Norketamine

Norketamine, or N-desmethylketamine, is what the liver makes of ketamine first. CYP3A4 and CYP2B6 strip a methyl group from the nitrogen, and the resulting molecule is the dominant circulating species after any route with significant first-pass metabolism ^[8].

It is an active metabolite, not an inert one. Norketamine is a non-competitive NMDA receptor antagonist in both cortex and spinal cord, with roughly a third to a fifth of ketamine's potency at that receptor ^[1]. Because oral ketamine is heavily first-pass metabolised, oral dosing produces far more norketamine relative to parent drug than intravenous dosing does, and population pharmacokinetic work has mapped that difference directly ^[2]. In children given ketamine for analgesia, modelling of the metabolite suggests it contributes materially to the pain relief observed, particularly in the later part of the effect ^[6].

Its second role is as an intermediate. Norketamine is hydroxylated onward to the hydroxynorketamines, including (2R,6R)-hydroxynorketamine, the metabolite at the centre of the argument about whether ketamine's antidepressant action requires NMDA blockade at all ^[8]. Norketamine itself has shown antidepressant-like activity in rodent work, and the (S)-enantiomer specifically has been reported to act without requiring AMPA receptor activation, which distinguishes it from both ketamine and the hydroxy metabolites ^[4][3].

Norketamine is not administered to people as a drug, so there is no safety profile for it as an exposure anyone chooses. What exists is the safety of ketamine, of which norketamine is an unavoidable component; separating the two in a human safety record is not currently possible.

The practical implication runs the other way. Because norketamine accumulates relative to parent drug with oral and prolonged dosing, the duration of effect and the residual impairment after ketamine can extend beyond what the parent drug's clearance would predict ^[2]. In analgesic use in children, metabolite modelling suggests part of the sustained effect belongs to norketamine rather than ketamine ^[6]. As an NMDA antagonist in its own right it should be presumed to carry the same class concerns as the parent at proportionate exposure; that presumption has not been tested directly, and it is a presumption.

Norketamine was identified as ketamine's principal metabolite during the pharmacokinetic characterisation that followed the drug's introduction in 1970, and for most of the subsequent two decades it was treated as a route of elimination rather than an object of interest. The analytical literature reflects that: much of the older work on norketamine is chromatography method development for detecting ketamine use rather than pharmacology ^[7].

That framing broke in 1997, when direct electrophysiological comparison showed norketamine to be a non-competitive NMDA receptor antagonist in rat cortex and spinal cord at roughly a third to a fifth of ketamine's potency ^[1]. An inactive end product became a weaker active drug present in larger quantities, and the pharmacokinetics of oral versus intravenous ketamine had to be re-read in that light ^[2].

The modern interest is downstream. Once the 2016 hydroxynorketamine work put the antidepressant mechanism onto the metabolic pathway rather than the parent drug, norketamine became the necessary intermediate in the most argued-over question in the field ^[8], and its own enantiomers were examined for antidepressant activity in their own right ^[4][5].

Norketamine is known to anesthetists and to forensic toxicologists and to almost nobody else. Among the former it is the reason oral ketamine is treated as a different proposition from intravenous ketamine rather than a convenient substitute; among the latter it is the marker that establishes ketamine exposure in blood, urine and hair long after the parent drug is gone ^[7].

In discussion of ketamine for depression it is usually skipped over, mentioned only as a waypoint on the route to the hydroxynorketamines. That undersells it slightly: the enantiomer-specific antidepressant work is real, and the question of whether (S)-norketamine could substitute for esketamine has been asked seriously in the literature rather than only in speculation ^[5]. It has no consumer reputation at all, because it is not sold and there is nothing to have an opinion about.