Frontiers in Neuroendocrinology xxx (2014) xxx–xxx

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Frontiers in Neuroendocrinology
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Review

Sex differences in addictive disorders

Liana Fattore a,b,⇑, Miriam Melis b,c, Paola Fadda b,c,d, Walter Fratta b,c,d
a
Institute of Neuroscience – Cagliari National Research Council of Italy, Cittadella Universitaria di Monserrato, Italy
b
Centre of Excellence ‘‘Neurobiology of Dependence’’, University of Cagliari, Monserrato, Italy
c
Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, Cittadella Universitaria di Monserrato, University of Cagliari, Monserrato, Italy
d
National Institute of Neuroscience (INN), University of Cagliari, Italy

a r t i c l e i n f o a b s t r a c t

Article history: Gender-dependent differences in the rate of initiation and frequency of misuse of addicting drugs have
Available online xxxx been widely described. Yet, men and women also differ in their propensity to become addicted to other
rewarding stimuli (e.g., sex, food) or activities (e.g., gambling, exercising). The goal of the present review
Keywords: is to summarize current evidence for gender differences not only in drug addiction, but also in other
Gender differences forms of addictive behaviours. Thus, we first reviewed studies showing gender-dependent differences
Drug addiction in drug addiction, food addiction, compulsive sexual activity, pathological gambling, Internet addiction
Pathological gambling
and physical exercise addiction. Potential risk factors and underlying brain mechanisms are also exam-
Internet addiction
Compulsive sex
ined, with particular emphasis given to the role of sex hormones in modulating addictive behaviours.
Food addiction Investigations on factors allowing the pursuit of non-drug rewards to become pathological in men and
Excessive exercise women are crucial for designing gender-appropriate treatments of both substance and non-substance
Sex hormones addictions.
Compulsive buying Ó 2014 Elsevier Inc. All rights reserved.
Reward

1. Introduction buying and pyromania. These behaviours, often referred to as

The term ‘‘addiction’’ is traditionally linked to the abuse of legal
and illegal substances. Most drugs of abuse affect the brain reward
system thus leading to addiction. However, engaging in non-drug
related activities, especially those involving ‘natural’ rewards,
could also activate the reward system and result in addiction.
Non-drug addictive behaviours are receiving increased attention
from clinicians due to the increasing number of subjects reporting
symptoms consistent with impairment of impulse control.
Definition of ‘‘behavioural addictions’’ has been recently
expanded to encompass any behaviour characterized by (i) a feel-
ing of tension or arousal before the action, (ii) gratification and/or
relief at the time of executing the act, (iii) an inability to resist an
urge or drive even against great obstacles or dangers, and (iv) the
absence of consideration for the negative consequences that may
affect family, friends, or work. As such, behavioural addictions
include compulsive food intake and sexual activity, pathological
gambling and Internet addiction, excessive exercising, compulsive
⇑ Corresponding author at: Institute of Neuroscience – Cagliari National Research
Council of Italy @ Department of Biomedical Sciences, University of Cagliari,
Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, Cittadella
Universitaria di Monserrato, 09042 Monserrato (Cagliari), Italy. Fax: +39 (0)70
6754312.
E-mail address: lfattore@in.cnr.it (L. Fattore).
‘‘impulse control disorders’’ or ‘‘impulsive–compulsive behav-
iours’’, result in actions that are harmful to oneself or to others,
and share common features such as compulsiveness, impulsivity,
impaired decision-making, craving, tolerance, withdrawal and high
rates of relapse. Many of these activities are daily customs contrib-
uting to our ultimate survival, and it is therefore not surprising to
find some controversy in diagnosing and treating these conditions.
Nowadays, behavioural addictions are increasingly documented
worldwide. In the United States, for example, prevalence rates of
these disorders have been estimated at 1–2% for pathological gam-
bling (Welte et al., 2001), 5% for compulsive sexual behaviour
(Schaffer and Zimmerman, 1990), and 5–6% for compulsive buying
(Black, 2007). Notably, behavioural addictions often display neuro-
biological and neuroanatomical similarities between natural and
drug reward processing. In humans, neuroimaging studies have
demonstrated that gambling (Breiter et al., 2001), playing video
games (Koepp et al., 1998; Hoeft et al., 2008) or shopping
(Knutson et al., 2007) activate some of those brain regions (i.e.
the mesocorticolimbic system and extended amygdala) activated
by drugs of abuse (Volkow et al., 2004). Thus, drug- and
food-related cues not only activate common neuroanatomical sub-
strates, but also result in similar activity-regulated gene expression
patterns within these brain areas (Kelley et al., 2005). Individuals
with decreased serotonergic and/or dopaminergic receptors, and
an augmented rate of synaptic dopamine catabolism, appear to

http://dx.doi.org/10.1016/j.yfrne.2014.04.003
0091-3022/Ó 2014 Elsevier Inc. All rights reserved.

Please cite this article in press as: Fattore, L., et al. Sex differences in addictive disorders. Front. Neuroendocrinol. (2014), http://dx.doi.org/10.1016/
j.yfrne.2014.04.003
2 L. Fattore et al. / Frontiers in Neuroendocrinology xxx (2014) xxx–xxx
be predisposed to use any substance and/or to engage in any
behaviour that increases dopamine release (Blum et al., 2011).
Additionally, compelling evidence demonstrated that non-drug
addictions can alter neural plasticity in brain regions that are
affected by drugs of abuse, and lead to neuroadaptations similar
to those reported after long-term drug use (for a recent review
see Olsen, 2011).
Men and women display different attitudes and skills, experi-
ence dissimilar emotions in response to environmental and social
stimuli, and show diverse susceptibility to stress, illnesses and
mental diseases. In this scenario, while a growing number of stud-
ies are now paying more attention to evaluate sex-dependent dif-
ferences in drug addiction, only few studies have examined
potential differences between men and women in non-substance
behavioural addictions, an issue that only recently is gaining rele-
vance. For example, in a study using multidimensional self-report
to measure addictive behaviours, men scored higher than women
in exercising, gambling, and having sex, while women scored
higher on compulsive shopping and food binging (MacLaren and
Best, 2010). The paucity of studies on gender differences in behav-
ioural addictions is particularly surprising when considering the
modulatory role of estradiol in effort-based decision making
(Uban et al., 2012), its interplay with dopamine in modulating
reward and cognitive processes (Becker, 1999; Jacobs and
D’Esposito, 2011), and the presence of estrogen receptors within
key brain regions implicated in motivation, reward and cost/bene-
fit decision making (Shughrue et al., 1997).
In this review, we summarized the data currently available on
sex-dependent differences in drug and non-drug addictions from
epidemiology to neurobiology and potential risks factors. Emphasis
is given to the more recently identified types of behavioural addic-
tions, such as pathological gambling or Internet addiction, and to
the role that sex hormones are likely to play in determining gender
differences. However, it should be kept in mind that behavioural
addictions always comprise complex interactions between a sub-
stance (more or less addictive) or an activity (more or less reward-
ing), an individual (more or less vulnerable) and an environment
(more or less tolerating).
2. Drug addiction
2.1. Gender differences in drug addiction
The brain reward system reinforces behaviours required for
species survival, including sex, eating and social interactions.
Drugs of abuse co-opt these neural pathways and subjugate nor-
mal reward-related behaviour, from which ensue uncontrollable
drug seeking and taking. Drug addiction develops after repeated
substance use and typically includes a strong desire to take the
drug, difficulties in controlling its use, persisting in its use despite
harmful consequences, and greater importance to obtain the drug
than to other goals or activities.
Men and women abuse the same drugs, but not always in the
same ways (UNODC, 2013). Significant gender differences have
been reported in the initiation of drug use, reasons for continuing
to use the drug as well as in the resumption of drug taking after
periods of abstinence (relapse), which remains an unmet clinical
need for addiction. According to the European Monitoring Centre
for Drugs and Drug Addiction (EMCDDA), women are more likely
than men to abuse prescribed drugs, like tranquilizers and seda-
tives, while men are more likely to abuse illicit drugs, such as
cocaine and heroin (EMCDDA, 2005). Yet, preclinical data revealed
usually higher responsiveness to drugs in females than in males.
For almost all drugs of abuse, enhanced vulnerability of females
to develop drug addiction has been widely recognized, although
Please cite this article in press as: Fattore, L., et al. Sex differences in addictive disorders. Front. Neuroendocrinol. (2014), http://dx.doi.org/10.1016/
j.yfrne.2014.04.003
some discrepancies have been also reported. Evidence from both
preclinical and clinical studies have been recently reviewed for
cocaine (Quinones-Jenab and Jenab, 2012), amphetamine
(Vansickel et al., 2010), opioids (Dahan et al., 2008), nicotine
(Pogun and Yararbas, 2009), alcohol (Witt, 2007), phencyclidine
(Carroll et al., 2005) and cannabinoids (Fattore et al., 2009) and,
therefore, will not be reviewed here.
Both intrinsic sex differences in brain organization and activa-
tional effects of circulating gonadal hormones have been proposed
to account for the observed sex-dependent differences (Lancaster,
1994; Becker et al., 2001; Hu et al., 2004). Enhancing effects of
estrogen, and attenuating effects of progesterone, on drug-induced
reward have been consistently reported (Quinones-Jenab and
Jenab, 2010; Anker and Carroll, 2011). Similarly, interactions of
estrogen with endogenous opioid peptides (Segarra et al., 2010)
and the HPA axis (Carroll and Anker, 2010) as well as with dopami-
nergic neurotransmission (Thompson and Moss, 1994; Becker,
1999; Jacobs and D’Esposito, 2011) have been proposed as mecha-
nisms underlying estrogen facilitative effects. Notably, recent
findings indicate that estrogen sensitivity of the different aspects
involved in drug-taking behaviour is not uniformly organized,
but rather regulated independently during development (Perry
et al., 2013). That is, pubertal estradiol affects at a greater extent
motivational rather that learning/acquisition processes. The hor-
monal status associated with the menstrual cycle has been shown
to play an important role in drug addiction treatment outcomes in
women. Accordingly, the severity of withdrawal symptoms may be
greatly different in the luteal and follicular phase of the menstrual
cycle (Sofuoglu et al., 1999; Snively et al., 2000; Terner and de Wit,
2006; Allen et al., 2010). Yet, human literature examining the role
of estrogen and menstrual cycle on subjective drug effects is still
limited. Other factors, however, have been proposed to take part
in the propensity to abuse drugs, among which pharmacokinetic,
pharmacodynamic, and sociocultural differences (Fattore et al.,
2008; Franconi et al., 2012), along with a different sensitivity to
aversive properties of drugs (Hashimoto and Wiren, 2008).
Discussion of historical, cultural, social and biological bases for
sex differences in drug addiction is beyond the scope of this
review, as all of the above issues have been systematically
reviewed recently by Becker et al. (2012). Indeed, they elegantly
collected current evidence on brain neurotransmitter systems
and neural circuitries likely contributing to sex differences in drug
abuse and dependence.
2.2. Underlying reasons for sex and gender differences in drug
addiction
The biopsychosocial model of drug addiction proposes that this
psychiatric disorder is regulated by complex interaction of genetic
(e.g. sex differences, ethnicity) and environmental factors (e.g.
sociocultural diversity, socioeconomic status, stress coping ability).
As a result, this model encompasses various facets of individuals,
including environment as being either a protective or risk factor.
This model also suggests that individual vulnerability may explain
the initiation to drug use, which itself results from biological and
psychosocial factors. The fine balance between risk and protective
factors will then confer/determine whether or not an individual
will become addicted to drugs.
2.2.1. Sociocultural and biological differences
Sociocultural and biological perspectives, when combined,
might provide satisfactory explanation for sex/gender differences
in drug addiction.
On one hand, the sociocultural perspective holds that tradi-
tional stigmatization of drug addicts might be a protective factor
for women. In fact, tighter cultural constraints are usually placed
 L. Fattore et al. / Frontiers in Neuroendocrinology xxx (2014) xxx–xxx
on women than men. Additionally, women might be more likely to
engage in culturally sanctioned activities, which will then assist
the adoption of culturally sanctioned prohibitions against drug
abuse. Looking at the patterns of drug use in men and women over
centuries could be particularly useful for appreciating the influence
that social and political conditions exert on the propensity to use
drugs. For example, when social policy allowed free access to drugs
of abuse, women resulted more likely to increase frequency of use,
while when restrictions were applied, women reduced drug intake.
This was the case for alcohol in England in middle 1700, for opioids
in the US in late 1800s – early 1900s, and for amphetamines in the
US in the late 1960s (as reviewed by Becker et al., 2012). That the
availability of a drug on the legal market may act as an incentive
for women resembles the preference showed by female patholog-
ical gamblers for the widely available legalized forms of gambling
(Lesieur and Blume, 1991). Another important aspect shared by
female drug users and pathological gamblers is the comorbidity
with dissatisfying social conditions (e.g., lack of education of job
status, poor financial income) or psychiatric disorders (anxiety,
depression, stress-related disorders).
On the other hand, the biological perspective contends that sev-
eral factors, including metabolic processes, might either alone or in
combination, help explaining sex differences concerning drug
addiction. Indeed, several factors such as those ruling pharmacoki-
netics and pharmacodynamics depend not only on the metabolic
rate, body size and content in fat and water (Ljunggren, 1957),
but they can also be affected by circulating sex hormones
(Carroll et al., 2004). For instance, sex differences in pharmacoki-
netics (e.g. plasmatic protein binding of drugs, volume of distribu-
tion, drug transport and metabolism) might explain why women
are more often overdosed (Soldin and Mattison, 2009). In fact, both
drug absorption and bioavailability show sex-dependent diversity
because routes of absorption, gastrointestinal transit times and bile
acidic composition differ in men and women (Soldin et al., 2011).
Additionally, higher drug concentrations detected in women can
also be due to a smaller distribution volume and/or lower clear-
ance (Chen et al., 2000). Furthermore, women appear to have a
greater/faster first pass metabolism (Wolbold et al., 2003), but
see (Greenblatt and von Moltke, 2008). For example, alcohol bio-
availability is greater in women probably because of a smaller dis-
tribution volume and reduced gastric metabolic activity (Parlesak
et al., 2002).
Generally, men have a higher basal metabolic rate. This differ-
ence in metabolism might be ascribed to diversity in adipose and
muscle tissue content in either sex (Ljunggren, 1957). Thus, male
high basal metabolic rate per unit body surface area reflects a
higher lean body mass due to a larger skeletal muscle apparatus
(Cunningham, 1982). In addition to metabolism, inactivation of
drug effects also takes place through the elimination process (i.e.
clearance). Elimination occurs via renal, hepatic and/or pulmonary
routes. Sex differences have also been found in this process.
Indeed, renal clearance is generally higher in men than women,
once body surface area, renal blood flow, glomerular filtration,
tubular secretion, and tubular reabsorption are standardized
(Gaudry et al., 1993; Silvaggio and Mattison, 1994; Berg, 2006).
Additionally, sex dimorphism in pharmacodynamics (e.g. differ-
ences in receptor number, binding and signalling downstream
from receptor activated) might account for the observations that
women are more sensitive to many drugs, including drugs of
abuse. For instance, mu-opioid receptor agonists (e.g. morphine)
display both a slower onset and offset in women than men
(Sarton et al., 2000), which can explain why women require higher
dosages of morphine to achieve the same antinociceptive effect
than men (Cepeda and Carr, 2003). Accordingly, a higher mu-opi-
oid receptor binding has been found in several cortical and subcor-
tical brain regions in women than in men (Cepeda and Carr, 2003).
Please cite this article in press as: Fattore, L., et al. Sex differences in addictive disorders. Front. Neuroendocrinol. (2014), http://dx.doi.org/10.1016/
j.yfrne.2014.04.003
3
Finally, both pharmacokinetics and pharmacodynamics can be
affected not only by circulating hormones, including those in oral
contraceptives, but also by drug–drug interactions. From a biolog-
ical point of view sex and gonadal hormones are still believed to
underlie most differences reported in drug sensitivity and vulner-
ability to drug abuse between men and women, though this is only
partly supported. Indeed, women appear to be more vulnerable to
rewarding and appetitive properties of several drugs of abuse,
including cocaine, cannabinoids, opioids, and alcohol. However,
several contradicting reports can be found in the literature con-
cerning pharmacokinetics and pharmacodynamics of cocaine. In
fact, while in humans no sex differences in plasma cocaine concen-
trations and its central and peripheral effects were described
(Mendelson et al., 1999), a sex dimorphism was also reported
(Lukas et al., 1996). In particular, males were found to be more sen-
sitive to subjective effects of cocaine, which correlated with a fas-
ter kinetic (Lukas et al., 1996). Similarly, male rats were found to be
more susceptible to cocaine toxic effects (Morishima et al., 1993),
although its brain concentrations have been reported to be similar
by others (Bowman et al., 1999).
Some human studies have described differences in drug bio-
availability according to hormonal changes such as those occurring
during the menstrual cycle (Lukas et al., 1996; Lynch et al., 2002),
but other studies reported no differences in cocaine pharmacoki-
netics during the diverse phases of the menstrual cycle
(Mendelson et al., 1999). For instance, when circulating estrogen
levels are high (i.e. follicular phase) cocaine plasma levels are
higher than during the luteal phase (i.e. when estrogen and proges-
terone are both circulating) (Lukas et al., 1996). Similarly, in both
non-human primates and rats no effect of the menstrual cycle
was revealed on plasma ethanol levels (Green et al., 1999) or in
other pharmacokinetic parameters of ethanol (Crippens et al.,
1999).
2.2.2. Organizational (permanent/structural) and activational
(transient) effects of sex hormones on the brain
The organization–activation theory posits that during early
brain development the exposure to sex hormones can have long
lasting (i.e. organizational) effects that will influence neuronal
activity and behaviour throughout life. Transient actions of sex
hormones on behaviour during adulthood are conceptualized as
activational effects and can occur throughout life (Arnold and
Breedlove, 1985). These actions are particularly manifest during
late adolescence, when distinct sex hormone-driven neurodevel-
opmental changes occur, which may, therefore, influence behav-
iours such as initiation to drug use.
Despite the efforts made to attribute definite biological pro-
cesses to either organizational or activational effects of sex hor-
mones, this rigid distinction is not always acceptable. Indeed,
several discrepancies among the studies have been reported where
positive, negative or no effects of sex steroids on human brain and
behaviour have been described. Nonetheless, concerning drug
addiction, organizational effects in both structural and functional
organization of the reward pathway have been reported as
accounting for many of the sex differences observed in drug abuse
(Becker, 1999; Carroll et al., 2004). For example, the developmental
patterns of dopamine receptors are markedly different in the
female and male brain, with adolescent male rats showing more
overproduction and elimination of D1 and D2 receptors than
females in the striatum and delayed pruning of these receptors
in the prefrontal cortex, while females but not males display
enhanced laterality of D1 receptors in striatum and nucleus
accumbens from 40 up to 120 post-natal days (Andersen and
Teicher, 2000). Once adult, females appear to have larger
post-mortem tissue concentrations of dopamine in the extracellu-
lar milieu in the striatum as well as a higher expression of D2
4 L. Fattore et al. / Frontiers in Neuroendocrinology xxx (2014) xxx–xxx
receptors (Becker, 1999; Lynch et al., 2002). Yet, when using the no
net flux method, microdialysis studies have found higher extracel-
lular concentrations of striatal dopamine in males than in females
(Xiao and Becker, 1994). These effects appear to be organizational
given that similar sex differences in striatal dopamine concentra-
tions are found when comparison were made between castrated
male rats and ovariectomized female rats (Das and Chaudhuri,
1995; Lynch et al., 2002). Thus, together with the notion that
increased striatal dopamine D2 receptor availability is a protective
factor for vulnerability to drug abuse and dependence (Volkow
et al., 2002, 2004), organizational effects of sex hormones might
account for higher striatal dopamine and dopamine transporter
availability in women than men (Mozley et al., 2001; Staley
et al., 2001).
Organizational effects of sex hormones can also play a role in a
variety of cannabinoid effects on behaviour, since females are usu-
ally more sensitive than males (Fattore, 2013). In particular, sex
differences were found in a form of endocannabinoid-mediated
short term plasticity at inhibitory synapses at dopamine neurons
within the ventral tegmental area (VTA) before onset of puberty
(Melis et al., 2013b). Thus, sex specific endocannabinoid signalling
at dopamine neurons might contribute to regulate responses to
aversive intrinsic properties to cannabinoids, thereby resulting in
faster acquisition/initiation of cannabinoid taking (Fattore et al.,
2007). In addition, organizational effects of sex steroids during crit-
ical developmental periods determine gender differences in the
antinociceptive properties of morphine (Cicero et al., 1996).
Accordingly, acute effects of sex steroids seem to have a minor part
in determining such gender-related differences, since short-term
castration does not alter them in a significant manner (Cicero
et al., 1996).
Preclinical studies aimed at examining organizational and acti-
vational effects of sex hormones on drug abuse, however, have
mainly focused on estrogen (Lynch et al., 2002) thereby neglecting
the role of other sex hormones, such as progesterone in females
and testosterone in males. In these studies, two approaches have
been taken in order to challenge the organization–activation the-
ory. The first one examines the changes during estrous and men-
strual cycle phases for rodents and primates, respectively, while
the second one takes advantage of a surgical removal of the gonads
(ovary and testis) to ablate serum levels of sex steroids. Subse-
quently, these latter are manipulated by administering animals
controlled hormone-replacement. Alternatively, a pharmacological
treatment with either receptor agonists or antagonists can be
administered to animals. Indeed, endogenous ovarian hormones
as well as estrogen and progesterone replacement have been
shown to influence cocaine non-contingent reward by altering
dopamine and serotonin levels in the VTA, dorsal and ventral stri-
atum (Becker, 1999; Russo et al., 2003). Particularly, ovary ablation
associated with progesterone replacement reduced cocaine non-
contingent reward, whereas this latter was enhanced when estro-
gen was added (Russo et al., 2003). Interestingly, when progester-
one was administered to ovariectomized rats concomitantly with
estradiol, it inhibited the enhancing effect of estradiol on cocaine
self-administration (Jackson et al., 2006). Similar results were
reported with other psychostimulants (Becker, 1999; Lynch et al.,
2002). In addition, while testis ablation had no effect on basal lev-
els of dopamine and serotonin in the VTA, removal of ovaries mark-
edly decreased monoamine levels, which could be restored by
hormonal replacement therapy. Ovary ablation also up-regulated
striatal dopamine D2 receptors (Gordon and Fields, 1989), thus
supporting the interplay between ovarian hormones and reward-
ing signal. Accordingly, rat striatal dopamine uptake is subject to
change in accordance with the estrous cycle, and it rises during
the morning when estrogen levels increase (Morissette and Di
Paolo, 1993). These observations justify and can explain the
Please cite this article in press as: Fattore, L., et al. Sex differences in addictive disorders. Front. Neuroendocrinol. (2014), http://dx.doi.org/10.1016/
j.yfrne.2014.04.003
expression of androgen and estrogen receptors in tyrosine hydrox-
ylase positive neurons of both VTA and substantia nigra pars com-
pacta (Kritzer, 1997; Creutz and Kritzer, 2002, 2004). Altogether,
these studies suggest that activational effects of ovarian hormones
may influence monoamine neurotransmission, and could therefore
contribute to many of the sex differences reported, including those
in psychostimulant abuse.
Sex dimorphisms have been also extensively described in alco-
holism, especially with regard to the rate of alcohol degradation,
which is higher in women than in men (Dettling et al., 2007).
Accordingly, female mice display a higher rate of alcohol degrada-
tion than their male counterparts, and administration of estradiol
and testosterone increases and decreases, respectively, alcohol
degrading enzymes (Kishimoto et al., 2002). Given the key role of
ethanol-derived molecules (i.e. acetaldehyde, salsolinol) in alcohol
stimulating properties on dopamine neurons of the VTA (Melis
et al., 2007, 2013a) it is tempting to speculate that the relationship
between activational effects of sex hormones and alcohol degrada-
tion rate may underlie sex differences in alcoholism (Lenz et al.,
2012). Sex-dependent differences in rat cannabinoid self-adminis-
tration and other behaviours also appear to be ascribed to activa-
tional effects of sex hormones (Fattore et al., 2007, 2010; Castelli
et al., 2013). Indeed, female rats display vulnerability towards can-
nabinoids in terms of faster acquisition, higher maintenance, later
extinction and stronger drug-seeking reinstatement when com-
pared to their male counterparts. This sex dichotomy relies on cir-
culating sex hormones since it was abolished following ovary
ablation (Fattore et al., 2007, 2010). Similarly, other behaviours
such as spontaneous locomotor activity, social behaviour and sen-
sorimotor gating proved to be sensitive to activational effects of
sex hormones (Castelli et al., 2013). Noteworthy, activational
effects of sex hormones were also shown to regulate the density
of type 1 cannabinoid (CB1) receptors. In particular, CB1 receptor
density is significantly lower in both the prefrontal cortex and
amygdala of cycling females than in males and in ovariectomized
females (Castelli et al., 2013). Importantly, both of these regions
are critically involved in decision-making and learning processes
underlying goal-directed behaviour (Schoenbaum et al., 1998;
Bechara et al., 1999), in which important gender differences have
been described (van den Bos et al., 2013). In addition, although
no sex dichotomy was found in CB1 receptor distribution in the
VTA of male and female rats, different responses to acute cannab-
inoid administration were observed in dopamine neuronal activity
(Lecca and Melis, unpublished observations). This sex-dependent
difference can be ascribed to activational effects of sex hormones
since it disappeared once ovaries were ablated (Lecca and Melis,
unpublished observations).
Furthermore, given that estrogens increase dopamine concen-
trations at the synapse, by causing a rapid reversal of the trans-
porter (Alyea et al., 2008), and that dopamine neurons express
steroid receptors (Kritzer, 1997; Creutz and Kritzer, 2002, 2004),
it appears that some of activational effects of sex hormones on
behaviour might be ascribed to the converging signal downstream
activation of these receptors (Mani, 2006). Accordingly, estrogen is
present at high levels within the brain, and its production appears
to be regulated by neuronal activity (Woolley, 2007). In fact, estro-
gen acts directly at synapses, and by changing neuronal excitabil-
ity, it affects synaptic transmission and activity-dependent
plasticity (Woolley, 2007). Estrogen is known to affect cells via
both genomic (slow) actions, which result in the transcriptional
regulation of target genes, and non-genomic (rapid) actions, which
result in the activation of signal transduction pathways within the
target cell. Evidence has been provided in support of the notion
that the effect of estrogen on neuronal excitability occurs through
the non-genomic mode of action, whereby estrogens acts at the
membrane and can promptly stimulate the activation of kinases
 L. Fattore et al. / Frontiers in Neuroendocrinology xxx (2014) xxx–xxx
and increase calcium cell entry (Vasudevan and Pfaff, 2008). Fur-
thermore, a reciprocal interplay between endocannabinoids and
estrogen in the acute modulation of inhibitory synapses has been
reported to be sex specific (Huang and Woolley, 2012). Particularly,
estrogen acutely suppresses synaptic inhibition in the hippocam-
pus via a sex-specific and tonic mobilization of one endocannabi-
noid, which is anandamide. Remarkably, no evidence of such a
tonic mobilization of anandamide was previously found in male
rats (Kim and Alger, 2004). Thus, Huang and Woolley (2012) high-
lighted substantial sex differences in the modulation of synaptic
function within the hippocampus, although it is well established
that estrogen acutely influences hippocampal functions and affec-
tive behaviours in a sex-dependent manner (Gillies and McArthur,
2010).
As a result, a better understanding of the contribution of both
organizational and activational effects of sex hormones – either
alone or in combination with other neurotransmitters – to drug
addiction may represent a valuable tool in the development of pre-
ventive and therapeutic strategies.
3. Non-drug behavioural addictions
Growing evidence indicate that eating, having sex, gambling,
spending time on the Internet or exercising can develop into com-
pulsive behaviours that are difficult to control and to cease before
the onset of harmful consequences. Recently, a genetic study sug-
gested that enhanced dopamine signaling and/or ventral striatum
reactivity is related to a higher risk of engaging in addictive behav-
iours (Davis and Loxton, 2013). In the same study, negativity and
anxiousness were found to be addiction-prone personality traits
(Davis and Loxton, 2013). As for drug addiction, important gender
differences have been described in non-drug addictive behaviours.
Notably, sex hormones (i.e. estrogen, testosterone) have been
shown to influence most of these behaviours, although in some
cases (i.e. compulsive sex activity, Internet addiction and excessive
exercise) specific studies are still lacking (Table 1).
3.1. Food addiction
Along with drugs of abuse, the most widely studied reward is
food. In humans, food, especially highly palatable ones (e.g. high-
fat, sweets, carbohydrates), may possess addictive properties. Food
represents the prototypical positive reinforcer in many rodent
studies, where it is commonly used to reinforce operant behaviour
in several behavioural tasks. Notably, neural circuits implicated in
Table 1
Gender differences in behavioural addiction: influence of sex hormones and potential underlying factors in males (M) and females (F). NA: data not available.
Addiction Prevalence (M vs F) Hormonal
influence
DRUG M > F prevalence of illegal drugs YES
F > M prevalence of prescribed drugs
F > M progression of the disorder (telescoping
effect)
FOOD F > M (especially chocolate) YES
SEX M>F NA
GAMBLING M > F prevalence of the disorder YES
F > M progression of the disorder (telescoping
effect)
INTERNET MPF NA
EXERCISE FPM NA
Please cite this article in press as: Fattore, L., et al. Sex differences in addictive disorders. Front. Neuroendocrinol. (2014), http://dx.doi.org/10.1016/
j.yfrne.2014.04.003
5
drug-induced reward widely overlap with those processing natural
reward and reinforcement, including food (Blum et al., 2011). In
keeping with this, a genetic variation in striatal dopamine signaling
has been recently associated with an elevated responsiveness to
palatable food (Davis et al., 2013). In addition, alterations in the
hedonic and/or homeostatic control systems may reflect a bias in
eating behaviour.
Food addiction has been postulated as a causal factor in phe-
nomena such as chronic overeating, binge eating, and obesity
(Corsica and Pelchat, 2010). Hence, it attracted much of scientific
and media interest. However, its exact definition is still controver-
sial due to conceptual hitches and lack of scientific data, and of a
validation at neurobiological level (Ziauddeen and Fletcher,
2013). On the other hand, it is unanimously accepted that food
craving, compulsive overeating and binge eating contribute to
the concept of food addiction (Davis and Carter, 2009).
Food craving can be defined as ‘‘an intense desire to consume a
particular food (or type of food) that is difficult to resist’’ (White
et al., 2002). Cues predictive of food availability are potent modu-
lators of appetite, food seeking and food intake. As in drug addicts,
exposure to food-related cues may result in craving for food, and
localized activation of the same central circuits that are known
to mediate cue-induced relapse to drug use (Tang et al., 2012).
Food craving requires consumption of specific foods to be satisfied,
while hunger can be satisfied by consumption of any food (Pelchat
and Schaefer, 2000). Conversely, compulsive overeating is a con-
cept more closely related to binge eating than to ‘‘addiction’’. In
fact, it is characterized by a frequent or continuous excessive eat-
ing over which the individual is unable to exert any control, and
which usually leads to weight gain and obesity. Typically, compul-
sive eating is not connected to hunger, and food intake may be
rapid but without compensatory behaviours (e.g. purging, laxative
use, exercise). The amount of food consumed is generally not large;
when it is, the disorder is referred to as binge eating. Although the
inability to control intake is reminiscent of drug addition, the
equivalence of food- and drug-related addictive behaviours is not
unanimously accepted (Corsica and Pelchat, 2010; DiLeone et al.,
2012). In addition, many other behavioural routes do exist to gain
weight, and many obese individuals do not show symptoms of
addiction (Gearhardt et al., 2009).
Irrespective of either a compulsive or binge component, uncon-
trolled food intake is one of the main features leading to obesity,
which tends to be slightly more prevalent in women than in men
(World Health Organization, 2010). Notably, while men reported
higher levels of addiction than women to substances (see above)
Potential factors underlying gender differences
Socio-cultural differences (M/F) (Becker et al., 2012)
Pharmacokinetics/pharmacodynamics (M/F) (Franconi et al., 2012)
Different sensitivity to the aversive properties of the drugs (F) (Hashimoto and
Wiren, 2008)
Different hedonic and/or homeostatic control systems (M/F) (Davis et al., 2013)
Hormonal fluctuations (F) (Greenberg et al., 1999)
Impulsivity (F) (Skegg et al., 2010)
Children sex abuse (M) (Skegg et al., 2010)
Dysphoria/anxiety/depression (F) (Desai et al., 2005; Wong et al., 2013)
Conduct disorders and impulsivity (M) (Martins et al., 2008)
Sensation-seeking and risk-taking behaviours (M) (Goudriaan et al., 2010)
Peer (M) and parental (F) gambling (Donati et al., 2013)
Psychiatric comorbidity (F) (Petry et al., 2005)
High testosterone level (M/F) (Stanton et al., 2011)
Parental alcohol problems (M) (Jang and Ji, 2012)
Attention deficits (F) (Yen et al., 2009)
Dysregulated eating behaviour (F) (Thome and Espelage, 2007; Mond and Calogero,
2009)
6 L. Fattore et al. / Frontiers in Neuroendocrinology xxx (2014) xxx–xxx
and several behaviours (see below for gambling and Internet use),
women reported higher levels of addiction to chocolate (Greenberg
et al., 1999). In support of the notion that sex hormones are critical
modulators of addictive behaviours in women, women crave choc-
olate or sweets mainly in the perimenstrum, that is the period of
the menstrual cycle around the onset of menstruation character-
ised by low circulating levels of estrogen and progesterone. Choc-
olate craving fluctuations with the menstrual cycle strengthen its
gender-specific nature. Actually, chocolate craving may have die-
tary (i.e. deficiency of magnesium), but also emotional and psycho-
logical basis. Indeed, chocolate contains several biologically active
substances, which induce activating/arousing (i.e. biogenic amines,
caffeine) or calming/anxiolytic effects (i.e. cannabinoid-like fatty
acids) (Bruinsma and Taren, 1999). Thus, it is not unlikely that
women become addicted to chocolate for self-medication pur-
poses. Yet, before menstruation women may also crave for unspec-
ified ‘‘sweets’’, and consume more of a sample of sweet food, but
not more of salty or bland foods (Bowen and Grunberg, 1990).
However, in a study aimed at characterizing psychoactive effects
of tasting chocolate, when evaluating the desire to consume more
of a specific type of chocolate, a significantly greater number of
men reported a desire for ‘‘more of the chocolate tasted’’ compared
to women, albeit having significantly lower chocolate craving and
liking scores (Nasser et al., 2011). In this study, however, women
could have been more concerned than men with their body weight
and about consumption of a high caloric food, or have not admitted
to desire more chocolate due to social desirability bias, two of the
factors discounted by the authors.
3.2. Sex addiction
Dysregulated sexuality is characterised by sexual thoughts,
feelings and behaviours that the subject experiences as distress-
ingly out of control, and in general is defined as any pathological
behaviour diverging from normal erotic standards. In particular,
sex addiction has been defined as any sex-related behaviour of
compulsive nature interfering with daily life, and ultimately
becoming unmanageable (Carnes, 2000) or, alternatively, any dri-
ven sexual behaviour with harmful consequences (Goodman,
1997). Crucial components of sex addiction are the inability to stop
despite adverse consequences, and the development of tolerance.
This latter implies an initial gradual increase in the amount of
activity until the occurrence of negative consequences, such as loss
of partner or problems in social relationships, career and work.
Recently, the increasing use of the Internet has offered new possi-
bilities for engaging in online sexual activity (Cooper et al., 2002)
and scoring positive on a sexual compulsivity scale (Daneback
et al., 2006).
Sexual addiction, also referred to as compulsive sexual behav-
iour, has been studied only in a very limited number of represen-
tative samples of the general population. In addition, no direct
comparisons between men and women suffering of this behav-
ioural disorder have been carried out so far. Yet, compulsive sexual
behaviour affects more men than women (Levine and Troiden,
1988), a difference that is perhaps culture-based. However, a sub-
stantial percent of women suffer from sexual compulsivity, in
which the disorder is intensely shame-based and especially diffi-
cult to treat (Turner, 2008).
A recent population study has provided the first evaluation of
the occurrence of ‘‘out of control sexual experiences’’, and its rela-
tionship to a range of sexual behaviours in a representative sample
(Skegg et al., 2010). Authors reported that nearly 13% of men and
7% of women reported having had sexual fantasies, urges or behav-
iours that they considered as out of control during the past year.
Though, only a small percent of the total sample (0.8% of men
and 0.6% of women) believed that these interfered with their lives
Please cite this article in press as: Fattore, L., et al. Sex differences in addictive disorders. Front. Neuroendocrinol. (2014), http://dx.doi.org/10.1016/
j.yfrne.2014.04.003
(Skegg et al., 2010). Noteworthy, women reported to have had high
numbers of opposite-sex partners, concurrent sexual relationships
or sex with a partner met on the Internet, while men reported to
have paid for heterosexual sex and had same-sex attraction
(Skegg et al., 2010). Besides epidemiological data, authors also pro-
vided important information on psychological and behavioural
traits of this population. Indeed, women with such ‘‘out of control
sexual experiences’’ were found to be more impulsive than other
women, while nearly one quarter of the men in the study were sex-
ually abused when children. Notably, an association with a trend
towards negative affective states was detected in both sexes
(Skegg et al., 2010). A comprehensive internet-based survey
reported a greater proportion of men seeking treatment for sexual
compulsivity, addiction or impulsivity, while women seeking
treatment scored higher on psychological symptoms and negative
affect (Winters et al., 2010). Since subjects with strong sexual
desire (as men) would be more responsive to sexual stimuli and
more likely to become sexually aroused and to pursue sexual activ-
ity, it is not surprising that men, in general, scored higher on sexual
desire than women (Giargiari et al., 2005; Regan and Atkins, 2006).
Despite these few studies, no other specific surveys have been car-
ried out so far on gender-related differences in sex addiction. Sim-
ilarly, whether or not sex hormones have a role in modulating
compulsion to sex has not been examined. The paucity of studies
performed on this behavioural disorder explains why our under-
standing of compulsive sexual behaviour is still in its infancy.
3.3. Pathological gambling
Gambling is defined as taking a risk of losing something valu-
able or important in the hope of gaining an advantage or a benefit.
This phenomenon has been observed worldwide for centuries.
Excessive and interfering patterns of gambling are referred to as
Pathological Gambling (PG), and many evidence now supports
the notion that PG has to be classified as a behavioural addiction.
Indeed, it is characterised by compulsive search for gambling
reward despite adverse consequences for gamblers and their fam-
ilies, preoccupation and irritability when unable to gamble, and a
high heritability and comorbidity with other substance addictions
(Potenza, 2006). Altered responses in reward circuits and poor
frontal regulation during exposure to a gambling scenario have
also been demonstrated by imaging studies (Potenza, 2006). Thus,
when the Fifth Edition of the Diagnostic and Statistical Manual of
Mental Disorders (DSM-5) was released at the American Psychiat-
ric Association’s Annual Meeting in May 2013, the ‘‘Substance-
related disorders’’ chapter was expanded to include PG disorder
(APA, 2013). This extension reflects the undeniable evidence that
gambling activates the brain reward system similarly to drugs of
abuse, and that gambling disorders bear a resemblance to patho-
logical substance use (Clark and Limbrick-Oldfield, 2013). That is,
drug abuse and PG share not only neurobiological substrates, but
also many behavioural features, among which are impulsive cop-
ing (i.e., the tendency to act or to respond rashly when upset or
emotionally distressed), sensation seeking (i.e., the search for
novel, complex, and intense sensations and experiences), and
risk-taking (i.e., the search for activities in which one must tolerate
the possibility of great losses to obtain greater material or psycho-
logical gain). Moreover, like drugs of abuse, gambling encompasses
the dopamine and opioid systems (Porchet et al., 2013). Most men
and women engage in low-frequency gambling without experienc-
ing PG symptoms. Yet, only a small percent develop uncontrolled
gambling and, regrettably, self-destructive gambling behaviour is
often undetected or unaddressed for significant periods of time.
In the United States, more than 78% of the nationally represen-
tative sample reported lifetime gambling activity, and 3% were
pathological gamblers according to DSM-IV criteria (Kessler et al.,
 L. Fattore et al. / Frontiers in Neuroendocrinology xxx (2014) xxx–xxx
2008). Similar statistics were reported in Canada (Marshall and
Wynne, 2004). PG classically involves resilient motivations to
engage in gambling, with elements of withdrawal and craving
resembling substance dependence (Grant and Kim, 2001). PG
usually begins in childhood or adolescence, with males tending
to start at an earlier age (Chambers and Potenza, 2003). Indeed,
males are more likely than females to have problematic gambling,
and an earlier age of onset has been suggested to predict more
severe problems later in life (Winters et al., 2002). Importantly,
women typically begin gambling significantly later than men, but
once started, the progression from occasional to pathological
gamblers is faster than in males (Tavares et al., 2001). This phe-
nomenon usually referred to as ‘‘telescoping effect’’ has also been
reported for drug addiction in women (Greenfield et al., 2010).
Accordingly, female gamblers reported shorter durations of gam-
bling than male gamblers despite similar durations of problematic
gambling before contacting the gambling helpline (Potenza et al.,
2001).
Among adolescents, the ratio of males to females with PG is
approximately 3–5:1 (Jacobs, 2004). With respect to girls, boys
typically begin gambling earlier, display heavier gambling and
report more gambling related problems (Desai et al., 2005). Game
preference was noted to change with age, and patterns of gambling
behaviour were found to significantly differ between genders. In
fact, boys typically prefer strategic forms of gambling, which allow
them to use knowledge of the game to influence or predict the out-
come, such as card and craps/dice games, sports betting, dog and
horse racing. Conversely, girls prefer non-strategic forms of gam-
bling, which involve little (if any) decision making or skills, and
where gamblers cannot influence or predict the outcome, such as
lottery, bingo and keno (Gupta and Derevensky, 1998; Lynch
et al., 2004; Welte et al., 2004). Moreover, while gambling is asso-
ciated with dysphoria/depression in girls (Desai et al., 2005), boys
are more likely to use gambling as a form of coping prevention and
escape stratagem (Bergevin et al., 2006). Thus, while for females
gambling may represent a means for avoiding distressing problems
or coping with loneliness, male gamblers may pursue self-
enhancement through the excitement of taking the risk associated
to large wins. Accordingly, gambling problems were found to be
associated with conduct disorder and impulsivity (i.e., externaliz-
ing behaviours) in boys, and with anxiety and depressive feelings
(i.e., internalizing behaviours) in girls (Martins et al., 2008).
Although female adolescent gamblers may have higher levels of
psychological distress, male adolescent gamblers display enhanced
impulsivity coping, sensation-seeking and risk-taking behaviours.
Boys may also have higher levels of social anxiety (sexual compe-
tition, male rivalry, stronger concerns with their social image) than
girls, which could help to explain the male preponderance in gam-
bling engagement (Wong et al., 2013). Yet, high levels of testoster-
one in male adolescents may also contribute to take greater
economic risks, and to be less responsive to monetary loss or
punishment (Stanton et al., 2011). Noteworthy, high levels of
testosterone in healthy young men are associated with increased
risk-taking under conditions of unknown probabilities
(Goudriaan et al., 2010). Accordingly, in healthy young women,
testosterone reduces sensitivity for punishment and heightens
sensitivity for reward (van Honk et al., 2004), thus strengthening
the crucial role of sex hormones in the predisposition to this addic-
tive disorder. Recently, the economic perception of gambling and
peer gambling behaviour were found to be predictors of at-risk/
problem gambling among male adolescents, while parental
gambling behaviour proved to be a potential risk factor in female
adolescents (Donati et al., 2013). These findings suggest that when
female and male adolescents with gambling problems are diag-
nosed, it is important to deeply investigate the family environment
and the peer group of PG girls and boys, respectively.
Please cite this article in press as: Fattore, L., et al. Sex differences in addictive disorders. Front. Neuroendocrinol. (2014), http://dx.doi.org/10.1016/
j.yfrne.2014.04.003
7
Among adult pathological gamblers, men tend to develop prob-
lems with ‘‘face-to-face’’ forms of gambling (e.g. poker) while
women are more likely to develop problems with less personally
interactive forms of gambling (e.g. bingo) (Potenza et al., 2001,
2006). A deeper analysis of gambling patterns suggested that, as
in adolescents, males usually engage in action-oriented (e.g. sports
gambling) and women in escape-oriented (e.g. slots) forms of gam-
bling (Potenza et al., 2001). Accordingly, women commonly
reported the gambling to forget about problems as a motivational
factor (Boughton and Falenchuk, 2007). Notably, women are also
more likely to opt for legalized gambling (Lesieur and Blume,
1991), which is consistent with their preference for using legal
rather than illegal drugs. The increased availability of legal forms
of gambling (Mark and Lesieur, 1992) as well as marketing gam-
bling as a fun and safe form of entertainment might explain the
recent gambling involvement among women relative to the past.
In general, younger age, lower education, poor income and coping
skills are major risk factors for PG (Johansson et al., 2009), although
they may slightly differ between males and females. A recent anal-
ysis of demographic and social variables associated with problem
gambling reported that increased likelihoods of PG is associated
in women with middle age, middle to low levels of income, a high
school diploma or less, never being married, higher levels of life
stress, and negative coping abilities. Conversely, in men a signifi-
cant association was found between PG and being separated, wid-
owed or divorced, lower levels of social support and negative
coping skills (Afifi et al., 2010). Yet, discrepant data were also
reported (Echeburúa et al., 2011). Gambling women also display
enhanced responsiveness to gambling-related cues, poorer thera-
peutic outcomes, greater propensity for suicide attempts, higher
levels of stress and negative affective states, and a more rapidly
deteriorating course with approximately 10% of PG women engag-
ing in prostitution to subsidize gambling (Ibanez et al., 2003; Desai
and Potenza, 2008; Martins et al., 2008; Grant et al., 2009;
Tschibelu and Elman, 2011). Such gender differences among prob-
lematic gamblers imply that the experience of gambling may
diverge between genders, and that targeting at-risk gamblers with-
out considering gender-specific effects may have limited success
for prevention. In accordance, gender differences in the rates of
recovery, treatment seeking and spontaneous recovery in PG have
been described. Moreover, women are more likely than men to rec-
ognize that they have gambling problems and to seek treatment.
However, women are less likely than men to recover naturally
without any help (Slutske et al., 2009).
Notably, sex-dependent interactive effects of alcohol and nico-
tine on gambling attitudes were described in recreational gam-
blers. That is, moderate-to-high alcohol drinking was associated
with heavier gambling in men than in women (Desai et al.,
2006), while a higher incidence of nicotine dependence was asso-
ciated with PG in women (Pilver et al., 2013). Conversely, no signif-
icant differences in two cognitive parameters typically altered in
PG, which are response inhibition and cognitive flexibility, were
identified between men and women with gambling problems
(Grant et al., 2012). Although women generally gamble less fre-
quently and heavily than men, gambling is associated with poorer
measures of mental health and substance abuse in women com-
pared to men (Desai et al., 2005, 2006). According to this, PG
comorbidity with psychiatric disorders (e.g. major depression, gen-
eralized anxiety disorder) and with substance use disorders is
more frequent in women than in men (Petry et al., 2005).
The high comorbidity of PG with emotional disorders in women
highlights the importance to target subsyndromal gambling in
women, as unidentified gambling symptoms can hamper treat-
ment of non-gambling patients with serious mental illness. On
the other hand, special attention should be also paid to the occur-
rence of depressive symptoms and specific personality/affective
8 L. Fattore et al. / Frontiers in Neuroendocrinology xxx (2014) xxx–xxx
traits, which may trigger or maintain the gambling behaviour.
Hence, a combination of psychological and pharmacological ther-
apy might be indicated in PG women that engage gambling to
escape from problems or to cope with social isolation.
Finally, from a biomedical point of view, it is very important to
be aware of the role that some frequently used medications may
have in inducing gambling. In fact, impulse control disorders, most
commonly PG (but also hypersexuality, impulsive eating and com-
pulsive shopping), are now clearly recognized in Parkinson’s dis-
ease (PD) patients on dopaminergic replacement therapy (DRT)
(Santangelo et al., 2013). Yet, similar disorders have also been
reported when dopamine agonists are used for other indications,
such as restless legs syndrome (RLS). Pramipexole and ropinirole
(for PD) as well as rotigotine (for RLS), for example, have been sig-
nificantly associated with PG and other impulse control disorders
(Schreglmann et al., 2012; Poletti et al., 2013). Although these dis-
orders may resolve by withdrawing dopamine agonists and by
managing PD motor symptoms with levodopa monotherapy
(Weiss and Marsh, 2012), they may cause significant financial loss
and psychosocial morbidity for patients and their families. Notably,
gender plays a role also in the prevalence rates of these DRT-
induced PG, since the vast majority of pathological gamblers with
PD are male (reviewed in Leeman and Potenza, 2011; Voon et al.,
2011).
3.4. Internet addiction
The Internet has been gaining worldwide popularity in the last
two decades, and computer and gaming station use is now ubiqui-
tous. The use of the Internet has brought a variety of convenience
to our modern life; yet, a misuse is a concern, and a loss of control
over Internet use might lead to negative impacts on our daily lives.
The growing popularity and frequency of Internet use has led to an
increasing number of reports highlighting the potential negative
consequences of excessive use. Internet Addiction (IA) usually
refers to that phenomenon when an individual is unable to control
his/her use of the Internet, which eventually causes marked dis-
tress and functional impairment in daily life. IA is one of the latest
forms of behavioural addiction that has roused the interest of psy-
chologists in these past years. Particularly, in China and South
Korea it currently represents a significant public health problem.
With the mounting number of Internet users, IA is becoming a seri-
ous concern worldwide, especially for teenagers whom use the
Internet to experiment on new ways to communicate or ‘‘socialize’’
through various texting systems like e-mails, blogs and forums.
Peculiarity of IA is time-consuming connections associated with
the loss of perception of the time spent in front of the computer
(excessive use), constant need for using the computer for longer
period of time (tolerance), discomfort and negative mood states
when the computer is no longer available (withdrawal), and inter-
personal problems (negative social consequences) (Block, 2008). In
the DSM-5, Internet Gaming Disorder is identified in Section III as a
condition warranting more clinical research and experience, before
it might be considered for inclusion as a psychiatric disorder. Cur-
rently, diagnostic criteria are limited to Internet gaming and do not
include general use of the Internet, online gambling or social
media.
Similarly to PG, boys are more likely than girls to engage in
playing video games or computer activities (Johansson and
Gotestam, 2004; Ko et al., 2005). Accordingly, in a representative
sample of high school Italian students, 5% was found moderately
addicted and 0.79% seriously addicted, with a significant male pre-
ponderance (Poli and Agrimi, 2012). The higher prevalence of IA in
boys than girls may be due to their greater interest in most activ-
ities that have been associated with problematic Internet use, such
as games, cybersex and gambling (Cooper et al., 2002). However,
Please cite this article in press as: Fattore, L., et al. Sex differences in addictive disorders. Front. Neuroendocrinol. (2014), http://dx.doi.org/10.1016/
j.yfrne.2014.04.003
discrepant results have been also reported, as gender was found
not related to adolescent IA in a sample of Chinese adolescents
(Shek and Yu, 2012).
Gender differences in the association between parental problem
drinking and early adolescent IA have been recently reported by Jang
and Ji (2012). The authors showed that early adolescent males with
parental alcohol problems are more likely than age-matched
females to experience IA (Jang and Ji, 2012). Also, attention-deficit
hyperactivity disorder (ADHD) was found to be associated with IA,
being the deficit of attention the most associated symptom of IA, fol-
lowed by impulsivity (Yen et al., 2009). Importantly, the association
between attention deficit and IA was more significant among
females than males (Yen et al., 2009). Similarly, potential risk factors
for problematic Internet use were identified in boys and girls, among
which high study-related stress, having social friends, poor relation-
ships with teachers and students, and conflictive family relation-
ships (Wang et al., 2011). Unfortunately, no specific study has been
conducted to evaluate whether sex hormones, like estrogen (as in
drug addiction) or testosterone (as in pathological gambling), may
influence the proclivity to spend excessive time surfing the Web.
Increased release and binding of dopamine in the ventral stria-
tum (Koepp et al., 1998) together with a decreased dorsal prefron-
tal activation (Matsuda and Hiraki, 2006) were identified as neural
processes underlying playing computer games. Notably, significant
gender differences have been described in brain activation and in
task-specific functional connectivity within the mesocorticolimbic
system (Hoeft et al., 2008). Particularly, males exhibit higher acti-
vation and connectivity than females. Authors attributed these
findings to higher motivational states and reward prediction in
males than in females. However, greater learning reward values
and cognitive state during computer video games in males may
also partially explain why males are more attracted to, and more
likely to become ‘‘hooked’’ on, video games than females. Intrigu-
ingly, the risk of IA is associated with an increased prevalence of
substance dependence (Ko et al., 2012), and this overlap may be
due to similarity in brain characteristics predisposing toward
internet and/or substance use (Hong et al., 2013). According to this,
subjects with IA and substance addiction may share similar pat-
terns of brain activation (Crockford et al., 2005; Han et al., 2010;
Ko et al., 2009, 2013).
3.5. Excessive physical exercise
Physical exercise improves cardiovascular health, strengthens
muscles and bones, promotes neuroplasticity, decreases anxiety,
offsets depression, and more generally promotes feelings of well-
being. However, when taken to extremes, exercise can result in a
behavioural addiction. Hence, exercise dependence is defined as
an inadequate pattern of exercise leading to clinically significant
negative consequences. The prevalence of exercise addiction is not
known, but a relatively small percentage of sportsmen and women
develop a severe dependence. Subjects present loss of control over
their physical activity, tolerance, and withdrawal symptoms when
they do not practice sport. Runners appear particularly susceptible
to addictive properties of exercise. Indeed, they report a feeling or
euphoria after a strenuous bout of exercise (i.e. runner’s ‘‘high’’), a
need to increase the distance run to achieve feelings of well-being
(tolerance), difficulties in job performance and social interactions
(addiction), and display depression, irritability, and anxiety, when
prohibited from running (withdrawal) (Adams and Kirby, 2002;
Aidman and Woolard, 2003; Allegre et al., 2006).
In line with preclinical studies where female rats typically dis-
play stronger wheel running behaviour than male rats (Boakes and
Dwyer, 1997), female habitual exercisers reported higher scores
than males when answering to the Exercise Dependence Question-
naire (Grandi et al., 2011). Similarly, women report more often
 L. Fattore et al. / Frontiers in Neuroendocrinology xxx (2014) xxx–xxx
than men to crave exercise and be nervous when unable to exercise
(Zmijewski and Howard, 2003). In particular, women unable to
exercise feel more tense, depressed, and anxious than men. They
also report to feel swollen, and that exercising prevents all of these
negative affective states (Zmijewski and Howard, 2003). However,
discrepant results were also reported. For example, no gender dif-
ferences in ‘‘addiction’’ to running and exercising were reported by
Furst and Germone (1993). Accordingly, a study carried out in col-
lege students (18–24 years old) reported men with higher levels of
‘‘addiction’’ than women to alcohol and tobacco as well as to gam-
bling, video games, and Internet use (Greenberg et al., 1999). Con-
versely, women were found to display higher levels of addiction to
caffeine and chocolate. Nonetheless, no gender-related differences
were detected in the sample studied in two other relatively fre-
quent types of addictions, namely addiction to physical exercise
and television (Greenberg et al., 1999). Indeed, with respect to lev-
els of addiction, it was found that exercise yielded the highest level
of addiction in both males and females (Greenberg et al., 1999).
Regrettably, as for compulsive sex activity and Internet addiction,
no study has investigated whether sex hormones may affect the
inclination to exercising excessively yet.
Noteworthy, since exercise dependence is often associated with
problematic attitudes toward eating (Thome and Espelage, 2007;
Mond and Calogero, 2009), future studies aiming at investigating
on gender differences in the attitude to becoming addicted to
physical exercise should also consider a disorganized eating pat-
tern as potential bias factor, especially in women.
3.6. Other behavioural addictions
Besides the abovementioned addictive behaviours, other com-
pulsive activities have been often referred to as ‘‘behavioural
addiction’’, which include compulsive shopping and pyromania.
Notably, gender differences have been described in these two
activities as well.
Compulsive buying has been described worldwide, with a life-
time prevalence of 5.8% in the US general population (Koran
et al., 2006). It has been classified as an addictive disorder
(Krych, 1989), but also as an obsessive–compulsive disorder
(Hollander, 1993) or a mood disorder (Lejoyeux et al., 1996). Com-
pulsive shoppers are constantly worried with shopping and spend-
ing, and report an increasing level of urge or anxiety that can lead
to a sense of completion only when a purchase is made. Although a
vast majority of people with compulsive buying problems have
been estimated to be women (Schlosser et al., 1994), a bias could
be due to the fact that women admit more readily than men that
they enjoy shopping. However, men tend to buy electronic or hard-
ware goods more than women, which in turn appear more inter-
ested in clothing, shoes, and compact discs (Black, 2007).
Firesetting is a severe and costly antisocial behaviour, a signifi-
cant social problem that causes enormous property damage each
year. It represents a crime easy to perform, though difficult to
detect, with a prevalence of lifetime of 1.7% in men and 0.4% in
women (Hoertel et al., 2011). Both men and women with a lifetime
history of firesetting typically display also generalized anxiety dis-
order, conduct and antisocial personality disorder, alcohol or canna-
bis use disorder, and obsessive–compulsive personality disorder
(Hoertel et al., 2011). Yet, pyromaniac women are significantly more
likely than men to have a lifetime diagnosis of alcohol abuse and
antisocial personality disorder as well as a diagnosis of schizoid per-
sonality disorder (Hoertel et al., 2011). Thus, although with a prev-
alence in male population, this disorder resemble at some extent
compulsive shopping disorder which, as pyromania, was found to
be associated with significant psychiatric comorbidity (especially
mood and anxiety disorders), disorders of impulse control and sub-
stance use disorders (Christenson et al., 1994; Torresan et al., 2009).
Please cite this article in press as: Fattore, L., et al. Sex differences in addictive disorders. Front. Neuroendocrinol. (2014), http://dx.doi.org/10.1016/
j.yfrne.2014.04.003
9
4. Conclusions
Behavioural addictions are complex disorders with interacting
factors, including environmental factors, comorbidity, personality
traits and stress responsivity. Several behaviours, besides ingestion
of psychoactive substances, produce immediate reward that may
engender persistent behaviour, despite the knowledge of adverse
consequences and diminished control over that behaviour. Behav-
ioural addictions involve dysfunction in several brain regions, prin-
cipally the frontal cortex and limbic system (reviewed in Leeman
and Potenza, 2013). Disruption in neurobiological processes under-
lying both sensitivity to reward and inhibitory control can lead to
compulsive behaviours. In some individuals, compulsive drug tak-
ing may result in drug addiction, compulsive food intake may lead
to obesity, and other forms of activities may deteriorate into
behavioural addictions.
Daily activities that activate brain reward circuits, such as eating,
exercising, or having sex, may lead to clinical concerns in vulnerable
individuals. Notably, they closely resemble brain and behavioural
features of drug addicts. This presupposes the need for research
and clinicians to consider addiction as a spectrum disorder. In con-
trast to drug addiction, only few studies have evaluated potential
differences between men and women in non-drug behavioural
addictions. For most of them, environmental and socio-cultural fac-
tors contributing to the different vulnerability in males and females
started to be investigated only recently. Thus, for example, it is not
known whether social deviance and antisocial personality traits
found to be more frequent among male than female smokers
(Grunberg et al., 1991), may render men more vulnerable than
women to develop other forms of behavioural addictions. Similarly,
whether or not engaging in addictive behaviours like Internet surf-
ing or pathological gambling may be perceived by girls as a mean of
challenging imposed social conventions, as cigarettes in the early
1900s (Brandt, 1996), is still to be defined. Moreover, males and
females experience dissimilar emotional and psychological needs,
and react differently to peer pressure, lack of full realization, or
other personal and social expectations. In addition, they are differ-
ently influenced by family history and legal policies, and display
diverse perception of self-image and health risks. All of these factors
interact with genetic background and sex hormonal fluctuations in
men and women, and determine a differential propensity to develop
a behavioural addiction. To complicate the matter, in men testoster-
one levels vary markedly over the course of the day, and are influ-
enced by both genetic and individual-specific environmental
factors (Panizzon et al., 2013). In contrast, in women the levels of
estrogens and progesterone vary markedly depending upon the
menstrual cycle, the pre- or postmenopausal age, and the use of oral
contraceptives. Moreover, although at a lesser extent, testosterone
is likely to affect motivated behaviours also in females, in which it
was found to exert rewarding effects (Triemstra and Wood, 2004).
Intriguingly, the reinforcing effects of testosterone appears to be
mediated by both androgens and estrogens (DiMeo and Wood,
2006). Targeting brain and genetic factors that allow pursuit of
non-drug rewards to become pathological are crucial for pinpoint-
ing effective treatments of both substance and non-substance
addictions. Further studies on gender differences in behavioural
control will be important for investigating the etiology of behav-
ioural addictions, and for designing gender-appropriate treatments.
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