A serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI), also known as a triple reuptake inhibitor (TRI or TUI), is a type of drug that acts as a combined reuptake inhibitor of the monoamine neurotransmitters serotonin, norepinephrine, and dopamine. Monoamine structures (including neurotransmitters) contain a singular amino group (mono) linked to an aromatic ring by a chain of two carbons. SNDRIs prevent reuptake of these monoamine neurotransmitters through the simultaneous inhibition of the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT), respectively, increasing their extracellular concentrations and, therefore, resulting in an increase in serotonergic, adrenergic, and dopaminergic neurotransmission. SNDRIs were developed as potential antidepressants and treatments for other disorders, such as obesity, cocaine addiction, attention-deficit hyperactivity disorder (ADHD), and chronic pain. The increase in neurotransmitters through triple reuptake inhibition (including the addition of dopaminergic action) has the potential to heighten therapeutic effects in comparison to selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), reducing symptoms of depression and anxiety in people struggling with mental illness, as well as potentially combating other ailments such as those listed above.
However, increased side effects and abuse potential are concerns when using these agents relative to their SSRI and SNRI counterparts. Additionally, SNDRIs include the naturally occurring drug cocaine, a widely used recreational and often illegal drug for the euphoric effects it produces. Ketamine and phencyclidine are also SNDRIs and are similarly encountered as drugs of abuse. To a lesser extent, MDMA also acts as a SNDRI.
