Serotonin releasing agent

A serotonin releasing agent (SRA) is a type of drug that induces the release of serotonin into the neuronal synaptic cleft. A selective serotonin releasing agent (SSRA) is an SRA with less significant or no efficacy in producing neurotransmitter efflux at other types of monoamine neurons, including dopamine and norepinephrine neurons.

SRAs, for instance fenfluramine, dexfenfluramine, and chlorphentermine, have been used clinically as appetite suppressants. However, these SRAs were withdrawn from the market due to toxicity in the 1990s and no SRAs were available or employable for clinical study for many years. In any case, a low-dose formulation was reintroduced for treatment of Dravet syndrome in 2020 and this allowed clinical and research use of SRAs in humans once again.

Aside from use as appetite suppressants, SSRAs have been proposed as novel antidepressants and anxiolytics, with the potential for a faster onset of action and superior effectiveness relative to the selective serotonin reuptake inhibitors (SSRIs).

A closely related type of drug is a serotonin reuptake inhibitor (SRI), for instance fluoxetine.

Effects and comparisons

Selectivities and serotonin increases

A number of somewhat selective SRAs have been well-studied, for instance fenfluramine and meta-chlorophenylpiperazine (mCPP). Although fenfluramine and mCPP are efficacious SRAs, they are also highly potent agonists of serotonin 5-HT2 receptors, including of the serotonin 5-HT2A, 5-HT2B, and particularly 5-HT2C receptors. Direct activation of serotonin receptors such as the serotonin 5-HT2C receptor with fenfluramine has been shown to be therapeutically relevant in humans, as dexfenfluramine produces appetite suppressant effects even when its serotonin release is blocked by concomitant treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine.