Clinical implications of the sex and gender differences associated with substance use disorders
Wednesday, December 2nd, 2015
Substance use disorders are exceedingly complex management issues which result in significant medical and social consequences. Epidemiological studies in the United States and Australia show that more men than women are affected by substance use disorders. However, there is evidence to suggest that women have distinctly different and potentially more hazardous patterns of substance use. These include: a greater tendency to escalate usage, relatively higher rates of relapse, and the telescoping phenomenon (which results in a more rapid progression from the initiation of substance use to drug dependence and adverse medical consequences). Proposed mechanisms for the variable impact of substance use disorders on men and women include biological and gender-based theories which incorporate environmental, psychological and social factors. Studies attribute the biological differences to direct and indirect oestrogen-mediated mechanisms, and the influence of dopamine on structures in the brain including the nucleus accumbens and striatal pathways. Psychosocial variables include psychiatric co-morbidities, family responsibilities, financial issues and perceptions of stigma. The differences in the progression and outcomes of substance use disorders between men and women pose the question as to whether their management can be enhanced by a gender-specific approach. This article outlines the various treatment facilities available in Australia and explores the types of facilities that women tend to use. Gender-specific programs and/or facilities have been shown to be most useful when they support sub-populations of women such as pregnant mothers, mothers with dependent children, and victims of domestic or sexual violence.
Both licit and illicit drug use contribute to a significant financial and disease burden in Australia.  Currently, epidemiological data suggests that more men are diagnosed with substance use disorders relative to women. [1-7] However, there are sex and gender differences which distinguish patterns of addiction and behavior in both groups. These sex differences have a biological basis, with associations between oestradiol-related central pathways and the propagation of drug seeking behaviours in women relative to men. [2,6,8]
The difference in the prevalence and impact of substance use disorders between genders incorporates environmental, psychological and social factors. Currently, fewer women access drug treatment programs relative to men.  This may be representative of the fact that fewer women suffer from substance use disorders, however it may also reflect hindrances towards seeking or accessing treatment. Such barriers towards treatment include increased perceptions of stigma, dependent family members, and financial circumstances. [10-12]
Therefore, although more men are diagnosed with substance use disorders, a different approach towards prevention and treatment may be required for women. A review of the current literature is necessary to question whether an argument can be made to support gender-specific programs to address substance use disorders.
Definitions, epidemiology and gender differences
The term ‘substance use disorder’ as defined in the Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5) combines substance abuse and dependence associated with both licit and illicit drugs, which were previously distinguished in DSM-4.  Where possible, we refer to substance use disorders based on DSM-5 criteria. However, DSM-4 terminology is retained in order to maintain consistency with previous epidemiologic studies and data.
Differences in epidemiologic data, psychological factors, and clinical management may exist between the various types of substances; however, this article will focus on general principles in order to better understand sex and gender differences associated with substance use disorders and management options.
Licit drug use disorders refer to the legal use of legal drugs. Tobacco and alcohol are the most frequently used drugs – 15% of Australians over the age of 14 were daily smokers in 2010 while 24% were ex-smokers.  In 2012, approximately 78% of all Australians aged 14 and over drank alcohol during the year, with 18% drinking at harmful levels. 
Illicit substance use disorders, on the other hand, refer to the illegal use of legal drugs or use of illegal drugs. Although relatively uncommon compared to licit drugs, approximately 42% of Australians aged 14 and over reported using illicit drugs in their lifetime, with 15% reporting use in the last 12 months.  Cannabis, followed by ecstasy and hallucinogens were the most common illicit drugs used.
There are consistent reports that suggest a higher prevalence of substance abuse in men relative to women. [1-7] This is in keeping with data from the Australian Bureau of Statistics pertaining to Gender Indicators, which showed that men reported higher rates of substance use disorders in the year prior to data collection (7% males relative to 3% females) and throughout their lifetime (35% males relative to 14% females).  This is consistent with studies conducted in the United States (US) where, for example, a large survey of over 40,000 adults stated that men are twice as likely (13.8%) than women (7.1%) to address DSM-4 criteria for any drug use disorder.
However, women have distinctly different patterns of drug use, which may be explained by a combination of sex and gender differences. [2,12] For instance, studies show that women tend to escalate drug use (relevant to alcohol, cannabis, opioids and cocaine) relative to men, which contributes to notion of the ‘telescoping phenomenon’. [2,6,12] The term suggests that the development of behavioural, psychological and medical consequences of a substance use disorder occur at a faster rate in women relative to men. [2,12] Notably, despite the use of relatively smaller quantities of drugs within a shorter timeframe, women show greater rates of adverse social and medical consequences.  Furthermore, Becker and Hu’s review  suggests that once drug addiction has been established, women find it more difficult to quit and are more prone to relapse following periods of abstinence in comparison with men.
Therefore, despite the fact that quantitatively more men may suffer from addiction, the differences in the pattern of drug seeking behaviour, escalation to use disorders, and treatment retention need to be addressed.
Sex differences relevant to drugs of addiction have been evidenced in both animal and human models.  Animal studies performed on rodents suggest that females are more likely to self-administer drugs of addiction (in this case cocaine) and have oestradiol-associated mechanisms to further propagate drug seeking mechanisms which are not present in male rodents. [2,6]
Oestrogen-mediated sex differences are evident in most phases of drug abuse including acquisition, maintenance, escalation and relapse. [2,8] Proposed mechanisms for this effect include direct interactions with the striatum and nucleus accumbens to facilitate dopamine release, and indirect interactions via sensitisation of receptors and changes in neuronal excitability. [6,8,14] The alterations in dopamine release act to regulate neurochemical responses and behaviours in favour of addiction, particularly to psychomotor stimulant drugs. [6,14]
Another contributing factor to the sex differences in drug addiction is the effect of the menstrual cycle on motivation behaviours. The impact of the menstrual cycle seems to be variable depending upon the timing of the cycle, hormone concentrations, and type of substance abused. For instance, increased euphoria, desire, and energy are enhanced when using cocaine in the follicular phase relative to the luteal phase.  In support of the notion that oestrogen plays a role in the perceived effects of drugs of addiction, the addition of oestradiol during the follicular phase resulted in a self-reported increase in the euphoric effects of dexamphetamine. 
Additionally, a review of 13 studies that investigated the impact of the menstrual cycle on smoking cessation suggested that women experience greater tobacco cravings and negative affect responses to tobacco withdrawal during the late luteal phase, where oestrogen and progesterone levels are diminishing.  The proposed mechanism for this is that the relatively higher oestrogen levels in the follicular phase may ‘alleviate some of the negative consequences’ associated with quitting smoking. Becker and Hu  support this theory by identifying a study that confirms the relationship between oestradiol, positive affect and decreased anxiety.
The variations in drug use and withdrawal symptoms during the menstrual cycle, such as increased euphoria when using cocaine during the follicular phase versus enhanced negative affect responses to tobacco withdrawal during the luteal phase, suggest that fluctuating oestrogen levels can have an impact on subjective experiences of substance use disorders.
It is difficult to truly isolate biological differences from psychosocial issues that may impact on the development and management of substance use disorders. However, there is evidence to support the significance of biological variations on the subjective experiences and outcomes associated with substance use disorders. These include the relationship between oestradiol and addiction behavior in animal studies, variations in drug-related experiences during the menstrual cycle, and the notion (detailed above) that women have a greater tendency to escalate drug use and develop adverse medical/psychological effects as a consequence of substance use disorders. The question remains as to whether the telescoping phenomenon in women requires a different management approach – are there any benefits of targeting women through specific programs or do mixed-gendered programs and facilities suffice?
In addition to the identified biological differences in substance use disorders, psychosocial factors may contribute to variations in addiction behaviours, treatment initiation and outcomes. Such factors include, but are not limited to, psychiatric co-morbidities, dependent family members, financial issues and perceptions of stigma.
Studies suggest that women with substance abuse disorders are more likely to have a prior diagnosis of a psychiatric disorder relative to men, with more women meeting criteria for anxiety, depression, and eating disorders.  Potential contributing factors to this difference in mental health outcomes include higher rates of experienced trauma such as sexual abuse and/or intimate partner violence, disrupted family environments, and a perception of over-responsibility (such as caring for a child or other family members) in women relative to men. [3,10,11,15] The correlation between psychiatric disorders with substance use disorders urges the need for more holistic treatment. Specialised services that incorporate mental health into the management of substance use disorders have shown to yield better outcomes with respect to treatment retention and continuity of care. 
In addition to psychiatric co-morbidities, previous studies document a greater perception of stigma amongst female substance abusers, whereby women experienced higher levels of guilt, embarrassment and shame relative to males. [11,15,17,18] This has an impact on the willingness to seek and/or continue treatment not only for substance use disorders but other necessary community services. The Network of Alcohol and Other Drug Agencies (NADA) report suggests that women identified having difficulty accessing services such as pre-natal classes and housing support due to perceived stigma, discrimination and fear of judgment from child protection services. 
Social factors that hinder management of substance use disorders in women relative to men include: lower education levels and financial income, housing issues, interaction with child protection services, and dependent children and/or other dependent family members. [10-12] Green’s research  and NADA’s report  suggest that women experience relatively greater difficulty in finding time to attend regular treatment sessions due to family responsibilities and transport issues. The social factors mentioned above, in conjunction with the perception of stigma, act as significant barriers for women to access treatment. These need to be addressed in order to successfully promote women to seek initial treatment while providing necessary support to facilitate long-term management.
Current use of treatment facilities
Briefly, the types of treatment facilities in Australia as outlined by the AIHW’s report include :
- Assessment only, whereby agencies identify the severity of the issue and refer accordingly
- Information and education only
- Support and case management only
- Counseling for individuals and groups through methods such as cognitive behavior therapy
- Withdrawal management (home, in-patient, or out-patient)
- Rehabilitation (residential treatment services, therapeutic communities or community-based rehabilitation)
- Other holistic approaches, which include relapse prevention, living skills classes, safer using, etc.
- Other health services include GP visits, hospital treatment and homelessness services.
In Australia, fewer women (32%) received treatment through alcohol and other drug treatment services relative to men (68%) in 2012-2013, which is consistent with studies conducted in the US where extensive research regarding the impact of gender on substance abuse is conducted.  It is unclear whether the reduced proportion of women seeking treatment is solely reflective of the relatively smaller number of women with addiction issues, or also inclusive of the financial and psychosocial factors that can prevent women from seeking treatment. 
Studies based in the US allow for the identification of gender differences between the types of facilities used for managing substance abuse disorders. Women are more likely to approach mental health or primary clinics rather than addiction treatment programs or specialty clinics. [3,19] It is proposed that this may be due to the perception that psychological distress and impairment associated in those substance use disorders may be better addressed by directly treating the mental health issue. 
There is limited research regarding the impact of this preference on treatment outcomes, however Mojtabai’s study  found that this pattern of treatment was less effective when compared to participants who sought help in specialty settings.  Management through facilities dedicated to substance use disorders was associated with a relatively reduced likelihood of continued substance use, with fewer participants reporting alcohol and substance use in the past month. [10,19] The study urges for better integration of substance use disorder management in the mental health system, and an efficient referral system across the ‘traditionally separate systems of care’. 
Future directions: utility of gender-based programs?
Services that provide comprehensive support by addressing medical, psychiatric and social issues (such as employment or child protection) have been shown to improve attendance, social adjustment and relapse rates in both men and women. [12,20] Previous research suggests that gender does not seem to predict patient retention, treatment completion, or patient prognosis once an individual begins treatment.  This seems to contradict the need for gender-specific programs, considering that treatment appears to offer equal benefit to both men and women. However, this needs to be considered in light of the fact that there are differences in the rates of treatment access between men and women, which may be explained in part by the psychosocial factors outlined above.
There is evidence to suggest the benefit of gender-specific programs or facilities in certain contexts. These include programs that focus on female-specific topics such as sexual abuse and body image, residential facilities for women with dependent family, and tailored care for pregnant mothers. [10,21] In 2005, the Drug and Alcohol Services Information System (DASIS) report in the US suggested that 41% of substance abuse treatment facilities that accepted female clients provided additional support programs specifically for women.  There are gender specific programs and facilities, including those dedicated to pregnant women, in most Australian states – although they may not be as numerous as those available in the US. For instance, out of 28 Network of Alcohol and Other Drug Agencies services in New South Wales, Australia, 7 provided women-only services. 
Gender specific psycho-education sessions on topics specific to women have received positive feedback in a few different studies. [11,16,19] These sessions allow for the discussion of more sensitive issues such as domestic violence, sexual abuse, parenting, weight and body image in a more comfortable scenario. [10,11,21] It is crucial that these programs are flexible and avoid the use of a confrontational style.  The presence of dynamic and interpersonal discussion is considered beneficial, and is suggested to occur more often and in an uninterrupted fashion in women-only programs.  The importance of self-expression without interruption is highlighted by the fact that unaddressed issues may result in adverse psychological effects.  Specific interventions that have been proven to be effective include but are not limited to: parenting skills for mothers on methadone maintenance, relapse prevention for women with post traumatic stress disorder, and relapse prevention for women with marital distress and alcohol dependence. [10,11,12]
Programs specific to women tend to offer facilities that allow for accompanying children (through child care support during clinics and day programs), and may also provide residential facilities for the client and dependent family. Such facilities have been shown to have better treatment outcomes including longer lengths of stay. [11,12,16] Furthermore, family inclusive practices may have services that aim to repair relationships with children and family members thus enhancing support systems and the quality of the home environment.
Pregnant women with substance use disorders can be at high risk of numerous medical and social issues affecting their mental and physical health, which in turn impacts upon their risk of obstetric complications and the subsequent health of their baby. Pregnant women are more likely to: be of younger age, have previously given birth, have limited social supports (including limited financial stability) and have a concomitant psychiatric diagnosis. Such populations require a multitude of coordinated services and can significantly benefit from residential services, which allow for increased social support for themselves and dependent family.  Programs dedicated to pregnant and perinatal women have demonstrated significantly improved patient engagement and pregnancy outcomes. [12,23,24] Specific intervention programs that have yielded beneficial results for expecting mothers include alcohol interventions for pregnant women, contingency management to increase abstinence in pregnant women, and comprehensive service models for pregnant women such as access to prenatal care.  The benefit of customised care was highlighted by a study which recorded higher infant birth weights (2934 grams vs. 2539 grams) and a smaller proportion of neonatal intensive care admissions (10% vs. 26%) when comparing cocaine-dependent mothers who received twice-weekly addiction counseling with those who did not. 
In addition to gender-specific treatment, future directions may include a transition to more gender-sensitive services.  Suggested strategies include: matching therapist and client gender, mixed-gender group sessions concurrently led by both male and female leaders, and gender-specific treatment information or content.  The results of client and therapist gender matching are unclear. Some studies suggest that clients reported a sense of greater empathy resulting in longer treatment durations and lower rates of relapse, whilst other showed no difference in outcomes. 
There are documented sex differences with respect to substance use disorders through direct and indirect oestrogen-mediated mechanisms, the dopamine influence on nucleus accumbens and striatal pathways, and variable impacts of the menstrual cycle. These occur in addition to gender differences, which incorporate psychosocial variables such as psychiatric disorders, family environment, domestic violence, and social stigma. Currently, men experience higher rates of substance abuse relative to women; however, women are more likely to escalate drug use and suffer from biological and/or psychological consequences at lower doses and shorter durations of drug use. Additionally, women are less likely to enter treatment relative to men.
Studies provide inconclusive results regarding the benefits of gender-specific programs over those that have a gender-mix. However, there may be a need to support sub-populations of women including pregnant mothers, mothers with dependent children, and victims of domestic or sexual violence. Therefore, future directions include the need to increase awareness regarding substance use disorders, facilitate treatment for women in general, provide ongoing support to relevant subgroups, and consider a more gender-sensitive approach during management of substance use disorders.
The author wishes to acknowledge Dr. Christine Phillips and Dr. Elizabeth Sturgiss for their support and feedback.
Conflicts of Interest
A Jain: firstname.lastname@example.org
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