Ketamine is metabolized into several compounds, and this study shows that norketamine is not the main metabolite circulating in the blood after a single 40-minute infusion of 0.5 mg/kg ketamine in patients with treatment-resistant bipolar depression. Instead, dehydronorketamine was the major metabolite in four out of nine patients, norketamine in three, and hydroxynorketamine in two. Large inter-patient variation in metabolite levels was observed. The findings suggest that future research on ketamine's effects should measure these downstream metabolites.
In a pilot study, d-serine levels may serve as a biomarker for clinical response in individuals with post-traumatic stress disorder (PTSD) treated with (R,S)-ketamine infusion combined with TIMBER psychotherapy. The work suggests that changes in d-serine could reflect treatment outcomes, offering a potential biological indicator for monitoring therapeutic efficacy.
Ibogaine blocks human alpha3beta4-nicotinic acetylcholine receptors (AChRs) by binding to a site in the receptor's ion channel, with about nine times higher potency than phencyclidine (PCP). Ibogaine binds with relatively high affinity (Kd = 0.46 ± 0.06 μM) to a single site in the channel and dissociates more slowly from the desensitized receptor than from the resting one, which may prolong the desensitized state. PCP inhibits ibogaine binding, indicating overlapping binding sites between the serine and valine/phenylalanine rings. The interaction is mainly via van der Waals contacts, with local conformational changes suggested by entropic contributions. These findings suggest ibogaine's mechanism involves stabilizing the receptor in a shut-down state.
Ibogaine analogs, especially 18-methoxycoronaridine (18-MC), bind to a specific site within the ion channel of the nicotinic acetylcholine receptor (AChR) when the receptor is in a desensitized state. The affinity of 18-MC for this site is about 0.17 μM in the desensitized state, much higher than in the resting state (12 μM). The binding site overlaps with the TCP locus, located between valine and leucine rings in the channel. These compounds enhance binding of the agonist cytisine only when the receptor is in a resting but activable state, not when desensitized. The findings suggest that ibogaine analogs inhibit the AChR by promoting receptor desensitization.