Stability and Reliability of Repeated Plasma Pregnenolone Levels After Oral Pregnenolone Dosing in Individuals with...

Substance use disorders (SUDs), including cocaine use disorder (CUD), have significant negative health risks and impose a substantial social burden, yet effective treatments are limited. Pregnenolone, a neuroactive steroid precursor, has been shown to reduce alcohol craving and normalize stress biology in individuals with CUD, but its clinical utility has been questioned due to limited data on bioavailability and the stability of blood levels in humans. Thus, this pilot study aimed to determine whether twice-daily oral pregnenolone (PREG) at 300 mg/day and 500 mg/day versus placebo in week two of PREG administration led to stable increased plasma pregnenolone levels in individuals with CUD. Seven treatment-seeking individuals with CUD, enrolled in an eight-week double-blind clinical trial, were randomized to receive placebo (n = 2) or pregnenolone at 300 mg/day (n = 3) or 500 mg/day (n = 2). For the first two weeks of the eight-week trial, participants were admitted to an inpatient Clinical Neuroscience Research Unit for repeated serial sampling of plasma pregnenolone concentrations over a 32.5 h period in week two of their inpatient stay while taking their assigned study drug under observation. Pregnenolone levels showed a significant main effect of the medication group (p = 0.039), with sustained higher levels in the 300 mg (p = 0.018) and 500 mg (p = 0.035) groups compared to placebo, and no significant difference between the two pregnenolone dosing groups. Moreover, correlation analyses showed that after observed study medication dosing on repeated sampling day 1, levels of pregnenolone were highly associated across time, with strong, positive correlations between time of dosing and 2 h (r = 0.80, p = 0.031), 4 h (r = 0.80, p = 0.031), 6 h (r = 0.86, p = 0.013), and 8 h post-dosing (r = 0.97, p < 0.001). These findings from this pilot study suggest that chronic twice-daily/"bis in die" (b.i.d.) oral administration of pregnenolone at both 300 mg/day and 500 mg/day achieved stable and reliable elevated plasma pregnenolone levels over 32.5 h in individuals with CUD, thereby supporting the good bioavailability of pregnenolone in these samples. These data indicate that twice-daily chronic dosing may overcome any potential concerns of poor bioavailability and rapid metabolism of pregnenolone in humans, and support further clinical investigations into pregnenolone's role in the treatment of cocaine use disorders.