Chronic pregnenolone effects in normal humans: attenuation of benzodiazepine-induced sedation

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Abstract

Pregnenolone is the major steroid precursor in humans. It is also a “neurosteroid” and possesses intrinsic behavioral and brain effects in animals, affecting the GABAA and other receptors. In two preliminary studies, we sought to characterize its tolerability and psychotropic effects in humans. In Study 1, 17 normal volunteers received pregnenolone and placebo for 4 weeks each (15 mg PO per day ×2 weeks followed by 30 mg PO per day ×2 weeks, vs. placebo ×4 weeks) in a within-subject, double-blind, cross-over design, with a 4 week drug-free washout period separating the two arms. Subjects’ behavioral responses were assessed at the beginning and end of the 4-week pregnenolone arm and the 4-week placebo arm. Pregnenolone was generally well-tolerated but, by itself, had no significant effects on mood, memory, self-rated sleep quality or subjective well-being. In Study 2, 11 subjects from Study 1 received a single dose of diazepam (0.2 mg/kg PO) immediately following completion of Study 1 in order to assess, in a between groups design, the impact of 4-weeks’ pre-treatment with pregnenolone (N=5) vs. placebo (N=6) on the acute sedative, amnestic and anxiolytic effects of this benzodiazepine. Pregnenolone-pretreated subjects showed significantly less sedation following diazepam (p<0.03); this effect was clinically apparent. Diazepam’s amnestic effects were non-significantly attenuated, and ratings of anxiety were unaffected. These pilot data, based on small samples, raise the possibility that chronically administered pregnenolone antagonizes certain acute effects of benzodiazepines and may enhance arousal via antagonist or inverse agonist actions at the benzodiazepine/GABAA receptor complex. Further larger-scale studies, utilizing a broader range of doses and experimental conditions, are warranted.

Introduction

Pregnenolone serves as the major precursor for all steroid hormones, although it possesses intrinsic physiological activity as well. Pregnenolone and its metabolite, pregnenolone sulfate (PS), have been termed “neurosteroids” as well as “neuroactive steroids” to reflect the facts that they are produced in situ in the brain (in addition to the adrenal glands and gonads), and that they have direct effects on major central nervous system (CNS) receptors, especially the GABAA, NMDA and sigma receptors (Holsboer et al., 1994, Rupprecht, 1997). Studies in animals have suggested that pregnenolone and PS have “antidepressant” (Reddy et al., 1998) and “anxiogenic” or “anxiolytic” (depending on dose) (Melchior and Ritzmann, 1994) effects as well as very potent effects on memory (Flood et al., 1992).

Because of their effects on excitatory and inhibitory neurotransmission, neurosteroids may play a conspicuous role in various psychiatric conditions (Majewska, 1992, Rupprecht, 1997). Pregnenolone and/or PS levels are low in aged humans, including those with dementia (Roberts and Fitten, 1990), and in individuals with major depression (George et al., 1994) and generalized anxiety disorder (Semeniuk et al., 2001). The therapeutic use of pregnenolone has been considered in these conditions, as well as in neurodegenerative diseases, peripheral nerve damage, epilepsy and substance dependence (Akhondzadeh and Stone, 1998, Gasior et al., 1999, Rupprecht, 1997).

Pregnenolone was first used in clinical practice as an anti-inflammatory agent in the 1940s, at approximately the same time cortisone was first used. However, because of cortisone’s superior anti-inflammatory effects, clinical development of pregnenolone was not pursued. Nonetheless, early open-label (McGavack et al., 1951) and placebo-controlled (Pincus and Hoagland, 1944, Pincus and Hoagland, 1945a, Pincus and Hoagland, 1945b) human trials with pregnenolone demonstrated significant improvements in mood, general well-being, psychomotor performance and learning in normal controls tested under stressful conditions, and side effects were reportedly minimal. Since these initial studies over 50 years ago, virtually no studies have examined the effects of exogenously administered pregnenolone in humans (with the exception of a small-scale study presented in abstract form (Sih et al., 1997)). The importance of re-assessing pregnenolone’s safety and behavioral effects in healthy volunteers is highlighted by the fact that pregnenolone is available over-the-counter in the United States as a “nutritional supplement” (Sahelian, 2000) and is unregulated by the US Food and Drug Administration. It is estimated that thousands of people are routinely consuming pregnenolone despite a paucity of controlled human data.

We sought in the current small-scale, placebo-controlled pilot studies to develop preliminary data regarding pregnenolone’s tolerability and behavioral effects and to estimate the size of its effects (γ) on mood and memory to power larger scale studies. We hypothesized that pregnenolone, relative to placebo, would enhance memory, mood, sleep quality and well-being in normal volunteers.

A second goal of these pilot studies was to characterize pregnenolone’s action at the GABAA/benzodiazepine/chloride ionophore receptor complex (GBCIR) in humans. In preclinical binding studies, PS behaves as a mixed agonist/antagonist, but in functional assays, it generally behaves as an allosteric GBCIR antagonist or inverse agonist (Akhondzadeh and Stone, 1998, Demirgoren et al., 1991, Lancel et al., 1994, Shen et al., 2000, Steiger et al., 1993, Majewska and Schwartz, 1987, Majewska et al., 1989, Reddy and Kulkarni, 1997c); (however, see Melchior and Ritzmann (1994)). Pregnenolone sulfate also inhibits GABA-gated chloride currents by enhancing receptor desensitization and stabilizing desensitized states (Shen et al., 2000), and it has effects opposite to those seen with alcohol on GABAA receptor number (Majewska, 1988). Consistent with these modes of action, pregnenolone and PS have been found to counteract the effects of alcohol and barbiturates on working memory, sedation, hypnosis and “anxiety” in mice (Melchior and Ritzmann, 1996, Czlonkowska et al., 1999, Majewska et al., 1989), and PS prevents the development of tolerance and attenuates signs of withdrawal following chronic benzodiazepine administration in mice (Reddy and Kulkarni, 1997b). Pregnenolone sulfate, at concentrations devoid of measurable direct effects, also reverses benzodiazepine-induced long-term electrophysiological depression, which may underlie benzodiazepine-induced amnesia, in hippocampal pyramidal cells (Akhondzadeh and Stone, 1998) . This further supports an antagonist role of this steroid at the GBCIR. In order to examine the putative action of pregnenolone (or of one of its metabolites) at the GBCIR in humans, we assessed its effect on the acute sedative, amnestic and anxiolytic effects of diazepam (Hommer et al., 1986, Wolkowitz et al., 1987) in a subset of our subjects. We hypothesized that pregnenolone pre-treatment, compared to placebo pre-treatment, would attenuate these behavioral effects of diazepam administration.

Section snippets

Subjects

Twenty-eight healthy normal controls were enrolled after being informed of potential risks and after signing a UCSF Institutional Review Board-approved consent form. Eleven of the subjects were male (age range 22–53) and 17 were female (ages range 22–62). During the course of the study, seven individuals dropped out for personal reasons unrelated to the study (e.g., scheduling conflicts), and one dropped out because of side effects (described below). In addition, 3 subjects were dropped from

Pregnenolone’s effects on mood, memory and sleep in normals

Pregnenolone, administered alone, had no significant effects on mood, memory, self-rated sleep quality or subjective well-being, although it tended to diminish depression ratings on the Beck Depression Inventory (p<0.09), compared to placebo (Table 1). Nonetheless, the size of the beneficial effects (γ) of pregnenolone on depression, negative affect ratings and sleep quality ratings ranged from 0.52 to 0.72, which is in the “moderate” effect range (Cohen, 1988); these effects were in the

Discussion

Pregnenolone used alone, compared to placebo, had no significant behavioral effects in our healthy volunteers. Contrary to our hypotheses, there were no improvements in mood or in verbal or visuospatial memory performance. The most striking finding to emerge from these pilot studies is that pregnenolone, compared to placebo, significantly attenuated the sedating effects of orally administered diazepam. This effect was subjectively and objectively discernible and was of a very large statistical

Acknowledgements

The authors gratefully acknowledge Drs Seth Himelhoch, Eugene Roberts, Louann Brizendine and Ray Sahelian for providing useful and thought-provoking comments during the design of this study and Dr John Poole for design and use of the VSLT.

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