Methamphetamine (Speed, Crank, Crystal, Ice)

History

  • 1885: Nagai Nagayoshi first isolated ephedrine from the Chinese shrub Ephedra distachya
  • 1893: Nagai Nagayoshi first synthesized methamphetamine
  • Early 1900’s: pharmaceutical formulations of methamphetamine were used as treatments for nasal congestion and asthma
  • World War II Era: methamphetamine was widely used by German, Japanese, and American troops to increase alertness and decrease fatigue
    • 1944: the FDA approved methamphetamine for the treatment of narcolepsy, depression, alcoholism, and hay fever
  • 1947: the FDA approved methamphetamine for the treatment of obesity
  • 1967: methamphetamine reached a peak with 31 million prescriptions in the US

Epidemiology

  • Current Prevalence of Abuse: methamphetamine is the second most commonly abused drug worldwide (after cannabis)
    • 5% of the US population has used methamphetamine

Clinical Indications (FDA-Approved)

  • Attention Deficit Hyperactivity Disorder (ADHD)
  • Obesity (see Obesity, [[Obesity]])

Synthesis of Methamphetamine

  • Synthesis: methamphetamine can be readily synthesized via simple reactions using readily available chemicals and over-the-counter cold medicines (ephedrine, pseudoephedrine)
    • Methamphetamine synthesis carries significant risks of explosion
    • Methamphetamine synthesis can result in the exposure of children to toxic byproducts

Routes of Methamphetamine Exposure

  • Intravenous (IV) Methamphetamine Injection: less common (route of abuse in 7% of cases)
  • Oral Methamphetamine Ingestion: less common (route of abuse in 3% of cases)
    • “Body Stuffing”: ingestion of methamphetamine packets to avoid arrest
    • “Body Packing”: concealment of large quantities of methamphetamine for transport
    • Intentional Ingestion
    • Therapeutic Methamphetamine Administration
      • Attention Deficit Disorder with Hyperactivity (ADHD)
      • Narcolepsy (see Narcolepsy, [[Narcolepsy]]): off-label use
      • Obesity (see Obesity, [[Obesity]]): short-term treatment
  • Methamphetamine Smoking: most common method of abuse (route of abuse in 68% of cases)
  • Methamphetamine Nasal Insufflation (“Snorting”): common (route of abuse in 31% of cases)
  • Trans-Rectal Methamphetamine Insertion (“Booty Bumping”)
  • Vaginal Methamphetamine Insertion
    • Vaginal Methamphetamine Abuse
    • “Body Packing”: concealment of large quantities of methamphetamine for transport
  • Urethral Methamphetamine Insertion
    • Urethral Methamphetamine Abuse

Pharmacology

  • Methamphetamine is a Phenethylamine Sympathomimetic Amine: substitutions on the phenethylamine ring structure determine the degree of central nervous system penetration, degree of degradation by monoamine oxidase, receptor binding affinity, and the variety of clinical effects
    • Amphetamine (alpha methyl phenethylamine) has single methyl group at the alpha position on the carbon chain
    • Methamphetamine has a second methyl group on the carbon chain: this increases lipophilicity and its central nervous system activity
  • Methamphetamine is an Indirect Neurotransmitter Which Moves into Cytoplasmic Vesicles in Presynaptic Adrenergic Neurons -> Displacement of Epinephrine, Norepinephrine, Dopamine, and Serotonin into the Cytosol: as cytosolic concentrations of these neurotransmitters increase, they diffuse out of neuron and into the synapse -> activation of postsynaptic receptors
    • Increased Expression and Activity of Tyrosine Hydroxylase: enzyme which is responsible for synthesizing dopamine
    • Monoamine Oxidase (MAO) Inhibition
    • Decreased Expression of Dopamine Transporters on Cell Surface
    • Inhibition of Monoamine Transporters
    • Reversal of Transport of Neurotransmitters Through Plasma Membrane Transporters

Metabolism

  • Renal: predominant route of excretion
  • Sweating: lesser route of excretion
  • Fecal: lesser route of excretion

Clinical Effects

  • Adrenergic Stimulation
  • Serotonergic Stimulation
    • Alterations in Mood: due to stimulant effects
    • Altered Responses to Hunger and Thirst: due to anorexiant effects
  • Dopaminergic Stimulation
    • Drug-Craving
    • Drug-Seeking Behavior and Psychiatric Symptoms: due to euphoric and hallucinogenic effects)

Methamphetamine Use Disorder (Chronic Abuse)

Clinical Manifestations

Cardiovascular Manifestations

  • Cardiomyopathy/Congestive Heart Failure (CHF) (see Congestive Heart Failure, [[Congestive Heart Failure]])
    • Epidemiology: may occur with either acute and chronic methamphetamine abuse
  • Myocardial Ischemia/Infarction (MI) (see Coronary Artery Disease, [[Coronary Artery Disease]])
    • Epidemiology: may occur with either acute and chronic methamphetamine abuse
  • Hypertension (see Hypertension, [[Hypertension]])

Gastrointestinal Manifestations

Neurologic Manifestations

  • Choreiform Movements (see Chorea, [[Chorea]])
  • Cognitive Deficits: controversial, but are generally believed to be moderate
    • Deficits in Episodic Memory
    • Deficits in Executive Functions
    • Deficits in Information Processing Speed
    • Deficits in Motor Skills
    • Deficits in Language
    • Deficits in Visuoconstructional Abilities
  • Methamphetamine-Induced Psychosis (see Psychosis, [[Psychosis]])
    • Epidemiology: occurs in 8-27% of cases
    • Clinical
      • Patient may have relatively long periods of psychosis
      • Recurrence of psychosis may occur during periods of methamphetamine abstinence

Otolaryngologic Manifestations

  • Excessive Tooth Decay (“Meth Mouth”)/Dental Abscess (see Dental Abscess, [[Dental Abscess]])
    • Epidemiology: excessive tooth decay is common with chronic methamphetamine abuse (and is more severe in those who use the drug intravenously than in those who use the drug by smoking/ingestion/inhalation)
    • Mechanisms
      • Bruxism
      • Decreased Saliva Production
      • Poor Dental Hygiene
  • Gingival Hypertrophy (see Gingival Hypertrophy, [[Gingival Hypertrophy]])
  • Nasopharyngeal Mucosal Injuries
    • Epidemiology: associated with insufflation (“snorting”)

Pulmonary Manifestations

  • Pulmonary Hypertension (see Pulmonary Hypertension, [[Pulmonary Hypertension]])
    • Epidemiology: likely associated with pulmonary hypertension

Treatment

  • Abstinence from Methamphetamine

Methamphetamine Intoxication

Physiology

  • Duration of Action: approximately 20 hrs
    • In contrast, cocaine (see Cocaine, [[Cocaine]]) has a duration of action of 30 min
    • In contrast, phencyclidine (see Phencyclidine, [[Phencyclidine]]) has a duration of action of <8 hrs

Diagnosis

  • Urine Toxicology Screen: positive for methamphetamine
    • False-Positive: the amphetamine portion of the urine toxicology screen may give false-positive results with exposure to other agents
      • Benzphetamine (see Benzphetamine, [[Benzphetamine]]) [MEDLINE]
      • Bupropion ((Wellbutrin, Zyban) (see Bupropion, [[Bupropion]]) [MEDLINE]
      • Selegiline ((Anipryl, L-Deprenyl, Eldepryl, Emsam, Zelapar) (see Selegiline, [[Selegiline]]): metabolized to l-methamphetamine
    • False-Negative: as urine toxicology screens are dependent upon renal clearance of methamphetamine, it may fail to detect the drug if insufficient time has elapsed for drug to be excreted in the urine

Clinical Manifestations

  • General Comments: variably ranges from asymptomatic to frank sympathomimetic crisis

Cardiovascular Manifestations

  • Aortic Dissection (see Aortic Dissection, [[Aortic Dissection]])
    • Physiology: due to vasoconstrictive and hypertensive effects of amphetamine
  • Arrhythmias
  • Cardiomyopathy/Congestive Heart Failure (CHF) (see Congestive Heart Failure, [[Congestive Heart Failure]])
    • Epidemiology: may occur with either acute and chronic methamphetamine abuse
  • EKG Abnormalities
    • Abnormal Q
    • Abnormal QRS
    • Abnormal QT
    • Poor R-Wave Progression
    • ST Changes
    • T Wave Changes
  • Heart Blocks
    • Left Bundle Branch Block (LBBB)
    • Right Bundle Branch Block (RBBB)
    • Other Heart Blocks
  • Hypertension (see Hypertension, [[Hypertension]])
  • Hypotension/Shock (see Hypotension, [[Hypotension]]): precipitous cardiovascular collapse may rapidly occur in patients with severe agitation (especially when restrained to avoid harm to themselves or others)
    • Physiology: likely results from neurotransmitter depletion, metabolic acidosis, and dehydration
    • Prognosis: shock is a poor prognostic factor [MEDLINE]
  • Myocardial Ischemia/Infarction (MI) (see Coronary Artery Disease, [[Coronary Artery Disease]])
    • Epidemiology: may occur with either acute and chronic methamphetamine abuse
    • Physiology
      • Coronary Vasospasm
  • Myocarditis (see Myocarditis, [[Myocarditis]])
  • Valvular Heart Disease
    • Physiology: due to serotonergic effects of methamphetamine

Dermatologic Manifestations

  • Diaphoresis (see Diaphoresis, [[Diaphoresis]])
  • Facial Flushing (see Flushing, [[Flushing]])
  • Formication (“Crank Bugs”) (see Formication, [[Formication]]): sensation that ants are crawling on the skin
    • Epidemiology: occurs with prolonged methamphetamine abuse
  • Skin Excoriations Due to Repeated Skin Picking
  • Track Marks
    • Epidemiology: may be present in cases with intravenous abuse

Gastrointestinal Manifestations

  • Acute Mesenteric Ischemia (see Acute Mesenteric Ischemia, [[Acute Mesenteric Ischemia]])
    • Epidemiology: associated with “body packing” or “body stuffing”
  • Diarrhea (see Diarrhea, [[Diarrhea]])
    • Physiology: due to sympathomimetic effects
  • Fulminant Hepatic Failure (see Fulminant Hepatic Failure, [[Fulminant Hepatic Failure]])
  • Malnutrition (see Malnutrition, [[Malnutrition]])
    • Epidemiology: may also be associated with vitamin deficiencies
  • Nausea/Vomiting (see Nausea and Vomiting, [[Nausea and Vomiting]])
    • Physiology: due to sympathomimetic effects

Hematologic Manifestations

Neurolopsychiatric Manifestations

  • General Comments
    • Psychiatric complaints are a common presenting symptom of methamphetamine intoxication in emergency department settings
  • Agitated Delirium (see Delirium, [[Delirium]])
    • Epidemiology: frequently present
    • Clinical: may be severe
  • Akathisia (see Akathisia, [[Akathisia]])
  • Amaurosis Fugax (Transient Loss of Vision)
  • Anxiety (see Anxiety, [[Anxiety]])
  • Cerebral Edema (see Increased Intracranial Pressure, [[Increased Intracranial Pressure]])
  • Choreiform Movements (see Chorea, [[Chorea]])
    • Epidemiology: common in acute methamphetamine intoxication
    • Physiology: altered dopaminergic neurotransmission
    • Clinical: the combination of chorea and inability to mentally focus has been termed “tweaking”
  • Disheveled Appearance
  • Homocidal or Suicidal Ideation/Violent Behavior
  • Hypersexuality
  • Hypervigilance
  • Intracerebral Hemorrhage (Hemorrhagic Cerebrovascular Accident) (see Intracerebral Hemorrhage, [[Intracerebral Hemorrhage]])
  • Ischemic Cerebrovascular Accident (CVA) (see Ischemic Cerebrovascular Accident, [[Ischemic Cerebrovascular Accident]])
  • Obtundation/Coma (see Obtundation-Coma, [[Obtundation-Coma]])
    • Physiology: due to depletion of catecholamine stores and/or co-ingestion of ethanol or other sedatives
    • Prognosis: coma is a poor prognostic factor [MEDLINE]
  • Paranoia/Delusions/Hallucinations/Psychosis (see Psychosis, [[Psychosis]]): frequently present
  • Retinal Vasculitis
  • Seizures (see Seizures, [[Seizures]])
    • Epidemiology: usually occur within 24 hrs of methamphetamine use and are self-limited
  • Subarachnoid Hemorrhage (SAH) (see Subarachnoid Hemorrhage, [[Subarachnoid Hemorrhage]])

Ophthalmologic Manifestations

  • Mydriasis (see Mydriasis, [[Mydriasis]]): pupils are usually minimally reactive

Otolaryngologic Manifestations

  • Nasopharyngeal Mucosal Injuries
    • Epidemiology: associated with insufflation (“snorting”)
  • Oropharyngeal Burns
    • Epidemiology: associated with smoking

Pulmonary Manifestations

  • Acute Lung Injury-ARDS (see Acute Lung Injury-ARDS, [[Acute Lung Injury-ARDS]])
  • Barotrauma: associated with forceful inhalation (however, the incidence of barotrauma is far lower than that observed with crack cocaine abuse for unclear reasons)
  • Bronchospasm (see Obstructive Lung Disease, [[Obstructive Lung Disease]])
  • Diffuse Alveolar Hemorrhage (DAH) (see Diffuse Alveolar Hemorrhage, [[Diffuse Alveolar Hemorrhage]])
  • Increased Minute Ventilation (VE): usually seen in severe intoxication
    • Increased Tidal Volume
    • Tachypnea (see Tachypnea, [[Tachypnea]])
  • Pneumonia (see Pneumonia, [[Pneumonia]])
  • Pulmonary Infarction (see Pulmonary Infarction, [[Pulmonary Infarction]])

Renal Manifestations

  • Acute Kidney Injury (AKI) (see Acute Kidney Injury, [[Acute Kidney Injury]]): due to rhabdomyloysis (see Rhabdomyolysis, [[Rhabdomyolysis]])
    • Prognosis: considered a poor prognostic factor [MEDLINE]
  • Hyperkalemia (see Hyperkalemia, [[Hyperkalemia]])
    • Physiology: due to rhabdomyolysis
    • Prognosis: hyperkalemia >5.6 mmol/L is a poor prognostic factor [MEDLINE]
  • Lactic Metabolic Acidosis (see Lactic Acidosis, [[Lactic Acidosis]])
    • Prognosis: metabolic acidosis is a poor prognostic factor [MEDLINE]

Reproductive Manifestations (During Pregnancy)

  • Placental Abruption
  • Placental Hemorrhage
  • Placental Insufficiency

Rheumatologic/Orthopedic Manifestations

Toxicologic Manifestations

Other Manifestations

  • Fever/Hyperthermia (see Fever, [[Fever]])
    • Prognosis: fever >39 degrees C is a poor prognostic factor [MEDLINE]

Treatment

  • Treatment of Seizures: seizures are usually self-limited
  • Treatment of Agitated Delirium: may require pharmacologic treatment and/or physical restraints

Methamphetamine Withdrawal

Acute Phase (“Crash”)

Clinical Manifestations

  • General Comments
    • Symptoms may develop within hours after stopping use (especially with prolonged and heavy methamphetamine abuse)
    • Symptoms peak within 1-2 days
    • Symptoms decrease within 2 wks
  • Agitation (see Delirium, [[Delirium]])
  • Anhedonia
  • Anxiety (see Anxiety, [[Anxiety]])
  • Compulsive/Uncontrolled Drug Use and Addiction
  • Drug Craving
  • Dysphoria
  • Fatigue (see Fatigue, [[Fatigue]])
  • Hypersomnia (see Hypersomnia, [[Hypersomnia]])
  • Insomnia (see Insomnia, [[Insomnia]])
  • Polyphagia (Increased Appetite) (see Polyphagia, [[Polyphagia]])
  • Vivid Dreams

Treatment

  • Antidepressants: have been used
  • Anti-Psychotics: have been used
  • Behavioral Therapy: has been used
  • Benzodiazepines (see Benzodiazepines, [[Benzodiazepines]]): have been used

Subacute Phase

Clinical Manifestations

  • General Comments: may persist for up to 3 wks
  • Appetite Changes
  • Depression (see Depression, [[Depression]])
  • Hypersomnia (see Hypersomnia, [[Hypersomnia]])
  • Insomnia (see Insomnia, [[Insomnia]])
  • Suicidal Ideation

Treatment

  • Antidepressants: have been used
  • Anti-Psychotics: have been used
  • Behavioral Therapy: has been used
  • Benzodiazepines (see Benzodiazepines, [[Benzodiazepines]]): have been used

References

  • Subarachnoid and intracerebral hemorrhage associated with necrotizing angiitis due to methamphetamine abuse–an autopsy case. Neurol Med Chir (Tokyo) 1991; 31:49–52
  • Stimulant-induced pulmonary toxicity. Chest. 1995 Oct;108(4):1140-9 [MEDLINE]
  • Fatal and nonfatal methamphetamine intoxication in the intensive care unit. J Toxicol Clin Toxicol. 1994;32(2):147-55 [MEDLINE]
  • GC-MS determination of amphetamine and methamphetamine in human urine for 12 hours following oral administration of dextro-methamphetamine: lack of evidence supporting the established forensic guidelines for methamphetamine confirmation. J Anal Toxicol. 1995;19(7):581 [MEDLINE]
  • Bupropion metabolites produce false-positive urine amphetamine results. Clin Chem. 1995;41(6 Pt 1):955 [MEDLINE]
  • Detection of amphetamine and methamphetamine following administration of benzphetamine. J Anal Toxicol. 1998;22(4):299 [MEDLINE]
  • Is methamphetamine use associated with idiopathic pulmonary arterial hypertension? Chest 2006;130:1657-63
  • Methamphetamine-Associated Cardiomyopathy. Clin Cardiol. 2013 Dec; 36(12): 737–742 [MEDLINE]