Investigation of Sex-Dependent Effects of Cannabis in Daily Cannabis Smokers
Ziva D. Cooper and Margaret Haney
Drug & Alcohol Dependence, 2014 March 1, 136, 85–91.
Background—Women exhibit an accelerated progression from first cannabis use to cannabis use disorder (CUD) and show pronounced negative clinical issues related to CUD relative to men. Whether sex-dependent differences in cannabis’ direct effects contribute to the heightened risk in women is unknown. This analysis directly compared cannabis’ abuse-related subjective effects in men and women matched for current cannabis use.
Methods—Data from four double-blind, within-subject studies measuring the effects of active cannabis (3.27–5.50% THC, depending on study) relative to inactive cannabis (0.00% THC) were combined for this analysis. Data from equal numbers of men and women from each study matched for current cannabis use were pooled (total n = 35 men; 35 women); cannabis’ effects were analyzed according to cannabis condition (active versus inactive) and sex.
Results—Active cannabis produced more robust subjective effects associated with abuse liability (‘Good,’ ‘Liking,’ ‘Take Again’) and intoxication (‘High,’ ‘Stimulated’) relative to inactive cannabis (p • 0.0001). Women reported higher ratings of abuse-related effects [‘Take Again’ and ‘Good’ (p • 0.05)] relative to men under active cannabis conditions but did not differ in ratings of intoxication. Active cannabis increased heart rate (p • 0.0001) equally for both sexes.
Conclusions—The results from this study suggest that when matched for cannabis use, women are more sensitive to the subjective effects related to cannabis’ abuse liability relative to men, which may contribute to the enhanced vulnerability to developing CUD. Thus, sex is an important variable to consider when assessing the development of CUD.
Keywords : Cannabinoids; Abuse liability; Sex-differences; Subjective effects
Cannabis is the most widely used illicit drug worldwide (United Nations Office in Drugs and Crime, 2013), and has the highest rates of abuse in the United States relative to other illicit drugs, with 18.1 million people reporting use in the previous month, a number that has increased by over 20% since 2007 (Substance Abuse and Mental Health Services Administration, 2012a). In the United States, the number of people seeking treatment for cannabis use increased by 21% between 2000–2010 (Substance Abuse and Mental Health Services Administration, 2012b). With a growing number of states legalizing cannabis for medical and non-medical purposes (Hoffmann and Weber, 2010; National Conference of State Legislature, 2013), it is conceivable that increased access and legalization may lead to higher rates of use and increased risk of dependence. Elucidating the variables that contribute to the development of abuse and dependence can improve prevention and treatment for such disorders.
The estimated probability of initiating cannabis use and subsequently developing a cannabis use disorder (CUD) is higher in men (Wagner and Anthony, 2007). However, women show an accelerated progression from first use to CUD relative to men providing evidence for a ‘telescoping effect’ (Hernandez-Avila, 2004; Ehlers et al., 2010; Khan et al., 2013). Sex-differences have also been reported in the overall effects that daily cannabis use can have on physical and mental well-being; the quantity of cannabis smoked per day was shown to be negatively associated with self-reported measures of Quality of Life, an effect that was more pronounced in women than men (Lev-Ran et al., 2012). Additionally, men and women differ in the magnitude of withdrawal symptoms, with women exhibiting greater physiological symptoms associated with withdrawal relative to men (Copersino et al., 2010); this is a variable that is hypothesized to contribute to relapse in cannabis-dependent treatment seekers (Haney et al., 2013).
Assessing cannabis’ acute effects is an important determinant when investigating variables that contribute to continued cannabis use and the development of abuse and dependence. Preclinical studies with laboratory animals demonstrate that females are more sensitive to the behavioral and physiological effects of cannabinoids compared to males (for review, see Craft et al., 2013). Of note, female rats are more sensitive to the reinforcing effects of cannabinoids with faster acquisition of cannabinoid self-administration, higher rates of responding for cannabinoids (Fattore et al., 2007), and increased rates of cue and drug-induced reinstatement (Fattore et al., 2010).
Very little has been reported on sex-dependent differences in smoked cannabis’ effects in humans; our laboratory reported subtle differences in cannabis’ acute effects between men and women in a pattern that reflects preclinical studies, with women reporting higher ratings of cannabis’ positive subjective effects relative to men (Cooper and Haney, 2009). Females have also been reported to rate feeling ‘more dizzy’ after smoking cannabis or receiving intravenous THC; no sex-dependent differences were observed in cardiovascular endpoints or subjective ratings of intoxication (Mathew et al., 2003). However, sex-dependent effects of cannabinoids were not the primary focus of these study, therefore, they were not designed with adequate power to assess these effects. In addition to the small sample size, the men and women in these studies were not matched according to pattern of cannabis use, an important consideration when comparing the acute effects of cannabis between groups since tolerance to cannabis’ effects occurs with repeated use (Haney et al., 1997; Hart et al., 2002).
The objective of the current study was to directly compare cannabis’ subjective and cardiovascular effects in men and women matched for frequency and magnitude of current cannabis use. Data obtained from the above-mentioned cannabis-administration study and three subsequent controlled laboratory studies with similar designs yielded a sample with adequate power to assess differences in cannabis’ effects between men and women while matching for cannabis use. Because three of the four studies were designed to assess medication effects, only data obtained under placebo medication conditions were used for this analysis.