How does auvelity work in the brain? A guide to its unique dual-action mechanism

October 6, 2025 •

2 min read

Approved by the FDA in 2022, Auvelity represents a significant milestone in antidepressant therapy, offering a novel oral mechanism of action not seen in over 60 years. To understand how does auvelity work in the brain?, one must explore the synergistic effects of its two active components, dextromethorphan and bupropion, which target different neurochemical systems for rapid symptom relief.

Quick Summary

Auvelity combines dextromethorphan and bupropion to modulate brain chemistry. Dextromethorphan primarily acts on the glutamate system via NMDA and sigma-1 receptors, while bupropion inhibits an enzyme to sustain dextromethorphan's effects and also boosts norepinephrine and dopamine.

Key Points

Dual-Component Action: Auvelity combines dextromethorphan and bupropion to produce its effects.
Glutamate Modulation: Dextromethorphan acts as an NMDA receptor antagonist, affecting glutamate signaling in depression.
Enzyme Inhibition: Bupropion inhibits the CYP2D6 enzyme, prolonging dextromethorphan's effects.
Monoamine Enhancement: Bupropion also acts as an NDRI, increasing norepinephrine and dopamine.
Rapid Onset: Auvelity can show improvement in depressive symptoms as early as one to two weeks.
Neuroplasticity: The drug may promote neuroplasticity by affecting glutamate signaling.

Unpacking the Dual-Action Formula: Dextromethorphan and Bupropion

Auvelity contains two active ingredients: dextromethorphan (DXM), commonly used as a cough suppressant, and bupropion (BUP), an antidepressant. These components work together for therapeutic effect. Dextromethorphan is quickly broken down by the liver enzyme CYP2D6. Bupropion inhibits this enzyme, allowing DXM to remain in the body longer and reach therapeutic levels in the brain.

Dextromethorphan's Neurobiological Impact

DXM in Auvelity affects several targets in the central nervous system, differing from traditional antidepressants.

Modulating Glutamate via the NMDA Receptor

Abnormal glutamate signaling, particularly through the NMDA receptor, is linked to major depressive disorder. DXM is an NMDA receptor antagonist, which helps regulate this system. This action is similar to ketamine, a rapid-acting antidepressant, though Auvelity is taken orally. Modulating glutamate may enhance neuroplasticity, which is often impaired in chronic depression.

Agonism at the Sigma-1 Receptor

DXM also acts as a sigma-1 receptor agonist. This receptor affects intracellular signaling and neurotransmitter systems, including glutamate and serotonin. Activating this receptor is thought to contribute to Auvelity's fast action.

Bupropion's Role in Neurotransmitter Regulation

Besides boosting DXM levels, bupropion has its own antidepressant effects.

Norepinephrine and Dopamine Reuptake Inhibition

Bupropion is a norepinephrine and dopamine reuptake inhibitor (NDRI). It increases these neurotransmitters in the synapse, improving nerve cell communication. These neurotransmitters are important for mood, motivation, and energy.

Comparison of Auvelity with Traditional Antidepressants

Auvelity's mechanism distinguishes it from conventional antidepressants. The table below highlights some key differences:


Feature	Auvelity	Traditional SSRIs/SNRIs
Mechanism of Action	Dual-action (NMDA antagonism + NDRI)	Monoamine reuptake inhibition (Serotonin, Norepinephrine)
Primary Target	Glutamate, NMDA, Sigma-1, Norepinephrine, Dopamine	Serotonin and/or Norepinephrine
Onset of Action	As early as 1-2 weeks in clinical trials	Typically 4-8 weeks to see full effect
Potential Neuroplasticity	Enhanced glutamatergic signaling promotes neuroplasticity	Less direct evidence for rapid neuroplasticity promotion
Potential Side Effects	Dizziness, headache, nausea, dry mouth, somnolence, sweating	Sexual dysfunction, weight gain, nausea, somnolence

Conclusion: The Multifaceted Action of Auvelity

Auvelity offers a new approach to treating major depressive disorder by acting on multiple pathways. The combination of DXM's effects on NMDA and sigma-1 receptors with bupropion's NDRI activity and metabolic inhibition creates a synergistic effect. This approach, targeting both glutamate and monoamine systems, provides a unique therapeutic option that differs from traditional antidepressants and may contribute to its rapid onset and efficacy.

Key Neurobiological Targets of Auvelity

Auvelity's mechanism involves several targets, including NMDA receptor antagonism, sigma-1 receptor agonism, CYP2D6 enzyme inhibition, and norepinephrine and dopamine reuptake inhibition. Modulating glutamate may also promote neuroplasticity.

Frequently Asked Questions

Auvelity's main mechanism involves the combination of dextromethorphan, an NMDA receptor antagonist, and bupropion, which increases dextromethorphan levels by inhibiting its metabolism.

Auvelity differs by primarily targeting glutamate signaling via the NMDA receptor, in addition to affecting monoamines. This leads to a faster onset of action compared to traditional antidepressants that focus mainly on serotonin.

Bupropion increases norepinephrine and dopamine as an NDRI, and it inhibits the CYP2D6 enzyme, which extends the therapeutic levels of dextromethorphan.

The faster onset is linked to dextromethorphan's effects on the glutamatergic system, which can cause quicker neurochemical changes than traditional antidepressants.

The NMDA receptor is a glutamate receptor involved in various brain functions, including mood. Dysfunction of the NMDA receptor and excessive glutamate activity are associated with depression.

Yes, Auvelity is thought to promote neuroplasticity by modulating glutamate signaling. This may help restore neural connections impacted by chronic stress and depression.

Some treatments like ketamine and esketamine also target the NMDA receptor. However, Auvelity is the only oral NMDA receptor antagonist approved for major depressive disorder.