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Sex Differences In Cannabinoid Pharmacology: A Reflection Of Differences In The Endocannabinoid System?

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Marijuana is the most widely used illicit drug in the U.S., and marijuana use by women is on the rise. Women have been found to be more susceptible to the development of cannabinoid abuse and dependence, have more severe withdrawal symptoms, and are more likely to relapse than men. The majority of research in humans suggests that women are more likely to be affected by cannabinoids than men, with reports of enhanced and decreased performance on various tasks. In rodents, females are more sensitive than males to effects of cannabinoids on tests of antinociception, motor activity, and reinforcing efficacy. Studies on effects of cannabinoid exposure during adolescence in both humans and rodents suggest that female adolescents are more likely than male adolescents to be deleteriously affected by cannabinoids. Sex differences in response to cannabinoids appear to be due to activational and perhaps organizational effects of gonadal hormones, with estradiol identified as the hormone that contributes most to the sexually dimorphic effects of cannabinoids in adults. Many, but not all sexually dimorphic effects of exogenous cannabinoids can be attributed to a sexually dimorphic endocannabinoid system in rodents, although the same has not yet been established firmly for humans. A greater understanding of the mechanisms underlying sexually dimorphic effects of cannabinoids will facilitate development of sex-specific approaches to treat marijuana dependence and to use cannabinoid-based medications therapeutically.




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Although research on sex differences in cannabinoid pharmacology

is increasing, knowledge of the mechanism(s) underlying sex

differences in behavioral effects of cannabinoids remains limited.

While activational hormonal factors have been shown to play a strong

role in modulating endocannabinoid system functioning in adults,

hormone-independent sex differences in this system have also been

reported. Very little is known about the organizational effects of hormones

during development of the endocannabinoid system. Understanding

hormonal and non-hormonal mechanisms will facilitate

development of sex-specific approaches to treat marijuana dependence

and to use cannabinoid-based medications therapeutically—for example,

in the treatment of pain and spasticity (Aggarwal et al., 2009). In addition,

elucidating endocrinological mechanisms that modulate the

endocannabinoid system could ultimately enhance treatment of a

wide variety of disorders in which dysregulation of the endocannabinoid

system has been implicated, including obesity (Akhas

et al., 2009; Cota et al., 2003), substance abuse (Beardsley et al., 2009),

and various neurological disorders (Williamson and Evans, 2000)...



Future directions

Given the paucity of studies in this area, considerable latitude exists

for future research. Some of the major unanswered questions

have been highlighted below:


1. Given the ubiquity of CB receptors at multiple levels of the neuraxis,

localization of sex differences in cannabinoid function is crucial.

For example, agonists can produce analgesia via supraspinal,

spinal and peripheral CB receptor activation (Guindon and

Hohmann, 2009)—are all levels of the neuraxis sexually dimorphic

in regard to cannabinoid function?


2. Do gonadal hormones act at genomic or membrane steroid receptors,

or both, to influence endocannabinoid system activity? For

example, in addition to its “slow” actions at genomic estrogen receptors

(ER), estradiol also influences pain and the opioid system

rapidly via membrane-bound ER (Eckersell et al., 1998; Evrard

and Balthazart, 2004). Does estradiol exert both types of effects

on the cannabinoid system as well?


3. Studies in humans are needed to confirm or refute sex difference

findings in rodents. Furthermore, the modulatory effects of estradiol

need to be studied in two ways: cannabinoid effects in cycling

women tested not only during follicular and luteal phases, but also

during ovulation, when the greatest changes in sensitivity have

been observed in rodents.

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