Amphetamines and other indirectly acting sympathomimetic agents are characterized by their ability to stimulate the central nervous system in addition to their peripheral a- and b-adrenergic actions.

Sympathomimetic agents are derived from the phenylethylamine molecule and increase the norepinephrine (noradrenaline) concentration in the synaptic cleft and presynaptic nerve terminal by blocking the reuptake of norepinephrine into the presynaptic nerve terminal. A second mode of action is by inhibiting the active uptake of norepinephrine into storage vesicles. Thirdly, they inhibit mitochondrial monoamine oxidase, an enzyme responsible for norepinephrine degradation. Some amphetamines with a hydroxyl substitution in the b position (e.g. ephedrine) are able to stimulate sympathetic receptors directly. The central excitatory effects are mediated by indirect noradrenergic mechanisms in the cortex, the reticular activating system, and the medullary respiratory center. A phenomenon unique to the amphetamines is 'aggregation toxicity'. Animal studies show that the behavioral and toxic effects of amphetamines are massively enhanced if mice given the drug are grouped together as opposed to being alone. In addition to 'aggregation toxicity', acute toxicity in solitary mice is increased by loud noise, high ambient temperature, and dehydration. These factors may have human relevance. MDMA, MDA, and MDEA are phenethylamine derivatives with unique psychoactive properties causing heightened emotional and sensory experiences, without producing marked visual or sensory distortions. They promote the release of serotonin and block its reuptake, and cause serotonin depletion; they are neurotoxic to serotonin terminals in every animal species studied ( Green §L§L 1995).

Amphetamine is readily absorbed across mucosal surfaces. Peak plasma concentration is seen within minutes of intravenous injection, within 30 min of intramuscular or topical administration, and within 3 h of ingestion. Plasma concentrations are low (ng/ml) because of extensive tissue distribution (3-6 l/kg). It is 20 per cent bound to plasma proteins, and cerebrospinal fluid levels are 80 per cent of those found in plasma. Following typical recreational doses, the duration of effects is usually around 4 to 8 h, but large doses and alkaline urine can prolong the effects to 24 h or more. Renal excretion of amphetamine, a weak base, largely depends on urine pH because of trapping of ions in the renal tubule. In patients with a urine pH below 6.6 the half-life ranges from 7 to 14 h; with a urine pH above 6.7 the range is 18 to 34 h. Following MDMA doses of 75 to 150 mg, effects occur within 1 h and last for 4 to 12 h.

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