PREGNENOLONE

Background

Pregnenolone is a neurosteroid made naturally in the brain. It is widely sold in health food stores (10mg, 25mg, 50mg, and 100mg) for improvement of sleep and memory. It was used in the 1940s and 1950s for inflammatory conditions, especially rheumatoid arthritis, at doses of up to 500mg/day before better drugs became available.

Mechanism of Action

Pregnenolone is synthesized from cholesterol and is a precursor of other hormones, including those made in the testes and ovaries; thus, it has been called the mother of all steroid hormones. Its possible effect on psychiatric symptoms is thought to be associated with its effect on NMDA receptors in the glutamate system, although it is also thought to affect GABA, sigma, acetylcholine, and dopamine receptors. Some researchers have noted in animal models that pregnenolone may increase brain myelination and synaptogenesis and, thus, be neuroprotective. Studies in rodents have also shown that pregnenolone improves memory and learning. When given orally, pregnenolone easily passes the blood-brain barrier and enters the brain. Also of interest are studies in rodents showing that olanzapine and clozapine increase the levels of pregnenolone in rat brains.

Use in Schizophrenia

There have been three published studies. Thirty-two patients with schizophrenia were given adjunct pregnenolone 100mg/day, 500mg/day, or placebo for 8 weeks.88 Those on 500mg had an improvement in negative symptoms, verbal memory, and attention. Patients liked taking the drug, and five patients continued taking it for 3 years. A study of 21 patients on escalating doses of adjunct pregnenolone up to 500mg/day or placebo for 8 weeks reported significant improvement in negative symptoms and nonsignificant improvement in cognitive symptoms (P=0.048).89 A study of 58 patients with schizophrenia or schizoaffective disorder who took pregnenolone 30mg/day, 200mg/day, or placebo for 8 weeks reported significant improvement in positive (but not negative) symptoms (P=0.010), and nonsignificant improvement in attention and working memory on the 30 mg dose but not the 200mg dose.90 Pregnenolone was well tolerated in all three studies and side effects (e.g., headache and restlessness) were minimal. One of the men who took pregnenolone for 3 years developed an enlarged prostate,88 although another study reported that pregnenolone had no effect on testosterone levels90

There are three large, ongoing, follow-up studies of pregnenolone, one SMRI-supported and two others, all using 500mg/day. There is also a completed study, not yet published, that used 50mg/day.

Use in Bipolar Disorder

A single study has been published using pregnenolone 100mg/day or placebo for 8 weeks as adjunctive medication in a heterogeneous sample of 70 patients with bipolar disorder or recurrent major depression; all subjects also had a history of substance abuse.91 Those on pregnenolone had a significant improvement in depression (Hamilton Rating Scale for Depression; P=0.03) compared to the placebo group and a trend toward improvement in manic symptoms. No improvement in memory or other cognitive symptoms was observed. SMRI is supporting an ongoing study using pregnenolone 500mg/day or placebo for 12 weeks in 80 patients with bipolar depression.

Assessment

Pregnenolone may turn out to be useful, but its effectiveness has not been established. Ongoing studies for both schizophrenia and bipolar disorder will hopefully clarify this issue.