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Randomized Controlled Trial
. 2019 Jan;28(1):16-21.
doi: 10.1111/ajad.12828. Epub 2018 Dec 11.

Neuroactive steroid levels and cocaine use chronicity in men and women with cocaine use disorder receiving progesterone or placebo

Verica Milivojevic  1 , Jonathan Covault  2 , Gustavo A Angarita  3 , Kristen Siedlarz  2 , Rajita Sinha  1
Affiliations
Randomized Controlled Trial

Neuroactive steroid levels and cocaine use chronicity in men and women with cocaine use disorder receiving progesterone or placebo

Verica Milivojevic et al. Am J Addict. 2019 Jan.

Abstract

Background and objectives: Neuroactive steroids (NAS) may play a role in addiction, with observed increases in response to acute stress and drug use, but decreases with chronic substance use, suggesting that NAS neuroadaptations may occur with chronic substance use. However, levels of NAS in addicted individuals have not been systematically examined. Here, we evaluated a panel of NAS in men and women with cocaine use disorder (CUD) who participated in a clinical laboratory study of progesterone.

Methods: Forty six CUD individuals were enrolled in a randomized placebo-controlled laboratory study to evaluate progesterone effects on levels of various NAS. On day 5 of a 7-day inpatient treatment regimen of 400 mg/day progesterone (15M/8F) or placebo (14M/9F), plasma levels of NAS known to be downstream of progesterone (allopregnanolone, pregnanolone), and NAS not in the progesterone synthesis pathway (androstanediol, testosterone, dehydroepiandrosterone [DHEA] and the NAS precursor, pregnenolone) were analyzed using highly sensitive gas chromatography/mass spectrometry (GC/MS). The relationship between each of the NAS and chronicity of cocaine use was also assessed.

Results: Progesterone versus placebo significantly increased the GABAergic NAS allopregnanolone and pregnanolone in both CUD men and women. Levels of pregnenolone, testosterone, its GABAergic metabolite androstanediol, and the non-GABAergic DHEA were unaffected by progesterone treatment, and testosterone and androstanediol levels were significantly higher in men than women. Importantly, lower pregnenolone and androstanediol levels were associated with greater years of cocaine use.

Scientific significance: GABAergic NAS that are upstream from the progesterone synthesis pathway appear susceptible to chronic effects of cocaine use. (Am J Addict 2019;28:16-21).

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Conflict of interest statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper.

Figures

Figure 1.
Figure 1.. Association of years of cocaine use with levels of pregnenolone (left) and androstanediol (right).
Regression analyses show that more years of cocaine use predict lower levels of pregnenolone and androstanediol.
Figure 2.
Figure 2.. Neuroactive steroid synthesis pathway.
The neuroactive steroids assessed in the study are shown in bold font. The progesterone pathway is highlighted in shaded grey area.
See this image and copyright information in PMC

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