Cannabis is one of the most widely used illicit substances, and there is growing interest in the therapeutic applications of cannabinoids. While known to modulate neuroendocrine function, the precise acute and chronic dose-related effects of cannabinoids in humans are not well-known. Furthermore, the existing literature on the neuroendocrine effects of cannabinoids is limited by small sample sizes (n = 6–22), heterogeneous samples with regard to cannabis exposure (lumping users and nonusers), lack of controlling for chronic cannabis exposure, differing methodologies, and limited dose–response data. Delta-9-tetrahydrocannabinol (Δ-9-THC) was hypothesized to produce dose-related increases in plasma cortisol levels and decreases in plasma prolactin levels. Furthermore, relative to controls, frequent users of cannabis were hypothesized to show altered baseline levels of these hormones and blunted Δ-9-THC-induced changes of these hormones.
Materials and methods
Pooled data from a series of laboratory studies with multiple doses of intravenous Δ-9-THC in healthy control subjects (n = 36) and frequent users of cannabis (n = 40) was examined to characterize the acute, chronic, and acute on chronic effects of cannabinoids on plasma cortisol and prolactin levels. Hormone levels were measured before (baseline) and 70 min after administration of each dose of Δ-9-THC. Data were analyzed using linear mixed models with +70 min hormonal levels as the dependant variable and baseline hormonal level as the covariate.
At socially relevant doses, Δ-9-THC raised plasma cortisol levels in a dose-dependent manner but frequent users showed blunted increases relative to healthy controls. Frequent users also had lower baseline plasma prolactin levels relative to healthy controls.
These group differences may be related to the development of tolerance to the neuroendocrine effects of cannabinoids. Alternatively, these results may reflect inherent differences in neuroendocrine function in frequent users of cannabis and not a consequence of cannabis use.
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The authors wish to acknowledge the critical clinical research contributions of the Biological Studies Unit, VA Connecticut Healthcare System including Elizabeth O’Donell, RN; Angelina Genovese, RN; Sonah Yoo, RPh; Robert Sturwold, RPh; and Mr. Willie Ford. This study was supported by the National Institute of Drug Abuse (DA12382-01 to DCD). In addition, the authors acknowledge the support from the (1) Department of Veterans Affairs Schizophrenia Biological Research Center (John Krystal), (2) National Institute of Mental Health (MH61019-02 to DCD), (3) National Institute of Alcohol Abuse and Alcoholism (R03 AA11413-02 to DCD), (4) Stanley Medical Research Institute (DCD), and (5) Donaghue Foundation (DCD).
Declaration of interest
There are no direct or indirect conflicts of interest for any of the authors relevant to the subject of this manuscript.
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Ranganathan, M., Braley, G., Pittman, B. et al. The effects of cannabinoids on serum cortisol and prolactin in humans. Psychopharmacology 203, 737 (2009). https://doi.org/10.1007/s00213-008-1422-2