Desmetramadol (INNTooltip International Nonproprietary Name), also known asO-desmethyltramadol (O-DSMT), is anopioidanalgesic and the mainactive metabolite oftramadol.[2] Tramadol is demethylated by theliver enzymeCYP2D6[3] to desmetramadol in the same way ascodeine, and so similarly to the variation in effects seen with codeine, individuals who have a less active form of CYP2D6 will tend to have reduced analgesic effects from tramadol. Because desmetramadol itself does not need to be metabolized to induce an analgesic effect, it can be used in individuals withCYP2D6inactivating mutations.
Desmetramadol is commonly encountered as adesigner drug online[4] in powder form or as an ingredient in pressed pills due to being unscheduled in many jurisdictions. Outside of its role as a metabolite, a chemical used in research, and as a recreational drug, desmetramadol has a very limited history of human usage and is not approved for medicinal use in any country as of 2025.
(+)-Desmetramadol is a G-protein biasedμ-opioid receptor fullagonist.[5] It shows comparatively far lower affinity for theδ- andκ-opioid receptors.[6] The two enantiomers of desmetramadol show quite distinct pharmacological profiles;[7] both (+) and (−)-desmetramadol are inactive asserotonin reuptake inhibitors,[8] but (−)-desmetramadol retains activity as anorepinephrine reuptake inhibitor,[9] and so the mix of both the parent compound and metabolites contributes significantly to the complex pharmacological profile of tramadol. While the multiple receptor targets can be beneficial in the treatment of pain (especially complex pain syndromes such as neuropathic pain), they increase the potential fordrug interactions compared to other opioids, and may also contribute toside effects. Desmetramadol is also anantagonist of theserotonin5-HT2C receptor, at pharmacologically relevant concentrations, via competitive inhibition.[10] This suggests that the apparent anti-depressant properties of tramadol may be at least partially mediated by desmetramadol, thus prolonging the duration of therapeutic benefit. Inhibition of the5-HT2C receptor is a suggested factor in the mechanism of anti-depressant effects ofagomelatine andmaprotiline. The potential selectivity and favorable side effect profile of desmetramadol compared totramadol, makes it more suitable for use as antidepressant, although clinical development appears to have stopped. Upon inhibition of the receptor, downstream signaling causesdopamine andnorepinephrine release, and the receptor is thought to significantly regulate mood, anxiety, feeding, and reproductive behavior. 5-HT2C receptors regulate dopamine release in thestriatum,prefrontal cortex,nucleus accumbens,hippocampus,hypothalamus, andamygdala, among others.[11] Research indicates that some suicide victims have an abnormally high number of 5-HT2C receptors in the prefrontal cortex.[12] There is some mixed evidence thatagomelatine, a 5-HT2Cantagonist, is an effectiveantidepressant.[13] Antagonism of 5-HT2C receptors by agomelatine results in an increase of dopamine and norepinephrine activity in the frontal cortex.
Desmetramadol is metabolized in the liver into the active metaboliteN,O-didesmethyltramadol viaCYP3A4 andCYP2B6. The inactive tramadol metaboliteN-desmethyltramadol is metabolized into the active metaboliteN,O-didesmethyltramadol byCYP2D6.[14]
^Borlak J, Hermann R, Erb K, Thum T (November 2003). "A rapid and simple CYP2D6 genotyping assay--case study with the analgetic tramadol".Metabolism.52 (11):1439–43.doi:10.1016/s0026-0495(03)00256-7.PMID14624403.
^Garrido MJ, Valle M, Campanero MA, Calvo R, Trocóniz IF (October 2000). "Modeling of the in vivo antinociceptive interaction between an opioid agonist, (+)-O-desmethyltramadol, and a monoamine reuptake inhibitor, (-)-O-desmethyltramadol, in rats".The Journal of Pharmacology and Experimental Therapeutics.295 (1):352–9.doi:10.1016/S0022-3565(24)38909-8.hdl:10171/21763.PMID10992001.
^Horishita T, Minami K, Uezono Y, Shiraishi M, Ogata J, Okamoto T, Shigematsu A (2006). "The tramadol metabolite, O-desmethyl tramadol, inhibits 5-hydroxytryptamine type 2C receptors expressed in Xenopus Oocytes".Pharmacology.77 (2):93–9.doi:10.1159/000093179.PMID16679816.S2CID23775035.
^Arndt T, Claussen U, Güssregen B, Schröfel S, Stürzer B, Werle A, Wolf G (May 2011). "Kratom alkaloids and O-desmethyltramadol in urine of a "Krypton" herbal mixture consumer".Forensic Science International.208 (1–3):47–52.doi:10.1016/j.forsciint.2010.10.025.PMID21112167.
^Bäckstrom BG, Classon G, Löwenhielm P, Thelander G (2010). "[Krypton--new, deadly Internet drug. Since October 2009 have nine young persons died in Sweden]".Läkartidningen.107 (50):3196–7.PMID21294331.
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