HHS Public Access

Author manuscript
Exp Clin Psychopharmacol. Author manuscript; available in PMC 2016 December 01.
Author Manuscript

Published in final edited form as:

Exp Clin Psychopharmacol. 2015 December ; 23(6): 415–421. doi:10.1037/pha0000053.

Sex differences in cannabis withdrawal symptoms among

treatment-seeking cannabis users
Evan S. Herrmann1, Elise M. Weerts1,2, and Ryan Vandrey1
1Behavioral Pharmacology Research Unit, Johns Hopkins University School of Medicine,
Baltimore, MD
2Division
of Behavioral Biology, Department of Psychiatry and Behavioral Sciences, Johns
Author Manuscript

Hopkins University School of Medicine, Baltimore, MD

Abstract
Over 300,000 individuals enter treatment for cannabis use disorders (CUDs) in the U.S. annually.
Cannabis withdrawal is associated with poor CUD treatment outcomes, but no prior studies have
examined sex differences in withdrawal among treatment-seeking cannabis users. Treatment-
seeking cannabis users (45 women and 91 men) completed a Marijuana Withdrawal Checklist
(MWC) at treatment intake to retrospectively characterize withdrawal symptoms experienced
during their most recent quit attempt. Composite Withdrawal Discomfort Scale (WDS) scores
were calculated using the 14 items on the MWC that correspond to valid cannabis withdrawal
symptoms described in DSM-5. Demographic and substance use characteristics, overall WDS
scores, and scores on individual WDS symptoms were compared between women and men.
Author Manuscript

Women had higher overall WDS scores than men, and women had higher scores than men on six
individual symptoms in two domains, mood symptoms (irritability, restlessness, increased anger,
violent outbursts) and gastrointestinal symptoms (nausea, stomach pain). Follow-up analyses
isolating the incidence and severity of WDS symptoms demonstrated that women generally
reported a higher number of individual withdrawal symptoms than men, and that they reported
experiencing some symptoms as more severe. This is the first report to demonstrate that women
seeking treatment for CUDs may experience more withdrawal then men during quit attempts.
Prospective studies of sex differences in cannabis withdrawal are warranted.

Keywords
Cannabis; Withdrawal; Sex Differences
Author Manuscript

Introduction
Cannabis is the most widely used illicit drug worldwide (World Health Organization, 2014).
In the U.S., about 9 percent of the population meets lifetime criteria for cannabis use
disorder (CUD; Haberstick et al., 2013; Stinson et al., 2006). CUD is associated with a

Corresponding Author: Evan S. Herrmann, Division on Substance Abuse, New York State Psychiatric Institute and Department of
Psychiatry, College of Physicians and Surgeons of Columbia University, New York, NY, USA, 11103, Phone: +1-646-774-6324,
FAX: +1-646-774-6141, [email protected].
 Herrmann et al. Page 2

variety of other problems, including mental illness, decreased school performance and
Author Manuscript

lifetime achievement, negative effects on brain development, and respiratory problems

(Volkow et al., 2014). Over 300,000 individuals enter treatment for CUDs in the U.S.
annually, and treatment outcomes are generally poor (Substance Abuse and Mental Health
Services Administration, 2014; Budney et al., 2007; Benyamina et al., 2008). Emerging
evidence suggests that cannabis withdrawal is a highly specific indicator of incidence and
severity of CUDs (Allsop et al., 2011), and that more severe withdrawal experiences are
associated with functional impairment during abstinence and relapse (Budney et al., 2008;
Haney et al., 2013).

A significant amount of scientific effort has been devoted to characterizing cannabis

withdrawal; laboratory and clinical outpatient studies have established the reliability,
validity, and time course of the syndrome. Individuals who abruptly quit heavy, frequent
cannabis use often experience mood-related symptoms (depressed mood, irritability,
Author Manuscript

nervousness/anxiety, restlessness, increased aggression, increased anger, violent outbursts),

gastrointestinal symptoms (nausea, decreased appetite, stomach pain), physiological
symptoms (shakiness, sweating, chills), sleep disturbance (sleep difficulty, strange/wild
dreams), and craving to smoke cannabis (American Psychiatric Association, 2013).
Withdrawal symptoms generally onset within the first 2–4 days of quitting, peak within the
first week of abstinence, and resolve within 2–3 weeks of quitting, with the exception of
strange dreams, which may persist for 30 days or longer (Kouri and Pope, 2000; Budney et
al., 2003). Studies have also demonstrated that cannabis withdrawal is similar to nicotine/
tobacco withdrawal with respect to the type and severity of symptoms (Budney et al., 2008;
Vandrey et al., 2008), suggesting it is an important factor that may both promote continuous
heavy cannabis use among individuals with CUDs and may influence treatment outcomes.
Author Manuscript

Similar to other drugs of abuse (e.g., nicotine, opioids and alcohol), several studies have
indicated that there are sex differences in the development and presentation of CUDs.
Women begin to use cannabis at a later age then men, but progress more quickly to cannabis
dependence and treatment entry (“telescoping;” Hernandez-Avila et al., 2004; Ehlers et al.,
2010; Khan et al., 2013). Despite having similar patterns of cannabis use, women seeking
treatment for CUDs have higher Severity of Dependence Scale scores than men (Copeland
et al., 2001). To our knowledge, only two studies have examined sex differences in cannabis
withdrawal (Agrawal et al., 2008; Copersino et al., 2010). Agrawal and colleagues (2008)
examined symptoms of cannabis withdrawal among individuals who reported cannabis use
during the past 12 months using data from the National Epidemiologic Survey on Alcohol
and Related Disorders. Women were more likely to report experiencing nausea, while men
were more likely to report goosebumps/pupil dilation (Agrawal et al., 2008). Copersino and
Author Manuscript

colleagues examined retrospective reports of quit attempts among non-treatment-seeking

cannabis users, and indicated that women were more likely to report nausea during the quit
attempt, while men were more likely to report craving for cannabis (Copersino et al., 2010).

The current study improves upon designs of the two prior studies that examined sex
differences in cannabis withdrawal. First, both prior studies only reported on the incidence
of cannabis withdrawal symptoms (i.e., the percentage of women and men who experienced
a given symptom), without examining overall withdrawal or individual symptom severity

Exp Clin Psychopharmacol. Author manuscript; available in PMC 2016 December 01.
 Herrmann et al. Page 3

(i.e., how uncomfortable or disruptive experienced symptoms were). Data indicate that
Author Manuscript

symptom severity predicts higher levels of functional impairment and that treatments
tailored to target specific withdrawal symptoms may be useful (Allsop et al., 2012). Thus,
characterizing sex differences in overall withdrawal and in the incidence and severity of
individual withdrawal symptoms among treatment-seeking cannabis users has the potential
to inform the development of sex-specific treatments for CUDs. Second, the two prior
reports provide little data on the frequency and intensity of use of cannabis and other
substances among the study samples. This is important because other studies have
documented differences in use of cannabis and of other drugs that may influence withdrawal
symptoms between women and men (e.g., men may use more cannabis, have more alcohol
problems, and smoke more tobacco than women; Copeland et al., 2001; Khan et al., 2013),
which could have tempered results. To address this issue, the current study utilized samples
of men and women who were well characterized regarding recent cannabis use, and
Author Manuscript

excluded individuals who met DSM-IV-TR criteria for alcohol or other drug use disorders,
allowing us to better isolate relations between sex and cannabis withdrawal. Finally, since
treatment seeking cannabis users report more withdrawal symptoms than non-treatment
seeking users (Pacek and Vandrey, 2014), the current study examined whether the sex
differences in withdrawal reported previously (Agrawal et al., 2008; Copersino et al., 2010)
generalize to cannabis users seeking treatment.

The aim of this study is to thoroughly characterize sex differences in cannabis withdrawal
among treatment-seeking cannabis users. Here, we examine the incidence and severity of
cannabis withdrawal symptoms that women and men retrospectively reported experiencing
during their most recent quit attempt. Women and men in this sample are comparable in
terms of recent cannabis use and other factors (e.g. alcohol use) that may influence
withdrawal symptoms.
Author Manuscript

Methods
Participants
Participants were frequent cannabis users presenting for treatment at an outpatient research
clinic that was conducting a clinical trial examining an investigational pharmacotherapy for
treatment of CUD. Participants were recruited for the trial via flyers, radio ads, newspaper
ads, online classifieds ads (craigslist), and word-of-mouth referrals. Participants were
recruited for the parent trial and included in the present study if they met the following
criteria: 1) were between 18 and 55 years old, 2) reported using cannabis on at least 50 of
the past 90 days, 3) were not using cannabis for medical reasons as prescribed by a
physician, 4) were interesting in quitting cannabis use within the next month, 5) reported
Author Manuscript

that cannabis helps them sleep better at night or that they have had trouble sleeping in the
past when abstaining from cannabis, 6) reported making at least one voluntary attempt to
quit cannabis in their lifetime, 7) did not report any current major medical problems (e.g.,
heart failure), 8) reported drinking less than 20 standard drinks/week, 9) did not meet DSM-
IV-TR abuse or dependence criteria for any substances other than cannabis, tobacco, or
caffeine, 10) did not meet DSM-IV-TR criteria for any current major psychiatric problem

Exp Clin Psychopharmacol. Author manuscript; available in PMC 2016 December 01.
 Herrmann et al. Page 4

(e.g. major depression, psychosis), and 11) were not enrolled in another treatment study or
Author Manuscript

taking investigational drugs.

Measures
Demographics and substance use characteristics—Participants completed a
questionnaire that collected information about basic demographic variables (e.g., age, race,
ethnicity, sex, educational attainment) and a Timeline Follow-Back (TLFB; Robinson et al.,
2014; Sobell and Sobell, 1992) interview to assess frequency and intensity of substance use
(e.g., cannabis alcohol, tobacco, opioids, etc.) during the 90 days prior to the assessment.
Since cannabis is not often administered in standardized units (i.e., the amount of cannabis
included in a “joint” or “blunt” can vary greatly from user to user), we utilized a cannabis
substitute and digital scale in order to better estimate the quantity of cannabis in each
consumption unit reported on the TLFB (Norberg et al., 2012). Participants also completed
Author Manuscript

the Marijuana Quit Questionnaire (MJQQ; Boyd et al., 2005; Copersino et al., 2006a),
which is a 176-item, individually administered, self-report questionnaire that collects data on
demographic information, cannabis use history, and information about prior attempts to quit
cannabis use (Copersino et al., 2006).

Marijuana Withdrawal Checklist—Participants who experienced at least one prior

period of cannabis abstinence completed a 29-item Marijuana Withdrawal Checklist (MWC;
Budney et al., 1999; 2003) at study intake to retrospectively assess withdrawal symptoms
they experienced during their most recent voluntary quit attempt. The symptoms included in
the MWC consists of a mixture of validated cannabis withdrawal symptoms and distractor
items: depressed mood, irritability, nervousness/anxiety, restlessness, increased aggression,
increased anger, violent outbursts, nausea, decreased appetite, stomach pain, shakiness,
Author Manuscript

sweating, sleep difficulty, strange/wild dreams, craving to smoke cannabis, diarrhea/loose

stools, dizziness, muscle spasms/aches, hiccups, stuffy nose, feverish feeling, hot flashes,
chills, increased appetite, headaches, fatigue/tiredness, yawning, difficulty concentrating,
and general physical discomfort. Participants could also write in a symptom they
experienced, but that was not listed elsewhere on the questionnaire. Participants were given
the following instructions:

“Please indicate whether or not you have experienced these symptoms and rate
their severity the last time you stopped smoking marijuana”

Participants then rated each of the 29 symptoms on a four-point scale (0=none, 1=mild,
2=moderate, 3=severe). A composite Withdrawal Discomfort Score (WDS) was calculated
as the sum of the MWC items known to be valid, reliable cannabis withdrawal symptoms
(American Psychiatric Association, 2013): depressed mood, irritability, nervousness/anxiety,
Author Manuscript

restlessness, increased aggression, increased anger, violent outbursts, nausea, decreased

appetite, stomach pain, shakiness, sweating, sleep difficulty, strange/wild dreams, and
general physical discomfort.

Data Analysis
Demographics and substance use characteristics—Demographics were compared
between women and men using independent-samples t-tests for continuous variables and

Exp Clin Psychopharmacol. Author manuscript; available in PMC 2016 December 01.
 Herrmann et al. Page 5

Fisher’s exact tests for categorical variables. Substance use data (percentage reporting use of
Author Manuscript

all substances, intensity of cannabis, tobacco, and alcohol use, and history of attempts to quit
using cannabis) was extracted from the TLFB interview and the MJQQ and were compared
between women and men using t-tests/Fisher’s exact tests.

Overall withdrawal scores—Composite WDS scores, scores on the 14 individual

validated cannabis withdrawal symptoms, and scores on “desire or craving to smoke
cannabis” were compared between women and men using t-tests. “Desire or craving to
smoke cannabis” is not typically included in composite WDS scores because it’s acceptance
as a valid symptom of cannabis withdrawal is controversial (Budney et al., 2003) and it is
not included in the DSM-V as a symptom of cannabis use disorder. Data are included here
as craving has been added a symptom for other drug use disorders, and may be relevant for
future studies.
Author Manuscript

Incidence of withdrawal symptoms—The average number of WDS symptoms

reported was compared between women and men using a t-test. The percentage of women
and men reporting experiencing each validated withdrawal symptom at some level (i.e.,
reporting “mild”, “moderate”, or “severe” and not “none”), and “desire or craving to smoke
cannabis” were compared using Fisher’s exact tests.

Severity of withdrawal symptoms—Mean scores on each validated withdrawal

symptom were calculated among the women and men who reported experiencing that
symptom to provide a metric of severity. The average severity of all WDS symptoms that
were reported and the average severity of individual symptoms reported were compared
between women and men using t-tests. All analyses were performed using SPSS v.21 (IBM
corp.), t-tests were 2-tailed, and statistical significance was determined at p < .05.
Author Manuscript

Results
Participant demographics/substance use
A total of 136 participants (45 women and 91 men) completed the screening interview, met
inclusion criteria, and were included in the present analyses. Participant demographics and
substance use characteristics are displayed in Table 1. Women and men significantly
differed on age of first cannabis use (16.0 years among women vs. 14.2 years among men, p
= 0.01) and the number of days in the past 90 days that they used cannabis (85.1 days among
women vs. 80.0 days among men, p = 0.03). Women and men did not differ in amount of
cannabis used in the last 90 days or in percentage than met DSM-IV criteria for cannabis
dependence. On average, both women and men reported several prior attempts to quit using
Author Manuscript

cannabis in their lifetime, and about three-fourths (i.e., 77% women, 70% men) reported
making at least one quit attempt within the past year. About three-fourths of women and
men reported using alcohol and tobacco at least once during the past 90 days, but were
generally light and infrequent users of these substances. A minority of participants reported
sporadic use of other substances (e.g., opioids, MDMA, etc.) in the past 90 days.

Exp Clin Psychopharmacol. Author manuscript; available in PMC 2016 December 01.
 Herrmann et al. Page 6

Marijuana Withdrawal Checklist

Author Manuscript

Overall withdrawal scores—Average scores on individual items and composite WDS

scores are displayed in Table 2. Women had significantly higher composite WDS scores
than men (mean scores of 14.9 vs. 10.6, respectively, p < 0.01). Women had significantly
higher scores than men on six individual items. These items were in two domains, mood
symptoms (irritability, increased anger, restlessness, violent outbursts), and gastrointestinal
symptoms (nausea, stomach pain).

Incidence of withdrawal symptoms—Incidence of withdrawal symptoms and the

average number of symptoms reported among women and men are displayed in Table 3.
Overall, women reported experiencing more withdrawal symptoms than men (7.9 symptoms
vs. 6.2 symptoms, respectively; p < 0.01). A greater proportion of women reported
experiencing irritability, violent outbursts, and nausea during their last quit attempt when
Author Manuscript

compared with men.

Severity of withdrawal symptoms—Symptom severity ratings among women and men

who reported experiencing each withdrawal symptom are displayed in Table 4. The average
severity of symptoms reported did not differ between women and men (mean severity
ratings of 1.81 vs. 1.66, respectively; p = 0.10). However, women who reported
experiencing nervousness/anxiety, restlessness, or increased aggression during their last quit
attempt reported that these symptoms were more severe compared with men who also
reported these symptoms.

Discussion
To our knowledge, this report is the first examination of sex differences in cannabis
Author Manuscript

withdrawal among treatment-seeking cannabis users, and the first to examine sex differences
in both the incidence and severity of cannabis withdrawal symptoms. Women and men were,
in general, well-matched on cannabis and other substance use characteristics that may have
affected withdrawal. Total withdrawal discomfort was over 40 percent higher (more half a
standard deviation) among women compared with men, and women reported more severe
withdrawal than men on six individual symptoms, which clustered in two areas, mood
symptoms (irritability, restlessness, increased anger, and violent outbursts), and
gastrointestinal symptoms (nausea, stomach pain). Women were more likely to report
experiencing an increase in irritability, violent outbursts, and nausea during cannabis
abstinence than men, and reported more symptoms in total during their last period of
abstinence compared with men. Regarding symptom severity, women who experienced
nervousness/anxiety, restlessness, and/or increased aggression reported experiencing these
Author Manuscript

symptoms more severely than men.

It is interesting that withdrawal severity was greater among women though they reported
very similar patterns of cannabis use to men, and a significantly later onset of cannabis use
compared with men. The neurobiological mechanism for this finding is somewhat uncertain,
but recent animal studies suggest a differential expression of the endocannabinoid system by
sex (e.g., Castelli et al., 2013; Craft et al., 2013) an influence of sex hormones on
cannabinoid receptor binding (Riebe et al., 2010; de Fonseca et al., 1994), and recent human

Exp Clin Psychopharmacol. Author manuscript; available in PMC 2016 December 01.
 Herrmann et al. Page 7

laboratory research suggests that women are more sensitive to acute cannabis effects than
Author Manuscript

men (Cooper and Haney, 2014). These studies provide some evidence suggesting that sex
differences in cannabis withdrawal may be biologically-mediated. However, human brain
imaging studies in this area are lacking and few controlled prospective studies evaluating the
acute and repeated effects of cannabis exposure have been adequately powered to evaluate
sex differences.

The results of this study parallel the findings of prior research conducted on cannabis
withdrawal and on other substance use disorders. Overall WDS scores and scores on
individual items observed here are comparable to the peak withdrawal scores reported
during periods of abstinence in prospective laboratory studies of cannabis withdrawal (e.g.,
Budney et al., 2003). This suggests that recall of withdrawal severity in this study was valid.
Further, the observation that women reported more severe cannabis withdrawal is consistent
with other reports on sex differences in withdrawal from alcohol (Stewart & Brown, 1995)
Author Manuscript

and tobacco (Hatsukami et al., 1995; Leventhal et al., 2007). This is potentially important
for treatment planning as findings from the larger substance abuse literature suggest women
and men differ in both withdrawal and treatment response. For example, evidence suggests
nicotine replacement therapy (e.g. Cepeda-Benito et al., 2004; Collins et al., 2004;
Hatsukami et al., 1995; Perkins, 2001; Wetter et al., 1999) and varenicline/buproprion
combination therapy (Rose & Behm, 2014) may be more effective for men than women,
while burproprion alone (Collins et al., 2004) and varenicline alone (Rose & Behm, 2014)
may be equally effective in both sexes. Since amelioration of withdrawal symptoms is
assumed to drive the efficacy of many pharmacotherapies for substance use disorders, data
on sex differences in withdrawal could be used to prospectively inform the development of
sex-specific pharmacotherapies.
Author Manuscript

That said, research on sex differences in CUD treatment response is lacking. A recent
Cochrane Review examined 14 studies of various pharmacotherapies for the treatment of
CUD (Marshall et al., 2014). Nine out of these 14 used cannabis withdrawal as an outcome
measure. Only one of these studies reported on the results of a formal comparison of
outcomes by sex (Cornelius et al., 2010), The fact that 13/14 of these studies did not
compared outcomes based by sex may at first seem surprising, however, 10/14 had samples
sizes of N=81 or less, and more than half of the trials were conducted with samples that
were 75% or more male. Thus, it is likely that the vast majority of studies examining
pharmacotherapies for CUD are not powered to detect sex differences in treatment response.
Given the sex differences in withdrawal reported here, and the sex differences observed in
response to pharmacotherapy for other substance use disorders (e.g., nicotine dependence;
Hatsukami et al., 1995; Rose & Behm, 2014), studies examining pharmacotherapies for
Author Manuscript

CUD should be appropriately powered to examine sex differences in treatment response.

This study must be considered in light of limitations. First, the study design (retrospective,
self-report) limits the conclusions that can be drawn. It is impossible to determine if the sex
differences in withdrawal we observed are true differences in withdrawal, or just differences
in the way women and men report previously experienced withdrawal symptoms (see
Pomerleau et al., 1994). Second, we did not ask women about menstrual cycle phase during
their most recent quit attempt. This may have influenced results because symptoms of

Exp Clin Psychopharmacol. Author manuscript; available in PMC 2016 December 01.
 Herrmann et al. Page 8

cannabis withdrawal overlap with many symptoms women may experience during
Author Manuscript

premenstrual and menstrual phases of the cycle. Third, it is possible that women experienced
higher levels of mood and gastrointestinal symptoms than men for reasons unrelated to
cannabis withdrawal. Women may experience greater levels of life stress than men (e.g.,
Klonoff et al., 2000), which could lead to higher levels of mood disturbances (e.g.
Fernandez-Guasti et al., 2012) and gastrointestinal disturbances (Mayer et al., 2001). Future
studies could partially ameliorate the three above-mentioned limitations by: 1) collecting
withdrawal data from participants while they are using cannabis as usual to characterize
baseline symptomatology, 2) prospectively examining gender differences in cannabis
withdrawal symptoms that occur during biochemically-verified periods of abstinence, and 3)
characterizing and/or controlling for menstrual phase during early abstinence. Fourth, the
majority of our sample was African American and resided in an urban environment. It is not
known if these findings will generalize to treatment-seeking cannabis users with different
Author Manuscript

ethnic, racial, or environmental backgrounds. Though most of the participants in the present
study reported use of other substances, mainly alcohol and tobacco, there were no gender
differences in the current pattern of other substance use in this sample. Thus, it is unlikely
that tobacco, alcohol, or other substance use impacted the study outcomes.

In summary, this study provides preliminary evidence that, among treatment-seeking

cannabis users, women experience a greater incidence and severity of mood-related and
gastrointestinal cannabis withdrawal symptoms compared with men. These findings extend
those of a prior study examining sex differences in cannabis withdrawal among non-
treatment-seeking users (Copersino et al., 2010). If the observed sex differences in cannabis
withdrawal reported here are validated by prospective studies that employ both objective
biological (e.g., neuroimaging, polysomnography) and subjective measures of withdrawal,
then the investigation of sex-specific therapeutic interventions is warranted.
Author Manuscript

References
Agrawal A, Pergadia ML, Lynskey MT. Is there evidence for symptoms of cannabis withdrawal in the
national epidemiologic survey of alcohol and related conditions? The American Journal on
Addictions. 2008; 17(3):199–208. [PubMed: 18463997]
Allsop DJ, Copeland J, Norberg MM, Fu S, Molnar A, Lewis J, Budney AJ. Quantifying the clinical
significance of cannabis withdrawal. PLoS One. 2012; 7(9):e44864. [PubMed: 23049760]
Allsop DJ, Norberg MM, Copeland J, Fu S, Budney AJ. The cannabis withdrawal scale development:
patterns and predictors of cannabis withdrawal and distress. Drug and alcohol dependence. 2011;
119(1):123–129. [PubMed: 21724338]
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5.
Washington, DC: Author; 2013.
Benyamina A, Lecacheux M, Blecha L, Reynaud M, Lukasiewcz M. Pharmacotherapy and
Author Manuscript

psychotherapy in cannabis withdrawal and dependence. 2008

Boyd SJ, Tashkin DP, Huestis MA, Heishman SJ, Dermand JC, Simmons MS, Gorelick DA.
Strategies for Quitting among Non- treatment- seeking Marijuana Smokers. The American Journal
on Addictions. 2005; 14(1):35–42. [PubMed: 15804875]
Budney AJ, Moore BA, Vandrey RG, Hughes JR. The time course and significance of cannabis
withdrawal. Journal of abnormal psychology. 2003; 112(3):393. [PubMed: 12943018]
Budney AJ, Novy PL, Hughes JR. Marijuana withdrawal among adults seeking treatment for
marijuana dependence. Addiction. 1999; 94(9):1311–1322. [PubMed: 10615717]

Exp Clin Psychopharmacol. Author manuscript; available in PMC 2016 December 01.
 Herrmann et al. Page 9

Budney AJ, Roffman R, Stephens RS, Walker D. Marijuana dependence and its treatment. Addiction
science & clinical practice. 2007; 4(1):4. [PubMed: 18292704]
Author Manuscript

Budney AJ, Vandrey RG, Hughes JR, Thostenson JD, Bursac Z. Comparison of cannabis and tobacco
withdrawal: Severity and contribution to relapse. Journal of substance abuse treatment. 2008;
35(4):362–368. [PubMed: 18342479]
Cepeda-Benito A, Reynoso JT, Erath S. Meta-analysis of the efficacy of nicotine replacement therapy
for smoking cessation: Differences between men and women. Journal of Consulting and Clinical
Psychology. 2004; 72:712–722. [PubMed: 15301656]
Castelli MP, Fadda P, Casu A, Spano MS, Casti A, Fratta W, Fattore L. Male and Female Rats Differ
in Brain Cannabinoid CB1 Receptor Density and Function and in Behavioural Traits Predisposing
To Drug Addiction: Effect of Ovarian Hormones. Curr Pharm Des. 2013
Collins BN, Wileyto EP, Patterson F, Rukstalis M, Audrain-McGovern J, Kaufmann V, Lerman C.
Gender differences in smoking cessation in a placebo-controlled trial of bupropion with behavioral
counseling. Nicotine & Tobacco Research. 2004; 6:27–37. [PubMed: 14982685]
Cooper ZD, Haney M. Investigation of sex-dependent effects of cannabis in daily cannabis smokers.
Drug and alcohol dependence. 2014; 136:85–91. [PubMed: 24440051]
Author Manuscript

Copeland J, Swift W, Rees V. Clinical profile of participants in a brief intervention program for
cannabis use disorder. Journal of substance abuse treatment. 2001; 20(1):45–52. [PubMed:
11239727]
Copersino ML, Boyd SJ, Tashkin DP, Huestis MA, Heishman SJ, Dermand JC, Gorelick DA.
Sociodemographic characteristics of cannabis smokers and the experience of cannabis withdrawal.
The American journal of drug and alcohol abuse. 2010; 36(6):311–319. [PubMed: 20678028]
Cornelius JR, Bukstein OG, Douaihy AB, Clark DB, Chung TA, Daley DC, Brown SJ. Double-blind
fluoxetine trial in comorbid MDD–CUD youth and young adults. Drug and alcohol dependence.
2010; 112(1):39–45. [PubMed: 20576364]
Craft RM, Marusich JA, Wiley JL. Sex differences in cannabinoid pharmacology: a reflection of
differences in the endocannabinoid system? Life Sci. 2013; 92:476–81. [PubMed: 22728714]
Ehlers CL, Gizer IR, Vieten C, Gilder DA, Stouffer GM, Lau P, Wilhelmsen KC. Cannabis
dependence in the San Francisco Family Study: age of onset of use, DSM-IV symptoms,
withdrawal, and heritability. Addictive behaviors. 2010; 35(2):102–110. [PubMed: 19818563]
Author Manuscript

Fernandez-Guasti A, Fiedler JL, Herrera L, Handa RJ. Sex, stress, and mood disorders: at the
intersection of adrenal and gonadal hormones. Hormone and metabolic research= Hormon-und
Stoffwechselforschung= Hormones et metabolisme. 2012; 44(8):607. [PubMed: 22581646]
Haberstick BC, Young SE, Zeiger JS, Lessem JM, Hewitt JK, Hopfer CJ. Prevalence and correlates of
alcohol and cannabis use disorders in the United States: Results from the national longitudinal
study of adolescent health. Drug and alcohol dependence. 2014; 136:158–161. [PubMed:
24440049]
Haney M, Bedi G, Cooper ZD, Glass A, Vosburg SK, Comer SD, Foltin RW. Predictors of marijuana
relapse in the human laboratory: robust impact of tobacco cigarette smoking status. Biological
psychiatry. 2013; 73(3):242–248. [PubMed: 22939992]
Hatsukami D, Skoog K, Allen S, Bliss R. Gender and the effects of different doses of nicotine gum on
tobacco withdrawal symptoms. Experimental and Clinical Psychopharmacology. 1995; 3(2):163.
Hernandez-Avila CA, Rounsaville BJ, Kranzler HR. Opioid-, cannabis-and alcohol-dependent women
show more rapid progression to substance abuse treatment. Drug and Alcohol Dependence. 2004;
74(3):265–272. [PubMed: 15194204]
Author Manuscript

Klonoff EA, Landrine H, Campbell R. Sexist discrimination may account for well-known gender
differences in psychiatric symptoms. Psychology of Women Quarterly. 2000; 24(1):93–99.
Khan SS, Secades-Villa R, Okuda M, Wang S, Pérez-Fuentes G, Kerridge BT, Blanco C. Gender
differences in cannabis use disorders: Results from the National Epidemiologic Survey of Alcohol
and Related Conditions. Drug and alcohol dependence. 2013; 130(1):101–108. [PubMed:
23182839]
Kouri EM, Pope HG Jr. Abstinence symptoms during withdrawal from chronic marijuana use.
Experimental and clinical psychopharmacology. 2000; 8(4):483. [PubMed: 11127420]

Exp Clin Psychopharmacol. Author manuscript; available in PMC 2016 December 01.
 Herrmann et al. Page 10

Leventhal AM, Waters AJ, Boyd S, Moolchan ET, Lerman C, Pickworth WB. Gender differences in
acute tobacco withdrawal: effects on subjective, cognitive, and physiological measures.
Author Manuscript

Experimental and clinical psychopharmacology. 2007; 15(1):21. [PubMed: 17295582]

Mayer EA, Naliboff BD, Chang L, Coutinho SV. V. Stress and irritable bowel syndrome. American
Journal of Physiology-Gastrointestinal and Liver Physiology. 2001; 280(4):G519–G524.
[PubMed: 11254476]
Marshall K, Gowing L, Ali R, Le Foll B. Pharmacotherapies for cannabis dependence. The Cochrane
Library. 2014
Norberg MM, Mackenzie J, Copeland J. Quantifying cannabis use with the timeline followback
approach: a psychometric evaluation. Drug and alcohol dependence. 2012; 121(3):247–252.
[PubMed: 21955364]
Perkins KA. Smoking cessation in women. CNS drugs. 2001; 15(5):391–411. [PubMed: 11475944]
Pomerleau CS, Tate JC, Lumley MA, Pomerleau OF. Gender differences in prospectively versus
retrospectively assessed smoking withdrawal symptoms. Journal of Substance Abuse. 1994; 6(4):
433–440. [PubMed: 7780301]
Riebe CJ, Hill MN, Lee TT, Hillard CJ, Gorzalka BB. Estrogenic regulation of limbic cannabinoid
Author Manuscript

receptor binding. Psychoneuroendocrinology. 2010; 35(8):1265–1269. [PubMed: 20207489]

Robinson SM, Sobell LC, Sobell MB, Leo GI. Reliability of the Timeline Followback for cocaine,
cannabis, and cigarette use. Psychology of addictive behaviors. 2014; 28(1):154. [PubMed:
23276315]
Rose JE, Behm FM. Combination treatment with varenicline and bupropion in an adaptive smoking
cessation paradigm. Am J Psychiat. 2014; 117:1199–1205. [PubMed: 24934962]
De Fonseca FR, Cebeira M, Ramos JA, Martin M, Fernandez-Ruiz JJ. Cannabinoid receptors in rat
brain areas: sexual differences, fluctuations during estrous cycle and changes after gonadectomy
and sex steroid replacement. Life sciences. 1994; 54(3):159–170. [PubMed: 8289577]
Sobell, LC.; Sobell, MB. Measuring alcohol consumption. Humana Press; 1992. Timeline follow-
back; p. 41-72.
Stewart DG, Brown SA. Withdrawal and dependency symptoms among adolescent alcohol and drug
abusers. Addiction. 1995; 90(5):627–635. [PubMed: 7795499]
Stinson FS, Ruan W, Pickering R, Grant BF. Cannabis use disorders in the USA: prevalence,
Author Manuscript

correlates and co-morbidity. Psychological Medicine. 2006; 36(10):1447–1460. [PubMed:

16854249]
Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics
and Quality. Treatment Episode Data Set (TEDS): 2002–2012. National Admissions to Substance
Abuse Treatment Services. Rockville, MD: Substance Abuse and Mental Health Services
Administration; 2014. BHSIS Series S-71, HHS Publication No. (SMA) 14-4850
Vandrey RG, Budney AJ, Hughes JR, Liguori A. A within-subject comparison of withdrawal
symptoms during abstinence from cannabis, tobacco, and both substances. Drug and alcohol
dependence. 2008; 92(1):48–54. [PubMed: 17643868]
Volkow ND, Baler RD, Compton WM, Weiss SR. Adverse health effects of marijuana use. New
England Journal of Medicine. 2014; 370(23):2219–2227. [PubMed: 24897085]
Wetter DW, Fiore MC, Young TB, McClure JB, de Moor CA, Baker TB. Gender differences in
response to nicotine replacement therapy: Objective and subjective indexes of tobacco withdrawal.
Experimental and Clinical Psychopharmacology. 1999; 7(2):135. [PubMed: 10340153]
Author Manuscript

Exp Clin Psychopharmacol. Author manuscript; available in PMC 2016 December 01.
 Herrmann et al. Page 11

Table 1

Participant Demographics and Cannabis Use History

Author Manuscript

Demographic and substance use characteristics among women (n=45) and men (n=91) included in withdrawal
analyses. Data shown are group means (±SD) or % of subjects. Groups were compared using t-tests for
continuous variables and Fisher’s exact tests for categorical variables. Significant (p < 0.05) sex differences
are highlighted with bold text.

Characteristic Women (n=45) Men (n=91) p-value

Demographics
Age (years) 34.1 (11.1) 32.5 (10.0) 0.41
Race (% Black) 87 84 0.80
Ethnicity (% Hispanic/Latino) 7 4 0.69
Education (years) 12.9 (1.5) 12.4 (1.8) 0.14
Employed (% full-time, part-time, or student) 31 43 0.2
Author Manuscript

Marital Status (% Married) 2 6 0.66

Substance use
Cannabis
Age first use (years) 16.2 (4.5) 14.2 (4.5) 0.01
Years first use to regular use 2.2 (3.8) 2.5 (3.5) 0.67
Days used in past 90 days 85.1 (9.6) 80.0 (14.1) 0.03
Amount used per day in past 90 days (grams) 3.0 (2.9) 2.8 (2.6) 0.71
Cannabis dependent (%) 80 77 0.83
Number of lifetime quit attempts 5.9 (8.7) 8.1 (15.6) 0.39
Made quit attempt in past year (%) 78 70 0.42
Other substances used in past 90 days
Tobacco (%) 76 71 0.86
Author Manuscript

Average cigaretes per day (among smokers) 5.9 (6.7) 5.9 (5.0) 0.99
Alcohol (%) 73 74 0.55
Average drinks per week (among drinkers) 4.2 (6.4) 4.6 (5.9) 0.74
Opioids (%) 2 11 0.10
MDMA (%) 7 5 1.00
Cocaine (%) 7 2 0.33
Hallucinogins (%) 2 0 0.33
Amphetamines (%) 0 1 1.00
Synthetic Cannabinoids (%) 0 1 1.00
Sedatives/Hypnotics (%) 0 0 -

Note. Cannabis dependence based on DSM-IV-TR criteria.

Author Manuscript

Exp Clin Psychopharmacol. Author manuscript; available in PMC 2016 December 01.
 Herrmann et al. Page 12

Table 2

Mean Withdrawal Scores.

Author Manuscript

Mean (±SD) Withdrawal Discomfort Scale (WDS) scores and mean (±SD) scores on individual symptoms
among women (n=45) and men (n=91). Scores were compared between women and men using t-tests.
Significant (p < 0.05) sex differences are highlighted with bold text.

Women (n=45) Men (n=91) p-value

mean WDS score 14.9 (7.9) 10.6 (6.6) < 0.01

depressed mood 1.2 (0.9) 1.0 (0.9) 0.20
irritability 1.7 (0.9) 1.3 (1.0) 0.01
nervousness/anxiety 1.0 (1.1) 0.8 (0.9) 0.25
restlessness 1.8 (1.1) 1.3 (1.0) < 0.01
increased aggression 1.0 (1.2) 0.7 (0.9) 0.07
increased anger 1.2 (1.2) 0.7 (0.9) < 0.01
Author Manuscript

violent outbursts 0.7 (0.9) 0.4 (0.8) 0.02

nausea 0.6 (0.9) 0.1 (0.4) < 0.01
decreased appetite 1.6 (1.2) 1.3 (1.1) 0.13
stomach pain 0.3 (0.5) 0.1 (0.3) 0.02
shakiness 0.3 (0.6) 0.2 (0.4) 0.11
sweating 0.5 (0.8) 0.4 (0.7) 0.25
sleep difficulty 2.3 (0.7) 2.1 (1.0) 0.05
strange/wild dreams 0.7 (0.9) 0.6 (0.9) 0.76

craving to smoke cannabis * 2.3 (0.7) 2.2 (0.9) 0.66

Note. WDS = 14-item Withdrawal Discomfort Scale. WDS sum scores range from 0 (no symptoms reported) to 42 (all 14 symptoms reported as
severe). Scores on individual symptoms range from 0 (none) to 3 (severe).
*
Craving is reported separately as it is not one of the symptoms included in the WDS total score.
Author Manuscript
Author Manuscript

Exp Clin Psychopharmacol. Author manuscript; available in PMC 2016 December 01.
 Herrmann et al. Page 13

Table 3

Incidence of Withdrawal.
Author Manuscript

Mean number of WDS symptoms reported, and the percentage of women and men who reported experiencing
each individual symptom among women (n=45) and men (n=91). Mean number of symptoms reported was
compared between women and men using a t-test and percentage reporting individual symptoms were
compared using Fisher’s exact tests. Significant (p < 0.05) sex differences are highlighted with bold text.

Women (n=45) Men (n=91) p-value

mean (±SD) number of WDS symptoms reported 7.9 (3.3) 6.2 (3.2) <0.01
depressed mood 76 64 0.12
irritability 89 73 0.05
nervousness/anxiety 51 51 1.00
restlessness 84 74 0.20
increased aggression 51 43 0.46
Author Manuscript

increased anger 60 53 0.07

violent outbursts 47 22 <0.01
nausea 40 7 <0.01
decreased appetite 73 67 0.56
stomach pain 22 10 0.07
shakiness 22 14 0.33
sweating 31 26 0.69
sleep difficulty 100 90 0.03
strange/wild dreams 47 40 0.46

craving to smoke cannabis * 100 96 0.30

Note. WDS = 14-item Withdrawal Discomfort Scale,

*
Author Manuscript

Craving is reported separately as it is not one of the symptoms included in the WDS total score.
Author Manuscript

Exp Clin Psychopharmacol. Author manuscript; available in PMC 2016 December 01.
 Herrmann et al. Page 14

Table 4

Severity of Symptoms Among Individuals Who Endorsed Them.

Author Manuscript

Mean (±SD) severity of Withdrawal Discomfort Scale (WDS) symptoms that were reported, and mean
severity scores on individual symptoms among women (n=45) and men (n=91). Scores were compared
between women and men using t-tests. Significant (p < 0.05) sex differences are highlighted with bold text.

Women Men p-value

mean severity of any WDS symptoms reported 1.81 (.05) 1.66 (0.5) 0.10
depressed mood 1.5 (0.7) 1.5 (0.6) 0.75
irritability 1.9 (0.7) 1.7 (0.7) 0.21
nervousness/anxiety 1.9 (0.8) 1.5 (0.7) 0.04
restlessness 2.2 (0.8) 1.8 (0.7) 0.02
increased aggression 2.0 (0.8) 1.6 (0.7) 0.05
increased anger 1.9 (0.7) 1.6 (0.7) 0.06
Author Manuscript

violent outbursts 1.5 (0.7) 1.6 (0.8) 0.74

nausea 1.6 (0.9) 1.3 (0.5) 0.56
decreased appetite 2.2 (0.8) 1.9 (0.7) 0.11
stomach pain 1.2 (0.4) 1.0 (0.0) 0.17
shakiness 1.3 (0.5) 1.1 (0.3) 0.18
sweating 1.7 (0.5) 1.4 (0.7) 0.17
sleep difficulty 2.3 (0.7) 2.2 (0.7) 0.46
strange/wild dreams 1.5 (0.7) 1.6 (0.7) 0.66

craving to smoke cannabis * 2.3 (0.7) 2.3 (0.8) 0.63

Note. WDS = 14-item Withdrawal Discomfort Scale. Severity scores range from 1 (mild) to 3 (severe).
*
Craving is reported separately as it is not one of the symptoms included in the WDS total score.
Author Manuscript
Author Manuscript

Exp Clin Psychopharmacol. Author manuscript; available in PMC 2016 December 01.