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
- Hypertension (see Hypertension, [[Hypertension]])
- Hyperthermia/Fever (see Fever, [[Fever]])
- Tachycardia (see Sinus Tachycardia, [[Sinus Tachycardia]])
- Vasospasm
- 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
- Anorexia (see Anorexia, [[Anorexia]])
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
- False-Positive: the amphetamine portion of the urine toxicology screen may give false-positive results with exposure to other agents
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
- Atrial Fibrillation (AF) (see Atrial Fibrillation, [[Atrial Fibrillation]])
- Bradycardia (see Bradycardia, [[Bradycardia]])
- Sinus Tachycardia (see Sinus Tachycardia, [[Sinus Tachycardia]]): frequently present
- Ventricular Tachycardia (VT) (see Ventricular Tachycardia, [[Ventricular Tachycardia]])
- 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
- Disseminated Intravascular Coagulation (DIC) (see Disseminated Intravascular Coagulation, [[Disseminated Intravascular Coagulation]])
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)
- Pneumomediastinum (see Pneumomediastinum, [[Pneumomediastinum]])
- Pneumothorax (see Pneumothorax, [[Pneumothorax]])
- 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
- Rhabdomyolysis (see Rhabdomyolysis, [[Rhabdomyolysis]])
- Vasculitis (see Vasculitis, [[Vasculitis]])
Toxicologic Manifestations
- Serotonin Syndrome (see Serotonin Syndrome, [[Serotonin Syndrome]])
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]