Dextromethorphan is a common ingredient in over-the-counter cough suppressants that acts on the part of the brain controlling the urge to cough. Beyond this function, dextromethorphan has a complex pharmacological profile involving specific brain receptors. This interaction produces effects distinct from its antitussive properties.
The Function of NMDA Receptors
The central nervous system contains N-methyl-D-aspartate (NMDA) receptors, which regulate synaptic plasticity, a process for how neurons communicate and form memories. These receptors act as channels that, when activated, allow ions to pass into nerve cells as part of the signaling process.
For these channels to open, two conditions must be met: the receptor must bind to the neurotransmitter glutamate, and the neuron must be in an electrically active state. When satisfied, the channel opens and permits calcium ions to enter the neuron. This calcium influx can strengthen the synapse, a process known as long-term potentiation (LTP), which is a cellular basis for learning.
By facilitating LTP, NMDA receptors help solidify the neural circuits that encode new information. The proper functioning of these receptors is a delicate balance, as too little or too much activation can disrupt normal brain function.
Dextromethorphan’s Antagonist Action
An antagonist is a substance that binds to a receptor but does not activate it, instead blocking it. Dextromethorphan is a noncompetitive antagonist at the NMDA receptor, meaning it binds to a different site than glutamate but still prevents the receptor’s channel from opening.
At doses exceeding those for cough suppression, dextromethorphan’s main effect becomes this NMDA receptor blockade. Although its chemical structure is similar to codeine, this action distinguishes it from classic opioids, which primarily affect opioid receptors.
This binding prevents the normal influx of calcium ions, interrupting the signaling pathway and altering neurotransmission. The degree of this blockade is dose-dependent, with higher concentrations causing more pronounced inhibition of NMDA receptor activity.
Therapeutic Applications of NMDA Antagonism
Dextromethorphan’s ability to block NMDA receptors has led to medical uses beyond cough suppression. A primary application is in treating major depressive disorder (MDD). The FDA-approved combination of dextromethorphan and bupropion, marketed as Auvelity, uses bupropion to increase dextromethorphan’s blood levels, enhancing its NMDA antagonist effects for a rapid antidepressant response.
This approach differs from medications targeting monoamine neurotransmitters like serotonin. The mechanism is thought to involve modulating glutamatergic pathways, which play a part in depression. By blocking NMDA receptors, dextromethorphan may help restore normal circuit function, offering an option for patients unresponsive to other antidepressants.
The antagonism of NMDA receptors has other therapeutic applications. A combination of dextromethorphan and quinidine treats pseudobulbar affect (PBA), a condition of uncontrollable laughing or crying. Research has also explored its potential for neuroprotection after events like a stroke and for pain management by addressing central sensitization.
Psychoactive Effects at High Doses
When consumed at high recreational doses, the extensive blockade of NMDA receptors leads to psychoactive effects. The primary experience is dissociation, a feeling of detachment from one’s thoughts, body, and environment. Users may feel as if they are observing themselves from the outside or that the world is not real.
These dissociative states result from the interruption of NMDA receptor function, which is needed for integrating sensory information. At high doses, sensory perceptions can become distorted, causing visual and auditory hallucinations, an altered perception of time, and confusion. The effects are often described in plateaus, with higher doses leading to more intense experiences.
These psychoactive properties contribute to dextromethorphan’s potential for misuse. The conversion of dextromethorphan to its metabolite, dextrorphan, is thought to contribute to these dissociative effects, which are linked to its antagonism of the NMDA receptor system at high concentrations.