Amfetamine overdose

Toxicity from amfetamines 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 amfetamine varies from that expected, or when higher doses are used either intentionally or accidentally.[16][17] Risk of toxicity is higher with injected forms of amfetamines, 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).[18] Use of other drugs (particularly alcohol) in combination with amfetamines is common, which complicates the clinical picture of acute toxicity.[19][20][21]

Amfetamines increase the release, and block the re-uptake, of the monoaminergic neurotransmitters dopamine, noradrenaline (norepinephrine), and serotonin in central neuronal synapses. Amfetamine and derivatives such as methamfetamine have the greatest effect on noradrenaline (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][22][23] However, amfetamines have also been shown to have widespread neurobiological downstream effects on non-monoaminergic systems, such as glutamate, endogenous opioid, endocannabinoid, and acetylcholine.[24]

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 haemodilution and hyponatraemia (facilitated by inappropriate antidiuretic hormone secretion and fluid retention) may result in cerebral oedema and seizures.[6][7] Rhabdomyolysis, metabolic acidosis, renal failure, disseminated intravascular coagulation (DIC) with risk of micro-infarcts, and acute respiratory distress syndrome may also occur after hyperthermia.[6][7][25] Acute renal failure may result from the direct toxicity of myoglobin on renal tubules or through renovascular ischaemia 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 amfetamine-induced increase in circulating noradrenaline (norepinephrine) prompts cardiovascular effects, most notably hypertension, with the risk of central nervous system haemorrhage. Tachycardia, with or without arrhythmias and increased cardiac workload, may lead to heart failure.[6][7][8][9]

Fatalities due to amfetamine toxicity occur through multiple mechanisms, including:[8][23][26][27]

Hyperthermia
Cardiovascular effects
Trauma (often associated with over-confidence or risk-taking while under the influence of the drug)
Intracranial or subarachnoid haemorrhage
Stroke
Hyponatraemia (in MDMA toxicity)
Sequelae of serotonin toxicity
Hepatic failure
DIC
Acute renal failure.

Level of arousal, co-operation, and behaviour[1]

Amfetamine 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 amfetamines taken in excess may disrupt attempts to diagnose and treat the patient. The Richmond Agitation-Sedation Scale (RASS) is a widely recognised and utilised 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 behaviour towards staff
+2 (Agitated): Frequent non-purposeful movement or patient-ventilator dyssynchrony
+1 (Restless): Anxious or apprehensive but movements not aggressive or vigorous
0 (Alert and calm): Spontaneously pays attention to carer
-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.

Pathophysiology

Classification

Level of arousal, co-operation, and behaviour[1]