Amphetamine Derivatives Toxicity

Amphetamine Derivatives Toxicity – 7 Interesting Facts

Amphetamine derivatives include several prescription and illicit drugs of abuse that act as norepinephrine, dopamine, and sometimes serotonergic agonists
Risk factors for use include young age and attendance at raves and discotheques
Diagnosis is suggested by a reported history of amphetamine derivative use along with the presence of sympathomimetic and/or serotonergic toxidrome
Laboratory testing, imaging, and continuous monitoring may be indicated to evaluate for sequelae of amphetamine derivative use
Management is comprised of supportive care and interventions that mitigate end-organ damage from the sympathomimetic and serotonergic effects of these drugs
Admit patients with ongoing clinical intoxication or signs/symptoms of end-organ damage for additional monitoring, with the level of care required determined by the severity of symptoms
Amphetamine derivative use in pregnancy may confer increased risk of placental abruption and intrauterine growth restriction

Alarm Signs and Symptoms

Chest pain
Hyperthermia
Hypertension
Hypoxemia
Tachydysrhythmia
Neurologic deficit(s)
Seizure

Introduction

Figure 1. Phenylethylamine basic structure. Substitutions that confer changes in receptor affinity can be made on each member of the carbon ring or in the ethyl backbone.

Amphetamine refers to the racemic mixture of β-phenylisopropylamine, which is representative of a broad group of compounds sharing a common phenylethylamine backbone¹
Chemical substitutions on the basic phenylethylamine structure (Figure 1) yield several different substances that can be classified as amphetamine derivatives
- Some commonly used amphetamine derivatives include:¹²
  - Methamphetamine
  - MDMA (methylenedioxymethamphetamine)
  - MDEA (methylenedioxyethylamphetamine)

Background Information

Amphetamine derivatives are used both recreationally and therapeutically
- Effects may include a combination of sympathomimetic and serotonergic effects, both during acute intoxication and with chronic use
  - Some derivatives are synthesized and used recreationally in order to:
    - Avoid detection on routine (often occupational) urine drug screening and/or to avoid prosecution due to production or use of substances considered controlled by the US Drug Enforcement Administration³
    - Increase attention and wakefulness, suppress appetite, or for entactogenic (ie, enhancing desire for closeness with others) and euphorigenic properties⁴
    - Examples include:
      - MDEA, colloquially called “Eve”
      - MDMA, colloquially called “ecstasy” or “Molly”
      - NBOMe (N-benzyl-oxy-methyl) or 2C series
      - PMA (paramethoxyamphetamine) and PMMA (paramethoxymethamphetamine), colloquially called “death”
      - Synthetic cathinones, colloquially called “bath salts,” are a subcategory that includes:
        
        N-ethylhexedrone
        
        Mephedrone (methylmethcathinone)
        
        Methedrone
        
        Methylenedioxypyrovalerone
  - Some amphetamine derivatives are used therapeutically for management of the following:
    - Attention-deficit/hyperactivity disorder (eg, lisdexamfetamine, methylphenidate)
    - Narcolepsy (eg, methamphetamine)
    - Nasal congestion (eg, pseudoephedrine)
    - Weight loss (eg, methamphetamine, phentermine, or historically, the combination agent “fen-phen” containing fenfluramine and phentermine)⁵
    - Dravet syndrome, a rare seizure disorder (eg, fenfluramine)⁶
Table 1 lists characteristics of more commonly used specific substances

Table 1. Characteristics of specific amphetamine derivatives.

Amphetamine derivative	Street names¹	Toxicodynamics	Noteworthy adverse effects
Methamphetamine	Crank Crystal Glass Ice Meth Speed Yaba	Structure is lipophilic, conferring greater CNS activity and resistance to degradation by monoamine oxidase¹	Cardiomyopathy and CAD⁷⁸Dental caries and xerostomia⁹Intestinal ischemia¹⁰¹¹Potent and prolonged effects¹
MDMA Related agents: MDEA MDA	Ecstasy E Adam Molly Eve Love drug	More potent serotonergic stimulation than adrenergic/dopaminergic stimulation	Inappropriate antidiuretic hormone release has been demonstrated in humans and rats,¹² and this may contribute to clinically significant hyponatremia in patients using MDMA¹³
PMMA and PMA	Death Ecstasy	High serotonergic potency compared to adrenergic and dopaminergic activity, but decreased CNS potency	Slower onset of activity,¹⁴ which may lead users to consume several doses in rapid succession¹
1-(8-Bromobenzo[1,2-b;4,5-b]difuran-4-yl)-2-aminopropane	Bromo-DragonFLY	Potent serotonin receptor agonist that confers hallucinogenic properties¹	Delayed seizure,¹⁵ peripheral vasoconstriction, ischemia, and death¹⁶
2-(4-Iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine)	2C series NBOMe N-Bomb Smiles Mr Happy Legal acid	Increased serotonin 2A subtype receptor activity, also strongly hallucinogenic¹⁷	Active even in microgram-range doses, which may contribute to unintentional overdose¹Seizures¹⁷Smooth muscle vasoconstriction and bronchospasm¹⁷
DOM Related agent: DOI	STP (serenity, tranquility, and peace pill)¹⁸	Selective serotonin receptor agonists at the 2A, 2B, and 2C subtypes used in research¹	Profound CNS depression¹⁹ and vasospasm with multi-limb ischemia¹⁸
Synthetic cathinones, including:MethcathinoneMethylenedioxypyrovaleroneMephedrone	Bath salts Plant food Cat Flakka Jeff	Structure is more polar than other amphetamine derivatives, leading to decreased ability to cross the blood-brain barrier¹Sympathomimetic effects predominate¹	Agitation¹Parkinsonism due to manganese contamination in select IV methcathinone users²⁰

Caption: CAD, coronary artery disease; CNS, central nervous system; DOI, 2,5-Dimethoxy-4-iodoamphetamine; DOM, 2,5-Dimethoxy-4-methylamphetamine; MDA, methylenedioxyamphetamine; MDEA, methylenedioxyethylamphetamine; MDMA, methylenedioxymethamphetamine; PMA, paramethoxyamphetamine; PMMA, paramethoxymethamphetamine.

Epidemiology

America’s Poison Centers documented 16,375 symptomatic exposures to amphetamines and related compounds in 2021²¹
- Methamphetamines comprised 9122 single-substance exposures
  - 6.9% experienced minor effects
  - 13.7% experienced moderate effects
  - 3.3% experienced major effects
  - 217 deaths were reported
- Synthetic cathinones, analogues, and precursors (ie, bath salts) comprised 195 single-substance exposures
  - 5.6% experienced minor effects
  - 14.4% experienced moderate effects
  - 4.6% experienced major effects
  - No deaths were reported
- Synthetic phenylethylamines, analogues, and precursors (excluding methamphetamine) comprised 1576 single-substance exposures
  - 8.4% experienced minor effects
  - 14.6% experienced moderate effects
  - 3.6% experienced major effects
  - 2 deaths were reported
Amphetamines and related compounds comprised 1.14% of the cases reported to www.poisonhelp.org in 2021 (number 15 of the top 15 most frequently reported substances)²¹

Etiology

Amphetamines stimulate release and inhibit reuptake of norepinephrine, dopamine, and serotonin²²²³
Stimulation of central and peripheral norepinephrine, dopamine, and serotonergic receptors leads to several desired and undesired effects including:³⁴²⁴²⁵
- Appetite suppression
- Hallucination
- Hyperthermia
- Hypertension
- Psychosis
- Seizure
- Tachycardia and tachydysrhythmias
Table 2 describes toxicokinetic properties of amphetamine derivatives

Table 2. Toxicokinetic properties of select amphetamine derivatives.¹²⁶²⁷²⁸²⁹

Property	d-Methamphetamine (meth)	MDMA (ecstasy)	Mephedrone (bath salts)
Absorption	Peak concentrations are typically reached in 15 minutes if insufflated or injected or 3 hours if ingested Bioavailability is approximately 60%-90%	Peak concentrations are typically reached 2-3 hours after ingestion	Time to reach peak concentration is not well established, but time to onset of effects after insufflation is 10-20 minutes and after ingestion is 20-40 minutes
Distribution	Volume of distribution is approximately 3-7 L/kg	Volume of distribution is approximately 3-7 L/kg Approximately 30% protein bound based on canine studies	Volume of distribution and protein binding are unknown
Metabolism	Primarily metabolized by hepatic N-demethylation* to amphetamine	Primarily metabolized by hepatic N-dealkylation,* demethylation,* and hydroxylation	Primarily metabolized by hepatic N-demethylation and β-keto reduction
Elimination	Plasma elimination half-life is approximately 12-34 hours, which may be prolonged in overdose situations Elimination depends on urine pH; it is enhanced (ie, more rapid) if urine is acidic†	Plasma elimination half-life is approximately 5-10 hours, which may be prolonged in overdose situations	Plasma elimination half-life is unknown

Caption: *Denotes cytochrome P450-mediated processes, specifically via the CYP1A2, CYP2D6, and CYP3A4 isozymes.

†Iatrogenic acidification of urine to enhance elimination is not recommended.

What are the Risk Factors?

Risk factors for use include:
- Age: amphetamine and derivatives are classically associated with usage among individuals in their late teens to early 40s³⁰
- Attending discotheques or other establishments associated with techno and house music³⁰
- Concomitant use of other sympathomimetic and serotonergic agents³¹
Risk factors for increased toxicity include:
- Impaired CYP3A4 activity³⁰³²
- Male sex: based on autopsy data from patients with detectable postmortem concentrations of amphetamine derivatives²²³¹
  - This may reflect higher rates of all-cause mortality or higher rates of mortality in the setting of amphetamine derivative use rather than a true sex-based predilection for use

Diagnosis

Approach to Diagnosis

Diagnosis is suggested by sympathomimetic or serotonergic findings on physical examination, along with history of amphetamine or amphetamine derivative use
- Suggestive examination findings may include:
  - Diaphoresis
  - Hyperreflexia
  - Hypertension
  - Hyperthermia
  - Mydriasis
  - Seizure
  - Tachycardia
- Investigate history for route, dose, use intention, and associated symptoms
Laboratory studies may be used to clarify clinical presentation, although toxicologic testing may not be available in a timely manner in the clinical setting
Imaging studies may be indicated to further evaluate for sequelae of use, depending on clinical symptoms
Diagnostic procedures such as ECG and angiography may be indicated to evaluate for dysrhythmia, ischemia, or necrotizing vasculitis

Workup

History

Obtain a focused substance use history:
- Specific substance used, if known
- Route of use: ingestion, injection, insufflation, smoking
- Timing and duration of use
- Intent of ingestion
- Coingestion of other substances
Assess for associated symptoms suggestive of intoxication or impaired organ function, including:
- Chest pain
- Palpitations
- Shortness of breath
- Anxiety
- Headache
- Focal neurologic symptoms
Inquire regarding any possible traumatic injuries sustained during the period of intoxication
Investigate use history to evaluate for possible substance use disorder³³
- Determine:
  - Frequency of use
  - Amount of substance used over time
  - Impairment of occupational and/or social functioning due to substance use

Physical Examination

Examination findings in acute intoxication may differ from those observed in patients who chronically use amphetamine derivatives
- Acute intoxication typically manifests with sympathomimetic and/or serotonergic effects
  - General examination
    - Diaphoresis³⁴
    - Hyperthermia³⁵
    - Findings suggestive of possible traumatic injury sustained during intoxication³⁶
  - Cardiovascular examination
    - Tachycardia³⁵³⁷
    - Pulse deficits due to vasospasm or dissection of the aorta or other arteries¹⁸³⁸
  - Pulmonary examination
    - Auscultation may reveal crackles³⁴
    - Tachypnea³⁵
  - Neurologic examination
    - Clonus
    - Central nervous system depression/coma¹⁹
    - Hyperreflexia
    - Focal neurologic deficit³⁹
    - Mydriasis
    - Seizure⁴⁰
  - Psychiatric
    - Hallucinations⁴¹
- Chronic use may be evident from symptoms of cardiac and vascular sequelae or damage to dopaminergic neurons
  - General examination
    - Compulsive repetitive behaviors including bruxism and skin picking¹
    - Poor dentition and extensive caries, especially in the setting of chronic methamphetamine smoking⁷⁹⁴²
  - Cardiovascular examination
    - Murmur due to valvulopathy⁴³
    - Displaced point of maximal impulse, jugular venous distention, peripheral and pulmonary edema due to cardiomyopathy⁷
  - Neurologic examination
    - Focal neurologic deficit due to cerebral aneurysm, hemorrhage, or ischemia¹
  - Psychiatric examination
    - Persistent or recurrent psychosis⁴⁴

Laboratory Tests

Testing for amphetamine derivates may not be available in a clinically useful timeframe
- Gold standard for drug detection is gas chromatography–mass spectrometry³⁵
Laboratory studies are indicated to assess the acutely altered or somnolent patient
- Testing should be based on clinical scenario; consider the following:
  - Arterial or venous blood gas to evaluate pH
  - CBC, which may reveal:
    - Leukocytosis³⁵³⁷
    - Evidence of hemoconcentration³
    - Thrombocytopenia¹
  - CMP (complete metabolic panel) to assess for the following:
    - Acidosis⁴²
    - Electrolyte abnormalities including hyponatremia and hyperkalemia⁴²
    - Elevated transaminase concentrations¹⁰⁴⁰⁴²
    - Renal injury³⁷⁴⁰
  - Creatine kinase to evaluate for rhabdomyolysis³⁷⁴⁵
  - Fibrinogen concentration if there is clinical suspicion for disseminated intravascular coagulation⁴⁰⁴⁶
  - Fingerstick blood glucose,¹⁴² which may be decreased¹⁴ or elevated³⁵
  - Lactic acid concentration if there is clinical concern for intestinal ischemia¹⁰
  - Prothrombin time and INR to evaluate for coagulopathy³⁵
  - Troponin concentration to assess for cardiac ischemia³⁸⁴⁵
Consider a urine drug screen with the following caveats:
- Use of a urine drug screen is not recommended to make clinical management decisions in cases of suspected acute amphetamine derivative toxicity¹
- Qualitative immunoassay-based urine drug screens:
  - Reflect recent exposure to detected substances but that does not necessarily reflect current intoxication¹
  - May be positive or negative in different clinical settings, depending on substance used and particular testing materials used⁴⁷
  - Result interpretation
    - False-positive results have been reported with appropriate use of prescription medications including bupropion, trazodone, and amantadine, as well as OTC agents containing pseudoephedrine and levmetamfetamine-containing nasal decongestant sprays¹⁴⁸
    - Selegiline is metabolized in vivo to amphetamine and methamphetamine, yielding a true-positive result on a urine drug screen, though this medication is used legitimately to treat Parkinson disease¹⁴⁹
    - False-negative results may be observed in patients using MDMA and cathinones

Imaging Studies

Imaging is not required to diagnose amphetamine-derivative toxicity
Specific tests may be indicated to further evaluate for sequelae of use, depending on clinical symptoms
- Chest radiograph to evaluate for pulmonary edema or evidence of aspiration pneumonitis in patients with hypoxemia¹¹⁵³⁴⁴⁹
- CT of head/neck to evaluate for hemorrhagic stroke, carotid dissection, or ischemic stroke in patients with focal neurologic deficits³⁹⁵⁰⁵¹⁵²
- CT of chest/abdomen/pelvis to evaluate for intestinal ischemia¹⁰⁵³⁵⁴ and/or aortic dissection³⁸⁵³⁵⁵
- Transthoracic or transesophageal echocardiogram to evaluate for cardiomyopathy and valvulopathy³⁷

Diagnostic Procedures

Obtain ECG to evaluate for dysrhythmia and ischemic changes
- Sinus tachycardia and premature ventricular complexes are most commonly observed, though monomorphic and polymorphic ventricular tachycardia and ventricular fibrillation have been reported as well¹⁵⁶⁵⁷
Angiography may be indicated for patients with chronic amphetamine derivative use
- Increased risk of developing necrotizing vasculitis that affects multiple organ systems, especially the brain and kidneys⁵⁸

Differential Diagnosis

Table

Table 3. Differential Diagnosis: Amphetamine derivatives toxicity.

Condition	Description	Differentiated by
Antimuscarinic toxicity	Agitation, hypertension, hyperthermia, mydriasis, tachycardia, urinary retention	Diaphoresis: patients will not be diaphoretic in cases of antimuscarinic toxicity
Cocaine or other sympathomimetic toxicity	Agitation, diaphoresis, hypertension, hyperthermia, mydriasis, tachycardia	Clinical history or urine drug screen results that suggest exposure to nonamphetamine sympathomimetic
Pheochromocytoma	Diaphoresis, headaches, hypertension, palpitations, tachycardia	History of genetic risk factors, elevated plasma or urinary metanephrine levels
Salicylate toxicity	Agitation/confusion or CNS depression, hyperthermia, hyperpnea, metabolic acidosis with respiratory alkalosis, tachycardia, pulmonary edema	Clinical history of salicylate consumption or elevated serum salicylate concentration
Serotonin toxicity from other serotonergic agonists	Clonus, agitation, autonomic instability, hyperreflexia, hypertension, hyperthermia, mydriasis, tachycardia	History of exposure to 1 or more serotonergic agents that do not belong to the class of amphetamine derivatives; clonus and hyperreflexia on examination are more specific for serotonin toxicity⁵⁹
Thyrotoxicosis	Diarrhea, encephalopathy with CNS excitation, hyperthermia, tachycardia, tachydysrhythmia	History of thyroid disease and/or thyrotropic medication use, low or undetectable TSH concentrations, elevated free thyroid hormone

Caption: CNS, central nervous system.

Treatment

Approach to Treatment

Overarching goal is to prevent end-organ damage (primarily due to hyperthermia and elevated blood pressure) until intoxication resolves
- Supportive care measures include monitoring, temperature control, respiratory support, and maintaining patient and staff safety
- Medications to address agitation, hypertension, and hyperthermia may be required
- Treatments including decontamination and enhanced elimination through hemodialysis may be indicated

Nondrug and Supportive Care

Monitoring
- Continuous telemetry monitoring is indicated for those with chest pain, dysrhythmias, or other evidence of cardiac ischemia and/or valvulopathy¹⁴²
- Frequent neurologic examinations and/or EEG monitoring are indicated for patients with intracranial hemorrhage, ischemia, or seizure¹⁴²
Cooling
- Evaporative or submersion cooling is indicated for hyperthermia with core temperature greater than 40 °C¹¹⁴⁵⁶⁰
  - Evaporative cooling may be performed by misting patient’s body with lukewarm water or wrapping patient in a sheet that has been soaked with cool (20 °C) water and continuously directing forced air (eg, from portable fan) over patient⁶¹
  - If submersion cooling is used, water temperature may be 2 to 20 °C⁴⁶
    - While submersion cooling may be effective at reducing core temperature, the authors acknowledge that it may preclude continuous telemetry monitoring, which is often indicated for patients with amphetamine derivative toxicity and can be logistically difficult in the emergency department setting
  - Treatment is recommended until a core temperature of 39 °C or less is achieved, preferably within 30 to 60 minutes⁴⁰⁴⁶
Respiratory support
- Provide supplemental oxygen as needed to maintain appropriate oxygen saturation (greater than 95% if previously healthy or between 88% to 92% if history of chronic obstructive pulmonary disease)¹³⁴⁴⁹
Patient and staff safety
- Pharmacologic sedation (eg, benzodiazepines) is preferred due to physical and psychologic adverse effects associated with use of physical restraints⁶²
- For combative and physically violent patients who are not responsive to verbal deescalation and unable to safely be medicated, hospital security may be required to temporarily restrain patients physically to prevent injury to themselves or to staff⁶²
  - 4-point restraints may be employed sparingly on a case-by-case basis in these settings

Drug Therapy

Benzodiazepines are recommended for agitation, restlessness, seizures, and/or vasospasm¹⁴¹⁶³
- Benzodiazepines should be titrated to clinical effect (ie, until patient is somnolent but arousable to verbal stimulus)¹
- Agents with rapid onset of action (eg, IV diazepam or IM midazolam) are preferred in both the prehospital and emergency department and inpatient settings¹
  - Initial dose of 5 to 10 mg IV diazepam or 5 to 10 mg IM midazolam (or equivalent dose of other available benzodiazepine) may be repeated every 5 to 10 minutes until appropriate level of sedation is achieved¹⁴²
  - Large doses may be required¹
Neuroleptic agents can also be considered for benzodiazepine-refractory agitation¹⁶³
- Treatment with haloperidol in the setting of cocaine and amphetamine toxicity has shown a trend towards mortality reduction in a rodent model,⁶⁴ suggesting a potential benefit for patients experiencing toxicity from dopaminergic agonism
- Neuroleptics should be used with caution in patients with these signs of amphetamine derivative toxicity as they may exacerbate hyperthermia and seizures¹⁶⁰
  - Haloperidol 5 to 10 mg IM⁶⁵ or droperidol 2.5 to 5 mg IM may be administered and repeated every 15 minutes until patient is asleep but arousable to verbal stimulus⁶³
  - Neuroleptic agents with significant antimuscarinic activity (eg, chlorpromazine, olanzapine, thioridazine) are not recommended in this setting
NMDA receptor antagonists (eg, ketamine) are sometimes used in the prehospital setting or in cases of agitation and combative behavior refractory to benzodiazepines and neuroleptic agents⁶⁶
- Ketamine should be used with caution as the increases in heart rate and blood pressure that may be observed can exacerbate any underlying sympathomimetic effects of amphetamine derivatives; additionally, hypersalivation may complicate respiratory effects of amphetamine derivative use and airway management⁶⁶
  - Ketamine 4 to 5 mg/kg IM may be considered as a third line agent in the setting of amphetamine derivative toxicity, if multiple doses of benzodiazepines or neuroleptic agents do not provide adequate sedation to maintain patient and staff safety⁶⁶
Antihypertensives can be used in cases in which hypertension remains persistent after resolution of agitation or if there is evidence of associated end-organ damage (eg, chest pain, encephalopathy)⁴²⁶⁷
- Continuous infusion of nicardipine or other dihydropyridine calcium channel blocker
  - Initiate nicardipine infusion at 5 mg/hour, increasing in increments of 2.5 mg/hour every 15 minutes until a maximum of 15 mg/hour titrated to effect, especially for patients with vasospasm⁴²
  - Target a reduction in mean arterial pressure of no more than 20% to 25% within first hour of treatment and continue titration of antihypertensives to achieve blood pressure of 160/110 mm Hg over the subsequent 2 to 6 hours, with the following exceptions:⁶⁸
    - More rapid titration may be indicated if there is concomitant:
      - Aortic dissection
      - Intracranial hemorrhage
      - Other specific pathology for which a subspecialty consultant recommends a different blood pressure target
    - Permissive hypertension may be indicated if there is concomitant ischemic cerebrovascular accident
Hyperthermia management
- Physical cooling measures are the effective management option for hyperthermia secondary to amphetamine derivatives¹¹⁴³⁴⁵
- Antipyretics (eg, acetaminophen) are ineffective at managing hyperthermia due to sympathomimetic and serotonergic effects and are not recommended⁶⁰
- Dantrolene is not recommended for treatment of hyperthermia in this setting¹⁴⁶
  - Amphetamine-associated hyperthermia is multifactorial in etiology,¹¹ and dantrolene does not treat the central mechanisms or peripheral vasoconstriction contributing to hyperthermia

Treatment Procedures

Decontamination
- Gastrointestinal decontamination with activated charcoal may be contraindicated due to changes in mental status and aspiration risk and is likely ineffective for patients who have used amphetamine derivatives by insufflation, injection, smoking, or sublingually⁴²
Enhanced elimination
- Consider hemodialysis for patients with any of the following that do not improve after initial resuscitation:¹
  - Oliguric or anuric renal failure
  - Acidemia
  - Electrolyte abnormalities

Persistent or Recurrent Disease

Consider endotracheal intubation and administration of barbiturates or propofol for patients with seizures refractory to multiple doses of benzodiazepines⁴²

Admission Criteria

Admission to ICU is warranted for any findings consistent with end-organ damage requiring frequent/continuous monitoring or titration of medications⁶⁷
Admission to a monitored medical unit is recommended for patients with persistent agitation/delirium, metabolic derangements, and/or vital sign abnormalities
Patients are appropriate for discharge from either the emergency department or inpatient setting once vital signs and mental status have returned to baseline⁴² and any laboratory abnormalities attributed to amphetamine derivative toxicity have a clear trend towards normalization
For patients who are asymptomatic upon presentation, 4 to 6 hours of observation in emergency department is recommended
Some patients with signs and symptoms of amphetamine derivative intoxication have exhibited worsening toxicity 8 hours post ingestion¹⁵

Special Considerations

Pregnancy

Use of amphetamine derivatives in pregnancy may increase risk of placental abruption⁴²⁶⁹
- Consider blood transfusion, Rh immune globulin, fetal heart rate assessment, tocometric monitoring, and emergent obstetric consultation for patients in second or third trimester of pregnancy with abdominal pain and vaginal bleeding⁷⁰
Amphetamines and their derivatives cross the placenta, which may result in fetal exposure⁶⁹
- Cardiac toxicity has been demonstrated in rodents with in utero amphetamine exposure
- Low birth weight and decreased head circumference have been reported⁶⁹

Follow-Up

Complications

Similar to cases of toxicity from other sympathomimetics, clinicians should be cognizant of the following possible complications of amphetamine derivative use:
- Aspiration pneumonitis and/or acute respiratory distress syndrome
- Hypertensive encephalopathy and/or intracranial hemorrhage
- Myocardial ischemia and infarction
- Rhabdomyolysis and renal failure
- Valvulopathy
- Vascular pathology including aneurysm and necrotizing arteritis
- Seizure
Complications secondary to injection drug use include:
- Risk of exposure to infection with HIV, hepatitis B and C if paraphernalia, particularly needles, are shared among multiple individuals⁷¹
- Risk of endocarditis, tetanus, and wound botulism from contamination with skin flora and other bacteria⁷¹
Withdrawal
- There is no accepted constellation of signs and symptoms that describes amphetamine withdrawal⁷²
- After a period of repeated use of amphetamine derivatives, patients may exhibit depressed mood, hunger, or increased need for sleep associated with cravings to use amphetamine derivatives¹
- Rodent models of frequent chronic amphetamine use suggest that behavioral changes after use is discontinued likely represent a decrease in effects of stimulants rather than a true withdrawal syndrome⁷³

Prognosis

Acute intoxication
- Without associated end-organ damage, acute amphetamine derivative intoxication is typically self-limited⁷⁴
Chronic use
- Long-term repeated use may result in dose-dependent damage to serotonergic neurons⁷⁵
- Patients with amphetamine derivative use disorder who experience recurrent intoxication, possibly with escalating doses, may be at increased risk of toxicity³³⁷⁶

Referral

Consultation with medical toxicology specialist or regional Poison Center may be helpful
Patients with history suggestive of amphetamine derivative use disorder³⁰ should be referred to specialty addiction care

Screening and Prevention

Screening

Screening patients for recreational drug use may create opportunities to increase their awareness of the potential harm conferred by amphetamine derivative use
- The authors recommend the National Institute on Drug Abuse SQSUS (Single-Question Substance Use Screening) question: “How many times in the past year have you used an illegal drug or used a prescription medication for nonmedical reasons?”⁷⁷
- SQSUS was similarly sensitive and specific to the DAST-10 (10-Item Drug Abuse Screening Test) for identifying a current substance use disorder in a primary care setting,⁷⁷ and its brevity facilitates its use in the emergency department
  - Its efficacy in reducing amphetamine derivative use in patients who screen positive is unknown

Prevention

Avoiding use of recreational drugs is a key means to preventing toxicity
Perceived harm attributed to amphetamine derivative use has deterred personal misuse and distribution,⁷⁸ so disseminating information about toxic effects of amphetamine derivatives may help discourage use

References

1.Spyres MB et al. Amphetamines. Nelson LS et al, eds. Goldfrank’s Toxicologic Emergencies. 11th ed. McGraw Hill; 2019:1099-1107.

View In Article

2.World Drug Report 2023. Ranking of prevalence of drug use, all drugs. United Nations Office on Drugs and Crime. Accessed November 14, 2023.