Pharmacological effects of amphetamines and their congeners are primarily mediated by increased synaptic release of monoamine neurotransmitters norepinephrine (NE), dopamine (DA), and, to a lesser extent, serotonin (5-HT). (A) (i) Amphetamines are competitive agonists for NET and DAT. (ii) Upon entering the presynaptic neuron, amphetamines bind to VMAT2, thereby inhibiting monoamine translocation from the cytosolic pool into storage vesicles. (iii) Amphetamines also weakly inhibit monoamine oxidase–mediated (MAO-mediated) monoamine breakdown, resulting in intracellular increase of monoamines. (iv) Amphetamines can further activate the intracellular trace amine-associated receptor 1 (TAAR1) to promote DA efflux. All processes contribute to reverse transport via NET or DAT, enhancing extracellular monoamine release. (v) Elevated monoamine release induces satiety and decreases feeding by activating postsynaptic α- and β-adrenergic (NE) and D1/D2 (DA) receptors. Increased DA signaling within the mesocorticolimbic system contributes to the addictive properties of amphetamines and their congeners. (B) Selective serotonergic drugs act either as (i) serotonin-releasing agents (SRAs), (ii) selective serotonin reuptake inhibitors (SSRIs), or (iii) selective 5-HT2C receptor agonists. SRAs (e.g., fenfluramine) increase synaptic 5-HT release, augmenting serotonergic function. Although SRAs’ precise mechanisms remain unclear, they may be comparable to NE and DA releasers, i.e. reversing SERT- or VMAT2-mediated 5-HT transport. SSRIs (e.g., sibutramine) selectively bind SERT to inhibit 5-HT re-uptake. Postsynaptic 5-HT2C receptors appear to mediate the main effects of 5-HT on food intake and are the target of selective 5-HT2C receptor agonists such as lorcaserin. Presynaptic autoreceptor 5-HT1A and postsynaptic 5-HT1B, 5-HT2B, and 5-HT6 receptors may also contribute to the regulation of food intake by 5-HT. Monoaminergic drugs act at pre- and postsynaptic neurons, and they also interact with monoaminergic signaling on astrocytes. Astrocytic expression of NET, DAT, SERT, and metabolizing enzymes such as MAO can regulate monoamine levels in the synaptic cleft, neurotransmitter release from astrocytes and its transport into presynaptic neurons, and postsynaptic neuron activity.