Ketamine Dependence Syndrome and Withdrawal Management

1. Pharmacology Relevant to Dependence

• Classified among the NMDA-receptor antagonist hallucinogens (along with PCP and DXM)
• Dependence liability: moderate to high (Kaplan & Sadock's Comprehensive Textbook of Psychiatry)
• Physical dependence potential: possible but not predictable
• Psychological dependence: common with repeated use

"Psychological dependence on both PCP and ketamine is common." - Kaplan and Sadock's Synopsis of Psychiatry

2. Epidemiology and Pattern of Use

• Rapid tolerance development (needing more to achieve the same dissociative effect)
• Reinforcing dissociative/euphoric properties
• Psychological craving during abstinence

3. DSM-5 Classification

• Other hallucinogen intoxication
• Other hallucinogen withdrawal (if criteria are met)
• Hallucinogen-induced disorders (psychosis, mood disorder, etc.)

4. Clinical Features of Ketamine Dependence

Acute Intoxication

Features of Chronic Heavy Use

• Ketamine-induced uropathy (KIU): the most distinctive complication. Upper and lower urinary tract damage - severe dysuria, frequency, urgency, reduced bladder capacity, urothelial damage, hydronephrosis. This can be irreversible.
• Hepatotoxicity: ketamine-associated biliary dilatation, cholestasis, elevated liver enzymes
• Cognitive deficits: impaired episodic memory, attention, and executive function even after cessation
• Psychiatric: depression, anxiety, psychosis (in predisposed individuals)
• GI symptoms: severe abdominal pain ("K cramps"), nausea

5. Ketamine Withdrawal Syndrome

Onset and Timeline

Withdrawal Symptom Profile

• Intense drug craving (most prominent feature)
• Anxiety and panic
• Dysphoria and depression
• Irritability and agitation
• Cognitive difficulties (concentration, memory)
• Vivid/disturbing dreams

• Diaphoresis
• Tachycardia and palpitations
• Tremor
• Feeling cold/chills (rebound sympathetic activity + hypothalamic dysregulation)
• Nausea, abdominal pain
• Fatigue and hypersomnia
• Myalgia

6. Withdrawal Management

General Principles

1. Assess severity - no validated ketamine-specific withdrawal scale exists; the Clinical Institute Narcotic Assessment (CINA) is sometimes adapted
2. Rule out co-morbid substance withdrawal - many ketamine users are polysubstance users; alcohol/benzodiazepine withdrawal must be prioritized as it is life-threatening
3. Inpatient vs. outpatient - inpatient is preferred for heavy/dependent users (>1g/day), those with polysubstance use, or severe psychiatric symptoms
4. Address organ complications - uropathy, hepatotoxicity, and abdominal pain need concurrent specialist involvement

Pharmacological Management

A. Benzodiazepines (most evidence for withdrawal)

• First-line for managing acute agitation, anxiety, and autonomic symptoms during ketamine withdrawal and intoxication
• Diazepam, lorazepam, or clonazepam are used
• Evidence: reported utility in both intoxication and withdrawal management in multiple case reports
• Mechanism: GABAergic sedation addresses rebound hyperexcitability and sympathetic overactivity

B. Haloperidol

• Used in intoxication and withdrawal-associated psychosis/agitation
• Doses: up to 10 mg reported (e.g., in Abbeycare inpatient protocols)
• Mechanism: D2 receptor antagonism controls hallucinations and agitation

C. Propranolol / Beta-blockers

• Used for autonomic symptoms (tachycardia, palpitations, hypertension, tremor)
• Example: propranolol 40 mg for cardiovascular withdrawal symptoms
• Particularly relevant given ketamine's sympathomimetic profile

D. Relapse Prevention (craving/maintenance phase)

• Naltrexone: opioid antagonist; case reports suggest benefit in reducing craving and relapse (possibly via dopaminergic/reward pathway modulation)
• Lamotrigine: glutamate-modulating anticonvulsant; case reports of reduced craving (mechanistically rational given ketamine's glutamatergic action)
• Paliperidone palmitate + bupropion combination: reported in a case report; paliperidone for residual psychotic symptoms and mood stabilization, bupropion for depressive symptoms and anti-craving effect

E. Other Supportive Agents

• Antiemetics (ondansetron, metoclopramide) for nausea/K-cramps
• Analgesics (paracetamol, NSAIDs) for abdominal and musculoskeletal pain
• Melatonin/low-dose sedatives for insomnia
• IV fluids for severe dehydration associated with K-cramps

The systematic review concluded: "All evidence was of very low quality... benzodiazepine regimens may be most salient for future exploration in intoxication and withdrawal, whereas naltrexone, lamotrigine, and paliperidone palmitate plus bupropion may merit further investigation for craving/relapse prevention." - Roberts et al., 2024

Non-Pharmacological Management

• Psychosocial interventions: Cognitive Behavioral Therapy (CBT), motivational interviewing, relapse prevention
• Contingency management
• Group therapy / peer support
• Ketamine-specific counseling (addressing triggers, coping with craving, harm reduction)

7. Organ-Specific Complications Requiring Concurrent Management

8. Key Points Summary

• Kaplan and Sadock's Synopsis of Psychiatry (9781975145569)
• Kaplan & Sadock's Comprehensive Textbook of Psychiatry (9781975175733)
• UK GOV/ACMD: Ketamine: An Updated Review of Use and Harms, 2025

38-Year-Old Male: Polysubstance (Ketamine + Amphetamine + Alcohol) with Seizure at 1 Week of Abstinence

IMMEDIATE CLINICAL PRIORITY

PART 1: DIFFERENTIAL DIAGNOSIS OF THE SEIZURE

1. Alcohol Withdrawal Seizure (Most Likely)

• Alcohol withdrawal seizures are generalized tonic-clonic seizures
• Can begin as early as 6 hours after the last drink; 90% occur within 48 hours
• However, in this patient's case, a seizure at 1 week is late - this suggests either:
  • Kindling phenomenon: each prior detoxification sensitizes the CNS, causing earlier, more severe, and more prolonged withdrawal in subsequent attempts
  • Delayed/prolonged withdrawal from heavy chronic alcohol use
  • Status epilepticus risk is higher at this late stage
• About 1/3 of patients with alcohol withdrawal seizures progress to delirium tremens
• Risk factors for severity in this patient: prior withdrawal history, high/long duration of alcohol intake, older age, polysubstance use - he has multiple risk factors
• More than half of withdrawal seizures co-occur with underlying epilepsy, brain lesions, or other substance use (Tintinalli's)

2. Amphetamine Withdrawal - Contributing Factor

• Neurochemical dysregulation: massive dopamine/norepinephrine depletion lowers seizure threshold
• Sleep deprivation (crash phase) - a known precipitant of seizures
• Hypoglycemia secondary to poor nutrition during stimulant crash
• Cerebrovascular effects of prior amphetamine use (vasospasm, hemorrhage) may have created structural substrate for seizures

• Crash phase: 24-72 hours - hypersomnia, hyperphagia, severe depression
• Withdrawal phase: 1-3 weeks - dysphoria, fatigue, craving, anhedonia
• At 1 week, this patient is in the middle of the amphetamine withdrawal phase - contributing to overall CNS instability

3. Ketamine - Less Likely as Direct Cause

• Prior heavy ketamine use may have caused cognitive/neurological changes that lower the seizure threshold
• Ketamine's NMDA antagonism causes long-term glutamate receptor upregulation (similar to alcohol) - abrupt discontinuation means unoppposed excitatory glutamatergic activity

4. Other Causes to Exclude (Differential Diagnosis)

"The diagnosis of alcohol withdrawal seizures requires the exclusion of traumatic brain injury, hypoxia, hypoglycemia, structural lesions, infections, use of illicit drugs, idiopathic epilepsy, withdrawal from other recreational drugs, withdrawal from prescription sedatives, and noncompliance with antiseizure medications." - Tintinalli's Emergency Medicine

PART 2: IMMEDIATE MANAGEMENT

Step 1 - Resuscitation (ABCDE)

• Airway: Position, suction if needed; if prolonged/status - RSI
• Breathing: Supplemental O₂, SpO₂ monitoring
• Circulation: IV access (2 large-bore), fluid resuscitation if signs of dehydration/autonomic instability
• Disability: GCS, BM glucose (point-of-care immediately - hypoglycemia is both a cause and complication)
• Exposure: Full assessment for trauma, signs of chronic liver disease, track marks, temperature

Step 2 - Thiamine BEFORE Glucose

Step 3 - Terminate Active Seizure

• Lorazepam 2-4 mg IV (first-line) - onset 2-5 minutes
• If IV access unavailable: Midazolam 10 mg IM (buccal/intranasal also options)
• Repeat every 5-10 minutes if seizure continues
• If refractory after 2 doses of benzodiazepine: second-line agents

Step 4 - Drug Treatment (Alcohol Withdrawal Seizure Protocol)

• Phenobarbital has a dual advantage: it addresses both alcohol and amphetamine withdrawal-related seizure risk via GABA potentiation, and has been shown in systematic review (Pourmand et al., 2023 meta-analysis, PMID 37060631) to be as effective as benzodiazepines for alcohol withdrawal, with potential superiority in polysubstance cases
• Avoid using standard sedation protocols blindly - amphetamine use means CNS stimulant withdrawal may require higher than expected benzodiazepine doses

Step 5 - Monitor with CIWA-Ar (Symptom-Triggered Therapy)

• Score >15: give benzodiazepine dose every hour until score <15
• Score 8-14: give dose every 2 hours until score <8
• Score <8: observation only

Step 6 - Workup (to run in parallel)

Step 7 - Supportive Care

• Rehydration with normal saline (correct electrolytes)
• Thiamine 100 mg IV daily for at least 3 days (Wernicke's prophylaxis)
• Folate 1 mg daily
• Magnesium sulfate IV if hypomagnesemia confirmed
• Aspiration precautions post-seizure
• Quiet, low-stimulation environment to reduce CNS excitation
• 1:1 nursing observation (delirium tremens risk ongoing)
• ICU consideration: alcohol withdrawal seizure + polysubstance + 1 week = high risk for DTs → threshold for ICU admission should be low

Disposition

• History of alcohol withdrawal seizure (this presentation itself)
• Polysubstance dependence
• Risk of delirium tremens (1/3 of those with AWS seizures progress)
• Hemodynamic instability
• Requirement for repeated/high-dose benzodiazepines

PART 3: HISTORY-TAKING STRATEGY

A. Presenting Complaint and Seizure History

• Witness account: Was there a warning (aura)? Tonic-clonic? Focal onset? Duration?
• Single seizure or multiple (cluster)?
• Full recovery / prolonged post-ictal confusion (may suggest structural lesion or non-convulsive status)
• Any tongue biting, urinary incontinence, injury?
• Previous seizures - first time or recurrent? Prior alcohol withdrawal seizures specifically?

• Exactly when was the last use of alcohol? Amphetamine? Ketamine? (timing is diagnostic)
• Was abstinence intentional or forced? (incarceration, hospitalization, supply unavailability)
• Any prior detoxifications? Were they medically supervised?
• Any symptoms before the seizure (tremor, sweating, anxiety, hallucinations)?

B. Substance-Specific History (each substance separately)

• Type, quantity (units/day), frequency - how many years?
• Pattern: binge vs. daily
• Morning drinking / drinking to avoid withdrawal ("eye opener")?
• Last drink and approximate blood alcohol level before stopping
• Previous withdrawal history: ever had shakes, sweats, hallucinations, fits, DTs?
• Previous medical detoxifications and what regime was used

• Type: methamphetamine vs. amphetamine sulphate vs. MDMA?
• Route: oral, smoked ("ice"), IV?
• Daily dose and duration of use
• Last use (is patient in crash/withdrawal phase?)
• Previous psychiatric symptoms during/after use (psychosis, paranoia)

• Daily dose (g/day) and duration
• Route: intranasal, oral, IV?
• Urinary symptoms (frequency, dysuria, haematuria - KIU screening)
• Abdominal pain episodes (K-cramps)

• Benzodiazepines? (prescribed or illicit - CRITICAL as BZD withdrawal also causes seizures)
• GHB/GBL? (withdrawal causes seizures, often missed)
• Opioids?
• Cannabis, alcohol, tobacco (all quantities)
• Any prescription medications?

C. Medical History

• Previous seizures and/or epilepsy diagnosis?
• Head trauma / TBI?
• Liver disease (jaundice, ascites, encephalopathy)?
• Renal disease (ketamine uropathy)?
• Psychiatric history (depression, psychosis, bipolar - common comorbidities)
• Current medications (including anti-epileptics - non-compliance?)
• Allergies (especially to benzodiazepines)

D. Social and Risk History

• Social support: lives alone? (risk of unwitnessed seizures)
• Housing: stable vs. homeless
• Employment
• Legal issues (motivation for abstinence - court order?)
• Prior treatment: rehab, community drug teams, 12-step programs
• Driving (seizure has DVLA/licensing implications)
• Dependants (children at home)

E. Mental State and Risk Assessment

• Current mood: depression, suicidal ideation (high risk in stimulant withdrawal crash)
• Psychotic symptoms (amphetamine-induced psychosis, alcohol-induced psychosis)
• Cognitive function (Wernicke's, chronic ketamine neurotoxicity)
• Insight into dependence and motivation to change

F. CAGE-AID / AUDIT / DAST Screening Tools

• AUDIT (Alcohol Use Disorders Identification Test) - severity of alcohol use disorder
• CAGE questionnaire
• DAST-10 (Drug Abuse Screening Test) for drug use severity
• CIWA-Ar ongoing for alcohol withdrawal monitoring
• PHQ-9 for depression once stabilized

PART 4: LONGER-TERM MANAGEMENT PLAN (POST-ACUTE)

Alcohol Use Disorder

• Pharmacotherapy: naltrexone, acamprosate, or disulfiram (once medically cleared, liver function permitting)
• Benzodiazepine taper if used during acute detoxification
• Carbamazepine: an alternative to benzodiazepines, especially if prior multiple detoxifications (anticonvulsant + anti-kindling effect); shown efficacious in high-risk cases by Skryabin et al. 2026 review

Amphetamine Use Disorder

• No FDA-approved pharmacotherapy
• Contingency management is the most evidence-based psychosocial intervention
• Bupropion has some evidence for reducing use
• Address depressive symptoms during prolonged withdrawal (SSRI if persistent)

Ketamine Use Disorder

• Refer to specialist addiction service
• Urology referral (screen for KIU)
• LFT monitoring (hepatotoxicity)
• Benzodiazepines for agitation/cravings acutely
• Naltrexone or lamotrigine for relapse prevention (case report level, as reviewed previously)

Integrated Care

• Addiction psychiatry consultation
• Urology (ketamine uropathy)
• Hepatology (alcoholic liver disease)
• Neurology (if structural seizure cause found or EEG abnormal)
• Psychosocial: CBT, motivational interviewing, relapse prevention, peer support

Summary Box

• Tintinalli's Emergency Medicine, 9th Ed. (9781260019933) - AWS, seizure management, CIWA-Ar
• Kaplan & Sadock's Synopsis and Comprehensive Textbook of Psychiatry - substance dependence
• Skryabin V et al. Alcohol Withdrawal Seizures: Neurobiological Mechanisms, Clinical Predictors, and Evidence-Based Management. J Psychiatr Pract 2026; PMID: 42095715
• Pourmand A et al. Phenobarbital in alcohol withdrawal: systematic review and meta-analysis. Am J Emerg Med 2023; PMID: 37060631
• Roberts E et al. Pharmacological Management of Ketamine Use Disorder: Systematic Review. J Addict Med 2024; PMID: 38922637

COMPLETE CLINICAL HISTORY

Addiction Psychiatry / Emergency Medicine Assessment

IDENTIFYING INFORMATION

PRESENTING COMPLAINT

HISTORY OF PRESENTING COMPLAINT

• Patient was sitting on the sofa when he became suddenly unresponsive
• Eyes deviated upward, followed by rhythmic jerking of all four limbs lasting approximately 2-3 minutes
• No warning reported; no cry at onset
• Tongue biting noted (left lateral border, observed on examination)
• Urinary incontinence occurred during the episode
• Patient was placed in the recovery position by partner
• Brief post-ictal confusion lasting approximately 15 minutes; patient did not fully recall the event
• Paramedics attended within 8 minutes; no further seizure activity en route

• Increasing restlessness and irritability over the past 2 days
• Coarse tremor of both hands noted by partner from day 3 of abstinence
• Profuse sweating, particularly at night, for the past 5 days
• Severe insomnia - sleeping only 2-3 hours per night
• Nausea and reduced appetite throughout the week; no vomiting
• Partner reports patient appeared to see "shadows moving" on the wall yesterday evening - patient initially dismissed this
• No fever reported
• No headache preceding the seizure
• No recent head trauma reported (partner confirms)
• Patient has been increasingly anxious and "on edge" over the past 3-4 days, describing a sense of impending doom

• Patient made a deliberate decision to stop all substances 7 days ago following a confrontation with his partner and concerns about his health
• Cessation was abrupt - no medical supervision, no tapering
• Last alcoholic drink: approximately 168 hours ago (one week)
• Last ketamine use: approximately 8 days ago
• Last amphetamine (methamphetamine) use: approximately 7 days ago
• No Wernicke's prophylaxis or any medication administered during this period
• Patient did not seek medical help at time of cessation

SUBSTANCE USE HISTORY

1. ALCOHOL

• Type: Predominantly vodka (supermarket own-brand) and lager
• Quantity: Approximately 30-35 units per day on a typical drinking day at peak use; approximately 25 units/day in the 3 months prior to cessation
• (1 unit = 10 ml pure alcohol; 1 standard 25 ml measure of spirits = 1 unit; 1 pint of strong lager ~3 units)
• Frequency: Daily, without days off, for the past 3 years
• Pattern: Continuous daily drinking; woke and drank first thing in the morning; described feeling "shaky and sick" if more than 4-5 hours without a drink
• First drink in the day: Within 30 minutes of waking - "eye-opener" (confirms morning drinking to relieve withdrawal)
• CAGE screening (administered verbally):
  • C - Cut down: "Yes, I've tried many times but can't stick to it"
  • A - Annoyed: "Yes, my partner and friends have commented on it"
  • G - Guilty: "Yes, I feel ashamed about how much I drink"
  • E - Eye-opener: "Yes, every morning"
  • Score: 4/4 - strongly suggestive of alcohol dependence

• Age of first use: 16 years (social drinking with friends)
• Age of regular/hazardous use: 22 years (binge drinking at weekends)
• Age of dependent use: Approximately 29-30 years (daily drinking with withdrawal symptoms if abstinent)
• Duration of current pattern: 3 years of daily heavy dependence

• Patient has attempted abstinence on approximately 5-6 occasions previously
• Each time, he reports increasingly severe withdrawal: initially only tremor and sweating; later episodes associated with "the shakes", visual disturbances ("seeing things"), and on one occasion approximately 18 months ago, describes "blacking out" - suspected withdrawal seizure though never formally assessed
• Never received medical detoxification
• Longest period of abstinence: 12 days (2 years ago), ended due to severe cravings and low mood

• Q1 (frequency): 4 - daily use
• Q2 (quantity): 4 - 10+ units on a typical day
• Q3 (6+ drinks): 4 - daily
• Q4 (inability to stop): 3
• Q5 (failure of expectations): 3
• Q6 (morning drink): 4
• Q7 (guilt): 2
• Q8 (memory gaps): 3
• Q9 (injury): 2
• Q10 (concern from others): 4
• Total AUDIT score: 33/40 - indicative of severe alcohol dependence

2. AMPHETAMINE (METHAMPHETAMINE / "ICE")

• Type: Crystal methamphetamine ("ice")
• Route: Predominantly smoked (using glass pipe); occasionally intranasal ("snorted") in earlier use
• Quantity: Approximately 0.5-1 g per day at peak; approximately 0.5 g/day in the month prior to cessation
• Frequency: Daily use for approximately 18 months; prior to that, weekend use for 2 years
• Pattern: Used primarily in the evening/night; frequently used to counteract sedation from alcohol and ketamine ("to feel awake and functional")
• Procurement: Obtained through a local dealer; patient spent approximately £200-250/week on methamphetamine alone

• Age of first use: 28 years (amphetamine sulphate powder at a music event)
• Progression to methamphetamine: 32 years
• Escalation to daily use: 36 years (coincided with period of unemployment and relationship stress)
• Dependence features:
  • Tolerance: Now requires 3x the original dose to achieve same effect; original recreational dose was approximately 0.1 g
  • Withdrawal / crash: Describes 2-3 day "crash" following cessation - hypersomnia (sleeping 18+ hours), profound low mood, ravenous appetite, fatigue; describes this as "unbearable depression"
  • Loss of control: Has tried to cut down "at least 10 times" - unable to sustain
  • Compulsive use: Continues to use despite knowing it worsens his health and relationship
  • Craving: Reports intense cravings currently - "the urge is overwhelming"
  • Continued use despite harm: Partner has threatened to leave on multiple occasions; patient has lost two jobs due to methamphetamine use

• Multiple short periods of 2-7 days, always relapsed
• No formal treatment received for methamphetamine use

• Significant weight loss - approximately 12 kg over 2 years (BMI now 18.5)
• Dental deterioration ("meth mouth") - multiple decayed and missing teeth
• Skin picking and excoriation lesions on forearms and chest
• Episodes of paranoia and auditory hallucinations during heavy use - lasted hours to days; no formal psychiatric assessment
• Significant insomnia pre-abstinence (sleep only 2-3 hours/night during heavy use periods)

3. KETAMINE

• Type: Ketamine powder (illicitly obtained; presumed pharmaceutical grade)
• Route: Intranasal ("racked up as lines")
• Quantity: Approximately 2-3 g per day at peak (over the past 12 months); 1.5-2 g/day in the month prior to cessation
• Frequency: Daily use
• Pattern: Used throughout the day, often beginning in the afternoon; described as a way to "take the edge off" and "numb everything"; used alongside alcohol

• Age of first use: 24 years (at a music festival; recreational dissociative effect)
• Progression to dependent use: 33-34 years
• Duration of heavy daily use: Approximately 2-3 years
• Dependence features:
  • Tolerance: "I used to get the K-hole on half a gram. Now I need 3 grams and barely feel it"
  • Loss of control: Unable to limit use once started
  • Compulsive use: Using on waking, before sleep, and at intervals throughout the day
  • Psychological craving: Describes strong urges, particularly when distressed or bored
  • Continued use despite harm: Aware of bladder symptoms but continued

• 2 attempts to stop; both lasted 3-4 days; experienced severe anxiety, dysphoria, insomnia, and intense cravings
• Never received formal ketamine detoxification

• Urinary frequency: Yes - urinating every 30-45 minutes at peak use
• Dysuria: Yes - burning pain on urination for approximately 18 months
• Haematuria: Yes - has noticed blood in urine on 3-4 occasions in the past year; never formally investigated
• Reduced bladder capacity: Partner confirms patient uses the toilet "constantly"
• Suprapubic pain: Yes - intermittent, worse when unable to access ketamine
• No formal urology assessment to date

• "K-cramps" (ketamine-associated abdominal pain): Yes - severe, episodic central/upper abdominal cramping, particularly during periods of abstinence or dose reduction; has attended A&E on 2 occasions for this (attributed to "stomach problems" without disclosure of drug use)
• Nausea: Yes - associated with K-cramps

• No jaundice reported; no known liver disease; no formal LFT testing

• Patient and partner both report significant memory difficulties over the past 2 years
• Difficulty concentrating; describes "brain fog"
• Partner reports personality change - emotionally blunted, less engaged

4. OTHER SUBSTANCES (systematic screen)

PAST PSYCHIATRIC HISTORY

• No formal psychiatric diagnoses on record
• However:
  • Depression: Patient describes recurrent low mood, particularly during stimulant withdrawal phases; has never sought treatment; "I just drank more to get through it"
  • Anxiety: Generalised anxiety and panic symptoms reported since late 20s; patient attributes this to drug use; no formal diagnosis or treatment
  • Paranoia/psychosis during methamphetamine use: As described above; resolved with cessation; no persistent psychotic symptoms between episodes
  • No history of manic or hypomanic episodes
  • Trauma: Patient discloses a difficult childhood - father had alcohol dependence, significant domestic violence witnessed at home; patient left home at 17; does not wish to discuss in further detail at this time
  • No previous psychiatric admissions
  • No history of deliberate self-harm or suicide attempts
  • Current suicidal ideation: "No, I don't want to die - I want to get better" - no active suicidal ideation or plan, but mood is very low (PHQ-9 to be completed when stabilised)

PAST MEDICAL HISTORY

• No formal diagnoses - patient has largely avoided healthcare ("I didn't want anyone to know what I was taking")
• Possible undiagnosed liver disease (heavy alcohol use, ketamine hepatotoxicity)
• Suspected ketamine-induced uropathy (as above) - never formally investigated
• Suspected previous alcohol withdrawal seizure (~18 months ago)
• Significant dental disease
• Malnutrition / weight loss

DRUG HISTORY AND ALLERGIES

• Patient has taken ibuprofen and paracetamol intermittently for "stomach cramps" and headaches
• No vitamins or supplements

FAMILY HISTORY

• Father: Alcohol dependence (heavy drinking throughout patient's childhood; deceased aged 54 from liver cirrhosis)
• Mother: Anxiety disorder; treated with diazepam (per patient's recollection) for many years
• One sibling (brother, age 34): Cannabis and cocaine use; not in contact
• No known family history of epilepsy (important given differential diagnosis)
• Partner: No known health problems

SOCIAL HISTORY

• Cohabits with long-term partner in a rented flat; relationship described as "strained but she hasn't left"
• Partner is the primary financial support at present

• Formerly employed as a delivery driver (full-time); lost job 8 months ago due to erratic attendance and suspected drug-impaired driving
• Currently registered as self-employed / freelance but not working regularly
• No benefits currently claimed; financial difficulties reported

• Estimates spending approximately £500-600/week across all substances (alcohol + methamphetamine + ketamine) at peak use
• Significant debt has accumulated

• One caution for possession of ketamine (Class B in UK) 3 years ago - not charged
• Driving while impaired suspected (by partner) but no formal charges
• Driving licence: Patient states he still drives occasionally - this must be reported per DVLA guidance for seizure

• No convictions; no current legal proceedings

• Stable; privately rented

• Partner (present, motivated to support recovery)
• No close friends described as drug-free ("most of my friends use as well")
• Estranged from family (left home at 17; no contact with parents; occasional contact with brother)

• Left school at 16 with GCSEs
• No further education

• None reported; open to any form of support

PREMORBID PERSONALITY

• Described as sociable, hard-working, and creative prior to heavy substance use
• Partner notes personality change over the past 3-4 years: increasing emotional blunting, irritability, social withdrawal, and reduced motivation
• No previous personality disorder diagnosis; features of emotionally unstable traits noted in context of childhood trauma and current presentation - formal assessment deferred until clinically stable

FORENSIC RISK ASSESSMENT (preliminary)

• Risk to self: Low-moderate - no active suicidal ideation, but high-risk period (stimulant withdrawal crash + alcohol withdrawal delirium risk = elevated mood instability)
• Risk to others: No current concerns raised; no history of violence
• Risk from others: Nil disclosed; partner appears supportive
• Safeguarding (children): No children in the household; no safeguarding concerns identified

SYSTEMS REVIEW (relevant positives and negatives)

MENTAL STATE EXAMINATION (at time of assessment, ~45 minutes post-seizure)

• Orientated to person and place; partially to time (unsure of exact date)
• Concentration: impaired (unable to complete serial 7s beyond 93, 86)
• Short-term memory: mildly impaired (recalls 2/3 words at 5 minutes)
• AMT score: 7/10 (impaired recall of dates)
• Full cognitive assessment deferred until medically stabilised

FORMULATION (Brief)

1. Alcohol withdrawal seizure (most likely primary cause) - F10.3 (ICD-10)
2. Alcohol dependence syndrome - F10.2
3. Stimulant (methamphetamine) use disorder - F15.2
4. Other hallucinogen (ketamine) use disorder - F16.2
5. Suspected ketamine-induced uropathy - to be investigated
6. Possible Wernicke's encephalopathy risk (nutritional depletion) - to be excluded
7. Risk of delirium tremens - ongoing monitoring required

PLAN (summarised from previous discussion)

1. Immediate: IV thiamine 200 mg BEFORE any glucose; IV lorazepam protocol; CT brain; full bloods including Mg, glucose, LFTs, toxicology screen; CIWA-Ar monitoring
2. Admission: Inpatient (HDU/ICU level monitoring given high DT risk)
3. Specialist referrals: Urology (ketamine uropathy), hepatology, addiction psychiatry
4. DVLA notification regarding seizure (patient consented and informed)
5. Psychosocial: Involve partner in care planning; referral to addiction services on stabilisation
6. Long-term: Medically supervised detoxification followed by residential rehabilitation or community addiction programme

• Always record exact times of last use for each substance - this drives seizure risk calculation
• CAGE 4/4 and AUDIT 33 are hard evidence of severe dependence, useful for documentation and treatment justification
• The "eye-opener" question is the single most specific indicator of alcohol dependence
• Prior withdrawal severity (kindling) is the strongest predictor of this episode's severity
• Deny BZD/GHB use must be verified with toxicology - these are frequently concealed and both cause dangerous withdrawal seizures
• The family history of epilepsy question is non-negotiable in a seizure presentation
• Driving status must be documented and DVLA notified after a seizure
• Childhood trauma and family history are not just social history - they are aetiological and guide psychotherapeutic approach

Can Ketamine Withdrawal Cause Anti-NMDA Receptor Encephalitis?

The Direct Answer

Understanding Anti-NMDAr Encephalitis

What Happens

1. The immune system produces IgG antibodies directed against the NR1 subunit (glycine-binding domain) of the NMDA receptor
2. These antibodies bind to the extracellular domains of NR1/NR2 subunits at glutamate synapses
3. Antibody binding causes receptor internalization - the NMDA receptor is physically removed from the synapse
4. The result is progressive NMDA receptor hypofunction across the brain
5. This is reversible with immunotherapy (because it is antibody-mediated, not structural)

Causes

• Associated with ovarian teratoma in ~38% of cases (the teratoma expresses neuronal tissue bearing NMDA receptors, triggering the immune response)
• In males and children: more commonly paraneoplastic from testicular germ cell tumors, thymoma, or other malignancies
• A significant proportion are idiopathic (no tumor found)
• Preceded by a viral prodrome in many cases (fever, headache, malaise) - triggering immune dysregulation
• NOT caused by drugs, drug use, or drug withdrawal

"Antibody binding causes the receptors to be removed from the synapse. If untreated, this syndrome, called anti-NMDA receptor autoimmune encephalitis, can progress from psychosis to include severe neurological symptoms, such as seizures, motor and..." - Neuroscience: Exploring the Brain, 5th Ed.

Why the Question Is Conceptually Brilliant

The NMDA Hypofunction Pathway - The Common Thread

What Ketamine Withdrawal Actually Does to NMDA Receptors

1. Receptor upregulation: NMDA receptors increase in number and sensitivity (homeostatic neuroadaptation - the brain compensates for constant blockade by making more receptors)
2. Glutamate system sensitization: Glutamatergic tone increases to overcome blockade
3. On abrupt cessation: The blockade is removed suddenly - now the upregulated, supersensitive NMDA receptor system is unopposed
4. Result: Rebound glutamate excitotoxicity - a state of NMDA hyperfunction (the opposite of what ketamine produces)

• Anxiety and agitation (glutamate surge in the amygdala)
• Dysphoria (disrupted reward circuitry)
• Cognitive disturbances
• Potentially lowers seizure threshold (but does not cause autoimmune encephalitis)

Clinical Importance: Why These Can Be Confused

Symptom Overlap

Key Clinical Features That Point AWAY from Withdrawal and TOWARD Anti-NMDAr Encephalitis

1. Orofacial dyskinesias (lip smacking, tongue thrusting, chewing movements) - these are virtually pathognomonic of anti-NMDAr encephalitis and do NOT occur in ketamine withdrawal
2. Viral prodrome (fever, headache, malaise) preceding psychiatric symptoms by 1-2 weeks
3. Progressive deterioration over days-weeks despite appropriate withdrawal management
4. Catatonia (waxy flexibility, mutism, posturing) - more characteristic of encephalitis
5. Central hypoventilation requiring ventilatory support
6. Failure of psychiatric symptoms to improve with standard withdrawal treatment
7. CSF pleocytosis (elevated white cells in CSF) - encephalitis; NOT seen in simple withdrawal
8. Abnormal EEG showing "extreme delta brush" pattern (specific for anti-NMDAr encephalitis)
9. Discovered tumor (ovarian teratoma, testicular germ cell tumor)
10. Symptoms that are more severe than expected for the degree of substance use

One-Way Pharmacological Paradox

Diagnostic Approach When Anti-NMDAr Encephalitis is Suspected Alongside Substance Use

• First-line: IV methylprednisolone + IV immunoglobulin (IVIG) ± plasma exchange
• Second-line: Rituximab or cyclophosphamide
• Tumor removal (if found) - often leads to dramatic improvement
• Symptom management: benzodiazepines (not antipsychotics - neuroleptic intolerance is common in anti-NMDAr encephalitis and can worsen the condition)

Summary

• Bradley and Daroff's Neurology in Clinical Practice (9780323642613) - autoimmune encephalitis, FDG-PET findings
• Neuroscience: Exploring the Brain, 5th Ed. (9781284286878) - NMDA receptor antibody mechanism
• Stahl's Essential Psychopharmacology (9781108838573) - NMDA hypofunction hypothesis
• Katzung's Basic and Clinical Pharmacology, 16th Ed. (9781260463309) - glutamate hypothesis
• Hiesgen J, Schutte C. Autoimmune Encephalitis Part 1: Epidemiology, Pathophysiology and Clinical Spectrum. S Afr Med J 2023; PMID: 36876355
• Rueda Carrillo et al. Ketamine and Its Emergence in Neurology. Cureus 2022