O-DSMT

Also known as desmetramadol and O-desmethyltramadol.
Key component of the pain medication tramadol.
Known for its strong pain-relieving effects.
Works primarily by mimicking natural painkillers in the body.
Influences other systems to help manage pain, especially in complex cases.
Mainly activates μ-opioid receptors.
Much stronger than tramadol, with studies showing it’s 2–4 times more potent.
Block the reuptake of norepinephrine, particularly with the (-)-enantiomer.
Research indicates it may cause fewer breathing issues compared to other strong painkillers.
For people with kidney problems, O-DSMT can build up, increasing risks like seizures or breathing difficulties, so doctors often lower the dose.
It's the primary active metabolite of tramadol.
O-DSMT is formed through the demethylation of tramadol by the liver enzyme CYP2D6, a process analogous to the metabolism of codeine to morphine.
As of May 7, 2025, O-DSMT is not approved for medicinal use in any country but is significant in research and has been noted as a designer drug due to its unscheduled status in some jurisdictions (source).
The (+)-enantiomer is identified as a G-protein biased full agonist, which means it preferentially activates the G-protein signaling pathway over the β-arrestin pathway. This bias is significant as it may reduce adverse effects like respiratory depression, a major concern with opioids.
Up to 200 times greater affinity for μ-opioid receptor than tramadol.
Also shows far lower affinity for δ- and κ-opioid receptors.
Both enantiomers are inactive as serotonin reuptake inhibitors, distinguishing it from tramadol, which has dual serotonin and norepinephrine reuptake inhibition properties (source).

Enantiomer Serotonin Reuptake Norepinephrine Reuptake

(+)-O-DSMT Inactive Inactive

(-)-O-DSMT Inactive Active (retains inhibition)

Antagonism at the 5-HT2C receptor at pharmacologically relevant concentrations. This antagonism can lead to increased release of dopamine and norepinephrine, potentially influencing mood, anxiety, feeding behavior, and reproductive behavior (source).
Genetic variations in CYP2D6 can significantly impact its efficacy and safety.
CYP2D6 poor metabolizers may experience reduced analgesia, while ultra-rapid metabolizers may face increased risks of side effects like respiratory depression and death due to higher O-DSMT levels (source).

Enantiomer	Serotonin Reuptake	Norepinephrine Reuptake
(+)-O-DSMT	Inactive	Inactive
(-)-O-DSMT	Inactive	Active (retains inhibition)