Epidemiological data suggest that rates of cannabis use are increasing in women, who are particularly vulnerable to the negative consequences of cannabis use and at risk for an accelerated development of cannabis use disorders (CUD). Limited human and preclinical data suggest that women are more sensitive to the rewarding, reinforcing, behavioral, and cognitive effects of cannabis and its principal psychoactive component, delta-9-tetrahydrocannabinol (THC). However, this has not been adequately tested in humans. Gender differences are observed in the endocannabinoid system (related to estradiol in women) and in the metabolism of THC. Whether they are related to differences in the acute responses to THC between men and women has never been studied. In summary, the human data on the gender differences in the acute effects of cannabinoids remains scant. The overarching goal of this proposal is to address this lack of information by examining the gender related effects of THC in well-matched healthy women and men. We hypothesize that relative to men, women will have greater rewarding effects, lower verbal memory deficits and lower increases in serum cortisol induced by THC. Methods: Healthy male and female subjects (n=100) will receive THC or placebo in a double blind, randomized, crossover (2x2), and counterbalanced design. Subjective effects will be captured on a self-report visual analog scale of feeling states (VAS) before and at various time points after the drug infusions. Verbal learning and spatial working memory will be assessed using the Hopkins Verbal learning Task (HVLT) and the CANTAB battery respectively once per test day. Vital signs and blood for levels of THC, 11-OH-THC, THC- COOH, and cortisol will be collected before and at various time points after the infusion on each test day. Percent body fat, serum estradiol and menstrual cycle history (in women) will be collected at baseline on each test day. Safety assessments will be conducted during each test day, the day after, one month, and three months after study participation. It is hoped that data from this study will shed light on the gender differences in the acute effects of cannabinoids. These data will also provide the basis for future studies examining the underlying basis of the gender differences and in developing gender specific treatments for cannabis use disorders.

Public Health Relevance

Cannabis use is increasing in women who are more vulnerable to the negative consequences of cannabis than men, but gender differences in the response to cannabinoids have not been adequately studied. This research proposal is the very first aimed to examine the acute subjective, cognitive, endocrine, cardiovascular, and pharmacokinetic effects of THC in well-matched, healthy men and women who have limited prior exposure to cannabis. The data from this study will be the first to characterize the gender related pattern of responses on a wide range of subjective and objective outcomes to THC and to explore the role of gonadal steroids in modulating these differences.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Exploratory/Developmental Grants (R21)
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Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
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Wetherington, Cora Lee
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Yale University
Schools of Medicine
New Haven
United States
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Skosnik, Patrick D; D'Souza, Deepak C (2017) Opposing Effects of Cannabis Use on Electroencephalographic Measures of Auditory Repetition Suppression in Schizophrenia and Healthy Controls. Biol Psychiatry Cogn Neurosci Neuroimaging 2:209-211
Sherif, Mohamed; Radhakrishnan, Rajiv; D'Souza, Deepak Cyril et al. (2016) Human Laboratory Studies on Cannabinoids and Psychosis. Biol Psychiatry 79:526-38