Etiology

Toxicity from amphetamines most often occurs in the context of recreational use. It may occur in naive, occasional, binge, or regular users. Intentional overdose also occurs. The actual composition of street drugs is widely variable, and overdose may occur when the content of active drugs is higher than in supplies previously used, when the type of amphetamine varies from that expected, or when higher doses are used either intentionally or accidentally.[14][15] Risk of toxicity is higher with injected forms of amphetamines due to high peak plasma levels. Occasionally toxicity may occur with attempts to conceal drugs in body cavities, either with the intent of smuggling (body packing) or as an emergency strategy to avoid discovery by authorities (body stuffing).[16] Use of other drugs (particularly alcohol) in combination with amphetamines is common, which complicates the clinical picture of acute toxicity.[17][18][19]

Pathophysiology

Amphetamines increase the release of, and block reuptake of, the monoaminergic neurotransmitters dopamine, norepinephrine, and serotonin in central neuronal synapses. Amphetamine and derivatives such as methamphetamine have the greatest effect on norepinephrine, while MDMA-related compounds have a greater effect on serotonin. In large amounts all produce similar symptoms of sympathetic overstimulation and may result in serotonin toxicity.[8][20][21] However, amphetamines have also been shown to have widespread neurobiologic downstream effects on non-monoaminergic systems, such as glutamate, endogenous opioid, endocannabinoid, and acetylcholine.[22]

Serious complications depend partly on individual susceptibility and the circumstances of use.[9] For example, MDMA-associated hyperthermia and profuse diaphoresis are common and exacerbated by the hot, crowded environment and vigorous physical activity of dance parties in which these drugs are often consumed. This scenario may lead to volume depletion with large amounts of sodium lost in sweat.[4][5] If the user drinks large amounts of water to counter thirst, the hemodilution and hyponatremia (facilitated by inappropriate antidiuretic hormone secretion and fluid retention) may result in cerebral edema and seizures.[6][7] Rhabdomyolysis, metabolic acidosis, renal failure, disseminated intravascular coagulation (DIC) with risk of microinfarcts, and acute respiratory distress syndrome may also occur after hyperthermia.[6][7][23] Acute renal failure may result from the direct toxicity of myoglobin on renal tubules or through renovascular ischemia in response to renal arteriolar vasoconstriction. Hepatocellular necrosis may occur secondary to hyperthermia, absence of the cytochrome P450 oxidase CYP2D6 gene, or possibly an immune-mediated mechanism.[6][7][8] An amphetamine-induced increase in circulating norepinephrine prompts cardiovascular effects, most notably hypertension, with the risk of central nervous system hemorrhage. Tachycardia, with or without arrhythmias and increased cardiac workload, may lead to heart failure.[6][7][8][9]

Fatalities due to amphetamine toxicity occur through multiple mechanisms, including:[8][21][24][25]

  • Hyperthermia

  • Cardiovascular effects

  • Trauma (often associated with overconfidence or risk-taking while under the influence of the drug)

  • Intracranial or subarachnoid hemorrhage

  • Stroke

  • Hyponatremia (in MDMA toxicity)

  • Sequelae of serotonin toxicity

  • Hepatic failure

  • DIC

  • Acute renal failure.

Classification

Level of arousal, cooperation, and behavior[1]

Amphetamine overdoses are classified clinically with a pragmatic assessment of patient arousal or sedation after treatment. This is important because, if they are not addressed, the psychostimulant effects of amphetamines taken in excess may disrupt attempts to diagnose and treat the patient. The Richmond Agitation-Sedation Scale (RASS) is a widely recognized and utilized scoring system for this purpose:[1]

  • +4 (Combative): Overtly combative or violent; immediate danger to staff

  • +3 (Very agitated): Pulls on or removes tube(s) or catheter(s) or has aggressive behavior toward staff

  • +2 (Agitated): Frequent nonpurposeful movement or patient-ventilator dyssynchrony

  • +1 (Restless): Anxious or apprehensive but movements not aggressive or vigorous

  • 0 (Alert and calm): Spontaneously pays attention to caregiver

  • -1 (Drowsy): Not fully alert, but has sustained (>10 seconds) awakening, with eye contact, to voice

  • -2 (Light sedation): Briefly (<10 seconds) awakens with eye contact to voice

  • -3 (Moderate sedation): Any movement (but no eye contact) to voice

  • -4 (Deep sedation): No response to voice, but any movement to physical stimulation

  • -5 (Unarousable): No response to voice or physical stimulation.

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