It reflects predictable dysfunction across brain systems governing behaviour, learning, and control.
Here are 5 core neurobiological processes underlying addiction and relapse: 🧵👇
(Click through to see all 5)
1/ Reward & Motivation
Chronic substance use floods the brain with dopamine, eventually downregulating D2 receptors.
This structurally shifts the brain from "liking" the drug (hedonic pleasure) to intensely "wanting" it (incentive salience).
The biological urge to use becomes overpowering, even when the substance ceases to provide actual pleasure.
Educating patients that the craving they feel is a structural reflex, not a reflection of character, relieves guilt and contextualises relapse.
2/ Conditioning
When a substance repeatedly spikes dopamine, the amygdala and hippocampus form pathological associative memories linking the high to neutral environmental cues (places, paraphernalia).
This Pavlovian learning rewires the brain to anticipate the substance, meaning a single stimulus can provoke involuntary cravings years into recovery.
It helps explain why conditioned cues can contribute to craving and relapse risk even after prolonged abstinence.
3/ Self-Regulation Impairment
Chronic use physically impairs the prefrontal cortex, dismantling the brain’s "brake" system.
This deficit reduces impulse inhibition, shifting behaviour to rigid, automatic habits mediated by the dorsal striatum.
Interventions must actively aim to strengthen executive function and disrupt automatic routines to help rebuild the patient's compromised cognitive control.
4/ Negative Mood and Stress Reactivity
Late-stage addiction relies on negative reinforcement.
The extended amygdala activates stress pathways, inducing severe psychological agony known as allostasis.
Patients no longer use to chase a high; they use compulsively to escape this withdrawal-induced dysphoria.
Recognising this shift highlights that treatment must prioritise the physiological stabilisation of the stress axis, rather than just reward blockade.
5/ Interoceptive Awareness
Addiction disrupts the insular cortex, which governs how we perceive internal bodily states.
This sensory dysregulation “causes” patients to misinterpret normal physiological signals, like mild anxiety or a racing heart, as severe withdrawal or an intense craving.
Incorporating mindfulness and biofeedback in treatment helps patients accurately reinterpret these somatic signals, preventing normal stress from leading to a relapse.
5 Core Neurobiological Processes Underlying Addiction and Relapse
1. Reward & Motivation: D2 downregulation shifts pleasure to intense “wanting”; psychoeducation reframes cravings and reduces guilt.
2. Conditioning: Learned associations mean cues (e.g., people, places, emotions) can trigger relapse even after abstinence.
4. Negative Mood & Stress: Late-stage addiction is associated with negative reinforcement via the extended amygdala (allostasis). Prioritise physiological stabilisation of the stress axis.
5. Interoceptive Awareness: Insular dysregulation misinterprets normal somatic signals as severe cravings. Incorporate biofeedback and mindfulness to help patients accurately reinterpret these cues.
To learn more about addiction and its implications in clinical practice, click the link below and check our course in The Academy.
More than 50% of patients with schizophrenia smoke tobacco. [Fond et al 2017]; [Dickerson et al 2018]; [Oluwoye et al 2019]
Despite heavily substantiated nicotine-induced metabolic and pharmacokinetic risks, this number refuses to drop.
This raises the question: “What does nicotine do that makes this specific patient population so uniquely dependent on it?”
Here’s a neurobiological breakdown of nicotine dependence in schizophrenic patients clinicians should know: 🧵👇
The Intrinsic Receptor Deficit
In the general population, chronic smoking leads to an upregulation of α4β2 nicotinic receptors.
In schizophrenia, this compensatory upregulation is impaired.
This suggests an intrinsic defect in the nicotinic receptor system.
Theoretically, for schizophrenia patients, smoking is an attempt to achieve receptor saturation to overcome this deficit, though it rarely leads to sustained cognitive improvement.
Chasing Prefrontal Dopamine
The prefrontal cortex (PFC) is often hypo-active in schizophrenia.
Nicotine attempts to bypass this.
By stimulating receptors on glutamatergic terminals, nicotine:
- Facilitates PFC activity
- Triggers a release of dopamine
This temporarily improves executive function and working memory.
Depression is not a single, uniform brain pattern.
It does not present the same way in every patient.
Sometimes it appears as rumination.
Sometimes as cognitive dysfunction.
Sometimes as emotional over-reactivity.
So how do we make sense of what’s happening beneath the surface? There is a structured way to approach this.
Here is a clinical breakdown of the Triple Network Model, a framework for understanding functional brain changes in depression 🧵👇
The Triple Network Model frames depression as dysregulation within and between three major functional brain systems.
Rather than locating the disorder in one isolated region, it conceptualises depression as a disturbance in large-scale network organisation.
This gives clinicians a more structured way to think about why depressive presentations can differ so markedly.
1/ Default Mode Network (DMN)
In depression, dysfunction of the DMN is linked to altered self-referential processing.
The DMN is primarily active at rest and is involved in emotional regulation, social cognition, future-oriented thinking, autobiographical memory, and self-focused mental activity.
When dysregulated, external information may be processed through a more self-referential lens.
Dysfunction in parietal DMN components is also linked to rumination.
PTSD treatment is not just about reducing symptoms.
The other half of the clinical equation is about interrupting the mechanisms that make the brain increasingly reactive over time.
To do so, there are 2 clinical PTSD concepts clinicians must take into full consideration in treatment planning: 🧵👇
PTSD develops through a combination of psychological and biological mechanisms.
This dual foundation also means that effective treatment must address both sides of the disorder, often integrating psychotherapy with pharmacotherapy.
This is where the following concepts come in, illustrating exactly what is happening in the dysregulated brain, helping clinicians align their intervention strategies with the underlying pathology.
1/ The Concept of Kindling
Following trauma, the brain’s stress systems become dysregulated, creating heightened fear conditioning where even neutral stimuli become associated with threat.
Kindling is the process where increasingly lower-severity stimuli begin to elicit significant negative emotional or physiological responses over time.
This explains why patients often react strongly to seemingly minor cues.
For decades, Major Depressive Disorder (MDD) has been clinically framed primarily through mood symptoms.
However, recent clinical studies have described a potential emerging biotype of MDD whose core pathology leans more towards cognition than just mood symptoms.
Here are 5 key clinical insights clinicians need to know about this emerging cognitive MDD biotype:🧵👇
Cognition has long been recognised as part of MDD, with impairments in areas such as attention, working memory, and processing speed already linked to poorer function and poorer treatment outcomes.
Even so, MDD remained primarily organised around mood symptoms, with cognitive dysfunction often treated as secondary rather than defining.
This emerging cognitive biotype shifts that framing by suggesting that, in some patients, cognition may be more central to the pathology itself.
1/ Impairment in Cognitive Control Domains
A key feature of the cognitive MDD biotype is impairment in cognitive control-related domains.
The most consistently affected functions are executive function and response inhibition.
In clinical terms, this places the subtype within higher-order cognitive processes involved in organising behaviour, regulating responses, and maintaining goal-directed performance.
While often framed as a brain reward-system dysfunction, clinical studies suggest that genetic factors are estimated to account for around 40-60% of addiction risk, with inherited vulnerability contributing to susceptibility. [Volkow et al., 2019]
This raises the next question: How does inherited risk translate into biological vulnerability, and what does that mean in clinical practice?🧵👇
The Polygenic Architecture of Vulnerability
What is inherited is not addiction itself, but vulnerability.
This vulnerability is polygenic: multiple variants, especially in dopamine and glutamate systems, increase susceptibility.
In effect, what is inherited may be a reward-system profile prone to dysregulated reinforcement.
This may explain why some individuals show greater neurobiological vulnerability even before substance exposure.
Altered Dopaminergic Regulation
Heritable vulnerability to addiction may be associated with alterations in dopaminergic regulation.
When dopamine balance is harder to maintain, the brain’s reward pathways may respond less efficiently to ordinary rewarding stimuli.
In that sense, inherited risk may begin at the level of reward regulation, not only at the point of substance exposure.