Substance Abuse and Addictive Disorders

What is substance abuse?

• Harmful consequences of use (social/legal/occupational)

What is substance dependende?

• Tolerance, withdrawal, and loss of control over use

What is substance use disorder?

• Cluster of cognitive, behavioral, and physiological symptoms indicating continued substance use despite significant substance related problems

• Addiction is not an official DSM-5 diagnostic term but commonly used to describe the most severe, chronic stage of substance use disorder

  • Loss of self control and compulsive drug seeking behavior despite desire to stop

  • Negative connotations with term

Epidemiology of Substance Use Disorder

• More prevalent in males than females

• More prevalent in younger individuals: peak rates in late adolescence and early adulthood, declining after age 26

• More common among:

  • White and Native American individuals

  • Unmarried or previously married adults

  • Lower education and income

• High income North American and Eastern/Western European show disproportionately high rates

  • High income North America → highest prevalence of cannabis, cocaine, and opioid dependence

  • Eastern European → highest alcohol use disorder

Etiology of Substance Use Disorder

• Genetic and environmental

  • Key genes implicated (do not need to know specific gene type)

    • ADH1B and ALDH2 for alcohol related

    • CHRNA5-CHRNA3-CHRNA4 for nicotine related

    • OPRM1, DRD2, DRD4, BDNF, and SLC6A4 associated with multiple substances

• Early initiation of substance use is critical risk factor

• Adverse childhood experience → dose response relationship between the number of traumatic events and substance use disorder risk

  • >= 4 ACEs < 18 y/o multiplies risk for smoking by 3, alcohol by 4, and any substance misuse by 7

DSM 5-TR Criteria for Substance Use Disorder

Requires meeting at least 2 of the 11 criteria within 12 month period

• Criteria organized into 4 domains

  • Impaired control

  • Social impairment

  • Risky use

  • Pharmacological criteria

• Severity

  • Mild: 2-3 criteria

  • Moderate: 4-5 criteria

  • Severe >= 6 criteria

Impaired Control

Criteria 1-4

• Larger amounts or longer use: taking the substance in larger amounts or over a longer period than originally intended

• Persistent desire or unsuccessful efforts to cut down: expressing a persistent desire to regulate substance use with multiple unsuccessful efforts to decrease or discontinue use

• Great deal of time spent: spending a great deal of time obtaining a substance, using it, or recovering from its effects and in severe cases all daily activities revolve around the substance

• Craving: experiencing an intense desire or urge for the drug, more likely when in an environment where the drug was previously obtained or used. Can be assessed by asking if there has ever been a time when urges were so strong the individual could not think of anything else

Social Impairment

Criteria 5-7

• Failure to fulfill major role obligations: recurrent substance use resulting in failure to fulfill major obligations at work, school, or home

• Continued use despite social/interpersonal problems: continuing substance use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the substance's effects

• Giving up important activities: important social, occupational, or recreational activities are given up or reduced because of substance abuse

Risky Use

Criteria 8-9

• Recurrent use in hazardous situations: recurrent substance use in situations in which it is physically hazardous

• Continued use despite physical/psychological problems: substance use is continued despite knowledge of having persistent or recurrent physical or psychological problem likely caused or exacerbated by the substance

  • The key issue is the individual’s failure to abstain despite the difficulty it is causing

Pharmacological Criteria: Criteria 10-11

• Tolerance: requiring a markedly increased dose to achieve the desired effect, or experiencing a markedly reduced effect when the usual dose is consumed. The degree of tolerance varies greatly across individuals and substances

• Withdrawal: experiencing characteristic withdrawal syndrome for the substance or raking the substance (or closely related substance) to relieve or avoid withdrawal symptoms

  • Note that withdrawal symptoms are not specific for certain substances, including phencyclidine, other hallucinogens, and inhalants

Screening

CAGE

• 2 or more on the questionnaire is (+)

• Not as sensitive to diagnosing someone with alcohol use disorder

• Good screener but not diagnostic tool

• Anyone who tests (+): should explore more

AUDIT

• Gold standard for alcohol screening

• Score of 8 or greater increases likelihood of alcohol use disorder

DAST-10

• Specifically for drug disorder, excludes alcohol

• Can be combined with AUDIT to include other substances

Alcohol Use Disorder General

• Mean age at AUD onset is 26.2 years

• Men have substantially higher rates than women

• Only 19.8% of individuals with lifetime AUD have ever received treatment

• Genetic factors account for 40-60% of AUD risk

• Alcohol activation of brain reward regions through increased dopamine release in the mesolimbic dopamine system → projects to the orbitofrontal and prefrontal cortices

  • Alcohol affects GABA, glutamate, cannabinoids, NE, 5HT, and HPA

  • Repeated exposure → neurotransmitter responses are blunted → tolerance and withdrawal symptoms

• Mental health conditions that show significant association

  • Anxiety

  • Depression

  • PTSD

  • Schizophrenia

  • Bipolar disorder

  • Antisocial and borderline personality

Pathophysiology of Alcohol Use Disorder

Drinking releases dopamine in mesolimbic pathway → repeated drinking → brain tries to balance and reduces natural dopamine activity → need more EtOH to get same reward, which builds tolerance

• GABA: increases

• Glutamate: decreases

• Overtime, brain will decreases GABA and increase glutamate

Withdrawal → too little GABA and too much glutamate

Alcohol Use Disorder Management

• First-line medications: naltrexone (first line) and acamprosate

  • Naltrexone: opioid receptor antagonist that reduces craving and alcohol consumption

    • Contraindications: acute hepatitis, liver failure, and opioid use

  • Acamprosate: modulates glutamatergic neurotransmission and promotes abstinence

    • Contraindications: severe kidney impairment

  • Disulfiram: causes adverse reaction (flushing, nausea, tachycardia, hypotension) with EtOH consumption by inhibiting aldehyde dehydrogenase (produced toxic levels of acetaldehyde)

    • Contraindications: advanced liver disease

• Second line medications: topiramate and GABA

  • Topiramate: potentiates GABA-A and inhibits glutamate activity

  • Gabapentin: increases abstinence rates but has abuse potential and overdose risk when combined with opioids

• Motivational Interviewing

  • Identify individual values and invoke inwardly motivated change to align behavior with said values

  • CBT

What is alcohol intoxication?

• Behavioral:

  • Disinhibition

  • Impaired judgment

  • Mood lability

  • Aggression

• Physical:

  • Slurred speech

  • Ataxia

  • Nystagmus

  • Impaired attention/memory

• Severe:

  • Stupor, coma

  • Respiratory depression

• Chronic use:

  • Acute rosacea

  • Palmar erythema

  • Hepatomegaly

  • Dupuytren’s contracture

  • Testicular atrophy

  • Gynecomastia

  • Elevations: GGT and transaminases, LDH, MCV

  • Decreases: BUN, LDL, RBC volume

What is alcohol withdrawal?

• Onset: 6-24 hours after cessation

• Autonomic:

  • Tremor,

  • Tachycardia (>100 bpm)

  • Hypertension

  • Hyperthermia

  • Diaphoresis

• Neuropsychiatric:

  • Anxiety

  • Restlessness

  • Insomnia

  • Agitation

• GI: Nausea, vomiting

• Severe complications (10% of symptomatic patients):

  • Seizure: peaks at 24 hours but can occur 8-48 hours after

  • Hallucinations: 12-24 hours after

  • Delirium tremens: severe confusion, disorientation, severe autonomic hyperactivity

    • Onset 72-96 hours

    • Can see complications beyond the 96 hours: do not cut off benzodiazepines right at 96 hours and continue until entire duration of symptoms has passed

  • MUST NOT MISS

• Duration: symptoms peak at day 2, improve by days 4-5

  • Residual anxiety/insomnia may persists for 3-6 months

Alcohol Withdrawal Management

• Ambulatory care is suitable for most uncomplicated cases

• Hospitalization for high-risk patients → history of seizures, concurrent medical or psychiatric illness, GABAergic drug dependence, lack of safe home environment, CIWA

• Long acting benzodiazepines with active metabolites (diazepam, chlordiazepoxide) effective for most patients

  • Carry risk of misuse and possible encephalopathy in advanced liver disease

• Short acting benzodiazepines without active metabolites (oxazepam, lorazepam) preferred for patients with liver disease

• Symptom-triggered medication reduces both the dose and duration of benzodiazepine treatment compared to fixed-schedule medication and is recommended in settings where frequent monitoring can be provided

• Severe withdrawal requiring intensive care warrants IV administration of midazolam, phenobarbital, etc…

  • CIWA >= 15 or starting to show signs of what could be DT or seizures

• Thiamine supplementation to prevent Wernicke's encephalopathy

• Symptom-triggered: diazepam 10mg or chlordiazepoxide 50-100 mg every hour if CIWA >= 10

• Fixed-dose taper: diazepam 10 mg every 6 hours on day 1, every 8 hours on day 2, every 12 hours on day 3, and at night on day 4

• Front loading: for severe withdrawal (CIWA >= 19) → diazepam 20 mg every 1-2 hours for 3 doses or 10 mg every hour and then transition to symptom triggered dosing

  • Reduces symptom duration, withdrawal seizure incidence, and delirium duration

• Alternatives:

  • Phenobarbital can be used as monotherapy or adjunctive to benzodiazepines

    • Advantages: rapid onset, long half life, wide therapeutic range, and minimal sedation at moderate doses

• DO NOT FOCUS ON DOSING/TIMING

Wernicke’s Encephalopathy

• Acute, potentially reversible neurological emergency caused by thiamine (vitamin B1) deficiency

• Symptom triad:

  • Mental status changes

  • Ocular abnormalities

  • Ataxia

• Clinical diagnosis based on the Caine criteria (require at least two of four signs):

  • Dietary deficiencies

  • Eye signs: nystagmus, lateral rectus palsy, conjugate gaze palsies

  • Cerebellar dysfunction

  • Either altered mental status or mild memory impairment

• MRI is the most valuable para-clinical tool, typically showing symmetric T2/FLAIR hyper-intense signals in specific brain regions

• Alcohol is the MC risk factor

  • Reduces thiamine absorption from gut and increases renal loss

  • Alcoholic liver damage impairs thiamine storage

  • Alcohol impairs thiamine dependent enzyme activity

  • Magnesium deficiency (common in heavy alcohol use) reduces thiamine cofactor function

• Treatment → high dose IV thiamine (500 mg TID for 2-3 days)

Korsakoff Syndrome

• Chronic, largely irreversible sequela of untreated or inadequately treated Wernicke encephalopathy

• Approximately 80-85% of patients with untreated WE develop KS

• Symptoms:

  • Severe anterograde and retrograde amnesia

  • Confabulation

  • Executive dysfunction

• MRI shows similar to Wernicke: symmetric T2/FLAIR hyper-intense signals in specific brain regions

• Treatment: prevention

Opioid Use Disorder General

• Third most prevalent substance use disorder worldwide

• Fentanyl has been the MC cause of opioid overdose deaths since 2016, accounting for 88% of opioid overdose deaths (47,369) in 2024

• Higher rates among men than women, young adults (ages 18-25) than older adults

• Risk factors:

  • History of anxiety disorder increases risk by 50%

  • History of another substance use disorder increases risk by 300%

  • Mood disorder, personality disorders, psychotic disorders, PTSD

  • ACE

  • Drug availability, peer substance use, social disadvantage, poor educational attainment

Opioid Use Disorder Management

First-line treatments

• Methadone: full u opioid receptor agonist

  • Can only be dispensed at federally regulated opioid treatment programs

  • Side effects

    • Sweating

    • Constipation

    • Sedation

    • QT prolongation

    • Endocrine suppression

• Buprenorphine: partial u opioid receptor agonist

  • Reduces cravings and withdrawal symptoms while blocking effects of illicit opioids

  • Sublingual formation taken 1-3 times daily at home: can be prescribed in office based setting

  • Risk of precipitated withdrawal if initiated while patient has opioids in system

  • Side effects

    • HA

    • Nausea

    • Sedation

    • Constipation

    • Endocrine suppression

• Naltrexone: opioid antagonist

  • Completely blocks opioid effects

  • Requires 7-10 days of opioid abstinence before initiation to avoid precipitated withdrawal

  • Side effects

    • N/V and abdominal pain

  • Naloxone is Narcan

Opioid Intoxication

Classic Triad

• Miosis (pinpoint pupils)

• Respiratory depression

• Decreases consciousness

CNS:

• Euphoria

• Sedation/drowsiness

• Impaired judgment

• Psychomotor retardation

Physical:

• Bradycardia

• Hypotension

• Hypothermia

• Constipation/nausea

Severe:

• Coma

• Apnea

• Death from respiratory arrest

Opioid Withdrawal

Onset

• 6 hours (short acting: fentanyl/heroin) to 1-3 days (long acting: methadone, buprenorphine)

• Autonomic: mydriasis, piloerection, hyperhidrosis, tachycardia, hypertension, hyperthermia, lacrimation, rhinorrhea, yawning

• Neuropsychiatric: anxiety, restlessness, irritability, dysphoria, insomnia, cravings

• GI: nausea, vomiting, abdominal cramping, diarrhea

• Musculoskeletal: myalgias, bone/joint aches

Duration:

• Days to weeks

• Protracted withdrawal (dysphoria, cravings, insomnia, hyperalgesia) may last months

Note:

• Uncomfortable but rarely life threatening

Withdrawal Score:

• COWS

  • Mild: 5-12

  • Moderate: 13-24

  • Severe: > 24

Opioid Withdrawal Management

Medications for withdrawal:

• Opioid agonists: methadone and buprenorphine (preferred)

• Alpha 2 receptor agonists: lofexidine (FDA approved) and clonidine

• Symptomatic: ibuprofen for pain, ondansetron for nausea

Withdrawal management without long-term MOUD is associated with increased relapse, morbidity, and death

Cannabis Use Disorder General

Cannabis is general term for all forms of cannabinoid compounds

• Have natural and synthetic

• Active ingredient is THC: acts on CB1 and CB2 cannabinoid receptors throughout CNS

• THC metabolites lipid soluble and accumulate in fat cells

• Intoxication lasts 2-4 hours but behavior changes can last many hours longer

Routes of ingestion

• Smoked, ingested, vaporized, edibles

About two-thirds of persons with CUD have at least one other current substance use disorder, most commonly alcohol or tobacco

• Almost half have a current non-substance psychiatric disorder

Cannabis potency has doubled over the past two decades

• Increased cannabis induced psychosis?

Psychosocial interventions is mainstay treatment

Cannabis Intoxication

• Psychological: euphoria, relaxation, altered time perception, impaired judgment, anxiety, paranoia

• Cognitive: impaired attention, concentration, working memory, reaction time

• Physical: conjunctival injection, increased appetite, dry mouth, tachycardia

• Severe: panic attacks, psychosis (especially with high THC), cannabinoid hyperemesis syndrome (cyclic vomiting with chronic heavy use)

Cannabis Withdrawal

• Onset: 1-2 days after cessation

  • Peak: days 2-6

• Psychological (predominant): irritability, anxiety, restlessness, depressed mood, anger/aggression

• Sleep: insomnia, disturbed sleep, strange/vivid dreams

• Physical (less common): decreased appetite, weight loss, abdominal cramps, muscle aches, tremor, headache, sweating, chills

• Duration: several weeks but some symptoms may persist longer

Usually mild and self limiting

• Behavioral/emotional symptoms more prominent than physical symptoms

Hallucinogens General

• Disrupt how the brain processes perception, mood, and reality mainly by altering serotonin, glutamate, or dissociative pathways

Hallucinogen Persisting Perception Disorder (HPPD):

• Rare chronic condition with re-experiencing of perceptual disturbances (visual snow, trails, halos, geometric patterns) when sober

• Can be episodic or continuous, lasting weeks to years

• Primarily after LSD use

Sedative Hypnotics General

Includes:

• Benzodiazepines and benzodiazepine-like drugs

• Barbiturates and barbiturate like drugs

• Carbamates

Benzodiazepines:

• Most widely prescribed medications: only small subset actually abuse them

• Intoxication: symptoms dose related

  • Lethargy, impaired mental function, poor memory, irritability, self neglect, emotional disinhibition

  • As it progresses: slurred speech, ataxia, impaired coordination

  • Retrograde amnesia can occur

  • Severe: paradoxical agitation, respiratory depression

  • Reversal with flumazenil (can elicit seizures)

• Withdrawal: similar to EtOH

Stimulant Use Disorder General

• 68-82% have a co-occurring mental health disorder and 72-78% had another substance use disorder

• Amphetamine, methamphetamine (also includes Adderall)

  • Enters the neuron → pushes dopamine out of storage vesicles through reverse transporters → dump dopamine into synapse → massive dopamine surge

• Cocaine, methylphenidate

  • Block reuptake transporters for dopamine and NE so that they stay longer in synapse

• Happens in nucleus accumbens (euphoria/addiction) and prefrontal cortex (focus/attention)

• Medical complications (vary by route of administration):

  • Cardiovascular: MI, arrhythmias, stroke, aortic dissection, sudden cardiac death

  • Pulmonary: coughing, bronchitis, pneumonitis (smoked), pneumothorax

  • Neuropsychiatric: cognitive impairment, psychosis, seizures, increased risk of schizophrenia and PD

  • Infectious: HIV, hepatitis B/C, endocarditis, osteomyelitis (injection), STIs

  • Other: nasal septum perforation (IN), meth mouth, malnutrition, weight loss

• Standard of care: contingency management

  • Provides tangible rewards (vouchers/prizes) to reinforce behaviors such as abstinence and treatment attendance

Stimulants Intoxication

• Psychological: euphoria, increased energy/confidence, grandiosity, hypervigilance, interpersonal sensitivity, impaired judgment

• Behavioral: talkativeness, psychomotor agitation, repetitive/stereotyped behaviors, aggression

• Autonomic: tachycardia or bradycardia, hypertension or hypotension, mydriasis, hyperthermia, diaphoresis

• Severe: paranoid ideation, hallucinations (auditory, tactile), psychosis, seizures, cardiac arrhythmias, myocardial infarction, stroke, hyperthermia, death

Stimulants Withdrawal

• Onset: within hours to several days after cessation

• BIG MOOD CRASH (looks like depression)

• Psychological: dysphoric mood (most prominent), anhedonia, fatigue, anxiety, irritability, emotional lability

• Sleep: insomnia or hypersomnia, vivid unpleasant dreams

• Physical: Increased appetite, psychomotor retardation or agitation

• Duration:

  • Typically 12-24 hours of somnolence/irritability

  • Depressive symptoms can meet criteria for major depression but usually resolve within 1 week (can last for 1 month)

• Note: suicidal ideation is the most serious withdrawal complication

Stimulants Intoxication Management

• First-line for agitation = benzodiazepines

• Antipsychotics for psychotic symptoms

• Hyperadrenergic states

  • Benzodiazepines

  • Phenobarbital

  • Propofol

  • Alpha 2 agonists

  • Beta blockers with alpha 1 antagonism

    • Not propranolol: increase vasospasm and lead to MI/stroke

  • CCB

  • Nitroglycerin

Nicotine General

• Stimulant that works by activating specific receptors in the brain, leading to a dopamine release (reward)

  • Nicotine acetylcholine receptor agonist: when nicotine binds → opens ion channels and sodium and calcium enter the neuron → neuron becomes excitable → leads to release of multiple neurotransmitters

    • Dopamine: reward/addiction

    • NE: alertness

    • Acetylcholine: attention

    • Glutamate: learning/memory

  • With repeated use: receptors become desensitized and brain up regulates more receptors

Nicotine Use Disorder Management

First line pharmacological treatment

• Varencicline

• Combination NRT (long acting patch and short acting form)

• Bupropion

• Single form NRT

Initial treatment duration is typically 12 weeks but can be extended to 6 months or longer for patients who need continued support to maintain abstinence

• Black box warning was removed from Chantix