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  • I am an addiction psychiatrist, working at the Philadelphia VA and in private practice on the Main Line. Three settings: specialty care outpatient clinic, integrated care and private practice. Addiction research has historically been done on males and findings have been generalized to females. Lately, we started to see that it is not the best approach. There are significant gender differences in all phases of substance use: acquisition, escalation, maintenance, relapse and treatment.
  • With my boss, Dave Oslin, we have written a review chapter on current addiction neurobiology in the APA neuropsychiatry textbook, that came out recently.I am not going to cover pregnant women and older women as much because these topics require separate talks. I am not going to cover specific screening tests for women. Significant gender difference in all stages of addiction: acquisition, escalation, dependence, withdrawal, relapse and treatment
  • Sex is a vulnerability factor in drug abuse
  • Addiction is multifactorial and heterogeneous disease with disfuctions occuring at different levels of the brain. With the advances of neuroimaging we understand more about the complexity of the addiction syndrome and levels of impairment
  • The interventions have to be tailored to the level of dysfunction. If urges and cravings are very powerful and drive the addiction , the subcortical areas have to be suppressed (quieted down) by medications to free up the frontal lobes to do the recovery work to reestablish cortical control, to regain the executive function
  • Food, sex, childrearing – whatever is essential for survival. The tragedy of addiction is that normal motivational circuitry is lost
  • Glutamate is excitatory neurotransmitter. 70 % of synapses in the brain are glutamatergic.Differences in dopamine release in drugs and natural reinforcers – no habituation, dopamine depletion (released every time beyond physiological limits)
  • Weak executive function and strong subcortical drives
  • The goal of treatment process is to reverse the changes. It is impossible to unlearn addiction – you have to learn learn new information and make new connections. To develop an alternative high.
  • Match up the stage of addiction, stress and hormonal levels. Try to establish a control group. Cannot compare a female alcoholic to a male social drinker.Differences between men and women emerge only when men are compared with women in the luteal phase; the subjective response to stimulants is similar in men and women in the follicular phase. (Men don not have progesterone!) Neuroactive steroids.
  • Males and Females are biologically different. The question remains as to how genetic sex and hormonal differences interact and whether the differences in the biology of motivational function can explain sex differences that promote uncontrolled and dysregulated patterns of addiction. Men and women differ in the relative size of mesolimbical and mesocortical structures that are implicated in responses to drugs – cerebral cortex, medial amygdala and hippocampus.There are still significant gaps in our knowledge due to lack of empirical research. There is an underlying sex difference due to sexually dimorphic development of the brain, that medicates sex differences in drug abuse. Sex differences in motivation might be in part genetic in origin. Gonadal hormones modulate the neural systems that mediate drug taking behaviors. Estradiol enhances the motivation to take drugs, while progesterone can counteract the effect of estradiol. Ultimately the research will aid in improved treatment and understanding of drug abuse in both male and females.
  • Neuroactive steroids such as estradiol, progesterone and allopregnenolone modulate the function of multiple neurotransmitter systems throughout various stages of development. Especially GABA and glutamate. Developmental/organizational differences in male and female neurobiology
  • Historically, drug abuse was considered to be a male disease. This male-centric approach failed to look at the factors underlying drug abuse in women- ovarian hormones. Adult men are 2-3 times more likely than women to have a drug abuse/dependence disorder. Women are more likely to initiate drug use at earlier age, engage in binge-like patterns of drug se, report greater difficulty in quitting, exhibit more intense drug cravings , more likely to relapse and resume higher levels of drug taking after relapse (clinical research)
  • As was the case from 2002 through 2009, the rate of substance dependence or abuse for males aged 12 or older in 2010 was about twice as high as the rate for females. For males in 2010, the rate was 11.6 percent, which was similar to the 11.9 percent in 2009, while for females, it was 5.9 percent in 2010, which did not differ significantly from the 6.1 percent in 2009 . Among youths aged 12 to 17, the rate of substance dependence or abuse among males was similar to the rate among females in 2010 (6.9 vs. 7.7 percent). Men are twice as likely as women to meet lifetime DSM-IV TR criteria for any drug use disorder . The gender differential for alcohol use disorders is higher than that for drug use disorders. Gender differential for tobacco use and dependence is less than for other substances of abuse.Females are catching up and exceeding males in their drug use, particularly among the younger populations.
  • In 2010, an estimated 57.4 percent of males aged 12 or older were current drinkers, higher than the rate for females (46.5 percent). However, among youths aged 12 to 17, the percentage of males who were current drinkers (13.7 percent) was similar to the rate for females (13.5 percent). The rate among males aged 12 to 17 dropped from 15.1 percent in 2009. Among young adults aged 18 to 25, an estimated 57.0 percent of females and 65.9 percent of males reported current drinking in 2010. These rates were similar to those reported in 2009 (57.7 and 65.9 percent, respectively). Pregnant WomenAmong pregnant women aged 15 to 44, an estimated 10.8 percent reported current alcohol use, 3.7 percent reported binge drinking, and 1.0 percent reported heavy drinking. These rates were significantly lower than the rates for nonpregnant women in the same age group (54.7, 24.6, and 5.4 percent, respectively). Binge drinking during the first trimester of pregnancy was reported by 10.1 percent of pregnant women aged 15 to 44. All of these estimates by pregnancy status are based on data averaged over 2009 and 2010. Alcohol Use by GenderIn 2010, an estimated 57.4 percent of males aged 12 or older were current drinkers, higher than the rate for females (46.5 percent). However, among youths aged 12 to 17, the percentage of males who were current drinkers (13.7 percent) was similar to the rate for females (13.5 percent). The rate among males aged 12 to 17 dropped from 15.1 percent in 2009. Among young adults aged 18 to 25, an estimated 57.0 percent of females and 65.9 percent of males reported current drinking in 2010. These rates were similar to those reported in 2009 (57.7 and 65.9 percent, respectively). Pregnant WomenAmong pregnant women aged 15 to 44, an estimated 10.8 percent reported current alcohol use, 3.7 percent reported binge drinking, and 1.0 percent reported heavy drinking. These rates were significantly lower than the rates for nonpregnant women in the same age group (54.7, 24.6, and 5.4 percent, respectively). Binge drinking during the first trimester of pregnancy was reported by 10.1 percent of pregnant women aged 15 to 44. All of these estimates by pregnancy status are based on data averaged over 2009 and 2010.  
  • Gender gap is minimal for tobacco, and minimal for prescription meds abuse
  • This pie chart really have to include alcohol and tobacco. Marijuana plays a greater role in progression of substance use in males, whereas tobacco plays a greater role in females. Sedatives and opiates are playing a greater role in females.
  • Epidemiological studies consistently demonstrate that the prevalence rates of drug and alcohol disorders are higher among men than among women (Conway et al,2006; Kessler et al, 1994; Regier et al, 1990)The National Institute on Alcohol Abuse and Alcoholism’s National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), more than 40,000 peoplewere surveyed. Men are twice as likely as womento meet lifetime DSM-IV TR criteria for any drug use disorder (13.8% men vs 7.1% women; Conway et al, 2006). Twelve-month prevalence rates of alochol abuse in NESARC were almost three times as high in men as compared with women (6.9% men vs. 2.6% women; Grant et al, 2004)In contrast, the rates of prescription drug abuse in women closely approach that of men. In 2006, NSDUH reported 12-month prevalence rates of buse or dependence for non-medical use of pain relievers to be …The gender differential for tobacco use and dependence is substantially less than for other substances of abuse.
  • Not population prevalence, but conditional prevalence (only among users)Male female differences at the earliest stage of drug involvement (Van Etten): differences in the rates of exposure. Males were more likely than females to have opportunities to try these drugs, but were not more likely than females to progress to actual use once an opportunity occurred. Results showed that an estimated 51% of US residents have had an opportunity to try marijuana; comparative estimates for cocaine, hallucinogens, and heroin are 23, 14, and 5%, respectively. Among those who eventually used each drug, the vast majority made the transition from first opportunity to first use within 1 year. Males were more likely than females to have opportunities to try these drugs, but were not more likely than females to progress to actual use once an opportunity occurred.
  • Gender differential is much smaller and in case of heroin it is even reversed. Conditional preference.Differences become less obvious when data is adjusted …
  • Based on National Comorbidity Survey
  • Older women are the main group to which the anxiolytics and sedatives are prescribed
  • Females develop more severe dependence and do it much faster than males for multiple substances of abuseIn the progression from legal drug use to illicit drug use cigarette smoking plays a relatively larger role for women than for men, and alcohol plays a relatively larger role for men than for women (Tuchman, 2010)
  • More females acquire self administration than males (rats and Rhesus Monkeys) Lynch & Carroll, 1999100% females acquiring as apposed to 37% of males in monkeys with PCP administration
  • It would be great to have a study in ovariectomized females : what happens to their substance use post- surgery?
  • Neuroactive steroids that modulate the function of multiple neurotransmitter systems and modify many functions of the brain.Natural fluctuations of hormones during the menstrual cycle correspond to differences in the physiological and subjective affects of substances of abuse.Over the course of menstrual cycle , there are peaks and valleys during which females are more or less susceptible to the reinforcing properties of substances of abuse. More gaba in the luteal phase – brain is less responsive – more inhibition. More estrogen in the follicular phase – enhances the pleasure from the stimulants. Premenstrual mood exacerbation is due to the withdrawal from GABA A and beta endorphins. No wonder that women use more alcohol and benzos and opiates during that phase. Valium – mother’s little helper. Mommy needs a glass of wine. To understand how reproductive hormones affect the brain, let’s review the normal menstrual cycle. The female menstrual cycle is the result of complex interactions between hypothalamus, pituitary and ovaries. Ovaries produce monthly surges of estrogen and progesterone . These surges vary day to day and week to week. Hormonal waves affect the cortex and subcortical structures and cause significant variations in stress responsivity, productivity and functionality. Two weeks up, two weeks down. The first two weeks due to the effects of estrogen and testosterone , women feel energized, social, productive, sexy, fertile, flirtacious. The husbands and boyfriends are great, children are wonderful and talented, bosses are just and understanding, girlfriends are amazing… Work is great, life is good. Their brains are working sharper and faster, memory is better, verbal fluency is excellent. The woman reaches the peak of her performance right before the ovulation to produce the best reproductive results. Then, after the ovulation, the ovaries start secreting progesterone, which has a calming and slowing effect on the brain. It causes the brain to be more sedated and gradually more irritable and less focused. Women prefer to be left alone, husbands and boyfriends start getting on their nerves, children get out of control, bosses at work are not reasonable, coworkers are irritating, work sucks and they feel like a failure. In the very last days of the cycle (4th week), progesterone collapses and its calming effect is abruptly withdrawn, leaving the brain upset, stressed and irritable. Many women say they cry more easily and often feel out of sorts, stressed, aggressive, negative, hostile, or even hopeless and depressed right before the periods begin. Dr. Brizendine calls it “crying over dog food commercial” phase. Ass compared to a flat-line of testosterone in males, that goes down a bit by the age of 80…Beta-endorphine withdrawal causes noradrenergic rebound and produces more anxiety.
  • Estrogens are synthesized in the male brains too from testosterone by local aromatase enzymes or synthesized de novo by neurons and glia. They affect learning, memory, mood , neurodevelopmental and neurodegenerative conditions.Estrogens are involved in mesolimbic DA system, HPA axis.Enhanced drug seeking and subjective effects in women are associated with higher levels of endogenous estrogens (Evans 2007, Terner and De Wit 2006)Endocellular estrogen receptors and cascades are very complicated to describe.Better brain perfusion in response to estrogens.Complex effects: intracellular estrogen receptors of different kindsActive neurohormones, not just peripheral reproductive organs
  • HPA (hypothalamic- pituitary-adrenal)
  • Withdrawal from ALLO creates a very uncomfortable state, that occurs right before the period.In substance abusing women, the persistence of distress and repeated adaptations may lead to depleted progesterone and ALLO levels (Girdler et al, 2007)The attenuating effects of progesterone suggest that the late luteal phase , which is characterized by GAGA A withdrawal, could represent the phase of increased vulnerability to stress and to cue-incuced cravings. Women treated with progesterone showed a decrease in the positive subjective effects of smoked and IV cocaine (Evans and Fotin, 2006; Sofuoglu et al, 2002). In addition, high circulating plasma levels of progesterone were asscociated with decreased craving following a streess or drug-related cue in cocaine dependent women (Sinha 2007)
  • The action of estradiol to enhance dopamine release and activate mesolimbic DA system mediates some of the gender differences in addiction Rats’ cycle is 4-5 daysDopamine release in striatumEstrogens are synthesized in the male brains too from testosteron by local aromatase enzymes or synthesized de novo by neurons and glia.Estrogen levels are higher in intact than in ovariectomized females
  • Females release more dopamine than males -> experience more cravings; greater severity of addictionEstrogen works similarly to endorphines inhibiting GABAergic interneurons leadig to more dopamine release.It is implicated in different responses to substances in different phases of menstrual cycle.
  • Higher ratings of “high” and “good drug effect”Nicotine in the luteal phase: more smoking, more cue-induced carvings. During short-term abstinence: more w/d, more depressive sx, more desire to smoke, more desire to relieve negative affect, more weight gain. Quitting during luteal phase produces poorer short-term abstinence-quit during follicular phase!Subjective measures were insensitive to menstrual cycle effects following alcohol, nicotine, marijuana and opioid administration in women. Enjoyment of cocaine might be dependent on the route of administration.
  • Stress is associated in heightened drug abuse vulnerability in women (Sinha 2007), primary factor is drug bingeing and relapse. Men and women process stress and conflict in different ways. Chronic substance abuse disrupts stress and reward systems of the brain. Longer activation of HPA axis and higher corticosterone and ACTH levels in females.Both males and females under stress are more likely to use drugs and alcoholWomen are more likely to relapse under stress that men
  • Most of the psychiatric admissions (65%) happen at the end of the menstrual cycle (4th week). Self-medication is more likely to occur in the luteal phase of the cycle
  • Brain performance can fluctuate with the hormonal changes. Schedule your oral exams and job interviews within the first couple of weeks preferably right before ovulation. There is a great individual variability in the brain performance. Any treatment studies in women should really be controlling for the days of the menstrual cycle.
  • ALLO= a neuroactive metabolite of progesteroneand works on GABA (gamma-aminobutyric acid) receptors in the brain. Hence, ALLO is a powerful anxiolytic, anticonvulsant, and anesthetic agent which decreases anxiety and depression.Unlike the predictable and reproducible peak BACs in men, day-to-day variability, with higher peaks in the premenstrual phase, has been observed. Increased BAC variability, faster ethanol metabolism, and less marked acute alcohol tolerance have been reported in women as compared to men.
  • Correlation between premenstrual symptomatology and alcohol use has been confirmed in multiple studiesFor other substances it has not been so widely demonstrated in the literature. Can we predict which substance in which phase of the cycle a woman would use? No! They enjoy substances more in follicular phase and have to use more to overcome progesterone’s effects in the luteal phase…Unfortunately, the studies do not always control for the phases of menstrual cycle.
  • Neuroimaging studies have also provided important information about the neuronal processes underlying sex differences in substance use disorders
  • The gender differential in brain activation by stress and drug cues provides important information about gender differences in reasons for drug use (Li et al, 2005)
  • Relationships are central in women’s lives—as part of their identities, as sources of self-esteem, as the context for decisionmaking and choices, and as support for day-to-day living and growth (Covington and Surrey 1997; Finkelstein 1993, 1996; Miller 1984). Connections are relationships that are healthy and supportive— mutual, empowering, and emotional resources. “Disconnections” involve relationships that are not mutual and empowering: one member is dominant, there is imbalance in the give and take, or a disparity exists in emotional supportiveness. Disconnections range from feeling “unheard” or “unknown” to extreme forms of disconnection, such as sexual abuse and violence. Disconnections create major difficulties for most women, such as lowered self-esteem, feelings of powerlessness, and lack of assertiveness. The experience of relationships as connections and disconnections is a central issue in personality development, with repeated severe disconnections potentially having serious psychological and behavioral consequences.
  • Depression and anxiety play a greater role in relapse in females than in males. Higher levels of cravings
  • Female alcoholics have 50-100% higher death ratesAlcohol leads to osteoporosisHigh rates of STDs and unwanted pregnancies in college studentsMortality rate is greater for woemn
  • Women generally surpass men in the number of psychiatric problems related to their drug/alcohol use , despite men having significantly higher consumption levels and dependence problemsMost of the individuals with substance use disorders have co-occurring psychiatric conditions. Patterns of comorbid psych disorders found in men and women with addictions parallel those found in the general population. Studies show, that regardless of the presence of SUD, women evidence higher rates of anxiety disorders, depression, eating disorders and BPD, whereas men evidence higher fates of APD (Brady et al, 1993; Sinha et al, 2002)
  • Men and women are biologically different. The biological differences in the structure of the brain predispose women to mood disorders. Throughout most of their lives, women are at a greater risk of becoming depressed than men. Depression ratio in childhood is 1:1, it doubles for females with the onset of puberty and stays that way throughout life. We used to think that the 2:1 female/male ratio goes back to 1:1 after menopause, but the current epidemiological data shows that it does not. Postmenopausal women continue to show more depressive symptoms than their male counterparts. The picture is amazingly stable across cultures.Depression plays greater role in relapse in women than in men!!!
  • Cortisol sensitizes the brain to the pleasurable effects of substances. Depressed subjects have chronically elevated levels of cortisol.
  • Dose response relationship: with attempted intercourse 5.7 times more likely to be depressed as compared to controls. Substance abuse can prevent full recovery from PTSD, and continuing PTSD symptoms may perpetuate use of substances and the development of substance use disorders. Two studies report double the lifetime prevalence of PTSD in women than in men: 11.3 percent versus 6 percent and 10.4 percent versus 5 percent (Breslau et al. 1991; Kessler et al. 1995, respectively). These studies found that women were twice as likely as men to develop PTSD after exposure to a trauma, suggesting that women are particularly vulnerable to PTSD or that the particular type of trauma experienced by women is more likely to result in PTSD. In a study that sampled 558 cocaine-dependent outpatient clients on current rates and symptoms of PTSD, women were three times more likely to meet diagnostic criteria for PTSD (Najavits et al. 2003).Najavits and colleagues (1997) cite studies demonstrating that women with substance use disorders have higher rates of PTSD (30 to 60 percent) in comparison to men, most often as the result of physical or sexual assault. Women with substance use disorders have also been found to have higher rates of repeated trauma by family perpetrators than men who abuse substances (Grice et al. 1995). Rape has been found to be the most likely form of violence to lead to PTSD for both women and men, and female rape victims may be particularly vulnerable to developing substance use disorders because of the traumatic nature of rape (Kessler et al. 1997).More research is needed in evaluating outcome and the role of PTSD and relapse. Women who relapse often are labeled as “resistant” when, in fact, victimizations that have not been addressed could account for the difficulty in stopping substance abuse (Root 1989). Trauma survivors sometimes use alcohol and drugs to medicate the pain of trauma and consequently are perceived as “treatment failures” because their trauma experience is misunderstood or not identified (Covington 2008a rev., 1999a). In an outcome study comparing women with and without PTSD in treatment for substance use disorders, the authors found that individuals with both PTSD and substance use disorders relapsed more quickly and that PTSD was a predictor of relapse (Brown et al. 1996).
  • I wanted to discuss tobacco and alcohol in more details because they are by far more common and legal. Women need to smoke more and more frequently to maintain blood nicotine levels. We know very little about sex differences in opioid and cannabis use.Underdosing of NRT is very common in addiction treatment, but women require a higher dose
  • NRT is very commonly underdosed and women require higher doses to begin with
  • Content of body water goes down with age.In alcoholic women, gastric ADH is almost non-existentWomen who suffer from alcohol abuse and dependence are likely to suffer from a variety of other problems, especially depression, both before and after the onset of substance abuse problem.
  • Women tend to hide their drinking. Often, the problem is not recognized by the medical community in a timely manner.
  • Significant gender differences in the activity of P450 enzymes and receptor distributionUnderdosing in NRT, women require higher doseMuch harder to treat psychopharmacologicallySubstantial differences in pharmacokynetics and pharmacodynamics between male and female patients. P450 3A4 activity is higher in women, but many other cytochromes are higher in males. Women have hogher risk of QTC prolomgation due to effects of reproductive steroids on the heart.
  • I cannot give you any specific summary on this: different studies report different results. It might be due to not controlling for the phases of menstrual cycle.Acamprosate is teratogenic in animal studies.Topiramate is teratogenic in animal studies.Depakote is not the best agent to use in women of childbearing age.Naltrexone is well tolerated.Buprenorphine and methadone are.Baclofen?Varenicline?One explanation for the findings of Jones et al.,12 who found improved outcomes in women maintained on buprenorphine compared to men in regard to illicit opioid consumption, could be the superior effects of the unique pharmacology of buprenorphine (a partial mu-agonist/kappa-antagonist) combined with basic pharmacodynamic sex differences. Specifically, women of reproductive age may respond better to buprenorphine due to their higher mu- and kappa-opioid receptor concentrations and/or unique differences in signal transduction compared to men12. Therefore, women in their reproductive years may predictably be more sensitive to mu- and kappa-opioid medications than men 8,27–29. As levels of estradiol and progesterone both may influence the opioid mechanisms,30–32 factors such as the phase of the menstrual cycle and age (i.e. menopause) may play an important role 27,33.Most studies have shown that cytochrome P-450 (CYP) 3A4 activity is higher in women than in men38The pharmacokinetics and pharmacodynamics of psychotropic medications show substantial differences between male and female patients 34–37. Many confounding factors (e.g., body weight, fat distribution, gastric absorption and emptying, and colonic transit times) seem to influence the metabolism of these drugs, but a complete understanding of these results remains elusive36
  • PCPs and mental health clinics
  • Transcript

    • 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 sourcesWHO 2002
    • 5. Model of Addiction Emotion ControlTemporal - 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 ControlAntidepressants 12 Step / CBTMood StabilizersTherapy Reward / Craving Euphoria Naltrexone Naltrexone Acamprosate Acamprosate Memory 6 Used with permission from David Oslin, 2012
    • 7. Addiction is a Compulsive Relapsing DisorderTwo essential features:• impaired ability to regulate the drive to obtain and use substances• reduced drive to obtain natural rewardsChange 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 monthCigarettes 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) -- 3.4Illicit Drugs 12.2% 6.3% Marijuana & hashish 8.3 4.4Prescription 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 deliveryGreenfield et al. Psychiatr Clin North Am. 2010;33:339-55; SAMHSA. Substance Use amongWomen 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 anddependence in males as compared to females…
    • 26. Are females less vulnerable to substance abuse than males?If given the opportunity, females are at least aslikely as males • to use drugs and alcohol • to become dependentLower prevalence of substance abuse in femalesis explained by less exposure and feweropportunities
    • 27. Opportunity to Use Drugs 70 60 Male 50 Female 40Percent 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 50Percent 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 PotentialMales are more likely to Females are more likelybecome 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 estrogenLeBlanc 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 activity2. Potassium – induced mechanisms3. 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 BehavioralResponse 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 3.0Females 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 UseAlcohol  Women drink to cope with stress, negative emotions; men drink to enhance positive emotions or conform to a groupStimulants  Women are attracted to meth for weight loss, increased energy & control of depressive symptoms  Over 70% of meth-dependent women report hx of abuseOpiates  Women more likely to hoard unused meds and use additional drugs (e.g., sedatives) to enhance Rx opioidsHeroin /  Women likely to be introduced to substance by a partnerIV drugs  Use less for shorter periods of time than men  Less likely to inject; more likely to share preparation equipmentTobacco  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 menGreenfield et al. Psychiatr Clin North Am. 2010;33(2):339-55; UCLA Integrated Substance 51Abuse Programs. 2006-2010.
    • 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. 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 InPharmacotherapy 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 trainingGodfrey. J Womens Health 2007;16:163-7; Grella et al. J Subst Abuse Treat 1999;17:37–44.
    • 72. Self-Help Support GroupsWomen-only and •Alcoholics Anonymousmixed gender •Narcotics Anonymous“12-step” •Cocaine Anonymousprograms •Crystal Meth Anonymous •Al-Anon, Al-AteenLifeRing •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 AASMART Recovery •Cognitive behavior therapy approachModeration •Harm reduction approachManagement •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!