Gender-related differences in addiction: a review of human studies

Abstract

Men typically report greater substance use and gambling than women, but the gender gap has been closing in recent years. Men and women engage in drug and gambling behaviors for different reasons and respond differently to drugs and gambling. Telescoping — a phenomenon in which women engage in drug use and/or gambling behaviors at a later age but progress faster to disordered engagement — was initially observed in alcohol and later in opioid, cannabinoid, cocaine, and gambling disorders. Biological and sociocultural gender-related factors may impact withdrawal symptoms and treatment responses among men and women. Further investigation of the neurobiological underpinnings of gender-related differences among addiction populations is required.

Introduction

Sex/gender differences (hereafter referred to as ‘gender-related differences,’ with the understanding of the American Psychiatric Association’s [1] definitions of sex as a person’s biological status such as male or female, and gender as the attitudes, feelings and behaviors associated with biological sex) in addiction have been widely described. Addiction is defined here as chronic, compulsive use of a drug or engagement in a behavior despite negative consequences. Generally, men report greater substance use and gambling than women, but the gender gap has been closing in recent years [2]. Drug use/gambling prevalence rates from the Substance Abuse and Mental Health Services Administration (SAMHSA) 2016 National Survey on Drug Use and Health (NSDUH) [3^••] and selected gender-related difference findings are highlighted in Table 1. According to the NSDUH, 7.5% of the population meet Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria for alcohol or any illicit substance and 0.4% meet DSM criteria for gambling disorder (GD) [4]; however, reports of clinically addicted individuals in this national survey (among others) did not stratify by gender. Some studies haves shown that women engage in drug use or gambling behaviors later than men but progress to addiction more rapidly than men, a gender-related phenomenon known as telescoping. Telescoping was initially observed in alcohol [5] and later in opioids [6], cannabinoids [6], cocaine [7], and gambling [8] disorders. Studies have provided mixed support for this phenomenon. Men are more likely to use drugs recreationally, whereas women are more likely to be prescribed drugs as medication. Nonetheless, women with addictions often experience a greater stigma and less social support than men [9^••]. Examination of gender-related differences (and similarities) is crucial for informing effective policy, prevention and treatment efforts. This review focuses on the current state of biological, psychological and behavioral gender-related differences (and similarities) ranging from prevalence rates to treatment outcomes in clinical populations for the following drug and behavioral addiction subtypes: alcohol, psychostimulants (mainly cocaine and amphetamine), cannabinoids, gambling, nicotine, and opioids.

Table 1.

Percent of individuals in the US reporting drug use/gambling in 2016 (ages 12 years and older) (Substance Abuse and Mental Health Service Administration’s National Survey on Drug Use and Health (SAMHSA’s NSDUH) [3^••]) and selected gender-related difference findings

	Lifetime prevalence		Selected gender-related differences
	Male	Female
Alcohol	82.4	78.2	Women compared to men demonstrate a ‘telescoped’ progression to addiction and alcohol-related physiological diseases.
Cigarettes	61.9	53.2	Women have poorer responses to nicotine replacement therapies than men.
Cocaine	17.9	11.2	Subjective effects of cocaine vary by menstrual cycle phase in cocaine-dependent women.
Gamblingb	82.4	76.5	Men wager on strategic forms of gambling while women wager on nonstrategic forms.
Heroin	2.5	1.2	Men report more use than women, but withdrawal, severity and treatment outcomes are similar.
Cannabis	48.0	40.2	Females are more sensitive to the behavioral and physiological effects of cannabis than males.
Methamphetamine	6.5	4.3	Methamphetamine withdrawal symptoms, relapse rates and treatment outcomes do not vary by sex.
All Illicit Drugsa	52.3	44.9

^aAll Illicit Drug Use includes the misuse of prescription medications or the use of cannabis, cocaine (including crack), heroin, hallucinogens, inhalants, or methamphetamine.

^bPercent of individuals in the US reporting drug any gambling in the past year in 2013 (age 18 and older) [29].

Alcohol

Men generally drink more than women but the gender gap is closing as shown by analyses of recent birth cohorts [10]. While several studies have shown alcohol addiction in women compared to men is ‘telescoped,’ these women were already enrolled in treatment, and some studies also reported no evidence of the telescoping effect [11]. In addition to potentially more rapid progression to addiction, data have also shown that women progress more rapidly than men to alcohol-related diseases such as liver disease, neurotoxicity, cardiomyopathy and peripheral neuropathy; see [12^••] for review. This may in part be due to differences in alcohol metabolism as alcohol dehydrogenase, the enzyme that catabolizes alcohol, is found in much higher concentrations in the stomach of males compared to females [13], although other factors (e.g. distribution volumes) warrant consideration.

There are mixed findings in gender-related differences reported on ratings of craving among alcohol-dependent individuals. With respect to alcohol withdrawal, men are more likely to experience more severe symptoms such as anxiety, insomnia and delirium tremens [14]; however, this study and other studies have not consistently controlled for amounts of alcohol consumed. In alcohol-dependent individuals, men and women show similar abstinence durations and relapse rates [12^••].

Psychostimulants

Generally, men report greater use of psychostimulants (cocaine, amphetamine, methamphetamine) than women [3^••]. Cocaine laboratory self-administration in humans has demonstrated gender-related differences; men compared to women report experiencing more euphoric and dysphoric experiences and assign high monetary values to a second dose of the cocaine [15]. Subjective mental and physical ‘good drug’ effects of cocaine have been reported to be higher in women as compared to men, and menstrual-cycle-phase-dependent have been observed, with greater effects during the follicular phase than the luteal phase [16]. Men also report higher reinforcing effects of amphetamine compared to women; however, the doses of amphetamine have not been consistently weight-adjusted [17]. With regard to craving, women show greater cue-induced cocaine craving as compared to men while stress-induced cocaine craving was similar across genders; however, these responses vary with menstrual cycle phases [18]. Currently, there is little or no evidence of gender-related differences in withdrawal symptoms, relapse rates and treatment outcomes with respect to psychostimulants [12^••].

Cannabinoids

Sex differences have been consistently documented among individuals who use cannabis; see [19^•] for review. According to the NSDUH, males are more likely to use cannabis than females and begin using at earlier ages [3^••]. Similar to alcohol, studies have shown the progression to cannabis-use disorder is ‘telescoped’ in women [20]. Mixed findings describe gender-related differences in subjective reports of ‘high’ due to cannabis and Δ9-tetrahydrocannabinol (THC) alone [21,22], which may be partially due to differences in tobacco-smoking comorbidity and/or dosing strategies. Data suggest that men experience greater cannabis-induced analgesia relative to women [23].

Females, compared to males, are more sensitive to the behavioral and physiological effects of cannabis and cannabis-like substances [24], such as fatigue, drowsiness and psychomotor suppression; however, the amount of cannabis per bodyweight was not been consistently controlled. It is possible that cannabinoid metabolism is responsible for some gender-related differences. For example, one preclinical study showed that female rats compared to male rats had higher brain levels of a THC metabolite [25]. However, in humans, metabolite levels in plasma following THC exposure has been shown to be both higher [26] and lower [27] in females compared to males. Treatment-seeking women endorse more severe cannabis withdrawal symptoms than treatment-seeking men [28]. While gender-related differences have been reported in the use, subjective effects and metabolism of cannabis, the neural and molecular bases for these differences remain poorly understood.

Gambling

Gambling occurs in 82.4% of men and 76.5% of women [29], and lifetime prevalence rates for GD are 0.6% for men and 0.2% for women. Historically, social norms have more strongly opposed gambling in women as compared to men [30]; however, this may be changing over time. Common forms of gambling vary by gender [31,32]. For example, men tend to participate in strategic forms (wagering on cards, sports and horse racing), while women tend to participate in nonstrategic forms (wagering on slot machines and bingo). Women also report gambling due to feelings of sadness, loneliness, and/or boredom whereas men report being triggered by viewing gambling-related stimuli [33]. Both genders report similar family histories and rates of legal difficulties due to gambling [33].

Similar to alcohol, most studies report that GD in women is ‘telescoped’ compared to men [8,30,34]. However, a recently published large twin-study not only did not find evidence of this effect, but showed that men were ‘telescoped’ compared to women [35^•]. While precise reasons for telescoping are currently unknown, it has been hypothesized to relate to anxiety comorbidity in women and alcohol use in men; however, recent findings suggest that these may not be the case [34,36,37]. The telescoping effect and its causes remain controversial in GD. With respect to GD treatment, women are more likely to seek treatment compared to men, which may in part be due to co-occurring psychiatric disorders [30,38–40]. Comorbidities of anxiety, depression and alcohol-use disorders with GD may exacerbate gambling-related symptoms across both genders [41,42]. Currently, there is no evidence for gender-related differences in treatment effectiveness for GD.

Nicotine

There is a large body of work demonstrating gender-related differences in tobacco-smoking behaviors [43]. Cigarette-smoking prevalence rates are higher among men than woman worldwide; however, the gap is narrowing in the US. Around 16.7% of adult men in the US smoke, whereas 13.6% of adult women smoke [44]. The comparable rates between adult men and women could be in part due to tobacco marketing of cigarette use promoting curbed appetite, weight loss, and independence in women [45]. Women metabolize nicotine and cotinine (a nicotine metabolite) faster than men in part due to estrogen [46]. Faster metabolism for women may explain why women typically experience more adverse effects related to nicotine than men [47] and why women experience worse treatment outcomes.

Clinical studies, particularly a series of studies by Perkins et al., showed that men are better able to detect nicotine from de-nicotinized cigarettes than women, suggesting that men are able to distinguish the physiological effects of nicotine better than women [48,49]. Further, Perkins and colleagues have shown that women experience greater relief from craving than men from a de-nicotinized inhaler [50^•]. These results suggest that women may be more reinforced by the non-nicotine conditioned stimuli (e.g. sensory cues) than the nicotine itself. Data suggest that women are more reactive to nicotine-associated cues and stress, which may, in part, contribute to a greater predisposition to relapse, especially following stress [51,52], and a poorer response to nicotine-replacement strategies than men [48]. Preclinical studies also support the clinical findings demonstrating gender-related differences in responses to nicotine [53]. Altogether, these findings suggest a potential underlying sexual dimorphism. While literature has shown distinct gender-related differences in smoking motivation, smoking behavior and treatment efficacy, the neural and molecular bases for these differences remain poorly understood.

Opioids

Generally, men report more frequent heroin use and use in greater quantities than women; however, the rate of heroin use among women is rapidly on the rise: from 2005 to 2012, past-year heroin use nearly doubled among women [3^••]. In terms of route of opioid administration, men are more likely to inject heroin, but nonmedical prescription opioid use has demonstrated mixed findings between genders. Gender-specific factors have predicted opioid use. For example, among men only alcohol and illicit drug use predicted opioid use and among women only tobacco smoking and psychological stress predicted opioid use [54]. The role of sex hormones on opioid self-administration is currently largely unknown. Similar to psychostimulants, heroin withdrawal symptoms, dependence severity and treatment outcomes (specifically methadone-maintained outpatient treatment) are comparable between sexes [12^••].

Conclusions

In summary, men generally engage in drug use and gambling more than woman. Drug use and gambling behaviors vary by gender with respect to motivation, urges, and subjective and physiological effects, which may be explained by biological and sociocultural differences. Women are more likely to seek treatment for substance-use or GDs; however, they often encounter greater stigma and less social support compared to men. Comorbidity with other substance addictions, GD, anxiety disorders and/or depression may complicate clinical courses across both genders. One important caveat of the aforementioned gender-related differences described in the current review is a lack of controlling for differences in body weight and drug dose. Consideration of sex as a biological variable in both drug and non-drug addictions is crucial for understanding the neurobiological bases of these addictions and designing gender-appropriate treatment. Knowledge of gender-related differences (and similarities) is needed to help reduce health disparities in treatment availability and treatment outcomes.