Women and Substance Abuse

Elena Volfson, MD, MPHAddiction Psychiatrist

Clinical Assistant Professor of Psychiatry Perelman School of Medicine

University of Pennsylvania03/16/2012

Disclosure

• Dr. Volfson has no financial interest to disclose

Outline

• Updates in general addiction neurobiology• Gender differences in epidemiology and

neurobiology• Hormones and substance abuse• Gender differences acquisition, escalation,

dependence, withdrawal, relapse and treatment• Gender differences in pharmacotherapy of

substance use

“Whether one is male or female is one of the most important

determinants of human health”

Quoted from multiple sourcesWHO 2002

5

Model of Addiction

CravingReward /Euphoria

ControlEmotion

Memory

Orbital Prefrontal Cortex

Ventral Tegmentum

Hippocampus

Nucleus Accumbens

Temporal - Parietal

Used with permission from David Oslin, 2012

6

Model of Addiction

CravingReward /Euphoria

ControlEmotion

Memory

12 Step / CBT

NaltrexoneAcamprosate

NaltrexoneAcamprosate

AntidepressantsMood StabilizersTherapy

Used with permission from David Oslin, 2012

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

Vulnerabilities in Development of Addiction

• Genetic• Developmental• Social• Drug-induced brain plasticity

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

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

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)

Neurobiological Changes with Chronic Substance Use

• Motivation/reward system DA/endorphine• Glutamate/GABA dysregulation• HPA axis dysregulation• Hypofrontality• Sex hormones dysregulation• Cravings• Relapse

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.)

Complexity of Gender ResearchApples to Apples?

• Menstrual cycle: 2-6 phases vs none• Hormones < > substance use• Stress < > substance use• Multiple stages of substance use from

recreational to dependence

Gender Differences in Brain

• Structural

• Functional

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

Epidemiology

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

NSDUH 2010: Alcohol Use by Gender

SUBSTANCE USE BY WOMEN, 2008

20

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.

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

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

22

Greenfield et al. Psychiatr Clin North Am. 2010;33:339-55; SAMHSA. Substance Use among Women During Pregnancy and Following Childbirth, 2009.

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

23Grella et al. BMC Psychiatry 2009;9:52.

Initiation of Drug Use by Substance NSDUH 2010

Multiple studies demonstrate higher rates of substance abuse and

dependence in males as compared to females…

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

Opportunity to Use Drugs

0

10

20

30

40

50

60

70

Marijuana Cocaine Hallucinogens Heroin

Perc

ent

Male

Female

Van Etten et al. (1999) -- 1993 NHSDA

Percent Use Given an Opportunity

Van Etten et al. (1999) -- 1993 NHSDA

Males And Females Are Equally Likely To Become Dependent On

• Cocaine

• Tobacco

• Heroin

• Inhalants

• Hallucinogens

• Opioid Analgesics

Anthony et al. (1994)

Gender Differences in Dependence Potential

Males are more likely to become dependent on

• Marijuana• Alcohol

Females are more likely to become dependent on

• Anxiolytics• Sedatives• Hypnotics

Anthony et al. (1994)

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)

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)

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)

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Menstrual Cycle

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

35LeBlanc ES. JAMA 2001;285:1489-99; Resnick SM. J Clin Endocrinol Metab 2006;9:1802-10.

Estrogen Effects on the Brain

• Estradiol enhances dopamine (DA) release through several mechanisms:

1. Enhances DA receptors activity 2. Potassium – induced mechanisms3. GABAergic neurons inhibition Becker and Hu, 2008

• Activation of HPA axis

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 deactivation37

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

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)

Hu and Becker, 2008

Differences in Behavioral Response in Males and Females i

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)

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)

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

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.

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.

Disorders with Premenstrual Exacerbation (Catamenial Disorders)

• Mood• Anxiety• Psychosis• Migraines• Substance Use

• Seizures• Allergies • Asthma• Sleep• Pain

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

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

Female smokers are much more sensitive to cigarette cues than male smokers

N = 5 Female Smokers - 6 NonSmoking Females

3.53.02.52.01.51.0 .5 0

N = 6 Male Smokers - 5 NonSmoking Males

T Value

Females

Males

T. Franklin, 2010

Differences in Initiation and Use

Greenfield et al. Psychiatr Clin North Am. 2010;33(2):339-55; UCLA Integrated Substance Abuse Programs. Methamphetamine.org. 2006-2010.

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 / IV drugs

Women likely to be introduced to substance by a partner 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

51

52

Differences in RelapseWomen 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.

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

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

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)

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)

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)

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)

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

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

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

Treatment for Alcohol Dependence

• Disulfiram (Antabuse)• Naltrexone oral (Revia) or injectable (Vivitrol)• Acamprosate ( Campral)• Topiramate (Topamax)• Ondansetron (Zofran)

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)

Gender Differences In Pharmacological Treatment of Substance Abuse

• Buprenorphine • Methadone• Acamprosate ( no difference)• Anticonvulsants (gabapentine and lamotrigine)• Baclofen• Varenicline (no difference)• Ondansetrone• Progesterone

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)

NSDUH 2006

Substance Abuse Treatment: Women of childbearing age

Reasons for Not Receiving Treatment in Past Year

NSDUH 2006

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.

Gender-Sensitive Treatment AvailabilityFacilities accepting women: 2005

70

SAMHSA. National Survey of Substance Abuse Treatment Services (N-SSATS), 2005.

Why Gender-Sensitive Programs?

Godfrey. J Womens Health 2007;16:163-7; Grella et al. J Subst Abuse Treat 1999;17:37–44.

Ancillary clinical/social services

Child care, transportation

Special needs services Prenatal care, HIV prevention

Tailored to women’s special needs

Interpersonal focus, nurturing and supportive, empowering

May provide programs for pregnancy and parenting

Pediatric, prenatal, post-partum services

Parenting classes, child activities

More likely to assist patients with:

Housing, job training, practical skills training

Self-Help Support Groups Women-only and mixed gender “12-step” programs

•Alcoholics Anonymous•Narcotics Anonymous•Cocaine Anonymous•Crystal Meth Anonymous•Al-Anon, Al-Ateen

LifeRing •No reference to “higher power”

Women for Sobriety

•Empowering approach… “My name is ___ and I am a competent woman.”

•Can be adjunct or independent of AA

SMART Recovery •Cognitive behavior therapy approach

Moderation Management

•Harm reduction approach•For problem drinkers who have experienced mild to moderate alcohol-related problems

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)

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)

Questions?

Comments?

Thank you!