Exogenous Progesterone Attenuates the Subjective Effects
of Smoked Cocaine in Women, but not in Men
Suzette M Evans*,1and Richard W Foltin1
1New York State Psychiatric Institute and Department of Psychiatry, College of Physicians and Surgeons of Columbia University, New York,
In a previous study, we showed that the positive subjective effects of cocaine were higher during the follicular phase compared to the
luteal phase of the menstrual cycle. The purpose of the present study was to determine if exogenously administered progesterone during
the follicular phase in females would attenuate the response to cocaine compared to the normal follicular phase, thus making the
response to cocaine similar to the luteal phase. To address the role of sex differences, males were also administered exogenous
progesterone during one inpatient stay. In all, 11 female and 10 male non-treatment-seeking cocaine smokers participated. Females had
three inpatient stays: one during a normal follicular phase, one during a normal luteal phase, and one during a follicular phase when
exogenous progesterone was administered. Males had two inpatient stays: one when exogenous progesterone was administered and the
other when placebo was administered. During each inpatient admission, there were four smoked cocaine administration sessions:
participants were administered six doses of cocaine (0, 6, 12, or 25mg cocaine base) at 14min intervals. Smoked cocaine increased heart
rate, blood pressure and several subjective effects such as ‘good drug effect’ and ‘drug quality’ cluster scores. Administration of
progesterone during the follicular phase in women attenuated the positive subjective effects of cocaine, whereas only minimal changes
were observed in men. These results indicate that progesterone modulates the response to cocaine in women and suggests that
fluctuations in endogenous progesterone levels account for some of the sex differences observed in humans.
Neuropsychopharmacology (2006) 31, 659–674. doi:10.1038/sj.npp.1300887; published online 7 September 2005
Keywords: cocaine; humans; sex differences; menstrual cycle; progesterone; subjective effects
Numerous preclinical studies have documented that female
rodents are more sensitive than male rodents to several
behavioral effects of stimulant administration (eg Roberts
et al, 1989; Sell et al, 2000), and these differences are related
to gonadal hormone levels in females (eg Roberts et al,
1987; Grimm and See, 1997; Quin ˜ones-Jenab et al, 1999; also
see review by Lynch et al, 2002). Several studies have
demonstrated that the greatest increase in behavioral
activity when stimulants are administered to female rodents
occurs during estrus compared to other phases of the
estrous cycle (Becker et al, 1982; Becker and Cha, 1989;
Diaz-Veliz et al, 1994; Quin ˜ones-Jenab et al, 1999; Sell et al,
2000). For example, during estrus, female rats (1) have
higher progressive ratio breakpoints for cocaine self-
administration (Roberts et al, 1989; Hecht et al, 1999), (2)
show greater disruptions in the regulation of cocaine self-
administration (Lynch et al, 2000), and (3) select the highest
cocaine dose (Lynch et al, 2000). Ovariectomy has been
shown to reduce the behavioral effects of stimulants (Becker
et al, 1982; Camp et al, 1986; Roberts et al, 1987; Haney
et al, 1994; Sircar and Kim, 1999), whereas exogenously
administered estradiol has been shown to restore or
enhance the behavioral effects of stimulants in ovariecto-
mized female rodents (Castner et al, 1993; Grimm and See,
1997; Sircar and Kim, 1999; Sell et al, 2000; Hu and Becker,
2003), including cocaine self-administration (Lynch et al,
2001; Hu et al, 2004; but see Caine et al, 2004).
Thus, the prevailing evidence in the preclinical literature
using laboratory rodents is that the differences in response
to stimulants observed between males and females are
related primarily to the ovarian hormone estrogen (see
reviews by Lynch et al, 2002; Mello and Mendelson, 2002;
Carroll et al, 2004; Festa and Quin ˜ones-Jenab, 2004).
However, while many of the increases in the reinforcing
effects of cocaine are observed during estrus in rodents,
both estradiol and progesterone levels are relatively low
during estrus (similar to the early follicular phase in human
females) and actually peak during proestrus (Butcher et al,
1974; Smith et al, 1975). There is increasing evidence in
laboratory animals that progesterone also modulates the
Online publication: 4 August 2005 at http://www.acnp.org/citations/
Received 17 March 2005; revised 18 July 2005; accepted 19 July 2005
*Correspondence: Dr SM Evans, New York State Psychiatric Institute
and Department of Psychiatry, College of Physicians and Surgeons
of Columbia University, 1051 Riverside Drive, Unit 66, New York,
NY 10032, USA, Tel: +1 212 543 5895, Fax: +1 212 543 6018,
Neuropsychopharmacology (2006) 31, 659–674
& 2006 Nature Publishing GroupAll rights reserved 0893-133X/06 $30.00
effects of stimulants, but the findings have been incon-
sistent. For instance, in one study (Quin ˜ones-Jenab et al,
2000), ovariectomized female rats pretreated with estrogen
plus progesterone exhibited a reduction in cocaine-induced
locomotor activity compared to female rats pretreated with
estrogen alone. In contrast, another study (Sell et al, 2000)
showed that ovariectomized female rats pretreated with
estrogen or estrogen plus progesterone showed an enhance-
ment in cocaine-induced locomotor activity compared to
female rats pretreated with progesterone alone. Further, in a
recent study, progesterone administration to ovariecto-
mized female rats blocked the conditioned place preference
for cocaine, whereas estrogen plus progesterone adminis-
tration enhanced the conditioned place preference (Russo
et al, 2003).
Sex differences in humans following cocaine administra-
tion have generally been more subtle (eg Kosten et al, 1996;
Lukas et al, 1996; Evans et al, 1999; Sofuoglu et al, 1999).
While Haney et al (1998) showed that human females had a
higher progressive ratio breakpoint for intravenous cocaine
than males, that study did not address or control for
menstrual cycle phase. Among studies in humans that have
addressed the role of menstrual cycle phase, several have
shown that the positive subjective effects of stimulants are
greater during the follicular phase than the luteal phase
(Justice and de Wit, 1999; Sofuoglu et al, 1999; Evans et al,
2002; but see Lukas et al, 1996; Mendelson et al, 1999).
Therefore, based on the limited human data available, in the
presence of estradiol and in the absence of progesterone (ie
the follicular phase), the effects of cocaine or amphetamine
appear to be increased compared to the luteal phase
(characterized by elevated estradiol and progesterone
levels). While the data in humans suggest that the increased
response to stimulants is due primarily to estradiol, the
evidence supporting this is not so straightforward. In one
study, Justice and de Wit (1999) found that the increased
response to amphetamine was related to estradiol levels in
the follicular phase, but not in the luteal phase. However, a
subsequent study from the same laboratory (Justice and de
Wit, 2000a) found minimal differences in response to
amphetamine between the early and late follicular phases of
the menstrual cycle, despite significantly higher estradiol
levels in the late follicular phase. Further, even high doses of
exogenously administered estradiol in the early follicular
phase produced minimal changes in the response to
amphetamine (Justice and de Wit, 2000b).
There is growing evidence in humans that progesterone
may reduce the behavioral effects of stimulants. When
compared to males, females in the follicular phase reported
a similar increase in positive subjective effects following
amphetamine, whereas during the luteal phase the response
in females was reduced compared to the follicular phase or
to males (White et al, 2002). Similarly, Sofuoglu et al (1999)
reported that ratings of ‘high’ were comparable following
smoked cocaine in men and follicular-phase women, but
were significantly lower in luteal-phase women compared to
follicular-phase women. In a subsequent study conducted
only in females (Sofuoglu et al, 2002), oral progesterone
attenuated the subjective effects, but not the cardiovascular
effects, of smoked cocaine during the follicular phase.
Lastly, in a mixed-gender sample, oral progesterone
administration attenuated cocaine-induced increases in
diastolic blood pressure and several positive subjective
effects of cocaine, but did not alter intravenous cocaine self-
administration (Sofuoglu et al, 2004). At this time, it is
unclear whether the differential response to stimulants in
females is due primarily to estradiol enhancing the effects of
stimulants or due primarily to progesterone attenuating the
effects of stimulants, or a more complex interaction between
the two hormones.
The purpose of the present study was to address the
possible mechanism underlying the menstrual cycle differ-
ences observed in females in response to cocaine by
extending and improving upon the recent findings in
humans suggesting that oral progesterone administration
reduces the response to cocaine. The strengths of the
present study are that (1) a full dose–response function for
smoked cocaine (0, 6, 12, and 25mg cocaine base) was
determined; (2) repeated doses of smoked cocaine (six
within a session) were administered; (3) females were tested
twice in the follicular phase (once in the presence of
exogenous progesterone and once during a normal folli-
cular phase) and in the normal midluteal phase of the
menstrual cycle; and (4) to address the role of sex
differences, males were also administered exogenous
progesterone and placebo under the same experimental
MATERIALS AND METHODS
Eleven female research volunteers (10 African-American
and one Hispanic), 27–43 years of age (mean¼38), and 10
male research volunteers (nine African-American and one
Hispanic) 28–42 years of age (mean¼37), with current
histories of smoking cocaine were solicited through news-
paper advertisements in New York, NY. Females reported
currently spending $100–1000 (mean¼$443) per week on
cocaine and using cocaine an average of four days each
week. Men reported currently spending $150–350 per week
on cocaine (mean¼$228) and using cocaine an average of 4
days each week. All participants reported smoking tobacco
cigarettes, with females smoking an average of nine
cigarettes/day and males smoking an average of 12
cigarettes/day. Men and women had similar education
levels (mean of 12.5 years for females and 11.9 years for
males). Although females were slightly heavier than males,
with females having a mean body mass index (BMI) of 28.6
(17–37) and males having a mean BMI of 25.5 (23–28), this
was not statistically significant. All participants were
medically and psychiatrically healthy based on a physical
examination, electrocardiogram, chest X-ray, complete
blood chemistries (including pseudocholinesterase levels),
urinalyses, and a structured clinical interview to assess
DSM-IV Axis I disorders (SCID I; First et al, 1994). None
were receiving psychiatric treatment or seeking treatment
for their drug use, and none of the participants were using
hormonal contraceptives, or any other prescription medica-
tion. Also, women were not pregnant (based on blood
pregnancy tests) or nursing, and had not had an abortion or
been pregnant within the previous 6 months. Lastly, none of
the female participants suffered from premenstrual dys-
Progesterone effects on cocaine in humans
SM Evans and RW Foltin
Each participant signed a consent form, approved by
the Institutional Review Board of The New York State
Psychiatric Institute. The consent form described the study,
outlined possible risks, and indicated that cocaine would be
administered, possibly on a daily basis. Participants were
paid for their participation in multiple weekly payments not
to exceed a value of $300 each week.
Design and Experimental Procedures
After signing the study consent form, all participants began
filling out daily rating forms each evening; they were paid to
report to the laboratory twice a week to return completed
forms and pick up new forms. For females, this was done to
ensure continued outpatient contact in order to monitor the
menstrual cycle and schedule the various inpatient phases.
The forms asked questions related to various aspects of
daily mood and physical symptoms that vary across the
menstrual cycle and females indicated whether they were
menstruating. Female participants
tracked for several weeks before the first inpatient
admission, and throughout the study, to determine
menstrual cycle length and time of ovulation. They were
instructed to notify the research nurse when menstruation
started. During the midfollicular phase, female participants
provided daily urine samples to determine the time of
ovulation using OvuQuicks(QUIDEL Corp., San Diego,
CA; Martini et al, 1994). This test is simple to use and is
96–99% accurate at detecting luteinizing hormone (LH)
in urine. The day of ovulation was used to schedule the
midluteal admission. To provide consistency, males filled
out a comparable daily rating form (excluding questions
regarding menses), and where appropriate questions were
modified (eg breast tenderness for females became skin
tenderness for males).
Participants were admitted to the NIH-funded Irving
Center for Clinical Research. While residing on the Clinical
Research Center, all participants had access to television,
radio, and video-taped movies, but were not permitted to
leave the unit unless accompanied by a staff member.
Participants who smoked tobacco cigarettes were allowed to
smoke throughout their inpatient stay. However, smoking
was not allowed during experimental sessions, which lasted
approximately 2.5h each.
Female participants were admitted to the unit for 4 days
(three nights) on three separate occasions. Two inpatient
admissions were scheduled during the follicular phase so
that cocaine administration sessions occurred between 6–10
days after the onset of menstruation. One follicular phase
was normal (elevated estradiol and negligible progesterone
levels), and the other follicular phase was designed to mimic
a midluteal phase by administering oral micronized
progesterone. The third inpatient admission was scheduled
during a normal midluteal phase (approximately 7–12 days
after the urinary ovulation test kit indicated that ovulation
had occurred) characterized by elevated estradiol and
progesterone levels. Male participants were admitted to
the unit for 4 days (three nights) on two separate occasions,
spaced 2–3 weeks apart. Half of the males were adminis-
tered oral micronized progesterone during the first admis-
sion and half were administered placebo during the first
admission. For both females and males, the day following
each inpatient admission, participants engaged in labora-
tory sessions twice each day for 2 days and were discharged
on the fourth inpatient day.
The dose of oral micronized progesterone selected was
chosen to produce progesterone levels comparable to those
observed during the normal midluteal phase of the
menstrual cycle in females. Oral micronized progesterone
is commercially available as Premarinsin 100- or 200-mg
doses. A pharmacokinetic study (Simon et al, 1993) showed
that the 100mg dose produced lower progesterone levels
(approximately 6.5ng/ml) and the 200mg dose produced
higher progesterone levels (13.8ng/ml) than the normal
midluteal levels observed in one of our previous studies
(10.0ng/ml; Evans et al, 2002), suggesting the need for an
intermediate dose of 150mg. This was accomplished by
having oral micronized progesterone compounded by the
Women’s International Pharmacy as 50mg capsules. During
each inpatient phase, participants were administered
150mg oral micronized progesterone or matching placebo
capsules at 2300h on the evening before the first cocaine
session since steady-state levels are reached after the second
dose (de Lignieres, 1999). Then, on the next two consecutive
days, participants were administered 150mg oral micro-
nized progesterone or matching placebo capsules at 0700
and 1100h, approximately 2h before each cocaine session,
since oral micronized progesterone levels peak in 1–3h
(Simon et al, 1993). Even though the mean terminal half-life
for doses between 100–300mg oral micronized progester-
one is between 16–18h (Simon et al, 1993), dosing was done
before each session since some studies have shown that
progesterone levels can start declining within 4h after
administration (Maxson and Hargrove, 1985).
During each inpatient phase, cocaine administration
sessions occurred at 0900h and again at 1300h on two
consecutive days, for a total of four sessions. During each
session, participants were administered up to six doses of
smoked cocaine (either 0, 6, 12, or 25mg cocaine base
depending on the session) at 14-min intervals. The dose
order within each phase was randomized and the dose order
across the phases was not identical for a given individual.
During experimental sessions, each participant was seated
in a comfortable lounge chair in front of a computer
monitor on which subjective-effects questions were dis-
played. A computer mouse was used for completion of the
subjective-effects questionnaires. An 18-gauge catheter
(Quik-Caths, Travenol Laboratories, Deerfield, IL) was
inserted into a subcutaneous vein in one arm for blood
collection. An electrocardiogram was continuously mon-
itored via chest electrodes (MAC PCs, Marquette Electro-
nics, Milwaukee, WI), while heart rate and blood pressure
were recorded every 2min (Sentry IIFModel 6100 auto-
mated vital signs monitor, NBS Medical, Costa Mesa, CA)
beginning 20min prior to drug administration. A Macin-
tosh computer located in an adjacent room was used for
automated data collection.
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