Addiction
Psychopathology of Drug Addiction
Introduction to Addiction Research
The lecture will cover addiction, a topic the presenter has researched for 25 years, including preclinical and clinical studies. The research includes molecular, cellular, and behavioral aspects, as well as clinical trials.
The lecture is divided into two parts:
Psychopathology of drug addiction: definitions.
Neuropharmacology of drug addiction: brain changes in drug dependence.
Learning Objectives
Overview of drug abuse disorder, including its prevalence, impact, and comorbidities.
Important definitions of addiction, differentiating between substance use, abuse, dependence, and addiction.
Description of the stages of mental health disorder related to drug addiction, from initial use to relapse, emphasizing the cyclical nature of addiction.
The Addict's Perspective
A letter from an individual suffering from heroin addiction highlights key characteristics of the disorder:
Acknowledgment of the drug's destructive impact on personal health, finances, and overall well-being.
Damaged relationships with family, friends, and significant others due to drug-seeking behavior.
Lack of control over drug use, despite recognizing the harm it causes.
Key Characteristics of Addiction
Lack of control is a central feature of drug addiction, where the drug dominates the person's life, affecting decisions and behaviors.
Substance use disorder is the preferred term to avoid the negative stigma associated with "drug addiction," focusing on the clinical and diagnostic aspects.
Socio-Economic Dimensions of Addiction
The cost of addiction is substantial:
Estimated at 65 billion in the UK in 2023 for smoking, illicit drug use, and alcohol, encompassing direct and indirect costs.
Costs include treatments (pharmacological and behavioral), crime (policing, incarceration), lost productivity (absenteeism, reduced performance), social services, and judiciary services.
Despite the high cost, research funding is disproportionately low compared to cardiovascular disorders, diabetes, and cancer, highlighting the need for increased investment.
Key Statistics on Addiction
Alcohol-related deaths: 25\% of deaths in the 20-39 age range in 2020 are alcohol-related, indicating a significant public health concern.
Alcohol-related medical conditions: Alcohol causes 200 medical conditions, including liver disease, cardiovascular disorders, neurological damage, and psychiatric illnesses.
Alcohol-related trips to the GP: 10 million annually in the UK, straining healthcare resources.
Cost of alcohol-related disorders to the UK: £25 billion. A 10\% reduction would have a major financial impact on healthcare and social welfare budgets.
Alcoholism is the third leading preventable disorder in the UK, after smoking and obesity.
Smoking is the number one preventable disorder in the UK, although its prevalence is decreasing due to public health campaigns, vaping, and increased taxation.
Opioid Epidemic in the United States
130 people die every day in the United States from opioid-related drug overdose, representing a severe public health crisis.
From 2000 to 2016, there was a steady increase in opioid-related deaths, which became vertical after 2015, driven by synthetic opioids.
Prescription drugs like OxyContin (oxycodone) contributed significantly to the crisis due to aggressive marketing as a safe opioid, minimizing addiction risks.
Tolerance and dependence developed, leading individuals to switch to heroin, which is cheaper and more accessible.
In 2013, the shift to fentanyl, 100 times more potent than morphine, caused a major increase in opioid-related deaths, as it is often mixed with heroin or sold as counterfeit pills.
Street fentanyl is the primary driver, obtained from underground sources, posing a significant risk due to its potency and inconsistent dosages.
Prevalence and Risks of Other Drugs
Cannabis: Most prevalent drug in the UK (40-50\% prevalence) among adults aged 16-59.
Associated with schizophrenia, especially when use begins in pre-adolescence due to interference with brain development, altering neuronal circuits.
Nicotine: Smoking prevalence has reduced by 10\% in the last 15 years due to vaping, smoking bans, and high costs, but nicotine addiction remains a significant problem.
Ambitious goal for Great Britain to be smoke-free by 2030, defined as a smoking rate of less than 5\%.
Harmful Drugs
Heroin is considered the most dangerous drug based on deaths per user, followed by cocaine and methamphetamine.
A Lancet study in 2010 evaluated danger rates by considering harm to the individual and society, including addiction, physical damage, and social costs.
Alcohol ranked first due to its significant social impact (crime, social services, healthcare costs), highlighting the broader societal burden.
Substance Use Disorder Definition
Key Characteristics of Substance Use Disorder
Substance use disorder is a chronic, relapsing disorder characterized by:
Loss of control over drug administration, leading to compulsive drug-seeking behavior.
Compulsion to seek and take the drug (craving), even in the face of negative consequences.
Emergence of negative emotional states when the drug is not on board (withdrawal symptoms), such as anxiety, depression, and irritability.
Influential Figures in Addiction Research
Marie Nyswander: Argued that substance use disorder is a brain disorder that should be treated as such, reducing stigma and pioneered methadone treatment for heroin dependence. - Did initial research in prisons because of recruitment of heroin-dependent individuals.
George Koop: Considered the father of psychopharmacology of drug addiction, contributing significantly to understanding the neurobiological basis of addiction.
Diagnosing Substance Use Disorder
Psychiatrists and psychologists use the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders) to diagnose substance use disorder, providing standardized criteria for assessment.
Diagnosis requires two or more criteria within a 12-month period:
Taking larger amounts of the drug than intended.
Unsuccessful efforts to reduce or control drug use.
Excessive time spent using, obtaining, or recovering from use.
Failure to fulfill major obligations due to drug use (work, school, family).
Experiencing withdrawal reactions (physical and emotional).
Tolerance effects, requiring increased doses to achieve the desired effect.
Craving or a strong desire to use the drug.
Risk Factors Contributing to Addiction
The Drug Itself: Obvious contributing factor due to its pharmacological properties and reinforcing effects. Some drugs are more addictive than others.
Environmental Factors: Peer pressure, accessibility, negative events, emotional distress. - Health and social inequalities: Higher prevalence in areas of deprivation due to increased stress and limited opportunities.
Stress: Self-medication with substance abuse to cope with chronic stress, anxiety, or trauma.
50\% comorbidity between substance use disorders (especially alcohol) and depression, indicating a complex interplay between mental health and addiction.
It is found that both depression triggers alcohol use and alcohol use triggers depression. Withdrawal symptoms of alcohol use and anxiety depression are vulnerability factors.
Neurochemical Changes: Drugs of abuse alter brain neurochemistry, increasing vulnerability by affecting dopamine, serotonin, and other neurotransmitter systems.
Genetics: 50-60\% of vulnerability factors are attributed to genetic mutations, influencing how individuals respond to drugs.
Example: A118G polymorphism of the μ-opioid receptor increases the risk of developing heroin dependence, affecting receptor function and drug sensitivity.
Gene mutations interact with the environment, influencing epigenetic modifications and gene expression.
Environmental stressors induce DNA methylation and isolation changes, which alter gene expression (epigenetics), contributing to long-term changes in behavior.
There are gene mutations of the receptor where heroin binds, which makes it much more sensitive to heroin, increasing the rewarding effects.
Genes involved in dopamine metabolism also play a role, affecting dopamine levels and reward processing.
Addiction Stages
Initiation: Peer pressure during adolescence often leads to recreational drug use, influenced by social norms and curiosity.
Recreational Use: Initial experiences may be aversive, but repeated use induces a sense of reward, driven by positive reinforcement.
Positive Reinforcement: Rewarding behaviors are repeated, strengthening the association between drug use and pleasure. - The pleasurable effect of the drug drives self-administration, leading to increased frequency and dosage.
Tolerance: Increased drug dosage is required to achieve the same effect, as the body adapts to the presence of the drug.
Dependence: Emergence of physical and emotional withdrawal symptoms when the drug is not on board, indicating physiological adaptation. - Physical withdrawal symptoms (e.g., abdominal pain, joint aches, shivering, diarrhea) are short-lived and treatable with pharmacotherapy, such as opioid replacement therapy.
Emotional withdrawal symptoms (anxiety, depression, social withdrawal) are long-lived and can be a major trigger for relapse, requiring psychological support.
Relapse Triggers
Relapse can be triggered by:
Stress (work, relationships, finances).
Trauma (past or recent).
Cues associated with the drug (people, places, paraphernalia).
Relapse is a significant problem, with 7 out of 10 heroin-dependent individuals relapsing within one month of abstinence, highlighting the chronic and relapsing nature of addiction.
Tolerance vs. Dependence vs. Addiction
These terms are distinct:
Tolerance: Reduced response to a drug, requiring higher doses to achieve the same effect.
Dependence: Physical and emotional withdrawal symptoms upon drug cessation, indicating physiological adaptation.
Addiction: Compulsive drug-seeking behavior despite negative consequences and loss of control, characterized by persistent drug use despite harm.
Neuropharmacology of Drug Addiction
Brain Regions Involved in Addiction
Nucleus Accumbens and Ventral Tegmental Area (VTA): Reward regions connected by dopaminergic neurons, playing a crucial role in pleasure and motivation.
Amygdala: Involved in fear and emotionality, playing a role in stress-induced relapse and conditioned drug-seeking behavior.
Hippocampus: Involved in learning and memory, particularly remembering the pleasurable effects of the drug and associated cues.
Caudate Putamen (CPU): Important for habit formation, turning voluntary drug-seeking into compulsive habits.
Prefrontal Cortex: Involved in executive functions, decision-making, and judgment, impaired in addiction, leading to poor impulse control.
Anterior Cingulate Cortex: Gives salience to rewards, making drug-related cues highly attractive.
The Brain's Reward Pathway
The reward pathway consists of dopaminergic neurons from the VTA projecting to the nucleus accumbens, releasing dopamine in response to rewarding stimuli.
This pathway is activated by food, social interaction, and sex, resulting in dopamine release and feelings of pleasure, reinforcing these behaviors.
Drugs of abuse hijack this reward system, causing a much greater release of dopamine than natural rewards, leading to intense euphoria and strong reinforcement.
Microdialysis Studies
Microdialysis is a technique used in preclinical studies to measure neurotransmitter release in specific brain regions, providing real-time data on brain activity.
Probes are placed in brain regions of animals (e.g., rats) to collect neurotransmitters, which are then analyzed using HPLC or mass spectrometry, quantifying neurotransmitter levels.
Amphetamine administration leads to a major release of dopamine in the nucleus accumbens, demonstrating its direct effect on the reward pathway.
Acute Effects and Mechanisms of Action of Drugs of Abuse
Drugs of abuse stimulate the reward pathway, leading to pleasure and positive reinforcement, which drives repeated drug use.
The acute effects of drugs occur through positive reinforcement, which is the stimulation of the reward pathway, leading to immediate pleasure and euphoria.
Drugs of abuse stimulate increases of dopamine release by different mechanisms. This includes:
Opioids, which stimulate mu-opiate receptors produce dopamine release by inhibiting GABA interneurons.
Cocaine blocks dopamine transporters, preventing the reuptake of dopamine from the synapse.
Alcohol facilitates GABA receptors, leading to neural inhibition and dopamine release.
Nicotine activates nicotinic receptors, increasing dopamine release in the reward pathway.
Cannabinoids, activate CB1 cannabinoid receptors, influencing dopamine release and reward processing.
Psychostimulants
Example: Amphetamine.
Induces the release of dopamine from synaptic endings, leading to increased alertness, stereotyped behavior, euphoria, reduced fatigue, and increased confidence, making it highly addictive.
Methylphenidate (Ritalin): An amphetamine derivative used for ADHD management, improving focus and attention.
Also used as an appetite suppressant and for managing narcolepsy, but carries a risk of abuse and addiction.
Cocaine blocks dopamine transporters, preventing the reuptake of dopamine, prolonging its effects in the synapse.
MDMA (Ecstasy) blocks serotonin transporters and increases dopamine, leading to euphoria, empathy, and altered perception, but also carries risks of neurotoxicity.
Opioids
Heroin stimulates opioid receptors on GABA interneurons in the VTA, inhibiting GABA release, which leads to increased dopamine release, resulting in intense euphoria and pain relief.
Psycho Depressants
Example: Alcohol.
Multiple neuropharmacological effects by depressing brain activity by:
Alcohol stimulates inhibitory GABA receptors, facilitating chloride influx and causing hyperpolarization, reducing neuronal excitability.
Inhibiting presynaptic calcium entry, which inhibits neurotransmitter release, reducing overall brain activity.
Causing an inhibition of dopamine release at high does, that result in withdrawl symtoms
Homeostatic, Compensatory Mechanism Which Opposes The Repetitive Effects of The Drug
The natural nervous system plays an important role in withdrawal by attempting to restore homeostasis.
Noradrenergic neurons release noradrenaline, leading to increased alertness and stress response.
During withdrawal, there is a major release of noradrenaline, and the system becomes hyperactive, causing anxiety, agitation, and other withdrawal symptoms.
This can be treated with an alpha-2 agonist blocked with stimulation of the neurons, such as clonidine, which reduces noradrenergic activity.
Suppress dopamine to stimulate sleep with medication.
Alcohol: A Case Study
Increases dopamine directly, it also stimulates the release of endogenous opioids (endorphins), contributing to its euphoric effects and reinforcing properties.
Euphoria has an effect on drug abuse. Dopamine is associated with motivation, while opiate peptides are involved in the pleasure affects, driving compulsive drug-seeking behavior.
Nicotine
Stimulates the release of dopamine by acting on nicotinic acetylcholine receptors, which are ligand-gated ion channels on dopaminergic neurons, leading to pleasure and reward.
Nicotine has an increase in the release of dopamine in the brain and the body acts with those receptors, reinforcing smoking behavior.
HPA Axis (Stress Axis)
Drugs of abuse influence the hypothalamic-pituitary-adrenal (HPA) axis, which modulates the stress response, affecting cortisol release and stress coping mechanisms.
Cocaine stimulates the HPA axis, increasing cortisol levels and stress response, while heroin can inhibit it, reducing stress response acutely but causing dysregulation long-term.
Dysregulation of the HPA axis impairs stress-coping mechanisms, increasing vulnerability to relapse.
Marie Nyswander viewed addiction as a urine disorder where the axis is not normalized, emphasizing the importance of hormonal balance in recovery.
Dependence and Withdrawal Symptoms
Different drugs have different withdrawal symptoms, reflecting their specific mechanisms of action and effects on the brain.
Cocaine: Deep sleep, lethargy, depression, anxiety, hunger, reflecting dopamine depletion and stress response.
Smoking: Irritability, craving, increased appetite, reflecting nicotine withdrawal and reward pathway dysregulation.
Alcohol: Tremors, nausea, sweating, fever, hallucinations, seizures, agitation, aggression, reflecting GABAergic and glutamatergic system imbalance.
Changes in the Brain During Dependence
Reward pathway becomes suppressed, reducing sensitivity to natural rewards.
Recruitment of stress pathways (e.g., HPA axis), increasing stress vulnerability.
Hyperfunction of the frontal cortex (impaired decision-making), leading to poor impulse control and compulsive drug-seeking behavior.
Neuroimaging Studies
PET (Positron Emission Tomography) imaging is used to visualize receptors in the brain, allowing quantification of neurotransmitter receptors and activity.
PET scans of cocaine-dependent individuals show a decrease in D2 receptors (dopamine receptors) in the brain, reflecting down regulation due to chronic stimulation.
Decrease associated with a high increase is associated with craving for cocaine and leading for re-lapse, highlighting the role of dopamine in addiction.
The down regulation of the stem is a homeostatic measure; a measure against the receptors when dopamine is continuously stimulated, attempting to restore balance.
This is a common trait, similar to Heroin. If they looked at it with Alcohol addiction, you see the same decrease. It is considered a biomass indicator, as well with gambling and internet gaming, reflecting common neurobiological mechanisms.
FMRI (Functional MRI) is used as well to look for brain activity, assessing changes in brain function during drug use and withdrawal.
Glutamate and Relapse:
In terms of the synapse, the placticity takes place, but NMDA are measured, as they are critical for synaptic plasticity.
NMDA receptors play a crucial role in glutamate and synaptic plasticity, influencing learning and memory processes.
Summary of Brain Changes During Addiction
Normal Brain: Balanced connectivity among reward systems, frontal cortex, amygdala, hippocampus, and striatum, allowing for flexible and adaptive behavior.
Addicted Brain: Increased connectivity within reward circuits, weakened inhibitory connections in the prefrontal cortex, and automatic behavior, leading to compulsive drug use.
Executive Function is a factor within the brain's control in terms of impulses. Therefore, not eating chocolate represents control, and the ability to resist the impulse.
Narcolepsy and Orexin
Individuals with narcolepsy, treated with amphetamine, do not typically become addicted, indicating a different neurobiological profile.
Narcoleptic patients have low levels of orexin, a neuropeptide involved in arousal, sleep suppression, and appetite regulation, suggesting a protective factor against addiction.
Orexin is implicated in positive reinforcement. Orexin levels lead to sleep reduction and appetite regulation, influencing reward processing and drug-seeking behavior.
Behavioral Addictions
Diagnostic criteria are similar to substance use disorders, including loss of control, compulsion, and negative consequences.
Behavioral problems include: gaming and gambling, which activate similar brain reward pathways.
Behaviorial Becomes re-enforced; dopamine release and the reward systems trigger, leading to compulsive engagement