The reuptake process is susceptible to drug manipulation. By blocking the action of serotonin reuptake inhibitors (SERTs), the amount of serotonin in the synaptic cleft increases. Selective serotonin reuptake inhibitors (SSRIs) act primarily at the 5HT transporter protein and have limited, if any, reaction with other neurotransmitter systems. SSRIs bind to the transporter protein directly and block the reuptake process. Consequently, more serotonin remains in the cleft where it is free to travel further to more distant receptors as well as continue to react with nearby receptors. Like the binding of substrates, antagonist binding to SERTs is also dependent on extracellular Na+ although ion dependency is different for each SERT antagonist. It is unclear whether SSRIs bind to the same SERT domain as serotonin or operate through more indirect mechanisms. Recent evidence suggests that binding of SSRIs to SERTs occurs at the same site as 5HT binding, but it has not been determined conclusively.

There are many SSRIs either in the market or in development. SSRIs currently available include citalopram, fluoxetine (Prozac), fluvoxamine, paroxetine (Paxil), and sertraline (Zoloft). In addition, while not as selective as the above mentioned, drugs of abuse such as cocaine, fenfluramine, and (3,4-methylenedioxy) methamphetamine (MDMA or ecstasy) are inhibitors of serotonin uptake.