Noribogaine, the active metabolite of ibogaine, was tested for the first time in patients on methadone opioid substitution therapy. In a randomized, double-blind, placebo-controlled trial with 27 patients, doses of 60, 120, or 180 mg were well tolerated, with common side effects including temporary changes in light perception, headache, and nausea. The drug showed dose-linear increases in blood concentration and a slow elimination half-life of 24–30 hours. Noribogaine caused a concentration-dependent increase in heart rate–corrected QT interval (QTcI), with average increases of about 16, 28, and 42 milliseconds at the three doses. There was a nonstatistically significant trend toward reduced opioid withdrawal symptoms, most notably at 120 mg, but study design issues may have affected results.
Psilocybin, a compound being developed for major depressive disorder, is converted to psilocin after absorption. A single ascending dose study (0.3 to 0.6 mg/kg) found a significant but shallow relationship between psilocin concentration and QTc interval prolongation. At a clinical dose of 25 mg, the mean peak psilocin concentration is 18.7 ng/mL, associated with a mean QTcF change of 2.1 milliseconds (upper 90% confidence interval: 6.6 ms). The upper confidence limit crossed 10 ms at 31.1 ng/mL psilocin. Even at a supraclinical concentration of 60 ng/mL, the mean QTcF increase is 9.1 ms (upper limit 17.9 ms). Psilocin's short half-life (about 4 hours) suggests no accumulation with monthly oral dosing.
Microdosing involves giving human subjects a subpharmacologic dose (1% of the pharmacologic dose or 100 µg, whichever is lower) of an investigational drug to obtain pre–phase 1 pharmacokinetic data. A key concern is nonlinear pharmacokinetics between microdoses and therapeutic doses, but methods to evaluate this nonlinearity are emerging. Currently, about 80% of drugs tested orally and 100% intravenously show scalable pharmacokinetics within a factor of 2. Microdosing has recently been applied in pediatrics, protein-based therapeutics, and intra-arterial microdosing for localized pharmacodynamics. Compared with other predictive methods, microdosing appears to provide a significantly better understanding of pharmacokinetics before phase 1, though the database remains limited.