activity within these regions.

However, this traditional view of habit formation in addiction has been challenged.

Studies show that individuals with addiction may display a blend of creative problem-solving to obtain drugs and ritualistic behaviours during consumption, suggesting a complex interplay between adaptive and maladaptive behaviours rather than a simple transition to habitual actions. [Volkow et al., 2019]

NEUROADAPTATIONS IN ADDICTION – THE CASCADE TOWARDS ADDICTION

The complex journey towards addiction is marked by drugs inducing enduring neuroplastic changes in midbrain dopamine (DA) neurons and their projections into the nucleus accumbens (NAc) and dorsal striatum.

Neuroplastic changes triggered by drugs also involve the amygdala (a region involved in emotions and stress response), the hippocampus ( involved in memory), and the prefrontal cortex ( involved in self-regulation and the attribution of salience [the assignment of relative value]).

These adaptations play a role in the development of conditioned responses, heightened incentive salience to drug cues, and behavioural inflexibility, ultimately contributing to the persistent risk of relapse.

NEUROBIOLOGICAL PROCESSES CENTRAL TO ADDICTION:

1. Conditioning:

The association of behaviours with specific cues, either sensory (Pavlovian conditioning) or action-based (operant conditioning), depends on their outcomes.

2. Reward and Motivation:

Reward refers to the positive reinforcement that follows an action, which increases the likelihood of that action being repeated in the future. Motivation is the process that initiates, guides and sustains goal-oriented behaviours, often driven by the anticipated reward.

3. Self-Regulation:

The ability to control impulses and delay gratification in response to cues or the presence of a drug.

4. Negative Mood and Stress Reactivity:

The responsiveness of an individual’s stress system and mood regulation may be dysregulated in addiction.

5. Interoceptive Awareness: [Quadt et al., 2018]

Interoception consists of the receiving, processing, and integrating internal bodily signals with external cues to construct a subjective representation of the experience.

1. CONDITIONING IN ADDICTION

Conditioning within the context of addiction is established when DA neurons fire in response to drug-predictive cues, thus anticipating an imminent reward.

Various types of cues, including environments, individuals, or even mental states associated with drug consumption, can later evoke the motivation to seek the drug independently.

Role of Glutamate in Conditioning:

Glutamatergic inputs to DA neurons in the VTA and MSNs in the NAc set the stage for the behavioural changes in reward responsiveness and habituation that underpin addiction.
This includes alterations in dendritic morphology and glutamate receptor dynamics, specifically AMPA and NMDA receptors, resulting in long-term potentiation (LTP) or depression (LTD).
Synaptic strength modulation occurs through presynaptic glutamate release and postsynaptic receptor dynamics.
Repeated drug use may lead to LTP, enhancing signal transmission between neurons, or LTD, decreasing signal transmission.
The insertion of calcium-permeable AMPA receptors enhances synaptic function and LTP. Changes in synaptic strength correlate with dendritic spine alterations.
While most glutamatergic synapses contain both AMPA and NMDA receptors, a small number of “Silent” synapses only express NMDA receptors and are implicated in chronic stress, addiction, and neurodegenerative disorders. [Volkow et al., 2019]

Role of Dopamine in Conditioning:

Exposure to drug-predictive cues can trigger DA bursts in the NAc, leading to the consolidation of conditioned responses in the dorsal striatum. (Conditioned reinforcement)
This directs attention towards the cue and motivates drug procurement mediated by the mesocorticolimbic DA system. (Incentive salience)
Subsequent drug use perpetuates DA release, maintaining the vicious cycle of drug intake and the potential for relapse.
Both conditioned behaviour and incentive salience contribute to cue-induced drug-seeking and the evolution of compulsive drug-seeking behaviours.

2. REWARD, ANTI-REWARD AND MOTIVATION IN ADDICTION

A hypodopaminergic state characterised by reduced sensitivity in the dopamine (DA) reward circuitry to reward consumption is a central feature of the reward deficiency state (RDS) in addiction.

Several gene polymorphisms (exceeding 39,632) influencing the glutamate and dopamine pathways have been identified, predisposing individuals to RDS and acting as a vulnerability factor for addiction.

Reward Deficiency Syndrome (RDS) is a polygenic trait that suggests cross-talk between different neurological systems, including the known reward pathway, neuroendocrine, and motivational systems.

In the dynamics of chronic substance use, individuals often become entrenched in a reward-anti-reward paradigm driven by neuroadaptations involving various neurotransmitters and neural circuits beyond the initial reward pathways.

Early phases of drug use result in dopamine (DA) release in the nucleus accumbens (NAc). However, with repeated use, the magnitude of drug-induced DA surges and their subjective reinforcing effects tend to wane in individuals with addiction compared to non-addicted controls.

Interestingly, in addicted individuals, the striatal DA response intensifies not in reaction to the drug itself but to cues conditioned by the drug, which are linked to heightened self-reported cravings.[Volkow et al., 2019]

These DA responses to conditioned cues often surpass the response to the drugs (i.e., the DA increase in response to the drug is lower than the increase in response to cues), suggesting a shift in the locus of reinforcement.

Volkow et al. suggest that this misalignment between the anticipated effects of the drug and the actual diminished pharmacological response may fuel the cycle of chronic substance use as individuals chase the elusive expected reward that has been conditioned. [Volkow et al., 2019]

Compounding this cycle is the engagement of an anti-reward system.

This system becomes prominent over time when drug use ceases, leading to a reduction in neurotransmitters like DA and serotonin in the reward circuits, accompanied by increased levels of stress-related neurochemicals like dynorphin, norepinephrine, and corticotropin-releasing factor (CRF).

The resultant state is characterised by dysphoria and a negative mood state indicative of withdrawal, further perpetuating the cycle of addiction.

Addicted subjects, particularly in early or protracted withdrawal, exhibit decreased levels of D2 receptors in the striatum, impacting both dorsal and ventral regions, leading to diminished motivational value and a general disinterest in non-drug-related activities-a hallmark of addiction.

Lower D2 receptor levels during withdrawal correspond with reduced baseline activity in frontal brain regions associated with salience attribution (orbitofrontal cortex) and inhibitory control (anterior cingulate gyrus). This leads to impulsivity and compulsivity, which may trigger drug reinstatement or relapse.

The diminished reward sensitivity to non-drug rewards potentially undermines their motivation to engage in and enjoy naturally rewarding activities and stimuli.

Furthermore, this blunted sensitivity also extends to negative reinforcers; when encountering negative consequences, there is decreased activity in the striatal and prefrontal areas of the brain.

This reduced reactivity is linked to poorer outcomes in addiction treatment. The impaired response to negative reinforcers might also limit an addicted individual’s ability to be discouraged by adverse consequences, such as incarceration or the loss of child custody. [Volkow et al., 2019]

REWARD DEFICIENCY AND ANTI-REWARD IN ADDICTION: ALLOSTASIS

Allostasis, or stability through change, has most often been linked with challenges to homeostasis, in which repeated challenges or stressors produce sufficient allostatic load to generate an allostatic state that can ultimately lead to a disease state. [Koob & Schulkin, 2019]

In relation to addiction, the development of a negative emotional state that occurs during acute withdrawal and persists into protracted abstinence has been defined as an allostatic state. [Koob and Le Moal, 2008]

Under normal homeostatic conditions, there is a balanced interaction between circuitry involved in reward and aversion, i.e., normal ability to like and dislike.

Under allostatic conditions (e.g., negative affect and withdrawal), there is a stressor that is mitigated by an opponent process (substance use) that results in the normalisation of the process, i.e., withdrawal −> substance use and relief from withdrawal.

Such a state has been hypothesised to involve both:

Diminished dopaminergic tone over time (i.e., hypodopaminergic condition) that contributes to a reward deficiency syndromeand
Increases in stress function contribute to chronic stress.

The combination of the two leads to allostatic load, contributing to a negative emotional state in humans (i.e., (hyperkatifeia or a hypernegative emotional state) characterised by irritability, physical pain, emotional pain, malaise, dysphoria, alexithymia, and the loss of motivation for natural rewards. [Koob & Schulkin, 2019]

3. SELF-REGULATION AND IMPULSE CONTROL IN ADDICTION

Self-regulation is an overarching term that describes the integrated framework for managing one’s behaviours, thoughts, and emotions across various contexts.

It involves planning, emotional modulation, response inhibition, and adherence to social norms and values.

Self-regulation consists of

Inhibitory control and;
Self-control.

Inhibitory control, an essential executive function, allows for the management of attention, behaviour, thoughts, and emotions to overcome strong predispositions or temptations, facilitating appropriate or necessary actions. [Diamond, 2013]

Self-control is the ability to resist short-term temptations to achieve long-term goals. It includes four key components: [Diamond, 2013]

Behavioural control: The ability to suppress inappropriate behaviours or responses.
Emotional control: Managing and regulating emotional reactions in varying situations.
Task focus: The capacity to maintain attention and persist in completing tasks despite competing distractions or desires.
Delaying gratification: The willingness to forgo immediate pleasures for greater future rewards, also known as delay discounting.

Within the context of addiction, self-regulation becomes compromised as the brain’s reward system develops an exaggerated sensitivity to drug-related cues.

This heightened reactivity diminishes the top-down regulatory control typically exerted by the prefrontal cortex.

The integrity of the substantia nigra (SN) -frontostriatal circuit has been associated with improved impulse control.

Enhanced cognitive control over the striatum exerted by prefrontal cortical regions is suggested to reduce impulsivity.

Clinical imaging studies have consistently shown a correlation between reduced striatal D2 receptor (D2R) density in addiction and decreased metabolic activity in various prefrontal regions, including the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), and dorsolateral prefrontal cortex (DLPFC).

These regions are integral to salience attribution, inhibitory control, emotion regulation, and decision-making processes.

A disrupted modulation of these PFC areas by striatal D2Rs in individuals with addiction likely contributes to:

Heightened motivational value assigned to drugs
Substantial loss of control over drug intake
Compulsive and impulsive patterns of drug consumption

The tonic firing of D2Rs, which plays a role in motivation, can counteract drug consumption through the regulation of PFC regions responsible for self-regulation, provided it is not accompanied by phasic firing associated with associative learning. [Volkow et al., 2019]

Thus, the decline of self-control mechanisms in addiction is tightly linked to the functional impairment in prefrontal cortex (PFC) circuits. This impairment often results from drug-induced neuroplastic adaptations in the striatal networks or, in some cases, direct damage to the PFC itself.

It is hypothesised that an increase in compulsive drug-seeking behaviour indicates a shift from ‘top-down’ prefrontal cortical control to ‘bottom-up’ striatal behavioural control, driven by progressive changes in dopamine transmission.

In summary, addiction reflects extensive neuroplastic changes that commence within mesolimbic pathways and propagate through the brain’s reward circuitry, ultimately impairing the PFC and its ability to regulate impulses. This neurobiological cascade results in the deterioration of self-regulatory capacities, leading to the persistent and often destructive patterns of drug-seeking behaviour seen in addiction. [Peters et al., 2016]

Consequently, individuals with addiction may struggle with the inhibitory control necessary to resist substance-related cues, leading to the maintenance of drug-seeking behaviour despite the awareness of adverse consequences. [Heatherton and Wagner, 2011]

4. NEGATIVE MOOD AND STRESS REACTIVITY IN ADDICTION

This process is known as the dark side of addiction.

The “dark side” of addiction emerges prominently during acute withdrawal, characterised by negative mood states and stress reactivity.

Withdrawal is marked by anhedonia, heightened stress response and marked dysphoria and anxiety.

This negative stress state, called hyperkatifeia, is defined as the manifestation of extreme negative emotional states during the withdrawal and negative affect stage of the addiction cycle (see later). Hyperkatifeia plays a crucial role in driving the progression of addiction via negative reinforcement.

Typically, such a constellation of symptoms is not present in individuals with minimal drug exposure. The onset of these withdrawal symptoms varies with the type of drug; opioids, in particular, trigger these negative effects more rapidly.

This phase is often accompanied by a significant risk of relapse as individuals may seek to alleviate intense distress and negative emotions through drug use.

The distress experienced during withdrawal correlates with decreased dopamine signalling in response to rewards, leading to anhedonia.

At the same time, there’s an increased sensitivity in the brain’s stress systems, notably within the extended amygdala, habenula, and hypothalamus, implicating neurotransmitters and neuropeptides such as corticotropin-releasing factor (CRF), norepinephrine, and dynorphin further exacerbating the negative mood state.

HPA Axis Activation And Stress:

Activation of the HPA axis impacts the neural circuits involved in drug reward and the development of drug-seeking behaviour.
Acute drug exposure triggers the hypothalamus-pituitary-adrenal (HPA) axis through the corticotropin-releasing factor (CRF), escalating the production of ACTH in the pituitary and cortisol in the adrenal cortex.
CRF can translate aversive experiences into pronounced dopamine increases in the NAc, which, although counterintuitive, is due to CRF’s influence on a specific subset of VTA DA neurons.
These particular neurons are more attuned to aversive stimuli than rewarding ones, underpinning the complex and sometimes paradoxical nature of stress responses in the context of addiction.
The significant changes in stress responsiveness and mood regulation within the neurocircuitry of addiction underlie one of the most challenging aspects of recovery: managing the negative emotional and physiological states that arise during withdrawal and that potentiate the cycle of relapse.
Stress is a well-known trigger for the reinstatement of drug-seeking behaviour in animal models, showcasing the intricate relationship between reward and stress systems.

Neurochemical Players in Stress-Induced Reinstatement:

Other neurochemicals involved in stress-induced reinstatement besides CRF include norepinephrine, dopamine, glutamate, dynorphin, hypocretin, and neuropeptide Y.
Repeated compulsive drug use elevates dynorphin concentrations within the nucleus accumbens and amygdala, inducing a state akin to dysphoria.
Elevated dynorphin acts as part of a negative feedback mechanism to inhibit dopamine synthesis, and activation of kappa opioid receptors by agonists reduces extracellular dopamine in the nucleus accumbens. [Uhl et al., 2019]
These neurotransmitters interact with key brain regions involved in the stress response and addiction, such as the bed nucleus of the stria terminalis (BNST), central amygdala, ventral tegmental area (VTA), nucleus accumbens (NAc), habenula, dorsal raphe, locus coeruleus, and various regions within the prefrontal cortex.

The Lateral Habenula:

The lateral habenula (LHb) emerges as a key neural structure in the mediation of negative states and avoidance behaviours in the context of addiction. It plays an important role in inhibiting midbrain dopamine neurons, a process crucial for regulating the brain’s response to unfavourable outcomes, i.e. negative reward prediction errors (RPEs).
Neurons in the LHb exhibit excitation in response to negative RPEs and inhibition with positive RPEs.
The LHb is instrumental in both reward prediction and learning by projecting glutamatergic signals to the rostromedial tegmental nucleus (RMTg), which in turn inhibits dopamine activity in the ventral tegmental area (VTA).
Substance abuse can interfere with the lateral habenula’s (LHb) function, distorting the processing of negative reward prediction errors (RPEs).
The LHb is also key in learning and memory related to avoidance behaviours, disruptions of which are evident in addiction. Its regulatory role in anxiety, linked to its connection with serotonin neurons in the dorsal raphe nucleus, also influences the negative states of addiction. [Graziane et al., 2018]

5. INTEROCEPTIVE AWARENESS IN ADDICTION

Interoceptive awareness consists of the following: [Quadt et al., 2018]

Afferent signalling from body to brain via neural, immune, and endocrine pathways.
Neural processing and integration of internal bodily state information.
Impact of this internal information on perceptions, thoughts, and actions.
Conscious awareness of these internal states as physical sensations and emotions.

The insular cortex is the central nervous system hub that processes and integrates these signals. Interoception is an important component of several addiction-relevant constructs, including arousal, attention, stress, reward, and conditioning. [Paulus and Stewart, 2014]

Interoceptive awareness plays an important role in the transition from goal-directed behaviours to more reflexive, compulsive actions, a transition that is intimately connected to both internal (interoceptive) and external (exteroceptive) cues.

The insula, especially its anterior region, is critically involved in interoception, processing and integrating physiological signals related to the body’s internal state within the context of ongoing activities.

It communicates this information to other key brain regions, such as the anterior cingulate cortex (ACC), ventral striatum, and ventromedial prefrontal cortex (PFC), responsible for initiating adaptive responses to those internal cues.

The heightened focus on interoceptive processes in addiction is linked to increased activity within the default mode network (DMN), a network also influenced by dopamine.

The DMN is typically engaged in self-referential thinking and mind wandering.

In addiction, enhanced activation of the DMN is postulated to lead to a disproportionate focus on the internal state of craving or discomfort, focusing the individual’s attention on their subjective experience of craving and the associated negative emotions. [Zhang and Volkow, 2019]

Salience Network’s Role in Addiction:

The salience network (SN) is a key player in discerning the most significant stimuli from an array of internal and external inputs, regardless of their positive or negative nature. The network is crucial for directing cognitive resources to these salient stimuli effectively.

In addiction, there is a marked disruption in the structural and functional connectivity of the SN, which is integral to its role in inter-network communication. This dysfunction is evidenced by changes in how the addicted brain processes both external cues and internal bodily states. [Cushnie et al., 2023]

The salience network (SN), with its two key nodes, the anterior insular cortex (AIC) and the dorsal anterior cingulate cortex (dACC), has been studied in addiction. Research has underscored the dACC’s involvement in the disruptions of inhibitory control related to drug use and the AIC’s critical role in interoception, craving, and relapse. [Cushnie et al., 2023]

The insula’s interaction with the brain’s dopaminergic system plays a crucial role in addiction and reward processing by integrating external cues and internal physiological sensations into the reward experience. This region, particularly the anterior insular cortex (AIC), which contains a high density of dopaminergic D1 receptors and receives significant dopaminergic inputs, responds to dopamine and influences dopaminergic signalling.

This functionality within the salience network underscores the significance of interoception in addiction, illustrating how both external cues and internal bodily sensations contribute to the reward experience and highlighting the complex interplay between bodily state awareness, drug experience valuation, and addictive behaviours.

STAGES OF ADDICTION

The five neurobiological processes of addiction can be effectively simplified into three interconnected stages:

Binge/intoxication
Withdrawal/negative affect
Preoccupation/anticipation

These three stages encapsulate complex changes in neuroplasticity, reward processing, motivation, stress responses, cognitive control, and alterations in associated brain regions and circuits. Central to SUDs is the compulsion to seek and consume the drug, the inability to limit intake, and the emergence of a negative emotional state in the absence of the drug.

The distress–addiction cycle was first introduced in 1997, and its conceptualisation has been refined over the years to delineate the neurobiological mechanisms of addiction. [Koob and Le Moal, 1997], [Koob, 2021]

The progression of addiction involves a transition from positive reinforcement, where drug intake is driven by impulsivity, to negative reinforcement, where compulsivity to avoid distress becomes the primary driver.

These stages correspond to distinctive domains of dysfunction:

1. Binge/Intoxication Stage: (Incentive Salience)

This stage is associated with increased extracellular dopamine, particularly in the mesolimbic system, upon exposure to drug-associated stimuli triggers.
This phase involves the DA reward system and brain regions, such as the prefrontal cortex and the central nucleus of the amygdala, which are implicated in the development of compulsive drug-seeking behaviours.

2. Withdrawal/Negative Affect Stage: (Reward Deficit and Stress Surfeit)

This stage is associated with a spectrum of uncomfortable emotional symptoms, including irritability, emotional pain, dysphoria, and stress, which can potentiate drug-seeking behaviour driven by negative reinforcement.
This phase is defined by a relatively new construct called hyperkatifeia, from the Greekkatifeia for dejection or negative emotional state.
Within-system neuroadaptations are defined as adaptations where the primary cellular response element to a drug adjusts to neutralise the drug’s effects, with the persistence of opposing effects even after the drug is no longer present.
This stage also involves between-system neuroadaptations, where non-dopaminergic systems become dysregulated due to chronic activation of the reward system. Elevated stress hormones and neurotransmitters during acute withdrawal from chronic drug administration lead to the activation of brain stress systems like corticotropin-releasing factor (CRF), norepinephrine, and dynorphin, which exacerbate negative emotional states and abstinence. [Koob and Volkow, 2016]

3. Preoccupation/Anticipation Stage: (Executive Dysfunction)

This stage is characterised by the involvement of the prefrontal cortex, which plays an important role in modulating the control of striatal-pallidal-thalamic-cortical systems, which regulate incentive salience and conditioned behaviour.
Glutamatergic projections from the prefrontal cortex modulate striatal circuitry, and cue-induced reinstatement involves glutamatergic and dopaminergic interactions within the PFC, insular cortex, and prelimbic cortex.
The dysfunction of the prefrontal-limbic system during this stage attenuates inhibitory control and exacerbates craving and relapse.
Stress-induced reinstatement in this stage involves dopaminergic systems in limbic and motor circuits, highlighting the importance of executive control in managing craving and potential relapse.
The insula, in particular, has an interoceptive role that integrates emotional and motivational aspects of drug use, providing a conscious awareness of cravings.

The 3 stage conceptual framework proposed by Koob and Volkow emphasises the importance of understanding the distinct neurobiological changes at each stage of addiction to develop more effective interventions and treatments.

Lastly, evidence indicates that abstinence from substance use can reverse some of the brain damage caused by addictive substances, exemplified by improvements in white matter integrity in the dorsolateral prefrontal cortex observed in individuals who maintain abstinence from cocaine.

In summary, SUD can be conceptualised as an intricate interplay between a ‘Go’ system that promotes cravings and habitual behaviours and a ‘Stop’ or ‘No-Go’ system that regulates inhibitory control, both of which are essential for understanding the complexity of addiction. [Koob and Volkow, 2016]

VULNERABILITY FACTORS FOR SUBSTANCE ADDICTION

Genetics:

Addictions are significantly heritable, with 40–60% of the risk attributed to genetic factors. [Volkow et al., 2019]

Genetic predisposition also links substance use disorders (SUD) with internalizing disorders, underpinning the frequent co-occurrence of SUD with anxiety and depression. [Volkow and Blanco, 2023]

Notably, variants in the ADH and ALDH enzyme-encoding genes that result in a more rapid conversion of alcohol to acetaldehyde, the accumulation of which is aversive, have a protective effect against the risk of alcoholism. [Volkow and Blanco, 2023]

Similarly, variants in the OPRM1 gene, which encodes the mu-opioid receptor, affect opioid responses, while changes in the CHRNA5 gene, linked to the alpha-5-subunit-containing nicotine receptor, increase susceptibility to tobacco dependence.

The Reward Deficiency Syndrome (RDS) theory posits a unified etiological framework for addictive and compulsive behaviours, supported by numerous gene polymorphisms, predominantly affecting the glutamate and dopaminergic systems. [Blum et al., 1996]

Dysfunctional reward processing, shared by individuals with mood disorders or certain personality disorders, features prominently in addiction and impulsivity. RDS, as a polygenic condition, implies interactions between the reward circuitry, neuroendocrine, and motivational systems, corroborated by studies across a spectrum of psychiatric conditions, alluding to shared reward system deficiencies. [Blum et al., 2022]

Research has demonstrated that a blunted reward circuitry response to psychoactive drugs or stimuli arising from genetic factors like the DRD2 A1 allele correlates with impaired dopamine functionality.

For instance, the A1 allele of the DRD2/ANKK1-TaqIA gene is associated with addictive disorders and executive function deficits. This genetic shortfall, signified by reduced D2 receptors, contributes to an aberrant reward pathway response. [Ariza et al., 2012]

Recent analyses have solidified the relationship between genetic variation in the dopaminergic receptor D2 and alcohol use disorders (AUD), as well as problematic alcohol consumption, highlighting gene-based associations with AUD severity. [Zhou et al., 2020]

GWAS studies show that addiction is a polygenic disease influenced by multiple genes and networks, though current polygenic scores poorly predict SUD risk.

Furthermore, epigenetic modifications are also believed to drive and sustain the long‐lasting changes associated with addiction. Read more on the specific epigenetic aspects linked to addiction.

Developmental Impact:

Emerging neuroscientific evidence suggests that adverse social environments and deprivation during formative years can impede the development of prefrontal-limbic connectivity.

For instance, early life adversity can disrupt the typical amygdala-medial PFC coupling, a process influenced by cortisol, potentially leading to heightened impulsivity and increased SUD risk. [Volkow et al., 2019]

Adolescence represents a critical period where incomplete maturation of the prefrontal cortex (PFC) circuitry, integral for self-regulation, coincides with increased susceptibility to risky behaviours, including drug use.

Brain maturation correlates with enhanced neural oscillation synchronization, which predicts cognitive performance. Perturbations in these developmental trajectories by drugs, genetic factors, or social deprivation may heighten adolescents’ propensity for risky behaviours.

Brain imaging studies align abnormalities in adolescent PFC function and structure with elevated SUD risk, affirming the PFC’s role in self-regulation and its disruption as a vulnerability factor. [Volkow et al., 2019]

Impact of Substance Use in Adolescence:

The frontal cortex, the last brain region to mature and crucial for executive functions like impulse control and decision-making, undergoes significant developmental changes during adolescence.

This period is marked by ongoing myelination, thinning of gray matter, and pruning of neuronal connections.

The still-developing prefrontal cortex in adolescents modulates limbic system activities, which include regulating emotional responses.

This developmental phase makes adolescents particularly prone to risk-taking and susceptible to the influence of drugs and alcohol. [Volkow et al., 2019]

As adolescents’ prefrontal cortex matures, their ability to control impulses improves, but concurrently, heightened activity in the nucleus accumbens enhances reward sensitivity, leading to increased risk-taking and impulsivity. Early drug exposure can further disrupt the maturation of the prefrontal cortex, elevating the lifelong risk of addiction. [Volkow et al., 2019]

The adolescent brain’s pronounced neuroplasticity not only accelerates addiction development compared to adults but also heightens adolescents’ responsiveness to environmental factors like stress, which can promote drug use.

Psychosocial Factors:

Epidemiological studies underscore the influence of high-stress social environments and poor social support on elevated drug experimentation and addiction risk.

Early childhood adversities, characterized by harmful social contexts, are consistently linked to delayed maturation of prefrontal-limbic connectivity, further implicating increased SUD risk.

Moreover, prolonged exposure to psychosocial adversity is associated with reduced striatal dopaminergic activity.

Studies suggest that environmental stressors, including childhood trauma, sensitise the mesostriatal dopamine system, exacerbating the system’s response to subsequent stress challenges. [Dahoun et al., 2019]

TREATMENT PRINCIPLES BASED ON NEUROSCIENTIFIC TARGETS IN ADDICTION

Pharmacological Interventions:

The following is a summary of the currently approved treatments for substance use disorders (SUDs). This article does not delve into specific dosages and detailed treatment protocols but rather provides an overview of the available options.

Opioid use disorder:

1. Buprenorphine:

Mechanism of action:

Partial mu-opioid receptor agonist
Nociceptin receptor agonist
Kappa opioid receptor antagonist

Formulations:

Buprenorphine/naloxone: Sublingual or buccal film
Buprenorphine Sublingual tablet
6-month buprenorphine subdermal implant
1-month extended-release buprenorphine injection

2. Methadone:

Full mu-opioid receptor agonist

Formulations:

Tablet
Oral solution
Injection

3. Naltrexone:

Mechanism of action:

Mu-opioid receptor antagonist
Kappa opioid receptor antagonist

Formulations:

Tablet
Naltrexone is also availablein adepot injection (380 mg).
[Kampman and Jarvis, 2015]

Treatment of acute withdrawal

4. Lofexidine

Alpha‐adrenergic agonist

Overdose reversal

5. Naloxone

Mu-opioid receptor antagonist

Alcohol Use Disorder : [Aubin, 2024]

Currently, the FDA‐approved medications to treat AUD, disulfiram, naltrexone and acamprosate reduce drinking through three different mechanisms of action:

1. Induction of unpleasant effects when consuming alcohol

2. Reduction of rewarding/reinforcing effects of alcohol

3. Reduction of negative state when abstinent

All three of these medications are available in tablet form.

Disulfiram

Aldehyde dehydrogenase inhibitor blocks the breakdown of alcohol, thereby increasing acetaldehyde levels.

Acamprosate

NMDA receptor antagonist and positive allosteric modulator of GABA receptors

Naltrexone

Mu-opioid and kappa opioid receptor antagonist

Current Approved Treatments: [Aubin, 2024]

Acamprosate
Disulfiram
Naltrexone
Nalmefene
Baclofen
Sodium oxybate

Alcohol Use Disorder – Evidence-Based Recommendations for Diagnosis and Pharmacotherapy

The Impact of Alcohol on The Brain – Neurobiology of Dependence and Alcohol-Related Brain Damage

Naltrexone | Naltrexone – Bupropion Combination – Mechanism of Action, Psychopharmacology and Clinical Application

Promising Candidates:

Anticonvulsants topiramate and zonisamide
Gabapentin is beneficial mainly for withdrawal symptoms.

Targeted Benefits:

Varenicline and ondansetron offer specific benefits for AUD patients with less severe addiction or co-occurring nicotine use and early-onset AUD, respectively.

Limited Success:

Certain antipsychotics demonstrate restricted efficacy.

Future Potential: [Celik et al., 2024]

Prazosin
Doxazosin
Mifepristone
Phosphodiesterase-4 Inhibitors: Ibudilast and Apremilast
N-acetylcysteine
Suvorexant
Psychedelics
Ghrelin

Nicotine Use Disorder:

1. Nicotine replacement therapies

Nicotine Transdermal patches
Gum
Lozenges
Inhalers
Nasal spray

2. Bupropion

Dopamine transporter blocker

3. Varenicline

Partial agonist of α4β2 nicotine receptor

Cytisine, a plant-based alkaloid and partial agonist of the α4β2 nicotinic receptor, has effectiveness similar to varenicline and is used for smoking cessation in Central and Eastern Europe, though it is not FDA-approved. [Volkow and Blanco, 2023]

Potential Future Treatment Targets:

Insight into the neurobiology of addiction, highlighting the role of neurotransmitters such as dopamine, glutamate, dynorphin, enkephalin, GABA, and serotonin, has facilitated the identification of potential treatment targets. [Volkow and Boyle, 2018]

Dopaminergic Modulation:

Enhancement of dopamine signalling through D2 receptors, which are often downregulated in addiction, leading to impaired prefrontal cortex (PFC) activity, can mitigate compulsive drug taking.

Glutamatergic Interventions:

Countering hyperactive glutamatergic projections from the PFC and amygdala to the ventral tegmental area and striatum can prevent drug-taking in response to cues or stressors.

Withdrawal State Management:

Addressing the negative affect during withdrawal with CRF or kappa antagonists may halt the escalation of drug use.

Comorbidity Consideration:

There is a high prevalence of comorbidity between SUD and mental illnesses
Patients with concurrent disorders present with more severe and resistant conditions.

Pharmacotherapy Targeting Endophenotypes:

Cognitive enhancers are being explored to bolster impulse control, planning, and decision-making.
Medications that modulate stress response and dysphoria are also considered to help prevent relapse.

Repurposing Medications: [Volkow & Boyle, 2018]

Repurposing existing medications for other indications presents a strategic avenue due to shared neuropathology between SUD and other mental illnesses. Bupropion, for instance, has found utility in smoking cessation beyond its original use as an antidepressant.

Naltrexone shows evidence of efficacy and safety in treating a wide range of substance use and behavioural addictions, such as alcohol, opioids, nicotine, stimulants, gambling, trichotillomania, and kleptomania, as supported by randomized, placebo-controlled trials.

Despite its broad anti-addiction efficacy and good tolerability, it remains underutilised, suggesting a common role for brain opioid pathways in the pathophysiology of addiction and underscoring the need for further research on naltrexone and similar opioid modulators. [Aboujaoude and Salame, 2016]

Combination Therapies:

Although limited, studies on drug combinations, like buprenorphine with naltrexone, show promise in decreasing the use of substances such as cocaine and heroin more effectively than monotherapies.
Pre-clinical studies have highlighted the potential of simultaneously targeting both the α1b and 5HT2A receptors to reduce alcohol consumption. This approach has led to exploring the combined use of prazosin (an α1b blocker) and cyproheptadine (5HT2A antagonist) in treating alcohol use disorders (AUD). Recent findings from a randomised controlled trial indicate that a three-month treatment regimen with a cyproheptadine-prazosin combination can significantly decrease total alcohol consumption (TAC) in cases of severe AUD.
The study revealed a reduction in drinking by more than 23 grams per day compared to placebo, with higher doses resulting in greater reductions.
Importantly, the higher and lower dose combinations demonstrated similar safety profiles, promising a viable new therapeutic avenue for AUD.
This points to a future where integrating such dual-receptor blockade could become a standard intervention in the management of alcohol dependency. [Aubin et al., 2024]

Redefining Efficacy Endpoints:

Research is advancing towards recognising clinically meaningful reductions in drug use and health outcome improvements as efficacy endpoints rather than solely abstinence.

Opioid Targets:

Mu-opioid receptor-centric therapies are most effective for opioid use disorders.
Novel pharmacological approaches involve modulation of reward circuits and withdrawal symptom management without engaging the mu-opioid receptor.

Oxytocin:

This neuropeptide, known for its role in social bonding, has shown potential in reducing the self-administration of various drugs and alleviating withdrawal symptoms in both preclinical and clinical settings.

Cannabinoids:

Medications that act on the endocannabinoid system without inducing cognitive impairment are under investigation.
Allosteric modulators of cannabinoid receptors may offer a promising path for medication development.

Stimulant Use Disorders:

Treatments for stimulant use disorders remain challenging.
Strategies include the use of longer-acting stimulant medications and medications that restore balance to glutamatergic projections.
N-acetylcysteine (NAC), despite mixed results, shows potential in reducing cravings and relapse.

Antiepileptic Drugs:

In managing SUD, antiepileptic drugs like gabapentin and topiramate may reduce use and withdrawal symptoms across various substances due to their modulatory effects on GABAergic signalling.

GLP-1 agonists:

Research is increasingly pointing towards the glucagon-like peptide-1 (GLP-1) system as a significant player in the neurobiology of addictive behaviours, suggesting that GLP-1 analogues could be promising for treating SUDs.
GLP-1 agonists operate at both presynaptic and postsynaptic levels to influence addiction-related neural pathways, impacting behaviours beyond intake and satiation to include drug and alcohol ‘wanting’ and ‘seeking.’ [Klausen et al., 2022 ]
They modulate GABA neurotransmission, indicating a therapeutic role for GLP-1 receptors in AUD.
They also affect key areas in the mesolimbic reward system, such as the VTA and NAc, and have been shown to reduce substance use and drug-seeking behaviours.
The overlap in brain dysregulations between obesity and addiction highlights the usefulness of GLP-1 receptor agonists for treating SUDs and AUD.
Although the precise mechanisms are not fully defined, central dopamine signalling modification is a crucial component of their effect on addiction endpoints.
Genetic associations link GLP-1 receptor variants with increased alcohol self-administration and changes in reward-responsive brain regions.
The GLP-1 analogue semaglutide, in particular, has demonstrated effects that include reducing alcohol consumption and altering central GABA neurotransmission, thereby supporting the potential utility of the GLP-1 system as a therapeutic target for AUD. [Chuong et al., 2023]
Furthermore, preliminary evidence from a retrospective cohort study indicates that semaglutide may also be beneficial in cannabis use disorder (CUD) within real-world populations. However, this finding necessitates further preclinical research to elucidate the mechanisms involved and clinical trials to validate semaglutide’s clinical application for CUD. [Wang et al., 2024]

Topiramate:

Topiramate’s mechanism of action in treating addiction involves three primary processes: [Wetherill et al., 2021]

Potentiation of GABA -A receptor-mediated inhibition, which decreases dopamine release in the cortico-mesolimbic system that mediates reward and reinforcement.
Blocking AMPA-type glutamate receptors, particularly in the nucleus paragigantocellularis, inhibits glutamatergic transmission, which may alleviate autonomic withdrawal symptoms by inhibiting noradrenergic neurons in the locus coeruleus.
Carbonic Anhydrase Inhibition contributes to its anticonvulsant properties and might be beneficial in managing withdrawal symptoms.

A recent study stated that Topiramate shows promise as a significant pharmacological agent in the treatment of alcohol use disorder (AUD), with the potential to address both the neurochemical and behavioural aspects of addiction. [Fluyau et al., 2023]

Topiramate shows the following benefits in AUD:

Reduces heavy drinking days and weeks, as indicated by a moderate effect size
Lowers alcohol cravings significantly.
Prolongs abstinence throughout treatment trials.
Decreases gamma-glutamyl transferase levels, a marker associated with heavy alcohol use.
May reduce anxiety, although its effects on alleviating alcohol withdrawal, minimising relapse, and decreasing depressive symptoms remain inconclusive.

Furthermore, topiramate has also demonstrated evidence of effectiveness in cocaine use disorder as well as in reducing the desire to use amphetamines and methamphetamines. [Siniscalchi et al., 2015], [Moghaddam et al., 2023]

Biological Therapeutics:

Vaccine development and passive immunization with antibodies that prevent drugs from entering the brain have shown promise in preclinical studies but require further human research.

Neuromodulation: [Volkow and Blanco, 2023]

Neuronal circuits disrupted in addiction, such as fronto-cortical circuitry and the insula, are targets for neuromodulation to enhance self-control and reduce cravings, respectively.
Non-invasive neuromodulation techniques include transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and low-intensity focused ultrasound, targeting the dorsolateral prefrontal cortex and the insula.
Peripheral nerve neuromodulation through percutaneous nerve field stimulation or trigeminal nerve stimulation shows promise in treating substance use disorders (SUDs).
Invasive methods like deep brain stimulation, which require surgical implantation of electrodes, are being explored for severe SUDs, with initial studies on the nucleus accumbens indicating potential benefits for alcohol and opioid use disorders.
Currently, the only FDA-approved neuromodulation treatments for SUDs are transcranial magnetic stimulation for smoking cessation and percutaneous nerve field stimulation for opioid withdrawal management.

NEUROBIOLOGICAL PRINCIPLES OF TREATMENT IN BEHAVIOURAL TREATMENTS IN ADDICTION

Neurobiological Mechanisms in Behavioral Interventions: [Fang et al., 2022]

Understanding the neurobiological mechanisms underlying behavioural interventions is key to refining treatment strategies for SUD.

Interventions in the Binge/Intoxication Phase:

In the treatment of addiction, specifically during the binge/intoxication phase, enhancing patient motivation to cease substance use is paramount. Motivational interviewing (MI) has been identified as an effective client-centred intervention targeting ambivalence towards change by targeting the motivation network.
Reviews and meta-analyses have demonstrated that MI can reduce substance use and alcohol consumption more effectively when combined with Cognitive Behavioural Therapy (CBT) than when applied in isolation.

Interventions in the Withdrawal / Negative Affect Phase:

To address withdrawal symptoms, which dominate the second stage of the addiction cycle, developing emotion regulation is pivotal.
CBT is known to improve adaptive emotion regulation skills, aiding individuals in recognising, experiencing, and appropriately adjusting to their emotions by targeting the executive control network. This approach has proven effective in reducing negative urgency in disorders like pathological gambling.
Additionally, Mindfulness-Based Interventions (MBIs) offer a way to nonjudgmentally focus on the present moment, which has been shown to diminish drug use and enhance positive affective states, thereby reducing addictive behaviours.

Interventions in the Preoccupation / Anticipation Phase:

In the preoccupation/anticipation stage, where cravings become the primary concern and potential trigger for relapse, treatments focus on managing these cravings and preventing a return to substance use.
CBT is effective in decreasing methamphetamine use and cravings.
Moreover, research reveals that CBT-based smoking cessation programs significantly improve cessation rates compared to control interventions.
MBIs may offer superior long-term efficacy compared to CBT, with mindfulness strategies providing immediate craving reduction, suggesting the potential for these techniques to not only lessen cravings but also diminish the likelihood of craving leading to substance use.

Contingency Management:

The principle of contingency management in substance use disorders centers on the strategic use of immediate and predictable positive reinforcements, such as monetary rewards or vouchers, to promote abstinence and reduce drug use. [Volkow and Blanco, 2023]
Contingency management targets the reward network.
By providing these incentives, the approach shifts attention from the immediate pleasure of drug use and the alleviation of withdrawal symptoms to the long-term benefits of reduced use or sustained abstinence. Effective implementation requires that incentives be substantial and delivered reliably and promptly.
Furthermore, interventions that last six months or longer tend to yield better outcomes. Abrupt discontinuation of these programs can lead to relapse, so a gradual reduction of the incentives is recommended to decrease this risk.

Twelve‐step facilitation:

Twelve-step mutual aid groups like Alcoholics Anonymous and Narcotics Anonymous are effective in promoting abstinence, either alone or within a broader treatment framework.
They engage the salience network and use peer support, successful recovery role models, and sponsor mentorship to facilitate recovery. These groups help reduce feelings of shame, loneliness, and guilt, and witnessing the success of others instills hope and motivation.
Furthermore, they foster changes in social networks that enhance self-efficacy and reduce impulsivity and cravings. Recent studies show that for alcohol use disorder, twelve-step programs are as effective or more so than treatments like Cognitive Behavioral Therapy (CBT), though evidence for their effectiveness against other SUDs is weaker. [Volkow and Blanco, 2023]

PREVENTATIVE INTERVENTIONS

Preventive Interventions:

Prevention aims to

Mitigate risk factors such as deviant behaviour, drug-using peers, and social neglect.
Enhance protective factors, including parental support and education.

Universal Interventions:

Target entire populations, e.g., all students in a school to improve impulse control and self-regulation.

Selective Preventive Interventions:

Target sub-populations at increased risk of SUDs, like those with high-risk personality traits or living in low-resource communities.

Indicated Prevention/Early Intervention:

Targets individuals showing early signs of substance use but not meeting full criteria for SUDs.

School-Based Drug Education:

Most common prevention strategy
Includes information provision, education on peer substance use prevalence, refusal skills training, and social/life skills development.

Community-Based Approaches:

Examples include Communities That Care (CTC), which empowers local communities to prevent youth problems like substance use, violence, and school dropout.

Selective School-Based Interventions:

Example: Preventure, designed for high-risk youth, uses CBT and motivational interviewing to teach coping skills.

Parent or Family-Based Interventions:

Focus on improving family dynamics, communication, and parental monitoring; shown to reduce adolescent substance use and maintain effects for over a year.

Digital and Mobile Health Interventions:

Use of educational videogames, smartphone applications, and text messaging to reach broader audiences and overcome barriers of traditional programs

CONCLUSION

Recognising addiction as a chronic brain disorder shaped by intricate biopsycho-social influences, the last thirty years have seen substantial progress in genetics, neuroscience, and technological innovation. This progress has profoundly expanded our grasp of the neurobiological mechanisms that underlie drug use and the evolution of addiction.

Recent scientific advances have clarified the influence of biological and sociocultural factors on the risk of addiction, delineating how disturbances in neural circuits related to reward, motivation, control, and emotion contribute to substance use disorders (SUDs).

Understanding these disruptions is critical for developing more efficacious interventions against SUDs. Given that addiction involves key brain networks, resulting in compulsive behaviour and negative withdrawal effects, applying this knowledge clinically is vital.

The implications of these findings extend into the broader spectrum of health conditions affected by substance abuse. Although this discussion primarily addresses substance addiction, the underlying principles are relevant to behavioural addictions, including pathological gambling and internet addiction disorder, underscoring the need for a holistic strategy to address the inherent human tendencies towards seeking pleasure and avoiding pain.