Pregnenolone Reduces Provoked Craving and Cocaine Use in Men and Women with Cocaine Use Disorder: A Pilot Trial

Chronic cocaine use is associated with decreases in neuroactive steroid levels. These adaptations may contribute to continued cocaine use and high relapse risk in individuals with cocaine use disorder (CUD). Thus, this pilot study assessed chronic treatment with 2 supraphysiologic doses of the neuroactive steroid precursor pregnenolone (PREG, 300 mg/day; 500 mg/day) to boost endogenous neuroactive steroid levels and assess its impact on provoked craving and cocaine use outcomes in an 8-week trial in men and women with CUD.

Fifty-five treatment-seeking individuals with CUD were randomly assigned to receive either placebo (PLA; n=18; 12M/6F), 300mg PREG/day (n=20; 15M/5F) or 500mg PREG/day (n=17; 12M/5F) for 8 weeks, along with outpatient weekly relapse prevention treatment. Plasma was collected at weeks 2, 5 and 7 to assess circulating pregnenolone levels. A subset of subjects participated in a 3-day experimental component of guided imagery exposure to stress, cocaine cue and neutral conditions in about week 2 of the trial to assess craving response. Cocaine use outcomes was also assessed over the 8-week treatment period. Intent-to-treat analyses were conducted using linear mixed effects models.

There were no differences between treatment groups on demographic variables and baseline cocaine use. Plasma pregnenolone levels were higher in the 300mg and 500mg PREG groups compared to PLA ( p's < 0.032). Participant trial completion rates were 100% for PLA, 90% for 300mg and 94% for 500mg PREG groups. Placebo group had increased craving in response to stress ( p < .001) and cocaine cue ( p < .001) provocation, whereas the PREG groups showed no increased in provoked cocaine craving. For cocaine use outcomes during the 8-week trial, a significant main effect of treatment group ( p = .005) on the weekly amounts of cocaine use showed e significantly lower amounts used in the 300mg PREG compared to the 500mg PREG group ( p = 0.01) and to PLA ( p = .047). There was also a trend for a treatment group main effect for days of cocaine used (p<.12).

These pilot findings suggest that supraphysiologic neuroactive steroid PREG doses reduces cocaine craving and may also improve cocaine use outcomes in treatment seeking individuals with CUD. Findings support further assessment and development of PREG in the treatment of CUD.