1. Women and Substance Abuse
Elena Volfson, MD, MPH
Addiction Psychiatrist
Clinical Assistant Professor of Psychiatry
Perelman School of Medicine
University of Pennsylvania
03/16/2012

2. Disclosure
• Dr. Volfson has no financial interest
to disclose

3. Outline
• Updates in general addiction neurobiology
• Gender differences in epidemiology and
neurobiology
• Hormones and substance abuse
• Gender differences
acquisition, escalation, dependence, withdraw
al, relapse and treatment
• Gender differences in pharmacotherapy of
substance use

4. Quoted from multiple sources
WHO 2002

5. Model of Addiction
Emotion Control
Temporal - Parietal Orbital Prefrontal Cortex
Reward / Craving
Euphoria
Ventral Tegmentum Nucleus Accumbens
Memory
Hippocampus
5 Used with permission from David Oslin, 2012

6. Model of Addiction
Emotion Control
Antidepressants 12 Step / CBT
Mood Stabilizers
Therapy
Reward / Craving
Euphoria
Naltrexone Naltrexone
Acamprosate Acamprosate
Memory
6 Used with permission from David Oslin, 2012

7. Addiction is a Compulsive Relapsing
Disorder
Two essential features:
• impaired ability to regulate the drive to
obtain and use substances
• reduced drive to obtain natural rewards
Change in the reward circuitry : substances
usurp normal learning circuitry to create
the pathology of addiction
Kalivas and O’Brien, 2008

8. Vulnerabilities in Development of
Addiction
• Genetic
• Developmental
• Social
• Drug-induced brain plasticity

9. Core Addiction Syndrome
• Common neuroplastic changes in
response to chronic administration of
different substances of abuse
• Addiction is “overlearned “ with
repeated associations between
substances and life events mediated by
dopamine release
• Addictive behaviors and chronic relapse
vulnerability are maintained by
glutamatergic neurotransmission
Kalivas and O’Brien, 2008

10. Core Addiction Syndrome
• Hypofrontality- subcortical glutamatergic
connections assume primacy and reduce
cortical control over drug-seeking
(automatic behavior)
• Drug-associated stimuli activate PFC
excessively, whereas natural reinforcers
(sex, food, danger etc.) elicit poor
response - maladaptive process

11. Staged Neuroplasticity of Addiction
• Abstinence
• Social Use
• Chronic Use
• Regulated relapse – conscious choice
• Compulsive relapse- inability to make a
conscious choice
(Kalivas and O’Brien 2008)

12. Neurobiological Changes with
Chronic Substance Use
• Motivation/reward system DA/endorphine
• Glutamate/GABA dysregulation
• HPA axis dysregulation
• Hypofrontality
• Sex hormones dysregulation
• Cravings
• Relapse

13. Pharmacologic Strategies to Treat
Addiction
• Dopaminergic (D1-D5)
• Glutamatergic (NMDA, AMPA, KA, metabotropic)
• GABA ergic (GABA A and B)
• Cholinergic (Ach M and N)
• Noradrenergic (Alpha and beta)
• Serotonergic (14 subtypes)
• Endogenous opioids (mu, delta, kappa, OFQ-N)
• Endogenous cannabinoids (CB1 and CB2)
• Many others (NPY, DARPP-32, galanin, orexin, CRF,
substance P, melanocortins, leptin, BDNF etc.)

14. Complexity of Gender Research
Apples to Apples?
• Menstrual cycle: 2-6 phases vs none
• Hormones <> substance use
• Stress <> substance use
• Multiple stages of substance use from
recreational to dependence

15. Gender Differences in Brain
• Structural
• Functional

16. Why Are Male and Female Brains
Different?
• Chromosomal sex determines gonadal sex;
gonadal hormones influence brain
development
• Hormones released are different between
males and females
• Hormone-Environment Interactions:
developmental and adult differences

17. Epidemiology

18. Substance Dependence or Abuse in the Past
Year, by Age and Gender: NSDUH 2010

19. NSDUH 2010: Alcohol Use by Gender

20. SUBSTANCE USE BY WOMEN, 2008
Past year Past month
Cigarettes 25.3% 21.7%
Alcohol 62.3% 45.9%
Binge (5+ drinks/day >1 day per month) -- 15.4
Heavy use (binge drinking >5 days per month) -- 3.4
Illicit Drugs 12.2% 6.3%
Marijuana & hashish 8.3 4.4
Prescription Drug Misuse 5.8% 2.4%
Pain relievers 4.3 1.8
Tranquilizers 2.2 0.8
SAMHSA. National Survey on Drug Use and Health, 2008. 20

21. NSDUH 2010: Tobacco Use by Pregnancy Status in
Women of Reproductive Age

22. Substance Use by Pregnant Women
• Of women in their first trimester, 19% used
alcohol, 22% used cigarettes, and 5% used marijuana
in the past month
• Of women in their second or third trimester, 1 in 7
used cigarettes
• Stimulants are primary drug for which pregnant
women seek treatment
• 65% of women relapse within 6 months of delivery
Greenfield et al. Psychiatr Clin North Am. 2010;33:339-55; SAMHSA. Substance Use among
Women During Pregnancy and Following Childbirth, 2009.
22

23. Substance Use by Lesbian/Bisexual Women
• Higher and riskier alcohol use
• Spend more time socializing in bars and party settings, and
drink more in these settings
• More IV drug use among bisexual women
• Mental health and substance use disorders may result, in part,
from stress related to sexual minority status
• Good news:
– Lesbian and bisexual women are twice as likely as
heterosexual women to receive treatment for mental health
or substance use disorders
Grella et al. BMC Psychiatry2009;9:52. 23

24. Initiation of Drug Use by Substance NSDUH 2010

25. Multiple studies demonstrate higher
rates of substance abuse and
dependence in males as compared
to females…

26. Are females less vulnerable to
substance abuse than males?
If given the opportunity, females are at least as
likely as males
• to use drugs and alcohol
• to become dependent
Lower prevalence of substance abuse in females
is explained by less exposure and fewer
opportunities

27. Opportunity to Use Drugs
70
60 Male
50 Female
40
Percent
30
20
10
0
Marijuana Cocaine Hallucinogens Heroin
Van Etten et al. (1999) -- 1993 NHSDA

28. Percent Use Given an Opportunity
80
Male
70
Female
60
50
Percent
40
30
20
10
0
Marijuana Cocaine Hallucinogens Heroin
Van Etten et al. (1999) -- 1993 NHSDA

29. Males And Females Are Equally Likely
To Become Dependent On
• Cocaine • Inhalants
• Tobacco • Hallucinogens
• Opioid Analgesics
• Heroin
Anthony et al. (1994)

30. Gender Differences in Dependence
Potential
Males are more likely to Females are more likely
become dependent on to become dependent on
• Marijuana • Anxiolytics
• Alcohol • Sedatives
• Hypnotics
Anthony et al. (1994)

31. Telescoping: Risk of Dependence is
Greater for Females
• Westermeyer et al, 2000 has demonstrated
telescoping phenomenon in females for tobacco,
caffeine, alcohol, cannabis, opiate, sedative, cocaine,
inhalant, amphetamine, hallucinogen and PCP
• Rate of escalation and rate of consumption are
greater, more severe dependence
• Within 24 months of cocaine use females were 3-4
times more likely than males to become dependent
(O’Brien and Anthony, 2005)
• Girls develop tobacco dependence symptoms faster
than boys (DiFranza et al, 2002)

32. Animal Models Confirm Greater
Female Vulnerability
• Females compared to males, self-administer more alcohol
( Hill, 1978; Lancaster & Spiegel, 1992); caffeine (Heppner et al., 1986), cocaine(Morse et
al., 1993; Matthews et al., 1999; Lynch & Carroll,1999; Hu et al., 2004), fentanyl(Klein et al.,
1997), heroin (Carroll et al., 2001), morphine(Alexander et al, 1978; Hill, 1978; Cicero et
al, 2000), nicotine (Donny et al., 2000), cannabinoids (Fattore, 2007)
• Females acquire stronger cocaine-induced conditioned
place preference quicker and at lower doses (Russo et al., 2003a;
Russo et al., 2003b)
• Females acquire self-administration faster than males (Lynch
& Carroll, 1999; Donny et al., 2000)

33. Gender Differences in Animal Models
• Due to circulating estrogens and
progesterones?
• But gonadectomized female rats continued
to acquire self-administration faster and
used more cocaine than both intact and
castrated males (Hu et al, 2004; 2008)
• Sexual dimorphism in brain organization
during early development due to
chromosomal sex and gonadal hormones
(Reisert et al, 1990; Kolbinger et al, 1991; Carruth et al, 2002)

34. Menstrual Cycle
34

35. Estrogen Effects on the Brain
• Estrogen enhances cholinergic and
glutamatergic systems leading to brain
activation in both male and female brains
• Memory, learning, cognitive function
• MRI shows increase blood flow to the brain in
response to estrogen
LeBlanc ES. JAMA 2001;285:1489-99; Resnick SM. J Clin Endocrinol Metab 2006;9:1802-10.
35

36. Estrogen Effects on the Brain
• Estradiol enhances dopamine (DA) release
through several mechanisms:
1. Enhances DA receptors activity
2. Potassium – induced mechanisms
3. GABAergic neurons inhibitionBecker and Hu, 2008
• Activation of HPA axis

37. Progesterone Effects on the Brain
• Progesterone and its metabolite,
allopregnanolone (ALLO), produces a sedating,
calming effect via GABA A receptors
• ALLO is anxiolytic, anticonvulsant, and
anesthetic
• Serotonine facilitates the metabolism of
progesterone into ALLO
• HPA axis deactivation
37

38. Estrogens and Substance Abuse
Vulnerability
• Enhanced drug seeking and subjective effects
of substances in women are associated with
higher levels of endogenous estrogens (Evans 2007,
Terner and De Wit 2006)
• Greater increase in dopamine induced by
substances of abuse in females results in more
robust ‘down-stream’ changes in the brain,
and greater liability for addiction (Hu and Becker,
2008)
• Telescoping phenomenon

39. Effects of Estradiol on Substance Use
in Animal Models
• Estradiol enhances and tamoxifen (estradiol
antagonist) inhibits acquisition of cocaine self-
administration in female rats, but not in male
rats (Becker, 2005)
• Pretreatment with estradiol changes
behavioral sensitization to cocaine (Hu and Becker,
2003)

40. Differences in Behavioral
Response in Males and Females i
Hu and Becker, 2008

41. Progesterone and Substance Abuse
Vulnerability
• Progesterone attenuates dopamine release and
responses to drugs of abuse
• Progesterone inhibits cocaine self-administration
(Jackson et al, 2006)
• Women treated with progesterone showed a decrease in
the positive subjective effects of cocaine ( Evens, 2006,
Sofuoglu, 2004)
• High circulating plasma levels of progesterone are
associated with decreased cravings following drug and
stress-related cues (Sinha, 2007)

42. Menstrual Cycle and Substances Of
Abuse
• Women reported higher enjoyment of cocaine
during follicular phase vs. luteal phase (Evans et
al, 2002) and lower ratings of “feeling high” during
the luteal phase (Sofuoglu et al, 1999)
• Women reported more positive subjective effects
of oral D-amphetamine during follicular vs. luteal
phase (Justice & de Wit, 1999)
• Women may be more vulnerable to relapse
during the follicular as compared with luteal
phase (Wilcox and Brizendine, 2006)

43. Gender Differences in Response to
Stress
• Uncontrollable stress increases drug self-
administration in animals and humans (Stewart et
al, 2000; Kosten et al, 2000; Koob et al, 2001; Sinha, 2001; de Wit et al, 2003)
• Gender differences in the neurobiological
response to stress (Fox and Sinha, 2009)
• Stress (high cortisol level) sensitizes the reward
circuitry to the pleasurable effects of the
substances and increases cravings (Sinha et al, 2006;
Sinha, 2007; Shalev et al, 2002; Stewart, 2000)
• Cortisol level varies across the menstrual cycle (
Nepomnaschy et al, 2011)

44. Mood Changes Across the Menstrual
Cycle
44

45. Brain Function Variability in Normal Women
is Controlled by Ovarian Hormones
• Mood: 20%
• Verbal performance: 25%
• Sexual interest: 30%
• Visual-spatial performance: 20%
Research and treatment studies have to
control for days of the menstrual cycle !!!
Brizendine L. The Female Brain. Morgan Road/Broadway Books 2006. 45

46. PMDD
• Normal levels of estrogen, progesterone,
gonadotropins, prolactin, cortisol and thyroid
• Women with PMDD react abnormally to
normal hormone levels due to dysfunctions in
serotonergic and GABAergic systems
• Seasonal variation in symptom severity due to
lower serotonin levels in fall and winter
Maskall et al. Am J Psychiatry 1997;154:1436-41.
Praschak-Rieder et al. Arch Gen Psychiatry 2008;65:1072-8. 46

47. Disorders with Premenstrual
Exacerbation (Catamenial Disorders)
• Mood • Seizures
• Anxiety • Allergies
• Psychosis • Asthma
• Migraines • Sleep
• Substance Use • Pain

48. PMDD and Substance Use
• GABA A and endorphine withdrawal state –
self medication
• Women with PMDD drink more heavily than
controls and have higher rates of alcohol
abuse and dependence (Tobin et al, 1994; Halliday et al,
1986; Mello et al, 1990; Allen, 1996; Sutker et al, 1983; Russel et al, 1986;
Svikis et al,2006)
• Benzodiazepines, opioids, barbiturates

49. Gender Differences in Brain Imaging
• In response to cues more areas are activated
in females
• Substance-induced brain shrinkage may be
greater in females
• Substance-induced perfusion deficits are
greater in males
• More neuronal damage and white matter
changes in males

50. Female smokers are much more sensitive to
cigarette cues than male smokers
3.5
3.0
Females
2.5
2.0
1.5
N = 5 Female Smokers - 6 NonSmoking Females
1.0
.5
Males 0
T Value
N = 6 Male Smokers - 5 NonSmoking Males
T. Franklin, 2010

51. Differences in Initiation and Use
Alcohol  Women drink to cope with stress, negative emotions; men
drink to enhance positive emotions or conform to a group
Stimulants  Women are attracted to meth for weight loss, increased
energy & control of depressive symptoms
 Over 70% of meth-dependent women report hx of abuse
Opiates  Women more likely to hoard unused meds and use
additional drugs (e.g., sedatives) to enhance Rx opioids
Heroin /  Women likely to be introduced to substance by a partner
IV drugs  Use less for shorter periods of time than men
 Less likely to inject; more likely to share preparation
equipment
Tobacco  Women have more difficulty quitting
 More susceptible to proximal cues paired with smoking
 Worry 2x as much about weight gain; relapse 3x more
often than men
Greenfield et al. Psychiatr Clin North Am. 2010;33(2):339-55; UCLA Integrated Substance 51
Abuse Programs. Methamphetamine.org. 2006-2010.

52. Differences in Relapse
Women relapse for different reasons than men
• Stress, weight gain, negative emotions
• Untreated psychiatric disorders, especially depression
and trauma-related symptoms (PTSD)
• Intimate partner issues
• Issues with children or ongoing parenting
• Isolation and poor social support
Greenfield et al. Psychiatr Clin North Am. 2010;33(2):339-55. 52

53. Gender Differences in Medical
Consequences of Substance Use
• Females have higher rates of liver problems
including cirrhosis, HTN, anemia, GI problems
• Higher rates of HIV and STDs
• Higher risk of breast cancer and heart disease
• Higher risk of lung cancer and COPD
• Higher rates of infertility, repeat miscarriages
and premature delivery

54. Gender Differences in Co-Occurring
Disorders
• Women with substance abuse show higher rates of
major depression, social phobia, post-traumatic stress
disorders, and eating disorders compared to men (Denier
etal, 1991; Fornari et al, 1994; Grealla et al, 1996, Merikangas et al,1998; Najavits et
al,1997, Sonne et al, 2003; Westermeyer et al,1996)
• Lifetime eating disorders co-occur with substance
abuse disorders in up to 40% of women (Godfrey et al, 2007;
Greenfield et al, 2010)
• Alcohol dependent women show higher comorbidity
in all diagnoses except for antisocial personality and
pathological gambling (higher in alcoholic men)

55. Mood Disorders: Gender Differences
• 2 : 1 ratio female to male
• In 165 cultures, it varies (1.7-2.2) : 1
• Remarkably stable across cultures
• Ratio in childhood is 1 : 1
• 2 : 1 with onset of puberty and continues to be
that way throughout life
55

56. Gender Differences in Co-Occurring
Disorders
• Women have a primary mental health disorder that
antedates the onset of substance abuse disorder
more often than men(Kessler, 2004)
• Women with depression were more than seven
times as likely as women without depression to have
alcohol dependence at 2-year follow up. In men,
there was no difference (Gilman and Abraham,2001)
• Women with a hx of MDD were twice as likely to
relapse to smoking at 1 year follow up as compared
to women without depression (Oncken et al, 2007)

57. Gender Differences in History of
Victimization and Violence
• Early life stress, childhood sexual abuse are more
common in girls than boys (Kendler et al, 2000)
• Prevalence rates of intimate partner violence among
women in drug treatment ranges 25-57% in contrast
with non-drug using women’s 1.5-16% (El-Bassel et
al,2000; Caetano et al, 2001; Tjaden et al, 1998)
• Lifetime rates of physical (71.3%) and sexual abuse
(44.5%) and PTSD (19%) are often found in drug-
dependent pregnant women (Moylan et al, 2001; Velez et
al, 2006)

58. Gender Differences in Nicotine
Metabolism
• Faster in women than men
• Equal in men and post-menopausal women
• Faster in women on oral contraceptives (OC)
than not on OC (Benowitz et al, 2006)
• Faster in pregnant women than non-pregnant
women (Dempsey et al, 2002)

59. Women and Tobacco
• Tobacco plays greater role in progression to illicit
drugs use in women than in men (Tuchman, 2010)
• Women are less likely to quit initially (Killen et al, 1997) or
to remain abstinent at follow-up (Killen et al, 1994; Kabat et
al, 1987)
• Females report positive mood increases to a greater
extent after smoking and show a greater decline in
positive mood during abstinence than men (Perkins,
1996)
• Faster nicotine metabolizers have poorer smoking
cessation outcomes from NRT (Lerman et al, 2006)

60. Treatment of Tobacco Dependence
• Combination nicotine replacement (patch and
losenges; patch and gum) is the most effective
• 2-4 mg of nicotine per cigarette
• 20 cig a day = 60-80 mg of nicotine
• Varenicline
• Bupropion SR or XL

61. Women and Alcohol
• Lower content of body water (51% vs 65% in
men)
• Lower levels of gastric ADH (25% of men’s)
• Menstrual cycle-related variability in peak BAC
• Safe level of drinking for non-pregnant healthy
females <65: no more than three standard
drinks per day and no more than 7 per week

62. Women and Alcohol
• Women start drinking later in life than men
and consume less alcohol
• Due to societal stigma, many women tend to
drink alone (married, employed, upper
socioeconomic strata)
• Somatization of alcohol problems is often
unrecognized by providers and medicated by
sedatives and tranquilizers

63. Treatment for Alcohol Dependence
• Disulfiram (Antabuse)
• Naltrexone oral (Revia) or injectable (Vivitrol)
• Acamprosate ( Campral)
• Topiramate (Topamax)
• Ondansetron (Zofran)

64. Gender Differences In
Pharmacotherapy of Substance Abuse
• Disulfiram for cocaine dependence effective only
in males, not females (Nich et al, 2004)
• NRT was more effective in males than females
(Cepeda-Benito, 2004)
• In a study of sertraline treatment of non-
depressed, alcohol-dependent individuals,
sertraline reduced drinking in males, but not
females (Pettinati et al, 2004)
• Response to oral naltrexone is similar in males
and females; however injectable Vivitrol was less
effective in women (Greenfileld et al, 2010; Garbutt et al, 2005;
Kranzler et al, 2004)

65. Gender Differences In Pharmacological
Treatment of Substance Abuse
• Buprenorphine
• Methadone
• Acamprosate ( no difference)
• Anticonvulsants (gabapentine and lamotrigine)
• Baclofen
• Varenicline (no difference)
• Ondansetrone
• Progesterone

66. Gender Differences in Treatment Entry,
Retention and Completion
• Women are less likely than men to enter
substance abuse treatment (Greenfield et al, 2007)
• Reasons include sociocultural, socioeconomic
factors, child custody issues, availability of
gender-specific treatment programs etc.
(Canterbury 2002; Greenfield, 2007)
• Women are more likely to seek treatment in
other settings (Weisner et al, 1992)

67. Substance Abuse Treatment: Women of childbearing age
NSDUH 2006

68. Reasons for Not Receiving Treatment in Past Year
NSDUH 2006

69. Characteristics of Women Entering Treatment,
Compared to Men
• Younger
• Less educated
• Less likely to be employed
• More likely to have physical/mental health problems
• More likely to have exchanged sex for substances
• Greater exposure to physical and sexual abuse
• Greater concerns about issues related to children
Kaskutas et al. Addiction 2005;100:60.

70. Gender-Sensitive Treatment Availability
Facilities accepting women: 2005
SAMHSA. National Survey of
Substance Abuse Treatment
Services (N-SSATS), 2005. 70

71. Why Gender-Sensitive Programs?
Ancillary clinical/social  Child care, transportation
services
Special needs services  Prenatal care, HIV prevention
Tailored to women’s  Interpersonal focus, nurturing
special needs and supportive, empowering
May provide programs for  Pediatric, prenatal, post-partum
pregnancy and parenting services
 Parenting classes, child
activities
More likely to assist  Housing, job training, practical
patients with: skills training
Godfrey. J Womens Health 2007;16:163-7; Grella et al. J Subst Abuse Treat 1999;17:37–44.

72. Self-Help Support Groups
Women-only and •Alcoholics Anonymous
mixed gender •Narcotics Anonymous
“12-step” •Cocaine Anonymous
programs
•Crystal Meth Anonymous
•Al-Anon, Al-Ateen
LifeRing •No reference to “higher power”
Women for •Empowering approach… “My name is ___
Sobriety and I am a competent woman.”
•Can be adjunct or independent of AA
SMART Recovery •Cognitive behavior therapy approach
Moderation •Harm reduction approach
Management •For problem drinkers who have experienced
mild to moderate alcohol-related problems

73. Gender Differences in Treatment
Entry, Retention and Completion
• Treatment outcomes are comparable with
men in retention rates, relapse rates (Greenfield et
al, 2007; Hser et al, 2001; Mangrum et al, 2006)
• Women have been shown to have greater
improvement in medical problems and more
likely to seek assistance after relapse (Hser et
al, 2005; McKay et al, 1996)

74. Psychosocial Substance Abuse Interventions for
Women with Trauma History
• The Addiction and Trauma Recovery Integration Model (ATRIUM;
Miller and Guidry 2001)
• Beyond Trauma: A Healing Journey for Women and A Healing
Journey: A Workbook for Women (Covington 2003)
• Helping Women Recover: A Program for Treating Addiction
(Covington 2008)
• Seeking Safety (Najavits 2000)
• Trauma Adaptive Recovery Group Education and Therapy (TARGET;
Ford et al. 2000)
• Trauma Recovery and Empowerment Model (TREM; Harris and The
Community Connections Trauma Work Group 1998)
• Treating Addicted Survivors of Trauma (Evans and Sullivan 1995)

75. Questions?
Comments?
Thank you!