Pharmacological Research 87 (2014) 60–70

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Pharmacological Research
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Genders and the concurrent use of cocaine and alcohol:

Pharmacological aspects
Manuela Graziani a,b,∗ , Paolo Nencini a,b , Robert Nisticò a,c
a
Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, Rome, Italy
b
Drug Addiction and Clinical Pharmacology Unit, University Hospital Umberto I, Sapienza University of Rome, Rome, Italy
c
IRCSS Santa Lucia Foundation, Rome, Italy

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

Article history: Aims: Gender-related differences in the pharmacological effects of addictive drug are an emerging issue.
Received 25 April 2014 This review examines gender differences in both pharmacokinetic and pharmacodynamic aspects of
Received in revised form 13 June 2014 alcohol and cocaine intake since they cause complex pharmacological interactions, not least the formation
Accepted 16 June 2014
of the active metabolite cocaethylene.
Available online 24 June 2014
Methods: The MEDLINE database was searched from 1990 to 2014 in order to find articles related to
gender differences in alcohol, cocaine and cocaethylene pharmacokinetics and pharmacodynamics.
Keywords:
Results: Besides the well known gender differences in alcohol pharmacokinetics, women appear more
Gender
Cocaine
susceptible to alcohol-mediated brain damage and seem to suffer more than men the acute effects of
Alcohol alcohol on hepatic and gonadal hormones. No significant gender differences have been found in the
Cocaethylene pharmacokinetics of cocaine taken alone; yet, in women pharmacological sensitivity to the drug seems
Pharmacology to vary in relation to menstrual cycle; moreover, progesterone attenuates subjective effects of cocaine
Pharmacodynamics in women. Higher ratings at a subjective measure of mental/physical well-being have been observed in
Pharmacokinetics women when given cocaine and alcohol, alone or in combination. Finally, among subjects dependent on
both alcohol and cocaine, men only benefit from naltrexone, whereas women used more cocaine during
the trial and were less compliant to therapy than men.
Conclusions: The observed subtle gender differences in the pharmacokinetics and pharmacodynamics of
both alcohol and cocaine may have no subtle influence on the natural history of the co-abuse of the two
drugs by women.
© 2014 Elsevier Ltd. All rights reserved.

Introduction
It has been estimated that 1% of the United States population
suffers from both alcohol and drug use disorders [1,2]. In partic-
ular, concurrent intake of cocaine and alcohol in both sexes is a
well documented, increasing type of multiple drug use [3–5]. A
recent report about prevalence of cocaine use among adolescents
in Europe indicates that about 70% of them reported that the first
use of cocaine was under the effects of alcohol [6]. In turn, there
is evidence that cocaine use in heavy drinkers increases the risk of
developing alcohol dependence by 3.8 times [7], whereas co-abuse
of cocaine and alcohol is associated with more severe psycholog-
ical problems [8] and in particular with an increment of suicidal
∗ Corresponding author at: Department of Physiology and Pharmacology “Vittorio
Erspamer”, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
Tel.: +39 06 49912494; fax: +39 06 4450618.
E-mail address: manuela.graziani@uniroma1.it (M. Graziani).
and homicidal behaviour [9] with respect to the use of cocaine or
alcohol alone.
Currently, few epidemiological data about gender prevalence
of the concurrent use of cocaine and alcohol are available [8].
A recent study by Martinotti et al. [10] aiming to examine the
clinical correlates of poly-substance dependence showed no differ-
ence in sex prevalence between mono- vs. poly-substance abusers,
while another aimed to explore possible gender differences among
cocaine-dependent patients show a higher frequency of alcohol
intake in male subjects [11]. Another report [5] examining sub-
stance use and dependence among cocaine dependent subjects
(N = 459, 52.9% female) recruited for treatment, reported that poly-
substance dependence was the rule: among this population 56% of
women reported a lifetime dependence on alcohol.
A study aimed to analyze the quantity and frequency of alcohol
use among Afro-Americans reported that female heavy drinkers
used more crack cocaine than light and moderate drinkers [12].
Interestingly, among women entering the criminal justice circuit,
co-abuse of alcohol and cocaine was related to high levels of

http://dx.doi.org/10.1016/j.phrs.2014.06.009
1043-6618/© 2014 Elsevier Ltd. All rights reserved.
 M. Graziani et al. / Pharmacological Research 87 (2014) 60–70
psychiatric distress [13]. Considering that epidemiological survey
converge in detecting an increase in the use of cocaine [14] in the
prevalence of heavy drinking [15,16] and in a progressively higher
percentage of women abusing psychotropic drugs [17–19], it is con-
ceivable that the concurrent use of cocaine and alcohol is spreading
among women.
Yet, few studies have addressed gender differences in the phar-
macological effects of combined cocaine–alcohol abuse, in spite
of the fact that growing literature is dealing with the biological
and molecular basis of gender-related differences in response to
drugs [20–24] and more generally with gender perspective in clin-
ical research [25]. This is not surprising because little information
is available about gender differences in the pharmacokinetic and
pharmacodynamic aspects of drug addiction [26–28]. The purpose
of this review is to provide an overview of gender differences in
pharmacokinetic and pharmacodynamic aspects of the concurrent
abuse of alcohol and cocaine. We choose to use the term gender
according to the definition of National Research Council in USA [29]:
“Gender refers to a person’s self-representation as male or female
and how the individual is responded to by social institutions, based
on the individual’s gender presentation. This definition includes
self-representation, which also includes biological aspects”.
In order to pursue our aim, we first reviewed gender differences
in the pharmacological aspects of alcohol and cocaine separately
and then we focused our attention on the effects of their combined
use. Although experimental findings are not the primary focus of
the present review, we have occasionally included animal or in vitro
studies, particularly when male and female differences found in
animals may suggest further studies in humans.
Method
We reviewed the literature related to gender differences in
alcohol, cocaine and cocaethylene pharmacokinetics (PK) and phar-
macodynamics (PD). The MEDLINE database was searched from
1990 to 2014, using PubMed. Keywords used were: alcohol, cocaine,
cocaethylene, ethanol, pharmacology, pharmacokinetics, phar-
macodynamics, sex/gender difference; individually or variously
paired. Importantly, search results were restricted to English lan-
guage with particular attention to human studies. Manual searches
of reference lists of pertinent reviews and studies, as well as
abstracts from relevant conferences were also conducted.
Aspects of gender differences in alcohol pharmacology
Epidemiological studies show that alcohol use starts at an early
age in both genders. The recent SAMSHA survey (2014) reports that
during 2012 56.5% of males and 47.9% of females aged 12 or older
were current drinkers; however, among youths aged 12–17, the
percentage of males who were current drinkers (13.3%) was sim-
ilar to the rate for females. Among young adults aged 18–25, an
estimated 57.5% of females and 62.9% of males reported current
drinking; in this age group, 45.8% of males and 33.2% of females
reported binge drinking. Among pregnant women aged 15–44, 8.5%
reported current alcohol use, 2.7% binge drinking, and 0.3% heavy
drinking; nevertheless, these rates were lower than those for non
pregnant women in the same age group.
Attitudes concerning drinking clearly differ between genders
[30], women perceiving greater social disapproval for drinking
although they tend to consume less quantity of alcohol [31–33].
Yet, recent findings confute the notion of gender differences in the
attribution to types I and II of alcoholism [34] showing that type
II alcoholism is not limited to male alcoholics, but also exists in
women, confirming that female alcoholics are represented in both
Cloninger’s Type I and Type II of alcoholism [35,36]. In addition,
61
Lesch type III category [37] that includes subjects that use alco-
hol to cope with their signs of depression, is dominated by women
[38], and in a recent study [39] genetic markers of alcoholism and
comorbid depression were identified in alcohol dependent females.
Finally, a study conducted on a multisite sample of college students
shows that female students were more likely to exceed weekly
alcohol intake limits than men [40]. In a review examining factors
associated with the risk of developing alcoholism, Schulte et al. [16]
found that among teenagers physiological and also psychosocial
factors differently interact with the gender in eliciting progression
into problematic drinking when adults.
However, the consequence of heavy alcohol use as well as alco-
holic complications may be heavier in women than in men: women
tend to be more vulnerable to alcohol-induced physical illnesses
[31,41] and display more severe cognitive and motor impairment
with significantly lower alcohol exposure compared with men [42].
Both pharmacokinetic and pharmacodynamic factors may con-
tribute to gender difference in the pattern of alcohol abuse and
response to alcohol intake.
Gender differences in alcohol
pharmacokinetic/pharmacodynamics
Several studies have demonstrated gender differences in alcohol
pharmacokinetic (PK) in different animal species [43–46] and in
humans. Table 1 shows a summary of the results of clinical studies
addressed to gender differences in PK parameters of alcohol.
For a given oral dose of alcohol (but not for intravenous adminis-
tration), women exhibit higher and more prolonged blood alcohol
levels [47–50] indicating that women own greater oral bioavail-
ability, as shown by an increased area under the curve (AUC)
with respect to men. As known, systemic bioavailability upon oral
administration of drugs is subject to a wide array of variables, such
as speed of gastric emptying, gastric enzyme activity, and first-
pass metabolism (pre-absorption metabolism, both in stomach and
liver), which differ between the two genders. Accordingly, in a
study aimed to explore factors underlying gender differences in
the bioavailability of alcohol, Baraona et al. [48] found a signifi-
cant delayed gastric emptying in women with respect to men: the
slower gastric emptying time may explain the gender-difference
in the shape of the curve, but not the difference in the peak alco-
hol levels. Moreover, it could not explain gender differences in the
AUC of alcohol, since the slower gastric emptying time observed
in women [22,24] is expected to reduce it. In fact, gastric alcohol
dehydrogenase (ADH) activity seems to contribute to the observed
gender differences in oral bioavailability of alcohol, as far as most
of the studies (see Table 2), although with some exceptions [54,56]
agree that gastric total ADH activity is significantly lower in women
than in men when the enzyme activity is measured at high alco-
hol concentrations (such as it happens in the stomach after alcohol
binge intake) [47,52,53,59] in young [52,53,58,60] and healthy sub-
jects [47,48,52]. Importantly, since alcoholism is associated with a
decrease in gastric alcohol dehydrogenase activity in both genders,
alcoholic women display a particularly low first-pass metabolism
of alcohol up to the point of showing little differences in blood alco-
hol concentrations upon oral or iv administrations [47]. Moreover,
many authors [52,53,58,60] found in men, but not in women, an
inverse correlation between gastric ADH activity and age. Further-
more, significant lower enzymatic activities in total ADH and class
I and II ADH isoenzymes were also showed in women human liver
[61].
When alcohol reaches the circulation, other physiological dif-
ferences between men and women emerge affecting alcohol
distribution [62]. On average, women have total body water (both
extracellular than intracellular water), blood and plasma volume,
and red blood cell volume smaller than men, while they have

Table 1
Gender difference in ethanol (Eth) pharmacokinetic parameters.
Reference Aim of the study
(publication year)
Gender-related differences in
[47] (1990)
gastric oxidation of Eth (first
pass metabolism = FPM)
[49] (1996) Gender-related differences
in FPM and disposition of
Eth
Influences of liver volume
[51] (1998) and/or gender differences in
lean body mass on gender
differences in Eth metabolism
[48] (2001) Gender difference in GE, FPM
[50] (2003) Comparison the
pharmacokinetics of Eth in
saliva and blood according to
gender
a
I = non-alcoholic; II = alcoholic.
62
Subjects N Subjects age (years) Subjects Eth dose (route of administration) Administration mode and time Findings/comments
(% female) categorya
31 (55) 22–53 I 0.3 g/kg b.w. (orally and In women lower FPM and
1 h after a standard breakfast
intravenously) higher area under the
concentration–time curve
(AUC) than men
M. Graziani et al. / Pharmacological Research 87 (2014) 60–70
12 (50) 17–61 II FPM = 50% of those of
non-alcoholic; in women FPM
abolished and higher AUC than
men
12 (50) <50 I 0.3 g/kg b.w. (orally and After a standardized lunch In women higher AUC; no
intravenously) gender difference in total
(gastric plus hepatic) FPM
Oral loading dose of 95% Eth 1 h after a standard breakfast No gender difference in alcohol
20 (50) 22–30 I diluted 1:6, after 30 min a elimination rate (AER) or in
constant rate of i.v. infusion of AER per unit liver volume; in
6% Eth (steady-state breath Eth women the AER per unit lean
concentration 50 mg/dL) body mass 33% greater than
men
Eth after metoclopramide Diminished hepatic FPM in
(gastric empty time enhanced) both genders
Eth after N-butylscopolamine Increased gastric FPM of Eth in
(gastric empty time delayed) both genders
55 (51) 0.3 g/kg b.w. as 5–10 to 40% 1 h after a standard fatty In women smaller volume of
<50 I solutions (orally and meal distribution, lower GE and FPM
intravenously) at highest Eth concentration
20 (50)
24 (50) <50 I 0.6 women and 0.7 g/kg 2 h after last meal In women absorption rate
b.w. men Eth (40% constant, maximum ethanol
solutions orally) concentrations and AUC lower
 M. Graziani et al. / Pharmacological Research 87 (2014) 60–70 63

Table 2
Gender differences in gastric alcohol-dehydrogenase (ADH) activity: in vitro evaluation (gastric biopsy specimens).

Reference Aim of the study Subjects N Subjects age Subjects Substrate for ADH Findings/comments
(publication year) (% female) (years) categorya isoenzymes (mM)

[47] (1990) Gender-related differences 28 (61) 22–53 I In women lower ADH activity
Eth 500
in gastric oxidation of than men
ethanol (Eth)
9 (33) 17–61 II In alcoholic ADH activity and
first pass metabolism
(FPM) = 50% of those of
non-alcoholic; in women ADH
activity lower than men

[52] (1993) Gender difference in 78 (55) <50 I At 16 mM eth., no gender and

gastric ADH activity Eth 16 or 580 age difference in ADH activity.
In women <50 lower ADH
activity at 580 mM Eth, lower
ADH activity in men >50 and
subjects with alcoholism.
100 (41) >50 I
10 (1) 30–75 II

[53] (1994) Influence of age, gender, 31 (52) <50 In women lower ADH
III Eth 100
gastric regions and ADH activities, but not significantly,
polymorphins infection on in both age groups
gastric ADH activity
>50
[54] (1997) Gastric Eth-metabolizing 37 (51) <50 No significant effects of gender
IV Eth 33 or 500
activities with regard to and age on ADH activity
gender, age, enzyme
pattern, and polymorphism
172 (13) >50

[55] (1998) Effect of modulation of 16 (50) <40 I Eth 100 No gender differences in ADH
gastric emptying (GE) on activity
FPM of ethanol in the
stomach and liver;
secondary aim: gastric
ADH activity

[56] (2000) Effects of gender and age 51 (35) <50 No effect of gender or age on
V Eth 33 or 500
on the expression pattern activity of ADH
and activities of stomach
ADH
64 (42) >50

[48] (2001) Gender difference in GE, 58 (33) <50 I Formaldehyde oxidation In women lower gastric ADH III
FPM and ADH activity activity
[57] (2001) Influence of age, gender, 37 (51) <50 No gender and age or HP
III 500
and Helicobacter pylori positive in gastric corpus
(HP) infection on gastric related differences in ADH
ADH activity activity
39 (51) >50

[58] (2002) Gender and other variables 18 (28) 20–40 Youngest women lower ADH
influence in gastric ADH V 150–500 activity than youngest men
activity No gender difference between
oldest groups; decreasing ADH
activity associated with
increasing Eth consumption
47 (38) 41–60
46 (61) 60–80
a
I = non-alcoholic; II = alcoholic; III = patients with chronic symptoms of dyspepsia; IV = gastric adenocarcinoma in non-alcoholic; hepatic adenocarcinoma in non-alcoholic;
V = patients with other than gastro-hepatic diseases.

a higher percentage of body fat. Consequently, alcohol, being
hydrophilic, shows a volume of distribution smaller in women than
in men [48], contributing to the female higher blood alcohol levels
with consequences on the effect of the drug in terms of onset and
duration of its action.
In summary, conditions such as young age, good health and
binge alcohol use, typically associated with subjects that more
frequently abuse of alcohol and cocaine in combination, concur
with physiological differences between genders to produce a higher
plasma alcohol concentration in females respect to males.
Pharmacodynamic (PD) factors also contribute to gender dif-
ferences in alcohol effects, upon either acute or chronic intake.
Notably, a gender-related PD difference is to be taken into account
when at similar plasma concentrations of a drug in males and
females do not correspond pharmacological effects of the same
magnitude [24], or when the same effect is observed in spite of
significant pharmacokinetic differences [24,63]. Hence, differences
between females and males in the response to acute alcohol intake
can be clearly assessed only when blood alcohol concentrations
(BAC) in both genders are equal, or alcohol doses are adjusted to
individual body weight.
Importantly, human studies have demonstrated that the effects
of acute alcohol intake on the central nervous system are different
between genders. In healthy females, but not in likewise healthy
64 M. Graziani et al. / Pharmacological Research 87 (2014) 60–70
males, a moderate dose of alcohol (inducing a blood alcohol con-
centration of 0.5‰), reduces frontal inter-hemispheric connectivity
(as indexed by transcranial magnetic stimulation applied to mea-
sure transcallosal inhibition), resulting in behavioural disinhibition
[64]. A recent study [65] conducted in non alcohol-dependent
young drinkers shows that alcohol-induced dopamine release
is greater in men than in women and that this gender-related
effect was apparent across the whole striatum and not only
in the ventral tegmental area-ventral striatum circuit; however,
in men, but not in women, ventro-striatal dopamine release
showed a significant positive correlation with alcohol-induced
subjective effects of activation (elation, feeling high, energy, excite-
ment, stimulation, vigour and talkativeness). With regard to acute
alcohol-related effects on cognitive-motor function, an interest-
ing study from Miller et al. [42] indicates that women display a
greater impairment than men on a range of tasks measuring driving
performance.
Chronic alcohol intake may also have different effects in males
and females. In particular, women are more vulnerable than men to
chronic alcoholism-related brain injury [66–69]. Despite lower and
shorter alcohol abuse, neuroimaging studies documented greater
cerebral volume loss in females than in males [70]. Moreover,
making use of diffusion tensor imaging techniques, Sasaki et al.
[68] found only in females a life-time alcohol consumption (LAC)-
related neurodegeneration in the right amygdala, even thought LAC
scores were lower in women than in men. A more recent study
from Ruiz et al. [71] shows that women with a drinking history
showed a greater sensitivity in frontal, temporal, ventricular and
corpus callosum regions than men. Indeed, alcoholism was asso-
ciated with larger ventricles and smaller corpus callosum among
women only. Interestingly an increase in the relative amount of the
white matter was observed among women in the first year of sobri-
ety whereas the same effect required a more prolonged abstinence
in men [71]. Another observation suggests that the NMDA recep-
tor subunit expression differentially influences male and female
chronic alcohol susceptibility to brain damage [72].
An increased susceptibility of young women to the acute effects
of alcohol on hepatic and gonadal hormones was also found. In
a recent study, Vatsalya et al. [73] examined the effects of acute
alcohol on gonadal hormones and Growth hormone – insulin like
growth factor-1 (IGF-1) axis. The results showed an increase of
estradiol levels in women [74], an effect that was attributed to
alcohol-induced changes in the redox state of the liver. Moreover,
in younger women, but not in the oldest and in men, a trend
for alcohol-related decrease in IGF-1 was found: being the liver
the primary source of IGF-1, this finding is consistent with the
greater susceptibility to hepatic injury observed in women follow-
ing chronic alcohol use [45].
Light to moderate alcohol intake throughout adult life is also an
important gender-associated risk factor for breast cancer [75–77]
also among those women who use postmenopausal hormones [78];
moreover during adolescent intake of alcohol appeared to increase
risk of proliferative benign breast disease [79].
Gender differences in cocaine
pharmacokinetics/pharmacodynamics
A summary of the results of clinical studies on gender differ-
ences in cocaine PK/PD relationship is shown in Table 3. Generally,
clinical studies did not find gender differences in cocaine plasma
levels either after a single dose administered intravenously [80],
or by intranasal [81,82] or smoked administration [83]. However,
Lukas et al. [84] reported that after an intranasal dose (0.9 mg/kg)
of cocaine hydrochloride, female occasional cocaine users (N = 7)
show lower drug plasma levels at the peak than men.
Again, after repeated cocaine smoking, no differences in plasma
levels of both cocaine [83] and its metabolites benzoylecgonine
and ecgonine methyl ester were found [85], except for higher ben-
zoylecgonine concentrations in women after the highest dose of
cocaine experimented (25 mg). When gender differences in cocaine
plasma levels after smoking repeated doses of 50 mg cocaine were
found [86], it could not be ruled out that this might be ascribed
to the fixed dose of cocaine, irrespective of mean body weight
differences between genders. Importantly, gonadal hormone fluc-
tuations related to menstrual cycle did not influence cocaine
plasma levels. In fact, no differences were found in women during
the follicular phase compared to the luteal phase of the menstrual
cycle after a single dose of intravenous [87] or smoked cocaine [83]
and also after repeated smoked cocaine doses [88].
When pharmacological effects of cocaine were tested, no gender
differences were again reported as far as positive subjective effects
concerned [85,86], even when body weight was taken into account
(i.e., mg cocaine/kg body weight) [81,87], yet Kosten et al. [82]
observed that following acute intranasal cocaine administration,
self-reported visual analogue “nervous” responses were greater for
women than men. Differences in the cocaine effects on heart rate
and blood pressure were disclosed by Evans et al. [86] after repeated
doses of smoked cocaine; on the contrary, a single administration
of either intravenous [87] or intranasal [82] cocaine did not yield
any significant difference in the response between genders.
As demonstrated also in non-human primates [89], unlike the
pharmacokinetics of cocaine, its pharmacodynamics is influenced
by menstrual cycle. Accordingly, the positive subjective effects of
cocaine were higher during the follicular phase compared to the
luteal phase of the menstrual cycle, when progesterone levels are
elevated [80,83,87,88]. That fluctuations in endogenous proges-
terone levels play a role in some of the differences in the effects
of cocaine observed in women was confirmed by Evans and Foltin
[85] who showed that the administration of progesterone during
the follicular phase in women attenuated the positive subjective
effects of cocaine, whereas only minimal changes were observed in
men.
To summarize, while no significant cocaine PK differences
between women and men were found, the few studies conducted in
humans exploring the role of gender and gonadal hormones on the
effects of cocaine show that pharmacological sensitivity to cocaine
may differ in relation to menstrual cycle fluctuations, and that pro-
gesterone can attenuate subjective effects of cocaine in women.
Gender differences in structural brain abnormalities associated
with chronic abuse cocaine have been also observed [90,91], includ-
ing gender-specific differences in the brain volume. A very recent
study by Rando et al. [92] gives evidence that abstinent cocaine
dependent subjects, compared with healthy controls, had smaller
grey matter volume (GMV) in a number of cortical regions and
larger GMV in the left cerebellum with a gender-specific pattern:
female cocaine dependent subjects were found to have lower GMV
in temporal, parietal and occipital cortices, while male were found
to have lower GMV in a large area of the superior frontal cortex.
Co-abuse of alcohol and cocaine
The interest in exploring gender differences in the concur-
rent use of alcohol and cocaine stems from evidence that alcohol
has important consequences on cocaine pharmacokinetics. Firstly,
alcohol inhibits demethylation of cocaine to benzoylecgonine cat-
alyzed by the hepatic carboxyesterase, permitting that higher
plasma concentrations of cocaine are maintained in presence of
alcohol [93]. Secondly, combined intake of alcohol and cocaine
results in the formation of cocaethylene (benzoylecgonine ethyl
ester) a fairly active and long-lasting metabolite homolog of
 M. Graziani et al. / Pharmacological Research 87 (2014) 60–70 65

Table 3
Clinical studies on sex difference in cocaine (Coc) pharmacokinetic parameters and pharmacodynamic effects.

Reference Primary or secondary aim Subjects Subjects N (% Subjects COC dose (route of Findings/comments
(publication year) of the study categorya female) age (years) administration)

[84] (1996) Gender differences in
plasma levels and
subjective effects after
acute Coc administration
II 14 (50) 21–35 0.9 mg/kg (intranasal) In women lower plasma
Coc levels and number of
episodes of intense good
and bad effects; in the
follicular phase peak
plasma Coc levels higher
than luteal phase

[82] (1996) Gender differences in II 34 (32) 25–42 2 mg/kg (intranasal) No gender difference in
subjective and AUC (N = 6) and in
cardiovascular responses cardiovascular response; in
to Coc women greater
self-reported “nervous”

[86] (1999) Gender differences in
subjective and
physiological effects of
repeated smoked Coc
II 20 (45) 26–43 Six 50 mg Coc base (14 min In women higher Coc
intervals), twice a day on 2 plasma level after the 6th
consecutive days (smoked) Coc dose; heart rate and
blood pressure more
elevated after the last dose
of the session; no gender
differences in acute
subjective effects

[83] (1999) Gender and menstrual
cycle effects in response to
smoked cocaine deliveries
II 44 (48) 20–45 0.4 mg/kg single and No effects of gender and
repeated (smoked as crack) menstrual cycle on plasma
Coc levels; in women lower
ratings of some of the
subjective effects and in
the luteal phase decreased
responses to some of the
subjective effects
compared with follicular
phase of menstrual cycle
and men

[80] (2001) Gender differences in
pharmacokinetic of Coc
and in women during
phase of menstrual cycle
I 34 (65)
20–30 0.2–0.4 mg/kg (i.v.) No gender difference in
Coc plasma level,
elimination half-life and
AUC or cardiovascular or
subjective effects “high”
measure and in women
during the follicular and
mid-luteal phases of the
menstrual cycle

[85] (2006) Gender difference in
relationship between
positive subjective effects
of Coc and fluctuations in
progesterone levels
II 21 (52) 27–43 Six doses of smoked Coc (0, No gender differences in
6, 12, 25 mg Coc base) at Coc and its metabolites
14 min intervals plasma levels; in women
higher benzoylecgonine
plasma levels at 25 mg; no
effect of gender on positive
subjective Coc effects; in
women in the follicular
phase positive subjective
effects greater

[81] (2007) Gender differences in I 18 (44) 25–44 0.06, 0.34, 0.69 and No gender differences in
plasma Coc levels and in 1.37 mg/kg (intranasal) Coc plasma levels and
subjective and ratings of positive
cardiovascular effects subjective effects
a
I = subjects cocaine-dependent (DSM-IV criteria); II = cocaine-user subjects.

cocaine [94–96]. In turn, formation and elimination of cocaethylene
depends on cocaine dose [97,98] and on its route of administration
[99].
Cocaethylene mimics cocaine pharmacological actions under
many conditions. In particular, it increases extracellular concen-
trations of dopamine in the nucleus accumbens, by inhibiting
its presynaptic reuptake [100]. This effect is consistent with the
repeated finding that, when compared to cocaine alone, the effects
of concurrent cocaine and alcohol use [97,101] resulted in an
enhancement and prolongation of the euphoria as well as a
decrease of paranoia and agitation [96,97]. It is worth noting that
cocaine antagonizes deficits in psychomotor performance [102]
and sedation [103] both induced by alcohol.
At the best of our knowledge, only McCance-Katz et al. [104]
examined gender differences in the effects induced by the admin-
istration of cocaine and alcohol, alone or in combination. In
this double-blind, placebo-controlled, randomized study, subjects
addicted to both cocaine and alcohol (women 47%) received
multiple doses of cocaine and/or alcohol: interestingly, the pro-
tocol was designed to reproduce a semi-naturalistic setting of
consumption, i.e. a day-long binge. Pharmacokinetic parameters
obtained by serial blood sampling, physiological measurements
 66
Table 4
Cocaethylene (CocEth): pharmacokinetic/pharmacodynamic (PK/PD) studies in humans.

Reference Aim of the study Subjects Subjects N (% Cocaine (Coc) dose (route Eth dose (route of CocEth dose (route Findings/comments
(publication year) categorya female) of administration)b administration)b of administration)b

[95] (1993) Subjective, cardiovascular I 9 (0) 100 mg (i.n.) 1 g/kg (oral) Drug combination effects: higher rates
and PK effects of Coc in of subjective good effects than Coc; an
acute alcohol intoxication increase in heart rate in comparison

M. Graziani et al. / Pharmacological Research 87 (2014) 60–70

with Coc and in blood pressure in
comparison with Eth; COC significantly
improved performance impaired by
alcohol in the simple reaction time
test. In the presence of Eth, higher Coc
plasma levels

[109] (1993) Comparison between IV 3 (0) 0.25 mg/kg Coc base (i.v.) 0.25 mg/kg CocEth: milder subjective and
cardiovascular and cocaethylene base comparable tachycardic effects than
subjective effects of CocEth (i.v.) Coc
and Coc

[110] (1994) Comparison between IV 6 (0) 0.25 mg/kg Coc base (i.v.) 0.25 mg/kg CocEth: smaller elimination rate
physiological, behavioural cocaethylene base constant, longer t1/2, lower magnitude
and PK effects of CocEth (i.v.) ratings of “high” and changes in heart
and Coc rate than Coc

[96] (1995) Comparison between III 8 (0) 0.92 mg/kg (i.n.) 0.48, 0.95 mg/kg Similar euphoric and cardiovascular
physiological, behavioural (i.n.) (heart rate, blood pressure) effects.
and PK effects of CocEth CocEth: slower clearance, smaller Vd,
and Coc longer t1/2 than Coc

[100] (1997) Subjective, cardiovascular, II 8 (0) 100 mg/kg (i.n.) 0.8 g/kg (oral) Drug combination effects: higher heart
endocrine and PK effects of rate, blood pressure, subjective effects
the combined use of Coc rate and plasma cortisol concentration
and Eth than Coc
a
i.v. = intravenous administration; i.n. = intranasal administration.
b
I = Coc and ethanol users not-dependent by DSM-IV-DSM-III criteria on drugs II = cocaine dependent subjects; III = subjects cocaine-dependent and alcohol abuser (DSM-IV criteria); IV = cocaine users.
Table 5
Cocaethylene (CocEth): pharmacokinetic/pharmacodynamic (PK/PD) studies including female subjects.

Reference Aim of the study Subjects Subjects N Coc dose (route of Eth dose (route of CocEth dose (route Findings/comments
(publication year) categorya (% female) administration)b administration) of administration)b

[111] (1998) Physiological, behavioural and III 8 (50) 4 doses of 1 mg/kg 1 g/kg following Gender data not published separately;
PK effects of concurrent use of every 30 min (i.n.) the first Coc dose; CocEth: greater subjective effects,
Coc and Eth 120 mg/k at 60 min higher heart rate and Coc

M. Graziani et al. / Pharmacological Research 87 (2014) 60–70

(oral) concentration and longer t1/2 than Coc

[98] (2000) Physiological and subjective II 6 (17) 0.25, 0.5 mg/kg 0.3, 0.6, 1.2 mg/kg Gender data not published separately.
effects and PK of CocEth using (i.v.) (i.v.) CocEth less potent than Coc in its
Coc as a comparator effects on cardiovascular and
subjective measures

[97] (2003) Pk, physiologic and subjective
effects of the combined use of
Coc and Eth
I 10 (20)
0.3, 0.6, 1.2 mg/kg 1 g/kg 1 h before 0.48, 0.95 mg/kg Gender data not published separately.
(i.v.) Coc (oral) (i.v.) Plasma concentrations, AUC,
cardiovascular and subjective effects of
CocEth increased proportionally to the
Coc. dose; effects commonly associated
with a 1.0 g/kg dose of Eth. did not
increase in the presence of Coc

[104] (2005) Gender differences in response I 17 (47) 1 mg/kg every 1 g/kg following Responses to Coc, Eth and combination
to administration of Coc and 30 min (i.n.) the initial Coc dose equivalent between genders Women:
Eth alone and in combination and a second drink higher heart rates following Eth
at 60 min (oral) administration; higher ratings for “Feel
Good” for Coc

[99] (2011) PK of CocEth formation I 6 (17) 2 mg/kg (oral) 1 g/kg before Coc 7.5 mg (i.v.) Gender data not published separately.
following Eth and Coc 1 mg/kg (i.v.) (oral) Greater formation of CocEth from the
administration by different 200 mg (smoked) oral and smoked compared to i.v.
route route; Coc and Eth combination
produced greater increases in heart
rate and rate-pressure than Coc alone
a
I = Coc and ethanol users not-dependent by DSM-IV-DSM-III criteria on drugs II = cocaine dependent subjects; III = subjects cocaine-dependent and alcohol abuser (DSM-IV criteria); IV = cocaine users.
b
i.v. = intravenous administration; i.n. = intranasal administration.

67
68 M. Graziani et al. / Pharmacological Research 87 (2014) 60–70
(heart rate and blood pressure) and subjective effects assessed
using visual analogue scales were monitored. The results showed
that responses to cocaine and alcohol, given alone or in combina-
tion were gender-independent for most measurements. However,
women reported a significant higher rating for “Feel Good” (a mea-
sure of mental/physical well-being) than men, reaching statistical
significance in the case of cocaine alone. Moreover, women showed
higher heart rates than men upon alcohol administration. Inciden-
tally, these results are consistent with experimental data showing
that female rats exhibit higher levels of motivation for cocaine
self-administration than male rats [105,106] being particularly sen-
sitive to the drug’s reinforcing effects [107,108].
None of the other studies reported in Tables 4 and 5 was aimed to
explore gender differences in PK and PD of cocaine and alcohol upon
their concurrent intake. As usual till recently [21], when female
subjects were included, data were not disaggregated for gender
and in any case sample sizes were small and did not allow explor-
ing gender-associated differences. Nevertheless, importance of not
taking a unisex approach to pharmacological aspects of interaction
between cocaine and alcohol comes from a clinical trial by Pettinati
et al. [112] evaluating the efficacy of high dose of the opioid antago-
nist naltrexone (150 mg/die) in patients with co-occurring cocaine
and alcohol dependence. The study was designed in such a way that
randomization to placebo or naltrexone groups occurred within
gender subgroups, to address the possibility of a separate evalu-
ation for women and men. The authors found that men (N = 116)
only appeared to benefit from the daily administration of naltrex-
one, whereas women (N = 48) used more cocaine during the trial
period. Moreover, although not significant, a trend indicated that
women had a lower rate of naltrexone adherence compared to men.
One of the possible explanations given by the authors was that the
observed differences in clinical responses depended from naltrex-
one side effects at 150 mg/day. Yet, a previous study [113] reported
that the exposure to naltrexone at 100 mg/die was well tolerated in
both genders. It can be suggested that at high doses of naltrexone,
the side effects experienced by women induce stopping treatment
and/or increase substance abuse. A randomized, double-blind trial
by Martinotti et al. [114] confirmed the efficacy of naltrexone at low
doses (50 mg) on alcohol drinking indices and craving in both gen-
ders. Interestingly, compared with naltrexone, pregabalin showed
a favourable trend for women. However, the authors suggest that
the mechanism involved could be less related to alcohol craving but
more associated with pregabalin anxiolytic effects, since anxiety is
frequently associated with alcohol dependence [115]. These results
emphasize the importance to stratify study participants by gender
in order to determine if gender could modify also pharmacological
responses to treatment, given that a specific gender effect has been
reported also in other forms of addiction [116,117].
Conclusion
Epidemiological data show a progressive reduction of the gap
between men and women in the abuse of psychoactive drugs.
How psychobiological and physiological peculiarities of the female
gender influence vulnerability to both drug addiction and toxico-
logical consequences of drug taking is however a line of research
still in its infancy. The present review shows that with respect to
males, females own subtle differences in the pharmacokinetics and
pharmacodynamics of both alcohol and cocaine and that these dif-
ferences may have no so subtle consequences in the natural history
of the co-abuse of the two drugs by women. These findings address
future research to the main goal of exploring gender differences
in cocaethylene PK–PD relationship. Knowledge of gender-based
differences should in turn be used to develop more appropriate
pharmacological treatments in conditions of co-abuse of alcohol
and cocaine. Therefore treatment efficacy should be designed on
the basis of gender randomization procedure, with equal-sized
study groups.
Acknowledgment
We thank Prof. Flavia Franconi for helpful comments on the
manuscript.
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