Pregnenolone Reduces Stress-Induced Craving, Anxiety, and Autonomic Arousal in Individuals with Cocaine Use Disorder

Abstract

Chronic cocaine use leads to adaptations in stress biology and in neuroactive steroid system. These adaptations are associated with high cocaine craving and increased relapse risk. This study tested whether potentiation of the neuroactive steroid system with the precursor pregnenolone (PREG) affects stress- and cue-induced cocaine craving, anxiety and autonomic response in individuals with cocaine use disorder (CUD). Thirty treatment-seeking individuals (21 Male, 9 Female) with CUD were randomized to placebo (PBO) or supraphysiologic PREG doses of 300 mg or 500 mg per day for 8 weeks. After 2 weeks of treatment, participants were exposed to 5-min personalized guided imagery provocation of stress, cocaine, or neutral/relaxing cues in a 3-day experiment, one condition per day on separate days, in a random, counterbalanced order. Repeated assessment of cocaine craving, anxiety, heart rate (HR), systolic (SBP) and diastolic blood pressure (DBP) were assessed on each day. PREG significantly increased pregnenolone levels compared to PBO. Both PREG doses decreased stress- and cocaine cue-induced craving and reduced both stress- and cue-induced anxiety only in the 500 mg/day group. The 500 mg/day PREG group also displayed decreased stress-induced HR, SBP and DBP. Findings indicate that pregnenolone decreases stress- and cocaine cue-provoked craving and anxiety and reduces stress-induced autonomic arousal in individuals with CUD.

Deleterious Interaction between the Neurosteroid (3α,5α)3-Hydroxypregnan-20-One (3α,5α-THP) and the Mu-Opioid System Activation during Forced Swim Stress in Rats

“…Other findings showed that pregnenolone and its GABAergic metabolites regulate alcohol motivation by reducing alcohol seeking and intake in rodents [52][53][54]. These results were confirmed in clinical studies in patients with history of cocaine and alcohol use disorders [55,56]. However, the data presented in this study suggest a negative interaction between 3α,5α-THP and the opioid system that might result in a deleterious behavior.…”

Neuroactive Steroids, Toll-like Receptors, and Neuroimmune Regulation: Insights into Their Impact on Neuropsychiatric Disorders

“…Pregnenolone supplementation significantly increases pregnenolone levels and effectively reduces stress and cocaine cueinduced craving and anxiety in individuals with CUD. Additionally, it demonstrates a notable reduction in stress-induced autonomic arousal [226].…”

“…For many years, neurosteroids have been proposed as a therapy to restore altered GABAergic transmission in conditions such as depression, PTSD, PPD, anxiety, and substance use disorders [11][12][13]61,225,226]. These neuropsychiatric conditions share, among other features, a dysregulation in hypothalamic-pituitary-adrenal (HPA) axis activity [44,46,[227][228][229][230][231][232][233], likely due to aberrant GABAergic signaling [234,235].…”

Sex‐specific susceptibility to psychotic‐like states provoked by prenatal THC exposure: Reversal by pregnenolone

“…[142][143][144] Remarkably, chronic treatment with supraphysiological doses of PREG reduces both stress-and cocaine cue-induced craving in individuals with cocaine use disorder. 145 PREG also acts as a potent negative allosteric modulator of CB1 receptor signaling 22 and blocks all the phenotypic signatures of cannabinoid intoxication. 22 However, at this stage, we could speculate that the rescue properties of PREG in PCE progeny cannot be ascribed to a negative modulation of CB1 receptor, but rather to its intracellular signaling.…”

“…Although the effects of σ1 receptor activation on dopamine system are conflicting, their ligands (including PREG) have been shown to attenuate dopamine signaling deregulation in response to psychostimulant drugs 142–144 . Remarkably, chronic treatment with supraphysiological doses of PREG reduces both stress‐ and cocaine cue‐induced craving in individuals with cocaine use disorder 145 . PREG also acts as a potent negative allosteric modulator of CB1 receptor signaling 22 and blocks all the phenotypic signatures of cannabinoid intoxication 22 .…”