Dextromethorphan Withdrawal Timeline

Dextromethorphan, also known as DXM, is a common ingredient in cough medications such as Robitussin, and until recently, there were no regulations regarding the sale of dextromethorphan in America. While no federal regulations exist currently, there are state-level bills and laws being passed to prohibit or otherwise regulate the sale of dextromethorphan to people under the age of 18, but these vary by state. Dextromethorphan, even though it is derived from morphine, does not have appreciable interactions with opioid receptors. The exact way that dextromethorphan works is still unclear, although it is known to interact with NMDA glutamate receptors as an antagonist, a σ (Sigma) receptor agonist, and an inhibitor of serotonin and norepinephrine reuptake.

Glutamate is a major excitatory neurotransmitter in the brain that has a multitude of roles, and the fact that dextromethorphan acts as an antagonist at NMDA glutamate receptors means that it can reduce the excitatory impact produced by glutamate. These glutamate interactions, among other somewhat mysterious mechanisms, is one of the ways it acts as a cough suppressant. The effects of dextromethorphan are also dose-dependent, with small amounts producing depressive effects and large amounts producing dissociative and hallucinogenic effects. The exact way this works is unclear, although it most likely has to do with the combination of NMDA antagonism, σ-1 receptor stimulation, and serotonin reuptake inhibition, somewhat similar to more classic hallucinogens.

Through long-term and heavy use of dextromethorphan, the systems that were affected will undergo changes. Alternatively known as upregulation (in the case of glutamate) and downregulation (in the case of serotonin and norepinephrine), these are regulatory processes performed by the brain in an attempt to maintain neurotransmitter balance. Since dextromethorphan reduces the impact of glutamate at NMDA receptors, the brain will “upregulate” these receptors, or turn up their sensitivity. With serotonin and norepinephrine, receptors were experiencing more stimulation due to dextromethorphan’s inhibition of their reuptake transporters. These neurotransmitter systems will undergo an opposite but similar process of “downregulation” where the brain reduces the sensitivity of their receptors. Once these upregulation and downregulation processes have begun to occur, someone will begin to feel unwell when they go too long without dextromethorphan. These are the symptoms of dextromethorphan withdrawal, and depending on someone’s use habits, they may range from a little uncomfortable, to potentially life-threatening.