Full length articleSex-dependent effects of cannabis-induced analgesia
Introduction
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 18.9 million people over the age of 12 reporting use in the previous month, a number that has increased by over 25% since 2007 (Substance Abuse and Mental Health Services Administration [SAMHSA], 2012). While epidemiological reports consistently demonstrate that men use cannabis more frequently than women (Substance Abuse and Mental Health Services Administration, 2012), seek treatment for cannabis use more often than women (TEDS, 2012) and are at a higher risk for developing Cannabis Use Disorder (CUD; Stinson et al., 2006), a trend is emerging with a growing number of women reporting cannabis use for medical purposes (McConnell et al., 2014, Finseth et al., 2015, Ryan-Ibarra et al., 2015). Given this emerging trend, identifying potential sex-differences in the therapeutic effects and risks associated with cannabis is a public health imperative that has not yet been explored.
Although being male is a risk factor for developing CUD, women show an accelerated progression from first use to CUD relative to men, providing evidence for a ‘telescoping effect’ (Hernandez-Avila et al., 2004, Ehlers et al., 2010, Khan et al., 2013). Recent controlled studies in male and female cannabis users matched for current use demonstrated that while both men and women showed similar levels of intoxication following cannabis administration; women report higher ratings associated with abuse liability, such as liking the drug and willingness to take again (Cooper and Haney, 2014). The increased sensitivity observed in that clinical study corresponds to preclinical findings demonstrating that female laboratory animals are more sensitive to a range of behavioral and physiological effects of cannabinoids (for review, see Craft et al., 2013). Relative to male rats, females 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 higher rates of cue and drug-induced reinstatement (Fattore et al., 2010). However, in addition to the increased susceptibility to the negative effects of cannabinoids, female rats are also more sensitive to cannabinoid-induced antinociception relative to males in both acute and chronic models of pain (Tseng and Craft, 2001, Craft et al., 2012, Craft et al., 2013). These preclinical findings suggest that while women may be more sensitive to the abuse-related effects of cannabis, cannabis may also be more effective as an analgesic in women relative to men; similar sex differences in analgesia have been shown with opioids (for review, see Campesi et al., 2012). Given that pain is one of the primary indications for which medical cannabis is used (Ilgen et al., 2013, Bonn-Miller et al., 2014), understanding if these preclinical findings translate to humans is critical to predicting clinical risks and outcomes associated with medical cannabis use in women, a growing population of users.
This retrospective analysis was designed to investigate if there are sex-dependent differences in cannabis’ analgesic effects in humans. Apart from one study in healthy, non-cannabis using participants that identified nabilone-induced decreases in hyperalgesia in women but not men (Redmond et al., 2008), most studies of cannabinoid-induced analgesia have tested only one sex (Hill et al., 1974, Buggy et al., 2003, Greenwald and Stitzer, 2000, Kraft et al., 2008, Ellis et al., 2009, Lee et al., 2013) or have not included sex as a factor in the data analysis (Noyes et al., 1975, Karst et al., 2003, Naef et al., 2003, Svendsen et al., 2004, Abrams et al., 2007, Nurmikko et al., 2007, Rog et al., 2007, Wilsey et al., 2008, Wilsey et al., 2013, Ware et al., 2010, Issa et al., 2014, Wallace et al., 2007). We published a study designed to compare the dose-dependent analgesic effects of THC administered orally (dronabinol) versus smoked cannabis with delta-9-tetrahydrocannabinol (THC), the primary psychoactive component of cannabis, in 15 men and 15 women. Included in the overall analysis was an exploratory assessment of potential sex-dependent analgesia across all the doses; 10 and 20 mg dronabinol, 1.98 and 3.56% THC cannabis, and a placebo dronabinol and inactive cannabis (0.0% THC) condition. While this overall analysis did not yield significant differences in pain responses between men and women (Cooper et al., 2013), differences in the analgesic effects of cannabis between men and women emerged upon a more in-depth investigation of separate dose conditions. This retrospective analysis was designed to further examine sex-dependent effects of specifically cannabis-induced analgesia and draws from a larger pool of participants (N = 21 men and N = 21 women). Using double-blind, placebo-controlled methods, the analgesic effects of active cannabis was compared to inactive cannabis. Pain response was assessed using the Cold Pressor Test (CPT), a laboratory model of pain that has predictive validity for clinical efficacy of opioid analgesics in non-pain populations (Zacny et al., 1996a, Conley et al., 1997) and has been used to demonstrate the analgesic effects of smoked cannabis and oral THC (Cooper et al., 2013). In addition to analgesia, cannabis’ subjective and cardiovascular effects in men and women were also compared to determine generalizability of cannabis’ sex-dependent effects.
Section snippets
Methods
Data from two outpatient studies carried out at New York State Psychiatric Institute were used for this analysis (total N = 49). These double-blind, within-subject studies, designed to assess the analgesic effects of cannabinoids in non-treatment seeking, recreational (non-medical) cannabis smokers, measured the subjective ratings of drug quality, drug effect, mood, and physiological effects of a single strength of active cannabis (3.56–5.60% THC, active strength varied according to study)
Demographics
Table 1 portrays the demographic information of the participants according to sex. Men and women did not differ in age, number of days per week cannabis was smoked, or number of cannabis cigarettes smoked per day. Men and women did not differ in number of tobacco cigarette smokers, or weekly alcohol drinkers. Although men and women did not differ in BMI, men weighed significantly more than women.
CPT: pain sensitivity and tolerance
Fig. 1 portrays the effects for inactive and active cannabis on pain sensitivity defined as latency
Discussion
The results from this retrospective analysis demonstrate that among cannabis smokers, men exhibit greater cannabis-induced analgesia relative to women as measured by the CPT. Active cannabis decreased pain sensitivity and increased pain tolerance among men. In women, active cannabis did not significantly decrease pain sensitivity. Although active cannabis produced a small increase in pain tolerance in women shortly after smoking, pain tolerance decreased relative to inactive cannabis later in
Contributors
Dr. Cooper designed the study, performed the analysis, and wrote the manuscript. Dr. Haney provided guidance in analysis and manuscript composition and reviewed the submitted version of the manuscript.
Role of funding
Source: This research was supported by US National Institute on Drug Abuse Grant DA19239, DA09236, and DA02775. Dr. Cooper’s research is funded by NIDA. She has received partial salary support for investigator-initiated studies from Insys Therapeutics Inc. and serves as a consultant to KannaLife Sciences and PharmaCann, LLC. Dr. Haney’s research is funded by NIDA. She has received partial salary support for investigator-initiated studies from Insys Therapeutics Inc. and Lifeloc Technologies and
Conflict of interest
Dr. Cooper and Dr. Haney have no conflicts of interest relating to the subject of this study to report.
Acknowledgements
The authors acknowledge and appreciate the exceptional assistance of Sarah Badach, Elyssa Berg, Olivia Derella, Michael Harakas, Divya Lakhaney, Divya Ramesh, Ursula Rogers, and Bennett Wechsler. We are grateful to Dr. Richard W. Foltin for his assistance in conducting this study, and Sandra D. Comer and Gillinder Bedi for guidance.
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